Blumgart's Surgery of the Liver, Biliary Tract and Pancreas 2 volume set [7 ed.] 9780323697842

Citation preview

Any screen. Any time. Anywhere. Activate the eBook version of this title at no additional charge.

Elsevier eBooks+ gives you the power to browse, search, and customize your content, make notes and highlights, and have content read aloud.

Unlock your eBook today. 1. Visit http://ebooks.health.elsevier.com/ 2. Log in or Sign up 3. Scratch box below to reveal your code 4. Type your access code into the “Redeem Access Code” box 5. Click “Redeem”

It’s that easy!

Place Peel Off Sticker Here

For technical assistance: email [email protected] call 1-800-545-2522 (inside the US) call +44 1 865 844 640 (outside the US) Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on http://ebooks.health.elsevier.com/. Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at http://ebooks.health.elsevier.com/ and may not be transferred to another party by resale, lending, or other means. 2022v1.0

BLUMGART’S

Surgery of the Liver, Biliary Tract and Pancreas

Prometheus, chained to the rocky Mount Caucasus, has his liver eaten by the eagle of Zeus. Prometheus by Jacob Jordaens, 1640. Walraff-Richartz Museum & Foundation Corboud, Cologne, Germany. Photo: Rheinisches Bildarchiv Cologne, rba_c007696

BLUMGART’S

Surgery of the Liver, Biliary Tract and Pancreas 7th EDITION  |  VOLUME 1 and 2 EDITOR-IN-CHIEF William R. Jarnagin, MD, FACS

ASSOCIATE EDITORS Peter J. Allen, MD William C. Chapman, MD, FACS Michael I. D’Angelica, MD, FACS Ronald P. DeMatteo, MD, FACS Richard Kinh Gian Do, MD, PhD Jean-Nicolas Vauthey, MD, FACS

EDITOR EMERITUS Leslie H. Blumgart, BDS, MD, DSc(Hon), FACS, FRCS(Eng, Edin), FRCPS(Glas)

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

BLUMGART’S SURGERY OF THE LIVER, BILIARY TRACT, AND PANCREAS Copyright © 2023 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-69784-2

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

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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 2017, 2012, 2007, 2000, 1994, and 1988 by Saunders, an imprint of Elsevier Inc.

Executive Content Strategist: Jessica McCool Content Development Specialist: Casey Potter Senior Content Development Manager: Laura Schmidt Publishing services Manager: Deepthi Unni Project Manager: Aparna Venkatachalam Design Direction: Maggie Reid Printed in India Last digit is the print number:  9  8  7  6  5  4  3  2  1

This book is dedicated to Dr. Leslie H. Blumgart. Known as the “Professor,” a term of respect and admiration, he is truly a giant in the field, one of the pioneering surgeons who helped establish and develop HPB surgery as a specialty in its own right. He served as a mentor and role model for a generation of surgeons, who strive to maintain the high standards that he established. For all that he has done for us and for the field of HPB surgery, we will be forever grateful.

EDITORS EDITOR-IN-CHIEF William R. Jarnagin, MD, FACS Chief, Hepatopancreatobiliary Surgery Benno C. Schmidt Professor of Surgical Oncology Memorial Sloan Kettering Cancer Center; Professor of Surgery Weill Medical College of Cornell University New York, New York

ASSOCIATE EDITORS Peter J. Allen, MD Professor of Surgery Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York William C. Chapman, MD, FACS Professor Chief, Division of General Surgery Chief, Abdominal Transplantation Section Washington University School of Medicine St. Louis, Missouri Michael I. D’Angelica, MD, FACS Attending Surgeon Hepatopancreatobiliary Surgery Enid A. Haupt Chair in Surgery Memorial Sloan Kettering Cancer Center; Associate Professor Department of Surgery Weill Medical College of Cornell University New York, New York

vi

Ronald P. DeMatteo, MD, FACS Vice Chair, Department of Surgery Chief, Division of General Surgical Oncology Leslie H. Blumgart Chair in Surgery Memorial Sloan Kettering Cancer Center New York, New York Richard Kinh Gian Do, MD, PhD Associate Professor of Radiology Weill Medical College of Cornell University; Assistant Attending Physician Department of Radiology Memorial Sloan Kettering Cancer Center New York, New York Jean-Nicolas Vauthey, MD, FACS Professor of Surgical Oncology Chief, Hepato-Pancreato-Biliary Section Bessie McGoldrick Professor in Clinical Cancer Research Department of Surgical Oncology University of Texas MD Anderson Cancer Center Houston, Texas

EDITOR EMERITUS Leslie H. Blumgart, BDS, MD, DSc(Hon), FACS, FRCS(Eng, Edin), FRCPS(Glas) Member Professor of Surgery and Attending Surgeon Memorial Sloan Kettering Cancer Center; Professor of Surgery Weill Medical College of Cornell University New York, New York

CONTRIBUTORS INDEX Ghassan K. Abou-Alfa, MD, MBA Attending Physician Medicine Memorial Sloan Kettering Cancer Center Professor Medicine Weill Medical College at Cornell University New York, New York Jad Abou-Khalil, MDCM MSc FRCSC Assistant Professor of Surgery Hepato-Biliary and Pancreatic Surgery The Ottawa Hospital, Clinician Investigator Clinical Epidemiology The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Alexandra W. Acher, MD Department of General Surgery, Division of Surgical Oncology University of Wisconsin, Madison, Wisconsin Rene Adam, MD, PhD Professor of Surgery Department of Hepato-Biliary Surgery Paul Brousse Hospital, Paris Saclay University, Director of University Research Unit “Chronotherapy, Cancers and Transplantation” Paris-Saclay University, Villejuif, French Guiana Pietro Addeo, MD PhD Attending Surgeon Hepato-Pancreato-Biliary Surgery and Liver Transplantation University of Strasbourg, Strasbourg, France Anil Kumar Agarwal, MS, MCh, FRCS, FACS Director Professor & Head GI Surgery & Liver Transplant GB Pant Institute of Postgraduate Medical Education & Research & MAM College, Delhi University, New Delhi, India Davit L. Aghayan, MD, PhD Postdoctoral Researcher The Intervention Center Oslo University Hospital, Oslo, Norway Visiting Professor Department of Surgery N1 Yerevan State Medical University after M. Heratsi, Yerevan, Armenia

Ola Ahmed, MD Department of Abdominal Organ Transplantation Washington University School of Medicine, St Louis, Missouri Matthew J. Aizpuru, MD Resident Physician Surgery Mayo Clinic, Rochester, Minnesota Marc-Antoine Allard, MD, PhD Centre Hépatobiliaire Hôpital Paul Brousse, Villejuif, France Peter J. Allen, MD Professor of Surgery Chief of Surgical Oncology Surgery Duke University, School of Medicine Durham, North Carolina Thomas A. Aloia, MD, MHCM Professor of Surgery Surgical Oncology UT MD Anderson Cancer Center, Houston, Texas Fernando A. Alvarez, MD Chief Division of HPB Surgery, Department of Surgery Clínica Universitaria Reina Fabiola, Córdoba, Argentina Neda Amini, MD Surgical resident Surgery Sinai hospital of Baltimore, Baltimore, Maryland Jesper B. Andersen, PhD Associate Professor and group leader University of Copenhagen, Department of Health and Medical Sciences Biotech Research and Innovation Centre, Copenhagen, Denmark Christopher D. Anderson, MD James D. Hardy Chair Department of Surgery University of Mississippi Medical Center, Jackson, Mississippi

vii

viii

CONTRIBUTORS

Roi Anteby, MD MPH Postdoctoral Research Fellow Surgery Massachusetts General Hospital, Boston, Massachusetts Resident General Surgery The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel Vittoria Arslan-Carlon, MD, FASA Chief, Anesthesiology Service Anesthesiology and CCM Memorial Sloan Kettering Cancer Center, New York, New York Beatrice Aussilhou, MD Department of HPB Surgery and Liver Transplantation Hôpital Beaujon Clichy, France Joseph Awad, MD Professor Medicine-Gastroenterology and Hepatology Vanderbilt University Chief Transplant Service VA Tennessee Valley, Nashville, Tennessee Michele L. Babicky, MD Hepatobiliary & Surgical Oncology Center for Advanced Surgery The Oregon Clinic, Medical Director, Hepatobiliary & Pancreatic Cancer Program Program Providence Portland Medical Center, Portland, Oregon Philippe Bachellier, MD, PhD Professor and Chairman Hepato-Pancreato-Biliary Surgery and Liver transplant, Pôle des Pathologies Digestives, Hépatiques et de la Transplantation Hôpital de Hautepierre-Hôpitaux Universitaires de Strasbourg University of Strasbourg, Strasbourg, France Vinod P. Balachandran, MD Assistant Attending Department of Surgery Assistant Member Immuno-Oncology Service, Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center Member Parker Institute for Cancer Immunotherapy David M. Rubenstein Center for Pancreatic Cancer Research Memorial Sloan Kettering Cancer Center, New York, New York

Fiyinfolu Balogun, MD, PhD Assistant Attending Physician Gastrointestinal Oncology, Medicine Memorial Sloan Kettering Cancer Center, New York, New York Andrew S. Barbas, MD Surgery Duke University, Durham, North Carolina Jeffrey Stewart Barkun, MD, MSc, FRSC (C) Professor of Surgery, McGill University Surgery Hepatobiliary & Transplant Surgery Surgery McGill University Health Centre, Montreal, Quebec, Canada Claudio Bassi, FRCS, FACS, FEBS Surgery Pancreas Institute University of Verona, Verona, Italy Olca Basturk, MD Associate Professor Pathology Memorial Sloan Kettering Cancer Center, New York, New York Maria del Pilar Bayona Molano, MD, DR-IR Associate Professor Interventional Radiology UT Southwestern Medical Center, Dallas, Texas Rachel E. Beard, MD, FACS Assistant Professor Surgery Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island Jacques Belghiti, MD Emerite Professor HPB Surgery & Liver Transplantation Hospital Beaujon, Clichy, France Sean A. Bennett, MD, MSc, FRCSC Assistant Professor Surgery Queen’s University, Kingston, Ontario, Canada William Bernal, MD, FRCP, FFICM Professor Liver Intensive Therapy Unit Institute of Liver Studies, Kings College Hospital, London, England

CONTRIBUTORS

Anton J. Bilchik, MD, PhD Professor of Surgery, Chief of Medicine Surgical Oncology Saint John’s Cancer Institute, Santa Monica, California Franz Edward Boas, MD, PhD Associate professor Interventional radiology City of Hope Cancer Center, Duarte, California Morgan Bonds, MD Assistant Professor of Surgery Surgical Oncology University of Oklahoma, Norman, Oklahoma Brooke C. Bredbeck, MD House Officer Surgery University of Michigan, Ann Arbor, Michigan Lynn Brody, MD Clinical Member Radiology Memorial Sloan Kettering Cancer Center, New York, New York Karen T. Brown, MD, FSIR Professor Department of Radiology University of Utah Health Science Center, Interventional Radiologist Department of Radiology University of Utah, Salt Lake City, Utah Jordi Bruix, MD, PhD Senior Consultant Bclc. Liver Unit Hospital Clinic Barcelona, Spain Elizabeth M. Brunt, MD Emeritus Professor (retired) Pathology and Immunology Washington University School of Medicine St Louis, Missouri Markus Büchler, Professor of Surgery, MD Professor Department of General, Visceral and Transplantation Surgery University of Heidelberg, Heidelberg, Germany

ix

Mark P. Callery, MD William V. McDermott Professor of Surgery Surgery Harvard Medical School, Chief, Division of General Surgery Beth Israel Deaconess Medical Center, Boston, Massachusetts Juan C. Camacho, MD Assistant Attending Radiologist Interventional Radiology Memorial Sloan Kettering Cancer Center, New York, New York Andre Campbell, MD Professor of Surgery UCSF, Department of Surgery Zuckerberg San Francisco General Hospital and Trauma Center San Francisco, California Danielle H. Carpenter, MD Associate Professor Department of Pathology Saint Louis University School of Medicine, St Louis, Missouri C. Ross Carter, MD, FRCS West of Scotland Pancreatic Unit Glasgow Royal Infirmary, Glasgow, Scotland Chung Yip Chan, MBBS, MMed(Surg), FRCS(Edin), MD Department of Hepatopancreatobiliary and Transplant Surgery Singapore General Hospital, Singapore See Ching Chan, MS, MD, PhD, FRCS Honorary Clinical Professor Surgery University of Hong Kong, Hong Kong, China Rohit Chandwani, MD, PhD Assistant Professor Surgery/Cell & Developmental Biology Weill Cornell Medicine, New York, New York William C. Chapman Sr., MD Professor of Surgery Surgery Washington University in St Louis, St Louis, Missouri Harvey S. Chen, MD General Surgeon Department of Surgery UCLA Medical Center, Los Angeles, California

x

CONTRIBUTORS

Daniel Cherqui, MD Professor HPB Surgery and Liver Transplantation Paul Brousse Hospital - Paris Saclay University, Villejuif, France TT Cheung, MBBS, MS, MD, FRCS, FACS, FCSHK, FHKAM Clinical Associate Professor Chief of Division of Hepatobiliary and Pancreatic Surgery The University of Hong Kong, Hong Kong, China Adrian Kah Heng Chiow, MBBS(Melb), FRCS(Ed), FAMS Hepatopancreatobiliary Unit, Department of Surgery Changi General Hospital, Singapore Clifford S. Cho, MD C. Gardner Child Professor Department of Surgery University of Michigan Medical School, Ann Arbor, Michigan Yun Shin Chun, MD, FACS Associate Professor Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas

Kevin Christopher Conlon, MB, MCh, FRCSI, FRCSEd, FRCSGlas, FACS, MBA, MA, FTCD Professor and Academic Head Department of Surgery Trinity College Dublin, Tallaght, Dublin 24 Consultant HPB Surgeon Department of HPB Surgery St Vincents University Hospital, Consultant Surgeon Tallaght University Hospital, Dublin, Ireland Louise C. Connell, MB Bch BAO, BSc, MRCPI Medical Oncologist Medicine, Gastrointestinal Oncology Memorial Sloan Kettering Cancer Center, New York, New York Carlos Uriel Corvera, MD Professor, Chief of Liver, Biliary and Pancreatic Surgery Surgery UCSF, School of Medicine Attending Surgeon Surgery VA Medical Center, San Francisco, California

Bryan M. Clary, MD, MBA Professor and Chair Department of Surgery University of California at San Diego, San Diego, California

Anne M. Covey, MD Attending Interventional Radiologist Diagnostic Radiology Memorial Sloan-Kettering Cancer Center, Professor of Radiology Diagnostic Radiology Weill Medical College of Cornell University, New York, New York

Jordan M. Cloyd, MD Surgical Oncologist Surgery The Ohio State University, Columbus, Ohio

Christopher H. Crane, MD Chief, Gastrointestinal Section Radiation Oncology Memorial Sloan Kettering Cancer Center, New York, New York

Maria V. Coats, PhD FRCS Consultant HPB Surgeon West of Scotland Pancreatic Unit Glasgow Royal Infirmary, Glasgow, United Kingdom

John M. Creasy, MD Fellow, Complex General Surgical Oncology Department of Surgery Duke University Medical Center, Durham, North Carolina

Joshua T. Cohen, MD Resident Department of General Surgery Brown University, Providence, Rhode Island

Jeffrey S. Crippin, MD Marilyn Bornefeld Chair in Gastrointestinal Research and Treatment Internal Medicine Washington University School of Medicine, St Louis, Missouri

CONTRIBUTORS

Nick Crispe Professor Pathology Adjunct Professor Immunology University of Washington Seattle, Washington Michael I. D’Angelica, MD, FACS Enid Haupt Chair in Surgery Surgery Memorial Sloan Kettering Cancer Center Professor of Surgery Surgery Weil Cornell School of Medicine New York, New York Leonardo Gomes Da Fonseca, MD Clinical Oncology Instituto do Cancer do Estado de Sao Paulo, University of Sao Paulo, Sao Paulo, Brazil Hany Dabbous Professor Tropical Medicine Ain Shams University, Cairo, Egypt Christopher Danford Gastroenterologist Gastroenterology Intermountain Medical Group, Salt Lake City, Utah Michael Darcy, MD Professor, Interventional Radiology Radiology Washington University in St Louis, St Louis, Missouri Mark Davenport, ChM, FRCS (Eng), FRCS (Paeds) Professor Paediatric Surgery Kings College Hospital, London, United Kingdom Yakira David, MBBS Fellow Gastroenterology Icahn School of Medicine at Mount Sinai, New York, New York Ryan William Day, MD Clinical Fellow Division of Transplant Surgery University of California, San Francisco, San Francisco, California

Jeroen de Jonge, MD, PhD Assistant Professor Hepatobiliary and Transplant Surgery. Erasmus MC Transplant Institute Erasmus MC Rotterdam, Rotterdam, Netherlands Eduardo de Santibanes, MD, PhD Professor Surgery University of Buenos Aires., Buenos Aires, Argentina Martin de Santibañes, MD, PhD Associate Professor of Surgery Hepato-Biliary-Pancreatic unit and liver transplantation unit Hospital Italiano, Buenos Aires, Argentina Roeland F. de Wilde, MD, PhD Surgeon HPB- & Transplant Surgery Erasmus MC University Medical Center, Rotterdam, Netherlands Jean Robert Delpero, Emeritus Professor Department of Surgery Institut Paoli Calmettes, Marseille, France Ronald P. DeMatteo, MD, FACS The John Rhea Barton Professor and Chair Department of Surgery The University of Pennsylvania Health System, Philadelphia, Pennsylvania Danielle K. DePeralta, MD Assistant Professor Surgical Oncology Northwell Health, New York, New York Niraj M. Desai, MD Assistant Professor Department of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland Shannan M. Dickinson, MBBS, FRANZCR Assistant Attending Department of Radiology Memorial Sloan Kettering Cancer Center, New York, New York Euan J. Dickson, MBChB, MD, FRCS Consultant Surgeon West of Scotland Pancreatic Unit Glasgow Royal Infirmary Glasgow, United Kingdom

xi

xii

CONTRIBUTORS

Christopher John DiMaio, MD Director of Interventional Endoscopy, Professor of Medicine Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York Richard Kinh Gian Do, MD, PhD Associate Attending Radiology Memorial Sloan Kettering Cancer Center, New York, New York Associate Professor Radiology Weill Medical College of Cornell University, New York, New York Safi Dokmak, MD, PhD HPB Surgery & Liver Transplantation Hopital Beaujon, Clichy, Hauts de seine, France Majella Doyle, MD, MBA Professor of Surgery Department of Surgery Washington University, St Louis, Missouri Jeffrey A. Drebin, MD, PhD Chair Department of Surgery Memorial Sloan Kettering Cancer Center, New York, New York Professor Department of Surgery Weill Cornell Medical College, New York, New York Michael R. Driedger, MD Surgical Oncology Specialist Division of Hepatobiliary and Pancreatic Surgery Mayo Clinic, Rochester, Minnesota General Surgery Hepato-Pancreato-Biliary Surgery Atrium Health, Charlotte, North Carolina Vikas Dudeja, MBBS, FACS Associate Professor Surgery University of Alabama at Birmingham, Birmingham, Alabama Mark Dunphy, DO Assistant Attending Physician Radiology Memorial Sloan Kettering Cancer Center, New York, New York

Truman M. Earl, MD, MSCI Professor of Surgery, Chief Division of Transplant and Hepatobiliary Surgery Department of Surgery, Division of Transplant and Hepatobiliary Surgery University of Mississippi Medical Center, Jackson, Mississippi Tomoki Ebata, MD, PhD Professor and Chairman Division of Surgical Oncology, Department of Surgery Nagoya University Graduate School of Medicine, Nagoya, Japan Brett Logan Ecker, MD Clinical Fellow Department of Surgery Memorial Sloan Kettering Cancer Center, New York, New York Bjorn Edwin, MD, PhD Professor The Intervention Centre Oslo University Hospital, Oslo, Norway Professor Department of HPB Surgery Oslo University Hospital, Oslo, Norway Professor Institute of Clinical Medicine University of Oslo, Oslo, Norway Aslam Ejaz, MD, MPH Assistant Professor Department of Surgery The Ohio State University, Columbus, Ohio Imane El Dika, MD Assistant Attending Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York Itaru Endo, MD, PhD Professor Department of Gastroenterological Surgery Yokohama City University Graduate School of Medicine, Yokohama, Japan C. Kristian Enestvedt, MD, FACS Associate Professor Department of Surgery; Division of Abdominal Organ Transplantation/Hepatobiliary Surgery; School of Medicine Oregon Health & Science University, Portland, Oregon

CONTRIBUTORS

R. Eliot Fagley, MD Section Head for Critical Care Medicine and Chief of Staff Anesthesiology and Pain Medicine Virginia Mason Medical Center Seattle, Washington Sheung Tat Fan, MD, PhD., D.Sc. Emeritus Professor of Surgery Department of Surgery The University of Hong Kong Hong Kong, China Director Liver Surgery and Transplant Centre Hong Kong Sanatorium & Hospital, Hong Kong, China Olivier Farges, MD, PhD Department of hepato-biliary and panceratic surgery Department of Surgery Hôpital Beaujon, AP-HP, University Paris 7, Clichy, France Michael Steven Farrell, MD, MS Acute Care Surgeon Trauma Lehigh Valley Health Network, Allentown, Pennsylvania Benjamin David Ferguson, MD, PhD Assistant Professor Department of Surgery University of New Mexico Albuquerque, New Mexico Joana Ferrer-Fàbrega, MD, PhD Associate Professor. Consultant HepatoBilioPancreatic Surgery and Liver & Pancreatic Transplantation Unit. ICMDiM. Hospital Clínic. University of Barcelona, Barcelona, Spain Cristina R. Ferrone, MD Professor of Surgery Surgery Massachusetts General Hospital, Boston, Massachusetts Ryan Fields, MD, FACS Chief, Surgical Oncology; Professor of Surgery Surgery Barnes-Jewish Hospital & The Alvin J. Siteman Comprehensive Cancer Center at Washington University School of Medicine, Kim & Tim Eberlein Distinguished Professor Surgical Oncology Washington University School of Medicine, Co-Leader Solid Tumor Therapeutics Program Alvin J. Siteman Comprehensive Cancer Center St Louis, Missouri

xiii

Mary Fischer, MD Anesthesiology and Critical Care Memorial Sloan Kettering Cancer Center, New York, New York Associate Professor Anestesiology New York Columbia Weill Medical College, New York, New York Yuman Fong, MD Sangiacomo Chair and Chairman Department of Surgery City of Hope National Medical Center, Duarte, California Philippa Francis-West, PhD Professor Craniofacial King’s College London, London, United Kingdom Åsmund Avdem Fretland, MD, PhD Attending Surgeon The Intervention Centre Oslo University Hospital Attending Surgeon Department of Hepato-Pancreato-Biliary Surgery Oslo University Hospital Oslo, Norway Jonathan A. Fridell, MD Chief, Abdominal Transplant Surgery Surgery Indiana University School of Medicine, Indianapolis, Indiana Scott L. Friedman, MD Fishberg Professor of Medicine Division of Liver Diseases Icahn School of Medicine at Mount Sinai Dean for Therapeutic Discovery Icahn School of Medicine at Mount Sinai New York, New York Eva Galka, MD, FACS Associate Professor of Surgery Department of Surgery, Division of Hepatobiliary, Pancreatic, & Gastrointestinal Surgery University of Rochester, Rochester, New York David A. Geller, MD, FACS Richard L. Simmons Professor of Surgery, Chief, Division of Hepatobiliary and Pancreatic Surgery Surgery University of Pittsburgh, Pittsburgh, Pennsylvania

xiv

CONTRIBUTORS

Scott R. Gerst, MD Attending Radiologist Radiology Memorial Sloan Kettering Cancer Center, Director Diagnostic Radiology, David H Koch Ctr for Cancer Care Diagnostic Radiology Memorial Sloan Kettering Cancer Center New York, New York Justin Theodore Gerstle, MD Chief, Pediatric Surgery Service Surgery Memorial Sloan Kettering Cancer Center New York, New York Associate Professor Surgery Weill Cornell Medical College, Cornell University New York, New York Sepideh Gholami, MD Assistant Professor Surgery University of California, Davis Sacramento, California Richard Gilroy, MBBS, FRACP Medical Director of Hepatology and Liver Transplantation Internal Medicine Intermountain Medical Center Murray, Utah Brian K.P. Goh, MBBS, MMed, MSc, FRCSEd Senior Consultant Hepatopancreatobiliary and Transplant Surgery Singapore General Hospital Singapore Clinical Professor Duke-National University of Singapore Medical School Singapore Gregory J. Gores, MD Executive Dean for Research, Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota John A. Goss, MD Surgery Baylor College of Medicine, Houston, Texas Brittany Dalia Greene, MD Resident Division of General Surgery, Department of Surgery University of Toronto Toronto, Ontario, Canada

Bas Groot Koerkamp, MD, MSc, PhD Associate Professor of Surgery Surgery, Division of Hepatopancreatobiliary Surgery and Abdominal Transplantation Erasmus MC, Rotterdam, Netherlands Thilo Hackert, MD, MBA Professor Department of Surgery University of Heidelberg Heidelberg, Germany Kate Anne Harrington, MB BCh BAO, FFR RCSI Radiology Memorial Sloan Kettering Cancer Center New York, New York Ewen M. Harrison, MB ChB, PhD, FRCS Professor of Surgery and Data Science Centre for Medical Informatics, Usher Institute University of Edinburgh Edinburgh, United Kingdom Consultant HPB Surgeon Clinical Surgery Royal Infirmary of Edinburgh Edinburgh, United Kingdom Kiyoshi Hasegawa, MD, PhD Professor Hepato-Biliary-Pancreatic Surgery Division Department of Surgery Graduate School of Medicine, University of Tokyo Tokyo, Japan Haley Hauser, BA Research Project Associate Gastrointestinal Oncology Service, Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York Julie K. Heimbach, MD Professor of Surgery transplantation surgery Mayo Clinic Rochester, Minnesota Alan W. Hemming, MD, MSc Professor of Surgery Surgery University of Iowa Iowa City, Iowa Jonathan Hernandez, MD Principal Investigator Surgical Oncology National Institute of Health Bethesda, Maryland

CONTRIBUTORS

Yuki Homma, MD, PhD Department of Gastgroenterological Surgery Yokohama City University Yokohama, Japan Christine A. Iacobuzio-Donahue, MD, PhD Attending Pathologist Pathology Memorial Sloan Kettering Cancer Center Affiliate Member Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center Director David M. Rubenstein Center for Pancreatic Cancer Research Memorial Sloan Kettering Cancer Center New York, New York Rami Imam, MD Anatomic Pathologist NYU Langone Hospitals New York, New York Oscar Cesar IMVENTARZA Sr., MD Chief Liver Transplantation Surgery & Transplantation Hospital Garrahan, Buenos Aires, Argentina Chief Liver Transplantation Surgery & Transplantation Hospital Argerich Buenos Aires, Argentina Matthew Kalahasty Iyer, MD, PhD Fellow Department of Surgery Duke University Hospital Durham, North Carolina William R. Jarnagin, MD, FACS Chief, Hepatopancreatobiliary Service Leslie H. Blumgart Chair in Surgical Oncology Memorial Sloan-Kettering Cancer Center New York, New York Professor of Surgery Weill Medical College of Cornell University New York, New York Shiva Jayaraman, MD, MESc, FRCSC, FACS Associate Professor of Surgery Surgery University of Toronto HPB and General Surgeon Surgery St. Joseph’s Health Centre, Unity Health Toronto Scientist Li Ka Shing Knowledge Institute Unity Health Toronto Toronto, Ontario, Canada

xv

Maria Jepperson Radiologist Radiology Intermountain McKay-Dee Hospital Murray, Utah Michelle R. Ju, MD Resident Surgery University of Texas Southwestern Medical Center Dallas, Texas Sean J. Judge, MD Resident Department of Surgery University of California Sacramento, California Christoph Kahlert, MD Universitätsklinikum Carl Gustav Carus Dresden Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie Universitätsklinkum Dresden Dresden, Germany Patryk Kambakamba, MD Hepatobiliary Group St. Vincent’s University Hospital Dublin, Ireland MD Department of Surgery Cantonal Hospital of Winterthur Winterthur, Switzerland Ivan Kangrga, MD, PhD Professor and Vice Chair for Health System Liaison Department of Anesthesiology Washington University in St. Louis, School of Medicine St Louis, Missouri S. Cheenu Kappadath, PhD Professor Department of Imaging Physics UT MD Anderson Cancer Center Houston, Texas Paul J. Karanicolas, MD, PhD, FRCSC, FACS Associate Professor Surgery University of Toronto Toronto, Ontario, Canada Seth S. Katz, MD,PhD Assistant Clinical Member Radiology Memorial Sloan Kettering Cancer Center New York, New York

xvi

CONTRIBUTORS

Yoshikuni Kawaguchi, MD, MPH, PhD Associate Professor/Lecturer Hepato-Biliary-Pancreatic Surgery Division Department of Surgery The University of Tokyo Tokyo, Japan Kaitlyn J. Kelly, MD Assistant Professor of Surgery Division of Surgical Oncology University of California San Diego San Diego, California Nancy E. Kemeny, MD Professor of Medicine Weill Medical College of Cornell University; Attending Physician Solid Tumor—GI Division Memorial Sloan-Kettering Cancer Center New York, New York Adeel Khan, MD, MPH Associate Professor of Surgery Division of Abdominal Transplant, Department of Surgery Washington University in St Louis St Louis, Missouri Tahsin M. Khan, MD Surgical Oncology Research Fellow Surgical Oncology Program National Cancer Institute, National Institutes of Health, Bethesda, Maryland Heung Bae Kim, MD Professor of Surgery Department of Surgery Harvard Medical School Boston, Massachusetts Director, Pediatric Transplant Center; Weitzman Family Chair in Surgical Innovation Boston Children’s Hospital Boston, Massachusetts Woon Cho Kim, MD, MPH Clinical Fellow Surgery University of California San Francisco San Francisco, California T. Peter Kingham, MD Assistant Professor Surgery Memorial Sloan Kettering Cancer Center New York, New York

Joseph Kingsbery, MD Gastroenterologist Medicine Bay Ridge Gastroenterology Brooklyn, New York Clinical Instructor Medicine NYU Grossman School of Medicine New York, New York Clinical Instructor Medicine NYP Weill Cornell Brooklyn, New York Allan D. Kirk, MD, PhD Professor and Chairman Department of Surgery Duke University Durham, North Carolina Russell C. Kirks Jr., MD Hepatobiliary and Pancreatic Surgeon St Joseph’s/Candler Savannah, Georgia David Klimstra, MD Chairman Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Professor Department of Pathology and Laboratory Medicine Weill Medical College of Cornell University New York, New York Stuart Knechtle, MD, FACS William R. Kenan, Jr. Professor of Surgery Surgery Duke University School of Medicine Durham, North Carolina Executive Director Duke Transplant Center Duke University School of Medicine Durham, North Carolina Jonathan B. Koea, MHB(Hons), MD Professor Department of Surgery North Shore Hospital Auckland, New Zealand Professor Department of Surgery University of Auckland Auckland, New Zealand Norihiro Kokudo, MD, PhD Professor Surgery National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku Tokyo, Japan

CONTRIBUTORS

Kevin M. Korenblat, MD Professor of Medicine Department of Internal Medicine Washington University School of Medicine, St Louis, Missouri Medical Director, Liver Transplant Barnes-Jewish Hospital St Louis, Missouri Lucy Zumwinkle Kornblith, MD Assistant Professor of Surgery Department of Surgery, Division of Trauma and Surgical Critical Care University of California San Francisco San Francisco, California Geoffrey Wayne Krampitz, MD, PhD Assistant Professor Surgery Thomas Jefferson University Philadelphia, Pennsylvania Simone Krebs, MD Assistant Attending Department of Radiology Molecular Imaging and Therapy Service Memorial Sloan Kettering Cancer Center New York, New York Assistant Professor Department of Radiology Weill Cornell Medicine New York, New York Takafumi Kumamoto Department of Gastroenterological Surgery Graduate School of Medicine Yokohama City University Yokohama, Japan Choon Hyuck David Kwon, MD, PhD Director of Laparoscopic Liver Surgery General Surgery Cleveland Clinic Cleveland, Ohio Professor of Surgery General Surgery Lerner College of Medicine of Case Western University, Cleveland, Ohio Section Head of HPB Surgery General Surgery Cleveland Clinic Cleveland, Ohio Kelly J. Lafaro, MD, MPH Assistant Professor Department of Surgery Johns Hopkins University Baltimore, Maryland

Hauke Lang, MA, MD, FACS Professor General, Visceral and Transplantation Surgery, Unimedizin Mainz Mainz, Germany Michael J. LaQuaglia, MD Clinical Fellow Pediatric Surgery Memorial Sloan Kettering Cancer Center New York, New York Michael P. LaQuaglia, MD Joseph H. Burchenal Professor Department of Surgery and Pediatrics Memorial Sloan Kettering Cancer Center New York, New York Professor of Surgery Department of Surgery Weill Cornell Medical School New York, New York Nicholas F. LaRusso, MD Charles H. Weinman Professor of Medicine Molecular Biology and Biochemistry Internal Medicine Mayo Clinic Rochester, Minnesota Rachel M. Lee, MD, MSPH Resident Physician Department of Surgery Emory University Atlanta, Georgia Ser Yee Lee, MBBS, MMed(Surgery), MSc, FAMS, FRCSEd, FACS Senior Consultant Department of Hepatopancreatobiliary and Transplant Surgery Singapore General Hospital Singapore Associate Professor Duke - National University of Singapore (NUS) Graduate Medical School Singapore Senior Consultant Surgical Associates Mount Elizabeth Medical Centre Singapore Riccardo Lencioni, MD Professor Department of Radiology University of Pisa School of Medicine Pisa, Italy Director Cancer Imaging Program Pisa University Hospital Pisa, Italy

xvii

xviii

CONTRIBUTORS

Javier C. Lendoire, MD,PhD Vice-Chairman Liver & Transplant Unit Hospital Dr Cosme Argerich Buenos Aires, Argentina Chairman Liver Transplant Division Instituto de Trasplantes y Alta Complejidad (ITAC) Buenos Aires, Argentina Galina Levin, MD Associate Attending Radiology Memorial Sloan Kettering Cancer Center New York, New York Kewei Li, MD, PhD Department of Pediatric Surgery West China Hospital of Sichuan University Chengdu, China Michael E. Lidsky, MD Assistant Professor Surgery Duke University Durham, North Carolina Jessica Lindemann, MD, PhD General Surgery Resident Department of Surgery Washington University School of Medicine St Louis, Missouri David Linehan, MD Professor, Chair Surgery University of Rochester Rochester, New York Roberto Carlos Lopez-Solis, MD, FACS Associate Professor General Surgery West Virginia University School of Medicine Morgantown, West Virginia Patrick Daniel Lorimer, MD General Surgeon Surgical Oncology Arizona Advanced Surgery, LLC Scottsdale, Arizona Ka Wing Ma Orthopaedic surgeon The University of Hong Kong Pokfulam, Hong Kong Shishir K. Maithel, MD, FACS Professor of Surgery Division of Surgical Oncology, Department of Surgery Emory University, Winship Cancer Institute Atlanta, Georgia

Giuseppe Malleo, MD, PhD Associate Professor of surgery Department of Surgery, Dentistry, Pediatrics and Gynecology Unit of Pancreatic Surgery, University of Verona Hospital Trust Verona, Italy Giovanni Marchegiani, MD, PhD Dr Giovanni Marchegiani Department of Surgery Verona University Policlinico Borga Roma Verona, Italy James F. Markmann, MD, PhD Chief, Division of Transplant Surgery Surgery Massachusetts General Hospital Boston, Massachusetts Claude E. Welch Professor of Surgery Harvard Medical School Boston, Massachusetts J. Wallis Marsh, MD, MBA Professor and Chairman Surgery West Virginia University School of Medicine Morgantown, West Virginia Robert CG Martin II, MD, PhD Professor of Surgery Sam and Loita Weakley Endowed Chair of Surgical Oncology Surgery, Division of Surgical Oncology University of Louisville Louisville, Kentucky Marco Massani, MD Chief Department of Surgery, Division of First General Surgery, Hepato-Pancreato-Biliary Regional Referral Centre Azienda ULSS 2 Marca Trevigiana, Ospedale Ca’ Foncello, Treviso, Italy Ryusei Matsuyama, MD, PhD Associate Professor Gastroenterological Surgery Yokohama City University School of Medicine Yokohama, Japan Aaron W.P. Maxwell, MD Director of Interventional Oncology Assistant Professor of Diagnostic Imaging Department of Diagnostic Imaging The Warren Alpert Medical School of Brown University, Providence, Rhode Island Oscar M. Mazza, MD Professor of Surgery Chief of Hepato-Biliary- Pancreatic Unit Hospital Italiano Buenos Aires, Argentina

CONTRIBUTORS

Ian D. McGilvray, MD, PhD Professor of Surgery Surgery University of Toronto Toronto, Ontario, Canada Head Hepatopancreatic Biliary Surgical Oncology University Health Network Toronto, Ontario, Canada Director Toronto Video Atlas of Surgery University Health Network Toronto, Ontario, Canada Caitlin A. McIntyre, MD Fellow in Surgical Oncology Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York Sophia K. McKinley, MD, EdM Resident physician Surgery Massachusetts General Hospital Boston, Massachusetts Jose Melendez Vice President and Chief Medical Officer HCA Healthcare St. Mark’s Hospital Salt Lake City, Utah Emmanuel Melloul, MD Lausanne University Hospital Visceral Surgery Lausanne University Hospital Lausanne, Switzerland Robin B. Mendelsohn, MD Associate Attending Medicine, Gastroenterology, Hepatology and Nutrition Service Memorial Sloan Kettering Cancer Center New York, New York Takashi Mizuno, MD., PhD. Associate Professor Division of Surgical Oncology, Department of Surgery Nagoya University Graduate School of Medicine Nagoya, Japan Hunter Burroughs Moore, MD, PhD Assistant Professor Surgery-Transplant University of Colorado Denver, Colorado Cristina Mosconi, MD Department of Radiology IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

xix

Santosh Nagaraju Transplant Surgeon Charleston Area Medical Center Health System Charleston, West Virginia Masato Nagino, MD, PhD Professor and Chairman Division of Surgical Oncology, Department of Surgery Nagoya University Graduate School of Medicine Nagoya, Japan David M. Nagorney, MD, FACS Professor of Surgery Department of Surgery Mayo Clinic Rochester, Minnesota Satish Nagula, MD Associate Professor Division of Gastroenterology, Department of Medicine Icahn School of Medicine at Mount Sinai New York, New York Amit Nair, MD, FRCS Assistant Professor Division of Transplantation/Hepatobiliary Surgery University of Rochester Medical Center Rochester, New York Navine Nasser-Ghodsi, MD Fellow Gastroenterology & Hepatology Mayo CLinic Rochester, Minnesota Nadia Naz, MD, FAAP Clinical Assistant Professor Division of Gastroenterology, Hepatology, Pancreatology, and Nutrition University of Iowa Health Care Iowa city, Iowa John P. Neoptolemos, BA, MB, BChir, MA (Cambridge), MD, FRCS, FMedSci. Professor of Surgery Department of General, Visceral and Transplantation Surgery University of Heidelberg, Heidelberg, Baden-Württemberg James Neuberger, DM, FRCP Hon Consultant Physician Liver Unit Queen Elizabeth Hospital Birmingham, United Kingdom Nicole M. Nevarez, MD Surgical Resident Department of Surgery University of Texas Southwestern Dallas, Texas

xx

CONTRIBUTORS

Timothy E. Newhook, MD Assistant Professor Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas

Franklin Olumba, MD Research Fellow Surgery Washington University in St Louis School of Medicine St Louis, Missouri

Takehiro Noda, MD, PhD Associate Professor Department of Gastroenterological Surgery Osaka University Suita, Japan

Susan Orloff, MD, FACS, FAASLD Professor of Surgery and Chief, Division of Abdominal Organ Transplantation/Hepatobiliary Surgery Department of Surgery Adjunct Professor Department of Microbiology & Immunology Oregon Health & Science University Portland, Oregon

Scott L. Nyberg, MD, PhD Professor Surgery Consultant in Transplantation Surgery Department of Transplantation Surgery Mayo Clinic, Rochester, Minnesota Elisabeth O’Dwyer, MB BCh BAO Molecular Imaging and Therapeutics Service Memorial Sloan Kettering Cancer Center New York, New York Colm J. O’Rourke, BA(Hons.), PhD Assistant Professor BRIC, Department of Health & Medical Sciences University of Copenhagen Copenhagen, Denmark Bruno C. Odisio, MD Associate Professor Interventional Radiology The University of Texas MD Anderson Cancer Center, Houston, Texas RYOSUKE okamura, MD, PhD Assistant Professor Department of Surgery Kyoto University Hospital Kyoto, Japan Karl Jürgen Oldhafer, Prof. Dr. Department of Surgery Asklepios Hospital Barmbek Hamburg, Germany Kim M. Olthoff, MD Donald Guthrie Professor of Surgery Division of Transplant Surgery, Department of Surgery University of Pennsylvania Associate Director Penn Transplant Institute Philadelphia, Pennsylvania

Christine E. Orr, MD, FRCPC Assistant Professor Department of Pathology and Molecular Medicine Queen’s University Kingston, Ontario, Canada Eileen M. O’Reilly, MD Section Head, HPB/Neuroendocrine; Co-Director Medical David M Rubenstein Center for Pancreas Cancer Research Medicine Memorial Sloan Kettering Cancer Center Professor of Medicine Medicine Weill Medical College of Cornell University New York, New York Chandrasekhar Padmanabhan, MD Assistant Professor Surgery Vanderbilt Univeristy Medical Center Nashville, Tennessee Alessandro Paniccia, MD Assistant Professor of Surgery Department of Surgery University of Pittsburgh Pittsburgh, Pennsylvania Theodore N. Pappas, MD Professor Surgery Duke University Durham, North Carolina Valérie Paradis, MD, PhD Professor Pathology Beaujon hospital, Clichy, France

CONTRIBUTORS

Rowan W. Parks, MD, FRCSI, FRCSEd Professor Clinical Surgery University of Edinburgh Edinburgh, United Kingdom

John A. Powelson, MD Associate Professor Department of Surgery Indiana University Medical School Indianapolis, Indiana

Timothy M. Pawlik, MD, MPH, MTS, PhD Professor and Chair Department of Surgery The Ohio State University Columbus, Ohio The Urban Meyer III and Shelley Meyer Chair for Cancer Research Wexner Medical Center at The Ohio State University Columbus, Ohio

Naveen Premnath, MD Hematology and Oncology University of Texas southwestern Dallas, Texas

Cassandra D. Pierce-Raglione, MD Director Emeritus Surgical Oncology Providence Portland Medical Center Portland, Oregon Venu G. Pillarisetty, MD Professor Surgery University of Washington Seattle, Washington James Francis Pingpank Jr., MD Associate Professor of Surgery Department of Surgery University of Pittsburgh Surgical oncologist UPMC Hillman Cancer Center Pittsburgh, Pennsylvania Henry A. Pitt, MD Distinguished Professor of Surgery Surgery Rutgers RWJ Medical School Chief of Oncologic Quality Rutgers Cancer Institute of New Jersey New Brunswick, New Jersey Patricio M. Polanco, MD Associate Professor Surgery University of Texas Southwestern Medical Center Dallas, Texas James J. Pomposelli, MD, PhD Surgical Director of Liver Transplantation Professor of Surgery Department of Surgery University of Colorado, Anschutz Medical Campus Aurora, Colorado

Motaz Qadan, MD, PhD Associate Professor of Surgery; Gapontsev Family Endowed Chair in Surgical Oncology Surgery Massachusetts General Hospital Boston, Massachusetts Nitya Raj, MD Assistant Attending Physician Department of Medicine, Division of Gastrointestinal Medical Oncology Memorial Sloan Kettering Cancer Center New York, New York Srinevas Reddy, MD Faculty Surgical Oncology Ascension Columbia St. Mary’s Hospital Milwaukee, Wisconsin Diane Reidy-Lagunes, MD, MS Associate Attending Medicine MSKCC Associate Professor of Clinical Medicine Weill Cornell Medical College New York, New York Marsha Reyngold, MD, PhD Assistant Attending Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York, New York Teresa C. Rice, MD Assistant Professor Department of Surgery, Division of Transplant Surgery Medical University of South Carolina Charleston, South Carolina Robert W. Rickert, Bachelor of Arts Medical Student Department of Surgical Oncology University of Louisville Louisville, Kentucky

xxi

xxii

CONTRIBUTORS

John Paul Roberts, MD Professor Surgery University of California San Francisco San Francisco, California

Roberto Salvia, MD, PhD Chief Executive of the Verona Pancreas Institute Department of Surgery Pancreas Institute Verona, Italy

Piera Marie Cote Robson, PhD, NP Clinical Nurse Specialist Departments of Nursing and Radiology Memorial Sloan Kettering Cancer Center New York, New York Flavio G. Rocha, MD Associate Professor of Surgery Division of Surgical Oncology Hedinger Chair and Division Head Surgery, Division of Surgical Oncology OHSU School of Medicine Portland, Oregon

Hrishikesh Samant, MD FACG Transplant Hepatologist Hepatology Ochsner Transplant Institute New Orleans, Louisiana Associate Professor Gastroenterology and Hepatology Lousiana State University Health Shreveport, Louisiana Director Hepatology Gastroenterology and Hepatology Ochsner-LSU Shreveport, Louisiana

Garrett R. Roll, MD, FACS Associate Professor Department of Surgery, Division of Transplant University of California San Francisco San Francisco, California

Kazunari Sasaki, MD Clinical Associate Professor General Surgery Stanford University Stanford, California

Vineet Syan Rolston, MD Assistant Professor Gastroenterology Memorial Sloan Kettering Cancer Center New York, New York

Mark A. Schattner, MD Chief Attending Department of Medicine Division of Gastroenterology, Hepatology, and Nutrition, Memorial Sloan Kettering Cancer Center New York, New York

Maxime Ronot, MD PhD Professional Radiology Beaujon University Hospital Clichy, France Alexander S. Rosemurgy II, MD Director of Hepatopancreaticobiliary Surgery Surgery Advent Health Tampa Tampa, Florida Charles B. Rosen, MD Professor Department of Surgery Mayo Clinic Rochester, Minnesota Chady Salloum, Doctor Service de chirurgie hepatobiliopancreatique et transplantation Hopital Paul Brousse Centre hepatobiliaire Villejuif, France

Gabriel T. Schnickel, MD, MPH Professor of Surgery Division of Transplant and Hepatobiliary Surgery, Department of Surgery UC San Diego San Diego, California Richard D. Schulick, MD, MBA, FACS Professor and Chair Department of Surgery Director University of Colorado Cancer Center University of Colorado School of Medicine Aurora, Colorado Max E. Seaton, MD Surgical Oncology Fellow Department of Surgery Jackson Memorial Hospital / University of Miami Miami, Florida Yongwoo David Seo, MD Resident Physician General Surgery University of Washington Seattle, Washington

CONTRIBUTORS

Jigesh A. Shah, D.O. Assistant Professor Surgery UT Southwestern Medical Center Dallas, Texas Kevin N. Shah, MD Assistant Professor Surgery Duke University Medical Center Durham, North Carolina Wong Hoi She, MBBS, FRCS, FCSHK, FHKAM Consultant Surgery Queen Mary Hospital, The University of Hong Kong Hong Kong, China Junichi Shindoh, MD, PhD Surgeon-in-chief Hepatobiliary-pancreatic Surgery Division Toranomon Hospital Tokyo, Japan Chaya Shwaartz, MD Assistant Professor of Surgery Abdominal Transplant & HPB Surgical Oncology Department of General Surgery University Health Network Toronto, Ontario, Canada Jason K. Sicklick, MD, FACS Professor Departments of Surgery and Pharmacology Division of Surgical Oncology University of California San Diego Cancer Center University of California San Diego School of Medicine UC San Diego Health San Diego, California Robert H. Siegelbaum, MD Associate Attending Radiologist Department of Radiology Memorial Sloan Kettering Cancer Center New York, New York Martin Derrick Smith, MBBCh, FCS(SA), FEBS FRCS(Edin) Professor Surgery University of the Witwatersrand, Johannesburg Johannesburg, Gauteng Kevin C. Soares, MD Assistant Attending Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York Assistant Professor Department of Surgery Weill-Cornell Medical College New York, New York

xxiii

Constantinos T. Sofocleous, MD, PhD, FSIR, FCIRSE Interventional Oncologist/Radiologist Department of Radiology Memorial Sloan-Kettering Cancer Center Professor Interventional Radiology Weill-Cornell Medical College New York, New York Stephen B. Solomon, MD Chief, Interventional Radiology Service Director, Center for Image-Guided Intervention Memorial Sloan-Kettering Cancer Center New York, New York Sanket Srinivasa, MBChB, PhD, FRACS Consultant Surgeon Waitemata¯ District Health Board North Shore Hospital Auckland, New Zealand Patrick Starlinger, MD, PhD Associate Professor Surgery Mayo Clinic Rochester, Minnesota Tommaso Stecca, MD Department of Surgery Division of First General Surgery, Hepato-Pancreato-Biliary Regional Referral Centre Azienda ULSS 2 Marca Trevigiana, Ospedale Ca’ Foncello, Treviso, Italy John A. Steinharter, MS Hepatopancreatobiliary Service Memorial Sloan Kettering Cancer Center New York, New York Medical Student Robert Larner, MD College of Medicine UVM, Burlington, Vermont Camille Stewart, MD Surgical Oncology Fellow Surgery City of Hope National Medical Center Duarte, California Lygia Stewart, MD Professor of Surgery Department of Surgery University of California San Francisco and SF VAMC, San Francisco, California Chief General Surgery Department of Surgery San Francisco VA Medical Center San Francisco, California Janis Stoll, MD Associate Professor of Pediatrics Gastroenterology, Hepatology and Nutrition Washington University School of Medicine St Louis, Missouri

xxiv

CONTRIBUTORS

Iswanto Sucandy, MD FACS Director Hepatobiliary Surgery Advent Health Tampa Tampa, Florida Associate Professor Surgery University of Central Florida Florida Paul V. Suhocki, MD Associate Professor Department of Radiology Duke University Medical Center Durham, North Carolina James H. Tabibian, MD, PhD, FACP Associate Professor Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA Los Angeles, California Director of Endoscopy Department of Medicine, Division of Gastroenterology Olive View-UCLA Medical Center Sylmar, California Nobuyuki Takemura, MD, PhD Hepato-Biliary Pancreatic Surgery Division Department of Surgery National Center for Global Health and Medicine (NCGM), Tokyo, Japan Laura H. Tang, MD, PhD Attending Pathologist Pathology and Laboratory Medicine Memorial Sloan-Kettering Cancer Center New York, New York Professor of Pathology Department of Pathology and Laboratory Medicine Weill Cornell Medical College New York, New York Cornelius A. Thiels, DO, MBA Assistant Professor Department of Surgery Mayo Clinic Rochester, Minnesota Taner Timucin, MD, PhD Associate Professor Surgery & Immunology Mayo Clinic Chair Division of Transplantation Surgery Mayo Clinic Rochester, Minnesota

Samer Tohme, MD Assistant Professor of Surgery Surgery University of Pittsburgh Pittsburgh, Pennsylvania Guido Torzilli, MD, PhD, FESA, FACS, FAFC(Hon), FCBCD(Hon), FCHB(Hon) Director Division of Hepatobiliary and General surgery Humanitas Research Hospital - IRCCS Rozzano, Milano Professor & Chairman Director General Surgery Residency Program Humanitas University Rozzano, Milano, Italy Hop S. Tran Cao, MD, FACS Associate Professor Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas Simon Hing Yin Tsang, MB ChB, FCSHK, FHKAM Honorary Clinical Associate Professor Department of Surgery The University of Hong Kong Hong Kong, China Consultant Surgeon Department of Surgery Queen Mary Hospital Hong Kong, China Simon Turcotte, MD, MSc Associate Professor of Surgery Hepatopancreatobiliary Surgery Full Scientist Cancer Axis Centre de Recherche du Centre Hospitalier de l’Université de Montréal Montréal, Quebec, Canada Thomas van Gulik, MD, PhD Professor Department of Surgery Amsterdam University Medical Centers, University of Amsterdam Amsterdam, Netherlands Andrea Vannucci, MD Associate Professor of Anesthesiology Department of Anesthesia and Critical Care University of Chicago - Pritzker School of Medicine Chicago, Illinois

CONTRIBUTORS

Jean-Nicolas Vauthey, MD Professor of Surgery Surgical Oncology MD Anderson Cancer Center Houston, Texas Fort Worth Living Legend Chair for Cancer Research Chief of Hepatopancreatobiliary Surgery Section Dallas Texas Jack R. Wands, MD Director Gastroenterology/Liver Research Center Rhode Island Hospital Providence, Rhode Island Julia Wattacheril, MD, MPH Associate Professor of Medicine Medicine Columbia University College of Physicians and Surgeons, New York, New York Sharon Marie Weber, MD Tim and MaryAnn McKenzie Chair of Surgical Oncology Surgery University of Wisconsin Director for Surgical Oncology UW Carbone Cancer Center University of Wisconsin Chair Surgical Oncology University of Wisconsin Fellowship Director Surgical Oncology University of Wisconsin Madison, Wisconsin Alice C. Wei, MD MSc FRCSC FACS Associate Attending Surgeon Surgery Memorial Sloan Kettering Cancer Center New York, New York Associate Professor Surgery Weill Medical College of Cornell University New York, New York Matthew Weiss, MD, MBA Deputy Physician-in-Chief, Director of Surgical Oncology Department of Surgery Northwell Health Cancer Institute Lake Success, New York Jürgen Weitz, Professor, MD, MSc Chair Department of Gastrointestinal, Thoracic and Vascular Surgery University Hospital Carl Gustav Carus, Technische Universität Dresden Managing Director National Center for Tumor Diseases (NCT/UCC) Dresden, Germany

Andrew David Wisneski, MD Resident & Research Fellow Surgery University of California San Francisco San Francisco, California Christopher L. Wolfgang, MD, PhD Chief, Surgical Oncology; Professor of Surgery, Pathology and Oncology Department of Surgery The Johns Hopkins Hospital Baltimore, Maryland Dennis Yang, MD Advanced Endoscopy Fellow Gastroenterology Advent Health Director Center for Interventional Endoscopy Advent Health Orlando, Florida Professor Medicine Loma Linda University Health Loma Linda, California Hooman Yarmohammadi, MD Associate Attending of Radiology Radiology Memorial Sloan-Kettering Cancer Center New York, New York Charles J. Yeo, MD, FACS Samuel D. Gross Professor & Chair Department of Surgery Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia, Pennsylvania Theresa Pluth Yeo, PhD, MPH, AOCNP, ACNP-BC, FAANP Co-Director Jefferson Pancreas Tumor Registry Department of Surgery Professor Jefferson College of Nursing Acute Care Nurse Practitioner Advanced Oncology Nurse Practitioner Surgery Thomas Jefferson University Hospital Philadelphia, Pennsylvania Adam Yopp, MD Associate Professor Surgery UT Southwestern Medical Center Dallas, Texas

xxv

xxvi

CONTRIBUTORS

Herbert Zeh, MD Professor and Chair of Surgery Surgery UT Southwestern Medical Center Dallas, Texas Fangyu Zhou, MD Postdoctoral Research Associate Surgery Washington University School of Medicine St Louis, Missouri Gazi B. Zibari, MD Academic Chairman Dept of Surgery Program Director Surgery Residency Transplant Willis Knighton Health System Director, John C. McDonald Regional Transplant Center Transplant Willis Knighton Health System Director, WK Advanced Surgery Center Willis-Knighton Health System Shreveport, Louisiana

George Zogopoulos, MD, PhD, FRCS(C), FACS Associate Professor Surgery and Oncology McGill University Attending Surgeon Hepato-Pancreato-Biliary and Abdominal Organ Transplant Surgery McGill University Health Centre Montreal, Quebec, Canada

PREFACE INDEX The seventh edition of Blumgart’s Surgery of the Liver, Biliary Tract, and Pancreas was forged largely during the global COVID-19 pandemic, one of the most significant and devastating healthcare crises of the past century. As such, this has been among the most challenging editions to complete but is ultimately faithful to its long history and Dr. Leslie Blumgart’s vision of embracing change to keep the book relevant to its readers. The COVID pandemic has profoundly impacted and disrupted all our lives, both professionally and personally, in ways none of us could ever have imagined. The completion of the seventh edition under such difficult circumstances thus represents a notable achievement and, on behalf of the section editors, I extend my sincere thanks to everyone who contributed. The seventh edition once again relies heavily on associate editors to comprehensively cover the extraordinary advances over the past 5 years. As world-renowned experts in the field, the associate editors bring great insight to the book based on extensive personal experience. Dr. Jean-Nicolas Vauthey of the University of Texas MD Anderson Cancer Center once again joins Dr. William Chapman of Washington University in St. Louis in taking primary oversight of sections dealing largely with hepatic resection and transplantation, reflecting the substantial contributions they have made in these areas. Drs. Ronald DeMatteo, Michael D’Angelica, and Peter Allen bring their expertise to bear in the sections on basic science/ physiology, biliary tract, and pancreatic disease, respectively. Dr. Richard Kinh Gian Do’s substantive improvements in the sections on liver, biliary, and pancreatic imaging include moving from modality-based to disease-based descriptions. Dr. T. Peter Kingham joins the editorship for this edition, taking charge of an expanded section on the technical aspects of liver, biliary, and pancreatic resection, including transplantation and minimally invasive approaches. The current edition reflects advances in the molecular biology of benign and malignant HPB diseases, as well as significant improvements in imaging, therapeutics, and overall disease management. Indeed, since the last edition, great advances have been made in many areas, most notably in our understanding of the molecular underpinnings of malignant disease and the related explosion of treatment options, imaging technology, and minimally invasive/robotic surgery, and these are prominently featured in their respective sections.

As previously described, the organization of the book has been modified in that the sections on radiology are no longer separated by modality but rather by organ and disease type to provide a more rational view of imaging assessment. In addition, the technical aspects of HPB resectional surgery is now focused in a separate section. Furthermore, several new chapters have been added, while others have been expanded. The general format has been maintained by covering all surgical aspects of the management of HPB disorders, whereas the radiologic, endoscopic, and other nonsurgical approaches are presented in detail and highlighted when they represent the preferred therapy. As with past editions, contributors were chosen largely based on their expertise and were asked to discuss specific topics based not only on the published literature but also on their own views and personal experience. Toward that end, overlap between chapters and discussion of controversy was encouraged to allow for conflicting points of view. The initial section remains dedicated to general topics of HPB anatomy, physiology, and pathophysiology and thereby provides a solid foundation on which the remainder of the book is constructed. Chapter 2, “Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas,” remains the cornerstone of this section; one of the most important chapters in the entire book, it provides the basis for understanding much of the material presented in subsequent chapters on physiology, molecular biology and immunology, imaging, and perioperative management. In summary, the seventh edition attempts to include all aspects of the anatomy, pathology, diagnosis, and surgical and nonsurgical treatments related to HPB disorders, and all of the changes that have occurred since the last edition. We hope the work is of value to a wide range of readers, from seasoned HPB practitioners to surgical trainees and physicians in related disciplines. We have expanded our list of contributors to ensure the broadest and most contemporary viewpoints possible. I would like to again express sincere thanks to the co-editors who have collaborated with me in this project, as well as all the contributors who generously gave their time to make this seventh edition possible. We hope that the readers find this text to be a valuable resource for many years to come. W.R. Jarnagin, MD New York, New York, 2022

xxvii

ACKNOWLEDGMENTS The Editors are indebted to our colleagues in surgery and other disciplines for their enthusiastic support and insightful contributions. We thank them for updating their areas of expertise, detailing recent advances, and highlighting areas of controversy and differing opinion – without them, this project would never have been possible. Special thanks to our respective staffs in New York, St. Louis, Houston, Durham (NC), and Philadelphia who have assisted in the preparation of this work. Finally, special thanks and appreciation are due to Erin Patterson, who provided much needed editorial support, and to Dee Simpson, Casey Potter, and all of the staff of our esteemed publisher, Elsevier, for their great support throughout the project.

xxviii

CONTENTS Preface William R. Jarnagin, Peter J. Allen, William C. Chapman Sr., Michael I. D’Angelica, Ronald P. DeMatteo, Richard Kinh Gian Do, Jean-Nicolas Vauthey and T. Peter Kingham

VOLUME 1 Introduction: Hepatobiliary and Pancreatic Surgery: Historical Perspective, 1 Jacques Belghiti and Jean Robert Delpero

PART 1  Liver, Biliary, and Pancreatic Anatomy and Physiology, 19

1 Embryologic Development of the Liver, Biliary Tract, and Pancreas, 20 Mark Davenport and Philippa Francis-West



2 Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas, 27 Ronald P. DeMatteo



3 Pancreatic Physiology and Functional Assessment, 54



4 Assessment of Hepatic Function: Implications for Perioperative Outcome and Recovery, 64



5 Liver Blood Flow: Physiology, Measurement, and Clinical Relevance, 70

Alessandro Paniccia and Richard D. Schulick

Sean Bennett and Paul J. Karanicolas

Edouard Girard and Simon Turcotte



6 Liver Regeneration: Mechanisms and Clinical Relevance, 87



7 Liver Fibrogenesis: Mechanisms and Clinical Relevance, 105

Jeroen de Jonge and Kim M. Olthoff Scott L. Friedman



8 Bile Secretion and Pathophysiology of Biliary Tract Obstruction, 116 Henry A. Pitt and Attila Nakeeb

9A Molecular and cell Biology of Hepatopancreatobiliary Disease: Introduction and Basic Principles, 126 Caitlin A. McIntyre and Rohit Chandwani

9B Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis, 131

11 Infections in Hepatic, Biliary, and Pancreatic Surgery, 183 Sanket Srinivasa and Ryan C. Fields

PART 2  Diagnostic Techniques, 191 12 Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease, 192 Marco Massani and Tommaso Stecca

13 Cross-Sectional Imaging of Liver, Biliary, and Pancreatic Disease: Introduction and Basic Principles, 208 Richard Kinh Gian Do

14 Imaging Features of Benign and Malignant Liver Tumors and Cysts, 214 Kate Anne Harrington

15 Imaging Features of Metastatic Liver Cancer, 236 Galina Levin and Richard Kinh Gian Do

16 Imaging Features of Gallbladder and Biliary Tract Disease, 249 Scott R. Gerst and Richard K. Do

17 Imaging Features of Benign and Malignant Pancreatic Disease, 266 Shannan M. Dickinson and Seth S. Katz

18 The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases, 284 Simone Krebs, Elisabeth O’Dwyer, and Mark Dunphy

19 Emerging Techniques in Diagnostic Imaging, 309 Richard Kinh Gian Do

20 Direct Cholangiography: Approaches, Techniques, and Current Role, 314 Robert H. Siegelbaum and Robin B. Mendelsohn

21 Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications, 328 Aaron W.P. Maxwell and Hooman Yarmohammadi

22 Endoscopic Ultrasound of the Biliary Tract and Pancreas, 340 Vineet Syan Rolston, Joseph Patrick Kingsbery, and Mark Andrew Schattner

23 Image-Guided Liver Biopsy, 349 Juan Camacho, Lynn A Brody, and Anne M Covey

24 Intraoperative Diagnostic Techniques, 358 Ola Ahmed and M. B. Majella Doyle

Takehiro Noda and Jack R. Wands

9C Advances in the Molecular Characterization of Liver Tumors, 145 Colm J. O’Rourke and Jesper B. Andersen

9D Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions, 149 Rami Iman and Christine Iacobuzio-Donahue

9E Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer, 160 Ryosuke Okamura and Jason K. Sicklick

10 Fundamentals of Liver and Pancreas Immunology, 169 Yongwoo David Seo, Ian Nicholas Crispe, and Venu G. Pillarisetty

PART 3  Anesthetic Management, Pre- and Postoperative Care, 366 25 Liver and Pancreatic Surgery: Intraoperative Management, 367 Mary Fischer, Vittoria Arslan-Carlon, and Jose Melendez

26 Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient, 381 Russell C. Kirks Jr, R. Eliot Fagley, and Flavio G. Rocha

27 Enhanced Recovery Programs in Hepatobiliary Surgery, 390 Timothy E. Newhook and Thomas A. Aloia xxix

xxx

CONTENTS

28 Postoperative Complications Requiring Intervention: Diagnosis and Management, 395 Franz Edward Boas and Stephen B. Solomon

29 The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health, 401 Piera Marie Cote Robson

42 Benign Biliary Strictures and Biliary Fistulae, 584 Carlos U. Corvera and Andrew D. Wisneski

C  Biliary Infection and Infestation, 620 43 Cholangitis, 620 Matthew Iyer and Vinod P. Balachandran

44 Recurrent Pyogenic Cholangitis, 632

PART 4  Techniques of Biliary Tract Intervention: Radiologic, Endoscopic, and Surgical, 435 30 Interventional Endoscopy for Biliary Tract Disease: Technical Aspects, 436 Yakira David, Dennis Yang, and Christopher DiMaio

31 Radiologic Hepatobiliary Interventions, 453 Karen T. Brown and Anne M. Covey

32 Bile Duct Exploration and Biliary-Enteric Anastomosis, 459 Brooke C. Bredbeck and Clifford S. Cho

Tan To Cheung, Wong Hoi She, Ka Wing Ma, and Simon Tsang

45 Biliary Parasitic Disease, 647 John A. Steinharter and Michael D’Angelica

D  Cystic Disease of the Biliary Tract, 661 46 Bile Duct Cysts in Adults, 661 Michael R. Driedger, Patrick Starlinger, and David M. Nagorney

SECTION II  Neoplastic, 678 A  General, 678 47 Tumors of the Bile Ducts: Pathologic Features, 678 Olca Basturk and David S. Klimstra

PART 5  Biliary Tract Disease, 471

B  Benign Tumors, 687

SECTION I  Inflammatory, Infective, and Congenital, 473

48 Benign Tumors and Pseudotumors of the Biliary Tract, 687

A  Gallstones and Gallbladder, 473 33 The Natural History of Symptomatic and Asymptomatic Gallstones, 473 Sean J. Judge and Sepideh Gholami

34 Cholecystitis, 479 Alexandra W. Acher, Kaitlyn J. Kelly, and Sharon M. Weber

35 Percutaneous Treatment of Gallbladder Disease, 489 Jad Abou Khalil, George Zogopoulos, and Jeffrey S. Barkun

36 Cholecystectomy Techniques and Postoperative Problems, 494 Morgan Bonds and Flavio Rocha

37A Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques, 503 Bryan Clary and Gabriel T. Schnickel

37B Stones in the Bile Duct: Minimally Invasive Surgical Approaches , 521 Michele L. Babicky and Paul D. Hansen

37C Stones in the Bile Duct: Endoscopic and Percutaneous Approaches, 529 Satish Nagula

38 Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?, 539 Joshua T. Cohen, Rachel E. Beard, Lygia Stewart, and Mark P. Callery

39 Intrahepatic Stone Disease, 550 Itaru Endo, Ryusei Matsuyama, Norifumi Kumamoto, and Yuki Homma

B  Biliary Stricture and Fistula, 566 40 Extrahepatic Biliary Atresia, 566 Alex G. Cuenca and Heung Bae Kim

41 Primary Sclerosing Cholangitis, 573 Navine Nasser-Ghodsi, James H. Tabibian, and Nicholas F. LaRusso

Eva Galka and David Linehan

C  Malignant Tumors, 695 49 Tumors of the Gallbladder, 695 Rachel M. Lee and Shishir K. Maithel

50 Intrahepatic Cholangiocarcinoma, 711 Jonathan B. Koea

51A Extrahepatic Biliary Tumors, 724 Kevin C. Soares, Michael I. D’Angelica, and William R. Jarnagin

51B Perihilar Cholangiocarcinoma: Presurgical Management, 742 Roeland F. de Wilde and Bas Groot Koerkamp

52 Interventional Techniques in Hilar and Intrahepatic Biliary Strictures, 749 Karen T. Brown

PART 6  Pancreatic Disease, 762 SECTION I  Inflammatory, Infective, and Congenital, 763 A  Congenital Disorders, 763 53 Congenital Disorders of the Pancreas: Surgical Considerations, 763 Ewen M. Harrison and Rowan W. Parks

B  Pancreatitis, 777 54 Definition and Classification of Pancreatitis, 777 Giovanni Marchegiani, Giuseppe Malleo, Roberto Salvia, and Claudio Bassi

55 Etiology, Pathogenesis, and Diagnostic Assessment of Acute Pancreatitis, 785 Ser Yee Lee, Adrian Kah Heng Chiow, Brian Kim Poh Goh, and Chung Yip Chan

CONTENTS

56 Management of Acute Pancreatitis and Pancreatitis-Related Complications, 801 Euan J. Dickson, Maria Coats, and C. Ross Carter

57 Etiology, Pathogenesis, and Diagnosis of Chronic Pancreatitis, 816 Kevin N. Shah and Theodore Pappas

58 Management of Chronic Pancreatitis: Conservative, Endoscopic, Surgical, 831 Thilo Hackert, John P. Neoptolemos, and Markus W. Büchler

xxxi

B  Liver Infection and Infestation, 950 70 Pyogenic Liver Abscess, 950 Martin de Santibañes, Oscar Mazza, and Eduardo de Santibañes

71 Amebiasis and Other Parasitic Infections, 960 Hrishikesh Samant, Hany Dabbous, and Gazi B. Zibari

72 Hydatid Disease of the Liver, 978 Javier C. Lendoire, Emmanuel Melloul, and Oscar Cesar Imventarza

C  Nonparasitic Liver Cysts, 999 SECTION II  Neoplastic, 842 A  General, 842 59 Tumors of the Pancreas and Ampulla, 842 Laura H. Tang, MD, PhD, and Christine E. Orr, MD, FRCPC

73 Simple Cysts and Polycystic Liver Disease: Clinical and Radiographic Features and Surgical and Nonsurgical Management, 999 Béatrice Aussilhou and Olivier Farges

B  Benign and Premalignant Tumors, 868

D  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure, 1025

60 Cystic Neoplasms of the Pancreas: Epidemiology, Clinical Features, Assessment, and Management, 868

74 Cirrhosis and Portal Hypertension: Pathologic Aspects, 1025

Neda Amini and Christopher L. Wolfgang

C  Malignant Tumors, 876 61 Pancreatic Cancer: Epidemiology, 876 Theresa Pluth Yeo, Geoffrey W. Krampitz, and Charles J. Yeo

62 Pancreatic Cancer: Clinical Aspects, Assessment, and Management, 887 Jeffrey A. Debrin

63 Duodenal Adenocarcinoma, 894 Sophia K. McKinley and Cristina R. Ferrone

64 Pancreas as a Site of Metastatic Cancer, 898 Patryk Kambakamba and Kevin C. Conlon

D  Endocrine Tumors, 903 65 Pancreatic Neuroendocrine Tumors: Classification, Clinical Picture, Diagnosis, and Therapy, 903 Haley Hauser, Diane Reidy-Lagunes, and Nitya Raj

66 Chemotherapy and Radiotherapy for Pancreatic Cancer: Adjuvant, Neoadjuvant, and Palliative, 914 Fiyinfolu Balogun, Naveen Premnath, and Eileen M. O’Reilly

67 Palliative Treatment of Pancreatic and Periampullary Tumors, 925 Motaz Qadan and Roi Anteby

VOLUME 2 PART 7  Hepatic Disease, 935 SECTION I  Inflammatory, Infective, and Congenital, 937 A  Hepatitis, 937 68 Chronic Hepatitis: Epidemiology, Clinical Features, and Management, 937 Christopher D. Anderson and Jeffrey S. Crippin

69 Hepatic Steatosis, Steatohepatitis, and Chemotherapy-Related Liver Injury, 943 Samer Tohme, Srinevas K. Reddy, and David A. Geller

Elizabeth M. Brunt and Danielle H. Carpenter

75 Nonhepatic Surgery in the Cirrhotic Patient, 1038 Truman M. Earl, Franklin Olumba, and William C. Chapman

76 Portal Hypertension in Children, 1045 Nadia Naz and Janis M. Stoll

77 Management of Liver Failure, 1049 William Bernal

78 Support of the Failing Liver, 1055 Harvey S. Chen, Matthew Aizpuru, Kewei Li, and Scott L. Nyberg

79 Management of Ascites in Cirrhosis and Portal Hypertension, 1061 Kevin M. Korenblat

80 Medical Management of Bleeding Varices: Primary and Secondary Prophylaxis for Variceal Bleeding, 1069 Richard Gilroy, Christopher Danford, and Maria Jepperson

81 Portal Hypertensive Bleeding: Acute Management, 1081 Joseph Awad and Julia Wattacheril

82 Portal Hypertensive Bleeding: Operative Devascularization, 1085 Anil Kumar Agarwal

83 Portal Hypertensive Bleeding: the Role of Portosystemic Shunting, 1096 Stuart J. Knechtle, Jigesh A. Shah, and Paul Suhocki

84 Techniques of Portasystemic Shunting: Selective and Nonselective Shunts, 1109 Alexander S. Rosemurgy and Iswanto Sucandy

85 Transjugular Portosystemic Shunting (TIPS): Indications and Technique, 1119 Pilar Bayona Molano and Michael Darcy

86 Budd-Chiari Syndrome and Veno-Occlusive Disease, 1130 C. Kristian Enestvedt and Susan L. Orloff

SECTION II  Neoplastic, 1152 A  General, 1152 87 Tumors of the Liver: Pathologic Aspects, 1152 Valérie Paradis

xxxii

CONTENTS

B  Benign and Premalignant Tumors, 1181 88A Benign Liver Lesions, 1181 Safi Dokmak and Maxime Ronot

88B Cystic Hepatobiliary Neoplasia, 1203 Olivier Farges and Valérie Paradis

C  Malignant Tumors, 1218 89 Hepatocellular Carcinoma, 1218 Leonardo Gomes da Fonseca, Joana Ferrer-Fàbrega, and Jordi Bruix

90 Hepatic Metastasis from Colorectal Cancer, 1226 Yun Shin Chun, Yoshikuni Kawaguchi, and Jean-Nicolas Vauthey

91 Hepatic Metastasis from Neuroendocrine Cancers, 1239 M. D. Smith and J. W. Devar

92 Hepatic Metastasis from Noncolorectal Nonneuroendocrine Tumors, 1252 Christoph Kahlert, Ronald P. DeMatteo, and Jürgen Weitz

93 Hepatic Tumors in Childhood, 1262 Michael J. LaQuaglia, J. Ted Gerstle, and Michael P. LaQuaglia

D  Treatment: Nonresectional, 1283 94A Hepatic Artery Embolization and Chemoembolization of Liver Tumors, 1283 Aaron W. P. Maxwell and Constantinos T. Sofocleous

94B Radioembolization for Liver Tumors, 1303 Cristina Mosconi, S. Cheenu Kappadath, and Bruno C. Odisio

95 External Beam Radiotherapy for Liver Tumors, 1311 Marsha Reyngold and Christopher H. Crane

96A Ablative Treatment of Liver Tumors: Overview, 1318 Riccardo Lencioni

96B Radiofrequency Ablation of Liver Tumors, 1321 Patrick D. Lorimer and Anton J. Bilchik

96C Microwave Ablation and Irreversible Electroporation of Liver Tumors, 1334 Robert CG Martin II and Robert Rickert

96D Cryotherapy and Ethanol Injection, 1359 Chandrasekhar Padmanabhan, T. Peter Kingham, and Kevin C. Soares

97 Regional Chemotherapy for Liver Tumors, 1369 Louise C. Connell and Nancy E. Kemeny

98 Systemic Chemotherapy for Colorectal Liver Metastasis: Impact on Surgical Management, 1388 Marc-Antoine Allard and René Adam

99 Advances in Systemic Therapy for Hepatocellular Carcinoma, 1397 Ghassan K. Abou-Alfa, Imane El Dika, and Eileen M. O’Reilly

100 Isolated Hepatic Perfusion for Unresectable Hepatic Metastases, 1410 James Francis Pingpank, Jr.

E  Treatment: Resection, 1416 101A Hepatic Resection: General Considerations, 1416 William R. Jarnagin

101B Hepatic Resection for Benign and Malignant Liver and Biliary Tract Disease: Indications and Outcomes, 1418 Hop S. Tran Cao, Jean-Nicolas Vauthey and Ryan William Day

102A Parenchymal Preservation in Hepatic Resectional Surgery: Rationale, Indications and Outcomes, 1441 Aslam Ejaz, Jordan M. Cloyd, and Timothy M. Pawlik

102B Segment-Oriented Anatomic Liver Resections: Indications and Outcomes, 1448 Cornelius A. Thiels and Alice C. Wei

102C Preoperative Portal Vein Embolization: Indications, Technique, and Results, 1455 Junichi Shindoh

102D Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy: Indications and Outcomes, 1466 Karl J. Oldhafer and Thomas M. Van Gulik

103 Adjuncts to Hepatic Resection: From Ultrasound Guidance to New Oncologic and Technical Horizons, 1472 Guido Torzilli, Guido Costa, Jacopo Galvanin, Fabio Procopio

PART 8  Liver and Pancreas ­Transplantation, 1527 SECTION I  General, 1528 104 Liver and Pancreas Transplantation Immunobiology, 1528 Andrew S. Barbas, Michael E. Lidsky, and Allan D. Kirk

SECTION II  Indications, 1539 105 Liver Transplantation: Indications and General Considerations, 1539 James Neuberger

106 Liver Transplantation: Perioperative Anesthetic Considerations, 1554 Andrea Vannucci and Ivan Kangrga

107 Liver Transplantation in Patients with Fulminant Hepatitis, 1569 Jessica Lindemann and Maria B. Majella Doyle

108A Liver Transplantation for Hepatocellular Carcinoma, 1580 Garrett Richard Roll and John Paul Roberts

108B Liver Transplantation for Nonhepatocellular Malignant Disease, 1591 Timucin Taner, Charles B. Rosen, Julie K. Heimbach, and Gregory J. Gores

109 Orthotopic Liver Transplantation: Standard Donation After Brain Death, Donation After Cardiac Death, and Live Donor – Indications and Outcomes, 1605 Teresa C. Rice, Fangyu Zhou, and William C. Chapman

110 Liver Transplantation in Children: Indications and Outcomes, 1618 Ola Ahmed and Adeel S. Khan

111 Early and Late Complications of Liver Transplantation, 1627 Hunter B. Moore and James J. Pomposelli

112 Whole Organ Pancreas and Pancreatic Islet Transplantation, 1639 Niraj M. Desai and James F. Markmann

CONTENTS

PART 9  Hepatobiliary Injury and Hemorrhage, 1648 113 Injuries to the Liver and Biliary Tract, 1649 Woon Cho Kim and Lucy Kornblith

114 Pancreatic and Duodenal Injuries, 1658 Michael Farrell and Andre Campbell

115 Aneurysm and Arteriovenous Fistula of the Liver and Pancreatic Vasculature, 1665 Max E. Seaton and Vikas Dudeja

116 Hemobilia and Bilhemia, 1676 Tahsin M. Khan and Jonathan M. Hernandez

PART 10  Techniques of Pancreatic and Hepatic Resection and Transplantation, 1682 117A Pancreaticoduodenectomy, 1683 Peter J. Allen

117B Distal and Central Pancreatectomy, 1691 John M. Creasy, Peter J. Allen, and Michael E. Lidsky

117C Total Pancreatectomy, 1703 Danielle K. Deperalta and Matthew J. Weiss

117D Transduodenal Resection of the Papilla of Vater, 1707 Chandrasekhar Padmanabhan, and William R. Jarnagin

118A Major Hepatectomy and Extended Hepatectomy, 1710 Brett L. Ecker and Michael I. D’Angelica

118B Segmental Resection, 1726 Camille Stewart, Kelly J. Lafaro, and Yuman Fong

119A Hepatic Resection for Biliary Tract Cancer: Gallbladder Cancer, 1740 Nicole M. Nevarez, Michelle R. Ju, and Adam C. Yopp

119B Hilar Cholangiocarcinoma: Standard and Extended Resections of Perihilar Cholangiocarcinoma, 1747 Takashi Mizuno, Tomoki Ebata, and Masato Nagino

xxxiii

120 Hepatic Resection in Cirrhosis, 1757 Norihiro Kokudo, Nobuyuki Takemura, and Kiyoshi Hasegawa

121 Resection Technique for Live Donor Transplantation, 1764 See Ching Chan and Sheung Tat Fan

122 Vascular Reconstruction Techniques in Hepato-Pancreato-Biliary (HPB) Surgery, 1774 Pietro Addeo and Philippe Bachellier

123 Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Techniques, 1783 Hauke Lang, Fernando A. Alvarez, and Eduardo de Santibañes

124 Ex Vivo and in Situ Hypothermic Hepatic Resection, 1802 Chaya Shwaartz, Allan Hemming, and Ian D. McGilvray

125 Techniques of Liver Replacement, 1818 John A. Goss, Roberto Lopez, J. Wallis Marsh, and James Pomposelli

126 Techniques of Pancreas Transplantation, 1844 Santosh Nagaraju, John A. Powelson, and Jonathan A. Fridell

127A Minimally Invasive Techniques in HPB Surgery: Laparoscopic and Robotic: General Principles and Considerations, 1853 T. Peter Kingham

127B Minimally Invasive Distal and Central Pancreatectomy, 1854 Shiva Jayaraman and Brittany Dalia Greene

127C Minimally Invasive Pancreaticoduodenectomy, 1860 Patricio M. Polanco and Herbert J. Zeh III

127D Minimally Invasive Segmental Hepatic Resection, 1869 Bjørn Edwin, Davit L. Aghayan, and Åsmund Avdem Fretland

127E Laparoscopic Major and Complex Liver Resection, 1882 Chady Salloum and Daniel Cherqui

127F Robotic-Assisted Placement of Hepatic Arterial Infusion Pump, 1900 Benjamin D. Ferguson and T. Peter Kingham

128 Minimally Invasive Surgery Techniques in Transplantation, 1903 Choon Hyuck David Kwon, Kazunari Sasaki, and Amit Nair

This page intentionally left blank

INTRODUCTION Hepatobiliary and pancreatic surgery: Historical perspective Jacques Belghiti and Jean Robert Delpero During the past decades, liver and pancreatic surgery have witnessed countless and tremendous changes, leading to disruptive innovations and continuous improvements regarding the safety, rapidity, precision, and overall efficiency of surgical procedures. The history of hepatobiliary and pancreatic surgery followed this dual path, and our goal was to unravel which innovations and, more importantly, which real progress marked the specialty. Because many innovations could not have happened outside a specific social environment and historical background, concomitant discoveries occurred frequently. In this context, while we report the work of various pioneers who are true heroes of our specialty, we also kept in mind that publication of the first series was probably the most relevant surrogate of innovation during the past 50 years.

HISTORY OF LIVER SURGERY The history of liver surgery can be divided into three distinct periods: ancient times when concerns were focused on the liver’s anatomy, from 1880 to World War II when surgical considerations were at the forefront, and over the last 50 years when good knowledge of anatomy and development of technology allowed safe liver resection.

The Ancient Period Among all organs inspected in a sacrificial animal, the liver impressed the early observers as the most voluminous of the body and with its richness in blood. In Mesopotamia, the Assyrians and the Babylonians (2000–3000 BCE) believed that the liver was at the core of life, soul, emotions, and intelligence.1 This belief continued through the ages, as confirmed by some literary passages from Greek tragedians referring to the liver as the seat of emotions. Even the Promethean myth may be interpreted in a way that the liver was chosen as the seat of the soul. In the following centuries in different cultures the link between the liver and the soul continued to persist. For example, in the Islamic world the prophet Mohammed used the term “moist liver” to refer to the soul, whereas among the modern Berber populations of North Africa, the depth of feelings is still used through the expression “You are my liver.”2 It is interesting to mention that we now know that liver disease affects brain functions. Throughout antiquity, the most common fortune-telling method was the inspection of sacrificed animals. The liver was the single organ exploiting the custom of predicting the future among the Babylonians, Etruscans, Greeks, and Romans with the inspection of sacrificed animals.3 Prediction of the future was based on specific findings obtained by observing the liver surface because two livers never looked the same. These priests developed sheep liver clay models that were used to instruct other priests. Models of sheep livers used by priests were found

in Mesopotamia and in Italy during the Etruscan period (Fig. 0.1). These clay liver models are part of the history of liver anatomy along with several terms that were later incorporated into current anatomic terminology, including the right and left lobes, the gallbladder fossa, the umbilical fissure, and the caudate lobe and its processes described as papillary.4 Pharaonic medicine did not pay much attention to the liver. However, the liver was considered important because it was the only organ to be preserved in the only canopic funerary jar with the human head called Amset (Fig. 0.2). In contrast, Greek academic achievements dominated the ancient period until 5th century BCE. Hippocrates (460–370 BCE) described the first rudiments of semiology and hepatic pathology. He described jaundice, edema, ascites, and palpation in search of hepatomegaly or splenomegaly and transmitted, through aphorisms, the first prognostic elements: “the prognosis is grim when in a yellow patient the liver is small and hard.” Ancient Greeks described the treatment of abscess, puncture of ascitic fluid collection, and cauterization of war wounds. Both Prometheus and Tityus described two tragic mythical creatures that were punished by the fury of Zeus, and in both cases the carnivore birds devoured the liver; in the myth of Prometheus the eagle returned every day, but in the myth of Tityus the vultures appeared at every new moon. In these myths the liver was chosen as the immortal seat of the soul, but it remained impossible to determine whether Greek authors conceived the capacity of the liver parenchyma to regenerate.1 The Roman anatomist Gallien (130–201) was considered the father of modern medicine and pharmacology. Through the production of hundreds of books he named the liver as the main organ of the human body, arguing that it was the first of the organs to emerge in the formation of a fetus. For him “the liver is the source of the veins and the principal instrument of sanguification.” Noticing the “cooked” aspect of food in the stomach and the central location of the liver in the venous system, he postulated that this digestive product resulted in chyme, which was transformed into blood in the liver, while the waste was eliminated in the bile and the excess water was carried by the urine. This arrangement, false in terms of blood circulation, remains accurate in terms of hepatic physiology.5 Several centuries later Avicenna (980–1037), the father of early modern medicine, acknowledged the central role of the liver as “the seat of the nutritive or vegetative faculties.” Throughout several centuries, many disorders were described as an alteration in the balance of humors produced by the liver, the gallbladder as the repository of fury, and the spleen as the receptacle of melancholy. Terms used to indicate the liver reflected the different interpretations of its role. In ancient Greek its name “hépar” might be related to pleasure, because this organ was looked on as the seat of the soul and of human feelings. In Romance languages the Latin 1

2

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

FIGURE 0.1  The liver of Piacenza. Etruscan Bronze with inscriptions dated to the late 2nd century BCE.  (From the Municipal Museum of Piacenza, Italy.)

FIGURE 0.3  Andreas Vesalius (1514–1564). (From De Humani Corporis Fabrica, 1543.)

FIGURE 0.2  Egyptian funerary canopic jar with human head guardian of the liver. (Imsety [Amset], 600 BCE). (From the Science Museum of London.)

term ficatum was linked to the ancient practice of fattening geese with figs to make their livers more delicious. In the Early Modern Age, the liver became a recurring image used to indicate courage. The English term “liver” may derive from the Germanic term lifere connected to “life.”1

The Renaissance The writings of Greek physician Galen had dominated European medical thinking for over a millennium. Breakthrough knowledge concerning both liver anatomy and pathology emerged during the Renaissance in Italy. These improvements resulted from human autopsies performed by great artists and anatomists. The pioneer of these improvements was Antonio

Benivieni (1443–1502) in Florence who attempted to discover in his patients the etiology of biliary tract diseases. Most of the next phase of development of anatomic knowledge was centered around the University of Padua. In 1543 Andreas Vesalius (1514–1564) published innovative views of all organs arranged in three-dimensional (3D) space and interrelated. These anatomic drawings influenced the practice of operative techniques during the 16th and the 17th centuries (Fig. 0.3). Many of the eponyms that we now use in surgery were taken from famous anatomists of this school, including Johann Georg Wirsung (born in Augsburg Germany, 1589–1643), a German anatomist who was a long-time prosector in Padua. Years later, Giovanni Battista Morgagni (1682–1771) was promoted to the prestigious chair of anatomy and became the president of the University of Padua. In 1761 he published an outstanding analysis of biliary tract disease reporting the incidence of stones in male and female patients and describing the possible mechanisms by which calculi might be formed. He also considered the balance between conservative medical management and treatment by operation. Graduated from the University of Padua, the English physician William Harvey (1578–1657) is considered the greatest contributor to the study of anatomy and physiology. His description of the systemic circulation and the properties of blood pumped by the heart to the brain and the rest of the body ended the idea that the liver was the seat of blood formation. Harvey’s student Francis Glisson (1597–1677) investigated the structure of the liver. His book Anatomia Hepatis, published in 1654, was the first major work devoted to the liver with the description of the hepatic capsule and of the investment of the hepatic artery, portal vein, and bile duct. Using casts and injection studies his description of hepatic anatomy appears close to images displayed today in 3D-computed tomography (CT) (Fig. 0.4). His name is given to the liver capsule, which is an important anatomic structure that continues to influence technical and oncologic approaches. Marcello Malpighi (1628– 1694), regarded as the founder of microscopic anatomy, was the

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

3

FIGURE 0.4  Francis Glisson (1597–1677).  (From Anatomia Hepatis, 1654.)

first to study liver glandular components. During the next century, scholars and anatomists focused on the formation of bile.

BILIARY SURGERY The presence of gallstones in Egyptian mummies and the first description in the 6th century of human biliary concretions by Greek physician Alexander Trallianus had not been linked to a pathologic condition until the first description of obstructive jaundice in the beginning of the 17th century.6 Until the publications of Giovanni Battista Morgagni, biliary symptoms were confused with multiple abdominal conditions and without attempted adequate therapy. Surgical therapy of the gallbladder started with Jean-Louis Petit (1674–1750), who was the first director of the French Royal Academy of Surgery created in 1731. He introduced the term biliary colic and identified gallbladder inflammation as different from liver abscesses. When the gallbladder adhered to the abdominal wall, he described a successful treatment of calculi removal through a small incision after a puncture. Nearly one century later, in 1853, Johann Ludwig Wilhelm Thudichum (1829–1901) from London, England, described a two-stage elective procedure, including the suture of the gallbladder to the abdominal wall, which served as a route for the removal of gallstone at a later date.7 In 1867 in Indianapolis, Indiana, John Stough Bobbs (1809–1870) unknowingly performed the first cholecystostomy.8 During surgery for an ovarian cyst, he found an inflamed sac and removed several gallstones in a large gallbladder. He closed the cholecystostomy incision and placed the gallbladder near the undersurface of the abdominal incision. The patient survived. This procedure was intentionally performed in 1878 by the American Marion Sims (1813–1883) and by the Swiss Theodor Kocher (1841–1917), who won the Nobel Peace Prize in medicine in 1909 for his work on the thyroid gland. His name is well known to surgeons who perform mobilization of the duodenum. While several surgeons were pursuing the construction of a gallbladder fistula and direct removal of stones, Carl Langenbuch (1846–1901) observed these measures as only

FIGURE 0.5  Carl Johann August Langenbuch (1846–1901), surgeon.

temporary relief. He was a brilliant surgeon who was appointed director of the Lazarus Hospital in Berlin at the age of 27 (Fig. 0.5). Concerned by clinical observations of patients suffering from biliary symptoms, on July 15, 1882, he performed the first cholecystectomy. He removed a chronically inflamed and thickened gallbladder containing two gallstones in a 43-year-old man who had been suffering from the disease for 16 years. The patient was discharged uneventfully from the hospital. This milestone procedure was performed after several years of investigations and accumulating results of animal experiments and numerous human cadaveric dissections showing that the gallbladder was not essential to life.8 His innovation was received by the surgical community with skepticism, and, in some cases, with considerable disbelief. The debate between surgeons in favor of cholecystectomy versus those in favor of cholecystostomy was based on various pathophysiologic concepts and because of the technical difficulty of the procedure, at a time when anesthesia was not effective. In 1886 Justus Ohage (1843–1935) performed the first cholecystectomy in the United States in Minnesota, while a French surgeon named Jean-François Calot (1861–1944) described in 1890 the anatomic triangle of Calot, facilitating the technical aspect of cholecystectomy.9 For the first time this debate was based on

4

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

statistics comparing the mortality of the two approaches.7 Initially considered as a risky procedure, William and Charles Mayo from the Mayo Clinic stated in 1899 that the cholecystectomy should be employed more frequently, and in 1903 William reported 65 cholecystectomies with only two deaths.7 With a low risk rate, the long-term beneficial effect of cholecystectomy was solemnly established in 1917 by Charles Mayo in his address to the Clinical Congress of Surgeons of North America,10 35 years after Langenbuch’s paper. As soon as the cholecystectomy was feasible, there were several attempts to operate on the common bile duct (CBD), all of which resulted in the death of the patient.11 Fatal issues resulted from the combination of jaundice, hemorrhage, infection, and technical difficulties.6 Ludwig Georg Courvoisier (1843–1918), a surgeon from Basel, Switzerland, was the first to describe the successful removal of a stone from the CBD in 1889. The risk of postoperative peritoneal infiltration by bile after surgical exploration of the CBD limited the expansion of this approach. It began in 1897 when the German surgeon Johannes Otto Kehr (1862–1916) introduced the use of a T-tube for drainage and decompressing the biliary tree after exploration of the CBD. The T-tube is still used more than one century later. Kehr was one of the most outstanding biliary surgeons, opening the era of extensive biliary surgery, performing bilioenteric anastomosis, and describing resection of cancerous gallbladders, including hepatic resection.12 The first bilioenteric bypass was performed in 1880 by Alexander von Winiwarter (1848–1917), a surgeon from Vienna, who anastomosed the gallbladder with the colon for a patient with a malignant obstructive process.13 A series of complications and re-operations ensued, but eventually after several months he was able to revise the original bypass to a cholecystojejunostomy. In 1887 two surgeons, Otto Kappeler in Switzerland and Dmitrievich Monastyrski in Saint Petersburg, almost simultaneously performed the first planned, one-stage cholecystojejunostomies in jaundiced patients with pancreatic cancer.13 In 1889 the French surgeon Felix Terrier (1837–1908) performed the first successful cholecystoduodenostomy. The development of the cholecystectomy required the reconstruction of the biliary tract using the CBD, and Oskar Sprengel from Dresden, Germany, published the first report of a choledochoenterostomy13 in 1891. The most innovative procedure was the use of a jejunal loop for relief of gastric obstruction, which was described in 1893 by César Roux (1857–1934) in Lausanne, Switzerland (Fig. 0.6), and adapted as a bilioenteric anastomosis with the gallbladder in 1904. This procedure was proposed at the French Congress of Surgery in 1908 with the CBD by Ambroise Monprofit, a surgeon from Angers, France.12 The Rouxen-Y remains the most common bilioenteric anastomosis with the lowest incidence of reflux and cholangitis. The approach of the ampulla to clear the CBD termination or to treat specific symptoms included papillotomy, sphincterotomy, and sphincteroplasty, which were gradually supplanted by the endoscopic approach.12 In the 1960s various biliary-type symptoms and even pancreatitis were attributed to an abnormal pressure profile of the sphincter of Oddi, leading some surgeons, and, thereafter, endoscopists to develop various form of sphincterotomy and sphincteroplasty to treat these patients. After several decades of debate, the treatment of such sphincter dysfunction has fallen into disuse.15 The development of biliary surgical procedures was associated with the occurrence of iatrogenic bile duct injury. The resulting biliary fistulas or strictures

FIGURE 0.6  César Roux (1857–1934), surgeon.

necessitated the development of a new means of rerouting bile in the digestive tract. To treat a persistent biliary fistula after a cholecystostomy for a gallbladder empyema, Arthur Mayo-Robson (1853–1933), a surgeon from Leeds, England, performed an anastomosis between the gallbladder and the colon in 1889. The gradual practice of cholecystectomy and the increased risk of cholangitis and diarrhea using the colon led to establishing internal biliary drainage with the CBD. In 1905 William J. Mayo reported the first successful hepaticoduodenostomy reconstruction.13 In 1909 Robert Dahl of Stockholm, Sweden, used a Roux-en-Y jejunal limb for the first time to manage a common hepatic duct fistula. Since its description, Dahl’s approach remains widely used for the repair of various levels of damaged bile duct. In 1954 the description of a long extrahepatic course of the left hepatic duct in the hilar plate by Couinaud allowed several surgeons to perform hilar and intrahepatic biliary-enteric anastomoses in patients developing high biliary strictures.16,17 However, the difficulty of these anastomoses with poor long-term results gave rise to the development of percutaneous and endoscopic methods for intubation and dilatation of the biliary tract, which are now the first-line treatment of biliary injuries. Direct reconstruction of the bile duct using various tissue substitutes, such as the gallbladder with gastric flaps, with or without stenting, was unsatisfactory, with numerous recurrent strictures due to the specific CBD arterial supply.18

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

Extensive surgery for biliary cancer was developed by Japanese surgeons starting at the end of the 1970s. Yuji Nimura (1943) from Nagoya was the pioneer of this approach, reporting the first large series of extended hepatobiliary and surrounding organ resection for locally advanced gallbladder and cholangiocarcinoma with a 3-year survival of 29%.19 This aggressive approach was rapidly adopted by western surgeons, including Fortner in New York, Blumgart in the UK,20 and Neuhaus in Berlin.21 In the 21st century, factors contributing to preserve the leadership of Japanese surgeons for extensive surgery for hepatopancreatobiliary (HPB) cancer included technical meticulosity, progress in imaging, and preoperative management of the patients. Technical improvement using fine vascular surgical techniques and various vascular grafts have enabled surgeons to reconstruct portal, enous, and arterial flows. Progress in imaging diagnostics has enabled visualization of 3D anatomy, the extent of cancer progression, and hepatic segment volume. The most important innovation is preoperative management of the patient, including biliary drainage, which shifted from percutaneous transhepatic to endoscopic nasobiliary and portal vein embolization (PVE) for volume modulation.22 Good visualization of the biliary tree was quickly deemed essential for accurate diagnosis and treatment of biliary diseases. In 1924 Evarts Graham and Warren Cole discovered the diagnostic procedure of cholecystography. The first operative cholangiography was performed in 1931 by Argentinian Pablo Mirizzi (1893–1964). In 1968 one of the most innovative exploratory and therapeutic biliary procedures was published by William McCune (1909–1998) from George Washington University. He reported the first endoscopic cannulation of the ampulla in living patients to visualize both the CBD and the pancreatic duct.23 In 1974 the first endoscopic treatment of choledocholithiasis with sphincterotomy of the ampulla was reported in Germany by Classen, with a first series of more than 200 patients published by Safrany in Munich.24 Endoscopic retrograde cholangiopancreatography (ERCP) allowed physicians for the first time to obtain high-quality images of the common bile and pancreatic ducts. At present, magnetic resonance cholangiopancreatography (MRCP) is a quick, noninvasive method that can accurately evaluate the liver, gallbladder, bile ducts, pancreas, and pancreatic duct for disease. Percutaneous transhepatic biliary drainage and ERCP are now important tools for radiologic and endoscopic interventional procedures in patients with biliary obstacles or with postoperative complications.

Laparoscopic Cholecystectomy The introduction of laparoscopic cholecystectomy was a surgical revolution with immediate acceptance by patients and surgeons based on clinical experience that became rapidly popular without randomized trials. Explorative abdominal laparoscopy was introduced in 1910 in Sweden by Hans Christian Jacobaeus (1879–1937). This procedure evolved as an effective diagnostic tool incorporating several technical improvements, including the Trendelenburg position, the use of carbon dioxide for insufflation, and the development of specific instruments. Since the 1970s, these instruments have also allowed gynecologists in Germany to use this approach for the exploration and treatment of gynecologic disorders. On September 12, 1985, Erich Muhe (1938–2005), from Erlangen, Germany, performed the first planned cholecystectomy using a local manufacturing laparoscope (Fig. 0.7). When he presented his

5

FIGURE 0.7  Erich Muhe (1938–2005), surgeon.

first series in front of his German colleagues in 1986, the technique was rejected and considered as dangerous with offending comments such as “Mickey Mouse surgery,” while others remarked “small brain–small incision.”25 Reasons for rejection by the hierarchic German academic system included the predominant interest in transplantation and cancer treatments requiring large incisions. They had little interest in a gallbladder procedure with rapid medical dissolution and extracorporeal shock wave lithotripsy (presented by Gustave Paumgartner from Munich). Even though Muhe’s technique was rejected, providentially the German Society of Surgery awarded him a top honor in 1992. Laparoscopic cholecystectomy has also been credited to French surgeons Philippe Mouret, François Dubois, and Jacques Perissat who were able to disseminate this innovation though video technology, publications in international scientific journals, and academic participation to a multinational congress. In 1989 Perissat presented his video at the American Gastrointestinal Endoscopic Surgeons (SAGES) meeting in Louisville, Kentucky. This presentation and Dubois’ 1990 publication of a series of 36 cases of laparoscopic cholecystectomy found a large American audience.26 This new technique was introduced in the United States in 1988 with the first large series published in 1991.27 The advantages of laparoscopic cholecystectomy over open cholecystectomy were immediately accepted with a progressive disappearance of reluctance or contraindications, including pregnancy, obesity, severe cholecystitis, Mirizzi syndrome, acute pancreatitis, and the presence of CBD stones. CBD stones are usually extracted with ERCP, with laparoscopic cholecystectomy performed the following day after ductal clearance. Laparoscopic cholecystectomy provoked profound changes in the practice of biliary tract surgery with a 2-fold increase in the number of cholecystectomies performed worldwide. The beneficial effect of technical innovations such as single-incision laparoscopic surgery and robotic-assisted cholecystectomy has yet to be demonstrated in 2020.

6

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

PANCREAS SURGERY For many years the pancreas remained off limits to anatomists because of its anatomic position and consistency. Considered as a “finger of the liver” in the Talmud, this organ was described around 300 BCE by Herophilus of Chalcedon and named by Rufus of Ephesus in Asia Minor (ca. CE 100) as the pancreas (etymologically: pan (pág), all; kréas, flesh).27 This name was chosen in anticipation of a soft pancreas because it was considered as a gland in continuity with the omentum. In the Galenic framework the pancreas was considered as a conduit for the vasculature of vital organs and as a structural prop for the omentum. Its function was primarily to protect the retroperitoneal vessels. The anatomic reports of Galen remained uncontested until Vesalius’ description of the mesenterico-portal circulation with a right venous trunk “supported by a glandulous body.” The view that the pancreas serves to “support” the intestines persisted when William Harvey described the blood circulation, considering that the pancreas was just a “pad” located behind the stomach to protect the great vessels of the retroperitoneum. When he was in Padua, Johann Georg Wirsung described in 1642 the ductal pancreatic system. He ignored the function of the duct, but he engraved his anatomic drawing on a copper plate (Fig. 0.8) and sent it to the main anatomists in Europe asking their opinion.28 The authorship of this discovery was challenged by his trainee Moritz Hoffmann, and this controversy was complicated by the assassination of Wirsung in dubious circumstances in 1643, after which the name of the main pancreatic duct was referred to as “ductus Wirsungianus.” Giovanni Domenico Santorini (1681–1737) studied a hundred

pancreatic dissections with the aid of magnifying glasses, and he is credited in 1724 with the discovery of an accessory pancreatic duct referred to as the Santorini duct. The first description of the tubercle or diverticulum that was later named the “ampulla of Vater” was attributed to Abraham Vater (1684– 1751). The sphincteric muscle surrounding the CBD was described in 1654 by the anatomist Francis Glisson, and its function was rediscovered over two centuries later by Ruggero Oddi (1866–1913).14 Experimental studies contributed to the comprehension of the role of the pancreas in the digestive processes with the cannulation of pancreatic ducts in dogs by Regnier de Graaf (1641–1673) from Leyden. Herman Boerhaave (1668–1738), also from Leyden, described the pancreatic veins and arteries with precision. Giovanni Battista Morgagni, in 1761, described the pathologic aspect of this organ, including the description of what could be a pancreatic cancer. The depiction of the common channel of the pancreatic duct with the CBD by Sommering in 1796 reinforced the understanding of the excretory function, which was elucidated by the French physiologist Claude Bernard (1813–1878). In 1812 Johann Friedrich Meckel (1781–1833) described the embryologic development of the pancreas with the fusion of dorsal and ventral primordia, opening the comprehension of the pancreas divisum and the annular pancreas. In 1869 Paul Langerhans reported a microscopic description of the pancreatic tissue, including acinar cells as well as specific islets (referred to as islets of Langherans) with endocrine function.29 In Europe, the ability to perform autopsies contributed to the further development of this knowledge, whereas in Japan the pancreas was not drawn in the book

FIGURE 0.8  Imprint of the pancreatic ducts by Johann Georg Wirsung, 1642. (From Bo Palace, Padua, Italy.)

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

by anatomist Kouan Kuriyama in 1759, which illustrated the first recorded human dissection.2 Nicholas Senn (1844–1908), who worked at the Rush Medical College of Chicago, observed how patients’ skin was injured by the percutaneous drainage of pancreatic cysts. Diedrich Kulenkampff, a surgeon from Bremen, confirmed in 1881 that the fistula following the drainage of a traumatic cyst contained an alkaline juice capable of hydrolyzing starch, proteins, and fats in the absence of bile. The contribution of experimental surgery was important for discrimination between exocrine and endocrine function. In 1889 Joseph von Mering and Oskar Minkowski discovered the link between diabetes and the pancreas, reporting that removal of the pancreas induced diabetes in dogs and that subcutaneous pancreatic grafts prevented diabetes in these animals.29 In 1909 Robert C. Coffey (1869–1933), from Portland, Oregon, published the first series of direct anastomosis of the pancreatic duct to the gastrointestinal tract. During the 19th century, experimental studies from Ivan Petrovich Pavlov (1849–1936) and his pupils from Russia added important contributions to the physiology of digestion, including the stimulation by the vagus nerve, the stimulation of pancreatic juice by a hormone called secretin, and the activation of this juice in the duodenal membrane by enterokinase.29 The beginning of pancreatic surgery in humans started with the treatment of cysts. In 1841 Friedrich Wilhelm Wandesleben (1800–1868) from Stromberg, Germany, reported the world’s first operation on the human pancreas. In a 28-year-old man he drained pus and watery fluid from a pseudocyst secondary to a nonpenetrating abdominal trauma, but the patient died from respiratory failure 5 months later. In 1881 Carl Thiersch (1822–1895), from Munich, Germany, published a successful cyst drainage in a 38-year-old man with a persistent fistula from the pancreatic tail; the patient survived the operation. The chocolate-colored liquid of this cyst may be attributed to a complication of acute pancreatitis, suggesting that this procedure was one of the first surgical treatments of this disease. The first successful percutaneous drainage by marsupialization of the cyst on the abdominal wall was reported in 1882 by Karl Gussenbauer (1842–1903), who was a disciple of Theodor Billroth. This procedure triggered an increase in the number of operations performed on cysts with a dramatic 3% drop in mortality rate.30 The differentiation between true pancreatic cysts from pseudocysts and cystic tumors was proposed in 1898 by Werner Körte (1853–1937) from Berlin. The first internal anastomosis of a pseudocyst with the duodenum was performed in 1911 by Louis Ombrédanne (1871–1956) from Paris, but the patient died 11 days after the procedure. In 1921 Rudolf Jedlička (1869–1926) in Prague, Czech Republic, performed what is considered to be the first pancreatic cystogastrostomy. The first cystojejunostomy was performed in 1923 by the German surgeon Adolf Henle (1864–1936). The first transgastric pancreatic cystogastrostomy was published in 1931 by Anton Jurasz (1882–1961), a professor of surgery at the University of Poznan (Poland). This innovative approach, known as the Jurasz procedure, became the standard approach for the treatment of mature pseudocysts in contact with the stomach. Resection of pancreatic lesions started in 1867 with the removal of a pancreatic cyst by the German George Albert Lücke (1829–1884) in Bern. In 1882 in Berlin Friedrich Trendelenburg (1844–1924) performed the first distal pancreatectomy (DP) with splenectomy for a small solid tumor of the pancreatic tail in a 41-year-old female patient who died postoperatively from respiratory failure. The first central pancreatectomy for a

7

cystic lesion without closing the remaining pancreas was performed in 1885 by the Viennese surgeon Theodor Billroth (1829–1894). One year earlier, a successful total pancreatectomy (TP) was also attributed to Billroth.30 In 1889 Giuseppe Ruggi (1844–1925) from Bologna, Italy, performed the first enucleation of a pancreatic mass. Patients with obstructive jaundice due to pancreatic carcinoma were treated with various palliative operations (see “Biliary Surgery”). Until the beginning of the 20th century, pancreatic procedures in the head of the pancreas were scarce without touching the duodenum and without specific treatment of both the pancreatic remnant and the pancreatic duct. In 1904 Domenico Biondi (1855–1914) from Bologna, Italy, removed a pancreatic tumor with ligation of the pancreatic duct. At the Johns Hopkins Hospital in 1898 William Stewart Halsted (1852–1922) performed the first successful resection of an ampullary cancer through a transduodenal approach. After an en bloc resection of the ampulla, both pancreatic and bile ducts were re-anastomosed. The same year Alessandro Codivilla (1861–1912) performed the first pancreaticoduodenectomy (PD) in a patient with a pancreatic tumor adherent to the duodenum. The procedure consisted of resection of the pancreatic head, the duodenum, and part of the stomach followed by a cholecystojejunostomy and Roux-en-Y gastrojejunostomy without anastomosis or closure of the pancreatic stump. The patient died in the postoperative period. The breakthrough innovation of this surgery should be attributed to Walther Carl Eduard Kausch (1867–1928) who performed a safe two-stage resection of the pancreatic head in 1909 in Berlin. In a jaundiced 49-year-old male patient, he performed a cholecystojejunostomy followed 2 months later by pancreatic head resection with the pylorus and the first and second part of the duodenum. The posterolateral gastroenterostomy was associated with an anastomosis of the pancreatic stump with the third part of the duodenum. After a transitory pancreatic fistula, the patient died 9 months later after numerous episodes of cholangitis.31 Anticipating the benefit of preoperative biliary drainage preventing postoperative complications due to the long-term preoperative jaundice, this procedure was a significant advance in pancreatic surgery, and some thought that the so-called Whipple procedure should be called the Kausch-Whipple procedure. Two innovations before the publication of a PD described by Whipple in 1935 deserve consideration. The first innovation was a one-stage PD with a pancreatic anastomosis by Georg Hirschel from Heidelberg in 1914, and the second was the biliary-enteric anastomosis using the main bile duct, described in 1922 by Ottorini Tenani from Florence, Italy.31 The two-stage procedure published in 1935 by Allen Oldfather Whipple (1881–1963) from the New York-Presbyterian Hospital (Fig. 0.9) was considered a surgical milestone, consisting of a complete resection of the head of the pancreas associated with a total duodenectomy, then suturing of the cut surface of the pancreas with nonabsorbable suture. This procedure resulted in a patient’s 2-year survival after treatment for carcinoma of the ampulla of vater.32 In Chicago in 1937 Alexander Brunschwig (1901–1969) introduced the concept of radical abdominal surgery with a dissection of the head of the pancreas on the right side of the superior mesenteric vein. Whipple modified this procedure, resulting in a single operative stage consisting of reconstruction with Roux en-Y jejunostomy and the end-to-side pancreatojejunostomy. This approach has become the standard technique for resection of the head of the pancreas.32,33 This accurate utilization of his experience with modification based on the published experience

8

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

FIGURE 0.9  Allen Oldfather Whipple (1881–1963), surgeon.

of other surgeons warrants his designation as the father of pancreatic surgery. However, during subsequent decades, surgical resection of malignancies of the head of the pancreas was limited by a high rate of postoperative mortality (around 30%), a low rate of long-term survival (around 5% for pancreatic cancer), and several functional disorders. For several years palliative bypass alone resulted in better quality of life and similar survival. At the end of the 1980s, the trend of centralization at highvolume centers with surgeons specializing in pancreatic surgery resulted in a dramatic improvement of postoperative mortality rates at less than 5% in several institutions in the United States34 and Germany.35 John L. Cameron (1936) was a pioneer of the concentration of pancreatic surgery in specialized centers. This strategy is presently recommended more and more often and has improved the result of the procedure with better management of postoperative complications requiring interventional radiology. The vast majority of immediate postresection complications are attributed to pancreatic leakage, and investigation into the best anastomotic technique raised considerable debate. Pancreaticojejunostomy was challenged by an anastomosis with the stomach aiming to inactivate pancreatic enzymes by the gastric acid, but this procedure did not show superiority.36 Trends in the modification of the anastomotic method of the pancreatojejunostomy incorporated various methods of duct-to-mucosal anastomosis, with or without invagination or seromuscular jejunal anastomosis, and include the so-called Blumgart anastomosis using transpancreatic U-sutures with favorable outcome in some nonrandomized trials.37 Another innovation was Peng’s binding pancreaticojejunostomy technique with a near-zero fistula rate, which was not validated externally.38 None of these

innovations resulted in significant progress except the external stenting of the main pancreatic published by R. Poon from Hong Kong, which can be recommended in patients with high risk of fistula.39 Studies on this specific postoperative event were clarified by the international, uniformly accepted definition for pancreatic fistulae published in 2005 by the International Study Group on Pancreatic Fistulae (ISGPF).40 Risk factors for postoperative pancreatic fistula (POPF) were dominated by the texture of the pancreatic gland and duct characteristics, such as the presence of a soft gland and/or a pancreatic duct less than 3 mm. The intraoperative tactile impression of the operative surgeon is currently surpassed by preoperative clinical and radiologic assessment,41 but some scores, available online, have been recently developed for a better prediction of the risk of POPF. Medical and pharmacologic approaches preventing POPF remain controversial, including routine use of octreotide, perioperative nutrition, and decreasing the amount of intravenous fluids in the perioperative phase.36 Long-term survival after PD revealed functional disorders in more than half of patients, including delayed gastric emptying, dumping syndrome, exocrine insufficiency, diarrhea, long-term weight loss, and diabetes. The first innovative technical procedure aiming to preserve the gastrointestinal function was PD with pylorus preservation (PPPD), which was reported in 1944 by K. Watson from the UK and popularized in 1978 by Traverso and Longmire from Los Angeles.31 In selected patients with localized tumors, this attractive procedure, which preserves both the entire stomach and pylorus function, gained worldwide popularity until the beginning of the 21st century, when multiple studies comparing classical PD with PPPD showed similar perioperative events and survival.42 Delayed gastric emptying, which occurs in 25% of patients, was not significantly influenced by pylorus preservation or by the route of enteric reconstruction (antecolic vs. retrocolic). In 1993 the Johns Hopkins group, led by John Cameron, examined the medical approach of such complications with robust controlled trials demonstrating the beneficial effect of erythromycin on delayed gastric emptying.43 The risk of postoperative diabetes observed in nearly one-third of patients after PD or DP is dramatically reduced in patients operated on for benign or low malignant potential tumors with pancreatic-sparing procedures.44 Recognition of hypersecreting endocrine tumors of the pancreas led to operations for these diseases. In 1926 at the Mayo Clinic in Rochester Russell M. Wilder (1885–1959) reported the first case of resection in the of pancreatic tumor with multiple intraabdominal metastases in which insulin was extracted.1 The first successful enucleation of an insulinoma based solely on the patient’s symptoms was reported in 1929 by Roscoe Graham in Toronto. Operating at the Mayo Clinic on a 49-year old woman with hyperinsulinism, James T. Priestley (1903– 1979) performed the first TP in 1942, as he was unable to find the tumor during the laparotomy. The patient was cured by the operation, and the small tumor causing the syndrome was discovered by pathologic examination.12 Accounting for less than 2% of all pancreatic neoplasms, neuroendocrine tumors of the pancreas include a wide range of heterogeneous neoplasms that are distinguished by symptoms related to the overproduction of the hormone from the cell of origin. The majority of these tumors are nonfunctional; however, they all may be identified with particular radiologic assessment, including nuclear medicine imaging. The scarcity of this disease and the complexity of the management of these patients with a favorable prognosis makes it necessary to centralize their management in high-volume

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

centers.44 Adenocarcinoma of the pancreas is a frequent tumor with a dreadful prognosis and the surgical approach remains the unique therapeutic option. During the 1960s and 1970s the lack of long-term survival motivated more radical resections, including TP with extensive lymph node dissection and vascular resection. This extensive approach was initiated by Joseph G. Fortner (1921–2007) from Memorial Hospital in New York, who proposed in 1973 a very unique extended technique of “regional pancreatectomy,” including portal and arterial resection.45 The high risk of this procedure contributed to its limited use.12 The rationale for TP aiming to remove multicentric malignant foci with more complete lymphadenectomy was not sustained by any survival benefit compared with partial resection, whereas the morbidity of TP remains substantial. TP is presently considered as an exceptional oncologic option in patients with localized malignant tumor. Extensive dissection of nerve plexus and lymph nodes around the origin of the superior mesenteric artery was reported by O. Ishikawa from Osaka, Japan,46 in 1988. However, several worldwide randomized controlled trials (RCTs), including one from Japan performed by Y. Nimura, showed that extended lymphadenectomy did not benefit from long-term survival; rather, it induced high morbidity and poor quality of life outcomes.47 Venous resection during PD was once considered in cases of tumor invasion, and initially in the 1950s restauration of the portal flow used a portocaval anastomosis with disastrous results. In the 1970s in Paris J.N. Maillard showed that a lateral venorrhaphy or a less than 3-cm resection was feasible after a complete mobilization of the mesentery. When larger resection is required to obtain cancer-free surgical margins, various types of autologous vein grafts are now used, including the left renal vein. The first approach using the artery during PD, which allowed early assessment of resectability,48 was another technical innovation described in 1993 by Nakao from Japan. Except for the uncommon cases of successful en bloc resection with the celiac artery, first reported in 1997 by Y Nimura,48 arterial involvement has remained a contraindication for resection. Improvement in imaging using high-resolution triphasic CT imaging with 3D reconstruction reduced the incidence of nontherapeutic laparotomies. In the beginning of the 21st century no more than 20% of patients were candidates for surgery, but gradually the use of chemotherapy resulted in two major advances, a higher rate of resection and an improved postoperative survival.49 In 2020 surgery was not perceived as the unique treatment for patients with nonmetastatic pancreatic duct adenocarcinoma (PDAC). After pancreatic resection, adjuvant multiagent chemotherapy (gemcitabine plus capecitabine or modified FOLFIRINOX) become the standard of care.50 The ability of neoadjuvant chemotherapy and radiotherapy to convert some patients from unresectable to resectable was an important advance. This strategy was effective in nearly two-thirds of patients with borderline resectable cancers characterized by tumor contact with either hepatic or mesenteric arteries or with the portal vein and mesenteric vein of greater than 180 degrees. Even in some patients initially considered as nonresectable for locally advanced tumors, this strategy allows a radiologic downstaging and more decisively a high rate of negative margins.51 However, the morbidity of neoadjuvant treatment restricts the expansion of this strategy to patients whose cancer is resectable. In 2020 pancreatic cancer surgery was performed in high-volume centers with less than a 5% mortality rate and a 5-year survival rate of around 30% using adjuvant chemotherapy.36 The trend to define a curative resection R0 with a free margin of 1 mm led to

9

dissection on the right side of the mesenteric artery with removal of the retroportal pancreatic parenchyma and lymphadenectomy of at least 15 lymph nodes.52 The concept of prophylactic surgery for benign precursors of pancreatic adenocarcinoma has changed the approach of pancreatic surgery over the last decade. The widespread use of high-quality imaging allowed the discovery of an increased number of asymptomatic cystic pancreatic lesions, including mainly intraductal papillary mucinous neoplasms (IPMNs). This cystic mucin-producing neoplasm with various grades of dysplasia has a risk of progression to adenocarcinoma with a dismal prognosis. The risk of pancreatic resection, including parenchyma-sparing procedures, was intended for select patients at risk for malignancy. The current consensus is to consider for resection patients with clinical symptoms and those in whom imaging detected a contrast-enhancing mural nodule ($5 mm), a main pancreatic duct diameter greater than 10 mm, or a solid mass. The best approach to surveillance of patients not submitted to resection or at risk for cancer in the remnant pancreas remains controversial.53 The development of surgery in patients with chronic pancreatitis (CP) started in the beginning of the 20th century with the removal of pancreatic duct stones. This was first reported by Alfred Pearce Gould (1865–1922) in London.29 The belief that pain of the pancreatitis is obstructive in nature led surgeons to try decompressing the parenchyma, with the first technical success reported by Merlin Du Val in 1954 in two patients operated on in the Bronx, New York. These patients underwent a transection of the pancreas at the junction of body and tail and a Roux-en-Y anastomosis with the pancreatic stump. In 1960 Partington and Rochell refined the decompression of the pancreas duct with a side-to-side longitudinal pancreaticojejunostomy after a complete opening of the pancreatic duct.54 However, the inconstant efficacy of the drainage procedure on long-term pain relief led doctors to consider the use of pancreatic resection. In the 1970s resection procedures were undertaken in patients with severe painful PC, including pyloruspreserving pancreaticoduodenectomy, spleen-preserving DP, or even TP.55 Considering the operative risk of these resections, procedures with a high rate of new-onset diabetes, and the intensification of exocrine pancreatic insufficiency, Hans Berger from Ulm University proposed an innovative partial resection of the head of the pancreas. Focusing on the inflammatory component of this disease, in 1980 he published a series of patients who underwent a partial resection of pancreatic head parenchyma preserving the duodenum and the CBD.56 This approach, simplified by Charles F. Frey in 1987, reported a procedure combining a smaller amount of pancreatic resection and the absence of dissection of the portal system, and with a longitudinal pancreaticojejunostomy drainage was adopted during the next decades in Europe and in the United States.57 A better knowledge of the natural history of patients with PC showing that pain can naturally disappear contributed to the decline of the surgical treatment of patients with PC. In 2020 the complications of PC, such as pseudocysts and the involvement of the biliary tree and duodenum, were challenged by endoscopic approach despite the poorer results of the latter.58 By the end of the 19th century a correct clinical and pathologic description of acute pancreatitis was published by Reginald Fitz (1843–1913) from Harvard University.59 In 1903 Von Mickulicz-Radecki (1850–1905), in Wroclau, Poland, advocated the drainage of pancreatic necrosis using gauze compresses, aiming to clean the necrosis and to prevent the false

10

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

closure of the originating cavity. During the subsequent decades, despite a mortality rate over 50%, surgery was considered the best treatment. A more conservative approach was applied in the 1930s after the discovery of the value of blood amylase, which allowed early diagnosis of acute pancreatitis avoiding hazardous laparotomy in early stages of this disease. Conservative approaches, which prevailed until the early 1970s, remained associated with persistent high mortality despite advances in intensive care. CT diagnosis of necrosis and the characterization of pancreatic necrosis as infected versus sterile was a considerable advancement. The drainage of solely infected pancreatic necrosis proposed in 1991 by E.L. Bradley from Emory University in Atlanta was a disruptive approach associated with improvement of survival.60 Open surgical necrosectomy was gradually substituted by less invasive interventions, including retroperitoneal surgical drainage, and percutaneous catheter drainage followed by endoscopic drainage when necessary, as demonstrated by several RCTs from the Netherlands.61 The Atlanta classification of acute pancreatitis using prognosis scores of organ failures and the Balthazar radiologic CT scoring system of necrosis facilitated the evaluation of therapeutic procedures often altered by inherent selection bias.62,63 The two main risks for acute pancreatitis, excessive alcohol intake and cholelithiasis, have long been recognized. In 1901 Eugene L. Opie (1873–1971) from Staunton, Virginia, observed the association of acute pancreatitis with gallstones impacted in the ampulla of Vater, causing him to propose a “common channel” hypothesis. Because the exact pathologic mechanism by which gallstones cause pancreatitis remains unclear, the role of ERCP also remains unclear except in patients with concurrent cholangitis or biliary obstruction.64 The history of pancreas transplantation started in 1893 when P. Watson Williams in Bristol, England, attempted to treat a 15-year-old boy developing diabetic ketoacidosis with subcutaneous xenotransplantation of a portion of a sheep’s pancreas.12 In 1921, at the University of Toronto, Frederick Grant Banting (1891–1941) reported the use of pancreatic extract and isolated insulin to treat diabetes mellitus in a man, for which he was awarded the Nobel Peace Prize in 1923. This discovery stimulated numerous animal studies with the first successful orthotopic transplantation in dogs in 1966 by Felix Largiarder in Zurich. In the same year, William Kelly (1922–2006) and Richard Lillehei (1928–1981) transplanted a segmental pancreas graft simultaneously with a kidney from a cadaver donor into a 28-year-old woman at the University of Minnesota. In 1967 Lillehei transplanted a whole pancreatic graft attached with the duodenum anastomosed to a Roux-Y jejunal host’s segment.65 Since the end of the 1970s, changes in surgical techniques involved venous drainage with a come-and-go from a recipient iliac vein to the mesenteric vein, and now drainage is done in the vena cava and pancreas. The benefit of combined kidney transplantation contributed to several technical changes. In 1983 Hans Sollinger from the University of Wisconsin described an innovative drainage of pancreatic secretion in the urinary bladder. In 1991 David Sutherland, from the University of Minnesota, showed the benefit of enteric drainage in a large series of transplanted patients.66 In 1970 Sutherland and his team performed the first successful pancreas transplant from a living donor, and in 1999 he introduced laparoscopic DP harvesting. The successful isolation of islet cells from the whole pancreas and their functional implantation in the spleen of dogs was a milestone.67 The use of islet cells isolated from a cadaver in a diabetic patient with CP reported in 1977 by John S.

Najarian from the University of Minnesota raised a lot of hopes. Despite better separation of islet cells from a cadaveric pancreas, the facility used to infuse these cells into the recipient via the portal vein had several challenges that persisted into 2020, including the inconstant insulin independence of recipients who required adequate islet cells from multiple donors and lifelong immune suppression. Laparoscopic procedures involving the pancreas started early in the 1990s for cancer staging, and within a few years both distal and proximal laparoscopic pancreatic resections were published. In 1994 Michel Gagner published the first case of laparoscopic PD in a patient with CP performed at the University of Montreal.68 Two years later, the same group published a series of 12 patients with islet cell tumors, including 8 distal pancreatectomies and 4 enucleations.69 The same year Alfred Cuschieri from the University of Dundee published a series of five patients who underwent DP with splenectomy for CP.70 These two series of DP have initiated an extensive development of this approach for patients with benign or low malignant lesions of the distal pancreas. The gathering of pancreatic surgery in high-volume centers with rapid acquisition of technical skill and reducing operative time and conversion rates contributed to the adoption of this approach in all pancreatic centers. Laparoscopic DP become the standard procedure.71 Unlike DP, the diffusion of laparoscopic PD in 2020 remains limited to experienced centers. The laparoscopic PD approach is a complex procedure, requiring three anastomoses with a high postoperative risk of fistula. In experienced hands, the robotic approach to DP, similar to the liver and the biliary tree, has the technical potential to compensate for the disadvantages of laparoscopy.

THE FORGOTTEN LIVER Until the middle of the 19th century, there was little interest in the liver from a medical perspective because its main functions were unknown. The anatomic repositioning of the liver in the blood circulation, the description in 1651 by Jean Pecquet (1622–1674) of the real course of the lymphatic system from the mesentery to the thorax, and the extinction of the belief in the influence of liver humors led to a decline in the view of the supremacy of the liver. Liver surgery was restricted to the treatment of penetrating injuries, abscesses, and ascites. Since antiquity, puncturing the peritoneal cavity to sample fluid was an accepted treatment for ascites. The risk of brutal evacuation was reported by the Byzantine surgeon Pauï d’Aegina (625–690) who used a special pin called the “skolopion.” During antiquity, it was recognized that a wound with great effusion of blood under the right side of the hypochondra would not “permit life to continue even for a moment.” In the medieval world, the question was who should proceed first: the surgeon and his attempts to stop such hemorrhage or the priest to hear confession from a subject likely soon to die.72 However, when parenchyma evisceration was present through the wound without massive external bleeding, exceptional cases of successful treatment were reported, allowing the surgeon to address the bleeding and to excise a piece of the liver.72 In 1816 the liver parenchymal compression was the most innovative approach described. It was described by Charles Bell (1774–1842), a surgeon in the British army at Waterloo. In 1888 Henry C. Dalton (1847–1917), a cardiac surgeon from Saint Louis University, reported successful control of bleeding in a patient suffering a laceration of the liver, using large and deep sutures. In a series of 69 cases of laparotomy for gunshot wounds, he

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

11

recorded a survival rate of 5 survival among 10 liver wounds.73 At the end of the 19th century, catgut suture and simple packing were procedures advocated in liver trauma. The treatment of liver cysts and abscesses was only individualized during the 17th century without a significant development until the 19th century. This time line happened probably because such collections are often missed by physical examination and by the lack of accurate distinction between all types of purulent collections of the right hypochondra, including cholecystitis, subphrenic abscesses, and complications of perforated ulcers. It quickly became apparent that external drainage was an effective treatment in some patients. However, this maneuver was associated with several complications related to the etiology of the collection and to the skill of the operator. The puncture and simple incision of hydatid cysts advocated in 1825 by Joseph Recamier in Paris was promptly followed by some fatal outcomes. This changed in 1887 when a Russian surgeon names Nikolai Sklifosovsky reported three cases treated by a three-step procedure, including trocar aspiration of cyst contents, then marsupialization of the cyst wall to the abdominal cavity, and finally, washing the cyst lining with ­“corrosive sublimate.”72

The Birth of Liver Surgery in the Middle of the 19th Century Once the treatment of liver abscesses and the control of some penetrating injuries were recognized, some skillful surgeons tried to resect “abnormal liver tissue,” as described by the founders of pathologic anatomy, including Carl Rokitansky (1804–1878) from the University of Vienna and Rudolf Virchow (1821–1902) in Berlin. Surgery became a science integrating anatomy, pathology, and physiology with the inclusion of the glycogenic function with the regulation of glucose in 1848 by Claude Bernard (1813–1878). In Boston, during the same period, John Collins Warren (1778–1856) of the Massachusetts General Hospital and founder of the New England Journal of Medicine performed the first public demonstration of a surgical procedure under ether anesthesia. Applying the revolutionary “germ theory” postulated by Louis Pasteur (1822–1895), the British surgeon Joseph Lister (1827–1912) developed the idea of sterile surgery (Fig. 0.10). This breakthrough innovation based on a new origin of infection and the changes in surgical practice were not easily accepted. Increasingly, however, the surgical community assimilated most of the familiar surgical accouterments and rituals of modern aseptic technique. The use of rubber gloves was promoted by William Steward Halsted (1852–1922) in 1890, and surgical masks were adopted in 1897 by Polish surgeon Johann von Mikulicz Radecki (1850–1905) from the University of Wroclaw. The use of anesthesia and the attention to asepsis contributed to shifting the act of surgery from a bloody act, when operations were done as rapidly as possible, to a meticulous procedure. The German school of surgery was a dominant force for several decades. This was illustrated by the career of Theodor Billroth in Berlin, Zurich, and Vienna, where he pushed intestinal surgery to a higher level with successful removal of the esophagus, larynx, and rectum, including his most famous accomplishment, the first successful gastrectomy for gastric cancer. He introduced the concept of audits, publishing all results good and bad, and transmitted through his most brilliant student Theodor Kocher (1841–1907). These surgeons were characterized by their great attention to antisepsis, hemostasis, wound closure, and drainage.74 This scrupulousness was influenced by

FIGURE 0.10  Joseph Lister (1827–1912).

laboratory attendance and experimental liver surgery on animals, which started in Berlin with Themistocles Gluck (1853– 1942). It was further influenced by Bernhard von Langenbeck (1881–1887) who advocated that animal work must first be done, developing a series of experiments in the rabbit, cat, and dog in which, by manipulating the portal flow, he was able to successfully remove a large volume of the liver.72 Carl Johann August Langenbuch performed the first cholecystectomy in 1882 (see Fig. 0.5). He performed the first elective hepatectomy on January 13, 1887, to remove a palpable mass in a 30-year-old woman. This mass, weighing 330 g, was apparently engorged liver parenchyma attached to the remaining liver by a bridge of fibrous tissue. The description of the resection did not mention any major vascular or biliary structures, and the abdominal incision was closed. Several hours later the patient was successfully operated on again for bleeding; after ligation of the bleeder vessel, evacuation of the blood, and closure of the abdomen the patient was discharged. After this, progressive technical improvements were popularized by Ernst von Bergmann (1836–1907). He was in favor of applying iodoform gauze on the raw surface of the liver with a partial closure of the abdomen so he could keep an eye on the impregnated gauze.72 The first liver resection in the United States was performed in 1890 by Louis McLane Tiffany (1844–1916), a professor of surgery at the University of Maryland, who reported the successful removal of a portion of the left lobe of the liver.72 Liver surgery in the United States was led by William Williams Keen (1837– 1932) who worked in the US Army as a surgeon during the Civil War and spent 2 years studying in Paris and Berlin. As a professor of surgery in Jefferson Medical College in Philadelphia, he started his experience in liver resection on October 9, 1891, by operating on a young woman for a palpable tumor that had enlarged during her pregnancy and appeared attached to the edge of her liver. The depiction of the procedure included

12

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

the use of the Paquelin cautery interposed by the ligation of large vessels, separating the liver substance from the tumor using his thumbnail, and approaching the two edges of the liver together with sutures.72 In 1899 W. Keen published a compilation of 76 cases of liver resection, including 17 of his own patients with a mortality rate of 15%.75 Before 1900, the restricted worldwide experience of liver resection reflected the rarity of palpable liver tumors, the reluctance to resect malignant tumors, and the difficulties of surgical extirpation while controlling bleeding. Thermocautery using heated vapor from a bottle filled with petroleum ether was an important technical innovation invented by the Frenchman Claude-André Paquelin (1836– 1905). The control of vascular pedicles of tumors was advocated by the French surgeon Louis-Félix Terrier, who emphasized the benefit of “pediculization” of liver tissue from which a tumorous lesion seemed to arise. The resection of the strangulated pedunculated tumors were occasionally performed some days later. In fact, the control of hemorrhage from intraparenchymal vessels was dominated by manual tamponade often completed by the placement of iodoform gauze in the liver wound. In Berlin Ernst von Bergmann (1836–1907), concerned about the liver resection procedure, was in favor using gauze through the incision to watch for delayed hemorrhage and bile leak. Surprisingly, this latter complication was seldom mentioned. The management of digital compression during liver resection was extensively described in textbooks published around 1900 in Germany and France. In his textbook published in 1894, Langenbuch annunciated that liver surgery would be a new and adventurous specialty. This orientation was emphasized by the French surgeon Joseph-Antoine Pantaloni, who published a textbook titled Chirurgie du foie et des voies biliaires in 1899. Remarkably, he argued that as soon as the operation advanced from the edge to the central portions of the liver, before parenchymal transection, hemostasis should be controlled either by using the assistant’s finger compression or by placement of broad parenchymal sutures. He showed that digital compression was also recommended to prevent air ingress into hepatic veins after observations of death from air embolism. Innovations concerning the suture of the liver were issued from ingenious procedures reinforcing the suture through very thin slices of decalcified and softened whalebone, similar to the pledgets used today.72

The Blossoming of Liver Surgery Knowledge of liver anatomy allowed the development of liver surgery. Galen’s concept of the liver as the place of manufacturing blood from ingested nutritive food described five lobes as five fingers enveloping the stomach to provide warmth for the digestion of food. This depiction of multiple lobes was issued from animal anatomy into human interpretation assuming one was similar to the other. Andreas Vesalius’ representation of the liver in correct topographic position with two lobes separated by the falciform ligament (1555) was a turning point in the representation of this organ (see Fig. 0.3). In his book published in 1654, Francis Glisson depicted accurate liver anatomy with his specific triple vascular system structure (see Fig. 0.4). At the end of the 19th century the Scottish surgeon James Cantlie (1851–1926) and the Austrian anatomist Hugo Rex (1861–1936) debunked the classical division along the falciform ligament, showing instead that the boundary between the right and left livers is located on the line connecting the gallbladder bed to the inferior vena cava (IVC), which corresponds to the course of the middle hepatic vein. This simultaneous

FIGURE 0.11  Claude Couinaud (1922–2008) working with his collection of liver casts.

anatomic discovery has been called the “Rex-Cantlie line.” The major innovation of Claude Couinaud (1922–2008) (Fig. 0.11) was to confirm that right lobes and left lobes are not right and left livers and it was possible to divide the liver parenchyma into eight autonomous segments without intercommunication between the pedicles (blood vessels and bile ducts) of different segments.76 This concept allowed surgeons to differentiate nonanatomic from anatomic resection. This latter type of resection is considered an oncologic resection, allowing transection along a well-defined line, avoiding necrosis, and preserving regeneration of the remnant liver. It is now well established that liver regeneration will occur not only if arterial and portal vascular inflow with biliary drainage are intact but also if there is complete venous drainage.77 Before a liver resection, ensuring anatomic vascularization of the liver remnant is the main goal of radiologic investigations, confirmed by intraoperative exploration handled by the surgeon himself. The possibility to obtain a pictorial view of the liver with penetrating imaging modalities was a breakthrough innovation allowing the location of nonpalpable tumors. In the middle of the 20th century, the first innovative imaging used was scintigraphy, which had the ability to clear colloidal particles from the blood into the Kupffer cells. The presence of a “cold” area due to the replacement of liver parenchyma by a malignant tumor, a benign lesion, a cyst, or an abscess was a considerable step

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

forward for liver surgery.72 Computerized axial tomography (CT scanning) resulted from an impressive collaboration between engineering and medicine involving an English electrical engineer, Sir Godfrey Hounsfield (1919–2004), and a physicist, Allan Cormack (1924–1998), culminating in them both winning the Nobel Peace Prize in 1979. Since its creation, this technology has gained impressive maneuverability with quick acquisition and accurate depiction of liver anatomy and its vascularization. Using 3D simulation, CT scanning allows visualization of intrahepatic blood vessels along with the calculation of the liver volume perfused by each pedicle. This technology initially developed in Germany at the end of the 20th century and was immediately adopted and developed in Japan and Korea for venous reconstruction in donor liver transplantations (LTs) and, subsequently, to prepare complex hepatectomies. The Nobel Peace Prize winning invention of magnetic resonance imaging (MRI) in 1977 by US physician and medical practitioner Raymond Vahan Damadian (1936) refined the exploration of the liver with better specification of both tumors and liver parenchyma analogous to a histologic approach. The development of ultrasound for scanning the liver started around 1960 and rapidly became the first step in medical assessment of patients with liver disease. The quick adoption of ultrasound resulted because it was simple to use, there was no special preparation associated with it, and there was considerable improvement in the images provided. Studies in the United States detected gallstones and dilation of the biliary tree, liver abscesses, or tumors and their respective relationships with major vessels. Ultrasonic scanning facilitates liver biopsy and percutaneous cholangiography, and provides a sensitive means of detecting ascites. Introduced in biliary surgery by Bernard Sigel in the United States, intraoperative ultrasound (IOUS) was a revolution in liver surgery. In 1980 in Japan it was further developed with technical refinement allowing an accurate visualization of vascular structures and disclosure of small lesions.78 IOUS made the liver transparent, allowing visualization of the complex layout of vessels impacting the surgical strategy. This innovation allowed identification of nonpalpable lesions and the development of oncologic resections according to the vascularization of the tumor. The introduction by Makuuchi of the concept of liver anatomic surgery using IOUS was a turning point in the practice of liver surgery (Fig. 0.13). This approach spread rapidly from Japan to France and Italy but appeared much later in the United States.

Technique of Liver Surgery One of the greatest innovations in liver surgery was the temporary pedicular clamping proposed by James Hogarth Pringle (1863–1941), who was a surgeon of the Royal Infirmary in Glasgow with a passion for the treatment of trauma. In his paper published in Annals of Surgery in 1908, he reported reduction in liver bleeding by pinching of the portal vein and hepatic artery.79 However, this maneuver was brutally attacked by European surgeons, predominantly the German school, who envisioned disastrous results from prolonged venous congestion of the splanchnic circulation.72 Despite support in 1912 from John Mc Dill, who had a long and distinguished career in the US Army, the Pringle maneuver remained in the shadows for decades. The association of systematic control of the intrahepatic pedicle and resection was also a disruptive innovation. Initiated by Louis-Félix Terrier, this approach was perfected by the Vietnamese surgeon Tôn Thất Tùng (1912–1982), who was

13

trained in the French school of medicine in Hanoi. His outstanding knowledge of liver anatomy acquired by digital dissection of over 200 human livers, gave him a unique vision of regional anatomic demarcation for the 1930s. His comprehension of the segmental nature of liver substance allied with terrific dexterity allowed him to introduce intraparenchymal control of portal pedicles with finger fracture. By pressing liver tissue between the thumb and forefinger, until only vessels remained, this “digitoclasia” presaged the use of “hepatoclasia,” which crushes the hepatic tissue with small Kelly clamps. His total commitment to his country during the colonial war between Vietnam and France and the latter against the United States have probably weakened his worldwide scientific reputation. He was one of the first exclusive liver surgeons who largely inspired French liver surgeons, inaugurating nearly 50 years in advance a true specialty. His intraparenchymal control of the first portal pedicles associated with hilar pedicle control remains the standard of liver surgery. The first publication in 1939 of the innovative approach by Tôn Thất Tùng included two successful cases of left lateral sectionectomies for patients with large hepatocellular carcinoma (HCC).80 In 1948, after 220 published cases of liver resections, with the vast majority including leftside resection, it seemed that major resections were impossible. However, in 1949 Ichio Honjo in Japan, in 1951 J.L. LortatJacob in France, and in 1952 J.K. Quattlebaum in the United states performed a right hepatectomy.12,81 Although the French case was not the first, its report was the most renowned, with an accurate description of the procedure and a visionary consideration of the anatomic resection. In Paris in October 1951 Jean Louis Lortat-Jacob (1908–1992) (Fig. 0.12) operated on a 42-year-old man for a suspicious hydatid cyst; he discovered three tumors in the right lobe, corresponding to colorectal metastasis. His familiarity with esophageal surgery and with intrathoracic esophagogastric anastomosis led him to extend the incision to the right chest and, using this large approach, he completely mobilized the right liver toward the retrohepatic IVC. In contrast to contemporary surgeons, he did not start the section of the parenchyma immediately; instead, with his perfect knowledge of liver anatomy (learned from his friend Claude Couinaud), he controlled afferent and efferent vessels. The first step was hilar control of the right vessels and ducts followed by the division of minor hepatic veins to the IVC, and then he encircled and divided the right hepatic vein. Mostly, by finger fracture, the parenchyma was transected with ligature of the intraparenchymal vessels and ducts. He confessed to be surprised that there was no bleeding, but he was worried about the capacity of the remnant liver, which was “no bigger than a fist,” to restore normal liver function. After an episode of jaundice and ascites, the patient was well 3 months later. During the report of this case on March 31, 1952, Lortat-Jacob imagined that the use of the right liver in transplantation could potentially solve some hepatic diseases once the problems of tolerance to tissue grafts and their rejection had been solved. Anticipating the use of a partial graft for LT, he was truly a visionary physician and surgeon who embodied the values of the modern liver surgeon.82 Two years earlier, in March 1949, Ichio Honjo (1913–1987), a professor of surgery in Fukuoka, Japan, performed a right hepatic lobectomy for rectal metastasis in a 22-year-old man. This innovative procedure was performed through a large incision in the right and left quadrant associated with a long midline component. The liver was completely mobilized and the right branches of both the artery and the

14

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

FIGURE 0.13  Masatochi Makuuchi (1946), surgeon.

FIGURE 0.12  Jean-Louis Lortat-Jacob (1908–1992), surgeon.

portal vein were controlled. Once inflow was controlled, intraparenchymal hemostasis was performed using silk sutures with the fear of compromising the vascularization of the remnant liver. The patient recovered uneventfully from this operation, which was reported in 1950 in a Japanese journal. This novel procedure escaped the attention of the Western surgical community until 1955 after its publication in an international journal. With this publication, Honjo inaugurated the next few decades of Japanese ascendency in liver surgery. In the 1980s the development of HCC in viral hepatitis was easier to detect radiologically and could be treated surgically. This situation was exploited by Japanese surgeons who were obsessed with minimal surgical risks. The establishment of the Liver Cancer Study Group of Japan in 1967 was focused on surgical mortality, which was approximately 1% in the 1990s.77 From this period, liver resection became a composite performance combining specific preoperative radiologic and biologic assessment, guided by IOUS, and including selective vascular clamping and sometimes preceded by PVE. The leadership of this school of thought was Masatoshi Makuuchi (1946), who can be considered one of the most innovative surgeons by the end of the 20th century (Fig. 0.13). Makuuchi brought many innovations to liver surgery. A true Leonardo Da Vinci of our specialty, he established the safety limits for the extent of liver resection in injured livers

using the indocyanine green (ICG) tolerance test, which is included in the so-called “Makuuchi criteria” for hepatic resection.77 He described the extrahepatic division of the right hepatic vein in hepatectomy,83 and introduced IOUS for the safety and quality of liver resections. He conceived preoperative PVE, which increases the volume of the future remnant liver and increases the tolerance of liver resection.84 Makuuchi was the first in the world to perform surgery with an adult living donor, and further developed his interest in this field using venous drainage of partial grafts to define criteria for venous reconstruction.85 He advocated hemihepatic vascular occlusion during liver resection in his first publication because it avoided splanchnic congestion and preserved vascularization of the remnant liver.86 Although the first Makuuchi maneuver did not have the same innovative success, his interest in the safety of vascular clamping led him to refine the procedure of the intermittent portal triad, and he was the first to demonstrate the safety of this type of clamping in harvesting a live liver graft.87 Apprehension concerning the risk of ischemia induced by pedicle clamping outweighed its potential benefit to reduce bleeding. Several innovations aiming to reduce ischemia of the future remnant parenchyma were described. The first innovation was the refrigeration of the parenchyma. In 1963 Tong Ta Tung published an article in The Lancet about liver resection using portal clamping associated with refrigeration of the patient placed in a bathtub filled with ice to drop the body temperature to 30°C.88 In 1974 Joseph Fortner (1921–2007) published a series of 29 patients with liver resection during vascular exclusion and hypothermic perfusion with only three postoperative deaths.89 In the early 1990s Rudolf Pichlmayr (1932–1997), a

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

transplant surgeon from Hannover, Germany, described a “bench procedure” with complete removal of a perfused liver allowing tumor resection in an organ free of blood. During this procedure, the patient remains anesthetized with a veno-venous bypass until the liver is reimplanted.90 Daniel Azoulay from the Bismuth group, determined to push the limits of unresectability, clarified the indications of total vascular exclusion (TVE) associated with refrigeration.91 However, the expansion of these major technical innovations remains limited with a decline due to the complexity of the procedure, the modest oncologic results, and the poor tolerance of diseased parenchyma with a high rate of postoperative liver failure.92 The selective clamping of a hepatic lobe, a section, or even a liver segment promoted in the mid-1980s by Makuuchi limited the ischemia of the future remnant liver and facilitated the demarcation of the anatomic territories. For major hepatectomy, the division of the unilateral portal pedicle could be done by extensive hilar or suprahilar dissection as advocated by Bernard Launois.12 Although the selective control of pedicles becomes more complex for sectorial pedicles, selective vascular occlusion is still used by several western and Asian teams. The persistence of significant hemorrhage during the parenchymal transection, despite an effective portal pedicle clamping, revealed that the main source of bleeding originated from the hepatic veins and their tributaries. This was when anesthesiologists maintained high central venous pressure for liver surgery to keep ahead of the anticipated blood loss. Therefore the control of venous bleeding led many surgeons to exclude the liver from the splanchnic and systemic circulations by total inflow occlusion associated with clamping the IVC below and above the liver. TVE was described in 1966 a few years after the first LT by John Heaney from San Antonio.72 At the end of the 1970s, Parisian Claude Huguet simplified and standardized this technique, which can be applied safely for as long as 60 minutes.93 With an incredible talent for detecting and assuming innovations, Henri Bismuth and his team at the Hospital Paul Brousse published in 1989 their experiences with 51 patients that showed that the use of TVE allowed resection for some centrally located hepatic tumors associated in some cases with the reconstruction of vascular structures.94 The routine use of TVE for major liver resection was doubted by a controlled study published in 1996, demonstrating that TVE is an invasive technique with nonnegligible morbidity and indicating that this procedure should be restricted.95 One year later, a controlled study issued from the group of John Wong in Hong Kong showed that liver resections under vascular inflow control were safer than those performed without.96 Although 1-hour continuous clamping is well tolerated in patients with normal underlying parenchyma, in 1992 K. Sugimachi from Fukuoka, Japan, introduced the concept of intermittent inflow occlusion in patients with chronic liver disease.97 After years of debate concerning the respective durations of occlusions and reperfusion, the increased duration of surgery and blood loss from the transected surface during the perfusion controlled study demonstrated that intermittent clamping was better tolerated than continuous clamping.98 The safety of a long duration of intermittent clamping, especially in patients with diseased parenchyma, was regularly reported in the early 2000s, rendering the attractive concept of ischemic preconditioning issued from cardiac surgery unnecessary in liver surgery. These debates on the safety of vascular clamping during liver resection were upended by R.M. Jones, a surgeon from Melbourne, Australia, who

15

demonstrated in 1998 that the reduction of the central venous pressure reduced intraoperative blood loss during liver surgery.99 This breakthrough innovation requiring a new approach to anesthesiology allowed expert surgeons to perform routine liver resection with limited use of clamping.100,101 To minimize blood loss during hepatic resection many different methods have been used to cut the parenchyma, leaving vessels and biliary ducts that can be ligated or clipped. The finger fracture technique was subsequently improved through the use of surgical instruments such as a small Kelly clamp for blunt dissection (clamp crushing or “Kellyclasia”). In the 1990s ultrasonic dissectors, which were initially devoted to neurosurgery, were rapidly adopted in liver surgery and remain universally utilized because of their simplicity and the fascinating way they can selectively destroy and aspirate parenchyma cells leaving vascular structures almost intact. At the beginning of the 21st century several devices were developed, including the harmonic scalpel, LigaSure, TissueLink, and radiofrequency. None of these technical innovations have yet to emerge as a significant improvement with significant reduction of blood loss, biliary fistula, and duration of hospital stay. With a lower cost-effectiveness, Kellyclasia was not inferior to these technical innovations and remains widely used in open liver surgery, especially when associated with clamping a precise delimitation of the hepatic veins, which represents a true oncologic plan.102,103 A better definition of malignant liver lesions justifying resection was an important step in the 1980s. Leslie Blumgart (1931), especially after his move to Memorial Sloan Kettering Cancer Center in New York, developed an oncologic practice with great experience in resection for neoplasms. Advocating since the 1970s the resection of hilar cholangiocarcinoma and liver metastases, he built a surgical team with the highest expertise in various primary and secondary malignant liver tumors.104 At the end of the 20th century, Blumgart contributed to the tremendous development of liver resection for colorectal liver metastasis in Western countries.105 Whereas the surgical resection of benign liver lesions was declining,106 the treatment of malignant tumors required a specific strategy, including anatomic resection for HCC and hilar cholangiocarcinoma and R0 resection in liver metastasis.107 The anterior approach to major hepatectomy minimizing manipulation of the tumor-bearing liver was proposed by the Hong Kong group of John Wong,108 and was facilitated by the “hanging maneuver” proposed by Belghiti and colleagues using a tape inserted between the anterior surface of the vena cava and the liver.109 Since its introduction, this maneuver has gained worldwide popularity for large-sized liver tumors or tumor invading surrounding tissues and was subsequently applied to various anatomic resections with favorable oncologic results.110 Although concomitant regional lymphadenectomy is not performed routinely, its prognostic value is important from the perspective of adjuvant treatment. The impact of postoperative morbidity on survival after resection of malignant tumors emphasizes the importance of measures such as preservation of venous drainage of the liver remnant and PVE.107 The unique regenerative abilities of the liver allow large liver resections and living donor LT (LDLT). The signals driving the process are complex but dominated by the portal flow. Enlargement of the left liver lobe was observed by Makuuchi in a patient with a hilar cholangiocarcinoma obstructing the right branch of the portal vein. This led him, in the 1980s, to develop an embolization of the right branch of the portal vein, which

16

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

caused atrophy of the right liver balanced by the enlargement of the future remnant liver.111 The introduction of this method was another disruptive innovation transforming the tolerance of patients after major resection of a diseased liver. In the 1990s PVE before major liver resection was widely adopted for several reasons, including its technical simplicity, its tolerance, and its efficiency.112–114 The expansion of preoperative modulation of the liver volume using a vascular approach with the association of arterial embolization or hepatic vein occlusion was challenged by the two-step surgical procedure named “associating liver partition and portal vein ligation for staged hepatectomy” (ALPPS). This approach was proposed by Santibañez from Buenos Aires, Argentina, and Clavien from Zurich, Switzerland.115 The high risk of this dual complex surgical procedure, which does not take into account the natural oncologic history and imposes a long hospital stay in a period aiming to enhance recovery after surgery (ERAS), explained why this innovation remains localized to certain centers only. In 2005 Guido Torzilli developed a conservative approach to multiple liver resections called parenchymalsparing hepatectomy. This approach offered advantages over major hepatectomy in terms of tolerance without impairment of survival.116 Since the beginning of the 21st century, the vast majority of patients operated on for malignant tumors had a diseased underlying liver parenchyma, including nonalcoholic steatohepatitis.117 Parenchymal modifications decrease the tolerance of surgery emphasizing the need to use quantitative liver function tests. Measuring clearance of ICG, Makuuchi’s group reported in 2003 a zero-mortality rate among more than 1000 hepatectomies.118 However, during the last decade patients submitted to resection have been older and at higher risk with multiple illnesses, resulting in a liver resection stability of around 3%.119 Therefore many liver surgeons put their hopes in the development of minimally invasive liver surgery.

shorter hospital stay. These advantages, however, were not sufficient to gradually replace conventional open liver resection. Even in experienced centers, right hepatectomy and resections of the posterior sector remains an exploratory procedure.125 To overcome the lack of 3D view and tactile sensation, which could impair oncologic value of LLR resection, intraoperative navigation using vascular and biliary reconstruction and an adjunct fluorescence camera for lesions not detectable with the naked eye have contributed to the improvement of LLR for resection of malignant tumors.126 The laparoscopic surgical community is making efforts to organize consensus conferences and to promote prospective registries with scoring systems to grade the technical difficulty of this procedure.127 In 2020, despite individual exploits such as living donor hepatectomies128 or even total hepatectomies in the LT procedure,129 the replacement of conventional open liver resection by LLR requires much more experience. The inexorable expansion of minimally invasive approaches has led the surgical community to explore robotic-assisted LLR. In 2003 Giulianotti published a series of abdominal procedures, including partial liver resection.130 Despite the high cost of the robotic-assisted laparoscopic instrument, sold by a manufacturers that have monopolized the field, this innovation has been increasingly adopted by liver surgeons in the United States, Europe, China, South Korea, and Brazil. In 2008 S.B. Choi from Seoul reported the first series of a successful left lateral sectionnectomy.131 The expansion of this procedure in the United States,132 China,133,134 and Korea was impressive.135 The expansion of robotics in liver surgery are not only based on improved manipulation and instrumentation but also on the overall development of the digital artificial intelligence platform, facilitating the evaluation of the learning curve, integrating 3D reconstruction, and assessing surgical margins to achieve the standardization of surgical procedure.

Minimal Approach

Liver Transplantation

The widespread use of laparoscopy in abdominal surgery, including biliary surgery, stimulated the development of laparoscopic liver resection (LLR). The first report in 1991 of LLR was from a gynecologic team who found incidentally superficial, small-sized benign tumors during laparoscopic surgery for gynecologic symptoms.120 This innovative approach was exploited by multiple abdominal surgeons12 until 1996 when Kaneko from Tokyo published the first series of 11 patients, including the first left lateral sectionectomy.121 This Japanese team, still at the forefront of this procedure, used an innovative approach with accurate indications, including liver metastasis and HCC associated with cirrhosis. During the following years, LLR focused on lesions located in anterolateral segments that are more accessible laparoscopically and on anatomic resections with a small transection plane in a caudal-to-cranial direction.122 In 1997 Huscher reported the first hemihepatectomy.123 However, the expansion of this procedure was considerably slowed by the risk of major bleeding due to technical difficulties when mobilizing the right liver such as dissecting the IVC and controlling vascular and biliary pedicles in a large and deep area of transection.122 Meanwhile advances in both instrumentations and technical skill caused the worldwide expansion of LLR, resulting in using this approach as a standard for left- and right-sided peripheral lesions as a routine procedure.124 The advantages of LLR include better exposure with a magnified view through a minimal approach and decreasing postoperative pain, pulmonary complications, and ascites, resulting in a

In the 1960s the success of kidney transplantation resulting from the use of effective immunosuppressive drugs opened the possibility to perform LT. This type of transplantation is forever attached to the name of Thomas Starzl (1926–2017) who initiated a procedure with multiple challenges.135 Impressed during his residency by the consequences of the surgical treatment of portal hypertension, he started in 1958 with a National Institutes of Health (NIH) grant and an important experimental study on liver replacement in dogs. Francis Moore and Thomas Starzl published two important series of 30 and 80 cases of canine transplants, respectively, in 1960.136 When Starzl moved to Denver in 1961, his activity was divided between kidney transplantation in humans and LT in dogs. His experience in animal models faced multiple problems, including anesthesia, organ preservation, reperfusion, hemodynamic tolerance of clamps, and bypass. The last key element highlighted by this work was “team construction,” which is essential to the cohesion of a team.135 With this background, in March 1963 he performed the first attempt at human LT in a 3-year-old who died intraoperatively. In 1964, after the failure of all attempts of LT by Starzl, Francis Moore in Boston, and Demirleau in Paris, a worldwide moratorium was imposed.136 A few years later, a new enthusiasm for clinical LTs was generated by the advances in immunosuppression and the understanding that tissue matching was less important in liver grafting than in kidney transplantation. In 1967 the first successful LT was performed by Starzl in a pediatric recipient, and in 1968 it was performed by

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

Roy Calne (1930), the other pioneer of LT, in Cambridge, UK.136 In 1968 the concept of brain death was accepted, which enabled a more controlled procurement procedure with improved graft quality. The first transplant unit outside of the United States was created by Roy Calne and associated with Roger Williams of Kings College Hospital in London. For nearly 20 years all immunologic and technical innovations were issued from Denver and Cambridge. In 1979 Roy Calne introduced the clinical use of cyclosporin, which improved graft tolerance with less toxicity.137 In June 1983, in Washington, DC, an NIH consensus conference evaluating the results of more than 500 cases in four centers worldwide with 1-year survival rates around 70% approved LT as a valid therapy for treatment of end-stage liver disease.138 US centers were located in Denver and Pittsburgh, where Starzl moved in 1981 (Fig. 0.14); European centers were located in Cambridge–King’s College, in Hannover headed by Pichlmayr, and in Groningen (the Netherlands) headed by Ruud Krom. In 1988 the use of University of Wisconsin (UW) solution extended the duration of organ preservation.139 The growing experience in the United States and in European units in which Henri Bismuth established the European Liver Transplant Registry (ELTR) in 1985 contributed to select indications for LT, which have changed over the years. These changes were established during consensus conferences. Apart from the rational indications of irreversible toxic or viral parenchymal damages, malignancy was considered from the beginning of this procedure as an indication of LT. The firsts patients transplanted had unresectable tumors, but a low survival with a high rate of recurrence imposed a restrictive selection. In 1996 V. Mazzaferro defined the selection of cirrhotic patients who could benefit from LT in case of limited HCC.140 The “Milan criteria” remains the focal point of the debates concerning this indication, and they represent nearly 20% of the worldwide indications of LT. This procedure treats the tumor and the underlying liver disease in patients with HCC, but many other primary and secondary liver tumors also can be cured by LT. The liver is the only organ whose transplantation can cure cancer. This characteristic can be partially attributed to the ability to administer more selective and less toxic immunosuppression regimens, because liver grafting stimulates less rejection compared with other transplanted organs. For several decades, the LT procedure described by T. Starzl was well standardized and replicated worldwide after being exported by numerous surgeons trained in his center. After the resection of the native liver and enclosing the retrohepatic vena cava, the graft implantation procedure included vena cava anastomoses above and below the liver followed by reperfusion with the portal vein and then hepatic artery perfusion. The hemodynamic tolerance of total caval clamping was facilitated by the use of veno-venous bypass introduced in 1984. The preservation of the IVC described by Calne in 1968 was reintroduced 20 years later by Tzakis.141 The “piggy-back” procedure requiring a single side-to-side caval anastomosis was rapidly widely used. In 1992 Jacques Belghiti from Beaujon Hospital in Paris described an LT procedure without the need for vena caval clamping.142 The preservation of the vena caval flow permitted the preservation of the portal flow with a temporary portocaval shunt allowing hemodynamic stability, which is particularly important in patients with fulminant hepatitis who receive an LT.143 It was shown in a number of Asian centers that the involvement of liver surgeons in the world of transplantation was a strong factor stimulating technical innovations. In Europe, the

17

FIGURE 0.14  Thomas Starzl (1926–2017), surgeon.

LT community benefited from the connection of liver surgery with LT, particularly in Henri Bismuth’s center. In 1984 Didier Houssin, also from this center, reported a reduced-size LT with ex vivo resection of an adult cadaveric liver to create an appropriately sized liver graft for an infant.144 However, this technical innovation, which increased the number of pediatric LTs, had a negative impact on the adult population awaiting LT and is rarely used today. On the other hand, the ex vivo splitting of a cadaveric liver described in 1988 by Pichlmayer in Germany allowed transplantation to two recipients, usually a pediatric recipient for the left liver and an adult for the right side.145 This procedure can increase the number of organs in the donor pool and is very attractive for that reason. It was later extended by Daniel Azoulay to include two adults.146 However, the development of this technically demanding procedure had a limited expansion because it needed a good graft and a choice of two suitable recipients with an excellent organization. The concept of auxiliary liver transplantation (ALTx) was initially proposed to avoid a difficult native hepatectomy implanting a healthy liver graft placed heterotopically.147 The high rate of vascular thrombosis, probably due to inadequate portal perfusion of the graft and inadequate drainage of hepatic blood flow, contributed to the abandonment of this approach. In 1991 G. Gubernatis from the Pichlmayer group published a successful case of fulminant hepatic failure using a new approach, in which a part of the native liver is resected and replaced by an auxiliary graft.148 The use of an auxiliary graft, expectations of spontaneous regeneration of the native liver, and eventual withdrawal of

18

Introduction  Hepatobiliary and Pancreatic Surgery: Historical Perspective

immunosuppression drugs is based on the physiologic position of the hepatic graft.149 The expansion of this innovation remains limited by the need of an excellent graft, the risk of vascular thrombosis, and the unpredictability of regeneration.150 The growth in indications and the improved results of LT has brought about the primary obstacle of it as an effective therapy, specifically, a wide discrepancy between candidates for the procedure and the number of available liver grafts. To overcome this situation, the transplant community attempted to establish a fair organ allocation, developed technical innovations, and extended the donor criteria. The organ allocation became rapidly crucial with several changes in prioritization of the candidates fluctuating from those who urgently need a graft and those who will get the most benefit. The medical and ethical debate concerning the allocation policy of cadaveric grafts remains focused on the Model for End-Stage Liver Disease (MELD) developed by Kamath and adopted in 2002 in the United States.151 The MELD remains, after several adjustments, the best predictor of wait-list and post-transplant mortality. The idea of removing part of the liver from a living donor was a strong motivation in pediatric transplantation. The unacceptability of a child dying while awaiting a graft stimulated the first attempt in 1988 by Raia in Brazil and the first success in 1989 by Strong in Australia, who transplanted a left lobe graft from mother to child.136 The worldwide development of LDLT for children was accelerated by the possibility of obtaining an excellent small graft from a parent without major risk and few ethical issues. The first Western series of 20 cases was published in 1991 with an overall graft survival of 75% and patient survival of 85%.152 LDLT was a true breakthrough innovation in Asian countries, allowing physicians to meet a need in countries where the availability of deceased donors was scarce. LDLT flourished in Japan where liver surgery was well developed but deceased donor graft donation was nonexistent. In 1989 Nagasue from Shimane performed the second successful pediatric case. In Kyoto University, Koichi Tanaka started a center in 1990 that concentrated a large number of cases and shortly became the world renowned for LDLT. He was the first to introduce microvascular surgery for hepatic artery reconstruction. During his time at Shinshu University, Makuuchi performed the world’s first adultto-adult LDLT, using a left liver graft in 1993.153 However, it became quickly apparent that recipients with severe liver failure needed a large graft volume. In 1996 C.M. Lo performed the first right lobe harvesting at the University of Hong Kong.154 This pivotal innovation, which facilitated and standardized worldwide adult LDLT, revealed that sufficient graft function and regeneration required complete venous drainage. This discovery, which prompted liver surgeons to revisit the anatomy of hepatic veins, was a subject of debate that ended with the rule to avoid graft congestion with venous reconstruction.85 Donor right hepatectomy is a major surgical procedure that exposes a donor with no illness or medical indication for surgery to an operation with significant morbidity and mortality and is the source of ethical concern. Because any undesirable event in the donor was unacceptable, the continuous attention to the postoperative course of the resected donor was one of the major advances that the surgeon community has benefited from with the LDLT experience. In this context S.Y. Lee in Seoul proposed the most intriguing technical innovations, using two left grafts from two donors in a single recipient.155 Although this technique minimizes donor risk, the requirements of increased medical expertise and resources did not lead to wide acceptance.

However, the Asan Medical Center in Seoul headed by S.Y. Lee rapidly became the mecca of LDLT with hundreds of cases per year exploring all technical refinements, including vascular/ biliary anastomosis, graft selection, countermeasures against small-for-size syndrome, and ABO-incompatible grafts.156 Although ethical issues related to the use of unrelated living donors have been raised in some countries in Asia, in the Middle East and in Africa this procedure will continue to remain the predominant form of LT in countries where the combination of demographic, social, religious, economic, and political factors limits the use of a deceased donor. In the United States and Europe, LDLT stagnates to less than 2% of LT despite the persistent organ shortage and some innovative approaches minimizing donor trauma.128 Proposed in 1995 by A. Casavilla in Spain and G. Kootstra in Maastrich, the use of donation after circulatory death (DCD) was put forth with considerable effort to expand the donor pool.157 The initial use of these marginal grafts was associated with higher biliary complications, which dramatically decrease with appropriate donor and recipient selection and advances in cooling and pretransplant organ perfusion. DCD organs represented the fastest growing pool of organs for donation in the United States and Europe. The renewed interest in preservation technology was stimulated by the growing use of grafts with greater preoperative damage aiming to improve tolerance to ischemia but also to assess viability and function before transplantation. Oxygenated hypothermic and normothermic machine perfusion (NMP) have emerged as valid novel modalities for advanced organ preservation. The use of machine perfusion has several theoretical benefits, including organ repair, that may lead to improved organ quality, pretransplantation viability assessment of the donor organ, and extension of the amount of time between organ recovery and LT. Liver hypothermic machine perfusion (HMP) has been translated from the experimental state to clinical reality over the last decade. In 2010 Jean Emond and his group from Colombia University were the first to publish a series of patients who underwent LT of grafts preserved by nonoxygenated HMP with outcomes similar to a matched static cold storage (SCS) control group. Five years later the same group showed fewer biliary complications and shorter hospital stays by transplanting a series of 31 marginal grafts preserved under hypothermic dynamic conditions at 4°C to 8°C.158 These results were confirmed by an international matched-case analysis, using a new machine perfusion called “hypothermic oxygenated perfusion” (HOPE).159 Although HOPE become a widely used technology, in 2016 P.J. Friend from Birmingham, UK, published the first successful clinical application of an NMP functioning at 37°C.160 The belief that cold storage is the best preservation procedure was cracked. In 2018 Friend published an RCT establishing the superiority of NMP regarding the utilization of liver grafts.161 The “almost” physiologic effect of NMP can open ex situ clinical and experimental studies ranging from parenchymal remodeling, drug action, immunologic modification, and the generation of a chimeric organ. In writing this historical description, we have drawn freely on the work of L. Blumgart12 in his chapter from the previous edition and the recent book of T. Helling and D. Azoulay.72 We are indebted to some excellent publications for allowing us to put into perspective several historical reviews, including S.A. Ahrendt,13 F. Glenn,6 T. Starzl,135 and S. Navarro.30 There will be some disputed claims concerning the “firsts,” we mentioned, but we tried to relate a fascinating surgical story. References are available at expertconsult.com.

18.e1

REFERENCES 1. Riva MA, Riva E, Spicci M, Strazzabosco M, Giovannini M, Cesana G. “The city of Hepar”: rituals, gastronomy, and politics at the origins of the modern names for the liver. J Hepatol. 2011;55(5): 1132-1136. 2. Reuben A. The body has a liver. Hepatology. 2004;39:1179-1181. 3. Jastrow M. The liver in antiquity and the beginnings of anatomy. Trans Stud Coll Physicians Phila. 1907;29:117-139. 4. Cavalcanti de A Martins A, Martins C. History of liver anatomy: Mesopotamian liver clay models. HPB (Oxford). 2013;15(4): 322-323. 5. Bonnichon P. [The liver and surgeons]. Hist Sci Med. 2007;41(1): 95-104. 6. Glenn F, Grafe Jr WR. Historical events in biliary tract surgery. Arch Surg. 1966;93(5):848-852. 7. Ammon HV, Hofmann AF. The Langenbuch paper. I. An historical perspective and comments of the translators. Gastroenterology. 1983;85(6):1426-1433. 8. Traverso LW. Carl Langenbuch and the first cholecystectomy. Am J Surg. 1976;132(1):81-82. 9. Spirou Y, Petrou A, Christoforides C, Felekouras E. History of biliary surgery. World J Surg. 2013;37(5):1006-1012. 10. Mayo CH. The relative merits of cholecystostomy and cholecystectomy. Surg Gynecol Obstet. 1917;24:281-284. 11. Cervantes J. Common bile duct stones revisited after the first operation 110 years ago. World J Surg. 2000;24(10):1278-1281. 12. Blumgart Book. 13. Ahrendt SA, Pitt HA. A history of the bilioenteric anastomosis. Arch Surg. 1990;125(11):1493-1500. 14. Hyun JJ, Kozarek RA. Sphincter of Oddi dysfunction: sphincter of Oddi dysfunction or discordance? What is the state of the art in 2018? Curr Opin Gastroenterol. 2018;34(5):282-287. 15. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet. 1975;140(2):170-178. 16. Jarnagin WR, Blumgart LH. Operative repair of bile duct injuries involving the hepatic duct confluence. Arch Surg. 1999;134(7):769775. doi:10.1001/archsurg.134.7.769. 17. Terblanche J, Allison HF, Northover JM. An ischemic basis for biliary strictures. Surgery. 1983;94(1):52-57. 18. Nimura Y, Hayakawa N, Kamiya J, et al. Combined vein and liver resection for carcinoma of the biliary tract. Br J Surg. 1991;78:727-731. 19. Blumgart LH, Hadjis NS, Benjamin IS, Beazley R. Surgical approaches to cholangiocarcinoma at confluence of hepatic ducts. Lancet. 1984;1(8368):66-70. doi:10.1016/s0140-6736(84)90002-3. 20. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg. 1999;230:808-818. 21. Nagino M, Ebata T,Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013;258(1):129-140. 22. McCune WS, Shorb PE, Moscovitz H. Endoscopic cannulation of the ampulla of vater: a preliminary report. Ann Surg. 1968;167:752-756. 23. Safrany L. Duodenoscopic sphincterotomy and gallstone removal. Gastroenterology. 1977;72(2):338-343. 24. Litynski GS. Erich Mühe and the rejection of laparoscopic cholecystectomy: a surgeon ahead of his time. JSLS. 1998;2(4):341-346. 25. Dubois F, Icard P, Berthelot G, Levard H. Coelioscopic cholecystectomy. Preliminary report of 36 cases. Ann Surg. 1990;211(1):60-62. 26. Reddick EJ, Olsen D, Spaw A, et al. Safe performance of difficult laparoscopic cholecystectomies. Am J Surg. 1991;161(3):377-381. 27. Tando Y, Yanagimachi M, Matsuhashi Y, Nakamura T, Kamisawa T. A brief outline of the history of the pancreatic anatomy. Dig Surg. 2010;27:84-86. 28. Bassi C, Malleo G. The unsolved mystery of Johann Georg Wirsung and of (his?) pancreatic duct. Surgery. 2011;149(1):153-155. 29. Howard JM, Hess W. History of the Pancreas: Mysteries of a Hidden Organ. Science & Business Media: Springer; 2012. 30. Navarro S. The art of pancreatic surgery. Past, present and future. The history of pancreatic surgery. Gastroenterol Hepatol. 2017;40(9): 648.e1-648.e11. 31. Fernandez-del CC, Warshaw AL. Surgical pioneers of the pancreas. Am J Surg. 2007;194:S2-S5. 32. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of vater. Ann Surg. 1935;102:763-779.

33. Whipple AO. Observations on radical surgery for lesions of the pancreas. Surg Gynecol Obstet. 1946;82:623-631. 34. Crist DW, Sitzmann JV, Cameron JL. Improved hospital morbidity, mortality, and survival after the Whipple procedure. Ann Surg. 1987;206(3):358-365. 35. Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg. 1990;211(4):447-458. 36. Malleo G, Bassi C. Pancreas: reconstruction methods after pancreaticoduodenectomy. Nat Rev Gastroenterol Hepatol. 2013;10(8): 445-446. 37. Grobmyer SR, Kooby D, Blumgart LH, Hochwald SN. Novel pancreaticojejunostomy with a low rate of anastomotic failure-related complications. J Am Coll Surg. 2010;210(1):54-59. 38. Maggiori L, Sauvanet A, Nagarajan G, et al. Binding versus conventional pancreaticojejunostomy after pancreaticoduodenectomy: a case-matched study. J Gastrointest Surg. 2010;14:1395-1400. 39. Poon RT, Fan ST, Lo CM, et al. External drainage of pancreatic duct with a stent to reduce leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy: a prospective randomized trial. Ann Surg. 2007;246(3):425-433. 40. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138:8-13. 41. Gaujoux S, Cortes A, Couvelard A, et al. Fatty pancreas and increased body mass index are risk factors of pancreatic fistula after pancreaticoduodenectomy. Surgery. 2010;148:15-23. 42. Gurusamy KS, Lusuku C, Halkias C, Davidson BR. Duodenumpreserving pancreatic resection versus pancreaticoduodenectomy for chronic pancreatitis. Cochrane Database Syst Rev. 2016;2: CD011521. doi:10.1002/14651858.CD011521.pub2. 43. Yeo CJ, Barry MK, Sauter PK, et al. Erythromycin accelerates gastric emptying after pancreaticoduodenectomy. A prospective, randomized, placebo-controlled trial. Ann Surg. 1993;218(3):229-238. 44. Cherif R, Gaujoux S, Couvelard A, et al. Parenchyma-sparing resections for pancreatic neuroendocrine tumors. J Gastrointest Surg. 2012;16:2045-2055. 45. Fortner JG. Regional pancreatectomy of cancer of the pancreas: a new surgical approach. Surgery. 1973;73:307-320. 46. Ishikawa O, Ohhigashi H, Sasaki Y, et al. Practical usefulness of lymphatic and connective tis- sue clearance for the carcinoma of the pancreas head. Ann Surg. 1988;208(2):215-220. 47. Nimura Y, Nagino M, Takao S, et al. Standard versus extended lymphadenectomy in radical pancreatoduodenectomy for ductal adenocarcinoma of the head of the pancreas. JHBPS. 2012;19:230-241. 48. Yamaue H. History of pancreatic surgery in Japan: Respect to the Japanese pioneers of pancreatic surgery. Ann Gastroenterol Surg. 2020;4:118-125. 49. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17): 1605-1617. 50. Strobel O, Neoptolemos J, Jäger D, et al. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol. 2019;16:11-26. 51. Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801-810. 52. Al Faraï A, Garnier J, Ewald J, et al. International Study Group of Pancreatic Surgery type 3 and 4 venous resections in patients with pancreatic adenocarcinoma: the Paoli-Calmettes Institute experience. Eur J Surg Oncol. 2019;45(10):1912-1918. 53. Tanaka M, Fernández-Del Castillo C, Kamisawa T. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17(5):738-753. 54. Partington PF, Rochelle RE. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg. 1960;152:1037-1043. 55. Frey CF, Child CG, Fry W. Pancreatectomy for chronic pancreatitis. Ann Surg. 1976;184(4):403-413. 56. Beger HG, Witte C, Krautzberger W, Bittner R. Experiences with duodenum-sparing pancreas head resection in chronic pancreatitis. Chirurg. 1980;51:303-307. 57. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas. 1987;2(6):701-707. 58. Cahen DL, Gouma DJ, Laramée P, et al. Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patients with chronic pancreatitis. Gastroenterology. 2011;141(5):1690-1695. 59. Fitz RM. The symptomatology and diagnosis of diseases of the pancreas. Proc N Y Path Soc. 1898;43:1-26.

18.e2 60. Bradley EL III, Allen K. A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg. 1991;161:19-24. 61. Boxhoorn L, Voermans RP, Bouwense SA. Acute pancreatitis. Lancet. 2020;396(10252):726-773. 62. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-111. 63. Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology. 2002;223:603-613. 64. Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN, American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology. 2018;154:1096-1101. 65. Lillehei RC, Simmons RL, Najarian JS, et al. Pancreatico-duodenal allotrans-plantation: experimental and clinical experience. Ann Surg. 1970;172:405-436. 66. Stephanian E, Gruessner RW, Brayman KL, et al. Conversion of exocrine secretions from bladder to enteric drainage in recipients of. Ann Surg. 1992;216(6):663-672. 67. Mirkovitch V, Campiche M. Successful intrasplenic autotransplantation of pancreatic tissue in totally pancreatectomised dogs. Transplantation. 1976;21:265-269. 68. Gagner M, Pomp A. Laparoscopic pylorus-preserving pancreatoduodenectomy. Surg Endosc. 1994;8:408-410. 69. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic resections of islet cell tumors. Surgery. 1996;120(6): 1051-1054. 70. Cuschieri A, Jakimowicz JJ, van Spreeuwel J. Laparoscopic distal 70% pancreatectomy and splenectomy for chronic pancreatitis. Ann Surg. 1996;223(3):280-285. 71. Björnsson B, Larsson AL, Hjalmarsson C, Gasslander T, Sandström P. Comparison of the duration of hospital stay after laparoscopic or open distal pancreatectomy: randomized controlled trial. Br J Surg. 2020;107(10):1281-1288. doi:10.1002/bjs.11554. 72. Helling TS, Azoulay D. Historical Foundations of Liver Surgery. Cham, Switzerland: Springer; 2020. 73. Dalton HC. Gunshot wound of stomach and liver treated by laparotomy and suture of visceral wounds with recovery. Ann Surg, 1888;8:81-100. 74. Rosen G. Billroth in 1870. Surgery. 1972;72(3):337-344. 75. Keen WW. Report of a case of resection of the liver for the removal of a neoplasm with a table of seventy-six cases of resection of the liver for hepatic tumors. Ann Surg. 1899;30:267-283. 76. Couinaud C. Liver anatomy: portal (and suprahepatic) or biliary segmentation. Dig Surg. 1999;16(6):459-467. 77. Kokudo N, Takemura N, Ito K, Mihara F. The history of liver surgery: achievements over the past 50 years. Ann Gastroenterol Surg. 2020;4(2):109-117. 78. Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol. 1983;(suppl 2): 493-497. 79. Pringle JH. V. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg. 1908;48(4):541-549. 80. Tôn Thất Tùng Mem Acad Chir (Paris).1939. 81. Sarmiento JM, Dodson TF, Julian K, Quattlebaum MD. American pioneer of hepatic surgery. J Am Coll Surg. 2008;207:607-611. 82. Belghiti J. The first anatomical right resection announcing liver donation. J Hepatol. 2003;39(4):475-479. 83. Makuuchi M, Yamamoto J, Takayama T, et al. Extrahepatic division of the right hepatic vein in hepatectomy. Hepatogastroenterology. 1991;38:176-179. 84. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527. 85. Sano K, Makuuchi M, Miki K, et al. Evaluation of hepatic venous congestion: proposed indication criteria for hepatic vein reconstruction. Ann Surg. 2002;236(2):241-247. 86. Makuuchi M, Mori T, Gunven P, Yamazaki S, Hasegawa H. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet. 1987;64:155-158. 87. Imamura H, Kokudo N, Sugawara Y, et al. Pringle’s maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transplantation. 2004;10(6):771-778.

88. Tung TT. A new technique for operating on the liver. Lancet. 1963;1:192-193. 89. Fortner JG, Shiu MH, Kinne DW, et al. Major hepatic resection using vascular isolation and hypothermic perfusion. Ann Surg. 1974;180:644-652. 90. Pichlmayr R, Grosse H, Hauss J, Gubernatis G, Lamesch P, Bretschneider HJ. Technique and preliminary results of extracorporeal liver surgery (bench procedure) and of surgery on the in situ perfused liver. Br J Surg. 1990;77:21-26. 91. Azoulay D, Eshkenazy R, Andreani P, et al. In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann Surg. 2005;241:277-285. 92. Azoulay D, Lim C, Salloum C, et al. Complex liver resection using standard total vascular exclusion, venovenous bypass, and in situ hypothermic portal perfusion: an audit of 77 consecutive cases. Ann Surg. 2015;262(1):93-104. 93. Huguet C, Nordlinger B, Bloch P, Conard J. Tolerance of the human liver to prolonged normothermic ischemia. A biological study of 20 patients submitted to extensive hepatectomy. J Arch Surg. 1978;113(12):1448-1451. 94. Bismuth HC, Castaing D, Garden OJ. Major hepatic resection under total vascular exclusion. Ann Surg. 1989;210:13-19. 95. Belghiti J, Noun R, Zante E, Ballet T, Sauvanet A. Portal triad clamping or hepatic vascular exclusion for major liver resection. A controlled study. Ann Surg. 1996;224(2):155-161. 96. Man K, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg. 1997;226:704-711. 97. Ezaki T, Seo Y, Tomoda H, Furusawa M, Kanematsu T, Sugimachi K. Partial hepatic resection under intermittent hepatic inflow occlusion in patients with chronic liver disease. Br J Surg. 1992;79(3):224-226. 98. Belghiti J, Noun R, Malafosse R, et al. Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg. 1999;229(3):369-375. 99. Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg. 1998;85(8):1058-1060. 100. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection. Ann Surg. 2002;236(4):397-407. 101. Capussotti L, Muratore A, Ferrero A, et al. Randomized clinical trial of liver resection with and without hepatic pedicle clamping. Br J Surg. 2006;93(6):685-689. 102. Lesurtel M, Selzner M, Petrowsky H, et al. How should transection of the liver be performed?: a prospective randomized study in 100 consecutive patients: comparing four different transection strategies. Ann Surg. 2005;242(6):814-822. 103. Takayama T, Makuuchi M, Kubota K, et al. Randomized comparison of ultrasonic vs clamp transection of the liver. Arch Surg. 2001;136(8):922-928. 104. Lidsky ME, Jarnagin WR. Surgical management of hilar cholangiocarcinoma at Memorial Sloan Kettering Cancer Center. Ann Gastroenterol Surg. 2018;2(4):304-312. 105. Weiss MJ, Ito H, Araujo RL, et al. Hepatic pedicle clamping during hepatic resection for colorectal liver metastases: no impact on survival or hepatic recurrence. Ann Surg Oncol. 2013;20(1):285-294. 106. Belghiti J, Cauchy F, Paradis V, Vilgrain V. Diagnosis and management of solid benign liver lesions. Nat Rev Gastroenterol Hepatol. 2014;11(12):737-749. 107. Agrawal S, Belghiti J. Oncologic resection for malignant tumors of the liver. Ann Surg. 2011;253(4):656-665. 108. Liu CL, Fan ST, Lo CM, Tung-Ping Poon R, Wong J. Anterior approach for major right hepatic resection for large hepatocellular carcinoma. Ann Surg. 2000;232:25-31. 109. Belghiti J, Guevara OA, Noun R, et al. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg. 2001;193:109-111. 110. Llado L, Muñoz A, Ramos E, et al. The anterior hangingapproach improves postoperative course after right hepatectomy in patients with colorectal liver metastases. Results of a prospective study with propensity-score matching comparison. Eur J Surg Oncol. 2016;42(2):176-183. 111. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527.

18.e3 112. Madoff DC, Odisio BC, Schadde E, et al. Improving the safety of major resection for hepatobiliary malignancy: portal vein embolization and recent innovations in liver regeneration strategies. Curr Oncol Rep. 2020;22(6):59. 113. Belghiti J, Ogata S. Assessment of hepatic reserve for the indication of hepatic resection. J Hepatobiliary Pancreat Surg. 2005;12(1):1-3. 114. Belghiti J, Liddo G, Raut V, et al. “Inherent limitations” in donors: control matched study of consequences following a right hepatectomy for living donation and benign liver lesions. Ann Surg. 2012;255(3):528-533. 115. de Santibañes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012;255(3): 415-417. 116. Torzilli G, Procopio F, Donadon M, Del Fabbro D, Cimino M, Montorsi M. Safety of intermittent Pringle maneuver cumulative time exceeding 120 minutes in liver resection: a further step in favor of the “radical but conservative” policy. Ann Surg. 2012;255(2):270-280. 117. Massoud O, Charlton M. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and hepatocellular carcinoma. Clin Liver Dis. 2018;22(1):201-211. 118. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg. 2003;138(11): 1198-1206. 119. Dokmak S, Ftériche FS, Borscheid R, Cauchy F, Farges O, Belghiti J. Liver resections in the 21st century: we are far from zero mortality. HPB (Oxford). 2013;15(11):908-915. 120. Reich H, McGlynn F, DeCaprio J, Budin R. Laparoscopic excision of benign liver lesions. Obstet Gynecol. 1991;78(5 Pt 2):956-958. 121. Kaneko H, Takagi S, Shiba T. Laparoscopic partial hepatectomy and left lateral segmentectomy: technique and results of a clinical series. Surgery. 1996;120:468-475. 122. Morise Z, Wakabayashi G. First quarter century of laparoscopic liver resection. World J Gastroenterol. 2017;23(20):3581-3588. 123. Hüscher CG, Lirici MM, Chiodini S, Recher A. Current position of advanced laparoscopic surgery of the liver. J R Coll Surg Edinb. 1997;42(4):219-225. 124. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg. 2009;250:825-830. 125. Wakabayashi G, Cherqui D, Geller DA, et al. Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. Ann Surg. 2015;261: 619-629. 126. Kobayashi K, Kawaguchi Y, Kobayashi Y, et al. Identification of liver lesions using fluorescence imaging: comparison of methods for administering indocyanine green. HPB (Oxford). 2021;23(2): 262-269. 127. Kawaguchi Y, Fuks D, Kokudo N, Gayet B. Difficulty of laparoscopic liver resection: proposal for a new classification. Ann Surg. 2018;267(1):13-17. 128. Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living donor hepatectomy for liver transplantation in children. Lancet. 2002;359(9304):392-396. 129. Dokmak S, Cauchy F, Sepulveda A, et al. Laparoscopic liver transplantation: dream or reality? The first step with laparoscopic explant hepatectomy. Ann Surg. 2020;272(6):889-893. 130. Giulianotti PC, Coratti A, Angelini M, et al. Robotics in general surgery: personal experience in a large community hospital. Arch Surg. 2003;138(7):777-784. 131. Choi SB, Park JS, Kim JK, et al. Early experiences of roboticassisted laparoscopic liver resection. Yonsei Med J. 2008;49:632-638. 132. Kingham TP, Leung U, Kuk D, et al. Robotic liver resection: a case-matched comparison. World J Surg. 2016;40:1422-1428. 133. Zhu P, Liao W, Ding ZY, et al. Learning curve in robot-assisted laparoscopic liver resection. J Gastrointest Surg. 2019;23(9):1778-1787. 134. Liu R, Wakabayashi G, Kim HJ, et al. International consensus statement on robotic hepatectomy surgery in 2018. World J Gastroenterol. 2019; 25(12):1432-1444. 135. Starzl TE, Fung JJ. Themes of liver transplantation. Hepatology. 2010;51(6):1869-1884. 136. Zarrinpar A, Busuttil RW. Liver transplantation: past, present and future. Nat Rev Gastroenterol Hepatol. 2013;10:434-440. 137. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2:1033-1036.

138. National Institutes of Health Consensus Development Conference Statement: Statement: liver transplantation—June 20-23, 1983. Hepatology. 1984;4(suppl 1):107S-110S. 139. Kalayoglu M, Sollinger HW, Stratta RJ, et al. Extended preservation of the liver for clinical transplantation. Lancet. 1988;1:617-619. 140. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693-699. 141. Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg. 1989;210(5): 649-652. 142. Belghiti J, Panis Y, Sauvanet A, Gayet B, Fékété F. A new technique of side to side caval anastomosis during orthotopic hepatic transplantation without inferior vena caval occlusion. Surg Gynecol Obstet. 1992;175(3):270-272. 143. Belghiti J, Noun R, Sauvanet A, et al. Transplantation for fulminant and subfulminant hepatic failure with preservation of portal and caval flow. Br J Surg. 1995;82(7):986-989. 144. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery. 1984;95:367-370. 145. Pichlmayr R, Ringe B, Gubernatis G, Hauss J, Bunzendahl H. Transplantation of a donor liver to 2 recipients (splitting transplantation)—a new method in the further development of segmental liver transplantation. Langenbecks Arch. Chir. 1988;373: 127-130. 146. Azoulay D, Castaing D, Adam R, et al. Split-liver transplantation for two adult recipients: feasibility and long-term outcomes. Ann Surg. 2001;233(4):565-574. 147. Terpstra OT. Auxiliary liver grafting: a new concept in liver transplantation. Lancet. 1993;342(8874):758. 148. Gubernatis G, Pichlmayr R, Kemnitz J, Gratz K. Auxiliary partial orthotopic liver transplantation (APOLT) for fulminant hepatic failure: first successful case report. World J Surg. 1991;15(5): 660-665. 149. Rela M, Kaliamoorthy I, Reddy MS. Current status of auxiliary partial orthotopic liver transplantation for acute liver failure. Liver Transpl. 2016;22(9):1265-1274. 150. Belghiti J, Sommacale D, Dondéro F, Zinzindohoué F, Sauvanet A, Durand F. Auxiliary liver transplantation for acute liver failure. HPB (Oxford). 2004;6(2):83-87. 151. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-470. 152. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg. 1991;214(4):428-437. 153. Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful livingrelated partial liver transplantation to an adult patient. Lancet. 1994;343:1233-1234. 154. Lo CM, Fan ST, Liu CL, et al. Extending the limit on the size of adult recipient in living donor liver transplantation using extended right lobe graft. Transplantation. 1997;63:1524-1528. 155. Lee S, Hwang S, Park K, et al. An adult-to-adult living donor liver transplant using dual left lobe grafts. Surgery. 2001;129(5): 647-650. 156. Moon DB, Lee SG, Chung YK, et al. Over 500 Liver transplants including more than 400 living-donor liver transplants in 2019 at Asan Medical Center. Transplant Proc. 2020;53(1):83-91. 157. Koostra G. Statement on non-heart-beating donor programs. Transplant Proc. 1995;27(5):2965. 158. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers. Am J Transplant. 2015;15(1):161169. doi:10.1111/ajt.12958. 159. Dutkowski P, Polak WG, Muiesan P, et al. First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis. Ann Surg. 2015;262(5):764-770. 160. Ravikumar R, Jassem W, Mergental H, et al. Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial. Am J Transplant. 2016;16(6): 1779-1787. 161. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557(7703):50-56.

PART 1

Liver, Biliary, and Pancreatic Anatomy and Physiology

1 Embryologic Development of the Liver, Biliary Tract, and Pancreas



2 Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas



3 Pancreatic Physiology and Functional Assessment



4 Assessment of Hepatic Function: Implications for Perioperative Outcome and Recovery



5 Liver Blood Flow: Physiology, Measurement, and Clinical Relevance



6 Liver Regeneration: Mechanisms and Clinical Relevance



7 Liver Fibrogenesis: Mechanisms and Clinical Relevance



8 Bile Secretion and Pathophysiology of Biliary Tract Obstruction



9A Molecular and cell Biology of Hepatopancreatobiliary Disease: Introduction and Basic Principles



9B Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis



9C Advances in the Molecular Characterization of Liver Tumors



9D Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions



9E Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer



10 Fundamentals of Liver and Pancreas Immunology



11 Infections in Hepatic, Biliary, and Pancreatic Surgery

19

CHAPTER 1 Embryologic development of the liver, biliary tract, and pancreas Mark Davenport and Philippa Francis-West INTRODUCTION

DEVELOPMENT OF LIVER AND BILE DUCTS

The liver’s essential structure is one of layers of metabolically active hepatocytes arrayed along and around a vascular network carrying nutrient-rich blood derived from the products of intestinal absorption, otherwise semi-isolated from the systemic circulation. The biliary ducts are interleaved and intimate within this system and provide an excretory apparatus linking back with the intestinal tract. The pancreas, by contrast, has two completely independent functional units. One is a relatively simple exocrine repository of initially inactive digestive enzymes; the other is a complex array of endocrine cells devoted to various homeostatic processes and feedback loops. The first period of development is considered to extend from fertilization to form a single-celled zygote, or ovum, in the Fallopian tube to the implantation of the multicellular blastocyst into the wall of the uterus and lasts about seven days. Gastrulation in week three generates the three embryonic tissue layers: the ectoderm, mesoderm, and endoderm, which will contribute to various cell types within different organs. The first eight weeks post-fertilization are conventionally described as the embryonic period. They involve the formation of the major organs of the body and are followed by the fetal period, which involves further growth and maturation, extending to the time of birth and delivery. Both the liver and pancreas start to develop during the embryonic period. Despite their very different functions and structures, the liver and pancreas initially arise from the same population of bipotent endodermal cells (Sox17, FoxA, Hhex, Gata-expressing), which can form either the liver or pancreas, depending on the growth factor signals from surrounding tissues. This region of endoderm also gives rise to the gallbladder and extrahepatic biliary system. Specification into the two different organs is dependent on the differential expression of the transcription factors PDX1 and PTF1A for the pancreas and HHEX, FOXA1/2, GATA4, HNF1b, and HNF4a for the liver. GATA4 and FOXA1/2 are known as “pioneer” transcription factors that are pre-assembled at liver-specific genes such as albumin, allowing a rapid induction of liver fate. Gestational age is different from post-fertilization because it is measured from the last menstrual period, which effectively adds two weeks to the timeline described. Actually, this is a term seldom used by embryologists, but becomes more valid clinically by the end of the whole process. Much of the work detailing the anatomy and timing of embryologic events was performed by Franklin Mall and later George Streeter in the Carnegie Institution in Baltimore, MD during the first part of the 20th century. From this ensued the widely-used classification of Carnegie Staging (stages 1–23).

Development of the liver can be divided into several phases (Fig. 1.1). During the early embryonic phase, there is induction of the liver diverticulum from the endoderm and growth with the formation of hepatoblasts to form the liver bud. The late embryonic period is defined by the onset of generation of hepatocytes, which will form the bulk of the liver, and of cholangiocytes, which will form the bile ducts. These two cell types arise from the bipotential hepatoblast that expresses markers of both hepatocytes and cholangiocytes. The fetal period is characterized by further differentiation of hepatocytes and cholangiocytes, which become organized into liver lobules and bile ducts, respectively. During this phase, there is maturation of the hepatocytes, together with further expansion of the liver and bile ducts at the periphery of the liver.1 This chapter provides an overview of key events and the growth factor signals and transcriptional factors required for liver development. More detailed information can be found in Gordillo et al.,2 Ober and Lemaigre,3 and Peruggoria et al.4

20

Weeks 4 to 5 Post-Fertilization (Carnegie Stages 10–15) At the start of this period, the embryo measures about two to three mm, has implanted into the endometrial layer of the uterine wall, and externally is characterized by the formation of somites. The primitive endodermal intestinal tube has formed but is blind, occluded at either end by the buccopharyngeal and cloacal membranes and conventionally divided according to its three supplying arteries as foregut, midgut, and hindgut. The liver and biliary tract arises initially as an endodermal bud from the distal foregut within the ventral mesogastrium, projecting into the mesenchyme of the septum transversum. This endodermal bud is formed from two endodermal origins: two lateral domains and the ventral midline of endoderm lip (VMEL), where the endoderm folds into the anterior intestinal portal.5 The lateral and VMEL endodermal domains will generate the posterior and anterior parts of the liver, respectively. The liver primordia develops into a funnel-shaped structure with a lumen evident throughout, and from about 45 days the thickerwalled gallbladder also becomes evident. Induction of the liver diverticulum is controlled by growth factors: bone morphogenetic proteins (BMPs) from the septum transversum and lateral plate mesoderm, together with fibroblast growth factors (FGFs) from precardiac mesoderm and signals from the surrounding endothelial cells (Table 1.1). Specifically, BMPs specify liver fate in the VMEL precursors, whereas FGFs induce liver formation in the lateral endodermal hepatic precursors. These growth factors induce or maintain the expression of the transcription factors FOXA1&2, HHEX,

  Chapter 1  Embryologic Development of the Liver, Biliary Tract, and Pancreas

21

20 - 27 days: (post fertilization) Hepatic diverticulum arises from foregut and portrudes into mesenchyme of septum transversum.

28 - 41 days: Completion of “funnel-like” extrahepatic duct abutting amorphous liver anlage. • Gallbladder visible later

12 weeks onward: On-going selection and deletion of intrahepatic bile ducts away from porta.

42 - 56 days:

• Formation & Transport of BILE

• Early cholangiocyte transformation

Hepatoblasts identifiable in liver.

57 - 70 days: • Formation of ductal plate and intrahepatic bile ducts FIGURE 1.1  Bile duct development timeline. Roman numerals refer to Carnegie stages of embryo development.

TABLE 1.1  Genes Involved in Early Liver, Bile Duct, and Pancreas Development DERIVATION

POSSIBLE FUNCTION

CHROMOSOME

BMP

Bone morphogenic protein

Growth factor family; multifunctional role.

FGF

Fibroblast growth factor

Growth factor family; multifunctional role.

VEGF

Vascular endothelial growth factor

PDX1 HES-1 PROX-1

Pancreas/duodenum homeobox protein 1 Hairy and enhancer of split 1 (Drosophila) Prospero homeobox 1

HNF-6 (ONECUT-1) NOTCH 1-4

Hepatocyte nuclear factor

The protein acts on endothelial cells, increasing permeability and inducing angiogenesis. Transcription factor; pancreas development Transcription factor family; target of Notch signaling Homeobox transcription factor; needed for hepatocyte formation. Transcription factor; needed for cholangiocyte formation.

Ch6 (Depends on member) Ch10 (Depends on member) Ch6

NEUROG3

Mutation produced irregular (“notches”) in wing tips of Drosophila. Neurogenin 3

SOX-9

SRY (sex determining region Y)-box 9

WNT

Wg & Int standing for wingless-related integration (Drosophila)

SHH LGR-4

Sonic hedgehog Leucine-rich repeat containing G proteincoupled receptor. Paired box - 6 CCAAT/enhancer binding protein Pancreas-specific transcription factor 1A

PAX-6 (C/EBP) PTF1A

Ch13 Ch3 Ch1 Ch15

Receptors for signaling network, which regulates interactions between physically adjacent cells. Basic Helix-loop-helix transcription factor; essential for endocrine lineage Forms DNA-binding proteins; needed for cholangiocyte differentiation. Growth factor family; multifunctional roles. Canonical: cell proliferation & survival; Planar Cell Polarity: coordinated cell polarity and behavior Early embryonic patterning, cell proliferation, and survival Gallbladder maturation

Ch9

Ch7 Ch11

Transcription factor; for endocrine cell lineage Transcription factor; needed for hepatocyte formation. Transcription factor; pancreas development

Ch11 N/A Ch10

Ch10 Ch17 (Depends on member)

22

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

HNF1b, HNF4a, and GATA4&6, which specify the liver primordium and are needed for hepatoblast differentiation. Repression of the b-catenin (canonical Wnt) and Notch signaling pathways are also required for liver induction. From the cranial aspect of the endodermal diverticulum emerge the primordial liver cells, known as the hepatoblasts. Hepatoblasts are the precursors of both hepatocytes and cholangiocytes and express markers of both lineages: hepatocytes (e.g., a-fetoprotein, albumin, HNF4a, HHEX) and cholangiocytes (HNF1b and CK19, a late differentiation marker). Initially hepatoblasts are cuboidal cells lining the invaginating diverticulum. Proliferation results in a “multilayered” pseudostratified endodermal structure and requires HHEX. Subsequently, the hepatoblasts reduce their cell–cell contacts, delaminate, and migrate into the septum transversum to become arranged in plates, initially three to four cells thick, which line the vascular sinusoids. This delamination phase requires the transcription factors PROX1, HNF6 (ONECUT1), and ONECUT2. The ingrowing columns of cells, known here as “cords” (sometimes “chords”), also have an intimate relationship with the mesenchymal-derived endothelial cells lining primitive vascular sinusoids. Proliferation and cell survival are controlled by paracrine Wnt, FGF, and hepatocyte growth factor (HGF) signaling from adjacent mesodermal cells, including from the closely opposed liver sinusoidal endothelial cells. The embryonic liver is populated not only by the hepatoblasts but also by hematopoietic cells, originally derived from the yolk sac and then from the aorta-gonad-mesenchyme region and placenta. Hematopoietic cells will form the bulk of the liver, and hematopoietic maturation becomes the dominant feature during the second trimester. Hematopoietic cells produce Oncostatin M (OSM), which also increases hepatoblast proliferation, contributing to liver growth until late fetal development.

Weeks 6 to 8 Post-Fertilization (Carnegie 16–23) The liver is by now a large, rounded mass of tissue called the liver anlage (German for “rudimentary organ or part”) and the dominant organ by mass within the abdomen. Later, it will push the embryonic gut into the base of the umbilicus before it returns, and complete closure of the anterior abdominal wall occurs at around 12 weeks gestation. Failure of this return phase leads to an omphalocele (or exomphalos), of which the liver can form a major part. Hepatoblasts are the parental cells for two key cellular progeny, hepatocytes and cholangiocytes, and differentiation occurs later at or around the seventh week (see Fig. 1.1). This common cellular origin has implications for malignant disease in adults. Notch signaling from the portal vein mesenchyme promotes cholangiocyte formation, and hence ductal development, whilst inhibiting hepatocyte development. Other growth factors needed for cholangiocyte cell fate include transforming growth factor (TGF)-b, BMPs, and FGFs. Cholangiocyte differentiation requires the HNF1b, HNF6, and SOX9 transcription factors. In contrast, hepatocyte induction requires FGF, HGF, and OSM signaling from the surrounding mesodermal cells, including the hematopoietic precursors and mesothelial cells that surround and line the liver lobes. Hepatocyte fate requires the transcription factors HNF4a and C/EBPa. The transcription factor PROX1 (and TBX3) determines which cell fate develops from the bipotential

hepatoblasts; in the absence of PROX1, fewer hepatocytes are formed, which is associated with an increase in cholangiocyte number. Intrahepatic bile ducts only appear distinctly from about seven weeks gestation, and formation is organized by the portal vein.6,7 At seven weeks, the portal venous network is infiltrating the liver anlage and becomes surrounded by a layer of mesenchyme. From this a cylindrical double cell layer of darkly staining cells adjacent to the portal vein emerges, which is termed the ductal (or limiting) plate. The bile ducts are generated from the dual-layer by a unique process of so-called transient asymmetry, whereby ductal plate cells resembling cholangiocytes (expressing SOX9 and CK19) on the side facing the portal tract are matched by ductal plate cells resembling hepatoblasts (expressing HNF4a) on the side facing the parenchyma.8–11 After the formation of a lumen, the nascent bile duct becomes symmetrical, as hepatoblasts are replaced by cholangiocytes to form a double cell layer composed entirely of cholangiocytes, which will remodel to form a single-cell layer bile duct. Bile duct development is discontinuous along the portal vein, and selective remodeling of this layer generates an interconnected, single cell–lined network of small bile ducts within the mesenchymal architecture. Ductal progression and elongation proceeds from the hilum to the periphery and appears to be controlled by the noncanonical Wnt pathway. Cholangiocytes that are not incorporated into the bile ducts dedifferentiate into hepatocytes. At some point, extra- and intrahepatic systems coalesce at the interface of the porta hepatis, although the process is again imperfectly understood.9,10 Hepatic arteries develop in association with the developing bile ducts and are thought to be induced by VEGF signals from the ductal plate. The onset of hepatocyte polarity and generation of the polygonal shape characterizes the latter stages of this phase with structurally distinct apical, lateral, and basolateral domains. The basolateral surface abuts the blood-containing sinusoids, but is separated from them by the cell-free space of Disse. The apical aspect abuts onto adjacent hepatocytes, within which is the biliary canaliculus, the smallest component of the biliary network. These are delineated by tight junctions (desmosomes), with the remainder of this apical surface given over to gap junctions, which can be conduits between cells. The surface area of both the canaliculus and basolateral surfaces are multiplied by the presence of microvilli. This implies that the canaliculus is of hepatocyte origin, with later connections to the intrahepatic bile ducts emanating from the center. Nevertheless, the hepatocyte differentiation phase is most pronounced during the fetal stages and is linked to the reducing hematopoietic cell number as hematopoiesis shifts to the bone marrow.

The Ninth Week Onwards: The Fetal Phase Bile acid synthesis starts at about six weeks, and bile is first observed in primitive cholangioles and then transported into the fetal gut from about 12 to 14 weeks gestation, implying completion of biliary continuity. The so-called “solid phase” of biliary development, formerly a widely held belief and an obvious corollary of biliary atresia, now appears erroneous.12 The other components of the mature liver parenchyma have different origins to the ones previously described. Kupffer cells are of a monocyte/macrophage lineage and appear at about five weeks gestation from fetal yolk sac precursors. Hepatic stellate cells are apparent by 10 weeks. These cells have

  Chapter 1  Embryologic Development of the Liver, Biliary Tract, and Pancreas

molecular characteristics of all three germ layers and their origin is unclear, although some do appear to arise from the septum transversum. Mesodermal cells from the early liver anlage form the mesenchymal framework of the liver, including its perisinusoidal Ito cell population. Fetal liver stromal tissue consists of cells that express features of epithelium (Ck-8), mesenchyme (vimentin and osteopontin), and vascular smooth muscle actin (aSma). The liver continues to develop throughout the fetal stage and after birth and is characterized by maturation, hepatocyte proliferation, and expansion of liver volume. Growth is controlled by OSM, glucocorticoids, HGF, and the canonical Wnt signaling pathway.13 Hepatocyte maturation is more advanced in the center of the liver. Proliferation is highest at the periphery in response to paracrine signals from the overlying mesothelial cells. The bile ductal network also continues to develop at the periphery of the liver in response to Notch signaling. Until the late fetal stage, the bile ducts are all narrow. Then, there is remodeling and enlargement of the ducts at the center of the liver, potentially in response to the onset of bile flow.1 Glycogen granules are present in fetal hepatocytes at about eight weeks, with the zenith of glycogen reserve achieved by the time of birth. Rapid onset of glycogenolysis over two to three days then depletes to about 10% of prenatal levels.

Vascular Events The liver has a dual vascular supply, the portal venous system and the hepatic arterial system, which then drains by common hepatic venous channels into the vena cava and right atrium. The embryonic origins of the portal venous system are complex and involve two sets of paired venous structures: the vitelline and the umbilical veins together with posterior body wall venous structures such as the cardinal veins, which culminate in the inferior vena cava (IVC). 1. Vitelline veins (paired): These carry blood from the gut to an evolving sinusoidal plexus and are originally from the yolk sac—hence the name (vitellus (Latin): color of yolk). Outside of the liver, they are interconnected to resemble a stepladder with the connections sometimes in front of and then behind the embryonic intestine. Remodeling and loss of some of these “steps” leads to the final arrangement of the S-shaped portal vein, which arises from the junction of the splenic vein and superior mesenteric veins anterior to the third part of the duodenum to then emerge from behind the junction of the first/second part of the duodenum to run in the free edge of the lesser omentum. 2. Umbilical veins (paired): These carry oxygenated blood passively back from the placenta to the right side of the developing heart at the sinus venosus. The right umbilical vein disappears early in gestation, leaving the other to be enveloped by the liver. This joins the left portal vein, which allows oxygenated blood into the sinusoids, although most continues into a low-pressure venous channel, the ductus venosus (or Duct of Arantius), which connects the left portal vein and the hepatic vein confluence. About 20% to 30% of this flow is shunted through this in the fetus, with progressive diminution as gestational age progresses. Oxygen saturation levels of about 80% can also be observed during the last trimester. By the time of birth and transition from the fetal circulation, the ductus closes functionally and later anatomically so the entire portal venous inflow is directed

23

solely into the sinusoids. There is then a measurable increase in portal venous pressure after ductus closure. Commencement of enteral nutrition and consequent increases in intestinal perfusion also lead to increased sinusoidal liver perfusion and bile flow. There are a number of different venous arrays within the posterior aspect of the abdominal cavity throughout embryonic and fetal life. The posterior cardinal veins are paired structures, which originally carry blood back from the lower half of the body. Their function declines during gestation, although they eventually will become the azygous1 and hemiazygous veins. The larger IVC is embryologically a much later structure and is formed from many different venous precursors, such as the subcardinal veins (to form the pre-renal portion) and supracardinal veins (to form the post-renal portion). The intrahepatic portion itself is an outgrowth from the right subcardinal vein subsumed in the evolving liver tissue (from about the sixth week) to anastomose with the hepatic vein confluence. The ingrowth and indeed timing of the hepatic arterial network has been less intensively studied. Nonetheless, this is perceived as a relatively late event around about the time of the formation and expansion from the porta of the intrahepatic bile ducts. Thus there is a peribiliary arteriole plexus from the terminal branches of the hepatic artery at the periphery of the liver lobule, with arterial blood contributing to the sinusoidal network thereafter.

Clinical Correlates Neonatal Cholestatic Syndromes There are a large number of distinct cholestatic conditions that present during the neonatal period, with persistent jaundice and acholic stools. Alagille’s syndrome is a multisystem genetic condition caused by loss of function mutations of the JAG1 gene, a ligand for the Notch signaling pathway.14 This leads to poor bile duct development (biliary hypoplasia), cardiac anomalies, vertebral anomalies (“butterfly” vertebrae), and an unusual “elfin-like” facies. Biliary atresia (see Chapter 40) encompasses a range of distinct variants, some of which may have their origins in embryonic life. Thus the biliary atresia splenic malformation14 can be characterized as having an absent or poorly developed common bile duct and often an atrophic gallbladder in association with either polysplenia or asplenia and vascular anomalies, such as a pre-duodenal portal vein and an absent IVC. The pre-duodenal position of the portal vein is because of impaired development of the vitelline veins. Although this is not really thought of as pathologic in itself, it is clearly at risk of damage during dissection. Situs inversus is also present in about half of these infants – presumably reflecting randomness of the acquisition of visceral asymmetry. It is speculated that these key anomalies date the pathology to 20 to 40 days post-fertilization during the establishment of asymmetry in the embryo.15 It is not known when the pathology of the nonsyndromic forms of biliary atresia occurs, but presumably it must be either during or after organogenesis but independent of mechanisms that establish asymmetry. What appears clear is that in the vast 1 Azygous: From the Greek azugos, from a- “without” 1 zugon “yoke,” the vein not being one of a pair.

24

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

majority, there is biliary obstruction biochemically evident by the time of birth.16

Congenital Portomesenteric Anomalies The final functional result of the developed portomesenteric venous system is complete separation of it and the systemic venous system outside of the liver. Because of its complex heritage, this may not always be so, and as a result, there are a number of aberrant portosystemic connections described. The commonest is probably persistence of the ductus venosus. Normally there is fibrosis and anatomic closure beyond the first few weeks postnatally. This can be delayed and lead to a proportion of portomesenteric blood leaking into the circulation, not having gone through the sinusoidal network. Nevertheless, most close spontaneously within 2 years and rarely require surgical or endovascular closure. The Abernethy malformation17 is an interconnection of the portal vein and IVC, typically assuming an “H” shape at the inferior margin of the liver between the confluence of the left and right portal veins and the IVC. This is a permanent connection, and the degree of the functional venous bypass dictates its clinical consequences. Sometimes the entire portomesenteric venous flow bypasses the liver, with aplasia of the intrahepatic portal veins. This actually has no real consequence on liver “function” because its blood supply is then entirely derived from arterial sources. Nevertheless, presumably because of differing oxygen saturations within the sinusoids, there is a predisposition to the development of neoplasia, both benign with focal nodular hyperplasia and malignant with hepatoblastoma18 (see Chapter 87). There are also potentially serious metabolic consequences with “unfiltered” blood entering the systemic venous system. Venous ammonia levels are usually high, and there is a predisposition to encephalopathy in later life and probably untoward effects on the developing brain, although this is poorly characterized. Surgical closure is certainly warranted and can reverse some of these histologic changes.18

PANCREAS The pancreas is induced within the endoderm at Carnegie Stage (CS) 12. The pancreatic precursors arise within three locations: the ventral endodermal domain, the VMEL (both the ventral endodermal domain and the VMEL are common progenitors with the liver), and a dorsal domain to give rise to the dorsal and ventral pancreatic buds. Between CS13 and CS19, the multipotent pancreatic progenitors proliferate, and by CS19, cells of the exocrine lineage, the bipotential duct cells and acini cells, have started to differentiate. Generation of the endocrine lineage starts at CS21. At the end of the embryonic period, the ventral bud starts to rotate to unite with the dorsal pancreatic anlage. This chapter gives a brief overview of pancreatic development. For detailed reviews of pancreatic development, please see Jennings et al.19 and Larsen & Botton.20

Development from Ventral and Dorsal Anlagen The pancreas is derived from ventral and dorsal anlagen, which arise from the foregut diametrically opposite each other and are distinct from about day 26 to 32 (Fig. 1.2). The ventral duct is an off-shoot of the bile duct and maintains this bile duct connection throughout. The dorsal anlage will give rise to the head, body, and tail of the pancreas, whereas the ventral

bud gives rise to the uncinate (Latin – “shaped like a hook”) process. Actual fusion of pancreatic parenchyma occurs after a rotation of the ventral duct around the axis of the foregut at about 50 to 55 days. This differential heritage can still be evident histologically by staining for pancreatic polypeptide (PP). Thus, PP cells localize to the area derived from the ventral anlage, while the dorsal pancreas has larger lobules with PP-poor islets. This process is also accompanied by a variable degree of interconnection of the ventral and dorsal ducts. Typically, the dominant flow of pancreatic secretions from body and tail and most of the head is preferentially directed through the ventral duct (of Wirsung). The entry of the smaller dorsal duct (of Santorini) is usually more proximal in the final duodenum and reputedly drains only the uncinate process. The final phase of pancreatic development occurs later on during gestation. Initially, the junction of bile and pancreatic duct is outside of the wall of duodenum, but during the last trimester there is gradual absorption of this junction into the wall of the duodenum. The final arrangement is a common chamber (the ampulla of Vater), with each duct emptying in it but surrounded by its own sphincter to maintain bile and pancreatic juice separation. Both pancreatic acinar tissue, ducts, and progenitor endocrine-active cells arise from the same multipotential precursor, with a process of layering and clustering of endodermal cells. Microlumens then form within the cluster and subsequently coalesce to form the lumen of a tubular gland. The first lineage decision is exocrine fate, with the generation of the bipotential ductal cells and the acini. Then endocrine cells are specified within the ducts to break away from the nascent glandular structure through the basal membrane into the surrounding mesenchyme. The endocrine cells aggregate and proliferate together as islet tissue. The first endocrine cells to form are the insulin-producing b-cells. Both insulin and glucagon can be detected in the fetal circulation by the fourth or fifth month of fetal development. As in the developing liver, pancreatic development involves a series of steps: induction and proliferation of the early pancreatic progenitors followed by differentiation along various cell lineages. In contrast to induction of the liver, where BMP signaling is required, development of the pancreas requires an absence of BMP signaling. The absence of SHH signaling is also required for pancreatic fate: ectopic SHH promotes liver formation while inhibiting pancreatic induction. Although molecularly extremely similar, the ventral and dorsal pancreatic buds are also induced by different combinations of growth factor signals, reflecting their origin next to cardiac mesoderm/ septum transversum/lateral plate mesoderm and notochord/ dorsal aorta, respectively. The developing pancreas is defined by PDX1, a member of the ParaHox group of homeodomain transcription factors, and SOX family genes are believed to be the key developmental genes required for normal human pancreas development16,17. PDX1 is an early marker for pancreatic progenitors that later “restricts” to the b-cells and is required for maintenance of bcell fate and function (Gao et al., 2014). Pancreas-specific transcription factor 1A (PTF1a) is also an early marker of pancreatic progenitor cells, expressed slightly later than PDX1, and is needed to maintain PDX1 expression, providing a positive feedback loop.21 SOX9 induces expression of FGFR3, a receptor

  Chapter 1  Embryologic Development of the Liver, Biliary Tract, and Pancreas

25

Septum transversum

A

Dorsal anlage

Ventral anlage

B

C

FIGURE 1.2  Development of pancreas. A, Initial separation with ventral anlage attached to developing biliary duct. B, Rotation of ventral anlage and bile duct behind duodenum. C, Fusion of the pancreatic anlagen with crossover of dorsal duct to now drain through the ventral orifice.

for FGFs which, together with Notch (and FGF10, BMP, retinoic acid and epidermal growth factor) signaling promotes proliferation of the pancreatic precursors. Mutations in PDX1, PTF1A, and SOX9 are all associated with pancreatic agenesis or hypoplasia. Mutations in GATA4 and 6 can also result in pancreatic agenesis. Because GATA4/6 normally repress Shh expression within the ventral pancreatic endoderm, this is because of ectopic Shh signaling and expansion of the hepatogenic domain. A key step in pancreatic development is the lineage decision by pancreatic progenitor cells between the endocrine and exocrine lineage. Notch signaling has been identified as a master regulator of this fate decision switch.22 Notch promotes ductal cell differentiation, while inhibiting endocrine cell differentiation. TGF-b signaling inhibits endocrine development. Specifically, the intracellular mediators of TGF-b signaling, Smad2 and Smad3, along with their inhibitor Smad7, have been found to play an intricate role in regulating pancreatic endocrine maturation and development. Genetic inactivation of Smad2 and Smad3 led to both a significant expansion of the embryonic endocrine compartment and a more robust islet proliferation in adult mouse pancreas after partial pancreatectomy. Genetic inactivation of Smad7 led to a significant decrease in the endocrine compartment with little b-cell proliferation after pancreatectomy in the adult mouse pancreas.23,24 In contrast to

TGF-b, activin signaling promotes proliferation of the endocrine lineage. All the endocrine cells arise from a NeuroG3expressing precursor cell, which is generated from the ductal tree and is present from weeks 7 to 35, with numbers peaking at week 12. The NeuroG3-expressing cells give rise to a- and g-cells, which produce glucagon and pancreatic polypeptides, respectively, and b- and d-cells, which secrete insulin and somatostatin, respectively. When NeuroG3 is deleted from cells, no pancreatic endocrine cells form,25 whereas forced overexpression of NeuroG3 leads to cells prematurely committing to an endocrine lineage, which endocrine lineage is formed is dependent on the timing of NeuroG3 overexpression.26 Thus NeuroG3 appears to be a critical and essential factor for endocrine differentiation. Each endocrine cell type is characterized by a specific combination of transcription factors. Differentiation along the distinct lineages is also regulated by different signaling pathways. For example, TGF-b promotes b-cell development. Initially, pancreatic cells can co-express different endocrine factors, but eventually the majority will become restricted to one lineage via antagonistic feedback loops between these transcription factors. Therefore loss of one transcription factor will result in an increased number of cells of another lineage. This bipotentiality and the ability of specific transcription factors to direct fate may be exploited for therapies.

26

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

In vivo total ablation of b-cells (about 99%) can lead to a-cell conversion to b-cells via a bihormonal cell stage (glucagon positive/insulin positive).27 Also, ectopic expression of PDX1 or PAX4 has been shown to induce a-cells or a-cell progenitors to convert to b-cells.28,29 In humans, loss of function mutations in NEUROG3, GLIS3, PAX6, MNX1, NEUROD1, and NKX2.2 are linked to permanent neonatal diabetes myelitis (reviewed by Jennings et al.19). The essential role for NeuroG3 in specification of the endocrine lineage has been previously discussed, and the roles of the other transcription factors is being elucidated. These factors may influence development of specific lineages via specification of cell fate, survival, and/or proliferation. For example, Nkx2.2 is expressed as early and is co-expressed with PDX1, acting as a marker of multipotent pancreatic progenitor cells. Nkx2.2 expression eventually becomes restricted to NeuroG3-positive cells, persisting in all endocrine lineages except for d-cells.30,31 Nkx2.2-null mutant mice develop with no b-cells, reduced PP cells, an 80% reduction in a-cells, and no effect on d-cells. Pax6 is also another marker of endocrine lineage, but unlike NeuroG3, it is not absolutely necessary for endocrine formation because null-mutant mice for Pax6 still form endocrine cells, albeit at a reduced rate.32

Clinical Correlates See Chapter 53 for more information. Imperfect pancreatic fusion or persistence of an anterior element of the anlagen may lead to an annular pancreas where there is a ring of tissue surrounding the second part of the duodenum. Although of itself it is thought to be relatively benign, it can be associated with duodenal stenosis or even atresia. Some also

seem to predispose to recurrent pancreatitis, presumably reflecting imperfect duct drainage. Failure or imperfect fusion of dorsal and ventral pancreatic ducts leaves most of the parenchyma draining through the entire length of the dorsal duct and complete separation of bile and pancreatic ducts, and is then known as pancreas divisum. This mode of drainage seems to be less efficient and predisposes to recurrent or chronic pancreatitis, at least in children. Its relevance to clinical pancreatitis in adults has been disputed (see Chapters 55 and 57). A common channel can be defined endoscopically in quite a high proportion of the population (,5%), most of whom are asymptomatic. Nevertheless, it does seem to predispose, again certainly in children, to recurrent pancreatitis and has been suggested as an etiologic factor for some choledochal malformations (see Chapter 46). Functionally, it allows free intermixing of bile and pancreatic secretions before they reach the duodenum. Such reflux into the biliary ducts can be quantified by measuring amylase in bile, and there is hypothetically a relationship that has been developed, particularly in Japan, with a predisposition to the development of neoplastic change in the bile duct and specifically the gallbladder.33

GENERAL READING • Scoehnwolf GC, Bleyl SB, Brauer PR, Francis-West PH, eds. Larsen’s Human Embryology. 5th ed. Churchill Livingstone, 2015. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

26.e1

REFERENCES 1. Tanimizu N, Kaneko K, Itoh T, et al. Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology. 2016;64:175-188. 2. Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver development. Development. 2015;142:2094-2108. 3. Ober EA, Lemaigre FP. Development of the liver: insights into organ and tissue morphogenesis. J Hepatol. 2018;68:1049-1062. 4. Perugorria MJ, Olaizola P, Labiano I, et al. Wnt–b-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121-136. 5. Tremblay KD, Zaret KS. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev Biol. 2005;280:87-99. 6. Crawford JM. Development of the intrahepatic biliary tree. Semin Liver Dis. 2002;22:213-225. 7. Desmet VJ, Van Eyken P, Sciot R. Cytokeratins for probing cell lineage relationships in developing liver. Hepatology. 1989;15: 125-135. 8. Antoniou A, Raynaud P, Cordi S, et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology. 2009;136:2325-2333. 9. Clotman F, Lannoy VJ, Reber M, et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development. 2002;129:1819-1828. 10. Coffinier C, Gresh L, Fiette L, et al. Bile system morphogenesis: defects and liver dysfunction upon targeted deletion of HNF1b. Development. 2002;129:1829-1838. 11. Strazzabosco M, Fabris L. Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol. 2012;56:1159-1170. 12. Tan CEL, Driver M, Howard ER, Moscoso GJ. Extrahepatic biliary atresia: a first-trimester event? Clues from light microscopy and immunohistochemistry. J Pediatr Surg. 1994;29:808-814. 13. Apte U, Zeng G, Thompson MD, et al. Beta-Catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1578-G1585. 14. Crosnier C, Attié-Bitach T, Encha-Razavi F, et al. JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology. 2000;32: 574-581. 15. Davenport M, Savage M, Mowat AP, Howard ER. Biliary atresia splenic malformation syndrome: an etiologic and prognostic subgroup. Surgery. 1993;113:662-668. 16. Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics. 2011;128(6):e1428-e1433.

17. Howard ER, Davenport M. Congenital extrahepatic portocaval shunts—the Abernethy malformation. J Pediatr Surg. 1997;32: 494-497. 18. Tyraskis A, Deganello A, Sellars M, et al. Portal venous deprivation in patients with portosystemic shunts and its effect on liver tumors. J Pediatr Surg. 2020;55:651-654. 19. Jennings RE, Berry AA, Strutt JP, et al. Human pancreas development. Development. 2015;142:3126-3137. 20. Larsen HL, Grapin-Botton A. The molecular and morphogenetic basis of pancreas organogenesis. Semin Cell Dev Biol. 2017;66:51-68. 21. Cras-Meneur C, Lin L, Kopan R, Permutt MA. Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window. Genes Dev. 2009;23:2088-2101. 22. Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature. 1999;400:877-881. 23. El-Gohary Y, Tulachan S, Guo P, et al. Smad signalling pathways regulate pancreatic endocrine development. Dev Biol. 2013;378: 83-93. 24. El-Gohary Y, Tulachan S, Wiersch J, et al. A smad signalling network regulates islet cell proliferation. Diabetes. 2014;63:224-236. 25. Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA. 2000;97:1607-1611. 26. Johansson KA, Dursun U, Jordan N, et al. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell. 2007;12:457-465. 27. Thorel F, Népote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464:1149-1154. 28. Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138:449-462. 29. Piccand J, Strasser P, Hodson DJ et al. Rfx6 Maintains the functional identity of adult pancreatic beta cells. Cell Rep. 2014;9:2219-2232. 30. Chiang MK, Melton D. Single-cell transcript analysis of pancreas development. Dev Cell. 2003;4:383-393. 31. Sussel L, Kalamaras J, Hartigan-O’Connor DJ, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 1998;125(12):2213-2221. 32. St-Onge L, Sosa-Pineda B, Chowdhury K, et al. Pax6 is required for differentiation of glucagon-producing a-cells in mouse pancreas. Nature. 1997:387;406-409. 33. Kamisawa T, Tu Y, Nakajima H, Egawa N, Tsuruta K, Okamoto A. The presence of a common channel and associated pancreaticobiliary diseases: a prospective ERCP study. Dig Liver Dis. 2007;39: 173-179.

CHAPTER 2 Surgical and radiologic anatomy of the liver, biliary tract, and pancreas Ronald P. DeMatteo* ANATOMY OVERVIEW Precise knowledge of the architecture of the liver, biliary tract, and pancreas and the related blood vessels and lymphatic drainage is essential for the successful performance of hepatopancreaticobiliary surgical operations.

LIVER The liver lies protected under the lower ribs, closely applied to the undersurface of the diaphragm and on top of the inferior vena cava (IVC) posteriorly (Fig. 2.1). Most of the liver bulk lies to the right of the midline, where the lower border lies near the right costal margin. The liver extends as a wedge to the left of the midline, between the anterior surface of the stomach and the left dome of the diaphragm. The upper surface is boldly convex and molded to the diaphragm, and the surface projection on the anterior body wall extends up to the fourth intercostal space on the right and to the fifth intercostal space on the left. The convexity of the upper surface slopes down to a posterior surface that is triangular in outline. The liver is invested with peritoneum except on the posterior surface, where the peritoneum reflects onto the diaphragm, forming the right and left triangular ligaments. The undersurface of the liver is concave and extends down to a sharp anterior border. The posterior surface of the liver is triangular in outline with its base to the right, and here the liver lying between the upper and lower “leaves” of the triangular ligaments is bare and devoid of peritoneum. The peritoneum reflects onto the right posterior liver from the medial aspect of Gerota’s fascia, which is associated with the right kidney. The right adrenal gland lies beneath this reflection. The anterior border of the liver lies under cover of the right costal margin, lateral to the right rectus abdominis muscle, but it slopes upward to the left across the epigastrium. Anteriorly, the convex surface of the liver lies against the concavity of the diaphragm and is attached to it by the falciform ligament, left triangular ligament, and upper layer of the right triangular ligament.

Retrohepatic Inferior Vena Cava The IVC runs to the right of the aorta on the bodies of the lumbar vertebrae, diverging from the aorta as it passes upward. Below the liver, the IVC lies behind the duodenum and head of the pancreas as a retroperitoneal structure passing upward behind the foramen of Winslow posterior to the right hilar structures of the liver. The renal veins lie in front of the arteries and

join the IVC at almost a right angle on the left and obliquely on the right. The IVC is embraced in a groove on the posterior surface of the liver. The IVC comes to lie on the right crus of the diaphragm, behind the bare area of the liver; it extends to the central tendon of the diaphragm, which it pierces on a level with the body of T8, behind and higher than the beginning of the abdominal aorta. While the IVC courses upward, it is separated from the right crus of the diaphragm by the right celiac ganglion and, higher up, by the right phrenic artery. The right adrenal vein is a short vessel that enters the IVC behind the bare area. There may be a small accessory right adrenal vein on the right that enters into the confluence of the right renal vein and the IVC. Also, occasionally, a right adrenal vein drains directly into the posterior liver. The lumbar veins drain posterolaterally into the IVC below the level of the renal veins, but above this level, there are usually no vena caval tributaries posteriorly.

Hepatic Veins The hepatic veins (Figs. 2.2–2.4) drain directly from the upper part of the posterior surface of the liver at an oblique angle directly into the vena cava. The right hepatic vein, which is larger than the left and middle hepatic veins, has a short extrahepatic course of approximately 1 to 2 cm. The left and middle hepatic veins may drain separately into the IVC but are usually joined, after a short extrahepatic course, to form a common venous channel approximately 2 cm in length that traverses to the left part of the anterior surface of the IVC below the diaphragm. In addition to the three major hepatic veins, there is the umbilical vein, which is single in most patients and runs beneath the falciform ligament between the middle and left hepatic veins; it empties into the terminal portion of the left hepatic vein, although, rarely, it drains into the middle hepatic vein or directly into the confluence of the middle and left hepatic veins. This should not be confused for the umbilical vein from fetal circulation. In approximately 15% of patients, an accessory right hepatic vein is present inferiorly (see Fig. 2.3). Hepatic venous drainage of the caudate lobe is directly into the IVC, as described later. This classic description of the anatomy of the liver is sufficient for gross appreciation and for mobilization of the liver to allow access for repair of injuries, liver transplantation, or the placement of probes onto or into the liver substance. Hidden beneath this external gross appearance is a detailed internal anatomy, an understanding of which is essential to the performance of precise hepatectomy. This internal anatomy has been called the functional anatomy of the liver.

Functional Surgical Anatomy * The authors acknowledge Dr. Lucy E. Hann who coauthored this chapter in the fifth edition of this book. Much of her initial contribution is included here.

The internal architecture of the liver is composed of a series of segments that combine to form sectors separated by scissurae 27

28

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY Gallbladder

Quadrate lobe Umbilical fissure

Left lobe Right lobe

Gallbladder

Caudate lobe

A

B

Left triangular ligament

Lumen of MHV and LHV LHV

IVC Lumen of RHV Right lobe

Left lobe Right adrenal vein Right triangular ligament

Ligamentum venosum

Ligamentum teres LEFT LOBE

RIGHT LOBE

C FIGURE 2.1  A, The liver as seen in situ has two main lobes, a large right and a smaller left, and conventional description places their line of fusion on the upper surface of the liver along the attachment of the falciform ligament at the inferior extent of which the ligamentum teres enters the umbilical fissure. B, With the liver flipped upward, the inferior surface of the right lobe is seen as the transverse hilar fissure, which constitutes the posterior limit of this lobe. The portion of the right lobe located anterior to the fissure is called the quadrate lobe, which is limited on the left by the umbilical fissure and on the right by the gallbladder fossa. Posterior to the hilar transverse fissure is a fourth lobe, the caudate lobe, which hugs the inferior vena cava (IVC) and extends upward on its left side. Thus the liver comprises two main lobes and two smaller lobes, separated by visible, well-defined fissures on the liver surface. C, The posterior aspect of the liver is shown. The IVC lies snugly in a deep groove within the bare area; the hepatic veins open directly into it. Within this bare area, the right suprarenal gland lies adjacent to the IVC, and the adrenal vein drains into the right of the IVC. The remainder of the bare area of liver is directly in contact with the diaphragm. To the left of the IVC, the caudate lobe slopes upward from the inferior to the posterior surface of the liver and is demarcated on the left by a fissure, within which lies the ligamentum venosum. The gastrohepatic omentum is attached to the ligamentum venosum, placing the caudate lobe within the lesser sac of the peritoneum. The left lobe of the liver is situated anteriorly in the supracolic compartment of the peritoneal cavity. The posterior surface of the left lobe is narrow; there is a very fine bare area on this side. While the vena cava traverses upward in the groove on the posterior surface of the liver, it is shielded on the right side by a layer of fibrous tissue that passes from the posterior edge of the liver backward toward the lumbar vertebrae and fans out posteriorly, especially in the upper part. Behind the IVC, a prolongation of this fibrous layer joins a less marked fibrous extension from the lateral edge of the caudate lobe. This layer of fibrous tissue, sometimes called the ligament of the vena cava, must be divided on the right, to allow surgical exposure of the IVC and the right hepatic vein, and on the left, to allow mobilization of the caudate lobe. Occasionally, the liver tissue embraces the vena cava completely, so that it runs within a tunnel of parenchyma. LHV, Left hepatic vein; MHV, middle hepatic vein; RHV, right hepatic vein.

that contain the hepatic veins (Fig. 2.5), as described by Couinaud (1957).1 Together or separately, these constitute the visible lobes described previously. The internal structure has been clarified by the publications of McIndoe and Counseller (1927),2 Ton That Tung (1939, 1979),3,4 Hjörtsjö (1931),5 Healey and Schroy (1953),6 Goldsmith and Woodburne (1957),7 Couinaud (1957),1 and Bismuth and colleagues (1982).8 Essentially, the three main hepatic veins within the scissurae divide the liver into four sectors, each of which receives a portal pedicle. The main portal scissura contains the middle hepatic vein and progresses from the middle of the gallbladder bed anteriorly to the left of

the vena cava posteriorly. The right and left parts of the liver, demarcated by the main portal scissura, are independent in terms of portal and arterial vascularization and biliary drainage (Fig. 2.6). These right and left livers are themselves divided into two by the remaining portal scissurae. These four subdivisions are referred to as segments in the description of Goldsmith and Woodburne (1957),7 but in Couinaud’s nomenclature (1957),1 they are termed sectors. The right portal scissura separates the right liver into two sectors: anteromedial (anterior) and posterolateral (posterior). With the body supine, this scissura is almost in the frontal

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

M L

R IVC

FIGURE 2.2  Transverse ultrasound image of the hepatic vein confluence shows the left (L), middle (M), and right (R) hepatic veins as they join the inferior vena cava (IVC).

29

plane. The right hepatic vein runs within the right scissura. The left portal scissura divides the left liver into two sectors, but the left portal scissura is not within the umbilical fissure because this fissure is not a portal scissura, and instead it contains a portal pedicle. The left portal scissura is located posterior to the ligamentum teres and within the left liver, along the course of the left hepatic vein. Although the description by Couinaud has been used widely, it is being replaced by an alternative terminology suggested by a committee of the International Hepato-Pancreatico-Biliary Association in 2000.9 The main difference is that, in the alternative terminology, Couinaud’s sectors are now referred to as sections (Table 2.1; see Chapter 103B for differences in the terminology of the various hepatic resections). Also, note that the left medial section, in the terminology of Strasberg (2005),9 is composed of one segment (i.e., segment IV). At the hilum of the liver, the right portal triad pursues a short course of approximately 1 to 1.5 cm before entering the substance of the right liver (Fig. 2.7). In some cases, the right anterior and posterior pedicles arise independently, and their origins may be separated by 2 cm. In some cases, it appears as if the left portal vein arises from the right anterior branch

M

M IVC R

R

A

IVC

B

R PV

IVC A

IVC

C

D

FIGURE 2.3  Two inferior accessory right hepatic veins. A, Contrast-enhanced computed tomographic (CT) image of the hepatic vein confluence. B, A small right inferior accessory vein (arrow) enters the IVC below the hepatic venous confluence. C, The second, larger right inferior accessory right hepatic vein (arrow) is seen more inferiorly. D, CT coronal reconstruction image shows the right hepatic vein (R) and one right inferior accessory vein (arrow). A, Aorta; IVC, inferior vena cava; M, middle hepatic vein; PV, portal vein; R, right hepatic vein.

30

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

VII VIII II I

V

III IV VI

FIGURE 2.4  The anterior surfaces of the major extrahepatic veins and the inferior vena cava are retroperitoneal and masked behind the layers of the falciform ligament, while it splits and passes to the right and left triangular ligaments. The left and middle hepatic veins usually join within the liver and not outside the liver as depicted here for visual simplicity.

A

II VIII VII RIGHT SCISSURA

MAIN SCISSURA

III

LEFT SCISSURA IV V

VI

B FIGURE 2.6  The functional division of the liver and its segments according to Couinaud’s nomenclature. A, As seen in the patient. B, In the ex vivo position.

Right portal pedicle RIGHT

Left portal pedicle LIVER

Umbilical fissure

LEFT

FIGURE 2.5  The portal vein, hepatic artery, and draining bile ducts are distributed within the liver in a beautifully symmetric pedicular pattern, which belies the asymmetric external appearance. Each segment (I to VIII) is supplied by a portal triad composed of a branch of the portal vein and hepatic artery and drained by a tributary of the right or left main hepatic ducts. The four sectors demarcated by the three main hepatic veins are called the portal sectors (now referred to as sections in the Brisbane terminology); these portions of parenchyma are supplied by independent portal pedicles. The hepatic veins run between the sectors in the portal scissurae; the scissurae containing portal pedicles are called the hepatic scissurae. The umbilical fissure corresponds to a hepatic scissura. The internal architecture of the liver consists of two hemilivers, the right and the left liver separated by the main portal scissura, also known as Cantlie’s line. It is preferable to call them the right and left liver rather than the right and left lobes because the latter nomenclature is erroneous; there is no visible mark that permits identification of a true hemiliver.

TABLE 2.1  Brisbane Terminology of Liver Anatomy and Resections COUINAUD SEGMENTS

SURGICAL RESECTION

Right hemiliver/right liver Left hemiliver/left liver Right anterior section Right posterior section Left medial section

5–8

Right hepatectomy

2–4 5, 8 6, 7 4

Left lateral section

2, 3

Left hepatectomy Right anterior sectionectomy Right posterior sectionectomy Left medial sectionectomy or Resection of segment 4 Left lateral sectionectomy or Bisectionectomy 2, 3 Right trisectionectomy or Extended right hepatectomy Left trisectionectomy or Extended left hepatectomy

ANATOMIC TERM

4, 5, 6, 7, 8 2, 3, 4, 5, 8

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

31

3

4

RAPV LPV

U 2

RPPV MPV

p

IVC IVC

A

FIGURE 2.8  Transverse sonogram shows the branching pattern of the left portal vein (P), which courses horizontally and into the umbilical fissure. The umbilical portion of the left portal vein (U) gives branches to the left hepatic segments (2 to 4). The left hepatic vein (arrow) and inferior vena cava (IVC) also are shown.

B FIGURE 2.7  A, Transverse sonogram at the level of the portal vein bifurcation. The main portal vein (MPV) bifurcates into the left and right portal veins (LPV and RPV). The RPV bifurcates shortly into the right anterior (RAPV) and right posterior (RPPV) branches, but the LPV has a longer horizontal course within the hilar plate. The inferior vena cava (IVC) is seen posteriorly. B, Coronal view of computed tomographic angioportography. Reconstruction shows the right hepatic vein (open arrow) and the portal vein (large arrow); anterior and posterior sectional branches of the RPV (small arrows) are seen to arise directly and separately from the main portal trunk.

(see Fig. 2.40). On the left side, however, the portal triad crosses over approximately 3 to 4 cm beneath segment IV (formerly called the quadrate lobe), embraced in a peritoneal sheath at the upper end of the gastrohepatic ligament and separated from the undersurface of segment IV by connective tissue (hilar plate). This prolongation of the left portal pedicle turns anteriorly and caudally within the umbilical fissure, giving branches of supply to segment II first and then segment III and recurrent branches (“feedback vessels”) to segment IV (Fig. 2.8; see Fig. 2.6). Beneath segment IV, the pedicle is composed of the left branch of the portal vein and the left hepatic duct, but it is joined at the base of the umbilical fissure by the left branch of the hepatic artery. The branching of the portal pedicle at the hilum (Fig. 2.9), the distribution of the branches to the caudate lobe (segment I) on the right and left sides, and the distribution to the segments of the right (segments V through VIII) and left (segments II through IV) hemiliver follow a remarkably

L

R

RA

RP

FIGURE 2.9  Contrast-enhanced computed tomographic image of the portal vein bifurcation. L, Left portal vein; R, right portal vein; RA, right anterior portal vein; RP, right posterior portal vein.

symmetric pattern and, as described by Scheele (1994),10 allow for the separation of segment IV into segment IVa superiorly and segment IVb inferiorly (see Fig. 2.6). This arrangement of subsegments mimics the distribution to segments V and VIII on the right side. The umbilical vein provides drainage of at least parts of segment IVb after

32

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

IVC MHV LHV II/III

p IVC

Ligamentum venosum

a

RPV FIGURE 2.10  Contrast-enhanced computed tomographic scan of the liver shows the intimate relationship of the caudate lobe (arrow), inferior vena cava (IVC), portal vein (p), and aorta (a).

MHV

Ligamentum venosum

II/III

IV

LPV Lesser omentum

VII IVC

PV

IVC

LPV

FIGURE 2.12  The caudate lobe (shaded) and segments II and III, rotated to the patient’s right. Superiorly, the left portion of the caudate lobe is linked by a deep anterior portion, embedded in the parenchyma immediately under the middle hepatic vein (MHV), reaching inferiorly to the posterior margin of the hilus of the liver and fusing anterolaterally to the inferior vena cava (IVC) on the right side to segments VI and VII of the right liver. The major blood supply arises from the left branch of the left portal vein (LPV) and the left hepatic artery, close to the base of the umbilical fissure of the liver. The hepatic veins (MHV, LHV) are short in course and drain from the caudate directly into the anterior and left aspect of the vena cava. LHV, Left hepatic vein; PV, main trunk of portal vein; RPV, right portal vein;

I

FIGURE 2.11  The main bulk of the caudate lobe (segment I; dark area) lies to the left of the inferior vena cava (IVC); the left and inferior margins are free in the lesser omental bursa. The gastrohepatic (lesser) omentum separates the left portion of the caudate from segments II and III of the liver, while it passes between them to be attached to the ligamentum venosum. The left portion of the caudate lobe inferiorly traverses to the right between the left portal vein (LPV) and IVC as the caudate process, where it fuses with the right lobe of the liver. Note the position of the middle hepatic vein (MHV).

ligation of the middle hepatic vein, and it is important in the performance of segmental resections. The caudate or segment I is the dorsal portion of the liver lying posteriorly; it embraces the retrohepatic IVC (Figs. 2.10 and 2.11). The caudate is intimately related to several major vascular structures. On the left, the caudate lies between the IVC posteriorly and the left portal triad inferiorly and the IVC and the middle and left hepatic veins superiorly (Fig. 2.12). The portion of the caudate on the right varies but is usually quite small. The anterior surface within the parenchyma is covered by the posterior surface of segment IV, the limit being an oblique plane slanting from the left portal vein to the left hepatic vein. Thus there is a caudate lobe with a constantly present left portion and a right portion of variable size. This portion of the caudate on the right is adjacent to the recently

described segment IX, which lies between it and segment XIII. The authors find segment IX of little practical clinical significance. The caudate is supplied by blood vessels and drained by biliary tributaries from the right and left portal triad. Small vessels from the portal vein and tributaries joining the biliary ducts also are found. The right portion of the caudate, including the caudate process, predominantly receives portal venous blood from the right portal vein or from the bifurcation of the main portal vein, whereas on the left side, the portal supply arises from the left branch of the portal vein almost exclusively. Similarly, the arterial supply and biliary drainage of the right portion is most commonly associated with the right posterior sectional vessels and the left portion with the left main vessels. The hepatic venous drainage of the caudate is unique in that it is the only hepatic segment that drains directly into the IVC. These veins can sometimes drain into the posterior aspect of the vena cava if a significant retrocaval caudate component is present. In the most common circumstance, the posterior edge of the caudate lobe on the left has a fibrous component, which fans out and attaches lightly to the crural area of the diaphragm, but it extends posteriorly, behind the vena cava, to link with a similar component of fibrous tissue (called the venal caval ligament) that protrudes from the posterior surface of segment VII and embraces the vena cava (see Figs. 2.1C and 2.11). In up to 50% of patients, this ligament is replaced by hepatic tissue, in whole or in part, and the caudate may completely encircle the IVC and may contact segment VII on the right side; a significant

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

retrocaval component may prevent a left-sided approach to the caudate veins. The caudal margin of the caudate lobe can have a papillary projection that occasionally may attach to the rest of the lobe via a narrow connection. It is bulky in 27% of cases and can be mistaken for an enlarged lymph node on computed tomography (CT) scan (Fig. 2.13). To summarize: 1. The liver is divided into two hemilivers by the main hepatic scissura, where the middle hepatic vein runs.

33

2. The left liver is divided into two sections. The Brisbane 2000 nomenclature describes the left lateral section (segments II and III) and the left medial section (segment IV). 3. The right liver is divided into an anterior section (segments V and VIII) and posterior section (segments VI and VII). 4. Segment I, the caudate lobe, lies posteriorly and embraces the IVC, its intraparenchymal anterior surface abutting the posterior surface of segment IV and merging with segments VI and VII on the right (Fig. 2.14; see Fig. 2.11).

IVa II I

VIII

VII

* v

A a

IVb

III

A V

I

VI

B

p

* v

III

IVb

a V

I

VI

B FIGURE 2.13  Computed tomographic image of the caudate lobe with papillary process. A, Caudate lobe (asterisk) positioned between the left portal vein (arrow) and inferior vena cava (v). a, Aorta. B, Papillary process of the caudate (p) represents the lower medial extension of the caudate (asterisk) and may mimic a periportal lymph node (Arrow) indicates left portal vein.

C FIGURE 2.14  Hepatic segmental anatomy as shown by computed tomography at A, the level of the hepatic veins, B, at the portal vein bifurcation, and C, below the hepatic hilus.

34

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Further details of segmental anatomy important in sectional or segmental resection are described in Chapters 101 and 102.

Surgical Implications and Exposure All methods for precise partial hepatectomy depend on control of the inflow vasculature and draining bile ducts and the outflow hepatic veins of the portion of liver to be excised, which may be a segment, a subsegment, or an entire lobe. The remnant remaining after partial hepatectomy must be provided with an excellent portal venous inflow, hepatic arterial supply, and biliary drainage and unimpeded hepatic venous outflow. The classification of the various partial hepatic resection procedures, incisions and exposure, necessary mobilization of the liver, and the methods of control of the structures within the portal triads and of the hepatic veins are described in detail in Chapters 101 and 102.

BILIARY TRACT Biliary exposure and precise dissection are the most important steps in any biliary operative procedure. A thorough understanding of biliary anatomy is necessary.

Intrahepatic Bile Duct Anatomy The right and left livers are drained by the right and the left hepatic ducts, whereas the caudate lobe is drained by several ducts that join both the right and left hepatic ducts. The intrahepatic ducts are tributaries of the corresponding hepatic ducts, which form part of the major portal triads that penetrate the liver, invaginating Glisson capsule at the hilum. Bile ducts usually are located above the corresponding portal branches, whereas hepatic arterial branches are situated inferiorly to the veins. Each branch of the intrahepatic portal veins corresponds to bile duct tributaries that join to form the right and left hepatic ductal systems, converging at the liver hilum to constitute the common hepatic duct. The umbilical fissure divides the left liver, passing between segments III and IV, which may be bridged by a tongue of liver tissue. The ligamentum teres passes through the umbilical fissure to join the left branch of the portal vein. The left hepatic duct drains the three segments—II, III, and IV—that constitute the left liver (Fig. 2.15). The duct that drains segment III is located slightly behind the left horn of the umbilical recess. It is joined by the tributary from segment IVb

II V

VIII

IV

VI III III IV V V II

VII I Right

A

Left

B

Left hepatic duct II VIII VII IV V

III Common hepatic duct

VI

C

Right hepatic duct

Common bile duct

FIGURE 2.15  A, Biliary drainage of the two functional hemilivers. Note the position of the right anterior and right posterior sections. The caudate lobe drains into the right and left ductal system. B, Inferior aspect of the liver. The biliary tract is represented in black, and the portal branches are represented in white. Note the biliary drainage of segment IV (segment VIII is not represented because of its cephalad location). C, T-tube cholangiogram shows the most common arrangement of hepatic ducts.

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

to form the left duct, which is similarly joined by the duct of segment II and the duct of segment IVa, where the left branch of the portal vein turns forward and caudally. The left hepatic duct traverses beneath the left liver at the base of segment IV, just above and behind the left branch of the portal vein; it crosses the anterior edge of that vein and joins the right hepatic duct to constitute the hepatic ductal confluence. In its transverse portion, it receives a few small branches from segment IV. The right hepatic duct drains segments V, VI, VII, and VIII and arises from the junction of two main sectional duct tributaries. The posterior or lateral duct and the anterior or medial duct are each accompanied by a corresponding vein and artery. The right posterior sectional duct has an almost horizontal course and constitutes the confluence of the ducts of segments VI and VII (Fig. 2.16). The duct then runs to join the right anterior sectional duct, as it descends in a vertical manner. The right anterior sectional duct is formed by the confluence of the ducts draining segments V and VIII. Its main trunk is located to the left of the right anterior sectional branch of the portal vein, which pursues an ascending course. The junction of these two main right biliary channels usually occurs above the right branch of the portal vein. The right hepatic duct is short and joins the left hepatic duct to constitute the confluence lying in front of the right portal vein and forming the common hepatic duct.

The caudate lobe (segment I) has its own biliary drainage.6 The caudate lobe is divided into right and left portions and a caudate process. In 44% of individuals, three separate ducts drain these three parts of the lobe, whereas in another 26%, a common duct lies between the right portion of the caudate lobe proper and the caudate process and an independent duct that drains the left part of the caudate lobe. The site of drainage of these ducts varies. In 78% of cases, drainage of the caudate lobe is into the right and left hepatic ducts, but in 15%, drainage is by the left hepatic ductal system only. In about 7%, the drainage is into the right hepatic system.

Extrahepatic Biliary Anatomy and Vascular Anatomy of the Liver and Pancreas The extrahepatic bile ducts are represented by the extrahepatic segments of the right and left hepatic ducts, joining to form the biliary confluence and the main biliary channel draining to the duodenum (Figs. 2.17 and 2.18). The confluence of the right and left hepatic ducts occurs at the right of the hilar fissure of the liver, anterior to the portal venous bifurcation and overlying the origin of the right branch of the portal vein. The extrahepatic segment of the right duct is short, but the left duct has a much longer extrahepatic course. The biliary confluence is separated from the posterior aspect of segment IVB of the liver by the hilar plate, which is the fusion of connective tissue enclosing the biliary and

VIII

A

35

Right posterior sectoral duct

VII Left hepatic duct VI Right anterior sectoral duct V

B FIGURE 2.16  A, Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectional duct and the vertical course of the anterior sectional duct. B, Trans-tubal cholangiogram shows a common normal variant: the right posterior sectional duct drains into the left hepatic duct. In this case, the posterior duct is anterior to the posterior sectional duct. Frequently in this variant, the posterior duct passes posteriorly to the anterior sectional pedicle.

36

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

a

b

c i

j

d

e f

k

g h

FIGURE 2.18  Endoscopic retrograde choledochopancreatogram showing the pancreatic duct (arrow), gallbladder, and biliary tree.

V VII FIGURE 2.17  Anterior aspect of the biliary anatomy and of the head of the pancreas: right hepatic duct (a), left hepatic duct (b), common hepatic duct (c), hepatic artery (d), gastroduodenal artery (e, cystic duct (f), retroduodenal artery (g), common bile duct (h), neck of the gallbladder (i), body of the gallbladder (j), fundus of the gallbladder (k). Note particularly the position of the hepatic bile duct confluence anterior to the right branch of the portal vein, the posterior course of the cystic artery behind the common hepatic duct, and the relationship of the neck of the gallbladder to the right branch of the hepatic artery. Note also the relationship of the major vessels (portal vein, superior mesenteric vein, and superior mesenteric artery) to the head of the pancreas.

vascular elements with the Glisson capsule (Fig. 2.19). Because of the absence of any major vascular interposition, it is possible to open the connective tissue constituting the hilar plate at the inferior border of segment IV and, by elevating it, to display the biliary confluence and left hepatic duct (Fig. 2.20).

VIII C II

VI B IV

III

A

Main Bile Duct and Sphincter of Oddi

FIGURE 2.19  Anatomy of the plate system. A, Cystic plate, above the gallbladder. B, Hilar plate, above the biliary confluence and at the base of segment IV. C, Umbilical plate, above the umbilical portion of the portal vein. Large, curving arrows indicate the plane of dissection of the cystic plate during cholecystectomy and of the hilar plate during approaches to the left hepatic duct.

The main bile duct, the mean diameter of which is approximately 6 mm, is divided into two portions: the upper is called the common hepatic duct and is situated above the cystic duct, which joins it to form the lower portion, the common bile duct (CBD). Insertion of the cystic is variable and may be as low as the intrapancreatic portion of the bile duct. The common duct courses downward anterior to the portal vein, in the free edge of the lesser omentum; it is closely applied to the hepatic artery, which runs upward on its left, giving rise to the right branch of the hepatic artery, which crosses the main bile duct usually posteriorly, although in approximately 20% of cases, it crosses anteriorly. The cystic artery, arising from

the right branch of the hepatic artery, may cross the common hepatic duct posteriorly or anteriorly. The common hepatic duct constitutes the left border of the triangle of Calot, the other corners of which were originally described as the cystic duct below and the cystic artery above.11 The commonly accepted working definition of the triangle of Calot recognizes, however, the inferior surface of the right lobe of the liver as the upper border and the cystic duct as the lower border.12 Dissection of the triangle of Calot is of key significance during cholecystectomy because in this triangle runs the cystic artery,

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

A

37

B

Umbilical fissure

Ligamentum teres Gallbladder fossa

C FIGURE 2.20  A, Relationship between the posterior aspect of segment IV and the biliary confluence. The hilar plate (arrow) is formed by the fusion of the connective tissue enclosing the biliary and vascular elements with the Glisson capsule. B, Biliary confluence and left hepatic duct exposed by lifting segment IV upward after incision of the Glisson capsule at its base. This technique, lowering of the hilar plate, generally is used to display a dilated bile duct above an iatrogenic stricture or hilar cholangiocarcinoma. C, Line of incision (left) to allow extensive mobilization of segment IV. This maneuver is of particular value for high bile duct strictures and in the presence of liver atrophy or hypertrophy. The procedure consists of lifting segment IV upward (A and B), then not only opening the umbilical fissure but also incising the deepest portion of the gallbladder fossa. Right, Incision of the Glisson capsule to gain access to the biliary system (arrow). (B, From Hepp J, Couinaud C. L’abord et l’utilisation du canal hépatique gauche dans les reparations de la voie biliare principale. Presse Med. 1956;64:947–948.)

often the right branch of the hepatic artery, and occasionally a bile duct, which should be displayed before cholecystectomy (see Chapter 36). If there is a replaced or accessory common or right hepatic artery, it usually runs behind the cystic duct to enter the triangle of Calot (Fig. 2.21). The common variations in the relationship of the hepatic artery and origin and course of the cystic artery to the biliary apparatus are shown in Fig. 2.22. Ignorance of these variations may provoke unexpected hemorrhage or biliary injury13 during cholecystectomy and may result in bile duct injury during efforts to secure hemostasis (see Chapter 42). The union between the cystic duct and the common hepatic duct may be located at various levels. At its lower extrahepatic portion, the CBD traverses the posterior aspect of the pancreas, running in a groove or tunnel. The retropancreatic portion of the CBD approaches the second portion of the duodenum obliquely,

accompanied by the terminal part of the pancreatic duct of Wirsung.

Gallbladder and Cystic Duct The gallbladder is a reservoir located on the undersurface of the right lobe of the liver, within the cystic fossa; it is separated from the hepatic parenchyma by the cystic plate, which is composed of connective tissue that extends to the left as the hilar plate (see Fig. 2.19). Sometimes the gallbladder is deeply embedded in the liver, but occasionally it occurs on a mesenteric attachment and may be susceptible to volvulus. The gallbladder varies in size and consists of a fundus, a body, and a neck (Fig. 2.23). The fundus usually, but not always, reaches the free edge of the liver and is closely applied to the cystic plate. The cystic fossa is a precise anterior landmark to the main liver incisura. The neck of the gallbladder makes an angle with the

38

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A

B CBD

HA

CD

Replaced or accessory RHA

C FIGURE 2.21  Hepatic artery variations shown by angiography. A, Replaced common hepatic artery arises from the superior mesenteric trunk. B, Left, The hepatic artery (large arrowhead) arises from the celiac axis. The small arrowheads indicate a drainage catheter in the bile duct. Right, An accessory right hepatic artery (large arrowhead) is arising from the superior mesenteric artery and lies lateral to the catheter (small arrowheads) in the common bile duct (CBD). C, The accessory right hepatic artery usually courses upward in the groove posterolateral to the CBD, appearing on the medial side of the triangle of Calot, usually running just behind the cystic duct (CD). This common variation occurs in about 25% of individuals. HA, Hepatic artery; RHA, right hepatic artery.

fundus and creates Hartmann’s pouch, which may obscure the common hepatic duct and constitute a real danger point during cholecystectomy. The cystic duct arises from the neck or infundibulum of the gallbladder and extends to join the common hepatic duct. Its lumen usually measures approximately 1 to 3 mm, and its length varies, depending on the type of union with the common hepatic duct. The mucosa of the cystic duct is arranged in spiral folds known as the valves of Heister.12 Although the cystic duct joins the common hepatic duct in its supraduodenal segment in 80% of cases, it may extend downward to the retroduodenal or retropancreatic area. Rarely, the cystic duct may join the right hepatic duct or a right hepatic sectional duct (Fig. 2.24).

BILIARY DUCTAL ANOMALIES Full knowledge of the frequent variations from the described normal biliary anatomy is required when any hepatobiliary procedure is performed (Fig. 2.25). The constitution of a normal biliary confluence by union of the right and left hepatic ducts, as described previously, is reported in only 72% of patients.6 There is a triple confluence of the right anterior and posterior sectional ducts and the left hepatic duct in 12% of individuals,1 and a right sectional duct joins the main bile duct directly in 20%. In 16% the right anterior sectional duct, and in 4% the right posterior sectional duct, may approach the main bile duct in this fashion. In 6%, a right sectional duct may join the left hepatic duct (the posterior duct in 5% and the

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

a

b

c

d

e

f

g

39

h

FIGURE 2.22  The main variations of the cystic artery: typical course (a), double cystic artery (b), cystic artery crossing anterior to main bile duct (c), cystic artery originating from the right branch of the hepatic artery and crossing the common hepatic duct anteriorly (d), cystic artery originating from the left branch of the hepatic artery (e), cystic artery originating from the gastroduodenal artery (f), cystic artery arising from the celiac axis (g), and cystic artery originating from a replaced right hepatic artery (h).

A

GB PV IVC

FIGURE 2.23  Longitudinal sonogram shows the relationship of the liver, gallbladder (GB), portal vein (PV), inferior vena cava (IVC), hepatic artery (curved arrow), and common bile duct (straight arrow).

anterior duct in 1%). In 3%, there is an absence of the hepatic duct confluence, and the right posterior sectional duct may join the neck of the gallbladder, or it may be entered by the cystic duct in 2%.1 In any event, these multiple biliary ductal variations at the hilus are important to recognize in resection and reconstructive surgery of the biliary tree at the hilus and during partial hepatectomy and cholecystectomy.

B FIGURE 2.24  A, T-tube cholangiogram shows a very low insertion of a right sectional duct into the common hepatic duct (arrow). B, Endoscopic retrograde choledochopancreatogram shows a low right sectional duct (large arrow) into which is draining the cystic duct (small arrow), an uncommon but important normal variant.

40

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY ra

ra

rp

A

lh

lh

rp

B

57%

12%

ra

ra

lh

rp

lh rp

C

20%

16% 16%

C1

ra rp

rp

D

lh

lh

6% 1%

5% D1

D2 III

IV

III

IV

ra

ra

rp II

E

ANOMALIES OF THE GALLBLADDER AND CYSTIC DUCT

4% C2

ra

II

rp

I

3%

I

2%

1%

E1

E2 ra rp lh

F

occur during cholecystectomy if the cystic plate is not preserved. This may lead to a postoperative biliary leak. In 67% of patients,6 a classic distribution of the main left intrahepatic biliary ductal system exists. The main variation in this region is represented by a common union between the ducts of segments III and IV in 25%, and in only 2% does the duct of segment IV join the common hepatic duct independently. Several anomalies of drainage of the intrahepatic ducts into the neck of the gallbladder or cystic duct have been reported (Fig. 2.27),1,14 and these must be kept in mind during cholecystectomy (see Chapter 33).

2%

FIGURE 2.25  Main variations of the hepatic duct confluence. A, Typical anatomy of the confluence. B, Triple confluence. C, Ectopic drainage of a right sectional duct into the common hepatic duct. D, Ectopic drainage of a right sectional duct into the left hepatic ductal system. E, Absence of the hepatic duct confluence. F, Absence of right hepatic duct and ectopic drainage of the right posterior duct into the cystic duct. C1, Right anterior (ra) duct draining into the common hepatic duct; C2, right posterior (rp) duct draining into the common hepatic duct; D1, Right posterior sectional duct draining into the left hepatic (lh) ductal system; D2, right anterior sectional duct draining into the left hepatic ductal system. (From Couinaud C. Le Foi: Études Anatomiques et Chirurgicales. Masson; 1957.)

Intrahepatic bile duct variations also are common (Fig. 2.26).6 The main right intrahepatic duct variations are represented by an ectopic drainage of segment V in 9%, of segment VI in 14%, and of segment VIII in 20%. In addition, a subvesical duct has been described in 20% to 50% of cases. This duct, sometimes deeply embedded in the cystic plate, joins either the common hepatic duct or the right hepatic duct. It does not drain any specific liver territory, never communicates with the gallbladder, and is not a satellite of an intrahepatic branch of the portal vein or hepatic artery. Although not of major anatomic significance, injury may

Many anomalies of the accessory biliary apparatus have been described (Fig. 2.28).15 Although rare, agenesis of the gallbladder,16-18 bilobar gallbladders with a single cystic duct but two fundi,19 and duplication of the gallbladder with two cystic ducts all have been described. A double cystic duct may drain a unilocular gallbladder,20 and congenital diverticulum of the gallbladder with a muscular wall may also be found.21 More frequently reported are anomalies of position of the gallbladder, which may be in an intrahepatic position, completely surrounded by normal liver tissue, or rarely may be found on the left of the liver.22 The mode of union of the cystic duct with the common hepatic duct may be angular, parallel, or spiral. An angular union is the most frequent and is found in 75% of patients.23 The cystic duct may run a parallel course to the common hepatic duct in 20%, with connective tissue ensheathing both ducts. Finally, the cystic duct may approach the CBD in a spiral fashion. The absence of a cystic duct is probably an acquired anomaly, representing a cholecystocholedochal fistula.

BILE DUCT BLOOD SUPPLY The bile duct may be divided into three segments: hilar, supraduodenal, and retropancreatic. The blood supply of the supraduodenal duct is essentially axial (Fig. 2.29).24 Most vessels to the supraduodenal duct arise from the superior pancreaticoduodenal artery, right branch of the hepatic artery, cystic artery, gastroduodenal artery, and retroduodenal artery. On average, eight small arteries, each measuring approximately 0.3 mm in diameter, supply the supraduodenal duct. The most important of these vessels run along the lateral and medial borders of the duct and have been called the 3 o’clock and 9 o’clock arteries. Of the blood vessels vascularizing the supraduodenal duct, 60% run upward from the major inferior vessels, and only 38% of arteries run downward, originating from the right branch of the hepatic artery and other vessels. Only 2% of the arterial supply is nonaxial, arising directly from the main trunk of the hepatic artery as it courses up parallel to the main biliary channel. The hilar ducts receive a copious supply of arterial blood from surrounding vessels, forming a rich network on the surface of the ducts in continuity with the plexus around the supraduodenal duct. The source of blood supply to the retropancreatic CBD is from the retroduodenal artery, which provides multiple small vessels running around the duct to form a mural plexus. The veins draining the bile ducts are satellites to the corresponding described arteries, draining into 3 o’clock and

41

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas VIII A

VII

seg V

VI

D

seg IV

a

67%

b 1%

91% VII

VIII

VII VI

II

II VIII

III

III c 1%

VI

II

4%

5%

III VII B

d 25%

seg VI

VIII

VII

VII VIII

VIII V

II

86%

V VII

e 1%

II

III

VIII

10% V

f 1% V

2%

III II

2% III

VII

VII VI

g 4% VI

V C

II

80%

seg VIII

V

20% III

FIGURE 2.26  The main variations of the intrahepatic ductal system. A, Variations of segment V. B, Variations of segment VI. C, Variations of segment VIII. D, Variations of segment IV. There is no variation of drainage of segments II, III, and VII. seg, Segment.

9 o’clock veins along the borders of the common biliary channel. Veins draining the gallbladder empty into this venous system, not directly into the portal vein, and the biliary tree seems to have its own portal venous pathway to the liver.

VI

A

B

C

RP

Biliary-Vascular Sheaths and Exposure of the Hepatic Bile Duct Confluence

D RP

E

ANATOMY OF BILIARY EXPOSURE

F

FIGURE 2.27  The main variations of ectopic drainage of the intrahepatic ducts into the gallbladder and cystic duct. A, Drainage of the cystic duct into the biliary confluence. B, Drainage of cystic duct into the left hepatic duct, associated with no biliary confluence. C, Drainage of segment VI duct into the cystic duct. D, Drainage of the right posterior (RP) sectional duct into the cystic duct. E, Drainage of the distal part of the right posterior sectional duct into the neck of the gallbladder. F, Drainage of the proximal part of the right posterior sectional duct into the body of the gallbladder.

Fusion of the Glisson capsule with the connective tissue sheaths surrounding the biliary and vascular elements at the inferior aspect of the liver constitute the plate system (see Figs. 2.19 and 2.20), which includes the hilar plate above the biliary confluence, the cystic plate related to the gallbladder, and the umbilical plate situated above the umbilical portion of the left portal vein.1 Hepp and Couinaud25 describe a technique whereby lifting segment IV upward and incising the Glisson capsule at its base offers good exposure of the hepatic hilar structures (see Fig. 2.20). This technique is referred to as lowering of the hilar plate. It can be carried out safely because only exceptionally (in 1% of cases) is there any major vascular interposition between the hilar plate and the inferior aspect of the liver, although tiny venules are common. This maneuver is of particular value in exposing the extrahepatic segment of the left hepatic duct because it has a long course beneath segment IV (see Chapter 42). It is not as effective in exposing the extrahepatic right duct or its secondary branches, which are short. The technique is of major

42

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A

1

2

3 d

C

a

B

e 1

1

2

b

f g

D

c

1

h

2

E 75% a

20% b

5% c

FIGURE 2.28  Main variations in gallbladder and cystic duct anatomy. A, Duplicated gallbladder. B, Septum of the gallbladder. C, Diverticulum of the gallbladder. D, Variations in cystic ductal anatomy. E, Different types of union of the cystic duct and common hepatic duct: angular union (a), parallel union (b), spiral union (c).

importance for the identification of proximal biliary mucosa during bile duct repair after injury. Basically, an incision is made at the posterior edge of segment IV, where the Glisson capsule is attached to the hilar plate. The upper surface of the hilar plate can be separated from the hepatic parenchyma and, by lifting segment IV upward, display the hepatic duct convergence, which is always extrahepatic. Bile duct incision allows performance of a mucosa-to-mucosa anastomosis (see Chapters 32 and 42). Rarely, it may be hazardous to approach the biliary confluence in this manner, especially when anatomic deformity has been created by atrophy or hypertrophy of liver lobes and in patients in whom there appears to be a very deep hilum that is displaced upward and rotated laterally. Frequently, by a simultaneous opening of the deepest portion of the gallbladder fossa and the umbilical fissure (see Fig. 2.20C), good exposure of the biliary duct confluence, and especially the right hepatic duct, can be obtained without the necessity for full hepatotomy.

Umbilical Fissure and Segment III (Ligamentum Teres) Approach The round ligament, which is the remnant of the obliterated umbilical vein, runs through the umbilical fissure to connect with the left branch of the portal vein. The round ligament is

FIGURE 2.29  The bile duct blood supply. Note the axial arrangement of the vasculature of the supraduodenal portion of the main bile duct and the rich network enclosing the right and left hepatic ducts: right branch of the hepatic artery (a), 9 o’clock artery (b), retroduodenal artery (c), left branch of the hepatic artery (d), hepatic artery (e), 3 o’clock artery (f), common hepatic artery (g), and gastroduodenal artery (h).

sometimes deeply embedded in the umbilical fissure. At the junction of the round ligament and the termination of the left portal vein, elongations containing channels that are elements of the left portal system course into the liver. The bile ducts of the left lobe of the liver (Figs. 2.30 and 2.31A) are located above the left branch of the portal vein and lie behind these elongations, whereas the corresponding artery is situated below the vein. Dissection of the round ligament on its left side and division of one or two vascular elongations of segment III allow display of the pedicle or anterior branch of the duct of segment III (Fig. 2.32). In the event of biliary obstruction with intrahepatic biliary ductal dilation, a dilated segment III duct is generally easily located above the left branch of the portal vein. It is often preferable to split the normal liver tissue just to the left of the umbilical fissure to widen the fissure further, which allows access to the ductal system with no need to divide any elements of the portal blood supply to segment III (see Fig. 2.32; see also Chapters 32 and 42).

Surgical Approaches to the Right Hepatic Biliary Ductal System Because of the lack of precise anatomic landmarks, exposure of the right intrahepatic ductal system is much more hazardous and imprecise than that of the left. In some cases of hilar cholangiocarcinoma, the planned surgical procedure—partial hepatectomy

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

43

the right branch of the portal vein, is opened through a short distance. The anterior sectional duct is displayed on the left aspect of the vein, and the dilated duct is opened longitudinally and sewn to a Roux-en-Y loop of jejunum (Fig. 2.33). Although this technique is rarely used, it may be valuable in selected cases. Preferably, the right-sided pedicles can be encircled and exposed by the technique used for pedicle exposure and control described for right-sided liver resection.

IV

II

Exposure of the Bile Ducts by Liver Resection This chapter does not detail exposure of the bile ducts by resection of liver substance. In essence, a segment of the left lobe may be amputated to expose the segment II or III ducts, or a similar procedure may be carried out after removal of the inferior tip of the right lobe. Finally, in some instances, removal of segment IV may be carried out to effect exposure of the biliary confluence. This procedure really represents a simple extension of the mobilization of segment IV after opening of the principal scissura and the umbilical fissure as described previously.

III

FIGURE 2.30  Biliary and vascular anatomy of the left liver. Note the location of the segment III duct above the corresponding vein. The anterior branch of the segment IV duct is not represented.

EXTRAHEPATIC VASCULATURE Celiac Axis and Blood Supply of Liver, Biliary Tract, and Pancreas

(see Chapters 51B, 101, 119B) or segment III duct bypass (see Chapters 32 and 42)—seems impossible at operation. In such a critical operative situation, intrahepatic right ductal system drainage is an option. Anatomically, the anterior sectional duct and its branches run on the left side of the corresponding portal vein. In essence, the end of the liver scissura, within which lies

The usual classic description of the arterial blood supply of the liver, biliary system, and pancreas is found in only approximately 60% of patients (Figs. 2.34–2.36). The right and the left hepatic arteries, the former in the right of the hilus of the liver

a

II b a III

b

IV c

c

d

A

B

FIGURE 2.31  A, The biliary and vascular anatomy of the left liver. Note the relationship of the left horn of the umbilical recess with the segment III ductal system: left portal vein (a), left hepatic duct (b), segment III system—note that the duct (black) lies adjacent to the portal venous branch indicated (c), ligamentum teres (d). B, Segment III ductal approach: exposure of the left horn of the umbilical recess (a), division of the left horn of the umbilical recess, including segment III portal vein branches (b), exposure and opening of segment III duct: hepaticojejunostomy to the segment III ductal system (c; see also Chapters 32 and 42).

44

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

c

A

B

FIGURE 2.32  A, The liver is split to the left of the ligamentum teres in the umbilical fissure. It may be necessary to remove a small wedge of liver tissue (c). B, Segment III duct is exposed at the base of the liver split, above and behind its accompanying vein, and is ready for anastomosis (see also Chapters 32 and 42).

A

B

FIGURE 2.33  A, Anterior sectional approach. If necessary, the liver substance is opened through a short distance in the line of the right anterior sectional pedicle. B, The duct is displayed anterior and to the left side of the corresponding vein. This can be facilitated by using a posterior pedicular approach as described by Launois (see Chapter 101B).

and the latter in the left at the base of the umbilical fissure, become enclosed in the sheath of peritoneum, forming the right and left portal triads. In this sheath, further branching to the right anterior and posterior sections of the liver and on the left to segments II, III, and IV occurs within the respective pedicles, which also come to enclose the portal vein branches and the tributary bile ducts from these sections and segments. The arterial supply of the CBD was described earlier; it arises from branches of the hepatic artery, the gastroduodenal artery, and the pancreaticoduodenal arcades. For practical surgical issues, the most important relationships in the anatomy of the pancreas concern the arterial blood supply and the venous drainage. The dorsal pancreatic artery is

a major branch, usually arising from the splenic artery, but it can arise directly from the hepatic artery. When splenectomy is performed, it is important to establish the site of origin of the dorsal pancreatic artery to avoid distal pancreatic ischemia. The superior mesenteric artery (SMA) arises from the aorta posteriorly behind the pancreas and runs forward and upward to run first behind and then to the left of the superior mesenteric vein (SMV; see Fig. 2.35).

Variations in the Hepatic Artery As a result of the complex embryologic development of the celiac axis and SMA, wide variations in the arterial supply of the liver are found (Fig. 2.37). These variations are important to

45

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas MH

LH

Left gastric Aorta

RH

Celiac trunk

HA

RGA SPDA

Splenic

Cystic

SA

LGA

PV

DP

GDA

Proper hepatic

Pancreas Supraduodenal

Post PDA MCA

Gastroduodenal

Right gastric

Common hepatic

FIGURE 2.34  The celiac trunk is a short, thick artery originating from the aorta just below the aortic hiatus of the diaphragm and extending horizontally and forward above the pancreas, where it divides into the left gastric, common hepatic, and splenic arteries. An inferior phrenic artery, usually arising from the aorta or the splenic artery, occasionally arises from the celiac trunk. The left gastric artery curves toward the stomach and extends along its lesser curve, forming anastomoses with the right gastric artery. The splenic artery, the largest of the three celiac branches, takes a tortuous course to the left, behind and along the upper border of the pancreas and at the hilus of the spleen, where it splits into numerous terminal branches. The splenic artery usually approaches and runs superiorly to the splenic vein. An uncommon but dangerous abnormality can occur when the splenic artery runs inferiorly and behind the splenic vein, close to the splenic vein–mesenteric vein confluence. The left gastroepiploic artery and the short gastric arteries originate from one of these terminal branches. The common hepatic artery passes forward into the retroperitoneum, then curves to the right to enter the right margin of the lesser omentum, just above the pancreas, and ascends; it approaches the common bile duct (CBD) on its left side and runs usually anterior to the portal vein. While it turns upward just above the pancreas, it gives rise to the gastroduodenal artery, which also may originate from the right hepatic artery. This descends to supply the anterior, superior, and posterior surfaces of the first inch of the duodenum. The gastroduodenal artery can be duplicated and often has a small branch running with it toward the pylorus. The right gastric artery passes to the left along the lesser curve of the stomach, and anastomosis is to the left gastric artery. The continuation of the common hepatic artery, beyond the origin of the gastroduodenal artery and right gastric artery, is known as the proper hepatic artery, which usually soon divides into a right and a left branch. The left branch extends vertically, directly toward the base of the umbilical fissure, and usually gives off a branch known as the middle hepatic artery (MH), which is directed toward the right of the umbilical fissure and is destined to supply segment IV of the liver. A further branch of the left hepatic artery (LH) courses to the left to supply the caudate lobe, and further smaller caudate branches arise from the left and right hepatic artery. The right hepatic artery (RH) usually passes behind the common hepatic duct and enters the cystic triangle of Calot; in some cases, it passes in front of the bile duct, which is important in surgical exposure of the CBD. The cystic artery usually arises from the right hepatic artery but has many variations.

MCV

GEA Ant PDA IPDA SMA

SMV

FIGURE 2.35  The primary arteries that supply the pancreas are the gastroduodenal artery (GDA), which arises usually from the common hepatic artery (HA) as it crosses the portal vein (PV) above the pancreas proper, and the dorsal pancreatic artery (DP), arising from the splenic artery (SA). The superior pancreaticoduodenal arteries (SPDAs) arise from the GDA and join the inferior pancreaticoduodenal arteries (IPDAs) from the superior mesenteric artery (SMA), forming two arcades along the anterior and posterior aspects of the head of the pancreas. The GDA, after giving rise to the pancreaticoduodenal artery (PDA), passes forward and to the left as the right gastroepiploic artery (GEA). The GDA is a good landmark for the identification of the portal vein above the pancreas, and surgical division of the GDA just at its origin from the common HA gives much greater access to the anterior surface of the portal vein at this site. The right gastric artery (RGA) also usually arises from the common HA just distal to the GDA, but it can arise from various sites. The GDA commonly divides into a larger right GEA and smaller SPDA. The right GEA runs forward between the first part of the duodenum and pancreas; the SPDA divides into anterior and posterior branches. The anterior superior PDA continues downward on the anterior surface of the head of the pancreas to anastomose with the IPDA, which arises from the SMA. The posterior superior PDA behaves similarly. Ant, Anterior; LGA, left gastric artery; MCA, middle colic artery; MCV, middle colic vein; Post, posterior; SMV, superior mesenteric vein.

p c

IVC

a

s

FIGURE 2.36  Computed tomographic image of the main portal vein shows the hepatic artery (solid arrows) coursing anterior to the portal vein (p). The interlobar fissure (open arrow), splenic vein (s), celiac axis (c), aorta (a), and inferior vena cava (IVC) are also shown.

46

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

G

A

B

E

F

C

D

I

H FIGURE 2.37  In approximately 25% of individuals, the right hepatic artery arises partially or completely from the superior mesenteric artery (A, C, E); in a similar proportion of patients, the left hepatic artery may be partially or completely replaced by a branch arising from the left gastric artery, coursing through the gastrohepatic omentum to enter the liver at the base of the umbilical fissure (D, F). Rarely, the right or left hepatic arteries originate independently from the celiac trunk or branch after a very short common hepatic artery origin from the celiac, and the gastroduodenal artery may originate from the right hepatic artery (B, C). Multidetector computed tomography (CT) angiogram demonstrating an accessory right hepatic artery (arrow) arising from the superior mesenteric artery (G). Multidetector CT angiogram demonstrating a replaced left hepatic artery arising from the left gastric artery (H). Another common arterial variant is the hepatic trifurcation (I).

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas RAS

Ligamentum teres IVb

RAS

47

LPV

III

IVa

RPS

II

LPV

RPS

PV

RPV CV

B RAS

LPV

SV SMV IMV

A

PV

RPS

C

FIGURE 2.38  A, The superior mesenteric vein (SMV) at the root of the lesser omentum is usually a single trunk; two, or sometimes even three, branches may unite as the vessel enters the tunnel beneath the neck of the pancreas (shaded) to form a superior mesenteric trunk. This trunk ascends behind the neck of the pancreas and is joined by the splenic vein (SV), which enters it from the left to form the portal vein (PV), which emerges from the retroperitoneal upper border of the neck of the pancreas and ascends toward the liver within the free edge of the lesser omentum, lying behind the bile duct and the hepatic artery and surrounded by the lymphatics and nodes of the lesser omentum. During this course, it receives blood through the coronary vein (CV), which communicates with esophageal venous collaterals, which connect with the gastric vein and the esophageal plexus. Sometimes a separate right gastric vein enters the PV in this area. A superior pancreaticoduodenal vein often enters the PV just above the level of the pancreas, and several smaller veins enter the SMV and PV from the right side beneath the neck of the pancreas. As the PV ascends behind the common bile duct and common hepatic duct, it approaches the hilus of the liver and bifurcates into two branches, a larger right (RPV) and a smaller left portal vein (LPV). The branch on the left courses below the left hepatic duct to enter the umbilical fissure, in company with the left hepatic artery, and subsequently branches to supply the left liver segments (II-IV). Just before its entry into the umbilical fissure, it gives off a major caudate vein, segment I, which runs posteriorly and laterally to the left. Sometimes this vein consists of two or more branches; the right portal branch, which is much shorter in length before its entry into the liver, divides at the extremity of the hilus into the right anterior (RAS) and posterior (RPS) sectional branches and is accompanied by the respective arterial branches and biliary tributaries. B, The division of the portal vein may arise more proximally, however, and C, the right anterior and posterior sectional portal veins may arise independently from the portal venous trunk. IMV, Inferior mesenteric vein.

recognize. Failure to show all arteries feeding the liver at angiography may not only result in errors of diagnosis but also seriously mislead the surgeon or the interventional radiologist. In most cases, the hepatic artery arises from the celiac axis as described earlier, but it may be entirely replaced by a common hepatic artery that originates from the SMA. In this instance, the hepatic artery passes posterior and then lateral to the portal vein while it ascends and lies posterolateral to the CBD in the hepatoduodenal ligament, where it is susceptible to operative injury if not recognized. This applies to a right replaced or an accessory hepatic artery. Other variations in the origin of the common hepatic artery include its origin directly from the aorta and the persistence of a primitive embryologic link between the celiac and superior mesenteric systems. These variations are of considerable importance in controlling the arterial blood supply to the liver during hepatic resection, liver transplantation, devascularization of the liver, placement of intraarterial hepatic infusion devices, and in the resection of the head of the pancreas.

Portal Vein The portal vein (Fig. 2.38) is formed behind the neck of the pancreas by confluence of the superior mesenteric and splenic

p

s

sm

FIGURE 2.39  Magnetic resonance imaging of the splenoportal confluence: postcontrast, T1-weighted, three-dimensional gradient-echo coronal maximum intensity projection. Shown are the splenic vein (s), portal vein (p), and superior mesenteric vein (sm).

veins (Fig. 2.39). The venous drainage of the pancreas usually runs parallel to the arterial supply. There are anterior and posterior and superior and inferior pancreaticoduodenal veins that drain to the portal vein and the SMV. The left gastric vein and the inferior mesenteric vein (IMV) usually drain into the splenic vein, but they can drain directly into the portal vein, whereas the various small splenic tributaries drain directly to the splenic vein.

48

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

The anatomic relationship of the pancreas to the SMV, the splenic vein, and the portal vein (see Fig. 2.38) is important in pancreatic resection (see Chapter 117). The uncinate process generally extends behind the SMV to a position adjacent to the SMA (see Fig. 2.35). Access to the portal vein behind the pancreas usually is obtained from below by elevating the pancreas from the surface of the SMV just before it joins the splenic vein. With the exception of the inferior pancreaticoduodenal veins, which enter the SMV at the inferior border of the pancreas, it is uncommon to see branches from the pancreas run directly posteriorly into the SMV. Fixation here is usually by an inflammatory or neoplastic process. Superiorly, the portal vein runs behind the pancreas and is identified first in the gap between the curvature of the splenic vein, splenic artery, common hepatic artery, and gastroduodenal artery. Division of the gastroduodenal artery provides much greater access to the superior surface of the portal vein, and this step is necessary to assess tumor involvement of the proximal portal vein. If difficulty is encountered in this area, division of the CBD, usually above the cystic duct, can provide excellent access to the right lateral aspect and anterior surface of the portal vein. The SMA can be approached behind the pancreas above the point at which it is embraced by the uncinate process at the origin from the aorta. This allows for dissection of the most proximal part of the SMA. Occasionally, the middle colic artery and other vessels of supply to the colon can arise from the more proximal SMA, such that they pass through the pancreas; this abnormality should be searched for carefully. Division of the middle colic artery is usually not a problem, however, because the colon is well supplied with blood, and ischemia typically does not occur. Of special importance to the surgeon is the direct relationship of the head of the pancreas to the duodenum and posteriorly to the right renal vein and the anterior surface of the IVC. The neck and body of the pancreas lie atop the SMA and the splenic vessels and their branches, the left renal vein, and, more laterally, the left kidney. The right gastroepiploic vein commonly drains into the anterior surface of the SMV just at the inferior border of the pancreas; this can often be involved by tumor, as can the anterior branch of the inferior pancreaticoduodenal vein; the middle colic vein may also join at this point. In mobilizing the SMV, these vessels are ligated so as to avoid bothersome hemorrhage. Abnormalities of the IVC are uncommon, with duplication of the vena cava and a left-sided vena cava seen rarely. Several variations in anatomy and rare congenital anomalies of the portal vein are of surgical significance (Figs. 2.40–2.43). For example, performance of right hepatic resection, with division of what appears to be the right portal vein in a patient with absence of the left portal vein (see Figs. 2.42 and 2.43) can be fatal. Agenesis of the right branch of the portal vein is associated with agenesis of the right hemiliver and left liver hypertrophy. This may be associated with biliary and hepatic venous anatomic anomalies, which can compromise surgical approaches to the liver and to biliary repair.26 Portal venous blood is derived from the venous drainage of the stomach, small bowel, spleen, and pancreas, and this drainage is important when considering surgery of the pancreas and in patients with portal hypertension; it is described

L RA

M

RP

FIGURE 2.40  Contrast-enhanced computed tomographic scan of variant portal vein branching with trifurcation pattern. L, Left portal vein; M, main portal vein; RA, right anterior portal vein; RP, right posterior portal vein. (From Covey AM, Brody LA, Getrajdman GI, et al. Incidence, patterns, and clinical relevance of variant portal vein anatomy. Am J Roentgenol. 2004;183:1055–1064.)

in detail along with the description of the anatomy of the pancreas.

PANCREAS The pancreas is a posteriorly situated retroperitoneal organ that lies transversely (Fig. 2.44). The organ is composed of a head, neck, body, and tail (see Chapter 1). The head is encompassed by the duodenum, whereas the tail rests in the splenic hilum (Figs. 2.45 and 2.46). A portion of the head inferiorly is termed the uncinate process and is intimately related to the SMV and SMA. Posteriorly, the pancreas is related to the IVC, aorta, left renal vein and kidney, and spleen. The portion lateral to the portal vein averages 56.4% of the total weight. The pancreatic capsule is loosely attached to the surface of the pancreas and is contiguous with the anterior layer of the mesocolon such that it can be dissected in continuity if necessary. The mesenteric attachments to the pancreas tend to be contiguous (see Fig. 2.46). The arterial blood supply and venous drainage and the relationships to the CBD are described and illustrated earlier (see Figs. 2.17, 2.29, 2.34, 2.35, and Fig. 2.38).

Pancreatic Duct The duct of Wirsung, beginning in the distal tail as a confluence of small ductules, runs through the body to the head, where it usually passes downward and backward in close juxtaposition to the CBD (see Fig. 2.45). The sphincter of Oddi (Fig. 2.47) has been thoroughly studied27,28 and consists of a unique

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

49

B

A

C

FIGURE 2.41  A, The portal vein anterior to the head of the pancreas and the duodenum may be in an abnormal position. B, Another rare but interesting anomaly is the entrance of the portal vein into the inferior vena cava. C, Very rare, the entrance of a pulmonary vein into the portal vein.

FIGURE 2.42  In a congenital absence of the left branch of the portal vein as described by Couinaud, the right branch courses through the right lobe of the liver, supplying it, and curves within the liver substance to supply the left lobe, which in such instances is usually smaller than normal.

FIGURE 2.43  Computed tomographic scan in a patient with Caroli’s disease shows a large right portal trunk. The left branch of the portal vein is absent, with findings confirmed at operation for left hepatic lobectomy.

50

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

D a a

i

S

v

v IVC

r

A

B

A

FIGURE 2.44  A, Magnetic resonance imaging of the pancreas, oblique axial reconstruction, T1-weighted three-dimensional gradient-echo technique. Aorta (a), inferior vena cava (i), common bile duct (CBD; arrow), superior mesenteric vein at the splenoportal confluence (v), superior mesenteric artery (arrowhead), and left renal vein (r) are shown. B, Normal pancreatic anatomy. Postcontrast computed tomographic scan at the level of the pancreas. A, Aorta; a, superior mesenteric artery; D, duodenum; IVC, inferior vena cava; S, stomach; v, superior mesenteric vein; long arrow, CBD; short arrow, inferior pancreaticoduodenal artery; open arrow, gastroduodenal artery.

Aorta

NECK

BODY

HEAD

POSITION OF THE COMMON BILE DUCT Superior mesenteric vein and artery

Uncinate process a

UNCINATE PROCESS b c

B

(i)

A

(ii)

C

FIGURE 2.45  A, The head of the pancreas is globular with an extension, the uncinate process, which curves behind the superior mesenteric vessels and may end even before it embraces the superior mesenteric vein (a), or it may pass completely behind between the aorta and the left of the patient’s superior mesenteric artery (b, c). All variations are commonly seen. Posteriorly, the head of the pancreas lies in juxtaposition to the inferior vena cava at the level of the entry of the left and right renal veins. The head of the pancreas forms a narrow neck in front of the superior mesenteric and splenic vein confluence. The neck joins to the body of the gland, which forms a narrow tail. B, The common bile duct (CBD) passes through the pancreas, either directly in the substance of the gland or initially with a posterior groove. C, The duct of Wirsung courses from left to right within the pancreas, curves downward approaching the CBD, and runs parallel with it, but separated from it, by the transampullary septum to enter the duodenum, 7 to 10 cm distal to the pylorus, at the papilla of Vater after traversing the sphincter of Oddi. An accessory duct, the duct of Santorini, runs more proximally in the head of the pancreas and usually terminates in the duodenum at an accessory papilla. Multiple variations of the ductal system occur, depending on the extent of development of the duct of Santorini, such that rarely the accessory duct can enter the duodenum inferior to the main duct. It can be in communication with the main duct directly (i), or it can occur in duplicate version known as pancreas divisum (ii). The duct of Santorini drains the body and tail of the organ, and the duct of Wirsung drains the head and the uncinate process.

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

51

Aorta Portal vein Vena cava

Aorta

Peritoneum Neck of pancreas

Middle colic vessels

Superior mesenteric artery Left renal vein Uncinate process of pancreas

Middle colic artery

Superior mesenteric artery

Third part of duodenum

Superior mesenteric vein Superior mesenteric artery

A

B Pancreas posterior view Portal vein Splenic artery

Common bile duct Pancreatic duct

Splenic Hepatic vein artery

Superior mesenteric artery

Uncinate process

Superior mesenteric vein

Left

Right Related Related to left kidney, to spleen left renal vein and adrenal gland

C

Related to inferior vena cava and aorta

FIGURE 2.46  A, The anterior surface of the pancreas, covered by the posterior layer of the omental bursa or lesser peritoneal sac, can often be obliterated by adhesions. The transverse mesocolon arises from the lower border of the pancreas and envelops the middle colic vessels as they arise from the superior mesenteric vessels just beneath the pancreatic neck. B, The relationship of the pancreatic neck and uncinate process to the aorta and superior mesenteric artery. Note the position of the left renal vein and duodenum. C, The posterior relationships of the duodenal loop and pancreas. Note the relationship to the inferior vena cava, aorta, and hilum of the spleen.

a

b c d e f g

FIGURE 2.47  Schematic representation of the sphincter of Oddi: notch (a), biliary sphincter (b), transampullary septum (c), pancreatic sphincter (d), membranous septum of Boyden (e), common sphincter (f), smooth muscle of duodenal wall (g).

52

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

D

A MRCP: PANCREAS DIVISUM

B Posterior

Anterior

FIGURE 2.48  A, Magnetic resonance imaging cholangiography (MRCP), T2-weighted coronal image at the level of the ampulla, shows the duodenum (D) and the pancreatic head with common bile duct (curved arrow) and pancreatic duct (straight arrow). B, MRCP of pancreas divisum. Anterior projection shows variant anatomy with the duct of Santorini (vertical arrow) between the duodenum above the duct of Wirsung (angled arrow). The two ducts are separate; the duct of Santorini drains mainly the neck and body of the pancreas, and the duct of Wirsung drains mainly the uncinate process portion of the head of the pancreas.

cluster of smooth muscle fibers distinguishable from the adjacent smooth muscle of the duodenal wall. The papilla of Vater at the termination of the CBD is a small, nipple-like structure that protrudes into the duodenal lumen and is marked by a longitudinal fold of duodenal mucosa. The duct of Wirsung runs downward and parallel to the CBD for approximately 2 cm and joins it within the sphincter segment in 70% to 85% of patients; it enters the duodenum independently in 10% to 13% of patients and is replaced by the duct of Santorini in 2% of patients (Fig. 2.48; see Fig. 2.45). Rarely, the duct of Santorini

and the duct of Wirsung are separate, which is known as pancreas divisum (see Fig. 2.45Cii and Fig. 2.48B; see Chapters 1 and 53). The islets of Langerhans, which provide the endocrine component of the gland, are scattered throughout the pancreas.

Annular Pancreas Annular pancreas is the development of a ring of pancreatic tissue that surrounds and often embraces the duodenum. This ring may contain a large duct and can be firmly affixed to the duodenal musculature. The duodenum beneath this annulus is

  Chapter 2  Surgical and Radiologic Anatomy of the Liver, Biliary Tract, and Pancreas

53

Splanchnic nerves Vagal nerves

Celiac ganglion

FIGURE 2.50  Note the distribution of sympathetic and parasympathetic nerves to the liver and pancreas from the celiac ganglion, mainly in association with major arteries.

A often stenosed such that dividing this ring does not always relieve chronic duodenal obstruction. This accounts for the common process of applying duodenojejunostomy to relieve strictures caused by such an annulus (see Chapters 1 and 53)

LYMPHATIC DRAINAGE Liver and Pancreas

i

PV BD

HA

SA

The lymphatic drainage of the liver and gallbladder is mainly to nodes in the hepatoduodenal ligament and along the hepatic artery; this is shown in Fig. 2.49. The lymphatic drainage of the pancreas is predominantly to the nodes that lie in juxtaposition to the arteries and veins (Fig. 2.50B).

NERVE SUPPLY TO THE LIVER AND PANCREAS The nerve supply to the liver and pancreas (see Fig. 2.50) is from branches of the celiac ganglion. It is composed of sympathetic and parasympathetic elements.

SV IMV

References are available at expertconsult.com. SMA

B

SMV

ii

FIGURE 2.49  A, The liver drains principally to hepatoduodenal nodes at the hilus and along the hepatic artery and portal vein. The gallbladder drains partly to the liver, but it also drains via the cystic node to nodes of the hepatoduodenal ligament and to suprapancreatic nodes. B, Numerous nodes (i) lie along the superior mesenteric vein along the borders of the pancreas, draining back into the splenic hilar nodes; along the superior border of the pancreas to the superior pancreatic nodes; and to the celiac trunk and nodes at the base of the common hepatic artery. A large node commonly lodges in intimate association with the surface of the superior border of the pancreas and the right side of the common hepatic artery. This node often needs to be dissected and elevated to gain access to the anterior surface of the portal vein. Removal of this node often improves access, as does division of the gastroduodenal artery. Posterior pancreaticoduodenal nodes (ii) lie along the posterior pancreatic duodenal arterial arcade. BD, Bile duct; HA, hepatic artery; IMV, interior mesenteric vein; PV, portal vein; SA, splenic artery; SMA, superior mesenteric artery; SMV, superior mesenteric vein; SV, splenic vein.

53.e1

REFERENCES 1. Couinaud C. Le Foi: Etudes Anatomiques et Chirurgicales. Masson; 1957. 2. Mcindoe AH, Counseller VS. The bilaterality of the liver. Arch Surg. 1927;15(4):589-612. 3. Ton That Tung. La Vascularisation Veineuse du Foie et Ses Applications aux Resections Hépatiques. Thèse; 1939. 4. Ton That Tung. Les Resections Majeures et Mineures du Foie. Masson; 1979. 5. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat (Basel). 1951;11(4):599-615. 6. Healey Jr JE, Schroy PC. Anatomy of the biliary ducts within the human liver; analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. AMA Arch Surg. 1953;66(5): 599-616. 7. Goldsmith NA, Woodburne RT. The surgical anatomy pertaining to liver resection. Surg Gynecol Obstet. 1957;105(3):310-318. 8. Bismuth H, Houssin D, Castaing D. Major and minor segmentectomies “réglées” in liver surgery. World J Surg. 1982;6(1):10-24. 9. Strasberg SM. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg. 2005;12(5):351-355. 10. Scheele J, Stangl R. Segment-orientated anatomical liver resections. In: Blumgart LH, ed. Surgery of the Liver and Biliary Tract. 2nd ed. Churchill Livingstone; 1994:1557-1578. 11 . Rocko JM, Di Gioia JM. Calot’s triangle revisited. Surg Gynecol Obstet. 1981;153(3):410-414. 12. Wood MD. Eponyms in biliary tract surgery. Am J Surg. 1979; 138:746-754 13. Champetier J, Davin JL, Letoublon C, et al. Aberrant biliary ducts (vasa aberrantia): surgical implications. Anat Clin. 1982;4:137-145. 14. Albaret P, Chevalier JM, Cronier P, et al. A propos des canaux hépatiques directement abouchés dans la voie biliaire accessoire. Ann Chir. 1981;35:88-92.

15. Gross RE. Congenital anomalies of the gallbladder: a review of one hundred and forty-eight cases, with report of a double gallbladder. Arch Surg. 1936;32(1):131-162. 16. Boyden EA. The accessory gallbladder: an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat. 1926; 38:177-231. 17. Rachad-Mohassel MA, et al. Duplication de la vésicule biliaire. Arch Fr Mal App Dig. 1973;62:679-683. 18. Sanders GB, Flores T, Arriola P. Congenital absence of the gallbladder and cystic duct: a review of the literature and report of a case. Am Surg. 1968;34(10):750-754. 19. Hobby JA. Bilobed gall-bladder. Br J Surg. 1970;57(11):870-872. 20. Perelman H. Cystic duct reduplication. JAMA. 1961;175:710-711. 21. Eelkema HH, Starr GF, Good CA. Partial duplication of the gallbladder, diverticulum type; report of a case. Radiology. 1958; 70(3):410-412. 22. Newcombe JF, Henley FA. Left-sided gallbladder. A review of the literature and a report of a case associated with hepatic duct carcinoma. Arch Surg. 1964;88:494-497. 23. Kune GA. The influence of structure and function in the surgery of the biliary tract. Ann R Coll Surg Engl. 1970;47(2):78-91. 24. Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg. 1979;66(6):379-384. 25. Hepp J, Couinaud C. L’abord et l’utilisation du canal hepatique gauche dans les reparations de la voie biliare principale. Presse Med. 1956;64:947-948. 26. Fields RC, Heiken JP, Strasberg SM. Biliary injury after laparoscopic cholecystectomy in a patient with right liver agenesis: case report and review of the literature. J Gastrointest Surg. 2008;12(9):1577-1581. 27. Boyden EA. The anatomy of the choledochoduodenal junction in man. Surg Gynecol Obstet. 1957;104(6):641-652. 28. Delmont J. Le sphincter d’Oddi: anatomie traditionelle et fonctionnelle. Gastroenterol Clin Biol. 1979;3:157-165.

CHAPTER 3 Pancreatic physiology and functional assessment Alessandro Paniccia and Richard D. Schulick

The pancreas is a complex retroperitoneal gland with both endocrine (e.g., glucose homeostasis) and exocrine (e.g., nutrient digestion) functions. An adult human pancreas measures approximately 15 cm in length and weighs between 60 to 100 g; however, its size can vary because of aging or pathologic conditions (e.g., pancreatitis, neoplasia).1,2 It is of endodermal origin and arises from two independent primordia: a ventral bud (derived from the hepatic diverticulum) and a dorsal bud (derived from the developing duodenum; see Chapter 1). Around the fifth week of gestation, the ventral bud rotates clockwise with the developing duodenum to fuse with the dorsal pancreatic bud.3,4 Ultimately, the ventral bud will form the inferior pancreatic head and the uncinate process. The dorsal bud will constitute the majority of the pancreatic gland, representing the superior pancreatic head, the body, and the tail of the adult pancreas (see Chapters 1 and 2). During this process, the main ducts of the ventral and dorsal pancreatic buds fuse to form the main pancreatic duct (duct of Wirsung). The major pancreatic duct drains most of the organ’s secretions through the major duodenal papilla (ampulla of Vater). A separate draining duct, arising from the dorsal pancreatic bud, usually persists and forms the minor pancreatic duct (duct of Santorini). The minor duct drains a portion of the pancreatic head secretions into the duodenum through the minor papilla, located 2 cm anterosuperior of the major papilla.5 The pancreas receives an abundant arterial vascular supply from branches of the celiac and superior mesenteric artery. The venous drainage follows the arterial supply, with venous effluents ultimately draining into the portal vein.6 Furthermore, the pancreas is supplied by several neural sources, including sympathetic fibers from the splanchnic nerves, parasympathetic fibers from the vagus nerve, and peptidergic neurons (releasing amines and peptides; see Chapter 2).7,8

ENDOCRINE PANCREAS The islets of Langerhans are the functional units of the endocrine pancreas and have a paramount role in maintaining glucose homeostasis. In light of their complex cytoarchitecture structure and regulatory system, they are de-facto microorgan(s) within the pancreas.9 The pancreas of a healthy adult has approximately one million islets that are evenly distributed throughout the pancreatic gland and account for 1% to 2% of the organ’s mass. Each islet ranges in size from 50 to 300 mm in diameter and contains a few hundred to a few thousand endocrine cells.5

Structure There are at least five major cell types in each islet of Langerhans: a, b, d, F, and e cells. In humans, pancreatic a-cells, which principally secrete glucagon, represent approximately 54

35% of all islet cells. Pancreatic b-cells, which are responsible for the production and secretion of insulin and amylin, represent approximately 55% of islet cells. Pancreatic d-cells, which principally secrete somatostatin, represent less than 10% of the islet cells, and pancreatic F cells, which secrete pancreatic polypeptide (PP), account for less than 5%. Finally, the e cells, which secrete ghrelin, account for less than 1% of human islet cells.10 The distribution and cellular composition of the different cell types within the islet vary among species. Previous animal models with rabbits, rats, and mice demonstrated that b cells occupy the core of the islet of Langerhans and that non–b-cells are distributed toward the outside of the islet.11 Recent studies in humans have demonstrated a different cytoarchitecture, where the majority of a-, b-, and d-cells reside along the islet blood vessels without a specific order.11 Furthermore, approximately 70% of human b-cells appear to be in contact with non–g-islet cells, suggesting a predisposition for paracrine interaction.9 The islet’s regional location within the human pancreas is also essential to islet cytoarchitecture.9 Islets located in the body and tail of the pancreas have a higher proportion of a cells and a lower proportion of F cells, whereas islets located in the uncinate process have a higher proportion of F cells and a lower proportion of a-cells. Notably, b-cells and d-cells are present in nearly equal proportions throughout the pancreas.5 The islets are rich in axonal terminals and blood capillaries that participate in extensive neurohumoral and nonneuronal paracrine regulation. Studies using three-dimensional reconstruction of the axonal terminal field revealed that the autonomic innervation to the human islet of Langerhans is different from that previously identified in rodents.8 Contrary to what was previously understood, human b cells receive minimal innervation from the parasympathetic cholinergic system.8 Instead, sympathetic neural terminals penetrate the human islet of Langerhans to innervate the smooth muscle cells of the blood vessels, allowing fine regulation of islet blood flow. Consequently, sympathetic nerves indirectly influence downstream endocrine cells by regulating the local blood flow containing secreted endocrine hormone.8 The islets of Langerhans receive approximately 20% of the pancreatic arterial flow, with distribution significantly influenced by the different phases of digestion.12 Furthermore, an insuloacinar portal system responsible for draining blood and secreted hormones from the islets of Langerhans to the pancreas’ acinar element exists in several species, including humans.13 Hormones secreted by the islet of Langerhans are directly transported to the acinar cells, where they can exert a local regulatory function. Besides, several neuropeptides, including neuropeptide-Y, gastrin-releasing peptide, and calcitonin gene-related peptide (CGRP), exert a local regulatory effect on endocrine and exocrine pancreatic function.

  Chapter 3  Pancreatic Physiology and Functional Assessment

Synthesis and Storage of Insulin In 1923 Banting and McLeod, two Canadian surgeons, were awarded the Nobel Prize in Physiology or Medicine for the discovery of insulin.14 This 51–amino acid polypeptide is primarily responsible for maintaining serum glucose between 4 mM and 8 mM (70–140 mg/dL) during periods of feeding and fasting.15 Moreover, insulin regulates lipid and protein metabolism. The gene responsible for encoding insulin is located on the short arm of chromosome 11 and leads to the translation of a preprohormone protein known as preproinsulin within the b-cell. Preproinsulin consists of a leading sequence of 24 amino acids, followed by three domains named “B,” “C,” and “A.” Successive cleavage processes take place starting at the time of translation until the final secretion. First, cleavage of the leading sequence in the endoplasmic reticulum leads to the formation of proinsulin. As the proinsulin is arranged into secretory granules in the trans-Golgi, additional proteases cleave the central 31 amino acid C-peptide. This process leads to the formation of a mature insulin peptide composed of an A-chain and B-chain held together by two disulfide bonds, ready to be released in the secretory vesicle. Cleaved C-peptide and other intermediate products, such as proinsulin, remain present in the secretory granules and are eventually released with mature insulin.5 The mature insulin peptide has a plasma half-life of 4 minutes. It is rapidly internalized by target organs expressing its receptor and degraded by the kidneys and liver.16 Notably, C-peptide has a plasma half-life of 30 minutes and is excreted unchanged by the kidneys, making it a clinically meaningful marker of endogenous insulin secretion.17

Stimulus-Secretion Coupling for Insulin Secretion The rise of islet cell transplantation has led to a renewed understanding of human b-cell regulation, building on earlier work completed in rodents (see Chapter 126). Insulin is released from b-cells through two mechanisms: unstimulated and stimulated secretion. Unstimulated secretion or basal insulin secretion occurs every 6 to 8 minutes.18 Stimulated secretion of insulin occurs in response to several stimuli, including glucose, amino acids (e.g., arginine), acetylcholine (ACh), glutamate, and incretins such as gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1). The change in extracellular glucose concentration, however, is the dominant factor controlling b-cell function. The primary glucose transporters on pancreatic b-cells are GLUT-2, highly expressed in rodents,19 and GLUT-1 and GLUT-3, both expressed at high levels on human b-cells (Fig. 3.1).20 The GLUT transporters allow equalization of the intracellular and extracellular glucose concentrations. If the glucose concentration exceeds 5 mmol/L, the intracellular b-cell glucokinase enzymes activate to allow fine regulation of insulin secretion.21 Acting as a “glucose sensor,” these enzymes are responsible for the phosphorylation of glucose to glucose6-phosphate.22,23 Glucose-6-phosphate accumulates in the b-cell, is metabolized, and contributes to an increase in cellular adenosine triphosphate (ATP). The b-cell membrane is rich in ATP-dependent potassium channels, which subsequently undergo closure in response to the surge in ATP, resulting in membrane depolarization.24,25 Depolarization activates voltage-gated L-type calcium channels, leading to an influx of calcium into the cell.15,26 The increased intracellular calcium concentration leads to margination of secretory granules, their fusion with the cell membrane, and exocytosis of their content,

55

including insulin and its intermediate products (e.g., Cpeptide).25 This process characterizes the “first phase” of insulin release, in which insulin is rapidly secreted within 3 to 5 minutes of glucose administration and terminates within 10 minutes. The loss of the first phase of insulin secretion is one of the earliest metabolic defects identified in type 2 diabetes mellitus (T2DM).27 The “second phase” of insulin secretion is longer lasting (reaching a plateau in insulin secretion after 2–3 hours), and its regulation is not entirely understood.28,29 Nevertheless, recent mathematic models suggest that the second phase is characterized by the recruitment and mobilization of intracellular granules containing insulin (as opposed to predocked granules as in the first phase) in a dose-dependent glucose response.30 The amino acid arginine (l-arginine) is another well-known insulin secretagogue. After uptake into the b-cells through a cationic amino-acid transporter (CAT), arginine leads to depolarization of cell membrane, which triggers calcium influx.31 Furthermore, l-arginine can stimulate the release of GLP-1, which acts at its receptor (GLP-1R) to augment glucose-stimulated insulin secretion from pancreatic b-cells.32,33 The incretin effect further potentiates insulin secretion from pancreatic b-cells through the enteroinsular axis.34,35 The incretin effect is the phenomenon whereby the presence of nutrients, especially carbohydrates, in the duodenal lumen stimulates cells in the gut mucosa to release potent insulin secretagogues.36 The ingestion of nutrients stimulates duodenal and jejunal K cells to produce and release GIP, a well-studied incretin. Also, GLP-1 is produced and released by the L cells (also known as enteroglucagone cells), located in the distal small bowel, colon, and rectum. It has been shown that orally administered glucose can stimulate insulin secretion as much as 25% more than intravenously administered glucose, likely through the incretin effect.37 GIP and GLP-1 play significant roles in the enteroinsular axis, mainly through activation of adenylate cyclase and subsequent increase in intracellular cyclic adenosine monophosphate (cAMP). The increase in cAMP leads to the activation of protein kinase A, with subsequent phosphorylation and activation of exocytosis-related proteins. Furthermore, cAMP activates L-type calcium channels, culminating in insulin release (see earlier). Acetylcholine (ACh) maintains a pivotal role in glucose homeostasis. In human islets, ACh acts primarily as a nonneuronal paracrine signal released from a-cells rather than as a neural signal, as previously described in rodent islets.38 ACh stimulates the insulin-secreting b-cell via the muscarinic ACh receptors M3 and M5, causing insulin release.39 The activation of the M3 receptor leads to calcium release from intracellular stores through a phospholipase C–mediated increase in inositol-1,4,5-triphosphate (IP3).40 Additionally, ACh stimulates the somatostatin-secreting d-cell via M1 receptors. Because somatostatin is known to inhibit insulin secretion, it appears that endogenous cholinergic signaling provides a direct stimulatory and indirect inhibitory input to b-cells, allowing further regulation of insulin secretion.39

Glucagon and Other Islet Hormones The islets of Langerhans secrete many additional hormones, including glucagon (a-cells), somatostatin (d-cells), pancreatic polypeptide (F cells), and ghrelin (e-cells).10 Furthermore, islets contain a variable, but small, number of cells responsible

56

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY Incretin GIP/GLP-1

Acetylcholine

Glucose

M3 M1 Gαq*

GLUT-1 GLUT-2 GLUT-3

†Gαs

PIP2

Glucokinase Glucose-6-P

Phospholipase-C

Adenylate Cyclase

Pyruvate L-Arginine

CAT

KREBS CYCLE

ATP-dependent K+ channel

DAG

cAMP

Protein Kinase C

Protein Kinase A

IP3

Close

↑ATP/ADP

Intracellular Ca2+ store

Protein Phosphorylation

Membrane depolarization Voltage-gated Ca2+ channel

Open

↑Cytosolic Ca2+

Insulin Insulin

FIGURE 3.1  Stimulus-secretion coupling for insulin secretion. Insulin is secreted after food ingestion. Glucose, acetylcholine (ACh), incretins, and amino acids are the most important physiologic secretagogues. Glucose enters the human b-cell mainly via the glucose transporters GLUT-1 and GLUT-3 and, to a lesser extent, via GLUT-2. Once in the b-cell, glucose is phosphorylated to glucose-6-phosphate by an intracellular glucokinase (GCK) and eventually is metabolized to produce adenosine triphosphate (ATP), leading to an elevation of the cytosolic ATP/diphosphate (ADP) ratio. The increase in the intracellular ATP content is responsible for the closure of the ATP-dependent K1 channel. The resulting increased membrane potential, caused by the closure of the ATP-dependent K1 channel, prompts the opening of voltage-dependent Ca21 channels, leading to an increase in intracellular Ca21 levels. Arginine is a positively charged amino acid that depolarizes the b-cell after its uptake by a cationic amino-acid transporter (CAT); the membrane depolarization leads to the opening of voltage-dependent Ca21 channels, allowing entry of Ca21 into the cell. The increase in intracellular Ca21 triggers exocytosis of insulin-containing secretory granules. ACh, released from vagal efferent and a-cell, binds to the muscarinic ACh receptor M3, which is coupled with a phospholipase C, resulting in the production of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Eventually, IP3 triggers the release of intracellular Ca21, and DAG causes activation of protein kinase C (PKC). The incretins (gastric inhibitory peptide [GIP] and glucagon-like peptide-1 [GLP-1]) bind to the extracellular domain of a G protein-coupled receptor to mediate signal transduction by activation of adenylate cyclase. The activated adenylate cyclase causes an increase of intracellular cyclic adenosine monophosphate (cAMP) concentrations leading to the activation of protein kinase A. Ultimately, the activation of protein kinase C and protein kinase A culminates with protein phosphorylation and secretion of insulin. *Gaq, Membrane-associated heterotrimeric G protein that activates phospholipase C (PLC); †Gas, membrane-associated heterotrimeric G protein that activates the cAMP-dependent pathway by activating adenylate cyclase; PIP2, phosphatidylinositol-4,5-bisphosphate.

for secreting pancreastatin, serotonin, and vasointestinal polypeptide (VIP).41–43 Glucagon, a 29–amino-acid peptide (molecular weight, 3.5 kDa), counteracts insulin’s effect by increasing blood glucose concentration through stimulation of glycogenolysis, gluconeogenesis, and ketogenesis.44 The secretion from islet a-cells directly into the portal system is mostly in response to protein ingestion. Glucagon at physiologic concentration exerts its function primarily in liver tissue through activation of cAMP pathways, where it promotes gluconeogenesis and, indirectly, ketogenesis.45 Besides, glucagon indirectly stimulates fatty oxidation through the carnitine acylcarnitine translocase system (CAT). This process increases the ketone bodies b-hydroxybutyric acid and acetoacetic acid, which constitute metabolic fuel for other tissues. Glucagon inhibition is caused by increased

blood glucose concentration and by paracrine effects of insulin and somatostatin within the islet.46 Somatostatin, which acts primarily as an inhibitory hormone, is secreted by the islet d-cell and by several other organs, including the hypothalamus and the D cells of the gastrointestinal (GI) tract. Among others, somatostatin inhibits insulin, glucagon, gastrin, and VIP. Its broad inhibition makes somatostatin and its pharmacologic analogs (e.g., octreotide) useful therapeutic agents in the medical management of secreting pancreatic neuroendocrine tumors (e.g., insulinoma; see Chapter 65) along with other medical diseases (e.g., Cushing’s disease, acromegaly, carcinoid).47 Furthermore, somatostatin analogs are used in the treatment of some surgical complications. For example, pasireotide, a multi-somatostatin receptor ligand, significantly

  Chapter 3  Pancreatic Physiology and Functional Assessment

decreased pancreatic leak complications after pancreatic surgery48 (see Chapter 117). Pancreatic polypeptide (PP) is produced and released by islet F cells; however, its physiologic role remains under investigation.49 Some studies suggest that the absence of PP secretion, resulting from the removal of the uncinate process (rich in islet F cells) during pancreaticoduodenectomy, can lead to pancreatogenic diabetes (type 3c).50 Ghrelin, produced by the e-cells, also known as the “hunger hormone,” is a centrally active neuropeptide that participates in metabolic regulation, growth hormone release, and energy balance.51,52 In particular, e-cells participate in the regulation of various function of b-cells, including control of blood glucose levels as well as cellular growth. An increased understanding of e-cells function and regulatory mechanism could lead to new therapeutic options for patients with diabetes mellitus.53

Pancreatitis Consequences on Endocrine Pancreas Function Pancreatic endocrine insufficiency is a dreaded consequence of acute pancreatitis (AP). Recent studies suggest that after hospitalization for the first episode of AP, there is as much as a 40% risk of prediabetes or diabetes mellitus54 (see Chapters 55 and 56). Approximately 15% of newly diagnosed diabetes mellitus occurs within 12 months from the first episodes of AP, and the risk remains high, increasing significantly with time. It appears that the development of endocrine insufficiency is at least partially related to the severity of the episode of AP with an estimated 2-fold increase in the prevalence of endocrine pancreatic insufficiency after an episode of necrotizing pancreatitis.55 The rate of insulin use within 5 years of the first episode of AP approaches 14%. Pancreatic necrosis and ethanol etiology represent strong risk factors for the development of pancreatic endocrine insufficiency.55 Alternative mechanisms have been proposed and are currently under investigation, including both patients and disease-related factors, such as age, body mass index, family history, duration of pancreatic disease, presence of exocrine insufficiency, and pancreatic surgery. It is worth mentioning that the risk for diabetes mellitus can be as high as 80% in patients with chronic pancreatitis (CP; see Chapters 57 and 58).56,57 Although pancreatogenic diabetes mellitus (type 3c) is most commonly the result of CP, it can also occur secondary to pancreatic cancer. In fact, the prevalence of diabetes mellitus in pancreatic ductal adenocarcinoma at the time of diagnosis is approximately 50%, and importantly, 75% of these patients are diagnosed with diabetes mellitus within 2 years before the diagnosis of cancer (see Chapter 62). Pancreatic polypeptide deficiency represents a distinctive feature of pancreatogenic diabetes and has been associated with reduced hepatic sensitivity to insulin.58,59

EXOCRINE PANCREAS The exocrine pancreas constitutes 80% to 90% of the gland mass and secretes the majority of digestive enzymes, as well as approximately 2000 mL of colorless, odorless, and isosmotic alkaline protein-rich fluid (pH, 7.6–9.0) daily. It is mainly regulated by the neuroendocrine system, and it is integrated anatomically and physiologically with the endocrine pancreas, which helps modulate its function.60

57

Exocrine Pancreas Structure The exocrine pancreas consists primarily of two distinct but integrated units: the acinus and the ductal network.

Acinus The acinus is a functional unit mainly dedicated to digestive enzyme production and secretion (6 as much as 20 g daily). It is composed of 15 to 100 pyramidal-shaped cells (as much as 30 mm apical base height) known as acinar cells.61 The acinar cells are polarized epithelial cells rich in rough endoplasmic reticulum and characterized by an abundance of secretory zymogen granules within the apex. The acinus is organized concentrically around a central lumen, which is in continuity with the proximal end of an intercalated duct, where it drains its secretions. Several acini form a pancreatic lobule, separated from other lobules by thin layers of connective tissue.

The Ductal Network The ductal network serves two critical functions: transporting exocrine secretions from the acini to the duodenum and producing a solution rich in bicarbonate and electrolytes (Fig. 3.2). The bicarbonate and water released in the ductal network facilitate the transport and flushing of acinar secretions throughout the pancreatic ducts and, most importantly, optimize the pH of the solution in which pancreatic enzymes are secreted.62 The ductal network starts with small intercalated ducts originating from different acini, which then join to form an intralobular duct. This serves to drain an individual pancreatic lobule. Intralobular ducts then drain into larger interlobular ducts, which then empty into the main pancreatic duct, releasing the pancreatic secretions into the duodenum, through the ampulla of Vater.63,64 The ductal network is composed of highly specialized epithelial cells with varying morphologies and functions.61 Cells of the intercalated duct are characterized by minimal cytoplasm and a squamous-shaped appearance. On the contrary, cells in the main pancreatic duct have an abundance of cytoplasm rich in mitochondria and are characterized by a cuboidal shape. Ductal cells contain substantial levels of cytoplasmic carbonic anhydrase, an enzyme necessary for bicarbonate production.65

Centroacinar Cells Cuboidal-shaped centroacinar cells are present at the junction between the acinus and the ductal cells of the intercalated duct. Recognized as morphologically distinct from acinar cells, centroacinar cells are smaller than acinar cells (~10 mm in diameter), have a high nuclear-to-cytoplasm ratio, and have long cytoplasmic processes that allow contact with other cells (i.e., centroacinar, acinar, and islet cells).61,66,67 The role of centroacinar cells remains under investigation, but some authors suggest that centroacinar cells could represent multipotent progenitor pancreatic cells and potentially be involved in malignant transformation.68,69

Ductal Epithelial Compartment Ductal epithelial compartments (also known as pancreatic duct glands) are distributed along the pancreatic ducts and resemble blind outpouchings or small branches originating from the pancreatic ducts. The cell lining of these outpouchings consists of columnar-shaped cells, characterized by abundant supranuclear

58

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A

B

C

Centroacinar cell

D

Intralobular duct

Intercalated duct

Small interlobular duct

Main/large interlobular duct Acinar

Ductal

FIGURE 3.2  Anatomic organization of the pancreatic ductal network. A, Centroacinar cells are present at the junction between the intercalated duct and the acinar cell (white arrowhead; scale bar: 10 mm). B, Intercalated duct (also known as terminal duct) originates at the acini level and is composed of a cell characterized by minimal cytoplasm and a squamous-shaped appearance. The intercalated ducts merge into intralobular ducts (white arrowhead) that are lined by cuboidal epithelia and serve to drain an individual pancreatic lobule (scale bar: 10 mm). C, Intralobular ducts join to form small interlobular ducts that eventually merge into (D) larger interlobular ducts that are lined by cuboidal epithelium (scale bar: 10 mm). Exocrine pancreatic secretions ultimately reach the main pancreatic duct and are released in the duodenum through the ampulla of Vater (not shown). (Adapted from Reichert M, Rustgi AK. Pancreatic ductal cells in development, regeneration, and neoplasia. J Clin Invest. 2011;121:4572–4578.)

cytoplasm and basal-located nuclei.61 Their physiologic function remains under investigation, although there is evidence to suggest that these cells undergo selective expansion during chronic epithelial injuries. Some authors have hypothesized that cells in the ductal epithelial compartment could contribute, at least in part, to the development of mucinous metaplasia and pancreatic intraepithelial neoplasia.70

Neurohormonal Regulation of Exocrine Pancreatic Function Digestive and Interdigestive Periods of Pancreatic Secretion Pancreatic exocrine secretion can be temporally categorized into an interdigestive and digestive secretion period. Between meals, the intestinal migrating myoelectric complex (MMC) is responsible for the cyclic stimulation of the exocrine pancreas (interdigestive period).71 The cholinergic stimuli that regulate the MMC cause cyclic pancreatic secretion of a fluid rich in bicarbonate (every 60–120 minutes). These secretions appear to facilitate the removal of bacteria and food debris from the small intestine; however, definitive agreement on their function has not been reached.72 The digestive secretion period begins after the ingestion of a meal bolus and is characterized by three distinct phases:

cephalic, gastric, and intestinal. Each phase is determined by the location of the meal bolus in the GI tract, and it is regulated by different secretory signals.72 The cephalic phase, elicited by the anticipation of food, smell, taste, and chewing act, stimulates exocrine secretion via the vagus nerve.73 In this initial phase, pancreatic secretions are mainly composed of digestive enzymes and low levels of bicarbonate, indicating an acinar-type secretion principally. ACh is the primary neurotransmitter, although acinar cells have been shown to express G protein-coupled receptors (GPCRs) for gastrin-releasing peptide (GRP) and VIP, suggesting a role for these peptides in the cephalic phase.74,75 The gastric phase is initiated once the meal reaches the stomach and is stimulated by gastric distention.76 A low volume of enzyme-rich secretion characterizes this phase, and it is accompanied by minimal water and bicarbonate secretion. The intestinal phase begins with the entry of chyme and gastric acid juice into the duodenum. In this phase, one of the main regulatory mechanisms is the vasovagal enteropancreatic reflex mediated through the dorsal vagus center. The presence of chyme in the duodenum activates efferent fibers of enteric neurons that stimulate intrapancreatic postganglionic neurons to release ACh. In addition, hydrogen ions (pH, # 4.5) stimulate duodenal S cells to release secretin into the bloodstream.

  Chapter 3  Pancreatic Physiology and Functional Assessment

Secretin acts primarily on ductal cells through its receptor GPCR, causing the release of fluid and bicarbonate and, to a lesser extent, acinar secretion.77

Water, Bicarbonate, and Ion Secretion from the Ductal Network The role of the ductal network is of paramount importance for the optimal function of the exocrine pancreas. The ductal network cells are primarily under the control of secretin, which stimulates the centroacinar and ductal cells to release water and bicarbonate.77 These secretions act as vehicles for the transport of inactive digestive zymogens from the acinar cells to the duodenum. Furthermore, their alkaline nature (pH, 7.6–9.0) helps neutralize the acidic chyme, in which nutrients are delivered from the stomach, resulting in an optimal neutral pH for the action of digestive enzymes. The concentration of sodium bicarbonate (NaHCO3) in pancreatic secretions can reach up to 140 to 150 mM, and chloride secretion varies inversely to bicarbonate concentration, keeping [HCO32] 1 [Cl2] constant at approximately 160 mM.65 Secretin promotes an increase of blood flow to the entire organ.77 During a meal, the blood flow to the pancreas increases as much as 4 mL/min from a baseline of 0.2 or 0.3 mL/min.72

Regulation of Exocrine Secretion Pancreatic secretions are tightly regulated through an intricate network of neural, humoral, and paracrine mediators. Many neurotransmitters, hormones, and growth factors have been reported to influence pancreatic exocrine function. These agents include but are not limited to, ACh and catecholamine, secretin (as earlier), nitric oxide (NO), VIP, GRP, neuropeptide Y, galanin, substance P, CGRP, gastrin/cholecystokinin (CCK), and enkephalins.60,78,79 Evidence suggests that muscarinic receptors (M1 and M3) are predominantly expressed on acinar cells and are involved in regulating exocrine function, making ACh the principal neurotransmitter.80 This is supported by studies examining the mechanism of action of CCK. During the intestinal phase of pancreatic secretion, the I cell of the duodenum (also present in the jejunum) releases CCK primarily in response to products of the digestion of fat, protein, and, to a lesser extent, starch. CCK then causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively. Although only low levels of CCK receptor protein have been identified on human acinar cells, intrapancreatic vagal nerve terminals express CCK receptors.81–83 These receptors bind CCK and release ACh in the proximity of acinar cells. This suggests that the cholinergic pathway regulates exocrine function. Additional studies support this hypothesis because the effect of CCK on pancreatic exocrine secretion can be prevented and almost abolished by atropine administration.7,84–86 Some ingested nutrients exert direct or indirect regulatory effects on pancreatic cells. Amino acids, especially phenylalanine, valine, methionine, and tryptophan, are potent stimulants of exocrine pancreatic secretion. Furthermore, intraluminal fatty acids, monoglycerides, and, to a lesser extent, glucose stimulate the secretion of digestive enzymes during the intestinal phase.72

Feedback Inhibitory Regulation Feedback regulation to the exocrine pancreas is provided by signals originating in the proximal and distal intestine.

59

The main factors identified are monitor peptide, luminal CCKreleasing factor (LCRF), secretin-releasing factors (e.g., phospholipase A2), and peptide tyrosine tyrosine (PYY).60,87–90 The action of these enzymes is dependent on the presence or the absence of intraluminal trypsin. Evidence suggests that trypsin inactivates monitor peptide and LCRF, therefore preventing augmentation of CCK release from the I cell. Once trypsin is occupied by the presence of meal chyme, monitor peptide and LCRF are not digested and can augment CCK release from the I cell. Eventually, the excess of digestive protease in the duodenal lumen leads to the digestion of both monitor peptide and LCRF, preventing further pancreatic enzyme secretion.72 Neuroendocrine L cells present in ileum and colon are stimulated by intraluminal oleic acid to release PYY. Oleic acid is a centrally active neuropeptide that exerts its action on the area postrema of the brain, decreasing vagal cholinergic mediation of CCK-stimulated pancreatic secretion.7,91

Digestive Enzymes The exocrine pancreas releases proteolytic, amylolytic, lipolytic, and nuclease digestive enzymes. These enzymes are stored in zymogen granules either as proenzymes (i.e., trypsinogen, chymotrypsinogen, procarboxypeptidase, prophospholipase, proelastase, mesotrypsin) or as active enzyme (i.e., a-amylase, lipase, DNase, RNase).92 In addition, the zymogen granules contain a trypsin inhibitor molecule known as pancreatic secretory trypsin inhibitor (PSTI).93 PSTI forms a stable complex with trypsin near its catalytic site, preventing its undesired activation.94 After acinar stimulation, the zymogen granules fuse with the apical acinar cell membrane, releasing their contents in the pancreatic intercalated ducts that will eventually reach the intestinal lumen. A brush-border glycoprotein peptidase present on the duodenal lumen, known as enterokinase, activates trypsinogen by removing its N-terminal hexapeptide fragment. The active form of trypsin is responsible for the catalytic activation of the remaining pancreatic proenzymes.92 One characteristic of the acinar cell is its capacity to adapt the synthesis of digestive enzymes as a function of diet. Although the mechanisms by which acinar cells are capable of this adaptation remain under investigation, it is reasonable to believe that the regulation occurs at the level of gene transcription.

Stimulus-Secretion Coupling in Acinar Cell An increase in the intracellular concentration of calcium is the major event that stimulates the acinar cells to release the secretory granules containing the digestive enzymes (Fig. 3.3).95 Transmembrane heterotrimeric G proteins are the principal receptors for pancreatic acinar cell secretagogues and produce secondary messengers that ultimately act to release intracellular calcium.96 Secretin and VIP bind to their specific GPCRs and cause activation of adenylate cyclase, generation of cAMP, and activation of protein kinase A.77 CCK, ACh, bombesin/GRP, PAR-2–activating protease, and substance P bind to their respective GPCRs, ultimately acting through the activation of phospholipase C and the production of IP3.83,97 IP3 binds to its receptor in the endoplasmic reticulum and stimulates Ca21 release. Ultimately, activated protein kinase A and protein kinase C phosphorylate specific intracellular proteins that lead to the secretion of pancreatic enzymes.

60

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

ACINAR LUMEN Gα q*

CCK

Gα q

CENTROACINAR CELL

IP3 PIP2

ACh

SUBSTANCE P

Intracellular Ca2+ store

Phospholipase-C

ACINAR CELL

Gα q DAG

↑ BOMBESIN

Gαq

Cytosolic Ca2+ Secretion

Protein Kinase C

Protein Phosphorylation

Protein Kinase A SECRETIN

†Gas Adenylate Cyclase

VIP

cAMP

Gα s

CENTROACINAR CELL

FIGURE 3.3  Stimulus-secretion coupling in pancreatic acinar cell. The primary secretagogues for acinar secretions bind to two types of cell surface heterotrimeric G protein receptors. Acetylcholine (ACh; the primary secretagogue for acinar secretion), cholecystokinin (CCK), substance P, and bombesin act through heterotrimeric G-protein–coupled receptors (GPCRs) associated with phospholipase C. This results in the production of two main messengers: inositol-1,4,5-triphosphate (IP3), which promotes the release of Ca21 from intracellular stores; diacylglycerol (DAG), which prompts the activation of protein kinase C (PKC). The increase in cytoplasmic Ca21 concentration and activated PKC leads to protein phosphorylation and digestive enzyme secretion. Secretin and vasoactive intestinal peptide (VIP) act through heterotrimeric GPCRs associated with adenylate cyclase. Elevation in cytoplasmic cyclic adenosine monophosphate (cAMP) levels causes the activation of protein kinase A (PKA), which ultimately leads to protein phosphorylation and digestive enzymes secretion. The centroacinar cells are terminal ductal cells in close contact with acinar cells and could represent progenitor multipotent pancreatic cells. *Gaq, Membrane-associated heterotrimeric G protein that activates phospholipase C (PLC); †Gas, membrane-associated heterotrimeric G protein that activates the cAMP-dependent pathway by activating adenylate cyclase; PIP2, phosphatidylinositol-4,5-bisphosphate.

Stimulus-Secretion Coupling in the Ductal Cell The apical and the basolateral portion of the ductal cells are involved in the stimulus-coupling secretion (Fig. 3.4). The apical membrane of ductal cells is equipped with cAMP-activated Cl2channels (also known as the cystic fibrosis transmembrane conductance regulator), Cl2-HCO32 exchanger (SLC26A3/A6), and water channels aquaporin (AQP) 5. The basolateral membrane is rich in a Na1-H1 exchanger, N1,K1-ATPase, K1 conductance channels, and AQP1 (localized in both apical and basolateral membrane). The interstitial portion of the ductal cells expresses receptors for the two major stimulants of ductal secretion: secretin and ACh.65,98 Secretin binds to its cellular receptor, leading to the activation of adenylate cyclase and protein kinase A. ACh binds to the cellular receptor causing activation of protein kinase C and an increase in intracellular calcium concentration.

The result is the activation of cAMP-dependent Cl2 channel that releases intracellular Cl2 into the ductal space, increasing the amount of Cl2 available for the Cl2-HCO32 exchanger. The high concentration of ductal Cl2 activates a Cl2HCO32 antiport that results in an exchange of Cl2 for HCO32. Furthermore, Na1 and H2O are released into the ductal space drowned by the ionic and osmotic gradient generated by the presence of bicarbonate in the duct lumen. Several K1 channels are present in the ductal cell membrane and appear to have an essential role in generating and maintaining the electrochemical driving force for anion secretion. Ductal HCO32 secretion is not only regulated by GI hormones and cholinergic nerves but is also influenced by luminal factors: intraductal pressure, calcium concentration, and pathologic activation of protease and bile reflux.65,98

  Chapter 3  Pancreatic Physiology and Functional Assessment

61

Pancreatic Ductal Lumen +

Na

–

–

Cl

H2O

HCO3–

Cl

SLC26A3/A6

CFTR HCO3–

Cl– Protein Kinase A cAMP

CO2 + H2O Carbonic Anhydrase

H+ + HCO3–

Adenylate Cyclase

H+

Na+

Na+

Gαs*

ATP CO2

Na+ H2O

K+

SECRETIN

H+

Na+

Na+

K+

Interstitial Fluid

Capillary

FIGURE 3.4  Stimulus-secretion coupling in pancreatic ductal cells. Carbon dioxide (CO2) diffuses from the blood across the duct cell’s basolateral membrane and is hydrated by carbonic anhydrase within the duct cell to form carbonic acid (H2CO3). Eventually, carbonic acid dissociates into H1 and HCO32. The extrusion of H1 via Na1-H1 exchanger, located across the basolateral membrane, leads to the accumulation of bicarbonate (HCO32) in the ductal cell. The intracellular bicarbonate (HCO32) is then secreted into the ductal lumen by a chloride/bicarbonate (Cl2/HCO32) exchanger (SLC26A3/A6) in exchange for luminal Cl2. The cystic fibrosis transmembrane conductance regulator (CFTR) channel recycles Cl2 back into the ductal lumen, making it available for a new exchange. Secretin, the most important ductal cell secretagogue, binds to its heterotrimeric G protein-coupled receptors, associated with adenylate cyclase located in the basolateral membrane. The resulting increase in cyclic adenosine monophosphate (cAMP) leads to the activation of protein kinase A (PKA), resulting in the activation of the CFTR channel. The activated CFTR channel accelerates the extrusion of Cl2 from the cell to the ductal lumen, causing the apical Cl2/HCO32 to operate at a faster rate, leading to an increase in HCO32 secretion into the ductal lumen. The net passage of bicarbonate across the duct cell generates an ionic and osmotic gradient, which favors paracellular passage of sodium and water into the ductal space. ATP, Adenosine triphosphate; *Gas, membrane-associated heterotrimeric G protein that activates the cAMP-dependent pathway by activating adenylate cyclase.

FUNCTIONAL ASSESSMENT Assessment of Endocrine Function The evaluation of the endocrine pancreas revolves around the assessment of b-cell function. These assessments should consider the capacity of the b-cell to produce insulin, the response of the b-cells to secretagogue stimuli and the peripheral tissue resistance to insulin (characteristic of T2DM). Although each of these factors is important for accurate assessment of b-cell function, their evaluation under physiologic conditions can be cumbersome. Among the challenges is the nonlinear relationship between insulin secretion and insulin sensitivity, the nonconstant clearance of circulating insulin and hepatic extraction, and the dynamic insulin response to secretagogues stimuli. Several test “models” have been developed to account for the full range of factors that influence b-cell function; however, many are challenging to execute and lack standardization or accuracy.99,100 Methods for evaluation of b-cell function include basal measurement of plasma concentration of b-cell products, intravenous (IV) stimulation tests, and oral stimulation tests.

The simplest evaluation methods of b-cell function require basal measurement of plasma concentration of fasting insulin, fasting C-peptide, fasting proinsulin/insulin ratio, and the homeostatic model assessment test. However, these tests often lack standardization and are hindered by their wide range of sensitivity and specificity.99 The IV stimulation tests are mainly used for research purposes, and their clinical application is limited. These tests include the IV tolerance test, the hyperglycemic glucose clamp, the graded glucose infusion, and the arginine stimulation test.99 The oral stimulation tests are more commonly used in clinical practice and include the oral glucose tolerance test (OGTT) and the mixed meal tolerance test (MTT). The OGTT and the MTT provide a more physiologic stimulus to insulin secretion because these tests elicit the full incretin effect101; furthermore, both tests take advantage of mathematical models that normalize insulin secretion levels to varying plasma glucose concentrations.99 The OGTT is widely used in clinical practice. After an overnight fast, subjects are administered an oral glucose load (approximately 75 g).102 Blood samples are collected at baseline and at subsequent intervals to

62

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

evaluate plasma concentration of insulin, glucose, C-peptide, and other parameters of interest. Impaired glucose tolerance is defined by a 2-hour glucose value during an oral glucose tolerance test (OGTT) of 7.8 mmol/L to 11.0 mmol/L, whereas overt T2DM presents values greater than or equal to 11.1 mmol/L.103 One of the significant limitations of this test is its dependency on the unpredictable and variable intestinal absorption of glucose.

Assessment of Exocrine Function Exocrine pancreatic insufficiency in adults is often the result of pancreatic inflammatory processes (e.g., CP) and often a clinical problem after pancreatic or gastric surgery, and it leads to maldigestion of fat, protein, and carbohydrates104 (see Chapters 58, 62, and 117). Ultimately, this will result in steatorrhea (.7 g of fecal fat in 24 hours), weight loss, and eventually malnutrition. The human pancreatic gland has a significant functional reserve; therefore more than 90% of pancreatic parenchyma must be lost before overt steatorrhea becomes evident.105 Imaging studies (e.g., computed tomography [CT], magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP]) can promptly identify advanced stages of pancreatic inflammation.106 Nevertheless, the mild or initial forms of CP are characterized by minimal anatomic changes and represent a diagnostic challenge.107 It is in the latter scenario that pancreatic function tests would find their best application. Pancreatic function tests (PFTs) can be grouped into two major categories: indirect tests and direct tests (Table 3.1). Indirect PFTs are noninvasive tests that focus on evaluating the consequences resulting from diminished or absent digestive enzymes (e.g., steatorrhea). Direct PFTs aim to quantify and characterize pancreatic secretory content (i.e., digestive enzyme, bicarbonate, and secretion volume); some tests require pancreatic stimulation by administering a meal or hormonal secretagogues (e.g., secretin, CCK). Direct PFTs are further divided into invasive, requiring GI instrumentation via a double-lumen gastroduodenal tube, and not invasive (often characterized by a lower sensitivity). Endoscopic versions of direct pancreatic tests have been developed (ePFT) in which pancreatic fluid secretions are collected directly from the second portion of the duodenum under direct visualization with an endoscope.108,109 Besides, endoscopic

TABLE 3.1  Tests of Exocrine Pancreatic Function INDIRECT TESTS

DIRECT TESTS

Fecal fat quantification Qualitative (Sudan stain) Quantitative (72-hour stool collection) 13 C-Mixed triglyceride breath test

Noninvasive Tests Serum trypsinogen Fecal chymotrypsin Fecal elastase-1 Invasive Tests Lundh test Secretin test CCK test Secretin-CCK test Secretagogues and Imaging Secretin-enhanced MRI Secretin-enhanced MRCP

CCK, Cholecystokinin; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography.

ultrasound allows for simultaneous structural evaluation of the pancreatic parenchyma.110 Several different protocols for each test have been developed, but a gold standard test has not been identified.

Indirect Pancreatic Test Indirect pancreatic tests are noninvasive tests that are well tolerated by patients, although they are characterized by lower sensitivity than direct tests, especially in the earlier stages of pancreatic exocrine insufficiency. One of the least invasive tests is the quantification of fecal fat. It can be qualitative (Sudan stain) or quantitative (72-hour stool collection) and often useful to evaluate the response to pancreatic enzyme replacement therapy.111 In the most common form, patients are required to assume a diet of 100 g/day fat for 5 days and to collect the complete volume of feces for 3 days, starting on day 3. Fecal content greater than 7 g/day is considered abnormal, and it is diagnostic for steatorrhea. This test poses an unpleasant burden on laboratory personnel, and its diagnostic utility is limited to the advanced stages of pancreatic insufficiency. An alternative test available to quantify fat malabsorption is the 13C–mixed triglyceride breath test. This test requires the oral administration of a 13C–market substrate and relies on the presence of intestinal pancreatic lipase activity. Ultimately, the 13C–market substrate is hydrolyzed by the intestinal lipase, yielding 13CO2 that is absorbed and eventually released across the pulmonary endothelium and quantified via mass spectrometry or infrared analysis. This test could represent a practical alternative to the fecal fat test, although it is subject to similar limitations of all indirect tests with limited accuracy for the early phases of pancreatic insufficiency.112,113

Direct Pancreatic Function Test Noninvasive direct PFTs aim to quantify the fecal or serum levels of pancreas-derived enzymes (e.g., serum trypsinogen, fecal chymotrypsin, and fecal elastase). Although easy to perform and well tolerated by patients, noninvasive PFTs are hindered by their low sensitivity, often leading to inconclusive results, especially in the early phases of CP. Furthermore, fecal measurement of pancreatic enzyme can lead to false-positive results in the setting of nonpancreatic GI disturbances and diarrhea. Serum trypsinogen is considered a sensitive and specific test for advanced pancreatic insufficiency, although its accuracy for earlier stages of pancreatic insufficiency is low. A serum trypsinogen concentration of less than 20 ng/mL is considered a reasonable cutoff for the diagnosis of pancreatic insufficiency.114 Fecal chymotrypsin concentration can be used for the evaluation of pancreatic insufficiency. Chymotrypsin is specifically synthesized and secreted by the acinar cells of the pancreas. This test is influenced by exogenous pancreatic enzyme administration and requires suspension of enzyme administration for at least 2 days before the test.115 Furthermore, chymotrypsin is not an ideal marker because it is degraded during intestinal transit and can be diluted in the presence of diarrhea, leading to false-positive results. Fecal elastase-1 appears to be a more reliable test compared with fecal chymotrypsin. Elastase-1 is not influenced by exogenous pancreatic enzyme administration, and it is more stable than chymotrypsin during intestinal transit. Evidence suggests

  Chapter 3  Pancreatic Physiology and Functional Assessment

that this study has a reasonably high sensitivity and specificity for pancreatic insufficiency.116 Results obtained with the fecal elastase-1 test reliably correlate with the one obtained using imaging studies (ERCP, magnetic resonance neurography [MRN])117 or the more sensitive direct invasive pancreatic tests (secretin test).118,119 Level of fecal elastase-1 less than or equal to 15 mg/g of stool (enzyme-linked immunoabsorbent assay on spot fecal sample) are diagnostic for pancreatic insufficiencies in patients with CP.120 Nevertheless, fecal elastase-1 tests are often unreliable after pancreatic resection, where pancreatic insufficiency results from a combination of factors not solely dependent on decreased pancreatic function (e.g., abnormal hormonal stimulation, abnormal mixing of food with digestive secretions, acidic intraluminal pH).120 Furthermore, fecal elastase-1 levels are not influenced by the exogenous administration of pancreatic enzyme, and therefore this test cannot be used to evaluate the response to pancreatic enzyme replacement therapy.116,121 Invasive direct PFTs require the use of a double-lumen collection tube, with one lumen terminating in the duodenum to collect pancreatic secretions and one lumen resting in the gastric antrum to prevent gastric fluid from entering the duodenum. Correct tube placement is confirmed via fluoroscopy before administration of meal or secretagogues, and then pancreatic secretions are collected for 1 to 2 hours. Alternatively, an endoscope can be used, and pancreatic fluid can be collected directly through the cannulation of the pancreatic duct or through the suction channel of the endoscope under direct visualization from the duodenum. Of historic interest is the Lundh test,122 where a physiologic stimulus to pancreatic secretion is obtained through the administration of a standardized meal (composed of 300 mL of solution containing 15% carbohydrate, 6% fat, and 5% protein). Endogenous secretin and CCK, released in response to the standardized meal, are necessary to stimulate pancreatic secretion, making the Lundh test dependent on normal duodenal mucosal function.72,121 The hormone-stimulated tests are the cornerstone of the direct invasive pancreatic tests. These tests use the exogenous administration of secretin, CCK, or a combination of secretin-CCK as a more reliable method of pancreatic stimulation.123,124 The secretin test requires IV administration of a synthetic secretin bolus (0.2 mg/kg), followed by a continuous collection of duodenal fluid in four aliquots of 15-minute intervals each. The test measures bicarbonate concentration in each of the four aliquot samples. Exocrine insufficiency is evident when bicarbonate concentrations less than 80 mEq/L are recorded in each of the four aliquots, and severe exocrine insufficiency is diagnosed when bicarbonate concentration is less than 50 mEq/L.125 Moreover, the test can quantify the total volume output as well as the total amount of bicarbonate secreted.

63

These measurements are employed as a secondary diagnostic test when bicarbonate concentrations are equivocal. Although theoretically useful, these tests are not commonly employed because they are hindered by the low accuracy caused by incomplete recovery of duodenal fluid. Alternative approaches have been developed to overcome the challenges of gastroduodenal tube placement. One of these approaches is the purely endoscopic secretin test (ePFT). This test has been shown to have similar accuracy to the classic secretin test. Duodenal aspirates are obtained through an endoscope at 0, 15, 30, 45, and 60 minutes after secretin stimulation and analyzed for bicarbonate concentration.109,126 Another attempt made to overcome the limitations of duodenal fluid collection consists of the use of ERCP for the analysis of pure pancreatic secretion collected directly from the pancreatic duct, but the results obtained with this method have been unsatisfactory.127 CCK tests using either CCK or a receptor agonist (e.g., cerulein) have been developed to measure pancreatic enzyme secretion. A simplified version of these tests measures lipase concentration from duodenal fluid collected over an 80-minute period and uses a cutoff lipase value of 780 IU/L.128 Acinar and ductal pancreatic exocrine function can be evaluated simultaneously using the secretin-CCK test. This test requires continuous collection of duodenal fluid and measurement of total secretion output, bicarbonate concentration, and digestive enzyme concentration.129 Some patients may have a more pronounced deficit of one specific enzyme; therefore measuring more than one digestive enzyme (i.e., amylase, lipase, and tryptase) in addition to bicarbonate can increase the sensitivity of this test. One pitfall of the secretin-CCK test is that the large amount of fluid released by the pancreas after secretin stimulation, combined with CCK-stimulated gallbladder contraction, ultimately results in dilution of the digestive enzymes. To avoid false positive results, some authors have advocated the use of perfusion markers, although no definitive agreement exists. Of recent interest are tests combining secretagogues with imaging techniques. Examples of these tests are the secretinenhanced MRI and the secretin-enhanced MRCP.130–133 Secretin-enhanced MRI uses diffusion-weighted MRI imaging to evaluate increase in pancreatic capillary blood flow and pancreatic secretion after stimulation with secretin. In addition, secretin-enhanced MRCP allows evaluation of duodenal filling as a function of pancreatic secretion.132,134 Although growing enthusiasm is developing around these tests, further studies are necessary to evaluate their performances with standard invasive tests. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

63.e1

REFERENCES 1. Gray H, Lewis WH, ed. Gray’s Anatomy of the Human Body. 20th ed. Bartleby; 2000. 2. Syed AB, Mahal RS, Schumm LP, Dachman AH. Pancreas size and volume on computed tomography in normal adults. Pancreas. 2012;41(4):589-595. 3. Cano DA, Soria B, Martín F, Rojas A. Transcriptional control of mammalian pancreas organogenesis. Cell Mol Life Sci. 2014; 71(13):2383-2402. 4. Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn. 2011;240(3):530-565. 5. Boron WF, Boulpaep EL. Medical Physiology. 2nd ed. Saunders/ Elsevier; 2012. 6. Moore KL, Dalley AF, Agur AMR, eds. Abdomen. In: Clinically Oriented Anatomy. LWW; 2013:265-268. 7. Mussa BM, Verberne AJM. The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function. Exp Physiol. 2013;98(1):25-37. 8. Rodriguez-Diaz R, Abdulreda MH, Formosa AL, et al. Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab. 2011;14(1):45-54. 9. Barker CJ, Leibiger IB, Berggren PO. The pancreatic islet as a signaling hub. Adv Biol Regul. 2013;53(1):156-163. 10. Jain R, Lammert E. Cell-cell interactions in the endocrine pancreas. Diabetes Obes Metab. 2009;11(Suppl 4):159-167. 11. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA. 2006;103(7):2334-2339. 12. Bonner-Weir S. The microvasculature of the pancreas, with emphasis on that of the islets of Langerhans. In: Go VLW, DiMagno EP, Gardner JD, et al., eds. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. Raven; 1993. 13. Merkwitz C, Blaschuk OW, Schulz A, et al. The ductal origin of structural and functional heterogeneity between pancreatic islets. Prog Histochem Cytochem. 2013;48(3):103-140. 14. Banting FG. An address on diabetes and insulin: being the Nobel Lecture delivered at Stockholm on September 15th, 1925. Can Med Assoc J. 1926;16(3):221-232. 15. Rorsman P, Braun M. Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol. 2013;75(1):155-179. 16. Marques RG, Fontaine MJ, Rogers J. C-peptide: much more than a byproduct of insulin biosynthesis. Pancreas. 2004;29(3):231-238. 17. Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med. 2013;30(7):803-817. 18. Song SH, Kjems L, Ritzel R, et al. Pulsatile insulin secretion by human pancreatic islets. J Clin Endocrinol Metab. 2002;87(1):213-221. 19. van de Bunt M, Gloyn AL. A tale of two glucose transporters: How GLUT2 re-emerged as a contender for glucose transport into the human beta cell. Diabetologia. 2012;55(9):2312-2315. 20. McCulloch LJ, van de Bunt M, Braun M, Frayn KN, Clark A, Gloyn AL. GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus. Mol Genet Metab. 2011;104(4):648-653. 21. Tan GD. The pancreas. Anaesth Intensive Care Med. 2014;15(10): 485-488. 22. Lenzen S. A fresh view of glycolysis and glucokinase regulation: history and current status. J Biol Chem. 2014;289(18):12189-12194. 23. Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes. 1998;47(3):307-315. 24. Rorsman P, Ramracheya R, Rorsman NJG, Zhang Q. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion. Diabetologia. 2014;57(9):1749-1761. 25. Yang SN, Shi Y, Yang G, Li Y, Yu J, Berggren PO. Ionic mechanisms in pancreatic b cell signaling. Cell Mol Life Sci. 2014;71(21):4149-4177. 26. Rutter GA, Hodson DJ. Minireview: Intraislet regulation of insulin secretion in humans. Mol Endocrinol. 2013;27(12):1984-1995. 27. Nagamatsu S, Ohara-Imaizumi M, Nakamichi Y, Kikuta T, Nishiwaki C. Imaging docking and fusion of insulin granules induced by antidiabetes agents: Sulfonylurea and glinide drugs preferentially

mediate the fusion of newcomer, but not previously docked, insulin granules. Diabetes. 2006;55(10):2819-2825. 28. Henquin JC. Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia. 2009;52(5):739-751. 29. Huang M, Joseph JW. Assessment of the metabolic pathways associated with glucose-stimulated biphasic insulin secretion. Endocrinology. 2014;155(5):1653-1666. 30. Stamper IJ, Wang X. Mathematical modeling of insulin secretion and the role of glucose-dependent mobilization, docking, priming and fusion of insulin granules. J Theor Biol. 2013;318:210-225. 31. Smith PA, Sakura H, Coles B, Gummerson N, Proks P, Ashcroft FM. Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. J Physiol. 1997;499(Pt 3): 625-635. 32. Clemmensen C, Smajilovic S, Smith EP, et al. Oral l-arginine stimulates GLP-1 secretion to improve glucose tolerance in male mice. Endocrinology. 2013;154(11):3978-3983. 33. Tolhurst G, Reimann F, Gribble FM. Nutritional regulation of glucagon-like peptide-1 secretion. J Physiol. 2009;587(Pt 1):27-32. 34. Diab DL, D’Alessio DA. The contribution of enteroinsular hormones to the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep. 2010;10(3):192-198. 35. Opinto G, Natalicchio A, Marchetti P. Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity. Arch Physiol Biochem. 2013;119(4):170-178. 36. Drucker DJ. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes. 2013;62(10):3316-3323. 37. Ahrén B. Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives. Diabetes Metab. 2013;39(3):195-201. 38. Rodriguez-Diaz R, Dando R, Jacques-Silva MC, et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med. 2011;17(7):888-892. 39. Molina J, Rodriguez-Diaz R, Fachado A, Jacques-Silva MC, Berggren PO, Caicedo A. Control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes. 2014;63(8):2714-2726. 40. Ruiz de Azua I, Gautam D, Guettier JM, Wess J. Novel insights into the function of b-cell M3 muscarinic acetylcholine receptors: therapeutic implications. Trends Endocrinol Metab. 2011;22(2):74-80. 41. Ohta Y, Kosaka Y, Kishimoto N, et al. Convergence of the insulin and serotonin programs in the pancreatic b-cell. Diabetes. 2011;60(12):3208-3216. 42. Sanlioglu AD, Karacay B, Balci MK, Griffith TS, Sanlioglu S. Therapeutic potential of VIP vs PACAP in diabetes. J Mol Endocrinol. 2012;49(3):R157-R167. 43. Valicherla GR, Hossain Z, Mahata SK, Gayen JR. Pancreastatin is an endogenous peptide that regulates glucose homeostasis. Physiol Genomics. 2013;45(22):1060-1071. 44. Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):10391048. 45. Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab. 2011;13(Suppl 1):118-125. 46. Gylfe E, Gilon P. Glucose regulation of glucagon secretion. Diabet Res Clin Pract. 2014;103(1):1-10. 47. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334(4):246-254. 48. Allen PJ, Gönen M, Brennan MF, et al. Pasireotide for postoperative pancreatic fistula. N Engl J Med. 2014;370(21):2014-2022. 49. Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides. 2012;46(6):261-274. 50. Maeda H, Hanazaki K. Pancreatogenic diabetes after pancreatic resection. Pancreatology. 2011;11(2):268-276. 51. Wierup N, Sundler F, Heller RS. The islet ghrelin cell. J Mol Endocrinol. 2014;52(1):R35-R49. 52. Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur J Endocriol. 2014;171(1):R21-R32. 53. Sakata N, Yoshimatsu G, Kodama S. Development and characteristics of pancreatic epsilon cells. Int J Mol Sci. 2019;20(8):1867. 54. Das SLM, Singh PP, Phillips ARJ, Murphy R, Windsor JA, Petrov MS. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut. 2014;63(5): 818-831.

63.e2 55. Zhi M, Zhu X, Lugea A, Waldron RT, Pandol SJ, Li L. Incidence of new onset diabetes mellitus secondary to acute pancreatitis: a systematic review and meta-analysis. Front Physiol. 2019;10:637. 56. Ito T, Otsuki M, Itoi T, et al. Pancreatic diabetes in a follow-up survey of chronic pancreatitis in Japan. J Gastroenterol. 2007;42(4): 291-297. 57. Lévy P, Barthet M, Mollard BR, Amouretti M, Marion-Audibert AM, Dyard F. Estimation of the prevalence and incidence of chronic pancreatitis and its complications. Gastroenterol Clin Biol. 2006;30(6-7):838-844. 58. Hart PA, Andersen DK, Mather KJ, et al. Evaluation of a mixed meal test for diagnosis and characterization of pancreatogenic diabetes secondary to pancreatic cancer and chronic pancreatitis. Pancreas. 2018;47(10):1239-1243. 59. Seymour NE, Volpert AR, Lee EL, Andersen DK, Hernandez C. Alterations in hepatocyte insulin binding in chronic pancreatitis: effects of pancreatic polypeptide. Am J Surg. 1995;169(1):105-110. 60. Barreto SG, Carati CJ, Toouli J, Saccone GTP. The islet-acinar axis of the pancreas: more than just insulin. Am J Physiol. 2010;299(1): G10-G22. 61. Cleveland MH, Sawyer JM, Afelik S, Jensen J. Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells. Sem Cell Dev Biol. 2012;23(6):711-719. 62. Hegyi P, Petersen OH. The exocrine pancreas: the acinar-ductal tango in physiology and pathophysiology. Rev Physiol Biochem Pharmacol. 2013;165:1-30. 63. Pandiri AR. Overview of exocrine pancreatic pathobiology. Toxicol Pathol. 2014;42(1):207-216. 64. Ashizawa N, Sakai T, Yoneyama T, Naora H, Kinoshita Y. Threedimensional structure of peripheral exocrine gland in rat pancreas: reconstruction using transmission electron microscopic examination of serial sections. Pancreas. 2005;31(4):401-404. 65. Ishiguro H, Yamamoto A, Nakakuki M, et al. Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. Nagoya J Med Sci. 2012;74(1-2):1-18. 66. Leeson TS, Leeson R. Close association of centroacinar/ductular and insular cells in the rat pancreas. Histol Histopathol. 1986;1(1): 33-42. 67. Pour PM. Pancreatic centroacinar cells. The regulator of both exocrine and endocrine function. Int J Pancreatol. 1994;15(1):51-64. 68. Seymour PA, Freude KK, Tran MN, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA. 2007;104(6):1865-1870. 69. Stanger BZ, Stiles B, Lauwers GY, et al. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell. 2005;8(3):185-195. 70. Strobel O, Rosow DE, Rakhlin EY, et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology. 2010;138(3): 1166-1177. 71. Zimmerman DW, Sarr MG, Smith CD, et al. Cyclic interdigestive pancreatic exocrine secretion: is it mediated by neural or hormonal mechanisms? Gastroenterology. 1992;102(4 Pt 1):1378-1384. 72. Pandol SJ. The Exocrine Pancreas. Morgan & Claypool Life Sciences; 2010. 73. Power ML, Schulkin J. Anticipatory physiological regulation in feeding biology: cephalic phase responses. Appetite. 2008;50(2-3): 194-206. 74. Anagnostides A, Chadwick VS, Selden AC, Maton PN. Sham feeding and pancreatic secretion. Evidence for direct vagal stimulation of enzyme output. Gastroenterology. 1984;87(1):109-114. 75. Holst JJ, Knuhtsen S, Jensen SL, Fahrenkrug J, Larsson LI, Nielsen OV. Interrelation of nerves and hormones in stomach and pancreas. Scand J Gastroenterol Suppl. 1983;82:85-99. 76. Kreiss C, Schwizer W, Erlacher U, et al. Role of antrum in regulation of pancreaticobiliary secretion in humans. Am J Physiol. 1996;270(5 Pt 1):G844-G851. 77. Chey WY, Chang TM. Secretin: historical perspective and current status. Pancreas. 2014;43(2):162-182. 78. Chandra R, Liddle RA. Neurohormonal regulation of pancreatic secretion. Curr Opin Gastroenterol. 2012;28(5):483-487. 79. Chandra R, Liddle RA. Recent advances in the regulation of pancreatic secretion. Curr Opin Gastroenterol. 2014;30(5):490-494. 80. Nakamura K, Hamada K, Terauchi A, et al. Distinct roles of M1 and M3 muscarinic acetylcholine receptors controlling oscillatory and non-oscillatory [Ca21]i increase. Cell Calcium. 2013;54(2):111-119.

81. Miyasaka K, Shinozaki H, Jimi A, Funakoshi A. Amylase secretion from dispersed human pancreatic acini: neither cholecystokinin a nor cholecystokinin B receptors mediate amylase secretion in vitro. Pancreas. 2002;25(2):161-165. 82. Niebergall-Roth E, Singer MV. Enteropancreatic reflexes mediating the pancreatic enzyme response to nutrients. Auton Neurosci. 2006;125(1-2):62-69. 83. Singer MV, Niebergall-Roth E. Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int. 2009;33(1):1-9. 84. Li Y, Hao Y, Owyang C. High-affinity CCK-A receptors on the vagus nerve mediate CCK-stimulated pancreatic secretion in rats. Am J Physiol. 1997;273(3 Pt 1):G679-G685. 85. Owyang C. Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am J Physiol. 1996;271(1 Pt 1):G1-G7. 86. Soudah HC, Lu Y, Hasler WL, Owyang C. Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol. 1992;263(1 Pt 1):G102-G107. 87. Li JP, Chang TM, Wagner D, Chey WY. Pancreatic phospholipase A2 from the small intestine is a secretin-releasing factor in rats. Am J Physiol Gastrointest Liver Physiol. 2001;281(2):G526-G532. 88. Liddle RA. Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol. 1995;269(3 Pt 1):G319-G327. 89. Moran TH, Kinzig KP. Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol. 2004;286(2): G183-G188. 90. Naruse S, Kitagawa M, Ishiguro H, Hayakawa T. Feedback regulation of pancreatic secretion by peptide YY. Peptides. 2002;23(2): 359-365. 91. Lin HC, Taylor IL. Release of peptide YY by fat in the proximal but not distal gut depends on an atropine-sensitive cholinergic pathway. Regul Pept. 2004;117(1):73-76. 92. Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007;52(1):1-17. 93. Kazal LA, Spicer DS, Brahinsky RA. Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas. J Am Chem Soc. 1948;70(9):3034-3040. 94. Pubols MH, Bartelt DC, Greene LJ. Trypsin inhibitor from human pancreas and pancreatic juice. J Biol Chem. 1974;249(7): 2235-2242. 95. Low JT, Shukla A, Thorn P. Pancreatic acinar cell: new insights into the control of secretion. Int J Biochem Cell Biol. 2010;42(10): 1586-1589. 96. Messenger SW, Falkowski MA, Groblewski GE. Ca21-regulated secretory granule exocytosis in pancreatic and parotid acinar cells. Cell Calcium. 2014;55(6):369-375. 97. Weiss FU, Halangk W, Lerch MM. New advances in pancreatic cell physiology and pathophysiology. Best Pract Res Clin Gastroenterol. 2008;22(1):3-15. 98. Steward MC, Ishiguro H. Molecular and cellular regulation of pancreatic duct cell function. Curr Opin Gastroenterol. 2009;25(5): 447-453. 99. Cersosimo E, Solis-Herrera C, Trautmann ME, Mallow J, Triplitt CL. Assessment of pancreatic b-cell function: review of methods and clinical applications. Curr Diabet Rev. 2014;10(1): 2-42. 100. Antuna-Puente B, Disse E, Rabasa-Lhoret R, Laville M, Capeau J, Bastard JP. How can we measure insulin sensitivity/resistance? Diabetes Metab. 2011;37(3):179-188. 101. Elrick H, Stimmler L, Hlad Jr., CJ, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24(10):1076-1082. 102. Cobelli C, Toffolo GM, Man CD, et al. Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab. 2007;293(1):E1-E15. 103. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 104. Nakamura H, Murakami Y, Uemura K, et al. Predictive factors for exocrine pancreatic insufficiency after pancreatoduodenectomy with pancreaticogastrostomy. J Gastrointest Surg. 2009;13(7): 1321-1327. 105. Lévy P, Domínquez-Muñoz E, Imrie C, Löhr M, Maisonneuve P. Epidemiology of chronic pancreatitis: burden of the disease and consequences. United European Gastroenterol J. 2014;2(5): 345-354.

63.e3 106. Tirkes T, Shah ZK, Takahashi N, et al. Reporting standards for chronic pancreatitis by using CT, MRI, and MR cholangiopancreatography: the consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer. Radiology. 2018;290(1):207-215. 107. Busireddy KK, AlObaidy M, Ramalho M, et al. Pancreatitisimaging approach. World J Gastrointest Pathophysiol. 2014;5(3): 252-270. 108. Law R, Lopez R, Costanzo A, Parsi MA, Stevens T. Endoscopic pancreatic function test using combined secretin and cholecystokinin stimulation for the evaluation of chronic pancreatitis. Gastrointest Endosc. 2012;75(4):764-768. 109. Tayler S, Parsi MA. Update on endoscopic pancreatic function testing. World J Gastroenterol. 2011;17(35):3957-3961. 110. Albashir S, Bronner MP, Parsi MA, Walsh RM, Stevens T. Endoscopic ultrasound, secretin endoscopic pancreatic function test, and histology: correlation in chronic pancreatitis. Am J Gastroenterol. 2010;105(11):2498-2503. 111. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19(42):7258-7266. 112. Keller J, Layer P, Brückel S, Jahr C, Rosien U. 13C-mixed triglyceride breath test for evaluation of pancreatic exocrine function in diabetes mellitus. Pancreas. 2014;43(6):842-848. 113. Nakamura H, Morifuji M, Murakami Y, et al: Usefulness of a 13Clabeled mixed triglyceride breath test for assessing pancreatic exocrine function after pancreatic surgery. Surgery. 2009;145(2): 168-175. 114. Jacobson DG, Curington C, Connery K, Toskes PP. Trypsin-like immunoreactivity as a test for pancreatic insufficiency. N Engl J Med. 1984;310(20):1307-1309. 115. Molinari I, Souare K, Lamireau T, et al. Fecal chymotrypsin and elastase-1 determination on one single stool collected at random: diagnostic value for exocrine pancreatic status. Clin Biochem. 2004;37(9):758-763. 116. Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8(7):405-415. 117. Bilgin M, Bilgin S, Balci NC, et al. Magnetic resonance imaging and magnetic resonance cholangiopancreatography findings compared with fecal elastase 1 measurement for the diagnosis of chronic pancreatitis. Pancreas. 2008;36(1):e33-e39. 118. Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996;39(4):580-586. 119. Stein J, Jung M, Sziegoleit A, Zeuzem S, Caspary WF, Lembcke B. Immunoreactive elastase I: clinical evaluation of a new noninvasive test of pancreatic function. Clin Chem. 1996;42(2):222-226. 120. Benini L, Amodio A, Campagnola P, et al. Fecal elastase-1 is useful in the detection of steatorrhea in patients with pancreatic diseases but not after pancreatic resection. Pancreatology. 2013; 13(1):38-42.

121. Nøjgaard C, Olesen SS, Frøkjaer JB, Drewes AM. Update of exocrine functional diagnostics in chronic pancreatitis. Clin Physiol Funct Imaging. 2012;33(3):167-172. 122. Lundh G. Pancreatic exocrine function in neoplastic and inflammatory disease; a simple and reliable new test. Gastroenterology. 1962;42:275-280. 123. Jowell PS, Robuck-Mangum G, Mergener K, Branch MS, Purich ED, Fein SH. A double-blind, randomized, dose response study testing the pharmacological efficacy of synthetic porcine secretin. Aliment Pharmacol Ther. 2000;14(12):1679-1684. 124. Somogyi L, Ross SO, Cintron M, Toskes PP. Comparison of biologic porcine secretin, synthetic porcine secretin, and synthetic human secretin in pancreatic function testing. Pancreas. 2003; 27(3):230-234. 125. Chowdhury RS, Forsmark CE. Review article: pancreatic function testing. Aliment Pharmacol Ther. 2003;17(6):733-750. 126. Stevens T, Conwell DL, Zuccaro, Jr, G, Lewis SA, Love TE. The efficiency of endoscopic pancreatic function testing is optimized using duodenal aspirates at 30 and 45 minutes after intravenous secretin. Am J Gastroenterol. 2007;102(2):297-301. 127. Draganov P, Patel A, Fazel A, Toskes P, Forsmark C. Prospective evaluation of the accuracy of the intraductal secretin stimulation test in the diagnosis of chronic pancreatitis. Clin Gastroenterol Hepatol. 2005;3(7):695-699. 128. Conwell DL, Zuccaro G, Morrow JB, et al. Analysis of duodenal drainage fluid after cholecystokinin (CCK) stimulation in healthy volunteers. Pancreas. 2002;25(4):350-354. 129. Lieb JG, Draganov PV. Pancreatic function testing: here to stay for the 21st century. World J Gastroenterol. 2008;14(20):31493158. 130. Balci NC, Smith A, Momtahen AJ, et al. MRI and S-MRCP findings in patients with suspected chronic pancreatitis: correlation with endoscopic pancreatic function testing (ePFT). JMRI. 2010;31(3):601-606. 131. Bian Y, Wang L, Chen C, et al. Quantification of pancreatic exocrine function of chronic pancreatitis with secretin-enhanced MRCP. World J Gastroenterol. 2013;19(41):7177-7182. 132. Chamokova B, Bastati N, Poetter-Lang S, et al. The clinical value of secretin-enhanced MRCP in the functional and morphological assessment of pancreatic diseases. Br J Radiol. 2018;91(1084): 20170677. 133. Hansen TM, Nilsson M, Gram M, Frøkjaer JB. Morphological and functional evaluation of chronic pancreatitis with magnetic resonance imaging. World J Gastroenterol. 2013;19(42):7241-7246. 134. Sanyal R, Stevens T, Novak E, Veniero JC. Secretin-enhanced MRCP: review of technique and application with proposal for quantification of exocrine function. AJR Am J Roentgenol. 2012; 198(1):124-132.

CHAPTER 4 Assessment of hepatic function: Implications for perioperative outcome and recovery Sean Bennett and Paul J. Karanicolas The limits of hepatic resectability are constantly expanding with our increased understanding of hepatic anatomy and refinements in surgical technique (see Chapters 2, 102, and 118B). In past years, partial hepatectomy was limited to anatomic resection and small-wedge resections, with a general consensus that two contiguous segments of hepatic parenchyma having adequate vascular inflow/outflow and biliary drainage was the minimum threshold for safe resection.1,2 This conventional definition served the surgical community well but has required refinement for two reasons. First, a variety of techniques have been developed that allow more extensive resection than this definition suggests, including induced hypertrophy of the future liver remnant (FLR; e.g., two-stage hepatectomy, portal vein embolization [PVE], associating liver partition and portal vein ligation for staged hepatectomy [ALPPS]), and nonanatomic parenchymal-sparing resections (see Chapter 102). Indeed, through these and other techniques, it may be possible to safely resect tumors from all segments of the liver while maintaining adequate postoperative liver function. Second, patients selected for partial hepatectomy are increasingly treated with preoperative chemotherapy or have other risk factors for background liver injury; in these patients, the minimal requirement of two contiguous segments of liver is likely too liberal and puts patients at an unacceptable risk for posthepatectomy liver failure (see Chapters 69, 89, 90, 98, 101, and 102). Given the trend toward more aggressive liver resections in patients at risk for background liver disease, thorough assessment of hepatic function is crucial. Liver function after hepatic resection is dependent on the quantity and quality of the FLR. Thus optimal assessment of fitness for liver resection would ideally incorporate some measure of FLR volume and function. This is particularly important in patients at risk for or documented evidence of background liver disease, including heavy alcohol consumption, hepatitis, cirrhosis, nonalcoholic steatohepatitis, and chemotherapy-associated liver injury, such as sinusoidal obstruction syndrome, steatosis, and chemotherapyassociated steatohepatitis (see Chapters 69 and 98). Surgeons contemplating major liver resection in patients with any of these risk factors should ensure that some measure of liver function, in addition to FLR volume, is considered. This chapter reviews these two critical components of FLR assessment in detail.

ASSESSMENT OF LIVER REMNANT VOLUME Extent of liver resection (i.e., the number of segments resected) is strongly correlated with risk of postoperative liver insufficiency. Although this is intuitive and easily assessed, it is actually the volume of liver remaining (i.e., the FLR) that is more predictive of outcome and thus critical to accurately measure. 64

Furthermore, assessment of number of segments remaining is not sufficient because of substantial variability among patients in segmental anatomy and liver volume. In most patients, the right side of the liver represents more than half of the total liver volume (TLV); however, there is a broad range, from 49% to 82%, with the left side of the liver conversely ranging from 17% to 49%.3 Thus formal radiologic assessment of volumetrics is required to accurately assess the FLR for anticipated major (i.e., .4 segments) liver resection (see Chapter 102).

Techniques of Volumetry Formal measurement of liver volumes is most commonly accomplished by using computed tomography (CT) or magnetic resonance imaging (MRI).4–7 Other imaging modalities may also be used, but CT and MRI are commonly obtained in patient care for characterization of lesions and operative planning, and therefore additional tests are typically not needed. Crosssectional images obtained from either of these modalities are sequentially marked with the planned resection line, following which the surface area is derived and multiplied by the slice thickness (Fig. 4.1). Excellent correlation has been demonstrated between the planned FLR and the actual FLR radiologically,8 as well as between the calculated resected liver volume and the surgical specimen.9,10 Because of the variability in total liver size based on patient body habitus, the FLR volume is typically expressed as a ratio of FLR to TLV. Although the measurement of the FLR is fairly standard, there are several variations to calculate the TLV. The simplest and most intuitive technique involves manually tracing the borders of the liver in a variety of planes and using software to calculate the total volume in the same manner as the FLR calculation. There are several limitations to this technique. Most notably, because resection is usually considered on the basis of hepatic tumors, the volume of the tumors is implicitly included in the measurement of the TLV. This is problematic because the tumor volume does not contribute to hepatic function and so provides a falsely elevated value of the TLV and hence a falsely diminished anticipated FLR ratio. Manually measuring the volume of each tumor and subtracting it from the TLV to yield the total functioning liver volume can correct this but can be labor intensive and prone to measurement error.11 Some software packages can perform automated subtraction of the tumor volume. The direct measurement technique of TLV is further limited by the fact that the parenchyma beyond tumors may be abnormal because of biliary or vascular obstruction. These limitations typically do not apply to the assessment of the FLR, which usually does not contain tumors. An alternative method referred to as the total estimated liver volume (TELV) was first proposed by Urata and colleagues in Japan for use in liver transplantation.12 Rather than measuring

  Chapter 4  Assessment of Hepatic Function: Implications for Perioperative Outcome and Recovery

65

Volumetric Thresholds

587.805 cm3 FIGURE 4.1  Volumetric assessment based on magnetic resonance imaging.

the TLV directly and subtracting the volume of liver tumors, this technique estimates the TLV based on body surface area (BSA). The formula was subsequently modified to apply to Western patients, based on the observation that Urata’s formula underestimated TELV by an average of 323 cm3.13,14 The resulting equation (TELV 5 2794 1 1267 3 BSA) has been extensively studied and found to yield a precise estimate of TLV across institutions with different CT scanners and three-dimensional reconstruction techniques.15 When the TELV is used as the denominator to calculate the FLR ratio (i.e., FLR/TELV), the resultant ratio is referred to as the standardized FLR (sFLR). The measured TLV was compared with the TELV in a study of 243 patients who underwent major liver resection (three or more segments).16 There was a strong correlation between the two measures across the population; however, in overweight patients (body mass index [BMI] . 25), TELV was significantly higher, yielding a lower sFLR in these patients. Based on the surgeons’ thresholds, 47 patients were deemed to have insufficient liver volume for resection using TLV compared with 73 patients using TELV. According to institutional practices at the time, patients who had sufficient liver volume based on TLV underwent resection. The subset of patients who had insufficient volume based on TELV had significantly higher rates of post-hepatectomy liver failure (PHLF) and mortality than did the patients who had sufficient volume based on both calculations. Therefore the authors concluded that TELV (i.e., sFLR) is a better measure of postoperative hepatic insufficiency risk. Increasingly sophisticated software packages are being developed that incorporate semi-automated and fully automated segmentation for both CT and MRI. A number of studies have shown these to be very accurate and time-efficient when compared with the gold standard of manual volumetry for TLV5,17–19 and individual liver segment volumes.20 These automated software packages have also been shown to be accurate and time-saving for living donor liver transplant patients21 and for planning a standard right trisectionectomy.22 Measuring the FLR for a resection not following a standard anatomic plane still requires manual volumetry.

Despite the refinement in methods to measure the FLR, the clinical application of the information gathered remains controversial. It has long been clear that patients with lower FLR are at increased risk for hepatic dysfunction, but the exact threshold below which resection should not be performed is debated. Several studies have attempted to address this fundamental question, yielding different conclusions.23–28 The variable results may be attributable to the heterogeneity of included patients (some having background liver disease and others healthy livers), methods used to calculate the FLR (TLV vs. TELV), indications for PVE, and definitions of hepatic dysfunction. Furthermore, only two studies analyzed their results using a formal receiving operator characteristic (ROC) curve to determine the optimal FLR threshold, and both studies were limited by small sample sizes.23,27 Allowing for these admittedly crucial differences, the optimal cutoff for patients with a normal background liver appears to be between 20% and 30%. A 2006 expert consensus statement recommended a minimum of 20% FLR for major hepatic resection in a patient with a healthy liver and to consider PVE for any FLR less than that.29 Patients who have received preoperative chemotherapy are at risk for background liver injury that impairs regeneration after partial hepatectomy30–32 (see Chapters 69, 98, and 102). There is general consensus that patients treated with extensive preoperative chemotherapy or who have evidence of background liver injury require a larger FLR to allow safe hepatectomy, although the exact threshold is again controversial. Two studies examined this question and performed formal ROC curve analyses, reporting optimal thresholds of 31% and 48.5%, respectively.23,33 The largest study includes 194 patients undergoing extended hepatectomy on the right side, stratified by extent of preoperative chemotherapy, with long-duration chemotherapy defined as greater than 12 weeks (86 patients).34 Using a minimum P-value approach, the authors concluded that the optimal cutoff value of FLR for preventing postoperative liver insufficiency in these patients was 30%. Patients who have received extensive chemotherapy and have an sFLR between 30% and 40% should be investigated closely for any suggestion of underlying liver dysfunction and could be considered for PVE. The optimal FLR threshold in patients with documented underlying liver disease is even less certain, given the additional variability of defining the extent of background liver injury. Some authors advocate for PVE in all patients with chronic liver disease before right side hepatectomy, and others apply a conservative threshold as high as 40%.35,36 Given the importance of background liver function, additional functional tests to assess the liver remnant should be considered before embarking on major hepatectomy in the setting of significant background liver disease.

Volumetry After Hypertrophy In patients at increased risk for PHLF, hypertrophy of the FLR may be induced by preoperative ipsilateral PVE (see Chapter 102C).37 Other techniques to achieve hypertrophy, such as the ALPPS procedure (see Chapter 102D) or radioembolization with yttrium-90 (see Chapter 94), are discussed in other chapters. Cross-sectional imaging is typically repeated 2 to 6 weeks after PVE, and the FLR (or sFLR) may be recalculated. The post-PVE FLR can be interpreted with the same thresholds previously discussed, although the degree of hypertrophy (DH), defined as absolute difference between FLR before and after PVE, appears to be more informative.38 The authors of this

66

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

study recommended that patients without cirrhosis undergoing PVE should have both an sFLR of at least 20% and a DH of at least 5% to undergo safe hepatectomy. In addition to its therapeutic intent, PVE functions as a diagnostic test analogous to a cardiac stress test; patients who do not experience substantial growth in the FLR after PVE should be suspected of harboring background liver disease and approached with caution. Recognizing that the DH is contingent on the duration from PVE to reimaging, surgeons have proposed incorporating some measure of growth rate into consideration. The kinetic growth rate (KGR) may be calculated by dividing the DH by the number of weeks elapsed since PVE.39 In one study of 107 patients who underwent liver resection for colorectal liver metastases with an sFLR volume of greater than 20%, KGR was a more accurate predictor of postoperative hepatic insufficiency than absolute sFLR or DH (area under the curve [AUC] 0.830).39 In this study, patients with a KGR less than 2% per week suffered a 21.6% hepatic insufficiency rate and an 8.1% 90-day mortality rate compared with no hepatic insufficiency or 90-day mortality in patients with a KGR greater than 2% per week. In a similar study of 153 patients who underwent major hepatectomy after PVE, post-PVE absolute FLR correlated poorly with liver failure.40 Both DH and KGR were good predictors of liver

failure (AUC 0.80 and 0.79, respectively). Notably, posthepatectomy liver failure did not develop in any patients with a KGR greater than 2.66% per week. In summary, for patients with insufficient FLR (or sFLR) to safely undergo hepatectomy, response to PVE provides a good measure of the remnant liver’s ability to hypertrophy. Post-PVE FLR should be interpreted in combination with some measure of extent of hypertrophy (either DH or KGR) to optimally predict a patient’s risk for post-hepatectomy liver insufficiency.

ASSESSMENT OF LIVER REMNANT FUNCTION Although a thorough assessment of the anticipated FLR volume is required before embarking on major hepatectomy, a complete assessment should ideally also account for the quality of the background liver that will be preserved. The optimal method to assess hepatic function would be accurate, noninvasive, inexpensive, specific to the remnant portion of the liver, and widely reproducible. Unfortunately, none of the techniques currently available fulfill all of these criteria, and therefore none are frequently used in routine assessment. Nevertheless, several newer techniques show promise and with further investigation may find a role in routine assessment of liver function (Table 4.1).

TABLE 4.1  Comparison of Tests Available for Assessment of Liver Function MODALITY

RATIONALE

ADVANTAGES

LIMITATIONS

Volume of liver remnant (MRI, CT)

Lower liver remnant volume is associated with worse outcomes

Response of liver remnant to portal vein embolization

Failure of liver to hypertrophy in response to portal vein embolization indicates underlying liver injury

• Does not incorporate measure of underlying liver function • Threshold for safe resection in setting of background liver disease unclear • Requires invasive procedure that may not be necessary in some patients

Clinical scoring systems (Child-Pugh, MELD, ALBI, etc.) ICG clearance

Scoring systems are associated with poor outcomes after other procedures ICG is metabolized by the liver, and poor ICG clearance is indicative of underlying liver dysfunction 99m Tc- GSA binds to hepatocyte receptors; 99mTc- IDA derivatives are metabolized by the liver; poor uptake of either are indicative of liver dysfunction Metabolized almost exclusively by the liver (P450), and poor clearance indicates underlying liver dysfunction

• Can be easily calculated with conventional imaging • Can be performed by surgeons • Incorporates planned resection • Can be easily calculated with conventional imaging • Can be performed by surgeons • Incorporates planned resection volume and underlying function • Easy to calculate • Noninvasive • Good measure of underlying liver function

• Time consuming • Measures total liver function, not specific to remnant • Altered based on environmental conditions • High inter-rater and inter-institution variability • Limited availability

Hepatobiliary scintigraphy

Other measures of metabolic function (lidocaine-MEGX, galactose, etc.)

MRI with Gd-EOBDTPA contrast

Taken up and cleared by hepatocytes, poor uptake indicates liver dysfunction

Transient elastography

Provides assessment of liver fibrosis

• Provides anatomic and functional information • May be specific to remnant liver by combining with CT • Correlated with other measures of total liver function

• Routinely available • Frequently used in preoperative assessment • May be specific to remnant liver • Provides other information • Noninvasive • Fast

• Not sensitive enough for background liver dysfunction

• • • • •

Not widely available Limited data related to clinical outcomes High interrater variability Time consuming Measures total liver function, not specific to remnant • Altered based on environmental conditions • Correlated with postresection clinical outcomes (PHLF and ICGR15) in only two small studies • Needs larger prospective trials • User dependent • Not correlated with clinical outcomes • Poor PPV

ALBI, Albumin-bilirubin score; CT, computed tomography; Gd-EOB-DTPA, gadolinium ethoxybenzyl dimeglumine; ICGR15, indocyanine green retention (15 minutes); MEGX, monoethylglycinexylidide; MRI, magnetic resonance imaging; PHLF, post hepatectomy liver failure; PPV, positive predictive value; SPECT, single-photon emission computed tomography; 99mTc-GSA, technetium-99m–labeled galactosyl serum albumin; 99mTc- IDA, technetium-99m–labeled iminodiacetic acid.

  Chapter 4  Assessment of Hepatic Function: Implications for Perioperative Outcome and Recovery

Clinical Scoring Systems The simplest, most widely available method to assess liver function relies on laboratory investigations either in isolation or combined into clinical scoring systems. Clinicians are familiar with conventional liver laboratory tests routinely used in clinical practice, including enzymatic measures of hepatocyte injury (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), and markers of hepatic metabolism bilirubin and synthetic function (albumin and international normalized ratio [INR]). Aberrations in any of these laboratory measures should prompt further investigation of background liver dysfunction, although none of them are sensitive or specific enough for surgeons to rely on exclusively. The Child-Turcotte-Pugh scoring system was developed to predict the risk of death in patients undergoing surgical management of portal hypertension. The Child’s score is easily calculated from three readily available laboratory tests (bilirubin, albumin, and INR) and two clinical findings (ascites and encephalopathy). The Child’s score is a good marker of global liver function in a patient with cirrhosis and may help in the selection of patients appropriate for resection, particularly in the setting of hepatocellular carcinoma. In general, surgery is reasonable to consider in patients with class A cirrhosis, should be approached cautiously in patients with class B cirrhosis, and should be avoided in patients with class C cirrhosis. In patients without cirrhosis, the Child’s score will almost always be normal even when there is substantial background liver dysfunction; in this setting, it does not predict postoperative liver dysfunction, and other tests are needed. Furthermore, it is important to recognize that significant portal hypertension may exist even in Child’s A cirrhosis. The Model for End-Stage Liver Disease (MELD) score is a mathematical equation frequently used in liver transplantation to allocate organs. The MELD score is similar to the ChildPugh score in that it incorporates simple laboratory investigations, including serum bilirubin, creatinine, and INR, although it is more cumbersome to calculate. It was initially validated for the prediction of short-term survival in patients with cirrhosis and has subsequently been validated for long-term survival as well. In patients with cirrhosis undergoing partial hepatectomy, a MELD score greater than 8 is a strong predictor of perioperative mortality and decreased long-term survival.41–43 In contrast, in patients without documented background liver injury, a MELD score is not strongly associated with inferior outcomes.44–46 First described in 2015, the albumin-bilirubin (ALBI) score categorizes patients into three risk groups based only on their serum albumin and bilirubin.47 The calculation of the score requires a complex equation; however, a simple nomogram has been created to determine into which group a patient falls: A1, A2, or A3 (from best to worst). This model was developed from 1313 patients with hepatocellular carcinoma (HCC) in Japan and was validated in patients from other geographic regions, patients undergoing hepatectomy, and unresectable patients treated with sorafenib.47 In patients undergoing resection, the ALBI was better able to predict survival than the Child-Pugh score and could better discriminate between Child-Pugh A patients. Further studies showed ALBI better able to predict both PHLF and survival after hepatectomy when compared with Child-Pugh48 and MELD.49 Thus, in patients with cirrhosis being considered for partial hepatectomy, Child-Pugh and MELD scores provide good

67

measures of global liver function. Surgeons should approach patients with Child-Pugh class B/C or MELD score greater than 8 with caution and consider alternative treatment approaches. Within the group of Child-Pugh A patients, use of the ALBI score can add further precision in predicting the risk for PHLF. Clinical scoring systems are not sensitive enough to detect background liver injury and subsequent risk of postoperative liver dysfunction in patients without cirrhosis; other methods of functional liver assessment are needed in these patients.

Measurement of Hepatic Uptake, Metabolism, and Elimination Indocyanine Green Clearance Indocyanine green (ICG) clearance is the quantitative measure of hepatic function most used worldwide. ICG is a water-soluble tricarbocyanine dye that binds to albumin and distributes rapidly and uniformly in the blood after intravenous (IV) injection. ICG is exclusively cleared from the bloodstream by the liver in a similar manner to bilirubin and toxins and then excreted unchanged into bile. Thus ICG clearance tests reflect blood flow–dependent clearance, hepatocyte uptake, and biliary excretion. The conventional measurement of ICG clearance involves IV injection of ICG, followed by serial collection of venous blood at 5-minute intervals for 15 minutes. ICG clearance can also be measured noninvasively by pulse-spectrophotometry, which allows for real-time monitoring of liver function.50,51 The results of ICG tests may be expressed as the percentage of ICG retained in the circulation 15 minutes after injection (ICG-R15), the plasma disappearance rate (ICG-PDR), and the elimination rate constant (ICG-k). Several studies have identified an association between elevated ICG-R15 and posthepatectomy complications, with proposed threshold values of ICG-R15 ranging from 14% to 20%.52–54 Despite the theoretical attractiveness of ICG clearance as a simple measure of hepatic function, several limitations have hampered enthusiasm for its widespread use. The results of ICG clearance tests are not reliable in patients with hyperbilirubinemia or in patients with intrahepatic shunting or sinusoidal capillarization. Further, ICG clearance testing is a measure of global liver function, so if there is heterogeneous uptake in the liver (e.g., the portion being resected does not function as well because of tumor, biliary obstruction, etc.), the results may be misleading. Finally, ICG testing does not incorporate the extent of resection, or conversely, the volume of the remnant that will remain. Researchers have attempted to mitigate some of these limitations by creating scoring systems and decision trees that incorporate ICG.55–57 In one study of patients with cirrhosis, a combination of sFLR greater than 25% and an sFLR/ICG-R15 ratio greater than 1.9 predicted safety to undergo hepatectomy.57

Nuclear Imaging Techniques Theoretically, nuclear imaging represents an attractive preoperative hepatic assessment, combining anatomic considerations (FLR volume) with both total and regional liver functional assessment. Several scintigraphic tests have been developed over the past few decades, but the most widely used radiopharmaceutical imaging methods for liver functional assessment are technetium-99m (99mTc)–labeled galactosyl serum albumin (GSA) scintigraphy and hepatobiliary scintigraphy (HBS) with

68

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

99m Tc-labeled iminodiacetic acid (IDA) derivatives. Both of these methods provide quantitative data on the total and regional hepatic function, although they are based on different principles and therefore interpretation varies. 99m Tc-GSA is an analogue of a glycoprotein (ascites sialoglycoprotein) that binds to receptors on the hepatocyte cell membrane and is taken up by the hepatocytes. Chronic liver disease results in diminished hepatocyte glycoprotein receptors and subsequent accumulation of plasma glycoproteins. To perform dynamic scintigraphy, an IV bolus of 99mTc-GSA is administered, and images are obtained by using a gamma camera positioned over the heart and liver. Several parameters may be calculated to document the extent of hepatic 99mTc-GSA uptake, including the hepatic uptake ratio (LHL15 [receptor index: uptake ratio of the liver to the liver plus heart at 15 min]) and the blood clearance ratio (HH15 [blood clearance index: uptake ratio of the heart at 15 min to that at 3 min]). In patients with cirrhosis, 99mTc-GSA uptake corresponds well with other conventional liver function tests, including ICG clearance, and predicts histologic severity of disease better than ICG clearance in a substantial proportion of patients.58,59 Several small studies have demonstrated an association between poor 99m Tc-GSA uptake and postoperative complications after liver resection.59–61 99m Tc-GSA uptake is limited by inter-operator and interinstitutional differences and does not provide a measure of regional liver function.62 To address this limitation, 99mTc-GSA scintigraphy may be combined with static single-photon emission computed tomography–CT (SPECT-CT) to allow a threedimensional measurement of 99mTc-GSA uptake. Results of dynamic SPECT-CT may help to predict postoperative liver failure; however, this method suffers from the same interobserver variability and environmental factors as dynamic 99mTcGSA scintigraphy.63–65 A single-arm prospective trial of 185 consecutive patients undergoing hepatectomy evaluated the predictive value of 99mTc-GSA SPECT-CT on PHLF and mortality.66 SPECT-CT was used to calculate the ICG clearance specific to the predicted FLR and demonstrated very good correlation with postoperative bilirubin and INR levels, with a PHLF rate of 8% and 90-day mortality of 0.5%. Furthermore, 7 patients who would not have met their criteria for resection based on the overall ICG-R15 x FLR underwent hepatectomy without PHLF. This demonstrates the heterogeneity of liver function and the importance of measuring the function of the FLR rather than the TLV. 99m Tc-mebrofenin is an organic IDA derivative with similar properties to ICG: It has high hepatic uptake, low displacement by bilirubin, and low urinary excretion. The test is administered in an identical manner to 99mTc-GSA scintigraphy, using a gamma camera and calculating similar parameters and ratios. The uptake ratio, however, is divided by the patient’s BSA to compensate for differences in metabolic requirements. 99mTcmebrofenin HBS correlates well with ICG clearance and appears to be a good marker of post-resection liver function.67–70 HBS may also be combined with SPECT-CT to allow for the calculation of both the function and volume of the FLR. An FLR function cutoff value of 2.7%/min/m2 was shown to have a negative predictive value (NPV) of 97.6% and a positive predictive value (PPV) of 57.1% for PHLF.68 The main limitation of HBS is, again, inter-observer and inter-institution variability. Although these techniques offer great advantages compared with more conventional methods, further research is

needed to ensure that results are reproducible across different settings before wider application.

Other Measures of Metabolic Function In addition to ICG, several other compounds are metabolized almost exclusively by the liver cytochrome P450 system and have been investigated as potential markers of hepatic function. For example, lidocaine is metabolized to monoethylglycinexylidide (MEGX) primarily in the liver. The MEGX test has been studied in transplantation and critical care medicine and appears to correlate with other measures of hepatic metabolism.71,72 A small study demonstrated higher rates of postoperative liver insufficiency among Child-Pugh A patients who had a low MEGX value.73 Unfortunately, the test is limited by poor reliability and the need for frequent monitoring; therefore its present application in preoperative assessment of liver function is investigational only. Galactose elimination capacity also accurately reflects metabolic function of the liver but is similarly limited by practical constraints and alterations due to environmental conditions.74

Magnetic Resonance Imaging Hepatic Agents MRI with contrast enhancement offers high-resolution crosssectional assessment of background liver anatomy and accurate characterization of hepatic tumors. MRI is more sensitive and specific than CT for the detection of primary and metastatic liver neoplasms and is used routinely at most centers before embarking on liver resection.75 Gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) is a liver-specific contrast agent that has as much as 50% hepatobiliary excretion in a normal liver.76 Gd-EOB-DTPA improves the detection and characterization of focal liver lesions and diffuse liver disease. Given the hepatic uptake and elimination of Gd-EOB-DTPA, contrast-enhanced MRI may also provide functional assessment of the background liver (Fig. 4.2). Several small studies have demonstrated correlation between Gd-EOB-DTPA uptake on MRI and conventional measures of liver function,77-80 and with 99mTc-mebrofenin HBS.81,82 Postoperative ICG-R15 can also be predicted well using preresection MRI.83 There are several theoretical and practical advantages to using Gd-EOB-DTPA–enhanced MRI to assess liver function. First, MRI is routinely available and frequently used in the preoperative assessment of these patients, so no additional testing is required. Second, functional assessment may be focused on the planned FLR in cases of heterogeneous uptake, rather than calculating uptake for the whole liver as is the case in most other functional quantitative tests. Finally, MRI provides visual assessment of background liver injury, including steatosis and fibrosis, which may further assist in preoperative decision making. MRI has been shown to be superior to sFLR volume and ICG-R1584–86 at predicting PHLF. The most precise predictors for PHLF seem to use a combination of relative liver enhancement (RLE, difference in signal intensity between the unenhanced and hepatobiliary phases) or hepatocellular uptake index (HUI, difference in signal intensity between liver parenchyma and the spleen) specific to the FLR and patient weight. For example, Asenbaum et al. calculated an AUC of 0.9 for predicting PHLF for their outcome of functional FLR, which equals (FLR 3 remnant RLE)/weight.86 Similar to using KGR as a measure of liver function after PVE, contrastenhanced MRI can compare RLE and HUI before and after

  Chapter 4  Assessment of Hepatic Function: Implications for Perioperative Outcome and Recovery

69

Transient Elastography Ultrasound transient elastography (TE) has been reported as a test to estimate the extent of liver fibrosis. Ultrasound TE has the clear advantages of being noninvasive and fast but is limited by significant inter-observer variability and anatomic variations.89,90 Two studies of patients with HCC undergoing hepatectomy found ultrasound TE to have a high NPV of 98% but relatively poor PPV.91,92 Therefore ultrasound TE may have a role in screening patients at low risk for PHLF, but a positive test should prompt further investigations and not necessarily preclude resection.

CT Texture Analysis A

Texture analysis is an established technique that characterizes regions of interest in an image based on spatial variations in pixel intensity. On CT imaging, texture analysis can potentially quantify regional variations in enhancement that cannot be assessed by inspection. Several studies have shown potential utility of this technique for tumor diagnosis, characterization, and prognostication. Texture variables of preoperative CT scans show promise for predicting postoperative hepatic failure in single-institution93 and multi-institution studies94 and may represent a new means of preoperative risk stratification.

CONCLUSION

B FIGURE 4.2  Magnetic resonance imaging with gadolinium ethoxybenzyl dimeglumine contrast on two patients demonstrating normal uptake (A) and diffusely decreased uptake (B).

PVE. Studies performing MRI pre-PVE, post-PVE days 14 and 28, and 10 days post hepatectomy have shown that the increase in RLE from baseline to 14 days post-PVE is an excellent predictor of PHLF, and that beyond 14 days there is minimal improvements in FLR, KGR, and RLE.87,88 The availability and common use of MRI, combined with its ability to provide information on both the volume and the function of the FLR, give it the potential to be an extremely useful tool for the assessment of patients being considered for major hepatic resection. Early prospective studies demonstrate a relationship between Gd-EOB-DTPA uptake and clinical outcome postresection. Larger trials demonstrating its NPV and PPV for PHLF and mortality are needed.

Hepatobiliary surgeons now have a variety of tools at their disposal to assist with preoperative assessment of hepatic function. The gold standard remains volumetric-based assessment of the FLR with cross-sectional imaging (CT or MRI). In patients in whom there is concern about insufficient liver volume or background liver injury, response to PVE provides a functional assessment of the FLR in addition to its therapeutic role. Quantitative measures of hepatic uptake, metabolism, and elimination, including ICG clearance, nuclear scintigraphy, and MRI hepatic-specific contrast agents, may have a role in assessment of patients with borderline FLR volume or background liver disease. MRI in particular seems poised to emerge as a complete package to diagnose occult metastases, assess FLR volumetry and FLR-specific function, and assess both the volumetric and functional response to PVE. Further refinement of these techniques may allow for the development of algorithms or decision aids that provide more precise prediction of postoperative hepatic insufficiency, ultimately decreasing postoperative morbidity and mortality. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

69.e1

REFERENCES 1. Adams RB, Aloia TA, Loyer E, et al. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford). 2013;15(2):91-103. 2. Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol. 2006;13(10):1261-1268. 3. Abdalla EK, Denys A, Chevalier P, et al. Total and segmental liver volume variations: implications for liver surgery. Surgery. 2004; 135(4):404-410. 4. Heymsfield SB, Fulenwider T, Nordlinger B, et al. Accurate measurement of liver, kidney, and spleen volume and mass by computerized axial tomography. Ann Intern Med. 1979;90(2):185-188. 5. Huynh HT, Karademir I, Oto A, Suzuki K. Computerized liver volumetry on MRI by using 3D geodesic active contour segmentation. Am J Roentgenol. 2014;202(1):152-159. 6. Karlo C, Reiner CS, Stolzmann P, et al. CT- and MRI-based volumetry of resected liver specimen: comparison to intraoperative volume and weight measurements and calculation of conversion factors. Eur J Radiol. 2010;75(1):e107-e111. 7. Suzuki K, Huynh HT, Liu Y, et al. Computerized segmentation of liver in hepatic CT and MRI by means of level-set geodesic active contouring. Conf Proc IEEE Eng Med Biol Soc. 2013:2984-2987. 8. Simpson AL, Geller DA, Hemming AW, et al. Liver planning software accurately predicts postoperative liver volume and measures early regeneration. J Am Coll Surg. 2014;219:199-207. 9. Dello SA, Stoot JH, van Stiphout RS, et al. Prospective volumetric assessment of the liver on a personal computer by nonradiologists prior to partial hepatectomy. World J Surg. 2011;35(2):386-392. 10. van der Vorst JR, van Dam RM, van Stiphout RS, et al. Virtual liver resection and volumetric analysis of the future liver remnant using open source image processing software. World J Surg. 2010:34(10): 2426-2433. 11. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology. 1997; 26(5):1176-1181. 12. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology. 1995;21(5):1317-1321. 13. Heinemann A, Wischhusen F, Puschel K, Rogiers X. Standard liver volume in the Caucasian population. Liver Transpl Surg. 1999; 5(5):366-368. 14. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery. 2000;127(5):512-519. 15. Vauthey JN, Chaoui A, Do KA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl. 2002;8(3):233-240. 16. Ribero D, Amisano M, Bertuzzo F, et al. Measured versus estimated total liver volume to preoperatively assess the adequacy of the future liver remnant: which method should we use? Ann Surg. 2013;258(5):801-806. 17. Suzuki K, Epstein ML, Kohlbrenner R, et al. Quantitative radiology: automated CT liver volumetry compared with interactive volumetry and manual volumetry. Am J Roentgenol. 2011; 197(4):706-712. 18. Huynh HT, Le-Trong N, Bao PT, Oto A, Suzuki K. Fully automated MR liver volumetry using watershed segmentation coupled with active contouring. Int J Comput Assist Radiol Surg. 2017; 12(2):235-243. 19. Winkel DJ, Weikert TJ, Breit HC, et al. Validation of a fully automated liver segmentation algorithm using multi-scale deep reinforcement learning and comparison versus manual segmentation. Eur J Radiol. 2020;126:108918. 20. Gotra A, Chartrand G, Vu KN, et al. Comparison of MRI- and CT-based semiautomated liver segmentation: a validation study. Abdom Radiol (NY). 2017;42(2):478-489. 21. Bokzurt B, Emek E, Arikan T, et al. Liver graft volume estimation by manual volumetry and software-aided interactive volumetry: which is better? Transplant Proc. 2019;51(7):2387-2390. 22. Lodewick TM, Arnoldussen CW, Lahaye MJ, et al. Fast and accurate liver volumetry prior to hepatectomy. HPB (Oxford). 2016; 18(9):764-772.

23. Ferrero A, Vigano L, Polastri R, et al. Postoperative liver dysfunction and future remnant liver: where is the limit? Results of a prospective study. World J Surg. 2007;31(8):1643-1651. 24. Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg. 2009;250(4): 540-548. 25. Lin XJ, Yang J, Chen XB, Zhang M, Xu MQ. The critical value of remnant liver volume-to-body weight ratio to estimate posthepatectomy liver failure in cirrhotic patients. J Surg Res. 2014;188(2): 489-495. 26. Pulitano C, Crawford M, Joseph D, Aldrighetti L, Sandroussi C. Preoperative assessment of postoperative liver function: the importance of residual liver volume. J Surg Oncol. 2014;110(4):445-450. 27. Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore SJ. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut. 2005; 54(2):289-296. 28. Shoup M, Gonen M, D’Angelica M, et al. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg. 2003;7(3):325-330. 29. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol. 2006;13(10):1271-1280. 30. Dello SA, Kele PG, Porte RJ, et al. Influence of preoperative chemotherapy on CT volumetric liver regeneration following right hemihepatectomy. World J Surg. 2014;38(2):497-504. 31. Narita M, Oussoultzoglou E, Chenard MP, et al. Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization. Surg Today. 2011;41(1):7-17. 32. Kele PG, van der Jagt EJ, Gouw AS, Lisman T, Porte RJ, de Boer MT. The impact of hepatic steatosis on liver regeneration after partial hepatectomy. Liver Int. 2013;33(3):469-475. 33. Narita M, Oussoultzoglou E, Fuchshuber P, et al. What is a safe future liver remnant size in patients undergoing major hepatectomy for colorectal liver metastases and treated by intensive preoperative chemotherapy? Ann Surg Oncol. 2012;19(8):2526-2538. 34. Shindoh J, Tzeng CD, Aloia TA, et al. Optimal future liver remnant in patients treated with extensive preoperative chemotherapy for colorectal liver metastases. Ann Surg Oncol. 2013;20(8):2493-2500. 35. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg. 2003; 237(2):208-217. 36. Suda K, Ohtsuka M, Ambiru S, et al. Risk factors of liver dysfunction after extended hepatic resection in biliary tract malignancies. Am J Surg. 2009;197(6):752-758. 37. Hemming AW, Reed AI, Howard RJ, et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg. 2003;237(5): 686-691. 38. Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg. 2007;94(11):1386-1394. 39. Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts posthepatectomy outcomes: toward zero liver-related mortality in patients with colorectal liver metastases and small future liver remnant. J Am Coll Surg. 2013;216(2): 201-209. 40. Leung U, Simpson AL, Araujo RL, et al. Remnant growth rate after portal vein embolization is a good early predictor of post-hepatectomy liver failure. J Am Coll Surg. 2014;219(4):620-630. 41. Delis SG, Bakoyiannis A, Biliatis I, Athanassiou K, Tassopoulos N, Dervenis C. Model for end-stage liver disease (MELD) score, as a prognostic factor for post-operative morbidity and mortality in cirrhotic patients, undergoing hepatectomy for hepatocellular carcinoma. HPB (Oxford). 2009;11(4):351-357. 42. Hsu KY, Chau GY, Lui WY, Tsay SH, King KL, Wu CW. Predicting morbidity and mortality after hepatic resection in patients with hepatocellular carcinoma: the role of model for end-stage liver disease score. World J Surg. 2009;33(11):2412-2419. 43. Teh SH, Christein J, Donohue J, et al. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: model of end-stage liver disease (MELD) score predicts perioperative mortality. J Gastrointest Surg. 2005;9(9):1207-1215.

69.e2 44. Rahbari NN, Reissfelder C, Koch M, et al. The predictive value of postoperative clinical risk scores for outcome after hepatic resection: a validation analysis in 807 patients. Ann Surg Oncol. 2011; 18(13):3640-3649. 45. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson WG, Kuo PC. Predictive indices of morbidity and mortality after liver resection. Ann Surg. 2006;243(3):373-379. 46. Teh SH, Sheppard BC, Schwartz J, Orloff SL. Model for end-stage liver disease score fails to predict perioperative outcome after hepatic resection for hepatocellular carcinoma in patients without cirrhosis. Am J Surg. 2008;195(5):697-701. 47. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidencebased approach-the ALBI grade. J Clin Oncol. 2015;33(6):550-558. 48. Wang YY, Zhong JH, Su ZY, et al. Albumin-bilirubin versus ChildPugh score as a predictor of outcome after liver resection for hepatocellular carcinoma. Br J Surg. 2016;103(6):725-734. 49. Fagenson AM, Gleeson EM, Pitt HA, Lau KN. Albumin-bilirubin score vs model for end-stage liver disease in predicting post-hepatectomy outcomes. J Am Coll Surg. 2020;230(4):637-645. 50. Okochi O, Kaneko T, Sugimoto H, Inoue S, Takeda S, Nakao A. ICG pulse spectrophotometry for perioperative liver function in hepatectomy. J Surg Res. 2002;103(1):109-113. 51. Sakka SG, Reinhart K, Meier-Hellmann A. Comparison of invasive and noninvasive measurements of indocyanine green plasma disappearance rate in critically ill patients with mechanical ventilation and stable hemodynamics. Intensive Care Med. 2000;26(10): 1553-1556. 52. Das BC, Isaji S, Kawarada Y. Analysis of 100 consecutive hepatectomies: risk factors in patients with liver cirrhosis or obstructive jaundice. World J Surg. 2001;25(3):266-272, discussion 272-263. 53. Fan ST, Lai EC, Lo CM, Ng IO, Wong J. Hospital mortality of major hepatectomy for hepatocellular carcinoma associated with cirrhosis. Arch Surg. 1995;130(2):198-203. 54. Lau H, Man K, Fan ST, Yu WC, Lo CM, Wong J. Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br J Surg. 1997;84(9):1255-1259. 55. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg. 2003; 138(11):1198-1206. 56. Du ZG, Li B, Wei YG, Yin J, Feng X, Chen X. A new scoring system for assessment of liver function after successful hepatectomy in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2011;10(3):265-269. 57. Kim HJ, Kim CY, Park EY, et al. Volumetric analysis and indocyanine green retention rate at 15 min as predictors of post-hepatectomy liver failure. HPB (Oxford). 2015;17(2):159-167. 58. Kwon AH, Ha-Kawa SK, Uetsuji S, Kamiyama Y, Tanaka Y. Use of technetium 99m diethylenetriamine-pentaacetic acid-galactosylhuman serum albumin liver scintigraphy in the evaluation of preoperative and postoperative hepatic functional reserve for hepatectomy. Surgery. 1995;117(4):429-434. 59. Nanashima A, Yamaguchi H, Shibasaki S, et al. Relationship between indocyanine green test and technetium-99m galactosyl serum albumin scintigraphy in patients scheduled for hepatectomy: clinical evaluation and patient outcome. Hepatol Res. 2004;28(4): 184-190. 60. Kim YK, Nakano H, Yamaguchi M, et al. Prediction of postoperative decompensated liver function by technetium-99m galactosylhuman serum albumin liver scintigraphy in patients with hepatocellular carcinoma complicating chronic liver disease. Br J Surg. 1997;84(6):793-796. 61. Takeuchi S, Nakano H, Kim YK, et al. Predicting survival and postoperative complications with Tc-GSA liver scintigraphy in hepatocellular carcinoma. Hepatogastroenterology. 1999;46(27):1855-1861. 62. Koizumi M, Yamada Y, Nomura E, Takiguchi T, Kokudo N. An easy and reproducible semi-automatic method for the evaluation of 99mTc-galactosyl human serum albumin. Ann Nucl Med. 1997; 11(4):345-348. 63. Beppu T, Hayashi H, Okabe H, et al. Liver functional volumetry for portal vein embolization using a newly developed 99mTc-galactosyl human serum albumin scintigraphy SPECT-computed tomography fusion system. J Gastroenterol. 2011;46(7):938-943. 64. Iimuro Y, Kashiwagi T, Yamanaka J, et al. Preoperative estimation of asialoglycoprotein receptor expression in the remnant liver from

CT/99mTc-GSA SPECT fusion images correlates well with postoperative liver function parameters. J Hepatobiliary Pancreat Sci. 2010;17(5):673-681. 65. Satoh K, Yamamoto Y, Nishiyama Y, Wakabayashi H, Ohkawa M. 99m Tc-GSA liver dynamic SPECT for the preoperative assessment of hepatectomy. Ann Nucl Med. 2003;17(1):61-67. 66. Okabayashi T, Shima Y, Morita S, et al. Liver function assessment using technetium 99m-galactosyl single-photon emission computed tomography/CT fusion imaging: a prospective trial. J Am Coll Surg. 2017;225(6):789-797. 67. Bennink RJ, Dinant S, Erdogan D, et al. Preoperative assessment of postoperative remnant liver function using hepatobiliary scintigraphy. J Nucl Med. 2004;45(6):965-971. 68. de Graaf W, van Lienden KP, Dinant S, et al. Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection. J Gastrointest Surg. 2010;14(2): 369-378. 69. Dinant S, de Graaf W, Verwer BJ, et al. Risk assessment of posthepatectomy liver failure using hepatobiliary scintigraphy and CT volumetry. J Nucl Med. 2007;48(5):685-692. 70. Erdogan D, Heijnen BH, Bennink RJ, et al. Preoperative assessment of liver function: a comparison of 99mTc-Mebrofenin scintigraphy with indocyanine green clearance test. Liver Int. 2004; 24(2):117-123. 71. Oellerich M, Armstrong VW. The MEGX test: a tool for the realtime assessment of hepatic function. Ther Drug Monit. 2001; 23(2):81-92. 72. Reichen J. MEGX test in hepatology: the long-sought ultimate quantitative liver function test? J Hepatol. 1993;19(1):4-7. 73. Ercolani G, Grazi GL, Calliva R, et al. The lidocaine (MEGX) test as an index of hepatic function: its clinical usefulness in liver surgery. Surgery. 2000;127(4):464-471. 74. Ranek L, Andreasen PB, Tygstrup N. Galactose elimination capacity as a prognostic index in patients with fulminant liver failure. Gut. 1976;17(12):959-964. 75. Zech CJ, Korpraphong P, Huppertz A, et al. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus conventional MRI or CT in the staging of colorectal cancer liver metastases. Br J Surg. 2014;101(6):613-621. 76. Van Beers BE, Pastor CM, Hussain HK. Primovist, Eovist: what to expect? J Hepatol. 2012;57(2):421-429. 77. Nilsson H, Blomqvist L, Douglas L, et al. Gd-EOB-DTPAenhanced MRI for the assessment of liver function and volume in liver cirrhosis. Br J Radiol. 2013;86(1026):20120653. 78. Nishie A, Ushijima Y, Tajima T, et al. Quantitative analysis of liver function using superparamagnetic iron oxide- and Gd-EOBDTPA-enhanced MRI: comparison with Technetium-99m galactosyl serum albumin scintigraphy. Eur J Radiol. 2012;81(6): 1100-1104. 79. Saito K, Ledsam J, Sourbron S, et al. Measuring hepatic functional reserve using low temporal resolution Gd-EOB-DTPA dynamic contrast-enhanced MRI: a preliminary study comparing galactosyl human serum albumin scintigraphy with indocyanine green retention. Eur Radiol. 2014;24(1):112-119. 80. Yoon JH, Lee JM, Kang HJ, et al. Quantitative assessment of liver function by using gadoxetic acid-enhanced MRI: hepatocyte uptake ratio. Radiology. 2019;290(1):125-133. 81. Geisel D, Ludemann L, Froling V, et al. Imaging-based evaluation of liver function: comparison of 99mTc-mebrofenin hepatobiliary scintigraphy and Gd-EOB-DTPA-enhanced MRI. Eur Radiol. 2015;25(5):1384-1391. 82. Rassam F, Zhang T, Cieslak KP, et al. Comparison between dynamic gadoxetate-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT for quantitative assessment of liver function. Eur Radiol. 2019;29:5063-5072. 83. Yoon JH, Choi JI, Jeong YY, et al. Pre-treatment estimation of future remnant liver function using gadoxetic acid MRI in patients with HCC. J Hepatol. 2016;65(6):1155-1162. 84. Chuang YH, Ou HY, Lazo MZ, et al. Predicting post-hepatectomy liver failure by combined volumetric, functional MR image and laboratory analysis. Liver Int. 2018;38(5):868-874. 85. Kim DK, Choi JI, Choi MG, et al. Prediction of posthepatectomy liver failure: MRI with hepatocyte-specific contrast agent versus indocyanine green clearance test. Am J Roentgenol. 2018;211(3): 580-587.

69.e3 86. Asenbaum U, Kaczirek K, Ba-Ssalamah A, et al. Post-hepatectomy liver failure after major hepatic surgery: not only size matters. Eur Radiol. 2018;28(11):4748-4756. 87. Geisel D, Raabe P, Ludemann L, et al. Gd-EOB-DTPA-enhanced MRI for monitoring future liver remnant function after portal vein embolization and extended hemihepatectomy: a prospective trial. Eur Radiol. 2017;27(7):3080-3087. 88. Theilig D, Steffen I, Malinowski M, et al. Predicting liver failure after extended right hepatectomy following right portal vein embolization with gadoxetic acid-enhanced MRI. Eur Radiol. 2019; 29(11):5861-5872. 89. Kawamoto M, Mizuguchi T, Katsuramaki T, et al. Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers. World J Gastroenterol. 2006;12(27):43254330.

90. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29(12):1705-1713. 91. Nishio T, Taura K, Koyama Y, et al. Prediction of posthepatectomy liver failure based on liver stiffness measurement in patients with hepatocellular carcinoma. Surgery. 2016;159(2):399-408. 92. Lei JW, Ji XY, Hong JF, et al. Prediction of posthepatectomy liver failure using transient elastography in patients with hepatitis B related hepatocellular carcinoma. BMC Gastroenterol. 2017;17(1):171. 93. Simpson AL, Adams LB, Allen PJ, et al. Texture analysis of preoperative CT images for prediction of postoperative hepatic insufficiency: a preliminary study. J Am Coll Surg. 2015;220:339-346. 94. Pak LM, Chakraborty J, Gonen M, et al. Quantitative imaging features and postoperative hepatic insufficiency: a multi-institutional expanded cohort. J Am Coll Surg. 2018;226(5):835-843.

CHAPTER 5 Liver blood flow: Physiology, measurement, and clinical relevance Edouard Girard and Simon Turcotte Circulation in the liver is unique because of a dual afferent blood supply, derived from the hepatic artery (HA) and the portal vein (PV; see Chapter 2). The oxygen-rich arterial blood and the nutrient-rich PV blood merge in the hepatic parenchymal microcirculation to sustain the complex functions of the liver before returning to the heart through the hepatic veins (HVs). This chapter outlines how liver blood flow (LBF) is controlled to maintain the hepatic perfusion within an acceptable physiologic range, describes techniques used for LBF measurement, and explores clinical situations in which blood flow is altered.

PHYSIOLOGY Liver Blood Supply The peculiar double afferent blood supply to the liver (see Chapter 2) results in 75% to 80% of the entering blood being partially deoxygenated PV blood draining the stomach, intestine, spleen, and pancreas. The remainder is well-oxygenated blood from the aorta, carried by the HA. Mixing of arterial and portal blood occurs in terminal branches in the sinusoidal microcirculation around hepatocytes arranged into roughly polyhedral-shaped lobules, from their periphery toward their centrilobular venule (Fig. 5.1). The centrilobular venules drain into the HVs and into the inferior vena cava (IVC). Although the liver mass constitutes approximately 2.5% of the total body weight, the liver receives nearly 25% of the cardiac output. The total LBF ranges between 800 to 1200 mL/min, which is equivalent to approximately 100 mL/min per 100 g liver wet weight. The liver blood volume is estimated to range from 25 to 30 mL per 100 g of liver wet weight, which accounts for 10% to 15% of the total body blood volume. The sinusoids hold 60% of the blood volume, whereas the remaining 40% lies in large vessels (HA, PV, and HV).1,2 Of note is the high compliance of the liver, calculated as the change in its blood volume per unit change in venous pressure. The liver thus acts as an important blood reservoir because its blood volume can expand considerably in cardiac failure or, in case of bleeding episodes, can compensate as much as 25% of the hemorrhage by rapid expulsion of blood into the circulation.3,4

Hepatic Artery The HA normally supplies approximately 25% of the total blood flow to the liver (25 to 30 mL/min per 100 g of liver tissue) in a high-pressure/high-resistance system. The mean pressure in the HA is similar to that in the aorta. The HA provides as much as 50% of the liver’s oxygen requirement because of the greater oxygen content found in arterial blood. In addition, the HA provides the exclusive blood supply to the intrahepatic bile ducts through the peribiliary plexus (Fig. 5.2). In the 70

hepatic lobules, the hepatic arterioles empty directly or via peribiliary plexi into the sinusoids. Direct artery-to-HV connections do not usually exist but may arise in liver disease. Within the liver parenchyma, the pressure in the arterial system is reduced toward that existing in the portal circulation and sinusoids. This is suggested to be achieved mainly by (1) the presinusoidal arteriolar resistance in the peribiliary plexus and (2) the intermittent closure of the arterioles, which protect the portal bloodstream from arterial pressure.5 In the event of HA occlusion, numerous intrahepatic collaterals can provide a source of arterial blood. Additionally, extrahepatic collateral supply can develop after HA ligation and depends on the site of occlusion. If the common HA is interrupted, revascularization occurs through extrahepatic collaterals arising from (1) the inferior phrenic arteries and (2) from the gastroduodenal arteries, which derive blood flow from the superior mesenteric artery.6 Ligation of the proper HAs leads to revascularization mainly via a hypertrophied inferior phrenic circulation, which can develop connections with HAs within the liver.7 If only the right or left HA is interrupted, intrahepatic translobar anastomoses reestablish arterial flow in the ligated system.8 Thus complete longterm dearterialization of the liver by any form of arterial vascular occlusion is difficult to achieve.

Portal Vein The PV normally carries approximately 75% of the total blood flow to the liver (90 mL/min per 100 g of liver weight) in a valveless, low-pressure/low-resistance venous system. The inferior and superior mesenteric veins join with the splenic vein to form the PV, and jointly they collect the venous outflow from the entire prehepatic splanchnic vascular bed (the intestinal tract from the lower esophagus to the rectum plus the pancreas and spleen). The PV pressure ranges between 6 and 10 mm Hg in humans when measured by direct cannulation.9 PV pressure depends primarily on the degree of constriction of mesenteric and splanchnic arterioles, coupled with the intrahepatic vascular resistance. Because portal blood is derived from postcapillary beds, it is partly deoxygenated. However, because of its large volume flow rate, it may supply 50% to 70% of the liver’s normal oxygen requirement. During fasting states, the oxygen saturation in the portal blood approaches 85%, which is greater than other systemic veins. Hepatic oxygen supply is diminished if portal blood flow is significantly reduced, but the effect is minimized by an increase in oxygen extraction from the HA blood and not by increasing flow.10

Hepatic Veins The HV system is the systemic drainage tract of the entire splanchnic circulation. A total LBF of 1.5 L/min is considered the normal value in the average male, but the range can be quite wide (1–2 L/min). In normal conditions, the free pressure in

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

71

Hepatic sinusoid Centrilobular venule Hepatic lobule

Hepatocytes

Bile canaliculi Reticuloendothelial cell

Centrilobular venule

Hepatic sinusoid

Bile canaliculi

A

Hepatocyte Portal triad Branch of bile duct Branch of hepatic portal vein Branch of hepatic artery

Hepatic lobules

Portal triad Branch of bile duct Branch of hepatic portal vein Branch of hepatic artery

Hepatic sinusoid Hepatocytes

C

B

Hepatocytes and sinusoids

Portal triad

FIGURE 5.1  The liver microcirculation. The liver is composed of thousands of roughly polyhedral structures called hepatic lobules, which are the basic functional units of the organ. Hepatic lobules of some mammals, such as the pig, are delimited on all sides by connective tissue but have much less connective tissue and their boundaries are more difficult to distinguish in humans. A, A small central vein projecting through the center of each hepatic lobule and several sets of blood vessels defining the periphery. The peripheral vessels are grouped primarily in connective tissue involving the portal tracts in the space of Mall, which include a branch of the portal vein, the hepatic artery, and the bile duct. These make up the portal triad. B, Both blood vessels to each lobule give off sinusoids, which run between plates of hepatocytes and drain into the central vein. C, Micrograph showing components of the portal triad within the space of Mall (hematoxylin and eosin; 3220). (From Mescher AL. Junqueira’s Basic Histology: Text and Atlas. 12th ed. McGraw-Hill; 2009.)

P

PP

A

the HVs and IVC is 1 to 2 mm Hg and is 1 to 5 mm Hg lower than the pressure measured in the sinusoids and PV. The portal pressure gradient, defined as the difference in pressure between the PV and the IVC, has been a useful clinical indicator of the perfusion pressure of the liver with portal blood.11 The pressure gradient in the liver is thus extremely low, in the range of 5 mm Hg compared with all other organs, where it is in the range of 115 mm Hg.12 Hepatic venous blood is normally approximately two-thirds saturated with oxygen, but this may be markedly reduced during periods of low delivery of oxygen to the liver, when oxygen is extracted by hepatocytes. In resting states, the liver accounts for approximately 20% of the total oxygen consumption of the body.

Hepatic Microcirculation FIGURE 5.2  Arterial peribiliary plexus. A cast of the portal vein (P), hepatic artery (A), and peribiliary arterial plexus (PP) of a rat, showing a connection between a small artery and the plexus (arrow). The peribiliary plexus forms a dense sheath around the bile duct. Bar 5 100 mm. (From Grisham JW, Nopanitaya W. Scanning electron microscopy of casts of hepatic microvessels: Review of methods and results. In Laut W, ed. Hepatic Circulation in Health and Disease. Raven Press; 1981:98.)

Although the organization of the liver into morphologic and functional units has been a matter of debate, the hexagonal polyhedral-shaped hepatic lobule, encompassing hepatic microvascular subunits consisting of a portal triad of terminal branches of the HA, PV, and bile duct; a network of sinusoids; and an efferent centrilobular venule is a widely accepted framework13,14 (see Fig. 5.1). The portal triads, surrounded by lymphatics and autonomous nerves, all travel together in

72

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A CLASSIC HEPATIC LOBULE

Drains blood from the portal vein and the hepatic artery to the hepatic or the central vein

B

PORTAL LOBULE Drains bile from hepatocytes to the bile duct

Hepatic arteriole Bile duct Portal vein Centrilobular venule

C

PORTAL ACINUS Supplies oxygenated blood to hepatocytes

Central vein Zone III least oxygenated Zone II Zone I most oxygenated

FIGURE 5.3  Structure-function conceptual liver units. To this day, there is no complete consensus on whether the microvascular unit of the liver should be referred to as a lobule, centering on a hepatic vein, or an acinus, centering on a “portal triad” consisting of a terminal branch of the hepatic artery, portal vein, and bile duct, encased within a limiting plate of cells defining the space of Mall. Three related conceptual units emphasizing different aspects of hepatocyte activity have been proposed. A, The classic lobule emphasizes the endocrine function of hepatocytes as blood flows past them toward the centrilobular venule. B, The portal lobule emphasizes the hepatocytes’ exocrine function and the flow of bile from regions of three classic lobules toward the bile duct in the portal triad at the center. The area drained by each bile duct is roughly triangular. C, The liver acinus concept proposed by Rappaport emphasizes the different oxygen and nutrient contents of blood at different distances along the sinusoids, with blood from each portal area supplying cells in two or more classic lobules. Each hepatocyte’s major activity is determined by its location along the oxygen/nutrient gradient: periportal cells of zone I get the most oxygen and nutrients and show metabolic activity generally different from the pericentral hepatocytes of zone III, exposed to the lowest oxygen and nutrient concentrations. (From Boron WF, Boulpaep EL, eds. Medical Physiology: A Cellular and Molecular Approach. Saunders Elsevier; 2005.)

parallel in the space of Mall, through the liver parenchyma, and form portal tracts. Lymphatics transport proteins and other macromolecules that are trapped extravascularly because of hindrance of hepatocellular uptake, as in the case of cirrhosis, which will, in turn, contribute to ascites formation (see Chapters 74 and 79). The hepatic sinusoids correspond to the capillary bed of the liver and represent the segment of the microcirculation in which supply of nutrients and removal of metabolic products by hepatocytes takes place. Bile canaliculi closely assemble around hepatocytes and collect bile flowing in an opposite direction from blood in the sinusoids. As depicted in Figure 5.3, histologic and physiologic studies of the liver have given rise to three related ways to view the liver’s microcirculation, emphasizing different functional aspects useful for the classification of various pathologic processes. Apart from the absence of a basement membrane, the structural peculiarity of hepatic sinusoids is their unique lining, consisting of endothelial cells with flattened processes perforated by small fenestrae. These open fenestrations are arranged in clusters of 10 to 50 pores, forming so-called “sieve plates” with a diameter of 150 to 175 nm (Fig. 5.4). The sieve plates occupy as much as 8% of the endothelial surface and are not uniform in size or distribution throughout the length of the sinusoids. There is a decrease in diameter but an increase of frequency from periportal to centrilobular zones, which results in higher centrilobular porosity.15,16 The fenestrae are dynamic structures that contract and dilate in response to alterations of sinusoidal blood flow and perfusion pressure.17 Red blood cells

(RBCs) remain restricted within the sinusoids, whereas molecules as large as albumin can pass through the fenestrations and enter the small space of Disse before making contact with the microvilli of the hepatocytes.12 As represented in Figure 5.5, other unique cellular components, such as the hepatic stellate cell (HSC)18 and the Kupffer cell (KC), are found in the hepatic sinusoids and may regulate the sinusoidal microcirculation in response to various mediators.19 External to the endothelium cell lining, HSCs (also known as fat-storing cells, Ito cells, or hepatic perisinusoidal lipocytes) are contractile cells distributed homogeneously around the exterior of the endothelial cells in the space of Disse, which is the space between the basal microvilli-rich surfaces of the hepatocytes and the sinusoidal lining cells. In addition to their well-known importance in retinol metabolism and as key actors in the hepatic fibrogenic response to injury (see Chapters 7 and 74), HSCs are capable of compressing the sinusoidal diameter by squeezing the endothelial cells and therefore play a central role in the regulation of blood flow through hepatic sinusoids.20,21 KCs are liver-specific macrophages, and, in contrast to HSCs, are anchored to the luminal side of the sinusoids. They account for approximately 15% of the liver-cell population and constitute approximately 80% of the total population of macrophages in the body.12 By their large bodies, with cytoplasmic process that sometimes reach the opposite wall of a sinusoid, KCs represent a flow hindrance and can secrete large amounts of the vasodilator nitric oxide, but their direct regulation role of the sinusoidal microcirculation is debated.12,22

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

Control of Liver Blood Flow The hepatic blood flow required to meet the physiologic function of the liver is mainly controlled by intrinsic physiologic mechanisms that are independent of extrinsic innervation and vasoactive agents. Instead, the interrelationship of arterial and portal inflow circuits is the major contributor to hepatic perfusion.

Liver-Intrinsic Blood Flow Regulation THE HEPATIC ARTERIAL BUFFER RESPONSE. Adequate and homogeneous blood flow to the liver is necessary to sustain hepatic PS H

E

E

PS

H FIGURE 5.4  Fenestrations in endothelial sinusoid lining. Electron microscopy of the luminal surface of the endothelium lining a sinusoid in the liver shows grouped fenestrations. At the border are seen cut edges of the endothelial cell (E) in this discontinuous sinusoid and hepatocytes (H). Between these two cells is the thin perisinusoidal space (PS), into which project microvilli from the hepatocytes surface. Blood plasma passes freely through the fenestrations into the perisinusoidal space, where the voluminous membrane of hepatocytes acts to remove many high- and low-molecular-weight blood components and nutrients for storage and processing. Proteins synthesized and secreted from hepatocytes, such as albumin, fibrinogen, and other blood proteins, are released into the perisinusoidal space (36500). (From Mescher AL. Junqueira’s Basic Histology: Text and Atlas, 12th ed. McGraw-Hill; 2009; and Eddie Wisse, Electron Microscopy Unit, Department of Pathology, University of Maastricht, The Netherlands.)

73

functions and clearance of metabolites. Because the liver does not control portal blood flow, which is simply the outflow of the extrahepatic splanchnic organs, the main mechanism by which hepatic blood flow can remain constant relies on modulation of the hepatic arterial flow (Fig. 5.6). Although this phenomenon was observed in the late 19th and early 20th centuries,23,24 it was characterized and coined as the hepatic arterial buffer response (HABR) by Lautt in 1981.25 HABR represents the ability of the HA to produce compensatory flow changes at the presinusoidal level in response to changes in PV flow (see Fig. 5.6): If portal blood flow is reduced, the HA dilates and increases its flow into the sinusoids, and the HA constricts when the portal flow is increased.26,27 In patients undergoing abdominal surgery, a temporary occlusion of the PV resulted in a sharp increase in HA flow of about 30%, whereas temporary occlusion of the HA did not have significant effect on PV flow. The HABR seems to operate under various physiologic and pathologic conditions and has even been suggested to operate prenatally.28 The HABR appears mainly regulated by the washout of adenosine, a potent vasodilator. Although adenosine is produced at a constant rate and secreted into the space of Mall (see Fig. 5.1), its concentration depends on the rate of washout from the space of Mall into the sinusoids. When portal blood flow decreases, less adenosine is washed away, and the elevated adenosine concentration leads to dilation of the HA. Of importance, the source of the extracellular adenosine found in the space of Mall remains to be elucidated. If portal blood flow is severely reduced, the buffer response results in the HA dilating maximally, as demonstrated by the inability to produce additional dilation in response to intraarterial infusion of adenosine. Conversely, when portal flow is doubled, the HA constricts to a maximal extent, as demonstrated by the inability of intraarterial norepinephrine to produce further constriction.27 Although the HABR is sufficiently powerful to regulate the vascular tone in the HA over the full range from maximal vasodilation to maximal vasoconstriction, this mechanism is capable of buffering 25% to 60% of the decreased portal flow.29 Although adenosine appears to be the main mediator of the HABR, a possible contribution of the afferent sensory nerves and neuropeptides is suggested by studies in fully denervated animal livers30 and in transplanted human livers,31,32 in which

Space of Disse

Hepatic sinusoid

Hepatocyte

Endothelial cell

Hepatic stellate cell

Kupffer cell

FIGURE 5.5  Hepatic stellate and Kupffer cells relation to the liver microcirculation. Contractile hepatic stellate cells are distributed homogeneously around the exterior of the endothelial cells in the space of Disse, the space between the basal microvilli-rich surfaces of the hepatocytes and the sinusoidal lining cells. Kupffer cells, which are liver-specific macrophages, are anchored to the luminal side of the sinusoids. They can secrete vasoactive mediators, and their large bodies may represent sinusoidal flow hindrance.

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY 20

20

18

18

16

16

14

14

Blood flow (mL/min)

Blood flow (mL/min)

74

12 10 8

†

†

*

6

10

§

8

† *

6

4

4

2

2

0

A

12

0 I

II

III

IV

V

B

I

II

III

IV

V

FIGURE 5.6  Hepatic arterial buffer response in cirrhotic (A) and control livers (B). Upon reduction of portal venous blood flow (red), there is a constant increase of hepatic arterial blood flow (blue). The portal flow is markedly diminished in cirrhotic liver, but the buffer response is preserved. Values are means 6 standard error of triplicate measurements per animal (n 5 6). *P , .05 vs. I and II; †P , .05 vs. I, II, and III. §P , .05 vs. I, II, II, and IV. (From Richter S, Mücke I, Menger MD, Vollmar B. Impact of intrinsic blood flow regulation in cirrhosis: Maintenance of hepatic arterial buffer response. Am J Physiol Gastrointest Liver Physiol. 2000;279(2):G454–G462.)

the HABR upon partial PV occlusion is partially impaired.33,34 It has also been shown that hydrogen sulfide (H2S), a vasoactive gaseous mediator produced within the liver, appears to almost double the HABR by increasing the HA conductance, and, in turn, its inhibition has the opposite effect.35 THE HEPATIC INFLOW IS NOT CONTROLLED BY LIVER-INTRINSIC METABOLIC NEEDS. Until the mid-1970s, the HA flow was believed to be under metabolic control of the liver. As for most organs, the liver metabolism, estimated by its oxygen requirements, was postulated to participate in vascular inflow control. It has, however, been established that the liver normally receives more oxygen than it requires and can extract more oxygen to compensate for reduced delivery.3,36,37 Additionally, the unique one-way sinusoidal flow arrangement precludes substances diffusing back from the hepatic parenchyma or venous blood into the HA resistance vessels. Among other studies, this concept has been exemplified by isovolemic hemodilution or upregulation of hepatic enzymes, leading to oxygen deprivation to the liver parenchyma, which does not result in HA dilation.10,38 Therefore the hepatic metabolic demands do not control the HA flow, even if the liver parenchymal cells can release large quantities of potent vasoactive molecules during metabolic stress. The term autoregulation refers to the tendency for local arterial blood flow to remain constant in the face of pressure changes in the arteries that perfuse a given organ. Overall, the degree of autoregulation is considered small in the liver, and mixed results have been reported in animal models.39 In fact, the adenosine washout may well account for HA autoregulation because endogenous adenosine produced by the HA tributaries can contribute to high presinusoidal adenosine concentration in situations where hepatic clearance is impaired by a reduction in the portal flow, leading to HA vasodilation.40 REGULATION OF INTRAHEPATIC RESISTANCE AT THE SINUSOIDAL LEVEL. Sinusoidal blood pressure and vascular resistance are so

low that a pressure gradient across the liver from the PV inflow to the HV outflow is only approximately 5 mm Hg. The lowpressure gradient is remarkable, considering that 30% of the inflow to the liver sinusoids is provided by the HA under arterial pressure. How the hepatic pressure gradient is maintained has been studied in multiple animal models. About 60 years ago, Knisley suggested the presence of sphincter-like structures at the entrance and exit of sinusoids that maintain the PV pressure gradients, but these proved to be species dependent.12,22,41 In humans, although smooth muscle cells are found throughout all segments of the hepatic microvascular subunits, no such sphincter-like structures have been described for controlling intrahepatic blood flow. In contrast, there is a growing body of evidence that contracting cells associated with the sinusoids, such as the HSCs and the sinusoidal endothelial cells, through a complex interplay with vasoactive mediators, may dynamically regulate the hepatic microvascular blood flow. With such a low sinusoidal perfusion pressure, local regulators at a single-cell level may actively control the flow within the sinusoids toward the HVs. It seems plausible that the HSCs could dilate to pull outward on the endothelial cells and enlarge the sinusoidal space (see Fig. 5.5); however, this does not seem to have been shown.22 Many endothelial mediators known to control vascular tone by acting on HSC contractility have been described (Table 5.1), notably: (1) the endothelium-derived relaxing factor nitric oxide (NO),42 (2) the endothelium-constricting factor endothelin-1 (ET-1),43,44 and (3) two vasodilatory gaseous molecules: carbon monoxide (CO)45,46 and H2S.47,48 With the exception of H2S, a direct contribution of these vasoactive agents to the HABR is not well established.39

Liver-Extrinsic Factors Affecting Liver Inflow ENDOGENOUS FACTORS Blood Gas Tensions. Hypercarbia (partial pressure of carbon dioxide in arterial blood [PaCO2] . 70 mm Hg) increases PV

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

75

TABLE 5.1  Liver-Intrinsic Vasoactive Molecules and Pathways Regulating the Microcirculation VASOACTIVE AGENT

FUNCTION

ENZYME SYSTEM

CELLULAR SOURCE AND DISTRIBUTION

Thromboxane A2

COX-1, COX-2

Angiotensin II Nitric oxide Nitric oxide

Vasoconstriction, platelet activation and aggregation, leukocyte adhesion Vasodilation, inhibition of platelet aggregation Vasoconstriction Vasodilation Vasodilation

Endothelin-1

Vasoconstriction

Endothelin-1 Carbon monoxide

Vasodilation Vasodilation

HO-1

Hydrogen sulfide

Vasodilation Vasodilation

HO-2 CSE (CBS)

Prostaglandin I2

TARGET CELL

PATHWAYS

SEC, KC

SEC, platelet, leukocyte

TxA2R

COX-1, COX-2

SEC

SEC, HSC

PGI2R

ACE eNOS iNOS

HSC SEC SEC, KC, VSMC, HSC, HC SEC, HSC, KC

HSC VSMC, HSC VSMC, HSC

AT1 sGC sGC

VSMC, HSC, SEC, KC SEC VSMC, HSC

ETAR, ETB2R ETB1R sGC

VSMC, HSC VSMC

sGC KATP channels

SEC, HSC, KC SEC, KC, VSMC, HSC, HC HC HSC, HC

ACE, Angiotensin-converting enzyme; AT1, type 1 of angiotensin II; CBS, cystathionine-synthase; COX-1, COX-2, cyclooxygenase-1 and 2, respectively; CSE, cystathionine-lyase; eNOS, endothelial constitutive nitric oxide synthase (type III); ETAR, endothelin type A receptor; ETB1R, endothelin type B1 receptor; HC, hepatocytes; HO-1, inducible heme oxygenase; HO-2, constitutive heme oxygenase; HSC, hepatic stellate cells; iNOS, inducible nitric oxide synthase (type II); KATP, adenosine triphosphate (ATP)-sensitive potassium channel; KC, Kupffer cells; PGI2R, prostaglandin I2 receptor; SEC, sinusoidal endothelial cells; sGC, soluble guanylate cyclase; TxA2R, thromboxane A2 receptor; VSMC, vascular smooth muscle cells. From Vollmar B, Menger MD. The hepatic microcirculation: Mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89:1269–1339.

flow and decreases HA flow in dogs,49 whereas hypocarbia (PaCO2 , 30 mm Hg) decreases both.50 Systemic hypoxia (partial pressure of oxygen in arterial blood [PaO2] , 70 mm Hg) causes a decrease in arterial flow but has no effect on the contribution from the PV.51 The response to metabolic acidosis is similar to that induced by hypercarbia, whereas metabolic alkalosis has essentially no significant effect.52 The sympathetic nervous system is thought to be responsible for the HA vasoconstriction observed in hypercarbia and hypoxia.53 Sympathetic Nervous System. The liver is a significant blood reservoir, and 50% of its blood volume may be mobilized by nerve stimulation.54 Denervation experiments have shown that the sympathetic nervous system is not involved in basal arterial tone in the liver.53 Hepatic sympathetic nervous stimulation causes HA vasoconstriction and reduced blood flow, which appears secondary to an autoregulatory response.1 Sensory denervated rats and pigs have a diminished arterial buffer response on partial occlusion of the PV.34 Portal pressure increases as a result of an increase in PV resistance, but portal flow does not decrease unless there is a decrease in intestinal or splenic blood flow caused by simultaneous sympathetic stimulation of these vascular beds. Although the HA contains both a-adrenergic and b-adrenergic receptors, the PV system is believed to contain only a-receptors.55 At low doses, epinephrine causes hepatic and mesenteric arterial vasodilation, whereas at high doses, vasoconstriction occurs in the HA and PV vascular beds and in the mesenteric circulation.1,55 Other Endogenous Vasoactive Agents. Intraportal administration of exogenous vasoactive agents affects HA resistance.56 The mechanisms underlying this intrahepatic transvascular effect are not understood, but it is likely that the close anatomic association between arterioles and venules could permit this and may be a means by which HA blood flow is finely controlled by endogenous agents, such as gut hormones. Gastrin, secretin, cholecystokinin, and vasoactive intestinal peptide

cause vasodilation of the HA. Hepatic blood flow is profoundly increased by glucagon as a consequence of its strong vasodilatory action on the mesenteric vasculature, but insulin has little hemodynamic effect on the hepatic circulation. In addition, antagonists of calcitonin gene–related peptide and neurokinin significantly reduce HA blood flow, suggesting the presence of their receptors on the arterial vasculature.33 Histamine causes HA dilation and, in the dog only, HV constriction. Bradykinin is a potent HA vasodilator that has little effect on the PV system. The HA vascular bed is dilated by most prostaglandins; however, prostacyclin does not affect HA flow but increases portal blood flow through a vasodilator effect on the prehepatic vascular bed. Vasopressin decreases portal flow and pressure by mesenteric arterial vasoconstriction but has variable effects on the HA. Serotonin is believed to mediate vasoconstriction of portal radicles. Liver-extrinsic NO causes vasodilation in the HA and mesenteric vascular beds. Endothelin molecules can exert a powerful and prolonged generalized systemic constriction21,57 that also has a direct effect on the hepatic blood flow. Endothelins reduce hepatic perfusion,58 increase portal pressure,59–62 and reduce sinusoidal diameter.21,59,63 Angiotensin decreases HA and portal blood flow and is one of the few substances to produce a significant vasoconstrictor effect on the HA. In contrast, H2S, either endogenously or exogenously, can reverse the norepinephrine-induced vasoconstriction in an NO-independent fashion.64 PHYSIOLOGIC STATES AND EXOGENOUS FACTORS Age. Liver size and blood flow decrease with age in humans. Similarly, apparent liver blood flow per unit volume of liver (liver perfusion) falls with age.65 Age does not seem to affect sinusoidal dimensions or sinusoidal density, but rather the geometry and the complexity of the sinusoidal network changes. These small age-related changes in the architecture

76

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

of the liver sinusoidal network may influence hepatic function and reflect broader aging changes in the microcirculation.66 The reduced elimination of both capacity-limited and flowlimited drugs, which is seen in the elderly, predisposed to adverse drug reactions, is likely because of these morphologic combined with physiologic changes.67 Reduction in the activity of drug-metabolizing enzymes are probably of less significance in the healthy aged population. Food Intake. Postprandial hemodynamic changes have been studied extensively in animals and humans. A meal induces a marked vasodilatation of the mesenteric artery with a consequent increase in PV flow, and compensatory vasoconstriction of the HA. The intrahepatic hemodynamic changes are greater in the right lobe of the liver, with a more significant increase of portal flow velocities on that side, in association with a bilateral reciprocal HA response that may be maximal on both sides.68 The meal composition did not influence the magnitude of the hemodynamic changes but rather the timing of the response.69,70 Anesthesia. The effect of anesthetic agents on the LBF has been mainly studied in animal models some 30 years ago. HA and PV blood flow decreases passively in parallel with cardiac output during halothane inhalation, with little change in vascular resistance.71,72 Enflurane has been found to have similar effects as those of halothane, although there is a decrease in HA vascular resistance as part of a generalized decrease in peripheral vascular resistance.71 NO concentrations of 30% to 70% reduce HA and PV flow, possibly as a result of a generalized stimulatory action on a-adrenergic receptors.73 Isoflurane seems to have minimal effects on HA and PV flows, and the intravenous (IV) agent fentanyl may have little effect on prehepatic splanchnic blood flow.74 Thiopentone in low doses vasoconstricts the HA and mesenteric vascular beds.75 The effect of regional anesthesia on the LBF is poorly characterized. Sympathetic block might logically improve flow by reducing splanchnic vascular resistance, whereas reductions in systemic vascular resistance and cardiac output might offset this beneficial effect.76 Thoracic epidural anesthesia caused a reduction in blood flow in mesenteric arteries that was associated with a decrease in systemic mean arterial pressure.77 Intermittent positive pressure ventilation predictably reduced splanchnic perfusion via a reduction in preload with a fall in cardiac output. The splanchnic circulation is also susceptible to more direct effects of positive pressure ventilation. The use of very large tidal volumes, high levels of positive end expiratory pressure (PEEP), and high inspiratory pressures have been shown to reduce splanchnic perfusion. These effects appear to be because of increased HV pressures and mesenteric vascular resistance, with reduced portal blood flow.76

MEASUREMENT OF LIVER BLOOD FLOW AND LIVER PERFUSION The earliest methods of measuring LBF involved direct invasive techniques, such as intravascular devices or venous outflow collection.23,78,79 Currently, measurement of hepatic venous pressure gradient (HVPG) remains the gold standard technique to assess portal hypertension11 (see Chapters 74 and 85). Indirect determination of blood flow by the use of a variety of indicatorclearance techniques were subsequently developed, often confounded by the presence of liver disease. Some of these techniques remain useful to estimate liver function when planning major hepatectomies. By far today, Doppler ultrasound (D-US)

BOX 5.1  Summary of Methods Commonly Used for Measuring Liver Blood Flow Flow in Single Vessels Transjugular hepatic veins and wedge pressure measurement Doppler ultrasound Four-dimensional flow magnetic resonance imaging (MRI) Total Liver Blood Flow Hepatocyte clearance of Indocyanine green (ICG) Hepatic Tissue Perfusion Contrast-enhanced ultrasound Contrast-enhanced computed tomography (CT) Contrast-enhanced MRI Isotopic imaging Scintigraphy (technetium 99m pertechnetate, albumin or sulfur-based colloids)

is the most common first-line noninvasive technique used to assess liver vascularization and guide clinical management. The available methods are discussed under three broad headings: (1) flow in single blood vessels, (2) total LBF, and (3) hepatic tissue perfusion. The techniques most commonly used for clinical use are listed in Box 5.1.

Flow in Single Vessels and Assessment of Portal Hypertension Invasive Techniques ELECTROMAGNETIC FLOWMETER PROBES. The direct and continuous measurement of HA and PV blood flow with electromagnetic flowmeter probes remains the best available means of assessing individual vessel flow. The technique has found widespread application in experiments using large animals, but not in clinical situations because of the vascular dissection required for placement of the probes. It is with this technique that total LBF in anesthetized subjects was determined to be approximately 1 L/min, of which approximately 25% was supplied by the HA.80 Electromagnetic flowmeter probes have been used in the investigational setting intraoperatively to assess the hemodynamic status of the cirrhotic liver81 and for intraoperative and postoperative measurement of PV and HA blood flow in liver resection and transplantation.31,32,82 A typical experimental preparation using electromagnetic flowmeter probes is illustrated in Figure 5.7. TRANSJUGULAR HEPATIC VENOUS PRESSURE MEASUREMENT. Because portal hypertension is responsible for most clinical consequences of cirrhosis, measurement of PV pressure is critical to guide the clinical management of patients with chronic liver diseases. Currently, the accuracy of invasive techniques has not been surpassed by noninvasive measurement. Direct measurements of portal pressure can be performed through transhepatic or transvenous catheterization of the PV, but are rarely used because of the risk of intraperitoneal bleeding and visceral perforation. Instead, measurement of HV direct pressure and wedge pressure by a transjugular approach has been developed as a safe and reproducible technique to assess portal hypertension (Fig. 5.8). As mentioned earlier, the pressure gradient between the PV and the IVC represents the liver portal perfusion pressure, and its normal value is as high as 5 mm Hg.

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

77

first-line technique. In patients with known cirrhosis, D-US has greater than 80% specificity diagnosing clinically significant portal hypertension, but the sensitivity may not exceed 70%, particularly in compensated patients.11 Inversion of flow within the PV is 100% specific for clinically significant portal hypertension. D-US is very accurate for detecting PV, HV, and HA thrombosis.88 Additionally, D-US is useful in the noninvasive follow-up of transjugular intrahepatic portosystemic shunt (TIPS; see Chapter 85).89

FIGURE 5.7  Experimental arrangement for measuring liver blood flow in the dog with electromagnetic flow probes. Probes are placed around the portal vein (PV) and common hepatic artery (CHA). The gastroduodenal vein (GDV) and gastroduodenal artery (GDA) are ligated as illustrated to ensure that the flows measured by the probes are those that actually perfuse the liver.

The HVPG is calculated with the difference between wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP; see Chapter 85). It is based on the concept that when the blood flow in a HV is blocked by a wedged catheter, the static column of blood transmits the pressure from the preceding communicated vascular territory, in this case, the hepatic sinusoids. Thus the WHVP is a measurement of the hepatic sinusoidal pressure and not of the portal pressure itself. In cirrhosis, even if the intersinusoidal communications are lost because of fibrosis and nodule formation, it has been well demonstrated that WHVP adequately reflects portal pressure.83,84 The use of balloon-tipped catheters is recommended to measure HVPG85 because the volume of the liver circulation that is measured is larger than that obtained by wedging the catheter tip, which enhances the reliability and accuracy of the measurement.86

Noninvasive Techniques DOPPLER ULTRASOUND. Named after Christian Doppler for the phenomenon he described, the principle of flow estimation by Doppler is simple: flow is a product of the average velocity of the blood measured in the vessel of interest and the crosssectional area of the vessel. Two forms of D-US devices exist. The first consists of a flowmeter with a US probe that is placed directly on the vessel; measurement with such a device is invasive. The second consists of a combined image scanner and flowmeter (duplex) by which flow in a vessel can be measured transcutaneously and noninvasively. In experiments performed on anesthetized dogs, good correlation was found between PV flow measured by a transcutaneous D-US and electromagnetic flowmeter probes fitted to the PV.87 Because the development of color Doppler and better probe resolution with high-frequency transducers has improved accuracy, and because the technique provides morphologic assessment of the liver, is cheap, and can be performed at the bedside, D-US has become a widespread

FOUR-DIMENSIONAL FLOW MAGNETIC RESONANCE IMAGING. Since its original description in the 1980s,90 phase contrastenhanced magnetic resonance imaging (MRI) has seen broad clinical acceptance for the visualization and quantitative evaluation of blood flow in the heart and large vessels.91 Further developments have led to time-resolved, three-dimensional (3D) phase-contrast MRI with 3D velocity encoding, which is often referred to as “four-dimensional (4D) flow MRI.” Although standard two-dimensional (2D) MRI allows for the evaluation of blood flow in a single 2D slice, 4D flow MRI can provide information on the temporal and spatial evolution of 3D blood flow, with full volumetric coverage of any vascular region of interest.92 This method can be used to monitor hepatic blood flow in patients with portal hypertension, in particular for noninvasive longitudinal hemodynamic monitoring before and after TIPS placement (Fig. 5.9).93

Total Blood Flow Clearance Techniques Substances reaching the liver via the HA or PV are equally well extracted,56 and the rate of disappearance from the bloodstream of an indicator substance exclusively cleared by the liver is proportional to LBF. First applied to humans by Bradley and colleagues in 1945,94 indirect clearance methods of LBF measurement rely on the Fick equation. The Bradley’s group originally used IV-injected bromosulfophthalein, removed from the bloodstream and excreted into the bile entirely by hepatocytes. The total hepatic blood flow was calculated by deriving a value for the rate of hepatic bromosulfophthalein removal using the rate of IV infusion of dye that maintained the arterial concentration at a constant level and the arteriovenous concentration difference of bromosulfophthalein. The mean value obtained in healthy individuals was 1.5 L/min. Other hepatic clearance techniques have been investigated in the past, such as colloidal clearance by the hepatic KC95 and hepatocyte removal of galactose,96 sorbitol,97 rose bengal,98 or propranolol.99 The more complete hepatic extraction of these substances overcomes the need to cannulate an HV in patients with normal liver function. A modification of the colloid extraction method developed in the 1980s allows the derivation of the ratio of HA to total LBF, termed the “hepatic perfusion index.” The basis of the technique is the ability to determine by dynamic scintigraphy the temporal separation of accumulating hepatic activity after reticuloendothelial uptake from the arterial and portal supplies after the IV administration of a bolus of technetium-99m–sulfur colloid.100 Indocyanine green (ICG) is now the most commonly used substance dependent on hepatocyte extraction into the bile. It was initially devised for the measurement of blood flow and later used for the assessment of liver function by measuring functional hepatocyte mass (see Chapter 3). HV cannulation

78

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

2-4 cm

A

B

mmHg 40

WHVP

WHVP 20

0

C

FHVP

FHVP

D

FIGURE 5.8  Measurement of hepatic venous pressure. A, Free hepatic venous pressure (FHVP) is measured by maintaining the tip of the catheter free in the hepatic vein at 2 to 4 cm from its opening into the inferior vena cava. B, Wedged hepatic venous pressure (WHVP) is measured by occluding the hepatic vein by inflating the angiographic balloon (arrow) at the tip of the catheter. Adequate occlusion of the hepatic vein is confirmed by slowly injecting 5 mL of contrast dye into the vein with the balloon inflated. Please note the typical wedged pattern distal to the balloon. C, A washout of contrast dye through communications with other hepatic veins (arrow) prevents a correct measurement of the hepatic venous pressure. D, Typical tracing of pressures measured in the hepatic vein obtained using a multichannel recorder and adequately calibrated transducers. (From Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 2013;7[2]:141–155.)

was initially performed to calculate the true extraction efficiency of ICG because of its incomplete hepatic removal.101 Many investigators now use a simplified version of the original method, in which ICG is administered as a single IV bolus instead of as an infusion, and hepatic extraction efficiency is determined from an analysis of the clearance curve derived from peripheral blood sampling or pulse dye densitometry, by using an optical sensor placed on the finger.102,103 ICG plasma disappearance rate is the most commonly used parameter, with a normal range between 16% and 25% per minute and nearcomplete disappearance at 20 minutes.104 It is now the most widely used quantitative liver function test in the clinical setting.105 Limitations of this technique include variations in hepatic blood flow caused by intrahepatic and extrahepatic shunting, or portal thrombosis, which is common in liver disease.

from the Fick equation.106 In principle, the hepatic blood flow is proportional to the amount of hepatic blood that has diluted an introduced indicator. This method involves the injection into the HA and PV of a labeled substance that is not removed by the liver; changes in HV concentration are measured by blood sampling or by monitoring the hepatic isotope activity with an external detector. Such a method is therefore independent of hepatocellular function and reliable, provided the indicator remains in the vascular space and is not excreted before sampling. A modified thermal dilution technique has been used to measure portal blood flow in humans.107 Indicator dilution methods overestimate true blood flow to hepatic tissue when intrahepatic or extrahepatic shunts are present, although it is possible to measure azygos blood flow by thermal dilution in patients with cirrhosis.108

Other Techniques of Physiologic Interest

INDICATOR FRACTIONATION. The measurement of regional blood flow by fractional distribution of cardiac output was first described by Sapirstein in 1956.109 Briefly, a known amount of

INDICATOR DILUTION. The indicator dilution method relies on the application of the Stewart-Hamilton principle, also derived

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

79

A

B

FIGURE 5.9  Four-dimensional flow magnetic resonance imaging (MRI)-based visualization and quantification of hemodynamics in the portal system before and after transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension. A, Segmentation of four-dimensional (4D)-flow angiograms obtained before (pre) and two weeks after (post) TIPS placement show arteries (red), veins (blue), portal vasculature (yellow), and TIPS (gray). B, Velocity-coded 4D-flow MRIs obtained before (pre) and 2 weeks after (post) TIPS placement show velocity distribution in the portal circulation. Color-coded streamlines show increased blood flow in the superior mesenteric vein (SMV), splenic vein (SV), and portal vein (PV) in response to TIPS placement. Note the high velocity in the TIPS, with a signal dropout at the proximal end of the TIPS are because of disordered flow. Ao, Aorta, IVC, inferior vena cava. (From Bannas P, Roldán-Alzate A, Johnson KM, et al. Longitudinal monitoring of hepatic blood flow before and after TIPS by using 4D-flow MR imaging. Radiology. 2016;281[2]:574–582.)

radioactive microspheres is injected into the left ventricle, and a reference sample is withdrawn from a peripheral artery at a known rate. The microspheres are then extracted from the various vascular beds, where they have lodged in proportion to the cardiac output. The HA blood flow can be determined directly by this method, but the portal flow contribution is found indirectly by addition of the flow values in the prehepatic splanchnic organs. Examination of the intrahepatic distribution of microspheres has provided a means of assessing the pattern of arterial flow in different liver regions.110 Because the microsphere method requires the postmortem removal of the organs of interest for radioactivity or colorimetric measurement, the additional determination of tissue weight enables flow per gram (i.e., tissue perfusion) to be calculated. Microspheres may be used to determine the extent of portosystemic shunts. The fractional distribution in the liver may be measured with respect to systemic (lung) activity after PV injection, or it may be estimated by injecting a second radioactive microsphere directly into the splenic or mesenteric venous system.111

Hepatic Tissue Perfusion Contrast-Enhanced Ultrasound If D-US allows to quantify flow in single vessels, contrastenhanced US with microbubble contrast agents allows to quantify hepatic tissue perfusion. Advantages over other imaging

techniques are the use of purely endovascular agents, which circumvent the issue of extravascular leakage, the equipment lightweight and readiness, and the avoidance of exposure to x-rays or radionuclide tracers.112 Dynamic image sequences are obtained after contrast injection, which then varies in local concentration over time. The change in intensity over time can then be modeled to obtain parameters describing the microcirculation. A software program is used to estimate liver perfusion along three main types of analysis: organ transit time of the contrast, tissue reperfusion kinetics, and enhancement intensity curves.113

Computed Tomography A concentrated iodinated contrast medium is used as tracer in computed tomography (CT), and it is injected at high flow. This technique is inexpensive, readily accessible, quick, highly reproducible, and provides morphologic information.112 It offers good spatial and temporal resolution, and quantification of the tracer is straightforward because the density concentration relationship is linear (Fig. 5.10). It is most commonly used to delineate acute liver parenchymal injuries and the precise localization and vascularization pattern of suspected liver lesions. The information gained by CT scan to guide clinical decision making outweighs risks related to radiation and the potential nephrotoxicity of iodinated contrast, which can also be reduced by optimizing the acquisition settings, improving detectors, and using reconstruction algorithms.114

80

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

FIGURE 5.10  Example of signal to time curve obtained on computed tomography (CT). The signal to time curve (image on the right) is obtained after positioning the regions of interest in the afferent vessels (aorta and portal vein). The change in tracer concentration over time is obtained by rapid signal sampling (in this case density). The perfusion parameters are extracted from an analysis of these curves. (From Ronot M, Lambert S, Daire JL, et al. Can we justify not doing liver perfusion imaging in 2013? Diagn Interv Imaging. 2013;94[12]:1323–1336.)

Magnetic Resonance Imaging Significant correlation between MRI and thermal dilution probe flow measurements using 1.0T T1-weighted sequences in pigs was first described in 1999.115 This technique does not necessitate radiation, with good spatial and temporal resolution. The main technique used for MRI perfusion measurement is dynamic contrast-enhanced MRI (DCE-MRI) after injection of a gadolinium chelate.92,116 Unlike CT, in which the tracer concentration curve over time is proportional to changes in attenuation measured in Hounsfield units, the curve is more difficult to obtain in MRI because the relationship between signal intensity and tracer concentration is not linear. Concentration is related to the relaxivity of the medium and requires measurement of T1, which can be performed using samples of increasing gadolinium concentration.112 Of note, MRI sequences that are affected by molecular diffusion (diffusion MRI) are influenced by the microperfusion. The diffusion MRI signal depends on the speed of the circulating blood and the microvascular architecture. The restriction in diffusion seen in cirrhotic liver may be because of changes in microperfusion components rather than reduction in pure hepatic diffusion.117 Ongoing research is evaluating specific use of MRI to assess liver perfusion.

Isotopic Imaging Scintigraphic methods to calculate liver perfusion parameters were first described in the 1970s. Images are generally acquired after IV injection of a radiopharmaceutical (technetium 99m pertechnetate, albumin, or sulfur-based colloids).112 Liver enhancement is analyzed by regions of interest and the arterial and portal components are separated; the renal enhancement peak represents the beginning of portal enhancement of hepatic parenchyma.118 Scintigraphic studies based on positron emission tomography have assessed the feasibility of studying hepatic perfusion.119 Isotopic imaging, however, is often hindered by poor spatial and temporal resolution.112

Other Techniques INERT GAS CLEARANCE. By exploiting the fact that radioactive gases such as krypton (85Kr) and xenon (133Xe) distribute equally between tissue and blood according to a specific partition coefficient, the rate of clearance of such gases can be measured after their injection into the hepatic blood supply. After injection and rapid diffusion throughout the liver, the gas

clears from the tissue into the blood and is almost completely eliminated from the body after a single passage through the lungs. The clearance rate is proportional to hepatic tissue perfusion, which may be calculated by using a standard formula.120 The first to use the inert gas method in the hepatic circulation were Aronsen and colleagues (1968a),121 who recorded the g-emissions of 133Xe after the injection of a saline solution of the isotope into the PV. b-Emissions of 85Kr are recorded by a Geiger-Müller tube or semiconductor (silicon) detector placed on or immediately above the exposed liver surface, whereas the g-emissions of 133Xe are monitored transcutaneously by a single scintillation crystal or a g-camera; the latter device allows simultaneous measurement of hepatic tissue perfusion in many regions of interest. Inert gas techniques involve minimal trauma to the patient, and their accuracy is not markedly affected by the presence of hepatic cellular disease or nonperfusion shunts. Reproducibility of the results, even within the same subject, has been a concern. LASER DOPPLER FLOWMETRY. Laser Doppler flowmetry (LDF) is a technique for the real-time measurement of microvascular RBC perfusion in the liver. By illuminating the tissue with lowpower laser light and capturing the backscattered light with independent photodetectors, the Doppler shift of moving cells can be transmitted as an electrical signal. Linearity of the LDF signal from the liver with total organ perfusion has been shown,122 and the technique has been shown to be sensitive to rapid changes in organ flow.123 The technique has been applied successfully to measure LBF during liver transplantation in humans.124 A major drawback of the technique is that, because of the small volume of tissue interrogated by the laser, the LDF signal can only be used to measure arbitrary, instead of absolute blood perfusion in a single area. IN VIVO FLUORESCENT MICROSCOPY. Intravital microscopy was first described in the microvessels of the frog tongue by Waller in 1846.125 Using this technique, individual sinusoids and terminal venules can be visualized, and changes in their diameters and the velocities with which erythrocytes pass through them can be seen.126 The introduction of fluorescent dyes has broadened the spectrum of in vivo microscopy in the liver from morphologic analysis to the study of pathologic events. From a hemodynamic point of view, however, intravital fluorescent microscopy has problems of interpretation.127 In perfused liver,

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

a 2.5-fold increase in PV blood flow has been found to be associated with only a 22% increase in sinusoidal RBC velocity, suggesting that changes in PV blood flow have only a minor effect on the capillary transit time.128 NEAR-INFRARED SPECTROSCOPY. Near-infrared spectroscopy is a noninvasive technique that uses light transmission and absorption to measure hemoglobin and mitochondrial oxygenation. In contrast to visible light, which can only penetrate a few millimeters, near-infrared light (700–1000 nm) can be detected through as much as 80 mm of tissue. The application of this technology to monitor liver oxygenation has been validated in models of endotoxic shock in pigs129 and by intraoperative quantification of congestion and mitochondrial redox during HV occlusion in living-donor transplantation.130

CLINICAL RELEVANCE Hemorrhagic Shock, Hypoperfusion, and Ischemia-Reperfusion Injury Total LBF decreases approximately in relation to the degree of the hemorrhage, and PV blood flow decreases in parallel to cardiac output; but similar to the coronary, pulmonary, and cerebral circulations, HA flow does not decrease until extremely low blood pressures are reached. As a result, the hepatic oxygen supply tends to be maintained, although oxygen extraction greatly increases to preserve normal total oxygen consumption.131 Hepatic blood volume can increase significantly in cardiac failure and can compensate as much as 25% of hemorrhage from its large-capacitance vessels.132 The clinical entity known as shock liver has long been recognized, typically related to cardiogenic or hemorrhagic shock.133 Hepatic dysfunction caused by hypoperfusion is manifested pathologically by centrilobular necrosis and clinically by abdominal pain, cholestatic jaundice, and marked elevation of serum aminotransferases. Three phases of liver injury attributed to ischemia were proposed by Champion and colleagues (1976),134 whereby the initial hepatic dysfunction would resolve as long as no additional insults (e.g., sepsis) were incurred. Gottlieb and colleagues (1983)135 showed that hepatic dysfunction in humans after trauma was related to a reduced hepatic blood flow rate as much as 70% of resting levels. Hepatic blood flow was markedly reduced after injury, and although total splanchnic oxygen delivery was decreased, oxygen consumption remained normal as a result of increased hepatic extraction. In the ischemic state, upregulation of acute-phase proteins (C-reactive protein, fibrinogen, ceruloplasmin, haptoglobin) is prioritized versus production of other hepatic proteins, such as albumin and transferrin.136 More recently, hemorrhagic shock has been recognized to result in generalized vascular endothelial dysfunction and impaired endothelial biosynthesis of NO. Endothelial NO that continues to be expressed by the liver during ischemia is believed to protect against the initial hepatic injury arising from severe hemorrhage. By contrast, more prolonged hemorrhagic shock (.6 hours duration) induces greatly increased production of NO because of activation of an inducible NO synthase enzyme in hepatocytes and KCs.137 In the transplantation era, the consequences of ischemia and reperfusion for the liver have been increasingly investigated and understood. The damage to the hepatic endothelium

81

and parenchyma that results from postischemic reperfusion is caused by numerous interrelated phenomena, including the action of locally liberated oxygen-derived free radicals and excess formation of vasoconstrictor agents.138 Endogenous NO tends to protect the liver in the early reperfusion period after hepatic ischemia.139 Ischemia is also the primary signal for heat-shock protein production in liver tissue. Experimental studies of heat-shock protein preconditioning through intermittent portal clamping demonstrated attenuated aminotransferase elevations and improved bile production after ischemia140.

Liver Atrophy Liver atrophy results from a significant reduction of LBF containing hepatotrophic substances (see Chapter 6). The degree of atrophy depends on the degree of blood flow deprivation and may be distributed according to the source of deprivation, including PV or HA blood flow or their combination. Atrophy and fatty degeneration of the canine liver after total portal diversion through an Eck fistula initially was reported more than a century ago.141 Partial or complete diversion of PV blood flow from the liver results in atrophy. Complete PV flow diversion with interruption of all PV collaterals results in more profound liver atrophy than the partial deviation of PV flow resulting from side-to-side portacaval anastomoses.142 Liver atrophy after portal diversion is not believed to be the result of a decrease in absolute volume flow, but instead it is because of the effective loss of hepatotrophic substances in the portal blood. Rats subjected to portal flow diversion with portacaval transposition had a decrease in relative liver weight143 despite the effective preservation of portal perfusion from the IVC.144 Dogs with “partial portacaval transposition”145 or “splanchnic flow division”146 with diversion of pancreaticogastroduodenosplenic blood had atrophy in liver lobes, although normal tissue perfusion was shown in all regions of the liver.147 Histologically, arterial obstruction results in ischemic changes, such as mitochondrial swelling, cell membrane disruption, platelet aggregation, and widening of the spaces of Disse.148 The fate of the liver after ligation of the HA depends largely on the extent of a functional collateral arterial circulation.6 If limited collaterals are present, liver infarction and necrosis may occur after HA ligation, resulting in death. Nevertheless, HA ligation results only in transient ischemic changes in the periphery of the hepatic acinus (zone III, see Fig. 5.3) in the presence of adequate collaterals. Atrophy after HA ligation can occur in liver segments that have compensatory collateral supply to prevent necrosis. The effects of HA flow absence are magnified by the presence of low PV blood flow, limited oxygen saturation, and superimposed infection.6

Impact of Acute and Chronic Bile Duct Obstruction on Liver Blood Flow Bile duct obstruction can affect hepatic hemodynamics significantly. In general, LBF is reduced in the presence of chronic biliary obstruction, leading to hepatic dysfunction. Conversely, acute increases in bile duct pressure from early obstruction result in a reflexive increase in LBF, which attempts to maintain adequate flow in the face of an increased pressure gradient opposing secretion and excretion of bile (see Chapter 8). Most evidence suggests that the hemodynamic response of the liver to biliary obstruction is related, directly or indirectly, to

82

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

changes in bile duct pressure. Given the limited space of Mall in the portal triad (see Fig. 5.1), it is conceivable that increased biliary pressures may compress the portal capacitance vessels, leading to increased arterial flow.149 Acute serial increases in bile duct pressure in dogs with complete bile duct obstruction increased HA blood flow by 250% but did not affect PV blood flow. Although increased portal vascular resistance is the accepted underlying cause, the primary site of this resistance change has been considered to be presinusoidal,150 sinusoidal,151 or postsinusoidal.152 The precise mechanism for reduction in LBF after chronic bile duct obstruction thus remains to be fully elucidated. It should be noted that the combination of biliary and PV obstruction greatly accelerates atrophic changes, which has important implications for resection of hilar cholangiocarcinoma (see Chapters 51 and 119B). Relief of long-term obstruction does not result in the return of normal hemodynamics, suggesting irreversible intrahepatic vascular damage.153 Furthermore, a 23% reduction in effective LBF persisted for one to five years after operative decompression in patients with choledocholithiasis and jaundice for more than two weeks preoperatively.154 Hunt (1979)155 serially measured LBF daily for one week after bile duct ligation in rats, using the 133 Xe clearance technique to document the early hemodynamic response. Total LBF decreased steadily after the first postoperative day to a plateau level of approximately 50% of the preoperative value five days after operation. Mathie and colleagues (1988)156 confirmed the decrease in total LBF after bile duct ligation by measuring the individual PV and HA components of LBF. Using electromagnetic flowmeters in dogs with complete bile duct ligation, HA and PV blood flow were observed to decrease by 36% and 44%, respectively; they also showed a 200% increase in intrahepatic portal resistance but a lesser increase in HA resistance. Similarly, dogs with chronic bile duct ligation had decreased PV flow and had developed sinusoidal portal hypertension and extensive portosystemic shunting.151 Chronic biliary obstruction can thus result in two hemodynamic consequences: portal hypertension associated with secondary biliary fibrosis (see Chapter 74) and shock after biliary tract decompression. Approximately 20% of patients with prolonged biliary obstruction experience clinically significant portal hypertension.157,158 The operative risk of biliary decompression in these patients is significant. Technical difficulties of stricture repair—dense fibrous adhesions, hilar ductal involvement, and infection—are complicated by the risk of hemorrhage from subhepatic and periductal varices and potential postoperative liver failure. In addition to the hemodynamic consequences of chronic bile duct obstruction, sudden decompression of the obstructed biliary tree also causes an abrupt decrease in wedged HV pressure, PV pressure, and arterial pressure within 30 minutes of decompression in jaundiced dogs, leading to hypotension and shock.152 Similarly, Steer and colleagues (1968)159 reported that rapid needle decompression of an obstructed biliary tree in jaundiced dogs induced a decreased arterial pressure, central venous pressure, and PV pressure within one hour. They concluded that sudden decompression of chronic biliary obstruction leads to sequestration of fluid within the liver, resulting in a decrease in the effective circulating plasma volume and subsequent hypotension.

Liver Resection and Regeneration The adult liver exhibits a remarkable potential to restore its cellular mass in response to injury through hepatocyte

hyperplasia. Hepatic regeneration of the normal liver remnant proceeds rapidly after partial hepatic resection160,161 (see Chapters 6). Partial liver resection without devascularization normally produces little change in total blood flow to the liver. This occurs because the major contributor to total flow, the PV, is affected less by events occurring within the liver than by control mechanisms in the arterial resistance vessels of the prehepatic splanchnic bed. On the other hand, the failure of the liver to directly control its PV flow may result in portal hyperperfusion of a reduced parenchymal mass. Because essentially the same total blood flow is redistributed to a smaller mass of liver tissue, a corresponding increase in tissue perfusion (mL/min per unit tissue weight) would be anticipated in the in situ remnant. Experimental studies support these expectations; an increase in hepatic tissue perfusion was observed in rats immediately after two-thirds hepatectomy.162–164 This increase in hepatic perfusion is primarily because of PV inflow, because HA blood flow is low, and because HA resistance is high even 24 hours after partial hepatectomy in rats. In humans, an immediate increase in tissue perfusion of approximately 120% occurs in the liver remnant.165 A 60% partial hepatectomy results in a doubling of the portal flow in the 40% of remnant liver tissue.166 Experimental evidence has suggested that intrahepatic shear stress from increased portal flow is a regulator of liver regeneration.167,168 The significance of blood flow in relation to liver regeneration, however, continues to be debated since Mann (1944)169 suggested that regenerative hyperplasia of the liver after partial resection was a function of portal blood flow and that the process could be prevented by portal flow diversion. However, regenerative hyperplasia normally occurs after partial liver resection in portacavally transposed animals, in which there is no direct supply of portal blood nor the usual posthepatectomy increase in hepatic tissue perfusion.170

Liver Blood Flow and Hemodynamic Studies in Liver Transplantation The HA buffer response is conserved after orthotopic liver transplantation (OLT) despite denervation.31,39 In a series of experiments by Payen and colleagues (1990),32 serial clamping of the PV every 12 hours for seven days after OLT resulted in reciprocal increases in HA flow. OLT of a normal donor organ does not normalize the splanchnic and systemic hemodynamic alterations of end-stage liver disease.171 In fact, total hepatic blood flow remains elevated six months after OLT172,173 mainly because of PV blood flow.31,174 This suggests that baseline LBF may be under direct sympathetic control, which is lost after OLT, leading to an unopposed rise. Azygos flow also remains elevated, and other portosystemic shunts have been documented up to four years after OLT.173 Ligation of these portosystemic collateral pathways has been shown to increase PV blood flow.175 The hemodynamic consequences of OLT in human patients are difficult to interpret for several reasons: (1) the causes of liver failure in end-stage transplant candidates are diverse; (2) immunosuppressive drugs are used, such as cyclosporine, which causes arterial hypertension; and (3) to control systemic hypertension after OLT, patients may also be given vasodilators, which can cause persistently increased cardiac output. Cardiac output data have been conflicting, with one group reporting persistently elevated values172 and others showing decreases two weeks and two months after OLT.173 Gadano and

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

colleagues (1995)176 emphasized that factors such as anemia and sepsis may account for the deranged hemodynamics after OLT. In a retrospective series of 970 patients, new-onset heart failure developed in as many as 10% of patients after OLT after a median follow-up of 5.3 years, the majority of which were of nonischemic etiology.177

Small-for-Size Syndrome The advent of living-donor partial liver transplantation and the enlargement of the resectable limit has introduced the phenomenon of small-for-size syndrome, whereby the pressure of the full portal flow traveling through a small liver remnant leads to a marked decreased arterial inflow, hypothesized to result from an intact HABR.178 In a porcine model, portal flow to split grafts with a graft-to-recipient liver volume ratio of 2:3 and 1:3 was inversely correlated to graft size.179 In patients with right lobe living-donor transplantation, the grafts are subjected to more than double increases of portal blood flow, whereas the arterial flow is strikingly decreased, likely to maintain total blood flow within an acceptable physiologic range.180,181 The consequences of inadequate HA flow range from mild cholestasis and delayed synthetic function to ischemic cholangitis and parenchymal infarct182 (see Chapter 111). Although arterial flow impairment appears to result from an active HABR, it has repeatedly been ascribed to the splenic artery steal syndrome in the past.183,184 This phenomenon describes the impaired HA flow by shifting the main blood flow to the splenic or gastroduodenal artery in patients with hypersplenism. In whole-organ liver recipients analyzed by D-US, HA vasoconstriction in response to portal hyperperfusion and exaggerated HABR produces a high resistive index with poor arterial perfusion.185 In a retrospective analysis of 650 OLTs, a 5.1% incidence of splenic artery syndrome has been reported, and prophylactic treatment with ligation of the splenic artery for patients at risk for development of splenic artery syndrome has been advocated.186 A prospective study has suggested that preoperative embolization of the splenic artery leads to improved postoperative living-donor graft function.187 Because splenic artery occlusion reduces the resistance to distal HA flow by reducing flow in the splenic circulation, and consequently PV flow, it has been suggested to revise the name of splenic artery steal syndrome to splenic artery syndrome, thereby underlining that the cause is portal hyperperfusion and not arterial siphoning.185

Portal Hypertension Portal hypertension is a state of sustained increase in the intraluminal pressure of the PV and its collaterals, associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy, and bleeding from gastroesophageal varices188 (see Chapters 74, 79, and 80). A mean HVPG greater than 12 mm Hg has classically been used to define portal hypertension because variceal bleeding does not occur at lower pressures than this.189 Measurement of HVPG is now considered one of the best surrogates of clinical events, using different thresholds to guide the management of cirrhotic patients, and a value of 10 mm Hg and greater is predictive of varices formation and liver decompensation (Table 5.2).11

Hemodynamics of Portal Hypertension Hemodynamic factors that influence portal hypertension are best understood by the flow-resistance principle that applies to the PV system. Portal pressure depends on two basic components: portal blood flow and hepatic portal vascular resistance. Portal hypertension may result from a significant increase in hepatic portal inflow from the prehepatic splanchnic vasculature, an increase in intrahepatic portal resistance, or both. Although simple in concept, multiple factors may influence both the components of the system and the pathophysiology of portal hypertension. Increased portal pressure, diminished hepatic portal blood flow, and an extensive extrahepatic collateral venous network supplied by a hyperdynamic splanchnic and systemic circulation characterize the hemodynamics of portal hypertension in cirrhotic patients. Extrahepatic shunts may account for at least 50% of the portal flow, whereas 80% of portal flow actually reaching hepatocytes has been observed to bypass the sinusoidal vascular bed via intrahepatic shunts.206 The magnitude of extrahepatic shunt flow in patients with cirrhosis was measured directly by thermal dilution assessment of azygos blood flow; a value 300 mL/min greater than in patients without portal hypertension was noted.108 The HA probably provides a greater relative contribution to the total LBF in patients with cirrhosis than in healthy individuals, although it also was shown that 33% of the arterial blood may flow through intrahepatic shunts to the systemic venous circulation.207 Vallance and Moncada proposed the hypothesis that the low peripheral vascular resistance in portal hypertension may be caused by the stimulated

TABLE 5.2  Prognostic Significance of Hepatic Venous Pressure Gradient Thresholds According to the Compensated or Decompensated Stage of Cirrhosis CLINICAL SETTING Compensated cirrhosis

Decompensated cirrhosis

HVPG (mm Hg) 10

12 16 16 20 22 30

83

INCREASED RISK OF THRESHOLD Presence189 and development of gastroesophageal varices190 First clinical decompensation in patients without varices191 Development of HCC192 Decompensation after surgery for HCC193,194 Variceal bleeding189,195–198 First clinical decompensation in patients with varices199 and mortality200 Variceal rebleeding and mortality201 Failure to control variceal bleeding in patients actively bleeding from varices202,203 Mortality in patients with alcoholic cirrhosis and acute alcoholic hepatitis204 Spontaneous bacterial peritonitis205

HCC, Hepatocellular carcinoma. From Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 2013;7(2):141–155.

84

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

production of NO induced by endotoxemia in 1991. The initial experimental evidence was provided by Pizcueta and others,208 who showed an increase in systemic and splanchnic vascular resistance in cirrhotic rats after the administration of an NO inhibitor. Although endotoxemia is likely responsible for the decompensation in end-stage cirrhosis, the hemodynamic alterations are because of NO in animal models.209,210 Constitutive NO synthase seems to be upregulated in discrete anatomic locations, such as in the endothelium of the mesenteric artery and in the esophageal, gastric, and jejunal mucosa.211 The direction of portal blood flow has been proposed as a contributor to the pathophysiology of portal hypertension. The progression of intrahepatic disease and increasing sinusoidal pressure has been postulated as contributing to reversal of flow in the PV, which further aggravates the injury by depriving the liver of nutrients.212 Gaiani and colleagues213 reported an incidence of 3.1% reversed, or hepatofugal, PV flow in 228 patients assessed. Intrahepatic portal flow reversal has been described in as many as 9% of patients and seen almost exclusively in those with Child’s C cirrhosis.214 In portal hypertension, the increased mesenteric blood flow in the hyperdynamic stage may be relatively less important than the elevated intrahepatic portal resistance caused by the interplay of local regulatory mechanisms affecting sinusoidal hemodynamics.215 The traditional view of the source of increased portal pressure is fibrotic encroachment around portal radicles, leading to increased resistance. The pathogenesis of cirrhosis involves initial hepatocyte necrosis and inflammation with subsequent transformation of HSCs into myofibroblasts. HSC activation results in the collagenization of the space of Disse216 (see Chapter 7). Several factors have been implicated in HSC activation, such as inflammatory mediators, cytokines, growth factors, and endothelin217 (see Chapter 10). Capillarization of sinusoidal endothelial cells occurs by defenestration or loss of endothelial cell pores and the appearance of a basement membrane.218 In the cirrhotic liver, the sites of vascular resistance are still unclear. However, because portal and hepatic venules can be found within fibrous septa, constriction or distortion of portal venules, hepatic venules, or both may be involved.219 Disruption of hepatic architecture, with the development of fibrous septa and abnormal nodules and circulation, leads to a sustained intrahepatic portal resistance and portal pressure. Although PV blood flow progressively decreases in cirrhosis, arterial resistance decreases and arterial flow increases, suggesting an intact buffer response. Studies in cirrhotic rats have demonstrated higher HA flows compared with normal control rats under baseline conditions.220 This finding was confirmed by using intraoperative measurements in patients with endstage cirrhosis undergoing living-donor liver transplantation.221 Clinically, the vasodilation of the splanchnic circulation likely serves to increase flow in the extrahepatic collateral circulation, leading to variceal hemorrhage.

Treatment of Portal Hypertension Medical and surgical management strategies for portal hypertension strive to improve patient survival by the reduction of pressure and flow in extrahepatic variceal vessels, mainly esophageal and gastric vessels, while preserving adequate portal flow to the liver (see Chapters 79–85). Portosystemic shunting and pharmacologic reduction of portal flow can provide effective decompression, but both deprive the liver of portal flow.

Multiple pharmacologic agents have been investigated to reduce portal hypertension by diminishing hepatic portal inflow from the mesenteric vascular bed. At a dose that decreases the heart rate by 25%, the b-blocker propranolol significantly reduced the risk of rebleeding in cirrhotic patients who were otherwise in good condition222 (see Chapter 80). Propranolol exerts its action by two mechanisms: decreased cardiac output as a result of b1-adrenergic cardiac receptor blockade and antagonism of b2-adrenoceptors in the splanchnic vasculature, which leaves the vasoconstrictive influence of a-adrenergic receptors unopposed, resulting in a decreased portal flow and pressure. Vasopressin causes generalized peripheral vasoconstriction,223 whereas the effect of somatostatin is specific to the splanchnic vascular bed224 and results from glucagon-release inhibition and direct vasoconstriction. Serotonin may play a significant role in maintaining increased portal pressure, and smooth muscle serotonin-receptor antagonists have been shown to lower the pressure in cirrhosis.225,226 Although it was originally thought that intrahepatic portal resistance in cirrhosis was irreversible, evidence has supported that it can be reduced pharmacologically.227 The nitrovasodilators isosorbide dinitrate and isosorbide mononitrate were observed to lower the portal pressure in portal hypertensive animals228 and to increase hepatic (but not azygos) blood flow in patients with cirrhosis,229 suggesting that they may act by reducing intrahepatic PV resistance. Application of nitroglycerin by transdermal tape to patients with cirrhosis resulted in a reduction in portal pressure without affecting hepatic blood flow,230 and IV nitroglycerin caused a 24% decrease in intrahepatic portal resistance in patients with cirrhosis.215 In animal models, intrahepatic portal resistance can be reduced by prostaglandin E2, the endothelin receptor antagonist isoprenaline, nitroprusside, papaverine, and verapamil.227,231–233 The use of TIPS, first reported by Rössle and colleagues (1989),234 now largely replaces shunt surgery. TIPS is currently the treatment of choice for recurrent variceal bleeding in patients who are refractory to conservative medical management235 (see Chapter 85). Surgical treatment of portal hypertension may be performed by one of the many portosystemic shunt procedures; the initial clinical application of the portacaval shunt was reported 50 years after its description by Eck236 (see Chapters 83 and 84). The hemodynamic consequences of shunt surgery depend on the particular shunt performed, the nature and severity of the disease, and the hemodynamic condition of the patient. End-to-side portacaval shunts divert all portal blood flow away from the liver, whereas less complete diversions reduce portal flow in proportion to the degree to which the shunt reduces portal pressure. The HA flow may increase by 100%, but even a maximal flow increase can usually only partly compensate for loss of portal flow.237 Hepatic oxygen consumption tends to be maintained by increased oxygen extraction from the available arterial supply. Total portacaval shunts are very effective in reducing portal pressure and preventing bleeding from esophageal varices. However, because of bypass of the hepatic circulation, liver failure and encephalopathy are common complications of the operation. Therefore partial shunts, such as the side-to-side, mesocaval, and proximal or distal splenorenal shunts, are preferred when technically feasible. Selective shunts, such as the distal splenorenal (Warren) shunt, in which the gastrosplenic collaterals are decompressed via the splenic vein into the left renal vein, leaving

  Chapter 5  Liver Blood Flow: Physiology, Measurement, and Clinical Relevance

the PV intact, are effective but usually too time consuming for use in emergency operations. Current consensus on treatment approaches are here summarized for prevention and treatment of variceal bleeding in patients with cirrhosis.188,238 PREVENTION OF VARICEAL BLEEDING. All patients with cirrhosis should be screened by endoscopy for varices at diagnosis. The treatment of underlying liver disease, when possible, may reduce portal hypertension and prevent its clinical complications. There is no pharmaceutical agent proven effective to prevent the formation of varices. Patients with small varices with red marks or Child-Turcotte-Pugh C cirrhosis have an increased risk of bleeding and should thus be treated with nonselective b-blockers. Patients with medium to large varices also can benefit from endoscopic band ligation for the prevention of the first variceal bleeding episode (primary prophylaxis; see Chapter 80). In centers where adequate resources and expertise are available, HVPG measurements can routinely be used for prognostic and therapeutic indications (see Table 5.2). A decrease in HVPG of at least 20% from baseline or to 12 mm Hg or less after chronic treatment with a nonselective b-blocker has been demonstrated to be clinically relevant in the setting of primary prophylaxis of variceal bleeding. TREATMENT OF ACUTE BLEEDING (SEE CHAPTER 81). Critical initial steps include airway protection, particularly in patients with altered mental status or those with hemodynamic instability, resuscitation with fluid and blood products, and correction of coagulopathy and thrombocytopenia. Patients with variceal hemorrhage are often bacteremic as a result of a concomitant infectious process (spontaneous bacterial peritonitis, urinary tract infection, or pneumonia), and clinical trials have shown better outcomes when empiric antibiotic therapy is initiated early. Vasoconstrictive drugs that reduce portal pressure (somatostatin and vasopressin analogues) and endoscopic variceal ablation (ligation and sclerotherapy) are the mainstay of initial management (see Chapters 80 and 81). As shown in single trials and by meta-analysis, this initial strategy controls 80% to 85% of bleeding episodes.239 Early assessment of prognosis is important to guide further management because patients at high risk for treatment failure benefit from early TIPS placement (within 72 hours; see Chapter 85).240 An HVPG of 20 mm Hg or higher, Child-Turcotte-Pugh class C, and active bleeding at endoscopy are the variables most consistently found to predict five-day rebleeding treatment failure.241 TIPS may not be an option in some cases, such as in face of portal thrombosis, in which case a surgical shunt or a devascularization procedure242 is indicated (see Chapters 82–84). Emergency portacaval shunt has a success rate of 95% in stopping bleeding in this context. The death rate of the operation is, however, not insignificant, but generally related to the status of the patient’s liver function. Approximately 40% of patients experience encephalopathy after portacaval surgical shunting. Hepatic insufficiency is accelerated, and liver failure is the cause of death in approximately two-thirds of those who die after an emergency portacaval shunt. Balloon tamponade should only be used in massive bleeding as a temporary measure until definitive treatment is instituted.238

Blood Flow in Hepatic Tumors It has been demonstrated that tumors of the liver, whether primary or secondary, are generally perfused with arterial blood.243

85

Hepatocellular carcinoma and liver metastases from neuroendocrine tumors are, however, more arterialized and less necrotic than most other liver tumors. The arterial uptake of hepatic solid lesions thus provides important differential diagnosis information when assessed by CT scan and MRI performed with IV contrast, provided that images are acquired at time of arterial enhancement in addition to venous enhancement244 (see Chapters 14, 15, 89, and 91). The neovasculature of tumor tissue lacks smooth muscle and therefore does not respond to vasoconstrictor agents, enabling increased delivery and retention of chemotherapeutic drugs. A variety of transarterial techniques have been used to selectively embolize and deliver chemotherapy to liver tumors, taking advantage of the fact that they derive disproportionately greater blood supply from the HA circulation compared with the surrounding liver (see Chapter 94). Embolization is often performed with Gelfoam, which dissolves after a few weeks, but other inert agents are also used and are probably more effective for occluding vessels. Some centers use inert particles without chemotherapy (i.e., bland embolization), but most combine the procedure with chemotherapy (i.e., transarterial chemoembolization [TACE]). Doxorubicin, mitomycin, and cisplatin in various combinations are the drugs most often given. The embolized material causes temporary blood flow interruption and potentially improves the uptake of chemotherapeutic agents in tumor tissue and, consequently, reduces systemic toxicity.245 Lipiodol and drug-eluting beads, which lodge in the tumor, have also been used as a carrier for chemotherapy. More recently, radioactive microspheres emitting Yttrium-90 have been used (see Chapter 94B). These procedures are mainly performed in the palliative setting for patients with liver confined malignancies not amenable to liver resection or transplantation. It remains unclear if the addition of chemotherapeutic agents provides much benefit beyond the necrosis produced by occlusion of the HA supply alone.246–252 Increasing evidence supports that HA infusion of chemotherapy delivered by catheters connected to subcutaneously placed ports or pumps can also be effectively used to deliver high doses of chemotherapy directly to the liver for the treatment of patients with colorectal cancer liver metastasis and unresectable intrahepatic cholangiocarcinoma253–257 (see Chapter 97).

Effect of Laparoscopy on Liver Blood Flow The use of a CO2 pneumoperitoneum in laparoscopic surgery has been demonstrated to substantially reduce PV in parallel with the rise of the intraperitoneal pressure.258,259 The reduction in hepatic blood flow is because of a number of factors, including mechanical compression of the mesenteric veins, humoral vasoconstriction of the mesenteric bed and increased portal venous pressure caused by hypercapnia, local absorption of CO2, and increased release of vasopressin.260 Conflicting data exist in support of the maintenance of the HABR effect in high-pressure pneumoperitoneum. Rat models using fluorescent microspheres supported preserved HA flow during decreased PV flow,261 but this was not supported by others262 who saw a parallel decrease in arterial and portal venous flows during laparoscopy. Most surgical teams use a 10 to 15 mm Hg pneumoperitoneum during laparoscopic liver resection, which allows good control of bleeding263 (see Chapter 127). A casematched analysis suggested that the positive pressure of pneumoperitoneum was probably the main factor explaining the

86

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

decreased blood loss during laparoscopy when compared with open liver surgery.264 Some groups have suggested the avoidance of head-up positioning and pressures greater than 15 mm Hg during laparoscopy to preserve LBF.265,266 So far, no major accident related to the use of a CO2 pneumoperitoneum during laparoscopic liver resection has been reported in approximately 6,000 cases.267 Furthermore, a swine model has been used to prospectively demonstrate that multiple gas embolisms frequently occur during laparaoscopic liver resection without significant modification of hemodynamics.268,269 Although PEEP

may increase central venous pressure, there is no strong published evidence that this or other lung protective ventilation strategies are significantly associated with increased bleeding during open or laparoscopic hepatectomy.270

Acknowledgments Thank you to Drs. Blumgart, Wheatley, Mathie, and Rocha for their previous contributions to this chapter. References are available at expertconsult.com.

86.e1

REFERENCES 1. Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev. 1971;51(1):23-65. 2. Lautt WW. Hepatic vasculature: a conceptual review. Gastroenterology. 1977;73(5):1163-1169. 3. Lautt WW. Method for measuring hepatic uptake of oxygen or other blood-borne substances in situ. J Appl Physiol. 1976;40: 269-274. 4. Lautt WW, Greenway CV. Hepatic venous compliance and role of liver as a blood reservoir. Am J Physiol. 1976;231(2):292-295. 5. Rappaport AM. The microcirculatory hepatic unit. Microvasc Res. 1973;6(2):212-228. 6. Rappaport AM, Schneiderman JH. The function of the hepatic artery. Rev Physiol Biochem Pharmacol. 1976;76:129-175. 7. Jefferson NC, Hassan MI, Popper HL, Necheles H. Formation of effective collateral circulation following excision of hepatic artery. Am J Physiol. 1956;184(3):589-592. 8. Mays ET, Wheeler CS. Demonstration of collateral arterial flow after interruption of hepatic arteries in man. N Engl J Med. 1974; 290(18):993-996. 9. Balfour Jr DC, Reynolds TB, Levinson DC, Mikkelsen WP, Pattison AC. Hepatic vein pressure studies for evaluation of intrahepatic portal hypertension. AMA Arch Surg. 1954;68(4):442-447. 10. Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology. 1987;7(5):952-963. 11. Berzigotti A, Seijo S, Reverter E, Bosch J. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 2013;7(2): 141-155. 12. Lautt WW. Hepatic Circulation: Physiology and Pathophysiology. San Rafael, California: Morgan & Claypool Life Sciences; 2009. 13. Ekataksin W, Kaneda K. Liver microvascular architecture: an insight into the pathophysiology of portal hypertension. Semin Liver Dis. 1999;19(4):359-382. 14. Malarkey DE, Johnson K, Ryan L, Boorman G, Maronpot RR. New insights into functional aspects of liver morphology. Toxicol Pathol. 2005;33(1):27-34. 15. Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol. 2002;1(1):1. 16. Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology. 1985;5(4):683-692. 17. Smedsrød B, De Bleser PJ, Braet F, et al. Cell biology of liver endothelial and Kupffer cells. Gut. 1994;35(11):1509-1516. 18. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125-172. 19. McCuskey RS. Morphological mechanisms for regulating blood flow through hepatic sinusoids. Liver. 2000;20(1):3-7. 20. Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin Liver Dis. 2001;21(3):337-349. 21. Zhang JX, Pegoli Jr W, Clemens MG. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol. 1994;266(4 Pt 1): G624-G632. 22. Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009;89(4):1269-1339. 23. Burton-Opitz R. The vascularity of the liver I: the flow of the blood in the hepatic artery. Q J Exp Physiol. 1911;4:93-102. 24. Gad J. Studies on the Relations of the Blood Stream of the Portal Vein to the Blood Stream in the Hepatic Artery. Dissertation, Berlin: G. Schade; 1873. 25. Lautt WW. Role and control of the hepatic artery. In: Lautt WW, ed. Hepatic Circulation in Health and Disease. New York: Raven Press; 1981:203-226. 26. Jakab F, Ráth Z, Schmal F, Nagy P, Faller J. The interaction between hepatic arterial and portal venous blood flows; simultaneous measurement by transit time ultrasonic volume flowmetry. Hepatogastroenterology. 1995;42(1):18-21. 27. Lautt WW, Legare DJ, Ezzat WR. Quantitation of the hepatic arterial buffer response to graded changes in portal blood flow. Gastroenterology. 1990;98(4):1024-1028. 28. Ebbing C, Rasmussen S, Godfrey KM, Hanson MA, Kiserud T. Hepatic artery hemodynamics suggest operation of a buffer response in the human fetus. Reprod Sci. 2008;15(2):166-178.

29. Lautt WW, Legare DJ, d’Almeida MS. Adenosine as putative regulator of hepatic arterial flow (the buffer response). Am J Physiol. 1985;248(3 Pt 2):H331-H338. 30. Mathie RT, Lam PH, Harper AM, Blumgart LH. The hepatic arterial blood flow response to portal vein occlusion in the dog: the effect of hepatic denervation. Pflugers Arch. 1980;386(1):77-83. 31. Henderson JM, Mackay GJ, Hooks M, et al. High cardiac output of advanced liver disease persists after orthotopic liver transplantation. Hepatology. 1992;15(2):258-262. 32. Payen DM, Fratacci MD, Dupuy P, et al. Portal and hepatic arterial blood flow measurements of human transplanted liver by implanted Doppler probes: interest for early complications and nutrition. Surgery. 1990;107(4):417-427. 33. Biernat J, Pawlik WW, Sendur R, Dembi≈Ñski A, Brzozowski T, Konturek SJ. Role of afferent nerves and sensory peptides in the mediation of hepatic artery buffer response. J Physiol Pharmacol. 2005;56(1):133-145. 34. Ishikawa M, Yamataka A, Kawamoto S, Balderson GA, Lynch SV. Hemodynamic changes in blood flow through the denervated liver in pigs. J Invest Surg. 1995;8(1):95-100. 35. Siebert N, Cantré D, Eipel C, Vollmar B. H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K(ATP) channels. Am J Physiol Gastrointest Liver Physiol. 2008;295(6):G1266-G1273. 36. Bredfeldt JE, Riley EM, Groszmann RJ. Compensatory mechanisms in response to an elevated hepatic oxygen consumption in chronically ethanol-fed rats. Am J Physiol. 1985;248(5 Pt 1): G507-G511. 37. Lautt WW. Control of hepatic and intestinal blood flow: effect of isovolaemic haemodilution on blood flow and oxygen uptake in the intact liver and intestines. J Physiol. 1977;265(2):313-326. 39. Eipel C, Abshagen K, Vollmar B. Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J Gastroenterol. 2010;16(48):6046-6057. 40. Ezzat WR, Lautt WW. Hepatic arterial pressure-flow autoregulation is adenosine mediated. Am J Physiol. 1987;252(4 Pt 2):H836-H845. 41. Knisely MH, Harding F, Debacker H. Hepatic sphincters; brief summary of present-day knowledge. Science. 1957;125(3256):1023-1026. 42. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524-526. 43. Hickey KA, Rubanyi G, Paul RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248(5 Pt 1):C550-C556. 44. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411-415. 45. Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28(1-3):52-61. 46. Lin H, McGrath JJ. Vasodilating effects of carbon monoxide. Drug Chem Toxicol. 1988;11(4):371-385. 47. Hosoki R, Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997;237(3):527-531. 48. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001;20(21):6008-6016. 49. Hughes RL, Mathie RT, Campbell D, Fitch W. Effect of hypercarbia on hepatic blood flow and oxygen consumption in the greyhound. Br J Anaesth. 1979;51(4):289-296. 50. Hughes RL, Mathie RT, Fitch W, Campbell D. Liver blood flow and oxygen consumption during hypocapnia and IPPV in the greyhound. J Appl Physiol Respir Environ Exerc Physiol. 1979;47(2): 290-295. 51. Hughes RL, Mathie RT, Campbell D, Fitch W. Systemic hypoxia and hyperoxia, and liver blood flow and oxygen consumption in the greyhound. Pflugers Arch. 1979;381(2):151-157. 52. Hughes RL, Mathie RT, Fitch W, Campbell D. Liver blood flow and oxygen consumption during metabolic acidosis and alkalosis in the greyhound. Clin Sci (Lond). 1981;60(4):355-361. 53. Mathie RT, Blumgart LH. Effect of denervation on the hepatic haemodynamic response to hypercapnia and hypoxia in the dog. Pflugers Arch. 1983;397(2):152-157.

86.e2 54. Greenway CV, Lautt WW. Hepatic circulation. In: Schultz SG, Wood JD, eds. Handbook of Physiology: The Gastrointestinal System. Oxford, England: American Physiological Society. Oxford University Press; 1989:1519-1564. 55. Richardson PD, Withrington PG. Liver blood flow. II. Effects of drugs and hormones on liver blood flow. Gastroenterology. 1981; 81(2):356-375. 56. Lautt WW, Legare DJ, Daniels TR. The comparative effect of administration of substances via the hepatic artery or portal vein on hepatic arterial resistance, liver blood volume and hepatic extraction in cats. Hepatology. 1984;4(5):927-932. 57. Miller WL, Redfield MM, Burnett Jr JC. Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest. 1989;83(1): 317-320. 58. Kurihara T, Akimoto M, Kurokawa K, et al. Relationship between endothelin and thromboxane A2 in rat liver microcirculation. Life Sci. 1992;51(26):PL281-PL285. 59. Bauer M, Zhang JX, Bauer I, Clemens MG. ET-1 induced alterations of hepatic microcirculation: sinusoidal and extrasinusoidal sites of action. Am J Physiol. 1994;267(1 Pt 1):G143-G149. 60. Isales CM, Nathanson MH, Bruck R. Endothelin-1 induces cholestasis which is mediated by an increase in portal pressure. Biochem Biophys Res Commun. 1993;191(3):1244-1251. 61. Tanaka A, Katagiri K, Hoshino M, Hayakawa T, Tsukada K, Takeuchi T. Endothelin-1 stimulates bile acid secretion and vesicular transport in the isolated perfused rat liver. Am J Physiol. 1994; 266(2 Pt 1):G324-G329. 62. Tran-Thi TA, Kawada N, Decker K. Regulation of endothelin-1 action on the perfused rat liver. FEBS Lett. 1993;318(3):353-357. 63. Okumura S, Takei Y, Kawano S, et al. Vasoactive effect of endothelin-1 on rat liver in vivo. Hepatology. 1994;19(1):155-161. 64. Fiorucci S, Antonelli E, Mencarelli A, et al. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology. 2005;42(3):539-548. 65. Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9(2):297-301. 66. Warren A, Chaberek S, Ostrowski K, et al. Effects of old age on vascular complexity and dispersion of the hepatic sinusoidal network. Microcirculation. 2008;15(3):191-202. 67. Woodhouse KW, Wynne HA. Age-related changes in liver size and hepatic blood flow. The influence on drug metabolism in the elderly. Clin Pharmacokinet. 1988;15(5):287-294. 68. Dauzat M, Lafortune M, Patriquin H, Pomier-Layrargues G. Meal induced changes in hepatic and splanchnic circulation: a noninvasive Doppler study in normal humans. Eur J Appl Physiol Occup Physiol. 1994;68(5):373-380. 69. Qamar MI, Read AE. Effects of ingestion of carbohydrate, fat, protein, and water on the mesenteric blood flow in man. Scand J Gastroenterol. 1988;23(1):26-30. 70. Goldberg RE, Rada C, Knelson M, Haaga J, Minkin S. The response of the portal vein to an oral glucose load. J Clin Ultrasound. 1990;18(9):691-695. 71. Hughes RL, Campbell D, Fitch W. Effects of enflurane and halothane on liver blood flow and oxygen consumption in the greyhound. Br J Anaesth. 1980;52(11):1079-1086. 72. Thulin L, Andreen M, Irestedt L. Effect of controlled halothane anaesthesia on splanchnic blood flow and cardiac output in the dog. Acta Anaesthesiol Scand. 1975;19(2):146-153. 73. Thomson IA, Hughes RL, Fitch W, Campbell D. Effects of nitrous oxide on liver haemodynamics and oxygen consumption in the greyhound. Anaesthesia. 1982;37(5):548-553. 74. Nagano K, Gelman S, Parks DA, Bradley Jr EL. Hepatic oxygen supply-uptake relationship and metabolism during anesthesia in miniature pigs. Anesthesiology. 1990;72(5):902-910. 75. Thomson IA, Fitch W, Hughes RL, Campbell D, Watson R. Effects of certain i.v. anaesthetics on liver blood flow and hepatic oxygen consumption in the greyhound. Br J Anaesth. 1986;58(1):69-80. 76. Harper D, Chandler B. Splanchnic circulation. BJA Educ. 2016; 16:66-71. 77. Gould TH, Grace K, Thorne G, Thomas M. Effect of thoracic epidural anaesthesia on colonic blood flow. Br J Anaesth. 2002; 89(3):446-451. 78. Burton-Opitz R. The vascularity of the liver: I. The flow of blood in the hepatic artery. Q J Exp Physiol. 1910;3:297-313.

79. MacLeod JJR, Pearce RG. The outflow of blood from the liver as affected by variations in the condition of the portal vein and hepatic artery. Am J Physiol. 1914;35:87-105. 80. Schenk Jr WG, Mcdonald JC, Mcdonald K, Drapanas T. Direct measurement of hepatic blood flow in surgical patients: with related observations on hepatic flow dynamics in experimental animals. Ann Surg. 1962;156(3):463-471. 81. Ohnishi K, Saito M, Sato S, et al. Portal hemodynamics in idiopathic portal hypertension (Banti’s syndrome). Comparison with chronic persistent hepatitis and normal subjects. Gastroenterology. 1987;92(3):751-758. 82. Takaoka F, Brown MR, Ramsay MA, Paulsen AW, Brajtbord D, Klintmalm GB. Intraoperative evaluation of EuroCollins and University of Wisconsin preservation solutions in patients undergoing hepatic transplantation. Transplantation. 1990;49(3):544-547. 83. Perelló A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virusrelated cirrhosis. Hepatology. 1999;30(6):1393-1397. 84. Iwao T, Toyonaga A, Ikegami M, et al. Wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis. Dig Dis Sci. 1994; 39(11):2439-2444. 85. Bosch J, Abraldes JG, Berzigotti A, García-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009;6(10):573-582. 86. Maleux G, Willems E, Fieuws S, et al. Prospective study comparing different indirect methods to measure portal pressure. J Vasc Interv Radiol. 2011;22(11):1553-1558. 87. Dauzat M, Layrargues GP. Portal vein blood flow measurements using pulsed Doppler and electromagnetic flowmetry in dogs: a comparative study. Gastroenterology. 1989;96(3):913-919. 88. Rossi S, Rosa L, Ravetta V, et al. Contrast-enhanced versus conventional and color Doppler sonography for the detection of thrombosis of the portal and hepatic venous systems. AJR Am J Roentgenol. 2006;186(3):763-773. 89. Abraldes JG, Gilabert R, Turnes J, et al. Utility of color Doppler ultrasonography predicting tips dysfunction. Am J Gastroenterol. 2005;100(12):2696-2701. 90. Bryant DJ, Payne JA, Firmin DN, Longmore DB. Measurement of flow with NMR imaging using a gradient pulse and phase difference technique. J Comput Assist Tomogr. 1984;8(4):588-593. 91. Pelc LR, Pelc NJ, Rayhill SC, et al. Arterial and venous blood flow: noninvasive quantitation with MR imaging. Radiology. 1992;185(3):809-812. 92. Stankovic Z, Allen BD, Garcia J, Jarvis KB, Markl M. 4D flow imaging with MRI. Cardiovasc Diagn Ther. 2014;4(2):173-192. 93. Bannas P, Roldán-Alzate A, Johnson KM, et al. Longitudinal monitoring of hepatic blood flow before and after TIPS by using 4D-flow MR imaging. Radiology. 2016;281(2):574-582. 94. Bradley SE, Ingelfinger FJ, Bradley GP, Curry JJ. The Estimation of hepatic blood flow in man. J Clin Invest. 1945;24(6):890-897. 95. Dobson EL, Jones HB. The behavior of intravenously injected particulate material; its rate of disappearance from the blood stream as a measure of liver blood flow. Acta Med Scand Suppl. 1952;273:1-71. 96. Keiding S. Galactose clearance measurements and liver blood flow. Gastroenterology. 1988;94(2):477-481. 97. Zeeh J, Lange H, Bosch J, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology. 1988;95(3):749-759. 98. Combes B. Estimation of hepatic blood flow in man and in dogs by I 131-labeled rose bengal; simultaneous comparison with sulfobromophthalein sodium. J Lab Clin Med. 1960;56:537-543. 99. George CF. Drug kinetics and hepatic blood flow. Clin Pharmacokinet. 1979;4(6):433-448. 100. Fleming JS, Humphries NL, Karran SJ, Goddard BA, Ackery DM. In vivo assessment of hepatic-arterial and portal-venous components of liver perfusion: concise communication. J Nucl Med. 1981;22(1):18-21. 101. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci. 1961;21:43-57. 102. Akita H, Sasaki Y, Yamada T, et al. Real-time intraoperative assessment of residual liver functional reserve using pulse dye densitometry. World J Surg. 2008;32(12):2668-2674.

86.e3 103. Okochi O, Kaneko T, Sugimoto H, Inoue S, Takeda S, Nakao A. ICG pulse spectrophotometry for perioperative liver function in hepatectomy. J Surg Res. 2002;103(1):109-113. 104. Sakka SG. Assessing liver function. Curr Opin Crit Care. 2007; 13(2):207-214. 105. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356(15):1545-1559. 106. Stewart GN. Researches on the circulation time and on the influences which affect it. J Physiol. 1897;22(3):159-183. 107. Biber B, Holm C, Winsö O, Gustavsson B. Portal blood flow in man during surgery, measured by a modification of the continuous thermodilution method. Scand J Gastroenterol. 1983;18(2): 233-239. 108. Bosch J, Groszmann RJ. Measurement of azygos venous blood flow by a continuous thermal dilution technique: an index of blood flow through gastroesophageal collaterals in cirrhosis. Hepatology. 1984;4(3):424-429. 109. Sapirstein LA. Fractionation of the cardiac output of rats with isotopic potassium. Circ Res. 1956;4(6):689-692. 110. Greenway CV, Oshiro G. Intrahepatic distribution of portal and hepatic arterial blood flows in anaesthetized cats and dogs and the effects of portal occlusion, raised venous pressure and histamine. J Physiol. 1972;227(2):473-485. 111. Groszmann RJ, Vorobioff J, Riley E. Splanchnic hemodynamics in portal-hypertensive rats: measurement with gamma-labeled microspheres. Am J Physiol. 1982;242(2):G156-G160. 112. Ronot M, Lambert S, Daire JL, et al. Can we justify not doing liver perfusion imaging in 2013? Diagn Interv Imaging. 2013;94(12): 1323-1336. 113. Quaia E. Assessment of tissue perfusion by contrast-enhanced ultrasound. Eur Radiol. 2011;21(3):604-615. 114. Flicek KT, Hara AK, Silva AC, Wu Q, Peter MB, Johnson CD. Reducing the radiation dose for CT colonography using adaptive statistical iterative reconstruction: a pilot study. AJR Am J Roentgenol. 2010;195(1):126-131. 115. Scharf J, Zapletal C, Hess T, et al. Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images. J Magn Reson Imaging. 1999;9(4):568-572. 116. Sourbron S. Technical aspects of MR perfusion. Eur J Radiol. 2010;76(3):304-313. 117. Luciani A, Vignaud A, Cavet M, et al. Liver cirrhosis: intravoxel incoherent motion MR imaging—pilot study. Radiology. 2008; 249(3):891-899. 118. Bolton RP, Mairiang EO, Parkin A, Ware F, Robinson P, Losowsky MS. Dynamic liver scanning in cirrhosis. Nucl Med Commun. 1988;9(3):235-247. 119. Kudomi N, Slimani L, Järvisalo MJ, et al. Non-invasive estimation of hepatic blood perfusion from H2 15O PET images using tissue-derived arterial and portal input functions. Eur J Nucl Med Mol Imaging. 2008;35(10):1899-1911. 120. Leiberman DP, Mathie RT, Harper AM, Blumgart LH. The hepatic arterial and portal venous circulations of the liver studied with a krypton-85 clearance technique. J Surg Res. 1978;25(2):154-162. 121. Aronsen KF, Ericsson B, Lindell SE, Nylander G. Disappearance rate of 133Xe from dog liver with different routes of administration. Nucl Med (Stuttg). 1968;7(2):119-124. 122. Shepherd AP, Riedel GL, Kiel JW, Haumschild DJ, Maxwell LC. Evaluation of an infrared laser-Doppler blood flowmeter. Am J Physiol. 1987;252(6 Pt 1):G832-G839. 123. Almond NE, Wheatley AM. Measurement of hepatic perfusion in rats by laser Doppler flowmetry. Am J Physiol. 1992;262(2 Pt 1): G203-G209. 124. Seifalian AM, Mallet SV, Rolles K, Davidson BR. Hepatic microcirculation during human orthotopic liver transplantation. Br J Surg. 1997;84(10):1391-1395. 125. Waller A. Microscopic examination of some of the principal tissues of the animal tongue, as observed in the tongue of the living frog and toad. Philos Mag J Sci. 1846;29:397-405. 126. Menger MD, Marzi I, Messmer K. In vivo fluorescence microscopy for quantitative analysis of the hepatic microcirculation in hamsters and rats. Eur Surg Res. 1991;23(3-4):158-169. 127. Sherman IA, Pappas SC, Fisher MM. Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis. Am J Physiol. 1990;258(2 Pt 2):H460-H465.

128. Sherman IA, Dlugosz JA, Barker F, Sadeghi FM, Pang KS. Dynamics of arterial and portal venous flow interactions in perfused rat liver: an intravital microscopic study. Am J Physiol. 1996;271 (1 Pt 1):G201-G210. 129. Nahum E, Skippen PW, Gagnon RE, Macnab AJ, Skarsgard ED. Correlation of transcutaneous hepatic near-infrared spectroscopy readings with liver surface readings and perfusion parameters in a piglet endotoxemic shock model. Liver Int. 2006;26(10):1277-1282. 130. Ohdan H, Mizunuma K, Tashiro H, et al. Intraoperative nearinfrared spectroscopy for evaluating hepatic venous outflow in living-donor right lobe liver. Transplantation. 2003;76(5):791-797. 131. Smith JJ, Roth DA, Grace RA. Oxygen saturation of hepatic blood during hemorrhagic shock in the dog. Circ Res. 1955;3(3):311-314. 132. Lautt WW. Regulatory processes interacting to maintain hepatic blood flow constancy: vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction. Hepatol Res. 2007;37(11):891-903. 133. Birgens HS, Henriksen J, Matzen P, Poulsen H. The shock liver. Clinical and biochemical findings in patients with centrilobular liver necrosis following cardiogenic shock. Acta Med Scand. 1978;204(5):417-421. 134. Champion HR, Jones RT, Trump BF, et al. A clinicopathologic study of hepatic dysfunction following shock. Surg Gynecol Obstet. 1976;142(5):657-663. 135. Gottlieb ME, Sarfeh IJ, Stratton H, Goldman ML, Newell JC, Shah DM. Hepatic perfusion and splanchnic oxygen consumption in patients postinjury. J Trauma. 1983;23(9):836-843. 136. Sganga G, Siegel JH, Brown G, et al. Reprioritization of hepatic plasma protein release in trauma and sepsis. Arch Surg. 1985; 120(2):187-199. 137. Peitzman AB, Billiar TR, Harbrecht BG, Kelly E, Udekwu AO, Simmons RL. Hemorrhagic shock. Curr Probl Surg. 1995;32(11): 925-1002. 138. Wendon JA. Local consequences of reperfusion in the liver. In: Grace PA, Mathie RT, eds. Ischaemia-Reperfusion Injury. London, UK: Blackwell Science; 1999:56-64. 139. Wang Y, Mathews WR, Guido DM, Farhood A, Jaeschke H. Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia. Shock. 1995;4(4):282-288. 140. Terajima H, Kondo T, Enders G, et al. Reduction of hepatic microcirculatory failure caused by normothermic ischemia/reperfusion-induced injury by means of heat shock preconditioning. Shock. 1999;12(5):329-334. 141. Hahn M, Massen, M, Nencki M, Pawlow J. Die eckische Fistel zwischen der Unteren Hohlvene und der Pfortader und ihre Folgen für den Organismus. Arch Exp Pathol Pharmacol. 1893;32:161-210. 142. Bollman JL. The animal with an Eck fistula. Physiol Rev. 1961;41:607-621. 143. Guest J, Ryan CJ, Benjamin IS, Blumgart LH. Portacaval transposition and subsequent partial hepatectomy in the rat: effects on liver atrophy, hypertrophy and regenerative hyperplasia. Br J Exp Pathol. 1977;58(2):140-146. 144. Ryan CJ, Guest J, Harper AM, Blumgart LH. Liver blood flow measurements in the portacavally transposed rat before and after partial hepatectomy. Br J Exp Pathol. 1978;59(2):111-115. 145. Marchioro TL, Porter KA, Brown BI, Otte JB, Starzl TE. The effect of partial portacaval transposition on the canine liver. Surgery. 1967;61(5):723-732. 146. Starzl TE, Francavilla A, Halgrimson CG, et al. The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood. Surg Gynecol Obstet. 1973;137(2):179-199. 147. Mathie RT, Leiberman DP, Harper AM, Blumgart LH. The role of blood flow in the control of liver size. J Surg Res. 1979;27(2): 139-144. 148. Mallet-Guy Y, Paillot JM, Switalska CH, Mallet-Guy P. Note sur les lésions ultrastructurales immédiates du foie après clampage expérimental de l’artère hépatique [Note on immediate ultrastructural lesions of the liver following experimental ligation of the hepatic artery]. Lyon Chir. 1972;68(3):170-175. 149. Kanda H, Nimura Y, Yasui A, et al. Hepatic blood flow after acute biliary obstruction and drainage in conscious dogs. Hepatogastroenterology. 1996;43(7):235-240. 150. Reuter SR, Chuang VP. The location of increased resistance to portal blood flow in obstructive jaundice. Invest Radiol. 1976;11(1): 54-59.

86.e4 151. Bosch J, Enriquez R, Groszmann RJ, Storer EH. Chronic bile duct ligation in the dog: hemodynamic characterization of a portal hypertensive model. Hepatology. 1983;3(6):1002-1007. 152. Tamakuma S, Wada N, Ishiyama M, Suzuki H, Kanayama T. Relationship between hepatic hemodynamics and biliary pressure in dogs: Its significance in clinical shock following biliary decompression. Jpn J Surg. 1975;5(4):255-268. 153. Aronsen KF, Nylander G, Ohlsson EG. Liver blood flow studies during and after various periods of total biliary obstruction in the dog. Acta Chir Scand. 1969;135(1):55-59. 154. Aronsen KF. Late effects of biliary stasis on the effective liver blood flow. Acta Chir Scand. 1968;134(3):278-281. 155. Hunt DR. Changes in liver blood flow with development of biliary obstruction in the rat. Aust N Z J Surg. 1979;49(6):733-737. 156. Mathie RT, Nagorney DM, Lewis MH, Blumgart LH. Hepatic hemodynamics after chronic obstruction of the biliary tract in the dog. Surg Gynecol Obstet. 1988;166(2):125-130. 157. Blumgart LH, Kelley CJ, Benjamin IS. Benign bile duct stricture following cholecystectomy: critical factors in management. Br J Surg. 1984;71(11):836-843. 158. Sedgwick CE, Poulantzas JK, Kune GA. Management of portal hypertension secondary to bile duct strictures: review of 18 cases with splenorenal shunt. Ann Surg. 1966;163(6):949-953. 159. Steer ML, Thomas AN, Rosson CT, Ketchum SA III, Hall AD. Chronic biliary obstruction: hemodynamic effects of decompression. Surg Forum. 1968;19:342-344. 160. Aronsen KF, Ericsson B, Nosslin B, Nylander G, Pihl B, Waldeskog B. Evaluation of hepatic regeneration by scintillation scanning, cholangiography and angiography in man. Ann Surg. 1970;171(4):567-574. 161. Blumgart LH, Leach KG, Karran SJ. Observations on liver regeneration after right hepatic lobectomy. Gut. 1971;12(11): 922-928. 162. Rice GC, Leiberman DP, Mathie RT, Ryan CJ, Harper AM, Blumgart LH. Liver tissue blood flow measured by 85Kr clearance in the anaesthetized rat before and after partial hepatectomy. Br J Exp Pathol. 1977;58(3):243-250. 163. Wheatley AM, Stuart ET, Zhao D, Zimmermann A, Gassel HJ, Blumgart LH. Effect of orthotopic transplantation and chemical denervation of the liver on hepatic hemodynamics in the rat. J Hepatol. 1993;19(3):442-450. 164. Wu Y, Campbell KA, Sitzmann JV. Hormonal and splanchnic hemodynamic alterations following hepatic resection. J Surg Res. 1993;55(1):44-48. 165. Mathie RT, Blumgart LH. Hepatic tissue perfusion studies during partial hepatectomy in man. Surg Gastroenterol. 1982;1:297-302. 166. Troisi R, Ricciardi S, Smeets P, et al. Effects of hemi-portocaval shunts for inflow modulation on the outcome of small-for-size grafts in living donor liver transplantation. Am J Transplant. 2005; 5(6):1397-1404. 167. Nobuoka T, Mizuguchi T, Oshima H, et al. Portal blood flow regulates volume recovery of the rat liver after partial hepatectomy: molecular evaluation. Eur Surg Res. 2006;38(6):522-532. 168. Schoen JM, Wang HH, Minuk GY, Lautt WW. Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide. 2001;5(5):453-464. 169. Mann FC. The William Henry Welch lectures. II. Restoration and pathologic reactions of the liver. J Mt Sinai Hosp. 1944;11:65-74. 170. Fausto N. Liver regeneration. J Hepatol. 2000;32(suppl 1):19-31. 171. Henderson JM. Abnormal splanchnic and systemic hemodynamics of end-stage liver disease: what happens after liver transplantation? Hepatology. 1993;17(3):514-516. 172. Hadengue A, Lebrec D, Moreau R, et al. Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients. Hepatology. 1993;17(2):175-178. 173. Navasa M, Feu F, García-Pagán JC, et al. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology. 1993;17(3):355-360. 174. Paulsen AW, Klintmalm GB. Direct measurement of hepatic blood flow in native and transplanted organs, with accompanying systemic hemodynamics. Hepatology. 1992;16(1):100-111. 175. Fujimoto M, Moriyasu F, Nada T, et al. Influence of spontaneous portosystemic collateral pathways on portal hemodynamics in living-related liver transplantation in children. Doppler ultrasonographic study. Transplantation. 1995;60(1):41-45.

176. Gadano A, Hadengue A, Widmann JJ, et al. Hemodynamics after orthotopic liver transplantation: study of associated factors and long-term effects. Hepatology. 1995;22(2):458-465. 177. Qureshi W, Mittal C, Ahmad U, et al. Clinical predictors of postliver transplant new-onset heart failure. Liver Transpl. 2013; 19(7):701-710. 178. Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010; 176(1):2-13. 179. Smyrniotis V, Kostopanagiotou G, Kondi A, et al. Hemodynamic interaction between portal vein and hepatic artery flow in smallfor-size split liver transplantation. Transpl Int. 2002;15(7):355-360. 180. Marcos A, Olzinski AT, Ham JM, Fisher RA, Posner MP. The interrelationship between portal and arterial blood flow after adult to adult living donor liver transplantation. Transplantation. 2000;70(12):1697-1703. 181. Rocheleau B, Ethier C, Houle R, Huet PM, Bilodeau M. Hepatic artery buffer response following left portal vein ligation: its role in liver tissue homeostasis. Am J Physiol. 1999;277(5):G1000-G1007. 182. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol. 2006;30(8): 986-993. 183. Manner M, Otto G, Senninger N, Kraus T, Goerich J, Herfarth C. Arterial steal: an unusual cause for hepatic hypoperfusion after liver transplantation. Transpl Int. 1991;4(2):122-124. 184. Nüssler NC, Settmacher U, Haase R, Stange B, Heise M, Neuhaus P. Diagnosis and treatment of arterial steal syndromes in liver transplant recipients. Liver Transpl. 2003;9(6):596-602. 185. Quintini C, Hirose K, Hashimoto K, et al. “Splenic artery steal syndrome” is a misnomer: the cause is portal hyperperfusion, not arterial siphon. Liver Transpl. 2008;14(3):374-379. 186. Mogl MT, Nüssler NC, Presser SJ, et al. Evolving experience with prevention and treatment of splenic artery syndrome after orthotopic liver transplantation. Transpl Int. 2010;23(8):831-841. 187. Umeda Y, Yagi T, Sadamori H, et al. Preoperative proximal splenic artery embolization: a safe and efficacious portal decompression technique that improves the outcome of live donor liver transplantation. Transpl Int. 2007;20(11):947-955. 188. de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53(4):762-768. 189. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5(3):419-424. 190. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254-2261. 191. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-488. 192. Ripoll C, Groszmann RJ, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol. 2009;50(5): 923-928. 193. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology. 1996;111(4):1018-1022. 194. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30(6):1434-1440. 195. Gluud C, Henriksen JH, Nielsen G. Prognostic indicators in alcoholic cirrhotic men. Hepatology. 1988;8(2):222-227. 196. Lebrec D, De Fleury P, Rueff B, Nahum H, Benhamou JP. Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gastroenterology. 1980;79(6): 1139-1144. 197. Merkel C, Bolognesi M, Bellon S, et al. Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices. Gastroenterology. 1992;102(3):973-979. 198. Vorobioff J, Groszmann RJ, Picabea E, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology. 1996;111(3): 701-709.

86.e5 199. Berzigotti A, Rossi V, Tiani C, et al. Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension. J Gastroenterol. 2011;46(5):687-695. 200. Merkel C, Marin R, Sacerdoti D, et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology. 2000;31(2):324-329. 201. Stanley AJ, Robinson I, Forrest EH, Jones AL, Hayes PC. Haemodynamic parameters predicting variceal haemorrhage and survival in alcoholic cirrhosis. QJM. 1998;91(1):19-25. 202. Abraldes JG, Villanueva C, Bañares R, et al. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol. 2008;48(2):229-236. 203. Moitinho E, Escorsell A, Bandi JC, et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology. 1999;117(3):626-631. 204. Rincon D, Lo Iacono O, Ripoll C, et al. Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis. Aliment Pharmacol Ther. 2007;25(7):841-848. 205. Sersté T, Bourgeois N, Lebrec D, Evrard S, Devière J, Le Moine O. Relationship between the degree of portal hypertension and the onset of spontaneous bacterial peritonitis in patients with cirrhosis. Acta Gastroenterol Belg. 2006;69(4):355-360. 206. Okuda K, Suzuki K, Musha H, Arimuzu N. Percutaneous transhepatic catheterization of the portal vein for the study of portal hemodynamics and shunts. A preliminary report. Gastroenterology. 1977;73(2):279-284. 207. Groszmann RJ, Kravetz D, Parysow O. Intrahepatic arteriovenous shunting in cirrhosis of the liver. Gastroenterology. 1977;73(1): 201-204. 208. Pizcueta P, Piqué JM, Fernández M, et al. Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. Gastroenterology. 1992;103(6):1909-1915. 209. Lee FY, Wang SS, Yang MC, et al. Role of endotoxaemia in hyperdynamic circulation in rats with extrahepatic or intrahepatic portal hypertension. J Gastroenterol Hepatol. 1996;11(2):152-158. 210. Niederberger M, Martin PY, Ginès P, et al. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology. 1995;109(5): 1624-1630. 211. Mathie RT. The hepatic haemodynamic effects of nitric oxide. In: Mathie RT, Griffith TM, eds. The Haemodynamic Effects of Nitric Oxide. London UK: Imperial College Press; 1999:292-317. 212. Warren WD, Muller Jr WH. A clarification of some hemodynamic changes in cirrhosis and their surgical significance. Ann Surg. 1959;150(3):413-427. 213. Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S, Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients. Gastroenterology. 1991;100(1):160-167. 214. Tarantino L, Giorgio A, de Stefano G, et al. Reverse flow in intrahepatic portal vessels and liver function impairment in cirrhosis. Eur J Ultrasound. 1997;6(3):171-177. 215. Groszmann RJ. Pathophysiology of portal hypertension. In: Gentilini P, ed. Liver Diseases and Renal Complications. New York: Raven Press; 1990:165-173. 216. Martinez-Hernandez A. The hepatic extracellular matrix. II. Electron immunohistochemical studies in rats with CCl4-induced cirrhosis. Lab Invest. 1985;53(2):166-186. 217. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story [published correction appears in Gut. 2015 Aug;64(8):1337]. Gut. 2015;64(5):830-841. 218. Varin F, Huet PM. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest. 1985;76(5):1904-1912. 219. Kelty RH, Baggenstoss AH, Butt HR. The relation of the regenerated liver nodule to the vascular bed in cirrhosis. Gastroenterology. 1950;15(2):285-295. 220. Richter S, Mücke I, Menger MD, Vollmar B. Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response. Am J Physiol Gastrointest Liver Physiol. 2000;279(2): G454-G462.

221. Aoki T, Imamura H, Kaneko J, et al. Intraoperative direct measurement of hepatic arterial buffer response in patients with or without cirrhosis. Liver Transpl. 2005;11(6):684-691. 222. Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med. 1981;305(23): 1371-1374. 223. Bosch J, Bordas JM, Mastai R, et al. Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: comparison with the effects on portal pressure. Hepatology. 1988;8(4):861-865. 224. Kravetz D, Bosch J, Terés J, Bruix J, Rimola A, Rodés J. Comparison of intravenous somatostatin and vasopressin infusions in treatment of acute variceal hemorrhage. Hepatology. 1984;4(3):442-446. 225. Hadengue A, Lee SS, Moreau R, Braillon A, Lebrec D. Beneficial hemodynamic effects of ketanserin in patients with cirrhosis: possible role of serotonergic mechanisms in portal hypertension. Hepatology. 1987;7(4):644-647. 226. Mastaï R, Rocheleau B, Huet PM. Serotonin blockade in conscious, unrestrained cirrhotic dogs with portal hypertension. Hepatology. 1989;9(2):265-268. 227. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1(4):325-337. 228. Blei AT, Gottstein J. Isosorbide dinitrate in experimental portal hypertension: a study of factors that modulate the hemodynamic response. Hepatology. 1986;6(1):107-111. 229. Navasa M, Chesta J, Bosch J, Rodés J. Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function. Gastroenterology. 1989;96(4):1110-1118. 230. Iwao T, Toyonaga A, Sumino M, et al. Hemodynamic study during transdermal application of nitroglycerin tape in patients with cirrhosis. Hepatology. 1991;13(1):124-128. 231. Ballet F. Hepatic resistance in isolated perfused normal and cirrhotic liver. In: Ballet F, Thurman RG, eds. Research in Perfused Liver. Montrouge, Ile-de-France, France: INSERM/John Libbey; 1991:339-360. 232. Reichen J, Le M. Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest. 1986;78(2):448-455. 233. Reichen J, Gerbes AL, Steiner MJ, Sägesser H, Clozel M. The effect of endothelin and its antagonist Bosentan on hemodynamics and microvascular exchange in cirrhotic rat liver. J Hepatol. 1998;28(6):1020-1030. 234. Rössle M, Richter GM, Nöldge G, Palmaz JC, Wenz W, Gerok W. New non-operative treatment for variceal haemorrhage. Lancet. 1989;2(8655):153. 235. Parker R. Role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Clin Liver Dis. 2014; 18(2):319-334. 236. Whipple AO. The problem of portal hypertension in relation to the hepatosplenopathies. Ann Surg. 1945;122(4):449-475. 237. Mathie RT, Blumgart LH. The hepatic haemodynamic response to acute portal venous blood flow reductions in the dog. Pflugers Arch. 1983;399(3):223-227. 238. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis [published correction appears in N Engl J Med. 2011 3;364(5):490. Dosage error in article text]. N Engl J Med. 2010;362(9):823-832. 239. Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Bañares R, Albillos A. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med. 2008;149(2):109-122. 240. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370-2379. 241. Bambha K, Kim WR, Pedersen R, Bida JP, Kremers WK, Kamath PS. Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut. 2008;57(6):814-820. 242. Dagenais M, Langer B, Taylor BR, Greig PD. Experience with radical esophagogastric devascularization procedures (Sugiura) for variceal bleeding outside Japan. World J Surg. 1994;18(2):222-228. 243. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30(5):969-977.

86.e6 244. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma [published correction appears in Hepatology. 2008;47(2):769]. Hepatology. 2008;47(1):97-104. 245. Liapi E, Geschwind JF. Chemoembolization for primary and metastatic liver cancer. Cancer J. 2010;16(2):156-162. 246. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41-52. 247. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734-1739. 248. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164-1171. 249. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010;33(3):541-551. 250. Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19(6):862-869. 251. Salem R, Lewandowski RJ, Kulik L, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140(2):497-507.e2. 252. Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046-2053. 253. Goéré D, Deshaies I, de Baere T, et al. Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg. 2010;251(4):686-691. 254. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: Results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol. 2009;20(9):1589-1595. 255. Kemeny NE. The re-birth of hepatic arterial infusion for colorectal liver metastases. J Gastrointest Oncol. 2013;4(2):118-120. 256. Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465-3471. 257. Groot Koerkamp B, Sadot E, Kemeny NE, et al. Perioperative hepatic arterial infusion pump chemotherapy is associated with

longer survival after resection of colorectal liver metastases: a propensity score analysis. J Clin Oncol. 2017;35(17):1938-1944. 258. Jakimowicz J, Stulti®ns G, Smulders F. Laparoscopic insufflation of the abdomen reduces portal venous flow. Surg Endosc. 1998; 12(2):129-132. 259. Schilling MK, Redaelli C, Krähenbühl L, Signer C, Büchler MW. Splanchnic microcirculatory changes during CO2 laparoscopy [published correction appears in J Am Coll Surg 1997;185(4):423]. J Am Coll Surg. 1997;184(4):378-382. 260. Hatipoglu S, Akbulut S, Hatipoglu F, Abdullayev R. Effect of laparoscopic abdominal surgery on splanchnic circulation: historical developments. World J Gastroenterol. 2014;20(48): 18165-18176. 261. Yokoyama Y, Alterman DM, Sarmadi AH, et al. Hepatic vascular response to elevated intraperitoneal pressure in the rat. J Surg Res. 2002;105(2):86-94. 262. Richter S, Olinger A, Hildebrandt U, Menger MD, Vollmar B. Loss of physiologic hepatic blood flow control (“hepatic arterial buffer response”) during CO2-pneumoperitoneum in the rat. Anesth Analg. 2001;93(4):872-877. 263. Tranchart H, O’Rourke N, Van Dam R, et al. Bleeding control during laparoscopic liver resection: a review of literature. J Hepatobiliary Pancreat Sci. 2015;22(5):371-378. 264. Tranchart H, Di Giuro G, Lainas P, et al. Laparoscopic liver resection with selective prior vascular control. Am J Surg. 2013;205(1):8-14. 265. Junghans T, Böhm B, Gründel K, Schwenk W, Müller JM. Does pneumoperitoneum with different gases, body positions, and intraperitoneal pressures influence renal and hepatic blood flow? Surgery. 1997;121(2):206-211. 266. Klopfenstein CE, Morel DR, Clergue F, Pastor CM. Effects of abdominal CO2 insufflation and changes of position on hepatic blood flow in anesthetized pigs. Am J Physiol. 1998;275(3): H900-H905. 267. Dagher I, Gayet B, Tzanis D, et al. International experience for laparoscopic major liver resection. J Hepatobiliary Pancreat Sci. 2014;21(10):732-736. 268. Jayaraman S, Khakhar A, Yang H, Bainbridge D, Quan D. The association between central venous pressure, pneumoperitoneum, and venous carbon dioxide embolism in laparoscopic hepatectomy. Surg Endosc. 2009;23(10):2369-2373. 269. Schmandra TC, Mierdl S, Hollander D, Hanisch E, Gutt C. Risk of gas embolism in hand-assisted versus total laparoscopic hepatic resection. Surg Technol Int. 2004;12:137-143. 270. Neuschwander A, Futier E, Jaber S, et al. The effects of intraoperative lung protective ventilation with positive end-expiratory pressure on blood loss during hepatic resection surgery: a secondary analysis of data from a published randomised control trial (IMPROVE). Eur J Anaesthesiol. 2016;33(4):292-298.

CHAPTER 6 Liver regeneration: Mechanisms and clinical relevance Jeroen de Jonge and Kim M. Olthoff INTRODUCTION TO LIVER REGENERATION The ability of the liver to regenerate was recognized by the Greeks in the ancient myth of Prometheus, the Titan god of forethought, who gave fire to the mortals and angered Zeus. Prometheus was chained to the Caucasus mountains and each day he would be tormented by Zeus’ eagle Ethon as it devoured his liver. Each night, the damaged liver would be restored so the eagle could begin anew, illustrating the liver’s unique power to regenerate. This regenerative capacity is what allows transplant surgeons to successfully remove or transplant portions of a liver, with the remnant portion then rapidly growing to the original volume, and also allows for restoration of function after hepatocyte mass loss from toxic injury or inflammation. The terms regeneration, hyperplasia, and hypertrophy are used synonymously in literature, but hyperplasia is the most precise from a cellular standpoint. The damaged or resected hepatic lobes do not grow back in the same way that a lizard’s tail regrows, but rather there is a hyperplastic response (defined as increasing in cell number) in the remnant liver, leading to its hypertrophic appearance (defined as enlarging liver size). This process is highly regulated and involves multiple cell types, extrahepatic signals, complex molecular pathways, and cellular interactions. A delicate balance is required for initiation of regeneration, exerting a growth response, and maintaining normal metabolic function. The inability to maintain this process leads to poor liver function and ultimately liver failure after surgery, whereas a successfully orchestrated response results in restoration of normal liver function.

CLINICAL RELEVANCE OF LIVER REGENERATION Hepatobiliary surgery is now routinely and safely accomplished for malignant and benign disease. This technical success in both resection and transplantation relies on the remarkable ability of the liver to regain most of its functional mass within a matter of weeks1 (see Chapters 101 and 109). Factors that limit the achievement of curative tumor resection and small-for-size (SFS) transplantations make up the high morbidity and mortality rates associated with insufficient volume of the liver remnant or transplanted graft. As hepatobiliary and transplant surgeons continue to expand the magnitude and complexity of liver resection and explore the limits of living donor liver transplantation (LDLT), understanding the mechanisms behind liver regeneration is essential for clinical practice. Many tumors that were previously considered to be unresectable are now amenable to complete resection through induction chemotherapy and innovative treatment strategies to increase liver remnant volume.2 There are several techniques, including portal vein embolization (PVE) or portal vein ligation (PVL), additional hepatic vein embolization, and (the most extreme) associating liver partition and PVL for staged hepatectomy (ALPPS; see Chapter 102D). They cause atrophy of the ipsilateral hemiliver and hypertrophy

of the contralateral side and are particularly valuable in patients who have underlying liver disease. Many patients with underlying liver disease are now considered suitable candidates for liver resection, even with Child-Pugh grade A cirrhosis and minimal portal hypertension.3–5 Regeneration also is crucial in liver transplantation. In deceased donor transplantation, hepatocyte loss occurs in the form of ischemia/reperfusion (I/R) injury because of the necessary preservation period from procurement to implantation and damage that may have occurred in the donor (see Chapters 105 and 111). Because of the scarcity of organs, more “marginal” organs are accepted for transplantation, which have increased need for regeneration and recovery in the environment of I/R injury (see Chapter 109). One of the landmark advances in liver transplantation is the ability to use segmental liver grafts obtained from either a deceased donor or a living donor. In the latter situation, success of the procedure relies on relatively rapid hepatic regeneration in both donor and recipient. The minimal amount of functional liver necessary for successful transplantation or for safe recovery in the donor is a major concern. Donor graft size, recipient weight, portal hypertension, I/R injury, and the recipient’s disease severity all contribute to the amount of post-transplant regeneration and recovery needed.6 Efforts to decrease the amount of liver removed from the donor to minimize donor risk results in smaller grafts for the recipients and real challenges in postoperative recovery.

BASIC CHARACTERISTICS OF LIVER REGENERATION Models of Liver Regeneration Liver regeneration is most clearly shown in the experimental model that was pioneered in 1931 by Higgins and Anderson.7 In this model, a simple two-thirds partial hepatectomy (PHx) is performed, without damage to the lobes left behind. This leads to enlargement of the residual lobes to make up for the mass of the removed lobes in five to seven days. Other well-known models of liver regeneration are associated with extensive tissue injury and inflammation and include the use of hepatic toxins, such as ethanol (EtOH),8 carbon tetrachloride (CCl4),9 and galactosamine (GalN)10; bile duct ligation11 or PVL12; and I/R injury.13 Newer models include transgenic albumin promoter urokinase-type plasminogen activator (u-PA) fusion constructs,14 Fah/Rag2 knock-out mice,15,16 and PHx in zebrafish.17 In each model, the different toxic agents injure specific liver cell subpopulations. Therefore, PHx is the preferred in vivo model to study the regenerative response. Debonera demonstrated that regenerative signaling observed in a rat liver transplant model of I/R injury is similar to that observed after PHx.18 The most recent instrument to study liver regeneration, when proliferation is impaired, is lineage tracings using cyclization recombinase 87

88

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

(Cre) recombinase–mediated cell labeling.19 In its classical setting, a traced cell population harbors two transgenes. The first expresses Cre under the control of cell-specific regulatory elements. The Cre activity is modulated by fusing a mutated ligand-binding domain of the estrogen receptor (ER), which is sensitive to tamoxifen but insensitive to estrogen. Upon addition of tamoxifen, CreER eliminates a locus of X-over P1 (loxP)– flanked stop cassette and induces transcription of the second transgene, coding for a reporter protein. Although this represents the gold standard for defining cell fate, this strategy is not without pitfalls, which may explain the sometimes-controversial results.20

ultimately undergo mitosis (M phase). The first peak of DNA synthesis occurs at 40 hours after resection in rodents and at seven to 10 days in primates. In small animals, the regenerative response returns the liver to the pre-resection mass in one week to 10 days. Clinical studies from living donor transplantation suggest that a significant amount of regeneration occurs in human within two weeks after resection and is nearly complete at three months after resection.23–25 After resection, hepatocyte proliferation starts in the periportal areas of the lobules and then proceeds to the pericentral areas by 36 to 48 hours. Liver histology at day three to four after PHx is characterized by clumps of small hepatocytes surrounding capillaries, which change into true hepatic sinusoids. The hepatic matrix composition also changes from high laminin content to primarily containing fibronectin and collagen types IV and I. After a 70% hepatectomy, restoration of the original number of hepatocytes theoretically requires 1.66 proliferative cycles per residual hepatocyte. In fact, most of the hepatocytes (95% in young and 75% in very old rats) in the residual lobes participate in one or two proliferative events.26 Hepatocytes have an almost unlimited capacity to regenerate as transplantation of several hundreds of healthy hepatocytes can repopulate a whole damaged liver in a calculated minimum of 69 doublings.27 Interestingly, the mechanisms associated with how a liver knows when to stop regenerating are much less clear than the starting mechanisms.

General Features of Liver Regeneration It is well established that liver regeneration after surgical resection is carried out by growth and proliferation of existing mature hepatocyte populations. These include hepatocytes, biliary and fenestrated endothelial cells, Kupffer cells, platelets, and Ito cells (stellate cells; Fig. 6.1). The kinetics of cell proliferation and the growth factors produced by proliferating hepatocytes suggest that hepatocytes provide the mitogenic stimuli leading to proliferation of the other cells. The degree of hepatocyte proliferation is directly proportional to the degree of injury.21,22 Immediately after liver resection, the rate of DNA synthesis in hepatocytes begins to increase as they exit the resting state of the cell cycle (G0) and enter G1, traverse to DNA synthesis (S phase), and

Vascular endothelial growth factor

Stellate cell Hepatocyte

Platelets Inactive hepatocyte Transforming growth factor growth factor β

Lipopolysaccharides

S phase

Extracellular proteases

Serotonin

Kupffer cell

Inhibition Hepatocyte growth factor

Tumor necrosis factor α

Farnesoid X receptor

G1 phase

Leukocyte Interleukin-6 Nucleus

G0 or G1 phase Sinusoidal endothelial cell Bile acids

Release Matrix metalloproteases

Epidermal growth factor

Transforming growth factor α

FIGURE 6.1  Pathways of liver regeneration initiated by major hepatectomy. After hepatectomy, nonparenchymal cells, such as stellate cells, Kupffer cells, leukocytes, and platelets, are activated by soluble factors. As a result, Kupffer cells release tumor necrosis factor-a and interleukin-6. The cytokines cause a priming of the remnant hepatocytes, and concurrently, extracellular proteases such as urokinase-type plasminogen activator convert inactive hepatocyte growth factor to its active form. The cytokines and the growth factors act in concert to initiate the reentry of quiescent hepatocytes (in the G0 phase) into the cell cycle from the G1 phase to the S phase, resulting in DNA synthesis and hepatocyte proliferation. The metabolic burden is indicated by the accumulation of bile acids in the blood, which enter the hepatocytes and drive increased protein and DNA synthesis. To signal the end of proliferation, transforming growth factor-b blocks further replication. (Original from Clavien P-A, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–1559. Reprinted with permission.)

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

Contribution of Liver Stem Cells to Regeneration In contrast to other regenerating tissues (bone marrow, skin), primary liver regeneration after surgical trauma is not dependent on a small group of progenitor cells (stem cells). However, in response to toxic liver damage inflicted by agents such as galactosamine, hepatocytes are unable to replicate. In this situation a population of cells known as “oval cells” proliferates to replace the hepatic parenchyma.28 In distinct approaches to determine whether cells other than hepatocytes themselves could be the source of new hepatocytes in oval cell injury, two groups found no evidence of such liver stem/progenitor cells.29,30 In the human situation, hepatic progenitor cells (HPCs) were presumed to participate in repopulation of the liver after acute massive necrosis and have also been identified in chronic liver disease.31 The human HPCs originate from the canals of Hering32–34 and play an important role in acetaminopheninduced injury.35 Huch et al. described conditions allowing for the long-term expansion of these adult bile duct–derived bipotent progenitor cells from human liver,36 which enables disease modeling, toxicology studies, and regenerative medicine. More recent studies have shown the contribution of HPC is very much context dependent, with hepatocyte senescence after injury being a major driver for HPC expansion and their hepatocytic differentiation. The rapidity of regeneration after PHx suggests a minimal involvement of stem cells in this response, but new stem/progenitor hepatocytes have been located either randomly throughout the lobule or at opposite ends of the portal vein-hepatic vein axis. It was reported that different regeneration stimuli trigger different regenerative responses; after toxic liver damage, stem cell–dependent proliferation is seen along the central vein,37,38 whereas homeostatic proliferation is

89

present throughout the whole liver.39 The presence of regenerative stem cells at the portal rim has refueled the streaming liver debate.40–42 Altogether, there remains considerable disagreement of the exact role of stem/progenitor cells in liver regeneration and homeostasis.19,43

Induction of Proliferation: Priming and Cell-Cycle Progression Within minutes after PHx, specific immediate early genes are activated in remnant hepatocytes.44,45 These 70 to 100 genes include proto-oncogenes, which play an important role in normal cell-cycle progression, such as c-jun, c-fos, c-myc, and K-Ras,46–48 and the transcriptional factors nuclear factor (NF)-kB, signal transducer and activator of transcription 3 (STAT3), activator protein-1 (AP-1), and CCAAT enhancer binding protein beta (C/EBPb).49,50 Historically, the onset of liver regeneration has been attributed to a flow-dependent response by which increased relative flow after PHx resulted in hepatocyte proliferation and hyperplasia.51 A more recent experimental partial liver transplant model demonstrates that increased portal flow is essential for liver regeneration. Nevertheless, portal hyperperfusion (flow that exceeds 250 mL/100 g/min) completely abolishes the process52 (see “Portal Inflow and Hepatic Outflow”). Very early experiments in parasymbiotic rats demonstrated the existence of humoral factors in the induction of liver growth after PHx.53 Interleukin (IL)-6 and tumor necrosis factor (TNF)-a have since been identified as the earliest factors triggering activation of several transcription factors during regeneration54,55 (Fig. 6.2). In IL-6 deficient or TNF-a receptor

Hepatocyte STAT3

Kupffer cell TNF-α

C3a/C5a

gp130

JAK P

IL-6R

JAK P

IL-6

TLR

–VE

P P

Activated NF-κB

SOCS3

STAT3 homodimer IL-6

TNF mRNA

IL-6 mRNA

P

SOCS3 mRNA

P TNF-α

Multiple biological responses: Cell survival/proliferation

FIGURE 6.2  Stimulated by components of the innate immune system, Kupffer cells produce and secrete interleukin (IL)-6 and tumor necrosis factor (TNF)-a to kick-start the regenerative response. IL-6 helps stimulate hepatocyte proliferation via signal transducer and activator of transcription 3 (STAT3) activation; in turn, this response is negatively regulated by suppression of cytokine signaling-3 (SOCS3). (Original from Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: The good, the bad and the ugly. J Pathol. 2009; 217:282–298. Reprinted with permission.)

90

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

deficient mice, liver regeneration after hepatectomy is delayed56 but not completely abolished.57,58 Therefore other blood-derived mitogens, such as hepatocyte growth factor (HGF), were identified as putative hepatic growth factor during liver regeneration.59 Hepatocytes in normal liver are not ready to respond to mitogenic signals without a set of “priming” events that switch them into a responsive state. This has been described by Fausto, who identified the priming factors involved in initiating and triggering the hepatic response to injury and concomitant growth factors and their receptors, which allow for competent hepatocytes to progress through the cell cycle.60 Priming is accomplished by the release of preformed cytokines that subsequently activate transcription factor complexes and allow the cell to exit G0 into G1 of the cell cycle. This group includes TNF-a and IL-6.61 TNF signaling through TNF receptor (TNFR)-I initiates liver regeneration after PHx with IL-6 as the key target. Knockout mice that lack TNFR-I showed an almost complete inhibition of NF-kB binding and a severe defect in hepatocyte replication after PHx. IL-6 reverses the deficiency in hepatocyte replication imposed by the lack of TNFR-I and corrects the defects in STAT3 and AP-1 binding but does not reverse the inhibition of NF-kB binding.55 This solved a long-standing riddle in the understanding of liver regeneration by identifying TNF as the initiator of IL-6. IL-6 activates the Janus kinase (JAK)/STAT3 and MAPK signaling pathways via the gp130/IL-6R complex. This leads to

activation of an array of immediate and delayed early genes required for normal liver-specific metabolic functions, repair, and hepatoprotection from injury.62–64 STAT3 is crucial for cells to progress from G1 to S phase and for activating the cmyc gene, a gene required for cell-cycle progression. Other intracellular signaling pathways that involve the receptor tyrosine kinases p38 mitogen-activated protein kinase (MAPK), protein kinase R-like ER kinase (pERK), and c-junNH2-terminal (JNK) are also rapidly activated. Progression through the cell cycle is regulated by cyclins and cyclindependent kinases (CDKs). Various combinations bind to form kinase complexes that are active at distinct points within the cell cycle and tightly controlled by several mechanisms, including binding by CDK–inhibitory proteins, such as p21. Feedback signals to this process are provided by suppression of cytokine signaling-3 (SOCS3) and transforming growth factor (TGF)-b, also regulated by IL-6. Other studies confirmed the importance of NF-kB65–67 and showed immediate upregulation of apoptotic genes (Fas and caspases) in livers that failed because of excessive resection68 (Fig. 6.3). So far, a few factors have been identified to be possibly responsible for the release of these priming cytokines and growth factors in the onset of liver regeneration. The first is endotoxin lipopolysaccharide (LPS), produced in the gut by Gram-negative bacteria. Circulating LPS is an extremely strong signal for Kupffer cells to produce TNF and start the cascade, resulting in hepatocyte replication. Rats treated

Chemokines, Hormones, Transmitters Survival factors (e.g., interleukins, (e.g., IGF-1) serotonin) GPCR

RTK

Growth factors (e.g., TGF- α, EGF )

Extracellular matrix Integrins

RTK

cdc42 Grb2/SOS

P13K AKT

G-Protein PKC

Akk α NF- κB

PKA

IκB

JAKs

FAK Src

Raf

Dishevelled GSK-3 β

MEK MEKK

APC

MAPK

β-catenin

MKK

TCF Myc: Max

Bcl-xL

Mad: Max

ERK JNKs Fos

Cytochrome C

CREB

Caspase-9 Gene regulation Apoptosis

Caspase-8

FADD

FasR

ARF mdm2

Bcl-2 Bad abnormality sensor

p53 Mt

β-catenin: TCF

Jun

Cell proliferation

CyclD p16 Gli Rb CDK4 p15 E2F CyclE CDK2

SMO

Cytokine receptor

STAT3, 5

Hedgehog

Patched

Cytokines (e.g., EPC)

Ras

Adenylate cyclase

Wnt

Fyn/Shc Frizzled

PLC

p27 p21

Bax

Bim

Death factors (e.g. FasL,TNF)

FIGURE 6.3  Intracellular pathways of liver regeneration. Multiple intracellular signaling pathways are rapidly activated. Progression through the cell cycle is regulated by cyclins and cyclin-dependent kinases (cdks), tightly controlled by several mechanisms, including binding by cdk–inhibitory proteins, such as p21. Modification of https://foundation.wikimedia.org/wiki/File:Signal_transduction_v1.png, uploaded by Roadnottaken, adapted from figure 23-12 in Molecular cell biology. Lodish, Harvey 5 ed: New York : W. H. Freeman and Co., 2003, p949. ISBN: 0-7167-4366-3

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

with antibiotics and germ-free rodents have a delayed peak of DNA replication after PHx, confirming the importance of LPS.69 Another major finding is the demonstration that cytokine activation and DNA replication are severely impaired in mice lacking the complement components C3a and C5a.70 In particular, mice lacking both C3a and C5a have impaired production of TNF and IL-6 after PHx and poor activation of NF-kB and STAT3.

Distinct Intracellular Pathways in Maintaining Liver Regeneration After the priming phase, concomitant growth factors are essential to progress hepatocytes into cell division. Growth factors include the potent hepatocyte mitogens HGF, TGF-a, and heparin-binding epidermal growth factor (HB-EGF). This process is further controlled by co-mitogens, such as insulin, glucagon, steroid and thyroid hormone, and epinephrine, which facilitate activity of the mitogens, and by downregulation of growth factor inhibitors, such as activin A and TGF-b. The HGF/c-Met pathway is important for sustaining DNA synthesis after injury and activates various downstream pathways that involve PI3K, ERK, and AKT.71 This pathway cross-talks with the Wnt/b-catenin signaling pathway, which has come to the forefront in liver biology over the last several years.72 Increased levels of HGF result in b-catenin dissociation along with nuclear translocation73 and upregulation of downstream targets of this pathway such as cyclin D1, c-myc, uPAR, matrix metalloproteinases (MMPs), and epidermal growth factor receptor.74 Vascular endothelial growth factor (VEGF) interacts with endothelial cells in the liver to increase HGF production from nonparenchymal cells.75 In the initiation of HGF, urokinase-type plasminogen activator (uPA) appears to play an important role. uPA and its downstream effector, plasminogen, increase within one to five minutes after PHx and rapidly cleave the HGF precursor, proHGF. Blocking uPA delays the appearance of HGF, and thereby delays liver regeneration, whereas blocking plasminogen-activator inhibitor (PAI) accelerates the release of HGF and liver regeneration.76 Another humoral factor that triggers the concerted regenerative response in hepatocytes has been discovered; extracellular adenosine triphosphate (ATP) has emerged as a rapidly acting signaling molecule that after PHx leads to rapid and transient activation of JNK signaling, induction of immediate early genes c-Fos and c-Jun, and activator protein-1 (AP-1) DNA-binding activity.77 Recent studies directly link mitochondrial bioenergetics to several markers of postoperative liver function after resection; early lactate clearance and postoperative alanine aminotransferase (ALT) strongly correlated with mitochondrial energy state,78 as well as with enhanced growth of the future liver remnant (FLR). The control of inflammatory signals is also necessary to allow for the progression of the regenerative pathways. The NFkB inhibitory and ubiquitin-editing A20 protein (tnfaip3) plays a key role in the liver’s protective response to injury, particularly its antiinflammatory effects.79 A20 is significantly upregulated in the liver after PHx and protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-kB.80,81 A20 also allows for proliferation and optimizes metabolic control and energy production after liver regeneration, as demonstrated by increased enzymatic activity of cytochrome c oxidase or

91

mitochondrial complex IV.82 A20-based therapies could be beneficial in future prevention and treatment of hepatic failure after liver resection. The cytokine induced form of nitric oxide synthase (iNOS) also seems to play an important role in scavenging oxygen radicals and protecting from apoptosis, caused by an uncontrolled inflammatory reaction mediated through IL-6 and TNF-b.83 The mechanisms of regeneration were also studied in the transplant setting, where microarray analysis of SFS rat liver grafts showed upregulation of vasoconstrictive and adhesion molecule genes at early time points after reperfusion, with later increases in genes associated with inflammation and cell death and downregulation of genes related to energy metabolism.84 These pathways have been confirmed in the situation of clinical deceased donor and LDLT.85,86

Remodeling of the Liver Remodeling of the newly regenerated liver tissue begins with the repopulation and maturation of nonparenchymal cells, such as endothelial, stellate, and biliary epithelial cells (see Chapter 1). Newly formed hepatocytes form clusters into which replicating endothelial cells invade to form new sinusoids. To restore normal architecture, stellate cells, which are located between endothelial cells and hepatocytes, synthesize extracellular matrix (ECM) proteins and TGF-g1, which can regulate the production of hepatic ECM. VEGF, angiopoietins 1 and 2, TGF-a, fibroblast growth factor (FGF)-1 and FGF-2, and HGF all are likely involved in the angiogenic process. Angiostatin, an inhibitor of angiogenesis, causes delayed and suppressed liver regeneration in mice.87,88 Remodeling of the ECM is associated with the activation of the urokinase/plasminogen pathway and the MMP pathway. MMPs not only remodel the ECM but also regulate immune responses89 and participate in modulation of vascular integrity at the endothelial cell–cell junctions in steatotic livers after I/R injury.90 MMPs, in combination with HGF, EGF, and TGF-b1, act to remodel the ECM, changing the levels of several ECM proteins, such as collagen, fibronectin, laminin, and entactin. The maturation and thickening of the ECM seems to have an inhibitory effect on proliferating hepatocytes, potentially signaling the end of rapid regeneration.91 The role of the ECM has been increasingly studied and plays an important role in regeneration, influencing proliferation, differentiation, and termination signals that regulate the regenerated liver size. The ECM was regarded as “that stuff between cells” but now is considered to be the dictator of metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis, and regeneration. The interaction between LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/b-catenin signaling and promote proliferation and tissue homeostasis.92 Also, the role of mechanical forces and mechanosensing in regulating liver regeneration is being increasingly studied. Increased shear stress after liver resection is picked up by the cells through mechanosensors on their membranes, which include glycocalyx, primary cilia, caveolae, ion channels, receptor tyrosine kinases, and G proteins and G protein-coupled receptors.93 These mechanosensing mechanisms either generate molecular signals that further activate downstream signaling pathways, such as Yes-associated protein (YAP), or directly transduce mechanical signals by regulating the actomyosin cytoskeleton. a-Catenin is now considered a key mechanosensor for direct cell–cell tension and pressure, leading to proliferation. Additionally, the ECM maintains

92

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

the differentiation state of hepatocytes. Increased rigidity favors hepatocyte proliferation,94 with hepatocytes remaining differentiated on softer support of fibrillar collagen meshwork and committing into dedifferentiation on stiffer support of monomeric collagen-coated dish.95 On rigid surfaces, hepatocytes exhibit epithelial to mesenchymal transition and switch into fibroblast-like morphology.96 In this context, it is interesting that temporary fibrosis is seen during normal liver regeneration and resolves over time.97,98

Maintaining Liver Function During Regeneration After volume loss, hepatocytes must adapt rapidly and seek a compromise between maintenance of continued differentiated function and cellular replication to permit survival. After toxic injury, resection, or transplantation, the balance is dramatically shifted to the crucial tasks of recovery and regeneration at the expense of normal hepatic metabolism. The success of restoring lost liver mass, repairing tissue injury, and resolving inflammation determines the ability of the liver to support normal metabolic function and determines the ability of the liver to recover. (Fig. 6.4). Several of the expressed immediate early genes encode enzymes and proteins that are involved in regulating gluconeogenesis, a very important process after PHx to compensate for the lost glycogen content and to produce sufficient glucose for the whole organism.99,100 There is rapid increased expression of genes involved in glucose homeostasis after PHx. Most notably, these include phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and hepatic insulin–like growth factor binding protein 1 (IGFBP-1), controlled at the level of transcription by insulin (downregulation), glucagon/adenosine 3’,5’-cyclic monophosphate (cAMP;

Metabolism: Synthesis Storage Degradation Homeostasis Detoxification

upregulation), and glucocorticoids (upregulation).44,101 Insulin itself can be a potent growth factor mediated through the insulin receptor, and insulin and glucagon have long been established as important “gut-derived” growth factors.102 Liver-specific transcription factors (hepatocyte nuclear factors [HNFs]) have an important role in determining the level of glucose production, fatty acid metabolism, and liver-specific secreted proteins. C/EPBa regulates expression of genes involved in hepatic glucose and lipid homeostasis, has antiproliferative properties, and is downregulated during liver regeneration after hepatectomy.103,104 During early regeneration, the liver accumulates fat before the major wave of parenchymal growth. Suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation after PHx, indicating that hepatocellular fat accumulation is specifically regulated during, and may be essential for, normal liver regeneration.105 Unlike pathologic steatosis, this transient regeneration-associated steatosis in hepatocytes is a physiologic process observed in every regenerating liver. Acute energy deprivation provokes hypoglycemia, mobilization of peripheral fats, and a switch to lipid usage.106 In mice, indirect calorimetry revealed that lipid oxidation is the primary energy source early after hepatectomy.107 This was regulated by downregulation of phosphatase and tensin homolog (PTEN), a key inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis that regulates growth and metabolic adaptations after hepatectomy. Some data show that decreasing lipid peroxidation levels by vitamin treatment after PHx produces an attenuation of cellular apoptosis and a marked increase in the proliferation process,

Recovery from injury: Regeneration Apoptosis Inflammation Restructuring

Liver function

A Increased need for recovery and regeneration

Increased metabolic stress Recovery regeneration

B

Patient factors: • Critical illness • Medical comorbidities • Infection • Complex surgery

Metabolic function Liver factors: • Age • Steatosis • Remnant size • Ischemia

FIGURE 6.4  Metabolic balance between regeneration and maintaining liver function. A, In times of relative quiescence, there is a balance within the liver of metabolic function and continuous liver cell replacement or restructuring as needed. B, In times of stress or after injury or resection, there is an increased need for metabolic function or regeneration and recovery. If metabolic need is great as a result of conditions within the patient, there may not be sufficient energy balance within the liver to regenerate sufficiently, and the liver may not recover. If the requirements for regeneration and repair are overwhelming, there may be decreased metabolic function, affecting patient outcome.

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

suggesting that the modulation of lipid peroxidation also has a role in the liver regeneration process.108 Hepatocytes in the periportal regions that divide and replicate after PHx require mitochondrial fatty acid beta oxidation. Peroxisome proliferator–activated receptor (PPAR)-a may be a crucial modulator controlling energy flux important for repair of liver damage and regeneration.109,110 Data from experimental models of liver transection, combined with PVL to promote liver regeneration, showed an overwhelming inflammatory response that interfered with the peroxisome proliferator-activated receptor-g coactivator (PGC-1a) mitochondrial biogenesis pathway. This resulted in the accumulation of immature and malfunctioning mitochondria in hepatocytes during the early phase of liver regeneration111 and showed close association with growth of the FLR.78 Also, increased expression of augmenter of liver regeneration (ALR), a potent hepatotrophic factor with important regulatory functions in cellular respiration, was shown. ALR is one of the strongest hepatic cell mitogens and also modulates mitochondrial biogenesis and ATP synthesis.112 In a microarray analysis of gene expression profiles after LDLT, it was demonstrated that C/EBPa was downregulated, as was HNF-4a and PPAR-a.85 Expression of many other liverspecific genes, such as IGFBP1 and G6Pase, is regulated in the basal state by HNF1. The transcriptional activity of HNF1 is upregulated during liver regeneration by binding of HNF1 to the growth-induced transcription factors STAT3 and AP-1.113 New insights into how the liver fulfills the adaptive response to metabolic needs during regeneration may come from the tight regulation of lipid, glucose, and bile acid (BA) metabolism through the class III NAD1-dependent histone deacetylase SIRT1 114. The role of SIRT1 as a key regulator of the regenerative response of the liver, controlling BA homeostasis, protein synthesis, and cell proliferation through deacetylation of farnesoid X receptor (FXR) and histones, and regulation of mTOR was established.115 SIRT1 is activated in situations of low energy availability and links nutritional status with metabolic homeostasis. It regulates adenosine monophosphate–activated protein kinase (AMPK). Contrary to SIRT1, mTOR is activated in high-energy conditions and controls cell growth and proliferation.116 mTORC1 promotes protein synthesis, and this axis is essential to regulate the cell cycle during liver regeneration after PHx. BA is also essential for the regeneration of the liver after PHx,117 although, when present in excess, BA can be toxic and promote hepatocyte death. Therefore a fine regulation of BA metabolism is essential to preserve liver homeostasis and a proper response to injury. FXR (NR1H4) is the master regulator of BA, lipid, and glucose metabolism. Through the activation of FXR, BAs regulate their hepatic metabolism and also promote hepatocellular proliferation. FXR is also expressed in enterocytes, where BAs stimulate the expression of FGF15/19, which is released to the portal blood. Through the activation of FGFR4 on hepatocytes, FGF15/19 regulates BA synthesis and finely tunes liver regeneration as part of the “hepatostat.”118,119

Termination of Proliferation The size of the liver is highly regulated and is controlled by the functional needs of the organism. This observation implies the existence of a master regulator of the liver/body mass ratio (i.e., a “hepatostat”). From LDLT we know that differences are present between donors and recipients in the percentage reconstitution of

93

the standard liver volume (80 vs. 93% at 3 months), which is probably caused by the need for functional liver mass to compensate for long-standing liver disease.23 The most well-known antiproliferative factors within the liver are TGF-b and related family members such as activin.120 TGF-b is produced mainly by hepatic stellate cells, but in the early phase it forms inhibitory complexes with SKI protooncogene (SKI) and SKI-like proto-oncogene (SnoN),121 rendering hepatocytes initially resistant to TGF-b.122 The downregulation of miR23b may further contribute to activation of the TGF-b1/Smad3 signaling pathway during the termination stage.123 Upon activation, Smad2, Smad3, and Smad4 assemble in a common complex, translocate into the nucleus, and activate target genes that negatively regulate the cell cycle.124 Reactive oxygen species (ROS) enhance synthesis and activation of TGF-b,125 which may account for the reduced regeneration after ischemia and reperfusion. Interacting with the TGFb/Smad signaling could restore regeneration in a model of SFS liver grafts.126 Similarly, activin A blocks hepatocyte mitogenesis and shows diminished signaling during liver regeneration when its cellular-receptor level is reduced. Its receptor level is restored once liver regeneration is terminated.127 The level of activin receptor mRNA expression was shown to be an important determinant in the magnitude of regeneration in PVL and PHx.128,129 Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine signaling that prevent the tyrosine phosphorylation of STAT proteins. Of the cytokines, both IL-1 and IL-6 are involved in the termination of proliferation.130 The administration of exogenous IL-1b suppressed DNA synthesis post-PHx,131 and increased expression of IL-1b has also been observed in a shrinking liver lobe of a rat PVL model, indicating that IL-1b is involved in the process of cellular atrophy.132 The suppression of IL-1b was shown to promote liver regeneration in rat models of classic 70% PHx and 90% extended hepatectomy.133 The IL-1 is secreted by Kupffer cells, regulated by prostaglandin E2 (PGE2), and suppressed by heparin and PGE1 after PHx.134 The effect is mediated through the IL-1 receptor as its antagonist (IL-1Ra), a competitive inhibitor of IL-1a and IL-1b and antiinflammatory protein, inhibits facilitated liver regeneration.135 IL-1 appears to contribute to the cessation of liver regeneration in a reduced-size liver transplantation model by reducing HGF and promoting TGF-b release.136 Another study showed that IL-1b inhibits the FGF19 signaling pathway, which regulates cell growth and metabolism of hepatocytes in liver regeneration.137 IL-6 signaling in the liver causes the rapid upregulation of SOCS3, which correlates with a feedback loop and the subsequent downregulation of phosphorylated STAT3, thereby terminating the IL-6 signal.138 Also the role of C/EBPa, a key regulator of liver proliferation, in the termination of regeneration has been demonstrated. Complex formation of C/EBPa and chromatin remodeling protein HDAC1 represses other key regulators of liver proliferation: C/EBPa, p53, FXR, SIRT1, PGC1a, and TERT. The C/EBPb-HDAC1 complexes also repress promoters of enzymes of glucose synthesis PEPCK and G6Pase. Proper cooperation of C/EBP and chromatin remodeling proteins seems essential for the termination of liver regeneration after surgery and for maintenance of liver functions.139 Additional work strongly implicates the detection of blood BA levels by nuclear receptors as a regulator of liver growth.117

94

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

The Hippo signaling pathway and its downstream effectors, YAP and transcriptional coactivator with PDZ-binding motif (TAZ), have also been identified as key regulators of cell proliferation and organ size.140 Overexpression of YAP in a transgenic mouse model leads to massive liver hyperplasia, reaching 25% of body weight. The core component of the mammalian Hippo pathway is a kinase cascade in which mammalian Ste20-like kinases 1/2 (MST1/2) phosphorylates and activates large tumor suppressor 1/2 (LATS1/2). LATS1/2 then phosphorylates the transcriptional coactivators, YAP and TAZ, downregulating their function and increasing their degradation by the proteasome.141 During regeneration in a rat model, YAP was activated one day after PHx through decreased activation of core kinases MST1/2, as well as LATS1/2 by three days after PHx. At day seven, reaching normal liver size, YAP nuclear levels and target gene expression returned to baseline.142 In aged mice, it was shown that MST1 and LATS1 activity was increased, leading to anomalous Hippo signaling and nonregenerating livers.143 It is therefore suggestive that the Hippo kinase pathway has a decisive role in determining overall liver size.144–147

A

LIVER ATROPHY Classically, atrophy is triggered by an obstruction of portal venous blood flow and/or results from chronic obstruction of the bile duct. When atrophy occurs unilaterally, the opposite lobe of the liver responds with a hypertrophic response. This response has been capitalized on by hepatobiliary surgeons and interventional radiologists, who perform selective PVE to induce hypertrophy of potentially small remnant lobes before resection, or ligate the portal vein intra-operatively in the two-staged ALPPS procedure (see Chapters 102C and 102D). In slow-onset atrophy, the liver frequently is significantly distorted, and anatomic landmarks can be markedly changed, most commonly seen accompanied by a rotation of the liver and portal triad structures (Fig. 6.5).

Mechanisms of Liver Atrophy The death of liver cells in atrophy generally is divided into necrosis and apoptosis. The distinction is important because necrosis is a nonregulated traumatic disruption of a cell that occurs when it encounters overwhelming injury, whereas apoptosis is an inducible, highly orchestrated cascade of events that

B

C FIGURE 6.5  Hepatic atrophy. A, Computed tomography (CT) appearance of the liver in a patient with papillary hilar cholangiocarcinoma involving the left hepatic duct. Note the atrophic left lobe and intrahepatic ductal dilation predominantly on the left. B, Gross appearance of the liver in the same patient. Inset shows intraluminal view of the common bile duct, with tumor extruding from the left hepatic duct (arrow).

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

is physiologic. Necrotic cells lose membrane integrity, leak lysosomal enzymes, and induce a large inflammatory response. Apoptosis is energy dependent and allows cells to shrink and die without inducing inflammation.

Portal Vein Embolization/Ligation–Induced Hepatic Atrophy For more information, see Chapter 102C. The liver has the remarkable potential to maintain its total volume by adjusting lobes differently in response to extrahepatic stimuli; atrophy of the ligated lobe is the result of apoptosis, whereas increased portal flow in the nonembolized lobe induces proliferation and activates several cytoplasmic growth–promoting signal transduction pathways.148,149 Ischemic necrosis of centrilobular areas of the liver predominates in the first three days of cell death. Areas peripheral to the necrotic liver cells predominantly undergo apoptotic cell death, and apoptosis persists long after necrosis subsides. Oxygen levels and mitochondrial function help determine which cells will undergo necrosis or apoptosis.150 Models of portal vein ischemia in rats have confirmed a caspase-dependent apoptosis and have indicated that Kupffer cells are involved in generating reactive oxygen substrates and other acute-phase reactants, culminating in mitochondrial dysfunction and apoptosis.151,152 Interestingly, in a research environment when the contralateral lobes are resected after PVL, the regenerative stimulus of a 70% hepatectomy can counteract the atrophy of the ipsilateral liver, leading to a low but prolonged regenerative response of the portally deprived liver lobe.153

Biliary-Induced Hepatic Atrophy The molecular mechanisms involved in biliary obstruction leading to hepatic atrophy are much more centered on apoptosis, with little or no involvement of acute necrosis. Cholestasis results in the accumulation of toxic bile salts, which induce apoptosis through the Fas-mediated pathway. In this case, TNF-a and Fas ligand bind to the Fas death receptors, leading to a cascade of intracellular events, including cytochrome c release from mitochondria and activation of apoptosis-mediating caspases. In Fas-deficient mice, bile duct ligation resulted in impaired apoptosis and less injury and fibrosis compared with wild-type mice.154–156 More recent data, however, suggest a nonischemic model of necrosis/oncosis as the predominant process leading to cell death after common bile duct ligation, with cell swelling and without apoptotic caspase 3 activation.157

Clinical Causes of Atrophy In addition to the purposeful ligation of the portal vein to induce hypertrophy, there are rare situations of portal vein thrombosis in noncirrhotic patients. If occurring acutely, this can be associated with bowel inflammation, pancreatitis, and hypercoagulable states. After umbilical vein catheterization in the newborn, liver volumes were shown to be 25% smaller than the expected standard liver volume. Creating a meso-portal surgical shunt between the superior mesenteric vein and the umbilical portion of the left portal vein achieved significant liver regeneration with a 28% increase in the liver volume.158 Perihilar cholangiocarcinoma is a frequent cause of biliary atrophy, induced by progressive occlusion of a major bile duct (see Chapter 51B). Biliary occlusion, often accompanied by portal vein compromise and leading to atrophy of the liver, occurs approximately 20% of the time with this disease and has significant

95

surgical implications. Benign post-cholecystectomy bile duct strictures can also lead to hepatic atrophy 10% to 15% of the time.159,160 Choledocholithiasis and hepatolithiasis are infrequent causes of atrophy, as are benign tumors, such as papillomas, cystadenomas, and granular cell tumors (see Chapters 37A, 39, and 48). Strictures caused by parasitic biliary infections, such as Clonorchis sinensis and Ascaris lumbricoides, also have been known to cause biliary obstruction and associated atrophy of the liver (see Chapter 45). Occlusion of the hepatic artery alone would not induce atrophy, although arterial radio-embolization techniques are currently used to treat hepatocellular carcinomas and increase resectability. Lobar radioembolization with Yttrium-90 or Holmium-166 can cause atrophy of a lobe through b emission, causing necrosis. This way, “radiohepatectomy” allows for growth of the contralateral lobe with a median increase of 24% after three months,161,162 which may enable resection.

CLINICAL FACTORS INFLUENCING LIVER REGENERATION Patient-Related Factors Age and Cellular Senescence Liver age is a significant factor in hepatocellular regeneration. Older livers do not regenerate as quickly as younger livers and show delayed regeneration after acute injury and impaired function after liver transplantation.163,164 Rodent models have shown reduced and delayed thymidine kinase uptake in older animals after PHx, and there is a striking difference in the magnitude of DNA synthesis and timing of hepatocyte replication between young and old livers.165 This aging effect was attributed to cellular senescence by Hayflick in 1961. First introduced to describe the limited proliferative ability of human fibroblasts in cell culture, senescence has been discovered in vivo in many types of tissues, and the number of senescent cells increases with age.166 In senescence, the p53 and Rb signaling pathways become activated, leading to activation of p21Cip1 (CDKN1A). p21Cip1 is the inhibitor of cyclin E/ CDK2 complex and promotes cell cycle arrest at the G1/S phase of the cell cycle. In old mouse livers, the CDK inhibitor p21 is expressed at high levels, as is cyclin B1, a regulator of G2/M phase of the cell cycle.167 Also, aging switches the C/EBPa pathway of growth arrest in liver from CDK inhibition to repression of E2F transcription. This blocks the activation of the c-myc promoter in old livers after PHx and in tissue culture models.168,169 Once it becomes senescent, the cell stops dividing permanently but remains metabolically active. When cells in an organ become senescent, the entire organism can be affected through the senescence-associated secretory phenotype (SASP). Senescence is generally considered beneficial as a tumor suppressive or anticancer process because the senescent cells cannot divide. On the other hand, cellular senescence may cause loss of regenerative capability of the liver.170 Any repetitive wave of insult that can cause damage to hepatocytes, such as alcohol intake, hepatitis viral infection, immune disorder, or autophagy deficiency, promotes senescence in hepatocytes and may compromise liver regeneration. The normal liver contains a basal level of senescent hepatocytes (3%–7%), but in chronic hepatitis and cirrhosis the liver may exhibit 50% to 100% of hepatocytes in senescence.166

96

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Senescent hepatocytes secrete SASP factors with an abnormal level of proinflammatory cytokine/chemokines, such as CCL2, stimulating the production of TGF-b from hepatic macrophages, which can promote the conversion of nonsenescent cells to senescent cells in a paracrine manner. The inhibition of TGF-b–TGFb-R1 interaction by specific inhibitors or the depletion of macrophages reduced senescence progress and enhanced liver regeneration.171 Aging has been also shown to be associated with a progressive decline in growth hormone secretion and Foxm1B expression.172 Treatment of old mice with growth hormone can restore hepatocyte proliferation with increased Foxm1B and cyclin B1 expression and significant reduction in p27 protein levels.173 Recently, a critical role of the glycogen synthase kinase 3b- cyclin D3 pathway in the loss of the regenerative capacity in old livers was shown, which could be overcome by exogenous growth hormone substitution.174

Biliary Obstruction or Diversion Cholestasis results in the accumulation of toxic bile salts, which induce apoptosis through the Fas-mediated pathway. In this pathway, TNF-a and Fas ligand bind to the Fas death receptors, leading to cytochrome c release from mitochondria and activation of apoptosis-mediating caspases. In Fas-deficient mice, bile duct ligation resulted in impaired apoptosis and less injury and fibrosis compared with wild-type mice.154–156 Other molecular mechanisms involved in reduced regenerative capacity with biliary obstruction are suppressed expression of c-myc,175 C/EBP, and cyclin E.176 Production of HGF,177 EGF,178 and IL-6 179 is also altered. Finally, biliary obstruction also impairs enterohepatic circulation, thus negatively affecting the regenerative capacity. Clinically relevant is that external biliary drainage for obstructive jaundice markedly suppresses liver regeneration after PHx,180 whereas internal biliary drainage preserves this capacity.181 The mechanism was demonstrated in a rat model in which oral bile acids were given before PHx. Liver regeneration was significantly increased through activation of the farnesoid X receptor signaling pathway.182

Diabetes Mellitus Insulin is one of the most important hepatotrophic factors in portal venous blood.102 The binding protein of IGF, a molecule similar to insulin, also rises substantially after PHx.183,184 Thus impaired secretion of insulin and IGF in diabetic patients prevents liver regeneration after PHx, as reflected by decreased synthesis of RNA, DNA, and protein on the first postoperative day.185 Enhancement of mitochondrial phosphorylate activity in the remnant liver after PHx is inhibited in proportion to the severity of impaired insulin secretion. Insulin gene transfer via the spleen enhances liver regeneration without causing liver damage and improves nutritional status after hepatectomy in diabetic rats.186 Multiple regression analysis in clinical PVE has shown that diabetes mellitus is a risk factor for reduced hypertrophy in the nonembolized lobe187 (see Chapter 102C). These results demonstrate the importance of insulin in hepatic regeneration, and strict glucose control should be aimed for in liver surgery and PVE.188

Nutritional Status The literature on the effect of nutritional status on liver regeneration is contradictory. Hepatic regeneration is metabolically intensive and requires a large amount of energy. Liver regeneration

after hepatectomy is associated with a derangement in energy metabolism, measured by a decrease in the ratio of ATP to its hydrolysis product inorganic phosphate. This depleted energy status is mirrored in biochemical indices of liver function, and restitution parallels the course of restoration of hepatic cell mass.189 Nutritional support is undoubtedly the most physiologic manner to enhance liver regeneration, but there still is little, if any, clear information regarding the effect of specific nutrients on liver regeneration in humans.190,191 From animal models, we know that malnutrition is associated with higher postoperative mortality and reduced regeneration after PHx.192 When improving nutritional status, enteral feeding should be preferred because rats given enteral nutrition showed much better weight gain after 70% hepatectomy than those given isocaloric nutrition parenterally.193 Recently, a small trial with supplementation with branched chain amino acids-enriched nutrients showed improved nutritional state in LDLT recipients in the early post-transplant period and shortened the post-transplant catabolic phase.194 Supplementation of glutamine, one of the sources of DNA and protein synthesis, has been shown to promote liver regeneration.195 Essential fatty acids, components of the cell membrane and precursors of several functional mediators, also play an important role in hepatic regeneration. Interestingly, dextrose supplementation has an inhibitory effect on liver regeneration, associated with increased expression of C/EBPa, p21, and p27,196 although this effect was not found in a previous study.197 On the other hand, the most recent preclinical studies investigated the effect of short-term starvation (12–23 hours) and showed beneficial results in protecting against apoptosis and necrosis, associated with I/R. Mechanisms involved higher levels of betahydroxybutyric acid and consequently an increase of heme oxygenase-1 and autophagy activity and inhibition of high-mobility group box 1 (HMBG1) release, NF-kB activation, and NLRP3 inflammasome activity.198 In this light, an interesting concept is the mathematical “network of interaction prediction model,”22 which indicates that halving the metabolic load for 48 hours after a 85% liver resection could rescue the regenerative process.

Gender Sex steroids are known to induce transient hepatocellular proliferation and to improve fatty acid metabolism.199 Estrogen receptors are found on hepatocytes and serum estradiol is increased substantially after PHx in rodents and humans.200 Pretreatment of rats with 17b-estradiol induces hepatocyte DNA synthesis in vitro and accelerates liver regeneration in vivo; administration of tamoxifen, a mixed estrogen agonist/ antagonist, slows regeneration when given soon after PHx.201 In contrast, testosterone levels decline in men and in male rats after PHx. Nevertheless, there is no clinical evidence that shows significant differences between the sexes in man after liver resection. In murine models, gender may also have a positive effect on regeneration of transplanted partial grafts.202 In humans, the latency of bilirubin level reduction was shorter in women than in men, suggesting that a female factor promotes bilirubin recovery after liver transplantation. Estrogen was shown to significantly promote Cytochrome P450 (CYP) 2A6, a bilirubin oxidase, facilitating bilirubin metabolism in regenerating liver.203 Generally, estrogen may be responsible for the better tolerance to various stresses because of a reduced

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

inflammatory response and a reduced oxygen radical production, leading to improved hepatic regeneration.204

Intrinsic Liver Disease Steatohepatitis The regenerative response of the liver can be seriously affected by preexisting intrinsic liver conditions, such as steatohepatitis, fibrosis, and cirrhosis (see Chapters 7, 69, and 74). Steatohepatitis is a condition met more frequently in the general population, and nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become an epidemic205 that poses significant challenges in the management of patients undergoing liver resection. Hepatic steatosis affects regeneration on several molecular levels.206 Lipid accumulation has been associated with hepatocyte mitochondrial damage caused by free radical injury. Steatotic livers in rats show delayed mitosis and increased mortality after PHx, which may be because of abnormal TNF and IL-6 signaling.207 The coordinated induction of Jnks and Erks is disrupted after PHx in fatty livers of ob/ob mice (a model for steatohepatitis), with enhanced AKT and inhibition of PEPCK.208 Cyclin D1 induction is abolished along with STAT3 and reduced ATP levels, which may arrest cell-cycle progression. Hepatocyte mitochondrial damage associated with lipid accumulation is caused by free radical injury from fatty acid oxidation. Abnormalities in induction of CYP450 may be one mechanism in the pathophysiology of these findings in fatty livers and may contribute to poor regeneration.209–211 The presence of underlying steatosis has a considerable impact on operative morbidity and mortality after major hepatic resection,212–214 with a significantly higher rate of complications if marked steatosis ($30%) is present.215 Interestingly, in a clinical setting of major hepatectomies, BMI did not impact liver regeneration during the first two months, but the kinetic growth rate per week between two and seven months postoperatively was less among overweight and obese patients. Also in this series, risk of a major complication was greatest among obese patients.216 Steatohepatitis, or acute inflammation in the setting of fatty infiltration, carries an even higher risk and eventually results in fibrosis and cirrhosis.217

Inflammation: Viral Hepatitis and Bacterial Infections Inflammation in general and some viral infections, such as hepatitis B and C and murine cytomegalovirus specifically,218–220 have been reported to inhibit hepatic regeneration (see Chapter 68). A factor that links inflammation directly to regeneration is mitochondrial calcium uptake 1 (MICU1), the gatekeeper of the mitochondrial calcium uniporter (MCU). Loss of MICU1 leads to an enhanced and sustained proinflammatory response post PHx with a failure of hepatocytes to enter the cell cycle and large-scale hepatic necrosis through Ca21 overload-induced mitochondrial permeability transition pore (PTP) opening.221 Prevention of mitochondrial Ca21 overload rescued liver regeneration in MICU1 knock-down mice. The precise mechanism responsible for viral infection– related suppression is unclear, although it may be partly mediated by the inhibition of cell cycle–dependent molecules. In hepatitis B virus (HBV) infection, it was shown that liver regeneration is delayed through a reduced activation of the insulin receptor. HBV induces expression of the insulin receptor via activation of the NF-E2-related factor 2, leading to increased

97

intracellular amounts of insulin receptor in the hepatocytes. However, intracellular retention of the receptor simultaneously reduces the amount of functional insulin receptors on the cell surface and thereby attenuates insulin binding. Consequently, hepatocytes are less sensitive to insulin stimulation leading to delayed liver regeneration.222 Concomitant bacterial infections also alter liver regeneration. Earlier reports showed enhanced liver regeneration in rats after inflammation before hepatic resection because of stimulation of lipopolysaccharide, upregulation of proinflammatory cytokines, such as IL-6 and TNF-a and HGF, 223,224 all of which are chief mediators of hepatic regeneration. More consistent with clinical observations, a recent study showed significantly delayed regeneration kinetics in a rat model of combined liver resection and intraperitoneal sepsis, with hyperinflammation and increased liberation of pro-inflammatory cytokines.225 The relation between inflammation and poor liver regeneration was confirmed in patients with early allograft dysfunction (EAD) occurring in the first week after liver transplantation. EAD was associated with an inflammatory response in the perioperative period, and a specific pattern of 25 cytokines, chemokines, and immunoreceptors. Patients with EAD showed higher MCP-1 (CCL2), IL-8 (CXCL8), and RANTES (CCL5) chemokine levels in the early postoperative period, suggesting upregulation of the NF-kB pathway, in addition to higher levels of chemokines and cytokines associated with T-cell immunity, including MIG (CXCL9), IP-10 (CXCL10), and IL-2R.226

Pharmacologic Therapy Many exogenous agents can affect liver regeneration, including frequently prescribed drugs and neoadjuvant chemotherapy. Numerous medications associated with induction of steatosis may interfere with liver regeneration and include certain antiarrhythmic agents, antibiotics, antiviral agents, anticonvulsants, steroids, calcium channel blockers, statins, and antiglycemic medications. b-Blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) may exert a direct negative influence on liver regeneration. b-Blockers decrease portal blood flow to the liver and, blocking the trophic effects of epinephrine and NSAIDs, directly inhibit cyclooxygenase, part of the CEBPb-mediated liver regenerative pathway, but there is no clinical evidence reflecting increased morbidity or mortality. Nonetheless, any potential harmful effect of any medication must be considered before resection. There are an increasing number of patients having liver surgery after neoadjuvant or induction chemotherapy. Major drawbacks of hepatotoxic chemotherapy are the sinusoidal obstruction syndrome (SOS), associated with oxaliplatin (Eloxatin, Sanofi Aventis) 227 and the chemotherapy associated steatohepatitis (CASH),228 which is associated with irinotecan (Campto, Pfizer). This chemotherapy-associated steatohepatitis increases postoperative mortality and specifically deaths from postoperative liver failure.229 Sinusoidal obstruction also impairs liver regeneration after extensive liver resections and increases postoperative morbidity, but may be prevented by administering concomitant Bevacizumab (Avastin, Hoffmann–LaRoche).230,231 Bevacizumab, a monoclonal antibody targeting VEGF, is given in combination with cytotoxic chemotherapy, to improve resectability232 and survival in patients with metastatic colorectal cancer.233 Well-designed preclinical studies have demonstrated that inhibition of angiogenesis can

98

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

inhibit wound healing.234 Bevacizumab does not appear to adversely affect the results of PHx in humans.235 Animal studies have demonstrated that liver regeneration depends on VEGF and angiogenesis.87 In a murine model, anti-VEGF receptor therapy slightly impaired liver regeneration and cell proliferation after PHx compared with control.236 Clinically, no differences in postoperative liver insufficiency were seen if stopped at least six to eight weeks before hepatic resection.237,238 Regarding the effect of Sorafenib (Nexavar, Bayer), a multikinase inhibitor used for treatment of hepatocellular carcinoma, conflicting results have been reported in experimental research. Sorafenib did not impact on liver regeneration when ceased before surgery; however, administration during and after hepatectomy affected liver regeneration in rodent models.239,240 Reduced phospho-ERK levels and wound-healing complications were observed. In another rat experiment however, no significant change in liver regeneration related to Sorafenib exposure was found.241

grafts, there is initiation of the cell-cycle pathways with upregulation of markers of liver regeneration as previously described. When ischemic injury is significant, there is a greater expression and activation of cytokines, transcription factors, and immediate early genes and a greater magnitude of hepatocellular replication up to a certain “point of no return,” after which the damage is too extensive and the liver or allograft is unable to maintain functional homeostasis and regenerative capabilities, which results in liver dysfunction and graft failure.98,244,245 Other studies have demonstrated that lack of blood flow occurring during cold preservation for transplantation markedly deteriorates the protective phenotype of liver sinusoidal endothelial cells (LSEC) by downregulating the expression of the transcription factor Kruppel-like Factor 2 (KLF2), which orchestrates the transcription of a variety of protective genes, including the endothelial synthase of NO (eNOS), the antithrombotic molecule thrombomodulin, and the antioxidant transcription factor Nrf2.246–248

Liver Transplantation

Minimal Transplanted Liver Mass

Regeneration also is crucial in liver transplantation (see Chapters 105 and 111). In deceased donor transplantation, hepatocyte loss occurs in the form of I/R injury because of the necessary preservation period from procurement to implantation and damage that may have occurred in the donor. Regenerative mechanisms are actively engaged after transplantation, depending on the length and degree of preservation injury.18,242 Similarly, hepatocytes lost to the alloimmune response require replacement. Regeneration also is necessary in the setting of transplanting an SFS graft into a larger recipient. This is the case in the setting of adult-to-adult living donor transplantation (AALDLT).6 Ischemic injury is minimized in AALDLT, in that the preservation period is short; however, this technique supplies a graft that is by definition too small, requiring vigorous immediate hepatocyte proliferation. By transplanting only 50% to 60% of what is the expected liver volume in adults, recipients (and donors) must rely on the rapid regeneration of a partial liver in addition to maintaining the basic metabolic functions required of the liver. The National Institutes of Health (NIH)-sponsored study in adult-to-adult living donor transplantation (A2ALL) has investigated the role of numerous donor and recipient factors in regeneration. The size of the remnant liver or graft had the greatest impact on rate and quantity of regeneration.23 In a pilot study investigating molecular mechanisms associated with human liver regeneration, differences in hepatic gene expression were noted between donors with complete regeneration compared with those with less successful regeneration. Genes mainly related to cell proliferation, inflammation and metabolism, metabolic pathways (aminoacyl tRNA synthesis), and stress pathways (acute phase response) were among the most significantly regulated pathways. In contrast, the poor regeneration group demonstrated very little change in expression before and after resection. The lack of significant change in genomic profile in the poorly regenerating livers suggests a possible inhibition or delay in initiation of recovery and regeneration molecular pathways.243

The amount of liver mass transplanted has been shown to be an important factor after transplantation. Early experimental studies addressing regeneration after transplantation showed that an SFS graft adapts to its environment and achieves a size equal to the original native liver.249 It became apparent that graft size-to-recipient ratio was crucial when it became clear that grafts that were too small had decreased survival.250 These findings correlated with early clinical experience in living donor transplantation, in that some SFS segmental grafts developed a “small-for-size syndrome” that was associated with significant functional impairment, shown by prolonged cholestasis and histologic changes consistent with ischemic injury and associated with poor outcome. Liver grafts with a graft volume of less than 40% of calculated standard liver volume were associated with poor graft survival and prolonged hyperbilirubinemia.251–254 The development of segmental graft dysfunction in the A2ALL study was also associated with worse patient outcome.23 Animal models of partial liver graft transplantation have studied the interplay between the regenerative response and ischemic injury in the setting of 50% and 30% size grafts. The partial grafts showed a robust regenerative response if the ischemic injury was minimal. It became apparent, however, that when these partial grafts were subjected to ischemic injury of moderate to prolonged time periods, there was a significant effect on survival, with extensive hepatic necrosis, the inability to initiate or maintain the regenerative response, and decreased survival. These findings show the diminished tolerance of SFS grafts for additional injury beyond transplantation itself.245,255 Although ischemic injury in AALDLT is minimized, the amount of critical liver mass required for transplantation in living donation remains in question. Most centers have defined liver mass as graft-to-recipient body weight ratio or as a percentage of the standard liver volume. No uniform method of measuring or reporting graft volume in relation to the recipient has been established. Clinical experience with living donor and split grafts has led to an accepted lower limit of 0.8% graft-to-recipient body weight ratio, or 40% of the standard liver volume, although significantly smaller liver segmental grafts up to 0.47% to 0.49% have been used successfully.256,257 Donor and recipient characteristics and graft factors significantly influence these minimal accepted standard volumes. Patients with fulminant hepatic failure, severe

Ischemic Injury Warm and cold ischemic injury is an unavoidable component of transplantation. After prolonged cold ischemia of whole liver

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

portal hypertension, and significant disease severity as manifested by a high Model for End-Stage Liver Disease (MELD) score (see Chapter 4) and patients with significant metabolic stress may require more liver volume than stable patients transplanted under elective conditions. The accumulation of additional stressful stimuli, such as sepsis or renal failure, may push a relatively small graft into failure.

Effect of Immunosuppression Within the graft environment, the host immune response needs to be inhibited to avoid acute allograft rejection, and inhibition of this response may interfere with the recovery of liver grafts, requiring active regeneration of hepatocytes. Glucocorticoids, routinely used in immunosuppression protocols, have been shown to inhibit cell cycle progression markedly in PHx models and in transplant models with ischemic injury.258–260 Cyclosporine and tacrolimus may have differential effects on regeneration in a dose-dependent fashion.261 Sirolimus, with its antiproliferative action, interferes with hepatocyte replication.262,263 The rapid hepatocyte replication and smaller liver mass also may interfere with metabolism and pharmacokinetics of certain drugs. Preliminary studies have shown that AALDLT recipients require lower doses of tacrolimus in the early postoperative period than patients receiving whole grafts.264 The ability to measure functional recovery of these recipients would help in the assessment of hepatocellular function and metabolic demands in these regenerating partial liver grafts.

Donor Age As with liver regeneration in the nontransplant setting, old grafts do not regenerate as quickly as young livers. A clinical study of living donors showed a greater graft/standard liver volume in the young donor livers post-transplant compared with middle-aged and old donor grafts. The old livers also had a higher prothrombin time in the early period postoperatively.265 Statistics from the United Network for Organ Sharing database show that the graft survival of older living donor grafts is inferior to younger grafts,266 and increasing donor and recipient age affected both short-term and long-term survival in the NIH A2ALL study.23,267 In the deceased donor transplant setting, grafts older than 55 to 60 years of age have poorer longterm survival combined with longer cold ischemic times.268 Age may affect the regeneration and recovery of the living donor and the recipient. Many groups limit the upper age limit of the donor into the 50 to 60 year range, although no definite age has been specified.

Portal Inflow and Hepatic Outflow In both liver resection and partial liver graft transplantation, in addition to the reduced cell mass, portal blood flow dynamics are altered, leading to increased portal blood flow and pressure. Hepatic regeneration is triggered by shear stress on the sinusoidal endothelium and is implicated in more rapid regeneration269,270 and increased recovery, if portal flow is increased to about two times baseline level.271,272 Ultimately, this is shown in a model of PVL, where the mere ligation of the portal vein branch is responsible for overwhelming alterations of both hepatic structure and physiology.273 In the ligated lobe, the total blood flow halves, with increased fraction of arterial blood flow and development of extensive necroapoptotic lesions and loss of higher liver functions. Meanwhile, a hyperperfusion (,230%) of mainly (.97%) portal blood flow with reverse hepatic artery

99

buffer response takes place in the nonligated lobe, with intensive rise in mitotic activity and increased functionality after 14 days. Significant portal hyperperfusion, on the other hand, is regarded as central to the problem in SFS grafts, leading to decreased regeneration and increased mortality.52,175,274,275 Significant and persistent portal hyperperfusion caused a loss of hepatic arterial buffer response with hypoxia and significantly increased anaerobic metabolism, hepatocellular injury, and loss of function.276 In a pig model of 20% inflow reduction to the left portal vein, a robust regenerative response and increase in total liver volume and function was seen on the right side mediated through TNF-a, IL-6, and NOS2 in the early phase, without causing atrophy or loss of liver function on the left side.277 In addition to portal venous inflow alteration, the hepatic venous outflow may be altered during surgery, even causing outflow obstruction of areas of the liver remnant or liver graft. Postoperative liver hypertrophy ratios and even function parameters were shown to be significantly impaired in living donor liver grafts with the large-outflow-obstruction areas, compared with small-outflow-obstruction areas.278 Segments with poor venous drainage become atrophied with time.279

Microbiome The intestinal content is rich in microorganisms and in metabolites generated from both the host and colonizing bacteria. Via the gut-liver axis, the microbiome exerts an immense impact on liver integrity and function, and research has emerged to support that the gut microbiota may promote liver regeneration.191,280 LPS are the major components of the outer membrane of gram-negative bacteria. Although it was initially thought that bacteria negatively influence liver regeneration, evidence indicates that endotoxin is necessary for liver regeneration. Gutderived endotoxin administered both before and after PHx induced hepatic DNA synthesis and release of several hepatotrophic factors such as insulin.281 Conversely, hepatic DNA synthesis in mice was impaired when gut-derived endotoxin was prevented from reaching the liver.282 In addition, conditions that eliminate bacteria or reduce endotoxin (gut sterilization using neomycin and cefazolin, reduction of endotoxin and BAs using cholestyramine, and neutralization of the lipid A portion of circulating endotoxin by polymyxin B) could inhibit DNA synthesis following 2/3 hepatectomy. The observed LPS-induced hepatocyte proliferation results from HGF activity. Treatment of rats with a combination of LPS and HGF increased JNK and AP-1 DNA binding, through c-JUN and STAT3 upregulation.283 LPS-HGF modulation of hepatocyte proliferation indicates potential contribution from the gut microbiota to the liver regeneration program. It is important to note, however, that not all endotoxin-releasing bacteria are beneficial for liver regeneration. In mice, orthotopic liver transplantation was associated with increased hepatic inflammation and increased portal endotoxin levels after surgery, often leading to liver injury and rejection.284 When Bifidobacterium, Lactobacillus, Bacteroides, and Eubacterium were increased and Enterobacteriaceae was reduced, portal LPS levels and Kupffer cell activation decreased, which was beneficial for preventing liver injury found in rats after orthotopic liver transplantation. These findings suggest differential effects of specific bacteria on liver regeneration. Interestingly, PHx caused fluctuating changes in

100

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

the gut microbiome, which paralleled the biological processes of regeneration.285 Besides the direct role of bacteria, microbial enzymes are responsible for the synthesis of various BAs, which play an important role as “hepatostat,” balancing the need for liver regeneration through activation of the FXR receptor (see earlier). In humans, cholic acid (CA) and chenodeoxycholic acid (CDCA) are primary BAs entering the intestinal lumen that undergo deconjugation, dehydroxylation, epimerization, and oxidation using bacterial enzymes. Conjugation increases the aqueous solubility of BAs and renders them largely impermeable to the intestinal epithelium, thus preventing them from exiting the intestinal lumen. The conversion from their primary form to the secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA) is also mediated via bacterial enzyme 7a-dehydroxylase. Therefore the composition of BAs depends on the bacterial composition.286

EXPERIMENTAL STRATEGIES TO PROMOTE LIVER REGENERATION Although there has yet to be developed any reliable intervention to improve liver regeneration in the clinical realm, numerous approaches have been successful in the experimental setting.287 Because fat metabolism has been shown to be of major importance, several experimental strategies have been developed to improve liver regeneration. In a model of high-fat-diet induced steatosis, supplementation of omega-3 fatty acids revealed improvements in I/R injury and regenerative capacity, interestingly in both lean and fat mice.288 In the situation of an SFS fatty liver remnant, the expression of ApoA-1 was decreased in hepatocytes with steatosis and was inversely associated with the concentration of oleic acid. Exogenous ApoA-1 administration effectively attenuated hepatocyte steatosis and promoted liver regeneration at day two after major hepatectomy. Because ApoA-1 treatment increased the expressions of PGC1a and its target genes, ApoA-1 may accelerate regeneration of SFS fatty liver grafts through regulating mitochondrial function.289 This mechanism was supported by another study that supplemented nicotinamide to promote liver regeneration and restore liver function after PHx in mice. Nicotinamide significantly upregulated the NAD–dependent protein deacetylase sirtuin1 (SIRT1), which also targets PGC1a and mitochondrial biogenesis.290 A third study supplementing fish oil during and after PHx in mice showed faster restoration of ALT and total bilirubin levels through AMPK activation.291 Another strategy that may be useful in an SFS situation is blockage of specific receptors or peptides. The blockage of the receptor for advanced glycation end-products (RAGE) showed improved survival in a rat hepatectomy model.292 TGF-b1, a potent growth inhibitory polypeptide, was found to rise after SFS transplantation, forming a heteromeric receptor complex. Phosphorylation of this complex activates Smad2 and Smad3, which leads to regulatory proteins that exert their inhibitory effect on hepatocyte proliferation.293 Inhibiting TGF-b dependent cell cycle arrest may hold future promise.126 Recently, preclinical evidence showed that silencing the Hippo core kinases MST1 and MST2 with small interfering RNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice after PH. This has

therapeutic potential to improve regeneration in nonregenerative disorders.143 Finally, the FXR, as the key mediator of proliferative bile salt signaling, was targeted by the potent obeticholic acid (OCA) in a model of PVE and in partial resection, showing accelerated liver regeneration through induction of intestinal FGF15.294,295 In the situation of cholestasis, however, it exacerbates biliary injury by forced pumping of BAs into an obstructed biliary tree.

CLINICAL IMPLICATIONS When to Stimulate Liver Regeneration Preoperatively? The assessment of hepatic function before resection is difficult (see Chapter 4), but we do know that the risk for perioperative complications increases when the remnant liver volume is too small, particularly in diseased or biliary compromised livers296,297 (see Chapters 101 and 102A). Hepatic function seems to recover quickly after resection but is difficult to measure. Conventional clinical blood tests and liver biopsy do not give the full picture of hepatic function. Child’s classification and MELD scores apply primarily to cirrhotics and can provide a good clinical assessment, but they are only rough estimates of functional reserve. Bilirubin, albumin, international normalized ratio, and platelet count become abnormal only in advanced cirrhosis. Magnetic resonance (MR) imaging or computed tomography (CT) can measure residual liver volume (LV) accurately, but quantitative functional testing is not as precise. Traditional techniques to measure the LV to be resected before hepatectomy can lead to inaccurate estimates of functional residual liver (FRL) volumes because of the presence of dilated bile ducts, multiple tumors, undetected lesions, compromised liver volume caused by cholestasis or previous chemotherapy, cholangitis, vascular obstruction, steatosis or cirrhosis, or segmental atrophy and/or hypertrophy from tumor growth (see Chapter 4). Accurate preoperative assessment by CT or MR volumetry is important because significant interpatient variation exists in hepatic volumes. In LDLT, total liver volume (TLV) and FRL can generally be relied on to predict postresection function because the donor liver is normal. However, the TLV of the recipient’s diseased liver is not a useful index of function. Values calculated from graft weight-to-recipient body weight ratio (GRBWR) or standardized liver volume (SLV) based on recipient BSA are used to predict minimum adequate graft volume.298,299 In segmental graft liver transplantation, a GRBWR greater than 0.8% or a graft weight ratio (graft weight divided by standard liver weight of recipient) greater than 40% have been generally recommended to achieve graft and patient survival greater than 90%253; however, these parameters can be stretched somewhat if the graft is younger and of excellent quality. In comparison, extended resection of 80% of functional parenchyma can be performed in the absence of chronic liver disease for hepatobiliary malignancies.300 Recommended minimal functional remnant LV after extended hepatectomy is greater than 25% in a normal liver and greater than 40% in an “injured” liver, with moderate to severe steatosis, cholestasis, fibrosis, or after chemotherapy.301 Quantitative liver function tests measure the liver’s ability to metabolize or extract test compounds and can identify patients with impaired function at earlier stages of disease but have limited application in predicting a liver’s ability to

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

regenerate after major resection. Indocyanine green clearance (IGC) is regarded as an accurate assessment of functional reserve and can help predict mortality,302 but more is being learned about measuring hepatic function in diseased livers using quantitative functional testing, such as methionine breath tests, cholate clearance, liver single-photon emission CT scans, and liver scintigraphy and phosphorus 31 MR spectroscopy.303 When compared with ICG and CT volumetric data, hepatobiliary scintigraphy is a reproducible accurate tool to assess functional liver uptake and excretion, preoperative liver function reserve, and remnant liver function and allows for monitoring of postoperative liver function regeneration.304 One of the drawbacks of hepatobiliary scintigraphy is that it does not give reliable information about liver function in patients with biliary obstruction, such as cholangiocarcinoma patients. In this case, the maximum liver function capacity (LiMAx) test has been proposed as a breath test for the perioperative assessment of liver function.305 This test is based on the metabolization of 13C-methacetin in the liver acinus by liver-specific enzyme CYP1A2 into acetaminophen and carbon dioxide (13CO2). The latter can then be determined in the exhaled air, and a ratio of 13CO2/12CO2 is built to eventually calculate the maximum liver function capacity. In the last years, several studies have been published regarding the use of the LiMAx test to predict mortality and perioperative liver function.306 Assessment of future remnant volume/function distinguishes those who will most likely benefit from preoperative liver enhancement techniques with PVE and additional hepatic vein embolization.

The Use of Portal Vein Embolization to Promote Regeneration The selective embolization technique increases tolerance to major hepatic resection by reducing the liver volume that requires resection and inducing hypertrophy of the FLR to approximate target limits in patients with large tumors or abnormal liver function (see Chapter 102C). Criteria for selection of patients for PVE before major hepatectomy are FLR size; factors compromising liver function, including previous chemotherapy, hepatitis, and cholestasis; and the planned complexity of the procedure.296,307 It is recommended when predicted FLR is less than 20% to 25% in a normal liver and less than 40% in a liver with compromised function.297,308 Stimulation by PVE increases circulating IL-6 and TNF-a,309,310 with activation of the mitogenic cascade, similar to PHx. In fact, marginal contralateral regeneration of less than 5% after PVE is a strong predictor of liver failure after subsequent liver resection.311 A significant increase in DNA synthesis and mRNA expression of HGF has been observed in the nonembolized or ligated lobe,132 whereas HGF expression is only slightly elevated and negative regulators of hepatocyte proliferation, such as TGF-b and IL-1b, are strongly expressed in the shrinking ligated lobe. It is important to keep in mind that these factors also may promote tumor outgrowth in the FLR, and continuation of chemotherapy during PVE for malignant conditions should be considered.312,313

Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy In 2012 a radical new surgical procedure was introduced to stimulate liver regeneration in patients with a small FLR314

101

(see Chapter 102D). In this two-step approach, the liver parenchyma is transected between segments 2/3 and 4, with concomitant ligation of the right portal vein. Between one week and ten days later, impressive hypertrophy of the left lateral segments has occurred, with a median volume increase of 74% (range 21%–192%)315 and, in a second stage, an extended right hemihepatectomy can be performed. The procedure was initially hampered by high mortality (11%–19%) and high morbidity (up to 40%),316,317 but with increasing experience and better patient selection, better results are gained without perioperative mortality.318 In an experimental model comparing ALPSS with PVL and PHx, the gene expression profile after ALPPS showed a more similar expression pattern to PHx than PVL at the early phase of the regeneration. Early transcriptomic changes and predicted upstream regulators, however, showed many overlapping molecular mechanisms and pathways,319 but unique differences were found in the IGF1R, ILK, and IL-10 pathways, whereas the activity of the interferon pathway was reduced.320 Although ALPPS is a unique technique to boost regeneration in selected patients, many recommend considering alternative approaches, such as adequate portal and hepatic vein embolization, before an all-operative approach is attempted.321,322

Ischemic Preconditioning to Stimulate Regeneration Liver resection, transplantation, and trauma can result in prolonged deprivation of tissue oxygen, converting cellular metabolism to anaerobic pathways. Reperfusion, and consequently the restoration of oxygen delivery, lead to liver injury. This phenomenon is known as I/R injury, which impairs liver regeneration.323 The first clinical attempt to minimize ischemic injury during liver resection was performed by interrupting long ischemic intervals with multiple short periods of reperfusion.324 The protective effect of ischemic preconditioning (IPC) involves many different mechanisms, including inhibition of apoptosis and preservation of cellular ATP content in patients undergoing major liver resection.325,326 A recent cDNA microarray study in humans demonstrated that IPC triggers the overexpression of IL-1Ra, iNOS, and Bcl-2, which counteracts the ischemia-induced proinflammatory and proapoptotic activation.327 IPC has also been described as promoting liver regeneration via the upregulation of cytokines, such as TNF-a, IL-6, and various heat shock proteins (HSPs), and the downregulation of TGF-b.328 IPC by 10 minutes of portal triad inflow occlusion and 10 minutes of reperfusion was shown to be effective both in liver resection, particularly in patients with mild to moderate steatosis,325 and liver transplantation.329,330 There was no difference in protecting potential between intermittent clamping (15 minutes ischemia and five reperfusion) or IPC with subsequent inflow occlusion for a maximum of 75 minutes, except for patients over 65 years of age, who benefited more from intermittent clamping to attenuate liver injury. Pharmacologic induction of HSPs could play a beneficial role in the recovery of liver function after hepatectomy, but clinical trials have not yet been conducted.

Regenerative Potential of the Liver After Chemotherapy As previously discussed, an increasing number of patients with tumors undergo extensive chemotherapy with multiple drugs before surgery (see Chapters 69 and 98). The complication

102

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

rate and mortality after major liver resection is increased in those patients compared with patients who are not receiving these drugs.228,229 The deleterious effect of chemotherapy on regeneration seems to increase with the total number of cycles given and shows a sharp rise after five courses.331 Therefore we advocate no more than six cycles of FOLFOX/FOLFIRI (5-FU, Leukovorin, Oxaliplatin/Irinotecan) containing chemotherapy before liver resection with three weeks in between. The anti-VEGF monoclonal bevacizumab has a long half-life and theoretically should be stopped six to eight weeks before surgery, necessitating close collaboration with the medical oncologist in the timing of surgery. Results from PVE before major liver resection under continuous bevacizumab, however, showed no deterioration in increase in FLR volume four weeks after PVE.238 Recently significantly impaired hypertrophy was reported in the same situation,332 but this may also be attributed to extensive concomitant chemotherapy.333 Thus the optimal window between the completion of bevacizumab and surgery remains uncertain.2

Regeneration and Harnessing Inflammation Liver regeneration involves an intricate play between many factors, especially ECM components and inflammatory chemokines, also involved in liver damage. Continuous enhancement of ECM and inflammatory chemokines (e.g., in cholestasis) negatively regulate liver regeneration.334 Upon tissue injury, danger signals (danger-associated molecular patterns [DAMPs]) are released from necrotic hepatocytes, such as high-motility group box 1 (HMGB-1), HSPs, and DNA fragments, and recognized via TLR receptors in resident macrophages (Kupffer cells). Attracted by the release of chemokines and inflammatory cytokines (TNF-a, IL-1b, and IL-6), neutrophils are the first cells to reach inflamed tissues. Armed with a plethora of enzymes, they invade the liver, facilitated by the lack of the common basal lamina and tight junctions of liver sinusoidal endothelial cells (LSECs), and find easy passage to the Disse space.335 During normal liver regeneration, neutrophils have crucial functions in liver repair by promoting the phenotypic conversion of proinflammatory monocytes/macrophages to proresolving macrophages, involving ROS, granulocyte colony-stimulating factor, and NADPH oxidase 2 (Nox2).336 Balancing the positive and negative effects of the inflammatory reaction is key for the outcome of liver regeneration in inflammatory environments, such as combined I/R injury, cholestasis or postoperative (bacterial) infection in liver resection, and transplantation. The advantages of inflammation in the regenerative process need to be weighed against the disadvantage of uncontrolled inflammation in which friendly inflammatory fire causes more harm than good. The key question is: Which of the known regenerative cytokines or signaling molecules can be harnessed without compromising regeneration? This complex balance becomes clear from evidence that the single perioperative administration of glucocorticoids reduced systemic inflammatory cytokine release (TNF-a and IL-6) and showed benefits in postoperative bilirubin levels and reduced postoperative complications. 337,338 Apparently, the positive effect of steroids to prevent a systemic inflammatory response syndrome (SIRS) outweighed the risk of abolishing the onset of liver regeneration. 339

NEW HORIZONS AND FUTURE PERSPECTIVES Therapeutic Use of Stem Cells In addition to hepatocyte proliferation and hepatic progenitor cells in liver regeneration, bone marrow (BM)–derived cells have the ability to engraft as hepatocytes.340–342 In the discussion of the mechanism whereby the hematopoietic stem cells acquire a hepatocyte phenotype, both fusion of stem cells and hepatocytes343,344 and transdifferentiation of stem cells into hepatocytes have been proven.345,346 Evidence for BM-to-hepatocyte transition has been demonstrated by analyzing liver samples after male-to-female BM transplantation in rodents and humans.347–349 Estimates of repopulation by hematopoietic stem cells vary from 0.01% up to 40% but are often overestimated.350 The highest levels of BM-derived hepatocytes were found in humans with severe liver disease, suggesting that tissue damage may promote engraftment as hepatocytes. The major fraction of mobilized BM stem cells expresses the chemokine receptor CXCR4. At the same time, the mRNA level of its ligand (SDF-1) is increased in the damaged liver tissue. These results provide a clue that CXCR4/SDF-1 interaction may be important for the mobilization of progenitor stem cells from BM to the damaged liver.351 Clinically, the release of adult stem cells from BM was demonstrated after partial liver resection for benign and malignant conditions352,353 and BM-derived stem cells increased the regeneration of contralateral liver after clinical PVE 2.5-fold.354 Additional studies report that mesenchymal stem cells (MSCs) also promote liver repair in cases of liver damage.341 MSCs, isolated from human umbilical cords,355 adipose tissue,356, BM,357 or rat BM358 improved the liver function of rodents undergoing acute liver damage (e.g., carbon tetrachloride injections). The therapeutic effects of MSCs or MSC-derived hepatocytes in liver injury can be explained by three primary mechanisms. First, MSCs generate cells that function as normal hepatocytes after fusing with metabolically defective hepatocytes.343,348,359 The second mechanism is soluble factors secreted by MSCs in response to acute damage. Infusion of human MSC–conditioned medium into rats treated with D-galactosamine (i.e., acute liver damage) improved liver function after 24 hours,360,361 with a 90% decrease in apoptosis and a threefold increase in the number of proliferating hepatocytes. The same was shown after 70% hepatectomy, with upregulated hepatic gene expression of cytokines and growth factors relevant for cell proliferation, angiogenesis, and antiinflammatory responses.362,363 Finally, the paracrine effects of MSCs may be exerted by sharing of shed microvesicles (MVs).364 Intercellular exchange of protein and RNA-containing microparticles is an increasingly important mode of cell–cell communication and MSCs may redirect the behavior of differentiated hepatic cells by horizontal transfer of mRNA shuttled by MVs.365,366 In the context of disease, infusion of (BM) MSC has shown some beneficial effects in patients with liver failure.367 In chronic liver failure, some Phase I trials involving the injection of autologous BM cells to cirrhotic patients have reported modest improvements in clinical scores.368,369 The latest publications in this field indicate that the use of MSCs is safe and has a beneficial effect on liver fibrosis.370–375

  Chapter 6  Liver Regeneration: Mechanisms and Clinical Relevance

Future studies should address the number of cells needed to obtain therapeutic effect and the frequency of administration in liver regeneration after liver surgery or transplantation.

Decellularized Hepatic Matrix and Hepatic Tissue Engineering Because of the shortage of organs for transplant, research on alternate modalities, such as hepatic tissue engineering, has gained momentum. The applications of such engineered organs could be seen not only in the setting of transplantation but also as support for failing liver function after large resections. An innovative advance in this field has been the realization of an important role of ECM in the maintenance of differentiated hepatocyte phenotype. Recently, strategies were developed to derive intact ECM from a liver using a decellularization process (Fig. 6.6). This strategy is based on removal of cells from an organ, leaving a complex mixture of structural and functional proteins that constitute the ECM,376 which is then re-seeded with an appropriate population of cells377,378 and connected to the blood stream and biliary system. Using the whole organ acellular matrix as a three-dimensional scaffold for seeding hepatocyte-like cells, a fully functional transplantable bioengineered liver graft may become a reality. One of the major remaining obstacles toward clinical application is now to choose a cell source for liver repopulation. So far, adult primary hepatocytes have been the primary choice, but scarcity of high-quality human hepatocytes limits tissueengineering applications. With the advent of technologies enabling reprogramming of adult somatic cells to a pluripotent state (induced pluripotent stem cell [iPS]), it may now become possible to generate the large numbers of inducible human hepatocytes (iHeps) needed to recellularize a liver bioscaffold.379–385 There is, however, concern about the plasticity of these cells to form bile ducts, a main

103

hurdle to usefulness in clinically transplantable liver matrix engineering. A solution to this problem may come from recently discovered bipotential liver organoids.36 These cells are positive for Lgr5, the receptor for the Wnt agonist R-spondin. They are able to differentiate into both hepatocytes and cholangiocytes, as precursors of bile ducts, depending on culture media composition. Recently these organoids were shown to be able to activate the regenerative program through the transcriptional regulation of stem-cell genes and regenerative pathways, including the YAP-Hippo signaling pathway.386 The intricate spatiotemporal environment of a decellularized liver matrix, with additional use of nonparenchymal cells of the liver, may provide the ideal niche for functional differentiation of such organoids. This is truly an evolving and timely field with much ongoing research in which knowledge of liver regeneration is crucial, and partnership between clinical scientists and bioengineers is essential.

The Role of miRNA in Liver Regeneration A family of tiny regulatory RNAs, known as microRNAs (miRNAs), was found to have profound roles in the control of diverse aspects of hepatic function and dysfunction, including hepatocyte growth, stress response, metabolism, viral infection and proliferation, gene expression, and maintenance of hepatic phenotype.387,388 miRNAs are small endogenous noncoding RNAs that post-transcriptionally repress the expression of protein-coding genes by base-pairing with the 39 untranslated regions (UTRs) of the target messenger RNAs.389,390 In 2002, miR-122 was identified as an abundant miRNA in the liver391 and characterized as the most frequent miRNA isolated in the adult liver.392 Using distinct protocols to silence miR-122, evidence for the overall importance of miR-122 in the regulation of liver metabolism was found.393,394 Silencing miR-122 in high-fat fed mice resulted in a significant reduction of hepatic steatosis, which was associated with reduced cholesterol synthesis rates and stimulation of hepatic fatty-acid oxidation. The clinical relevance of miRNAs was shown in differences in spontaneous recovery from acute liver failure. Patients with spontaneous recovery from acute liver failure showed significantly higher serum levels of miR-122 and liver tissue levels compared with nonrecovered patients, with strong downregulation of miRNA target genes that impair liver regeneration, including heme oxygenase-1, programmed cell death 4, and the cyclin-dependent kinase inhibitors p21, p27, and p57.395 After partial liver resection, miR-122 and miR-21 are upregulated, but other miRs are downregulated: miR-22a, miR-26a, miR-30b, miR378, Let-7f, and Let-7g. Inhibition of miR33 improves liver regeneration after PHx in mice, indicating that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration.396–399 Also in liver transplantation, distinct patterns of successful and failed regeneration could be discerned, with inhibition of miRNA 150, 663, and 503 being associated with successful regeneration.400

SUMMARY FIGURE 6.6  Decellularized liver scaffold. A pig liver was treated with 4% Triton X-100 and 0.1% NH3 for approximately 16 hours at a low flow rate of 60 mL/min. Vascular structures such as the vena cava retain their strength, whereas the liver extracellular matrix is totally disposed of all cell types.

In the last century, knowledge about liver regeneration has rapidly evolved from a truly mythical black box event into a growing understanding of the pathways involved in this amazingly complex multistep process. Much has been learned

104

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

about the dynamics and redundant intracellular signaling pathways of liver regeneration, but less is still known about the exact signals that initiate and stop liver regeneration. Our advanced knowledge on liver regeneration and prevention of liver failure have led to safer extreme liver resections for benign and malignant diseases and the use of living liver donors in liver transplantation. Despite our better understanding, there has been little structured advance in therapeutic options in cases of liver failure caused by insufficient liver regeneration. New challenges lie

ahead in the use of therapeutic strategies to enhance liver regeneration in patients in whom normal regeneration fails. This will push the possibilities of liver resection to the next level. Furthermore, while promoting liver cell proliferation, we must be very cautious not to stimulate tumor growth in patients with primary or metastatic liver tumors as a consequence of our therapy. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

104.e1

REFERENCES 1. Marcos A, Fisher RA, Ham JM, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation. 2000;69(7):1375-1379. 2. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356(15):1545-1559. 3. Chen X, Zhai J, Cai X, et al. Severity of portal hypertension and prediction of postoperative liver failure after liver resection in patients with Child-Pugh grade A cirrhosis. Br J Surg. 2012;99(12): 1701-1710. 4. Boleslawski E, Petrovai G, Truant S, et al. Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis. Br J Surg. 2012;99(6):855-863. 5. Zhong JH, Li H, Xiao N, et al. Hepatic resection is safe and effective for patients with hepatocellular carcinoma and portal hypertension. PLoS One. 2014;9(9):e108755. 6. Abu-Gazala S, Olthoff KM. Current status of living donor liver transplantation in the United States. Annu Rev Med. 2018;70:225-238. 7. Higgins GM, Anderson RM. Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol. 1931;12:186-202. 8. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis. 2002;22(2):137-144. 9. Reynolds ES. Liver parenchymal cell injury. I. Initial alterations of the cell following poisoning with carbon tetrachloride. J Cell Biol. 1963;19:139-157. 10. Dabeva MD, Shafritz DA. Activation, proliferation, and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol. 1993;143(6):1606-1620. 11. Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol. 1984;65(3):305-311. 12. Bilodeau M, Aubry MC, Houle R, Burnes PN, Ethier C. Evaluation of hepatocyte injury following partial ligation of the left portal vein. J Hepatol. 1999;30(1):29-37. 13. Jaeschke H. Mechanisms of reperfusion injury after warm ischemia of the liver. J Hepatobiliary Pancreat Surg. 1998;5(4):402-408. 14. Heckel JL, Sandgren EP, Degen JL, Palmiter RD, Brinster RL. Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell. 1990;62(3):447-456. 15. Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol. 2007; 25(8):903-910. 16. Strom SC, Davila J, Grompe M. Chimeric mice with humanized liver: tools for the study of drug metabolism, excretion, and toxicity. Methods Mol Biol. 2010;640:491-509. 17. Kan NG, Junghans D, Izpisua Belmonte JC. Compensatory growth mechanisms regulated by BMP and FGF signaling mediate liver regeneration in zebrafish after partial hepatectomy. FASEB J. 2009;23(10):3516-3525. 18. Debonera F, Aldeguer X, Shen X, et al. Activation of interleukin-6/ STAT3 and liver regeneration following transplantation. J Surg Res. 2001;96(2):289-295. 19. Stanger BZ. Cellular homeostasis and repair in the mammalian liver. Annu Rev Physiol. 2015;77:179-200. 20. Lemaigre FP. Determining the fate of hepatic cells by lineage tracing: facts and pitfalls. Hepatology. 2015;61(6):2100-2103. 21. Bucher NLR, Swaffield MN. The rate of incorporation of labeled thymidine into the deoxyribonucleic acid of regenerating rat liver in relation to the amount of liver excised. Cancer Res. 1964;24: 1611-1625. 22. Furchtgott LA, Chow CC, Periwal V. A model of liver regeneration. Biophys J. 2009;96(10):3926-3935. 23. Olthoff KM, Emond JC, Shearon TH, et al. Liver regeneration after living donor transplantation: adult-to-adult living donor liver transplantation cohort study. Liver Transpl. 2015;21(1):79-88. 24. Everson GT, Hoefs JC, Niemann CU, et al. Functional elements associated with hepatic regeneration in living donors after right hepatic lobectomy. Liver Transpl. 2013;19(3):292-304. 25. Emond JC, Fisher RA, Everson G, et al. Changes in liver and spleen volumes after living liver donation: a report from the adultto-adult living donor liver transplantation cohort study (A2ALL). Liver Transpl. 2015;21(2):151-161.

26. Stocker E, Heine WD. Regeneration of liver parenchyma under normal and pathological conditions. Beitr Pathol. 1971;144(4): 400-408. 27. Rhim JA, Sandgren EP, Degen JL, Palmiter RD, Brinster RL. Replacement of diseased mouse liver by hepatic cell transplantation. Science. 1994;263(5150):1149-1152. 28. Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev. 2003;120(1):117-130. 29. Schaub JR, Malato Y, Gormond C, Willenbring H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep. 2014;8(4):933-939. 30. Yanger K, Knigin D, Zong Y, et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell. 2014;15(3):340-349. 31. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol. 1998;29(3):455-463. 32. Rodrigo-Torres D, Affo S, Coll M, et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology. 2014;60(4):1367-1377. 33. Carpentier R, Suner RE, van Hul N, et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterol. 2011;141(4):1432-1438. 34. Carpino G, Cardinale V, Onori P, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat. 2011;220(2):186-199. 35. Kofman AV, Morgan G, Kirschenbaum A, et al. Dose- and timedependent oval cell reaction in acetaminophen-induced murine liver injury. Hepatology. 2005;41(6):1252-1261. 36. Huch M, Gehart H, van Boxtel R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160(1-2):299-312. 37. Ang CH, Hsu SH, Guo F, et al. Lgr5(1) pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis. Proc Natl Acad Sci USA. 2019;116(39): 19530-19540. 38. Tsai JM, Koh PW, Stefanska A, et al. Localized hepatic lobular regeneration by central-vein-associated lineage-restricted progenitors. Proc Natl Acad Sci U S A. 2017;114(14):3654-3659. 39. Lin S, Nascimento EM, Gajera CR, et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature. 2018;556(7700):244-248. 40. Cao W, Chen K, Bolkestein M, et al. Dynamics of proliferative and quiescent stem cells in liver homeostasis and injury. Gastroenterology. 2017;153(4):1133-1147. 41. Alwahsh SM, Rashidi H, Hay DC. Liver cell therapy: is this the end of the beginning? Cell Mol Life Sci. 2017;75(8):1307-1324. 42. Alison MR. The many ways to mend your liver: a critical appraisal. Int J Exp Pathol. 2018;99(3):106-112. 43. Gilgenkrantz H, Collin de l’Hortet A. Understanding liver regeneration: from mechanisms to regenerative medicine. Am J Pathol. 2018;188(6):1316-1327. 44. Mohn KL, Laz TM, Melby AE, Taub R. Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. J Biol Chem. 1990;265(35):21914-21921. 45. Haber BA, Mohn KL, Diamond RH, Taub R. Induction patterns of 70 genes during nine days after hepatectomy define the temporal course of liver regeneration. J Clin Invest. 1993;91(4):1319-1326. 46. Thompson NL, Mead JE, Braun L, Goyette M, Shank PR, Fausto N. Sequential protooncogene expression during rat liver regeneration. Cancer Res. 1986;46(6):3111-3117. 47. Morello D, Fitzgerald MJ, Babinet C, Fausto N. c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2K/cmyc transgenic mice. Mol Cell Biol. 1990;10(6):3185-3193. 48. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836-847. 49. Cressman DE, Diamond RH, Taub R. Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology. 1995;21(5): 1443-1449. 50. FitzGerald MJ, Webber EM, Donovan JR, Fausto N. Rapid DNA binding by nuclear factor kappa B in hepatocytes at the start of liver regeneration. Cell Growth Differ. 1995;6(4):417-427.

104.e2 51. Starzl TE, Porter KA, Francavilla JA, Benichou J, Putnam CW. A hundred years of the hepatotrophic controversy. Ciba Found Symp. 1977(55):111-129. 52. Hessheimer AJ, Fondevila C, Taura P, et al. Decompression of the portal bed and twice-baseline portal inflow are necessary for the functional recovery of a “small-for-size” graft. Ann Surg. 2011;253(6): 1201-1210. 53. Moolten FL, Bucher NL. Regeneration of rat liver: transfer of humoral agent by cross circulation. Science. 1967;158(798):272-274. 54. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6- deficient mice. Science. 1996;274(5291):1379-1383. 55. Yamada Y, Kirillova I, Fausto N, Peschon JJ. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997;94(4):1441-1446. 56. Streetz KL, Luedde T, Manns MP, Trautwein C. Interleukin 6 and liver regeneration. Gut. 2000;47(2):309-312. 57. Michalopoulos G, Houck KA, Dolan ML, Leutteke NC. Control of hepatocyte replication by two serum factors. Cancer Res. 1984; 44(10):4414-4419. 58. Fujita J, Marino MW, Wada H, et al. Effect of TNF gene depletion on liver regeneration after partial hepatectomy in mice. Surgery. 2001;129(1):48-54. 59. Fausto N. Liver regeneration. J Hepatol. 2000;32(suppl 1):19-31. 60. Webber EM, Fausto N, Godowski PJ. In vivo response of hepatocytes to growth factors requires an initial priming stimulus. Hepatology. 1994;19(2):489-497. 61. Aldeguer X, Debonera F, Shaked A, et al. Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration. Hepatology. 2002;35(1):40-48. 62. Taub R. Hepatoprotection via the IL-6/Stat3 pathway. J Clin Invest. 2003;112(7):978-980. 63. Zimmers TA, McKillop IH, Pierce RH, Yoo JY, Koniaris LG. Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology. 2003;38(2):326-334. 64. Wuestefeld T, Klein C, Streetz KL, et al. Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration. J Biol Chem. 2003;278(13):11281-11288. 65. Arai M, Yokosuka O, Chiba T, et al. Gene expression profiling reveals the mechanism and pathophysiology of mouse liver regeneration. J Biol Chem. 2003;278(32):29813-29818. 66. Fukuhara Y, Hirasawa A, Li XK, et al. Gene expression profile in the regenerating rat liver after partial hepatectomy. J Hepatol. 2003;38(6):784-792. 67. Togo S, Makino H, Kobayashi T, et al. Mechanism of liver regeneration after partial hepatectomy using mouse cDNA microarray. J Hepatol. 2004;40(3):464-471. 68. Morita T, Morita T, Togo S, et al. Mechanism of postoperative liver failure after excessive hepatectomy investigated using a cDNA microarray. J Hepatobiliary Pancreat Surg. 2002;9(3):352-359. 69. Cornell RP, Liljequist BL, Bartizal KF. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice. Hepatology. 1990;11(6):916-922. 70. Strey CW, Markiewski M, Mastellos D, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198(6):913-923. 71. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 2004;101(13):4477-4482. 72. Monga SP. Role of Wnt/beta-catenin signaling in liver metabolism and cancer. Int J Biochem Cell Biol. 2011;43(7):1021-1029. 73. Monga SP, Mars WM, Pediaditakis P, et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002;62(7):2064-2071. 74. Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276(5309):60-66. 75. LeCouter J, Moritz DR, Li B, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science. 2003;299(5608):890-893. 76. Currier AR, Sabla G, Locaputo S, Melin-Aldana H, Degen JL, Bezerra JA. Plasminogen directs the pleiotropic effects of uPA in liver injury and repair. Am J Physiol Gastrointest Liver Physiol. 2003;284(3):G508-G515.

77. Tackett BC, Sun H, Mei Y, et al. P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. Am J Physiol Gastrointest Liver Physiol. 2014; 307(11):G1073-G1087. 78. Alexandrino H, Rolo A, Teodoro JS, et al. Bioenergetic adaptations of the human liver in the ALPPS procedure - how liver regeneration correlates with mitochondrial energy status. HPB (Oxford). 2017;19(12):1091-1103. 79. da Silva CG, Cervantes JR, Studer P, Ferran C. A20—an omnipotent protein in the liver: prometheus myth resolved? Adv Exp Med Biol. 2014;809:117-139. 80. Longo CR, Patel VI, Shrikhande GV, et al. A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism. Hepatology. 2005;42(1): 156-164. 81. da Silva CG, Studer P, Skroch M, et al. A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology. 2013;57(5):2014-2025. 82. Damrauer SM, Studer P, da Silva CG, et al. A20 modulates lipid metabolism and energy production to promote liver regeneration. PLoS One. 2011;6(3):e17715. 83. Rai RM, Lee FY, Rosen A, et al. Impaired liver regeneration in inducible nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA. 1998;95(23):13829-13834. 84. Man K, Lo CM, Lee TK, Li XL, Ng IO, Fan ST. Intragraft gene expression profiles by cDNA microarray in small-for-size liver grafts. Liver Transpl. 2003;9(4):425-432. 85. de Jonge J, Kurian S, Shaked A, et al. Unique early gene expression patterns in human adult-to-adult living donor liver grafts compared to deceased donor grafts. Am J Transplant. 2009;9(4): 758-772. 86. Kurian SM, Fouraschen SM, Langfelder P, et al. Genomic profiles and predictors of early allograft dysfunction after human liver transplantation. Am J Transplant. 2015;15(6):1605-1614. 87. Drixler TA, Vogten MJ, Ritchie ED, et al. Liver regeneration is an angiogenesis-associated phenomenon. Ann Surg. 2002;236(6):703711; discussion 711-712. 88. Vogten JM, Drixler TA, te Velde EA, et al. Angiostatin inhibits experimental liver fibrosis in mice. Int J Colorectal Dis. 2004;19(4): 387-394. 89. Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix Biol. 2015;44-46:147-156. 90. Kato H, Kuriyama N, Duarte S, Clavien PA, Busuttil RW, Coito AJ. MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury. J Hepatol. 2014;60(5):1032-1039. 91. Kim TH, Bowen WC, Stolz DB, Runge D, Mars WM, Michalopoulos GK. Differential expression and distribution of focal adhesion and cell adhesion molecules in rat hepatocyte differentiation. Exp Cell Res. 1998;244(1):93-104. 92. Planas-Paz L, Orsini V, Boulter L, et al. The RSPO-LGR4/5ZNRF3/RNF43 module controls liver zonation and size. Nat Cell Biol. 2016;18(5):467-479. 93. Song Z, Gupta K, Ng IC, Xing J, Yang YA, Yu H. Mechanosensing in liver regeneration. Semin Cell Dev Biol. 2017;71:153-167. 94. Bomo J, Ezan F, Tiaho F, et al. Increasing 3D matrix rigidity strengthens proliferation and spheroid development of human liver cells in a constant growth factor environment. J Cell Biochem. 2016;117(3):708-720. 95. Hansen LK, Wilhelm J, Fassett JT. Regulation of hepatocyte cell cycle progression and differentiation by type I collagen structure. Curr Top Dev Biol. 2006;72:205-236. 96. Godoy P, Hengstler JG, Ilkavets I, et al. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis. Hepatology. 2009;49(6):2031-2043. 97. Cordero-Espinoza L, Huch M. The balancing act of the liver: tissue regeneration versus fibrosis. J Clin Invest. 2018;128(1):85-96. 98. Konishi T, Schuster RM, Lentsch AB. Liver repair and regeneration after ischemia-reperfusion injury is associated with prolonged fibrosis. Am J Physiol Gastrointest Liver Physiol. 2018;316(3): G323-G331. 99. Haber BA, Chin S, Chuang E, Buikhuisen W, Naji A, Taub R. High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. J Clin Invest. 1995;95(2):832-841.

104.e3 100. Rosa JL, Bartrons R, Tauler A. Gene expression of regulatory enzymes of glycolysis/gluconeogenesis in regenerating rat liver. Biochem J. 1992;287 (Pt 1):113-116. 101. Diamond RH, Du K, Lee VM, et al. Novel delayed-early and highly insulin-induced growth response genes. Identification of HRS, a potential regulator of alternative pre-mRNA splicing. J Biol Chem. 1993;268(20):15185-15192. 102. Starzl TE, Porter KA, Kashiwagi N. Portal hepatotrophic factors, diabetes mellitus and acute liver atrophy, hypertrophy, and regeneration. Surg Gynecol Obstet. 1975;141(6):843-858. 103. Mischoulon D, Rana B, Bucher NL, Farmer SR. Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture. Mol Cell Biol. 1992;12(6):2553-2560. 104. Costa RH, Kalinichenko VV, Holterman AX, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38(6):1331-1347. 105. Shteyer E, Liao Y, Muglia LJ, Hruz PW, Rudnick DA. Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology. 2004;40(6):1322-1332. 106. Rui L. Energy metabolism in the liver. Compr Physiol. 2014; 4(1):177-197. 107. Kachaylo E, Tschuor C, Calo N, et al. PTEN down-regulation promotes beta-oxidation to fuel hypertrophic liver growth after hepatectomy in mice. Hepatology. 2017;66(3):908-921. 108. Ronco MT, deAlvarez ML, Monti J, et al. Modulation of balance between apoptosis and proliferation by lipid peroxidation (LPO) during rat liver regeneration. Mol Med. 2002;8(12):808-817. 109. Anderson SP, Yoon L, Richard EB, Dunn CS, Cattley RC, Corton JC. Delayed liver regeneration in peroxisome proliferator-activated receptor-alpha-null mice. Hepatology. 2002;36(3):544-554. 110. Xie G, Yin S, Zhang Z, et al. Hepatocyte peroxisome proliferatoractivated receptor alpha enhances liver regeneration after partial hepatectomy in mice. Am J Pathol. 2018;189(2):272-282. 111. Budai A, Horvath G, Tretter L, et al. Mitochondrial function after associating liver partition and portal vein ligation for staged hepatectomy in an experimental model. Br J Surg. 2019;106(1): 120-131. 112. Han LH, Dong LY, Yu H, et al. Deceleration of liver regeneration by knockdown of augmenter of liver regeneration gene is associated with impairment of mitochondrial DNA synthesis in mice. Am J Physiol Gastrointest Liver Physiol. 2015;309(2):G112-G122. 113. Leu JI, Crissey MA, Leu JP, Ciliberto G, Taub R. Interleukin-6induced STAT3 and AP-1 amplify hepatocyte nuclear factor 1-mediated transactivation of hepatic genes, an adaptive response to liver injury. Mol Cell Biol. 2001;21(2):414-424. 114. Ruderman NB, Xu XJ, Nelson L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010;298(4):E751-E760. 115. Garcia-Rodriguez JL, Barbier-Torres L, Fernandez-Alvarez S, et al. SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. Hepatology. 2014;59(5):1972-1983. 116. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40(2):310-322. 117. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312(5771):233-236. 118. Alvarez-Sola G, Uriarte I, Latasa MU, et al. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017;66(10):1818-1828. 119. Alvarez-Sola G, Uriarte I, Latasa MU, et al. Bile acids, FGF15/19 and liver regeneration: from mechanisms to clinical applications. Biochim Biophys Acta Mol Basis Dis. 2017;1864(4 Pt B): 1326-1334. 120. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958): 577-584. 121. Macías-Silva M, Li W, Leu JI, Crissey MAS, Taub R. Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration. J Biol Chem. 2002;277(32):28483-28490. 122. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg. 2003;197(4):634-659.

123. Yuan B, Dong R, Shi D, et al. Down-regulation of miR-23b may contribute to activation of the TGF-beta1/Smad3 signalling pathway during the termination stage of liver regeneration. FEBS Lett. 2011;585(6):927-934. 124. Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-beta receptormediated signalling through Smad2, Smad3, and Smad4. EMBO J. 1997;16(17):5353-5362. 125. Koli K, Myllarniemi M, Keski-Oja J, Kinnula VL. Transforming growth factor-beta activation in the lung: focus on fibrosis and reactive oxygen species. Antioxid Redox Signal. 2008;10(2): 333-342. 126. Zhong Z, Tsukada S, Parsons CJ, et al. Inhibition of TGF-b/ Smad signaling improves regeneration of small-for-size rat liver grafts. Liver Transpl. 2010;16(2):181-190. 127. Date M, Matsuzaki K, Matsushita M, Tahashi Y, Sakitani K, Inoue K. Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injury. J Hepatol. 2000; 32(2):251-260. 128. Takamura K, Tsuchida K, Miyake H, Tashiro S, Sugino H. Possible endocrine control by follistatin 315 during liver regeneration based on changes in the activin receptor after a partial hepatectomy in rats. Hepatogastroenterology. 2005;52(61):60-66. 129. Takamura K, Tsuchida K, Miyake H, Tashiro S, Sugino H. Activin and activin receptor expression changes in liver regeneration in rat. J Surg Res. 2005;126(1):3-11. 130. Liu M, Chen P. Proliferation-inhibiting pathways in liver regeneration (Review). Mol Med Rep. 2017;16(1):23-35. 131. Boulton R, Woodman A, Calnan D, Selden C, Tam F, Hodgson H. Nonparenchymal cells from regenerating rat liver generate interleukin-1alpha and -1beta: a mechanism of negative regulation of hepatocyte proliferation. Hepatology. 1997;26(1):49-58. 132. Uemura T, Miyazaki M, Hirai R, et al. Different expression of positive and negative regulators of hepatocyte growth in growing and shrinking hepatic lobes after portal vein branch ligation in rats. Int J Mol Med. 2000;5(2):173-179. 133. Tsutsumi R, Kamohara Y, Eguchi S, et al. Selective suppression of initial cytokine response facilitates liver regeneration after extensive hepatectomy in rats. Hepatogastroenterology. 2004;51(57): 701-704. 134. Goss JA, Mangino MJ, Callery MP, Flye MW. Prostaglandin E2 downregulates Kupffer cell production of IL-1 and IL-6 during hepatic regeneration. Am J Physiol. 1993;264(4 Pt 1):G601-G608. 135. Sgroi A, Gonelle-Gispert C, Morel P, et al. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice. PLoS One. 2011;6(9):e25442. 136. Franco-Gou R, Rosello-Catafau J, Casillas-Ramirez A, et al. How ischaemic preconditioning protects small liver grafts. J Pathol. 2006;208(1):62-73. 137. Zhao Y, Meng C, Wang Y, et al. IL-1beta inhibits beta-Klotho expression and FGF19 signaling in hepatocytes. Am J Physiol Endocrinol Metab. 2016;310(4):E289-E300. 138. Campbell JS, Prichard L, Schaper F, et al. Expression of suppressors of cytokine signaling during liver regeneration. J Clin Invest. 2001;107(10):1285-1292. 139. Jin J, Hong IH, Lewis K, et al. Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration. Hepatology. 2015;61(1):315-325. 140. Dong J, Feldmann G, Huang J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120-1133. 141. Miyamura N, Nishina H. YAP regulates liver size and function. Cell Cycle. 2017;17(3):267-268. 142. Grijalva JL, Huizenga M, Mueller K, et al. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2014;307(2): G196-G204. 143. Loforese G, Malinka T, Keogh A, et al. Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO Mol Med. 2016;9(1):46-60. 144. Plouffe SW, Hong AW, Guan KL. Disease implications of the Hippo/YAP pathway. Trends Mol Med. 2015;21(4):212-222. 145. Wu H, Wei L, Fan F, et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun. 2015;6:6239. 146. Zheng T, Wang J, Jiang H, Liu L. Hippo signaling in oval cells and hepatocarcinogenesis. Cancer Lett. 2011;302(2):91-99.

104.e4 147. Konishi T, Schuster RM, Lentsch AB. Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2018;314(4):G471-G482. 148. Gock M, Eipel C, Linnebacher M, Klar E, Vollmar B. Impact of portal branch ligation on tissue regeneration, microcirculatory response and microarchitecture in portal blood-deprived and undeprived liver tissue. Microvasc Res. 2011;81(3):274-280. 149. Wei W, Hua C, Zhang T, et al. Size of portally deprived liver lobe after portal vein ligation and additional partial hepatectomy: result of balancing proliferation and apoptosis. Sci Rep. 2020;10(1):4893. 150. Nishimura Y, Romer LH, Lemasters JJ. Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine. Hepatology. 1998;27(4):1039-1049. 151. Kohli V, Selzner M, Madden JF, Bentley RC, Clavien PA. Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia-reperfusion injury in the rat liver. Transplantation. 1999; 67(8):1099-1105. 152. Picard C, Starkel P, Sempoux C, Saliez A, Lebrun V, Horsmans Y. Molecular mechanisms of apoptosis in the liver of rats after portal branch ligation with and without retrorsine. Lab Invest. 2004;84(5):618-628. 153. Wei W, Zhang T, Fang H, et al. Intrahepatic size regulation in a surgical model: liver resection-induced liver regeneration counteracts the local atrophy following simultaneous portal vein ligation. Eur Surg Res. 2016;57(1-2):125-137. 154. Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ. Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology. 2002;123(4): 1323-1330. 155. Gujral JS, Liu J, Farhood A, Jaeschke H. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation. Hepatology. 2004;40(4):998-1007. 156. Miyoshi H, Rust C, Roberts PJ, Burgart LJ, Gores GJ. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. Gastroenterology. 1999;117(3):669-677. 157. Fickert P, Trauner M, Fuchsbichler A, et al. Oncosis represents the main type of cell death in mouse models of cholestasis. J Hepatol. 2005;42(3):378-385. 158. Elnaggar AS, Griesemer AD, Bentley-Hibbert S, et al. Liver atrophy and regeneration in noncirrhotic portal vein thrombosis: effect of surgical shunts. Liver Transpl. 2018;24(7):881-887. 159. Hadjis NS, Blumgart LH. Role of liver atrophy, hepatic resection and hepatocyte hyperplasia in the development of portal hypertension in biliary disease. Gut. 1987;28(8):1022-1028. 160. Pottakkat B, Vijayahari R, Prasad KV, et al. Surgical management of patients with post-cholecystectomy benign biliary stricture complicated by atrophy-hypertrophy complex of the liver. HPB (Oxford). 2009;11(2):125-129. 161. Vouche M, Lewandowski RJ, Atassi R, et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013; 59(5):1029-1036. 162. Garlipp B, de Baere T, Damm R, et al. Left-liver hypertrophy after therapeutic right-liver radioembolization is substantial but less than after portal vein embolization. Hepatology. 2014;59(5):1864-1873. 163. Burroughs AK, Sabin CA, Rolles K, et al. 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome. Lancet. 2006;367(9506):225-232. 164. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006;6(4):783-790. 165. Taguchi T, Fukuda M, Ohashi M. Differences in DNA synthesis in vitro using isolated nuclei from regenerating livers of young and aged rats. Mech Ageing Dev. 2001;122(2):141-155. 166. He S, Sharpless NE. Senescence in health and disease. Cell. 2017;169(6):1000-1011. 167. Ledda-Columbano GM, Pibiri M, Cossu C, Molotzu F, Locker J, Columbano A. Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP. Hepatology. 2004;40(4):981-988. 168. Iakova P, Awad SS, Timchenko NA. Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell. 2003;113(4):495-506.

169. Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab. 2009;20(4):171-176. 170. Huda N, Liu G, Hong H, Yan S, Khambu B, Yin XM. Hepatic senescence, the good and the bad. World J Gastroenterol. 2019;25(34):5069-5081. 171. Bird TG, Muller M, Boulter L, et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med. 2018;10(454):eaan1230. 172. Wang X, Kiyokawa H, Dennewitz MB, Costa RH. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc Natl Acad Sci U S A. 2002;99(26):16881-16886. 173. Krupczak-Hollis K, Wang X, Dennewitz MB, Costa RH. Growth hormone stimulates proliferation of old-aged regenerating liver through forkhead box m1b. Hepatology. 2003;38(6):1552-1562. 174. Jin J, Wang GL, Shi X, Darlington GJ, Timchenko NA. The ageassociated decline of glycogen synthase kinase 3beta plays a critical role in the inhibition of liver regeneration. Mol Cell Biol. 2009;29(14):3867-3880. 175. Tracy Jr TF, Bailey PV, Goerke ME, Sotelo-Avila C, Weber TR. Cholestasis without cirrhosis alters regulatory liver gene expression and inhibits hepatic regeneration. Surgery. 1991;110(2):176182; discussion 182-183. 176. Nakano K, Chijiiwa K, Tanaka M. Lower activity of CCAAT/enhancer-binding protein and expression of cyclin E, but not cyclin D1, activating protein-1 and p21(WAF1), after partial hepatectomy in obstructive jaundice. Biochem Biophys Res Commun. 2001;280(3):640-645. 177. Hu RH, Lee PH, Yu SC, Ho MC. Profile of hepatocyte growth factor in patients with obstructive jaundice. Hepatogastroenterology. 2003;50(54):1987-1990. 178. Bissig KD, Marti U, Solioz M, et al. Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy. J Hepatol. 2000;33(2):275-281. 179. Fujiwara Y, Shimada M, Yamashita Y, et al. Cytokine characteristics of jaundice in mouse liver. Cytokine. 2001;13(3):188-191. 180. Suzuki H, Iyomasa S, Nimura Y, Yoshida S. Internal biliary drainage, unlike external drainage, does not suppress the regeneration of cholestatic rat liver after partial hepatectomy. Hepatology. 1994;20(5):1318-1322. 181. Saiki S, Chijiiwa K, Komura M, Yamaguchi K, Kuroki S, Tanaka M. Preoperative internal biliary drainage is superior to external biliary drainage in liver regeneration and function after hepatectomy in obstructive jaundiced rats. Ann Surg. 1999;230(5): 655-662. 182. Ding L, Yang Y, Qu Y, et al. Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats. Mol Med Rep. 2015;11(6):4431-4437. 183. Demori I, Balocco S, Voci A, Fugassa E. Increased insulin-like growth factor binding protein-4 expression after partial hepatectomy in the rat. Am J Physiol Gastrointest Liver Physiol. 2000; 278(3):G384-G389. 184. Ghahary A, Minuk GY, Luo J, Gauthier T, Murphy LJ. Effects of partial hepatectomy on hepatic insulinlike growth factor binding protein-1 expression. Hepatology. 1992;15(6):1125-1131. 185. Yamada T, Yamamoto M, Ozawa K, Honjo I. Insulin requirements for hepatic regeneration following hepatectomy. Ann Surg. 1977;185(1):35-42. 186. Matsumoto T, Yamaguchi M, Kuzume M, Matsumiya A, Kumada K. Insulin gene transfer with adenovirus vector via the spleen safely and effectively improves posthepatectomized conditions in diabetic rats. J Surg Res. 2003;110(1):228-234. 187. Imamura H, Shimada R, Kubota M, et al. Preoperative portal vein embolization: an audit of 84 patients. Hepatology. 1999; 29(4):1099-1105. 188. Yokoyama Y, Nagino M, Nimura Y. Mechanisms of hepatic regeneration following portal vein embolization and partial hepatectomy: a review. World J Surg. 2007;31(2):367-374. 189. Mann DV, Lam WW, Hjelm NM, et al. Metabolic control patterns in acute phase and regenerating human liver determined in vivo by 31-phosphorus magnetic resonance spectroscopy. Ann Surg. 2002;235(3):408-416. 190. Holecek M. Nutritional modulation of liver regeneration by carbohydrates, lipids, and amino acids: a review. Nutrition. 1999; 15(10):784-788.

104.e5 191. Cornide-Petronio ME, Alvarez-Mercado AI, Jimenez-Castro MB, Peralta C. Current knowledge about the effect of nutritional status, supplemented nutrition diet, and gut microbiota on hepatic ischemia-reperfusion and regeneration in liver surgery. Nutrients. 2020;12(2):284. 192. Skullman S, Ihse I, Larsson J. Influence of malnutrition on regeneration and composition of the liver in rats. Acta Chir Scand. 1990;156(10):717-722. 193. Delany HM, John J, Teh EL, et al. Contrasting effects of identical nutrients given parenterally or enterally after 70% hepatectomy. Am J Surg. 1994;167(1):135-143; discussion 143-144. 194. Yoshida R, Yagi T, Sadamori H, et al. Branched-chain amino acidenriched nutrients improve nutritional and metabolic abnormalities in the early post-transplant period after living donor liver transplantation. J Hepatobiliary Pancreat Sci. 2012;19(4):438-448. 195. Ito A, Higashiguchi T. Effects of glutamine administration on liver regeneration following hepatectomy. Nutrition. 1999;15(1): 23-28. 196. Weymann A, Hartman E, Gazit V, et al. p21 is required for dextrose-mediated inhibition of mouse liver regeneration. Hepatology. 2009;50(1):207-215. 197. Nishizaki T, Takenaka K, Yanaga K, et al. Nutritional support after hepatic resection: a randomized prospective study. Hepatogastroenterology. 1996;43(9):608-613. 198. Miyauchi T, Uchida Y, Kadono K, et al. Up-regulation of FOXO1 and reduced inflammation by beta-hydroxybutyric acid are essential diet restriction benefits against liver injury. Proc Natl Acad Sci U S A. 2019;116(27):13533-13542. 199. Repa JJ, Lund EG, Horton JD, et al. Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding. J Biol Chem. 2000;275(50):39685-39692. 200. Francavilla A, Gavaler JS, Makowka L, et al. Estradiol and testosterone levels in patients undergoing partial hepatectomy. A possible signal for hepatic regeneration? Dig Dis Sci. 1989;34(6): 818-822. 201. Francavilla A, Polimeno L, DiLeo A, et al. The effect of estrogen and tamoxifen on hepatocyte proliferation in vivo and in vitro. Hepatology. 1989;9(4):614-620. 202. Yokoyama Y, Nagino M, Nimura Y. Which gender is better positioned in the process of liver surgery? Male or female? Surg Today. 2007;37(10):823-830. 203. Kao TL, Chen YL, Kuan YP, et al. Estrogen-estrogen receptor alpha signaling facilitates bilirubin metabolism in regenerating liver through regulating cytochrome P450 2A6 expression. Cell Transplant. 2018;26(11):1822-1829. 204. Sutti S, Tacke F. Liver inflammation and regeneration in druginduced liver injury: sex matters! Clin Sci (Lond). 2018;132(5): 609-613. 205. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018; 67(1):123-133. 206. Della Fazia MA, Servillo G. Foie gras and liver regeneration: a fat dilemma. Cell Stress. 2018;2(7):162-175. 207. Selzner M, Rudiger HA, Sindram D, Madden J, Clavien PA. Mechanisms of ischemic injury are different in the steatotic and normal rat liver. Hepatology. 2000;32(6):1280-1288. 208. Yang SQ, Lin HZ, Mandal AK, Huang J, Diehl AM. Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology. Hepatology. 2001;34(4 Pt 1):694-706. 209. Farrell G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med. 1999;20(1-2):55-70, 137. 210. Kurumiya Y, Nozawa K, Sakaguchi K, Nagino M, Nimura Y, Yoshida S. Differential suppression of liver-specific genes in regenerating rat liver induced by extended hepatectomy. J Hepatol. 2000;32(4):636-644. 211. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37(5):1202-1219. 212. Behrns KE, Tsiotos GG, Nagorney DM, DeSouza NF, Krishna MK, Ludwig J. Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg. 1998;2(3):292-298. 213. Vetelainen R, van Vliet A, Gouma DJ, van Gulik TM. Steatosis as a risk factor in liver surgery. Ann Surg. 2007;245(1):20-30.

214. de Meijer VE, Kalish BT, Puder M, Ijzermans JN. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;97(9):1331-1339. 215. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7(8):1034-1044. 216. Amini N, Margonis GA, Buttner S, et al. Liver regeneration after major liver hepatectomy: impact of body mass index. Surgery. 2016;160(1):81-91. 217. De A, Duseja A. Natural History of simple steatosis or nonalcoholic fatty liver. J Clin Exp Hepatol. 2020;10(3):255-262. 218. Tralhao JG, Roudier J, Morosan S, et al. Paracrine in vivo inhibitory effects of hepatitis B virus X protein (HBx) on liver cell proliferation: an alternative mechanism of HBx-related pathogenesis. Proc Natl Acad Sci U S A. 2002;99(10):6991-6996. 219. Marshall A, Rushbrook S, Davies SE, et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology. 2005; 128(1):33-42. 220. Sun R, Gao B. Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). Gastroenterology. 2004;127(5):1525-1539. 221. Antony AN, Paillard M, Moffat C, et al. MICU1 regulation of mitochondrial Ca(21) uptake dictates survival and tissue regeneration. Nat Commun. 2016;7:10955. 222. Barthel SR, Medvedev R, Heinrich T, Buchner SM, Kettern N, Hildt E. Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor. Cell Mol Life Sci. 2016;73(21):4121-4140. 223. Weiss YG, Bellin L, Kim PK, et al. Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats. Am J Physiol Gastrointest Liver Physiol. 2001;280(5):G968-G973. 224. Sekine K, Fujishima S, Aikawa N. Plasma hepatocyte growth factor is increased in early-phase sepsis. J Infect Chemother. 2004; 10(2):110-114. 225. Seehofer D, Stockmann M, Schirmeier A, et al. Intraabdominal bacterial infections significantly alter regeneration and function of the liver in a rat model of major hepatectomy. Langenbecks Arch Surg. 2007;392(3):273-284. 226. Friedman BH, Wolf JH, Wang L, et al. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl. 2012;18(2):166-176. 227. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460-466. 228. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24(13):2065-2072. 229. Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005;200(6):845-853. 230. Rubbia-Brandt L, Tauzin S, Brezault C, et al. Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans. Mol Cancer Ther. 2011;10(4):687-696. 231. Vigano L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731-740; discussion 741-742. 232. Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26(4): 702-708. 233. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342. 234. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91(3): 173-180.

104.e6 235. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol. 2007;14(2):759-765. 236. Van Buren G II, Yang AD, Dallas NA, et al. Effect of molecular therapeutics on liver regeneration in a murine model. J Clin Oncol. 2008;26(11):1836-1842. 237. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg. 2008;206(1):96-106. 238. Zorzi D, Chun YS, Madoff DC, Abdalla EK, Vauthey JN. Chemotherapy with bevacizumab does not affect liver regeneration after portal vein embolization in the treatment of colorectal liver metastases. Ann Surg Oncol. 2008;15(10):2765-2772. 239. Hora C, Romanque P, Dufour JF. Effect of sorafenib on murine liver regeneration. Hepatology. 2011;53(2):577-586. 240. Andersen KJ, Knudsen AR, Kannerup AS, et al. Postoperative but not preoperative treatment with sorafenib inhibits liver regeneration in rats. J Surg Res. 2014;191(2):331-338. 241. Shi JH, Liu SZ, Wierod L, et al. RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver. J Surg Oncol. 2012;107(4):393-401. 242. Olthoff KM. Molecular pathways of regeneration and repair after liver transplantation. World J Surg. 2002;26(7):831-837. 243. Hashmi SK, Baranov E, Gonzalez A, Olthoff K, Shaked A. Genomics of liver transplant injury and regeneration. Transplant Rev (Orlando). 2015;29(1):23-32. 244. Debonera F, Que X, Aldeguer X, et al. Partial liver grafts with prolonged cold preservation initiate blunted regenerative responses. Am J Transplant. 2002;2(suppl 3):156. 245. Debonera F, Wang G, Xie J, et al. Severe preservation injury induces Il-6/STAT3 activation with lack of cell cycle progression after partial liver graft transplantation. Am J Transplant. 2004;4(12):1964-1971. 246. Peralta C, Jimenez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol. 2013;59(5):1094-1106. 247. Gracia-Sancho J, Villarreal Jr G, Zhang Y, et al. Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation. 2010;90(2):142-149. 248. Russo L, Gracia-Sancho J, Garcia-Caldero H, et al. Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers. Hepatology. 2012;55(3):921-930. 249. Kam I, Lynch S, Svanas G. Evidence that host size determines liver size: studies in dogs receiving orthotopic liver transplants. Hepatology. 1987;7(2):362-366. 250. Francavilla A, Zeng Q, Polimeno L, et al. Small-for-size liver transplanted into larger recipient: a model of hepatic regeneration. Hepatology. 1994;19(1):210-216. 251. Emond JC, Renz JF, Lim RC, et al. Functional analysis of grafts from living donors: implications for the treatment of older recipients. Ann Surg. 1996;224(4):544-554. 252. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation. 1999;67(2):321-327. 253. Lo CM, Fan ST, Liu CL, et al. Minimum graft size for successful living donor liver transplantation. Transplantation. 1999;68(8): 1112-1116. 254. Zhong Z, Schwabe RF, Kai Y, et al. Liver regeneration is suppressed in small-for-size liver grafts after transplantation: involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply. Transplantation. 2006;82(2):241-250. 255. Selzner N, Selzner M, Tian Y, Kadry Z, Clavien PA. Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: a TNF-?/IL-6-dependent mechanism. Hepatology. 2002;36(4 I):812-818. 256. Kokai H, Sato Y, Yamamoto S, et al. Successful super-small-for-size graft liver transplantation by decompression of portal hypertension via splenectomy and construction of a mesocaval shunt: a case report. Transplant Proc. 2008;40(8):2825-2827. 257. Lee SG. A complete treatment of adult living donor liver transplantation: a review of surgical technique and current challenges to expand indication of patients. Am J Transplant. 2014;15(1): 17-38.

258. Debonera F, Krasinkas AM, Gelman AE, et al. Dexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation. Hepatology. 2003;38(6):1563-1572. 259. Nagy P, Schnur J, Kiss A, Thorgeirsson SS. Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver. Hepatology. 1998;28(2):423-429. 260. Tamasi V, Kiss A, Dobozy O, Falus A, Vereczkey L, Monostory K. The effect of dexamethasone on P450 activities in regenerating rat liver. Biochem Biophys Res Commun. 2001;286(2):239-242. 261. Francavilla A, Starzl TE, Barone M, et al. Studies on mechanisms of augmentation of liver regeneration by cyclosporine and FK 506. Hepatology. 1991;14(1):140-143. 262. Francavilla A, Carr BI, Starzl TE, Azzarone A, Carrieri G, Zeng QH. Effects of rapamycin on cultured hepatocyte proliferation and gene expression. Hepatology. 1992;15(5):871-877. 263. Palmes D, Zibert A, Budny T, et al. Impact of rapamycin on liver regeneration. Virchows Arch. 2008;452(5):545-557. 264. Trotter JF, Stolpman N, Wachs M, et al. Living donor liver transplant recipients achieve relatively higher immunosuppressant blood levels than cadaveric recipients. Liver Transpl. 2002;8(3): 212-218. 265. Ikegami T, Nishizaki T, Yanaga K, et al. The impact of donor age on living donor liver transplantation. Transplantation. 2000; 70(12):1703-1707. 266. Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living donor liver transplantation. Am J Transplant. 2004;4(8):1302-1307. 267. Olthoff KM, Merion RM, Ghobrial RM, et al. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg. 2005;242(3):314-323, discussion 323-325. 268. Cassuto JR, Patel SA, Tsoulfas G, Orloff MS, Abt PL. The cumulative effects of cold ischemic time and older donor age on liver graft survival. J Surg Res. 2008;148(1):38-44. 269. Jiang SM, Zhou GW, Zhang R, et al. Role of splanchnic hemodynamics in liver regeneration after living donor liver transplantation. Liver Transpl. 2009;15(9):1043-1049. 270. Byun SH, Yang HS, Kim JH. Liver graft hyperperfusion in the early postoperative period promotes hepatic regeneration two weeks after living donor liver transplantation: a prospective observational cohort study. Medicine (Baltimore). 2016;95(46):e5404. 271. Eguchi S,Yanaga K, Sugiyama N, Okudaira S, Furui J, Kanematsu T. Relationship between portal venous flow and liver regeneration in patients after living donor right-lobe liver transplantation. Liver Transpl. 2003;9(6):547-551. 272. Tomassini F, D’Asseler Y, Giglio MC, et al. Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study. HPB (Oxford). 2018;21(5):557-565. 273. Kovacs T, Mathe D, Fulop A, et al. Functional shift with maintained regenerative potential following portal vein ligation. Sci Rep. 2017;7(1):18065. 274. Xiang L, Huang L, Wang X, Zhao Y, Liu Y, Tan J. How much portal vein flow is too much for liver remnant in a stable porcine model? Transplant Proc. 2016;48(1):234-241. 275. Bucur PO, Bekheit M, Audebert C, et al. Modulating portal hemodynamics with vascular ring allows efficient regeneration after partial hepatectomy in a porcine model. Ann Surg. 2017;268(1): 134-142. 276. Kohler A, Moller PW, Frey S, et al. Portal hyperperfusion after major liver resection and associated sinusoidal damage is a therapeutic target to protect the remnant liver. Am J Physiol Gastrointest Liver Physiol. 2019;317(3):G264-G274. 277. Brige P, Hery G, Palen A, et al. Portal vein stenosis preconditioning of living donor liver in swine: early mechanisms of liver regeneration and gain of hepatic functional mass. Am J Physiol Gastrointest Liver Physiol. 2018;315(1):G117-G125. 278. Kawaguchi Y, Hasegawa K, Okura N, et al. Influence of outflowobstructed liver volume and venous communication development: a three-dimensional volume study in living donors. Liver Transpl. 2017;23(12):1531-1540. 279. Scatton O, Plasse M, Dondero F, Vilgrain V, Sauvanet A, Belghiti J. Impact of localized congestion related to venous deprivation after hepatectomy. Surgery. 2008;143(4):483-489. 280. Liu HX, Keane R, Sheng L, Wan YJ. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015; 63(6):1502-1510.

104.e7 281. Cornell RP. Gut-derived endotoxin elicits hepatotrophic factor secretion for liver regeneration. Am J Physiol. 1985;249(5 Pt 2): R551-R562. 282. Cornell RP. Restriction of gut-derived endotoxin impairs DNA synthesis for liver regeneration. Am J Physiol. 1985;249(5 Pt 2): R563-R569. 283. Gao C, Jokerst R, Gondipalli P, et al. Lipopolysaccharide potentiates the effect of hepatocyte growth factor on hepatocyte replication in rats by augmenting AP-1 activity. Hepatology. 1999;30(6): 1405-1416. 284. Arai M, Mochida S, Ohno A, Arai S, Fujiwara K. Selective bowel decontamination of recipients for prevention against liver injury following orthotopic liver transplantation: evaluation with rat models. Hepatology. 1998;27(1):123-127. 285. Bao Q, Yu L, Chen D, Li L. Variation in the gut microbial community is associated with the progression of liver regeneration. Hepatol Res. 2019;50(1):121-136. 286. Liu HX, Rocha CS, Dandekar S, Wan YJ. Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration. J Hepatol. 2016;64(3):641-650. 287. Yamanaka K, Houben P, Bruns H, Schultze D, Hatano E, Schemmer P. A systematic review of pharmacological treatment options used to reduce ischemia reperfusion injury in rat liver transplantation. PLoS One. 2015;10(4):e0122214. 288. Linecker M, Limani P, Kambakamba P, et al. Omega-3 fatty acids protect fatty and lean mouse livers after major hepatectomy. Ann Surg. 2016;266(2):324-332. 289. Li CX, Chen LL, Li XC, et al. ApoA-1 accelerates regeneration of small-for-size fatty liver graft after transplantation. Life Sci. 2018;215:128-135. 290. Wan HF, Li JX, Liao HT, et al. Nicotinamide induces liver regeneration and improves liver function by activating SIRT1. Mol Med Rep. 2018;19(1):555-562. 291. Yao H, Fu X, Zi X, Jia W, Qiu Y. Perioperative oral supplementation with fish oil promotes liver regeneration following partial hepatectomy in mice via AMPK activation. Mol Med Rep. 2017;17(3):3905-3911. 292. Cataldegirmen G, Zeng S, Feirt N, et al. RAGE limits regeneration after massive liver injury by coordinated suppression of TNFalpha and NF-kappaB. J Exp Med. 2005;201(3):473-484. 293. Lonn P, Moren A, Raja E, Dahl M, Moustakas A. Regulating the stability of TGFbeta receptors and Smads. Cell Res. 2009;19(1): 21-35. 294. Olthof PB, Huisman F, Schaap FG, et al. Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model. Br J Surg. 2017;104(5):590-599. 295. van Golen RF, Olthof PB, Lionarons DA, et al. FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis. Sci Rep. 2018;8(1):16529. 296. Yigitler C, Farges O, Kianmanesh R, Regimbeau JM, Abdalla EK, Belghiti J. The small remnant liver after major liver resection: how common and how relevant? Liver Transpl. 2003;9(9):S18-S25. 297. Olthof PB, Wiggers JK, Groot Koerkamp B, et al. Postoperative liver failure risk score: identifying patients with resectable perihilar cholangiocarcinoma who can benefit from portal vein embolization. J Am Coll Surg. 2018;225(3):387-394. 298. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery. 2000;127(5):512-519. 299. Higashiyama H, Yamaguchi T, Mori K, et al. Graft size assessment by preoperative computed tomography in living related partial liver transplantation. Br J Surg. 1993;80(4):489-492. 300. Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg. 2002;137(6):675-680; discussion 680-681. 301. Shoup M, Gonen M, D’Angelica M, et al. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg. 2003;7(3):325-330. 302. Lau H, Man K, Fan ST, Yu WC, Lo CM, Wong J. Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br J Surg. 1997;84(9):1255-1259. 303. Corbin IR, Corbin IR, Buist R, et al. Regenerative activity and liver function following partial hepatectomy in the rat using (31) P-MR spectroscopy. Hepatology. 2002;36(2):345-353.

304. Dinant S, de Graaf W, Verwer BJ, et al. Risk assessment of posthepatectomy liver failure using hepatobiliary scintigraphy and CT volumetry. J Nucl Med. 2007;48(5):685-692. 305. Stockmann M, Lock JF, Riecke B, et al. Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity. Ann Surg. 2009;250(1):119-125. 306. Wittauer EM, Oldhafer F, Augstein E, et al. Porcine model for the study of liver regeneration enhanced by non-invasive 13C-methacetin breath test (LiMAx test) and permanent portal venous access. PLoS One. 2019;14(5):e0217488. 307. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg. 2001; 88(2):165-175. 308. Hemming AW, Reed AI, Howard RJ, et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg. 2003; 237(5):686-691; discussion 691-693. 309. Koga M, Ogasawara H. Induction of hepatocyte mitosis in intact adult rat by interleukin-1 alpha and interleukin-6. Life Sci. 1991; 49(17):1263-1270. 310. Feingold KR, Soued M, Grunfeld C. Tumor necrosis factor stimulates DNA synthesis in the liver of intact rats. Biochem Biophys Res Commun. 1988;153(2):576-582. 311. Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg. 2007;94(11):1386-1394. 312. Covey AM, Brown KT, Jarnagin WR, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg. 2008; 247(3):451-455. 313. Pamecha V, Levene A, Grillo F, Woodward N, Dhillon A, Davidson BR. Effect of portal vein embolisation on the growth rate of colorectal liver metastases. Br J Cancer. 2009;100(4):617-622. 314. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255(3): 405-414. 315. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260(5):839-846; discussion 846847. 316. Schadde E, Schnitzbauer AA, Tschuor C, Raptis DA, Bechstein WO, Clavien PA. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. Ann Surg Oncol. 2015;22(9):3109-3120. 317. de Santibanes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012; 255(3):415-417. 318. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, Croome KP. Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases? Surgery. 2014;157(2):194-201. 319. Colak D, Al-Harazi O, Mustafa OM, et al. RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL. Sci Rep. 2020;10(1):5213. 320. Borger P, Schneider M, Frick L, et al. Exploration of the transcriptional landscape of ALPPS reveals the pathways of accelerated liver regeneration. Front Oncol. 2019;9:1206. 321. Vauthey JN, Mise Y. Commentary on “Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases?” Surgery. 2014;157(2):207-210. 322. Esposito F, Lim C, Lahat E, et al. Combined hepatic and portal vein embolization as preparation for major hepatectomy: a systematic review. HPB (Oxford). 2019;21(9):1099-1106. 323. Selzner M, Camargo CA, Clavien PA. Ischemia impairs liver regeneration after major tissue loss in rodents: protective effects of interleukin-6. Hepatology. 1999;30(2):469-475. 324. Makuuchi M, Mori T, Gunven P, Yamazaki S, Hasegawa H. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet. 1987;164(2):155-158.

104.e8 325. Clavien PA, Selzner M, Rudiger HA, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg. 2003;238(6):843-850; discussion 851-852. 326. Rudiger HA, Kang KJ, Sindram D, Riehle HM, Clavien PA. Comparison of ischemic preconditioning and intermittent and continuous inflow occlusion in the murine liver. Ann Surg. 2002;235(3):400-407. 327. Barrier A, Olaya N, Chiappini F, et al. Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion. FASEB J. 2005;19(12):1617-1626. 328. Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2007;293(3):H1654-H1661. 329. Jassem W, Fuggle S, Thompson R, et al. Effect of ischemic preconditioning on the genomic response to reperfusion injury in deceased donor liver transplantation. Liver Transpl. 2009; 15(12):1750-1765. 330. Franchello A, Gilbo N, David E, et al. Ischemic preconditioning (IP) of the liver as a safe and protective technique against ischemia/reperfusion injury (IRI). Am J Transplant. 2009;9(7):16291639. 331. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243(1):1-7. 332. Aussilhou B, Dokmak S, Faivre S, Paradis V, Vilgrain V, Belghiti J. Preoperative liver hypertrophy induced by portal flow occlusion before major hepatic resection for colorectal metastases can be impaired by bevacizumab. Ann Surg Oncol. 2009;16(6):1553-1559. 333. Vauthey JN, Zorzi D. In search of the black sheep: is it bevacizumab or extended chemotherapy? Ann Surg Oncol. 2009; 16(6):1463-1464. 334. Zhang S, Li TS, Soyama A, et al. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver. Sci Rep. 2016;6:26540. 335. Alvarenga DM, Mattos MS, Araujo AM, Antunes MM, Menezes GB. Neutrophil biology within hepatic environment. Cell Tissue Res. 2017;371(3):589-598. 336. Yang W, Tao Y, Wu Y, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun. 2019;10(1):1076. 337. Orci LA, Toso C, Mentha G, Morel P, Majno PE. Systematic review and meta-analysis of the effect of perioperative steroids on ischaemia-reperfusion injury and surgical stress response in patients undergoing liver resection. Br J Surg. 2013;100(5):600-609. 338. Richardson AJ, Laurence JM, Lam VW. Use of pre-operative steroids in liver resection: a systematic review and meta-analysis. HPB (Oxford). 2013;16(1):12-19. 339. Schmidt SC, Hamann S, Langrehr JM, et al. Preoperative highdose steroid administration attenuates the surgical stress response following liver resection: results of a prospective randomized study. J Hepatobiliary Pancreat Surg. 2007;14(5):484-492. 340. Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol. 2009; 217(2):282-298. 341. Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137(2):466-481. 342. Friedman RS, Krause DS. Regeneration and repair: new findings in stem cell research and aging. Ann N Y Acad Sci. 2009;1172: 88-94. 343. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003; 422(6934):897-901. 344. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422(6934): 901-904. 345. Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science. 2004;305(5680):90-93. 346. Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol. 2004;6(6):532-539. 347. Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from nonhepatic adult stem cells. Nature. 2000;406(6793):257.

348. Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6(11):1229-1234. 349. Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31(1):235-240. 350. Hall SR, Pedroza-Gonzalez A, Pan Q, et al. Overestimation of hematopoietic stem cell frequencies in human liver grafts. Hepatology. 2012;57(6):2547-2549. 351. Khurana S, Mukhopadhyay A. Characterization of the potential subpopulation of bone marrow cells involved in the repair of injured liver tissue. Stem Cells. 2007;25(6):1439-1447. 352. Gehling UM, Willems M, Dandri M, et al. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol. 2005; 43(5):845-853. 353. De Silvestro G, Vicarioto M, Donadel C, Menegazzo M, Marson P, Corsini A. Mobilization of peripheral blood hematopoietic stem cells following liver resection surgery. Hepatogastroenterology. 2004;51(57):805-810. 354. am Esch JS II, Knoefel WT, Klein M, et al. Portal application of autologous CD1331 bone marrow cells to the liver: a novel concept to support hepatic regeneration. Stem Cells. 2005;23(4):463-470. 355. Yan Y, Xu W, Qian H, et al. Mesenchymal stem cells from human umbilical cords ameliorate mouse hepatic injury in vivo. Liver Int. 2009;29(3):356-365. 356. Banas A, Teratani T, Yamamoto Y, et al. IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells. 2008;26(10):2705-2712. 357. Kuo TK, Hung SP, Chuang CH, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134(7):2111-2121. 358. Abdel Aziz MT, Atta HM, Mahfouz S, et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Clin Biochem. 2007;40(12):893-899. 359. Kallis YN, Alison MR, Forbes SJ. Bone marrow stem cells and liver disease. Gut. 2007;56(5):716-724. 360. Parekkadan B, van Poll D, Suganuma K, et al. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One. 2007;2(9):e941. 361. van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cellderived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47(5):1634-1643. 362. Fouraschen SM, Pan Q, de Ruiter PE, et al. Secreted factors of human liver-derived mesenchymal stem cells promote liver regeneration early after partial hepatectomy. Stem Cells Dev. 2012;21(13): 2410-2419. 363. Tautenhahn HM, Bruckner S, Baumann S, et al. Attenuation of postoperative acute liver failure by mesenchymal stem cell treatment due to metabolic implications. Ann Surg. 2016;263(3):546-556. 364. Herrera MB, Fonsato V, Gatti S, et al. Human liver stem cellderived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14(6B):1605-1618. 365. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487-1495. 366. Deregibus MC, Cantaluppi V, Calogero R, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110(7):2440-2448. 367. Peng L, Xie DY, Lin BL, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011;54(3):820-828. 368. Lin WR, Brittan M, Alison MR. The role of bone marrow-derived cells in fibrosis. Cells Tissues Organs. 2008;188(1-2):178-188. 369. Houlihan DD, Newsome PN. Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology. 2008; 135(2):438-450. 370. Zhao Q, Ren H, Zhu D, Han Z. Stem/progenitor cells in liver injury repair and regeneration. Biol Cell. 2009;101(10):557-571. 371. Chang YJ, Liu JW, Lin PC, et al. Mesenchymal stem cells facilitate recovery from chemically induced liver damage and decrease liver fibrosis. Life Sci. 2009;85(13-14):517-525.

104.e9 372. Roderfeld M, Rath T, Voswinckel R, et al. Bone marrow transplantation demonstrates medullar origin of CD34(1) fibrocytes and ameliorates hepatic fibrosis in Abcb4(-/-) mice. Hepatology. 2010;51(1):267-276. 373. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2012;22(6):845-854. 374. Pan XN, Zheng LQ, Lai XH. Bone marrow-derived mesenchymal stem cell therapy for decompensated liver cirrhosis: a metaanalysis. World J Gastroenterol. 2014;20(38):14051-14057. 375. Sakai Y, Takamura M, Seki A, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell. Regen Ther. 2017;6:52-64. 376. Caralt M, Uzarski JS, Iacob S, et al. Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am J Transplant. 2014;15(1):64-75. 377. Sabetkish S, Kajbafzadeh AM, Sabetkish N, et al. Whole-organ tissue engineering: decellularization and recellularization of threedimensional matrix liver scaffolds. J Biomed Mater Res A. 2014; 103(4):1498-1508. 378. Zhou Q, Li L, Li J. Stem cells with decellularized liver scaffolds in liver regeneration and their potential clinical applications. Liver Int. 2014;35(3):687-694. 379. Hay DC, Fletcher J, Payne C, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A. 2008;105(34):1230112306. 380. Hay DC, Zhao D, Fletcher J, et al. Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells. 2008;26(4): 894-902. 381. Sullivan GJ, Hay DC, Park IH, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2009;51(1):329-335. 382. Berger DR, Ware BR, Davidson MD, Allsup SR, Khetani SR. Enhancing the functional maturity of iPSC-derived human hepatocytes via controlled presentation of cell-cell interactions in vitro. Hepatology. 2015;61(4):1370-1381. 383. Huang P, He Z, Ji S, et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature. 2011; 475(7356):386-389. 384. Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature. 2011;475(7356): 390-393.

385. Yu B, He ZY, You P, et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell. 2013;13(3):328-340. 386. Aloia L, McKie MA, Vernaz G, et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nat Cell Biol. 2019;21(11):1321-1333. 387. Elmen J, Lindow M, Schutz S, et al. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452(7189):896-899. 388. Ambros V. The functions of animal microRNAs. Nature. 2004; 431(7006):350-355. 389. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-297. 390. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27(1):91-105. 391. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12(9):735-739. 392. Chang J, Nicolas E, Marks D, et al. miR-122, a mammalian liverspecific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 2004;1(2):106-113. 393. Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438(7068):685-689. 394. Esau C, Davis S, Murray SF, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3(2):87-98. 395. John K, Hadem J, Krech T, et al. MicroRNAs play a role in spontaneous recovery from acute liver failure. Hepatology. 2014; 60(4):1346-1355. 396. Song G, Sharma AD, Roll GR, et al. MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology. 2010;51(5): 1735-1743. 397. Chen X, Murad M, Cui YY, et al. miRNA regulation of liver growth after 50% partial hepatectomy and small size grafts in rats. Transplantation. 2011;91(3):293-299. 398. Cirera-Salinas D, Pauta M, Allen RM, et al. Mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle. 2012;11(5): 922-933. 399. Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122 - a key factor and therapeutic target in liver disease. J Hepatol. 2015; 62(2):448-457. 400. Salehi S, Brereton HC, Arno MJ, et al. Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate. Am J Transplant. 2013;13(5): 1282-1295.

CHAPTER 7 Liver fibrogenesis: Mechanisms and clinical relevance Scott L. Friedman Liver fibrosis represents a scarring response to either acute or chronic liver injury. After acute liver injury, parenchymal cells regenerate to successfully preserve hepatocellular mass and function. This acute process is associated with an inflammatory and fibrogenic response but with limited deposition of extracellular matrix (ECM). In contrast, prolonged liver injury leads to sustained production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines. These events culminate in the accumulation of ECM, forming septa that coalesce into broad bands of scar tissue encircling nodules of hepatocytes and leading to altered microvascular structure1,2 (Fig. 7.1). This late stage of fibrosis, termed cirrhosis, ultimately impairs liver function and leads to portal hypertension and its complications, including ascites, encephalopathy, and hepatocellular carcinoma, or primary liver cancer (see Chapters 74 and 79). Typically, progression of fibrosis to cirrhosis evolves for decades before clinical events ensue, but disease may progress more rapidly after repeated episodes of severe acute alcoholic hepatitis and subfulminant hepatitis (especially because of drug toxicity). In addition, there have been reports of rapidly progressive acute hepatitis C virus (HCV) with fibrosis in men coinfected with human immunodeficiency virus (HIV),3 a syndrome that has become much rarer, with good control of HIV using highly active antiretroviral therapies.4 Genetic and environmental factors also influence the course of liver diseases. For example, in HCV infection, polymorphisms in a number of candidate genes involving the inflammatory (e.g., Toll-like receptor 4 [TLR4])5 or the immune6 responses may influence the progression of liver fibrosis in humans. Although genetic polymorphisms in these and other pathways have been linked to progression risk in HCV, they have become far less relevant with the development of directacting antiviral drugs that cure the infection in more than 95% of patients, regardless of the disease stage or risk factors.7 Unfortunately, the development of a similar genetic risk score for nonalcoholic fatty liver disease (NAFLD) has been elusive, possibly because the disease is more heterogeneous. Nonetheless, genetic determinants have been identified that influence the risk and severity of NAFLD8 (see Chapter 69). The main etiologies of liver fibrosis in Western countries are chronic HCV and hepatitis B virus (HBV) infection, alcohol abuse, and nonalcoholic steatohepatitis (NASH; see Chapters 68 and 69). As a generalized tissue response to chronic injury, fibrosis also occurs in many other organs (heart, lung, kidneys) and typically represents the result of an ongoing inflammation. Remarkably, as many as 45% of all deaths are related to some kind of fibrosis,9 which underscores the importance of this response and explains the growing interest in this field of research. For decades, fibrosis was considered an irreversible disease that progresses to cirrhosis with a greater risk for hepatocellular carcinoma and with development of liver failure. This meant that the only potential treatment for liver fibrosis was liver transplantation once cirrhosis was present.

Research during the past 35 years has yielded increasing insight into the cellular and molecular mechanisms of this disease, uncovering an orchestrated pathophysiology, identifying the hepatic stellate cell (HSC) as the central cell type in fibrogenesis,10 and, most importantly, revealing the potential reversibility of the disease and the hope for effective antifibrotic drugs.

MOLECULAR AND CELLULAR MECHANISMS OF FIBROSIS The anatomic arrangement of the parenchymal and nonparenchymal cells of the liver contributes to its unique role as an immune organ and helps explain how the liver responds to an insult. The liver is composed primarily of epithelial cells (hepatocytes and cholangiocytes), as well as resident nonparenchymal cells that include resident hepatic macrophages (Kupffer cells), sinusoidal endothelium, and HSCs. In addition to Kupffer cells, several specialized immune cells have been characterized, including dendritic cells, natural killer (NK) cells, and natural killer T (NKT) cells, which reveal that the liver represents a key organ in the regulation of innate immunity11,12 (see Chapter 10). The liver capsule extends as septae into the liver, delineating hepatic lobules that form the structural units of the liver. The lobule forms a hexagonal structure with portal triads (including branches of the hepatic portal vein, the hepatic artery, and the bile duct) localized in the periphery of the lobule and with a portal vein branch in the center (see Fig. 7.1; see Chapter 5). Hepatocyte plates radiate outward from the central vein and are separated from each other by sinusoids. The latter form the connecting element between the branches of the hepatic portal veins and hepatic arteries with the central vein. Kupffer cells, NK cells, NKT cells, and dendritic cells, all of which are important components of the innate immune system, reside in the hepatic sinusoids. The subendothelial space between the sinusoidal endothelium and hepatocytes is also termed the space of Disse. Thus the HSCs, which lie in the space of Disse, have direct contact with endothelial cells and hepatocytes. Sinusoidal endothelial cells are highly fenestrated, which allows for unimpeded flow of plasma from sinusoidal blood into the space of Disse. Through this arrangement, hepatocytes and HSCs are exposed directly to plasma derived largely from venous blood draining the intestine.

Common Triggers of Hepatic Fibrogenesis Ongoing insult to the liver will lead to an increased inflammatory state with activation of HSCs, which ultimately tilts the profibrotic and antifibrotic balance toward fibrosis. Viral infection, reactive oxygen species (ROS), endoplasmic reticulum stress with protein misfolding,13 damage associated molecular patterns (DAMPs), pathogen-associated molecular patterns,14 and bile acids are among the most common stress signals for the 105

106

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY Normal liver Portal triad Bile duct

Hepatocytes

HSC Sinusoidal space of Disse Portal vein

Sinusoidal endothelial cells

Terminal hepatic vein

KC

Hepatic arteriole

A Fibrotic liver HSC activation and proliferation

Loss of endothelial fenestrations

Loss of hepatocyte microvilli

Distortion of veins

Increase in fibril-forming collagen in space of Disse

B

Fibril-forming collagens (types I, III,V) Basement membrane collagens (types IV,VI) Glycoconjugates (laminin, fibronectin, glycosaminoglycans, tenascin)

FIGURE 7.1  Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). A, Sinusoids are separated from hepatocytes by a low-density basement membrane–like matrix confined to the space of Disse, which ensures metabolic exchange. Upon injury, the HSCs become activated and secrete large amounts of extracellular matrix (ECM), resulting in progressive thickening of the septa. B, Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow and hepatocytes and the development of portal hypertension. (From Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis, Annu Rev Pathol 2011;6:425–456.)

  Chapter 7  Liver Fibrogenesis: Mechanisms and Clinical Relevance

107

Small intestine Gram-neg. bacteria↑

Kupffer cells (macrophages)

LPS in portal blood ↑ T cells Inflammatory TNF-α cytokines

Alcohol

ROS

Mito. oxidant production

NASH HCV

Oxidative stress↑

Sensitized to apoptosis

HBV

Neutrophils

qHSCs

Apoptosis ROS NADPH

aHSCs

FXR Bile acids

Free fatty acids

via EGFR

Proliferation Contractility Fibrogenesis Altered matrix degradation HSC chemotaxis Infammatory signaling

Myofibroblasts FIGURE 7.2  Pathways of cellular injury and fibrosis. This diagram depicts the key pathways of cellular injury and fibrosis. The main causes of chronic liver injury are alcohol, nonalcoholic steatohepatitis (NASH), viral infection, and injury from bile acids in cholestatic conditions. All factors activate hepatic stellate cells (HSCs), which is a key event in liver fibrogenesis. Alcohol can promote gram-negative bacterial overgrowth of the small intestine and/or reduced gut integrity, thereby increasing lipopolysaccharide (LPS) in the portal blood. LPS activates Kupffer cells (hepatic macrophages), which increase the mitochondrial oxidant production in hepatocytes by way of tumor necrosis factor-a (TNF-a), thereby sensitizing them to apoptosis. Kupffer cells also promote local accumulation of T cells and neutrophils, which, along with apoptotic hepatocytes, stimulate the activation of HSCs. Damage to hepatocytes by NASH or infection with hepatitis B or C viruses (HBV, HCV) promotes oxidative stress, further sensitizing hepatocytes to apoptosis. Free fatty acids also increase the intracellular oxidative stress of hepatocytes. Bile acids inhibit activation of HSCs via a farnesoid X receptor (FXR) pathway. aHSCs, Activated HSCs; EGFR, endothelial growth factor receptor; ERK-1, extracellular signal-regulated kinase-1; mito., mitochondrial; NADPH, reduced nicotinamide adenine dinucleotide phosphate; qHSCs, quiescent HSCs; ROS, reactive oxygen species; TNF-a, tumor necrosis factor-a.

liver (Fig. 7.2). Additionally, free cholesterol promotes fibrogenesis by indirect activation of HSCs,15 which may be relevant to the pathogenesis of NAFLD (see Chapter 69). In alcoholic liver disease, ethanol decreases gut motility, increases epithelial permeability, and promotes overgrowth of gram-negative bacteria. Consequently, lipopolysaccharide (LPS) concentration is elevated in portal blood, through the TLR4 signaling complex, to generate ROS via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.16–19 Oxidants then upregulate nuclear factor kappa B (NF-kB) in Kupffer cells, which leads to increased tumor necrosis factor-a (TNF-a) production (see Fig. 7.2). In turn, TNF-a induces neutrophil infiltration and stimulates mitochondrial oxidant production in hepatocytes, which are then sensitized to undergo apoptosis. Furthermore, ROS and acetaldehyde, the main degradation product of alcohol, both activate HSCs and stimulate inflammatory signals. Interestingly, many of the same gut defects in alcoholic liver disease are now also implicated in NASH, with additional focus on the nature of the microbiome as well as the integrity of the gut mucosa as determinants of this disease.8,20–22 Bile acids are hepatotoxic agents and typically target hepatocytes but may also injure biliary epithelium.23 In addition to their potential role in provoking damage, bile acids are also ligands for

nuclear receptors, in particular the farnesoid X receptor (FXR), which drives an entire cellular program that can alter hepatocellular metabolism and bile secretion and composition.24 Remarkably, the therapeutic benefit of vertical sleeve gastrectomy has also been ascribed to FXR signaling in an animal model, raising the possibility that intestinal FXR alone may be sufficient to drive weight loss and improve metabolic parameters in NASH.25,26 Oxidant stress, mediated by ROS, is a common mediator of injury in many liver diseases in which damaged hepatocytes become apoptotic or necrotic, thereby releasing ROS27 and NADPH oxidase, which both activate HSCs.28 Injured hepatocytes also release inflammatory cytokines and soluble factors that activate Kupffer cells and stimulate the recruitment of activated T cells. This inflammatory milieu further stimulates the activation of resident HSCs. NAFLD is increasingly prevalent because of increased rates of childhood and adult obesity in the United States and Western Europe29 (see Chapter 69). In fact, the percentage of liver transplantations performed for this indication is rapidly rising and is overtaking viral hepatitis not only because of curative antiviral therapy for HCV but also because of the rising prevalence of metabolic syndrome, which predisposes to NAFLD.30 NAFLD can progress to NASH, with consequent fibrosis and cirrhosis.22 Although a hierarchy of disease causality is still lacking,

108

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

hepatocytes and biliary cells, by changes in the composition of the ECM, by proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin, and by fibrogenic cytokines that include transforming growth factor-b (TGF-b1), connective tissue growth factor (CTGF), angiotensin II, and leptin.1 Recent studies using single cell RNA sequencing have uncovered significant heterogeneity among stellate cells in both normal and injured liver in both man and mouse,34–36 reinforcing earlier studies that documented stellate cell heterogeneity based on the types of intracellular filaments they express as assessed by immunohistochemistry.37 Activation of HSCs is accompanied by loss of retinoid droplets and accumulation of a-smooth muscle actin, a myogenic

there are multiple convergent defects that clearly drive disease progression and fibrosis in NASH, including insulin resistance, oxidant stress, altered adipokine balance, lipotoxicity, effects of the microbiome, and enhanced inflammation.21,22,31,32

Hepatic Stellate Cell Activation: Hepatic Myofibroblasts

Molecular Phenotype

The HSC is a central regulator of the liver’s fibrotic and repair responses (Fig. 7.3).10 In a healthy liver, the HSC is a quiescent cell type that contains cytoplasmic retinoid droplets, representing the major storage site for vitamin A in the body, and expresses the markers desmin and glial fibrillary acidic protein.33 During liver injury, HSCs undergo activation in response to a range of inflammatory and injury signals produced by damaged

Quiescent

Activated

Functions

Features

• ECM homeostasis

Features

• Metabolic reprogramming

• Matabolic homeostasis Liver Injury

• Vasoregulation

• Infectious

• Retinoid metabolism

• Metabolic

• Autophagy fuels activation

• Increased NK-cell–mediated cell death of senescent HSCs

• Cell injury amplification • ‘‘Classic’’ activated changes: • Retinoid

• Congestive

•

• Autoimmune

•

• Alcohol

Senescent/Inactivated/ Apoptotic

loss

•↑

Chemotaxis

• Inactivated HSCs ‘‘primed’’ for reactivation

↑ Fibrogenesis

• ↑ Contractility ↑ ECM turnover • ↑ Inflammatory signaling • ↑ Proliferation

Senescent

• Toxic Cellular Phenotype

• Drugs

Inactivated

Organ Phenotype

Apoptotic

Normal

Fibrosis/Cirrhosis

Regression

FIGURE 7.3  Functions, features, and phenotypes of hepatic stellate cells in normal and diseased liver. Hepatic stellate cells may exist as several different phenotypes with distinct molecular and cellular functions and features, each of which contributes significantly to liver homeostasis and disease. Quiescent stellate cells are critical to the normal metabolic functioning of the liver. Liver injury provokes transdifferentiation of quiescent stellate cells to their activated phenotype, leading to metabolic reprogramming, increased autophagy to fuel the metabolic demands, amplification of parenchymal injury, and the development of “classic” phenotypic features of activated hepatic stellate cells/myofibroblasts. Through these changes, activated stellate cells drive the fibrotic response to injury and the development of cirrhosis. As liver injury subsides, activated stellate cells can be eliminated by one of three pathways: apoptosis, senescence, or reversion to an inactivated phenotype. Senescent stellate cells are more likely to be cleared by natural killer (NK)-cell–mediated cell death, whereas inactivated stellate cells remain “primed” to respond to further liver injury. This reduction in the number of activated stellate cells contributes to the regression of fibrosis or cirrhosis and repair of the liver in most, but not all, patients. The relative contribution of these three pathways of stellate cell clearance to fibrosis regression is not yet clear. ECM, Extracellular matrix; HSCs, hepatic stellate cells. (From Lee YM, et al. Pathobiology of liver fibrosis—a translational success story. Gut 2015;64:830–841).

  Chapter 7  Liver Fibrogenesis: Mechanisms and Clinical Relevance

filament that confers increased cellular contractility. Activated HSCs are characteristically positive for a–smooth muscle actin and desmin and are called hepatic myofibroblasts (MFB),33 a cell type that is also characteristic of wound healing in a range of tissues, including the skin, kidney, lung, bone marrow, and pancreas.9,38–41 The relative importance of each fibrogenic cell type in liver fibrogenesis may depend on the origin of the liver injury. Fate-tracing studies using genetically engineered reporter mice implicate stellate cells as the dominant source of MFBs in parenchymal liver disease42; however, a contribution from biliary portal fibroblasts is important in cholestatic liver disease.43,44 HSC activation can be divided conceptually into two phases. First there is initiation, with early changes in gene expression and phenotype, resulting from paracrine stimulation, primarily because of changes in surrounding ECM, as well as exposure to lipid peroxides and products of damaged hepatocytes. Next there is perpetuation, which results from the effects of these stimuli on maintaining the activated phenotype and generating fibrosis. Within the nucleus, a growing number of transcription factors regulate HSC activation, including peroxisome proliferator– activated receptors (PPARs), retinoid receptors, liver X receptor, REV-ERBa, NF-kB, FXR, GATA4, vitamin D receptor, JunD, Kruppel-like factor 6, and FOXF1.45,46 A number of general and cell type–specific membrane receptors and signaling pathways also control HSC biology, including receptor tyrosine kinases, chemokine receptors, and integrins.45,47 Not only is HSC activation under transcriptional control, but a growing range of epigenetic changes further regulates this HSC transdifferentiation into myofibroblasts.48–50 As previously noted, portal fibroblasts and bone marrow– derived MFBs51–53 have also been identified as collagenproducing cells in the injured liver, although their overall contribution is minor. Earlier studies implicated epithelialmesenchymal transition as a source of fibrogenic cells, but more recent findings strongly refute its importance in liver.54

Functions of Hepatic Myofibroblasts Hepatic MFBs have functions that are distinct from their quiescent cells of origin. They are profibrogenic and promitotic, they have a chemotactic and vasoregulatory role, and they control the degradation of ECM. They also have important immune and phagocytic functions.55–58 The regulation of ECM accumulation and degradation by HSCs is reviewed in the next section.

Fibrogenesis The major profibrogenic signal in liver is the cytokine TGF-b1. TGF-b1 is secreted mainly by MFBs59 but also by platelets cells60 and liver macrophages.61 It functions by activating the type II TGF-b receptor, which recruits the type I TGF-b receptor. SMAD2 and SMAD3 then associate with the TGF-b1 receptor, are phosphorylated, and recruit SMAD4. This triheteromeric complex then translocates to the nucleus, where it activates profibrogenic transcription factors.62 TGF-b also activates the mitogen-activated protein kinase (MAPK) p38 pathway, which stimulates additional SMAD-independent collagen type 1 synthesis62 and, in contrast to the SMAD-dependent collagen type 1 synthesis, also leads to a post-transcriptionally regulated stabilization of the collagen type 1 messenger RNA (mRNA).63 Local activation of TGF-b1 at the cell surface by integrins has led to the prospect of antagonizing integrins as an antifibrotic therapy.64 In addition to TGF-b1, CTGF65 and

109

Hedgehog signaling have also been implicated as important fibrogenic mediators in liver injury and repair.66,67

Proliferation The predominant stimulus to MFB proliferation is the mitogen platelet-derived growth factor (PDGF)68 in addition to other mitogens, including epidermal growth factor, VEGF, and fibroblast growth factor.47 All pathways downstream of the b-PDGF receptor, the key receptor isoform in HSCs, promote proliferation. First, c-Jun N-terminal kinase is stimulated through MAPK; second, PDGF receptor stimulates the RAS/RAF complex, followed by mitogen-induced extracellular kinase and extracellular signal-regulated kinase engagement; and third, the PI3K pathway is activated, leading to AKT (protein kinase B) activation and phosphorylation of the 70S6 kinase.68

Immunoregulation The liver is a microenvironment of diminished immunogenicity, which is necessary to cope with the high exposure of antigens from the portal vein69,70 (see Chapter 10). This feature also accounts for the tolerance of liver transplantation across ABO barriers and may contribute to the chronic nature of HBV or HCV, in which the virus persists despite the development of an immune response. Upon entry of the antigen to the sinusoid, classic antigen-presenting cells (Kupffer cells, dendritic cells) are first encountered. Subsequently, HSCs in the space of Disse may contact antigens.58 Indeed, HSCs display a wide range of immunoregulatory functions and are an essential part of the liver’s immune response.56,57 Hepatic MFBs produce a range of proinflammatory and antiinflammatory cytokines (see Chapter 10) and recruit lymphocytes through secretion of chemokines (monocyte chemoattractant protein-1, interleukin-8 [IL-8], C-C chemokine 21 [CCL21], regulated on activation, normal T-cell expressed and secreted [RANTES], C-C chemokine receptor 5 [CCR5]),71–73 thus amplifying the inflammatory response. Nevertheless, upon activation, they exert a profound immunosuppressive activity by inducing T-cell apoptosis.74 In the setting of liver transplantation, MFB can induce T-cell apoptosis via programmed death ligand-174 and may foster local immunotolerance of the liver. In liver fibrosis, MFBs may further regulate the contribution of lymphocytes to the course of hepatic fibrosis by ingesting disease-associated lymphocytes75 or by activating in response to engulfment of apoptotic bodies.76 The interaction between HSCs and immune cells is bidirectional. T cells activate HSCs by interferon-g (IFN-g), which upregulates both stimulatory (CD80, CD86, CD54) and inhibitory (B7-H1) surface molecules and enhances both inflammatory and suppressive cytokines. The inhibitory molecules, however, are thought to override the stimulatory counterparts, resulting in immunosuppression. Lymphocytes can also mediate hepatic fibrosis by activating HSCs. CD8-positive T lymphocytes are more fibrogenic toward stellate cells than CD4 T lymphocytes.55 This may explain, in part, why patients co-infected with untreated HIV and HCV have accelerated fibrosis because their CD4:CD8 cell ratios are reduced. Of the CD4-positive T lymphocytes, previously called T-helper cells, the humoral immunity mediated by T-helper 2 cells (Th2) is profibrogenic in liver injury, whereas the cellmediated immunity by the Th1 cells via IFN-g, TNF-a, and IL-2 is antifibrogenic.77 HSCs can also function as antigen-presenting cells.58 They can interact with bacterial LPS directly via TLR4, which amplifies

110

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

their activation. TLR4 signaling leads to downregulation of a TGF-b pseudoreceptor, BMP (bone morphogenic protein), and activin membrane-bound inhibitor, which thereby amplifies fibrogenic activity of MFBs.78 Signaling through TLR4 may be elicited not only by exogenous ligands, including LPS, but also by endogenous ligands, including high-mobility group box 1 protein.79 The discovery of endogenous ligands for TLR4 has been part of a larger recognition that many cells, including HSCs, possess an intracellular complex known as the inflammasome, which transduces signals arising from cellular damage.80–82 The inflammasome is especially pertinent to understanding the pathogenesis of inflammation and fibrosis in NAFLD and NASH.

Vasoregulation MFBs play an important role in the regulation of sinusoidal blood flow and may contribute to portal hypertension that is characteristic of advanced liver disease (see Chapter 74). The release of endothelin-1 (ET-1) can stimulate their contraction through the endothelin type A (ETA) receptor,83 thereby promoting tissue contraction, increasing portal resistance, and generating portal hypertension. On the other hand, MFBs and endothelial cells also secrete nitric oxide (NO), which is the physiologic antagonist of ET-1.84

Structural Features of Hepatic Fibrogenesis In hepatic fibrosis, the total amount of collagen is increased up to sixfold, whereas the parenchymal mass (e.g., hepatocytes) is progressively diminished (see Chapter 74). The composition of the ECM changes with progression of disease (see Fig. 7.1). Collagen type IV in the space of Disse is replaced by interstitial, or fibrillar, collagens, primarily types I and III. Additionally, the discontinuous basal membrane beneath the sinusoidal endothelial cells is replaced by a continuous basement membrane, and sinusoidal fenestrations are reduced. This decreased porosity (also known as capillarization), combined with perisinusoidal fibrosis, scar contraction, and formation of intrahepatic shunts, contribute to increased hepatic venous pressure and portal hypertension. Fibrillar collagens that are produced by MFBs also interact with MFBs via discoidin domain receptors and integrins,85 thereby inhibiting apoptosis and increasing MFB proliferation. With the maturation of the fibrotic scar, not only is the amount of collagen increased, but the scar also becomes increasingly insoluble through chemical cross-linking by lysyl oxidase 2 (LOXL2), tissue transglutaminase, and a disintegrin and metalloproteinase with thrombospondin-type repeats metalloproteinase with thrombosponin type I motif (ADAMTS2).86 Indeed, HSCs are an important source of these cross-linking enzymes.87 Cross-linking makes the fibrous septa progressively resistant to proteolysis by matrix metalloproteinases (MMPs). The longstanding clinical dogma that the slower the pace of injury, the less reversible the scar, is supported by animal studies in which even advanced fibrosis of short duration is reversible. Thus the reversibility of a scar may be limited primarily by the extent of collagen cross-linking. Clinically, increased septal thickness and smaller nodule size as assessed by liver biopsy, both of which reflect more advanced stages of fibrosis, are significant predictors of worse clinical outcomes.88 Efforts to therapeutically increase the solubility of collagen have tested an antibody to LOXL2, which has marked antifibrotic effects in animal models of fibrosis in liver and other organs.89 These findings led to its evaluation in clinical trials to treat fibrosis and cancer, which unfortunately showed no efficacy. These negative

results may indicate a lack of sufficient penetration of the antibody to sites of cross-linking rather than disproving the role of LOXL2 in matrix homeostasis, however.

Regulation of Collagen Deposition and Degradation The deposition and degradation of collagen are tightly regulated. MMPs are the key enzymes that degrade fibrillar collagens (collagen types I and III) and noncollagenous ECM substrates.90 The tissue inhibitor metalloproteinases (TIMPs) are their major antagonists by inactivating proteases and by inhibiting MFB apoptosis.91 Both altered levels of interstitial collagenases and increased levels of MMP inhibitors in liver injury create an imbalance that favors reduced degradation of fibrillar collagens in hepatic fibrosis. The interstitial collagenases MMP-1, MT1-MMP, MMP-8, and MMP-13 in humans and MMP-13 in rodents unwind the triple-helical collagen type I, which is the principal collagen in the fibrotic liver, so that each a-chain is presented to the active site of the enzyme that cleaves the collagen.90 Other MMPs (e.g., MMP-2) cannot unwind the triple-helical collagen and thus cannot degrade intact collagen type I alone. In early liver injury, MMP-2 degrades the low-density basement membrane present in the subendothelial space.92 Its replacement with fibril-forming matrix impairs hepatocyte differentiation and function. During progressive fibrosis, expression of MMP-1 (humans) or MMP-13 (rodents) is decreased, and MMP-2 expression increases.64 In parallel, the expression of TIMP-1 and TIMP-2, which inhibit the collagen-degrading MMPs, is increased.93,94 Matrix type 1 metalloproteinase (MT1-MMP) is another interstitial collagenase whose contribution to overall matrix degradation in liver has not been established.95 Hepatic macrophages are key cellular determinants of matrix degradation, with some contribution by dendritic and other inflammatory cells.96 In mouse models, macrophages augment fibrogenesis during progression of liver fibrosis, whereas during resolution, they hasten matrix degradation through increased production of MMP-13.97 More importantly, there is substantial heterogeneity of macrophages in liver injury and resolution to account for these divergent activities, with a subset known as Ly6Clo cells implicated in degrading matrix during fibrosis regression.82,98,99 Despite these major advances in identifying the key fibrolytic cell in liver fibrosis regression, it is not clear which is the major interstitial collagenase in fibrosis regression because MMP-1 is only expressed at low levels in liver. As noted, other interstitial collagenases may be more important in ECM degradation.

DIAGNOSIS AND CLINICAL MONITORING OF HEPATIC FIBROSIS Many patients with chronic liver disease may initially present with late-stage fibrosis because earlier stages are often asymptomatic. Thus clinicians must have a high index of suspicion for occult fibrosis, especially in patients with unexplained elevations of liver enzymes, splenic enlargement, stigmata of liver disease, and/or laboratory or imaging findings suggestive of portal hypertension (see Chapter 77). When chronic liver disease is suspected, the liver biopsy remains the gold standard for diagnosing and staging liver fibrosis. However, it is an invasive procedure with risk of adverse events and, equally important, a high likelihood of sampling variability,100,101 as well as inter- and intra-pathologist variability.100

  Chapter 7  Liver Fibrogenesis: Mechanisms and Clinical Relevance

At least one third of biopsies may differ by one fibrosis stage between the right and left hepatic lobes in HCV102 and NAFLD.101 Smaller biopsy specimens are associated with an increase in reported diagnoses of mild and moderate fibrosis at the cost of more severe fibrosis, representing an understaging of fibrosis.100 There are several commonly used histologic staging systems for fibrosis (see Chapter 74). The Histology Activity Index score reported by Knodell includes three stages,103 whereas the Ishak score differentiates six stages, including two stages of cirrhosis (“incomplete” and “complete” cirrhosis).104 The METAVIR score (an acronym derived from a French Investigator group) is a simple, widely applied five-stage scoring system105 that is the most commonly used worldwide for staging HCV infection. It incorporates the fibrosis scores F0 to F4, and the activity scores A0 to A3, which assess the amount of necroinflammation. For NAFLD, a separate scoring system for grading inflammation and staging fibrosis has been widely adopted,106 which captures key histologic features of disease progression that are distinct from viral liver disease (see Chapter 69). Specifically, NAFLD and NASH, as well as alcoholic liver disease, are primarily centrilobular in distribution rather than periportal like viral liver diseases. The NAFLD Brunt/Kleiner stages are stage 0 5 no fibrosis, stage 1 5 perisinusoidal or periportal fibrosis (1a: mild, zone 3; 1b: moderate, zone 3; 1c: portal/periportal), stage 2 5 periportal and perisinusoidal fibrosis, stage 3 5 bridging fibrosis, and stage 4 5 cirrhosis. For fibrosis staging, there is increasing reliance on absolute quantification of collagen in liver biopsy samples as assessed by computerized morphometry, instead of using a discontinuous scoring system composed of separate stages. Indeed, collagen proportionate area assessment is far more predictive of clinical outcomes, even in NASH, and therefore its use is rapidly gaining popularity because it is objective and quantitative.107–109 There is a great need for reliable, quantitative noninvasive diagnostics for fibrosis, and recent studies indicate progress. Crosssectional imaging studies such as computed tomography (CT) and magnetic resonance (MR) imaging can demonstrate features of advanced liver disease, such as nodularity and signs of portal hypertension (splenomegaly, enlarged caudate lobe, esophageal varices). Advances in MR methods include MR elastography,110 MR fat fraction, and other related technologies.111 There are also efforts to develop newer MR probes that may enable quantification of total liver collagen or elastin content.112,113 Biochemical parameters associated with hepatocyte injury (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), cholestatic liver injury (bilirubin, alkaline phosphatase), impaired liver synthetic function (apolipoproteins, cholesterol, coagulation factors, a2-macroglobulin, hyaluronic acid, albumin, globulins), or impaired hepatic clearance of endogenous or exogenous substances from the circulation (bilirubin, bile acid, caffeine, lidocaine metabolites, bromsulphalein, methacetin, indocyanine green, cholate, or ammonia)114 can provide information on the presence and cause of the disease. These tests all assess impaired liver function in fibrosis and may prove to be more quantitative and sensitive than tests of liver injury or morphology. Indeed, pulmonary function tests (e.g., spirometry) have been a mainstay of clinical assessment in lung disease rather than tissue analysis of lung for decades. Continued progress in using functional rather than structural assessment of liver disease is expected but not yet widely adopted in clinical trials or clinical practice.

111

Biochemical Tests A more direct approach incorporates serum molecules associated with fibrosis, including those involved in deposition or degradation of ECM, as well as specific fibrogenic cytokines associated with fibrosis. A number of combination serum tests have been evaluated for predicting fibrosis stage and outcomes, with improving sensitivity and specificity. To date, no single molecule, but rather combinations of different components, demonstrate the best sensitivity and negative predictive values to exclude significant fibrosis. The most studied combination serum tests are the ASTto-platelet ratio index,115 the Fibrosis-4 (FIB-4) index,116 the enhanced liver fibrosis (ELF) test,117,118 and the FibroTest (FT; Biopredictiv, Paris).119 Newer biomarker scores include the HepaScore120 and measurement of collagen propeptides.111,121 All these biochemical tests range from sufficient to excellent in ruling out significant fibrosis (F3 to F4) when the proper cutoff value is chosen,118 but they are less useful in distinguishing mild from moderate fibrosis. Ongoing efforts are seeking to combine blood tests with other modalities (e.g., liver stiffness) to enhance their diagnostic accuracy.122 The sensitivities of the tests vary based on the etiology of the liver disease. A further difficulty of these tests is the absence of an ideal gold standard, in view of the liver biopsy’s significant sampling variability and interlaboratory differences. The lack of a true gold standard means that the utility of serum tests can never be fairly evaluated when compared with biopsy.123 Overall, the performance of serum markers is approximately comparable.122 Although it is unlikely that these markers alone will suffice in assessing short-term disease progression in clinical trials of antifibrotic drugs or in management of chronic liver diseases, they do predict long-term outcomes and therefore remain of great interest.124,125

Cytokines and Chemokines Associated With Hepatic Fibrosis Of the cytokines and chemokines that are associated with hepatic fibrosis, TGF-b1 is the dominant stimulus for the production of ECM by HSCs. Hepatic mRNA levels of TGF-b1 are increased in chronic liver disease in association with increases in mRNA levels of type I collagen.126 TGF-b serum levels not only correlate with fibrosis scores but also may indicate necroinflammation, although their measurement is not sufficiently predictive to be used as a clinical biomarker.

Stiffness Assessments An alternative approach to fibrosis assessment is the measurement of liver stiffness using a number of devices, the first of which, Fibroscan (FS), uses vibration-controlled transient elastography; other devices that use either vibration controlled– or shear wave elastography127 are now widely available but have less clinical validation than FS. As noted previously, stiffness can also be assessed by MR elastography, which has the advantage of assessing the entire liver128 and can be combined with other MR-based methods to assess liver fat content or other imaging characteristics.129,130 For FS, the stiffer the liver tissue, the faster a wave propagates. Results are expressed in kilopascals (kPa). With the Fibroscan, the virtual cylinder of tissue that is assessed is at least 200 times larger than a biopsy sample and therefore is far more representative of the hepatic parenchyma. Thus FS may provide

112

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

a more accurate and reproducible picture of cirrhosis than liver biopsy. There is also potential value to FS in early stages of disease, where fibrosis may be unevenly distributed and thus underestimated by liver biopsy. Furthermore, FS has very low interobserver variability. However, its accuracy is limited in patients with obesity, ascites, or acute hepatitis. FS has been evaluated extensively.122,131 It is important to remember that stiffness can arise from edema or inflammation, not only fibrosis, and thus interpretation of the results in the proper clinical context is essential because acute hepatitis can yield stiffness values comparable to cirrhosis. Also, the ability to perform the test and the accuracy of data may be reduced in obese patients, although newer probes can better overcome this problem. When FS has been combined with FT in HCV patients, both tests agreed in 70% to 80% of subjects, with increasing concordance in higher stages of liver fibrosis. Compared with the liver biopsy, results were confirmed in 84% to 94% of cases, with a tendency of FS/FT to underestimate fibrosis.132 To assist in this effort, an additional technology has been added to FS, called controlled attenuation parameter (CAP score), which can estimate liver fat content and therefore is especially useful in assessing patients with NAFLD or NASH133 (see Chapter 69). In patients with more advanced disease, assessment of vascular changes can predict outcomes. Specifically, the measure of the pressure gradient across the liver, or hepatic venous pressure gradient (HVPG), is highly predictive of clinical deterioration.134 Because the technique cannot be widely replicated in large clinical trials, however, efforts are underway to develop noninvasive imaging approaches that can capture the same information as HVPG without the need for hepatic catheterization.135 In aggregate, all these noninvasive approaches can accurately distinguish between patients with little or no fibrosis and those with advanced disease, but they are less reliable at discriminating intermediate stages of fibrosis. They show a high level of variability because of interlaboratory differences, but on the other hand, the patients at risk for false-positive results are well defined. Although the combination of FT, FS, or the ELF panel in NAFLD patients are potential alternatives to liver biopsy, their value in individual patient management still needs to be validated and standardized.136 Despite its limitations, to date no single test can match the overall information from liver biopsy histology (inflammation, fibrosis, steatosis, architecture), and thus phase 3 clinical trials testing drugs for fibrosis or NASH still require liver biopsy as an endpoint (see later), although phase 2 proof-of-concept trials may rely on noninvasive markers instead of biopsy. The role of noninvasive alternatives so far lies first in improving the fibrosis staging and grading made from liver biopsies and, second, in reducing the number of liver biopsies by screening patients with abnormal liver tests to identify patients with a higher probability of liver fibrosis who need further evaluation or therapy. There is great interest in establishing the value of noninvasive tests in predicting disease progression or response to therapy by combining serum markers with noninvasive tests of liver function and hepatic blood flow. To date, however, this goal has not fully materialized.

THERAPEUTIC STRATEGIES The elucidation of pathways of hepatic fibrogenesis has provided a rational framework for developing antifibrotic therapies in chronic liver disease (Fig. 7.4). Methods to attack several

points are under development, and it may ultimately be advantageous to combine more than one therapy for maximal efficacy. To date, no antifibrotic therapy has been approved for clinical use, but dozens are currently in clinical trials, primarily for NASH with fibrosis.

Reversibility of Fibrosis: “Point of No Return” Fibrosis is no longer considered as an irreversible and progressive state in all patients. Liver fibrosis of different etiologies is usually reversible by removing the causative agent.137 For example, a decrease in the viral load of HBV patients,138 clearance of HCV with pegylated IFN and ribavirin or direct-acting antivirals,139 cessation of ethanol intake, weight loss or bariatric surgery in patients with NASH,140 decreased iron or copper in hemochromatosis or Wilson disease, or immunosuppressive therapy in autoimmune diseases can limit fibrosis progression experimentally and clinically. Even cirrhosis can regress in some patients. In fact, removing the causative agent is still the most effective antifibrotic therapy. As previously noted, efforts to treat fibrosis are focused almost exclusively on NASH because this represents a growing fraction of patients with advanced liver disease, and there are no approved therapies.22,141 Although fibrosis, inflammation, and bile duct proliferation decrease when the damaging stimulus is withdrawn, regenerative nodules may become autonomous and grow progressively. This raises a key question of whether there is a “point of no return” for advanced fibrosis, wherein even complete clearance of the underlying disease will no longer yield an improvement. Increased cross-linking of the collagen fibrils over years makes the fibrous septa progressively resistant to proteolysis by metalloproteinases, and hypoxia stimulates secretion of proangiogenic factors by HSCs, such as VEGF and angiopoietin-1, which induce proliferation and motility.142 However, antagonism of VEGF in particular may be deleterious because it also plays a role in restoration of liver architecture after cessation of experimental liver injury.143 Overall, as many as 70% of patients with cirrhosis will have regression of fibrosis once the primary etiology is mitigated, but in those in whom the disease still progresses, there may be a positive feedback loop between angiogenesis and fibrogenesis, which persists even when the primary etiology is cleared, leading to sustained abnormalities of the intrahepatic vasculature. The tremendous efficacy of direct-acting antivirals in curing HCV in even advanced patients with cirrhosis provides an opportunity to better refine the “point of no return,” but is limited by the fact that biopsies are not routinely performed in patients with a sustained virologic response (i.e., cure of HCV) from these medications.144 Nonetheless, as we learn more about regression of fibrosis after cure of HCV, it is likely that antifibrotic treatments will be considered for those with HCV cirrhosis who do not show reversibility well after virologic cure (e.g., . 3–5 years).

Prevention of Hepatocyte Apoptosis in Liver Injury Apoptosis of hepatocytes during liver injury is a proinflammatory event associated with Kupffer cell and HSC activation.145 In the surgical setting, reduced hepatocyte damage is pursued by decreasing the time of vascular occlusion (Pringle maneuver) during resection or shortening the ischemia-reperfusion time in transplant surgery. Experimental approaches to reduce ischemia-reperfusion injury, (e.g., intermittent clamping or drugs) merit continued development to preserve hepatocyte integrity.

  Chapter 7  Liver Fibrogenesis: Mechanisms and Clinical Relevance

2. Target receptor-ligand interactions

1. Control or cure primary disease

NASH

Other*

FXR agonist Vitamin E PPARγ agonist Lipogenesis inhibitor

Immunosuppression UDCA Remove iron or copper Alcohol abstinence

Viral suppression

Adiponectin CB1R antagonist ACE-I or ARB Ghrelin

PPARα, δ, γ agonist ET-1 antagonist Tyrosine kinase antagonists FXR agonist

Quiescent HSC

SVR Liver Injury

HBV

113

Activated HSC

HCV

*e.g., Wilson disease Autoimmune liver disease Hereditary hemochromatosis Alcoholic liver disease

Normal liver

Cirrhotic liver

Liver Injury Latent TGF-β

TGF-β

CTGF

mAb

Block activation ↑ Collagen ↑ Proliferation ↓ Matrix Degradation

↓NF-κB TIMP antagonist ACE-I LOXL2 mAb CB1R antagonist ↑Macrophage fibrolytic activity ↑NK-cell activity ↑ Matrix Degradation ↑ Apoptosis Prevent Cross-Linking

Stellate cell 3. Inhibit fibrogenesis

4. Promote resolution of fibrosis

FIGURE 7.4  Mechanisms by which antifibrotic therapies may lead to fibrosis regression. 1. Disease-specific therapies that control or cure the underlying disease are still the most effective antifibrotic approach. 2. Targeting receptor-ligand interactions with either established or experimental drugs to reduce hepatic stellate cell (HSC) activation will attenuate fibrosis development, with multiple potential strategies under development. 3. Inhibition of the most potent of the profibrogenic pathways, for example, preventing activation of latent TGF-b, or blocking the activity of CTGF, are among the more promising antifibrotic strategies. 4. Resolution of fibrosis can be promoted by enhancing the apoptosis of activated hepatic stellate cells either with drugs or through the activity of either NK cells or fibrolytic macrophages, and by increasing degradation of extracellular matrix, or by preventing its cross-linking with antagonists to LOXL2. ACE-I, Angiotensin converting enzyme-I inhibitor; CB1R; cannabinoid receptor type 1; CTGF, connective tissue growth factor; ET-1, endothelin 1; FXR, farnesoid X receptor; HBV, HCV, hepatitis B and C virus, respectively; LOXL2, lysyl oxidase 2; mAb, monoclonal antibody; NASH, nonalcoholic steatohepatitis ; NF-kB, nuclear factor kappa B; NK, natural killer; PPAR, peroxisome proliferator–activated receptor; SVR, sustained virologic response; TGF-b, transforming growth factor-b; TIMP, tissue inhibitor of metalloproteinase; UDCA, ursodeoxycholic acid. (From Lee YM, Wallace MC, and Friedman SL. Pathobiology of liver fibrosis—a translational success story, Gut 2015;64:830–841.)

Caspase Inhibitors Apoptosis is a functional antagonist to mitosis. Together they regulate homeostatic cell turnover. The two main pathways of apoptosis are the extrinsic pathway, which is death ligand– death receptor–mediated and is dependent on caspase-8, and the intrinsic pathway, which is regulated by BCL2-induced mitochondrial dysfunction and downstream activation of caspase-9 and its effector caspases: 3, 6, and 7. Caspase inhibitors were developed to minimize apoptotic death of hepatocytes in chronic liver injury by inhibiting the caspases that contribute to the apoptotic cascade, with the lingering concern that such an approach could promote the survival of preneoplastic hepatocytes. Nonetheless, caspase inhibitors have been well tolerated in clinical trials to date but with no clear evidence of efficacy in patients with inflammatory liver diseases or acute-on-chronic liver failure.

Inhibition of Hepatic Stellate Cell Activation or Inactivation of Myofibroblasts Oxidant stress in the form of ROS released by injured hepatocytes through the action of NADPH oxidase is a potent fibrogenic stimulus. Thus antioxidants, including vitamin E,146 silymarin, cysteamine,147 or S-adenosyl-l-methionine,148 may benefit fibrosis, particularly in patients with alcohol-induced liver disease and NASH, in which oxidant stress plays an especially important role. In principle, antioxidants should be efficacious in all inflammatory liver diseases; however, efforts to establish the activity of antioxidants are confounded by the uneven quality of commercially available products, especially as these compounds are typically available over-the-counter and their potency is not monitored. Given their widespread use in diabetes, PPARg agonists have been tested in clinical trials both in NASH and HCV, but

114

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

their activity is modest and is associated with unwanted weight gain, especially in patients with NASH.146 With an improved formulation, PPARg ligands may overcome some of their unwanted adverse effects in clinical trials and merit further evaluation. A combined PPARa,d agonist, elafibranor, showed promise in phase 2 trials,149 but recent phase 3 data failed to confirm efficacy in NASH. Other PPAR agonists with different subtype specificity are also in clinical trials for NASH. WNT signaling has been implicated in pulmonary and renal fibrosis and has also been reported to promote hepatic fibrosis by enhancing HSC activation and survival. On the one hand, this suggests that WNT antagonism may be a useful target in liver fibrosis, but on the other hand, WNT is a critical signal for liver regeneration, and thus its antagonism could be deleterious.150 In fact, efforts are underway to explore the value of therapeutic WNT agonism to reverse cirrhosis and advanced liver disease.

Induction of Myofibroblast Apoptosis Because the natural resolution of fibrosis leads to apoptosis and clearance of MFBs, approaches that exploit these endogenous pathways of resolution merit attention. In addition to apoptosis, activated HSCs/MFBs can also revert to an inactivated state, driven in part by PPARg signaling.151,152 Recent studies have uncovered specific transcriptional regulators, such as Tcf21,153 that promotes deactivation of stellate cells,154 which could be exploited therapeutically to promote HSC quiescence and reduce fibrosis. One approach to driving MFB apoptosis is TIMP antagonism. Because TIMP is antiapoptotic and blocks matrix proteases,91 reduced expression or neutralization favors clearance of MFBs through increased apoptosis and enhanced breakdown of scar.155 Although animal studies reinforced this strategy of inhibiting TIMP-1,156 this approach has not been translated to humans yet. Delivery to stellate cells of an shRNA to block heat shock protein 47 (hsp47), which is required for proper collagen folding, has been reported in an animal model.157 Hsp47 inhibition leads to accumulation of misfolded collagen, which promotes HSC apoptosis to reduce the number of fibrogenic cells.95 A phase 2 trial using this formulation in patients post–HCV SVR is underway, with improvement in histology as the primary endpoint. There are also receptor-ligand–mediated pathways of MFB apoptosis that are potential therapeutic targets. For example, activation of the cannabinoid 1 (CB1) receptor leads to increased collagen deposition and protects MFB from apoptosis, whereas the CB2 receptor is proapoptotic via induction of intracellular oxidative stress. Correspondingly, CB1 knockout mice or CB1 antagonist–treated mice,158 as well as CB2 receptor– stimulated mice,159 display less fibrosis and more MFB apoptosis than control mice after CCl4 or thioacetamide (TAA) treatment or bile duct ligation (BDL). Also, CB2 knockout mice developed increased fibrosis in a CCl4 model.160 Whereas trials of a systemic CB1 receptor antagonist for obesity and NASH were discontinued because of central nervous system (CNS) effects, newer peripheral CB1 antagonists that do not enter the CNS are under development.

Blocking Myofibroblast–Extracellular Matrix Interactions The ECM and MFBs interact in a positive feedback mechanism that could be amenable to therapeutic antagonism. MFBs interact with ECM via a/b-integrins,161 thereby decreasing apoptosis and increasing proliferation of MFBs. Thus blocking

the MFB-ECM interaction could lead to increased MFB apoptosis. This has been confirmed by a3b2-integrin disruption with echistatin, neutralizing antibodies, or siRNA.162 Related to this has been the proposal to block integrins as a means of attenuating TGF-b activation64,163; such efforts are nearing clinical testing and hold great promise for human studies.

Antagonizing Compounds That Mediate Inflammation As inflammation precedes and stimulates liver fibrosis, the use of antiinflammatory drugs has been proposed. A number of agents have antiinflammatory activity. For example, corticosteroids have been used for decades to treat autoimmune hepatitis. Pentoxifylline may exert its antifibrotic activity by downregulating TGF-b1 and CTGF signaling,164 but it can upregulate TIMP-1, thereby reducing its antifibrotic effect. It also inhibits NF-kB in Kupffer cells, thereby reducing TNF-a production, the impact of which is uncertain. A more rational antiinflammatory strategy may be the antagonism of chemokines because they are increasingly implicated in human liver disease.72,73,165 Small-molecule antagonists of chemokine receptors are well tolerated and currently in clinical trials based on promising studies in animals and humans.166 The renin-angiotensin system may also amplify inflammation and has assumed major importance in the understanding of hepatic fibrosis. Angiotensin II is a vasoconstrictive peptide that is expressed by activated HSC in chronically injured livers.167 It induces hepatic inflammation and stimulates fibrogenic actions of HSCs, including cell proliferation, cell migration, secretion of proinflammatory cytokines, and collagen synthesis.168 Inhibitors of this system have been in clinical use for antihypertensive therapy for a substantial time, which makes their use in humans attractive. Preliminary studies in patients with chronic HCV and NASH suggest a positive effect on fibrosis progression by administering blocking agents, but definitive trials are lacking. Ursodeoxycholic acid (UDCA) has a beneficial effect on fibrosis in primary biliary cirrhosis. Similarly, a modified derivative of UDCA, nor-UDCA, reduces inflammation, fibrosis, and portal pressure in an animal model.169 Interestingly, UDCA also activates the pregnane X receptor, which has antifibrotic properties.170 More recently, ligands for FXR, another nuclear receptor, have been developed, which are also antifibrotic in animal models and in a Phase 3 clinical trial in NASH171; however, these promising results did not yet earn US Food and Drug Administration (FDA) approval.

Selectively Antagonizing Pathways of Hepatic Stellate Cell Activation Fibrogenic, proliferative, proangiogenic, vasoconstrictive, and proinflammatory mediators work synergistically toward hepatic fibrogenesis in the setting of chronic liver injury. Thus efforts are underway to antagonize the specific mediators driving these pathways. Multiple approaches have been directed toward blocking the profibrogenic TGF-b signaling pathway. However, systemically blocking the TGF pathway has theoretical limitations, because apart from stimulating wound healing and fibrosis, TGF-b is also a central inhibitor of uncontrolled inflammation and essential in inducing epithelial differentiation and in triggering apoptosis. This raises safety concerns for the general and long-term use of TGF-b inhibition, especially in patients with

  Chapter 7  Liver Fibrogenesis: Mechanisms and Clinical Relevance

chronic hepatic inflammation. The use of integrin antagonists that inactivate TGF-b only at the stellate cell surface (see earlier) may mitigate this concern, but clinical data are still awaited. To antagonize PDGF, imatinib mesylate (Gleevec), a clinically approved tyrosine kinase inhibitor, attenuates proliferation and migration and fibrosis in animal models,172,173 and newer related drugs such as nilotinib, show promise as well.174 Sorafenib, a multi-kinase inhibitor approved for treatment of liver cancer, also shows antifibrotic activity in animal models,175 attesting to the contribution of receptor tyrosine kinases such as PGDFR in fibrosis as well as cancer. However, sorafenib has adverse effects (e.g., rash, diarrhea, hand-foot syndrome), which may be acceptable to patients with cancer but would not be acceptable to asymptomatic patients with fibrotic liver disease. Thus better-tolerated kinase inhibitors are an appealing class of antifibrotic compounds. Apart from blocking HSC-stimulating factors, activating HSC inhibitory factors is yet another possibility. Hepatocyte growth factor (HGF) inhibits HSC activation.176 However, potential procarcinogenic effects are probable and would limit its therapeutic use. In rodents, the blockade of the ETA receptor, which leads to vasoconstriction or scar-contraction upon binding of ET-1, and the administration of vasodilators (prostaglandin E2 and NO donors) have antifibrotic qualities.83,84 At one point, ET receptor blockade was highly attractive; however, clinical trials of these drugs for other indications demonstrated unacceptable

115

liver toxicity,177 and thus their development was halted until safety concerns can be more thoroughly addressed. Bone marrow–derived mesenchymal stem cells have an antifibrotic effect, and multiple clinical trials have been conducted. A key problem with autologous and stem cell and bone marrow therapies to date has been their incomplete characterization, such that the exact composition of cells being transplanted is not standardized.178 Recent human trials reinforce the safety of stem cell therapies,179,180 but evidence of clinical efficacy is still awaited. A key goal of future studies is to understand and fully control the cellular composition of stem cell therapies to reliably demonstrate efficacy and reproducibility.

Enhancing Extracellular Matrix Degradation Although no antifibrotic drug is approved for clinical use in patients with liver fibrosis, the broad and rational development of a range of promising compounds means that success is likely in the near future. The challenge ahead is to further refine therapeutic targets and to establish efficacy of these new drugs in vivo in animal models and in clinical trials. Equally challenging is the need to define clear and robust endpoints for clinical trials to ensure that a therapeutic benefit is apparent, based on improvement in noninvasive markers, improvement in biopsy, and, most importantly, by improving clinical outcomes. References are available at expertconsult.com.

115.e1

REFERENCES 1. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015;64(5):830-841. 2. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425-456. 3. Fierer DS, Uriel AJ, Carriero DC, et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis. 2008;198(5):683-686. 4. Rout G, Nayak B, Patel AH, et al. Therapy with oral directly acting agents in hepatitis C infection is associated with reduction in fibrosis and increase in hepatic steatosis on transient elastography. J Clin Exp Hepatol. 2019;9(2):207-214. 5. Guo J, Loke J, Zheng F, et al. Functional linkage of cirrhosispredictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology. 2009;49(3):960-968. 6. Powell EE, Edwards-Smith CJ, Hay JL, et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology. 2000;31(4):828-833. 7. Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152(5): 1090-1099.e1091. 8. Sookoian S, Pirola CJ. Genetics of nonalcoholic fatty liver disease: From pathogenesis to therapeutics. Semin Liver Dis. 2019;39(2): 124-140. 9. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210. 10. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397-411. 11. Grant CR, Liberal R. Liver immunology: How to reconcile tolerance with autoimmunity. Clin Res Hepatol Gastroenterol. 2017;41(1):6-16. 12. Wang Y, Zhang C. The roles of liver-resident lymphocytes in liver diseases. Front Immunol. 2019;10:1582. 13. Hernandez-Gea V, Hilscher M, Rozenfeld R, et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol. 2013;59(1):98-104. 14. Luan J, Ju D. Inflammasome: a double-edged sword in liver diseases. Front Immunol. 2018;9:2201. 15. Tomita K, Teratani T, Suzuki T, et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology. 2014;59(1): 154-169. 16. Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: translational approaches to develop targeted therapies. Hepatology. 2016;64(4):1343-1355. 17. Ma J, Cao H, Rodrigues RM, et al. Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1-p38MAPKalphadependent mechanisms. JCI Insight. 2020;5(14):e136496. 18. Cho YE, Kim DK, Seo W, Gao B, Yoo SH, Song BJ. Fructose promotes leaky gut, endotoxemia, and liver fibrosis through ethanolinducible cytochrome P450-2E1-mediated oxidative and nitrative stress. Hepatology. 2021;73(6):2180-2195. 19. Rachakonda V, Bataller R, Duarte-Rojo A. Recent advances in alcoholic hepatitis. F1000Res. 2020;9. 20. Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68(2):280-295. 21. Noureddin M, Sanyal AJ. Pathogenesis of NASH: The Impact of Multiple Pathways. Curr Hepatol Rep. 2018;17(4):350-360. 22. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922. 23. Higuchi H, Gores GJ. Mechanisms of liver injury: an overview. Curr Mol Med. 2003;3(6):483-490. 24. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17 (17-18):988-997. 25. Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014; 509(7499):183-188. 26. Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21(2):159-165.

27. Nieto N, Friedman SL, Cederbaum AI. Cytochrome P450 2E1derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells. J Biol Chem. 2002;277(12):9853-9864. 28. Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther. 2004;308 (3):1191-1196. 29. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. 30. Younossi Z, Tacke F, Arrese M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69(6):2672-2682. 31. De Minicis S, Day C, Svegliati-Baroni G. From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des. 2013;19(29):5239-5249. 32. Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15(6):349-364. 33. Friedman SL. Hepatic stellate cells – protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125-172. 34. Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019;575(7783):512-518. 35. Dobie R, Wilson-Kanamori JR, Henderson BEP, et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 2019;29(7):1832-1847.e8 36. Xiong X, Kuang H, Ansari S, et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell. 2019;75(3):644-660.e5 37. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis. 2001;21(3): 311-335. 38. Darby IA, Zakuan N, Billet F, Desmouliere A. The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci. 2016;73(6):1145-1157. 39. Bollong MJ, Yang B, Vergani N, et al. Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis. Proc Natl Acad Sci U S A. 2017;114(18):4678-4684. 40. Thannickal VJ. Mechanisms of pulmonary fibrosis: Role of activated myofibroblasts and NADPH oxidase. Fibrogenesis Tissue Repair. 2012; 5(suppl 1):S23. 41. Duffield JS. Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest. 2014;124(6):2299-2306. 42. Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823. 43. Wells RG. The portal fibroblast: not just a poor man’s stellate cell. Gastroenterology. 2014;147(1):41-47. 44. Lemoinne S, Cadoret A, Rautou PE, et al. Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles. Hepatology. 2015;61(3):1041-1055. 45. Tsuchida T, Lee YA, Fujiwara N, et al. A simple diet- and chemicalinduced murine nash model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69(2):385-395. 46. Marcher AB, Bendixen SM, Terkelsen MK, et al. Transcriptional regulation of hepatic stellate cell activation in NASH. Sci Rep. 2019;9(1):2324. 47. Pinzani M. Pathophysiology of liver fibrosis. Dig Dis. 2015;33(4): 492-497. 48. Moran-Salvador E, Mann J. Epigenetics and liver fibrosis. Cell Mol Gastroenterol Hepatol. 2017;4(1):125-134. 49. Page A, Paoli P, Salvador EM, White S, French J, Mann J. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol. 2016;64(3): 661-673. 50. Moran-Salvador E, Garcia-Macia M, Sivaharan A, et al. Fibrogenic activity of MECP2 is regulated by phosphorylation in hepatic stellate cells. Gastroenterology. 2019;157(5):1398-1412.e9. 51. Xu J, Liu X, Koyama Y, et al. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol. 2014;5:167. 52. Xu J, Kisseleva T. Bone marrow-derived fibrocytes contribute to liver fibrosis. Exp Biol Med (Maywood). 2015;240(6):691-700.

115.e2 53. Karin D, Koyama Y, Brenner D, Kisseleva T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation. 2016;92(3):84-92. 54. Chu AS, Diaz R, Hui JJ, et al. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology. 2011;53(5):1685-1695. 55. Safadi R, Ohta M, Alvarez CE, et al. Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin10 from hepatocytes. Gastroenterology. 2004;127(3):870-882. 56. Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta. 2013;1832(7):1061-1069. 57. Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest. 2017;127(1):55-64. 58. Winau F, Hegasy G, Weiskirchen R, et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007;26(1):117-129. 59. Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest. 1995;96(1):447-455. 60. Bachem MG, Melchior R, Gressner AM. The role of thrombocytes in liver fibrogenesis: effects of platelet lysate and thrombocytederived growth factors on the mitogenic activity and glycosaminoglycan synthesis of cultured rat liver fat storing cells. J Clin Chem Clin Biochem. 1989;27(9):555-565. 61. Fabregat I, Caballero-Diaz D. Transforming growth factor-betainduced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;8:357. 62. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-beta in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8(11):1419. 63. Tsukada S, Westwick JK, Ikejima K, Sato N, Rippe RA. SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells. J Biol Chem. 2005;280(11):10055-10064. 64. Henderson NC, Arnold TD, Katamura Y, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617-1624. 65. Huang G, Brigstock DR. Regulation of hepatic stellate cells by connective tissue growth factor. Front Biosci. 2012;17:2495-2507. 66. Chung SI, Moon H, Ju HL, et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J Hepatol. 2016;64(3):618-627. 67. Du K, Hyun J, Premont RT, et al. Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells. Gastroenterology. 2018;154(5):1465-1479.e13. 68. Borkham-Kamphorst E, Weiskirchen R. The PDGF system and its antagonists in liver fibrosis. Cytokine Growth F R. 2016;28:53-61. 69. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003;3(1):51-62. 70. Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol. 2016;13(3): 277-292. 71. Gao B, Xu M. Chemokines and alcoholic hepatitis: Are chemokines good therapeutic targets? Gut. 2014;63(11):1683-1684. 72. Roh YS, Seki E. Chemokines and chemokine receptors in the development of NAFLD. Adv Exp Med Biol. 2018;1061:45-53. 73. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147(3):577-594.e71. 74. Yu MC, Chen CH, Liang X, et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology. 2004;40(6):1312-1321. 75. Muhanna N, Doron S, Wald O, et al. Activation of hepatic stellate cells after phagocytosis of lymphocytes: A novel pathway of fibrogenesis. Hepatology. 2008;48(3):963-977. 76. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest. 2003;83(5):655-663. 77. Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A. 1997;94(20):10663-10668. 78. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48(1):322-335.

79. Ge X, Arriazu E, Magdaleno F, et al. High mobility group box-1 drives fibrosis progression signaling via the receptor for advanced glycation end products in mice. Hepatology. 2018;68(6):2380-2404. 80. Wree A, Eguchi A, McGeough MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis. Hepatology. 2014;59(3):898-910. 81. Alegre F, Pelegrin P, Feldstein AE. Inflammasomes in liver fibrosis. Semin Liver Dis. 2017;37(2):119-127. 82. Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66(6):1300-1312. 83. Khimji AK, Rockey DC. Endothelin and hepatic wound healing. Pharmacol Res. 2011;63(6):512-518. 84. Rockey DC. Endothelial dysfunction in advanced liver disease. Am J Med Sci. 2015;349(1):6-16. 85. Olaso E, Arteta B, Benedicto A, Crende O, Friedman SL. Loss of discoidin domain receptor 2 promotes hepatic fibrosis after chronic carbon tetrachloride through altered paracrine interactions between hepatic stellate cells and liver-associated macrophages. Am J Pathol. 2011;179(6):2894-2904. 86. Kesteloot F, Desmouliere A, Leclercq I, et al. ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice. Hepatology. 2007;46(5):1620-1631. 87. Perepelyuk M, Terajima M, Wang AY, et al. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol. 2013;304(6):G605-G614. 88. Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histologicalhemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol. 2006;44(1):111-117. 89. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16(9):1009-1017. 90. Campana L, Iredale JP. Regression of Liver Fibrosis. Semin Liver Dis. 2017;37(1):1-10. 91. Murphy FR, Issa R, Zhou X, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem. 2002; 277(13):11069-11076. 92. Zhou X, Hovell CJ, Pawley S, et al. Expression of matrix metalloproteinase-2 and -14 persists during early resolution of experimental liver fibrosis and might contribute to fibrolysis. Liver Int. 2004; 24(5):492-501. 93. Ramachandran P, Iredale JP. Macrophages: central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol. 2012;56(6): 1417-1419. 94. Ramachandran P, Iredale JP. Liver fibrosis: a bidirectional model of fibrogenesis and resolution. QJM. 2012;105(9):813-817. 95. Birukawa NK, Murase K, Sato Y, et al. Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth. J Biol Chem. 2014;289(29): 20209-20221. 96. Jiao J, Sastre D, Fiel MI, et al. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology. 2012;55(1):244-255. 97. Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178(8):5288-5295. 98. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-194. 99. Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012;109(46):E3186-E3195. 100. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449-1457. 101. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898-1906. 102. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97(10):2614-2618.

115.e3 103. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1(5):431-435. 104. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22(6):696-699. 105. METAVIR csg. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology. 1994; 20(1 Pt 1):15-20. 106. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810-820. 107. Huang Y, de Boer WB, Adams LA, MacQuillan G, Bulsara MK, Jeffrey GP. Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome. J Hepatol. 2014;61(1):22-27. 108. Calvaruso V, Di Marco V, Bavetta MG, et al. Quantification of fibrosis by collagen proportionate area predicts hepatic decompensation in hepatitis C cirrhosis. Aliment Pharmacol Ther. 2015; 41(5):477-486. 109. Tsochatzis E, Bruno S, Isgro G, et al. Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis. J Hepatol. 2014;60(5):948-954. 110. Watt GP, Lee M, Pan JJ, et al. High prevalence of hepatic fibrosis, measured by elastography, in a population-based study of Mexican Americans. Clin Gastroenterol Hepatol. 2019;17(5):968-975.e65. 111. Karsdal MA, Daniels SJ, Holm Nielsen S, et al. Collagen biology and non-invasive bioarkers of liver fibrosis. Liv Int. 2020;40(4): 736-750. 112. Zhou IY, Catalano OA, Caravan P. Advances in functional and molecular MRI technologies in chronic liver diseases. J Hepatol. 2020;73(5):1241-1254. 113. Montesi SB, Desogere P, Fuchs BC, Caravan P. Molecular imaging of fibrosis: recent advances and future directions. J Clin Invest. 2019;129(1):24-33. 114. Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral longterm Treatment Against Cirrhosis Trial. Hepatology. 2012;55(4): 1019-1029. 115. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518-526. 116. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. 117. Vesterhus M, Hov JR, Holm A, et al. Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis. Hepatology. 2015;62(1):188-197. 118. Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology. 2019;70:1521-1530. 119. Bril F, McPhaul MJ, Caulfield MP, et al. Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. J Investig Med. 2019;67(2):303-311. 120. Leroy V, Sturm N, Faure P, et al. Prospective evaluation of FibroTest(R), FibroMeter(R), and HepaScore(R) for staging liver fibrosis in chronic hepatitis B: comparison with hepatitis C. J Hepatol. 2014;61(1):28-34. 121. Holm Nielsen S, Mortensen JH, Willumsen N, et al. A fragment of collagen type VI alpha-3 chain is elevated in serum from patients with gastrointestinal disorders. Sci Rep. 2020;10(1):5910. 122. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156(5):1264-1281.e64. 123. Mehta SH, Lau B, Afdhal NH, Thomas DL. Exceeding the limits of liver histology markers. J Hepatol. 2009;50(1):36-41. 124. Mayo MJ, Parkes J, Adams-Huet B, et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology. 2008;48(5):1549-1557. 125. Ngo Y, Munteanu M, Messous D, et al. A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C. Clin Chem. 2006;52(10):1887-1896.

126. Houglum K, Bedossa P, Chojkier M. TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload. Am J Physiol. 1994;267(5 Pt 1):G908G913. 127. Deffieux T, Gennisson JL, Bousquet L, et al. Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography. J Hepatol. 2015;62(2):317-324. 128. Smith AD, Porter KK, Elkassem AA, Sanyal R, Lockhart ME. Current imaging techniques for noninvasive staging of hepatic fibrosis. AJR Am J Roentgenol. 2019:1-13. 129. Zhu B, Wei L, Rotile N, et al. Combined magnetic resonance elastography and collagen molecular magnetic resonance imaging accurately stage liver fibrosis in a rat model. Hepatology. 2017; 65(3):1015-1025. 130. Jayakumar S, Middleton MS, Lawitz EJ, et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: analysis of data from a phase II trial of selonsertib. J Hepatol. 2019;70(1):133-141. 131. Kennedy P, Wagner M, Castera L, et al. Quantitative elastography methods in liver disease: current evidence and future directions. Radiology. 2018;286(3):738-763. 132. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343-350. 133. de Ledinghen V, Vergniol J, Foucher J, Merrouche W, le Bail B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liv Int. 2012;32(6):911-918. 134. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-488. 135. Ravaioli F, Montagnani M, Lisotti A, Festi D, Mazzella G, Azzaroli F. Noninvasive assessment of portal hypertension in advanced chronic liver disease: an update. Gastroenterol Res Pract. 2018; 2018:4202091. 136. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. 137. Friedman SL, Bansal MB. Reversal of hepatic fibrosis — fact or fantasy? Hepatology. 2006;43(2 suppl 1):S82-S88. 138. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865): 468-475. 139. D’Ambrosio R, Aghemo A, Rumi MG, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012;56(2):532-543. 140. Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149(2):379-388; quiz e315-e376. 141. Younossi ZM, Tampi R, Priyadarshini M, Nader F, Younossi IM, Racila A. Burden of illness and economic model for patients with nonalcoholic steatohepatitis in the United States. Hepatology. 2019; 69(2):564-572. 142. Nakamura T, Torimura T, Sakamoto M, et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology. 2007;133(1): 91-107.e01. 143. Yang L, Kwon J, Popov Y, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology. 2014;146(5):1339-1350.e31. 144. Lee YA, Friedman SL. Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C? Antiviral Res. 2014;107C:23-30. 145. Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fibrosis. Hepatology. 2004;39(2):273-278. 146. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(17):1-5. 147. Dohil R, Schmeltzer S, Cabrera BL, et al. Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;33(9):1036-1044.

115.e4 148. Medici V, Virata MC, Peerson JM, et al. S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol Clin Exp Res. 2011;35(11): 1960-1965. 149. Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147-1159.e45. 150. Perugorria MJ, Olaizola P, Labiano I, et al. Wnt-beta-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16(2):121-136. 151. Kisseleva T, Cong M, Paik Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A. 2012;109(24):9448-9453. 152. Troeger JS, Mederacke I, Gwak GY, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology. 2012;143(4):1073-1083.e22. 153. Nakano Y, Kamiya A, Sumiyoshi H, Tsuruya K, Kagawa T, Inagaki Y. A deactivation factor of fibrogenic hepatic stellate cells induces regression of liver fibrosis in mice. Hepatology. 2020;71(4): 1437-1452. 154. Wang S, Friedman SL. Hepatic fibrosis: a convergent response to liver injury that is reversible. J Hepatol. 2020;73(1):210-211. 155. Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest. 1998;102(3):538-549. 156. Yoshiji H, Kuriyama S, Miyamoto Y, et al. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology. 2000;32(6):1248-1254. 157. Sato Y, Murase K, Kato J, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagenspecific chaperone. Nat Biotechnol. 2008;26(4):431-442. 158. Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoid signaling and liver therapeutics. J Hepatol. 2013;59(4):891-896. 159. Munoz-Luque J, Ros J, Fernandez-Varo G, et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther. 2008;324(2):475-483. 160. Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005;128(3):742-755. 161. Schnittert J, Bansal R, Storm G, Prakash J. Integrins in wound healing, fibrosis and tumor stroma: high potential targets for therapeutics and drug delivery. Adv Drug Deliv Rev. 2018;129: 37-53. 162. Zhou X, Murphy FR, Gehdu N, Zhang J, Iredale JP, Benyon RC. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem. 2004;279(23): 23996-24006. 163. Li Y, Pu S, Liu Q, et al. An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis. J Control Release. 2019;303:77-90. 164. Raetsch C, Jia JD, Boigk G, et al. Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis. Gut. 2002;50(2):241-247.

165. Xu Z, Zhang X, Lau J, Yu J. C-X-C motif chemokine 10 in nonalcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication. Expert Rev Mol Med. 2016;18:e16. 166. Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11(6):e0158156. 167. Bataller R, Schwabe RF, Choi YH, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112(9):1383-1394. 168. Bataller R, Sancho-Bru P, Gines P, et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125(1):117-125. 169. Traussnigg S, Schattenberg JM, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol. 2019;4(10): 781-793. 170. Beuers U, Kullak-Ublick GA, Pusl T, Rauws ER, Rust C. Medical treatment of primary sclerosing cholangitis: a role for novel bile acids and other (post-)transcriptional modulators? Clin Rev Allergy Immunol. 2009;36(1):52-61. 171. Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184-2196. 172. Kuo WL, Yu MC, Lee JF, Tsai CN, Chen TC, Chen MF. Imatinib mesylate improves liver regeneration and attenuates liver fibrogenesis in CCL4-treated mice. J Gastrointest Surg. 2012;16(2):361-369. 173. Kim Y, Fiel MI, Albanis E, et al. Anti-fibrotic activity and enhanced interleukin-6 production by hepatic stellate cells in response to imatinib mesylate. Liver Int. 2012. 32(6):1008-1017. 174. Liu Y, Wang Z, Kwong SQ, et al. Inhibition of PDGF, TGF-beta, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist nilotinib. J Hepatol. 2011;55(3):612-625. 175. Hong F, Chou H, Fiel MI, Friedman SL. Antifibrotic activity of sorafenib in experimental hepatic fibrosis: refinement of inhibitory targets, dosing, and window of efficacy in vivo. Dig Dis Sci. 2013;58(1):257-264. 176. Narmada BC, Chia SM, Tucker-Kellogg L, Yu H. HGF regulates the activation of TGF-beta1 in rat hepatocytes and hepatic stellate cells. J Cell Physiol. 2013;228(2):393-401. 177. Kenna JG, Stahl SH, Eakins JA, et al. Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists. J Pharmacol Exp Ther. 2015;352(2):281-290. 178. Moore JK, Stutchfield BM, Forbes SJ. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther. 2014;39(7):673-685. 179. Moroni F, Dwyer BJ, Graham C, et al. Safety profile of autologous macrophage therapy for liver cirrhosis. Nat Med. 2019;25(10): 1560-1565. 180. Newsome PN, Fox R, King AL, et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2018;3(1):25-36.

CHAPTER 8 Bile secretion and pathophysiology of biliary tract obstruction Henry A. Pitt and Attila Nakeeb OVERVIEW Bile secretion is one of the major functions of the liver, which serves two major purposes: (1) the excretion of hepatic metabolites—including bilirubin, cholesterol, drugs, and toxins— and (2) the facilitation of intestinal absorption of lipids and fat-soluble vitamins. More recently, through their interaction with the gut microbiome, bile acids also have been found to have important signaling functions. Through receptor activation, bile acids regulate lipid, glucose, and energy metabolism. Alterations in bile secretion also may contribute to cholelithiasis (see Chapter 33) and its potential complications, such as cholecystitis (see Chapter 34) and choledocholithiasis (see Chapters 37 and 38). On the other hand, obstruction of bile flow results in alterations of coagulation, the immune system, and all organ functions. This chapter will discuss the physiology of bile secretion, the pathophysiology of bile obstruction, and the management of obstructive jaundice.

BILE SECRETION Bile Formation The two primary roles of bile in normal physiology are the excretion of organic compounds, such as bilirubin and cholesterol, and the intestinal absorption of lipids. Bile secretion results from the active transport of solutes into the canaliculus, followed by the passive flow of water. Water constitutes approximately 85% of the volume of bile. The major organic solutes in bile are bilirubin, bile salts, phospholipids, and cholesterol. Bilirubin, the breakdown product of spent red blood cells, is conjugated with glucuronic acid by the hepatic enzyme glucuronyl transferase and is excreted actively into the adjacent canaliculus. Normally, a large enzyme reserve exists to handle excess bilirubin production, which might exist in hemolytic states. Bile salts are steroid molecules synthesized by hepatocytes. Bile salts account for approximately 72% of the biliary lipids. The primary bile salts in humans, cholic and chenodeoxycholic acid, account for approximately 80% of those produced. The primary bile salts, which are then conjugated with either taurine or glycine, can undergo bacterial alteration in the intestine to form the secondary bile salts, deoxycholate and lithocholate. The purpose of bile salts is to solubilize lipids and facilitate their absorption. Phospholipids are synthesized in the liver in conjunction with bile salt synthesis and account for approximately 24% of biliary lipids. Lecithin is the primary phospholipid in human bile, constituting more than 95% of its total. The final major solute of bile is cholesterol, which accounts for 4% of the lipids. Cholesterol also is produced primarily by the liver with a small contribution from dietary sources. 116

The normal volume of bile secreted daily by the liver is 750 to 1000 mL. Bile flow depends on neurogenic, humoral, and chemical control. Vagal stimulation increases bile secretion, whereas splanchnic stimulation causes vasoconstriction with decreased hepatic blood flow and thus results in diminished bile secretion. Gastrointestinal hormones—secretin, cholecystokinin, gastrin, and glucagon—all increase bile flow, primarily by increasing water and electrolyte secretion. This action probably occurs at a site distal to the hepatocyte. Finally, the most important factor in regulating the volume of bile flow is the rate of bile salt synthesis by hepatocytes. This rate is regulated by the return of bile salts to the liver by the enterohepatic circulation.

Bile Composition The components of hepatic and gallbladder bile are essentially the same, but the concentration varies considerably because of the ability of the gallbladder to absorb water (Table 8.1). The gallbladder absorbs water both actively via sodium-hydrogen (Na1/H1) pumps and passively through aquaporin channels. Both chloride (Cl2) and bicarbonate (HCO32) are absorbed by the gallbladder epithelium via the cystic fibrosis transmembrane regulator (CFTR).1 The secretion of hydrogen ions and the absorption of bicarbonate by the gallbladder alter the acid-base balance from basic in hepatic bile to acidic in gallbladder bile. The gallbladder mucosa also absorbs calcium (Ca12) and magnesium (Mg12). Nevertheless, calcium absorption is not as efficient as the absorption of sodium and water, which leads to a significantly greater relative increase in the concentration of calcium in the gallbladder. Similarly, the concentration of bilirubin, which is not actively absorbed by the gallbladder, may be as high as 10-fold. Thus precipitation of calcium bilirubinate crystals, the major component of pigment gallstones, is much more likely to occur within the gallbladder. In addition, the biliary lipids, bile salts, phospholipids, and cholesterol all become more concentrated in the gallbladder. While gallbladder bile becomes concentrated, several changes occur in the capacity of bile to solubilize cholesterol. The solubility in the micellar fraction is increased, but the stability of the phospholipid-cholesterol vesicles is greatly decreased. Because cholesterol crystal precipitation occurs preferentially by vesicular, rather than micellar, mechanisms, the net effect of concentrating bile is an increased tendency to form cholesterol crystals.2

Bile Salt Secretion Bile is secreted from the hepatocyte into canaliculi, which drain their contents into small bile ducts. Secretion of bile salts is the major osmotic force for the generation of bile flow. Bile acids are formed at a rate of 500 to 600 mg per day. The bulk of the bile salt pool is maintained in the gallbladder, followed by the liver, the small intestine, and the extrahepatic bile ducts.

117

  Chapter 8  Bile Secretion and Pathophysiology of Biliary Tract Obstruction

TABLE 8.1  Composition of Hepatic and Gallbladder Bile CHARACTERISTICS*

HEPATIC BILE

GALLBLADDER BILE

Sodium 160 Potassium 5 Chloride 90 Bicarbonate 45 Calcium 4 Magnesium 2 Bilirubin 1.5 Proteins 150 Bile acids 50 Phospholipids 8 Cholesterol 4 Total solids — pH 7.8 Significant ranges may be seen.

270   10   15   10   25    4   15 200 150   40   18 125 7.2

*All determinations are milliequivalents per liter, except for pH.

Bile acids are synthesized from cholesterol via two main pathways: a classic pathway leads to the formation of cholic acid, and an alternative pathway results in the synthesis of chenodeoxycholic acid. The classic pathway is the predominant mode of bile acid synthesis in humans. As a result, 60% to 70% of the bile acid pool consists of cholic acid and its metabolite deoxycholic acid, with chenodeoxycholic acid occurring less commonly in human bile.3,4 In plasma, bile acids circulate bound to either albumin or lipoproteins. In the space of Disse within the liver, bile salt

uptake into the hepatocytes is very efficient. This process is mediated by sodium-dependent and sodium-independent mechanisms. The sodium-dependent pathway accounts for more than 80% of taurocholate uptake but less than 50% of cholate uptake.5 In recent years, a number of transport proteins have been identified that play a key role in this process (Fig. 8.1). The bile salt transporter is termed the sodiumtaurocholate cotransporting polypeptide (NTCP) and is exclusively expressed in the liver and located in the basolateral membrane of the hepatocyte. Sodium-independent hepatic uptake of bile acids is mediated primarily by a family of transporters termed the organic anion transporting polypeptides (OATPs). In contrast to NTCP, these transporters have a broader substrate affinity and transport a variety of organic anions, including the bile salts. OATP-C is the major sodium-independent bile salt uptake system, but OATP-A also takes up bile acids, and OATP-8 mediates taurocholate uptake. Intracellular bile acid transport occurs within a matter of seconds. Two mechanisms may be responsible for bile acid transcellular movement: One involves transfer of bile acids from the basolateral membrane to the canalicular membrane via bile acid–binding proteins6; the other moves cellular bile salts through vesicular transport. In contrast, the transport of bile salts across the canalicular membrane of hepatocytes represents the rate-limiting step in the overall secretion of bile salts from the blood into bile. Bile salt concentrations are 1,000-fold greater within the canaliculi than in the hepatocytes. This gradient necessitates an active transport mechanism, which is an adenosine triphosphate (ATP)-dependent process. The ATP-binding cassette transporter ABCB 11 (formerly known as the bile salt export pump [BSEP])

Bile Salt Transport

Biliary Lipids/Bilirubin/Drug Transport

Hepatocyte

Hepatocyte Bile Canaliculus

Bile Salt Uptake

BSEP

NTCP

BS Na+

BS

HBAB

??Biliary Lipid Uptake and Intracellular Transport??

MDR3

BS

BL MDR1

OATP-A D/OA

Bile

??Bile Salt Intracellular Transport??

BRCP BS

OATPs

BL

BS

MRP2 BS

BS ER/Golgi

D/OA

D/OA B

MRP2 B, D/OA

Vesicles

OATP-C B

ER

Na+

BS, B, D/OA MRP3

Na+/K+-ATPase Basolateral (Sinusoidal) Domain +

K

FIGURE 8.1  Bile formation in human liver. ATP, Adenosine triphosphate; B, bilirubin; BL, biliary lipids; BRCP, breast cancer–related protein; BS, bile salts; BSEP, bile salt export pump; D/OA, drugs/organic anions; ER, endoplasmic reticulum; HBAB, hepatic bile acid–binding protein; MDR1 and MDR3, multidrug-resistance proteins 1 and 3, respectively; MRP3, MDR-related protein-3; NTCP, Na1-taurocholate cotransporting polypeptide; OATPs (A, C, 8), organic anion transporting polypeptides.

118

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

plays a key role in this process.7 The ABC transporters mediate the transport of metabolites, peptides, fatty acids, cholesterol, and lipids in the liver, intestines, pancreas, lungs, kidneys, brain, and in macrophages. Although ABCB 11 is the major transporter for monovalent bile salts into the canaliculus, MDR-related protein-2 (MRP2), a member of the multidrug-resistant protein family, also transports sulfated and glucuronidated bile salts into the canaliculus. MRP2 also mediates the export of multiple other organic anions, including conjugated bilirubin, leukotrienes, glutathione disulfide, chemotherapeutic agents, uricosurics, antibiotics, toxins, and heavy metals.8 Recent studies suggest that bile acids are signaling molecules that regulate lipid, glucose, and energy metabolism.9 This function of bile acids is mediated primarily by the nuclear receptor farnesoid X receptor (FXR) and the G-protein–coupled receptor TGR5. Bile acids in the small and large intestine regulate the gut microbiome, incretin secretion, and the production of fibroblast growth factors 15 and 19 (FGF15/FGF19).10 These FGFs, in turn, modulate lipid, glucose, and energy metabolism and may play a role in the rapid improvement in glycemic control after gastric bypass surgery. In addition, FXR and TGR5 receptors exist in other tissues, such as the heart and the kidneys, and, therefore, may help to explain the dysfunction that occurs in these organs with biliary obstruction.11

vesicles are made up of lipid bilayers of cholesterol and phospholipids. In their simplest and smallest form, the vesicles are unilamellar, but an aggregation may take place, leading to multilamellar vesicles. Present theory suggests that in states of excess cholesterol production, these large vesicles also may exceed their capability to transport cholesterol, and crystal precipitation may occur (Fig. 8.2).

Bilirubin Secretion Heme is released at the time of degradation of senescent erythrocytes by the reticuloendothelial system. Heme is the source of approximately 80% to 85% of the bilirubin that is produced daily. The remaining 15% to 20% is derived largely from the breakdown of hepatic hemoproteins. Both enzymatic and nonenzymatic pathways for the formation of bilirubin have been proposed. Although both may be important physiologically, the microsomal enzyme heme oxygenase—found in high concentration throughout the liver, spleen, and bone marrow—plays a major role in the initial conversion of heme to biliverdin, which is then reduced to bilirubin by the cytosolic enzyme biliverdin reductase before being released into the circulation. In this “unconjugated” form, bilirubin has a very low solubility and is bound avidly to plasma proteins, primarily albumin, before

Biliary Lipid Secretion Compared with bile salts, the biliary lipids, phospholipids and cholesterol play a secondary role in the formation of bile. Phospholipids and cholesterol are formed primarily from lowdensity lipoproteins circulating in plasma and from de novo synthesis by hepatocytes. Less is known about the secretion of biliary lipids compared with bile salt secretion; however, biliary lipid secretion is crucial for cholesterol disposal, intestinal absorption of dietary lipids, and cytoprotection against bile acid–induced hepatocyte and cholangiocyte injury.12 Phospholipid secretion involves the delivery of phospholipids to the inner leaflet of the canalicular plasma membrane. In humans, the MDR3 transporter translocates phospholipids from the inner to the outer leaflet of the canalicular membrane. Progressive familial intrahepatic cholestatis type 3 develops in humans with an MDR3 deficiency.3 These patients have no phosphatidylcholine in bile and therefore do not form mixed micelles with bile salts. As a result, toxic bile salts injure the biliary epithelium, resulting in neonatal cholestasis, cholestasis of pregnancy, and cirrhosis in adults. Less is known about the role of transporter proteins in cholesterol secretion, but the ABC transporters ABCG5 and ABCG8 have been demonstrated to be involved in the elimination of plant steroids.13 Cholesterol is highly nonpolar and insoluble in water and, therefore, also is insoluble in bile. The key to maintaining cholesterol in solution is the formation of micelles, a bile salt–phospholipid–cholesterol complex. Bile salts are amphipathic compounds that contain both a hydrophilic and hydrophobic portion. In aqueous solutions, bile salts are oriented with the hydrophilic portion outward. Phospholipids are incorporated into the micellar structure, allowing cholesterol to be added to the hydrophobic central portion of the micelle. In this way, cholesterol can be maintained in solution in an aqueous medium. The concept of mixed micelles as the only cholesterol carrier has been challenged by the demonstration that much of the biliary cholesterol exists in a vesicular form. Structurally, these

HEPATIC BILE Micelles Unilamellar vesicle (phospholipid-rich)

– H2O GALLBLADDER BILE

Unilamellar vesicle (cholesterol-enriched) Fusion

Large, cholesterol-rich multilamellar vesicles

Cholesterol monohydrate crystal nucleation FIGURE 8.2  Concentration of bile leads to net transfer of phospholipids and cholesterol from vesicles to micelles. Phospholipids are transferred more efficiently than cholesterol, leading to cholesterol enrichment of the remaining (remodeled) vesicles. Aggregation of these cholesterolrich vesicles forms multilamellar liquid crystals of cholesterol monohydrate. (From Vessey DA. Metabolism of drugs and toxins by the human liver. In Zakin D, Boyer TD, eds. Hepatology: A Textbook of Liver Disease. 2nd ed. WB Saunders 1990:1492.)

  Chapter 8  Bile Secretion and Pathophysiology of Biliary Tract Obstruction

uptake and further processing by the liver. The liver is the sole organ capable of removing the albumin-bilirubin complex from the circulation and esterifying the potentially toxic bilirubin to water-soluble, nontoxic, monoconjugated and deconjugated derivatives. In the sinusoidal membrane of the hepatocyte, bilirubin is taken up by OATP-C, a membrane transporter belonging to the OATP family.14 OATP-C is involved with the uptake of both conjugated and unconjugated bilirubin, but unconjugated bilirubin also can cross hepatic sinusoidal membranes by a diffusion process. In the hepatocyte, bilirubin binds to a driver of glutathione-S-transferase and is catalyzed by bilirubin uridine-59-diphosphate glycosyltransferase to form bilirubin glucuronides. Mutations in the gene encoding bilirubin UDP-glycosyltransferase are associated with the unconjugated hyperbilirubin syndromes, Crigler-Najjar and Gilbert syndromes.15 Bilirubin glucuronides are excreted into the bile canaliculus primarily via MRP2, which also plays a role in the transport of glucuroniductal bile salts and a wide spectrum of organic anions, including the antibiotic ceftriaxone. MRP3, which is expressed in the basolateral membrane of hepatocytes and cholangiocytes, also participates in the transport of bilirubin monoglucuronide. In addition, MRP3 may prevent intracellular accumulation of conjugated bilirubin, bile salts, and other organic anions in cholestatic situations.

119

Cholesterol

LIVER

Newly synthesized bile acid (≈ 0.6 g/24 hr)

Blood (cholesterol) SMALL BOWEL

2-4 g bile acid pool cycling PORTAL 6-10x/day VEIN COLON

Fecal bile acids (≈ 0.6 g/24 hr) FIGURE 8.3  Enterohepatic circulation of bile salts. Cholesterol is taken up from plasma by the liver. Bile acids are synthesized at a rate of 0.6 g/24 hr and are excreted through the biliary system into the small bowel. Most of the bile salts are reabsorbed in the terminal ileum and are returned to the liver to be extracted and reextracted. (Modified from Dietschy JM. The biology of bile acids. Arch Intern Med. 1972;130:482–474.)

Bile Flow The bile ducts, gallbladder, and sphincter of Oddi act in concert to modify, store, and regulate the flow of bile. Bile flow is primarily driven by bile salt secretion. During its passage through the bile ductules, canalicular bile is modified by the absorption and secretion of electrolytes and water. Bicarbonate secretion by the bile ducts plays an important role in bile salt–independent bile flow. The gastrointestinal hormone secretin increases bile flow primarily by increasing the active secretion of chloride-rich fluid by the bile ducts. Bile duct secretion also is stimulated by other hormones, such as cholecystokinin and gastrin. The bile duct epithelium is capable of water and electrolyte absorption, which may be of primary importance in the storage of bile during fasting in patients who have previously undergone cholecystectomy. The main functions of the gallbladder are to concentrate and store hepatic bile during the fasting state and deliver bile into the duodenum in response to a meal. The usual capacity of the human gallbladder is about 40 to 50 mL. Only a small fraction of the bile produced each day would be stored, were it not for the gallbladder’s remarkable absorptive capacity. The enterohepatic circulation provides an important negative feedback system on bile salt synthesis. Should the recirculation be interrupted by resection of the terminal ileum or by primary ileal disease, abnormally large losses of bile salts occur. This situation increases bile salt production to maintain a normal bile salt pool. Similarly, if bile salts are lost through an external biliary fistula, increased bile salt synthesis is necessary. Except for those unusual circumstances in which excessive losses occur, however, bile salt synthesis matches losses, maintaining a constant bile salt pool size. During fasting, approximately 90% of the bile acid pool is sequestered in the gallbladder.

Enterohepatic Circulation Bile salts are synthesized and conjugated in the liver; secreted into bile; stored temporarily in the gallbladder; passed from the

gallbladder into the duodenum; absorbed throughout the small intestine, especially in the ileum; and returned to the liver via the portal vein. This cycling of bile acids between the liver and the intestine is referred to as the enterohepatic circulation (Fig. 8.3). The total amount of bile acids in the enterohepatic circulation is defined as the circulating bile pool. In this highly efficient system, nearly 95% of bile salts are reabsorbed. Thus, of the total bile salt pool of 2 to 4 g, which recycles through the enterohepatic cycle 6 to 10 times daily, only about 600 mg is actually excreted into the colon. Bacterial action in the colon on the two primary bile salts, cholate and chenodeoxycholate, results in the formation of the secondary bile salts, deoxycholate and lithocholate. In fact, the bile acid signature of an individual is very dependent on gut microbial modification.10,11 Bacterial enzymes modify primary bile acids through deconjugation, dehydrogenation, dehydroxylation, and sulfation reactions. In turn, bile acids restrict bacterial proliferation and overgrowth. However, the physiology of bile salts, biliary lipids, bilirubin, bile flow, and the enterohepatic circulation is dramatically altered when the bile ducts become obstructed.

BILIARY OBSTRUCTION The evaluation and management of the patient with biliary obstruction is a common problem facing the general surgeon. Over the past 40 years, significant advances have been made in our understanding of the pathophysiology, diagnosis, and management of the jaundiced patient. Similarly, advances have been made in perioperative and operative management that have resulted in improved survival of the jaundiced patient. Obstructive jaundice affects multiple organ systems, including hepatic, renal, cardiovascular, hematologic, and immune systems. This section will review the causes, pathophysiology, and management of biliary obstruction.

120

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

TABLE 8.2  Classification of Jaundice DEFECT IN BILIRUBIN METABOLISM

PREDOMINANT HYPERBILIRUBINEMIA

EXAMPLES

Increased production

Unconjugated

Impaired hepatocyte uptake Reduced conjugation Altered transport and excretion Biliary obstruction

Unconjugated Unconjugated Conjugated Conjugated

Congenital hemoglobinopathies, hemolysis, multiple transfusions, sepsis, burns Gilbert disease, drug induced Neonatal jaundice, Crigler-Najjar syndrome Hepatitis, cirrhosis, Dubin-Johnson syndrome, Rotor syndrome Choledocholithiasis, benign strictures, chronic pancreatitis, sclerosing cholangitis, periampullary cancer, biliary malignancies

Causes of Jaundice Jaundice may result from (1) increased production of bilirubin, (2) impaired hepatocyte uptake of bilirubin, (3) reduced conjugation of bilirubin, (4) altered transport or excretion of bilirubin into the bile canaliculus, or (5) obstruction of the intrahepatic or extrahepatic biliary tree (Table 8.2). Overproduction, impaired uptake, and reduced conjugation of bilirubin all lead to a predominantly unconjugated hyperbilirubinemia. Altered transport and excretion and biliary ductal obstruction result in hyperbilirubinemia that is primarily conjugated. Some patients have multiple defects in normal metabolism. For example, secondary hepatocellular dysfunction may develop in a patient with biliary obstruction from a tumor. Therefore these classification systems may be simplifications of more complex disease processes. Diseases that cause bile duct obstruction may be further divided into conditions that cause (1) complete obstruction, (2) intermittent obstruction, (3) chronic incomplete obstruction, or (4) segmental duct obstruction (Box 8.1). Patients with complete biliary obstruction will have clinical jaundice, and those with intermittent obstruction may experience symptoms (pain, pruritus, fevers) and biochemical changes without necessarily experiencing clinical jaundice. Hepatic fibrosis can eventually develop in patients with chronic incomplete obstruction (see Chapter 7) and biliary cirrhosis (see Chapters 7 and 74).

Pathophysiology Biliary obstruction produces local effects on the bile ducts, which lead to derangements of hepatic function and, ultimately, to widespread systemic effects. Jaundiced patients are at increased risk for hepatic dysfunction, renal failure, cardiovascular impairments, nutritional deficiencies, bleeding problems, infections, and wound complications. Importantly, perioperative mortality and morbidity are increased in patients with biliary obstruction.

Hepatobiliary Hepatocytes are arranged in plates along which blood flows from portal to central veins. Within these plates, the small apical domains of adjacent hepatocytes form a tubular lumen, the canaliculus, which is the site of primary bile formation. From the canalicular network, bile flows to the small ductules and subsequently to the larger ducts. With biliary obstruction, the bile canaliculi become dilated, and the microvilli are distorted and swollen. In patients with long-standing obstruction, intrahepatic bile ductule proliferation occurs with an increase in the length and tortuosity of the canaliculi. The biliary system normally has a low pressure (5–10 cm H2O); however, in the setting of complete or partial biliary obstruction, biliary pressure can approach 30 cm H2O. While

BOX 8.1  Lesions Commonly Associated With Biliary Tract Obstruction Type I: Complete Obstruction Tumors of the head of the pancreas Common bile duct ligation Cholangiocarcinoma Gallbladder cancer Parenchymal liver tumors (primary or secondary) Type II: Intermittent Obstruction Choledocholithiasis Periampullary tumors Duodenal diverticula Choledochal cyst Polycystic liver disease Biliary parasites Hemobilia Type III: Chronic Incomplete Obstruction Strictures of the common bile duct Congenital biliary atresia Traumatic (iatrogenic) Sclerosing cholangitis Post radiotherapy Stenosis of biliary-enteric anastomosis Chronic pancreatitis Cystic fibrosis Sphincter of Oddi stenosis Type IV: Segmental Obstruction Traumatic Intrahepatic stones Sclerosing cholangitis Cholangiocarcinoma

biliary pressure increases, the tight junctions between hepatocytes and bile duct cells are disrupted, resulting in an increase in bile duct and canalicular permeability. Bile contents can freely reflux into liver sinusoids, causing a marked polymorphonuclear leukocyte infiltration into the portal triads. This inflammatory response is followed by increased fibrinogenesis with deposition of reticulin fibers, which undergo conversion to type I collagen (see Chapter 7). The extrahepatic bile ducts exhibit mucosal atrophy and squamous metaplasia, followed by inflammatory infiltration and fibrosis in the subepithelial layers of the bile duct.16 In addition to the structural effects of biliary obstruction on the bile ducts, elevated biliary pressure can alter bile production by hepatocytes. In the setting of biliary obstruction and

  Chapter 8  Bile Secretion and Pathophysiology of Biliary Tract Obstruction

elevated biliary pressure, bile becomes less lithogenic because of a relative decrease in cholesterol and phospholipid secretion compared with bile acid secretion. With the relief of biliary obstruction and the normalization of biliary pressures, the recovery of cholesterol and phospholipid secretion is more rapid than bile acid secretion; therefore bile is more lithogenic in this setting. This phenomenon may lead to premature occlusion of decompressive biliary stents placed for the management of obstructive jaundice. Several authors have reported impairment of both macrovascular and microvascular perfusion of the liver in obstructive jaundice (see Chapter 5). Intravital fluorescence microscopy has shown a significant increase in the number of nonperfused sinusoids after three days of extrahepatic obstruction. This alteration in hepatic perfusion may help explain the increased risk for hepatocellular dysfunction when performing liver resections in patients with obstructive jaundice (see Chapter 101). Extrahepatic biliary obstruction and jaundice also can alter important secretory, metabolic, and synthetic functions of the liver. When biliary pressure rises higher than 20 cm H2O, hepatic bile secretion is diminished, and hepatocytes cannot excrete efficiently against the high pressure. As a result, excretory products of the hepatocytes reflux directly into the vascular system, leading to systemic toxicity (see Chapters 10 and 43). Patients with jaundice have a decreased capacity to excrete drugs, such as antibiotics, that are normally secreted into bile.17 The increased concentration of bile acids associated with obstructive jaundice results in inhibition of the hepatic cytochrome P450 enzymes and, therefore, a decrease in the rate of oxidative metabolism in the liver. In addition, bile acids in abnormally high concentrations can induce apoptosis (programmed cell death) in hepatocytes. The synthetic function of the hepatocyte also is decreased with obstructive jaundice, as evidenced by decreased plasma levels of albumin, clotting factors, and secretory immunoglobulins (IgA).16 Kupffer cells are tissue macrophages that are the predominant cell type of the hepatic reticuloendothelial system (see Chapters 10 and 11). Normally, infectious agents, damaged blood cells, cellular debris, fibrin degradation products, and endotoxin absorbed or formed in the portal circulation are effectively filtered by Kupffer cells and removed from the systemic circulation. Kupffer cells also play an interactive role with hepatocytes, modulating synthesis of hepatic proteins. Obstructive jaundice has been shown to have profound effects on Kupffer cells, including decreased endocytosis, phagocytosis, clearance of bacteria and endotoxin, and expression of the major histocompatibility complex class II antigen, with a consequent diminished ability to process antigen.18,19 Biliary obstruction also has been shown to increase levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-a and interleukin (IL)-6 (see Chapters 10 and 11).

Cardiovascular In addition to hepatic dysfunction, obstructive jaundice may cause severe hemodynamic and cardiac disturbances. Experimental animals with obstructive jaundice tend to be hypotensive and exhibit an exaggerated hypotensive response to hemorrhage. Studies in experimental animals have demonstrated that bile duct ligation (1) decreases cardiac contractility; (2) reduces left ventricular pressures; (3) impairs response to b-agonist drugs, such as isoproterenol and norepinephrine; and (4) decreases peripheral vascular resistance. Padillo and others20 have shown in

121

13 patients a negative correlation between serum bilirubin and left ventricular systolic work. Successful internal biliary drainage in these patients was associated with a significant increase in cardiac output, compliance, and contractility. The combination of depressed cardiac function and decreased total peripheral resistance most likely makes the jaundiced patient more susceptible to the development of postoperative shock than nonjaundiced patients.

Renal The association between jaundice and postoperative renal failure has been known for many years. The reported incidence of postoperative acute kidney injury has been reported to be as high as 10% but varies depending on the nature of the procedure. Moreover, the mortality rate in patients with jaundice in whom renal failure developed has been reported to be as high as 70%.21 Important factors that may play a role in the development of renal failure in obstructive jaundice include (1) depressed cardiac function, (2) hypovolemia, (3) bile salt–mediated effects on renal FXR and TGR5 receptors, and (4) endotoxemia. The decreased cardiac function associated with obstructive jaundice leads to a decrease in renal perfusion. Decreased cardiac output also may result in stretching of the atrium and increased production of atrial natriuretic peptide (ANP). This hormone is known to cause natriuresis, to counter the action of water- and sodium-retaining hormones, to inhibit the thirst mechanism, and to produce peripheral vasodilation. Plasma levels of ANP have been shown to be increased in both experimental animals and in patients with extrahepatic biliary obstruction.20 In addition to the direct effects of jaundice on the heart and peripheral vasculature, the increased serum levels of bile acids associated with obstructive jaundice have a direct diuretic and natriuretic effect on the kidney that results in significant extracellular volume depletion and hypovolemia. The infusion of bile into the renal artery of dogs results in increased urine flow, natriuresis, and kaliuresis. This diuretic effect may be mediated by increased prostaglandin E2 production by the kidney22 and/ or by their effect on FXR and TGR5 receptors. Another significant factor in the development of renal failure is endotoxemia (Fig. 8.4). Approximately 50% of patients with obstructive jaundice have endotoxin in their peripheral blood.23 This phenomenon may be the result of decreased hepatic clearance of endotoxin by Kupffer cells and a lack of bile salts in the gut lumen that normally prevent absorption of endotoxins and inhibit anaerobic bacterial growth. Endotoxin also causes renal vasoconstriction and redistribution of renal blood flow away from the cortex and disturbances in coagulation that include the activation of complement, macrophages, leukocytes, and platelets. As a result, glomerular and peritubular fibrin is deposited. This factor, in combination with reduced renal cortical blood flow, results in the tubular and cortical necrosis observed in jaundiced patients with renal failure (see Chapter 10).

Coagulation Disturbances of blood coagulation are commonly present in jaundiced patients. The most frequently observed abnormality is prolongation of the prothrombin time. This problem results from impaired vitamin K absorption from the gut, secondary to a lack of intestinal bile. This coagulopathy is usually reversible with parenteral administration of vitamin K. Decreased bile

122

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Obstructive jaundice

↓ Kupffer cell clearance

↑ Systemic bile salts ↓ Gut bile salts

↓ Clearance of cardiotoxins?

Endotoxemia

↑ Systemic bilirubin

Cardiovascular system

↓ LV function

ANP and hypodipsia

ANP and cytokines

↓ Plasma volume

↓ Peripheral resistance

↓ Blood pressure

Renal system

Coagulation system

Prostaglandins and cytokines

Peritubular fibrin deposition

Altered intrarenal hemodynamics

Direct parenchyma toxicity

↑ Renal vascular resistance ↓ Renal permeability

Renal impairment or acute renal failure FIGURE 8.4  Obstructive jaundice leads to renal impairment or acute kidney injury. ANP, Atrial natriuretic peptide; LV, left ventricular.

levels in the small intestine may result in diminished absorption of other fat-soluble vitamins and fats, which results in weight loss and loss of calcium. This latter factor, as well as the earliermentioned increase in circulating endotoxin, may further contribute to clotting abnormalities. In experimental animals, endotoxin affects metabolism of factors XI and XII and causes platelet and direct endothelial damage.23 Moreover, endotoxin release in patients with jaundice results in a low-grade, disseminated intravascular coagulation, with increased fibrin degradation products. Hunt and colleagues have shown that patients with jaundice with circulating endotoxin or increased fibrin degradation product levels before surgery are at increased risk for hemorrhagic complications. In addition to problems with endotoxemia, patients with coexisting cirrhosis often have additional problems related to thrombocytopenia from hypersplenism and fibrinolysis. Portal hypertension in patients with cirrhosis also exacerbates these coagulation disorders.

Immune System Surgery in patients with jaundice is associated with a higher rate of postoperative septic complications compared with those without jaundice, due in large measure to defects in cellular immunity that make them more prone to infection (see Chapters 10 and 11). Cainzos and colleagues24 have demonstrated an association between jaundice and altered delayedtype hypersensitivity. Only 16% of 118 patients with jaundice

were immunocompetent, compared with 76% of 59 healthy controls, when tested with a panel of seven skin antigens. As mentioned earlier, the ability of the reticuloendothelial system, specifically Kupffer cells, to clear bacteria and endotoxin from the circulation also is reduced in obstructive jaundice. Studies in humans also have demonstrated decreased T-lymphocyte proliferation,25 decreased expression of adhesion molecules,26 and altered monocyte functions.27 Septic manifestations in jaundiced patients result from cellular immune insufficiency (T-lymphocytes) induced by release of cytokines (TNF-a, IL-1, IL-6, interferon-g), prostaglandins, and other inflammatory mediators.16 The absence of bile from the intestinal tract also plays a role in the infectious complications seen in patients with obstructive jaundice. Bacterial translocation from the gut is increased in the setting of bile duct obstruction.28 Obstruction causes a disruption of the enterohepatic circulation and results in loss of the emulsifying antiendotoxin effect of bile acids; therefore a larger pool of endotoxin is available within the intestine for absorption into the portal circulation. The combination of reduced or absent bile in the intestine and impaired cellular immunity and reticuloendothelial cell function appears to be a major factor contributing to more frequent infective complications in the jaundiced patient. Acute cholangitis is a bacterial infection of the biliary ductal system, which varies in severity from mild and self-limited to severe and life threatening (see Chapter 43). The clinical triad

  Chapter 8  Bile Secretion and Pathophysiology of Biliary Tract Obstruction

associated with cholangitis—fever, jaundice, and pain—was first described in 1877 by Charcot. Cholangitis results from a combination of two factors: significant bacterial concentrations in the bile and biliary obstruction. Although bile from the gallbladder and bile ducts is usually sterile, in the presence of common bile duct stones or other obstructing pathology, the incidence of positive cultures increases. Likewise, instrumentation of the biliary tree also greatly increases rates of bile colonization. The most common organisms recovered from the bile in patients with cholangitis include Escherichia coli, Klebsiella pneumonia, the enterococci, and Bacteroides fragilis.29 Even in the presence of high biliary bacterial concentrations, however, clinical cholangitis and bacteremia will not develop unless obstruction causes elevated intraductal pressures.30 Normal biliary pressures range from 7 to 14 cm H2O. In the presence of bacteribilia and normal biliary pressures, hepatic venous blood and perihepatic lymph are sterile. With partial or complete biliary obstruction, however, intrabiliary pressures rise to 20 to 30 cm H2O, and organisms rapidly appear in both the blood and lymph. The fever and chills associated with cholangitis are the result of systemic bacteremia caused by cholangiovenous and cholangiolymphatic reflux. The most common causes of biliary obstruction are choledocholithiasis (see Chapter 37), benign strictures (see Chapter 42), biliary-enteric anastomotic strictures (see Chapter 32), and periampullary or proximal biliary cancers (see Chapters 49, 50 and 59). Before 1980, choledocholithiasis was the cause of approximately 80% of the reported cases of cholangitis. In recent years, however, malignant strictures have become a frequent cause, especially after the placement of biliary stents. Endoscopic cholangiography, percutaneous transhepatic cholangiography, and stent placement via either the endoscopic or percutaneous route are all known to cause bacteremia, and these procedures are frequently performed in patients with a presumptive diagnosis of malignant obstruction.31

Wound Healing Delayed wound healing and a high incidence of wound dehiscence and incisional hernia have been observed in patients with jaundice undergoing surgery. Patients with obstructive jaundice have decreased activity of the enzyme propyl hydroxylase in their skin. Propyl hydroxylase is necessary for the incorporation of the amino acid proline into collagen, and its activity has been used as a measure of collagen synthesis. Grande and colleagues32 measured skin propyl hydroxylase activity in 95 patients with extrahepatic bile duct obstruction and 123 nonjaundiced control patients undergoing cholecystectomy. The patients with jaundice had only 11% of the skin propyl hydroxylase activity of the controls. In the subgroup of patients with jaundice secondary to malignancy, propyl hydroxylase activity was less than 7% of controls. With relief of obstruction, the activity increased to 22% of controls. Interestingly, in patients with jaundice secondary to benign obstruction, the activity increased to 100% of controls.

Other Factors Other problems that face patients with jaundice are anorexia, weight loss, and malnutrition. Appetite is adversely influenced by the lack of bile salts in the intestinal tract. In addition, patients with pancreatic or periampullary malignant lesions may have partial duodenal obstruction or abnormal gastric emptying, in some cases secondary to tumor infiltration of the celiac

123

nerve plexus. Patients with pancreatic or ampullary tumors also may have pancreatic endocrine and exocrine insufficiency. This latter problem may further compound other nutritional defects that, in turn, may exacerbate the immune deficits of the patient with jaundice. Several recent observations suggest that the many physiologic derangements induced by obstructive jaundice take a long time to reverse. For example, Koyama and colleagues33 have shown that hepatic mitochondrial function does not return to normal even seven weeks after relief of obstruction. This same prolonged effect of obstructive jaundice has been noted with lymphocyte, polymorphonuclear, and Kupffer cell function. Therefore, even patients who have had temporary relief of biliary obstruction via percutaneous or endoscopic stents are likely to remain at risk for significant complications after surgery because derangements in hepatic function are likely still present at the time of operation. Moreover, an analysis by Strasberg and colleagues34 suggests that preoperative jaundice may adversely affect long-term survival in patients with resected pancreatic cancer.

Management Historically, the only option for the relief of obstructive jaundice was operative intervention. With the development of therapeutic techniques such as percutaneous (see Chapters 31 and 52) and endoscopic stenting (see Chapters 20 and 30), balloon dilation, and endoscopic sphincterotomy, however, many nonoperative options for the relief of obstructive jaundice are now available. The surgeon must determine the safest and most effective therapy for each individual patient and must adequately prepare each patient for surgery or nonoperative therapeutic intervention. Patients with obstructive jaundice and those with hepatocellular disease severe enough to cause jaundice are prone to many secondary problems. Patients with jaundice are at increased risk for the development of kidney injury, gastrointestinal bleeding, infections, and wound complications (see earlier section on Pathophysiology). Cardiac, pulmonary, and renal function must be considered in every patient undergoing major abdominal surgery. In addition, special attention must be focused on the patient with jaundice’s nutritional status, coagulability, immune function, and presence or absence of biliary sepsis. Complications related to portal hypertension, such as ascites, varices, and encephalopathy, also may develop in patients with chronic liver disease and cirrhosis, and these abnormalities may require specific treatment (see Chapters 74 and 77–85).

Cardiopulmonary In assessing cardiopulmonary status, the patient’s age, history of recent myocardial infarction, and the presence of congestive heart failure, significant valvular heart disease, or a disturbance of normal cardiac rhythm all have been correlated with increased operative risk.35 In addition, patients with severe pulmonary disease may not be candidates for extensive abdominal surgery (see Chapter 26).

Renal Patients with jaundice, especially those with cirrhosis and cholangitis, are at increased risk for renal insufficiency. The maintenance of adequate blood volume and the correction of dehydration are extremely important if renal complications

124

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

are to be avoided. Fluid management can be quite complex in patients with jaundice because both excess and insufficient fluids may be problematic. Therefore selected patients may benefit from invasive hemodynamic monitoring to assist with goal-directed fluid management. Certain oral bile salts have been shown to be efficacious in preventing the development of postoperative kidney injury. In a study by Cahill,36 54% of 24 patients with jaundice not given oral bile salts before surgery were found to have systemic endotoxemia, which was associated with renal impairment in twothirds of the cases. In comparison, none of the eight patients with jaundice given 500 mg of sodium deoxycholate every eight hours for 48 hours before surgery had portal or systemic endotoxemia. Moreover, none of these eight patients had evidence of renal impairment (see Chapter 26).

Nutrition Malnutrition is a significant risk factor for surgery in the setting of obstructive jaundice (see Chapter 26). Halliday and colleagues37 noted that patients who died in the postoperative period after surgery for obstructive jaundice had a significant reduction in body weight, midarm circumference, total body potassium, and reactivity to skin test antigens preoperatively. In a study from Italy,38 enteral hyperalimentation was found to significantly decrease operative morbidity and mortality in a group of patients treated with 20 days of preoperative percutaneous biliary drainage. Although most patients with benign biliary problems are adequately nourished, various degrees of malnutrition are frequently present in patients with malignant obstruction. Therefore patients with malignant obstructive jaundice should be evaluated for evidence of malnutrition and have nutritional support instituted if necessary.

Coagulation Patients with obstructive jaundice, cholangitis, or cirrhosis all are prone to excessive intraoperative bleeding. The most common clotting defect in patients with obstructive jaundice is prolongation of the prothrombin time (PT), which is usually reversible by the administration of parenteral vitamin K. Patients with severe jaundice and/or cholangitis also may develop disseminated intravascular coagulation (DIC), which may require infusion of platelets and fresh frozen plasma. Reversal of DIC also requires control of the underlying sepsis, which should include biliary drainage in patients with cholangitis in addition to systemic antibiotics. In cirrhotic patients, clotting abnormalities are often multifactorial and include thrombocytopenia secondary to hypersplenism, prolongation of PT and partial thromboplastin time (PTT), and fibrinolysis. Vitamin K should be administered if the PT is prolonged. If no effect is seen and/or if the PTT is also prolonged, fresh frozen plasma should be given. Thrombocytopenia usually can be managed by intraoperative platelet infusions. If the patient has a shortened clot lysis time and hypofibrinogenemia, e-aminocaproic acid may be indicated (see Chapter 26).

Pruritus Pruritus is often a distressing problem in the jaundiced patient. The exact cause of pruritus remains obscure, but increased circulating levels of bile salts, histamines, and central nervous system opiate receptors have been implicated. In some patients, relief from itching can be obtained by bile salt–binding agents,

such as cholestyramine. Various sedatives and antihistamines also can provide relief of itching in jaundiced patients. However, relief of biliary obstruction remains the most effective method for managing pruritus, and improvement can occur rapidly after stent placement, although occasionally it can take a week or so.

Cholangitis Biliary sepsis also has been identified as a major risk in jaundiced patients (see Chapter 43). Cholangitis occurs when partial or complete obstruction of the bile duct exists, resulting in increased intraluminal pressure and infected bile proximal to the obstruction. Patients with cholangitis may present with right upper quadrant abdominal pain, fever, and/or jaundice (Charcot’s triad). Patients with “toxic” cholangitis—Charcot’s triad plus shock and mental confusion (Reynold’s pentad)— have significant mortality with appropriate antibiotic therapy alone and therefore require emergent biliary decompression. Gigot and associates39 identified seven prognostic factors that are indications for urgent biliary decompression: (1) acute kidney injury, (2) liver abscess, (3) cirrhosis, (4) high malignant stricture, (5) percutaneous transhepatic cholangiography, (6) female gender, and (7) advanced age. However, emergent surgical treatment is associated with significant morbidity and mortality; therefore both percutaneous and endoscopic biliary drainage have been proposed as effective therapy for the 5% to 10% of patients with cholangitis who are unresponsive to conservative therapy. Lai and colleagues40 have shown, in a series of 82 patients with severe acute cholangitis, that endoscopic drainage is associated with a lower morbidity (34% vs. 66%) and mortality (10% vs. 32%) than operative drainage. Current concepts in the initial management and treatment of cholangitis have been summarized in the Tokyo Guidelines.41,42

Preoperative Drainage The preoperative relief of jaundice and the reversal of its systemic effects by either endoscopic or transhepatic biliary decompression has been proposed as a method to decrease the risk of surgery in jaundiced patients. However, several prospective randomized studies have shown that the routine use of preoperative biliary drainage (PBD) does not reduce operative morbidity or mortality in patients with obstructive jaundice (see Table 8.3).43–48 In addition, meta-analyses also concluded that preoperative biliary drainage increased (P , .001), rather than decreased, overall complications from surgery and the drainage procedure provided no benefit in terms of reduced mortality or decreased hospital stay.49–51 In addition, insufficient evidence exists to determine whether endoscopic plastic or metal stents or percutaneous transhepatic drains are better than no drainage.49 However, endoscopic ultrasound (EUS)guided biliary drainage may have an advantage over percutaneous drainage when ERCP fails.52 Moreover, several retrospective studies have documented a higher incidence of infectious complications (wound infection, pancreatic fistula) and even mortality in patients undergoing pancreatic or biliary tract resection after preoperative biliary decompression.51,53 A criticism of some of the prospective studies is that the duration of preoperative drainage (10–18 days) may have been inadequate to reverse the multiple metabolic and immunologic abnormalities associated with severe obstructive jaundice. Both animal and human studies demonstrate that the recovery of various metabolic and immune functions requires at least

  Chapter 8  Bile Secretion and Pathophysiology of Biliary Tract Obstruction

125

TABLE 8.3  Prospective Randomized Trials of Preoperative Biliary Drainage (PBD) FIRST AUTHOR

TYPE OF DRAINAGE MORTALITY, PBD

MORTALITY, NO PBD

MORBIDITY, PBD

MORBIDITY, NO PBD

Hatfield McPherson45 Pitt46 Lai44 Wig48 van der Gaag47 Total (%)

Percutaneous Percutaneous Percutaneous Endoscopic Percutaneous Endoscopic

4/28 6/31 2/38 6/44 4/20 12/94 34/255 (13.3)

7/29 17/34 30/37 28/43 12/20 75/102 169/265 (63.8)*

4/28 13/31 20/38 18/44 10/20 37/94 104/255 (40.0)

43

4/29 11/34 3/37 6/43 1/20 15/102 40/265 (15.1)

*P , .001 vs. no PBD.

six weeks to pass after the relief of biliary obstruction.54 Similarly, animal studies strongly suggest that return of bile to the intestinal tract has significant advantages over external biliary drainage.55 Although the data suggest that routine PBD may be of limited benefit, PBD may have some value in selected patients with advanced malnutrition, biliary sepsis, and hilar malignancies that require liver resection.56 Regarding the latter, most of the published data regarding PBD focus on patients with periampullary malignancy. Patients with proximal biliary obstruction undergoing major hepatic resection represent an entirely different subgroup, but a multicenter European study suggests that those requiring right hepatectomy benefit from preoperative drainage of the future liver remnant (see Chapters 51, 52, and 101). In patients with perihilar cholangiocarcinoma, percutaneous drainage is associated with less cholangitis and pancreatitis compared with endoscopic drainage.57,58 Preoperatively placed transhepatic catheters also may be of value in the operating room during difficult biliary dissections in patients with proximal biliary tumors or strictures, and they may aid in the placement of long-term

transhepatic stents. Finally, preoperative drainage is required in patients receiving neoadjuvant therapy. In these patients, metal stents have fewer problems with cholangitis at no additional cost, although plastic stents are preferable for patients with hilar cholangiocarcinoma in whom surgery is planned.59

SUMMARY Over the past few decades, tremendous strides have been made in our understanding of bile secretion and our ability to care for the jaundiced patient. Clinicians now have a better understanding of normal bile salt, biliary lipid, and bilirubin physiology and can classify the diseases that cause jaundice as defects in normal metabolism. Similarly, investigators have elucidated the multiple pathophysiologic effects of jaundice that explain why jaundiced patients are at risk for increased perioperative morbidity and mortality. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

125.e1

REFERENCES 1. Swartz-Basile DA, Lu D, Basile DP, et al. Leptin regulates gallbladder genes related to absorption and secretion. Am J Physiol Gastrointest Liver Physiol. 2007;293(1):G84-G90. 2. Klein AS, Lillemoe KD, Yeo CJ, Pitt HA. Liver, biliary tract, and pancreas. In: O’Leary JP, ed. The Physiologic Basis of Surgery. 2nd ed. Williams & Wilkins; 1996:441-478. 3. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology. 2004;126(1):322-342. 4. Di Ciaula A, Garruti G, Lunardi Baccetto R, et al. Bile acid physiology. Ann Hepatol. 2017;16(Suppl 1):S4-S14. 5. Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018;18(2):71-87. 6. Crawford JM. Role of vesicle-mediated transport pathways in hepatocellular bile secretion. Semin Liver Dis. 1996;16(2):169-189. 7. Henkel AS, Gooijert KE, Havinga R, Boverhof R, Green RM, Verkade HJ. Hepatic overexpression of Abcb11 in mice promotes the conservation of bile acids within the enterohepatic circulation. Am J Physiol Gastrointest Liver Physiol. 2013;304(2):G221-G226. 8. Gerk PM, Vore M. Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J Pharmacol Exp Ther. 2002;302(2):407-415. 9. Li T, Chiang JY. Bile acids as metabolic regulators. Curr Opin Gastroenterol. 2015;31(2):159-165. 10. Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41-50. 11. Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol. 2017;101(1):47-64. 12. Arrese M, Accatino L. From blood to bile: recent advances in hepatobiliary transport. Ann Hepatol. 2002;1(2):64-71. 13. Lee MH, Lu K, Hazard S, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001;27(1):79-83. 14. Cui Y, Konig J, Leier I, Buchholz U, Keppler D. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 2001;276(13):9626-9630. 15. Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016;79(3):378-386. 16. Pavlidis ET, Pavlidis TE. Pathophysiological consequences of obstructive jaundice and perioperative management. Hepatobiliary Pancreat Dis Int. 2018;17(1):17-21. 17. Blenkharn JI, Habib N, Mok D, et al. Decreased biliary excretion of piperacillin after percutaneous relief of extrahepatic obstructive jaundice. Antimicrob Agents Chemother. 1985;28(6):778-780. 18. Nehez L, Andersson R. Compromise of immune function in obstructive jaundice. Eur J Surg. 2002;168(6):315-328. 19. Puntis MC, Jiang WG. Plasma cytokine levels and monocyte activation in patients with obstructive jaundice. J Gastroenterol Hepatol. 1996;11(1):7-13. 20. Padillo J, Puente J, Gomez M, et al. Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: hemodynamic and hormonal assessment. Ann Surg. 2001;234(5):652-656. 21. Fogarty BJ, Parks RW, Rowlands BJ, Diamond T. Renal dysfunction in obstructive jaundice. Br J Surg. 1995;82(7):877-884. 22. Green J, Better OS. Circulatory disturbance and renal dysfunction in liver disease and in obstructive jaundice. Isr J Med Sci. 1994;30(1): 48-65. 23. Hunt DR, Allison ME, Prentice CR, Blumgart LH. Endotoxemia, disturbance of coagulation, and obstructive jaundice. Am J Surg. 1982;144(3):325-329. 24. Cainzos M, Alcalde JA, Potel J, Puente JL. Hyperbilirubinemia, jaundice and anergy. Hepatogastroenterology. 1992;39(4):330-332. 25. Fan ST, Lo CM, Lai EC, Yu WC, Wong J. T lymphocyte function in patients with malignant biliary obstruction. J Gastroenterol Hepatol. 1994;9(4):391-395. 26. Plusa S, Webster N, Primrose J. Obstructive jaundice causes reduced expression of polymorphonuclear leucocyte adhesion molecules and a depressed response to bacterial wall products in vitro. Gut. 1996;38(5):784-787. 27. Treglia-Dal Lago M, Jukemura J, Machado MC, da Cunha JE, Barbuto JA. Phagocytosis and production of H2O2 by human

peripheral blood mononuclear cells from patients with obstructive jaundice. Pancreatology. 2006;6(4):273-278. 28. Deitch EA, Sittig K, Li M, Berg R, Specian RD. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg. 1990;159(1):79-84. 29. Thompson Jr JE, Pitt HA, Doty JE, Coleman J, Irving C. Broad spectrum penicillin as an adequate therapy for acute cholangitis. Surg Gynecol Obstet. 1990;171(4):275–282. 30. Lipsett PA, Pitt HA. Biliary infection: prophylaxis and treatment. In: Toouli J, ed. Surgery of the Biliary Tract. Churchill Livingstone; 1993:59-70. 31. Wang Y, Fu W, Tang Z, Meng W, Zhou W, Li X. Effect of preoperative cholangitis on prognosis of patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. Medicine (Baltimore). 2018;97(34):e12025. 32. Grande L, Garcia-Valdecasas JC, Fuster J, Visa J, Pera C. Obstructive jaundice and wound healing. Br J Surg. 1990;77(4):440-442. 33. Koyama K, Takagi Y, Ito K, Sato T. Experimental and clinical studies on the effect of biliary drainage in obstructive jaundice. Am J Surg. 1981;142(2):293-299. 34. Strasberg SM, Gao F, Sanford D, et al. Jaundice: an important, poorly recognized risk factor for diminished survival in patients with adenocarcinoma of the head of the pancreas. HPB (Oxford). 2014;16(2):150-156. 35. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977;297(16):845-850. 36. Cahill CJ. Prevention of postoperative renal failure in patients with obstructive jaundice—the role of bile salts. Br J Surg. 1983;70(10): 590-595. 37. Halliday AW, Benjamin IS, Blumgart LH. Nutritional risk factors in major hepatobiliary surgery. JPEN J Parenter Enteral Nutr. 1988; 12(1):43-48. 38. Foschi D, Cavagna G, Callioni F, Morandi E, Rovati V. Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. Br J Surg. 1986;73(9):716-719. 39. Gigot JF, Leese T, Dereme T, Coutinho J, Castaing D, Bismuth H. Acute cholangitis. Multivariate analysis of risk factors. Ann Surg. 1989;209(4):435-438. 40. Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326(24):1582-1586. 41. Miura F, Okamoto K, Takada T, et al. Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis. J Hepatobiliary Pancreat Sci. 2018;25(1):31-40. 42. Mayumi T, Okamoto K, Takada T, et al. Tokyo Guidelines 2018: management bundles for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25(1):96-100. 43. Hatfield AR, Tobias R, Terblanche J, et al. Preoperative external biliary drainage in obstructive jaundice. A prospective controlled clinical trial. Lancet. 1982;2(8304):896-899. 44. Lai EC, Mok FP, Fan ST, et al. Preoperative endoscopic drainage for malignant obstructive jaundice. Br J Surg. 1994;81(8): 1195-1198. 45. McPherson GA, Benjamin IS, Hodgson HJ, Bowley NB, Allison DJ, Blumgart LH. Pre-operative percutaneous transhepatic biliary drainage: the results of a controlled trial. Br J Surg. 1984;71(5): 371-375. 46. Pitt HA, Gomes AS, Lois JF, Mann LL, Deutsch LS, Longmire Jr WP. Does preoperative percutaneous biliary drainage reduce operative risk or increase hospital cost? Ann Surg. 1985;201(5): 545-553. 47. van der Gaag NA, Rauws EA, van Eijck CH, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med. 2010;362(2):129-137. 48. Wig JD, Kumar H, Suri S, Gupta NM. Usefulness of percutaneous transhepatic biliary drainage in patients with surgical jaundice—a prospective randomised study. J Assoc Physicians India. 1999;47(3): 271-274. 49. Lee PJ, Podugu A, Wu D, Lee AC, Stevens T, Windsor JA. Preoperative biliary drainage in resectable pancreatic cancer: a systematic review and network meta-analysis. HPB (Oxford). 2018;20(6): 477-486. 50. Fang Y, Gurusamy KS, Wang Q, et al. Meta-analysis of randomized clinical trials on safety and efficacy of biliary drainage before surgery for obstructive jaundice. Br J Surg. 2013;100(12):1589-1596.

125.e2 51. Sewnath ME, Karsten TM, Prins MH, Rauws EJ, Obertop H, Gouma DJ. A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg. 2002; 236(1):17-27. 52. Sharaiha RZ, Khan MA, Kamal F, et al. Efficacy and safety of EUS-guided biliary drainage in comparison with percutaneous biliary drainage when ERCP fails: a systematic review and metaanalysis. Gastrointest Endosc. 2017;85(5):904-914. 53. Sohn TA, Yeo CJ, Cameron JL, Pitt HA, Lillemoe KD. Do preoperative biliary stents increase postpancreaticoduodenectomy complications? J Gastrointest Surg. 2000;4(3):258-267; discussion 267-268. 54. Clements WD, Halliday MI, McCaigue MD, Barclay RG, Rowlands BJ. Effects of extrahepatic obstructive jaundice on Kupffer cell clearance capacity. Arch Surg. 1993;128(2):200-204; discussion 204-205. 55. Roughneen PT, Gouma DJ, Kulkarni AD, Fanslow WF, Rowlands BJ. Impaired specific cell-mediated immunity in experimental biliary

obstruction and its reversibility by internal biliary drainage. J Surg Res. 1986;41(2):113-125. 56. Farges O, Regimbeau JM, Fuks D, et al. Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg. 2013;100(2):274-283. 57. Tang Z, Yang Y, Meng W, Li X. Best option for preoperative biliary drainage in Klatskin tumor: a systematic review and meta-analysis. Medicine (Baltimore). 2017;96(43):e8372. 58. Al Mahjoub A, Menahem B, Fohlen A, et al. Preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma: Is percutaneous transhepatic biliary drainage safer and more effective than endoscopic biliary drainage? A meta-analysis. J Vasc Interv Radiol. 2017;28(4):576-582. 59. Walter D, van Boeckel PG, Groenen MJ, et al. Cost efficacy of metal stents for palliation of extrahepatic bile duct obstruction in a randomized controlled trial. Gastroenterology. 2015;149(1): 130-138.

CHAPTER 9A Molecular and cell biology of hepatopancreatobiliary disease: Introduction and basic principles Caitlin A. McIntyre and Rohit Chandwani INTRODUCTION In recent years, there has been an increased understanding of the molecular and cellular processes that govern hepatopancreatobiliary (HPB) diseases. These processes, which include those that are immune-mediated, involve chronic inflammation or processes of neoplastic transformation and are driven by factors such as genomic alterations, epigenetic modification, and dysregulated cell signaling pathways. These principles are integrally intertwined, as evidenced by crosstalk between genetic and epigenetic regulation, post-translational modifications, and cell signaling pathways. The primary goal of this section is to provide a foundation outlining the biologic principles that govern benign and malignant HPB diseases and bring light to the complex interactions between such principles. Each of these themes will be explored in depth in Chapters 9B to 9E.

SIGNALING PATHWAYS For further information, see Chapters 9B to 9E. Cell signaling pathways play an integral role in the mechanisms of numerous cellular processes. There is significant crosstalk between pathways, and the same signaling pathway may serve multiple functions within the same cell or organ, which is dependent on the stage of development, surrounding microenvironment, or other selective pressure. A number of cell signaling pathways are important for normal pancreatic and liver development. Differentiation and proliferation of both hepatocytes and cholangiocytes are components of normal liver development (see Chapter 1). These processes involve multiple pathways at various stages of development and include Notch, Hedgehog, Wnt/b-catenin, PI3K (phosphatidylinositol-3 kinase)/PTEN, mTOR, nuclear factor (NF)kB, and transforming growth factor (TGF)–b signaling.1 In malignancy, these signaling pathways are often hijacked, and RAS and p53 signaling are also commonly altered in HPB malignancies.

Notch Signaling The Notch pathway plays a significant role in cell fate determination and homeostasis of several adult tissues. Notch receptors and ligands are transmembrane proteins, with four Notch receptors (Notch1–4) and five Notch ligands (Dll1, Dll3, Fll4, Jagged1, and Jagged2) found in mammals.2 Interactions between receptor and ligand on adjacent cells results in several proteolytic cleavages of the Notch receptor at three distinct sites (S1, S2, and S3), releasing the Notch intracellular domain (NICD). NICD translocates to the nucleus, where it binds CBF1/RBPj, displacing co-repressor complexes, and recruits coactivator molecules, including Mastermind-like (Maml).3 In the liver, Notch signaling is critical to the development of the 126

intrahepatic biliary system (see Chapter 1) and is also crucial in liver regeneration (see Chapter 6). This pathway is activated during liver repair and has a clear role in biliary regeneration, although its utility in hepatocyte regeneration is less clear.4 Notch1 and Jagged1 are both induced by hepatectomy and injury, directing the formation of biliary cells. Alagille syndrome, which is characterized by an autosomal dominant mutation in Notch2 or Jagged2 (encodes a ligand in the Notch pathway), results in malformation of the intrahepatic biliary tree as well as other abnormalities.5–7 In liver malignancies, the role of Notch signaling is ambiguous. Notch1 knockout mice develop proliferation and dedifferentiation of endothelial cells with eventual spontaneous development of hepatic angiosarcoma, suggesting a tumor suppressive role.8 By contrast, constitutive expression of both activated Notch1 and the intracellular domain of Notch2 lead to spontaneous hepatocellular carcinoma (HCC) at 12 months.9,10 In the pancreas, Notch signaling is similarly critical to tissue homeostasis. Activation in pancreatic progenitors prevents specification into either endocrine or exocrine lineages, whereas inhibition of the pathway results in premature differentiation to neurogenin-3 (Ngn31) expressing endocrine cells. As in the liver, injury to the adult tissue unveils developmental Notch signaling to permit regeneration following pancreatitis.11

Hedgehog Sonic hedgehog (SHH) is an essential pathway involved in cell growth and tissue patterning. Canonical SHH signal transduction consists of multiple Hedgehog (Hh) ligands, two transmembrane receptors (Patched [PTCH1, PTCH2] and Smoothened [SMO]), and the glioma-associated oncogene homolog (GLI) family of transcription factors (GLI1, GLI2, GLI3). When Hh ligands bind to the receptor Patched, it blocks the inhibitory effect of Patched on the co-receptor Smoothened. Active SMO leads to GLI protein activation with nuclear translocation and activation of target genes. Hedgehog signaling is involved in normal pancreatic and liver development, with mouse models indicating the need for Shh for appropriate organogenesis. Hh ligands are largely absent in the adult liver but are reactivated in response to liver injury and at times of liver regeneration. In injury, epithelial cells produce Hh ligands that act in a paracrine fashion on mesenchymal-type cells. The pathway is critical to crosstalk among multiple cell types and specifically promotes viability of progenitor cells and activates hepatic stellate cells. Hedgehog signaling plays a role in chronic liver disease with upregulation of PTCH and GLI factors in nonalcoholic fatty liver disease (NAFLD), biliary cirrhosis, and hepatitis B (HBV) and C (HCV).12–14 Hedgehog signaling has also been identified in the development of HCC,

  Chapter 9A  Molecular and Cell Biology of Hepatopancreatobiliary Disease: Introduction and Basic Principles

with correlative data suggesting poorer outcomes in patients with increased SMO.15–17 Similarly, in the pancreas, Hedgehog signaling is enhanced early in tumorigenesis and in stromal fibroblasts, with conflicting data suggesting either supportive or restraining roles for enhanced Hedgehog signaling.18,19

Wnt/b-Catenin The Wnt/b-catenin pathway is critical for both pancreatic and liver development and for regeneration. b-Catenin, a cytoplasmic protein, is typically maintained in a phosphorylated state and targeted for degradation by adenomatous polyposis coli (APC) product, casein kinase 1 (CK1), and glycogen synthase kinase-3 (GSK3)-b. Nevertheless, when Wnt proteins, typically glycosylated and acylated moieties, engage the Frizzled (Fz) receptor in the context of a ternary complex, hypophosphorylated b-catenin is released where it can translocate to the nucleus and induce target gene expression.20 Similar to Notch, fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) signaling, Wnt signaling is central in the determination of endodermal patterning. Wnt is initially suppressed in early liver development and then activated later, and this pathway is critical to metabolic zonation in the liver. In both hepatectomy and injury models, b-catenin is important for regeneration and the hepatocyte proliferation that occurs. In the pancreas, the absence of b-catenin in animal models leads to disrupted development of the exocrine pancreas.21 Similarly, gain-of-function experiments show that Wnt pathway activation also results in a hypoplastic pancreas after abnormal acquisition of intestinal features.22 Wnt/b-catenin pathways are commonly altered in benign and malignant tumors of the liver. Mutations or deletions of the b-catenin gene, CTNNB1, or mutations in other genes or aberrant expression of proteins in the pathway, result in cytoplasmic stabilization and nuclear translocation of b-catenin and ultimately dysregulated transcription of cell cycle regulatory proteins. b-Catenin mutated hepatic adenomas account for approximately 10% to 15% of hepatic adenomas and are associated with an increased risk for transformation into HCC23 (see Chapters 87–89). Additionally, abnormal expression of b-catenin is noted in 17% to 40% of HCC and 50% to 75% of hepatoblastoma.24–28 In pancreatic cancer, b-catenin stabilization results in the formation of pancreatic tumors, affirming an oncogenic role across the spectrum of HPB disease.

Innate Immune Response Pathways Many signaling pathways are involved in normal immune function and in dysregulation of immune mechanisms and chronic inflammation. Toll-like receptors (TLR) are cell surface receptors found on dendritic cells and macrophages and play a key role in the innate immune system.29 They recognize pathogenassociated molecular patterns (PAMPs; specific microbial components that are conserved between species) or damage-associated molecular patterns (DAMPs; components of dying cells) and activate multiple signaling pathways in immune cells, including the myeloid differentiation primary response (MyD88) and TIR-domain-containing-adapter-inducing interferon-b (TRIF) pathways, resulting in activation of NF-kB and, ultimately, an inflammatory response. TLRs (specifically TLR2, TLR4, and TLR9 expressed on Kupffer cells) have been shown to play a role in the development of alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and HCC, likely through interactions with host intestinal flora, which subsequently

127

results in activation of multiple proinflammatory pathways30 (see Chapters 69, 74, and 89). Cytokines are small peptide molecules secreted by both immune and nonimmune cells that act through cell surface receptors. Examples include interferons (IFNs), interleukins (ILs), and tumor necrosis factors (TNF). IFNs have been shown to play a role in host defenses against viruses, and IFN-a has been used to treat HCV infection (see Chapter 10).

Key Metabolic Pathways A number of signaling pathways are imperative for normal metabolism of glucose and fatty acids in the liver. These include the PI3K/Akt/mTOR, AMP-activated protein kinase, and protein-kinase A (PKA) pathways. Transcription factors such as FOXO1, liver X receptor (LXR), farnesoid X receptor (FXR), SRE-binding protein 1 (SREBP1), and peroxisome proliferator-activated receptors (PPAR) are key regulators of metabolism in the liver. Many of these pathways are dysregulated in liver disease, including NAFLD and HCC (see Chapters 69 and 89). Recent emphasis has been placed on the mechanisms behind the development of NAFLD and NASH, given that this spectrum of disease is increasing in incidence worldwide and accounts for a subset of HCC cases annually. Interestingly, previous data have demonstrated that approximately 50% of HCC cases associated with NAFLD are in patients who are not cirrhotic,31 further highlighting the importance of better understanding the mechanisms behind NAFLD. The development of NAFLD is multifactorial in origin and is a complex interaction between insulin resistance, dysregulation of fatty acid metabolism, the microbiome, activation of the innate immune system, and increased inflammation through cytokine signaling. Insulin and glucagon signaling through the PI3K/Akt/mTOR and PKA pathways, respectively, regulate gluconeogenesis and fatty acid metabolism in the liver; dysregulation of these pathways contributes to insulin resistance.32 Additionally, TLRs have been shown to contribute to insulin resistance through fatty acid activation of TLR4 in mouse models.33 PPARs are essential transcription factors for fatty acid b-oxidation, and dysregulation of these factors is believed to contribute to the development of NAFLD. For example, prior data have demonstrated that PPAR-a expression was decreased in patients who had NASH, steatosis, ballooning of hepatocytes, and fibrosis on liver biopsy compared with those who did not.34

Signaling Pathways in Cancer Dysregulated cellular signaling is a hallmark of cancer, and certain pathways are frequently altered in HPB cancers. Many of these signaling pathways do not play a significant role in normal development or response to injury, but instead, when mutated, lead to aberrant cell growth. Two commonly altered signaling pathways in HPB cancers are the p53 and RAS pathways because TP53 and KRAS are among the most frequently mutated genes in pancreatic and biliary cancers.35,36 TP53 encodes a tumor suppressor protein, which is present in normal cells and has a diverse role in many cellular functions including DNA repair, cell cycle regulation, and apoptosis. TP53 alterations can result in either gain-of-function or loss-of-function mutations of p53, ultimately resulting in uncontrolled cell proliferation and tumor development. Although KRAS is one of the most commonly altered genes, additional mutations occur in other members of the RAS pathway, including NRAS and

128

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

BRAF. Mutations in this pathway result in constitutive activation of RAS/RAF and increased signaling through MEK/ERK, resulting in uncontrolled cell proliferation. A number of additional signaling pathways are dysregulated in HPB cancers, including MYC, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). Unlike the frequently altered p53 and RAS pathways, these additional pathways can be targeted with small molecule inhibitors, and recent studies have supported the use of these agents in hepatobiliary cancers. For example, sorafenib, which targets the Raf/VEGF/PDGF pathways, has been shown to improve overall survival (OS) in patients with advanced HCC (see Chapter 89) and is US Food and Drug Administration (FDA)-approved for first-line therapy in these patients.37 Similarly, regorafenib, which targets VEGF2, is approved as a second-line agent in patients with HCC.38 Pemigatinib, a small molecule inhibitor of FGFR2, has recently demonstrated a survival benefit in patients with intrahepatic cholangiocarcinoma (CC; see Chapter 50).39

EMERGING THEMES For more information, see Chapters 9B to 9E.

Oncogenic Viruses Chronic primary infections of the liver and the biliary tree have been shown to have an association with the development of cancer; the most common of these infections are HBV and HCV (see Chapter 68). HBV and HCV are strongly associated with the development of HCC; approximately 44% of worldwide cases of HCC are attributed to HBV, whereas 21% are attributed to HCV.40 The mechanism of carcinogenesis differs between the two viruses. Genomic instability from HBV viral DNA integration into the host cell genome is the primary mechanism of carcinogenesis in HBV infection; however, this is coupled with the effects of viral proteins, epigenetic regulation, and aberrant cell signaling.41 On the contrary, HCV infection results in persistent inflammation leading to cirrhosis, which is believed to be a mechanism of carcinogenesis in HCV. Nevertheless, given that not all patients with HCC arising in the setting of HCV infection have cirrhosis, virus-specific proteins and immune-mediated mechanisms also play a significant role in carcinogenesis.42

Chronic Inflammation Chronic inflammation results from dysregulation of the immune system and can ultimately lead to fibrosis and cancer development. Foreign antigens or self-antigens produced by damaged hepatocytes lead to recruitment of immune cells and release of proinflammatory cytokines and chemokines, such as IL-1b, IL-6, and TNF-a. Specifically, neutrophils and macrophages are directed to the site of injury, and subsequently, natural killer (NK) cells, dendritic cells, and T-cells are recruited. In response to release of inflammatory mediators released by immune cells, quiescent hepatic stellate cells (HSCs) are activated and differentiate into myofibroblast-like cells (see Chapter 7). Studies in mice have demonstrated that HSCs are the primary source of myofibroblasts in cholestatic, toxin-induced, and fatty liver diseases.43 These myofibroblast-like HSCs deposit extracellular matrix (ECM), a process that is promoted by matrix metalloproteinases (MMPs). Persistent liver inflammation results in further hepatocyte damage, and continued

release of proinflammatory cytokines from hepatocytes, lymphocytes, and even the ECM itself. Withdrawal of the inciting agent can halt progression of this process; however, persistent inflammation results in continued deposition of collagen and liver fibrosis. Examples of inflammation in the liver and carcinogenesis are seen in both CC (see Chapter 50) and HCC (see Chapter 89). Liver fibrosis and cirrhosis are associated with the development of HCC, which can result from multiple benign processes including steatosis, viral infection, or alcohol-induced liver disease. Although the cause of the underlying liver cirrhosis may differ, the pathophysiology of the development of cirrhosis and subsequent carcinogenesis are parallel. Similarly, longstanding primary sclerosing cholangitis (PSC) and chronic biliary stasis are associated with the development of CC, although immune activation in this case is less well understood. Analogous associations between chronic inflammation and malignancy are also seen in pancreatic cancer because chronic pancreatitis is associated with an increased risk for pancreatic adenocarcinoma.44,45

Cellular Plasticity Cellular plasticity refers to changes to lineage specification and cell fate that occur with physiologic stress and are most commonly epigenetic or transcriptional in origin. Plasticity in cell fate is a hallmark of multiple inflammatory and neoplastic pathologies in HPB disease. Importantly, both the liver and pancreas do not display significant evidence of stem cell compartments, such that plasticity of terminally differentiated cells is critical to responses to injury. In the pancreas, acinarto-ductal metaplasia (ADM) is the transition of acinar cells to ductal cells and occurs in the setting of chronic inflammation or pancreatitis (see Chapters 57 and 58). ADM is a precursor to pancreatic intraepithelial neoplasia (PanIN) and, ultimately, pancreatic ductal adenocarcinoma (PDAC; see Chapter 59) and represents a complex transdifferentiation event (i.e., direct conversion from acinar-to-ductal) that is also accompanied by features suggestive of a dedifferentiated phenotype (i.e., reversion within the pancreatic lineage). Notch and b-catenin pathways are reactivated, and several progenitor markers are expressed. Acinar cells readily acquire features of both ductal and progenitor cells in response to pancreatic injury, a cellular plasticity that is critical to tissue homeostasis.46 Loss of acinar cell identity after injury is reversible with regeneration, such that the pancreas can regain its normal architecture and function. Regeneration of the acinar compartment is dependent on the reactivation of several aforementioned developmental pathways, including b-catenin signaling, Hedgehog signaling, and the Notch pathway. In tumorigenesis, the reprogramming of acinar cells is enforced by oncogenic KRAS, such that the acinar compartment cannot undergo this process of redifferentiation. In the liver, hepatocytes can differentiate into cholangiocytes at times of injury or chronic inflammation, leading to the development of CC. In chronic liver disease, ductular proliferations containing cells that simultaneously express markers of hepatocytes and bile ducts are found. Interestingly, data have demonstrated that CCs that microscopically appear similar to HCC or combined HCC-CC are not necessarily derived from biliary epithelium (see Chapter 50). Evidence for biliary epithelial cell conversion into hepatocytes exists in rodent models of liver injury with either iethoxycarbonyl-1,

  Chapter 9A  Molecular and Cell Biology of Hepatopancreatobiliary Disease: Introduction and Basic Principles

4-dihydrocollidine (DDC) or thioacetamide (TAA), wherein lineage-tracing makes clear that the hepatocyte compartment can be reconstituted in part by bile duct epithelial cells.47 Epithelial-mesenchymal transition (EMT) occurs in both normal development and pathologic processes such as cancer progression. EMT is a process during which epithelial cells undergo a series of transitions (e.g., loss of cell-to-cell adhesion, changes in morphology) to gain increased mobility.48 This is important in the escape of tumor cells from the primary site and the development of distant metastases. In hepatobiliary disease, this accounts for metastatic disease to the liver, which is more common than primary liver tumors. EMT is well understood to reflect another outcome of cellular plasticity, whereby a mesenchymal cell fate is acquired by either internalization or downregulation of epithelial transcripts such as E-cadherin, along with concomitant increases in intermediate filament proteins, such as vimentin.49

Immune Cell Engagement The liver is a lymphoid organ in many respects and plays an important role in immune tolerance. Given first-pass metabolism from the portal vein, there is significant antigen exposure to cells in the liver. A subset of cells within the liver are resident immune cells, including lymphocytes and Kupffer cells (macrophages). Many cell types in the liver have the potential to act as antigen presenting cells (APCs). These include the resident immune cells, such as Kupffer cells, hepatic dendritic cells, and sinusoidal endothelial cells, yet even hepatocytes and biliary epithelial cells can act as APCs during chronic inflammation and express class II major histocompatibility complexes (MHCs; see Chapters 5 and 7).50 Immune-mediated diseases are common in the liver and biliary tract. Immune-mediated cholangiopathies include primary biliary cirrhosis (PBC), PSC, and autoimmune cholangitis (see Chapters 41, 43, and 74). These are diseases of the intrahepatic biliary tree of which the underlying causes are largely unknown but believed to be immune in origin and ultimately result in biliary stasis. PBC is an autoimmune disorder characterized by disappearance of the intrahepatic bile ducts, and patients are characteristically antimitochondrial antibody–positive, whereas PSC is characterized by progressive inflammation and fibrosis of the intra- and extrahepatic bile ducts. Inflammatory-mediated destruction of the biliary tree can result in fibrosis, and ultimately cirrhosis, in many patients with PBC and PSC, given the persistent chronic inflammation. Similarly, we see immune cell engagement in primary liver pathophysiology. Autoimmune hepatitis involves antibody-mediated destruction of hepatocytes thought to be precipitated by environmental triggers, which results in activation of both the innate and adaptive immune systems; however, the mechanisms of it are not well understood. Viral hepatitis infection involves various components of the immune system. HBV and HCV infections both involve activation of the innate immune system, and immune evasion results in a chronic infection, which is more common in HCV. Another important area to address regarding immune cell engagement is the use of immunotherapy in hepatobiliary malignancies. Immunotherapy has been largely ineffective in most HPB cancers. For example, recent trials evaluating pembrolizumab (KEYNOTE-240) and nivolumab (CheckMate 459) in HCC did not demonstrate a meaningful survival benefit

129

compared with best supportive care and sorafenib, respectively51,52 (see Chapter 99). Tumor mutational burden (TMB) is defined as the number of mutations per coding area of tumor genome and has been shown to correlate with neoantigen expression. Neoantigen expression, and ultimately TMB, is related to response to immunotherapeutic agents.53,54 There are additional biomarkers that can inform of the response to immunotherapy, including PD-L1 expression, but these have been shown to be poorly correlated with TMB.55 HPB cancers are thought to be poorly responsive to immunotherapy secondary to the dearth of neoantigen expression resulting in a lack of immune cell engagement.56 A subset of HPB tumors have an increased TMB, including microsatellite stable PDAC (see Chapters 9D, 61, and 62) and CC (see Chapters 9C, 9E, 50, and 51), viral-induced HCC (see Chapters 9B, 68, and 89), and liver-fluke associated CC (see Chapters 9C, 9E, and 50). Immunotherapy has been shown to be more effective in this subset of patients. For example, KEYNOTE-158 evaluated pembrolizumab in patients with noncolorectal cancers with high microsatellite instability (MSIhi), including PDAC and CC, and demonstrated an overall response rate of 18.2% and 40.9%, respectively57 (see Chapters 50, 66, 67, and 99).

Complex Genomic Alterations The genomic landscape of HPB cancers has been well characterized over the last decade, and there has been an increased understanding of the driver genes that underlie carcinogenesis in these malignancies. In PDAC, the four well-established driver genes are KRAS, TP53, CDKN2A, and SMAD435 (see Chapters 9D and 59). Similar drivers, such as KRAS and TP53, are noted in biliary tract cancers, as well as additional, commonly altered genes such as IDH1, IDH2, and PIK3CA36 (see Chapters 9C and 9E). Alterations in KRAS and TP53 have been shown to be associated with decreased overall survival in PDAC and CC.36,58 In addition to single nucleotide variants, copy number alterations (CNA) and large-scale chromosomal aberrations, including chromothripsis, are noted in CC, gallbladder cancer, and PDAC (see Chapters 9C–9E, 49, 50, and 59). Although there are distinguishing mutations in the genomic drivers, HPB cancers are overall characterized by a paucity of mutational events. Previous studies have demonstrated a lower rate of somatic point mutations in pancreatic and hepatobiliary cancers compared with other cancer types.59 As mentioned previously, a lower TMB is associated with fewer neoantigens and a decreased response to immunotherapeutic agents. By contrast, HCC in particular is noteworthy for profound structural variants and depression of transposable elements, which can also be found in the regenerative nodules of cirrhotic patients, long before the development of apparent malignancy.60 Unlike other tumor types such as non–small cell lung cancer and colorectal cancer, HPB cancers are also characterized by very few actionable genomic alterations, although recent studies have demonstrated some promise. For example, ivosidenib is a targeted inhibitor of mutated IDH1 and has recently been shown to improve progression-free survival compared with placebo in patients with IDH1-mutated intrahepatic CC61 (see Chapters 9C, 9E, and 50). Additionally, data suggest that patients diagnosed with PDAC who have germline

130

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

BRCA1 and BRCA2 mutations treated with platinum-based chemotherapy and poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors have improved outcomes62–64 (see Chapters 9D, 61, and 62). Additional drivers of tumorigenesis have been identified and successfully targeted in a subset of KRAS-wildtype PDAC. These include ALK alterations that can be targeted with tyrosine kinase inhibitors,65,66 NRG1 rearrangements that have been treated with ERBB inhibitors,67 and NTRK fusions.68

Epigenetic Mechanisms Epigenetic alterations involve those exclusive of changes to the DNA sequence itself and include chromatin modification and post-transcriptional regulation. Recent studies have provided increasing evidence that epigenetic regulation plays a role in the development of many cancers, and, in particular, emerging evidence has supported this finding in HPB cancers. In PDAC, mutations have been found in the genes that encode MLL2 (KMT2D), MLL3 (KMT2C), and KDM6A, which encode proteins responsible for post-translational modifications, and ARID1A, which encodes a protein subunit of the SWI/SNF complex that is integral for chromatin remodeling69,70 (see Chapter 9D). Among these, ARID1A and KDM6A appear to confer a basal or squamous transcriptional phenotype to PDAC, which is associated with poorer outcomes and with chemoresistance. Epigenetic mechanisms are also critical to defining organotropism and metabolic rewiring in metastatic disease.71 Chromatin-based enhancer reprogramming also occurs in the absence of a genetic event and permits metastasis of established tumors.72 Together, these data suggest that epigenetic regulators and chromatin plasticity drive aggressive behavior in this cancer. In CC, mutations to the isocitrate dehydrogenase enzymes IDH1 and IDH2 are common resulting in the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG).

a-Ketoglutarate (a-KG), a key intermediate in the tricarboxylic acid (TCA) cycle, is diminished, and histone and DNA demethylases that require a-KG are affected so that there are resultant increases in DNA hypermethylation and altered gene expression (see Chapters 9C and 9E). Recently, it has been shown that p53 also preserves a-KG levels such that mutations to this tumor suppressor represent an alternate means by which cancers appear to hijack chromatin-modifying enzymes to alter transcriptional landscapes.73 In HCC, chromatin regulators also appear central across the spectrum of malignancy, with elegant studies indicating that clonal mutations to these regulators first appear in cirrhosis and accumulate in full-blown HCC.60 The key chromatin regulators mutated include ARID1A, BAP1, and ARID2, with ARID1A notably displaying distinct oncogenic and tumor suppressive roles in initiation and progression of HCC74 (see Chapters 9B and 9C).

CONCLUSION In conclusion, the molecular and cellular basis of HPB disease is a complex interaction between genetic alterations, epigenetic modifications, and immune dysregulations that alter several key conserved signaling pathways. The confluence of these mechanisms serves broadly to disrupt epithelial cell fate and homeostasis of the organ. Much progress has been made in understanding these processes in the last decade, allowing for improved therapeutic intervention for some disease. Subsequent chapters in this section will explore these principles in more depth to provide a greater understanding of molecular and cellular mediators that define benign and malignant HPB diseases. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

130.e1

REFERENCES 1. Shin D, Monga SP. Cellular and molecular basis of liver development. Compr Physiol. 2013;3:799-815. 2. Fleming RJ, Purcell K, Artavanis-Tsakonas S. The NOTCH receptor and its ligands. Trends Cell Biol. 1997;7:437-441. 3. Li XY, Zhai WJ, Teng CB. Notch signaling in pancreatic development. Int J Mol Sci. 2015;17(1):48. 4. Adams JM, Jafar-Nejad H. The roles of Notch signaling in liver development and disease. Biomolecules. 2019;9(10):608. 5. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16:243-251. 6. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79:169-173. 7. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16:235-242. 8. Dill MT, Rothweiler S, Djonov V, et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology. 2012;142:967-977.e2. 9. Dill MT, Tornillo L, Fritzius T, et al. Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology. 2013;57:1607-1619. 10. Villanueva A, Alsinet C, Yanger K, et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012;143:1660-1669.e7. 11. Bhanot U, Kohntop R, Hasel C, et al. Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis. J Pathol. 2008;214:312-319. 12. Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711-1721. 13. Jung Y, McCall SJ, Li YX, et al. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology. 2007;45:1091-1096. 14. Pereira Tde A, Witek RP, Syn WK, et al. Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest. 2010;90:1690-1703. 15. Machado MV, Diehl AM. Hedgehog signalling in liver pathophysiology. J Hepatol. 2018;68:550-562. 16. Che L, Yuan YH, Jia J, et al. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin J Cancer Res. 2012;24: 323-331. 17. Sicklick JK, Li YX, Jayaraman A, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27:748-757. 18. Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cells. 2014;25:735-747. 19. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A. 2009;106:4254-4259. 20. Barker N, Morin PJ, Clevers H. The Yin-Yang of TCF/beta-catenin signaling. Adv Cancer Res. 2000;77:1-24. 21. Wells JM, Esni F, Boivin GP, et al. Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol. 2007;7:4. 22. Munoz-Bravo JL, Flores-Martinez A, Herrero-Martin G, et al. Loss of pancreas upon activated Wnt signaling is concomitant with emergence of gastrointestinal identity. PLoS One. 2016;11: e0164714. 23. Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. 2006;43:515-524. 24. de La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998;95:8847-8851. 25. Miyoshi Y, Iwao K, Nagasawa Y, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998;58:2524-2527. 26. Nhieu JT, Renard CA, Wei Y, et al. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999;155:703-710.

27. Eichenmuller M, Trippel F, Kreuder M, et al. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol. 2014;61:1312-1320. 28. Koch A, Denkhaus D, Albrecht S, et al. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res. 1999;59:269-273. 29. Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol. 2015;109:14.12.1-14.12.10. 30. Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, nonalcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 2013;28(suppl 1):38-42. 31. Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827-838. 32. Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4:177197. 33. Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116: 3015-3025. 34. Francque S, Verrijken A, Caron S, et al. PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164-173. 35. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-1806. 36. Simbolo M, Fassan M, Ruzzenente A, et al. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget. 2014;5:2839-2852. 37. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. 38. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66. 39. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21: 671-684. 40. Baecker A, Liu X, La Vecchia C, et al. Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. Eur J Cancer Prev. 2018;27:205-212. 41. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64:S84-S101. 42. Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2013;13:123-135. 43. Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823. 44. Kirkegard J, Mortensen FV, Cronin-Fenton D. Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112:1366-1372. 45. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328:1433-1437. 46. Willet SG, Lewis MA, Miao ZF, et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J. 2018;37. 47. Deng X, Zhang X, Li W, et al. chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell. 2018;23:114-122.e3. 48. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018;12: 361-373. 49. Aiello NM, Maddipati R, Norgard RJ, et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev Cell. 2018;45:681-695.e4. 50. Franco A, Barnaba V, Natali P, et al. Expression of class I and class II major histocompatibility complex antigens on human hepatocytes. Hepatology. 1988;8:449-454. 51. Yau T, Park JW, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874v875.

130.e2 52. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38:193-202. 53. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463-1469. 54. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207-211. 55. Yarchoan M, Albacker LA, Hopkins AC, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019;4(6):e126908. 56. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377:25002501. 57. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1-10. 58. Qian ZR, Rubinson DA, Nowak JA, et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 2018;4:e173420. 59. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214-218. 60. Brunner SF, Roberts ND, Wylie LA, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. 2019;574:538-542. 61. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796-807. 62. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317-327.

63. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132-1138. 64. O’Reilly EM, Lee JW, Lowery MA, et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018;124:1374-1382. 65. Shimada Y, Kohno T, Ueno H, et al. An oncogenic ALK fusion and an RRAS mutation in KRAS mutation-negative pancreatic ductal adenocarcinoma. Oncologist. 2017;22:158-164. 66. Singhi AD, Ali SM, Lacy J, et al. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J Natl Compr Canc Netw. 2017;15:555-562. 67. Heining C, Horak P, Uhrig S, et al. NRG1 fusions in KRAS wildtype pancreatic cancer. Cancer Discov. 2018;8:1087-1095. 68. O’Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019;30:viii36-viii40. 69. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518: 495-501. 70. Witkiewicz AK, McMillan EA, Balaji U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744. 71. McDonald OG, Li X, Saunders T, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49:367-376. 72. Roe JS, Hwang CI, Somerville TDD, et al. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell. 2017;170:875888.e20. 73. Morris JP IV, Yashinskie JJ, Koche R, et al. Alpha-Ketoglutarate links p53 to cell fate during tumour suppression. Nature. 2019;573:595-599. 74. Sun X, Wang SC, Wei Y, et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell. 2017;32:574-589.e6.

CHAPTER 9B Molecular and cell biology of liver carcinogenesis and hepatitis Takehiro Noda and Jack R. Wands OVERVIEW OF MOLECULAR ETIOLOGY Recent advances in molecular genetics have emphasized the multistep process of tumorigenesis. It is evident that cancer is a genetic disease involving aberrant chromosome rearrangements, genetic mutations, and epigenetic silencing of tumor suppressor genes.1 Independent of the etiology, hepatocellular carcinoma (HCC) generally develops where sustained hepatocyte turnover occurs in the setting of injury-inflammation-regeneration, which leads to the accumulation of chromosomal aberrations (see Chapters 68 and 89). The monoclonal populations of hepatocytes become preneoplastic and, after additional genomic alterations, change into dysplastic cells and eventually HCC.2 Accumulated genetic alterations in preneoplastic lesions and HCC result in the activation, as well as inactivation, of many growth factor signal transduction pathways involved in hepatic transformation. It is believed that increased hepatocyte turnover associated with chronic liver injury may be a major feature of hepatic oncogenesis. However, another central question is whether hepatitis viruses, the leading cause of HCC worldwide, directly contribute to the development of this disease. Accumulating evidence suggests that chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection play a direct role in the molecular pathogenesis of HCC through specific viral–cellular protein interactions3 (see Chapter 68). In this chapter, we discuss the molecular mechanisms of liver carcinogenesis and focus on the role of HBV and HCV.

EPIDEMIOLOGY Primary liver cancer was the fourth leading cause of cancer death in 2015 after lung, colorectal, and stomach cancer.4 It is estimated that 782,000 new patients with the disease were diagnosed in 2012.5 The 5-year survival rate is less than 15% in developed countries, and the United States has a survival rate of 20.3%, making liver cancer the second most fatal tumor after pancreatic cancer.6 Presumably because of its poor prognosis, liver cancer is the second leading cause of cancer death in men and the sixth among women in the world. It is estimated that about 745,000 individuals worldwide died from this disease in 2012.5 It is one of the few neoplasms with a steadily increasing incidence and mortality in the United States.7 Primary liver cancer comprises a heterogeneous group of malignant tumors with different histologic features. The unfavorable prognosis varies from hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to mixed hepatocellular cholangiocarcinoma (HCC-CCA), fibrolamellar HCC, and the pediatric neoplasm hepatoblastoma8 (see Chapters 50, 87, and 89). The most common is HCC, which accounts for 70% to 85% of all hepatic tumors.9 Approximately 80% of HCC is

caused by chronic infection with HBV or HCV (see Chapter 68). The HCC burden is unevenly distributed worldwide; areas where tumors are most prevalent include West and Central Africa and East and Southeast Asia, with China alone accounting for more than 50% of the world cases.5 The incidence of HCC varies with both geographic location and ethnicity. For example, HCV is the leading etiology of HCC in the United States, Europe, Japan, and South America, whereas HBV is the major cause in the majority of Asian and African countries.10 Trends in HCC incidence are likely to be different in regions of high and low persistence of HBV and HCV infection.11 Comparative studies performed between 1977 and 1982 and between 1993 and 1997 show that the incidence of HCC in Hong Kong, Shanghai, Singapore, and Japan has begun to decrease.12 The fall in incidence is apparently because of vaccination against HBV, which has been accomplished in greater than 80% of newborns,13 because chronic HBV infection in those countries is usually acquired through mother-to-newborn or sibling-tosibling transmission at a young age. Although HBV vaccination reduces the incidence of HCC, many unvaccinated persons are still infected with HBV (257 million in 2015), mostly in Asia and sub-Saharan Africa.14 The incidence of HCC has increased in some countries, such as Australia, the United States, and the United Kingdom, probably as the result of chronic HCV infection and nonalcoholic steatohepatitis (NASH; see Chapter 69). The annual incidence of liver cancer increased from 2.6 per 100,000 population for the years 1978 to 1980 to 8 per 100,000 in 2010, of which at least 3 of 4 cases are because of HCC.15 Reasons for this increased incidence are not entirely clear but may reflect a greater prevalence of NASH and role of persistent HCV infection.16 Recent advances in direct-acting antiviral (DAA) agents for HCV will cure most individuals with chronic HCV infection, and it has been estimated that reducing the frequency of chronic HCV infection by 90% would eliminate 15% of HCC in the United States.17 However, there is debate over the effects of DAA agents on tumor progression.18 The age of onset of HCC varies in different parts of the world. HCC tends to occur later in life in Japan, North America, and European countries, where the median age of onset is above 60 years. In contrast, in parts of Asia and most African countries, HCC is commonly diagnosed in the age range of 30 to 60 years.19 In the United States, however, recent trends have revealed a peak incidence shifting toward a relatively younger age group.15 Significant gender and ethnic variation in incidence, as well as mortality from HCC, has also been found; male rates are nearly triple that of females.5 The most likely explanation for gender variation is that men have more risk factors, such as exposure to hepatitis virus infection, excessive alcohol

131

132

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

intake, smoking, and increased iron stores in the liver.11 In addition, androgen levels may accelerate the progression of HCC through interaction with the HBV genome.20,21 The incidence of HCC also varies with race and ethnicity in the same area. In the United States, the incidence and subsequent mortality rates are two times greater in Asians than African Americans, which are two times greater than those found in Caucasians.11 These variations are explained, in part, by the accumulation of major risk factors in each ethnic group.

RISK FACTORS Unlike most malignancies, HCC has well-established extrinsic risk factors that account for at least 80% of tumors (namely chronic infection with HBV or HCV; see Chapter 68). Key epidemiologic aspects of HBV- and HCV-induced HCC are summarized in Table 9B.1. Chronic HBV infection is the leading cause of HCC, and it has been estimated that there are 350 to 400 million HBV carriers, which account for 5% of the global population. About 59% of HCC patients in developing countries and 23% of HCC patients in developed countries are chronically infected with HBV.22 Risk factors for HBV-related HCC include demographic features such as male sex, older age, Asian or African ancestry, family history of HCC, viral properties (higher levels of HBV replication; HBV genotype; longer duration of infection; co-infection with HCV, human immunodeficiency virus [HIV], or hepatitis delta virus), clinical factors (cirrhosis), and environmental factors (exposure to aflatoxin, heavy intake of alcohol or tobacco).23 The 5-year cumulative incidence rates of HCC from HBV-related cirrhosis are 17% in highly endemic areas and 10% in Europe and the United States.24 HBV can cause HCC in the absence of cirrhosis, although approximately 70% to 90% of HBV-related HCC cases develop in patients with this disease.25 Nucleoside/nucleotide analogues that suppress viral replication are associated with risk reduction of HCC in patients with chronic hepatitis B.26 Aflatoxin B1 (AFB1) is produced by Aspergillus flavus and related fungi that contaminate corn, rice, and peanuts in China and sub-Saharan Africa. High rates of dietary exposure to AFB1 increase the risk for HCC 4-fold. When people with chronic HBV infections are exposed to AFB1, the relative risk for HCC dramatically increases to about 60-fold.27 This synergistic effect between AFB1 exposure and chronic HBV infection is an important observation because in some regions of the world, AFB1 exposure and chronic HBV infection rates are high. Chronic HCV infection is the second leading cause of HCC. The estimated number of HCV carriers worldwide is 180 million, which accounts for 2% of the global population. Approximately 33% of HCC tumors in developing countries and 20% of HCC in developed countries are attributable to persistent HCV infection.22 According to cross-sectional and case-control studies, HCC risk is increased 15- to 20-fold in HCV-infected people compared with the HCV-negative population.28 Patients with HCV-induced cirrhosis are at particularly high risk for the development of HCC, with an annual incidence of HCC ranging from 0.5% to 10%. Sustained virologic response (SVR) with DAA agents has emerged as the most dominant modifier of HCC in patients with HCV. 23 Although DAA is likely to change the epidemiology of HCVrelated HCC in those who are treated, most HCV-infected populations remain untreated. The DAAs offer a chance for

TABLE 9B.1  Comparison of Epidemiologic Features between HBV- and HCV-Induced HCC HBV*

HCV

Virus carriers (% of global population)

350-400 million (5%)

180 million (2%)

Highly prevalent areas

Asia, sub-Saharan Africa, Melanesia, Micronesia

Africa, South and East Asia, South America

Relative risk of HCC

5- to 100-fold*

15- to 20-fold

5-year cumulative incidence rates of HCC from cirrhosis

10% (Europe and United States) 17% (East Asia)

17% (Europe and United States) 30% (Japan)

HBV, Hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. *Depends on multiple factors, including HBV load, presence of cirrhosis, and exposure to aflatoxin B1. From El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: Where are we? Where do we go? Hepatology. 2014;60:1767–1775, and El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–1273.

cure of patients with advanced cirrhosis, older age, and alcohol use. These patients had a poor response to interferon (IFN)-based therapies. However, there was no evidence for differential occurrence of HCC or recurrence risk after SVR attributable to DAA or IFN-based therapy.29 Excessive ethanol consumption (.50–70 g/day) is another well-defined risk factor for HCC. Alcoholic cirrhosis is the second most common risk factor for HCC in the United States and Europe.19,30 There was a linear increase of a relative risk for HCC by 5-fold when 60 to 140 g/day alcohol was consumed. The 5-year cumulative HCC incidence in alcoholic cirrhosis without HBV and HCV infection is 8%31; however, it is unlikely that ethanol itself has a direct carcinogenic effect. Rather, excessive ethanol ingestion indirectly affects hepatocarcinogenesis through the promotion of cirrhosis. Indeed, greater than 80% of HCC tumors found in alcoholics develop in the background of a cirrhotic liver. A synergistic effect between heavy alcohol consumption and hepatitis virus infection has been observed in several studies. The relative risk for HCC attributable to heavy alcohol consumption alone was only 2.4-fold, whereas in combination with chronic HCV infection, it increased to 50-fold.32 Others have reported that concomitant HCV infection in alcoholics increases the risk for HCC 2-fold, whereas HBV infection moderately increases this risk 1.2- to 1.5-fold.30,33 Growing evidence now suggests that metabolic dysfunction, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are important risk factors for HCC, especially in developed countries34 (see Chapter 69). Several large cohort studies revealed that obesity is a definitive risk factor for HCC, with the 1.5- to 4-fold increased risk. Men are more susceptible to obesity-associated HCC than women. NAFLDassociated HCC also occurs frequently in the absence of cirrhosis.35 Diabetes mellitus has also been established as a moderately strong risk factor for HCC, with a two- to fourtimes higher risk.11,36 The use of metformin is associated with decreased risk, and the use of insulin or sulfonylureas may increase HCC risk. Longer duration of diabetes may be associated with an incremental increase in risk.37–39 More recently,

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

NASH, the more aggressive form of NAFLD, is considered to be a cause of a large proportion of cryptogenic cirrhosis, which is risk for HCC development. However, the overall incidence of HCC in patients with NAFLD is lower than in patients with other well-established etiologies, such as chronic viral infection.36 Cigarette smoking is one risk factor for HCC. The HCC risk of current and former smoking was 1.55 and 1.39 times, respectively.40 Cirrhosis of any cause increases the risk for HCC, with an annual incidence between 2% and 4%.

GENETIC AND EPIGENETIC ALTERATIONS Chronic inflammation accompanied by sustained cycles of injury and regeneration of hepatocytes over 20 to 40 years promotes the development of liver fibrosis, cirrhosis, and eventually HCC (Fig. 9B.1A; see Chapter 7). Pathologically, HCC occurs early within cirrhotic nodules, which can form in areas of adenomatous hyperplasia or dysplasia. These cells eventually become more atypical, and the malignant transformation process is completed.41 HCC is like other malignancies and represents a DNA disease with accumulation of many alterations in oncogenes and tumor suppressor genes. The accumulation of genetic aberrations that induces cellular transformation may take 20 to 40 years, suggesting that liver carcinogenesis involves a multistep process. Cirrhosis may represent end-stage liver disease as a result of persistent HBV or HCV infection. Because about 80% of HCC tumors originate from cirrhotic liver, it is evident that continuous rounds of cellular injury, followed by regeneration fundamentally contributes to the oncogenic processes. The sustained cycles of injury and repair increase the chance of genomic alteration. Furthermore, the host inflammatory response to viral infection, including activation of stellate cells, causes the release of proinflammatory cytokines, which accelerate hepatic carcinogenesis by augmenting oxidative stress and DNA damage.42–44 Continuous rounds of this process in the presence of inflammation not only increase the chance of genomic alterations but also produce chromosome instability. For example, hyperploidy has been observed in 43% of dysplastic peritumoral regions and in about 50% of HCC tumors.45 The molecular mechanisms underlying such genomic instability include telomerase dysfunction, defective segregation of chromosomes, and an impaired DNA damage response (see Fig. 9B.1B). Recent advances in genome-wide analysis, including whole-genome sequencing and DNA array technologies, have provided more detailed information on the alterations of oncogenic or tumor suppressive genes.46–48 Accordingly, development of molecularly targeted therapy for HCC will be challenging. Nevertheless, several frequently mutated genes, such telomerase reverse transcriptase (TERT), the tumor suppressor gene (TP53), the b-catenin gene (CTNNB1), the axis inhibition protein 1 gene (AXIN1), the AT-rich interactive domain 1A [SWI-like] gene (ARID1A), tuberous sclerosis complex 1/2 (TSC1/TSC2), and the nuclear factor (erythroid derived 2)-like 2 (NFE2L2), are found in HCC. The key genes of major signaling pathways are involved by genetic alterations; TP53 in p53-Rb and CTNNB1 and AXIN1 of WNT (wingless type)/b-catenin pathways, as well as ARID1A in chromatin remodeling, TSC1/ TSC2 in phosphatidylinositol-3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway, NFE2L2 in nuclear factor

133

(erythroid-2 like) factor 2(NRF2)-KEAP1 pathway.49 Newly identified alterations in these genes can suggest potential therapeutic and diagnostic opportunities. Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. Absence of telomerase activity and shortening of telomeres have been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can progress to HCC.50 In human HCC, telomere shortening has been shown to have a positive correlation with increased chromosome instability— chromosomal gains, losses, and translocations—by promoting chromosomal fusions.51 In some HBV-induced HCC tumors, the viral genome is integrated into the TERT locus, which results in increased expression of telomerase.48,52 Direct sequencing of the TERT promoter region has revealed that 59% of HCCs have recurrent somatic mutations, which may result in the activation of TERT, and TERT promoter mutation are frequently associated with CTNNB1 mutations.53 Other findings related to telomerase biology indicate amplification of telomerase RNA component gene (TERC) mRNA and allelic loss of chromosome 10p, where a putative telomerase inhibitor resides.54,55 Re-activated telomerase enzyme maintains the shortened telomere length in these tumor cells and prevents them from undergoing apoptosis. DNA damage-response pathways are safeguards that regulate cell-cycle checkpoints and prevent DNA-damaged cells from further proliferation. Several studies report that the functions of key regulatory molecules, including p53, mouse double-minute 2 (MDM2), retinoblastoma 1 (RB1), and p16INK4a (also known as CDKN2A [cyclin-dependent kinase inhibitor 2A]) were impaired in human HCC. The p53 protein, encoded by the TP53 gene, is a master molecule that maintains genome integrity by inducing cell-cycle arrest, followed by activation of DNA repair systems. Moreover, TP53 is one of the most mutated genes in HCC, and the mutations often result in loss of function. The frequency ranges between 11% and 35%, depending on the regions of the world. The regional difference in the frequency is attributable to a specific mutation caused by AFB1 exposure. TP53 missense mutations in codon 249 (R249S) were found in more than 50% of AFB1-related HCC and appeared to be the main cause of AFB1-induced liver cancer.56,57 Therefore TP53 mutations in HCC can be frequently found in Africa and Asia where people are exposed to a high level of AFB1. Other mutations of TP53 are found in 20% to 40% of HCC without molecular evidence of AFB1 exposure.11 The aberration of the p53 pathway can be caused by molecules that inappropriately regulate p53 functions. The MDM2 is an E3 ubiquitin ligase targeting tumor suppressor proteins, including p53 and RB1. Strikingly, gankyrin (encoded by Proteasome 26S Subunit, Non-ATPase 10[PSMD10]), which promotes such protein degradation by MDM2, was highly overexpressed in human HCC.58,59 More recently, genomewide copy number variation analysis identified IFN regulatory factor 2 (IRF2) as a novel tumor suppressor gene in HCC that activates the p53 pathway and revealed that IRF2 loss-offunction mutations were frequently and exclusively found in HBV-related HCC.46 The CDKN2A gene encodes for two splice-variant products, including p16INK4a and p14ARF, which positively regulate the p53 and RB1 signaling pathways. The expression of the CDKN2A gene was suppressed in 30% to 70% of human HCC as a result of methylation of the

134

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

FIGURE 9B.1  ​A, Diagram showing progression of liver disease and genetic events accompanied by chronic inflammation. B, Common mechanisms underlying hepatocarcinogenesis. A number of factors contribute to chromosome instability and other genetic alterations, which lead to the formation of hepatocellular carcinoma.

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

promoter region.60–63 Loss of heterogeneity of chromosome 9p, where CDKN2A is located, was found in 15% to 20% of tumors.64–66 Interestingly, CDKN2A deletion rarely occurs in HCC when TP53 is also mutated.67 Taken together, impairment of the p53 and RB1 pathways is a common genetic feature of HCC development, growth, and progression. The canonical WNT pathway plays a central role in the development of many tumor types and is a key regulator of b-catenin, which is encoded by the CTNNB1 gene. CTNNB1 is one of the most frequently mutated genes in HCC, ranging from 20% to 40%.57,68 The activating mutations frequently occur in exon 3, which result in the nuclear accumulation of b-catenin, thereby inducing WNT-responsive gene expression. Indeed, nuclear accumulation of b-catenin is associated with a more aggressive phenotype and with poor prognosis in HCC patients.69 Another frequently mutated gene in the canonical WNT pathway is AXIN1, a gene encoding a cytoplasmic protein that negatively regulates WNT signaling. AXIN1 mutations are found in about 10% of HCC.46,70 Loss-of-function mutations of AXIN1 lead to a decrease in degradation of b-catenin and to nuclear localization of this protein. Epigenetic regulation of the genome is a fundamental determinant of global gene expression. Epigenetic regulators have come to be recognized as tumor suppressors because next-generation sequencing of cancer genomes has defined frequent mutations in epigenetic regulators, including chromatin remodeling proteins and histone-modification proteins. In HCC, the AT-rich interactive domain ARID family, including ARID1A, ARID1B, and ARID2, was found to be mutated in 6% to 17% of HCC genomes.46,48,71 Through the interaction with the switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex, ARID family proteins bind transcription factors and recruit the remodeling activity to a specific gene. Mechanisms underlying tumor development by loss-offunction mutations of ARID family genes are not known in detail, but it is highly likely that ARID mutations are associated with tumor proliferation, dedifferentiation, and inhibition of apoptosis.72 MLL and MLL3 are histone methyltransferases that positively regulate gene transcription. The MLL gene translocations are frequently found in infant leukemia, but the significance of loss-of-function mutations of MLL family in HCC remains to be determined.73 TSC1/TSC2 are both negative modulators of mTOR cascade, and their inactivation promotes mTOR signaling.74 The mutations of TSC1 or TSC2 are described in 2% to 5% of HCC.49,75 TSC1/TSC2 mutations are closely associated with the scirrhous HCC subtype, defined by marked stromal fibrosis.76 NRF2 encoded by NFE2L2 is centrally involved in counteracting such oxidative stress by enhancing adaptive oxidative stress and hence survival. NRF2 is negatively regulated and targeted to proteasomal degradation by Kelch-like ECH-associated protein 1 (KEAP1). The activating NFE2L2 mutation is identified in 6% to 7% of adult HCC.46 The dysregulation of the KEAP1-NRF2 molecular pathway is observed in human HCC. The protein NRF2 is frequently mutated and activated at early steps of the tumorigenic process.77 These key genetic alterations in HCC are summarized in Table 9B.2. It is evident that the expression and function of oncogenes and tumor suppressor genes are affected by copy number because of chromosomal gains and losses and by point mutations

135

TABLE 9B.2  Genetic Alterations Frequently Found in HCC GENE SYMBOL

GENETIC ALTERATION

FREQUENCY (%)

Promoter activation

20-60

CTNNB1

Gain-of-function mutation

20-40

AXIN1

Loss-of-function mutation

3-16

TP53

Loss-of-function mutation

11-35

CDKN2A

Loss of heterozygosity

Promoter inactivation

15-20

Telomere Maintenance TERT WNT/b-Catenin

Cell Cycle

30-70 Proliferation IRF2

Loss-of-function mutation

5

IGF2R

Allelic loss

0-13

ARID1A/1B

Loss-of-function mutation

7-17

ARID2

Loss-of-function mutation

6-16

TSC1

mTOR signaling

2

TSC2

mTOR signaling

5

Oxidative stress

5

Epigenetic Modifier

PI3K-mTOR Pathway

Nrf2-Keap1 Pathway NFE2L2 HCC, Hepatocellular carcinoma. From Ding J, Wang H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 2014;346:17–23; and Marquardt JU, Thorgeirsson SS. SnapShot: Hepatocellular carcinoma, Cancer Cell. 2014;25:550; and Totoki Y, Tatsuno K., Covington K. R., et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–1273.

in the genes. However, recent studies have revealed that epigenetic mechanisms—such as DNA methylation and short, noncoding RNA (21–23 nucleotides) species, or microRNA (miRNA)—also contribute to aberrant expression of oncogenes and tumor suppressor genes. In human HCC, aberrant DNA methylation patterns have been detected.2,78,79 More importantly, hypermethylation has been observed at the earliest stages of HCC development, and the extent of hypermethylation tends to increase with tumor progression.80 Specific gene targets for hypermethylation include CDKN2A, prostaglandin-endoperoxide synthase 2 (PTGS2), CDH1, PYCARD, GADD45B, and DLC1. Among these genetic elements, it has been shown that CDKN2A, GADD45B, and PTGS2 expression were directly affected by methylation, using human HCC cell lines.61,62,81,82 In addition, miRNA contributes to mRNA instability by hybridizing with its complementary target sequence, followed by degradation, so that a protein cannot be generated. Several studies reveal aberrant expression of some miRNAs in human HCCs compared with the adjacent, non-tumorous counterparts. Many miRNAs perform tumor suppressor function by downregulating oncogene expression. Nevertheless, other miRNAs are oncogenic functions by downregulating tumor suppressor genes or upregulating oncogene expression levels

136

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

to promote liver cancer development. For example, miR-21 is expressed in human HCC; it targets the phosphatase and tensin (PTEN) tumor suppressor gene.83 Also, miR-21 promotes hepatic lipid accumulation and hepatocarcinogenesis by interacting with the HBP1-p53-SREBP1C pathway.84 MicroRNA-122, which targets the cyclin G1 cell-cycle regulator, is abundant in normal hepatocytes and is essential for homeostasis of hepatocytes. Its implication in hepatocarcinogenesis was revealed using knockout mice and clinical samples.85,86 The MicroRNA 193a-5p appears to prevent liver tumorigenesis by reducing levels of nucleolar and spindle-associated protein 1 (NUSAP1).87 The expression of miR-26a is diminished in murine and human tumors, resulting in enhanced activity of cyclin D2 and E2 to promote cell proliferation. Moreover, when exogenous miR-26a is overexpressed in mice prone to form multiple HCCs, substantial protection from disease progression is observed, indicating a possible therapeutic approach for this disease.88 These findings indicate that epigenetic and posttranscriptional regulation of gene expression plays an important role in hepatic oncogenesis.

SIGNAL TRANSDUCTION PATHWAYS Genetic alterations of oncogenes and tumor suppressor genes impinge on a wide variety of signal transduction pathways involved in proliferation and tumor cell viability. Although the spectrum of affected signal transduction pathways in HCC cells is more heterogeneous compared with that of affected signals in other tumor types, key pathways are commonly dysregulated in human HCC, such as the WNT/b-catenin, erythroblastosis (ERB)-B receptor tyrosine kinase (ERBB)/extracellular signalregulated protein kinase (ERK)/PI3K, and insulin-like growth factor (IGF)/insulin receptor substrate (IRS)/ERK/PI3K cascades (Fig. 9B.2). The WNT/b-catenin pathway has a role in physiologic embryogenesis and regulates cell proliferation, motility, and differentiation. WNT proteins are ligands that bind to Frizzled (FZD) cell-surface receptors to stabilize b-catenin in the cytoplasm, followed by translocation to the nucleus, where it upregulates WNT-responsive genes.89 In the absence of WNT signaling, the amount of cytosolic b-catenin is low as a result of proteolytic degradation produced by the action of glycogen synthetase kinase-3b (GSK-3b)/adenomatosis polyposis coli (APC)/AXIN kinase destruction complex. However, when WNT ligands bind to the FZD/low-density-lipoprotein receptor-related protein-5/6 (LRP-5/6)/Disheveled (DVL) receptor complex, phosphorylation of b-catenin by GSK-3b is inhibited to allow its accumulation in the cytoplasm. The b-catenin molecules are then transported into the nucleus and bind to T-cell factor (TCF)/leukocyte enhancer factor (LEF) transcription factors; this complex acts as transcriptional regulators. Finally, the TCF/LEF/b-catenin complex promotes activation of target genes, including cyclin D1 (CCND1), myelocytomatosis viral oncogene (MYC), PTGS2, and JUN, which leads to proliferation of HCC cells.90 The frequency of b-catenin nuclear accumulation varies between 17% and 75%, as determined by immunohistochemical staining.69,91,92 Nuclear accumulation of b-catenin is an excellent biomarker for activation of WNT signaling in HCC. The activation of b-catenin occurs at an earlier stage of the oncogenic process in dysplastic cells, suggesting that the WNT/b-catenin cascade is directly involved in tumor formation.2,93–95

The major cell-surface molecules in WNT/b-catenin signaling are FZD receptors. There are 10 FZD receptors (FZD1 to FZD10) in humans. Indeed, studies reveal that 23% to 59% of HBV-related HCCs overexpress the FZD7. Through the interaction with a FZD-ligand WNT3, overexpressed FZD7 leads to the activation of this pathway in human tumors and HCC cell lines.96,97 The functional consequences of FZD7 overexpression are enhanced cell motility and invasion. In murine HCC models, overexpression of FZD7 occurs in dysplastic nodules and HCC tissue but not in normal liver.95,98 The FZD7 overexpression is a common event during hepatic oncogenesis in that it promotes tumor cell motility and invasion. Receptor tyrosine kinases (RTKs) and subsequent signal transduction, including the mitogen-activated protein kinase (MAPK) pathway and the PI3K/AKT pathway, play a central role in tumor cell proliferation and survival. The ERBB family (especially ERBB1), MET proto-oncogene, and IGF-1 receptor (IGF-1R) are the RTKs frequently activated in HCC cells. The ERBB family consists of four RTKs, including ERBB1/EGFR/HER1, ERBB2/HER2/NEU, ERBB3/HER3, and ERBB4/HER4.99 When ligands bind to the ERBB1 receptor, autophosphorylation occurs that leads to an association with the growth factor receptor–bound protein 2 (GRB2) adaptor molecule and PI3K. When phosphorylated ERBB1 binds to GRB2, the complex activates the rat sarcoma (RAS) oncoprotein, resulting in enhancement of RAF serine/threonine kinase activity. Activated RAF kinase triggers MEK/ ERK kinases, as well as ERK, which translocates to the nucleus and upregulates the transcription of oncogenes such as FBJ murine osteosarcoma viral oncogene homolog, JUN, and MYC. When phosphorylated ERBB1 binds to PI3K, ERBB1 activates PI3K and the downstream AKT kinase. AKT phosphorylates a number of important molecules, including mTOR, GSK-3b, and inhibitor of kappa B kinase (IKK) to promote proliferation and viability of tumor cells. TSC1/ TSC2 are both negative modulators of AKT/mTOR cascade. ERBB1 and ERBB3 were overexpressed in 68% and 84% of HCC, respectively, which correlates with an aggressive phenotype.100 Ligands for ERBB include epidermal growth factor (EGF), transforming growth factor (TGF)-a, heparin-binding EGF (HB-EGF), amphiregulin, b-cellurin, and epiregulin. In this regard, TGF-a and HB-EGF proteins may play a role in the pathogenesis of HCC. TGF-a was frequently upregulated at an earlier stage of tumor formation.101,102 The upregulation of TGF-a was linked to the oncogenic process.103 The HB-EGF protein was a potent mitogen for hepatocytes, detected in about 60% of HCC cases.104 Moreover, overexpression of HBEGF was found at an earlier stage of HCC with moderately or well-differentiated features,105 suggesting that HB-EGF is an important ligand in initiation of this disease. As a consequence, MAPK activity is increased in HCC, compared with adjacent non-tumorous tissues.106,107 The IGF signaling cascade regulates energy metabolism and cell growth. It consists of ligands, receptors, adaptors, and subsequent MAPK and PI3K/AKT pathways. The ligands IGF-1, IGF-2, and insulin bind to receptors of IGF-1R homodimers and heterodimers consisting of IGF-1R and insulin receptors and activate their kinase domain. Activated receptors phosphorylate adaptor proteins such as IRS-1 and IRS-2, which are able to trigger the MAPK and PI3K/AKT signaling cascades. Negative regulators are IGF-2R and IGF-binding proteins (IGFBPs). IGF2R is a decoy receptor to which IGF-2 exclusively binds, but no

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

137

FIGURE 9B.2  ​Schematic diagram showing the major components of three signal-transduction pathways involved in hepatic oncogenesis. In the WNT/b-catenin cascade, accumulation of b-catenin is regulated by WNT ligands. The ERBB and IGF/IRS pathways both use downstream activation of several kinases, including the RAS/RAF/MEK/ERK and PI3K/AKT cascades. AKT, v-Akt murine thymoma viral oncogene homolog; APC, antigen-presenting cell; AXIN, ***; ERK, extracellular signal-regulated protein kinase; DVL, Disheveled (receptor); ERBB, erythroblastosis (ERB)-B receptor tyrosine kinase; FZD, Frizzled (receptor); GRB2, growth factor receptor–bound protein 2; GSK, glycogen synthetase kinase; GTP, guanosine triphosphate; IGF-1R, insulin-like growth factor-1 receptor; IKK, inhibitor of kB kinase; I/R, ischemia/reperfusion; IRS, insulin receptor substrate; LEF, leukocyte enhancer factor; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; SOS, son of sevenless homolog; TCF, T-cell factor; TGF, transforming growth factor; transcr., transcription; WNT, wingless type.

138

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

activation of downstream molecules occurs. IGFBP-3, a predominant form of IGFBPs, is a neutralizing peptide that binds to circulating IGF-1 and IGF-2.108 Many lines of evidence have established that dysregulation of IGF pathway is involved in the malignant transformation, cancer development, and even resistance to anticancer agents. The same is true for HCC. Comprehensive analysis of 104 HCC cases revealed that IGF pathway activation, namely the presence of phosphorylated IGF-1R, was found in 21% of the cases.109 Overexpression of IGF-2, downregulation of IGFBP-3, or allelic losses of IGF2R, which all lead to the activation of the pathway, was found in 25% of the cases. Another report revealed that the IGF-2 ligand was overexpressed in 16% to 40% of tumors, as well as in dysplastic tissue, suggesting that IGF-2 may act by autocrine and/or paracrine mechanisms.110 IRS adaptor molecules are also important in HCC development. IRS-1 is overexpressed in the majority of human HCCs.111,112 Constitutive MEK/ERK pathway activation may also occur via downregulation of a RAF kinase inhibitor protein (RKIP); this event promotes HCC cell proliferation and migration.113 Indeed, downregulation of RKIP was found in 90% of human HCC and suggests that it plays a role as a tumor suppressor protein. The PI3K/AKT/mTOR and RAS/RAF/mitogen-activated protein kinase pathways are activated in around 5% to 10% of HCC by amplification of the FGF19/CCND1 locus. Also, inactivating mutations of TSC1 or TSC2 (2%–5%) lead to activation of mTOR signaling in a subset of HCC.49,114 Homozygous deletion of PTEN, an inhibitor of the PI3K kinase, has been identified in approximately 1% to 3% of HCC. The angiogenic pathway is the most important molecular target in HCC because HCC is usually a highly vascular tumor.115 Angiogenesis is a complex process regulated by many factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). VEGF and its receptors VEGF-R1, -2, and -3 are overexpressed in HCC, and overexpression of VEGF is associated with poor prognosis.116,117 PDGF recruits pericytes and smooth muscle cells around new vessels. bFGF is involved in endothelial cell migration, capillary branching, and the activity of proteases, which are essential for angiogenesis. These growth factors bind and stimulate their corresponding receptors on angiogenic cells and activate the subsequent signal pathways, including MAPK, PI3K/AKT, SRC, and phospholipase C (PLC)-g pathways. Sorafenib is a smallmolecule multikinase inhibitor that inactivates VEGF receptors, PDGF receptors, v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and B-Raf proto-oncogene (BRAF).118 It is the first drug proven to be effective in advanced HCC119 (see Chapter 99). The antiangiogenic approach may become a mainstream of the systemic treatment of HCC, and in fact, many clinical trials for use of such agents are currently underway.120 Oxidative stress is a process whereby the body receives stimulation from harmful endogenous or exogenous factors. Free radicals, including reactive oxygen species (ROS) and reactive nitrogen species, which are common metabolic products of several oxidation-reduction (redox) reactions in the cells, are increased when oxidative stress occurs. A transcription factor, NRF2, was found to play a key role in promoting HCC pathogenesis.121 The oxidative stress pathway is altered by activating mutations of NRF2 (coded by NFE2L2) or inactivating KEAP1

in 5% to 15% of the cases, preventing proteasome degradation of NRF2 physiologically induced by KEAP1/CUL3 complex ubiquitinylation.46

LIVER CANCER STEM CELLS There exists a hierarchy in a tumor in terms of the potential to divide and of cell-specific functions that differentiated cells exert. A small population of tumor cells with the highest potential and an undifferentiated state gives rise to a bulk tumor population. Such undifferentiated tumor cells, called cancer stem cells (CSCs) or tumor-initiating cells, are able to self-renew and produce differentiated cells by asymmetric division.122,123 The clinical importance of CSC theory is that CSCs are generally resistant to conventional anticancer agents and radiotherapy, and when CSCs are brought to distant organs, they can form metastatic lesions. Therefore eradication of cancer cells is so difficult that we should target a few therapeutic-resistant CSCs, as well as the more differentiated bulky tumor cell population sensitive to conventional treatment. In HCC, identification of surface markers has moved toward a deeper understanding of liver CSCs. Liver CSC surface markers include CD133, CD90, epithelial cell adhesion molecule (EpCAM), CD13, CD24, OV6, and CD44.124 They are necessary for the effective targeting of liver CSCs to find specific pathways for the expansion and maintenance of stem cell properties. The pathways of TGFb, Janus-activating kinase (JAK)/signal-transducer and activator of transcription 3 (STAT3), NOTCH, and PI3K/AKT/mTOR are identified as regulatory networks essential for the activation and functions of liver CSCs.125–127 Taken together, analysis of the cancer cells in HCC supports the presence of cells with stem cell properties. However, definitive specific markers for these putative CSCs have not yet been found and a liver CSC has not been isolated and characterized.

HEPATITIS B VIRUS (SEE CHAPTER 68) HBV is the prototype member of the Hepadnaviridae family. Viral members of this group also infect ducks, ground squirrels, and woodchucks. These small, partially double-stranded DNA viruses contain four overlapping open reading frames (ORFs), including preC/core, preS/S, P, and X, except for the duck, in which X is missing (Fig. 9B.3A and B). PreC/core ORF encodes the precore protein, a precursor of hepatitis B early antigen (HBeAg), and core protein (HBcAg), a component of the nucleocapsid. PreS/S ORF encodes for three proteins, including large (L), middle (M), and small (S; HBsAg) proteins. The S accounts for approximately 90% of all protein produced from preS/S transcripts. The P gene encodes for a DNA-dependent DNA polymerase, which also has reverse transcriptase and RNase H activities. The partially double-stranded HBV genome (approximately 3.2 kb in length) exists within a nucleocapsid. The X region encodes for a multifunctional protein, HBx. Although HBx is not a component of HBV particles, it is believed to play a crucial role in viral replication. Acute and chronic infection of the liver with HBV appears not to produce cytopathic effects on hepatocytes; however, several components of the viral particles activate the host’s immune response, and cytotoxic T cells (CTLs) eliminate HBV-infected hepatocytes.128,129 Such immune responses induce sustained cycles of hepatocyte injury and regeneration that contribute to cirrhosis and HCC tumor formation.

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

139

FIGURE 9B.3  ​A, Structure of the hepatitis B virus (HBV) DNA genome, showing the four open reading frames involved in generation of preC/core, preS/S, P, and X proteins. B, Structure of infectious HBV particle, showing the nucleocapsid containing an HBV genome and polymerase (P) and an envelope derived from the lipid bilayer, where preS/S proteins are embedded. C, Life cycle of HBV, showing viral entry through receptors, followed by uncoating and translocation of HBV DNA to the nucleus, where it is repaired to generate a covalently closed circular DNA (cccDNA) form that serves as the template for transcription of the pregenomic and other viral mRNA necessary for replication. (Used with permission from Wands JR. Prevention of hepatocellular carcinoma. N Engl J Med 2004;351:1567–1570. All rights reserved.)

140

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A liver bile acids transporter, sodium taurocholate cotransporting polypeptide (NTCP, encoded by SLC10A1) was identified as a functional host cell receptor for HBV entry.130–132 EGF receptor (EGFR) plays a role as a cofactor of NCTP for HBV internalization.133 After internalization of HBV, the envelope glycoprotein is subsequently removed (see Fig. 9B.3C). The partially double-stranded DNA is repaired to form a covalently closed circular DNA (cccDNA) moiety in the nucleus to serve as a stable template for transcription of the pregenomic mRNA and other species required for productive viral replication. This cccDNA template remains in the nucleus during chronic viral infection and may persist in the liver for the lifetime of the individual.134 HBV can promote carcinogenesis by three different mechanisms: (1) a classic retrovirus-like insertional mutagenesis with the integration of viral DNA into host cancer genes like TERT; (2) the promotion of genomic instability as the result of both the integration of viral DNA into the host genome and the activity of viral proteins; and (3) the ability of wild-type and mutated/truncated viral proteins (HBx, HBc, and preS) to affect cell functions, activate oncogenic pathways, and sensitize liver cells to mutagens.135 The DNA of the HBV integrates randomly into hepatocyte chromosomes and acts as a nonselective insertional mutagenic agent. Secondary chromosomal rearrangements involving duplications, translocations, and deletions reveal that the major oncogenic effect of HBV integration may be increased by genomic instability of the host’s cellular DNA. The presence of integrated HBV DNA sequences in cellular DNA from human HCCs was initially reported in the early 1980s.136 Integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion. In about 80% of patients with HBVrelated HCC, fragments of viral DNA have been found integrated into the host genome.137 HBV integration at specific genomic sites is thought to provide a growth advantage to a clonal cell population that eventually accumulates additional mutations. Most HCCs contain integrated forms of a high molecular weight. However, a large-scale analysis of HBV DNA integration sites revealed that, in some special instances, the integration event can disrupt the function of specific regulatory genes.138 The insertion of viral DNA into the TERT locus is observed in HBV-induced HCC and then telomerase reactivation is found. The HBV integration event into the TERT locus is an important pathologic event in these tumors. Another gene family recurrently affected by HBV integration includes those involved in calcium signaling. Studies indicate that HBV DNA had inserted into the gene encoding for SERCA (sarco/ endoplasmic reticulum calcium adenosine triphosphatase), which plays a pivotal role in regulating intracellular calcium levels and shows as a second messenger involved in cell proliferation and programmed cell-death pathways.139 Collectively, cellular genes involved in chromosomal integrity and in growth factor–mediated signaling pathways are occasionally targeted by HBV integration events, but in the vast majority of tumors, the viral integration is random throughout the host genome.138,140 Thus integration of HBV into hepatocyte DNA produces specific and nonspecific genetic alterations that contribute to hepatocarcinogenesis. Recently, next-generation sequencing of 399 HBV integration breakpoints from 81 HBV-induced HCCs has shown that recurrent HBV integration points are near coding genes, including TERT, MLL4 coding mixed lineage leukemia protein 4, and CCNE1 coding

cyclin 1.141 The expression of integrated genes is upregulated in tumors compared with the normal tissue. Studies on murine models expressing HBV-related transgenes such as HBx, as shown in Fig. 9B.4, as well as truncated preS/S regions, provide evidence for their role in hepatic tumor development.142,143 HBx is a multifunctional regulatory protein that is both required for HBV cDNA transcription/ viral replication and thought to contribute to HBV oncogenicity. HBx is a 154–amino-acid molecule highly conserved among mammalian hepadnaviruses, and it has multifunctional and pleiotropic properties that modulate cellular functions, including transcription, signaling cascades, DNA repair, protein degradation, and cell-cycle control.144 During viral replication, HBx is localized in the cytosol with a minor fraction present in the nucleus. Cytosolic HBx activates the RAS/ RAF/MEK/ERK, PI3K/AKT pathway, SRC kinase, and JAK / STAT cascades, leading to increased cell proliferation.145 Constitutive expression of HBx also promotes hepatocarcinogenesis, in combination with activation of the insulin/IGF-1/ IRS-1/MEK/ERK cascade.146 In addition, nuclear HBx has been reported to act as a transcriptional coactivator, although it does not directly bind to DNA. The mechanism of chromatin remodeling of HBx can be either transcriptional activation or repression of transcription by different mechanisms. HBx binds many nuclear proteins and regulates the transcription, including cyclic adenosine monophosphate (cAMP) response element–binding protein (CREB), activating transcription factor 2 (ATF2), activating enhancer binding protein 2 (AP-2), and CREB-binding protein/p300.145 Suppressor of zeste 12 homolog (SUZ12) is an essential component of the polycomb repressive chromatin remodeling complex 2 (PRC2) that silences target genes by repressive trimethylation of H3 on Lys27, H3K27me3.147 HBx induces the downregulation of the chromatin remodeling components SUZ12 and the overexpression of SUZ12/PRC2 direct target genes, including the hepatic CSC markers BMP and activin membrane-bound inhibitor (BAMBI) and EpCAM.148 EpCAM and DLK1 overexpression is also mediated by HBx demethylation of CpG islands involving a complex containing enhancer of zeste homolog 2 (EZH2), ten-eleven translocation 2 (TET2) enzyme, and DNA methyltransferase (DNMT3L).149,150 Several reports indicate an interaction between HBx and p53 tumor suppressor protein. HBx binds to p53 in the nucleus and inhibits expression of p53-responsive genes. Nuclear HBx also alters the association of p53 with transcription factors, such as excision repair cross-complementation group 3 (ERCC3) and transcription factor IIH (TFIIH), which are involved in nucleotide excision repair.151–153 Moreover, HBx expression has been shown to block p53-mediated apoptosis, and it provides a clonal selective advantage to HBV-infected hepatocytes.153–155 Interestingly, HBx can trigger the release of calcium ion from mitochondria, leading to the enhanced replication of HBV DNA through interaction with a proline-rich tyrosine kinase 2 (PYK2) and SRC kinase.156 Calcium release and localization of HBx in mitochondrial membranes cause oxidative stress, in which ROS are produced.157,158 ROS directly damage DNA, leading to aberrant DNA replication. HBx also influences the androgen signaling pathway, which may explain, in part, the known male predominance of HBV-induced HCC.159 Taken together, these findings indicate that HBx plays a complex and pleiotropic role in the multistep process of tumor development.

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

141

FIGURE 9B.4  ​Characteristics of the HBx protein and its involvement in tumor formation. HBx plays a crucial role in hepatitis B virus (HBV)-induced carcinogenesis. HBx is located in the cytoplasm and activates cellular signaling cascades. This viral nonstructural protein also inhibits p53-mediated apoptosis. Nuclear HBx modulates a set of transcription factors through interaction with a RNA polymerase complex. The HBV genome integrates into the host genome during persistent viral infection and promotes chromosome instability. AKT, v-Akt murine thymoma viral oncogene homolog; ERK, extracellular signal-regulated protein kinase; HBx, hepatitis B virus X protein; IRS, insulin receptor substrate; JAK, Janus-activating kinase; MEK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3kinase; PYK, proline-rich tyrosine kinase; RAF, Raf-1 proto-oncogene; RAS, rat sarcoma (oncoprotein); SRC, sarcoma; STAT, signal-transducer and activator of transcription; transcr., transcription.

142

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Evidence has been accumulating that the risk for HCC is substantially increased by viral factors, such as the level of HBV replication produced by naturally occurring mutations in the core and precore promoter regions.160–162 A high viral replication phenotype places the infected liver at greater risk for transformation, as shown in Fig. 9B.3C. Finally, with the development of diagnostic techniques sensitive enough to detect very low levels of serum HBV DNA (,100 copies/mL), it has become increasingly apparent that many patients with chronic HCV infection also are infected with low levels of HBV. In this setting, HBV maintains its oncogenic properties, and evidence has accumulated that occult HBV infection, defined as less than 10,000 virions per mL of serum, may be associated with chronic hepatitis and cirrhosis of heretofore unknown origin.134

HEPATITIS C VIRUS (SEE CHAPTER 68) HCV is a member of the Flaviviridae family and is the only member of the genus Hepacivirus.163 The HCV genome consists of a single positive-strand RNA of approximately 9.6 kb in length (Fig. 9B.5A). HCV RNA contains a large (approximately 9.0 kb) ORF in which structural and nonstructural coding regions are located near the 59 and 39 ends of the viral genome, respectively. Both 59 and 39 untranslated (UTR) domains have been found to be essential for viral RNA replication. Translation of the HCV RNA can be initiated by an internal ribosome entry site (IRES) located in the 59 UTR. The single ORF encodes for a polyprotein precursor, consisting of about 3,000 amino acids; it is cleaved into 10 smaller proteins by the action of several proteases derived from both host and virus. These 10 viral-related molecules include three structural (core [C], E1, and E2) and 7 nonstructural (NS; NS1, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins. The core forms a nucleocapsid that contains the HCV genome. The nucleocapsid is covered by an envelope composed of a lipid bilayer, in which the two structural proteins E1 and E2 are embedded. The function of NS1 (or called p7) is hypothesized to be a transmembrane protein with ion channel activity. NS2 is a metalloprotease that cleaves between NS2 and NS3. The NS3 is a serine protease that produces NS4A, NS4B, NS5A, and NS5B viral proteins; it also has RNA helicase and nucleoside triphosphatase (NTPase) activity. NS4A acts as a cofactor for NS3 activity, and NS4B is an integral membrane protein located on the cytoplasmic side of endoplasmic reticulum (ER); it has been implicated in the assembly of replicase complex. The NS5A protein is believed to act as a component of RNA replicase complex, and it plays a role in evasion of the host’s cellular immune response. The NS5B is an RNA-dependent RNA polymerase essential for the replication of the HCV genome. The life cycle of HCV consists of at least six different stages: attachment/entry, translation, processing, genome replication, assembly, and release into the circulation (see Fig. 9B.5B). HCV particles attach to the hepatocyte cell-surface membrane and enter the cell via key proteins such as CD81, SR-BI, claudin-1, and occludin. After entry into the hepatocyte, the nucleocapsid is delivered to the cytoplasm, and the HCV RNA is released and immediately translated. The large polyprotein is processed on the cytoplasmic side of the ER, and nonstructural proteins form a complex and initiate replication of the RNA genome in collaboration with some host proteins. Viral

particles are assembled from the structural proteins, and the RNA genome becomes encased between membranes derived from lipid droplets and the ER. Assembled particles are delivered to the plasma membrane and released into the blood by exocytosis. Importantly, the entire process related to HCV replication is restricted to the cytoplasm; unlike HBV, the viral RNA does not form a DNA intermediate, and thus the HCV genome does not integrate into the host’s cellular DNA. HCV is an RNA virus with a predominantly cytoplasmic life cycle.164 All potentially pro-oncogenic events are therefore likely to be restricted to the cytoplasm, suggesting indirect mechanisms of hepatocarcinogenesis. Although HCV infection leads to chronic inflammation, steatosis, fibrosis, and oxidative DNA damage, several HCV proteins, including core protein, have been shown to have direct oncogenic effects and to upregulate mitogenesis.165 The accumulation of oxidative stress and DNA damage in a setting of restricted cell-cycle checkpoint control and/or accelerated cell division is thought to compromise gene and chromosome stability and to form the genetic basis for malignant transformation.166 These mechanisms promote chronicity of HCV infection, which promotes hepatic inflammation, cirrhosis, and HCC (Fig. 9B.6). At least four HCV proteins, including core, NS3, NS5A, and NS5B, have been proposed to have cellular transforming potential when transiently or stably expressed in cultured cells or in transgenic mice expressing the different viral proteins or the intact HCV polyprotein as depicted in Fig. 9B.6. The HCV core protein has been shown to have transforming potential in vitro.167 The core protein is also localized at the cytoplasmic surface of the ER and on lipid droplets and relates to the induction of liver steatosis and is localized to the outer membrane of mitochondria, leading to alterations of apoptosis and lipid metabolism.168,169 In addition, HCV core binds numerous cellular proteins and modulates the RAF/MEK/ ERK signal transduction pathway.135 The core protein also augments the TGF-b pathway by upregulating TGF-b expression in hepatic stellate cells to promote fibrosis.170 Enhanced proliferation of HCC cells has been demonstrated by overexpression of the HCV core protein in vitro. This phenomenon was because of upregulation of WNT1 expression, suggesting a functional link between HCV core expression during active viral replication and subsequent activation of the WNT/bcatenin signaling cascade.171 The core has been shown to induce ROS production via interaction with heat shock protein Hsp60.172 NS3 has been shown to complex with the wild-type p53 protein.173 By modulating the activity of p53, NS3 inhibits transcription of the leucine carboxyl methyltransferase 2 (LCMT2) gene, which encodes a cell-cycle regulator, p21WAF1/CIP1. In addition, it has been found to repress LCMT2 promoter activity in a dose-dependent manner and stimulates cell growth.174 The NS3 protein binds and co-localizes with the mitochondrial antiviral signaling protein, MAVS, that activates NF-kB and IFN regulatory factor 3.175 The NS5A protein may act as a transcriptional modulator through interactions with other cellular proteins, such as GRB2, p53, p21WAF1/CIP1, and CDK2. The functional consequences have been inhibition of hepatocyte apoptosis, leading to persistent HCV infection.176 One potential mechanism by which NS5A may be able to exert an effect on gene expression and cellular growth is through functional associations with p53 and TATA box–binding proteins (TBPs). The overexpression

  Chapter 9B  Molecular and Cell Biology of Liver Carcinogenesis and Hepatitis

143

FIGURE 9B.5  ​Diagram of hepatitis C virus (HCV) and the replication process. A, Components of the HCV genome showing the structure of HCV RNA. HCV proteins, including their role in HCV replication, are presented. B, Life cycle of HCV showing the known steps of viral replication, including attachment/entry, translation, replication, processing, assembly, and release of virus into the blood. IRES, Internal ribosome entry site; NS, nonstructural; NTPase, nucleoside triphosphatase; UTR, untranslated region.

of NS5A also induces oxidative stress and activates the signaling pathways such as STAT3, PI3K, and NF-kB, resulting in the stabilization and accumulation of b-catenin in the cytoplasm and nucleus through inactivation of GSK-3b.177–180 Another possible pathway activated in HCV-induced HCC involves oxidative stress generated by increased production of ROS during persistent viral infection. Indeed, ROS production in the liver has been found to be increased in HCV core transgenic mice.181 Moreover, iron loading in transgenic mice expressing the full-length HCV genome promotes HCC formation, again implicating chronic oxidative stress in the pathogenesis of HCV-mediated HCC.182 The mechanisms underlying oxidative

stress–induced hepatocarcinogenesis involve increased chromosome instability and mutations in the host cellular DNA produced by the action of ROS.183,184 Moreover, HCV directly induces lipid accumulation in hepatocytes as a result of ER stress because viral replication occurs on the ER membranes, where the core impedes ER functions.185 Hepatic steatosis induced by HCV infection promotes oxidative stress and ROS production.186 Collectively, many of the HCV proteins are believed to contribute to hepatocyte transformation during persistent viral infection through stimulation of cell proliferation, increased cell survival, induction of genomic instability, and promotion of immune evasion.

144

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

FIGURE 9B.6  ​Pathogenic role of hepatitis C virus (HCV) proteins. This diagram illustrates how HCV proteins, including core, NS3, NS5A, and NS5B, may modulate cellular function. Such proteins promote hepatocarcinogenesis in diverse ways via activation of signaling pathways and stellate cells, and they suppress immune responses to the virus and generate oxidative stress in the liver. AKT, v-Akt murine thymoma viral oncogene homolog; CDK2, cyclin-dependent kinase 2; ERK, extracellular signal-regulated protein kinase; GRB2, growth factor receptor-bound protein 2; GSK-3b, glycogen synthetase kinase-3b; MEK, mitogen-activated protein kinase; NS, nonstructural; PI3K, phosphatidylinositol-3-kinase; pol, polymerase; TGF-b, transforming growth factor-b; WNT, wingless type.

FUTURE DIRECTIONS In the postgenomic era, comprehensive examination of tumors via next-generation sequencing and microarray technologies makes it highly likely that molecular genetic changes evolving from normal liver to dysplasia to HCC will be more precisely defined. Over the past few decades, significant progress has been made in epigenetic analysis, miRNA function, and genomic profiling of HCC, which will greatly enhance our understanding of the molecular oncogenesis of HCC. Some novel driver mutations of HCC have been identified and tremendous effort has been applied to the development of drugs that target these key genetic mutations. Furthermore, the benefit of immunotherapy

for HCC has been highlighted and the development of immune checkpoint inhibitors are under intense investigation. Clinical trials exploring the efficacy and safety of molecular-targeted agents or immune checkpoint inhibitors are now ongoing. The characterization of the molecular biology of liver carcinogenesis and hepatitis may lead to the development of preventive approaches and the establishment of new treatment strategies for HCC. These investigations emphasize the importance of unraveling the molecular mechanisms of liver carcinogenesis, which may ultimately result in “personalized” medical approaches for this devastating disease. References are available at expertconsult.com.

144.e1

REFERENCES 1. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674-687. 2. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339-346. 3. Branda M, Wands JR. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology. 2006;43(5): 891-902. 4. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 [published correction appears in Lancet. 2017;389(10064):e1]. Lancet. 2016;388(10053):1459-1544. 5. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-E386. 6. SEER. Cancer Statistics Factsheets: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute. Available at: http://seer.cancer. gov/statfacts/html/livibd.html. 7. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152(4):745-761. 8. Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010. 9. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006; 45(4):529-538. 10. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7(8):448-458. 11. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7): 2557-2576. 12. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, eds. Cancer Incidence in Five Continents. Vol 8. Lyon: IARC Scientific Publication No. 155, 2002. 13. Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348-1355. 14. Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035. 15. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60(5):1767-1775. 16. McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni Jr JF. International trends and patterns of primary liver cancer. Int J Cancer. 2001;94(2):290-296 17. Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin Gastroenterol Hepatol. 2015;13(12):2140-2151. 18. Llovet JM, Villanueva A. Liver cancer: effect of HCV clearance with direct-acting antiviral agents on HCC. Nat Rev Gastroenterol Hepatol. 2016;13(10):561-562. 19. Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: The BRIDGE Study. Liver Int. 2015;35(9):2155-2166. 20. Ma WL, Hsu CL, Wu MH, et al. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma [published correction appears in Gastroenterology. 2008;135(5): 1805.]. Gastroenterology. 2008;135(3):947-955.e9555. 21. Wu MH, Ma WL, Hsu CL, et al. Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. Sci Transl Med. 2010;2(32):32ra35. 22. American Cancer Society. Global Cancer Facts & Figures. 2nd ed. 2011. Available at: https://www.cancer.org/research/cancer-factsstatistics/global.html. 23. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477-491.e1. 24. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48(2):335-352.

25. Chayanupatkul M, Omino R, Mittal S, et al. Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection. J Hepatol. 2017;66(2):355-362. 26. Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014;147(1):143-151.e5. 27. Kew MC. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int. 2003;23(6): 405-409. 28. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-1273.e1. 29. Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol. 2017; 67(6):1204-1212. 30. Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol. 2002;155(4):323-331. 31. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 suppl 1):S35-S50. 32. Hassan MM, Hwang LY, Hatten CJ, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206-1213. 33. Jee SH, Ohrr H, Sull JW, Samet JM. Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea. J Natl Cancer Inst. 2004;96(24):1851-1856. 34. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64(5):1577-1586. 35. Yang JD, Ahmed Mohammed H, Harmsen WS, Enders F, Gores GJ, Roberts LR. Recent trends in the epidemiology of hepatocellular carcinoma in Olmsted county, Minnesota: a US populationbased study. J Clin Gastroenterol. 2017;51(8):742-748. 36. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51(5):1820-1832. 37. Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62(4):606-615. 38. Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer. 2010;116(8):1938-1946. 39. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108(6): 881-892. 40. Abdel-Rahman O, Helbling D, Schöb O, et al. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies. J Evid Based Med. 2017;10(4):245-254. 41. Theise ND, Park YN, Kojiro M. Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis. 2002;6(2):497-512. 42. Bataller R, Brenner DA. Liver fibrosis [published correction appears in J Clin Invest. 2005;115(4):1100]. J Clin Invest. 2005;115(2): 209-218. 43. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma [published correction appears in Gastroenterology. 2006;130(1):287]. Gastroenterology. 2005;129(5):1375-1383. 44. Ogata H, Kobayashi T, Chinen T, et al. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology. 2006;131(1):179-193. 45. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25(27):3778-3786. 46. Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012; 44(6):694-698. 47. Huang J, Deng Q, Wang Q, et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44(10): 1117-1121.

144.e2 48. Fujimoto A, Totoki Y, Abe T, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44(7):760-764. 49. Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46(12):1267-1273. 50. Nault JC, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol. 2019;16(9):544-558. 51. Plentz RR, Caselitz M, Bleck JS, et al. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology. 2004;40(1):80-86. 52. Ferber MJ, Montoya DP, Yu C, et al. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003;22(24):3813-3820. 53. Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions [published correction appears in Nat Commun. 2013;4:2577. Zucman Rossi, Jessica (corrected to Zucman-Rossi, Jessica)]. Nat Commun. 2013;4:2218. 54. Nishimoto A, Miura N, Horikawa I, et al. Functional evidence for a telomerase repressor gene on human chromosome 10p15.1. Oncogene. 2001;20(7):828-835. 55. Takeo S, Arai H, Kusano N, et al. Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis. Cancer Genet Cytogenet. 2001;130(2):127-132. 56. Gouas D, Shi H, Hainaut P. The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy. Cancer Lett. 2009;286(1):29-37. 57. Tornesello ML, Buonaguro L, Tatangelo F, Botti G, Izzo F, Buonaguro FM. Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics. 2013;102(2):74-83. 58. Higashitsuji H, Itoh K, Nagao T, et al. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 2000;6(1):96-99. 59. Higashitsuji H, Higashitsuji H, Itoh K, et al. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53 [published correction appears in Cancer Cell. 2005;8(2):169. Sumitomo, Haruhiko (corrected to Sumitomo, Yasuhiko)]. Cancer Cell. 2005;8(1):75-87. 60. Jin M, Piao Z, Kim NG, et al. p16 is a major inactivation target in hepatocellular carcinoma. Cancer. 2000;89(1):60-68 61. Liew CT, Li HM, Lo KW, et al. High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene. 1999;18(3): 789-795. 62. Matsuda Y, Ichida T, Matsuzawa J, Sugimura K, Asakura H. p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology. 1999;116(2):394-400. 63. Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer. 2001;84(7):982-989. 64. Boige V, Laurent-Puig P, Fouchet P, et al. Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res. 1997;57(10):1986-1990. 65. Laurent-Puig P, Legoix P, Bluteau O, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120(7): 1763-1773. 66. Nagai H, Pineau P, Tiollais P, Buendia MA, Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene. 1997;14(24):2927-2933. 67. Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene. 2001;20(48):7104-7109. 68. Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology. 2009;49(3):821-831. 69. Inagawa S, Itabashi M, Adachi S, et al. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res. 2002;8(2):450-456.

70. Satoh S, Daigo Y, Furukawa Y, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virusmediated transfer of AXIN1. Nat Genet. 2000;24(3):245-250. 71. Li M, Zhao H, Zhang X, et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011;43(9):828-829. 72. Wu JN, Roberts CW. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 2013;3(1):35-43. 73. Nakagawa H, Shibata T. Comprehensive genome sequencing of the liver cancer genome. Cancer Lett. 2013;340(2):234-240. 74. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSCmTOR pathway in human disease. Nat Genet. 2005;37(1):19-24. 75. Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-511. 76. Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017;67(4):727-738. 77. Orrù C, Szydlowska M, Taguchi K, et al. Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. J Hepatol. 2018;69(3):635-643. 78. Kanai Y, Hui AM, Sun L, et al. DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology. 1999;29(3):703-709. 79. Yu J, Zhang HY, Ma ZZ, Lu W, Wang YF, Zhu JD. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res. 2003;13(5):319-333. 80. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163(4):1371-1378. 81. Higgs MR, Lerat H, Pawlotsky JM. Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest. Cancer Res. 2010;70(12):4901-4911. 82. Murata H, Tsuji S, Tsujii M, et al. Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells. Lab Invest. 2004;84(8):1050-1059. 83. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2): 647-658. 84. Wu H, Ng R, Chen X, Steer CJ, Song G. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut. 2016;65(11):1850-1860. 85. Kojima K, Takata A, Vadnais C, et al. MicroRNA122 is a key regulator of a-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma [published correction appears in Nat Commun. 2012;3:985]. Nat Commun. 2011;2:338. 86. Tsai WC, Hsu SD, Hsu CS, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122(8):2884-2897. 87. Roy S, Hooiveld GJ, Seehawer M, et al. microRNA 193a-5p regulates levels of nucleolar- and spindle-associated protein 1 to suppress hepatocarcinogenesis. Gastroenterology. 2018;155(6):1951-1966.e26. 88. Kota J, Chivukula RR, O’Donnell KA, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137(6):1005-1017. 89. Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology. 2007;45(5):1298-1305. 90. Wands JR, Kim M. WNT/b-catenin signaling and hepatocellular carcinoma. Hepatology. 2014;60(2):452-454. 91. Fujito T, Sasaki Y, Iwao K, et al. Prognostic significance of betacatenin nuclear expression in hepatocellular carcinoma. Hepatogastroenterology. 2004;51(58):921-924. 92. Ishizaki Y, Ikeda S, Fujimori M, et al. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int J Oncol. 2004;24(5):1077-1083. 93. Calvisi DF, Factor VM, Loi R, Thorgeirsson SS. Activation of betacatenin during hepatocarcinogenesis in transgenic mouse models: relationship to phenotype and tumor grade. Cancer Res. 2001;61(5):2085-2091. 94. Calvisi DF, Factor VM, Ladu S, Conner EA, Thorgeirsson SS. Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice. Gastroenterology. 2004;126(5):1374-1386.

144.e3 95. Merle P, de la Monte S, Kim M, et al. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology. 2004;127(4):1110-1122. 96. Kim M, Lee HC, Tsedensodnom O, et al. Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/betacatenin signaling pathway in hepatocellular carcinoma cells. J Hepatol. 2008;48(5):780-791. 97. Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59(5):1107-1117. 98. Merle P, Kim M, Herrmann M, et al. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol. 2005;43(5):854-862. 99. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127-137. 100. Ito Y, Takeda T, Sakon M, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 2001;84(10):1377-1383. 101. Schaff Z, Hsia CC, Sarosi I, Tabor E. Overexpression of transforming growth factor-alpha in hepatocellular carcinoma and focal nodular hyperplasia from European patients. Hum Pathol. 1994;25(7):644-651. 102. Zhang J, Wang WL, Li Q, Qiao Q. Expression of transforming growth factor-alpha and hepatitis B surface antigen in human hepatocellular carcinoma tissues and its significance. World J Gastroenterol. 2004;10(6):830-833. 103. Russell WE, Kaufmann WK, Sitaric S, Luetteke NC, Lee DC. Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. Mol Carcinog. 1996;15(3):183-189. 104. Inui Y, Higashiyama S, Kawata S, et al. Expression of heparinbinding epidermal growth factor in human hepatocellular carcinoma. Gastroenterology. 1994;107(6):1799-1804. 105. Ito Y, Takeda T, Higashiyama S, et al. Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep. 2001;8(4):903-907. 106. Osada S, Kanematsu M, Imai H, Goshima S, Sugiyama Y. Evaluation of extracellular signal regulated kinase expression and its relation to treatment of hepatocellular carcinoma. J Am Coll Surg. 2005;201(3):405-411. 107. Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun. 1997;236(1):54-58. 108. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia [published correction appears in Nat Rev Cancer. 2009 Mar;9(3):224]. Nat Rev Cancer. 2008;8(12):915-928. 109. Tovar V, Alsinet C, Villanueva A, et al. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol. 2010;52(4):550-559. 110. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25(27):3787-3800. 111. Cantarini MC, de la Monte SM, Pang M, et al. Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology. 2006;44(2):446-457. 112. Nishiyama M, Wands JR. Cloning and increased expression of an insulin receptor substrate-1-like gene in human hepatocellular carcinoma. Biochem Biophys Res Commun. 1992;183(1):280-285. 113. Lee HC, Tian B, Sedivy JM, Wands JR, Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology. 2006;131(4):1208-1217. 114. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226-1239.e4. 115. Kaseb AO, Hanbali A, Cotant M, Hassan MM, Wollner I, Philip PA. Vascular endothelial growth factor in the management of hepatocellular carcinoma: a review of literature. Cancer. 2009;115 (21):4895-4906. 116. Dhar DK, Naora H, Yamanoi A, et al. Requisite role of VEGF receptors in angiogenesis of hepatocellular carcinoma: a comparison with angiopoietin/Tie pathway. Anticancer Res. 2002;22(1A): 379-386. 117. Tseng PL, Tai MH, Huang CC, et al. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular

carcinoma (HCC) and adverse outcome of HCC patients. J Surg Oncol. 2008;98(5):349-357. 118. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer [published correction appears in Nat Rev Drug Discov. 2007;6(2):126]. Nat Rev Drug Discov. 2006;5(10):835-844. 119. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. 120. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382(20):1894-1905. 121. Karin M, Dhar D. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis. 2016;37(6):541-546. 122. Sell S, Leffert HL. Liver cancer stem cells [published correction appears in J Clin Oncol. 2008;26(22):3819]. J Clin Oncol. 2008;26(17):2800-2805. 123. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755-768. 124. Ding J, Wang H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 2014;346(1):17-23. 125. Wen W, Han T, Chen C, et al. Cyclin G1 expands liver tumorinitiating cells by Sox2 induction via Akt/mTOR signaling. Mol Cancer Ther. 2013;12(9):1796-1804. 126. Wu K, Ding J, Chen C, et al. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology. 2012;56(6):2255-2267. 127. Zhao W, Wang L, Han H, et al. 1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel a2d1 subunit. Cancer Cell. 2013;23(4): 541-556. 128. Bertoletti A, Ferrari C. Kinetics of the immune response during HBV and HCV infection. Hepatology. 2003;38(1):4-13. 129. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis. 2003;23(1):47-58. 130. Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology. 2014;147(1):48-64. 131. Ni Y, Lempp FA, Mehrle S, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014;146(4): 1070-1083. 132. Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus [published correction appears in Elife. 2014;3:e05570]. Elife. 2012;1:e00049. 133. Iwamoto M, Saso W, Sugiyama R, et al. Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization. Proc Natl Acad Sci U S A. 2019;116(17): 8487-8492. 134. Wands JR. Prevention of hepatocellular carcinoma. N Engl J Med. 2004;351(15):1567-1570. 135. Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834-3847. 136. Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med. 1981;305(18):1067-1073. 137. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett. 2011;305(2):123-143. 138. Murakami Y, Saigo K, Takashima H, et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut. 2005;54(8):1162-1168. 139. Chami M, Gozuacik D, Saigo K, et al. Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis. Oncogene. 2000;19(25):2877-2886. 140. Paterlini-Bréchot P, Saigo K, Murakami Y, et al. Hepatitis B virusrelated insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22(25):3911-3916. 141. Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012; 44(7):765-769.

144.e4 142. Chisari FV, Klopchin K, Moriyama T, et al. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989;59(6):1145-1156. 143. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351(6324):317-320. 144. Murakami S. Hepatitis B virus X protein: structure, function, and biology. Intervirology. 1999;42(2-3):81-99. 145. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78(23):12725-12734. 146. Longato L, de la Monte S, Kuzushita N, et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology. 2009;49(6):1935-1943. 147. Squazzo SL, O’Geen H, Komashko VM, et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 2006;16(7):890-900. 148. Studach LL, Menne S, Cairo S, et al. Subset of Suz12/PRC2 target genes is activated during hepatitis B virus replication and liver carcinogenesis associated with HBV X protein. Hepatology. 2012;56(4):1240-1251. 149. Fan H, Zhang H, Pascuzzi PE, Andrisani O. Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene. 2016;35(6):715-726. 150. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64(suppl 1):S84-S101. 151. Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer. 1999;80(6):875-879. 152. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A. 1994;91(6):2230-2234. 153. Wang XW, Gibson MK, Vermeulen W, et al. Abrogation of p53induced apoptosis by the hepatitis B virus X gene. Cancer Res. 1995;55(24):6012-6016. 154. Elmore LW, Hancock AR, Chang SF, et al. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci U S A. 1997;94(26):14707-14712. 155. Huo TI, Wang XW, Forgues M, et al. Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis. Oncogene. 2001;20(28): 3620-3628. 156. Bouchard MJ, Wang LH, Schneider RJ. Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science. 2001;294(5550):2376-2378. 157. Bouchard MJ, Puro RJ, Wang L, Schneider RJ. Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication. J Virol. 2003;77(14):7713-7719. 158. Yang B, Bouchard MJ. The hepatitis B virus X protein elevates cytosolic calcium signals by modulating mitochondrial calcium uptake. J Virol. 2012;86(1):313-327. 159. Chiu CM, Yeh SH, Chen PJ, et al. Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci U S A. 2007;104(8): 2571–2578. 160. Baptista M, Kramvis A, Kew MC. High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology. 1999;29(3): 946-953. 161. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology. 2003;124(2): 327-334. 162. Kuang SY, Jackson PE, Wang JB, et al. Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci U S A. 2004;101(10):3575-3580. 163. Tellinghuisen TL, Rice CM. Interaction between hepatitis C virus proteins and host cell factors. Curr Opin Microbiol. 2002;5(4): 419-427. 164. Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol. 2007;5(6):453-463.

165. McGivern DR, Lemon SM. Tumor suppressors, chromosomal instability, and hepatitis C virus-associated liver cancer. Annu Rev Pathol. 2009;4:399-415. 166. Bartosch B, Thimme R, Blum HE, Zoulim F. Hepatitis C virusinduced hepatocarcinogenesis. J Hepatol. 2009;51(4):810-820. 167. Ray RB, Lagging LM, Meyer K, Ray R. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol. 1996;70(7):4438-4443. 168. Schwer B, Ren S, Pietschmann T, et al. Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J Virol. 2004;78(15):7958-7968. 169. Rouillé Y, Helle F, Delgrange D, et al. Subcellular localization of hepatitis C virus structural proteins in a cell culture system that efficiently replicates the virus. J Virol. 2006;80(6):2832-2841. 170. Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology. 2004;126(2):529-540. 171. Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology. 2005;41(5):1096-1105. 172. Kang SM, Kim SJ, Kim JH, et al. Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNF-alpha-mediated apoptosis. Cancer Lett. 2009;279(2):230-237. 173. Ishido S, Hotta H. Complex formation of the nonstructural protein 3 of hepatitis C virus with the p53 tumor suppressor. FEBS Lett. 1998;438(3):258-262. 174. Kwun HJ, Jung EY, Ahn JY, Lee MN, Jang KL. p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3. J Gen Virol. 2001;82(Pt 9):2235-2241. 175. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005;102(49):17717-17722. 176. Reyes GR. The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis. J Biomed Sci. 2002;9(3):187-197. 177. Sarcar B, Ghosh AK, Steele R, Ray R, Ray RB. Hepatitis C virus NS5A mediated STAT3 activation requires co-operation of Jak1 kinase. Virology. 2004;322(1):51-60. 178. Street A, Macdonald A, Crowder K, Harris M. The Hepatitis C virus NS5A protein activates a phosphoinositide 3-kinasedependent survival signaling cascade. J Biol Chem. 2004;279(13): 12232-12241. 179. Street A, Macdonald A, McCormick C, Harris M. Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular beta-catenin and stimulation of beta-cateninresponsive transcription. J Virol. 2005;79(8):5006-5016. 180. Milward A, Mankouri J, Harris M. Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion. J Gen Virol. 2010;91(Pt 2):373-381. 181. Moriya K, Fujie H, Shintani Y, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med. 1998;4(9):1065-1067. 182. Furutani T, Hino K, Okuda M, et al. Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology. 2006;130(7):20872098. 183. Machida K, Cheng KT, Lai CK, Jeng KS, Sung VM, Lai MM. Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J Virol. 2006;80(14):7199-7207. 184. Naganuma A, Dansako H, Nakamura T, Nozaki A, Kato N. Promotion of microsatellite instability by hepatitis C virus core protein in human non-neoplastic hepatocyte cells. Cancer Res. 2004;64(4):1307-1314. 185. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126(2): 586-597. 186. Koike K. Hepatitis C as a metabolic disease: implication for the pathogenesis of NASH. Hepatol Res. 2005;33(2):145-150.

CHAPTER 9C Advances in the molecular characterization of liver tumors Colm J. O’Rourke and Jesper B. Andersen OVERVIEW Tumors of the hepatobiliary (HB) system are among the most challenging tumors to effectively manage in the clinic. At time of diagnosis, only approximately 25% of gallbladder carcinoma (GBC) patients,1 30% of cholangiocarcinoma (CCA) patients,2 and 30% of hepatocellular carcinoma (HCC) patients3 are eligible for curative therapy through surgical resection (see Chapters 49– 51 and 89). The direct result of this is overall 5-year survival rates of less than 5% in GBC,4 7% to 20% in CCA,2 and less than 18% in HCC.5 Tumors spanning the HB system are unified by late diagnosis, innate aggressive behavior, rapid chemoresistance, and dismal prognosis.6 These cancers display ominous epidemiologic trends,7,8 are highly resistant to most systemic therapies,9 and are projected to increase in global health burden over upcoming decades.2,5,10 To mitigate such adverse projections, robust molecular characterization of HB cancers is fundamental. In this chapter, we discuss the diverse molecular characterization strategies that have been pursued to elucidate the molecular basis of these diseases. In particular, we focus on the contribution of mutations, structural alterations, and epigenome remodeling in HB cancers. Finally, we evaluate the impact of integrative -omics approaches to stratify these heterogeneous cancers into homogenous, clinically impactful subtypes.

Mutational Burden and Signatures To understand the molecular origins of the intrinsically aggressive disease trajectories of HB malignancies, increased mutational burden and/or rates may be suggested as a plausible mechanism. Surprisingly, comparative mutational profiling across cancers indicates these subsets of tumors are exceptionally unremarkable in this regard, falling approximately midway between leukemias (toward the lower end) and melanomas (at the upper end of the spectrum).11 On average, whole-exome sequencing (WES) studies have detected nonsynonymous mutation frequencies of 39 per tumor (median) in intrahepatic CCA (iCCA; see Chapter 50),12 35 per tumor (median) in extrahepatic CCA (eCCA; see Chapter 51),12 64 per tumor (median) in GBC12 (see Chapter 49), and 64 per tumor (median) in HCC13 (see Chapter 89). Although it is clear that there is significant variation in mutational burden between HB cancers, significant heterogeneity also exists within HB cancer subtypes. Certain etiologic backgrounds have been confirmed to correlate with higher mutational loads, such as liver fluke-associated CCA versus noninfected CCA.14 The mutation loads of HB tumors are of particular interest, given that tumor mutation burden (TMB) is positively correlated with increased likelihood of neoantigen production, potentially resulting in beneficial response to checkpoint inhibitor therapies. Beyond the exome, whole-genome sequencing (WGS) studies remain somewhat underevaluated in HB cancers, with some

notable exceptions,15–17 but this approach holds significant potential to inform on important features of cancer biology. Such areas include the pro-tumorigenic impact of retrotransposon reanimation,18 viral integration with insertional mutagenesis,19 enhancer function,20 and intergenic long ncRNAs (lncRNAs).21 WGS analysis has also been applied to successfully discern multicentric HCC from HCC with intrahepatic metastasis,15 a distinction that is important in determining patient eligibility for surgical resection. Diverse exogenous and endogenous mutagenic processes are active in individual HB patients, collectively contributing to the total mutation burden of a given tumor. Analysis of mutational signature patterns in whole-exome and whole-genome sequencing data enable such mutagenic processes to be extrapolated, providing insight into the evolutionary processes that shaped the cancer genome. In total, 81 mutational signatures have been identified,22 although the causative mutagenic process is only known for some of these signatures. General signatures found across HB cancers include those associated with nucleotide excision repair deficiency, 5-methylcytosine deamination, and aging.17,23,24 Examples of mutation signatures found to be enriched in specific HB cancers include an aflatoxin-associated signature in HCC23,25 and an APOBEC-associated signature in eCCA and GBC.12 Further, a liver cancer– specific signature has also been identified, associating with alcohol exposure, transcription-coupled damage, and betacatenin (CTNNB1) mutations.26 The existence of such a liverspecific signature is perhaps unsurprising, given the associated hepatic exposure to diverse mutagens when carrying out its physiologic function in detoxification.

Structural Rearrangements Although less prevalent than single nucleotide variants (SNVs), structural variants (SVs) occur frequently in cancer genomes and are more likely to affect endogenous gene expression and function. Recurrent structural alteration signatures have been identified in HCC and are associated with diverse clinicopathologic and molecular features, including alcohol consumption, tumor protein P53 (TP53) mutation status, and size of genomic alterations.26 Copy number alterations (CNAs) typically affect genes also observed to be recurrently mutated. Specifically, recurrent amplification of oncogenes has been reported, including cyclin D1 (CCND1) and MYC proto-oncogene, BHLH transcription factor (MYC) in HCC,23 and CCND1 (11q13.3) in CCA.24 Telomerase reverse transcriptase (TERT) amplification occurs in approximately 10% of HCC patients.23 Conversely, tumor suppressor genes frequently undergo copy number loss, most commonly in cyclin dependent kinase inhibitor 2A (CDKN2A) in HCC23 and CCA.24 Consistent with such overlap of gene targets shared by mutation and structural processes, an inverse correlation between mutation (M-class) 145

146

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

and structural copy number (C-class) was observed in iCCA, indicative of different perturbation mechanisms driving the same disease phenotype.27 Such findings highlight the importance of applying multiple genomic readouts (mutation and copy number analysis) to HB tumors when considering allocation of patients to targeted therapy trials. Additional pathogenetic mechanisms have also been reported to induce genomic insults with a single event. Chromothripsis involves the localized catastrophic shattering of a chromosomal arm followed by random re-ligation of the sections by the endogenous DNA damage and replication system.28 Such wanton repair yields a multitude of structural variants, with current criteria for chromothripsis calling invoking more than 30 rearrangements and more than 10 translocations on a single arm.29 Although chromothripsis is estimated to occur in 2% to 3% of cancer genomes, a WGS study of 88 HCC specimens detected enrichment of these events in 6% of tumors.30 Specifically, chromothripsis was found to affect chromosome arm 1q, 8q, and 5p. Interestingly, such regions are the recurrent targets of non–shattering-associated chromosomal anomalies also, indicating convergent perturbation of resident genes by these two independent phenomena as important in hepatocarcinogenesis. Biliary tumors have also been reported to exhibit chromothripsis, linked in particular to whole-genome duplications.31 Indeed, genome duplication has been shown to be frequent and highly clonal in iCCA.32 Additionally, TP53 mutations have been linked with localized chromosome shattering in liver30 and other cancers.33 Recurrently mutated genes are diverse and heterogeneous across HB malignancies, exhibiting low-to-intermediate mutation frequencies. Furthermore, the exact mechanism of genomic perturbation appears to be redundant to some extent, with common targets such as TP53 altered by SNVs and SVs. However, neither mutational loads nor mutational mechanisms appear to alone govern the aggressive behavior of these tumors, exemplified by the apparently unremarkable clinical trajectory of hypermutated patients and patients harboring chromothriptic events. Therefore the molecular basis for the overall aggressive behavior of HB cancers compared with other cancers, as well as the heterogeneous disease trajectories between HB patients, appears to lie in the specific genes and networks affected.

Mutational Landscapes in Hepatobiliary Cancers Statistical modeling predicts that three driver gene mutations are sufficient to induce advanced cancer,34 and pan-cancer analysis of tumors suggests that cancer genomes contain four to five mutations on average, 57% of which are clinically actionable.35 However, with two recent notable exceptions (fibroblast growth factor receptor 2 [FGFR2] fusions36 and isocitrate dehydrogenase 1 [IDH1] mutations37 in iCCA), genomic alteration-guided targeted therapies have not drastically impacted treatment of HB malignancies (see Chapter 9E). One reason is that many of the most recurrently altered genes remain undruggable. These include undruggable hotspot mutations in the notorious oncogene, KRAS proto-oncogene, GTPase (KRAS), which are detected in approximately 5% of biliary tract cancers (BTCs)17 and 1% of HCCs.35 Diverse mutations also arise in the tumor suppressor gene, TP53, in 31% of HCCs35 and 16% of BTCs,17 with these alterations being similarly undruggable (see Chapters 9B, 9C, and 9E). Additionally, recurrent alterations are found in genes whose pathobiologic roles in HB malignancies remain poorly characterized. Prime examples of

these include recurrent alterations in chromatin remodeler complex members,23,24 with emerging evidence supporting a tumor suppressor-like role for these genes in HB transformation, including AT-rich interaction domain 1A (ARID1A)38 and BRCA1-associated protein 1 (BAP1).39 Another issue is the relatively low recurrence frequencies of candidate driver alterations between patients, making design of sufficiently powered trials difficult, especially for BTCs, which are considered rare diseases. In fact, genomic evidence highlights that BTCs are highly distinct based on tumor location within the biliary tract. IDH1/2 mutations and FGFR2 fusions exclusively occur in iCCA,12 whereas protein kinase CAMPactivated catalytic subunit alpha (PRKACA) and protein kinase CAMP-activated catalytic subunit beta (PRKACB) fusions preferentially occur in eCCA12 and erb-B2 receptor tyrosine kinase 2/3 (ERBB2/3) mutations preferentially occur in GBC.12,40 These data suggest that BTC patients should potentially be stratified by anatomic location before trial development, further challenging statistical power in these rare patient demographics. Remarkably, a minority of HB patients appear to lack any single known driver alteration.31 A logical explanation for this is that rare variant genes with extremely low alteration frequencies have driver-like capabilities in their altered forms. Successfully identifying such instances will require careful functional validation using gene editing technologies, such as CRISPR. However, formally testing such rare variants may be complicated further if some variants only exert driver-like function in combination with other specific genomic insults. Even among the most commonly mutated genes, tendencies towards mutual exclusivity have been reported in HB cancers, such as between IDH1 and TP53 in iCCA41 (see Chapters 9E and 50). Therefore contextualizing specific genetic insults among the wider oncogenic programs will be paramount to successfully modeling HB tumors, and this importantly includes consideration of genetic and nongenetic mechanisms (Fig. 9C.1).

Epigenome Reprogramming in Hepatobiliary Cancers Epigenome reprogramming is pervasive throughout HB transformation.42 This involves coordinated biochemical modification of DNA, RNA, and proteins, triggering alterations in gene expression programs that are entirely reversible, unlike mutations. The importance of epigenome remodeling to HB carcinogenesis is highlighted by detection of recurrent mutations in epigenetic genes in HB cancers, such as ARID1A, ARID2, BAP1, lysine methyltransferase 2D (KMT2D), lysine methyltransferase 2C (KMT2C), and polybromo1 (PBRM1).43 Such mutants globally affect epigenome homeostasis, contributing to tumor development. However, cancer-associated epigenome reprogramming also occurs in the absence of mutations in epigenome regulators, in which instance the tumor microenvironment plays an important role. Genetic insult-bearing hepatocytes undergo transformation into HCC in the presence of an apoptotic microenvironment in mice, but transform into iCCA in a necroptotic microenvironment44 (see Chapter 9E). These data highlight the potential for microenvironment-triggered epigenome reprogramming, in particular emphasizing the potential of epigenome alterations to dynamically adapt to challenges such as chemotherapy. DNA methylation, the addition of a methyl group to cytosine to generate 5’-methylcytosine (5mC), is by far the best characterized epigenetic modification in HB cancers. Although

  Chapter 9C  Advances in the Molecular Characterization of Liver Tumors

Intrahepatic CCA (iCCA) ARID1A, BAP1, FGFR2, IDH1/2, KRAS, PIK3CA, SMAD4, TP53

147

Perihilar CCA (pCCA) ARID1A, ELF3, KRAS, PIK3CA, PRKACA/B, SMAD4, TP53

Hepatocellular Carcinoma (HCC) CTNNB1, EEF1A1, KEAP1, LZTR1, SMARCA4, TERT, TP53

Extrahepatic CCA (eCCA)

Gallbladder cancer (GBC) ERBB2/3, KMT2C/D, KRAS, PIK3CA, TP53

Distal CCA (dCCA) ARID1A, ELF3, KRAS, PIK3CA, PRKACA/B, SMAD4, TP53

FIGURE 9C.1  Overview of hepatobiliary (HB) cancers and the most frequently genetically altered genes. ARID1A/B, AT-rich interaction domain 1A/B; BAP1, BRCA1-associated protein 1; CTNNB1, catenin beta 1; EEF1A1, eukaryotic translation elongation factor 1 alpha 1; ELF3, E74-like ETS transcription factor 3; ERBB2/3, erb-b2 receptor tyrosine kinase 2/3; FGFR2, fibroblast growth factor receptor 2; IDH1/2, isocitrate dehydrogenase 1/2; KEAP1, kelch-like ECH associated protein 1; KMT2C/D, lysine methyltransferase 2C/D; KRAS, KRAS proto-oncogene, GTPase; LZTR1, leucine zipper-like transcription regulator 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PRKACA/B, protein kinase cAMP-activated catalytic subunit alpha/beta; SMAD4, SMAD family member 4; SMARCA4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin; TERT, telomerase reverse transcriptase; TP53, tumor protein p53.

global loss of 5mC is a hallmark of cancers, including HCC, CCA appears to be the exception to the rule and retains 5mC levels comparable to normal cells.45 This is likely in part contributed to by IDH1 and IDH2 mutations (enzymes which function as rate-limiting competitors for Ten-Eleven-Twelve [TET] deoxygenases involved in the DNA demethylation pathway) that are prevalent in approximately 10% to 25% of iCCAs42 and 1% of HCCs.23 IDH mutations result in production of the oncometabolite, 2-hydroxyglutarate (2-HG), in place of a–ketoglutarate (a-KG). a-KG is required as a cofactor by multiple enzymes, including TET demethylases, so 2-HG production compromises DNA demethylation leading to DNA hypermethylation. At the cellular level, mutant IDH can inhibit differentiation of hepatic progenitors which, in conjunction with mutated KRAS, prompts stem cell pool expansion and neoplastic transformation into iCCA in vivo.46 Most notably, the phase III ClarIDHy trial evaluated the mutant IDH1 inhibitor, ivosidenib, in IDH1 mutant iCCA patients and found treatment to significantly increase progression-free survival from median 1.4 months (placebo group) to 2.7 months37 (see Chapters 9E and 50). However, it remains difficult to extrapolate the extent to which this therapeutic benefit arises from

epigenetic effects as distinct from other a-KG-dependent processes, especially metabolism. DNA methylation alterations occur during the earliest stages of transformation and can still be detected in advanced stage tumors, including signatures associated with hepatitis B, hepatitis C, alcohol consumption,47 and nonalcoholic steatohepatitis (NASH; see Chapter 69).48 Later in HB tumor evolution, de novo DNA methylation reprogramming has been reported to contribute to postsurgical HCC recurrence.49 Like mutations, patterns of aberrant methylation are recurrent across HB tumors, suggesting that altered functionality of these affected loci are pro-oncogenic. In general, aberrant DNA methylation primarily targets developmental pathways, reactivating HOX,50 WNT,51 and SOX1752 signaling; however, excluding IDH mutants, which represent a minority of HB tumors, the exact mechanisms promoting characteristic epigenome remodeling in wild-type tumors remain unclear. One example of such a mechanism involves ubiquitin like with PHD and ring finger domains 1 (UHRF1), which is overexpressed in a subset of aggressive HCC, causing DNA methyltransferase 1 (DNMT1) destabilization and DNA hypomethylation.53 Further, although the existence of “epi-drivers” has been suggested, such as ephrin B2

148

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

(EFNB2) and septin 9 (SEPT9),54 functionally confirming their existence remains elusive because of technical challenges in precisely editing the epigenetic landscape of narrow genomic windows. Beyond DNA methylation, other epigenetic modalities remain less well described. Mutations in chromatin remodeling complex members are among the most common alterations detected in CCA and HCC, presumably leading to altered chromatin accessibility profiles. Integrative genomic analysis previously highlighted the histone modification profiles of HCC to be grossly altered compared with normal liver, with remodeling most drastic at enhancer regions.55 Altered epigenetic landscapes at such loci were associated with altered transcription of candidate epi-drivers catechol-o-methyltransferase (COMT) and flavin containing dimethylaniline monooxygenase 3 (FMO3), genes which are influential in HCC prognosis. Multiple studies have also highlighted important roles for micro-RNA (miRs) in HB cancers. These approximately 22 nucleotide noncoding transcripts bind to their target mRNA(s), causing sequestration and degradation of the mRNA, thereby functioning as posttranscriptional regulators. These small miRs have a large impact on diverse features of HB cancers, including miR-21-mediated resistance of CCA to heat shock protein inhibitors through regulation of dnak heat shock protein family (HSP40) member (DNAJB5)56 and miR-1249-mediated resistance to gemcitabine and cisplatin through the regulation of the clonal expansion of CD1331 BTC cells.57 Clearly, many diverse and recurrent perturbation mechanisms are active and exert clinically impactful consequences in HB cancers, emphasizing the need for integrated molecular profiling.

Molecular Subtyping of Hepatobiliary Cancers Although iCCA is the least prevalent anatomic subtype among BTCs, it has received the greatest attention regarding molecular subtyping (see Chapters 9E and 50). Single gene mutation–based stratification of these tumors into IDH1/2-gr, KRAS-gr, TP53-gr, and the remainder (referred to as “undetermined” [Udt-gr]) demonstrated unique oncogenic programs associated with each subtype that translated into distinct therapeutic vulnerabilities in vitro.58 Specifically, IDH-gr tumors were hypersensitive to RNA synthesis inhibitors, KRAS-gr to topoisomerase inhibitors, TP53gr to polo-like kinase 1 (PLK1) inhibitors, and Udt-gr to mammalian target of rapamycin (mTOR) inhibitors. Transcriptomic approaches have suggested survival subclasses based on KRAS mutations and EGFR-HER2 signaling,59 as well as “proliferation” and “immune” subtypes.60 DNA methylation-based approaches argue for iCCA stratification into four subgroups based on IDH1/2 status and DNA methylation profiles classified as low, intermediate, or high,61 as well as highlighting DNA hypermethylation-associated CpG.TpG mutation events.16 An immunebased subclassification approach has also been suggested for iCCA. In this scheme, tumors can be stratified into lymphoid, myeloid, mesenchymal, and immune-desert phenotypes.62 The validity of this approach is further supported by single cell RNAsequencing (scRNAseq) studies, which have identified fundamental cross-talk networks between iCCA-associated immune cells, tumor cells, and microenvironment cells.63,64

Although GBC has not been molecularly stratified to date, four molecular subclasses of eCCA have recently been identified.65 These include a metabolic subclass associated with bile acid metabolism signatures, a proliferation subclass associated with MTOR signaling, a mesenchymal subclass associated with transforming growth factor-beta (TGF-b) signaling, and an immune subclass associated with high lymphocyte infiltration. Compared with BTC, molecular stratification of HCC is much more formalized and can be split into six biological subtypes: AKT/mTOR, P53/cell cycle regulation, epigenetic modifiers, MAP kinase, oxidative stress, telomere maintenance, and Wnt/b-catenin.66 Significant mutual inclusivity (CTNNB1 and TERT) and exclusivity (CTNNB1 and TP53) of key drivers has been consistently highlighted.66 In addition, approximately 25% of HCCs exhibit an inflammatory phenotype, which was further stratified into adaptive T cell response and exhaustion subtypes.67 Such immune diversity has also been emphasized in scRNAseq studies, especially the role of tumor-associated macrophages (TAMs) in the inflammatory response and patient outcome68 (see Chapter 9B). Independent of diagnosis, molecular subtypes that span iCCA and HCC have also been reported in the Asian population.69 The TIGER-LC consortium integrated genomics, transcriptomics, and metabolomics, unveiling two clusters of tumors independent of classification as iCCA or HCC. One subtype was associated with mitotic checkpoint anomalies and mutations in epithelial cell transforming sequence 2 oncogene (ECT2) and PLK1. In contrast, the other subtype was characterized by obesity, bile acid metabolism, and T cell infiltration. These findings emphasize the potentially over-constraining implications of umbrella diagnostic terms, such as HCC and BTC, and may support molecularly guided basket trial approaches in HB cancers as a whole.

Future Perspectives In 2020 the clinical impact of molecular characterization of HB tumors was epitomized by the US Food and Drug Administration (FDA) approval of pemigatinib as a second-line treatment for FGFR2 fusion-positive advanced iCCA and ivosidenib as a second-line treatment for IDH1 mutant advanced iCCA after successful phase III trials36,37 (see Chapter 50). Although the clinical management of these patients has been historically changed, these cases represent only a small minority of the HB cancer demographic. Significant additional work is required to apply molecular characterization into tangible therapeutic strategies for the majority of HB patients. Although molecular characterization has largely focused on inter-patient differences, these same approaches must now be applied to characterize intra-patient differences over time because HB cancers are dynamic diseases. This will necessitate molecular profiling of precursor lesions to understand primary tumor induction, metastatic lesions to understand tumor dissemination, and preand post-treatment samples to decipher the molecular basis of treatment response and chemoresistance. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

148.e1

REFERENCES 1. Qadan M, Kingham TP. Technical aspects of gallbladder cancer surgery. Surg Clin North Am. 2016;96(2):229-245. 2. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. 3. She WH, Chok KSh. Strategies to increase the resectability of hepatocellular carcinoma. World J Hepatol. 2015;7(18):2147-2154. 4. Goetze TO. Gallbladder carcinoma: prognostic factors and therapeutic options. World J Gastroenterol. 2015;21(43):12211-12217. 5. Villanueva, A. Hepatocellular carcinoma. N Engl J Med. 2019;380: 1450-1462. 6. Peery AF, Crockett SD, Barritt AS, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology. 2015;149(7):1731-1741.e3. 7. Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era [published correction appears in Nat Rev Clin Oncol. 2015;12(8): 436]. Nat Rev Clin Oncol. 2015;12(7):408-424. 8. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71(1):104-114. 9. McNamara MG, Lopes A, Wasan H, et al. Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer. J Hepatol. 2020;73(5):1109-1117. 10. Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol. 2020;72(1):95-103. 11. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218. 12. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-1010. 13. Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-511. 14. Chan-On W, Nairismägi ML, Ong CK, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45(12): 1474-1478. 15. Furuta M, Ueno M, Fujimoto A, et al. Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J Hepatol. 2017;66(2):363-373. 16. Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116-1135. 17. Wardell CP, Fujita M, Yamada T, et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 2018;68(5):959-969. 18. Shukla R, Upton KR, Muñoz-Lopez M, et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 2013;153(1):101-111. 19. Fujimoto A, Furuta M, Totoki Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer [published correction appears in Nat Genet. 2016;48(6):700]. Nat Genet. 2016;48(5):500-509. 20. Zhang X, Choi PS, Francis JM, et al. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet. 2016;48(2):176-182. 21. Cao C, Sun J, Zhang D, et al. The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of b-catenin in HCC cells. Gastroenterology. 2015;148(2):415-426.e18. 22. Alexandrov LB, Kim J, Haradhvala NJ, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578(7793): 94-101. 23. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169(7):1327-1341.e23. 24. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles [published correction appears in Cell Rep. 2017;19(13):2878-2880]. Cell Rep. 2017;18(11):2780-2794.

25. Huang MN, Yu W, Teoh WW, et al. Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors. Genome Res. 2017;27(9):1475-1486. 26. Letouzé E, Shinde J, Renault V, et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun. 2017;8(1):1315. 27. Kim YH, Hong EK, Kong SY, et al. Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations. Oncotarget. 2016;7(17):23825-23836. 28. Stephens PJ, Greenman CD, Fu B, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144(1):27-40. 29. Molenaar JJ, Koster J, Zwijnenburg DA, et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483(7391):589-593. 30. Fernandez-Banet J, Lee NP, Chan KT, et al. Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma. Genomics. 2014;103(2-3):189-203. 31. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020;578(7793): 82-93. 32. Dong LQ, Shi Y, Ma LJ, et al. Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma. J Hepatol. 2018;69(1):89-98. 33. Rausch T, Jones DT, Zapatka M, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012;148(1-2):59-71. 34. Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A. 2015;112(1):118-123. 35. Bailey MH, Tokheim C, Porta-Pardo E, et al. Comprehensive characterization of cancer driver genes and mutations [published correction appears in Cell. 2018;174(4):1034–1035]. Cell. 2018; 173(2):371-385.e18. 36. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020; 21(5):671-684. 37. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [published correction appears in Lancet Oncol. 2020;21(10):e462]. Lancet Oncol. 2020;21(6):796-807. 38. Weber J, Öllinger R, Friedrich M, et al. CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice. Proc Natl Acad Sci U S A. 2015;112(45): 13982-13987. 39. Artegiani B, van Voorthuijsen L, Lindeboom RGH, et al. Probing the tumor suppressor function of BAP1 in CRISPR-engineered human liver organoids. Cell Stem Cell. 2019;24(6):927-943.e6. 40. Li M, Liu F, Zhang F, et al. Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut. 2019;68(6):1024-1033. 41. Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018;24(17): 4154-4161. 42. O’Rourke CJ, Lafuente-Barquero J, Andersen JB. Epigenome remodeling in cholangiocarcinoma. Trends Cancer. 2019;5(6): 335-350. 43. O’Rourke CJ, Munoz-Garrido P, Aguayo EL, Andersen JB. Epigenome dysregulation in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1423-1434. 44. Seehawer M, Heinzmann F, D’Artista L, et al. Necroptosis microenvironment directs lineage commitment in liver cancer [published correction appears in Nature. 2018]. Nature. 2018;562(7725):69-75. 45. Udali S, Guarini P, Moruzzi S, et al. Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate. Hepatology. 2015;62(2): 496-504. 46. Saha SK, Parachoniak CA, Ghanta KS, et al. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer [published correction appears in Nature. 2015;528(7580):152]. Nature. 2014;513(7516):110-114.

148.e2 47. Hlady RA, Tiedemann RL, Puszyk W, et al. Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis. Oncotarget. 2014;5:9425-9443. 48. Jühling F, Hamdane N, Crouchet E, et al. Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut. 2021;70(1):157-169. 49. Ding X, He M, Chan AWH, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology. 2019;157(6):1630-1645.e6. 50. Shu Y, Wang B, Wang J, Wang JM, Zou SQ. Identification of methylation profile of HOX genes in extrahepatic cholangiocarcinoma. World J Gastroenterol. 2011;17(29):3407-3419. 51. Goeppert B, Konermann C, Schmidt CR, et al. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology. 2014;59(2):544-554. 52. Merino-Azpitarte M, Lozano E, Perugorria MJ, et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol. 2017;67(1):72-83. 53. Mudbhary R, Hoshida Y, Chernyavskaya Y, et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell. 2014;25(2):196-209. 54. Villanueva A, Portela A, Sayols S, et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology. 2015;61(6):1945-1956. 55. Hlady RA, Sathyanarayan A, Thompson JJ, et al. Integrating the epigenome to identify drivers of hepatocellular carcinoma. Hepatology. 2019;69(2):639-652. 56. Lampis A, Carotenuto P, Vlachogiannis G, et al. MIR21 drives resistance to heat shock protein 90 inhibition in cholangiocarcinoma. Gastroenterology. 2018;154(4):1066-1079.e5. 57. Carotenuto P, Hedayat S, Fassan M, et al. Modulation of biliary cancer chemo-resistance through microRNA-mediated rewiring of the expansion of CD1331 cells. Hepatology. 2020;72(3):982-996. 58. Nepal C, O’Rourke CJ, Oliveira DVNP, et al. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology. 2018;68(3):949-963.

59. Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142(4): 1021-1031.e15. 60. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals two classes that have different outcomes. Gastroenterology. 2013;144(4):829-840. 61. Goeppert B, Toth R, Singer S, et al. Integrative analysis defines distinct prognostic subgroups of intrahepatic cholangiocarcinoma. Hepatology. 2019;69(5):2091-2106. 62. Job S, Rapoud D, Dos Santos A, et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology. 2020;72(3):965-981. 63. Zhang M, Yang H, Wan L, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol. 2020;73(5):1118-1130. 64. Ma L, Hernandez MO, Zhao Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell. 2019;36(4):418-430.e6. 65. Montal R, Sia D, Montironi C, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol. 2020;73(2):315-327. 66. Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020;72:215-229. 67. Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153(3):812-826. 68. Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell. 2019;179(4):829845.e20. 69. Chaisaingmongkol J, Budhu A, Dang H, et al. Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell. 2017;32(1):57-70.e3.

CHAPTER 9D Advances in the molecular characterization of pancreatic cancer and pre-malignant lesions Rami Iman and Christine Iacobuzio-Donahue PANCREATIC CANCER OVERVIEW Pancreatic ductal adenocarcinoma (PDA), commonly referred to as “pancreatic cancer” is the fourth most common cause of cancer in both men and women. PDA remains a devastating diagnosis, with an overall survival rate of no greater than 10%.1,2 In 2020 approximately 57,600 Americans will be diagnosed with PDA, and approximately 47,050 will die of it1 (see Chapters 61 and 62). The past two decades have seen an exponential increase in our understanding of the molecular basis and etiology behind PDA.3–6 Still, the clinical management of this disease, including primary prevention, early detection, and better targeted treatment options, has not changed significantly during the past decade. Currently, the only cure for this disease is surgical resection. Unfortunately, only approximately 20% of the patient population is seen with resectable disease.7 This chapter aims (1) to show that even though every tumor has a number of common molecular events, it is the differences among tumors that have clinical implications and (2) to set the stage for the future, which will include a discussion of successful early detection and treatment strategies for this deadly disease.

Progression Model of Pancreatic Ductal Adenocarcinoma In the first era of pancreatic cancer research (Figs. 9D.1 and 9D.2), the fields of molecular biology and pathology combined to establish a paradigm that PDA culminates from a multistep progression model.3 The second era of pancreatic research (see Figs. 9D.1 and 9D.2) led to the identification of targetable recurrent alterations in PDA and possible targets for therapy (Fig. 9D.3). This slow, sequential process may be the reason PDA is primarily a disease of people in their sixth and seventh decades of life. Definable pathologic markers on this stepwise progression, which follows a similar model first developed in colon carcinogenesis, are lesions referred to as pancreatic intraepithelial neoplasia (PanIN)3 (Fig. 9D.4A–C). These lesions are believed to be precursor lesions to pancreatic cancer. PanIN lesions are thought to develop years before the emergence of PDA and are pathologically graded as low-grade PanIN lesions without cytologic dysplasia (PanIN-1) (see Fig. 9D.4A) to intermediate lesions (PanIN-2) with cytologic abnormalities such as pseudostratification, crowding, or nuclear enlargement (see Fig. 9D.4B) to high-grade lesions (PanIN-3) that consist of full-thickness dysplasia/carcinoma in situ (see Fig. 9D.4C). Although low-grade PanIN lesions are common incidental findings, high-grade PanIN lesions are more common in the pancreata of patients with PDA (see Chapter 59). Key evidence supporting that PanIN lesions are precursors to PDA is that similar hallmark molecular defects are found in PanIN lesions adjacent to invasive cancers.8–12 Kirsten rat sarcoma oncogene (KRAS) mutations are frequently found in

early PanIN lesions, including PanIN-1,13 whereas genes involved in DNA repair mechanisms or transforming growth factor-b (TGF-b) signaling, such as for tumor protein 53 (TP53) and SMAD4, respectively, are altered in the latter stages of this progression model.14 It has also been shown that a higher frequency of PanIN lesions may be found in pancreata of patients with an inherited risk of PDA, again supporting the hypothesis that PanINs are true precursors to PDA.13 Once a PDA has formed, additional genetic changes continue to occur with time, thereby creating subclones (intratumoral heterogeneity) that seed metastases (e.g., peritoneal or distant).15 It has been estimated that it takes an average of 6.8 years for a parental pancreatic ductal adenocarcinoma (PDAC) clone to give rise to a given metastatic lesion.15

Intraductal Papillary Mucinous Neoplasm The intraductal papillary mucinous neoplasm (IPMN) is a well-accepted clinical and pathologic entity (see Fig. 9D.4D; see Chapters 59 and 60).16 IPMNs typically produce radiographically identifiable pancreatic ductal dilation, which may predominantly involve the main pancreatic ducts (main duct type IPMN), the secondary ducts (branch duct type IPMN), or both types of ducts (mixed type) (see Chapter 17). The distinction between the branch duct type and main duct type IPMNs is important, because the former are more likely to involve the head and uncinate process of the pancreas and are associated with lower-grade dysplasia and fewer invasive carcinomas.17 Approximately 30% to 40% of resected IPMNs harbor an invasive adenocarcinoma, and adenocarcinoma is most strongly associated with main duct IPMNs. Approximately half of invasive carcinomas arising within IPMNs are so-called colloid (mucinous) carcinomas, and most of the remainder are tubular adenocarcinomas; the latter is histologically indistinguishable from invasive ductal adenocarcinomas that arise in the setting of PanINs.18 Colloid carcinomas associated with IPMNs have a relatively good prognosis compared with other pancreatic carcinomas of the ductal type and have a 5-year survival of 60%19 (see Chapters 61 and 62). PanINs and IPMNs show some overlapping features (see Chapter 59). For example, both are inherently intraductal lesions composed predominantly of columnar, mucin-producing cells that may grow in a flat configuration or may produce papillae; these lesions show a range of cytologic and architectural atypia and can give rise to invasive adenocarcinomas of the pancreas (see Fig. 9D.4E). An important feature that distinguishes the two lesions is that PanINs are microscopic lesions and IPMNs are macroscopic. Nevertheless, recognition of an IPMN and its distinction from a PanIN lesion is important for two reasons: (1) IPMN-associated colloid carcinomas have a significantly better prognosis than either PanIN- or IPMN-associated tubular adenocarcinomas20 and (2) IPMNs have a propensity to 149

150

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY 1st era

1988

KRAS mutations

1994

1996

2nd era 2000

2005

DPC4 FANC gene inactivation mutations Sporadic and familial p16 inactivation pancreatic genome BRAC2 inactivation surveyed

2010

p53

Pancreatic carcinoma sequenced

FIGURE 9D.1  Genetic landmark discoveries in pancreatic cancer research. The first era is highlighted by the discovery of tumor suppressor genes such as DPC4 and loss of p16. The second era is highlighted by genomic profiling of discovery and validating sets of isolated and purified tumors from pancreatic cancer patients.

be multifocal lesions, therefore, patients who undergo partial pancreatectomy and are left with a remnant pancreas need to be followed for life, even when the lesion originally resected was a noninvasive IPMN.21 Genetic analyses of IPMNs have disclosed abnormalities in many of the same genes altered in conventional ductal adenocarcinoma, including mutations in the KRAS2, TP53, and CDKN2A genes, although the frequency and stage of neoplastic progression at which these alterations occur in IPMNs differ from PanINs.16,22 For example, in contrast to PanINs, IPMNs harbor KRAS mutations in only half of analyzed cases.23 Moreover, abnormalities in SMAD4, which are

present in 30% of PanIN-3 and 55% of PDA, are rare in IPMNs.24 IPMNs may also contain genetic alterations of genes that are specific to this form of neoplasia. Activating mutations in GNAS have been found in more than 70% of IPMNs, and a subset shows genetic inactivation of RNF43.23 Interestingly, correlations between phenotypic differentiation of IPMNs (described later) and mutations have been identified: GNAS mutations are more common in gastric and intestinal type IPMNs than in pancreaticobiliary type IPMNs, whereas KRAS mutations are more common in gastric and pancreaticobiliary type IPMNs.23 Molecular testing of pancreatic cyst fluid for GNAS and KRAS mutations may help support a diagnosis of IPMN and distinguish it from other cystic lesions, including neuroendocrine tumors with cystic degeneration, benign pseudocysts, and solid and cystic pseudopapillary neoplasms. However, a negative result does not rule out a mucinous cystic neoplasm.25 Another distinction between PanINs and IPMNs relates to the expression of the caudal differentiation factor CDX2, a marker of intestinal differentiation. Most IPMNs express CDX2, in particular IPMNs associated with an invasive colloid carcinoma, whereas this is uncommon both in PanINs and in the subset of IPMNs that give rise to invasive cancers resembling ductal adenocarcinomas.26 CDX2 expression in IPMNs is generally associated with expression of MUC2, an intestinal epithelial apomucin, whereas the absence of CDX2 expression usually is associated with expression of MUC1, a biliary apomucin, and concomitant lack of expression of MUC2. These findings have suggested that there may be two divergent pathways of carcinogenesis within the pancreatic ducts.18 The first is a

first era

second era

Primary tumor

Generated cell line

Xenografted

24 discovery tumors

Generated cell line

DNA analysis: Sequencing LOH Gene cloning

mRNA analysis: SAGE arrays

Validation studies: Functional work Immunohistochemistry on clinical specimens

Sequencing

Oligonucleotide arrays

39 genes in another 90 tumors

Deletions and amplifications

Gene expression analysis

Discovery of core signaling pathways disrupted in PDA

FIGURE 9D.2  Simplified flowchart of genetic discoveries performed in the two eras of genetic research. In the first era (left), resected pancreatic cancers were xenografted, and genomic DNA was isolated for genetic analysis of a region or putative tumor suppressor or oncogene. In the second era (right), combining advances in equipment and techniques and high-throughput sequencing allowed a genomic survey of the pancreatic cancer genome. LOH, Loss of heterozygosity; mRNA, messenger RNA; PDA, pancreatic ductal carcinoma; SAGE, serial analysis of gene expression. Data from Ding J, Wang H: Multiple interactive factors in hepatocarcinogenesis, Cancer Lett 346: 17–23, 2014; and Marquardt JU, Thorgeirsson SS: SnapShot: hepatocellular carcinoma, Cancer Cell 25: 550, 2014; and Totoki Y, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes, Nat Genet. 46: 1267–73, 2014.

  Chapter 9D  Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions Surgery

Surgery

Standard Treatment (current)

Molecular Testing

151

Gemcitabine

BRCA2//FANC

High cyto HuR Hedgehog cellular signaling pathway

Targeted Treatment (future) DNA damaging agents: Mitomycin C Cisplatin PARP-inhibitors Gemcitabine

Variable Outcomes

IPI-9

Improved Outcomes

FIGURE 9D.3  Targeted treatment strategy of PDA. Left, The current strategy. Right, The future. IPI-9 is the abbreviation for IPI-926, an agent that inhibits the Hedgehog cellular signaling pathway (the stromal component of PDA). cyto, Cytoplasmic; HuR, human antigen R; PDA, pancreatic ductal adenocarcinoma; PARP, poly (ADP-ribose) polymerase. (Courtesy Jennifer Brumbaugh, Thomas Jefferson University, Philadelphia.)

so-called intestinal pathway that gives rise to CDX2- and MUC2expressing IPMNs that progress to colloid carcinomas, which have a better prognosis. The second is a pancreatobiliary pathway that gives rise to CDX2-negative, MUC2-negative, and MUC1-expressing PanINs and a subset of IPMNs, both of which can progress to conventional ductal adenocarcinomas, which have a poorer prognosis. MUC5AC, a gastric foveolar mucin, is a secretory product normally expressed by surface mucus cells in the stomach and bronchial tract. MUC5AC expression is typically absent in the normal pancreas and hyperplastic lesions, whereas MUC5AC has consistently been shown to be aberrantly expressed in PDAC and its associated premalignant lesions, including all subtypes of IPMNs.27 It has been suggested that MUC5AC expression in pancreatic tumors may play a role in the tumor cells evading the host immune response, as well as contributing to the invasive motility of pancreatic cancer cells.28 Overexpression of MUC5AC relays a poorer prognosis in PDAC.29

Intraductal Tubulopapillary Neoplasm Intraductal tubulopapillary neoplasm (ITPN) is an intraductal neoplasm of the pancreas with distinct genetic and immunophenotypic features that are different from IPMNs and conventional ductal adenocarcinoma (see Chapter 59). ITPNs were first described in 2009 and included as a distinct diagnostic entity in the 2010 World Health Organization (WHO) classification of tumors of the gastrointestinal tract.30 ITPNs account for 3% of intraductal neoplasms of the pancreas.30 They have a slight female predominance and typically

present with nonspecific abdominal symptoms.31 Histologically, ITPNs are composed of nodules with back-to-back tubular glands lined by cuboidal cells with eosinophilic to amphophilic cytoplasm. Rare papillae may be seen, although the predominant architectural pattern is tubular.30 The glandular crowding results in the formation of large circumscribed cribriform structures with central comedo type necrosis. Intracellular mucin is typically minimal. An invasive carcinoma is identified in up to 70% of cases.32 The prognosis of ITPNs with an invasive carcinoma is regarded as better overall than that of ductal adenocarcinoma, with a 5-year overall survival rate of 71% in ITPN in contrast to a 5-year overall survival rate of 21% in PDAC.31 The immunophenotype of ITPNs shares some overlap with pancreaticobiliary type IPMNs. Expression of MUC1 and MUC6 is commonly seen in both ITPNs and pancreaticobiliary type IPMNs, whereas MUC5AC expression, which is highly expressed in all subtypes of IPMNs, is rarely reported in ITPNs.27 MUC2 labeling, which is observed in the intestinal type IPMNs, is consistently not seen in ITPNs.30 Genetic alterations characteristic of PDAC and IPMNs are typically absent in ITPNs. Mutations in KRAS, for example, are seen in 7.1% of ITPNs, whereas they are observed in 80% of IPMNs.33 GNAS mutations, which are found in more than 70% of IPMNs, have not been reported in ITPNs.33 Somatic mutations in PIK3CA have also been described in 27% of ITPNs, whereas these alterations are typically absent in IPMNs.34 Although both intraductal pancreatic neoplasms share morphologic and immunophenotypic characteristics,

152

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

A

B

C

D

E

both are recognized as distinct intraductal entities based on the differences in their genetic alterations.

Intraductal Oncocytic Papillary Neoplasm Intraductal oncocytic papillary neoplasm (IOPNs) were formally considered as a variant of IPMNs; however, advancements in the understanding of the molecular and immunophenotypic features of IOPNs have led to the reclassification of these lesions as a distinct diagnostic entity in the 2018 WHO

FIGURE 9D.4  Pathologic features of precursor lesions of pancreatic ductal adenocarcinoma (PDA) (see Chapter 59). A, Pancreatic intraepithelial neoplasia (PanIN). PanIN-1, flat lesion composed of columnar cells with basally located benign-appearing nuclei and supranuclear mucin. B, PanIN-2 showing mild cytologic and architectural atypia, including crowding, nuclear enlargement, and tufting. C, PanIN-3 showing complex papillary architecture with budding of epithelial cells into lumen and severe cytologic atypia of lining cells. D, Intraductal papillary mucinous neoplasm (IPMN) with low-grade dysplasia showing well-formed papillae lined by mucin-containing cells. D, IPMN with high-grade dysplasia with complex branching papillae and cells showing marked cytologic atypia. E, Invasive, moderately differentiated PDA forming angular abortive glands and invading perineural spaces.

classification of tumors of the gastrointestinal tract (see Chapters 59 and 60). IOPNs account for 4.5% of all intraductal neoplasms of the pancreas.35 They typically present in female patients most commonly either as an incidental finding or with symptoms associated with tumoral mass effect. IOPNs have a unique histologic appearance characterized by complex arborizing papillae with delicate fibrovascular cores lined by cuboidal to columnar cells with granular, eosinophilic cytoplasm and a round, centrally located nucleus with a prominent eccentric

  Chapter 9D  Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions

nucleolus. Architecturally, the cells form cribriform spaces with intraluminal mucin. IOPNs are essentially regarded to exhibit high-grade dysplasia due to the degree of architectural and cellular complexity commonly seen.35 Although there are overlapping clinicopathologic characteristics between IOPNs and IPMNs, IOPNs exhibit distinct molecular alterations. IOPNs are reported to harbor recurrent mutations in ARHGP26, ASXL1, EPHA8, and ERBB4, although none occur at a high enough frequency to be considered entity-defining genomic alterations.36–38 Mutations in KRAS and GNAS, by contrast, have rarely been reported.36 The recently described novel DNAJB1-PRKACA oncogenic fusion has been found to be a mutated subset of intraductal pancreatic neoplasms with oncocytic morphology.39 The novel fusion was first described in the fibrolamellar variant of hepatocellular carcinoma and had previously been considered to be diagnostic of this entity.40 Immunohistochemically, IOPNs exhibit diffuse labeling for MUC1 and MUC6 in 50% and 29% of cases, respectively. Interestingly, 61% of IOPNs label for HepPar-1, a marker of hepatocellular differentiation. In situ hybridization for albumin, a more specific marker for hepatocellular differentiation, is consistently negative in these cases.37 The distinction between IOPNs and IPMNs is critical as IOPNs are regarded to have a better overall prognosis. Invasive carcinoma is associated with IOPNs in about 30% of cases.41 The predominant morphology of invasive tumors is that of a tubular adenocarcinoma composed of oncocytic tumor cells similar to the preneoplastic lesion.41 Invasive carcinoma associated with IOPNs has a relatively good prognosis with a 5-year survival approaching 100%.41

GENETICS OF PANCREATIC DUCTAL ADENOCARCINOMA (SEE CHAPTER 9A) Genomic (DNA) Alterations in Pancreatic Cancer The multitude of genetic abnormalities in pancreatic cancer have many characteristics similar to other solid tumors; thus they include point mutations in critical genes, chromosomal (copy number) aberrations, mitochondrial DNA mutations, telomeric abnormalities, and epigenetic silencing by methylation of defined promoter DNA sequences. An individual pancreatic tumor contains on average 63 genetic alterations, primarily point mutations. Only a small subset of these mutations is required for tumorigenesis.4 The field of analyzing the genetics of pancreatic cancer can be broken down chronologically (see Fig. 9D.1). First, landmark studies starting in the late 1980s and spanning nearly two decades are highlighted by the discovery of KRAS activation, SMAD4 and BRCA2 mutations, and CDKN2A silencing (see Figs. 9D.1 and 9D.2, left). Some of these discoveries spurred new lines of investigation in the field of pancreatic cancer as well as specific classification of PDA subtypes.42 More recently, with the help of advanced DNA sequencing technology, investigators have been able to sequence the entire genomes of various pancreatic cancer subtypes (see Figs. 9D.1 and 9D.2, right).

Copy Number Aberrations Although now considered primitive, valuable cytogenetic analysis performed more than a decade ago found that chromosomal

153

aberrations occur in virtually every pancreatic cancer. Cytogenetic analyses of pancreatic cancers have shown multiple, nonrandom numeric, and structural changes.43,44 The most common numeric abnormalities include losses of chromosomes 6, 12, 13, and 18 and gains of chromosomes 7 and 20. Structural abnormalities (intrachromosomal break points) frequently involve 1p and 1q, 3p, 4q, 6q, 7q, 17p, 11p, 11q, 15q, 16q, and 19q.45 The technical limitations of conventional cytogenetics have presented challenges for identifying genes that are affected by chromosomal breaks. Allelotyping identifies areas of gross chromosomal loss by using polymorphic microsatellite markers to determine regions of genomic loss compared with matched healthy tissues, also known as loss of heterozygosity (LOH) analysis. Allelotyping operates on the basic principle of the twohit hypothesis, which postulates that tumor suppressor genes require biallelic inactivation. This most commonly happens by intragenic mutation in one allele, followed by loss of genetic material in the other allele. Identifying regions of single or biallelic loss or mutation holds the potential to understand the role of neighboring novel and well-known tumor suppressor genes. A landmark allelotype analysis of pancreatic cancers was performed using approximately 80 pancreatic cancer xenografts and 386 microsatellite markers.46 This work discovered allelic losses in chromosome regions in proximity to tumor suppressor genes CDKN2A, TP53, and SMAD4. Allelotype analysis of PanIN lesions also has been performed using microdissected samples, and as expected, LOH is seen in many of the same chromosomal regions as invasive cancer, including 9p, 17p, and 18q.47,48 Although the changes are conserved in most synchronous precursor lesions (i.e., the same allele is lost in PanIN and associated cancers), there is occasional clonal divergence between high-grade PanIN lesions harboring genetically distinct changes from the synchronous invasive cancer.48 These findings may have important clinical implications in regard to tumor heterogeneity and clonal cancer cell drug resistance. Comparative genome hybridization (CGH) identifies genomic amplifications and deletions and differentially labels normal and tumor genomic sequences with different dyes. The relative ratio of the two dyes indicates regions of cancer-associated losses or gains, with a ratio of 1:1 consistent with no change in copy number compared with healthy DNA. Conventional CGH is performed on metaphase spreads and suffers from both low resolution and the inability to precisely map the various regions of amplifications and deletions.49 The resolution of array CGH is significantly better than the conventional technique, ranging from 500 to 30 kb, permitting the precise mapping of deletion and amplicon boundaries and genes targeted therein. Array technology also provides the ability to use probes more efficiently to study amplification of a larger number of genes. Array CGH analysis of pancreatic cancers has identified numerous recurrent copy number aberrations, including amplifications of the myelocytomatosis oncogene (c-MYC) (8q), epidermal growth factor receptor gene (EGFR) (7p), KRAS (12p), AKT2 (19q), and NCOA3 (20q) and deletions of SMAD4 (18q), CDKN2A (9p), FHIT (3p), and MAP2K4 (17p).50–52 Utilizing high-density single-nucleotide polymorphism arrays, Calhoun and colleagues51 surveyed all the commercially available pancreatic cancer cell lines. In brief, this study provided high-resolution and detailed break-point mapping of these cell lines and found two subclasses of cancer cell lines, original chromosomal instability (CIN) and holey CIN genotypes.51

154

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Perhaps global classification of tumor cells with high-density arrays will become part of a prognostic or predictive molecular signature panel in the future.

500

Specific Gene Mutations

Oncogenes Perhaps the best evidence that KRAS activation is an early and important event in tumorigenesis comes from decades of research on pancreatic cancer. The KRAS oncogene on chromosome 12p is the most commonly altered oncogene, with as many as 90% of pancreatic cancers containing mutations on codons 12, 13, and 61.58 Activating mutations impair the intrinsic guanosine triphosphate (GTP)ase activity of the KRAS gene product, resulting in a protein that is constitutively active in intracellular signal transduction. KRAS mutation happens early in the pathway to oncogenesis, with approximately 30% of PanIN-1 lesions harboring KRAS mutations.59,60 The first mouse model of pancreatic cancer was generated by constitutive overexpression of mutant KRAS2 in murine pancreatic ductal epithelium, underscoring its importance in pancreatic oncogenesis.61 This model

300 %

Allelotyping provides insight into areas harboring tumor suppressor genes, but it cannot qualify areas of enhanced genomic expression, as happens with oncogene activation. Simplistically, wild-type tumor suppressor genes can “put the brakes” on the speeding vehicle (the cell), but if mutated, these “brakes” become defective, and the vehicle cannot stop. Using a similar automobile analogy, protooncogenes, in a mutated form known as oncogenes, become the “accelerators,” and these “go signals” are often critical in transforming normal cells to a malignant phenotype. Much like other solid tumors, genes altered in pancreatic cancer include three functional classes: oncogenes, tumor suppressor genes, and caretaker genes. A family of caretaker genes recognized as disrupted in pancreatic cancer are genes of the Fanconi anemia complementation group, which are involved in homologous recombination-based DNA damage repair.53 Patients with Fanconi anemia present with a wide variety of clinical issues, including aplastic anemia and a high risk of developing cancer. BRCA2 is a member of this DNA repair pathway and is mutated in a subset of familial pancreatic cancers.54 This has led to the search for mutations in other Fanconi anemia genes in pancreatic cancer. Somatic mutations of two genes in the core complex, FANCC and FANCG, were discovered but are rare in sporadic pancreatic cancers.55 Through other modern techniques, Jones and colleagues5 discovered FANCN (PALB2) as another mutated gene found in familial pancreatic cancers. Mutations in this core complex and in this DNA repair mechanism have major therapeutic implications (Fig. 9D.5 and Table 9D.1; see “Familial Pancreatic Cancer”).56 Unlike most in vivo experiments, xenografted mice with isogenic cell lines (FANCC deficient and proficient) experienced regression of tumor after a single dose of the available mitomycin C intrastrand cross-linking drug.57 Although other than FANN, FANCC, and FANCG, mutations in the Fanconi complementation group have not yet been described, and the frequency of these mutations in PDA appear to be low, it is likely that defects in other FANC genes yet to be thoroughly investigated (i.e., FANCA) are the direct cause of some familial and sporadic PDAs.

100

10

20 Days

FIGURE 9D.5  Preclinical model shows an example of a successful targeted treatment strategy against a Fanconi-deficient tumor. A single-dose treatment with mitomycin C (5 mg/kg) of pancreatic cancer cell lines xenografted into nude mice. Note the hypersensitivity and tumor regression in the FANCC-deficient PL11 cells (squares) compared with the retrovirally corrected FANC-proficient PL11 cells (triangles). Solid lines indicate treated mice; gray lines indicate no-treatment controls. Similar sensitivity was seen in the BRCA2-deficient CAPAN1 xenografted cells. (From van der Heijden MS, et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res. 2005;11[20]:7508–7515.)

was further developed into a powerful and useful preclinical model for PDA progression.62 Several good sources on mouse modeling and pancreatic cancer have been published.63–66 Rarely, pancreatic cancers with wild-type KRAS genes harbor point mutations of BRAF, another gene in the RAS/RAF/ mitogen-activated protein kinase (MAPK) signaling pathway, thereby explaining why mutations of these genes occur in mutually exclusive patterns in pancreatic cancer.67 This highlights the importance of identifying different molecular targets that lead to similar pathways in pancreatic cancer development and of finding a drug that can target one pathway, not one gene. Studies have shown that targeting KRAS may have potential in modulating angiogenesis in tumorigenesis. Matsuo and colleagues68 showed that oncogenic overexpression of KRAS increases production of angiogenesis, promoting CXC chemokines and vascular endothelial growth factor (VEGF) from human pancreatic duct epithelial cells. This upregulation acts through the MAPK pathway and c-JUN signaling.68 KRAS mutation has been shown to be associated with increased VEGFA expression and poorer prognosis in pancreatic carcinoma.69 Yet, targeting KRAS activation in PDA patients has shown no success. Perhaps KRAS activation is a critical early event in pancreatic tumorigenesis, but once cells become malignant, there is no need for constitutive KRAS activation, or for oncogenic addiction, for that matter. Other oncogenes implicated in pancreatic cancers include MYC and EGFR, which can be mutated (GNAS) or amplified (MYC) in various subsets of cancers. Overexpression of MYC transcripts occurs in approximately 50% to 60% of pancreatic

  Chapter 9D  Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions

155

TABLE 9D.1  Genetic Syndromes With Inherited Predisposition to Pancreatic Cancer SYNDROME/DISEASE GENE(S)

GENETIC TESTING CONSIDERATIONS

RISK OF PANCREATIC ADENOCARCINOMA

AVAILABLE TARGETED THERAPY/ CLINICAL CORRELATES

BRCA1: 2.26-fold* BRCA2: 3- to 9-fold†

Cross-linking chemotherapeutics (mitomycin C, cisplatin, chlorambucil, melphalan) PARP inhibitors

Hereditary breast/ ovarian cancer syndrome (HBOCS)

BRCA1 BRCA2

NCCN test criteria require personal or family history of breast and ovarian cancer

Peutz-Jeghers syndrome (PJS)

STK11 (LKB1)

Diagnosis of index case is generally 132-fold; lifetime risk 36%§ based on clinical findings/ working definition‡

Hereditary pancreatitis

PRSS1, SPINK1, Testing guidelines are based on symptoms with or without family CFTR, CTRC history of pancreatitis¶

FAMM melanoma syndrome

CDKN2A

HNPCC-Lynch syndrome

Bethesda Guidelines† (tumor MSI/ MLH1, MSH2, IHC) and Amsterdam Clinical MSH6, PMS2 Criteria II (germline studies)

Documented patients/families with multiple melanomas

Reports of a PJS-associated cancer with loss of the wild-type STK11 allele, together with a germline mutation in the other allele Some sporadic PDAs exhibit somatic mutations of STK11||

50- to 67-fold; lifetime risk 44%a,b

Tumor susceptibility is presumably due to mitogenic stimulation and clonal outgrowth of PDA cells as part of the normal healing responses that occur subsequent to repeated rounds of tissue destructionb

13- to 39-fold†

Somatic p16 alterations were identified in 80% of PDAsc MSI-H pancreatic cancer may have a better prognosis after resection, possibly because of intensive immunoreaction to the tumord

Familial adenomatous APC polyposis (FAP)

APC is considered in individuals with $20 colon adenomas

Relative risk 4.46e Lifetime risk 2%f

Some theorize that pancreaticobiliary secretions affect the development of adenomas and cancer in this areag

Cystic fibrosis (CF)

Genotyping identifies patients with class IV and V mutations, which are likely to represent those with a functioning pancreash

Relative risk 5.3i

Modifier genes or environmental factors may also be important in stratifying risk (e.g., mucin genes are found in both CF and PDA)j

CFTR

*

From Thompson D, et al. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94(18):1358–1365.

†

From Brand RE, et al. Advances in counseling and surveillance of patients at risk for pancreatic cancer. Gut. 2007;56(10):1460–1469.

‡

From Giardiello FM, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987;316(24):1511–1514.

§

From Giardiello FM, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119(6):1447–1453.

||

From Su GH, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol. 199;154(6):1835–1840.

¶

From Ellis et al. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent, and privacy issues. Pancreatology. 2001;1(5):405–415.

a

From Lowenfels AB, et al. Hereditary pancreatitis and the risk of pancreatic cancer: International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. 1997;89(6):442–446.

b

From Howes N, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004;2(3):252–261.

c

From Rozenblum E, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57(9):1731–1734.

d

From Nakata B, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002;8(8):2536–2540.

e

From Giardiello FM, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34(10):1394–1396.

f

From Burt RW. Colon cancer screening. Gastroenterology. 2000;119(3):837–853.

g

From Wallace MH, et al. Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Sur. 1998;85(6):742–750.

h

From Krysa J, et al. Pancreas and cystic fibrosis: the implications of increased survival in cystic fibrosis. Pancreatology. 2007;7(5–6):447–450.

i

From Maisonneuve P, et al. Risk of pancreatic cancer in patients with cystic fibrosis. Gut. 2007;56(9):1327–1378.

j From Singh AP, et al. MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-transcriptional mechanisms. Oncogene. 2007;26(1):30–41.

FAMM, Familial multiple mole; HNPCC, hereditary nonpolyposis colorectal cancer; IHC, immunohistochemical; MIS-H, microsatellite instability, high frequency; MSI, microsatellite instability; NCCN, National Comprehensive Cancer Network; PARP, poly (ADP-ribose) polymerase; PDA, pancreatic ductal adenocarcinoma. Modified from Showalter SI, et al. Identifying pancreatic cancer patients for targeted treatment: the challenges and limitations of the current selection process and vision for the future. Expert Opin Drug Deliv. 2010;7(3):1–12.

cancers and has been shown to cooperate with KRAS.50,70,71 NTRK gene fusions have also been detected in less than 1% of pancreatic adenocarcinomas.72 First-generation TRK inhibitors appear to be well tolerated in patients with NTRK fusion-positive pancreatic cancer, although acquired resistance through both kinase domain mutation in NTRK genes and downstream

mutations in the MAPK pathway remains a therapeutic challenge.72,73

Tumor Suppressor Genes CDKN2A, on chromosome 9p, is the most commonly inactivated gene in pancreatic cancers, occurring in 90% of patients.74,75

156

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

CDKN2A belongs to the cyclin-dependent kinase inhibitor family and inhibits cell cycle progression through the G1-S checkpoint mediated by cyclin-dependent kinases such as CDK4 and CDK6. Homozygous deletions (40%), intragenic mutation with loss of the second allele (40%), and epigenetic silencing by promoter methylation (10% to 15%) all contribute to gene inactivation. Loss of CDKN2A function occurs throughout the process of oncogenesis, with lesions appearing in different PanINs: 30% of PanIN-1A and PanIN-1B, 55% of PanIN-2, and 71% of PanIN-3 lesions show loss of nuclear p16 protein expression.76 The CDKN2A homozygous deletions encompass the methylthioadenosine phosphorylase (MTAP) gene in approximately 30% of pancreatic cancers, which offers potential therapeutic benefit because targeted therapies have been developed that specifically inhibit the growth of MTAP-deficient cells.77 As many as 80% of pancreatic cancers contain an inactivation of the TP53 gene on chromosome 17p. Such inactivation most often occurs via intragenic mutation combined with loss of the second allele, although homozygous deletions also occur in some PDAs. The TP53 (p53) protein leads to cell cycle arrest and activates apoptosis in the presence of DNA damage. It is believed that loss of TP53 function allows cells to survive and divide, despite the presence of damaged DNA, leading to accumulation of additional genetic abnormalities and, eventually, to neoplasia. Nuclear overexpression of the TP53 protein does not correlate well with mutation status. By immunohistochemistry, TP53 accumulation is seen only in the advanced PanIN-3 lesions, consistent with TP53 being a “late” genetic event in pancreatic cancer progression.78 PDA cells with a mutant TP53 have been shown to have a greater propensity for metastases.79 Of note, in an experimental model, the BRCA2 gene could not be artificially disrupted in cancer cells with intact wild-type TP53 status.80,81 Inactivation of the SMAD4 gene on chromosome 18q21 occurs in 55% of pancreatic cancers by homozygous deletions (30%) or by intragenic mutations and loss of the second allele (25%). Loss of SMAD4 function interferes with intracellular signaling cascades downstream of the TGF family of cell surface receptors, leading to decreased growth inhibition and uncontrolled proliferation. Although SMAD4 alterations are most common in PDA, they are also frequently seen in other carcinomas, occurring in approximately 15% of colorectal carcinoma and 10% of gastric carcinoma.82 Similar to TP53, loss of SMAD4 function is a late genetic event in pancreatic carcinoma progression, with loss of SMAD4 seen only in a few PanIN-3 lesions.78 Examination of resected tumor specimens found that SMAD4 inactivation portends a poorer prognosis and greater potential to metastasize.42,83 Moreover, in a study of PDA patients who underwent autopsy, loss of SMAD4 was highly correlated with extensive metastatic burden. Identification of downstream targets might allow restoration of SMAD4-dependent signaling in pancreatic cancer, yielding an improved prognosis.84 Several tumor suppressor genes are inactivated in smaller numbers (5% to 10%) of pancreatic cancers, including STK11 (chromosome 19p),85 TGFBR1 (chromosome 9q), TGFBR2 (chromosome 3p), RB1 (chromosome 13q),86 and MAP2K4 (chromosome 17p).87 MAP2K4 function has been explored in a number of models, yet the main reason for its loss in pancreatic cancer is still unknown.88 Separately, DNA-level abnormalities in the switch/sucrose nonfermentable (SWI/SNF) complex gene member ATrich interaction domain 1A (ARID1A) have been reported in approximately 14% of PDAs in provisional TCGA data, mostly

gene deletions and truncating mutations, whereas another 6% of PDA have decreased messenger RNA (mRNA) ARID1A levels without corresponding DNA abnormality, suggesting an epigenetic aberration.82,89 ARID1A and other SWI/SNF members remodel chromatin, thus controlling the transcription and expression of various genes. Abnormalities in ARID1A have been associated with upregulation of the phosphoinositide-3kinase (PI3K) pathway as well as sensitivity to PI3K and AKT inhibition.90 Mixed-lineage leukemia 3 (MLL3 or KMT2C) is a gene involved in histone methylation and transcriptional coactivation. It functions as a tumor suppressor and is recurrently mutated in approximately 18% of pancreatic carcinoma, with the most common mutation type being truncating mutations (frameshift and nonsense mutations).82,89

Other Caretaker Genes In addition to classic oncogenes or tumor suppressor genes, caretaker genes (beyond Fanconi anemia–related genes) have been shown to play a role in oncogenesis. In theory, caretaker genes do not influence cell growth and proliferation directly but rather prevent the accumulation of DNA damage and cumulative mutations within key exonic sequences that make up the human genome. Loss of function of the DNA damage repair genes (MLH1, hMSH2) occurs in a small subset of pancreatic cancers in the familial setting but has been reported to occur in approximately 17% of sporadic, nonfamilial cases.91–93 Histologically, these microsatellite instability (MSI) cancers comprise poorly differentiated cancers with a syncytial growth pattern, expanding tumor margins, extensive necrosis, and intratumoral lymphocytic infiltrates. This uncommon variant has been termed medullary cancer to distinguish it from the more common PDAC.94 Although findings in colon cancer have attempted to correlate MSI status with response to 5-fluorouracil, other studies have questioned these claims.95

Telomere Length Abnormalities Telomeres are hexameric repeats of the sequence TTAGGG at the ends of chromosome arms that confer stability to chromosomes during cell division and prevent the ends from becoming “promiscuous.”96 In other words, intact telomere structure guards against chromosomal fusion and thus may prevent CIN.97,98 In fact, telomeric dysfunction has been hypothesized to be one of the more important gateways of CIN, a signature of most solid cancers characterized by aneuploidy and extensive chromosomal rearrangements. The development of direct visualization of in situ telomere length was a breakthrough for understanding telomere length abnormalities and cancer development.99 A study by van Heek and colleagues11 showed that telomere length abnormalities are one of the earliest demonstrable genetic aberrations in pancreatic cancer, with greater than 90% of the lowest grade PanIN lesions showing marked shortening of telomeres, compared with normal duct epithelium.11 It has been hypothesized that intact telomeres may serve as “caretakers” in the pancreatic ducts and that the loss of telomeres in PanIN lesions sets the stage for progressive accumulation of chromosomal abnormalities, eventually culminating in neoplasia.

Alternative Genetic Silencing: Epigenetic Abnormalities Although the classic two-hit hypothesis postulated that tumor suppressor gene silencing occurs by a combination of intragenic mutations and allelic loss, it has become apparent since the

  Chapter 9D  Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions

1990s that epigenetic mechanisms of silencing are probably as important in terms of frequency and prevalence in many cancers.100 Epigenetic silencing occurs predominantly through hypermethylation of so-called CpG islands in the promoter region of tumor suppressor genes, leading to transcriptional abrogation. In cancers, preferential hypermethylation of the promoter occurs in the neoplastic cells with consequent downregulation of gene expression, but this does not occur in the corresponding normal counterpart. Epigenetic silencing is seen frequently in pancreatic cancers and tends to involve genes that function in tumor suppression or in critical homeostatic pathways (e.g., CDKN2A, Ecadherin, retinoic acid b, osteonectin, SOCS1) or in both.101,102 Aberrant methylation of genes is also found in precursor lesions of pancreatic cancers and tends to occur in intermediateor late-stage lesions (PanIN-2 and PanIN-3).103 Although there has been extensive work on the role of promoter hypermethylation in the pathogenesis of cancers, more recent data suggest that promoter hypomethylation in candidate genes also may be important in cancer development and progression. Genes showing preferential hypomethylation in pancreatic cancers (SERPINB5, S100P, MSLN, PSCA, and CLDN4) are usually overexpressed in the cancers compared with healthy pancreas, suggesting that epigenetic mechanisms can affect gene expression in either direction.104 Aberrant epigenetic silencing by promoter methylation also has been reported in IPMNs, including methylation of the SOCS1 and CDKN2A genes.105 Global analyses of gene expression in IPMNs have revealed the overexpression of LCN2, LGALS3, CTSE, CLDN4, and three members of the trefoil factor family, TFF1, TFF2, and TFF3.106,107 These global analyses also have shown that CLDN4, CXCR4, S100A4, and MSLN all are expressed at significantly higher levels in invasive IPMNs than in noninvasive IPMNs, suggesting that these proteins may contribute to the process of invasion.108

Core Signaling Pathways Disrupted in Pancreatic Cancer The modern era of molecular biology has progressed to allow high-throughput surveying of the pancreatic cancer genome (see Figs. 9D.1 and 9D.2, right), bringing some clarity to our understanding of the interactions of molecular pathways in tumorigenesis. This high-throughput analysis revealed that pancreatic cancers contain an average of 63 genes that are genetically altered.4 In this work, Jones and colleagues used a combination of modern molecular techniques to report that 67% to 100% of all pancreatic cancer genomes surveyed had a genetic abnormality in 12 core signaling pathways and processes. These pathways, confirmed by later studies as well, include apoptosis, DNA damage control, regulation of G1-to-S phase transition, Hedgehog signaling, hemophilic cell adhesion, integrin signaling, c-JUN N-terminal kinase signaling, KRAS signaling, regulation of invasion, small GTPase-dependent signaling (other than KRAS), TGFB signaling, and WNT/NOTCH signaling.4,89 Recently, genetic aberrations in the axon guidance pathway genes have been identified in genes in the SLIT/ROBO pathway (mutations and deletions in SLIT, ROBO1, and ROBO2), ephrins (EPHA5 and EPHA7), and class 3 semaphorins (amplifications and mutations in SEMA3A and SEMA3E).89 These genes have been implicated in cell growth, metastasis, and invasion,109 overlapping with some of the pathways listed in the previous paragraph. Unlike certain subtypes of leukemia that are driven by single “targetable” oncogenes, we have learned that pancreatic cancers

157

result from genetic alterations of large numbers of genes that function through a distinct number of pathways. The study by Jones and colleagues4 suggested that it may be beneficial to target the physiologic effects of disrupted pathways rather than individual target genes. In fact, targeting multiple pathways or multiple points in the pathway may be in line with the early preclinical and clinical success stories of the concept of “synthetic lethality.”110

FAMILIAL PANCREATIC CANCER Approximately 10% of pancreatic cancers show familial aggregation111 (see Chapter 61). The presence of two first-degree family members with pancreatic cancer confers a 6- to 18-fold increased risk of the disease in other first-degree relatives. This risk is increased 32- to 57-fold in families with three or more first-degree relatives with pancreatic cancer.112,113 Only a minority of these familial cancers is caused by a recognized cancer syndrome associated with germline mutations in known genes. Included in Table 9D.1 are possible “targeted therapies” for the genes and disorders germane to pancreatic cancer. Thus this table underscores the significance for understanding the inherited lesion that may have contributed to the pancreatic cancers found in these families. For example, as mentioned earlier in this chapter, Fanconi anemia is characterized as a rare, autosomally recessive cancer syndrome that results initially from a mutation in one of the multiple FANC/BRCA complementation groups in the FANC/ BRCA pathway.114 One gene in this pathway, BRCA2, is associated with a greatly increased risk of cancer when deleted via a biallelic mutation. The BRCA genes play a critical role in DNA repair via RAD51 repair pathways.115 Loss of functional BRCA1 and BRCA2 conveys CIN to cells by impairing the critical function of DNA double-stranded break repair.110 It has been well established that DNA damaging agents such as mitomycin C or cisplatin effectively kill cells with loss of BRCA2 or related genes (see Fig. 9D.5).116 Currently, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have similar promising results as intrastrand cross-linking agents in early-phase trials in other cancer types (ovarian, breast).117 Certainly, pancreatic cancer is a logical tumor system in which to test novel PARP inhibitors in combination with other DNA-damaging agents. Targeting the FANCBRCA pathway with PARP inhibitors similarly has been shown to lead to synthetic lethality, creating a convenient and fortuitous therapeutic window.110 The makeup of this therapeutic window relies on the fact that healthy cells will have an intact DNA repair mechanism and thus will be capable of managing and repairing the damage put forth by a DNA-damaging agent. In contrast, the tumor will be unable to repair such damage due to loss of a key aspect of this repair mechanism (i.e., BRCA2; see Fig. 9D.5). Identification of mutations in the FANC-BRCA pathway in familial cancers has the potential to shed light on the treatment of sporadic cancers as well. It has been suggested that perhaps as many as 25% of sporadic breast and ovarian cancers manifest a BRCA-like phenotype.118 The data have been derived from BRCA1, FANCC, FANCG, and FANCF methylation studies.118 Further studies are warranted, but future banking of sporadic pancreatic cancers to study all of the tumor characteristics, such as posttranscriptional modification, polymorphisms, and CGH analysis, along with thorough analysis of family history may reveal a “BRCAness” among certain sporadic pancreatic tumors,

158

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

aiding in the personalization of therapy.119 Focused DNA-repair microarray analysis may also shed light on other cancer susceptibility genes. Of note, a recent report demonstrated that PALB2, formerly known as FANCN, is a gene inherited in a mutant form that produces a stop codon in a small percentage of familial PDAs. This gene was discovered to be mutated in 3 of 96 familial pancreatic cancers, each producing a different stop codon.5 Truncating mutations in PALB2 were not found in any of the 1084 patients of similar ethnicity used as a control cohort in a similar study, thus ruling out a polymorphic sequence variant. This information suggests that next to BRCA2, PALB2 is the second most commonly mutated gene in hereditary pancreatic cancer.5 Thus most familial pancreatic cancers have no known genetic bases at this time, although many believe an autosomal dominant inheritance of a rare mutant allele is the most likely cause of these cancers. Of apparently “sporadic” (nonfamilial) pancreatic cancer patients, 7% harbor germline mutations in the BRCA2 gene, and this low-penetrance pattern is peculiar to cancers arising in the Ashkenazi Jewish population.120 Perhaps no single gene is responsible for the other familial forms of PDA, the carcinogenesis of which may be the best example that core pathways collaborate with the environment121; thus no single gene from one pathway will prove to be disrupted in the complex process of tumorigenesis in this familial form of pancreatic cancer. Several other known genetic syndromes associated with PDA exist, including familial atypical mole and multiple melanoma syndrome (FAMM) and Peutz-Jeghers syndrome (PJS). FAMM results from the microdeletion of CDKN2 on chromosome 9p21.3, particularly p16INK4a122,123 (see Chapter 61). As a result, CDK4/6 function is uninhibited. FAMM kindred have also been reported to harbor CDK4 mutations that prevent CDKN2 binding, as opposed to CDKN2 microdeletions, in some cases.124 Patients with FAMM have an approximately 80% lifetime risk of melanoma and a 20% lifetime risk of PDA.125 PJS is an autosomal dominant syndrome caused by mutations of the tumor suppressor STK11 (LKB1). This syndrome is best known for polyps throughout the small and large intestine with an arborizing pattern of musculature, and these patients develop various types of carcinoma, including PDA. PDA develops in approximately one-fourth of patients with PJS by age 75 years.126 Another condition that may progress to PDA is hereditary pancreatitis (see Chapters 54, 55, and 57). These patients carry germline mutations in the PRSS1 gene, which encodes cationic trypsinogen. Multiple mutations have been described; the original was R117H, which resulted in the elimination of a hydrolysis site in trypsin and an inability to inactivate trypsin.127 Patients with hereditary pancreatitis are at a 35-fold relative risk for PDA by age 75 years. Diet modification, including lowering triglyceride intake, as well as abstaining from smoking or drinking, are advised to decrease the risk of progression to chronic pancreatitis.

TRANSCRIPTOMIC (RNA) ABNORMALITIES IN PANCREATIC CANCER (SEE CHAPTER 9A) Several studies have analyzed pancreatic cancers and compared their gene expression profile with healthy pancreas tissue to identify differentially overexpressed and underexpressed genes.128–135 A comprehensive analysis of pancreatic cancer using high-density

oligonucleotide microarrays identified 217 genes as overexpressed 3-fold or greater in cancers versus healthy tissue.132 Six genes (keratin 19, retinoic acid–induced 3, secretory leukocyte protease inhibitor, stratifin, tetraspan 1, and transglutaminase 2) were found to be overexpressed in pancreatic cancer by three platforms: oligonucleotide, cDNA microarrays, and serial analysis of gene expression (SAGE). The future role of one or all of these six genes in early detection or therapy remains to be elucidated. The identification of differentially expressed genes not only serves the further understanding of the basic biology of pancreatic cancers, it also provides a fertile ground to identify markers for early diagnosis, imaging, and novel therapeutic strategies. Mesothelin (MSLN) was identified by SAGE as a gene overexpressed in pancreatic cancers, and it was confirmed by immunohistochemistry to be restricted to the neoplastic epithelium.136 This identification led to the development of a pancreatic cancer vaccine targeted to the mesothelin antigen and the development of antimesothelin antibodyconjugated immunotoxins.137 Phase 1 clinical trials showed that investigated antimesothelin drugs are well tolerated, and patients with advanced cancers often achieve stable disease on antimesothelin therapy.138,139 In 2013, the US Food and Drug Administration (FDA) granted the antimesothelin drug CRS207 approval for use in combination therapy with GVAX, a drug that stimulates the granulocyte-macrophage colonystimulating factor.140

Posttranscriptional Regulation (see Chapter 9A) In recent years, strong evidence has shown that posttranscriptional regulation of genes can directly affect both the tumorigenesis process141,142 and cancer cell susceptibility to chemotherapy.95,143,144 Posttranscriptional gene regulation can have the same effect on gene expression as a genetic mutation or methylation of a promoter. One potent mechanism of posttranscriptional regulation involves RNA-binding proteins. One such RNA-binding protein that has been shown to be important in a number of tumor systems is Hu antigen R (HuR), a ubiquitously expressed member of the HU family that mediates cellular response to stress and DNA damage by posttranscriptional regulation.145 Elevated HuR cytoplasmic expression is detected in tumors with poor pathologic features and poor predicted outcomes.142 It is has been shown that during times of certain cellular stressors, brought on by agents such as ultraviolet C (UVC) irradiation, heat shock, hypoxia, tamoxifen,146 and actinomycin D, HuR can bind to certain apoptotic or survival mRNA transcripts by binding to AU-rich elements in the 39 untranslated region (UTR) of these mRNAs. In regard to tumorigenesis, HuR has been shown to bind to and stabilize proteins such as p21, p53, and cyclin A.144 For instance, Gorospe and colleagues144 showed that HuR can enhance translation of proteins such as p53 under stress from UVC irradiation. Thus the role of HuR in cellular stress and damage gives it a likely pivotal role in both the tumorigenesis process and in the acute cellular response to chemotherapy in pancreatic cancer cells. In vitro and in vivo studies have shown that PDAs with HuR overexpression were dramatically sensitive to gemcitabine, the standard chemotherapeutic treatment for pancreatic cancer, when compared with a control group.143,147 Patients who had low cytoplasmic HuR levels had a 7-fold increase in mortality compared with patients who had elevated cytoplasmic HuR levels (Fig. 9D.6).143

  Chapter 9D  Advances in the Molecular Characterization of Pancreatic Cancer and Pre-malignant Lesions 1.0

Cytoplasmic HuR High Low

+

Proportion alive

0.8 +

++ +

++ +

+

0.6

0.4

+

0.2

0.0 200

400

600

800

1000 1200

17 ACCs revealed hot spot–activating mutations, including GNAS p.R201C in two tumors and BRAF p.V600E in one tumor, as well as mutations in tumor suppressors, including SMAD4, TP53, retinoblastoma 1 (RB1), phosphatase and tensin homolog (PTEN), and ARID1A.152 In addition to point mutations and indels, SND1-BRAF fusions were identified in 6 of 44 (14%) either pure or mixed differentiation ACCs. Transfectants expressing this fusion have shown increased MAPK pathway activity as well as sensitivity to the MAP/extracellular signal-regulated protein kinase (ERK) kinase (MEK) inhibitor trametinib.151 Epigenetic changes have also been identified, including MSI in 10% to 20% of ACCs.152,153

Pancreatic Neuroendocrine Tumors (see Chapters 59 and 65)

++

0

159

1400

Days postsurgery FIGURE 9D.6  Tumor human antigen R (HuR) cytoplasmic status can stratify pancreatic cancer patients treated with standard-of-care chemotherapy (gemcitabine) into two groups: responders (high cytoplasmic HuR) versus nonresponders (low cytoplasmic HuR). (From Costantino CL, et al. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009;69[11]:4567–4572.)

MicroRNAs MicroRNAs (miRNAs) are defined as short, noncoding regions of RNA sequences (22 nucleotides) that can potently regulate gene expression patterns; miRNAs have been shown to regulate a number of disease- and developmental-related genes, and they are tissue specific in expression.148 These miRNA-specific attributes make them putative, powerful, and unique candidate biomarkers.149 Discovering the presence of miRNAs in pancreatic cancer may be extremely valuable, although understanding the significance of these miRNAs may be more difficult and tedious, as miRNAs have been shown to distinguish between various disease states and tissues, including pancreatitis, PDA, IPMN, and healthy specimens.149 Further, it has been shown that a miRNA molecular signature can stratify long- and shortterm survivors.150

Pancreatic neuroendocrine tumors (PanNETs) also have different molecular profiles than either PDAs or ACCs. PanNETs lack KRAS, SMAD4, and CDKN2A mutations, and only very rarely (approximately 3%) harbor TP53 mutations. Instead, the sporadic forms of this tumor frequently harbor death domain– associated protein/gene (DAXX)/alpha-thalassemia X-linked mental retardation protein/gene (ATRX) mutations (43%) or multiple endocrine neoplasia type 1 (MEN1) mutations (44%).154 In addition to sporadic forms, PanNETs are also seen as a component of various inherited tumor syndromes associated with germline mutations, including MEN1, due to mutations that cause loss of function of the MEN1 and VHL genes in MEN and von Hippel Lindau syndromes, respectively.155,156 PanNETs occurring in association with these syndromes are thought to follow a less aggressive course more often.

FINAL THOUGHTS AND PERSPECTIVES

MOLECULAR GENETICS OF OTHER PANCREATIC NEOPLASMS

We are currently at an interesting and critical time in studying the molecular aspects of pancreatic cancer. The research community has incredible resources at its disposal, ranging from patient databases to complex sequencing equipment. This coming of age of pancreatic cancer research must include surgeons, pathologists, molecular biologists, and medical oncologists collaborating toward ultimately better and more personalized patient care. Current research will also need to provide better early detection markers so that physicians can have more opportunities to prevent cancer from forming, instead of attempting to cure it before it is too late.

Acinar Cell Carcinoma (see Chapter 59)

References are available at expertconsult.com.

Unlike PDA, acinar cell carcinomas (ACCs) activating mutations in KRAS are uncommon.151 Whole-exome sequencing of

159.e1

REFERENCES 1. Siegel R, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. 2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209249. 3. Hruban RH, Iacobuzio-Donahue C, Wilentz RE, Goggins M, Kern SE. Molecular pathology of pancreatic cancer. Cancer J. 2001;7(4):251-258. 4. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;33:1801-1806. 5. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217. 6. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3(92):92ra66. 7. Allen VB, Gurusamy KS, Takwoingi Y, Kalia A, Davidson BR. Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer. Cochrane Database Syst Rev. 2013;(11):CD009323. 8. Biankin AV, Kench JG, Dijkman FP, Biankin SA, Henshall SM. Molecular pathogenesis of precursor lesions of pancreatic ductal adenocarcinoma. Pathology. 2003;35(1):14-24. 9. Luttges J, Zamboni G, Longnecker D, Klöppel G. The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol. 2001;25(7):942948. 10. Maitra A, Ashfaq R, Gunn CR, et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol. 2002;118(2):194-201. 11. van Heek NT, Meeker AK, Kern SE, et al. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol. 2002;161(5):1541-1547. 12. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60(7):2002-2006. 13. Shi C, Hong SM, Lim P, et al. KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol Cancer Res. 2009;7(2):230-236. 14. Murphy SJ, Hart SN, Lima JF, et al. Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. Gastroenterology. 2013;145(5):1098-1109. 15. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114-1117. 16. Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004;28(8):977-987. 17. Correa-Gallego C, Do R, Lafemina J, et al. Predicting dysplasia and invasive carcinoma in intraductal papillary mucinous neoplasms of the pancreas: development of a preoperative nomogram. Ann Surg Oncol. 2013;20(13):4348-4355. 18. Adsay NV, Merati K, Andea A, et al. The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol. 2002;15(10):1087-1095. 19. Maire F, Hammel P, Terris B, et al. Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma. Gut. 2002;51(5):717-722. 20. Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol. 2001;25(1):26-42.

21. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg. 2004;239(6):788-797. 22. Sessa F, Solcia E, Capella C, et al. Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and cerbB-2 abnormalities in 26 patients. Virchows Arch. 1994;425(4):357367. 23. Amato E, Molin MD, Mafficini A, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014; 233(3):217-227. 24. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, et al. Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol. 2000;157(3):755-761. 25. Singhi AD, Nikiforova MN, Fasanella KE, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin Cancer Res. 2014;20(16):4381-4389. 26. Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an “intestinal” pathway of carcinogenesis in the pancreas. Am J Surg Pathol. 2004;28(7):839-848. 27. Muraki T, Uehara T, Sano K, et al. A case of MUC5AC-positive intraductal neoplasm of the pancreas classified as an intraductal tubulopapillary neoplasm? Pathol Res Prac. 2015;211:1034-1039. 28. Hoshi H, Sawada T, Uchida M, et al. MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways. Int J Oncol. 2013;42:887-893. 29. Takikita M, Altekruse S, Lynch CF, et al. Associations between selected biomarkers and prognosis in a population-based pancreatic cancer tissue microarray. Cancer Res. 2009;69(7):2950-2955. 30. Yamaguchi H, Shimizu M, Ban S, et al. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2009;33:1164-1172. 31. Basturk O, Berger MF, Yamaguchi H, et al. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. Mod Pathol. 2017;30(12):1760-1772. 32. Suda K, Hirai S, Matsumoto Y, et al. Variant of intraductal carcinoma (with scant mucin production) is of main pancreatic duct origin: a clinicopathology study of four patients. Am J Gastroenterol. 1996;91:798-800. 33. Yamaguchi H, Kuboki Y, Hatori T, et al. The discrete nature and distinguishing molecular features of pancreatic intraductal tubulopapillary neoplasms and intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant. J Pathol. 2013;231:335341. 34. Yamaguchi H, Kuboki Y, Hatori T, et al. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas. Am J Surg Pathol. 2011;35:1812-1817. 35. D’Onforio M, De Robertis R, Tinazzi Martini P, et al. Oncocytic intraductal papillary mucinous neoplasms of the pancreas: imaging and histopathological findings. Pancreas. 2016;45(9):1233-1242. 36. Xiao HD, Yamaguchi H, Dias-Santagata D, et al. Molecular characteristic and biological behaviours of the oncocytic and pancreatobiliary subtypes of intraductal papillary mucinous neoplasm. J Pathol. 2011;224:508-516. 37. Basturk O, Chung SM, Hruban RH, et al. Distinct pathways of pathogenesis of intraductal oncocytic papillary neoplasms and intraductal papillary mucinous neoplasms of the pancreas. Virchows Arc. 2016;469(5):523-532. 38. Mohri D, Asaoka Y, Ijichi H, et al. Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. J Gastroenterol. 2012;47(2): 203-213. 39. Vyas M, Hechtman JF, Zhang Y, et al. DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma. Mod Pathol. 2020;33(4):648-656. 40. Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343:1010-1014.

159.e2 41. Wang T, Askan G, Adsay V, et al. Intraductal oncocytic papillary neoplasms: clinical-pathologic characterizations of 24 cases, with an emphasis on associated invasive carcinomas. Am J Surg Pathol. 2019;43(5):656-661. 42. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):18061813. 43. Griffin CA, Hruban RH, Morsberger LA, et al. Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res. 1995;55(11):2394-2399. 44. Sirivatanauksorn V, Sirivatanauksorn Y, Gorman PA, et al. Nonrandom chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping. Int J Cancer. 2001;91(3): 350-358. 45. Rigaud G, Moore PS, Zamboni G, et al. Allelotype of pancreatic acinar cell carcinoma. Int J Cancer. 2000;88(5):772-777. 46. Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, et al. Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res. 2004;64(3):871-875. 47. Luttges J, Galehdari H, Bröcker V, et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol. 2001;158(5):1677-1683. 48. Yamano M, Fujii H, Takagaki T, et al. Genetic progression and divergence in pancreatic carcinoma. Am J Pathol. 2000;156(6):21232133. 49. Mahlamaki EH, Höglund M, Gorunova L, et al. Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic cancer. Genes Chromosomes Cancer. 1997;20(4):383-391. 50. Aguirre AJ, Brennan C, Bailey G, et al. High-resolution characterization of the pancreatic adenocarcinoma genome. Proc Natl Acad Sci USA. 2004;101(24):9067-9072. 51. Calhoun ES, Hucl T, Gallmeier E, et al. Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays. Cancer Res. 2006;66(16):7920-7928. 52. Holzmann K, Kohlhammer H, Schwaenen C, et al. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res. 2004;64(13):4428-4433. 53. D’Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003;3(1):23-34. 54. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62(13):3789-3793. 55. van der Heijden MS, Yeo CJ, Hruban RH, et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63(10):2585-2588. 56. van der Heijden MS, Brody JR, Gallmeier E, et al. Functional defects in the fanconi anemia pathway in pancreatic cancer cells. Am J Pathol. 2004;165(2):651-657. 57. van der Heijden MS, Brody JR, Dezentje DA, et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res. 2005;11(20):7508-7515. 58. Caldas C, Hahn SA, Hruban RH, et al. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 1994;54(13):3568-3573. 59. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6(8):2969-2972. 60. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 1997;57(11):2140-2143. 61. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4(6):437-450. 62. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7(5):469-483. 63. Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007;7(9):645-658.

64. Karreth FA, Tuveson DA. Modelling oncogenic Ras/Raf signalling in the mouse. Curr Opin Genet Dev. 2009;19(1):4-11. 65. Olive KP, Tuveson DA. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res. 2006;12(18):5277-5287. 66. Tuveson DA, Hingorani SR. Ductal pancreatic cancer in humans and mice. Cold Spring Harb Symp Quant Biol. 2005;70:65-72. 67. Calhoun ES, Jones JB, Ashfaq R, et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol. 2003;163(4):1255-1260. 68. Matsuo Y, Campbell PM, Brekken RA, et al. K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through mitogen-activated protein kinase signaling pathways. Mol Cancer Res. 2009;7(6):799-808. 69. Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma. Cancer. 2001;92(3):488-499. 70. Han H, Bearss DJ, Browne LW, et al. Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res. 2002;62(10):2890-2896. 71. Stellas D, Szabolcs M, Koul S, et al. Therapeutic effects of an antimyc drug on mouse pancreatic cancer. J Natl Cancer Inst. 2014;106(12):dju320. doi:10.1093/jnci/dju320. 72. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731-747. 73. O’Reilly EM, Hechtman JF. Tumor response to TRK inhibition in a patient with pancreatic adenocarcinoma harboring NTRK gene fusion. Ann Oncol. 2019;30(suppl 8):viii36-viii40. 74. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27-32. 75. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126-3130. 76. Wilentz RE, Geradts J, Maynard R, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res. 1998;58(20):4740-4744. 77. Chen ZH, Zhang H, Savarese TM. Gene deletion chemoselectivity: codeletion of the genes for p16(INK4), methylthioadenosine phosphorylase, and the alpha- and betainterferons in human pancreatic cell carcinoma lines and its implications for chemotherapy. Cancer Res. 1996;56(5):1083-1090. 78. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol. 2003;16(9):902-912. 79. Morton JP, Timpson P, Karim SA, et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA. 2010;107(1):246-251. 80. Gallmeier E, Hucl T, Calhoun ES, et al. Gene-specific selection against experimental Fanconi anemia gene inactivation in human cancer. Cancer Biol Ther. 2007;6(5):654-660. 81. Hucl T, Rago C, Gallmeier E, et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res. 2008;68(13):5023-5030. 82. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404. 83. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15(14):4674-4679. 84. Cao D, Ashfaq R, Goggins MG, et al. Differential expression of multiple genes in association with MADH4/DPC4/SMAD4 inactivation in pancreatic cancer. Int J Clin Exp Pathol. 2008;1(6):510517. 85. Sahin F, Maitra A, Argani P, et al. Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod Pathol. 2003;16(7):686691. 86. Jaeger D, De Schutter E, Bower JM. The role of synaptic and voltage-gated currents in the control of Purkinje cell spiking: a modeling study. J Neurosci. 1997;17(1):91-106. 87. Su GH, Hilgers W, Shekher MC, et al. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 1998;58(11):2339-2342.

159.e3 88. Cunningham SC, Gallmeier E, Hucl T, et al. Targeted deletion of MKK4 in cancer cells: a detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss. Cancer Res. 2006;66(11): 5560-5564. 89. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399-405. 90. Samartzis EP, Gutsche K, Dedes KJ, et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget. 2014;5(14):5295-5303. 91. Borelli I, Casalis Cavalchini GC, Del Peschio S, et al. A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns. Fam Cancer. 2014;13(3):401-413. 92. Ghimenti C, Tannergård P, Wahlberg S, et al. Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer. 1999;80(1-2):11-16. 93. Nakata B, Wang YQ, Yashiro M, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002;8(8):2536-2540. 94. Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol. 2000;156(5):1641-1651. 95. Brody JR, Hucl T, Costantino CL, et al. Limits to thymidylate synthase and TP53 genes as predictive determinants for fluoropyrimidine sensitivity and further evidence for RNA-based toxicity as a major influence. Cancer Res. 2009;69(3):984-991. 96. Gisselsson D. Chromosome instability in cancer: how, when, and why? Adv Cancer Res. 2003;87:1-29. 97. Greenberg RA, Rudolph KL. Telomere structural dynamics in genome integrity control and carcinogenesis. Adv Exp Med Biol. 2005;570:311-341. 98. Raynaud CM, Sabatier L, Philipot O, et al. Telomere length, telomeric proteins and genomic instability during the multistep carcinogenic process. Crit Rev Oncol Hematol. 2008;66(2):99-117. 99. Meeker AK, Hicks JL, Iacobuzio-Donahue CA, et al. Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin Cancer Res. 2004;10(10):3317-3326. 100. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 2000;16(4):168-174. 101. Sato N, Fukushima N, Maitra A, et al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using highthroughput microarrays. Cancer Res. 2003;63(13):3735-3742. 102. Ueki T, Toyota M, Sohn T, et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 2000;60(7):18351839. 103. Fukushima N, Sato N, Ueki T, et al. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol. 2002;160(5):1573-1581. 104. Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 2003;63(14):4158-4166. 105. Sato N, Ueki T, Fukushima N, et al. Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2002;123(1):365-372. 106. Sato N, Fukushima N, Maitra A, et al. Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol. 2004;164(3):903-914. 107. Terris B, Blaveri E, Crnogorac-Jurcevic T, et al. Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol. 2002;160(5):1745-1754. 108. Sato N, et al: Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol. 2004;164(4):903-914. 109. Mehlen P, Delloye-Bourgeois C, Chédotal A. Novel roles for slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer. 2011;11(3):188-197. 110. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22): 3785-3790.

111. Petersen GM, Hruban RH. Familial pancreatic cancer: where are we in 2003? J Natl Cancer Inst. 2003;95(3):180-181. 112. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64(7):2634-2638. 113. Tersmette AC, Petersen GM, Offerhaus GJ, et al. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res. 2001;7(3):738-744. 114. Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene. 2006;25(43):5875-5884. 115. Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25(43):5864-5874. 116. Hussain S, Wilson JB, Medhurst AL, et al. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet. 2004;13(12):1241-1248. 117. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. 118. Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4(10):814-819. 119. Martin SA, Hewish M, Lord CJ, et al. Genomic instability and the selection of treatments for cancer. J Pathol. 2010;220(2):281289. 120. Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56(23):5360-5364. 121. Yeo TP, Hruban RH, Brody J, et al. Assessment of “gene-environment” interaction in cases of familial and sporadic pancreatic cancer. J Gastrointest Surg. 2009;13(8):1487-1494. 122. Gruis NA, van der Velden PA, Sandkuijl LA, et al. Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet. 1995;10(3):351-353. 123. Ranade K, Hussussian CJ, Sikorski RS, et al. Mutations associated with familial melanoma impair p16INK4 function. Nat Genet. 1995;10(1):114-116. 124. Zuo L, Weger J, Yang Q, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996;12(1):97-99. 125. Rustgi AK. Familial pancreatic cancer: genetic advances. Genes Dev. 2014;28(1):1-7. 126. Korsse SE, Harinck F, van Lier MG, et al. Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance. J Med Genet. 2013;50(1):59-64. 127. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14(2):141-145. 128. Argani P, Rosty C, Reiter RE, et al. Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 2001;61(11):4320-4324. 129. Crnogorac-Jurcevic T, Efthimiou E, Capelli P, et al. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene. 2001;20(50):7437-7446. 130. Geng M, Wallrapp C, Müller-Pillasch F, et al. Isolation of differentially expressed genes by combining representational difference analysis (RDA) and cDNA library arrays. Biotechniques. 1998;25(3):434-438. 131. Iacobuzio-Donahue CA, Ryu B, Hruban RH, et al. Exploring the host desmoplastic response to pancreatic carcinoma: gene expression of stromal and neoplastic cells at the site of primary invasion. Am J Pathol. 2002;160(1):91-99. 132. Iacobuzio-Donahue CA, Ashfaq R, Maitra A, et al. Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res. 2003;63(24):8614-8622. 133. Iacobuzio-Donahue CA, Maitra A, Olsen M, et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 2003;162(4):1151-1162. 134. Ryu B, Jones J, Hollingsworth MA, et al. Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res. 2001;61(5):18331838.

159.e4 135. Ryu B, Jones J, Blades NJ, et al. Relationships and differentially expressed genes among pancreatic cancers examined by largescale serial analysis of gene expression. Cancer Res. 2002;62(3):819826. 136. Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001;7(12):3862-3868. 137. Thomas AM, Santarsiero LM, Lutz ER, et al. Mesothelin-specific CD8(1) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004;200(3):297-306. 138. Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007;13(17):51445149. 139. Hassan R, Cohen SJ, Phillips M, et al. Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res. 2010;16(24):6132-6138. 140. Le DT, Brockstedt DG, Nir-Paz R, et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res. 2012;18(3):858868. 141. Lopez de Silanes I, Fan J, Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene. 2003;22(46):71467154. 142. Lopez de Silanes I, Lal A, Gorospe M. HuR: post-transcriptional paths to malignancy. RNA Biol. 2005;2(1):11-13. 143. Constantino CL, Witkiewicz AK, Kuwano Y, et al. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009;69(11):4567-4572. 144. Gorospe M. HuR in the mammalian genotoxic response: posttranscriptional multitasking. Cell Cycle. 2003;2(5):412-414.

145. Hinman MN, Lou H. Diverse molecular functions of Hu proteins. Cell Mol Life Sci. 2008;65(20):3168-3181. 146. Hostetter C, Licata LA, Witkiewicz A, et al. Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor-positive breast cancer cells. Cancer Biol Ther. 2008;7(9):1496-1506. 147. Richards NG, Rittenhouse DW, Freydin B, et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg. 2010;252(3):499-505. 148. Rosenfeld N, Aharonov R, Meiri E, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 2008;26(4):462-469. 149. Mardin WA, Mees ST. MicroRNAs: novel diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma? Ann Surg Oncol. 2009;16(11):3183-3189. 150. Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007; 297(17):1901-1908. 151. Chmielecki J, Hutchinson KE, Frampton GM, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-1405. 152. Jiao Y, Yonescu R, Offerhaus GJ, et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428-435. 153. Liu W, Shia J, Gönen M, et al. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014;43(8):1264-1270. 154. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199-1203. 155. Charlesworth M, Verbeke CS, Falk GA, et al. Pancreatic lesions in von Hippel-Lindau disease? A systematic review and metasynthesis of the literature. J Gastrointest Surg. 2012;16(7):14221428. 156. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1-2):2-15.

CHAPTER 9E Advances in the molecular characterization of biliary tract and gallbladder cancer Ryosuke Okamura and Jason K. Sicklick BILIARY TRACT CANCERS First described by Durand-Fardel in 1840,1 biliary tract tumors arise from cholangiocytes residing in the biliary tree. The biliary tract cancers include intrahepatic cholangiocarcinoma (IHCC, within the liver; see Chapter 50), extrahepatic cholangiocarcinoma (EHCC, within the extrahepatic biliary tree; see Chapter 51), and gallbladder cancer (GBCA, within the gallbladder; see Chapter 49). Recently, it has been recognized that some subtypes of IHCC can arise from hepatic progenitor cells or have stem cell features2 (see Chapter 9C). Thus combined or mixed hepatocellular cholangiocarcinoma (C-HCC), which has cells with a phenotype that is intermediate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is occasionally seen and considered to be a subtype of IHCC (see Chapters 47, 50, and 89). These biliary tract cancers constitute a rare set of malignancies and mostly present as locally advanced or metastatic disease. Because of their rarity, as well as their common cell of origin, systemic treatment for all these tumor types has been identical, but chemotherapeutic regimens lack significant response rates. In patients with advanced disease, goals of systemic chemotherapy are still palliative in nature (see Chapters 47 and 49–51). With fairly recent developments in next-generation sequencing (NGS) and other molecular techniques; however, comprehensive molecular profiling now enables the identification of unique genetic signatures among these cancers and is important in clinical trial design using drugs to target specific pathways.

CLASSIFICATION The vast majority of biliary tract tumors are adenocarcinomas,3 and they most often arise at or near the biliary confluence. The latter fall under the general category of EHCCs (see Chapter 51), which are further subcategorized into hilar CCA (also known as Klatskin tumor) and distal CCA, with the transition occurring proximal to the cystic duct in the current American Joint Committee on Cancer TNM Classification and National Comprehensive Cancer Network (NCCN) guidelines.4,5 These are further categorized as perihilar CCA by their precise location with reference to the biliary bifurcation and the hepatic lobar ducts. This classification is most useful for descriptive purposes and for operative planning. In contrast to the perihilar tumors, the distal CCAs account for a relatively small fraction of all bile duct tumors. Mid-bile duct tumors are even less common and often turn out to represent tumors of the gallbladder or cystic duct. Diffuse involvement of the entire biliary tree is a very rare condition, affecting a very small fraction of patients with biliary tract cancer. CCA may also arise from the intrahepatic bile ducts, giving rise to the subgroup known as IHCC (or peripheral CCA; see Chapter 50). IHCCs can also be subcategorized 160

by their growth characteristics into three groups: mass-forming, periductal-infiltrating, or intraductal growing types.6 Until recently, International Classification of Disease (ICD) codes combined IHCC with HCC under the code for primary liver tumor,7,8 but these are clearly different entities, and the second and third editions of the ICD for Oncology (ICD-O-2/3) have attempted to correct for this issue. In ICD-O-2, hilar tumors were assigned a unique histology code, but this was cross-referenced to the topography code for intrahepatic rather than extrahepatic tumors. Under the third ICD-O-3 edition, hilar tumors are cross-referenced to either location.9 In addition to the aforementioned coding issues, many tumors previously referred to as liver adenocarcinoma of unknown primary site were likely unrecognized IHCCs. Together, these changes in ICD classification have influenced observed changes in the incidence rates of IHCC and EHCC.

EPIDEMIOLOGY Although rare, biliary tract cancer has a distinctly higher incidence in certain demographic groups and geographic regions (see Chapters 49, 50, and 51). GBCA has a higher incidence among females and in South America, whereas IHCC is more common in Asia.10 The peak incidence of the biliary tract cancers is the seventh decade of life, with a slightly higher male predilection.1 In the United States, an estimated 6,300 new IHCC cases were diagnosed, whereas 12,360 new EHCC or GBCA cases were diagnosed in 2019.11–13 Outside of the United States, the incidence rates vary globally, presumably reflecting differences in infectious causes, environmental risk factors (i.e., sedentary lifestyles, alcohol, smoking, and diet), exposure to toxic chemicals, and genomics. The highest incidence rate is in Northeast Thailand (age-standardized incidence rate [ASIR]: 85/100,000 population), where it occurs approximately 100 times more often than in the West.14 High prevalence of carcinogenic liver flukes is associated with the high incidence rates of biliary tract cancers. Nevertheless, in the United States, IHCC and EHCC incidence rates have steadily increased from 1999 to 2013 across sex and racial/ethnic groups (estimated annual percent change [eAPC]: 3.2% for IHCC and 1.8% for EHCC). Also, in other countries (e.g., Japan, Australia, and many European countries), increased rates for IHCC are widely reported.14 In contrast, the overall GBCA incidence rate has been stable or declining, although it increased among African Americans (eAPC: 1.8%) and people aged less than 45 years (eAPC: 1.8%).10,15 The increased incidence of IHCC and EHCC may be attributable, in part, to the fact that several risk factors (e.g., cirrhosis and obesity) have increased globally over recent decades.14 The increased detection of early stage or smaller tumors may also be considered a reason, as would be expected if the increase were only because of an improvement

  Chapter 9E  Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer

in diagnostic modalities, such as magnetic resonance imaging (MRI) and computed tomography (CT).7,16,17 Epidemiologic data over the last few decades have also shown that the mortality rate of IHCC is rising globally, whereas the mortality rates of EHCC and GBCA have decreased in most countries.18,19 The GBCA mortality rates declined after the increase of cholecystectomy. Despite recent imaging modality developments, most patients presenting with unresectable or metastatic disease still typically die within 12 months of diagnosis. In addition to a lack of highly efficacious systemic therapies, sepsis from cholangitis, frequently related to interventions performed for biliary obstruction and progressive liver failure, contribute to the high mortality.16 Although biliary tract tumors remain relatively rare, there has been increased interest in studying the biology of these diseases in recent years.

CHRONIC BILIARY INFLAMMATION AND CHOLESTASIS Clinical Risk Factors There are multiple risk factors for biliary tract cancers. The heterogeneous tumor phenotypes and molecular findings can be explained by a complicated interaction between the unique genetic background of a patient and their exposure to the risk factors.14 Reported risk factors for these tumors are a diverse group of conditions that include infectious causes, congenital conditions, inflammatory diseases, drugs, environmental exposures, and toxins.14,20,21 Congenital biliary duct cysts (including Caroli disease; see Chapter 46) and cholangitis (including primary sclerosing cholangitis [PSC]; see Chapter 41) are established as well-known risk factors. The high prevalence of these diseases affects the high incidence rates in the female population of Asian countries (e.g., China and Japan). In addition, previous studies found that biliary cirrhosis, cholelithiasis, hepatolithiasis, alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), nonspecific cirrhosis, diabetes type II, thyrotoxicosis and chronic pancreatitis, obesity, chronic hepatitis B virus infection (HBV), hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection, and smoking were associated with the development of biliary tract cancers21,22 (see Chapters 49–51). A recent systematic review suggests that the rising global incidence of IHCC may be associated with increases in diabetes type II, alcoholic liver diseases, and cholelithiasis.23 Liver flukes (Opisthorchis viverrini and Clonorchis sinensis) are also major causes in East Asia, especially in Thailand and Laos. Thorotrast, which was previously used as an intravascular contrast agent, is also carcinogenic and associated with a 64-fold increased odds ratio of developing CCA.24 Occupational exposures to 1,2-dichloropropane or asbestos have become well-known as strong risk factors in recent years. Some studies using nationwide databases support that inflammatory bowel disease is associated with the increased risk for these cancers as well.25,26 Based on the aforementioned predisposing factors, a common theme of chronic biliary epithelial inflammation appears to be a predisposing factor for the development of biliary tract cancers. PSC is the most common condition predisposing to CCA, with incidence rates of 0.5 to 1.5 per 100 person-years reported in patients with PSC (400-fold the risk in the general population).27,28 Although the incidence of CCA in pediatric PSC patients is very rare, CCA in adult PSC patients is seen most

161

commonly less than 1 year after the diagnosis of PSC.29,30 Congenital abnormalities of the biliary tree, congenital hepatic fibrosis, and choledochal cysts (cystic dilatations of the bile ducts) also carry a 15% risk of malignant change.31,32 Furthermore, with untreated choledochal cysts, the risk of biliary tract cancers increases to 28%.33,34 Biliary stasis, reflux of pancreatic juice, activation of bile acids, and deconjugation of carcinogens are speculated as mechanistic drivers of carcinogenesis related to the theme of chronic inflammation.35

Biology of Clinical Risk Factors Several underlying mechanisms play a role in the induction of chronic biliary inflammation and cholestasis.

Bile Content and Deconjugation of Xenobiotics Polymorphisms in bile salt transporter proteins (i.e., BSEP, ATP8B1, and ABCB4) can lead to unstable bile content and deconjugation of environmental toxins (i.e., xenobiotics) previously conjugated in the liver.36,37 In the background of congenital bile duct abnormalities, this process increases the risk of CCA.38 Individuals who are heterozygous for bile salt transporter polymorphisms are thought to have an increased predisposition to cancer as adults, following exposure to cofactors that result in chronic inflammation in the biliary tree.38

DNA Mutagens Promutagenic DNA adducts have been identified in biliary tract cancer tissue, indicating exposure to DNA-damaging agents.39 Although the mechanisms have not been fully elucidated, Thorotrast has a very long half-life and induces biliary tract cancers, possibly because of the release of alpha particles with high linear energy transfer, inducing mutations in various oncogenes and tumor suppressor genes, which leads to their activation.40 Inflammatory conditions, such as chronic viral infections (e.g., HBV and HCV) or alcoholic/nonalcoholic hepatitis, promote carcinogenesis by producing reactive oxygen and nitrogen species from inflammatory and epithelial cells, activating reparative tissue proliferation, and creating a local environment rich in cytokines and other growth factors, ultimately resulting in DNA damage.41,42 Exposures to 1,2-dichloropropane and asbestos fibers also increase DNA doublestrand breaks.43,44

Inherited Syndrome Lynch syndrome, an autosomal dominant predisposition for DNA mismatch repair, is associated with a high incidence of colorectal, endometrial, stomach, ovary, pancreas, ureter and renal pelvis, bile duct, and brain tumors. The associated lifetime risk for bile duct cancer in patients with Lynch syndrome is 1% to 4% (Cancer.Net, https://www.cancer.net/cancer-types/lynchsyndrome). Although hereditary and not environmental, deficiency of DNA repair is a recurrent theme in the development of biliary tract cancers.

MOLECULAR PATHOGENESIS The molecular pathogenesis of biliary tract tumors has recently become an area of vigorous investigation (see Chapters 9A and 9C). In the era of advanced molecular analyses, including NGS, rapid progress is being made in our understanding of the genomic basis of these malignancies. Tumor profiling of biliary tract cancers has revealed that molecular profiles differentiate

162

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

IHCC, EHCC, and GBCA and that every tumor has both biologically complex and individually unique molecular alterations, suggesting individualized therapeutic options. It is beyond the scope of this chapter to document every known molecular alteration reported or associated with biliary tract cancers. Instead, we focus on recurrent themes in altered signaling pathways that together result in the pathogenic phenotypes and potential drug targets (Fig. 9E.1).

Biology of Biliary Epithelial Injury and Repair Similar to the development of other tumors, biliary tract carcinogenesis is thought to be a multistep process dependent on the interaction between environmental factors and host genetic factors. Most of the putative environmental risk factors for

Chronic biliary inflammation + cholestasis

Cellular injury

CCA result in chronic biliary inflammation, leading to tissuerepair mechanisms and, ultimately, carcinogenesis. Conceptually, exposure to an inflammatory stimulus would not have the same effect on each cell because of changes in perfusion (e.g., centrilobular versus periportal), as well as differential levels of cytochrome P450 (CYP) expression, exposure to bile salt concentrations, and exposure to inflammatory components (e.g., cytokines and immune surveillance cellular components, such as Kupffer cells and hepatic stellate cells; see Chapters 7 and 10). Based on this, the concept of heterogeneity can be inferred where distinct clonal populations may arise based on differential response to stimuli. In this section, we review the underlying host factors associated with bile tract cancers.

Reactive cellular repair + clonal proliferation

Malignant transformation

Tumor growth + metastasis

Genomic Alterations ARID1A BAP1 BRAF CDKN2A/B loss ERBB2 FGFR1-3 fusions

Risk Factors Alcohol

Liver flukes

Cholangitis

NAFLD

Choledochocal cyst

Obesity

Cirrhosis

PSC

Diabetes

Smoking

HBV/HCV

Thyrotoxicosis

Lifestyle

Toxins

Dysregulated Signaling Pathways

IDH1/2 KRAS MET PBRM1 PIK3CA TP53

Epigenetic Alterations APC CDH1 CDKN2A GSTP1 hMLH1

p14ARF p15 p16INK4a RASSF1A SOCS-3

Worse Prognosis COX-2 EGFR ERBB2 HGF/MET Hippo IDH1/2 IGF PI3K/AKT/mTOR PLK1/2 RAS/RAS/MEK/ERK

Better Prognosis Chemokines Interleukins JAK/STAT

microRNA (miR) Alterations miR21 miR22 miR125a miR127

Inflammatory signaling Mitogenic Factors Biliary epithelium

Bcl-2 COX-2 CXCR4

ERBB2 IL-6/STAT3 Notch-1

Biliary tract adenocarcinoma

Proliferative epithelium Transforming events

Epithelial-Stromal Interactions IL-6/STAT

miR199a miR199a* miR376a miR424

Epithelial-Mesenchymal Transition (EMT)

TGF-β

miR200c miR204

miR214

Tumor-Stromal Interactions Hedgehog (Hh) Notch

Stromal cells (Hepatic stellate cells + myofibroblasts)

PDGF PLK

Mesenchymal cancer cell

FIGURE 9E.1  Vogelgram of biliary carcinogensis.  The progression from benign biliary epithelium to biliary tract adenocarcinoma occurs through a series of stages, including chronic biliary inflammation and cholestasis caused by several risk factors, followed by cellular injury, reactive cellular repair, clonal proliferation, malignant transformation, tumor growth, and metastasis. Each one of these steps is regulated by many factors, including epithelial-stromal interactions, mitogens, genomic alterations, epigenetic alterations, microRNAs, dysregulated signaling pathways, epithelialtomesenchymal transitions, and tumor-stromal interactions. APC, Adenomatosis polyposis coli; ARID1A, AT-rich interaction domain 1A; BAP1, BRCA1-associated protein 1; Bcl-2, B-cell chronic lymphocytic leukemia/lymphoma; BRAF, B-Raf protooncogene; CDH1, cadherin 1; CDKN, cyclindependent kinase inhibitor; COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; ERBB2, ERB-B2 receptor tyrosine kinase 2; FGFR1-3, fibroblast growth factor receptor 1–3; GSTP1, glutathione-S-transferase pi 1; HBV, hepatitis B virus; HCV, hepatitis C virus; HGF, hepatocyte growth factor; hMLH1, human mutL homolog 1; IDH1/2, isocitrate dehydrogenase 1/2; IGF, insulin-like growth factor; IL-6, interleukin-6; JAK, Janus-activating kinase; KRAS, Kirsten rat sarcoma; mTOR, mechanistic target of rapamycin; NAFLD, nonalcoholic liver disease; PBRM1, polybromo 1; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol-3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit alpha; PLK, polo-like kinase; PSC, primary sclerosing cholangitis; SOC-3, general sugar transporter; STAT, signal-transducer and activator of transcription; TGF-, transforming growth factor-b; TP53, tumor protein 53.

  Chapter 9E  Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer

Genetic Polymorphism at Cytochrome P450 Genetic polymorphisms exist in the CYP450 enzyme complex, a large family of constitutive and inducible enzymes that play a central role in the oxidative metabolism of both environmental toxins and endogenous compounds. These polymorphisms play a critical role in how endogenous and exogenous toxins are biotransformed by the liver. Similar to many other cancers, which rely on a sequence of chronic injury and repair, the development of CCA may be partially regulated by the host ability to respond toxic to insults. Several CYPs are involved in the metabolism of oxysterols, that are cholesterol oxidation products with expression that may be dysregulated in inflammation-related diseases, including cancer. For instance, 1,2-dichloropropane, a DNA mutagen as previously mentioned, influences the proliferation and apoptosis of cholangiocytes via CYP450.45 CYP39A1, which can metabolize 24-hydroxycholesterol, is downregulated in 70% of CCA and plays an important role in the inflammatory response and oxidative stress.46 Low expression of CYP39A1 correlates with disease metastasis. Also, CYP2A6 and CYP2E1 are upregulated in Opisthorchis-associated CCA and indicate that enhanced CYP2A6 activity and diminished CYP2E1 activity are involved in the progression of CCA.47 Finally, molecular profiling of EHCC specimens demonstrated significant enrichment of CYP-metabolic pathways, including transcription factors such as glutathione-S-transferase a1 (GSTA1) and GSTA3, which may cause abnormal gene expression and tumorigenesis through CYP450-metabolic pathways.48 Differential CYP activity may be involved in the initiation and/or progression of disease via modulation of chronic inflammation, metabolism of exogenous compounds (e.g., drugs, tobacco, and nitrosamines), viral hepatitis, parasitic infestation, and recurrent cholangitis.14

MRP2/ABCC2 Multidrug resistance–associated protein 2 (MRP2/ABCC2) is one of the adenosine triphosphate-binding cassette (ABC) transporters expressed on the apical membrane of hepatocytes and cholangiocytes. ABCC2 plays an important role in the biliary clearance of endogenous and exogenous toxic compounds. The ABCC2 variant c.3972C.T in exon 28 has been shown to be associated with the risk of carcinogenesis.49

MUTYH and NEIL1 It was recently found that the human mutY DNA glycosylase (h-MUTYH) and Nei-like DNA glycosylase (NEIL) 1 genes encode DNA glycosylases involved in repair of oxidative base damage, and mutations in these genes are associated with CCA.50 NEIL1 G83D was identified in PSC and CCA.51

Activation-Induced Cytidine Deaminase Other work has also suggested that chronic inflammation can play a critical role leading up to CCA. The proinflammatory cytokine-induced aberrant production of activation-induced cytidine deaminase (AID), a member of the DNA/RNA-editing enzyme family, links bile duct inflammation to an enhanced genetic susceptibility to mutagenesis that leads to CCA.52 Ectopic AID production is induced in response to tumor necrosis factor-a (TNF-a) stimulation via a nuclear factor kappa B (NF-kB)–dependent pathway. Aberrant expression of AID in biliary cells results in the generation of somatic mutations in tumor-related genes, including tumor protein 53 (TP53), c– myelocytomatosis viral oncogene (c-MYC), and the promoter

163

region of the cyclin-dependent kinase inhibitor A (CDKN2A) sequences. In human tissue specimens, reverse transcription polymerase chain reaction analyses revealed that AID was significantly increased in 28 of 30 (93%) CCA tissues, whereas only trace amounts of AID were detected in the normal liver. Immunohistochemistry showed that all of the CCA tissue samples examined showed overproduction of endogenous AID protein in cancer cells. Moreover, immunostaining for AID was detectable in 16 of 20 biliary epithelia in PSC.

Human CYP1A2 and Arylamine N-Acetyltransferases (NAT1 and NAT2) The CYP1A2, NAT1, and NAT2 genes have been shown to be potential modifiers of an individual’s susceptibility to certain types of cancers. In a previous study evaluating the relationship between CYP1A2, NAT1, and NAT2 polymorphisms in Thai CCA patients, a total of 216 CCA patients and 233 control subjects were genotyped using PCR.53 Two CYP1A2 alleles (CYP1A2*1A wild type and *1F), six NAT1 alleles (NAT1*4 wild type, *3, *10, *11, *14A, and *14B), and seven NAT2 alleles (NAT2*4 wild type, *5, *6A, *6B, *7A, *7B, and *13), were analyzed. The CYP1A2*1A/*1A genotype conferred a decreased risk of the cancer (adjusted odds ratio [OR], 0.28; 95% confidence interval [CI], 0.08 to 0.94) compared with CYP1A2*1F/1*F. Frequency distributions of rapid NAT2*13 and two slow alleles, *6B and *7A, were associated with lower risk of CCA. This study suggests that the NAT2 polymorphism might be a modifier of individual risk of CCA.

Trefoil Factor Family Trefoil factor family 1 (TFF1) is critical for mucosal protection and tumor suppression in the stomach. To examine its role in CCA, specimens with varying degrees of dysplasia were examined. These included IHCC as a result of hepatolithiasis, biliary epithelial dysplasia with hepatolithiasis, hepatolithiasis without dysplasia or carcinoma, IHCC without hepatolithiasis, and control normal livers.54 TFF1 expression in the biliary epithelium was increased in hepatolithiasis compared with control livers (P , .01). In biliary epithelial dysplasia and noninvasive IHCC with hepatolithiasis, TFF1 was extensively expressed, and MUC5AC gastric mucin was usually colocalized with TFF1. However, TFF1 expression was significantly decreased in invasive IHCC, despite preserved expression of MUC5AC. A total of four missense mutations were detected: three were found in two noninvasive IHCC with hepatolithiasis (29%) and one in invasive IHCC (11%). Loss of heterozygosity of the TFF1 gene was not detectable. The decreased expression of TFF1 in invasive IHCC may be explained by the methylation of the TFF1 promoter region. Upregulation of TFF1 coupled with MUC5AC in biliary epithelium in hepatolithiasis, biliary epithelial dysplasia, and noninvasive IHCC may reflect gastric metaplasia and early neoplastic lesion. Under such conditions, decreased TFF1 expression is critical for the maintenance of the epithelial barrier and mucosal protection and can lead to increased cell proliferation and then to the invasive character of IHCC.

Biliary Epithelial Proliferation Ultimately, the underlying chronic biliary inflammation, which may be modified by toxin exposure, along with modulation by endogenous host factors or inherited gene polymorphisms, may lead to an exaggerated repair response that results in cholangiocyte proliferation.

164

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Mitogenic Factors Identification of several mitogenic stimuli with resultant increases in DNA, RNA, protein synthesis, and immune modulation have been implicated in the carcinogenesis of biliary tract tumors. The liver fluke Opisthorchis viverrini can generate mitogenic substances, such as glutathione-S-transferases (GSTs), which act as a secretory product that may play an important role in promoting the genesis of CCA. GST has a proliferative function on NIH-3T3 murine fibroblasts and MMNK1 nontumorigenic human bile duct epithelial cells in a dose-dependent manner, with subsequent in vitro activation of both phospho-AKT (v-akt murine thymoma viral oncogene homolog 1; pAKT) and phospho-ERK (extracellular signal regulated kinase; pERK).55 Other mitogens can activate these pathways. Recombinant human TFF2 can stimulate proliferation and trigger phosphorylation of epidermal growth factor receptor (EGFR) with downstream ERK activation, displaying potential mitogenic impact in CCA via EGFR/mitogen-activated protein kinase (MAPK) activation.56 Moreover, TFF family members have been assessed as potential biomarkers in CCA. Gene copy number, messenger ribonucleic acid (mRNA) levels, and protein expression were evaluated in bile duct epithelium biopsies collected from individuals with CCA, precancerous bile duct dysplasia, and from disease-free control participants. The TFF1, TFF2, and TFF3 mRNA levels were significantly increased in CCA tissue. In healthy tissues, cellular senescence results in irreversible growth arrest. This is prevented, however, in malignant cells by maintenance of chromosomal length via telomerase activity. This is observed in CCA cells but not in normal cholangiocytes. Interleukin-6 (IL-6) is partially responsible for this because it

acts as an autocrine promoter of the cell growth of CCA. IL-6 stimulation leads to enhanced telomerase, decreased cellular senescence, and thereby increased CCA growth.57 Moreover, in conjunction with hepatocyte growth factor (HGF), IL-6 increases CCA cell growth in vitro and induces a rapid release of prostaglandin synthesis, followed by downstream signal transduction via MAPKs, protein kinase C, and calmodulin.58 Taken together, these, and probably other mitogens, drive the proliferation of CCA.

Malignant Transformation Gene Expression Analysis In 2009 Miller and colleagues investigated the molecular alterations in carcinomas of the biliary tree, including IHCC, EHCC, and GBCA, using frozen specimens from patients who underwent surgical resection.59 Unsupervised hierarchical clustering analysis revealed that cancers from these different sites did not cluster separately, implying that there was no difference in the global gene expression patterns between the biliary cancer subgroups. However, as NGS techniques have advanced, unique molecular patterns across the subtypes of biliary tract cancer have been revealed. The molecular spectrum of biliary tract cancers is depicted in Fig. 9E.2.60 IDH1/2 and BAP1 mutations, as well as FGFR2 fusions, are more common in IHCC, whereas KRAS (23%–38%), TP53 (14%–49%), and SMAD4 mutations are more frequent in EHCC. Finally, activating ERBB2/ERBB3 and PIK3CA mutations, as well as inactivating PTEN and TSC1 mutations, are more commonly observed in GBCA61 (see Chapter 9C).

IHCCA Specific targetable GAs

Prevalence

EHCCA Targeted therapies

FGFR2 fusions

10% to 20%

BGJ398, Ponatinib, JNJ425756493, PRN1371, TAS-120, FGFR antibodies and FGFR trap molecules

IDH1/2

22% to 28%

AG-120, AG-881

BAP1

15% to 25%

Histone deacetylase (HDAC) inhibitors like vorinostat and panobinostat

Specific targetable GAs

Prevalence

Targeted therapies

HER2/neu (mutation)

11% to 20%

Tyrosine, kinase inhibitors like afatinib, neratinib, and dacomitinib

PRKACA and PRKACB

9%

Protein kinase A inhibitors under development

ARID1A

5% to 12%

Histone deacetylase (HDAC) inhibitors like vorinostat and panobinostat

GBC Specific targetable GAs

Prevalence

Targeted therapies

EGFR

4% to 13%

Erlotinib, Cetuximab

HER2/neu (amplification)

10% to 15%

Trastuzumab, Lapatinib, Pertuzumab, T-DMI

ERBB3

0% to 12%

Seribantumab (MM-121), Pertuzumab, Trastuzumab, T-DM1

PTEN

0% to 4%

mTOR inhibitors like Everolimus, AKT inhibitor like MK2206, PI3K inhibitors like BKM 120, BYL719 and SF1126

PIK3CA

6% to 13%

mTOR inhibitors like Everolimus, AKT inhibitor like MK2206, PI3K inhibitors like BKM 120, BYL719 and SF1126

FIGURE 9E.2  Molecular patterns of biliary tract cancers.  From Jain A, Javle M. Molecular profiling of biliary tract cancer: A target rich disease. J Gastrointest Oncol. 2016;7(5):797–803.

  Chapter 9E  Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer

Pre–Next-Generation Sequencing With the revolutionary changes that are occurring in genomics, the cost, sequencing time, and analysis time of NGS has significantly decreased during the past decade. Whole-exome sequencing (WES) and targeted sequencing of several hundred cancerspecific genes have provided significant insight and a deeper understanding of the oncogenes and tumor-suppressor genes involved in biliary tract carcinogenesis. In the era preceding NGS, several studies showed abnormal expression of the Kirsten rat sarcoma (KRAS) oncogene in 21% to 100% of cases, as well as alteration in the TP53 tumor suppressor gene in up to 37% of archival CCA specimens.62 These genetic alterations were associated with a more aggressive phenotype in biliary tract tumors.62 KRAS and TP53 mutations were also been identified in bile and pancreatic juice of affected patients,62,63 but neither KRAS nor TP53 mutational analysis was shown to be superior to conventional cytopathology in the diagnosis of pancreaticobiliary tumors. However, combined pathologic analysis and mutation analysis increased diagnostic sensitivity.62–64

Next-Generation Sequencing in Biliary Tract Cancers Compared with older studies, which relied on sequencing one gene a time, more recent studies have capitalized on NGS to narrowly or broadly characterize tumors. Although the biliary tract cancers were frequently grouped together by biologic, histologic, and clinical trial assignment, their somatic genomic landscapes are distinct from each other, suggesting that different treatment strategies are necessary for clinical trial design in each individual cancer. The first study to begin delineating these differences was reported by Borger and colleagues in 2012.65 They studied 287 tumors from gastrointestinal cancer patients, including biliary tract, colorectal, gastroesophageal, hepatic, pancreatic, and small intestine carcinomas, and evaluated 15 known cancer genes for 130 site-specific gene mutations (Table 9E.1). Since this publication in 2012, several additional studies have been reported using WES analysis in biliary tract cancers. Study differences in alteration frequencies of each gene can be attributable to tissue sources (primary tumor or metastatic sites), sample size, depth of sequencing, and other factors. The most common genomic alterations are listed in Table 9E.2.

IDH1 and IDH2 Mutations Combining several cohorts of biliary tract cancers, mutations in IDH1 and IDH2 were found in 15% to 29% and 3% to 6% of IHCC cases, respectively, whereas none or few were identified in EHCC or GBCA cases (see Chapters 9C and 50). Therefore IDH1 mutations were defined as a molecular feature of IHCC and also suggested as a potential therapeutic target specific to IHCC. IDH1 and IDH2 play roles in normal cellular metabolism and in conferring cellular protection against oxidative damage.66 Mutant IDH blocks hepatocyte differentiation and promotes IHCC by cooperating with KRAS mutations.67 In a multicenter randomized controlled study, the ClarIDHy study, a small molecule IDH inhibitor, ivosidenib, improved progression-free survival in CCA patients with mutant IDH1.68 Also, preclinical studies have suggested that IDH1 mutations in other types of cancer confer sensitivity to PARP inhibitors69–71(see Chapter 9C).

FGFR2 Fusions FGFR2 is a receptor tyrosine kinase (RTK), which plays an important role in cell differentiation, growth, and angiogenesis.72 FGFR genomic alterations occur more frequently in IHCC

165

TABLE 9E.1  Most Common Somatic Mutations by Biliary Tract Tumor Subtype IHCC (N 5 40)

EHCC (N 5 22)

GBCA (N 5 25)

AKT1

3%

0%

0%

APC

0%

0%

4%

BRAF

3%

0%

0%

CTNNB1

0%

0%

4%

IDH1

20%

0%

0%

IDH2

3%

0%

0%

KRAS

5%

23%

4%

NRAS

5%

0%

4%

PIK3CA

0%

0%

12%

PTEN

3%

0%

0%

TP53

5%

14%

4%

AKT1, v-AKT murine thymoma viral oncogene homolog 1; APC, adenomatosis polyposis coli; BRAF, B-Raf protooncogene; CTNNB1, b1-catenin; EHCC, extrahepatic cholangiocarcinoma; GBCA, gallbladder cancer; IDH1/2, isocitrate dehydrogenase 1/2; IHCC, intrahepatic cholangiocarcinoma; KRAS, Kirsten rat sarcoma; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; PIK3CA, phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin; TP53, tumor protein 53. From Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17:72–79.

TABLE 9E.2  Common Somatic Alterations by Biliary Tract Tumor Subtype IHCC

EHCC

GBCA

BAP1

10%-20%

0%-5%

2%

BRAF

3%-7%

0%

0%-6%

ERBB2

0%-4%

4%-7%

4%-16%

FGFR2

5%-50%

0%

IDH1

15%-29%

0%-5%

0%

IDH2

3%-6%

0%

0%

KRAS

6%-25%

23%-38%

4%-13%

PIK3CA

0%-6%

0%

6%-12%

TP53

5%-18%

14%-49%

4%-47%

EHCC, Extrahepatic cholangiocarcinoma; GBCA, gallbladder cancer; IHCC, intrahepatic cholangiocarcinoma.

patients of younger age (#40 years), earlier cancer stage presentation (TNM stage I/II), and Caucasian race.73 FGFR2 alterations, mostly fusions, are seen in 5% to 50% of IHCC and these FGFR2 activating alterations confer sensitivity to FGFR inhibitors (e.g., erdafitinib and pemigatinib).74 Clinical trials have demonstrated the meaningful antitumor activity and better overall survival time of FGFR inhibitors in IHCC harboring fusions75–77 (see Chapters 9C and 50).

ERBB Family ERBB2 (as also known as HER2/neu) is a member of the ERBB family in the same capacity as EGFR and has been already well-established in many types of cancer. Amplification or overexpression of ERBB2 leads to tumor proliferation and

166

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

oncogenesis of CCA cells. Amplification and mutation of ERBB2 more frequently occurs in GBCA and EHCC than IHCC.78 ERBB2 amplification and activating mutations may confer sensitivity to ERRB2-targeted drugs, which are now being evaluated in ERBB2-altered biliary tract cancers. According to data from the pre-NGS era, overexpression of EGFR can be seen in 11% to 27% of IHCC cases and 5% to 19% of EHCC cases.79,80 A subgroup analysis of the randomized controlled study evaluating the additional efficacy of an anti-EGFR small molecule inhibitor to chemotherapy indicated a longer progression-free survival in patients with CCA.81

Other Targetable Genomic Alterations Alterations in DNA repair or homologous recombinant gene are targetable with drugs that are associated with DNA repair mechanisms. For instance, the BAP1 (BRCA1 associated protein-1) gene encodes an enzyme regulating the ubiquitin-proteasome protein degradation pathway and acts as a tumor suppressor gene. Inactivation of this gene leads to carcinogenesis, whereas germline BAP1 inactivation increases susceptibility to several malignancies, including CCA.82 BAP1 mutations are seen in 10% to 20% of IHCC cases and 0% to 5% of EHCC/ GBCA cases. Clinical and preclinical studies suggest that BAP1-mutation can be a target from EZH2 inhibitors, PARP inhibitors, and HDAC inhibitors. NTRK fusions are also known drivers of oncogenesis by activating the downstream effectors, including the MAPK and PI3K/AKT pathways.83 Although this alteration is exceedingly rare in biliary tract cancers, the antitumor activity of NTRK inhibitors is remarkable. Clinical trials demonstrating the efficacy of NTRK inhibitors (i.e., larotrectinib and entrectinib) for patients with NTRK fusions included a few patients with CCA, who all responded, and their responses were often long-lasting.84,85 A nonrandomized study demonstrated that molecularly matched therapeutic regimens based on NGS genomic profiling was significantly associated with longer progression-free survival and higher disease control rate than regimens unmatched to genomic alterations (mostly gemcitabine-based regimens) in advanced biliary tract cancers (Okamura R, Kurzrock R, Mallory RJ, et al. Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers. Int J Cancer. 2021;148(3):702-712. doi:10.1002/ijc.33230).

Epigenetic Alterations Many human cancers have aberrant epigenetic alterations. Epigenetic mechanisms involved in gene regulation include DNA methylation, histone modification, and noncoding RNAs. Studies defining the role of these epigenetic alterations in the tumorigenesis of biliary tract cancers have emerged. Aberrant promoter hypermethylation of specific genes, such as cell-cycle associated and DNA repair genes, is associated with tumor progression and metastasis in CCA. Point mutation in CpG islands of the cell-cycle regulator, P16INK4A, result in inactivation of the gene and lead to the proliferation or vascular invasion of CCA cell.86 Inactivation of the MLH1 gene, a DNA mismatch repair gene, contributes to the tumorigenesis of CCA.87 The DNA mismatch repair deficiency is a major molecular pathway of genetic instability in cancer. High microsatellite instability (MSI-High) is one of the most predictive biomarkers of responsiveness toward immune checkpoint blockade. Furthermore, promoter hypermethylation of SOCS-3 (regulator of glucose transport), which is implicated in IL-6/signal-transducer and

activator of transcription 3 (STAT3) activation, has been noted in 27% of CCA cells. Other relevant aberrantly methylated genes include runt-related transcription factor 3 (RUNX3), which is altered in 42% of IHCC tumors, and p14ARF, which prevents TP53 degradation and hence cell-cycle arrest, has been reported as altered in 18% of tumors.20 Histone methylation can also result in transcriptional activation, although it depends on the type of amino acid and its position in the histone tail.88 Histone deacetylase (HDAC) regulates cell cycle progression and differentiation, and its overexpression in CCA is associated with the malignant behavior and poorer disease-free survival in CCA.89 The inhibition of HDAC suppresses the tumor growth in CCA cells.90 Noncoding RNAs also regulate the tumorigenesis in CCA and may be important targets for cancer therapy. A long, noncoding RNA (lncRNA), actin filament associated protein 1 antisense RNA1 (AFAP1-AS1), is reported to promote the tumor growth and metastasis of CCA cells in vivo.91 The BRCA-1 associated protein-1 (BAP1) is a chromatin modulator, and BAP1-dependent expression of lncRNA, nuclear paraspeckle assembly transcript 1 (NEAT-1), modulates sensitivity to gemcitabine in CCA.92 Targeting these epigenetic alterations by specific inhibitors may be a promising treatment option in CCA.

microRNA Alterations Emerging evidence has recently suggested that the expression of noncoding RNAs, such as microRNAs (miRs), is important in carcinogenesis because they can modulate the expression of many genes that regulate critical properties, such as cell survival, autophagy, stemness, and response to therapy. As a result, miRs have been linked to tumor heterogeneity, as well as significant determinants of genomics-based patient stratification. Several miRs are reported to promote the tumorigenesis of cholangiocarcinoma (e.g., miR-21, miR-155) and to suppress the tumor development. For instance, the increased expression of miR-21 is associated with the tumor growth and metastasis of CCA and modulates chemotherapy-induced apoptosis by regulating PTEN-dependent activation of phosphatidylinositol3-kinase (PI3K) signaling pathway.93 MiR-1249 expression is increased in biliary tract cancers and mediates chemotherapy resistant, by regulating the clonal expansion of CD1331 cells.94 Also, the expression of miR-24 leads to the decrease of a tumor suppressor gene MEN1, and miR-24 inhibition possibly attenuates the tumor progression of CCA.95 miRs are promising as biomarkers for predicting survival and treatment response.

Tumor Growth and Metastasis Dysregulated Signaling Pathways The progression and metastasis of biliary tract tumors appear to be driven by a variety of cellular signaling pathways involved in responses to embryonic/stem cell signaling pathways (e.g., Hh, WNT, NOTCH, HIPPO), growth factors (e.g., EGF, FGF, HGF/ mesenchymal-to-epithelial transitions [MET], VEGF), intracellular signal transduction (e.g., KRAS/RAF/MEK/ERK), cytokine signaling (e.g., IL-6/STAT), and cell-cycle progression (e.g., polo-like kinases [PLKs]).2

Embryonic Signaling It is increasingly recognized that embryonic signaling pathways are important in the carcinogenesis of numerous types of cancer. The Hedgehog (Hh), Wnt/b-catenin, NOTCH, and HIPPO

  Chapter 9E  Advances in the Molecular Characterization of Biliary Tract and Gallbladder Cancer

167

signaling pathways are important regulators of proliferation, survival, self-renewal, and development in embryos and cancers in adults (see Chapter 1). The Hh pathway was initially reported be overexpressed in CCA.96 Hh has been also shown to regulate tumor-stromal interactions in the liver that stimulate the proliferation, migration, and invasion of CCA cells.97 Hh also directly regulates the viability of CCA.98 Similarly, the NOTCH pathway has been shown to regulate cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) while working in concert with TP53 to regulate cell viability.99 Aberrant expression of NOTCH receptors 1 and 3 play a role during cancer progression, and the NOTCH pathway protein DLL4 correlates with poor survival in EHCC and GBCA.100 Multiple studies have suggested that the Wnt/bcatenin pathway also plays the key role in progression of CCA cells, although genomic mutations in genes, including adenomatosis polyposis coli (APC), are rare. Finally, the HIPPO signaling pathway regulates proliferation and apoptosis of cholangiocarcinoma cells via the yes-associated protein 1 (YAP1) and also promotes angiogenesis by regulating the expression of secreted pro-angiogenic proteins.101,102 Nuclear YAP expression was shown to represent a biomarker of response to FGFR-directed therapy.103 Overall, these developmental signaling pathways appear to be important in disease progression, whereas cross talk between these pathways needs further investigation.

inhibition of the two pathways can prevent RAS-induced lineage conversion from hepatocytes to CCA.106

Growth Factor Receptor

Tumor-Stromal Interactions

FGFR2 gene fusions are found in 9% to 25% of IHCC and promote cell proliferation, survival, and apoptosis of cancer cells. FGFR inhibitors for CCA with FGFR fusions have already been approved by the US Food and Drug Administration (FDA; see Chapters 9C and 50). Overexpression of EGFR occurs in 10% to 32% of CCAs, although somatic mutations in EGFR family members are rare. Furthermore, aberrant phosphorylation of EGFR activates MAPK, and p38 signaling can increase cyclooxygenase-2 (COX-2). In turn, this can inhibit apoptosis while enhancing tumor growth. However, although in vitro EGFR inhibition with erlotinib has shown cell proliferation of CCA cells, in vivo dual blockage of EGFR and ERBB1/ ERBB2 with lapatinib is necessary. The hepatocyte growth factor (HGF)/MET pathway is rarely mutated in biliary tract tumors, but amplification of MET, the HGF receptor, has been reported in IHCC. In turn, HGF/MET can activate many pathways, including MAPK, PI3K, and STAT, and can stimulate migration and invasion in CCA cells. VEGF is a signal protein produced by cells that stimulates angiogenesis. Alterations occur in almost half of IHCCs and correlate with a poor prognosis. Although the application of targeted therapies such as sorafenib, which targets wild-type BRAF and vascular endothelial growth factor receptor (VEGFR), has been studied, the preclinical data have been disappointing in CCA models.

Hepatic stellate cells (HSCs) are stromal cells in benign hepatic parenchyma that possess both neural and myofibroblastic features (see Chapter 7). HSCs are the major cell type involved in hepatic fibrosis and cirrhosis. In addition, portal myofibroblasts can contribute to hepatic fibrosis. The tumor-stromal microenvironment is a key component of the development and progression of CCA. Several pathways appear to regulate this process. For instance, the Hh pathway regulates HSC.113 In turn, HSCs stimulate the proliferation, migration, and invasion of CCA cells and also promote angiogenesis through Hh pathway activation. This renders CCA cells more susceptible to necrosis by Hh inhibition.97 Moreover, myofibroblast-derived platelet-derived growth factor-BB protects CCA cells from TRAIL (TNFa–related apoptosis-inducing ligand) cytotoxicity by a Hh-dependent process.114 Finally, expression of the Hh target gene osteopontin is an independent predictor of survival in IHCC patients.115 In addition, other mechanisms activate tumor-associated angiogenesis and lymphangiogenesis. CCA cells have an interaction with vascular endothelial cells via VEGFR2VEGFA, which leads to tumor angiogenesis via upregulation of the PI3K/AKT pathway.116,117 Cancer-associated fibroblasts upregulate the ERK/JNK pathway and stimulate lymphatic endothelial cells via VEGFR3 engagement. That promotes lymphangiogenesis and tumor cell intravasation in CCA.118

IL-6/JAK/STAT Cytokine Signaling

SUMMARY

IL-6 is an inflammatory cytokine and mediates JAK/STAT activation, which modulates cell growth and survival of CCA cells.104 The overexpression of IL-6 may result from epigenetic silencing of SOCS-3 in CCA cells.105 Binding of IL-6 to its receptor (gp130) results in heterodimerization with the Janus kinases (JAK1, JAK2, or TYK2). In turn, this drives activation of STAT3 (i.e., the JAK/STAT pathway) and/or the MAPK pathway. NOTCH and JAK-STAT signaling cross-talk during RAS-induced CCA. A preclinical study suggested that combined

Polo-Like Kinases The Polo-like kinases (PLKs) are a family of serine/threonine kinases involved in key regulatory processes, including cell-cycle progression (G2/M transition) and cytokinesis. Targeting PLK-1 has been shown to increase the efficacy of 5-fluorouracil,107 whereas PLK-2 is a mediator of Hh signaling in CCA.108 A preclinical study showed that inhibition of PLK can sensitize CCA cells to cisplatin-induced apoptosis with proteasomal Bcl-2 degradation.109

Epithelial-to-Mesenchymal Transition EMT, MET, and, epithelial-mesenchymal interactions (EMI) are often lumped together under the term EMT.110 In the former phenomenon, however, epithelial cells lose their polarity and cell-cell adhesion while gaining migratory and invasive properties to become mesenchymal. This is thought to be involved in the initiation of metastasis. TGF-b1, an EMT-related protein, is highly expressed in CCA. A previous study indicates that the high TGF-b1 levels correlate with cancer metastasis and survival in patients with CCA.111 Also, Snail and b-catenin regulate EMT in CCA, and overexpression is found in about 50% of IHCCs.112

In the last decade, we have gained significant insight into the environmental risk factors, genomic alterations, tumor heterogeneity, and epithelial-mesenchymal interaction/transitions associated with the development of biliary tract adenocarcinomas. We are gaining a more comprehensive understanding of the molecular pathogenesis of CCA, which relies on the underlying themes of chronic inflammation to the biliary epithelium, host-mediated response, and subsequent development

168

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

of the malignant phenotype. Many new candidates for targeted therapy based on molecular profiling have emerged, including the MET, EGFR, ERBB2, FGFR, JAK/STAT, RAS/ RAF/MAPK, PI3K/AKT/mTOR, Wnt/Hh/Notch/Hippo, and IDH pathways. Data have also emerged on the role of epigenetics and miRs, providing the potential for further studies in these areas. Identifying and cataloging somatic alterations

and associating these alterations with clinical outcomes may assist in the development of novel therapeutic interventions, enhance early diagnosis, identify at-risk individuals, and ultimately improve survival. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

168.e1

REFERENCES 1. Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology. 2004;66(3):167-179. 2. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152(4):745-761. 3. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996; 224(4):463-475. 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Hepatobiliary Cancers. Version 3.2019. NCCN.org. 5. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 1992;215(1):31-38. 6. Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. 3rd English ed. Kanehara & Co., Ltd. 2010. 7. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002;37(6):806-813. 8. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(suppl 6):VI1-VI9. 9. Khan SA, Emadossadaty S, Ladep NG, et al. Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J Hepatol. 2012;56(4):848-854. 10. Van Dyke AL, Shiels MS, Jones GS, et al. Biliary tract cancer incidence and trends in the United States by demographic group, 1999–2013. Cancer. 2019;125(9):1489-1498. 11. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. 12. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33(6): 1353-1357. 13. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40(3):472-477. 14. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019;39(suppl 1):19-31. 15. Henley SJ, Weir HK, Jim MA, Watson M, Richardson LC. Gallbladder cancer incidence and mortality, United States 1999–2011. Cancer Epidemiol Biomarkers Prev. 2015;24(9):1319-1326. 16. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24(2):115-125. 17. Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut. 2001;48(6):816-820. 18. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71(1):104-114. 19. Torre LA, Siegel RL, Islami F, Bray F, Jemal A. worldwide burden of and trends in mortality from gallbladder and other biliary tract cancers. Clin Gastroenterol Hepatol. 2018;16(3):427-437. 20. Patel T. New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma. J Gastroenterol. 2014;49(2):165-172. 21. Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98(12):873-875. 22. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol. 2012;57(1):69-76. 23. Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol. 2020;72(1):95-103. 24. Mori T, Kato Y. Epidemiological, pathological and dosimetric status of Japanese thorotrast patients. J Radiat Res. 1991;32(suppl 2):34-45. 25. Sørensen JØ, Nielsen OH, Andersson M, et al. Inflammatory bowel disease with primary sclerosing cholangitis: A Danish populationbased cohort study 1977-2011. Liver Int. 2018;38(3):532-541. 26. Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PloS One. 2017;12(10): e0186643. 27. Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in patients with primary sclerosing cholangitis

(PSC): a comprehensive review. Clin Rev Allergy Immunol. 2020; 58(1):134-149. 28. Boonstra K, Weersma RK, van Erpecum KJ, et al. Populationbased epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58(6):2045-2055. 29. Deneau MR, El-Matary W, Valentino PL, et al. The natural history of primary sclerosing cholangitis in 781 children: a multicenter, international collaboration. Hepatology. 2017;66(2):518-527. 30. Bowlus CL, Lim JK, Lindor KD. AGA clinical practice update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: expert review. Clin Gastroenterol Hepatol. 2019;17(12):2416-2422. 31. Scott J, Shousha S, Thomas HC, Sherlock S. Bile duct carcinoma: a late complication of congenital hepatic fibrosis. Case report and review of literature. Am J Gastroenterol. 1980;73(2):113-119. 32. Soares KC, Arnaoutakis DJ, Kamel I, et al. Choledochal cysts: presentation, clinical differentiation, and management. J Am Coll Surg. 2014;219(6):1167-1180. 33. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg. 1994;220(5):644-652. 34. Ohtsuka T, Inoue K, Ohuchida J, et al. Carcinoma arising in choledochocele. Endoscopy. 2001;33(7):614-619. 35. van Mil SW, Klomp LW, Bull LN, Houwen RH. FIC1 disease: a spectrum of intrahepatic cholestatic disorders. Semin Liver Dis. 2001;21(4):535-544. 36. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001;21(4):551-562. 37. Thompson R, Strautnieks S. BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis. 2001;21(4): 545-550. 38. Kubo S, Kinoshita H, Hirohashi K, Hamba H. Hepatolithiasis associated with cholangiocarcinoma. World J Surg. 1995;19(4):637-641. 39. Khan SA, Carmichael PL, Taylor-Robinson SD, Habib N, Thomas HC. DNA adducts, detected by 32P postlabelling, in human cholangiocarcinoma. Gut. 2003;52(4):586-591. 40. Zhu AX, Lauwers GY, Tanabe KK. Cholangiocarcinoma in association with Thorotrast exposure. J Hepatobiliary Pancreat Surg. 2004;11(6):430-433. 41. Wongjarupong N, Assavapongpaiboon B, Susantitaphong P, et al. Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis. BMC Gastroenterol. 2017;17(1):149. 42. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. 43. Sato Y, Kubo S, Takemura S, et al. Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan. Int J Clin Exp Pathol. 2014;7(8):4745-4754. 44. Cortez BA, Rezende-Teixeira P, Redick S, Doxsey S, MachadoSantelli GM. Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression. Oncotarget. 2016;7(8):8979-8992. 45. Zhang X, Zong C, Zhang L, et al. Exposure of mice to 1,2dichloropropane induces CYP450-dependent proliferation and apoptosis of cholangiocytes. Toxicol Sci. 2018;162(2):559-569. 46. Khenjanta C, Thanan R, Jusakul A, et al. Association of CYP39A1, RUNX2 and oxidized alpha-1 antitrypsin expression in relation to cholangiocarcinoma progression. Asian Pac J Cancer Prev. 2014; 15(23):10187-10192. 47. Yongvanit P, Phanomsri E, Namwat N, et al. Hepatic cytochrome P450 2A6 and 2E1 status in peri-tumor tissues of patients with Opisthorchis viverrini-associated cholangiocarcinoma. Parasitol Int. 2012; 61(1):162-166. 48. Qi DC, Wu B, Tao SL, Zhou J, Qian HX, Wang D. Analysis of differentially expressed genes in malignant biliary strictures. Genet Mol Res. 2014;13(2):2674-2682. 49. Hoblinger A, Grunhage F, Sauerbruch T, Lammert F. Association of the c.3972C.T variant of the multidrug resistance-associated protein 2 Gene (MRP2/ABCC2) with susceptibility to bile duct cancer. Digestion. 2009;80(1):36-39. 50. Forsbring M, Vik ES, Dalhus B, et al. Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma. Carcinogenesis. 2009;30(7):1147-1154.

168.e2 51. Galick HA, Marsden CG, Kathe S, et al. The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation. Oncotarget. 2017;8(49):85883-85895. 52. Komori J, Marusawa H, Machimoto T, et al. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology. 2008;47(3):888-896. 53. Prawan A, Kukongviriyapan V, Tassaneeyakul W, Pairojkul C, Bhudhisawasdi V. Association between genetic polymorphisms of CYP1A2, arylamine N-acetyltransferase 1 and 2 and susceptibility to cholangiocarcinoma. Eur J Cancer Prev. 2005;14(3):245-250. 54. Sasaki M, Tsuneyama K, Nakanuma Y. Aberrant expression of trefoil factor family 1 in biliary epithelium in hepatolithiasis and cholangiocarcinoma. Lab Invest. 2003;83(10):1403-1413. 55. Daorueang D, Thuwajit P, Roitrakul S, et al. Secreted Opisthorchis viverrini glutathione S-transferase regulates cell proliferation through AKT and ERK pathways in cholangiocarcinoma. Parasitol Int. 2012;61(1):155-161. 56. Kosriwong K, Menheniott TR, Giraud AS, Jearanaikoon P, Sripa B, Limpaiboon T. Trefoil factors: tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma. World J Gastroenterol. 2011;17(12):1631-1641. 57. Yamagiwa Y, Meng F, Patel T. Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci. 2006;78(21):2494-2502. 58. Wu T, Han C, Lunz JG III, Michalopoulos G, Shelhamer JH, Demetris AJ. Involvement of 85-kd cytosolic phospholipase A(2) and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells. Hepatology. 2002;36(2):363-373. 59. Miller G, Socci ND, Dhall D, et al. Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract. J Exp Clin Cancer Res. 2009;28(1):62. 60. Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol. 2016;7(5):797-803. 61. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nature Gen. 2015;47(9):1003-1010. 62. Isa T, Tomita S, Nakachi A, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology. 2002;49(45):604-608. 63. Itoi T, Takei K, Shinohara Y, et al. K-ras codon 12 and p53 mutations in biopsy specimens and bile from biliary tract cancers. Pathol Int. 1999;49(1):30-37. 64. Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology. 2002;40(3):269-278. 65. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72-79. 66. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932-941. 67. Saha SK, Parachoniak CA, Ghanta KS, et al. Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513(7516):110-114. 68. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807. 69. Molenaar RJ, Radivoyevitch T, Nagata Y, et al. IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin Cancer Res. 2018;24(7): 1705-1715. 70. Lu Y, Kwintkiewicz J, Liu Y, et al. Chemosensitivity of IDH1mutated gliomas due to an impairment in parp1-mediated DNA repair. Cancer Res. 2017;77(7):1709-1718. 71. Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017;9(375):eaal2463. 72. Sia D, Losic B, Moeini A, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun. 2015;6:6087. 73. Jain A, Borad MJ, Kelley RK, et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precis Oncol. 2018;2:1-12.

74. Pearson A, Smyth E, Babina IS, et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. Cancer Discov. 2016;6(8):838-851. 75. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5): 671-684. 76. Javle M, Kelley RK, Roychowdhury S, et al. AB051. P-19. A phase II study of infigratinib (BGJ398) in previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. Hepatobiliary Surg Nutr. 2019;8(suppl 1):AB051. 77. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120(2):165-171. 78. Weinberg BA, Xiu J, Lindberg MR, et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. J Gastrointest Oncol. 2019;10(4):652-662. 79. Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206(3):356-365. 80. Yoshikawa D, Ojima H, Iwasaki M, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98(2):418-425. 81. Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2): 181-188. 82. Kobrinski DA, Yang H, Kittaneh M. BAP1: role in carcinogenesis and clinical implications. Transl Lung Cancer Res. 2020;9(suppl 1): S60-S66. 83. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precis Oncol. 2018;2018:PO.18.00183. doi:10.1200/PO.18.00183 84. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. 85. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020; 21(2):271-282. 86. Hong SM, Choi J, Ryu K, Ro JY, Yu E. Promoter hypermethylation of the p16 gene and loss of its protein expression is correlated with tumor progression in extrahepatic bile duct carcinomas. Arch Pathol Lab Med. 2006;130(1):33-38. 87. Limpaiboon T, Khaenam P, Chinnasri P, et al. Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma. Cancer Lett. 2005;217(2):213-219. 88. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):11481159. 89. Morine Y, Shimada M, Iwahashi S, et al. Role of histone deacetylase expression in intrahepatic cholangiocarcinoma. Surgery. 2012; 151(3):412-419. 90. Baradari V, Höpfner M, Huether A, Schuppan D, Scherübl H. Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol. 2007;13 (33):4458-4466. 91. Shi X, Zhang H, Wang M, et al. LncRNA AFAP1-AS1 promotes growth and metastasis of cholangiocarcinoma cells. Oncotarget. 2017;8(35):58394-58404. 92. Parasramka M, Yan IK, Wang X, et al. BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma. Mol Cancer. 2017;16(1):22. 93. Meng F, Henson R, Lang M, et al. Involvement of human microRNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology. 2006;130(7):2113-2129. 94. Carotenuto P, Hedayat S, Fassan M, et al. Modulation of biliary cancer chemo-resistance through microRNA-mediated rewiring of the expansion of CD1331 cells. Hepatology. 2020. 95. Ehrlich L, Hall C, Venter J, et al. miR-24 inhibition increases menin expression and decreases cholangiocarcinoma proliferation. Am J Pathol. 2017;187(3):570-580. 96. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846-851.

168.e3 97. Kim Y, Kim MO, Shin JS, et al. Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. Ann Surg Oncol. 2014;21(8):2684-2698. 98. El Khatib M, Kalnytska A, Palagani V, et al. Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma. Hepatology. 2013;57(3):1035-1045. 99. El Khatib M, Bozko P, Palagani V, Malek NP, Wilkens L, Plentz RR. Activation of Notch signaling is required for cholangiocarcinoma progression and is enhanced by inactivation of p53 in vivo. PloS One. 2013;8(10):e77433. 100. Yoon HA, Noh MH, Kim BG, et al. Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma. World J Gastroenterol. 2011; 17(35):4023-4030. 101. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18(11):2780-2794. 102. Marti P, Stein C, Blumer T, et al.YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors. Hepatology. 2015;62(5):1497-1510. 103. Rizvi S, Yamada D, Hirsova P, et al. A hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma. J Biol Chem. 2016;291(15):8031-8047. 104. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144(4):829-840. 105. Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology. 2007;132(1):384-396. 106. Sun L, Wang Y, Cen J, et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat Cell Biol. 2019;21(8):1015-1026. 107. Thrum S, Lorenz J, Mössner J, Wiedmann M. Polo-like kinase 1 inhibition as a new therapeutic modality in therapy of cholangiocarcinoma. Anticancer Res. 2011;31(10):3289-3299.

108. Fingas CD, Mertens JC, Razumilava N, et al. Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma. Hepatology. 2013;58(4):1362-1374. 109. Sydor S, Jafoui S, Wingerter L, et al. Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells. World J Gastroenterol. 2017;23(22): 4007-4015. 110. Sicklick JK. Correcting the misnomers of epithelial-mesenchymal relations. J Surg Res. 2013;182(1):36-39. 111. Kimawaha P, Jusakul A, Junsawang P, Loilome W, Khuntikeo N, Techasen A. Circulating TGF-b1 as the potential epithelial mesenchymal transition-biomarker for diagnosis of cholangiocarcinoma. J Gastrointest Oncol. 2020;11(2):304-318. 112. Huang XY, Zhang C, Cai JB, et al. Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. PLoS One. 2014;9(5):e96860. 113. Sicklick JK, Li YX, Choi SS, et al. Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest. 2005;85(11): 1368-1380. 114. Fingas CD, Bronk SF, Werneburg NW, et al. Myofibroblastderived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology. 2011;54(6):2076-2088. 115. Sulpice L, Rayar M, Desille M, et al. Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. Hepatology. 2013; 58(6):1992-2000. 116. Gaudio E, Barbaro B, Alvaro D, et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology. 2006;130(4):1270-1282. 117. Roy S, Glaser S, Chakraborty S. Inflammation and progression of cholangiocarcinoma: role of angiogenic and lymphangiogenic mechanisms. Front Med (Lausanne). 2019;6:293. 118. Obulkasim H, Shi X, Wang J, et al. Podoplanin is an important stromal prognostic marker in perihilar cholangiocarcinoma. Oncol Lett. 2018;15(1):137-146.

CHAPTER 10 Fundamentals of liver and pancreas immunology Yongwoo David Seo, Ian Nicholas Crispe, and Venu G. Pillarisetty INTRODUCTION The immune system manifests two strategies of host defense termed innate and adaptive immunity (Fig. 10.1).1 Innate immunity refers to the nonspecific first line of defense against danger signals from pathogens or tumor cells. The repertoire of innate immune cells includes natural killer (NK) cells, macrophages, and dendritic cells (DCs). Innate immune cells sense both tissue injury and pathogens through pattern recognition receptors (PRRs) that trigger a rapid response. PRRs bind to well-conserved molecules from microbes, including lipopolysaccharide, other bacterial cell wall moieties, and pathogen nucleic acids. PRR signaling and the ensuing response may lead to destruction of the invading pathogen or tumor via phagocytosis or release of various cytotoxic or inflammatory agents. Innate immunity may also activate antigen-presenting cells (APCs), leading to the activation of T and B cells and leading to adaptive immunity, and such crosstalk bridges the nonspecific initial response to a highly specialized system capable of long-lasting immunologic memory. Adaptive immunity involves antigen-specific responses, which occur de novo during an initial immune response or rapidly upon repeat exposure to a particular pathogen. The adaptive immune system comprises T and B lymphocytes that circulate within the blood, lymphatic tissues, and nonlymphoid organs, including the liver. T and B cells express specific cellsurface receptors capable of recognizing particular antigens. T-cell activation requires presentation of antigen by APCs such as DCs. APCs mediate antigen presentation to T cells within the context of major histocompatibility complex molecules (MHC I or MHC II). In addition, APCs provide a critical “second signal” through co-stimulatory molecules, and the response is further modulated by secreted cytokines (Fig. 10.2). Classically, CD41 helper T cells recognize antigen in the context of MHC II, whereas CD81 cytotoxic T cells engage antigen loaded onto MHC I molecules. Several subsets of CD41 cells (T helper, or Th cells) orchestrate and polarize the immune response to address particular challenges. Although activation of innate and adaptive immunity is essential for combating pathogens and malignant cells, overly exuberant immune responses can result in severe tissue damage. The immune system is normally able to distinguish self from nonself and is controlled by numerous regulatory mechanisms. During T-cell development, autoreactive cells are deleted through negative selection in the thymus. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) regulate immune responses in the periphery and prevent autoimmunity. Immunoinhibitory receptors, including programmed death-1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), modulate T-cell function, working in concert with suppressor cells to regulate immune responses. As will be discussed later, Tregs, MDSCs, and immunoinhibitory pathways in the liver cooperate to create a highly tolerogenic milieu. Intrahepatic tolerance is a

fundamental aspect of liver immunology that reflects its position at the interface between ingested exogenous antigens and the systemic circulation. The balance between tolerance and immunity in the liver is tightly regulated by intrahepatic immune cells and associated signaling pathways. Several features of liver immunology point to the skewing of this balance toward tolerance under normal physiologic conditions. First, the fact that the liver is one of the most common sites for metastatic disease suggests that malignant cells are able to exploit intrahepatic immunosuppression. Second, compared with other solid organ transplants, liver allografts do not require immunosuppression in certain strains of mice and require less immunosuppression in humans. Third, the immune system is often unable to clear chronic hepatitis B and C viral infections. Additionally, oral ingestion or portal vein injection of foreign proteins can lead to tolerance in animal models. Conversely, the liver is the site of several autoimmune processes, including primary sclerosing cholangitis and primary biliary cirrhosis. Despite the prominent role that the intrahepatic immune system plays in disease, the study of liver immunology remains underdeveloped. On the other hand, in a normal physiologic state, the pancreas does not appear to have a major impact on the overall immune response. However, malignancies of the pancreas such as ductal adenocarcinoma demonstrate significant immune evasion, which pose unique therapeutic challenges. Here, we review our current understanding of liver and pancreatic immunology and the complex interplay of cells and cytokines therein.

Anatomic Considerations in Liver Immunology Because the vascular supply of the liver derives principally from the portal venous system draining the gut, a heavy antigen load is delivered to the liver. Portal venous blood flows slowly through the vast network of hepatic sinusoids, which are discontinuously lined by fenestrated endothelium lacking a basement membrane (Fig. 10.3; see Chapters 2 and 5). The sluggish flow of blood allows for the efficient capture of antigens by leukocytes traveling in the blood within the sinusoids and by the endothelial cells lining the sinusoids. The liver reticuloendothelial system, comprising liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), is very efficient at extracting antigens from portal blood. LSECs capture and process antigen at levels comparable to professional APCs, such as DCs.2 The microscopic anatomy of the liver also favors the ability of bloodborne leukocytes to interact with hepatic parenchymal cells and resident immune cells of the liver. The microanatomic and rheologic features of the hepatic sinusoids facilitate highly efficient antigen presentation and interactions among immune cells.

Tolerance and Immunosuppression From a teleologic perspective, tolerance to oral antigens is clearly advantageous. In experimental animal models and clinical liver transplantation studies, a greater propensity for graft acceptance 169

170

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

INNATE IMMUNITY

ADAPTIVE IMMUNITY

B

PMN B MAC

NK

B

B

DC

CD4

CD4

CD4

CD4 CD4 PMN

CD4

MAC CD8 DC

Tumor or microbe antigen Cytokine HOURS 0-12

CD8

CD8

CD8

CD8

CD8

Antibody DAYS 1-5

FIGURE 10.1  Innate and adaptive immunity. A, Innate immunity includes the body’s initial defenses against infection. It includes certain complement proteins, epithelial barriers, natural killer (NK) cells, neutrophils (polymorphonuclear [PMN]), phagocytes such as macrophages (MACs), and antigen-presenting cells such as dendritic cells (DCs). Innate immune cells may directly kill tumor or infected cells, and then present antigen to adaptive immune cells. B, In contrast, adaptive immunity refers to the precisely targeted immune mechanisms that occur later in the immune response. The adaptive immune system has B-cell–mediated humoral (dissolved) and T-cell–mediated cellular components. The innate and adaptive immune systems overlap extensively, communicating by direct cellular contact or cytokine secretion. B-cell secretion of antibodies functions to block infections and trigger the destruction of pathogenic organisms. T-cell–mediated immunity occurs after antigen presentation and leads to direct cellular lysis by CD8 T cells with support from the CD4 arm.

has been noted compared with transplantation of other solid organs. A liver transplant protects a kidney allograft transplanted simultaneously from the same donor.3 Unfortunately, primary and metastatic tumors in the liver exploit intrahepatic immunosuppression to evade destruction by the immune system. A deeper understanding of liver tolerance may support therapeutic interventions to stimulate immunity for cancer or control liver immune cell function for inflammatory conditions.

LIVER IMMUNE CELLS Among the liver’s nonparenchymal cells (NPCs), one quarter are leukocytes. The composition of the intrahepatic leukocyte population is markedly different from that seen in other organs. The liver contains most of the cellular components of innate and adaptive immunity. Importantly, liver immune cells demonstrate unique functional properties that tend to promote a tolerogenic milieu.

Antigen-Presenting Cells Experimental and clinical observations that antigens passing through the liver can lead to tolerance make the understanding of intrahepatic antigen presentation particularly relevant.4 APCs play a crucial role in driving adaptive immune responses

and bridging innate to adaptive immunity. DCs, LSECs, KCs, and B cells all play a role in antigen presentation within the liver. The context in which an APC presents an antigen can dramatically alter the response of antigen-specific T cells. Specifically, when antigen presentation occurs in conjunction with the appropriate co-stimulatory molecules, T cells proliferate and develop an immunogenic phenotypic and functional profile (Fig. 10.4). In contrast, antigens presented in the absence of co-stimulation or presence of immunoinhibitory signals lead to anergy or activation-induced T-cell death, two of the mechanisms of peripheral tolerance induction and maintenance.

Dendritic Cells DCs are a heterogeneous population of leukocytes primarily responsible for the capture of antigens in the periphery and subsequent presentation to immune effector cells. DCs are the most potent APCs of the immune system. Immature DCs are specialized to capture antigens and then migrate to lymph nodes, where they can interact with T cells. After an encounter with a pathogenic stimulus, such as bacterial lipopolysaccharide, DCs undergo phenotypic and functional changes, whereby their ability to capture antigens is diminished, but they increase their expression of class II and T-cell co-stimulatory molecules. Co-stimulatory molecule expression is essential in facilitating

171

  Chapter 10  Fundamentals of Liver and Pancreas Immunology Effector function

Proinflammatory Intracellular pathogens

-γ

IFN

CD8 T GFβ, IL -1

0

2

Naïve T or B cell

APC

Th1

IFN-γ TNF, IL-1

Portal vein

Bile duct

Sinusoid

Antiinflammatory Tolerance Proinflammatory Intracellular pathogens Lymphocyte

Th2

IL-4 IL-5, 13

1

Dendritic Plate of cell hepatocytes Arteriole

Th17

IL-17 TNF, IL-21

Signal 3 Treg

IL-10 TGF-β

Allergy, asthma Helminth infections Extracellular pathogens Autoimmunity

Central vein

A

Immunosuppression Tolerance LSEC

Bcell

Kupffer cell

Hepatocyte

Antibody production TGF-β, IFN Autoimmune disease IL-10

FIGURE 10.2  Antigen-presenting cell (APC) instruction of T and B cells. Signals 1 (antigen presentation), 2 (co-stimulation), and 3 (cytokine production) between APCs and naïve T or B cells govern the subsequent adaptive immune response. Naïve CD41 T cells can differentiate into four types of T cells—Th1, Th2, Th17, and Treg—each with a distinct cytokine profile and specific effector function. In turn, programmed CD41 T cells modulate CD81 T cells that can differentiate into either cytotoxic or regulatory cells capable of killing foreign pathogens or suppressing immune responses, respectively. B cells can also differentiate into cytokine and antibody-producing cells, which play a role in responses against tumors, pathogens, and autoimmune diseases. APCs, Antigen-presenting cells; IFN-g, interferon-g; IL, interleukin; TGF-b, transforming growth factor-b; TNF, tumor necrosis factor.

antigen presentation and efficient T-cell activation. Inflammatory conditions often promote a process of maturation, whereby DCs increase expression of MHC and co-stimulatory molecules, enabling efficient antigen presentation and T-cell activation. However, liver DC phenotype and function is somewhat unique, as we discuss later. When compared with DCs from the spleen, CD11c1 liver DCs were immature and only weakly immunostimulatory.5 In contrast to spleen DCs, liver DCs were heterogeneous in their expression of MHC class II and co-stimulatory molecules. Myeloid (CD11b1) and lymphoid (CD8a1) liver DCs, which each comprise approximately 10% of the total population of DCs in the liver, were as able to activate T cells as their splenic counterparts were. The bulk of the remaining cells, which had lowto-no expression of CD11b and CD8a, were poor T-cell stimulators. The presence of these atypical DCs accounted for the weakly activating nature of liver DCs on the whole. More recently, using a transgenic mouse in which CD11chi DCs can be depleted selectively, we found that activation of antigen-specific CD81 T cells in the liver only occurred in the presence of CD11chi DCs.6 As in the mouse, freshly isolated DCs from human liver exhibit tolerogenic properties when compared with autologous blood DCs. Human liver DCs are weaker stimulators of T cells and produce the antiinflammatory cytokine interleukin-10 (IL-10), which induces the differentiation of naïve CD41 T cells into regulatory T cells with suppressive function.7

Space of Disse Kupffer cell

Hepatic sinusoid

Lymphocyte

Blood from portal vein

Immature DC

Blood to central vein

Lymph drains from space of Disse and enters lymphatic capillaries in the portal area

B

C FIGURE 10.3  Microvascular hepatic anatomy. A, The liver is organized as lobules defined by their relation to portal vascular bundles and central veins. B, Liver sinusoidal endothelial cells (LSECs) line the hepatic sinusoids and have fenestrated membranes. A variety of immune cells exist within the sinusoids and are able to traverse the sinusoidal membrane to enter and exit the space of Disse, which is in contact with hepatocytes (From Crispe IN. Hepatic T cells and liver tolerance, Nat Rev Immunol. 2003;3:51–62.) C, Scanning electron micrograph of LSEC (320,000) demonstrated the classic fenestrated cell membrane. (From Katz SC. Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol. 2004;173:230–235.)

172

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

Teff IL-2

IFN-γ

Carcinoma

-1

PD

PD-L1

Teff PD-L1 PD-1

Carcinoma

Teff

MDSC

DC CTLA4 B7

-1

Treg

/2

Teff IL-10 TGF-β

FIGURE 10.4  Context of antigen presentation determines T-cell activation status. The three main APCs are dendritic cells (DCs), macrophages, and B cells. The immune response depends on the context in which antigens are presented to T cells. The type of APC and the presence or absence of co-stimulatory molecules are important in determining whether a T cell has no response (anergy) or is activated. Presentation of antigen by an APC to a T cell typically result in triggering of an adaptive immune response (left), unless suppressor cells or immunoinhibitory signals intervene (right). APC, Antigen-presenting cell; IFN, interferon; IL, interleukin; MDSC, myeloid-derived suppressor cells; PD-L1, programmed death ligand-1; Teff, effector T cell; TGF-b, transforming growth factor-b; Treg, regulatory T cells. (From Khan H, et al: The prognostic value of liver tumor T cell infiltrates, J Surg Res 191:189–195, 2014.)

Kupffer Cells Liver macrophages, referred to as Kupffer cells, are the primary phagocytic cells of the liver (see Chapter 7). KCs represent the largest pool of macrophages in the body, derived in part from monocytic precursors in the blood and partly from fetal precursors that seed the liver early and maintain themselves by cell division in situ. They are typically found in the hepatic sinusoids; however, they also can migrate through the space of Disse to interact with hepatocytes (see Fig. 10.3). KCs play a major role in antigen presentation and have been implicated in portal venous tolerance, possibly by regulating T-cell responses to antigens in the context of immune tolerance to liver allografts.8 On the other hand, more recent murine model work has demonstrated the ability of KCs within the sinusoids to effect CD8 T-cell activation to antigens in an intercellular adhesion molecule-1 dependent manner.9 Multiple lines of evidence from flow cytometry, lineagetracing, and single-cell RNA sequencing suggest that KCs consist of two subsets. In the mouse, there is clear evidence that one subset derives from precursors in the yolk sac and/or the fetal liver and maintains itself locally for the life of the animal. These cells express more molecules linked to endocytosis and to immune tolerance, which the alternative subset of KCs derives from blood monocytes, and are increased in abundance during emergency repopulation of the liver. Recent evidence has shown that embryo-derived KCs remain resistant to irradiation via upregulation of a kinase inhibitor Cdkn1a, which may have implications in understanding radiation-induced liver

diseases.10 In humans, lineage-tracing experiments are not possible, but genes expressed by two clusters of macrophage-like cells identified on the basis of differential gene expression argue for the same dichotomy. The distinction between KC subsets and DCs in human liver is complicated by the concern that cell surface markers that clearly distinguish macrophages from DCs in other tissues may not be absolute among liver myeloid cells, and this remains an active area of investigation.

Liver Sinusoidal Endothelial Cells LSECs are highly specialized cells that line the hepatic sinusoids. They are distinguished by the presence of fenestrations in their cellular membranes (see Fig 10.3; see also Chapter 7). The fenestrations are believed to facilitate the selective passage of antigens between the sinusoid and the hepatic parenchyma and may also increase the surface area available for antigen presentation. This strategic placement puts LSECs in the ideal position to interact with antigens and immune cells passing between the liver and the portal venous system. Several studies have shown that, in addition to serving as a structural component of the hepatic sinusoids, LSECs are immune cells with the ability to capture and present antigen to T cells.11 As with KCs, considerable controversy surrounds the immunologic function of LSECs. In contrast to earlier work, we have shown that although LSECs are highly capable of capturing various antigens in vivo and in vitro, they lack the ability to activate T cells in the absence of exogenous co-stimulation.2 The differences in results may derive from the use of more specific methods of cell isolation in the latter study. The finding that LSECs are not independently capable of triggering a T-cell–mediated immune response does not, however, exclude the possibility that LSECs, in concert with DCs or KCs, play an important role in antigen presentation in the liver.

Effector Cells T Cells Like other liver immune cell populations, intrahepatic T cells have unique properties enabling them to contribute to maintenance of a tolerogenic milieu. T cells are a heterogeneous population of adaptive immune cells with both effector and suppressor subtypes. CD41 helper T cells orchestrate immune responses, CD81 cytotoxic T cells destroy infected host or malignant cells, and Tregs play an immunomodulatory role. The liver also contains multiple nonclassical T-cell subsets, including NKT cells and gd T cells. The nature of the interactions between APCs and T cells polarizes T-cell differentiation and thus determines the outcome of a particular immune response. The liver contains a full complement of T-cell subsets, although the relative proportions of each population are different when compared with lymphoid organs. Conventional or classical T cells express the ab T-cell receptor in association with either CD4 or CD8. These are the most prevalent T cells in the body and account for about one third of the murine liver T-cell population. In contrast, unconventional T cells expressing NK markers or the gd T-cell receptor comprise a greater proportion of liver T cells, approximately 50% and 10%, respectively. Immunosuppressive Tregs expressing FOXP3 are heavily represented in the liver. Among the classical T cells, the liver also contains Th17 cells, which are capable of producing the highly inflammatory cytokine IL-17. Th17 cells play an important role in the promotion of inflammatory and fibrotic disorders affecting the liver.

  Chapter 10  Fundamentals of Liver and Pancreas Immunology

The diversity of conventional T cells is based on their recognition of specific peptide antigen motifs within the context of MHC class I or II molecules expressed by APCs. The ab T-cell receptor is highly variable, and numerous T cells, each recognizing a different antigen presented by APCs, are present in the immune system. CD81 T cells respond to peptides presented on MHC class I molecules, which are expressed by nearly every cell in the body, excluding erythrocytes. Activated CD81 T cells become cytotoxic T lymphocytes. CD41 helper T cells recognize antigens presented on MHC class II molecules on the surface of professional APCs. CD41 T-cell subsets, Th1 and Th2 cells, then regulate and amplify the immune response by secreting cytokines, which affect nearby effector cells.

gd T Cells The gd T-cell receptor is relatively invariant and can recognize multiple nonpeptide antigens without the need for MHC presentation. gd T cells represent 10% of liver T cells, whereas they comprise only a small proportion (,5%) of T cells in the blood or lymphoid organs. gd T cells also are abundant at other environmental interfaces, including the skin and mucosal surfaces. Through secretion of activating and modulatory cytokines, gd T cells help orchestrate early responses to atypical bacterial and viral pathogens. gd T cells can also promote antitumor immunity through their early secretion of interferon-g (IFN-g).12 Conversely this cell type has immunosuppressive properties as well.13 The high proportion of gd T cells in the liver suggests that they have an important immunologic role, but further investigation is required. As with most lymphocyte populations, heterogeneity among liver gd T cells precludes simple generalizations concerning their functions.

Natural Killer T Cells NKT cells share characteristics of conventional T cells and NK cells and are defined by the presence of several T cell and NK cell surface markers. Most NKT cells react against glycolipid antigens in the context of CD1d, which is an MHC class I–like glycoprotein. CD1d is expressed on APCs and hepatocytes. NKTs express invariant T-cell receptor chains that are conserved across species, suggesting an important role for NKT cells in the innate immune response to pathogens. Activated NKT cells are capable of producing IFN-g and IL-4, which are the prototypical Th1 and Th2 cytokines, respectively. NKT cells constitute a relatively large proportion of T cells found in the liver compared with other organs. In addition, a local expansion of NKT cells is seen in several models of liver injury, such as partial hepatectomy. NKT cells play a role in inflammatory diseases and in clearance of infection from the liver. Depletion of NKT cells abrogated the effects of experimentally induced hepatitis in a mouse model, and mice lacking NKT cells are susceptible to viral and bacterial infections. NKT cells also play a part in tumor surveillance in the liver. In murine primary and metastatic tumor models, NKT cells can mediate tumor rejection, in part because of their ability to secrete IFN-g.14 Work in other murine models suggests that liver NKTs have the capacity to suppress T-cell proliferation and hence contribute to immunosuppression in the liver.13

Natural Killer Cells NK cells are innate responders and, unlike T cells, do not possess receptors for specific peptide antigens. By expressing a variety of activating and inhibitory receptors, NK cells can bind ligands on

173

their target cells. The resulting activation of NK cells causes the release of lytic granules, or cytokines such as IFN-g, which kill the infected host or tumor cell in an MHC-unrestricted fashion. NK cells are a major component of murine and human liver lymphocytes and mediate inflammatory reactions seen in viral and autoimmune hepatitis. Bulk human liver NK cells possess weaker lytic capabilities when compared with autologous blood NK cells15 because the liver has a greater proportion of NK cell subtypes with weaker cytolytic function when compared with blood NK cells.

B Cells B cells mediate adaptive immune responses, delivering humoral immunity through antibody production. B cells may also function as APCs. Although hepatic B cells have received very little attention, they make up a significant proportion of liver lymphocytes. They play prominent roles in viral and autoimmune disease affecting the liver.16 MDSCs in the liver suppress hepatic B cells through downregulation of CD80, which is a costimulatory molecule involved in T-cell activation.17 This may be a mechanism through which hepatic B-cell function is altered to contribute toward intrahepatic tolerance.

OVERVIEW OF PANCREATIC IMMUNOLOGY The immune milieu of the exocrine pancreas is less exhaustively studied than that of the liver, and there is a less conspicuous immune cell compartment in the absence of disease. Besides lacking the richness of antigen-presenting cells and specialized cell types, such as the sinusoidal endothelial cells, many conditions such as pancreatic adenocarcinoma have been characterized by a dense stromal fibrosis, which was initially thought to exclude components of the effector cells from the peritumoral area.18 However, more recent work has highlighted a nuanced view of the balance of T-cell activation and immunosuppressive elements within the pancreas, which will be highlighted in subsequent sections.

Immunoinhibitory Pathways of the Liver and Pancreas Suppressive or co-inhibitory signaling pathways are important mediators of tolerance and immune evasion within both the liver and pancreas. The immunoinhibitory receptors receiving the most attention in laboratories and clinical trials are the checkpoint molecules CTLA-4 and PD-1.19,20 The PD-1 and CTLA-4 axes are pivotal regulators of T-cell activity that can be usurped by tumors to induce T-cell suppression (see Fig. 10.4). CTLA-4 is expressed on activated T cells and constitutively on Tregs, and blocking the activity of CTLA-4 enables T-cell functional rescue. Like CTLA-4, PD-1 is a co-inhibitory receptor but with distinct biologic properties. PD-1 has two known ligands: programmed death ligand-1 (PD-L1) and PD-L2. Many tumors and suppressive immune cells express PD-L1, and PD-1 engagement by PD-L1 results in T-cell functional exhaustion.21 Exhausted T cells have a markedly diminished capacity for cytokine production, proliferation, and tumor lysis. Tregs are a subset of CD41 T cells that mediate tolerance by suppressing antigen-specific T cells.22 Differentiation of Tregs is programmed by the FOXP3 transcription factor, which is also useful for identifying Tregs experimentally. Immunosuppression by Tregs is mediated through numerous mechanisms, including secretion of tolerogenic cytokines and expression of PD-L1. MDSCs work in concert with Tregs to promote an

174

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

immunosuppressive environment. MDSCs are a heterogeneous group of cells derived from a myeloid lineage pathway. Phenotypically, MDSCs have features of immature neutrophils, monocytes, or NK cells. MDSCs express PD-L1 and promote T-cell suppression through production of suppressive cytokines such as IL-10. Tregs and MDSCs are likely both important contributors to baseline liver tolerance, as well as suppression of immune responses to cancer in the liver and pancreas.

TABLE 10.1  Host Defense Responses to Lipopolysaccharide and Endotoxemia ACUTE-PHASE RESPONSE

Elevated core temperature Antimicrobial response

Immunologic

Complement activation Leukocytosis (neutrophilia) Proinflammatory response (IL-1a, IL-1B, TNF-a, IL-1R, TGF-b, protease inhibitors) B-cell stimulation, antibody production

Coagulation

Decreased protein C Decreased antithrombin III Increased cell adhesion Activation of coagulation cascade Increased tissue factor production Prostaglandin production Platelet aggregation, platelet-activating factor Fibrinogen

Metabolic

Lipolysis Mobilized amino acids Altered glucose metabolism Increased corticosteroid production

CYTOKINES Cytokines are small proteins that play a primary role in the human response to a variety of stimuli. These nonstructural proteins participate in the communication between cells. Pleiotropic in nature, many cytokines can produce both proinflammatory and antiinflammatory effects, depending on the timing, levels, and context in which they are secreted. Cytokines are crucial mediators in the development of hepatic diseases, as well as regeneration and repair, so it is reasonable to suppose they play a similar role in pancreatic pathophysiology. Elucidation of the mechanisms of these mediators will allow an enhanced understanding of the natural history of liver, biliary, and pancreatic surgical diseases. Although produced by all nucleated cells, constitutive production of most cytokines is low in the absence of noxious stimuli. This section reviews these stimuli, as well as the specific mediators involved, in the pathophysiology of liver, biliary, and pancreatic disease.

Immune Recognition and Toll-Like Receptors Immune response to microbial pathogens and biologic insults requires quick identification of the threat to minimize damage to the host. The innate immune system is a first-line defense against microbial pathogens, providing the ability to distinguish self from non-self via cell-surface receptors expressed in many cell types. Additionally, central to this defense mechanism is the ability to recognize cellular damage. The liver, biliary system, and pancreas play a vital role in development of immunologic responses because of their close physiologic relationship with the gut. Portal blood entering the liver contains a diverse load of antigens and microbial products, which functions to shape immunologic tolerance, as well as an organized response of inflammatory mediators.23 Recognition of cellular damage and microbial products is accomplished via intracellular and cell-surface–expressed pattern recognition receptors (PRRs).24 An example of essential PRRs in the liver is the family of Toll-like receptors (TLRs). TLRs are a family of at least 10 transmembrane receptors found in cells throughout the human body. Although essential for protective immunity in the normal state, aberrant or prolonged responses can produce catastrophic effects on the host. Accordingly, TLRs have been demonstrated to be essential in the development of multiple hepatic diseases and continue to be investigated as potential therapeutic targets.

Endotoxins and the Immune Response Exclusive to gram-negative bacteria, lipopolysaccharide (LPS) is one of the most studied pathogen-associated activators of inflammation. An activator of proinflammatory cytokines, LPS plays a large role in tissue damage and development of septic shock, classifying it as an endotoxin.25 Although the exact mechanism of LPS pathogenesis in human disease remains undefined, its role in activation of the host innate immune response

HOST DEFENSE

Thermoregulation

IL, Interleukin; IL-1R, interleukin-1 receptor; TGF-b, transforming growth factor-b; TNF-a, tumor necrosis factor-a.

is well understood (Table 10.1). Increasing insight into the downstream effects of the LPS response is likely to open up potential areas for targeted treatment. The host innate immune recognition and response to LPS is highly ordered and is crucial to preventing overwhelming infection and resultant sepsis. Although it is crucial that the high sensitivity of the system allows rapid mobilization of host protective mechanisms, self-limitation of this response is just as vital, preventing irreversible tissue damage and allowing return to homeostasis. Extensive study has recognized a strictly ordered sequence of interactions with multiple extracellular and cellsurface host proteins, including LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2), and TLR4.26,27 Initiation of the host innate immune response to LPS is binding of it to LBP to form the LPS-LBP complex.28 The importance of LBP in beginning this inflammatory cascade is noted by the rise in LBP ribonucleic acid (RNA) and protein synthesis during the initial acute phase of endotoxic shock.29 LBP, a 58 kDa glycoprotein secreted by hepatocytes into the bloodstream, binds the lipid A portion of LPS with high affinity and facilitates transfer to, and the subsequent effects of, CD141 cells. The initial signal-transducing component of this pathway is TLR4. Although expressed at low levels in healthy hepatic cells, increasing evidence points to altered LPS-TLR4 complex signaling in the pathogenesis of chronic liver disease. This complex, with the addition of the extracellular protein MD-2, functions to catalyze the intracellular signaling cascade.30 This system of signaling and enhanced response to LPS to activate the innate immune response is advantageous to the host in that it can provide enhanced protection from gramnegative induced infection. However, an unregulated response can cause an extremely damaging host response, as is seen with overwhelming sepsis. Specific regulatory mechanisms are needed to prevent the potential shock, multisystem organ failure, or possible death that can result without modulation of the previously described signaling pathways.

  Chapter 10  Fundamentals of Liver and Pancreas Immunology

Macrophages previously exposed to LPS demonstrate reduced responses to repeat stimulation; this LPS tolerance is important for the negative regulation of the systemic inflammatory response.31 At the cell-surface level, RP 105 (radioprotective 105), a homolog of TLR4, can function to competitively inhibit the interaction between LPS and TLR4.32 At the TIR domain of TLR4, overexpression of TRIAD3A, an E3 ubiquitinprotein ligase inhibitor, functions to promote degradation of TLR4 and downregulation of NF-kB.33 These examples, along with multiple additional proteins that function to regulate TLR4 signaling, can prove to be potential targets to counteract destructive inflammatory responses.

Tumor Necrosis Superfamily The tumor necrosis factor (TNF) superfamily is composed of more than 20 primarily type II transmembrane proteins with more than 30 receptors. This family of ligands acts on the immune response, cell proliferation, and apoptosis.34,35 Induction of the inflammatory response by TNF-a acts on vascular endothelial cells, producing vasodilation and capillary permeability that increase trans-endothelial passage of fluid via alterations of adhesion molecules, increased production of nitric oxide, and cyclooxygenase (COX). Further cellular damage and deleterious inflammatory effects are produced by the triggering effect of TNF-a on secondary mediators, such as IL-1, IL-6, IL-10, IFN-g, platelet-activating factor, epinephrine, cortisol, and growth hormone. This activation contributes to the wide range of physiologic effects seen with overwhelming septic shock.36 TNF-a has long been investigated as a potential chemotherapeutic agent because of its antiproliferation properties and effects on vascular permeability.37 Systemic use has been limited, however, by its significant side effects. Low-dose TNF-a administration in healthy volunteers produced an acute activation of neutrophils, accompanied by a rapid increase in plasma concentrations of IL-6, IL-8, and acute-phase proteins. Additionally, participants demonstrated a sustained decrease in lymphocytes, basophils, and eosinophils.38 Because of the increased doses of TNF-a needed in chemotherapeutic regimens, such as with isolated limb perfusions, continuous monitoring of systemic leakage and infusion rate adjustment is necessary.39

Interleukin-6 IL-6 is involved in inflammation through effects on cell differentiation, proliferation, and apoptosis, and is active in other functions, including immune regulation and oncogenesis.43 IL-6 belongs to a nine-member superfamily of cytokines, which includes leukemia inhibitory factor, oncostatin M, cardiotrophin-1, neurotrophic factor, and IL-11. Signal transduction for all members of this family uses the signaltransducing receptor glycoprotein 130 kDa (gp130), making this a potential target for future therapies. Upon formation of gp130 homodimers by ligand binding, signaling is carried forward primarily by the Janus activating kinase/signal transducer and activator of transcription pathway. IL-6 has a wide range of effects, both in the hematopoietic system and in the innate immune response, including a substantial role in the balance between IL-17–producing T cells and regulatory T cells. IL-6 overproduction and upregulation of Th17 cells is thought to be a critical factor in development of multiple autoimmune disorders.43 IL-6 and IL-11, with known effects on cell proliferation, are felt to play a crucial role in the development of hepatocellular carcinoma (Fig. 10.5). Current studies are underway investigating inhibition of these cytokines in solid tumors.

Transforming Growth Factor-b Transforming growth factor-b (TGF-b) is another pleiotropic cytokine involved in many aspects of cellular function, including differentiation, migration, angiogenesis, and apoptosis.44 It is stored as an intracellular latent form until it is activated by several factors, including MMPs, integrins, and thrombospondin 1.46 The downstream effects of this cytokine are quite context- and cell-dependent. The primary signaling mechanism is through the phosphorylation of SMAD2 and SMAD3, allowing

Epithelial/ Immune cells Malignant cells Fibroblasts IL-6

IL-11

gp130

Interleukin-1 IL-1 is a potent factor in activation of the innate immune system and inflammatory response. Because the cytoplasmic domain of the IL-1 receptor type I is homologous to those of TLRs, similar activation of proinflammatory immune responses would be expected.40 Unlike most other cytokine families, however, the IL-1 family includes members that actively function in suppression of the innate immune response.41 IL-1 primarily produces an immune response via gene expression of multiple inflammatory mediators. This is observed with the IL-1–mediated production of COX-2 and inducible nitric oxide synthase, as well as increased expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.42 These products, as well as interaction with and potentiation of other cytokines, result in the symptoms of inflammation, vasodilation, and movement of activated inflammatory cells to tissues, which are seen with activation of the innate immune response. Stimulation of IL-1 can occur via LPS, as is seen with other cytokine families. However, other factors, such as TNF-a, complement C5a, hypoxia, or IL-1 ligands per se, can induce increased IL-1 messenger RNA transcription.

175

RAS/ERK

JAK/STAT3

PI3K/AKT

Tumor cell proliferation

Tumor cell survival EMT/ invasion Malignant cells

Metastasis Angiogenesis Inflammation Microenvironment

FIGURE 10.5  Interleukin (IL)-6 and IL-11 signaling in cancer. IL-6 and IL-11, produced by immune cells, fibroblasts, and epithelial and malignant cells, activate the JAK/STAT3, SHP-2-RAS-ERK, and PI3K-AKT pathways, through which they induce cell proliferation, survival, EMT/ invasion, metastasis, angiogenesis, and inflammation. AKT, Protein kinase B; EMT, epithelial-to-mesenchymal transition; ERK, extracellular signal-regulated kinase; gp130, glycoprotein 130; JAK, Janus activating kinase; PI3K, phosphatidylinositol-3-kinase; RAS, rat sarcoma (protein); STAT, signal transducer and activator of transcription. (From Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 26:54–74, 2014.)

176

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

translocation into the nucleus and resultant gene activation.47 Additionally, activation can occur via SMAD-independent pathways, primarily through MAPKs. Paradoxically, TGF-b can function to arrest growth, as well as act as a tumor promoter. The functional switch can occur at many points in the signaling pathway. In the SMAD-dependent pathway, location of formation of the active complex appears to play a role in conversion to oncogenic properties because increased phosphorylation of the linker region of SMAD3, in preference to the C-terminal region, is seen in many advanced tumors.48 Although less common, mutations can also play a role in tumor development, which is seen with increased SMAD4 inactivation in pancreatic carcinoma.49 Additionally, aberrant TGF-b signaling has been implicated in the progression of hepatic fibrosis through the increased production of connective tissue growth factor by hepatic progenitor cells50 (see Chapter 7).

Type I Interferons (Interferon-a and Interferon-b) Type I IFNs refers to a family of structurally similar cytokines that are crucial in the immune response to viral infection. IFNa is secreted by immune cells, whereas IFN-b is secreted by multiple cell types, such as fibroblasts, in response to viral infection. Type I IFNs have direct antiviral action by triggering virally infected cells to produce enzymes that interfere with viral RNA or DNA replication. They also lead to the increased expression of MHC class I molecules on the surface of virally infected cells, increasing their likelihood of being killed by cytolytic CD81 T cells. Additionally, type I IFNs inhibit cellular proliferation. IFN-a has been used clinically in the treatment of viral hepatitis and as an adjuvant therapy for melanoma.

Type II Interferons (Interferon-g) IFN-g, a type II IFN, is the archetypal proinflammatory cytokine associated with antitumor immune responses. IFN-g activates macrophages and plays a crucial role in bridging innate and adaptive immunity by increasing antigen presentation through the MHC class I and II pathways.51 It is produced by T cells, B cells, NKT cells, DCs, and macrophages. IFN-g promotes Th1-driven cytotoxic T-cell responses, which are essential for clearance of virally infected cells or tumors. In addition, IFN-g promotes MHC expression on APCs and enhances NK cell cytotoxic activity. Increases in serum IFN-g levels have been correlated with favorable clinical responses to immunotherapy treatments. However, IFN-g is a double-edged sword. In addition to promoting APC activation and antiviral immunity, it participates in adaptive resistance, a phenomenon whereby the activation of T cells leads to IFN-g secretion and the activation of genes encoding co-inhibitory molecules, in particular PD-L1.52,53

Cytokine Regulation in the Liver and Pancreas Hepatic response to inflammation and parenchymal injury produce a variety of effects in the host, both locally and systemically. Although cytokine expression in the liver is low at baseline, as a nonspecific first line of defense from bacterial products from the hepatic circulation, a rapid, orchestrated response is needed for host protection. Hepatic cytokine contribution has been demonstrated in human studies, where cannulation of the hepatic vein after intravenous endotoxin administration revealed that large amounts

of both TNF-a and IL-6 in the systemic circulation were derived from the splanchnic bed.54 Increasing evidence has also defined the role of hepatic stellate cells in recruitment and induction of infiltrating leukocytes, amplifying the inflammatory response. Infiltration of T cells and NK cells can enhance production of TNF-a, FASL, and TGF-b in virally induced hepatic injury.55 Increasing levels of these cytokines are found in both hepatic injury and regeneration.

Cytokines and the Pancreas Defining the effects of specific cytokines in pancreatic dysfunction is complicated by the pleiotropic effect of these molecules. Pancreatic islet cells produce multiple cytokines in the healthy state, regulating b-cell function and replication. Increasing IL-1 levels stimulates b-cell proliferation to respond to exogenous stressors. Nevertheless, prolonged stress has been implicated in islet cell dysfunction and destruction. Mouse models have demonstrated the role of TGF-b in the progression of type 1 diabetes, and elevated concentrations of this cytokine have been implicated in increased microvascular complications in children with diabetes.56 TGF-b has also been studied as a contributing factor in the development of chronic pancreatic inflammation (see Chapters 57 and 58) and pancreatic adenocarcinoma (see Chapter 59). Elevated levels are found in patients with chronic pancreatitis, correlating with progression of fibrosis and insulin resistance. It has been postulated that insensitivity to TGF-b stimulation, with resultant elevated levels, results in a switch from inhibitory effects to increased proliferation of pancreatic adenocarcinomas, in concert with additional cytokine influence. Accordingly, elevated TGF-b1 and TGF-b2 receptor levels have been associated with advanced cancers, with a trend toward worse overall survival.57

Nitric Oxide Altered redox states and oxidative stress have been extensively studied in a multitude of disease states because of their participation in inflammation and apoptosis.58 Oxidative stress implies an imbalance between oxidant and antioxidant agents; when the capacity of the antioxidant system is overwhelmed, a harmful level of redox state is achieved and the potential for cellular damage arises. Central to the balance of redox states in hepatocytes is nitric oxide (NO). NO is a small, hydrophobic molecule with a short half-life. Created by nitric oxide synthase (NOS), NO can be greatly increased via production by inducible NO synthase (iNOS). iNOS is expressed in all hepatic cells, and its production can be induced by IL-1, TNF-a, and LPS.59 NO plays a complicated role in hepatocyte cellular function. In steady-state low-redox conditions, NO plays a protective role in the liver, having been demonstrated to inhibit apoptosis and abate mitochondrial dysfunction.60,61 NO also functions as a cytoprotective molecule by acting as an electron acceptor for S-nitrosylation, causing inhibition of caspase activity.62 Upregulation of iNOS is also an important factor in the propagation of the inflammatory response, which can play a protective role. NO induces the expression of heat-shock protein 70.63 These proteins may function by refolding damaged proteins in the liver, modulating caspase activation, and regulating expression of heme oxygenase-1, conferring a protective mechanism from apoptosis. NO also can bind soluble guanyl cyclase, which can increase intracellular cyclic guanosine monophosphate, suppressing apoptosis and caspase activity.64

  Chapter 10  Fundamentals of Liver and Pancreas Immunology

TABLE 10.2  Roles of iNOS in Hepatic Injury CONDITION/INDUCERS

NO EFFECT MECHANISM

In Vivo Endotoxemia

Protective Toxic

Inhibition of apoptosis Oxidative stress Circulatory failure

TNF-a

Protective

Inhibits apoptosis

CCl4

Protective

Decreases oxidative stress

Liver Regeneration

Protective

Inhibits apoptosis

Ischemia/reperfusion

Toxic

Oxidative damage

Hemorrhagic shock

Toxic

Direct toxicity, activates inflammation

Alcoholic liver injury

Protective

Unclear

TNF-a, FAS antibody

Protective

Inhibits caspase/apoptosis HSP70 upregulation

H2O2

Protective

Heme oxygenase-1 upregulation

Acetaminophen

Protective

Modulates GSH levels

In Vitro

CCl4, Carbon tetrachloride; GSH, reduced glutathione; H2O2, peroxide; HSP70, 70-kDa heatshock protein, iNOS, inducible nitric oxide synthase; NO, nitric oxide; TNF-a, tumor necrosis factor-a. Modified from Li J, Billiar TR. Nitric oxide. IV. Determinants of nitric oxide protection and toxicity in the liver. Am J Physiol. 1999;276:G1069–G1073.

In conditions of oxidative stress and altered redox states, upregulation of iNOS has been associated with deleterious effects because of continued oxidative damage and propagation of inflammation. Studies in mice have demonstrated reduced hepatic damage with inhibition of NO synthesis, and iNOS has been implicated in ethanol-induced hepatic injury.65 Viral hepatitis has also been associated with increased iNOS expression, with several studies suggesting an association between levels of iNOS induction and disease severity.66 Thus it appears that the NO functioning in either a protective or destructive role can vary depending on cellular levels and redox conditions (Table 10.2).

IMMUNE SYSTEM IN NONMALIGNANT LIVER DISEASES Intrahepatic immune cells play prominent roles in myriad inflammatory, infectious, and neoplastic diseases affecting the liver. Our understanding of liver immune cell biology and crosstalk among intrahepatic immune cell subsets has greatly informed our appreciation of liver disease pathogenesis. The following sections highlight the role of the hepatic immune system in a variety of diseases affecting the liver.

Transplantation Transplant immunology has shed significant light on the unique properties of the liver as an immunologic organ (see Chapter 104). Unlike other organs, the liver can be accepted across MHC barriers in animal models of transplantation.67 In addition, systemic donor-specific tolerance often develops in liver allograft recipients.68 In humans, liver transplants confer protection for other organs from the same donor,69 and recipients can often be weaned off immunosuppression altogether.70

177

BOX 10.1  Factors Contributing to Hepatic Tolerance • Immunosuppression via release of soluble MHC class I antigens • Distinct lymphocyte population with distinct functions (KCs, DCs, NK, and NKT cells, LSECs) • Constant antigen load from the portal circulation • Induction of activated T-cell apoptosis • Microchimerism • Immature phenotype and tolerogenic function of resident liver APCs (DCs, KCs, LSECs) • Altered Th1 versus Th2 profile within the liver (favoring Th2) • Presence of suppressor cells (Tregs and MDSCs) • Immunoinhibitory pathways (CTLA-4, PD-1) APCs, Antigen-presenting cells; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; DCs, dendritic cells; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells; MDSC, myeloidderived suppressor cells; MHC, major histocompatibility complex; NK, natural killer; NKT, natural killer T cell; PD-1, programmed death-1; Treg, regulatory T cells. Modified from Gershwin ME, Vierling JM, Manns MP, eds. Liver Immunology. Hanley and Belfus; 2003.

The unique ability of allografts to resist rejection and promote extrahepatic tolerance speaks to the immunosuppressive properties of hepatic immune cells. The development of mouse models of orthotopic liver transplantation has provided an opportunity to gain mechanistic insight into the regulation of immune responses in the liver.71 Factors that contribute to hepatic tolerance (Box 10.1) include microchimerism and induction of activated T-cell apoptosis. Defined as the persistence of donor cells in allograft recipients, microchimerism has been postulated to be a prerequisite for organ allograft acceptance.72,73 The high antigenic load derived from the donor liver coupled with persistence of donor APCs within lymphoid tissues of the recipient may provide a continuing source of allostimulation.74,75 The persistent activation of alloreactive recipient T cells is thought to result in exhaustive deletion and induction of systemic tolerance. The role of specific donor-derived liver APCs, such as DCs and KCs, in contributing to chimerism-induced tolerance remains unclear. Although freshly isolated liver DCs have been shown to exhibit tolerogenic potential via the production of IL-10,7 others have shown that donor-derived liver DCs prime recipient T cells to differentiate into proinflammatory subtypes that promote rejection.76 The immunoregulatory role of KCs has also been extensively investigated. KCs have been implicated in the induction of oral tolerance and in lymphocyte apoptosis, which has been a proposed mechanism of immunosuppression in liver transplantation.77 More recently, KCs have been shown to play a crucial role in induction of antigen-specific T-cell tolerance78 and are thought to suppress T-cell response via the production of prostaglandins.79 Despite evidence of the tolerogenic potential of KCs, the use of gadolinium chloride to suppress KC function has not been shown to impact survival of liver allografts in mouse models of liver transplantation. The disparate findings concerning the role of KCs in liver transplantation may reflect the opposing effects of tolerogenic MDSCs and proinflammatory macrophages, both of which share considerable phenotypic overlap with KCs. The overall bias of intrahepatic T-cell responses toward tolerance and apoptosis might account for the survival of liver allografts.80 Activated T cells and their subsequent apoptosis within the liver are thought to be another critical component in the induction of hepatic tolerance and the acceptance of liver allografts. Recently, hepatic stellate cells (HSCs) have been

178

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

found to mediate liver T-cell apoptosis via the PD-L1/PD-1 axis.81 HSCs may also induce expansion of Tregs as another mechanism of influencing T-cell tolerance.82 Although the hepatic immune system has been shown to clearly play an important role in liver and systemic tolerance, definitive mechanisms in humans remain elusive. It is likely that multiple suppressive cell types and several overlapping immunoinhibitory pathways interact to form a network of tolerance within the intrahepatic space. Understanding the mechanisms controlling the tolerogenic propensity of the liver is of great significance in transplantation because it will permit the design of novel approaches to reduce immunosuppressive-related morbidity and mortality.

Hepatitis Hepatitis B virus (HBV) and hepatitis C virus (HCV) are noncytopathic and hepatotropic and cause acute and chronic liver disease (see Chapter 68). The worldwide burden of disease is immense, with an estimated 500 million people infected with either of these two viruses. The cost to society is magnified when the increased risk for cirrhosis and liver cancer in those infected with HBV and HCV are taken into account. Immunemediated or inflammatory destruction of liver parenchyma is a common final pathway in viral hepatitis. The presence of large numbers of KCs and DCs in the liver, which produce TNF-a in response to viral antigens, leads to high local levels of inflammatory cytokines and untoward host cell damage. Similarly, T cells, NKT cells, and NK cells in the liver produce IFN-g, which also serves to amplify the local immune response by activating KCs and DCs. Consistent with this, chronic active hepatitis is morphologically identified by piecemeal necrosis and a predominantly mononuclear cell infiltrate.83 Despite immune cell activation and inflammatory cytokine production, the host is frequently unable to clear HBV or HCV. Therefore, to achieve successful viral control and limit collateral damage, a sustained, antigen-specific immune response is necessary.84,85 Recognition of multiple viral epitopes by the host is also advantageous because it offers some protection against the emergence of mutants that escape the immune system. Unfortunately, effective T-cell responses against HBV and HCV are susceptible to suppression by the PD-1/PD-L1 immunoinhibitory access and Treg.86 The tolerogenic predisposition of the liver may suppress adaptive immunity to HBC and HCV, accounting in part for the persistence of these infections. Emerging research tools that will undoubtedly shed more light on the immune mechanisms underlying viral persistence and resistance to treatment include the development of chimeric mice that are reconstituted with human hepatocytes and immune cells.87 The transplantation of human hepatocytes into immunodeficient mice will allow for large-scale screening of therapeutics against human hepatitis viruses, and an immunocompetent humanized murine HCV infection model has also been developed.88 Chimeric murine models will enable researchers to study the in vivo effects of human hepatotropic viruses on human immune responses to infection for the first time.

Autoimmune Hepatitis Autoimmune hepatitis (AIH) is an idiopathic disorder that leads to cirrhosis as a manifestation of an overactive hepatic immune system (see Chapter 105). AIH likely reflects an imbalance between proinflammatory immune responses and immunosuppressive factors, the latter including PD-1/PD-L1, Treg, and

MDSC. It has a female predominance and is characterized by elevated levels of immunoglobulin G (IgG) autoantibodies.89 An experimental model of autoimmune hepatitis is based on the treatment of mice with concanavalin A (ConA), a plant lectin known to activate T cells in vitro. A single intravenous injection of ConA leads to severe liver damage and is associated with the activation of CD41 T cells and the production of TNF-a and IFN-g. Further studies showed that NKT cells are the most important subset of CD41 T cells involved in mediating ConA hepatitis. The importance of NKT cells in mediating autoimmune liver damage is also supported by the observation that injection of a-galactosylceramide, an activator of NKT cells through CD1d binding, leads to a similar form of injury as that seen in ConA hepatitis. AIH has also been linked with dysfunction of Tregs, leading to a hyperfunctional Th17 compartment and excessive inflammation.90 The pathogenesis of AIH highlights the critical importance of balance between proinflammatory and antiinflammatory immune processes within the liver.

Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is an autoimmune liver disease that leads to the destruction of intrahepatic bile ducts and subsequent cholestasis and cirrhosis91,92 (see Chapter 105). Most cases of PBC are associated with antimitochondrial (95%) and antinuclear (50%) antibodies directed against self-antigens. Dysregulated CD41 helper T cells and CD81 cytotoxic T lymphocytes are thought to be important in the pathogenesis of PBC. This is supported by the findings of lymphoid infiltration of the portal tracts and aberrant expression of MHC class II on biliary epithelial cells. Because biliary epithelial cells are the primary target of injury in PBC, their expression of MHC molecules and cytokines likely plays an important role in the pathogenesis of this disease. The degree of Th17 activity within the liver of PBC patients has been associated with severity of disease, and IL-17 promotes excessive fibrosis.93 In addition to pathogenic T-cell function, biliary epithelial cells from patients with primary biliary cirrhosis attract mononuclear cells via the chemokine CX3CL1 and overexpress the inflammatory cytokines IL-6 and TNF-a.94

Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) results from fibrosis of the intrahepatic and extrahepatic bile ducts95 (see Chapters 41 and 105). The pathogenesis is thought to result from immune activation within the liver after bacteria gain access to the portal circulation via a diseased intestinal epithelium. The disease is associated with T cells infiltrating the portal tracts. In addition, an increase in production of circulating proinflammatory cytokines has been shown to correlate with disease progression. Pathologic Th17 cell activation in response to bacteria and PRR activity contributes to inflammation in PSC patients.96 The end result is biliary cirrhosis and a markedly elevated risk for cholangiocarcinoma (CCA). Most cases of PSC are associated with underlying inflammatory bowel disease, specifically ulcerative colitis.

Ischemia/Reperfusion Injury Liver ischemia/reperfusion (I/R) injury is a well-recognized consequence of trauma, circulatory shock, partial hepatectomy, and liver transplantation (see Chapters 106 and 113). It contributes to the shortage of organs available for transplantation and is a major determinant of postoperative allograft dysfunction and morbidity.97 During liver I/R, the release of endogenous

  Chapter 10  Fundamentals of Liver and Pancreas Immunology

molecules signal danger to the host by activating innate immune cells through their interaction with TLRs.98 Such “danger signals,” or danger-associated molecular patterns (DAMPs), can be classified as intracellular proteins, nucleic acids, or components of the extracellular matrix that are released after host cell injury. The ensuing host innate immune response results in untoward collateral tissue damage that culminates in hepatocyte death and a systemic inflammatory response. The injury stems from the inability of TLRs on innate immune cells to distinguish infectious ligands from DAMPs released by autologous tissue. The need for effective approaches to manage patients with I/Rinduced organ damage is highlighted by the fact that current treatment is merely supportive care. In a murine model of segmental liver I/R, hepatic DCs and TLR9 played critical roles in modulating the host immune response.7 Hepatocyte DNA released during ischemia binds TLR9 in a variety of liver immune cells that then cause liver damage. In contrast, DCs respond to host DNA by curtailing injury via production of antiinflammatory IL-10, which confers protection by suppressing the function of inflammatory monocytes that migrate to the liver from the bone marrow. Human liver DCs also have a propensity to secrete large amounts of IL-10 at baseline and after TLR activation.7 T cells also play a role in I/R tissue injury, with Th17 cells promoting influx of neutrophils.99 Improved understanding of the complex interactions between DAMPs and PRRs on immune cells will promote the development of rational, more effective approaches to limit liver I/R injury. TNF-a also appears to play a central role in I/R injury. Murine models have demonstrated a significant increase in TNF-a levels after 90 minutes of ischemia, followed by 60 minutes of reperfusion.100 Although the exact mechanism stimulating TNF-a release is not yet defined, it appears that production is significantly influenced by KC activation. In rats, KCs isolated from the liver after I/R demonstrated a several hundred-fold increase in TNF-a production compared with controls. Treatment with anti–TNF-a antibodies significantly decreased both TNF-a and IL-6 production.101 Mediation of the effects of TNF-a occurs primarily through activation of NF-kB. Translocation to the nucleus and binding activity of NF-kB increased as much as 66% after 5 minutes of ischemia.102 Additionally, inhibition of NF-kB activation has demonstrated significantly decreased hepatic apoptosis and caspase-3 activity.103 This is similar to findings with induction of heme oxygenase-1, which functions to suppress TNF-a/TNFR1directed hepatic apoptosis.104 NOS also appears to be a factor in hepatic ischemiareperfusion injury. The endothelial isoform of NOS (eNOS) has most clearly been defined as a protective molecule during reperfusion. eNOS knockout mice demonstrated increased severity of hepatic injury after ischemia compared with their wild-type counterparts. Additionally, TNF-a expression was upregulated to a level five times that in the wild-type mice,105 suggesting a protective effect from cytokine injury. This protection has demonstrated effects beyond the liver because NO has also been shown to reduce the incidence of onset of hepatopulmonary syndrome in transplanted rats.106

IMMUNE SYSTEM IN MALIGNANT LIVER DISEASES Evidence on the importance of the hepatic immune system in malignancy comes from data, which reveal that (1) when compared with autologous blood, human liver specimens from

179

patients with malignancy contain a disproportionately higher percentage of NK cells with reduced antitumor function15 and (2) the hepatic T-cell infiltrate predicts survival after surgery in patients with metastatic colorectal liver cancer.107 Tumorinfiltrating lymphocytes (TILs) indicate a specific host response to tumor antigens. TILs may be used with therapeutic intent or studied for prognostic information.108 TILs have been demonstrated to predict outcomes in a wide variety of solid tumors, with the magnitude of this effect being dependent on tumor site and disease stage.109 An increasing number of studies have focused on TILs as predictors of outcome for primary and metastatic liver tumors. Our evolving understanding of intrahepatic antitumor immunity promises to enable development of novel therapeutic approaches using immunomodulatory agents and adoptive cell therapy.

Immune Response to Primary Liver Cancer Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide (see Chapter 89). The immune response to neoplastic cells has been shown to be a potential determinant of survival in HCC patients.110–112 High densities of DCs, T-cell subsets, and tumor-associated macrophages have all been reported to be favorable prognostic factors in HCC.113 TIL responses to HCC occur in a more complex biologic context than metastatic tumors, given the underlying inflammatory processes that drive HCC carcinogenesis and progression. HCC TILs have been compared with T cells in adjacent normal liver tissue, and HCC TILs reflect a more immunosuppressed state. HCC TIL populations have been shown to contain a higher number of Tregs compared with normal surrounding liver.114 Increased ratios of Tregs (FOXP31) to total T cells (CD31) were independently associated with poorer differentiation. Furthermore, high FOXP31 to CD81 TIL ratios were associated with shorter overall and disease-free survival times in HCC patients on both univariate and multivariate analysis.114 Immune suppression within HCC may also be attributed to increased expression of PD-1 on TILs. As noted earlier, PD-1 is an immunoinhibitory receptor that suppresses T-cell division and cytokine production.115 PD-1 is engaged by PD-L1, which has been detected on HCC tumor cells. The presence of Tregs and PD-11 TILs reflect an immunosuppressive milieu but may represent a therapeutic opportunity because anti–PD-1 antibodies are now in clinical use for a variety of solid tumors. TIL responses have also been studied in patients with biliary tract cancers. CCA is the second most common primary intrahepatic malignancy, and most patients are not candidates for potentially curative surgical intervention (see Chapter 50). A study of 123 patients with intrahepatic CCA who underwent curative surgical resection revealed that IL-171 (Th17) and FOXP31 (Treg) TILs were enriched predominantly within CCA tumors, whereas CD81 TILs were most abundant at the tumor margin. IL-171 TIL counts were an independent predictor of decreased patient survival, reflecting the importance of the Th17/Treg balance in liver diseases.116 Similar to HCC, tumor expression of PD-L1 was correlated with CCA stage and tumor differentiation.117 Improving our understanding of CCA immune responses and tumor-driven immunosuppression may offer insights into novel therapeutic options and improve risk stratification.

Immune Response to Metastatic Cancer in the Liver The high prevalence of metastatic disease to the liver is likely because of multiple factors, including the unique characteristics

180

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

of the liver immune system. As delineated earlier, the primary mediators of innate and adaptive immunity found in the liver (DCs and T cells) are unique in their distribution of subtypes and skew toward tolerogenic function.5,13 In addition, the liver contains suppressive cells, such as Tregs and MDSCs, that may also promote the establishment of metastatic colonies within the intrahepatic space. Several studies suggest that intrahepatic adaptive immune responses to colorectal cancer liver metastases (CRCLM) are predictive of recurrence and death after resection (see Chapter 90). Both CD41 and CD81 T cells are activated within CRCLM, and activated CD41 T helper cells may promote tumor-selective activity of cytotoxic CD81 T lymphocytes.118 After hepatic resection, patients with high numbers of CD81 intratumoral T cells were more likely to survive 10 years or longer. Among patients who survived for 10 years or more, 31% had high levels of CD81 T cells. In contrast, only 8% of those who survived less than 2 years had a high level of CD81 TIL.107 Ratios of TIL subsets have been studied as well and may provide more biologic insight than individual TIL counts. In patients with CRCLM, high CD81 to CD41 TIL ratios were an independent predictor of long-term survival after resection, after adjusting for multiple variables, including clinical risk score. In a more recent study, high CD41 to CD31 and CD81 to CD31 TIL ratios were a significant correlate of improved and recurrence-free survival.119 As reported in the setting of primary liver cancer, TIL ratios, including FOXP31 Treg, are predictive of outcome after CRCLM resection. High FOXP31 to CD41 and FOXP31 to CD81 TIL ratios were independent predictors of shorter overall survival. Overall survival at 5 years for patients with a high FOXP31 to CD41 TIL ratio was 34% compared with 51% for patients with a low ratio (odds ratio [OR] 5 1.6; P 5 .03). Similarly, 5-year survival was 35% in those with a high FOXP31 to CD81 ratio compared with 46% in those with a low FOXP31 to CD81 TIL ratio (hazard ratio [HR] 5 1.5; P 5 .05)119. FOXP31 TIL counts were also found to be predictors of outcome after resection of neuroendocrine tumor liver metastases.120 Tumor MHC I expression has also been correlated to immune infiltrates and outcome.121 A critical finding from studies of CRCLM is that although patients with favorable TIL profiles are more likely to have a good outcome, the majority of individuals do not demonstrate an effective intratumoral immune response. We speculate that immunosuppressive intrahepatic immune cells and immunoinhibitory pathways limit the function of effector T cells. This presents a therapeutic opportunity to deliver effective adoptive cellular immunotherapy in conjunction with suppressive pathway inhibition to overcome the factors curtailing endogenous antitumor immunity.

Immune Response to Pancreatic Adenocarcinoma Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States and has a rising incidence122 (see Chapters 61 and 62). It has been recognized in murine models and human tissue that PDA is surrounded by dense stromal fibrosis; however, although there is a dearth of effector cells within mouse models, in human PDA there appears to still be significant populations of T cells into the tumor milieu.123 Early evidence demonstrated improved survival with higher densities of CD81 T cells and DCs124; conversely, myeloid cell types, including MDSCs, and Tregs were enriched in poorly differentiated PDA.125 Immunosuppressive

M2 phenotype macrophages also appear to suppress tumor killing activity by effector T cells via secretion of cytokines such as IL-10 and TGF-b; DCs in the circulation and within the microenvironment also appear to be suppressed by IL10 and TGF-b secretion from MDSCs and tumor cells.126 Increased Treg within the tumor microenvironment and in peripheral blood has been associated with decreased survival127; higher expression of leukocyte adhesion molecules, such as CD166, produced by endothelial cells in the stroma appear to enhance Treg migration into the PDA microenvironment.128 PDA cells also appear to evade the immune response using checkpoint molecules, including by expressing PD-L1129; similar mechanisms modulating CTLA-4 have also been described.130 The immunosuppressive milieu also tends to shift CTL phenotypes away from the effector Th1 to the more suppressive Th2 subtype via IL-10131,132; higher ratios of the Th2 to Th1 ratio seen in PDA has been associated with worse outcomes.133 Despite this, there is recent evidence that demonstrates the presence of clonally expanded effector T cells, further lending credence to the idea that the adaptive immune response against PDA exists but is kept at bay by the immunosuppressive microenvironment.134 This complex interplay between activation and suppression, modulated by both cellular and soluble components of the adaptive response (Table 10.3), has likely contributed to the difficulty in medical therapy against the disease.

Current Advances in Immunotherapy Against Liver and Pancreatic Malignancies (see Chapters. 66, 6,7 and 99) Although many investigators have attempted to manipulate the immune system for the treatment of cancer,135 few attempts have been made to directly target intrahepatic immune cells. The primary goal of cancer immunotherapy, particularly for liver tumors, is to deliver or induce potent antitumor immunity while reversing intrahepatic suppression. Reversal of intrahepatic tolerance has been accomplished in animal models by activating liver immune cells, depleting suppressor cells, or blocking immunoinhibitory pathways, such as the PD-1/PD-L1 axis. IL-12 production by DCs activates NK cells toward protection against tumor in a mouse melanoma liver metastasis model.136 Despite having less lytic potential than blood NK cells, human liver NK cells have the capacity to become potent antitumor cells when activated in the presence of KCs and TLR3 ligands.15 In addition to DCs, recent work on the role of peritumoral monocytes in patients with HCC has garnered much attention among immunologists and hepatologists alike. Activated monocytes in the peritumoral stroma of HCC have been shown to foster a state of tolerance and promote tumor progression via the expression of an immunosuppressive molecule, PD-L1.137 Furthermore, tumor expression of PD-L1 was recently shown to serve as a predictor of recurrence in patients with resected HCC.138 Recent trials have finally put into clinical practice the promises of immunotherapy that have been shown mechanistically (see Chapter 99). Before these trials, the tyrosine kinase inhibitor sorafenib had been the one and only data-driven choice for systemic therapy for advanced HCC.139,140 Although there was the introduction of levatinib (a vascular endothelial growth factor [VEGF] receptor kinase inhibitor) as a noninferior alternative to sorafenib,141,142 there has been a rapid increase in the number of immunotherapeutics approved for both second-line

  Chapter 10  Fundamentals of Liver and Pancreas Immunology

181

TABLE 10.3  Factors Involved in Modulating T Cell Programming in Pancreatic Adenocarcinoma FUNCTION IN T-CELL PROGRAMMING

RELEVANCE TO PDA IMMUNE MICROENVIRONMENT

IL-2

• Promotes differentiation, survival, and function of Treg

• IL-2 mediates increased proliferation and expansion of Treg within the tumor microenvironment to decrease tumor targeting

IL-4

• Shifts macrophages from activated M1 subtype to immunosuppressive M2 subtype

• May play a role in enhanced activity of the M2 subtype within the tumor milieu

IL-10

• Inhibits expression of IL-12, thereby downregulating T-cell activation

• Immunosuppressive M2 macrophages produce IL-10 to reduce T-cell activation in and around the tumor

IL-12

• Induces Th1 differentiation • Increases IFN-g production, thereby enhancing cytotoxic activity

• Administration of IL-12 in vitro modulated T cells from PDA patients toward Th1 subtype

IFN-g

• Induces Th1 differentiation • Increases antigen processing and presentation to T cells • Upregulates expression of class I and II MHC molecules

• Cytotoxic cells targeting the tumor kill malignant cells in part via release of IFN-g

TGF-b

• Inhibits T-cell activation and proliferation • Induces differentiation of Treg and Th17 • Inhibits macrophage activation

• PDA tumor cells release TGF-b, thereby directly reducing T-cell activation

TNF-a

• Causes systemic inflammation and fever

• Monoclonal antibodies against TNF-a have demonstrated decreased infiltration of Treg into PDA

CTLA-4

• Competes with the binding of activating co-stimulatory molecules on T cells, leading to decreased activation • Serves as an immune checkpoint via increased expression in T cells after activation

• A phase II trial involving ipilimumab, a CTLA-4 inhibitor, did not demonstrate any benefit in survival or outcomes in patients with advanced PDA

PD-1

• Binds to ligands present on APCs to downregulate T-cell activity • Terminates peripheral effector cell activity

• PDA expresses higher levels of PD-L1, the ligand for PD-1, which leads to decreased T-cell activation

• CCR2

• Important in monocyte chemotaxis

• CCR2 appears to mediate recruitment of M2 macrophages into the PDA microenvironment, thereby decreasing immune activation

• CXCR4

• Important in homing to bone marrow niche, as well as T-cell co-signaling

• CXCR4 and PD-1 combination blockade with chemotherapy showed enhanced disease control rate in a phase II trial • CXCR4 blockade leads to increased trafficking of T cells to PDA

Cytokines

Soluble Factors

Cell Surface Receptors

CCR, Chemokine receptor type; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR, C-X-C chemokine receptor type; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN-g, interferon gamma, IL, interleukin; M-CSF, macrophage colony stimulating factor; PD-1, programmed cell death protein 1; TGF-b, transforming growth factor beta, Th, T helper; TNF-a, tumor necrosis factor alpha. Modified from Seo YD, Pillarisetty VG. T cell programming in pancreatic adenocarcinoma: A review. Cancer Gene Therapy. 2017;24(3): 106–113.

and now first-line treatments. Pembrolizumab, a PD-1 inhibitor, was one of the first to gain US Food and Drug Administration (FDA) approval for treatment of advanced HCC not responsive to sorafenib143; nivolumab (another PD-1 inhibitor) and combination nivolumab plus ipilimumab (a CTLA-4 inhibitor) have since been added to this list of second-line therapies.144,145 Most recently, combination atezolizumab (a PD-L1 inhibitor) and bevacizumab (a direct VEGF inhibitor) demonstrated improved overall and disease-free survival rates compared with sorafenib in unresectable HCC as first-line therapy.146 Although the immunosuppressive nature of the intrahepatic space has long been thought to be the cause of ineffective antitumor immunity, it seems this suppressive milieu can be overcome with combination immunotherapy as noted previously.

Another rapidly expanding indication for immunotherapy is the treatment of deficient mismatch repair and microsatellite instability-high (dMMR/MSI-H) tumors in the liver, most notably CRCLM. dMMR tumors were early on shown to respond to immune checkpoint inhibition across tumor types, likely as a result of higher mutation burden, leading to more immunogenicity147; this has led to the first FDA approval of a drug agnostic of disease site, namely pembrolizumab for dMMR/MSI-H tumors.148 Although hepatobiliary tumors have a low prevalence of MSI-H phenotypes, colorectal cancer has one of the highest rates at 6% to 20%.149 Nivolumab and nivolumab plus ipilimumab have demonstrated durable response rates in MSI-H tumors, particularly in the setting of previous systemic therapy failures.150 Most notably, pembrolizumab has recently shown superior progression-free survival compared with conventional

182

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

systemic chemotherapy (16.5 months vs. 8.2 months) as firstline therapy for MSI-H metastatic CRC, further cementing the role of immunotherapy as a mainstay of treatment of unresectable CRCLM.151 Still in transition from concept to bedside, genetically modified chimeric antigen receptor T cells (CAR-Ts) offer another potential avenue to providing effective antitumor immunity for CRCLM. CAR-Ts are produced from patient autologous T cells, using a retroviral system to engineer expression of an immune receptor that is activated upon engagement of tumor antigens such as carcinoembryonic antigen (CEA). A phase I Hepatic Immunotherapy for Metastases (HITM) trial demonstrated the safety and encouraging signals of clinical efficacy of hepatic artery anti-CEA CAR-T infusions in patients with CRCLM.152 Within pancreatic adenocarcinoma, initial trials evaluating efficacy of PD-1 and PD-L1 blockade did not demonstrate any meaningful improvement in clinical outcomes18; multiple subsequent trials using different combinations of immunotherapy have failed to show any benefit. However, there has been recent work that aims to activate the effector component while simultaneously breaking the immunosuppressive elements. Mouse model work initially demonstrated that combination blockade of PD-1 and CXCR4 (a chemokine receptor for CXCL12, thought to be immunosuppressive and produced by cancerassociated fibroblasts) yielded tumor killing in a synergistic way.153 This was confirmed by our work using an organotypic slice culture model of PDA, in which ex vivo treatment of

combination PD-1 monoclonal antibody and AMD3100 (an FDA-approved CXCR4 inhibitor) released T cells from the stroma, allowing them to get adjacent to tumor cells and then achieve tumor kill.134,154 The recent phase II COMBAT trial in metastatic PDA using combination CXCR4 and PD-1 blockade confirmed the increase in CD8 T-cell infiltration while decreasing MDSC and Treg populations; furthermore, it demonstrated a disease control rate of 77% out to 2 years when combined with chemotherapy.155

FUTURE DIRECTIONS The examples listed above encapsulate our ability to translate understanding of the nuanced immune microenvironment of complex diseases of the liver and pancreas and to turn these concepts into targetable therapies that confirm our hypotheses in treatment settings. Much more work needs to be performed to elucidate the complex interplay between the adaptive immune response, immune tolerance, immune evasion, and suppression within morbid diseases such as HCC and PDA. However, recent advances give hope that the paradigmshifting era of immunotherapies will soon make headway into decreasing the mortality of advanced liver and pancreatic malignancies. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

182.e1

REFERENCES 1. Janeway Jr CA. How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci U S A. 2001; 98(13):7461-7468. 2. Katz SC, Pillarisetty VG, Bleier JI, Shah AB, DeMatteo RP. Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol. 2004;173(1):230-235. 3. Creput C, Durrbach A, Samuel D, et al. Incidence of renal and liver rejection and patient survival rate following combined liver and kidney transplantation. Am J Transplant. 2003;3(3):348-356. 4. Li W, Chou ST, Wang C, Kuhr CS, Perkins JD. Role of the liver in peripheral tolerance: induction through oral antigen feeding. Am J Transplant. 2004;4(10):1574-1582. 5. Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP. Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol. 2004; 172(2):1009-1017. 6. Plitas G, Burt BM, Stableford JA, Nguyen HM, Welles AP, DeMatteo RP. Dendritic cells are required for effective cross-presentation in the murine liver. Hepatology. 2008;47(4):1343-1351. 7. Bamboat ZM, Stableford JA, Plitas G, et al. Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol. 2009;182(4): 1901-1911. 8. Sun Z, Wada T, Maemura K, et al. Hepatic allograft-derived Kupffer cells regulate T cell response in rats. Liver Transpl. 2003; 9(5):489-497. 9. Ebrahimkhani MR, Mohar I, Crispe IN. Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology. 2011; 54(4):1379-1387. 10. Soysa R, Lampert S, Yuen S, et al. Fetal origin confers radioresistance on liver macrophages via p21cip1/WAF1. J Hepatol. 2019;71(3): 553-562. 11. Knolle PA, Limmer A. Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol. 2001;22(8):432-437. 12. Gao Y, Yang W, Pan M, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med. 2003; 198(3):433-442. 13. Katz SC, Pillarisetty VG, Bleier JI, et al. Conventional liver CD4 T cells are functionally distinct and suppressed by environmental factors. Hepatology. 2005;42(2):293-300. 14. Teng MW, Westwood JA, Darcy PK, et al. Combined natural killer T-cell based immunotherapy eradicates established tumors in mice. Cancer Res. 2007;67(15):7495-7504. 15. Burt BM, Plitas G, Zhao Z, et al. The lytic potential of human liver NK cells is restricted by their limited expression of inhibitory killer Ig-like receptors. J Immunol. 2009;183(3):1789-1796. 16. Novobrantseva TI, Majeau GR, Amatucci A, et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest. 2005;115(11): 3072-3082. 17. Thorn M, Point GR, Burga RA, Nguyen CT, Joseph Espat N, Katz SC. Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-11CD11b1 myeloid cells. J Leukoc Biol. 2014; 96(5):883-894. 18. Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic stellate cells sequester CD81 T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013;145(5):1121-1132. 19. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of antiPD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465. 20. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25): 2704-2715. 21. Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003; 9(5):562-567. 22. Shevach EM. CD41 CD251 suppressor T cells: more questions than answers. Nat Rev Immunol. 2002;2(6):389-400. 23. Carvalho FA, Aitken JD, Vijay-Kumar M, Gewirtz AT. Toll-like receptor-gut microbiota interactions: perturb at your own risk! Annu Rev Physiol. 2012;74:177-198. 24. Michelsen KS, Arditi M. Toll-like receptors and innate immunity in gut homeostasis and pathology. Curr Opin Hematol. 2007; 14(1):48-54.

25. Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res. 2004; 10(4):201-222. 26. Gioannini TL, Weiss JP. Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells. Immunol Res. 2007; 39(1-3):249-260. 27. Miyake K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol. 2007;19(1):3-10. 28. Thomas CJ, Kapoor M, Sharma S, et al. Evidence of a trimolecular complex involving LPS, LPS binding protein and soluble CD14 as an effector of LPS response. FEBS Lett. 2002;531(2):184-188. 29. Hallatschek W, Fiedler G, Kirschning CJ, et al. Inhibition of hepatic transcriptional induction of lipopolysaccharide-binding protein by transforming-growth-factor beta 1. Eur J Immunol. 2004;34(5): 1441-1450. 30. Nagai Y, Akashi S, Nagafuku M, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002; 3(7):667-672. 31. Medvedev AE, Sabroe I, Hasday JD, Vogel SN. Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J Endotoxin Res. 2006;12(3):133-150. 32. Divanovic S, Trompette A, Atabani SF, et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol. 2005;6(6):571-578. 33. Chuang TH, Ulevitch RJ. Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors [published correction appears in Nat Immunol. 2004;5(9):968]. Nat Immunol. 2004;5(5):495-502. 34. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;334(26):1717-1725. 35. Grewal IS. Overview of TNF superfamily: a chest full of potential therapeutic targets. Adv Exp Med Biol. 2009;647:1-7. 36. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med. 1994;45:491-503. 37. Roberts NJ, Zhou S, Diaz LA Jr, Holdhoff M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget. 2011;2(10):739-751. 38. Corssmit EP, Heijligenberg R, Hack CE, Endert E, Sauerwein HP, Romijn JA. Effects of interferon-alpha (IFN-alpha) administration on leucocytes in healthy humans. Clin Exp Immunol. 1997;107(2): 359-363. 39. Sorkin P, Abu-Abid S, Lev D, et al. Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment. Arch Surg. 1995;130(10):1079-1084. 40. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519-550. 41. Garlanda C, Riva F, Polentarutti N, et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A. 2004;101(10):3522-3526. 42. True AL, Rahman A, Malik AB. Activation of NF-kappaB induced by H(2)O(2) and TNF-alpha and its effects on ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2000; 279(2):L302-L311. 43. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759-771. 44. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830-1835. 45. Massagué J. TGFbeta in cancer. Cell. 2008;134(2):215-230. 46. Ge G, Greenspan DS. BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein. J Cell Biol. 2006;175(1): 111-120. 47. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685-700. 48. Wrighton KH, Lin X, Feng XH. Phospho-control of TGF-beta superfamily signaling. Cell Res. 2009;19(1):8-20. 49. Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 1998;58(23):5329-5332. 50. Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793-d807. 51. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163-189.

182.e2 52. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73(6): 1733-1741. 53. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37. 54. Fong YM, Marano MA, Moldawer LL, et al. The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest. 1990;85(6):1896-1904. 55. Melhem A, Muhanna N, Bishara A, et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol. 2006;45(1):60-71. 56. Zorena K, Raczy≈Ñska D, Wi≈õniewski P, et al. Relationship between serum transforming growth factor b 1 concentrations and the duration of type 1 diabetes mellitus in children and adolescents. Mediators Inflamm. 2013;2013:849457. 57. Javle M, Li Y, Tan D, et al. Biomarkers of TGF-b signaling pathway and prognosis of pancreatic cancer. PLoS One. 2014;9(1):e85942. 58. Wink DA, Vodovotz Y, Grisham MB, et al. Antioxidant effects of nitric oxide. Methods Enzymol. 1999;301:413-424. 59. Sass G, Koerber K, Bang R, Guehring H, Tiegs G. Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice. J Clin Invest. 2001;107(4):439-447. 60. Chen T, Zamora R, Zuckerbraun B, Billiar TR. Role of nitric oxide in liver injury. Curr Mol Med. 2003;3(6):519-526. 61. Wang Y, Vodovotz Y, Kim PK, Zamora R, Billiar TR. Mechanisms of hepatoprotection by nitric oxide. Ann N Y Acad Sci. 2002;962: 415-422. 62. Kim YM, Kim TH, Chung HT, Talanian RV, Yin XM, Billiar TR. Nitric oxide prevents tumor necrosis factor alpha-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology. 2000; 32(4 Pt 1):770-778. 63. Kim YM, de Vera ME, Watkins SC, Billiar TR. Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biol Chem. 1997;272(2):1402-1411. 64. Rodrigo R, Montoliu C, Chatauret N, et al. Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease. Neurochem Int. 2004;45(6):947-953. 65. McKim SE, Gäbele E, Isayama F, et al. Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice. Gastroenterology. 2003;125(6):1834-1844. 66. Atik E, Onlen Y, Savas L, Doran F. Inducible nitric oxide synthase and histopathological correlation in chronic viral hepatitis. Int J Infect Dis. 2008;12(1):12-15. 67. Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology. 1994;19(4):916-924. 68. Kamada N, Davies HS, Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981;292(5826):840-842. 69. Rasmussen A, Davies HF, Jamieson NV, Evans DB, Calne RY. Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation. 1995;59(6):919-921. 70. Mazariegos GV, Reyes J, Marino IR, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997;63(2): 243-249. 71. Qian SG, Fung JJ, Demetris AV, Ildstad ST, Starzl TE. Orthotopic liver transplantation in the mouse. Transplantation. 1991;52(3): 562-564. 72. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet. 1992; 339(8809):1579-1582. 73. Starzl TE, Murase N, Thomson A, Demetris AJ. Liver transplants contribute to their own success. Nat Med. 1996;2(2):163-165. 74. Sriwatanawongsa V, Davies HS, Calne RY. The essential roles of parenchymal tissues and passenger leukocytes in the tolerance induced by liver grafting in rats. Nat Med. 1995;1(5):428-432. 75. Suzuki G, Kawase Y, Koyasu S, Yahara I, Kobayashi Y, Schwartz RH. Antigen-induced suppression of the proliferative response of T cell clones. J Immunol. 1988;140(5):1359-1365. 76. Bosma BM, Metselaar HJ, Gerrits JH, et al. Migration of allosensitizing donor myeloid dendritic cells into recipients after liver transplantation. Liver Transpl. 2010;16(1):12-22.

77. Callery MP, Kamei T, Flye MW. Kupffer cell blockade inhibits induction of tolerance by the portal venous route. Transplantation. 1989;47(6):1092-1094. 78. Breous E, Somanathan S, Vandenberghe LH, Wilson JM. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology. 2009;50(2):612-621. 79. You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology. 2008;48(3):978-990. 80. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003;3(1):51-62. 81. Charles R, Chou HS, Wang L, Fung JJ, Lu L, Qian S. Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway. Transplantation. 2013;96(1):17-24. 82. Dangi A, Sumpter TL, Kimura S, et al. Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance. J Immunol. 2012; 188(8):3667-3677. 83. Ferrari C, Urbani S, Penna A, et al. Immunopathogenesis of hepatitis C virus infection. J Hepatol. 1999;31(suppl 1):31-38. 84. Gerlach JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(1) T-cell response in acute hepatitis C. Gastroenterology. 1999;117(4):933-941. 85. Maini MK, Boni C, Lee CK, et al. The role of virus-specific CD8(1) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 2000;191(8):1269-1280. 86. Fuller MJ, Callendret B, Zhu B, et al. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A. 2013;110(37): 15001-15006. 87. Manz MG, Di Santo JP. Renaissance for mouse models of human hematopoiesis and immunobiology. Nat Immunol. 2009;10(10): 1039-1042. 88. Chen J, Zhao Y, Zhang C, et al. Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res. 2014;24(9):1050-1066. 89. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;32(suppl 1):181-197. 90. Grant CR, Liberal R, Holder BS, et al. Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology. 2014;59(3):1007-1015. 91. Bergasa NV, Mason A, Floreani A, et al. Primary biliary cirrhosis: report of a focus study group. Hepatology. 2004;40(4):1013-1020. 92. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308. 93. Yang CY, Ma X, Tsuneyama K, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology. 2014;59(5):1944-1953. 94. Shimoda S, Harada K, Niiro H, et al. CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis. Hepatology. 2010;51(2):567-575. 95. Lee CK, Jonas MM. Pediatric hepatobiliary disease. Curr Opin Gastroenterol. 2007;23(3):306-309. 96. Katt J, Schwinge D, Schoknecht T, et al. Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology. 2013;58(3):1084-1093. 97. Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation. 1992;53(5):957-978. 97. Lotze MT, Zeh HJ, Rubartelli A, et al. The grateful dead: damageassociated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60-81. 98. Kono H, Fujii H, Ogiku M, et al. Role of IL-17A in neutrophil recruitment and hepatic injury after warm ischemia-reperfusion mice. J Immunol. 2011;187(9):4818-4825. 99. Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, Campbell DA Jr. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest. 1990;85(6):1936-1943. 100. Wanner GA, Müller PE, Ertel W, Bauer M, Menger MD, Messmer K. Differential effect of anti-TNF-alpha antibody on proinflammatory cytokine release by Kupffer cells following liver ischemia and reperfusion. Shock. 1999;11(6):391-395. 101. Li C, Browder W, Kao RL. Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. Am J Physiol. 1999;276(2):H543-H552.

182.e3 102. Giakoustidis DE, Giakoustidis AE, Iliadis S, et al. Attenuation of liver ischemia/reperfusion induced apoptosis by epigallocatechin3-gallate via down-regulation of NF-kappaB and c-Jun expression. J Surg Res. 2010;159(2):720-728. 103. Kim SJ, Eum HA, Billiar TR, Lee SM. Role of heme oxygenase 1 in TNF/TNF receptor-mediated apoptosis after hepatic ischemia/ reperfusion in rats. Shock. 2013;39(4):380-388. 104. Hines IN, Kawachi S, Harada H, et al. Role of nitric oxide in liver ischemia and reperfusion injury. Mol Cell Biochem. 2002; 234-235(1-2):229-237. 105. Diao TJ, Chen X, Deng LH, et al. Protective effect of nitric oxide on hepatopulmonary syndrome from ischemia-reperfusion injury. World J Gastroenterol. 2012;18(25):3310-3316. 106. Katz SC, Pillarisetty V, Bamboat ZM, et al. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16(9):2524-2530. 107. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-1321. 108. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1):93-103. 109. Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328-2339. 110. Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25(18):2586-2593. 111. Sasaki A, Tanaka F, Mimori K, et al. Prognostic value of tumorinfiltrating FOXP31 regulatory T cells in patients with hepatocellular carcinoma. Eur J Surg Oncol. 2008;34(2):173-179. 112. Cai XY, Qiu SJ, Wu ZQ, et al. Zhonghua Yi Xue Za Zhi. 2005; 85(10):671-675. 113. Mathai AM, Kapadia MJ, Alexander J, Kernochan LE, Swanson PE, Yeh MM. Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic features and clinical outcomes of hepatocellular carcinoma. Am J Surg Pathol. 2012;36(7):980-986. 114. Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD81 T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009;69(20):8067-8075. 115. Gu FM, Gao Q, Shi GM, et al. Intratumoral IL-171 cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2012;19(8):2506-2514. 116. Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol. 2009;100(6):500-504. 117. Wagner P, Koch M, Nummer D, et al. Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer [published correction appears in Ann Surg Oncol. 2009 Apr;16(4):1084. Rahbari, Nuh (added)]. Ann Surg Oncol. 2008;15(8):2310-2317. 118. Katz SC, Bamboat ZM, Maker AV, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20(3):946-955. 119. Katz SC, Donkor C, Glasgow K, et al. T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases. HPB (Oxford). 2010; 12(10):674-683. 120. Turcotte S, Katz SC, Shia J, et al. Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol Res. 2014;2(6):530-537. 121. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 122. Emmrich J, Weber I, Nausch M, et al. Immunohistochemical characterization of the pancreatic cellular infiltrate in normal pancreas, chronic pancreatitis and pancreatic carcinoma. Digestion. 1998;59(3):192-198. 123. Fukunaga A, Miyamoto M, Cho Y, et al. CD81 tumor-infiltrating lymphocytes together with CD41 tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):e26-e31. 124. Shibuya KC, Goel VK, Xiong W, et al. Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate

that is altered by multimodal neoadjuvant treatment. PLoS One. 2014;9(5):e96565. 125. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells [published correction appears in Nat Med. 2004;10(2):209]. Nat Med. 2004;10(1):48-54. 126. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP31 regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006;12(18):5423-5434. 127. Nummer D, Suri-Payer E, Schmitz-Winnenthal H, et al. Role of tumor endothelium in CD41 CD251 regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst. 2007; 99(15):1188-1199. 128. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717-1725. 129. Tassi E, Gavazzi F, Albarello L, et al. Carcinoembryonic antigenspecific but not antiviral CD41 T cell immunity is impaired in pancreatic carcinoma patients. J Immunol. 2008;181(9):6595-6603. 130. Bellone G, Turletti A, Artusio E, et al. Tumor-associated transforming growth factor-beta and interleukin-10 contribute to a systemic Th2 immune phenotype in pancreatic carcinoma patients. Am J Pathol. 1999;155(2):537-547. 131. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011;60(10): 1419-1430. 132. De Monte L, Reni M, Tassi E, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med. 2011;208(3):469-478. 133. Seo YD, Jiang X, Sullivan KM, et al. Mobilization of CD81 T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer. Clin Cancer Res. 2019;25(13):3934-3945. 134. Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD41 T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-2703. 135. Miller G, Lahrs S, Pillarisetty VG, Shah AB, DeMatteo RP. Adenovirus infection enhances dendritic cell immunostimulatory properties and induces natural killer and T-cell-mediated tumor protection. Cancer Res. 2002;62(18):5260-5266. 136. Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009; 206(6):1327-1337. 137. Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15(3):971-979. 138. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34. 139. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. 140. Alsina A, Kudo M, Vogel A, et al. Effects of subsequent systemic anticancer medication following first-line lenvatinib: a post hoc responder analysis from the phase 3 REFLECT study in unresectable hepatocellular carcinoma. Liver Cancer. 2020;9(1):93-104. 141. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. 142. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published correction appears in Lancet Oncol. 2018;19(9):e440]. Lancet Oncol. 2018;19(7):940-952. 143. Kudo M, Matilla A, Santoro A, et al. Checkmate-040: nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status. J Clin Oncol. 2019; 37(suppl 4):327.

182.e4 144. Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) 1 ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2019;37(suppl 15):4012. 145. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. 146. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. 147. Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site - When a biomarker defines the indication. N Engl J Med. 2017;377(15):1409-1412. 148. Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12(1):54. 149. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study [published correction appears in Lancet Oncol. 2017 Sep;18(9):e510]. Lancet Oncol. 2017;18(9):1182-1191.

150. Andre T, Amonkar M, Norquist JM, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(5): 665-677. 151. Saied A, Licata L, Burga RA, et al. Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. Cancer Gene Ther. 2014;21(11):457462. 152. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212-20217. 153. Jiang X, Seo YD, Chang JH, et al. Long-lived pancreatic ductal adenocarcinoma slice cultures enable precise study of the immune microenvironment. Oncoimmunology. 2017;6(7):e1333210. 154. Bockorny B, Semenisty V, Macarulla T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020; 26(6):878-885.

CHAPTER 11 Infections in hepatic, biliary, and pancreatic surgery Sanket Srinivasa and Ryan C. Fields Infections cause significant morbidity and mortality in patients undergoing hepatopancreatobiliary (HPB) surgery. In the era of more extensive resections in elderly comorbid patients with the greater use of perioperative chemoradiotherapy and biliary instrumentation, surgical-site infection (SSI) rates after HPB procedures can be as high as 20% to 40% with an added substantial risk of intraabdominal infections.1 Infection is associated with increased hospital stay, operative times, transfusions, blood loss, intensive care unit use, and readmission rates.2 In addition to these short-term sequelae, long-term sequelae include worse oncologic outcomes.3 This chapter will outline the range of infectious complications that may accompany resections of the liver, biliary tree, and pancreas with important surgery-specific risk factors discussed. Potential strategies for mitigating infection risk in the perioperative period are also discussed.

RISK FACTORS FOR SURGICAL-SITE INFECTION There are inherent protective host mechanisms within the liver and pancreas (Table 11.1; see Chapter 10). Some of these are altered in the perioperative phase or from the pathology mandating intervention, such as bacterial colonization of bile from preoperative stenting or instrumentation of the hepatic inflow.4,5 There are two important sources of risk regarding the development of a postoperative SSI. Both patient-specific factors and surgery-related factors combine to yield varying degrees of risk. Surgery-related risk factors are discussed specifically as they pertain to hepatic, pancreatic, and biliary operations.

Patient-Related Risk Factors Patient-related risk factors may not always be modifiable at the time of operation, but it is important to be aware of them while the patient receives care. They include age, nutritional status, diabetes, smoking, obesity, coexisting infections at a remote body site, colonization with microorganisms, altered immune response, and length of preoperative stay.6 Interventions to modify these risk factors can be employed throughout the perioperative period from initial consultation until long-term follow-up (Tables 11.2 to 11.4).

SURGERY-SPECIFIC RISK FACTORS Hepatic Resection (See Chapters 101 and 102) Preoperative Risk Mitigation Hepatic resection removes Kupffer cell mass, which is the liver’s principal mechanism for clearing the portal inflow of enteric microorganisms and their associated toxins. Hepatic resection also decreases bile production with a consequent impairment of the chemical and immunologic effects of bile

salts. Resection with biliary reconstruction or biliary stenting also bypasses the sphincter of Oddi and predisposes patients to bilioenteric reflux and cholangitis.4 Depending on the extent of resection, a normal healthy liver in a reasonable surgical candidate may be able to compensate for these changes. However, this may not be the case for the patient with diseased liver parenchyma. The preoperative mitigation of the risk of postoperative infectious complications after hepatic resection therefore begins with a full appreciation of the preexisting condition of the patient’s liver. Adjunctive assessments such as liver biopsy and measurement of portal venous pressures may be necessary when there is uncertainty concerning the health of the liver. Yang and colleagues (2014)32 found cirrhosis and hepatolithiasis to be independent preoperative risk factors for the development of postoperative SSIs. Garwood and colleagues (2004)33 showed that the extent of hepatic resection, age, and comorbidity is associated with postoperative infectious complications. Schindl and colleagues (2005)34 established a relationship among the extent of resection, residual liver volume, and the development of infection. Although a precise residual liver volume to predict postoperative infection could not be found, there was a significant relationship linking severe hepatic dysfunction and postoperative infection (see Chapter 102). Furthermore, severe hepatic dysfunction could be predicted by small residual liver volume and high body mass index (BMI). Nanashima and colleagues (2014)35 similarly demonstrated that liver failure was significantly associated with deep SSIs. A recent study has similarly proposed that the future liver remnant (FLR) should be more than 45% in patients older than 69 to minimize postoperative complications including sepsis.36 If the risk of postoperative hepatic dysfunction is deemed too high for formal resection, then other treatment modalities may be needed. For example, parenchymal-sparing techniques, such as segmental hepatectomy (see Chapter 102B), ablation (see Chapters 95 and 96), or arterial-based modalities (see Chapters 94, 97, and 100) may be required. Preoperative portal vein embolization can be considered in certain patients in whom the FLR volume is too low and/or of poor quality. There is also increasing enthusiasm in facilitating resection by using hepatic vein embolization or ALPPS (see Chapters 102C and 102D). When the risk of postoperative complications is prohibitive, then not operating or ablating may be the prudent course of action. It should, however, be noted that nonoperative strategies such as yttrium-90 radioembolization are also associated with infectious complications,5 and efficacy for many of these modalities has yet to be established. The use of systemic chemotherapy is increasingly common in the overall treatment plan for patients undergoing hepatic resection, especially in patients with colorectal liver metastases (see Chapters 50 and 97–99). Neoadjuvant chemotherapy may increase the risk of infection due to its negative effects on the

183

184

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

TABLE 11.1  Normal Host Defense Mechanisms in the Hepatobiliary System and Pancreas Physical

Chemical Immunologic

HEPATOBILIARY

PANCREAS

Biliary sphincter Hepatic tight junctions Bile flow Mucus Cilia Bile salts Kupffer cells Immunoglobulin A Fibronectin Complement

Pancreatic sphincter Pancreatic tight junctions Pancreatic juice flow Mucus Cilia Pancreatic fluid — Immunoglobulin A Complement

liver, including steatosis, steatohepatitis, and sinusoidal obstruction syndrome (see Chapter 69). It is, however, an important part of multimodal management of hepatic tumors, especially colorectal liver metastases, and confers superior oncologic outcome.37 Scilletta and colleagues (2014)38 suggested that neoadjuvant chemotherapy was not a significant risk factor for SSIs in patients undergoing liver resection for colorectal hepatic metastases. Nordlinger and colleagues (2008)39 conducted a randomized controlled trial comparing liver resection for resectable colorectal liver metastases in patients with and without perioperative chemotherapy. Perioperative chemotherapy was defined as six cycles of 5-fluororuracil plus leucovorin and oxaliplatin (FOLFOX4) before and after surgery. There were 182 patients within each arm of the study. Infectious complications that were analyzed included wound, intraabdominal, and urinary infections. There was a trend toward higher rates of these complications in the perioperative chemotherapy group, but it was not statistically significant. In the setting of resectable colorectal cancer liver metastasis, chemotherapy before hepatectomy is safe from a postoperative infectious standpoint and remains indicated overall to achieve optimal oncologic outcomes. Liverdirected chemotherapy via hepatic artery infusion pumps also does not seem to increase the risk of infectious complications40 (see Chapters 69, 97, and 98). Preoperative nutrition also requires careful consideration. A recent review by Walcott-Sapp et al. (2018)41 has expanded on the importance of recognizing malnutrition before hospital admission and considering oral supplementation with highcalorie, high-protein drinks and avoiding unnecessary preoperative fasting in the immediate preoperative phase. A recent trial by Russell et al. (2019)42 also evaluated the value of immunonutrition in patients undergoing elective hepatectomy, but the majority of patients did not have malnutrition and there were no differences in outcome between the two groups (see Chapters 26 and 27). Other preoperative contributors to postoperative infectious complications after hepatic resection include advanced age, presence of diabetes mellitus, obesity, presence of an open wound, hypernatremia, hypoalbuminemia, elevated serum bilirubin, dialysis, comorbid conditions, repeat hepatectomy, and hepatic steatosis.33,42–47 Because many of these preexisting conditions may not be modifiable before the time of operation, any resection must be considered in light of the general condition of the patient.

Operative Risk Mitigation There are several operative risk factors that are associated with postoperative infectious complications. These include bile leaks, surgery duration, increased blood loss, and iatrogenic bowel perforation.35,44,45,48–50 It is thus important to mitigate these factors; one deliberate strategy can be intraoperative identification and treatment of bile leaks. Numerous strategies have been proposed for this including the use of indocyanine green, methylene blue, hydrogen peroxide, or air51 (see Chapters 24 and 25). An intraoperative air leak test has been shown to be effective in the detection of bile leaks, thus, decreasing the rate of postoperative biliary complications.52 This maneuver involves the placement of a transcystic catheter that is used to inject air into the biliary tree after the upper abdomen is submerged in saline and the distal common bile duct is occluded. Bile leaks are identified at the site of streaming air bubbles and are directly repaired. The authors compared the rates of postoperative biliary complications among 103 patients who underwent air-leak testing and 120 matched patients who underwent hepatic resection before air-leak testing was used. None of the hepatic resections in either group were accompanied by biliary reconstruction. The authors noted a significantly lower rate of postoperative bile leaks in the air leak–tested group (1.9% vs. 10.8%, P 5 .001). Minimally invasive approaches (laparoscopic/robotic) have also reported lower rates of wound infections and lower rates of pulmonary complications with comparable rates of bile leak and noninferior oncologic outcomes.53,54 Although laparoscopic liver resections are commonly used for minor hepatectomy, major hepatectomy is also increasingly performed using minimally invasive techniques.55 Regarding parenchymal transection techniques, no one method or combination of methods has been shown to be convincingly superior, although a recent network meta-analysis has suggested (with significant caveats) that energy devices may be best in reducing overall complications56 (see Chapter 118). It is thus recommended that the surgeon use the technique that is most familiar, while limiting the amount of necrotic liver parenchyma left behind.57 It is also important to suction any pooled blood and bile at the end of the operation.

Perioperative Antibiotics A reasonable approach to the prevention of SSI in the setting of hepatic resection would be to administer antimicrobial prophylaxis for all elective hepatic resections regardless of anticipated bilioenteric reconstruction. The recommended antimicrobial agent for biliary tract procedures from the Clinical Practice Guidelines for Antimicrobial Prophylaxis (https:// www.ashp.org) is cefazolin. This online resource is frequently updated and can be used to guide antibiotic choice in line with institutional considerations. Other options include cefoxitin because it is a single agent with broad coverage. Whatever agent is used, it should be given within 60 minutes of skin incision and re-administered appropriately intraoperatively to maintain adequate tissue levels. There is no evidence to support routine use of postoperative antibiotics.

Drains The rationale for leaving an intraabdominal drain is to detect and prevent biloma formation in the event of bile leakage after hepatic resection (see Chapters 28 and 118). Bile leakage and

Chapter 11  Infections in Hepatic, Biliary, and Pancreatic Surgery

185

TABLE 11.2  General Preoperative Interventions to Prevent Surgical-Site Infection INTERVENTION

EVIDENCE

REFERENCES

Reduce hemoglobin A1c levels to ,7% before operation Smoking cessation 30 days before operation Administer specialized nutritional supplements or enteral nutrition to patients at severe nutritional risk for 7-14 days preoperatively; preoperative parenteral nutrition should not be routinely used, except selectively in patients with severe underlying malnutrition Adequately treat preoperative infections, such as urinary tract infections

Class II data Class II data Class I and class II data with significant heterogeneity

Mangram et al. (1999)7 Mangram et al. (1999)7 Anonymous (1991)8; Mangram et al. (1999)7; Weimann et al. (2006)9

Class II data

Mangram et al. (1999)7

Modified from Horan TC, Gaynes RP, Martone WJ, Jarvis W, Emori TG. CDC definitions of nosocomial surgical site infections: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol. 1992;13:606–608.

TABLE 11.3  General Perioperative Interventions to Prevent Surgical-Site Infection INTERVENTION

EVIDENCE

Remove hair only if it will interfere with the operation; hair removal by clipping immediately before the operation or with depilatories; no preoperative or perioperative shaving of surgical site Use an antiseptic surgical scrub or alcohol-based hand antiseptic for preoperative cleansing of the operative team members’ hands and forearms Prepare the skin around the operative site with an appropriate antiseptic agent, including preparations based on alcohol, chlorhexidine, or iodine/iodophors Administer prophylactic antibiotics for most clean-contaminated and contaminated procedures, and selected clean procedures; use antibiotics appropriate for the potential pathogens Administer prophylactic antibiotics within 1 hr before incision (2 hr for vancomycin and fluoroquinolones)

Class I data

Anderson et al. (2008)10; Bratzler (2006)11; Kjønniksen et al. (2002)12; Mangram et al. (1999)7; Springer (2007)13

Class II data

Anderson et al. (2008)10; Mangram et al. (1999)7

Class II data

Anderson et al. (2008)10; Digison (2007)14; Mangram et al. (1999)7

Strong class I data

Use higher dosages of prophylactic antibiotics for morbidly obese patients Use vancomycin as a prophylactic agent only when there is a significant risk of MRSA infection

Limited class II data Class I data

Anonymous (1999)15; Bratzler (2006)11; Classen et al. (1992)16; Mangram et al. (1999)7; Springer (2007)13 Anonymous (1999)15; Bratzler (2006)11; Classen et al. (1992)16; Mangram et al. (1999)7; Springer (2007)13 Forse et al. (1989)17; Mangram et al. (1999)7

Provide adequate ventilation, minimize operating room traffic, and clean instruments and surfaces with approved disinfectants Avoid “flash” sterilization

Class II and class III data Class II data

Carefully handle tissue, eradicate dead space, and adhere to standard principles of asepsis Leave contaminated or dirty infected wounds open, with the possible exception of wounds following operations for perforated appendicitis Redose prophylactic antibiotics with short half-lives intraoperatively if operation is prolonged (for cefazolin if operation .3 hr) or if there is extensive blood loss Maintain intraoperative normothermia

Class III data

MRSA, Methicillin-resistant Staphylococcus aureus. Modified from Kirby JP, Mazuski JE. Prevention of SSI. Surg Clin North Am. 2009;89(2):365–389, viii.

Strong class II data

REFERENCES

Limited class I, class II data

Anderson et al. (2008)10; Anonymous (1999)15; Bolon et al. (2004)18; Finkelstein et al. (2002)19; Mangram et al. (1999)7 Anderson et al. (2008)10; Mangram et al. (1999)7 Anderson et al. (2008)10; Mangram et al. (1999)7 Anderson et al. (2008)10; Mangram et al. (1999)7 Brasel et al. (1997)20; Cohn et al. (2001)21; Mangram et al. (1999)7

Limited class I, class II data

Mangram et al. (1999)7; Scher (1997)22; Swoboda et al. (1996)23

Class I data, some contradictory class II data

Anderson et al. (2008)10; Barone et al. (1999)24; Bratzler (2006)11; Mangram et al. (1999)7; Sessler & Akca (2002)25; Springer (2007)13; Walz et al. (2006)26

186

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

TABLE 11.4  General Postoperative Interventions to Prevent Surgical-Site Infection INTERVENTION

EVIDENCE

REFERENCES

Discontinue prophylactic antibiotics within 24 hours after the procedure (48 hr for cardiac surgery and liver transplant procedures); preferably, discontinue prophylactic antibiotics after skin closure Maintain serum glucose levels ,200 mg/dL on postoperative days 1 and 2

Class I data

Anonymous (1999)15; Bratzler (2006)11; DiPiro et al. (1986)27; Mangram et al. (1999)7; Springer (2007)13

Class II data

Monitor wound for the development of surgical-site infection

Class III data

Anderson et al. (2008)10; Bratzler (2006)11; Carr et al. (2005)28; Furnary et al. (1999)29; Lazar et al. (2004)30; Springer (2007)13; Zerr et al. (1997)31 Anderson et al. (2008)10; Mangram et al. (1999)7

Modified from Kirby JP, Mazuski JE. Prevention of SSI. Surg Clin North Am. 2009;89(2):365–389, viii.

subsequent biloma formation is an important contributor to infectious complications after hepatic resection. However, the overall trend reflected in the literature does not support the routine use of drains in elective hepatic surgery. Foregoing prophylactic drainage after elective hepatic surgery is consistent with the general notion that drainage may be unnecessary in most gastrointestinal (GI) operations. Petrowsky and colleagues (2004)58 studied the value of prophylactic drainage in GI surgery in a systematic review and meta-analysis, concluding that many GI operations can be safely performed without the use of drains. Regarding liver surgery specifically, this article suggests that surgical drains do not necessarily prevent biloma formation and do not always prevent the need for percutaneous drainage. A grade A recommendation was given against prophylactic drainage in elective hepatic resection. This is supported by several randomized studies59–61 and a systematic review.62 A more recent multicenter international prospective study also concluded that intraoperatively placed surgical drains do not prevent the need for additional percutaneous drainage.63 Another study evaluating hepatectomy within the United States showed that routine drain placement did not prevent nor diagnose bile leaks and was associated with more interventions, a higher rate of readmissions, and longer length of stay.64 However, practical considerations such as urgent access to image-guided drain insertion postoperatively if required often affect clinical decision making and individual high-risk cases (e.g., central resections, complex nonanatomical resections, and high bilioenteric anastomosis) may warrant prophylactic drain placement. A reasonable strategy may be to avoid routine drain placement unless specific concerns exist and remove drains as early as possible postoperatively.

Postoperative Risk Mitigation (see Chapter 27) Nasogastric Decompression

Pessaux and colleagues (2007)65 conducted a randomized clinical trial examining the utility of postoperative nasogastric decompression after elective hepatectomy. The authors randomized 200 patients to nasogastric tube use versus no nasogastric tube. The use of a nasogastric tube was significantly associated with an increased rate of pneumonia and atelectasis but did not reduce overall surgical complications, medical morbidity, inhospital mortality, duration of ileus, or length of hospital stay. The authors concluded that routine nasogastric decompression offers no benefit. A recent randomized trial confirmed this finding.66 There is no role for routine nasogastric tube placement in elective hepatectomy.

Early Enteral Nutrition and Enhanced Recovery Pathways The concept of early enteral nutrition has been studied in patients undergoing liver resection. Richter and colleagues (2006)67

conducted a systematic review of early enteral nutrition following open liver resection, concluding that it is safe and that it decreases the incidence of postoperative complications compared with parenteral nutrition. The authors noted a statistically significant lower rate of wound infections and catheter-related infections with early enteral feeding versus parenteral nutrition. However, pneumonias and intraabdominal abscesses were not significantly decreased. It should be noted that enteral nutrition in this review was, in general, started on the second postoperative day via an operative jejunal tube. Placement of jejunal feeding catheters in the otherwise healthy liver resection patient is not to be encouraged. In general, resumption of oral intake with caloric supplementation as soon as practical is recommended unless contraindicated, in which case enteral nutrition is preferable to parenteral nutrition. Enhanced recovery after surgery (ERAS) pathways have shown promise in improving postoperative outcomes in patients undergoing liver surgery68 (see Chapter 27). Important components of ERAS pathways include continuing nutrition as long as 2 hours before hepatic resection, avoidance of a nasogastric tube, and early postoperative diet resumption. A recent randomized trial has shown decreased overall complications, although there was no statistically significant differences in infectious complications likely due to a small sample size.69 An updated systematic review similarly shows decreased overall complications in two of four trials.70 ERAS pathways should therefore be considered for those patients undergoing routine hepatectomy.

Blood Glucose Control Dysglycemia has been studied in patients undergoing hepatectomy specifically. Huo and colleagues (2003)71 demonstrated increased hepatic decompensation in diabetic patients undergoing hepatic resection for hepatocellular carcinoma. Little and colleagues (2002)72 showed an association with increased mortality in diabetic patients undergoing hepatectomy for colorectal cancer metastasis. Ambiru and colleagues (2008)73 and Li and associates (2017)74 demonstrated an increase in SSI in HPB surgery patients with poor postoperative blood glucose control. Therefore tight glycemic control is paramount after hepatectomy and can be achieved using sliding scales and continuous insulin infusions.

Preoperative Biliary Drainage in the Hilar Cholangiocarcinoma Patient (see Chapter 51B) Preoperative biliary drainage before hepatic resection for extrahepatic hilar cholangiocarcinoma requires careful consideration. Postoperative outcomes after liver resection tend to be worse in patients with obstructive jaundice.75 However, preoperative

Chapter 11  Infections in Hepatic, Biliary, and Pancreatic Surgery

instrumentation of the biliary system is associated with cholangitis and increased infectious complications.76,77 Liu and colleagues (2011)78 concluded that preoperative drainage should not be routinely performed if it can be avoided. However, there are data to suggest that there is a role for preoperative biliary decompression in certain scenarios, including very small FLR patients79 and perhaps for right-sided resections.80 It is thus reasonable to consider biliary drainage via endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography and portal vein embolization in patients with a very small FLR.

Pancreatic Resection The most commonly performed resections include pancreaticoduodenectomy and distal pancreatectomy (typically with splenectomy when performed for cancer). These may also be accompanied by major vascular resection and multivisceral resection when resecting borderline resectable or locally advanced disease. Hence the studies of infectious complications after pancreatectomy focus on these two procedures. Enucleation and central pancreatectomy are less common procedures (see Chapter 117). Infectious complications after pancreatic resection may include SSI or organ/deep space infection. The latter can be further categorized by the contributing anastomosis: intraabdominal abscesses, or infected fluid collections can be related to an infected bile, pancreatic, or enteric leak, or a combination of these. Organ/space infection after distal pancreatectomy is typically related to pancreatic leak and less commonly due to iatrogenic injury to surrounding structures (colon, stomach) (see Chapter 28). Patients are also at risk for the development of abscesses not related to anastomotic leakage or secondary to an infected hematoma. Furthermore, these patients can develop infections in remote sites, including bloodstream infections, cholangitis, respiratory tract infections, urinary tract infections, and Clostridium difficile infections. General risk factors for SSI discussed earlier apply to patients undergoing pancreatic resection; however, there are risk factors specific to pancreatic resection that warrant discussion including potential strategies to decrease incidence or limit consequences by prompt diagnosis and initiation of treatment.

Preoperative Risk Mitigation Age

Elderly patients undergoing pancreatic resection may not necessarily be at higher risk of infectious complications but are more likely to experience a greater decline in function and higher mortality if they have a complication that is suggestive of diminished physiologic reserve.81 It is thus worth considering overall frailty and patient comorbidity should be considered alongside the potential for oncologic gain rather than age alone.

Body Mass Index and Nutritional Status Elevated BMI is a risk factor for infectious complications following pancreatic cancer. House and colleagues (2008)82 studied postoperative complications in 356 patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma with the goal of identifying preoperative patient and radiographic factors associated with postoperative morbidity. Complications developed in 38% of this patient population; the most common pancreatic complications were fistula/abscess, wound infection, and delayed gastric emptying. Wound infection rates were

187

significantly higher in those patients with a BMI greater than or equal to 30 (P 5 .03). The authors also determined that the degree of visceral fat as seen on preoperative axial imaging correlated with higher rates of overall complications and pancreatic fistula. This may also be related to the quality of the pancreas, as a soft, fat-replaced pancreas is likely to be at increased risk of postoperative pancreatic fistula.83 Greenblatt and colleagues (2011)84 used the ACS-NSQIP database in an attempt to formulate a prediction tool for patients undergoing pancreaticoduodenectomy. The authors examined preoperative factors that might predict perioperative morbidity and mortality. Although this study was not designed to predict who would incur an infectious complication specifically, the authors found that the most frequent complications after pancreaticoduodenectomy included sepsis (15.3%), SSI (13.1%), and respiratory complications (9.5%). The overall complication rate in 1342 patients was 27.1%. Elevated BMI was a significant predictor of morbidity (after adjusting for confounding variables), and morbidity increased incrementally with BMI. Other predictors included older age, male gender, dependent functional status, chronic obstructive pulmonary disease, steroid use, bleeding disorder, leukocytosis, elevated serum creatinine, and hypoalbuminemia. Kelly and colleagues (2011)85 attempted to identify preoperative and operative risk factors for the development of complications after distal pancreatectomy. The authors also used the multi-institutional prospective ACS-NSQIP database. Their efforts concerned the development of a risk score for patients undergoing distal pancreatectomy. The study population included 2322 patients. The overall 30-day complication and mortality rates were 28.1% and 1.2%, respectively. Similar to the analysis conducted by Greenblatt and colleagues (2011),84 this study was not designed to specifically address infectious complications. However, the most common complications were sepsis, SSI, and pneumonia. Multivariate analysis determined that high BMI was a preoperative predictor of postoperative morbidity. The other preoperative variables associated with postoperative complications included male gender, smoking, steroid use, neurologic disease, preoperative systemic inflammatory response syndrome/sepsis, hypoalbuminemia, elevated creatinine, and abnormal platelet count. Poor preoperative nutritional status is another important risk factor for SSI and other postoperative morbidity in patients undergoing pancreatic resection. La Torre and colleagues (2013)86 noticed a relationship between malnutrition and morbidity after pancreatic surgery in their retrospective evaluation of data collected from 143 patients undergoing pancreatic resection for cancer. Malnutrition was defined by using several different validated screening tools and was an independent risk factor for overall morbidity, which included SSI. Shinkawa and colleagues (2013)87 confirmed these findings in an examination of 64 patients with pancreaticoduodenectomy with regard to potential perioperative risk factors for SSI. Using multivariate logistic regression analysis on perioperative factors, the authors identified pancreatic fistula and a nutritional risk index (NRI) of 97.5 or less as independent risk factors for SSI. As noted previously, modification of preoperative risk factors may be difficult or even impossible before pancreatectomy. This is particularly true if the indication for resection is cancer or suspicion of cancer, which is common. In these instances, proceeding to the operating room expeditiously may be the prudent course of action, especially in the clearly resectable and

188

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

otherwise healthy operative candidate. However, more than one-third of patients about to undergo pancreaticoduodenectomy can be considered borderline candidates from a medical standpoint.88 These patients are at significant risk for postoperative morbidity (including infectious complications) as well as mortality. Therefore, as suggested by Tzeng and colleagues,99 surgeons should strongly consider improving the condition of the patient to mitigate infectious/overall morbidity and mortality in these “borderline resectable type C” patients before surgery. Those patients receiving neoadjuvant therapy should take advantage of this time and use it as a “window of opportunity” to modify BMI, improve nutritional/functional status, control hypertension, and/or quit smoking. For patients seen with surgically resectable tumors but significant reversible functional deficits, it may be worthwhile to administer neoadjuvant therapy while the patient is medically optimized. Regardless of whether neoadjuvant therapy consists of chemoradiation or chemotherapy alone, either type of preoperative therapy is considered safe with regard to postoperative complications.89–92

Preoperative Biliary Drainage (see Chapters 30 and 117) Preoperative biliary drainage in the setting of an obstructing pancreatic head mass continues to be debated. Earlier studies suggested that perioperative mortality is higher when pancreaticoduodenectomy is performed in the presence of hyperbilirubinemia.93–95 More recent work has also shown preoperative jaundice to be a poor prognostic factor with regard to overall survival for patients undergoing resection of the head of the pancreas for adenocarcinoma.96 However, routine preoperative biliary drainage in this setting may not be ideal. Healthy patients with an intact sphincter of Oddi and a normal biliary system have sterile bile. However, obstructive jaundice in the setting of a mass in the head of the pancreas results in bile stasis. This in turn promotes colonization of the biliary system, especially after the bile ducts are interrogated and drained via stents.97 The presence of bacteria in the biliary system is known as bacterobilia. When normal host defense mechanisms present in the liver and biliary tree are overwhelmed by a critical level of bacterobilia and the biliary tree is not adequately drained, then pathogenic enteric organisms may reach the systemic circulation through the liver, causing sepsis (i.e., cholangitis).4 It is rare for a patient with pancreatic cancer to be seen with cholangitis without having undergone attempts at biliary decompression. However, should this happen, the required treatment is antibiotics with biliary drainage as described in the Tokyo Guidelines.98,99 In the United States, typical drainage procedures include decompression via the percutaneous transhepatic approach or via endoscopic retrograde cholangiography. More commonly, cholangitis develops during or soon after attempted biliary decompression in the patient who is undergoing elective preoperative biliary drainage. Unfortunately, these patients who develop cholangitis preoperatively are at increased risk for postoperative complications, especially those related to infection and pancreatic fistula.100,101 The mere presence of bacterobilia, often related to preoperative biliary drainage, increases the risk of infectious complications in the postoperative setting.97,102–108 Therefore preoperative biliary drainage in a patient with resectable disease should be given thoughtful consideration, especially in light of a multicenter, randomized trial that showed routine preoperative biliary drainage increases the rate of postoperative complications in general.109

There are patients who routinely undergo preoperative biliary drainage. One group includes those patients with borderline resectable pancreatic head cancers who receive several months of neoadjuvant therapy before surgery. Although these patients may experience an increase in postoperative infectious complications with prolonged preoperative biliary drainage, the procedure appears to be relatively safe, and its associated risks are not prohibitive.110,111 With the increasing use of neoadjuvant chemotherapy and the requirement for tissue diagnosis via endoscopic ultrasound, it is likely that most patients will undergo preoperative stenting. Another group of patients in whom preoperative biliary drainage may be routinely indicated includes symptomatic patients with significant jaundice who are expected to wait more than 1 week for surgical referral. Preoperative biliary drainage in this cohort also appears to be relatively safe, as demonstrated by Howard and colleagues (2006).4 The authors of this study examined the relationship between bacterobilia (based on intraoperative bile cultures) and infectious complications in 138 patients undergoing an operation (including a biliary enteric anastomosis) for obstructive jaundice. Eighty-six (62%) patients had preoperative biliary stenting, whereas 52 (38%) did not. Ninety-one patients had bacterobilia, 69 from the stented group and 22 from the other group. Overall infectious complications occurred in 31 patients (22.4%), with the majority occurring in the stented group (23 vs. 8). However, this difference was not statistically significant. Stented patients did have a significantly higher rate of wound infection (P 5 .03) and bacteremia (P 5 .04) on subset analysis. The authors concluded that preoperative stenting increases the number of patients with positive intraoperative bile cultures, bacteremia, and wound infection. However, they also noted that preoperative stenting does not increase overall infectious morbidity, noninfectious morbidity, mortality, or hospital length of stay. The authors ultimately state that preoperative biliary drainage is not unreasonable in the jaundiced patient awaiting referral to an appropriate surgical center.

Operative Risk Mitigation (see Chapter 117) Preoperative Antibiotics

The current Clinical Practice Guidelines for Antimicrobial Prophylaxis recommend a single preoperative dose of cefazolin. The guidelines do not recommend continuing antimicrobial coverage beyond 24 hours postoperatively. Despite these guidelines, antimicrobial prophylaxis specifically for pancreatic resections has not been well evaluated in terms of the specific agent to use and its duration. Donald and colleagues (2013)112 suggested that guideline-recommended antimicrobial prophylaxis may not be appropriate for patients undergoing pancreaticoduodenectomy. They presented an argument for broadening perioperative antibiotic coverage with the use of piperacillin-tazobactam. Other authors have advocated for the selection of perioperative antimicrobial prophylaxis that is based on preoperative bile cultures obtained at the time of preoperative biliary drainage.113,114 An option is to administer cefoxitin preoperatively for reasons previously mentioned in the section “Hepatic Resection.”

Wound Protectors Dual-ring wound protectors are increasingly used in open abdominal surgery as they provide retraction and decrease the incidence of SSIs.115 In two trials evaluating their use in pancreaticoduodenectomy, conflicting results have been obtained.

Chapter 11  Infections in Hepatic, Biliary, and Pancreatic Surgery

The study by Bressan et al. (2018)116 showed a significant decrease in SSI (21% vs. 44%) in patients randomized to receiving wound retractors. All patients in this study had preoperative biliary stents. The trial by De Pastena et al. (2020),117 however, did not demonstrate any improvement in SSI in patients who were randomized to receiving wound protectors (7% in both groups, P 5 .59), even when the groups were stratified by whether preoperative biliary stenting was required (9% vs. 8%, P 5 .54). The difference in outcomes may be explained by the low baseline incidence of SSI in the study by De Pastena et al. A pragmatic approach may thus be to consider the use of wound protectors depending on the patient’s individual risk of SSI (e.g., whether they have had preoperative stents, etc.), the additional exposure provided in terms of retraction, and the institutional incidence of SSI to determine whether a clinically significant improvement is likely to be seen.

Other Operative Risk Factors Pancreatic fistula is one of the most important risk factors determining postoperative morbidity following pancreatic resection.87,118,119 Behrman and colleagues (2008)118 retrospectively studied 196 pancreatectomy patients with an aim to identify risk factors for intraabdominal sepsis. Approximately 16% of these patients developed an infected intraabdominal fluid collection, and overt pancreatic fistula as well as soft pancreatic remnants, were found to be statistically significant factors associated with its development. The authors also observed that infected fluid collections may occur relatively early in the postoperative course, and surgeons should have a low threshold to image and drain these collections. Sugiura and colleagues (2012)119 retrospectively examined risk factors for SSI in 408 patients who underwent pancreaticoduodenectomy. An incisional SSI developed in 61 patients, whereas an organ/space infection developed in 195 patients. The following were identified as significant risk factors for incisional SSI on multivariate analysis: length of operation greater than 480 minutes (odds ratio [OR], 3.22), main pancreatic diameter less than or equal to 3 mm (OR, 2.18), and abdominal wall thickness greater than 10 mm (OR, 2.16). Also, the following were significant risk factors for the development of organ/ space SSI: pancreatic fistula (OR, 7.56), use of semi-closed drainage system (OR, 3.68), BMI greater than 23.5 (OR, 3.04), main pancreatic duct diameter less than or equal to 3 mm (OR, 2.21), and operation longer than 480 minutes (OR, 1.78). Schmidt and colleagues (2009)120 studied preoperative and perioperative risk factors for the development of a pancreatic fistula in pancreaticoduodenectomy patients. Their multivariate analysis showed that an invaginated pancreatic anastomosis and closed suction intraperitoneal drainage were predictive of a pancreatic fistula, whereas chronic pancreatitis and preoperative biliary stenting were protective of a pancreatic fistula. Schoellhammer and associates (2014)121 have suggested that no one pancreatic anastomosis is superior and that more studies are needed to identify the best anastomotic technique. Recent work has suggested that externalized pancreatic duct stents may decrease pancreatic fistulae in high-risk anastomoses.122 A recent randomized trial studied pasireotide as a possible adjunct to prevent postoperative pancreatic fistula.123 Pasireotide is a somatostatin analogue with a longer half-life than octreotide. The authors randomly assigned 300 patients undergoing either pancreaticoduodenectomy or distal pancreatectomy to either perioperative pasireotide or placebo. The primary end

189

point was the occurrence of pancreatic fistula, leak, or abscess of grade 3 or higher. This end point was significantly lower in those patients treated with pasireotide (9% vs. 21%, P 5 .006). The authors concluded that this perioperative medication decreases the rate of clinically significant postoperative fistula, leak, or abscess in patients undergoing pancreatic resection. These findings, however, have not been widely replicated in other institutions in nonrandomized studies.124 Pancreatic fistula remains a clinically relevant problem in distal pancreatectomy also. Hamilton and colleagues (2012)125 conducted a randomized controlled trial examining the efficacy of mesh-reinforced stapled closure of the distal pancreas. The authors randomly assigned 54 patients to mesh reinforcement and 46 patients to non-mesh reinforcement, in which the primary outcome was clinically significant pancreatic leak. International Study Group of Pancreatic Fistula (ISGPF) grade B and C leaks occurred more frequently in the patients without mesh reinforcement (20% vs. 1.9%, P 5 .0007). Other operative risk factors contributing to postoperative infectious morbidity after pancreatic resection include longer operative times114,119,126–128 and need for perioperative blood transfusion.126 Procter and colleagues (2010)127 performed a retrospective analysis of 299,359 general surgical procedures (including pancreatectomy), identified through the ACSNSQIP database, looking for risk factors associated with infectious complications. Their multivariate analysis suggested that increased operative duration is an independent risk factor for infectious complications and hospital length of stay. This was confirmed by Ball and colleagues (2010),126 who conducted a retrospective analysis on only pancreaticoduodenectomy patients identified via the ACS-NSQIP database. Their study involved 4817 patients and determined that longer operative times were associated with both morbidity and mortality. Also, there was a linear relationship between preoperative RBC transfusion and 30-day morbidity. This led the authors to suggest blood transfusion and operative time as quality indicators for pancreaticoduodenectomy. The use of intraperitoneal drains remains contentious among pancreatic surgeons. Despite a large amount of literature within the recent past suggesting that intraperitoneal drainage may be unnecessary and even harmful,129–136 a randomized prospective multicenter trial concluded that “elimination of intraperitoneal drainage in all cases of pancreaticoduodenectomy increases the frequency and severity of complications.”137 This most recent study randomized 137 patients undergoing pancreaticoduodenectomy. Half of the patients had an intraperitoneal drain left in place, whereas the other half did not. These patients were followed prospectively for a range of complications. The study was stopped early because there was a substantial difference in mortality between the two groups. The drained patients had a mortality of 3%, whereas the undrained group experienced a 12% mortality rate. Beyond this, pancreaticoduodenectomy without intraperitoneal drainage was significantly associated with an increase in the number of complications per patient, an increase in the number of patients who had at least one complication rated at grade 2 or higher, and a higher average complications severity. From an infectious standpoint, pancreaticoduodenectomy without intraperitoneal drainage was associated with a higher rate of intraabdominal abscess (25% vs. 10%, P 5 .027). This study therefore provides strong evidence supporting the placement of intraperitoneal drains at the time of pancreaticoduodenectomy. Taken in the context of other contemporary

190

PART 1  LIVER, BILIARY, AND PANCREATIC ANATOMY AND PHYSIOLOGY

literature on this subject, the best approach to peritoneal drainage remains unclear and should be individualized to the specific patient. Also, placing a drain intraoperatively does not always obviate the need for a percutaneous drainage procedure in the early postoperative period.131 If placed at the time of pancreaticoduodenectomy, the timing of drain removal is also controversial. Recent prospective studies, including a randomized trial, have suggested that early drain removal based on drain amylase levels can lower the rate of postoperative complications, including infectious ones.138,139 A reasonable strategy would be to leave a non-suction drain posterior to the pancreaticojejunostomy and measure daily drain amylase for the first 3 postoperative days and remove the drain on day 3 if drain amylase is less than 30 and outputs are acceptable in quantity and character in an otherwise well patient. Minimally invasive pancreatic resections, either laparoscopic or robotic, have begun to be implemented worldwide and are discussed separately in a dedicated chapter (see Chapter 127). Laparoscopic distal pancreatectomy has been shown to be associated with improved short-term outcomes, decreased blood loss, and decreased infectious complications.140 Minimally invasive pancreaticoduodenectomy has a steep learning curve and may be regarded as in the evaluation stage outside of highvolume expert centers. In one study evaluating the last decade of outcomes across the United States, laparoscopic pancreaticoduodenectomy was associated with decreased pulmonary complications although no formal data on infectious complications were reported.141 To summarize, risk mitigation at the operative level for a pancreaticoduodenectomy or distal pancreatectomy consists of the efficient performance of the operation using careful operative technique in an effort to avoid unnecessary blood loss. There are no universally agreed on techniques to reduce pancreatic fistula during the performance of pancreaticoduodenectomy. The pancreaticoenteric anastomosis during pancreaticoduodenectomy is still performed according to surgeon preference but must be done meticulously. With regard to distal pancreatectomy, stapled closure of the pancreas with bioabsorbable mesh buttress appears promising in the prevention of pancreatic fistula. Perioperative administration of pasireotide has demonstrated efficacy in reducing pancreatic fistula after pancreaticoduodenectomy and distal pancreatectomy in one study but is not otherwise widely used. The use of intraperitoneal drains and the timing of their removal remain controversial, but most surgeons use drains especially after

pancreaticoduodenectomy. Minimally invasive techniques confer benefit in distal pancreatectomy and remain under evaluation for pancreaticoduodenectomy.

Postoperative Risk Mitigation (see Chapter 27) Two hundred and sixty-five HPB surgery patients were studied by Ambiru and colleagues (2008)73 and were prospectively evaluated for the development of SSI. Multivariate analysis showed that poor postoperative blood glucose was an independent risk factor for SSI. The rate of SSI was 20% in those patients with blood glucose levels below 200 versus 52% in those without insulin infusion therapy (P , .01). Therefore blood glucose control in the postoperative setting is of particular concern in the post-pancreatectomy patient, especially because some patients who were not previously diabetic may eventually require insulin therapy. A high proportion of patients undergoing pancreatic resection experience some sort of complication with infectious complications being relatively common. It is not unreasonable therefore to expect a complication and remain vigilant to avoid “failure-to-rescue” scenarios. Early detection of deviation from the normal postoperative course must be recognized with prompt diagnosis and treatment of complications.

Infectious Complications and Oncologic Outcome The oncologic outcomes from HPB malignancy remain poor with a few notable exceptions (e.g., colorectal liver metastases). An increasing body of evidence shows that postoperative complications not only delay immediate recovery but also worsen long-term oncologic outcome.3,142 This may be partly due to an inability to receive adjuvant therapy but also has to do with postoperative immune modulation adversely impacting tumor biology. Decreasing the burden of infectious complications is thus paramount from both a perioperative and oncologic standpoint.

SUMMARY HPB surgery is increasingly carried out in elderly patients often with advanced malignancy. Infectious complications are a major contributor to morbidity and mortality but can be addressed throughout the perioperative period using patient-specific and institutional interventions to mitigate risk and improve perioperative and oncologic outcomes. References are available at expertconsult.com.

190.e1

REFERENCES 1. Ceppa EP, Pitt HA, House MG, et al. Reducing surgical site infections in hepatopancreatobiliary surgery. HPB (Oxford). 2013; 15(5):384-391. 2. Kent TS, Sachs TE, Callery MP, Vollmer Jr CM. The burden of infection for elective pancreatic resections. Surgery. 2013;153(1): 86-94. 3. Kasahara N, Noda H, Kakizawa N, et al. A lack of postoperative complications after pancreatectomy contributes to the long-term survival of patients with pancreatic cancer. Pancreatology. 2019; 19(5):686-694. 4. Howard TJ, Yu J, Greene RB, et al. Influence of bactibilia after preoperative biliary stenting on postoperative infectious complications. J Gastrointest Surg. 2006;10(4):523-531. 5. Devulapalli KK, Fidelman N, Soulen MC, et al. 90Y radioembolization for hepatic malignancy in patients with previous biliary intervention: multicenter analysis of hepatobiliary infections. Radiology. 2018;288(3):774-781. 6. Kirby JP, Mazuski JE. Prevention of surgical site infection. Surg Clin North Am. 2009;89(2):365-389, viii. 7. Mangram AJ, Horan TC, Pearson ML, Silver LC, WR Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27(2):97-132; quiz 133-134; discussion 96. 8. Anonymous. Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. N Engl J Med. 1991;325(8):525-532. 9. Weimann A, Braga M, Harsanyi L, et al. ESPEN Guidelines on Enteral Nutrition: surgery including organ transplantation. Clin Nutr. 2006 Apr;25(2):224-244. 10. Anderson DJ, Kaye KS, Classen D, et al. Strategies to prevent surgical site infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(suppl 1):S51-S61. 11. Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43(3): 322-330. 12. Kjønniksen I, Andersen BM, Søndenaa VG, Segadal L. Preoperative hair removal–a systematic literature review. AORN J. 2002; 75(5):928-938, 940. 13. Springer R. The Surgical Care Improvement Project—focusing on infection control. Plast Surg Nurs. 2007;27(3):163-167. 14. Digison MB. A review of anti-septic agents for pre-operative skin preparation. Plast Surg Nurs. 2007;27(4):185-189, quiz 190-181. 15. Anonymous. ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999;56(18):1839-1888. 16. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281-286. 17. Forse RA, Karam B, MacLean LD, Christou NV. Antibiotic prophylaxis for surgery in morbidly obese patients. Surgery. 1989; 106(4):750-756; discussion 756-757. 18. Bolon MK, Morlote M, Weber SG, et al. Glycopeptides are no more effective than beta-lactam agents for prevention of surgical site infection after cardiac surgery: a meta-analysis. Clin Infect Dis. 2004;38(10):1357-1363. 19. Finkelstein R, Rabino G, Mashiah T, et al. Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections. J Thorac Cardiovasc Surg. 2002;123(2):326-332. 20. Brasel KJ, Borgstrom DC, Weigelt JA. Cost-utility analysis of contaminated appendectomy wounds. J Am Coll Surg. 1997;184(1): 23-30. 21. Cohn SM, Giannotti G, Ong AW, et al. Prospective randomized trial of two wound management strategies for dirty abdominal wounds. Ann Surg. 2001;233(3):409-413. 22. Scher KS. Studies on the duration of antibiotic administration for surgical prophylaxis. Am Surg. 1997;63(1):59-62. 23. Swoboda SM, Merz C, Kostuik J, Trentler B, PA Lipsett PA. Does intraoperative blood loss affect antibiotic serum and tissue concentrations? Arch Surg. 1996;131(11):1165-1171; discussion 1171-1172.

24. Barone JE, Tucker JB, Cecere J, et al. Hypothermia does not result in more complications after colon surgery. Am Surg. 1999; 65(4):356-359. 25. Sessler DI, Akca O. Nonpharmacological prevention of surgical wound infections. Clin Infect Dis. 2002;35(11):1397-1404. 26. Walz JM, Paterson CA, Seligowski JM, Heard SO. Surgical site infection following bowel surgery: a retrospective analysis of 1446 patients. Arch Surg. 2006;141(10):1014-1018; discussion 1018.27. 27. DiPiro JT, Cheung RP, Bowden Jr TA, Mansberger JA. Single dose systemic antibiotic prophylaxis of surgical wound infections. Am J Surg. 1986;152(5):552-559. 28. Carr JM, Sellke FW, Fey M, et al. Implementing tight glucose control after coronary artery bypass surgery. Ann Thorac Surg. 2005;80(3):902-909. 29. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67(2):352-360; discussion 360-362. 30. Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004;109(12):1497-1502. 31. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg. 1997;63(2):356-361. 32. Yang T, Tu PA, Zhang H, et al. Risk factors of surgical site infection after hepatic resection. Infect Control Hosp Epidemiol. 2014;35(3): 317-320. 33. Garwood RA, Sawyer RG, Thompson L, Adams RB. Infectious complications after hepatic resection. Am Surg. 2004;70(9):787-792. 34. Schindl MJ, Redhead DN, Fearon KCH, et al. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut. 2005;54(2):289-296. 35. Nanashima A, Arai J, Oyama S, et al. Associated factors with surgical site infections after hepatectomy: predictions and countermeasures by a retrospective cohort study. Int J Surg. 2014;12(4):310-314. 36. Watanabe Y, Kuboki S, Shimizu H, et al. A new proposal of criteria for the future remnant liver volume in older patients undergoing major hepatectomy for biliary tract cancer. Ann Surg. 2018;267(2): 338-345. 37. Khoo E, O’Neill S, Brown E, Wigmore SJ, EM Harrison EM. Systematic review of systemic adjuvant, neoadjuvant and perioperative chemotherapy for resectable colorectal-liver metastases. HPB (Oxford). 2016;18(6):485-493. 38. Scilletta R, Pagano D, Spada M, et al. Comparative analysis of the incidence of surgical site infections in patients with liver resection for colorectal hepatic metastases after neoadjuvant chemotherapy. J Surg Res. 2014;188(1):183-189. 39. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008; 371(9617):1007-1016. 40. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases. J Am Coll Surg. 2005;201(1):57-65. 41. Walcott-Sapp S, Billingsley KG. Preoperative optimization for major hepatic resection. Langenbecks Arch Surg. 2018;403(1):23-35. 42. Russell K, Zhang H-G, Gillanders LK, et al. Preoperative immunonutrition in patients undergoing liver resection: a prospective randomized trial. World J Hepatol. 2019;11(3):305-317. 43. Kurmann A, Wanner B, Martens F, et al. Hepatic steatosis is associated with surgical-site infection after hepatic and colorectal surgery. Surgery. 2014;156(1):109-116. 44. Elola-Olaso AM, Davenport DL, Hundley JC, et al. Predictors of surgical site infection after liver resection: a multicentre analysis using National Surgical Quality Improvement Program data. HPB (Oxford). 2012;14(2):136-141. 45. Okabayashi T, Nishimori I, Yamashita K, et al. Risk factors and predictors for surgical site infection after hepatic resection. J Hosp Infect. 2009;73(1):47-53. 46. Pessaux P, van den Broek MAJ, Wu T, et al. Identification and validation of risk factors for postoperative infectious complications following hepatectomy. J Gastrointest Surg. 2013;17(11):1907-1916.

190.e2 47. Sadamori H, Yagi T, Shinoura S, et al. Risk factors for organ/ space surgical site infection after hepatectomy for hepatocellular carcinoma in 359 recent cases. J Hepatobiliary Pancreat Sci. 2013; 20(2):186-196. 48. Arikawa T, Kurokawa T, Ohwa Y, et al. Risk factors for surgical site infection after hepatectomy for hepatocellular carcinoma. Hepatogastroenterology. 2011;58(105):143-146. 49. Kobayashi S, Gotohda N, Nakagohri T, et al. Risk factors of surgical site infection after hepatectomy for liver cancers. World J Surg. 2009;33(2):312-317. 50. Nakahira S, Shimizu J, Miyamoto A, et al. Proposal for a subclassification of hepato-biliary-pancreatic operations for surgical site infection surveillance following assessment of results of prospective multicenter data. J Hepatobiliary Pancreat Sci. 2013;20(5):504-511. 51. Vaska AI, Abbas S. The role of bile leak testing in liver resection: a systematic review and meta-analysis. HPB (Oxford). 2019;21(2): 148-156. 52. Zimmitti G, Vauthey JN, Shindoh J, et al. Systematic use of an intraoperative air leak test at the time of major liver resection reduces the rate of postoperative biliary complications. J Am Coll Surg. 2013;217(6):1028-1037. 53. Fuks D, Cauchy F, Ftériche S, et al. Laparoscopy decreases pulmonary complications in patients undergoing major liver resection: a propensity score analysis. Ann Surg. 2016;263(2):353-361. 54. Ito K, Ito H, Are C, et al. Laparoscopic versus open liver resection: a matched-pair case control study. J Gastrointest Surg. 2009;13(12): 2276-2283. 55. Wakabayashi G, Cherqui D, Geller DA, et al. Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. Ann Surg. 2015;261(4): 619-629. 56. Kamarajah SK, Wilson CH, Bundred JR, et al. A systematic review and network meta-analysis of parenchymal transection techniques during hepatectomy: an appraisal of current randomised controlled trials. HPB (Oxford). 2020;22(2):204-214. 57. Yanaga K, Kanematsu T, Takenaka K, et al. Intraperitoneal septic complications after hepatectomy. Ann Surg. 1986;203(2):148-152. 58. Petrowsky H, Demartines N, Rousson V, et al. Evidence-based value of prophylactic drainage in gastrointestinal surgery: a systematic review and meta-analyses. Ann Surg. 2004;240(6):1074-1084; discussion 1084-1085. 59. Belghiti J, Kabbej M, Sauvanet A, Vilgrain V, Panis Y, Fekete F. Drainage after elective hepatic resection. A randomized trial. Ann Surg. 1993;218(6):748-753. 60. Fong Y, Brennan MF, Brown K, Heffernan N, Blumgart LH. Drainage is unnecessary after elective liver resection. Am J Surg. 1996;171(1):158-162. 61. Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg. 2004;239(2):194-201. 62. Gurusamy KS, Samraj K, Davidson BR. Routine abdominal drainage for uncomplicated liver resection. Cochrane Database Syst Rev. 2007(3):CD006232. 63. Brooke-Smith M, Figueras J, Ullah S, et al. Prospective evaluation of the International Study Group for Liver Surgery definition of bile leak after a liver resection and the role of routine operative drainage: an international multicentre study. HPB (Oxford). 2015;17(1):46-51. 64. Brauer DG, Nywening TM, Jaques DP, et al. Operative site drainage after hepatectomy: a propensity score matched analysis using the American College of Surgeons NSQIP Targeted Hepatectomy Database. J Am Coll Surg. 2016;223(6):774-783.e2. 65. Pessaux P, Regimbeau JM, Dondéro F, Plasse M, Mantz J, Belghiti J. Randomized clinical trial evaluating the need for routine nasogastric decompression after elective hepatic resection. Br J Surg. 2007;94(3):297-303. 66. Ichida H, Imamura H, Yoshimoto J, Sugo H, Ishizaki Y, Kawasaki S. Randomized controlled trial for evaluation of the routine use of nasogastric tube decompression after elective liver surgery. J Gastrointest Surg. 2016;20(7):1324-1330. 67. Richter B, Schmandra TC, Golling M, Bechstein WO. Nutritional support after open liver resection: a systematic review. Dig Surg. 2006;23(3):139-145. 68. Hughes MJ, McNally S, Wigmore SJ. Enhanced recovery following liver surgery: a systematic review and meta-analysis. HPB (Oxford). 2014;16(8):699-706.

69. Ni X, Jia D, Guo Y, Sun X, Suo J. The efficacy and safety of enhanced recovery after surgery (ERAS) program in laparoscopic digestive system surgery: a meta-analysis of randomized controlled trials. Int J Surg. 2019;69:108-115. 70. Rouxel P, Beloeil H. Enhanced recovery after hepatectomy: a systematic review. Anaesth Crit Care Pain Med. 2019;38(1):29-34. 71. Huo TI, Lui WY, Huang YH, et al. Diabetes mellitus is a risk factor for hepatic decompensation in patients with hepatocellular carcinoma undergoing resection: a longitudinal study. Am J Gastroenterol. 2003;98(10):2293-2298. 72. Little SA, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y. Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer. J Gastrointest Surg. 2002;6(1):88-94. 73. Ambiru S, Kato A, Kimura F, et al. Poor postoperative blood glucose control increases surgical site infections after surgery for hepato-biliary-pancreatic cancer: a prospective study in a highvolume institute in Japan. J Hosp Infect. 2008;68(3):230-233. 74. Li Q, Wang Y, Ma T, Lv Y, Wu R. Clinical outcomes of patients with and without diabetes mellitus after hepatectomy: a systematic review and meta-analysis. PLoS One. 2017 Feb 9;12(2):e0171129. 75. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg. 2000;191(1):38-46. 76. Ferrero A, Tesoriere RL, Viganò L, Caggiano L, Sgotto E, Capussotti L. Preoperative biliary drainage increases infectious complications after hepatectomy for proximal bile duct tumor obstruction. World J Surg. 2009 Feb;33(2):318-325. 77. Hochwald SN, Burke EC, Jarnagin WR, Fong Y, Blumgart LH. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg. 1999;134(3):261-266. 78. Liu F, Li Y, Wei Y, Li B. Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci. 2011;56(3):663-672. 79. Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford). 2009;11(5):445-451. 80. Farges O, Regimbeau JM, Fuks D, et al. Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg. 2013;100(2):274-283. 81. Tamirisa NP, Parmar AD, Vargas GM, et al. Relative contributions of complications and failure to rescue on mortality in older patients undergoing pancreatectomy. Ann Surg. 2016;263(2):385-391. 82. House MG, Fong Y, Arnaoutakis DJ, et al. Preoperative predictors for complications after pancreaticoduodenectomy: impact of BMI and body fat distribution. J Gastrointest Surg. 2008;12(2):270-278. 83. Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer Jr CM. A prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreatoduodenectomy. J Am Coll Surg. 2013;216(1):1-14. 84. Greenblatt DY, Kelly KJ, Rajamanickam V, et al. Preoperative factors predict perioperative morbidity and mortality after pancreaticoduodenectomy. Ann Surg Oncol. 2011;18(8):2126-2135. 85. Kelly KJ, Greenblatt DY, Wan Y, et al. Risk stratification for distal pancreatectomy utilizing ACS-NSQIP: preoperative factors predict morbidity and mortality. J Gastrointest Surg. 2011;15(2):250-259, discussion 259-261. 86. La Torre M, Ziparo V, Nigri G, Cavallini M, Balducci G, Ramacciato G. Malnutrition and pancreatic surgery: prevalence and outcomes. J Surg Oncol. 2013;107(7):702-708. 87. Shinkawa H, Takemura S, Uenishi T, et al. Nutritional risk index as an independent predictive factor for the development of surgical site infection after pancreaticoduodenectomy. Surg Today. 2013;43(3):276-283. 88. Tzeng C-WD, Katz MHG, Fleming JB, et al. Morbidity and mortality after pancreaticoduodenectomy in patients with borderline resectable type C clinical classification. J Gastrointest Surg. 2014;18(1):146-155; discussion 155-156. 89. Araujo RLC, Gaujoux S, Huguet F, et al. Does pre-operative chemoradiation for initially unresectable or borderline resectable pancreatic adenocarcinoma increase post-operative morbidity? A case-matched analysis. HPB (Oxford). 2013;15(8):574-580. 90. Cheng TY, Sheth K, White RR, et al. Effect of neoadjuvant chemoradiation on operative mortality and morbidity for pancreaticoduodenectomy. Ann Surg Oncol. 2006;13(1):66-74.

190.e3 91. Cho SW, Tzeng C-WD, Johnston WC, et al. Neoadjuvant radiation therapy and its impact on complications after pancreaticoduodenectomy for pancreatic cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). HPB (Oxford). 2014;16(4):350-356. 92. Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248(6):1014-1022. 93. Böttger TC, Junginger T. Factors influencing morbidity and mortality after pancreaticoduodenectomy: critical analysis of 221 resections. World J Surg. 1999;23(2):164-171; discussion 171-172. 94. Braasch JW, Gray BN. Considerations that lower pancreatoduodenectomy mortality. Am J Surg. 1977;133(4):480-484. 95. Lerut JP, Gianello PR, Otte JB, Kestens PJ. Pancreaticoduodenal resection. Surgical experience and evaluation of risk factors in 103 patients. Ann Surg. 1984;199(4):432-437. 96. Strasberg SM, Gao F, Sanford D, et al. Jaundice: an important, poorly recognized risk factor for diminished survival in patients with adenocarcinoma of the head of the pancreas. HPB (Oxford). 2014;16(2):150-156. 97. Limongelli P, Pai M, Bansi D, et al. Correlation between preoperative biliary drainage, bile duct contamination, and postoperative outcomes for pancreatic surgery. Surgery. 2007;142(3): 313-318. 98. Gomi H, Solomkin JS, Takada T, et al. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):60-70. 99. Miura F, Takada T, Strasberg SM, et al. TG13 flowchart for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):47-54. 100. Kitahata Y, Kawai M, Tani M, et al. Preoperative cholangitis during biliary drainage increases the incidence of postoperative severe complications after pancreaticoduodenectomy. Am J Surg. 2014;208(1):1-10. 101. Kondo K, Chijiiwa K, Ohuchida J, et al. Selection of prophylactic antibiotics according to the microorganisms isolated from surgical site infections (SSIs) in a previous series of surgeries reduces SSI incidence after pancreaticoduodenectomy. J Hepatobiliary Pancreat Sci. 2013;20(3):286-293. 102. Cortes A, Sauvanet A, Bert F, et al. Effect of bile contamination on immediate outcomes after pancreaticoduodenectomy for tumor. J Am Coll Surg. 2006;202(1):93-99. 103. di Mola FF, Tavano F, Rago RR, et al. Influence of preoperative biliary drainage on surgical outcome after pancreaticoduodenectomy: single centre experience. Langenbecks Arch Surg. 2014;399(5):649-657. 104. Jagannath P, Dhir V, Shrikhande S, Shah RC, Mullerpatan P, Mohandas KM. Effect of preoperative biliary stenting on immediate outcome after pancreaticoduodenectomy. Br J Surg. 2005; 92(3):356-361. 105. Lermite E, Pessaux P, Teyssedou C, Etienne S, Brehant O, Arnaud JP. Effect of preoperative endoscopic biliary drainage on infectious morbidity after pancreatoduodenectomy: a case-control study. Am J Surg. 2008;195(4):442-446. 106. Povoski SP, Karpeh Jr MS, Conlon KC, Blumgart LH, Brennan MF. Preoperative biliary drainage: impact on intraoperative bile cultures and infectious morbidity and mortality after pancreaticoduodenectomy. J Gastrointest Surg. 1999;3(5):496-505. 107. Povoski SP, Karpeh Jr MS, Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg. 1999;230(2):131-142. 108. Sivaraj SM, Vimalraj V, Saravanaboopathy P, et al. Is bactibilia a predictor of poor outcome of pancreaticoduodenectomy? Hepatobiliary Pancreat Dis Int. 2010;9(1):65-68. 109. van der Gaag NA, Rauws EAJ, van Eijck CHJ, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med. 2010;362(2):129-137. 110. Gerke H, White R, Byrne MF, et al. Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage. Dig Liver Dis. 2004;36(6):412-418. 111. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated

morbidity in 300 consecutive patients. Ann Surg. 2001;234(1): 47-55. 112. Donald GW, Sunjaya D, Lu X, et al. Perioperative antibiotics for surgical site infection in pancreaticoduodenectomy: does the SCIP-approved regimen provide adequate coverage? Surgery. 2013;154(2):190-196. 113. Sudo T, Murakami Y, Uemura K, et al. Specific antibiotic prophylaxis based on bile cultures is required to prevent postoperative infectious complications in pancreatoduodenectomy patients who have undergone preoperative biliary drainage. World J Surg. 2007;31(11):2230-2235. 114. Sudo T, Murakami Y, Uemura K, et al. Perioperative antibiotics covering bile contamination prevent abdominal infectious complications after pancreatoduodenectomy in patients with preoperative biliary drainage. World J Surg. 2014;38(11):2952-2959. 115. Zhang L, Elsolh B, Patel SV. Wound protectors in reducing surgical site infections in lower gastrointestinal surgery: an updated meta-analysis. Surg Endosc. 2018;32(3):1111-1122. 116. Bressan AK, Aubin JM, Martel G, et al. Efficacy of a dual-ring wound protector for prevention of surgical site infections after Pancreaticoduodenectomy in patients with intrabiliary stents: a randomized clinical trial. Ann Surg. 2018;268(1):35-40. 117. De Pastena M, Marchegiani G, Paiella S, et al. Use of an intraoperative wound protector to prevent surgical-site infection after pancreatoduodenectomy: randomized clinical trial. Br J Surg. 2020;107(9):1107-1113. 118. Behrman SW, Zarzaur BL. Intra-abdominal sepsis following pancreatic resection: incidence, risk factors, diagnosis, microbiology, management, and outcome. Am Surg. 2008;74(7):572-578; discussion 578-579. 119. Sugiura T, Uesaka K, Ohmagari N, Kanemoto H, Mizuno T. Risk factor of surgical site infection after pancreaticoduodenectomy. World J Surg. 2012;36(12):2888-2894. 120. Schmidt CM, Choi J, Powell ES, et al. Pancreatic fistula following pancreaticoduodenectomy: clinical predictors and patient outcomes. HPB Surg. 2009;2009:404520. 121. Schoellhammer HF, Fong Y, Gagandeep S. Techniques for prevention of pancreatic leak after pancreatectomy. Hepatobiliary Surg Nutr. 2014;3(5):276-287. 122. Andrianello S, Marchegiani G, Malleo G, et al. Pancreaticojejunostomy with externalized stent vs pancreaticogastrostomy with externalized stent for patients with high-risk pancreatic anastomosis: a single-center, phase 3, randomized clinical trial. JAMA Surg. 2020;155(4):313-321. 123. Allen PJ. Pasireotide for postoperative pancreatic fistula. N Engl J Med. 2014;371(9):875-876. 124. Dominguez-Rosado I, Fields RC, Woolsey CA, et al. Prospective evaluation of pasireotide in patients undergoing pancreaticoduodenectomy: the Washington University experience. J Am Coll Surg. 2018;226(2):147-154.e1. 125. Hamilton NA, Porembka MR, Johnston FM, et al. Mesh reinforcement of pancreatic transection decreases incidence of pancreatic occlusion failure for left pancreatectomy: a singleblinded, randomized controlled trial. Ann Surg. 2012;255(6): 1037-1042. 126. Ball CG, Pitt HA, Kilbane ME, Dixon E, Sutherland FR, Lillemoe KD. Peri-operative blood transfusion and operative time are quality indicators for pancreatoduodenectomy. HPB (Oxford). 2010;12(7):465-471. 127. Procter LD, Davenport DL, Bernard AC, Zwischenberger JB. General surgical operative duration is associated with increased risk-adjusted infectious complication rates and length of hospital stay. J Am Coll Surg. 2010;210(1):60-65.e1-2. 128. Wang A, Zhou J, Ma XJ, Liao Q, Li G-, Zhao YP. [Analysis of surgical site infection rate in pancreas operation and its related risk factors]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2007;29(4):562-565. 129. Adham M, Chopin-Laly X, Lepilliez V, Gincul R, Valette PJ, Ponchon T. Pancreatic resection: drain or no drain? Surgery. 2013;154(5):1069-1077. 130. Behrman SW, Zarzaur BL, Parmar A, Riall TS, Hall BL, Pitt HA. Routine drainage of the operative bed following elective distal pancreatectomy does not reduce the occurrence of complications. J Gastrointest Surg. 2015;19(1):72-79; discussion 79. 131. Conlon KC, Labow D, Leung D, et al. Prospective randomized clinical trial of the value of intraperitoneal drainage after

190.e4 pancreatic resection. Ann Surg. 2001;234(4):487-493; discussion 493-494. 132. Correa-Gallego C, Brennan MF, D ºAngelica M, et al. Operative drainage following pancreatic resection: analysis of 1122 patients resected over 5 years at a single institution. Ann Surg. 2013; 258(6):1051-1058. 133. Fisher WE, Hodges SE, Silberfein EJ, et al. Pancreatic resection without routine intraperitoneal drainage. HPB (Oxford). 2011;13(7):503-510. doi:10.1111/j.1477-2574.2011.00331.x. 134. Mehta VV, Fisher SB, Maithel SK, et al. Is it time to abandon routine operative drain use? A single institution assessment of 709 consecutive pancreaticoduodenectomies. J Am Coll Surg. 2013; 216(4):635-642; discussion 642-644. 135. Paulus EM, Zarzaur BL, Behrman SW. Routine peritoneal drainage of the surgical bed after elective distal pancreatectomy: is it necessary? Am J Surg. 2012;204(4):422-427. 136. van der Wilt AA, Coolsen MME, de Hingh IHJT, et al. To drain or not to drain: a cumulative meta-analysis of the use of routine abdominal drains after pancreatic resection. HPB (Oxford). 2013;15(5):337-344. 137. Van Buren G II, Bloomston M, Hughes SJ, et al. A randomized prospective multicenter trial of pancreaticoduodenectomy with

and without routine intraperitoneal drainage. Ann Surg. 2014; 259(4):605-612. 138. Bassi C, Molinari E, Malleo G, et al. Early versus late drain removal after standard pancreatic resections: results of a prospective randomized trial. Ann Surg. 2010;252(2):207-214. 139. Kawai M, Tani M, Terasawa H, et al. Early removal of prophylactic drains reduces the risk of intra-abdominal infections in patients with pancreatic head resection: prospective study for 104 consecutive patients. Ann Surg. 2006;244(1):1-7. 140. Plotkin A, Ceppa EP, Zarzaur BL, Kilbane EM, Riall TS, Pitt HA. Reduced morbidity with minimally invasive distal pancreatectomy for pancreatic adenocarcinoma. HPB (Oxford). 2017;19(3): 279-285. 141. Tran TB, Dua MM, Worhunsky DJ, Poultsides GA, Norton JA, Visser BC. The First Decade of Laparoscopic Pancreaticoduodenectomy in the United States: costs and Outcomes Using the Nationwide Inpatient Sample. Surg Endosc. 2016;30(5):1778-1783. 142. Memeo R, de Blasi V, Adam R, et al. Postoperative infectious complications impact long-term survival in patients who underwent hepatectomies for colorectal liver metastases: a propensity score matching analysis. J Gastrointest Surg. 2018;22(12): 2045-2054.

PART 2

Diagnostic Techniques

12 Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease



13 Cross-Sectional Imaging of Liver, Biliary, and Pancreatic Disease: Introduction and Basic Principles



14 Imaging Features of Benign and Malignant Liver Tumors and Cysts



15 Imaging Features of Metastatic Liver Cancer



16 Imaging Features of Gallbladder and Biliary Tract Disease



17 Imaging Features of Benign and Malignant Pancreatic Disease



18 The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases



19 Emerging Techniques in Diagnostic Imaging



20 Direct Cholangiography: Approaches, Techniques, and Current Role



21 Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications



22 Endoscopic Ultrasound of the Biliary Tract and Pancreas



23 Image-Guided Liver Biopsy



24 Intraoperative Diagnostic Techniques

191

CHAPTER 12 Clinical investigation of hepatopancreatobiliary and pancreatic disease Marco Massani and Tommaso Stecca INTRODUCTION The clinical approach to the patient diagnosed with hepatopancreatobiliary (HPB) disease must be systematic without neglecting clinical elements that could prove illuminating in the diagnostic process. The correct interpretation of symptoms and signs could be challenging, demanding great judgment, because even subtle clinical manifestations may forecast unattended events. A meticulous, detailed history and physical examination, followed by a few laboratory tests, are of great value. The clinical history should focus on the symptoms of HPB disease and their nature and pattern of onset and progression as well as potential risk factors. The modern and almost ubiquitous availability of second-level radiologic or endoscopic investigations must not subtract the physician from the analytical approach to the patient; “scan first, clinic later” must be avoided. This chapter describes the common symptoms and signs of HPB disease, the value of basic investigations, and how this initial assessment guides further management. Clinical presentations and investigations of specific HPB diseases are also detailed.

LIVER DISEASE The liver is an organ with a broad set of critical biologic functions, a unique dual vascular supply, and several distinct cell types that contribute to its physiologic functions and its potential pathology. Liver disease encompasses infectious, malignant, and chronic disease processes arising from a wide range of etiologies, which generally present with a few clinical patterns classified as hepatocellular, cholestatic, or mixed.1 In hepatocellular diseases (e.g., steatosis, alcoholic liver disease [ALD], and viral hepatitis), the clinical and biochemical scenario is dominated by liver damage, inflammation, and necrosis. In cholestatic diseases (e.g., bile duct—gallstones or malignant—obstruction, biliary cirrhosis), bile flow obstruction predominates. In the mixed form, both characteristics are present. The results from the last Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) on the burden of chronic liver disease (CLD) revealed that globally in 2017, cirrhosis caused more than 1.32 million deaths (66.6% in males) compared with less than 899,000 deaths in 1990. These deaths constituted 2.4% of all deaths, with an age-standardized death rate of 16.5 per 100,000 population, which was at its lowest in the high-income countries and at its highest in sub-Saharan Africa. Globally, 31.5% of cirrhosis deaths in males were caused by hepatitis B, followed by alcohol-related liver disease (27.3%), hepatitis C (25.5%), nonalcoholic steatohepatitis (NASH; 7.7%), and other causes (8.0%). In females, hepatitis C (26.7%) was the leading cause, followed by hepatitis B (24.0%), alcohol-related liver disease (20.6%), NASH (11.3%), 192

and other causes (17.3%).2 However, the scenario of CLDs in the United States has changed over the past 30 years. Hepatitis C is decreasing, whereas hepatitis B and alcohol-related liver disease remain stable. In contrast, the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing alongside the epidemic of obesity and type-2 diabetes mellitus (T2DM).3 In 2014, in the United States, the average yearly healthcare expenses in patients with CLD was $19,390 dollars, with nationwide healthcare expenses estimated at $29.9 billion (2.6% of the total nationwide for adults; see Chapters 68, 69, and 74).4 Many patients come to the clinician’s attention not because of complaints of symptoms but because of the alteration of biochemical liver enzyme (aminotransferases) or function test results (prothrombin time/INR [PT/INR], bilirubin, and albumin) as part of routine physical examination or screening blood tests.5 Almost 10% to 17% of patients with unexplained liver enzyme elevation have previously unsuspected CLD.6 Clinicians should be able to accurately and efficiently recognize CLD given the high prevalence of morbidity associated with the liver tests and their significant costs and the consequences associated with cirrhosis. The patient evaluation path should lead to the determination of the etiologic diagnosis, severity (grading), and stage of disease.

CLINICAL HISTORY The physician should begin the history by focusing on the symptoms of liver disease (the nature, pattern of onset and progression) and on potential risk factors to provide clues toward the underlying etiology of liver injury, which may help to differentiate acute injury from CLD. The duration of liver injury, particularly in the absence of symptoms, is not always certain. The clinical history should then proceed with a systematic inquiry into family history, drug history, social circumstances, employment, and travel. Commonly, it is the set of symptoms and the way in which they have arisen, rather than a specific symptom, that directs the determination of etiology.7 Presenting symptoms may include abdominal discomfort, anorexia, nausea, vomiting, fatigue, malaise, fever, rash, itching, or jaundice. Fatigue (described as lethargy, weakness, malaise, an increased need for sleep, or a loss of energy) is the most common and characteristic symptom. Typically, fatigue arises after exertion and is often intermittent and variable in severity. Abdominal pain is a common presenting symptom to be investigated for site, severity, radiation, and the rapidity of onset. Localization in the right upper quadrant, because of the distention or irritation of the richly innervated Glisson capsule, is usually marked by tenderness over the liver area. Severe pain may also indicate gallbladder disease, liver abscess, veno-occlusive disease, or

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

193

acute hepatitis. A history of weight loss may point to a malignant process. Nausea and vomiting should be recorded along with a history of itching, jaundice, and the color of urine and stools. Jaundice is the hallmark symptom of liver disease and is best detected by the examination of the sclera or the mucous membranes below the tongue. The loss of functioning hepatocellular mass leads to hypoalbuminemia, which can manifest as a shortness of breath, ankle swelling, abdominal distension, and ascites, all of which can occur in many acute and chronic HPB disorders. Gastroesophageal varices and splenomegaly are consequences of portal hypertension and can clinically manifest as hematemesis or melena, thus requiring urgent endoscopic investigation. The increased peripheral conversion to estrogen resulting from the decreased hepatic metabolism and catabolism of androstenedione results in palmar erythema, spider nevi, gynecomastia, decreased body hair, and testicular atrophy. Terry nails (white nails) are characterized by a silver-white pallor that can range from the proximal to the entire nail bed, obscuring the nail lunula. Accurate recording of alcohol intake is important in assessing the cause of liver disease, focusing on whether alcohol abuse or dependence is present (the CAGE questionnaire is recommended)8 and on planning management and treatment because heavy alcohol use impacts CLD outcomes. A past medical history should be obtained and include any major illnesses and any abdominal surgery. A record of comorbidities and exercise tolerance should be made because this will guide the surgeon in assessing fitness for future intervention if required.

PHYSICAL EXAMINATION A physical examination is a fundamental complement to, rather than a substitute for, diagnostic investigations. Indeed, physical signs need to be used with additional clinical criteria to augment the probability of identifying patients with CLD. Physical signs are generally of low sensitivity for the diagnosis, and signs with higher specificity are associated with clinically decompensated disease.9 Typical findings in CLD are: jaundice (Fig. 12.1), hepatomegaly (Fig. 12.2), liver tenderness, splenomegaly, spider nevi, palmar erythema (Fig. 12.3), and scratching injuries. Ascites, edema, sarcopenia, collateral circulation, hepatic fetor, and encephalopathy are signs of advanced disease. Signs related to

FIGURE 12.2  Massive hepatomegaly.

FIGURE 12.3  Palmar erythema.

FIGURE 12.1  Jaundice.

alcohol abuse are gynecomastia (Fig. 12.4), parotidomegaly, facial telangiectasia, Dupuytren contracture, and testicular atrophy (see Chapters 74, 76, and 77). When inspected under natural light, jaundice can be noted within the sclera or the mucous membranes below the tongue. Jaundice can usually be observed when the bilirubin level is above 43 mmol/L (2.5 mg/dL). Hyperpigmentation is typical of

194

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 12.5  Spider nevus in a patient with cirrhosis.

FIGURE 12.4  Bilateral gynecomastia.

advanced CLD, such as primary biliary cirrhosis and sclerosing cholangitis, whereas in hemochromatosis, pigmentation is slategray. Spider nevi are superficial, tortuous, arterial skin lesions with a central arteriole and numerous small radiating vessels (Fig. 12.5). Usually found in the vascular territory of the superior vena cava (arms, face, and upper torso), more than two or three is likely to be abnormal. Palmar erythema may also develop in healthy individuals and is frequently found during pregnancy. Hippocratic fingers (clubbing; Fig. 12.6), white nails (Terry nails), koilonychia (Fig. 12.7), and asterixis are all features of CLD. During eye examination attention should be paid to the pallor, scleral icterus, xanthelasma, and Kayser-Fleischer rings. Physical findings of hepatic encephalopathy include asterixis and flapping tremors of the body and tongue. When there is a portal-venous shunt, a characteristic fruity, ammoniacal, odor—called fetor hepaticus—occurs because of exhaled thiols. During abdominal examination, particular attention should be paid to any scars from previous abdominal surgery, abdominal distension, and areas of discoloration. Ascites (Fig. 12.8) is appreciated by detecting shifting dullness by careful percussion. Portal hypertension may present with cutaneous manifestations such as visible collateral veins radiating from the umbilicus called caput medusae (Fig. 12.9). Palpation of the abdomen should begin with a general light palpation, looking for obvious masses and areas of tenderness. The healthy liver is usually impalpable. Reduction in liver size is also important because this may occur in cirrhosis and certain types of hepatitis. A lobe may undergo hypertrophy and become palpable, and this may occur in the presence of hemiliver atrophy or after liver resection. Marked hepatomegaly is typical of cirrhosis, veno-occlusive disease, infiltrative disorders such as amyloidosis, metastatic or primary cancers of the liver,

FIGURE 12.6  Clubbing of fingernails.

FIGURE 12.7  Koilonychia.

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

BOX 12.1  Causes of Hepatomegaly Variant Anatomy Riedel lobe Low-lying diaphragm Inflammatory Hepatitis Abscesses, amebic and pyogenic Schistosomiasis Cirrhosis, early Sarcoid Biliary obstruction, especially extrahepatic FIGURE 12.8  Ascites with an everted umbilicus and venous distension in a patient with cirrhosis.

Metabolic Amyloid Steatohepatitis Glycogen storage disease Hematologic Leukemias Lymphomas Myeloproliferative disorders Sickle cell disease Porphyrias Tumors Primary, benign and malignant Secondary Cardiovascular Cardiac failure Hepatic vein obstruction

FIGURE 12.9  Caput medusae.

and alcoholic hepatitis. Careful assessment of the liver edge may also reveal unusual firmness, the irregularity of the surface, or frank nodules. A hard, knobby liver often indicates the presence of metastases, whereas smooth enlargement may be because of cirrhosis. Causes of hepatomegaly are listed in Box 12.1. Splenomegaly may occur in many medical conditions. Splenomegaly can be difficult to find but is significant in liver disease. Percussion may be useful, and if ascites is present, the spleen may be ballotable. If the spleen is sufficiently enlarged, the notch on its anterior border may become palpable (Fig. 12.10). Causes of splenomegaly are listed in Box 12.2.

CLINICAL FEATURES OF LIVER DISEASE Portal Hypertension Portal vein pressure normally ranges from 7 to 12 mm Hg. Portal hypertension is characterized by an abnormal increase in pressure within the portal venous system and is defined as a hepatic venous pressure gradient (HVPG) higher than 5 mm Hg10 (see Chapter 74). It becomes clinically significant at values $10 mm Hg. According to the hydraulic analogy of Ohm’s law, the main determinants of portal pressure are blood flow and vascular resistance. The primary factor is a marked increase in the intrahepatic vascular resistance to portal blood flow because of both

FIGURE 12.10  Splenomegaly.

195

196

PART 2  DIAGNOSTIC TECHNIQUES

invasive procedure, and concerns about serious complications and sampling variations may limit its use11 (see Chapter 23). An accurate diagnosis can be made relying on the presence of portal-hypertension-related complications, namely esophageal and gastric varices, variceal bleeding, ascites, spontaneous bacterial peritonitis, splenomegaly, and hepatic encephalopathy (see Chapters 74 and 76). The increased flow through portosystemic collaterals remodels the esophageal and gastric vessels (more common in noncirrhotic portal hypertension). Variceal bleeding may be a life-threatening complication and is seen when the pressure gradient reaches 12 mm Hg with continuous bleeding when greater than 20 mm Hg (see Chapters 80 and 81). Arterial vasodilatation, sodium and water retention, and increased sinusoidal pressure are determinants of ascites progression (see Chapter 79). The net positive balance of ammonia induced by intrahepatic portosystemic shunts, decreased urea and glutamine synthesis, and shortened muscle mass are responsible for hepatic encephalopathy. Ammonia reaches cerebral astrocytes through hepatic portosystemic shunts and is metabolized into glutamine, thus providing an osmotic pull toward cerebral edema (see Chapter 77).

BOX 12.2  Causes of Splenomegaly Infection Acute: viral, bacterial Chronic: tuberculosis, brucellosis Parasitic: malaria, schistosomiasis Hematologic Leukemias Hemolytic anemias Hemoglobinopathies Portal hypertension, especially extrahepatic Neoplastic Lymphomas Myeloproliferative disorders Secondary deposits Inflammatory Rheumatoid Systemic lupus Amyloidosis

mechanical obstruction from fibrosis and the contraction of the portohepatic bed. Second, arteriolar splanchnic dilation and hyperdynamic circulation aggravate and perpetuate portal hypertension syndrome.11 Any condition that interferes with portal venous blood flow or vascular resistance can lead to portal hypertension. The causes are listed in Table 12.1 and can be classified according to the anatomic location in prehepatic, hepatic, and posthepatic cases.12 The definitive diagnosis requires the use of invasive interventional radiology methods to measure the HVPG by hepatic vein catheterization. Serum surrogate markers for cirrhosis include the aspartate aminotransferase-to-platelet ratio index, the Forns index, and the FibroTest. Ultrasound (US) allows us to assess the hepatic parenchyma and the surrounding structures (splenomegaly is the most sensitive sign of portal hypertension). Doppler US can be used to assess hepatic vein flow patterns and waveforms. Tissue elastography is a noninvasive method of measuring liver stiffness and predicting liver fibrosis. The results are expressed in kPa, but they should be interpreted with caution in the setting of acute liver damage in CLD because of the effect of edema and inflammation. Liver biopsy is still the gold standard for the diagnosis of CLD even though it is an

Alcoholic Liver Disease ALD covers a wide range of hepatic injuries related to the amount of alcohol consumed and to the duration of drinking, including simple steatosis, fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis.13 ALD is a chronic, relapsing disease affecting approximately 10% of the general population in Western countries, and it is one of the 30 most frequent causes of death in the world. Diagnosis can be made based on clinical and laboratory features alone in patients with a history of prolonged alcohol abuse for which no other causes can be found.14 The 2014 World Health Organization (WHO) report on alcohol stated that Eastern European countries have the highest annual per capita alcohol consumption (11–13 L per person), and North Africa and the Middle East have the lowest (0–2 L per person). The estimated annual per capita consumption in the United States is 10 L per person.15 A recent study by the Global Burden of Disease 2016 Alcohol Collaborators reported that the safest level of drinking is none.16 An alcohol intake of 60 g per day is associated with hepatic steatosis in 60% to 90% of individuals; less than half of those individuals who continue to drink will develop fibrosis, and only 10% to 20% will eventually

TABLE 12.1  Etiologies of Portal Hypertension HEPATIC

PREHEPATIC

PRESINUSOIDAL

SINUSOIDAL

POSTSINUSOIDAL

POSTHEPATIC

Portal vein thrombosis Splenic-arteriovenous fistula

Schistosomiasis Nodular regenerative hyperplasia Cholangiopathy

Cirrhosis Acute hepatitis

Veno-occlusive disease Sinuoidal obstruction syndrome

Budd-Chiari syndrome Congestive heart failure

Liver metastases Sarcoidosis Amyloidosis Polycystic liver disease Congenital hepatic fibrosis

Acute fatty liver of pregnancy Amyloidosis Mastocytosis Gaucher disease

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

develop cirrhosis. Alcoholic liver damage can be found in otherwise asymptomatic people. Clinical features of more severe, symptomatic ALD are jaundice, ascites, or encephalopathy, but many have nonspecific symptoms, especially anorexia, nausea, vomiting, abdominal discomfort, or diarrhea. Some patients present with infections such as pneumonia or are found to have injuries such as rib fractures. Patients also present because of damage to other organs such as the pancreas, brain, heart, or peripheral nerves. Typical laboratory findings include transaminase levels with aspartate aminotransferase levels more than twice that of alanine aminotransferase levels; an increased mean corpuscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio; a prolonged prothrombin time; a low albumin level; and a decreased platelet count.13 According to the European Association for the Study of Liver Diseases (EASL),17 the American Association for the Study of Liver Diseases (AASLD),18 and the American College of Gastroenterology (ACG)19 guidelines, liver biopsy is not routinely recommended for all suspected ALD cases, but it is useful in cases of aggressive forms. Histologic features are hepatic steatosis, inflammation, and Mallory-Denk bodies. US, computerized tomography (CT), and magnetic resonance imaging (MRI) detect liver steatosis, cirrhosis, and portal hypertension with different levels of sensitivity and specificity according to the stage of fibrosis. Transient elastography has excellent diagnostic accuracy for the diagnosis of advanced fibrosis and cirrhosis. The ChildTurcotte-Pugh (CTP) score and Model for End-Stage Liver Disease (MELD) assess the severity and prognosis of liver disease. Severe forms of ALD are defined as a MELD score $18, with mortality ranging between 30% and 60% without therapy.14

Autoimmune Liver Disease The term autoimmune liver diseases encompasses a group of chronic immune-mediated disorders that are distinct in the target of liver injury, the pattern of serologic tests, and their clinical findings (see Chapter 105). The diagnosis is obtained from the characteristic phenotype of each disorder and the exclusion of secondary liver diseases (e.g., viral, alcoholic, or drug-induced hepatitis). The most important autoimmune liver diseases are as follows: • Autoimmune hepatitis (AIH): AIH is characterized by hepatocellular injury and typical interface hepatitis at histology. AIH is about four times more common in females than males. Serologic findings include increased levels of transaminases, marked polyclonal hypergammaglobulinemia, and typical non–organ-specific autoantibodies.20 • Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis): PBC is characterized by autoimmune injury of small bile ducts that leads to chronic nonsuppurative cholangitis and subsequent fibrosis. PBC is the most common chronic cholestatic liver disease in women. Biochemical signs of cholestasis and the presence of anti-mitochondrial antibodies (AMAs) are the main serologic findings.21 • Primary sclerosing cholangitis (PSC): PSC is a chronic immunemediated disease affecting intra- and extrahepatic bile ducts, leading to cholestasis, liver fibrosis, multifocal biliary strictures, liver cirrhosis, and, ultimately, liver failure (see Chapter 41). PSC has a male predominance (more than 60%) and diagnosis is confirmed through magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). PSC is characterized by the absence of any disease-specific autoantibodies and poor response to immunosuppression. It must also

197

be taken into account that in approximately 70% of PSC patients, inflammatory bowel disease (IBD) is diagnosed (e.g., mainly ulcerative colitis)22. Such diseases, characterized either by hepatocellular injury (i.e., AIH) or by predominant cholestatic features (i.e., PBC and PSC), have a progressive course that may cause liver failure and may even require transplantation.

Budd-Chiari Syndrome Budd-Chiari syndrome is the eponym used for referring to a heterogeneous group of conditions characterized by partial or complete hepatic venous outflow obstruction (see Chapter 86). It is a rare and potentially life-threatening condition, and the estimated incidence in Western countries is one in 2.5 million cases per person per year. The obstruction can be located at any level, from the small hepatic veins to the junction of the inferior vena cava. The increase in hepatic sinusoidal pressure leads to portal hypertension and liver congestion, which may ultimately progress to hepatic fibrosis and cirrhosis. The most common causes are, for example, an underlying hypercoagulable or a prothrombotic state because of congenital diseases or myeloproliferative disorders, malignancy, and pregnancy. Secondary causes are direct compression from primary or secondary liver masses or abscesses and the extension of a thrombus from renal cell carcinoma. The clinical presentation ranges from acute failure to asymptomatic (up to 20% of cases), and it depends on the rapidity and extent of obstruction and the presence of collateral veins. The classic triad comprises abdominal pain, ascites, and hepatomegaly. Laboratory analyses provide little help in the diagnosis but are useful in understanding the etiology and predicting the severity of disease, the likelihood of mortality, and the possible response to therapy. Imaging techniques (US, MRI, and CT) play an important role in the diagnosis, classification, and severity assessment of the disease, documenting intrahepatic collaterals and areas of reduced perfusion and necrosis as well as providing appropriate images for therapeutic planning.23,24

Hemochromatosis Hemochromatosis is defined as a systemic iron overload most commonly caused by the autosomal-recessive inheritance of a C282Y substitution in the HFE gene (hereditary hemochromatosis [HH] type 1). It can also be caused by mutations in other genes (non-HFE-related: HAMP, HJV, TFR2, SLC40A1) or by acquired iron overload (hematologic disorders, excessive iron supplementation, metabolic syndrome, and chronic alcoholism).25 Type 1 HH is the most common mutation associated with a clinical disease, with the frequency of a homozygous C282Y mutation reported to be 0.4% in European countries. Diagnosis involves a strategy that combines clinical, imaging, and biologic data. Patients are asymptomatic for many years and develop symptoms at approximately 30 to 40 years of age in men and 40 to 50 years of age in women. The disease is frequently first recognized by elevated iron indices (transferrin saturation and serum ferritin) or by parameters that indicate organ-specific iron overload (mild hypertransaminasemia and hyperglycemia). Common presenting symptoms that may lead to clinical diagnosis of HH include fatigue, arthralgia, and a loss of libido. Chronic iron overload organ damage results in clinical HH including hepatic cirrhosis and hepatocellular carcinoma, dilated cardiomyopathy or cardiac rhythm disorders, diabetes mellitus, hypogonadism, chronic fatigue, lethargy, joint pain, and skin bronzing. Liver biopsy has

198

PART 2  DIAGNOSTIC TECHNIQUES

been replaced by the combined evaluation of biochemical and imaging findings, but it still has a role in assessing hepatic complications such as fibrosis. Transient elastography is a useful noninvasive test for detecting significant liver fibrosis, and liver MRI can be used to assess the presence of elevated hepatic iron in a quantitative fashion.26,27

prothrombin time require further assessment, indicating a pathologic state. Acute fatty liver of pregnancy may present to the surgeon with liver subcapsular hematoma or rupture with massive intraabdominal bleeding. Laparotomy for clot evacuation and hemostasis may be required. The management is supportive, and mortality is high.32,33

Polycystic Liver Disease

Acute Liver Failure

Adult polycystic liver disease (PLD) is a rare inherited autosomal dominant condition characterized by more than 20 fluidfilled biliary epithelial-lined cysts in the liver (see Chapter 73). Three PLD entities are recognized in adults. PLD can occur in the setting of two distinct hereditary disorders: as the primary presentation of autosomal-dominant PLD or associated with polycystic kidneys in autosomal-dominant polycystic kidney disease (ADPKD). Microhamartomas (Von Meyenburg complexes) may occur in isolation or in the context of PLD and ADPKD, are usually asymptomatic, and require no management or follow-up examination. Genetic mechanisms or signaling defects are the root cause of ductal structures becoming separated from the biliary tree, finally resulting in cyst formation. The proteins affected in ADPKD are located at the cilium, which has led to its classification it as a ciliopathy. On the other hand, hepatic cysts in ADPLD are lined by cholangiocytes; therefore this form is defined as a cholangiopathy.28,29 Although PLD is most often asymptomatic, one in five patients experience symptoms, with the most common symptoms being abdominal pain or distention, early satiety, nausea, dyspnea, and lower back pain. In rare cases, cyst compression may lead to ascites, biliary obstruction, and portal thrombosis. Patients can experience acute liver cyst complications, including infection, rupture, torsion, and hemorrhage. Cross-sectional imaging (CT or MRI) characterizes liver cyst burden and determines appropriate treatment. In symptomatic patients, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation.30,31

Acute liver failure (ALF) is the clinical manifestation of sudden and severe hepatic injury, and it has an incidence of fewer than 10 cases per million persons per year in the developed world (see Chapters 77 and 78). In the developing world, viral causes predominate (see Chapter 68), with hepatitis E infection recognized as a common cause; other rare viral causes of acute liver failure include hepatitis B virus, herpes simplex virus, cytomegalovirus, Epstein–Barr virus, and parvoviruses. In the United States and western Europe, most cases arise from druginduced liver injury, mostly commonly because of acetaminophen. Other causes of ALF are neoplastic infiltration, BuddChiari syndrome, heatstroke, mushroom ingestion, metabolic diseases such as Wilson’s disease, acute ischemic hepatocellular injury, or hypoxic hepatitis. Nevertheless, a large proportion of cases are still of unknown origin. The clinical presentation usually includes hepatic dysfunction, abnormal liver biochemical values, and coagulopathy; encephalopathy may develop, with multiorgan failure and death occurring in up to half the cases.34,35 Diagnostic liver biopsy is not routinely recommended. Various prognostic evaluation systems are in use worldwide, of which the Model for End-Stage Liver Disease (MELD) and the King’s College Hospital criteria are the best known. A MELD score of 30.5 (fixed cutoff value) should be used for prognosis, and higher scores predict a need for liver transplantation.36 When symptoms seriously progress under continuous supportive medical care, deceased-donor liver transplantation (DDLT) becomes the only therapeutic option. In countries where cadaveric donors are scarce, living-donor liver transplantation (LDLT) is another option.

Liver Disease in Pregnancy

Benign Liver Masses37,38 (see Chapter 88)

Pregnancy-associated liver diseases occur in 3% to 5% of pregnant women. There are many potential causes of liver disease in pregnancy, including non-pregnancy related pre-existing liver disease (viral, cirrhosis and portal hypertension, autoimmune) or those that are coincidental with pregnancy (autoimmune, viral, vascular, and drug-induced hepatotoxicity). Pregnancyrelated liver disease can be classified according to the time of onset (early or late pregnancy): hyperemesis gravidarum in the first trimester; intrahepatic cholestasis in the second half; and acute fatty liver of pregnancy, preeclampsia with hepatic involvement including hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome and liver rupture/infarction in the third trimester. Pregnancy-associated diseases can carry a high mortality rate for both mothers and babies and require rapid diagnosis and urgent delivery if at the severe end of the spectrum. In cirrhotic women who become pregnant, hepatic decompensation occurs in 10% and this can be predicted by the MELD score. Many physiologic changes occur in a pregnant woman, some of which can mimic those seen in CLD, including hyperdynamic circulation, a procoagulation state, palmar erythema, spider nevi, gallstones, and an increase in alkaline phosphatase and alpha fetoprotein. Elevations in transaminases, bilirubin, or

Hepatic Hemangioma Hepatic hemangioma is the most frequent benign liver lesion with a prevalence of 5% in the population, and it is more frequent in women between 30 and 50 years of age. It consists of “cavernous” vascular spaces lined by endothelial cells, varying in dimension (capillary hemangiomas, giant or cavernous hemangiomas), while remaining asymptomatic. Radiologic investigations such as CT and MRI are extremely reliable in the diagnosis because of the unique centripetal vascularization (see Chapter 14). Spontaneous bleeding is rare. For smaller lesions that may have an uncertain diagnosis, radiologic follow-up is preferable, but it is not required after a diagnosis of classical hemangioma. Surgery must be considered and is reserved in cases of lesions that have grown beyond 10 cm or in patients symptomatic for compression or recurrent pain (generally after thrombotic/hemorrhagic phenomena).

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is the second most common benign liver lesion, with a prevalence of 3%. Up to 90% of cases of FNH are diagnosed in women between 35 and 50 years of age. Generally, FNHs are small, solitary lesions of less than 5 cm, but they can be larger and multiple in 20% to 30% of

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

cases. FNH originates from the hepatic stellate cell response to an irritative stimulus such as increased blood flow, which produces the typical central radial scar. In most cases, the size is stable over time, the lesions are asymptomatic, and complications (rupture and malignant degeneration) are extremely rare. Biopsy is not indicated to confirm the diagnosis of typical FNH. Surgical treatment is reserved for cases of symptomatic, exophytic lesions or those with increases in size. Patients with definitive radiologic diagnosis do not need follow-up.

Hepatocellular Adenoma Hepatocellular adenoma (HA) is a rare benign liver lesion affecting less than 0.012% of the population that is commonly diagnosed in women between 35 and 40 years of age. HAs can be solitary or multiple, ranging in dimension from a few millimeters up to 30 cm. HAs are characterized by specific radiologic peculiarities but also by a significant risk for complications such as rupture, bleeding, and malignant degeneration (in lesions greater than 5 cm). Numerous studies have shown a causative role of sex hormones (oral contraceptives or hormone-releasing intrauterine devices and anabolic hormones in men) in their development. The recent increase in incidence is closely related to the increased prevalence of obesity and metabolic syndrome. MRI has the greatest sensitivity in identifying HA but also in diagnosing the different variants of adenoma. Liver biopsy can help identify HA subtypes and the specific underlying genetic alterations. Surgical treatment is always expected in men because of the nonnegligible risk for malignant degeneration. In women, however, surgery must be considered in the case of adenomas greater than 5 cm in size, in lesions that are exophytic, and in those with an increase in size of more than 20% during radiologic follow-up (see Chapters 88 and 89).

Simple Hepatic Cysts The vast majority of simple hepatic cysts are benign and derive from a congenital failure of a bile duct to communicate with the bile tree. These cysts are generally less than one centimeter in diameter, but they can grow up to 30 cm. These cysts are often asymptomatic, but patients with larger lesions can manifest with abdominal pain and epigastric and postprandial fullness. The presence of multiple cysts (more than 20); cysts larger than 5 cm; or cysts with internal septa, calcifications, fenestrations, internal loculations, alterations of the wall, or “daughter” cysts must lead to further investigations because of their malignant potential (cystadenoma or cystadenocarcinoma) or the potential for congenital diseases (polycystic liver disease) or parasitic infections (hydatid cysts). Simple liver cysts, asymptomatic and without signs of suspicion, do not require treatment or radiologic follow-up. Symptomatic simple liver cysts, on the other hand, can be treated surgically by laparoscopic “fenestration” (see Chapter 73).

GALLBLADDER AND BILIARY TRACT DISEASE Gallbladder The most common form of gallbladder disease is cholelithiasis, which affects more than 20 million Americans, with an annual direct cost of more than 6.3 billion dollars (see Chapter 33). The usual presentation of uncomplicated gallstones is biliary colic (see Chapter 34). The pain is characteristically steady, is moderate to severe in intensity, and is epigastric or in the right quadrant postprandially; the pain lasts several hours and then

199

gradually subsides. The pain often radiates to the back and to the right shoulder. If pain persists with the onset of fever or leukocytosis, it should raise suspicion for complications such as acute cholecystitis (AC), gallstone pancreatitis, or ascending cholangitis. Upper right quadrant tenderness and guarding exacerbated by inspiration (Murphy’s sign) suggest AC. A palpable, distended gallbladder—“Courvoisier’s gallbladder”39—in the presence of obstructive jaundice may suggest malignant obstruction of the biliary tree mainly because of pancreatic head lesions. Nevertheless, a nonpalpable gallbladder does not exclude a malignant process and is the rule in hilar obstruction. On the other hand, an intermittently palpable gallbladder may suggest the presence of a periampullary carcinoma.40 Acute cholecystitis in the presence of bacteria-containing bile may progress to suppurative infection in which the gallbladder fills with purulent material, a condition referred to as empyema of the gallbladder.

Gallstones and Biliary Colic The prevalence of gallstone disease varies significantly among ethnicities and its incidence increases with age and is higher in women. In developed countries, gallbladder stones are present in 10% to 20% of the adult population. As stated by the third National Health and Nutrition Examination Survey, in the United States 6.3 million men and 14.2 million women aged 20 to 74 had gallbladder disease.41 In Europe, according to the Multicenter Italian Study on Cholelithiasis (MICOL), the overall incidence of gallstone disease was 18.8% in women and 9.5% in men.42 Symptoms (biliary colic) occur in 1% to 4% of patients annually, and 20% become symptomatic within 20 years of diagnosis. Nearly 35% to 50% of symptomatic patients do not experience further biliary pain, even if no definitive predictive factor for biliary recurrence has been clearly identified in symptomatic patients. After the first episode of colic, 1% to 3% of patients per year will manifest a complication (AC, acute cholangitis, acute biliary pancreatitis, obstructive jaundice), whereas in asymptomatic patients, the rate is 0.1% to 0.3% annually.43 Major risk factors for cholesterol gallstones (the most common type in Western countries) include advancing age, sex, race, family history, pregnancy, and parity. Additional risk factors include high-calorie and low-fiber diets, low physical activity, rapid weight loss, metabolic syndrome, hormonal therapy, and obesity. Biliary colic, radiating pain, and the use of analgesics are symptoms that are significantly associated with the presence of gallstones.44 The pain is usually severe in intensity with an abrupt beginning or with a progressive crescendo that is thought to relate to the distention of the gallbladder after acute and usually transient obstruction of the cystic duct. The symptoms are often present shortly after a meal and last from 30 minutes to a few hours and then resolve. A duration longer than 5 hours most often indicates AC. The patient is afebrile with tenderness in the epigastrium but no peritonism.45 Even though dyspepsia, heartburn, bloating, and flatulence are often present in these patients, they are not characteristic of gallstone disease, and they usually persist after cholecystectomy. Laboratory tests are usually normal and do not contribute to the diagnosis of uncomplicated colic. With an accuracy for detecting gallstones reaching 95%, abdominal US is the imaging technique of choice. In the case of a normal US finding, MRI is recommended, while in patients with unexplained

200

PART 2  DIAGNOSTIC TECHNIQUES

acute and/or recurrent pancreatitis endoscopic US (EUS) is helpful43 (see Chapters 16, 20, 22, and 30). Several risk factors for cholesterol, pigment, and mixed gallstones exist and general preventive measures are plausible. A healthy lifestyle and diet, regular physical activity, and an ideal body weight might prevent gallstones and biliary colic. The administration of ursodeoxycholic acid (UDCA) to the general population as a preventive drug has no indication, and conflicting results are available on the protective effect of statins or ezetimibe. There have been no randomized clinical trials, clinical observations, or prospective studies assessing the benefit of cholecystectomy in asymptomatic patients. Approximately 0.7% to 2.5% of this group of patients will develop symptoms related to gallstones with an annual incidence of complications of 0.1% to 0.3%. The overall morbidity and mortality risk of surgery outweighs the probability of complications, thus giving no recommendation for routine surgical treatment. On the other hand, cholecystectomy should be performed in symptomatic patients. Half of them will have recurring colic within 1 year, but surgical treatment may not be necessary if symptoms have not occurred within the last 5 years or after one isolated episode.43

Gallstones in the Bariatric Population The prevalence of obesity among adults in the United States has increased dramatically during recent decades among all race/sex groups but also worldwide with a greater surge of obesity prevalence in lower- and middle-income developing countries than in higher-income countries. In the United States, according to the third National Health and Nutrition Examination Survey, 58 million people are at least 20% overweight, with a greater prevalence in black and Hispanic females, where obesity approaches 50%.46,47 Increased BMI and female sex are decisive risk factors for the development of gallstones, acting together with diabetes mellitus and insulin resistance. Additionally, increasing BMI, waist circumference, and serum triglycerides increase the risk for symptomatic gallstones. The pathogenic mechanisms involved in the formation of gallstones are the supersaturation of bile with cholesterol, increased propensity to cholesterol crystallization, stone aggregation, and defective gallbladder emptying. Additional factors are insulin resistance, dyslipidemia, sedentary lifestyle, hormone replacement therapy, and fast-food consumption. Gallbladder stasis and increased cholesterol saturation in bile have been implicated as major predisposing factors in the development of sludge and gallstones if weight loss, either with very-low-calorie diets or with bariatric surgery without cholecystectomy, is too rapid (more than 1.5 kg/week). The lithogenic effect is seen after 4 weeks, although it generally appears within 7 to 18 months. Approximately one-third of patients may develop gallstones after bariatric surgery, with a greater risk after a gastric bypass procedure with 28% to 71% of these patients becoming symptomatic and up to one-third of patients eventually requiring urgent cholecystectomy by 3 years.47,48 Lytholytic hydrophilic UDCA has become the standard prophylactic treatment for gallstone formation after rapid weight reduction. Nevertheless, the adoption of prophylactic cholecystectomy is still controversial. Some centers routinely perform it; however, this may be associated with an increase in the overall operative time, the length of stay (LOS), and related complications.43,48

Acute Cholecystitis Cholecystitis may be acute or chronic. Four different forms of AC are described: acalculous, xanthogranulomatous, emphysematous, and torsion of the gallbladder (see Chapter 34). Acalculous cholecystitis is typical of critically ill patients; xanthogranulomatous cholecystitis is because of an impacted stone and is characterized by wall thickening and increased intraluminal pressure; emphysematous cholecystitis is caused by gas-forming anaerobes; and torsion of the gallbladder results in compromised vascular supply.45 AC is the most common complication of gallstone disease and occurs in 10% to 20% of untreated patients. Chronic cholecystitis is the result of repeated episodes of AC and is characterized by thickened gallbladder walls, mucosal atrophy, and fibrosis. In patients discharged home without operation after an episode of AC, the probability of gallstonerelated events is 14%, 19%, and 29% at 6 weeks, 12 weeks, and 1 year, respectively.49 According to the 2016 European Association for the Study of Liver Disease guidelines, the 2016 World Society of Emergency Surgery guidelines, and the 2018 Tokyo Guidelines, the diagnosis of AC is based on clinical findings, laboratory data, and imaging. The Tokyo Guidelines for the diagnosis and management of AC were originally published in 2007 and have recently been updated. These are summarized in Box 12.3. Patients with AC have severe and worsening right upper quadrant pain lasting for several hours, radiating to the interscapular area or right shoulder. It is usually associated with tenderness on palpation (Murphy’s sign). Nausea and vomiting are often present. Systemic signs of inflammation are fever and elevated C-reactive protein and white blood cell (WBC) count. Blood urea nitrogen, creatinine, albumin, and arterial blood gas analysis may be required to further assess the severity of AC. US is the first-choice imaging method for the morphologic diagnosis of AC because of its low invasiveness, ease of use, costeffectiveness, and widespread use.43,49,50

Biliary Obstruction Biliary obstruction can occur anywhere along the extrahepatic biliary system and can have various benign and malignant etiologies. These include choledocholithiasis, choledochal cysts, Mirizzi’s syndrome, infectious diseases (parasitic cholangiopathy), inflammatory and autoimmune disease (AIDS cholangiopathy, autoimmune cholangiopathy), and neoplastic strictures (cholangiocarcinoma, pancreatic head cancer, ampullary carcinoma).51 Malignant biliary tract obstruction is often asymptomatic until the disease is significantly advanced. Jaundice is usually the presenting symptom in up to 90% of pancreatic head cancer

BOX 12.3  The 2018 Tokyo Guidelines Diagnostic Criteria for Acute Cholecystitis . Local signs of inflammation A 1. Murphy’s sign 2. Right upper quadrant mass/pain/tenderness B. Systemic signs of inflammation 1. Fever 2. Elevated C-reactive protein 3. Elevated white blood cells count C. Imaging findings Imaging findings characteristic of acute cholecystitis Suspected diagnosis: one item in A 1 one item in B Definite diagnosis: one item in A 1 one item in B 1 C

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

201

and distal cholangiocarcinoma (dCCA) patients and may also be seen with gallbladder carcinoma (see Chapters 49, 51, and 62). Accompanying symptoms are pale stools, dark urine, itching, right upper quadrant discomfort, nausea, weight loss, anorexia, and night sweats. Symptoms suggestive of pancreatic carcinoma include dull epigastric pain radiating to the back, Courvoisier’s gallbladder, dyspepsia, new-onset diabetes, or acute pancreatitis (AP). Hilar cholangiocarcinoma (hCCA) is a rare malignancy that affects hepatic duct confluence (see Chapter 51B). Patients typically present with jaundice because of a proximal biliary stricture, which in a significant proportion of patients (up to 15% of resected patients) can have benign pathology (inflammatory strictures, sclerosing cholangitis, or IgG4-related cholangiopathy).52 Laboratory tests depict a cholestatic process, and direct serum bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase are elevated. Tumor markers are usually nonspecific. CA 19-9 is elevated not only in pancreatic cancer but also in other gastrointestinal (GI) cancers (cholangiocarcinoma, gastric cancer, colorectal cancer, esophageal cancer, and hepatocellular cancer) and benign processes (AC or AP) as well as biliary obstruction per se, thus limiting its specificity.51 Diagnostic modalities include transabdominal US, CT scan, and MRI/MRCP (see Chapter 13). MRCP has excellent sensitivity and specificity for demonstrating the level and presence of biliary obstruction. Additional modalities that are both diagnostic and allow therapeutic interventions include EUS with EUS-BD or without guided biliary drainage, ERCP, and percutaneous transhepatic cholangiopancreatography (PTC)52,53 (see Chapters 20, 22, 30, 31, 37C, and 51B).

than 4 mm versus in 32.5% of patients with a duct diameter of greater than 4 mm.55 Stones found in the CBD may be primary, secondary, residual, or recurrent. Primary stones may arise intrahepatically or within the CBD and occur more often in the Asian population (see Chapters 39 and 44). These stones are thought to originate as a consequence of bacteriobilia and are often attributed to biliary stasis (bile duct stricture, papillary stenosis, periampullary diverticulum, the reflux of the duodenal contents into the bile duct) and abnormalities of the sphincter of Oddi. Secondary stones are the most common stone type in the United States. These stones migrate from the gallbladder to the CBD through the cystic duct.56 Secondary CBD stones may recur after cholecystectomy or after endoscopic sphincterotomy with a wide range of incidences from 4% to 24%. Risk factors for recurrence are periampullary diverticulum type I or II, angulation along the course of the CBD, multiple CBD stones, bile duct dilation, and muddy stones. Residual stones are missed at the time of cholecystectomy but present within 2 years, whereas recurrent stones develop more than 2 years after surgery.45,57 Many patients are asymptomatic and are incidentally found to have choledocholithiasis during an abdominal US for cholelithiasis or abnormal liver function tests. Symptomatic patients complain of right upper quadrant or epigastric pain, nausea, vomiting, intermittent or persistent jaundice, colorless stools, dark urine, and AP. Transabdominal US is the most appropriate initial imaging study in most patients even though its sensitivity ranges from 13% to 89%. CT scans may be performed after US, particularly when malignancy is suspected. Endoscopic US and MRCP have better sensitivity for detecting CBD stones than transabdominal US or conventional CT and are less invasive than ERCP.57,58

Asymptomatic Bile Duct Dilatation

Cholangitis

An incidentally found asymptomatic dilated common bile duct (CBD) is a common finding because of the widespread use of abdominal imaging. The mean diameter of a normal CBD ranges from 4 to 8 mm, but in most studies, a CBD diameter greater than 7 mm is considered abnormal. Patient presentation can be asymptomatic or symptomatic, with normal or abnormal liver function tests. A recent systematic review documented that in 9% to 73% of patients a diagnosis can be found and is most commonly benign. The most common causes are: CBD stones, chronic pancreatitis (CP), periampullary diverticulum, and cholecystectomy. Malignancy is identified in 12% of patients. Potential predictors of malignancy include jaundice, age, and coexisting CBD and intrahepatic duct dilation. There are no definitive recommendations on the approach, imaging modalities, or follow-up. However, the symptomatic patient and/or patients with abnormal liver function tests need further investigation. The truly asymptomatic patient should be followed closely with clinical and laboratory follow-up to help decide whether any additional imaging would be appropriate. Even though these patients often undergo further evaluation with different radiologic techniques, EUS is the primary imaging modality of choice.54

Acute cholangitis is characterized by biliary infection and concomitant obstruction with various benign and malignant causes (see Chapter 43). The bacteriobilia and the elevated intraductal pressure allow bacterial and endotoxin translocation into the vascular and lymphatic system. Cholangitis is a potentially lifethreatening condition if not treated with antibiotic therapy and if biliary obstruction is not resolved. The diagnosis is based on clinical presentation, laboratory results, and diagnostic imaging. Acute cholangitis has long been diagnosed on the basis of Charcot’s triad of fever, jaundice, and abdominal pain. Patients with more severe forms may also have hypotension and altered mental status, a constellation called Reynold’s pentad. US and CT scan with contrast help to identify the underlying cause and to exclude other diagnoses. Other imaging modalities include MRCP, MRI, EUS, and ERCP. Poor prognostic predictive factors include a WBC count greater than 20,000 cells/mm3, total bilirubin greater than 10 mg/dL, temperature greater than 39°C, serum albumin less than 3.0 g/dL, and age greater than 75.43,45,59,60 The diagnostic criteria for acute cholangitis are based on the Tokyo Guidelines, relying on the three items of systemic inflammation, cholestasis, and imaging, with moderate diagnostic accuracy (sensitivity 91.8%, specificity 77.7%). The Tokyo Guidelines for the diagnosis and management of acute cholangitis were originally published in 2007 and have recently been updated.61 These are summarized in Box 12.4.

Choledocholithiasis Choledocholithiasis, commonly from gallbladder stones, is the main etiology of nonmalignant biliary obstruction (see Chapter 37). It is estimated that up to 10% of patients concomitantly have a stone or multiple stones in the CBD after cholecystectomy. In 1987 Taylor and Armstrong demonstrated that stones migrated in only 3% of patients with a normal cystic duct diameter of less

Acalculous (“Functional”) Biliary Pain Patients may complain of symptoms typical of biliary pain without detectable gallstones. When no structural abnormalities exist or pain continues after cholecystectomy, biliary pain is

202

PART 2  DIAGNOSTIC TECHNIQUES

BOX 12.4  The 2018 Tokyo Guidelines for the Diagnosis and Management of Acute Cholangitis . Systemic inflammation A 1. Fever and/or shaking chills 2. Laboratory data: evidence of inflammatory response B. Cholestasis 1. Jaundice 2. Laboratory data: abnormal liver function tests C. Imaging 1. Biliary dilatation 2. Evidence of the etiology on imaging (stricture, stone, stent etc.) Suspected diagnosis: one item in A 1 one item in either B or C Definite diagnosis: one item in A, one item in B and one item in C Note: A-2: Abnormal white blood cell counts, increase of serum C-reactive protein levels, and other changes indicating inflammation B-2: Increased serum ALP, GGT, AST, and ALT levels Other factors that are helpful in diagnosis of acute cholangitis include abdominal pain (right upper quadrant or upper abdominal) and a history of biliary disease, such as gallstones, previous biliary procedures, and placement of a biliary stent. In acute hepatitis, marked systematic inflammatory response is observed infrequently. Virologic and serologic tests are required when differential diagnosis is difficult. Thresholds: A-1. Fever . 38°C A-2. Evidence of inflammatory response WBC (31000 microliters) , 4 or . 10 CRP (mg/dL)  1 B-1. Jaundice T-Bil $2 (mg/dL) B-2. Abnormal liver function tests ALP (IU) . 1.5 3 STD GGT (IU) . 1.5 3 STD AST (IU) . 1.5 3 STD ALT (IU) . 1.5 3 STD (STD is upper limit of normal value.) ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; GGT, gamma glutamyl transpeptidase; T-Bil, total bilirubin; WBC, white blood cells.

considered “functional.” In these patients, the symptoms may be caused by an alternative diagnosis or may originate in a dysfunctional biliary system.62,63 Box 12.5 includes the Rome III criteria for the diagnosis of functional gallbladder disorder.64 These patients have normal laboratory tests and upper endoscopy findings and a scrupulous search for gallstone disease is negative. Furthermore, in an attempt to identify the gallbladder as the culprit in acalculous biliary pain, several studies have used cholecystokinin infusion to reproduce the pain; however, this test has no validity. Thus functional biliary pain is a diagnosis of exclusion. Laparoscopic cholecystectomy results in only 50% of patients obtaining symptom relief compared with 81% in gallstone disease.63 Surgery should not be offered on the basis of a symptomatic diagnosis, and patients should be counseled regarding the uncertainty of its outcome.

Sphincter of Oddi Dysfunction The sphincter of Oddi is composed of three sphincters of smooth muscle fibers that surround the distal CBD, main pancreatic duct, and the ampulla of Vater. Its contractility regulates antegrade and retrograde flow through the pancreatobiliary tree. A

BOX 12.5  Rome III Criteria for Functional Gallbladder Disorder Diagnostic Criteria Must include all of the following: 1. Criteria for functional gallbladder and sphincter of Oddi disorder 2. Gallbladder is present 3. Normal liver enzymes, conjugated bilirubin, and amylase/lipase Diagnostic Criteria for Functional Gallbladder and Sphincter of Oddi Disorders Must include episodes of pain located in the epigastrium and/or right upper quadrant and all of the following: 1. Episodes lasting 30 minutes or longer 2. Recurrent symptoms occurring at different intervals (not daily) 3. The pain builds up to a steady level 4. The pain is moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency department visit 5. The pain is not relieved by bowel movements 6. The pain is not relieved by postural change 7. The pain is not relieved by antacids 8. Exclusion of other structural disease that would explain the symptoms Supportive Criteria The pain may present with one or more of the following: 1. Pain is associated with nausea and vomiting 2. Pain radiates to the back and/or right infrasubscapular region 3. Pain awakens from sleep in the middle of the night

BOX 12.6  Rome III Criteria for Functional Biliary Sphincter of Oddi Disorders Must include both of the following: 1. Criteria for functional gallbladder and sphincter of Oddi disorder (see Box 12.5) 2. Normal amylase/lipase Supportive criterion Elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporally related to at least two pain episodes

dyskinetic or stenotic sphincter results in the clinical syndrome called “sphincter of Oddi dysfunction” (SOD), formerly called “papillitis” (Box 12.6).64,65 The most adopted classification system is the Milwaukee classification scheme proposed by Hogan and Geenen in 1988.66 SOD is classified into biliary types I, II, and III based on upper abdominal symptoms and biochemical and imaging findings. The classification was then broadened to include patients with pancreatic-type pain and relapsing pancreatitis. The diagnosis, however, is still controversial and the classification system has been questioned. Some authors believe that the symptoms could be a consequence of sludge/gravel passage with papillary stenosis (type I), stone passage without stenosis (type II), or a functional disorder (type III).67 The Evaluating Predictors and Interventions of SOD (EPISOD) trial and the EPISOD2 observational study demonstrated that SOD type III patients with a presumed hypertensive and/or dyskinetic sphincter of Oddi did not benefit from endoscopic sphincterotomy even after 5 years of follow-up, as recently demonstrated by Cotton et al. Thus SOD type III should now be termed functional pain.68–70 The diagnosis is typically made after cholecystectomy. Biliary SOD can present as episodic, postprandial right upper quadrant

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

pain with or without cholestasis. Pancreatic SOD is characterized by more prolonged pain, radiating to the back, and can be associated with pancreatitis. It is important to point out that clinicians must ensure that a diagnosis of occult malignancy is not being missed in patients with ductal dilation and abnormal pancreatic or liver function tests. There is no gold-standard technique for the diagnosis of SOD. Manometry is not widely available and requires expertise; measurements vary according to catheter equipment, sphincter lumen size and spasm, and probe position.67,71

PANCREAS Pancreatic diseases, including CP, pancreatic cancer, and diabetes mellitus occur in more than 10% of the world population. However, there is a lack of robust estimates of the worldwide incidence and mortality of pancreatic disease in the general population. According to the 2018 update of the burden and cost of GI, liver, and pancreatic diseases in the United States in 2014, there were more than 3.0 million hospital admissions in the United States for a GI disease at a cost of $30.6 billion dollars. Pancreatitis was one of three most common discharge diagnoses overall. The combined cost of pancreatitis, GI hemorrhage, and gallbladder disease was nearly $12 billion dollars.72 The clinical manifestations of pancreatic diseases vary. Patients with AP or CP may present with hypertriglyceridemia, vitamin B12 malabsorption, hypercalcemia, hypocalcemia, hyperglycemia, ascites, pleural effusions, and chronic abdominal pain with or without an increase in blood pancreatic enzymes (see Chapters 54–58). Weight loss, jaundice, itching, abdominal pain radiating to the back, early satiety, and anemia may indicate a malignant pancreatic process. The relative inaccessibility of the pancreas to direct clinical examination and the nonspecificity of the abdominal pain associated with pancreatic disease may make the diagnosis difficult. The number of observations of hyperamylasemia and hyperlipasemia in the general population are increased because general practitioners tend to include amylase and lipase more frequently in routine blood tests and because of the constant evaluation of this biochemical alteration in the emergency departments. With neither amylase nor lipase being specific for pancreatitis, it is important for the clinician to be aware of different causes of hyperamylasemia and hyperlipasemia, especially when the clinical diagnosis of pancreatitis is unclear; these causes include benign pancreatic hyperenzymemia (also known as Gullo’s syndrome), diabetic ketoacidosis, head injury, trauma, acute liver failure, chronic renal failure, severe burns, shock, abdominal and cardiac surgery, toxic epidermal necrolysis, and Stevens-Johnson syndrome.73,74 Pancreatic disease may also occur in patients with IBD because of the disease itself (Crohn disease) or because of side effects of medications used in the treatment (azathioprine, 6-mercaptopourine, 5-aminosalicylate, and corticosteroid treatment).75 Imaging technologies have given clinicians an unprecedented toolbox to aid in clinical decision making. Currently, endoscopy, CT, and MRI are the core imaging methodologies for pancreatic diseases. Depending on the imaging modality used, the resulting images can reflect the anatomy, metabolism, or molecular aspects of the tissue of interest.76

Acute Pancreatitis AP is the most common disease of the exocrine pancreas and is one of the most common reasons for hospitalization with a GI disease (see Chapters 55 and 56). Estimates of AP incidence

203

and mortality in the general population vary greatly in the published literature and the epidemiology of pancreatitis has changed over time for many reasons, including population growth and migration, changes in patterns of alcohol consumption and tobacco smoking, rising rates of obesity and the recognition of metabolic causes of pancreatitis, and the increasing use and improving quality of imaging modalities. A recent systematic review and meta-analysis by Xiao et al. reported a global pooled incidence of AP of 34 cases per 100,000 individuals in the general population per year, with no statistically significant difference between the sexes. The disease predominantly affects those who are middle-aged or older. North America and West Pacific regions have a high incidence of disease (more than 34 cases per 100,000 individuals in the general population per year), whereas Europe is a low-incidence region (29 cases per 100,000 individuals in the general population per year). After the first episode of AP, recurrence will develop in 21% of patients and CP will develop in 36% of patients after recurrent AP. Xiao reported a pooled mortality from an episode of AP of 1.16 per 100,000 individuals in the general population per year, with persistent organ failure and infected pancreatic necrosis being the major determinants.77,78 Although the case fatality rate for AP has decreased over time, the overall population mortality rate for AP has remained unchanged.79 The most common causes of AP are gallstone disease and alcohol abuse, which account for almost 75% of recognized cases. Numerous drugs have been involved in AP pathogenesis, the most strongly associated of which are azathioprine, 6-mercaptopurine, didanosine, valproic acid, angiotensin-converting enzyme (ACE) inhibitors, and mesalamine. AP has been associated with genetic mutations in the genes encoding cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C, calcium-sensing receptor, and claudin-2. Other causes of AP are hypertriglyceridemia, ERCP, trauma, surgery, viral infection, exposure to smoking and other environmental toxins, or effects of coexisting diseases such as obesity and diabetes, autoimmune pancreatitis as part of the multiorgan disorder called IgG4-related disease, and “nonalcoholic duct destructive pancreatitis” (also called idiopathic duct-centric CP).80,81 The clinical presentation of AP is characterized by constant, usually severe, upper abdominal pain, constant in intensity and persistent for several hours. The pain is mostly epigastric, occasionally generalized and radiating to the back or to the chest or flanks. Patients experience pain relief when sitting forward or worsening when lying flat. Symptoms may mimic the acute presentation of almost any acute abdominal pain but also myocardial infarction, pneumonia, and pleurisy. However, an acute episode may also be painless. Nausea and vomiting are also common, and sequestered fluid in the small bowel may lead to rapid and severe dehydration. Hiccoughs can also occur because of diaphragmatic irritation secondary to the extension of the inflammatory process tracking up via the retroperitoneum. The presentation of the patient can also be critical and dominated by a clinical picture of profound shock with tachycardia, tachypnea, hypotension, anuria, and mental status alteration. On the other hand, patients may be have a paucity of symptoms, with few physical signs. The patient may be afebrile on admission, but the progression of the inflammatory process leads to fever, facial flushing, and mild jaundice. Pancreatic ascites and pleural effusion may be present. Abdominal examination reveals epigastric tenderness and guarding. Abdominal

204

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 12.11  Cullen sign (periumbilical bruising).

FIGURE 12.12  Grey-Turner sign (flank bruising).

distension with diminished peristalsis is a sign of the presence of a paralytic ileus. Later features may include mottled skin or livedo reticularis and lace-like purplish discoloration of the skin, which may appear up to 3 days from the clinical onset. Abdominal periumbilical ecchymosis, Cullen sign (Fig. 12.11), ecchymosis of the flank, and Grey-Turner sign (Fig. 12.12) result from the diffusion of fat necrosis and inflammation associated with retroperitoneal or intraabdominal bleeding. Although not specific, these signs are associated with a severe course and high mortality.79,80

Diagnosis and Severity Scoring According to the 2012 revision of the Atlanta classification, the diagnosis of AP is established by the presence of at least two of the following criteria: abdominal pain consistent with the disease, serum lipase or amylase levels that are at least three times the upper limit of the normal range, and characteristic findings from abdominal imaging.82 AP is divided into two phases. The first “early phase” occurs in the first week after onset (coinciding with the first day of pain), and the clinical scenario is dominated by the systemic inflammatory response. In this setting, the presence and degree of organ failure determine the severity and treatment. After the second week, the “late phase” starts, which can last for several weeks and is characterized by local complications and persistent organ failure.80 Most episodes of AP are

mild and self-limiting. The last version of the classification system updated the definitions of severity in AP: Mild AP consists of no organ failure and no local or systemic complications.83 Moderately severe AP is defined as local or other systemic complications and/or transient organ failure lasting less than 48 hours. Severe AP is defined as persistent organ failure lasting more than 48 hours. The determinant-based classification in 2012 introduced a fourth group with higher mortality, termed “critical,” characterized by persistent organ failure and infected pancreatic necrosis.84 The ability to understand which patient will have a severe course of disease allows the clinician to triage the patient to an intensive care unit (ICU) and start an effective treatment early. The degree of the elevation of the serum amylase or lipase level has no prognostic value.80 The prediction of severity is based on clinical, biochemical, and imaging findings (Box 12.7).79 Several scoring systems have been validated to incorporate those findings in various combinations, including the Acute Physiology and Chronic Health Evaluation II (APACHE II), the APACHE combined with scoring for obesity (APACHE-O), the Glasgow scoring system, the Harmless Acute Pancreatitis Score (HAPS), PANC 3, the Japanese Severity Score (JSS), Pancreatitis Outcome Prediction (POP), and the Bedside Index for Severity in Acute Pancreatitis (BISAP). All of these methods have a high false-positive rate, are complex, and are not routinely used.80 Pancreatic imaging is performed to determine the etiology of AP when the clinical situation is uncertain, to determine the severity, to evaluate complications, and to guide intervention. According to the American College of Gastroenterology Guidelines, a transabdominal US is recommended in all patients with suspected AP.79 Because the majority of patients will have a mild, self-limited disease, CT scans are not routinely advocated. A CT scan is not required at the timepoint of admission unless the diagnosis is equivocal, clinical predictors suggest a severe course, conservative treatment is not followed by clinical improvement, or the patient is deteriorating. Moreover,

BOX 12.7  Acute Pancreatitis: Predictors of Severity Clinical Findings: Age .55 years Obesity (BMI . 30 Kg/m2) Altered mental status Comorbid disease Systemic inflammatory response syndrome (defined by the presence of . 2 of the following: pulse . 90 beats/min, respirations . 20/min or PaCO2 .32 mm Hg, temperature .38°C or ,36°C, WBC count .12,000 or ,4000 cells/mm3 or .10% immature cells). Laboratory Findings BUN . 20 mg/dL Rising BUN HCT . 44% rising HCT Elevated creatinine Radiologic Findings Pleural effusion Pulmonary infiltrates Multiple or extensive extrapancreatic collections BMI, Body mass index; BUN, blood urea nitrogen; HCT, hematocrit; WBC, white blood cell.

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

contrast-enhanced CT (CECT) is relatively contraindicated in patients with iodinated contrast agent allergies or impaired renal function. The initial CT assessment should be performed 72 to 96 hours after the onset of symptoms.76 In the diagnostic process, EUS, MRCP, and ERCP are indicated to evaluate the biliary duct system (see Chapters 16, 17, 20, 22, 30, and 37C). ERCP should be performed early (,24 hours) in patients with acute cholangitis. MRCP is an accurate modality and its selective use reduces the need for ERCP.85 Nevertheless, negative findings on MRCP do not exclude the presence of small CBD stones (,5 mm), for which EUS is superior.86 Contrastenhanced US (CEUS) has been used in some centers for the diagnostic evaluation of patients with pancreatitis. One study found CEUS to be equivalent to CECT and clinical scoring, with a sensitivity and specificity in detecting severe AP of 91% and 100%, respectively, compared with CT.87

Chronic Pancreatitis Before 2016, CP was defined by relying on clinicopathologic features that were the expression of signs and symptoms of defined pathology (chronic inflammation, irreversible fibrosis without infection; see Chapters 57 and 58). This definition led to years of delay between symptom onset and diagnosis, failing to identify the etiology and to predict the clinical course. In 2016 an International Working Group defined CP as “a continuing inflammatory disease of the pancreas, characterized by irreversible morphologic change, and typically causing pain and/or permanent loss of function.” The new definition addresses the disease mechanism as a “pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental, and/ or other risk factors who develop persistent pathologic responses to parenchymal injury or stress.” In addition, it defines the endstage disease as “pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction, and dysplasia.”88 The evaluation of the patient should start with a thorough history and a review of all risk factors, the characteristics of the pain, related conditions (e.g., steatorrhea and/or vitamin deficiency), and physical examination. Patients usually suffer from debilitating abdominal pain, malnutrition, osteoporosis, fat-soluble vitamin deficiency, and pancreatic endocrine failure (type 3c diabetes mellitus).89 A systemic review by Sankaran et al. in 2015 of high-quality cohort studies quantified the frequency of transition from the first episode of AP to recurrent acute pancreatitis (RAP) and CP. After the first episode of AP, RAP developed in 21% of patients; and after RAP, CP developed in 36% of patients. Transition was higher in patients with alcohol-induced versus biliary pancreatitis.90 According to the systematic review by Xiao et al., the global pooled incidence of CP is 10 cases per 100,000 individuals in the general population per year.77 The diagnosis relies on exposure risk, underlying predisposition, and imaging and pancreatic function tests. The M-ANNHEIM multiple risk factor classification, published in 2007,91 and the TIGAR-O (Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and Severe Acute Pancreatitis and Obstructive) Pancreatitis Risk/Etiology Checklist version 2.0, updated in 2019,92 are used to categorize the etiology and evaluate the impact and interaction of various risk factors on the course of the disease. Cross-sectional imaging is recommended for the first-line diagnosis. In 2017 a systematic review and meta-analysis of 43 studies compared the performances of

205

CT, MRI, and EUS, demonstrating that the sensitivity and specificity did not differ significantly among these modalities93 (see Chapters 16, 17, and 22). However, EUS should be used if there is uncertainty after cross-sectional imaging.94 Secretinenhanced MRCP should be used if the former modalities are not diagnostic, thus identifying subtle ductal abnormalities that may provide morphologic clues for the diagnosis.89 The prevalence of exocrine pancreatic insufficiency (EPI) ranges from 40% to 75% in patients with CP, and the risk is highest in those with alcohol and/or tobacco use or fibrocalcific pancreatitis. EPI is investigated with direct and indirect pancreatic function tests, including hormonal (CCK stimulation test and secretin stimulation test) and nonhormonal (fecal elastace-1 test, 13Cmixed triglyceride test, serum trypsinogen/trypsin test) tests. Because of the low sensitivity, these tests should be used only to support the diagnosis.95 Genetic testing is recommended in patients in whom the etiology of CP is unclear; the primary goal is to identify pancreatitis-associated disorders that promote the pathogenic process, provide prognostic information, and identify possible targets for therapy. Patients should be evaluated for cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal-type 1 (SPINK1), and cystic fibrosis transmembrane conductance receptor (CFTR) gene mutations.89

Pancreatic Cancer Clinical manifestations of pancreatic cancer are heterogeneous and may be absent until the lesion is unresectable (see Chapter 62). Typical symptoms include epigastric or mid-back pain, anorexia, early satiety, weight loss, diabetes mellitus, and obstructive jaundice. The clinical manifestations also include appetite loss, pale stools, dark urine, unusual bloating, unusual belching, constipation, and diarrhea. These symptoms may help the clinician suspect the diagnosis; however, approximately 50% of patients are more likely to have had three or more consultations for cancer symptoms before referring to the HPB surgeon.96,97 Up to 80% of patients lose glycemic control over 3 years before the diagnosis of pancreatic cancer. New-onset diabetes is an early manifestation and a unique phenomenon of pancreatic cancer.98,99 Abdominal pain is the most common presenting complaint, insidious in nature, and frequently has been present for 1 or 2 months at the time of diagnosis. This abdominal pain has a visceral gnawing quality and is generally epigastric but may radiate to the flanks and/or to the back.100 The pain frequently exacerbates at night, is sleep disturbing, and may worsen in the postprandial period and in the supine position.101 The compromise of the body and tail of the pancreas usually gives rise to severe back pain that is the result of splanchnic nerve and/or celiac plexus infiltration. Perineural invasion is a characteristic of pancreatic cancer and has a high prevalence of approximately 80% to 100%. It is related to a poor prognosis and is strongly associated with local recurrence after curative resection.102,103 Postprandial pain may be secondary to an increase in secretory ductal pressure because of neoplastic obstruction of the duct of Wirsung. Because of CBD obstruction, on physical examination, the gallbladder may be distended and palpable (Courvoisier’s gallbladder). An abdominal mass, fixed and hard, accompanied by ascites is a late sign and usually heralds inoperability. The Trousseau sign of malignancy or Trousseau’s syndrome (thrombophlebitis migrans) is a systemic sign of neoplastic disease, but it is uncommon and nonspecific. Together with pain, jaundice and weight loss are generally later clinical features. Weight loss may be the only presenting symptom until pain indicates peripancreatic tissue invasion. Lesions of the pancreatic

206

PART 2  DIAGNOSTIC TECHNIQUES

head usually manifest as jaundice and severe pruritus; when jaundice occurs with tumors of the body or tail of the pancreas, it usually signifies hilar liver or nodal metastases. CT, MRI, and EUS are the imaging technologies usually involved in the detection of solid or cystic pancreatic lesions (see Chapters 16, 17, and 22). CT is required for full staging of the disease. Multiphasic CECT is the most ubiquitous imaging test with a sensitivity of 89% to 97% compared with histopathology.104,105 Its sensitivity reaches 100% for tumors larger than 2 cm, but it falls to 77% for smaller tumors.106 Tumors less than 1 cm can be isoattenuating on CT, thus making their detection challenging.76 MRCP and MRI have a better sensitivity for small, isoattenuating lesions that subtly narrow the pancreatic duct. EUS combined with endoscopic-guided fine-needle aspiration has a sensitivity of 90% for detecting pancreatic cancer, but it is not widely available.107 Numerous novel studies about the molecular imaging of pancreatic cancer have been published so far, although these imaging techniques are early in clinical development. A promising agent would be one with high specificity (.90%) and sensitivity for cancer over benign disease.76 Vascular endothelial growth factor receptor 2 (VEGFR2) is overexpressed during the neoangiogenic neoplastic process and has been detected in mouse adenocarcinoma vasculature using CEUS with a contrast agent of VEGFR2-targeted microbubble.108 The same approach has been adopted using Thy1-targeted microbubble (a membrane glycoprotein), which was able to reliably detect pancreatic cancer as small as 3 mm in mouse models.109 Other potential targets have been found in the tumoral stroma (IGF-1110 and SPARC111), in the cytoskeleton (plectin112), and in the abnormal glycosylation of carbohydrate antigen 19-9 (CA19-9, the sialyl Lewis antigen).113

ASSESSMENT OF FITNESS FOR MAJOR HEPATOPANCREATOBILIARY SURGERY (SEE CHAPTERS 26 AND 27) The median age for HPB cancer diagnosis is 66 years114 and the number of patients will continue to rise in the future, thus making surgical resections high risk because of age, frailty, and multiple comorbidities. Preoperative care needs special attention to decrease morbidity and mortality.115 Elderly patients’ health status requires an accurate assessment, which can be achieved by a multidimensional diagnostic tool, the comprehensive geriatric assessment (CGA), which evaluates the medical, functional, and psychosocial status of these patients116 and helps to identify vulnerable patients at increased risk for poor surgical outcomes. The functional status and the resulting risk of postoperative complications can be assessed by various screening tools, such as the Activities of Daily Living (ADL), the Instrumental Activities of Daily Living (IADL),117 the Time Get-Up-and-Go (TUG) test,118 the Six-Minute Walk Test (6MWT),119 and the Cardiopulmonary Exercise Test (CPET).120 Frailty is a clinically relevant domain defined by the presence of three or more of the following criteria: unintentional weight loss of more than 10 lbs in the previous year, self-reported exhaustion, weakness measured by grip strength, slow walking speed, and low levels of physical activity.121 Frail patients are at increased risk for postoperative complications, increased LOS, and discharge to nursing facilities.122 Several tools assess frailty, including the Groningen Frailty Index (GFI), the Vulnerable Elders Survey-13 (VES-13), and Fried’s

frailty criteria assessment. Sarcopenia is a term describing morphometric data indicating a loss of skeletal mass and can be preoperatively assessed by CT-based measurements, and its presence has been associated with poorer surgical outcomes.123 Malnutrition has been shown to correlate with increased morbidity, the severity of postoperative complications, and the LOS. Some of the more common parameters are weight loss, serum protein levels, immunocompetence, and anthropometric indicators.124 Various tools exist for clinical use, including the Mini Nutritional Assessment examination (MNA), the Short Nutritional Assessment Questionnaire (SNAQ) Nutritional Risk Screening-2002 (NRS-2002), and the Geriatric 8 (G8). Postoperative delirium is associated with poorer surgical outcomes including morbidity, mortality, and discharge to nursing facilities. Patients at risk can be assessed by the MiniMental Status Examination (MMSE), the Mini-Cog assessment, and the Montreal Cognitive Assessment (MoCA).125 As of yet, there is no consensus on the screening tool that should be used to adequately identify vulnerable oncogeriatric HPB patients. In 2013, Badgwell et al. identified the following CGA variables associated with a poorer outcome: weight loss greater than 10% within 6 months, American Society of Anesthesiologist (ASA) risk assessment score $2, Eastern Cooperative Oncology Group (ECOG) performance score $2, polypharmacy, and distant metastatic disease.126 In 2014 Huisman et al. demonstrated that a TUG score greater than 20 identified twice as many surgical oncogeriatric patients as an ASA score $3 at risk for postoperative complications (50% vs. 24.8%).118 Other tools and scoring systems have been devised over time to assist in quantifying the surgical risk. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator (http://riskcalculator. facs.org) collects high-quality standardized clinical data on preoperative risk factors and postoperative complications. It offers surgeons the ability to estimate patient-specific postoperative risk in a patient-friendly format, helping to decide which operation to perform and offering insights about the morbidity and mortality risk.127 The Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM), developed in 1991 by Copeland et al., has been evaluated extensively in both general surgery and HPB surgery. When used correctly, POSSUM can usefully predict morbidity and mortality in the surgical treatment of HPB patients.128–131 During the preoperative evaluation of HPB patients, other factors must be assessed to determine the postoperative risk. Postresection liver failure (PLF) remains the most important factor associated with postoperative mortality after major liver resections.132–134 Liver function can be determined by combined analysis of results from volumetric liver assessments, liver functional MRI, and the indocyanine green clearance retention test (see Chapters 4 and 102). Total liver volume (TLV), future remnant liver volume (FRLV), and remnant liver volume percentage (RLV%) can be calculated by CT- or MRI-based volumetric liver analysis. In healthy livers, approximately 25% of the liver parenchyma needs to be preserved to prevent PLF. In damaged, postchemotherapy or cirrhotic livers, up to 50% of the liver parenchyma needs to be spared.135–138 MRI-based T1 relaxometry with the liver-specific contrast agent gadolinium-ethoxybenzyl diethylene-triaminepentaacetic acid (Gd-EOB-DTPA) is an emerging method for assessing overall and segmental liver function.139 Functioning areas of the liver exhibit shortening of the T1 relaxation time, and reduced liver function correlates with

  Chapter 12  Clinical Investigation of Hepatopancreatobiliary and Pancreatic Disease

decreased Gd-EOB-DTPA accumulation in hepatocytes during the hepatobiliary phase. The indocyanine green retention rate at 15 minutes (ICG-R15) has been widely used as a routine guideline in Eastern countries for making appropriate surgical decisions in hepatocellular carcinoma patients and is considered the most predictive test of operative mortality after hepatectomy compared with other tests such as the aminoacidic clearance test or the aminopyrine breath test.140 The ICG retention value at 15 minutes (ICG R15) describes the percentage of circulatory

207

retention of indocyanine green during the first 15 minutes after bolus injection. In healthy patients, it is between 8% and 15% and the cutoff indicative of the need for a major hepatectomy is between 14% and 17%.141,142 Minor resections may be performed for values that reach 22%, and limited hepatectomies may be performed for values up to 40%. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

207.e1

REFERENCES 1. Byass P. The global burden of liver disease: a challenge for methods and for public health. BMC Med. 2014;12(1):1-3. 2. Sepanlou SG, Safiri S, Bisignano C, et al. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245-266. 3. Younossi ZM, Stepanova M, Younossi Y, et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020;69(3):564-568. 4. Stepanova M, De Avila L, Afendy M, et al. Direct and indirect economic burden of chronic liver disease in the United States. Clin Gastroenterol Hepatol. 2017;15(5):759-766.e5. 5. Udell JA, Wang CS, Fitzgerald JM, Mak E, Yoshida EM. Does this patient with liver disease have cirrhosis? Clinical scenarios of cirrhosis. Blood. 2012;2115(8):832-842. 6. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98(5):960-967. 7. Ghani M, Hoofnagle JH. Approach to the patient with liver disease. In: Fauci A, Longo D, eds. Harrison’s Gastroenterology and Hepatology. 1st ed. New York: McGraw Hill; 2010:322-331. 8. Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA J Am Med Assoc. 1984;252(14):1905-1907. 9. De Bruyn G, Graviss EA. A systematic review of the diagnostic accuracy of physical examination for the detection of cirrhosis. BMC Med Inform Decis Mak. 2001;1:1-11. 10. Gracia-Sancho J, Marrone G, Fernández-Iglesias A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol. 2019;16(4):221-234. 11. Tetangco EP, Silva RG, Lerma EV. Portal hypertension: etiology, evaluation, and management. Dis Mon. 2016;62(12):411-426. 12. Simonetto DA, Liu M, Kamath PS. Portal hypertension and related complications: diagnosis and management. Mayo Clin Proc. 2019;94(4):714-726. 13. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20(33):11684-11699. 14. Addolorato G, Abenavoli L, Dallio M, et al. Alcohol associated liver disease 2020: a clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis. 2020;52(4):374-391. 15. World Health Organization. Global Status Report on Alcohol and Health - 2014. 2014 ed. World Health Organization; 2014. Available at: https://apps.who.int/iris/handle/10665/112736. 16. Griswold MG, Fullman N, Hawley C, et al. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018;392(10152):1015-1035. 17. Thursz M, Gual A, Lackner C, et al. EASL Clinical practice guidelines: management of alcohol-related liver disease. J Hepatol. 2018; 69(1):154-181. 18. O’Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease. Hepatology. 2010;51(1):307-328. 19. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113(2):175-194. 20. Lohse AW, Chazouillères O, Dalekos G, et al. EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004. 21. Hirschfield GM, Beuers U, Corpechot C, et al. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172. 22. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis – a comprehensive review. J Hepatol. 2017;67(6):1298-1323. 23. Martens P, Nevens F. Budd-Chiari syndrome. United European Gastroenterol J. 2015;3(6):489-500. 24. Bansal V, Gupta P, Sinha S, et al. Budd-Chiari syndrome: imaging review. Br J Radiol. 2018;91:20180441. 25. Brissot P, Pietrangelo A, Adams P, et al. Haemochromatosis. Nat Rev Dis Primers. 2018;4:18016. Available at: https://doi.org/10.1038/ nrdp.2018.16. 26. Radford-Smith DE, Powell EE, Powell LW. Haemochromatosis: a clinical update for the practising physician. Intern Med J. 2018; 48(5):509-516. 27. Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114(8): 1202-1218.

28. Cnossen WR, Drenth JPH. Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management. Orphanet J Rare Dis. 2014;9(1):1-13. 29. Lazaridis KN. The cholangiopathies konstantinos. Mayo Clin Proc. 2015;90(6):791-800. 30. Patel A, Chapman AB, Mikolajczyk AE. A practical approach to polycystic liver disease. Clin Liver Dis. 2019;14(5):176-179. 31. van Aerts RMM, van de Laarschot LFM, Banales JM, Drenth JPH. Clinical management of polycystic liver disease. J Hepatol. 2018; 68(4):827-837. 32. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067-1076. 33. Westbrook RH, Dusheiko G, Williamson C. Pregnancy and liver disease. J Hepatol. 2016;64(4):933-945. 34. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010;376(9736):190-201. 35. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013; 369(26):2525-2534. 36. Flamm SL, Yang YX, Singh S, et al. American Gastroenterological Association Institute guidelines for the diagnosis and management of acute liver failure. Gastroenterology. 2017;152(3):644-647. 37. Colombo M, Forner A, Ijzermans J, et al. EASL clinical practice guidelines on the management of benign liver tumours. J Hepatol. 2016;65(2):386-398. 38. Marrero JA, Ahn J, Rajender Reddy K, Americal College of Gastroenterology. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014;109(9):1-20. 39. Verghese A, Dison C, Berk SL. Courvoisier’s “law”—an eponym in evolution. Am J Gastroenterol. 1987;82(3):248-250. 40. Kennedy A, Blumgart JH. Carcinomas of the ampulla of vater and the duodenum. J Clin Pathol. 1971;24(8):765. 41. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117(3):632-639. 42. Attili AF, Carulli N, Roda E, et al. Epidemiology of gallstone disease in Italy: prevalence data of the multicenter Italian study on cholelithiasis (M.I.COL.). Am J Epidemiol. 1995;141(2):158-165. 43. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016;65(1):146-181. Available at: https://doi.org/10.1016/j.jhep.2016.03.005. 44. Berger MY, Van Der Velden JJIM, Lijmer JG, et al. Abdominal symptoms: Do they predict gallstones? A systematic review. Scand J Gastroenterol. 2000;35(1):70-76. 45. Wilkins T, Agabin E, Varghese J, Talukder A. Gallbladder dysfunction: cholecystitis, choledocholithiasis, cholangitis, and biliary dyskinesia. Prim Care. 2017;44(4):575-597. 46. Oria HE. Pitfalls in the diagnosis of gallbladder disease in clinically severe obesity. Obes Surg. 1998;8(4):444-451. 47. Bonfrate L, Wang DQH, Garruti G, Portincasa P. Obesity and the risk and prognosis of gallstone disease and pancreatitis. Best Pract Res Clin Gastroenterol. 2014;28(4):623-635. 48. Talha A, Abdelbaki T, Farouk A, Hasouna E, Azzam E, Shehata G. Cholelithiasis after bariatric surgery, incidence, and prophylaxis: randomized controlled trial. Surg Endosc. 2020;34(12):5331-5337. Available at: https://doi.org/10.1007/s00464-019-07323-7. 49. Ansaloni L, Pisano M, Coccolini F, et al. 2016 WSES guidelines on acute calculous cholecystitis. World J Emerg Surg. 2016;11(1):1-23. 50. Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):41-54. 51. Chu D, Adler DG. Malignant biliary tract obstruction: evaluation and therapy. J Natl Compr Canc Netw. 2010;8(9):1033-1044. 52. Tirotta F, Giovinazzo F, Hodson J, et al. Risk factors to differentiate between benign proximal biliary strictures and perihilar cholangiocarcinoma. HPB. 2020;22(12):1753-1758. 53. Dhindsa B, Mashiana H, Dhaliwal A, et al. EUS-guided biliary drainage: a systematic review and meta-analysis. Endosc Ultrasound. 2020;9(2):101. 54. Smith I, Monkemuller K, Wilcox CM. Incidentally identified common bile duct dilatation: a systematic review of evaluation, causes, and outcome. J Clin Gastroenterol. 2015;49(10):810-815. 55. Taylor T V, Armstrong CP. Migration of gall stones. BMJ. 1987; 294(6583):1320-1322. 56. Copelan A, Kapoor BS. Choledocholithiasis: diagnosis and management. Tech Vasc Interv Radiol. 2015;18(4):244-255.

207.e2 57. Yoo ES,Yoo BM, Kim JH, et al. Evaluation of risk factors for recurrent primary common bile duct stone in patients with cholecystectomy. Scand J Gastroenterol. 2018;53(4):466-470. 58. Cohen J, Pleskow D. The long road to stone management in the bile duct – What else to wish? Endoscopy. 2019;51(10):907-908. 59. Kimura Y, Takada T, Kawarada Y, et al. Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):15-26. 60. Lan Cheong Wah D, Christophi C, Muralidharan V. Acute cholangitis: current concepts. ANZ J Surg. 2017;87(7-8):554-559. 61. Kiriyama S, Kozaka K, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):17-30. 62. Warwick AM, Bintcliffe F, Wu E, Stell D. Natural history of acalculous biliary symptoms. Ann R Coll Surg Engl. 2013;95(7):511-514. 63. Shaffer E. Acalculous biliary pain: new concepts for an old entity. Dig Liver Dis. 2003;35(suppl 3):20-25. 64. Behar J, Corazziari E, Guelrud M, Hogan W, Sherman S, Toouli J. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology. 2006;130(5):1498-1509. 65. Costamagna G. Sphincter of Oddi dysfunction: the never-ending story has come to a conclusion. Gastrointest Endosc. 2018;87(1):211-212. 66. Hogan WJ, Geenen JE. Biliary dyskinesia. Endoscopy. 1988;20 (suppl 1):179-183. 67. Small AJ, Kozarek RA. Sphincter of Oddi dysfunction. Gastrointest Endosc Clin N Am. 2015;25(4):749-763. 68. Cotton PB, Pauls Q, Keith J, et al. The EPISOD study: long-term outcomes. Gastrointest Endosc. 2018;87(1):205-210. 69. Cotton PB, Durkalski V, Romagnuolo J, et al. Effect of endoscopic sphincterotomy for suspected sphincter of oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial. JAMA. 2014;311(20):2101-2109. 70. Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES. Gallbladder and sphincter of Oddi disorders. Gastroenterology. 2016; 150(6):1420-1429.e2. 71. Hyun JJ, Kozarek RA. Sphincter of Oddi dysfunction: sphincter of Oddi dysfunction or discordance? What is the state of the art in 2018? Curr Opin Gastroenterol. 2018;34(5):282-287. 72. Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2020;156(1):254-272. 73. Muniraj T, Dang S, Pitchumoni CS. Pancreatitis or not? – Elevated lipase and amylase in ICU patients. J Crit Care. 2015;30(6):1370-1375. 74. Rosell-Camps A, Martínez-Cepas P, Riera-Llodrá JM, VenturaEspejo L, Riutord-Arrom N. Benign pancreatic hyperenzymemia, also known as Gullo’s syndrome. Lab Med. 2020;51(4):423-425. 75. Fousekis FS, Katsanos KH, Theopistos VI, et al. Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study. BMC Gastroenterol. 2019;19(1):1-8. 76. Dimastromatteo J, Brentnall T, Kelly KA. Imaging in pancreatic disease. Nat Rev Gastroenterol Hepatol. 2017;14(2):97-109. 77. Xiao AY, Tan MLY, Wu LM, et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol. 2016;1(1):45-55. 78. Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol. 2019;16(3):175-184. 79. Tenner S, Baillie J, Dewitt J, Vege SS. American college of gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108(9):1400-1415. 80. Forsmark CE, Vege SS, Wilcox CM. Acute pancreatitis. N Engl J Med. 2016;375(20):1972-1981. 81. Majumder S, Takahashi N, Chari ST. Autoimmune pancreatitis. Dig Dis Sci. 2017;62(7):1762-1769. 82. Banks, P. A., Bollen, T. L., Dervenis, C., Gooszen, H. G., Johnson, C. D., Sarr, M. G., Tsiotos, G. G., Vege, S. S., & Acute Pancreatitis Classification Working Group (2013). Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut, 62(1), 102–111. https://doi. org/10.1136/gutjnl-2012-302779. 83. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis - 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-111. 84. Dellinger EP, Forsmark CE, Layer P, et al. Determinant-based classification of acute pancreatitis severity. Ann Surg. 2012;256(6): 875-880.

85. Rocha APC, Schawkat K, Mortele KJ. Imaging guidelines for acute pancreatitis: when and when not to image. Abdom Radiol. 2020;45(5):1338-1349. 86. Kondo S, Isayama H, Akahane M, et al. Detection of common bile duct stones: comparison between endoscopic ultrasonography, magnetic resonance cholangiography, and helical-computedtomographic cholangiography. Eur J Radiol. 2005;54(2):271-275. 87. Ripollés T, Martínez MJ, López E, Castelló I, Delgado F. Contrast-enhanced ultrasound in the staging of acute pancreatitis. Eur Radiol. 2010;20(10):2518-2523. 88. Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16(2):218-224. 89. Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG clinical guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115(3):322-339. 90. Sankaran SJ, Xiao AY, Wu LM, Windsor JA, Forsmark CE, Petrov MS. Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-analysis. Gastroenterology. 2015;149(6): 1490-1500.e1. 91. Schneider A, Löhr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol. 2007;42(2):101-119. 92. Whitcomb DC. Pancreatitis: TIGAR-O version 2 Risk/Etiology Checklist with topic reviews, updates, and use primers. Clin Transl Gastroenterol. 2019;10(6):e00027. 93. Issa Y, Kempeneers MA, van Santvoort HC, Bollen TL, Bipat S, Boermeester MA. Diagnostic performance of imaging modalities in chronic pancreatitis: a systematic review and meta-analysis. Eur Radiol. 2017;27(9):3820-3844. 94. Gardner TB, Levy MJ. EUS diagnosis of chronic pancreatitis. Gastrointest Endosc. 2010;71(7):1280-1289. 95. Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis evidencebased report on diagnostic guidelines. Pancreas. 2014;43(8): 1143-1162. 96. Lyratzopoulos G, Neal RD, Barbiere JM, Rubin GP, Abel GA. Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol. 2012; 13(4):353-365. 97. Holly EA, Chaliha I, Bracci PM, Gautam M. Signs and symptoms of pancreatic cancer: a population-based case-control study in the San Francisco Bay area. Clin Gastroenterol Hepatol. 2004;2(6): 510-517. 98. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10(1):88-95. 99. Aggarwal G, Kamada P, Chari S. Prevalence of diabetes mellitus in common cancers. Am J Gastroenterol. 2011;106:S54-S55. 100. Modolell I, Guarner L, Malagelada JR. Vagaries of clinical presentation of pancreatic and biliary tract cancer. Ann Oncol. 1999; 10(suppl 4):82-84. 101. Bockman DE, Büchler M, Beger HG. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology. 1994;107(1):219-230. 102. Mannell A, Van Heerden JA, Weiland LH, Ilstrup DM. Factors influencing survival after resection for ductal adenocarcinoma of the pancreas. Ann Surg. 1986;203(4):403-407. 103. Bapat AA, Hostetter G, Von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer. 2011;11(10):695-707. 104. Valls C, Andía E, Sanchez A, et al. Dual-phase helical CT of pancreatic adenocarcinoma: assessment of resectability before surgery. Am J Roentgenol. 2002;178(4):821-826. 105. Lee ES, Lee JM. Imaging diagnosis of pancreatic cancer: a stateof-the-art review. World J Gastroenterol. 2014;20(24):7864-7877. 106. Bronstein YL, Loyer EM, Kaur H, et al. Detection of small pancreatic tumors with multiphasic helical CT. Am J Roentgenol. 2004;182(3):619-623. 107. Harewood GC, Wiersema MJ. Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol. 2002;97(6):1386-1391. 108. Deshpande N, Ren Y, Foygel K, Rosenberg J, Willmann JK. Tumor angiogenic marker expression levels during tumor growth:

207.e3 longitudinal assessment with molecularly targeted microbubbles and US imaging. Radiology. 2011;258(3):804-811. 109. Foygel K, Wang H, MacHtaler S, et al. Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology. 2013;145(4):885-894.e3. 110. Zhou H, Qian W, Uckun FM, et al. IGF1 receptor targeted theranostic nanoparticles for targeted and image-guided therapy of pancreatic cancer. ACS Nano. 2015;9(8):7976-7991. 111. Thomas S, Waterman P, Chen S, et al. Development of secreted protein and acidic and rich in cysteine (SPARC) targeted nanoparticles for the prognostic molecular imaging of metastatic prostate cancer. J Nanomed Nanotechnol. 2011;2(112):2157-7439-2-112. 112. Kelly KA, Bardeesy N, Anbazhagan R, et al. Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med. 2008;5(4):657-668. 113. Viola-Villegas NT, Rice SL, Carlin S, et al. Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology. J Nucl Med. 2013;54(11):1876-1882. 114. Horner MJ. SEER Cancer Statistics Review 1975-2006 National Cancer Institute SEER Cancer Statistics Review 1975-2006 National Cancer Institute. Cancer. Published online 2011:16-17. 115. Mckenzie G, Ii RCGM. Optimizing outcomes for liver and pancreas surgery. Optim Outcomes Liver Pancreas Surg. Published online 2018. 116. Caillet P, Canoui-Poitrine F, Vouriot J, et al. Comprehensive geriatric assessment in the decision-making process in elderly patients with cancer: ELCAPA study. J Clin Oncol. 2011;29(27):3636-3642. 117. Adamina M, Kehlet H, Tomlinson GA, Senagore AJ, Delaney CP. Enhanced recovery pathways optimize health outcomes and resource utilization: a meta-analysis of randomized controlled trials in colorectal surgery. Surgery. 2011;149(6):830-840. 118. Huisman MG, van Leeuwen BL, Ugolini G, et al. “Timed Up & Go”: a screening tool for predicting 30-day morbidity in oncogeriatric surgical patients? A multicenter cohort study. PloS one. 2014;9(1):e86863. Available at: https://doi.org/10.1371/journal. pone.0086863. 119. Pecorelli N, Fiore JF, Gillis C, et al. The six-minute walk test as a measure of postoperative recovery after colorectal resection: further examination of its measurement properties. Surg Endosc. 2016; 30(6):2199-2206. 120. Junejo MA, Mason JM, Sheen AJ, et al. Cardiopulmonary exercise testing for preoperative risk assessment before pancreaticoduodenectomy for cancer. Ann Surg Oncol. 2014;21(6):1929-1936. 121. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56(3):M146-M156. 122. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010; 210(6):901-908. 123. Peng P, Hyder O, Firoozmand A, et al. Impact of sarcopenia on outcomes following resection of pancreatic adenocarcinoma. J Gastrointest Surg. 2012;16(8):1478-1486. 124. Schiesser M, Kirchhoff P, Müller MK, Schäfer M, Clavien PA. The correlation of nutrition risk index, nutrition risk score, and bioimpedance analysis with postoperative complications in patients undergoing gastrointestinal surgery. Surgery. 2009;145(5): 519-526.

125. Robinson TN, Wallace JI, Wu DS, et al. Accumulated frailty characteristics predict postoperative discharge institutionalization in the geriatric patient. J Am Coll Surg. 2011;213(1):37-42. 126. Badgwell B, Stanley J, Chang GJ, et al. Comprehensive geriatric assessment of risk factors associated with adverse outcomes and resource utilization in cancer patients undergoing abdominal surgery. J Surg Oncol. 2013;108(3):182-186. 127. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217(5):833-842.e3. 128. Copeland GP, Jones D, Walters M. POSSUM: a scoring system for surgical audit. Br J Surg. 1991;78(3):355-360. 129. Neary WD, Heather BP, Earnshaw JJ. The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM). Br J Surg. 2003;90(2):157-165. 130. Wang H, Wang H, Chen T, Liang X, Song Y, Wang J. Evaluation of the POSSUM, P-POSSUM and E-PASS scores in the surgical treatment of hilar cholangiocarcinoma. World J Surg Oncol. 2014;12:191. 131. Kocher HM, Tekkis PP, Gopal P, Patel AG, Cottam S, Benjamin IS. Risk-adjustment in hepatobiliarypancreatic surgery. World J Gastroenterol. 2005;11(16):2450-2455. 132. Schreckenbach T, Liese J, Bechstein WO, Moench C. Posthepatectomy liver failure. Dig Surg. 2012;29(1):79-85. 133. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer. 2006;94(7):982-999. 134. van den Broek MA, Olde Damink SW, Dejong CH, et al. Liver failure after partial hepatic resection: definition, pathophysiology, risk factors, and treatment. Liver Int. 2008;28(6):767-780. 135. van der Vorst JR, van Dam RM, van Stiphout RS, et al. Virtual liver resection and volumetric analysis of the future liver remnant using open source image processing software. World J Surg. 2010;34(10):2426-2433. 136. Dello SA, van dam RM, Slangen JJ, et al. Liver volumetry plug and play: Do it yourself with ImageJ. World J Surg. 2007;31(11): 2215-2221. 137. Dello SA, Stoot JH, van Stiphout RS, et al. Prospective volumetric assessment of the liver on a personal computer by nonradiologists prior to partial hepatectomy. World J Surg. 2011;35(2):386-392. 138. Schindl MJ, Redhead DN, Fearon KCH, Garden OJ, Wigmore SJ. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut. 2005;54(2):289-296. 139. Haimerl M, Verloh N, Fellner C, et al. MRI-based estimation of liver function: Gd-EOB-DTPA-enhanced T1 relaxometry of 3T vs. The MELD score. Sci Rep. 2014;4:5621. Available at: https:// doi.org/10.1038/srep05621. 140. Morris-Stiff G, Gomez D, Prasad R. Quantitative assessment of hepatic function and its relevance to the liver surgeon. J Gastrointest Surg. 2009;13(2):374-385. 141. Makuuchi M, Kosuge T, Takayama T, et al. Surgery for small liver cancers. Semin Surg Oncol. 1993;9(4):298-304. 142. Lam CM, Fan ST, Lo CM, Wong J. Major hepatectomy for hepatocellular carcinoma in patients with an unsatisfactory indocyanine green clearance test. Br J Surg. 1999;86(8):1012-1017.

CHAPTER 13 Cross-sectional imaging of liver, biliary, and pancreatic disease: Introduction and basic principles Richard Kinh Gian Do INTRODUCTION Cross-sectional imaging of the liver, biliary tree, and pancreas can be performed with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Positron emission tomography (PET) is most often performed in combination with CT (PET-CT) and has more recently been performed in conjunction with MRI (PET-MRI). This chapter will emphasize basic principles of ultrasound, CT, and MRI that highlight the strengths and limitations of each technique for the ordering clinicians.

ULTRASOUND Ultrasound as an imaging modality has tremendous versatility, is low-cost, and has real-time capability and portability. Ultrasound is considered safe at clinical, diagnostic levels, with no confirmed harmful biologic effects on the operator or patient. Use of Doppler ultrasound also allows for the assessment of blood flow dynamics (see Chapter 5). Despite these advantages, certain limitations influence the applicability of ultrasound. Ultrasound waves are unable to penetrate bone or air, which can obscure lesions and limit the field of view. The quality of ultrasound imaging and its interpretation are also operator dependent, which means they are influenced by skill and experience. Different ultrasound transducers are optimized for specific frequencies. Lower-frequency transducers have poorer resolution with greater depth of penetration and thus are used to image deeper structures such as abdominopelvic tissues. Higher-frequency transducers have better spatial resolution, but higher-frequency sound attenuates rapidly and has poorer tissue penetration. Higher frequency ultrasound is best used for superficial soft tissues, such as the thyroid, and it can also be used to assess liver surface nodularity. Echogenicity of tissue refers to the reflection or transmission of ultrasound waves relative to surrounding tissues. Based on gray scale imaging, a structure on the image display can be characterized as anechoic (uniformly black), hypoechoic (dark gray), or hyperechoic (light gray) (Fig. 13.1). Acoustic artifacts often occur, many of which are clinically useful. For example, acoustic enhancement is described when there is increased through-transmission of sound waves in fluid-containing structures, making tissue behind the fluid appear artificially bright, a characteristic of cystic structures (see Fig. 13.1). Certain artifacts are useful to hepatobiliary imaging in particular. Acoustic shadowing occurs when a structure attenuates sound more rapidly than surrounding tissues and casts a dark acoustic shadow beyond the object. This occurs with strong reflectors, such as calcifications, or strong attenuators, such as dense tumors. Acoustic shadowing is a feature of gallstones and, in 208

conjunction with mobility, aids in distinction between gallstones and gallbladder polyps (see Chapter 33). Comet tail artifact is a type of reverberation that occurs when two reflective interfaces are closely spaced, such as within a punctate crystal, producing posterior echoes that are parallel, evenly spaced echogenic bands with a triangular tapered shape. Comet tail artifact allows for the identification of surgical clips and is also a feature of gallbladder adenomyomatosis. Twinkle artifact is a color Doppler artifact that helps to detect and verify crystals and calcifications, particularly if a calculus does not demonstrate acoustic shadowing. Twinkle artifact occurs posterior to strong reflectors and appears as turbulent color Doppler flow with a mix of red and blue pixels; however, spectral Doppler tracing demonstrates noise. Additional artifacts have been described and are outside the scope of this chapter; the reader is referred to specialized texts.1–3

Liver Ultrasound A normal liver is smooth in contour and uniform in echogenicity. Hepatic parenchyma is hypoechoic to the spleen and either isoechoic or minimally hyperechoic to renal parenchyma (see Fig. 13.1C). Liver size is most commonly determined sonographically by a longitudinal image of the right lobe. Treece et al. found that when the liver measures 15.5 cm or greater in the midhepatic line, hepatomegaly is present in 75% of patients.4 In the right midclavicular line, the normal mean length is 10 cm, with a standard deviation of 1.5 cm.5 In most patients the measurement of liver length suffices, but hepatic shape can be variable, and thus three-dimensional ultrasound volumetric analysis can aid evaluation.6,7 Ultrasound images are obtained through available acoustic windows, avoiding bone and air, which will vary the appearance of the liver compared with the standard transverse planes of CT and MRI. Doppler ultrasound is used to identify and evaluate blood flow in vessels based on the backscatter of blood cells (see Fig. 13.1D). Doppler imaging allows for the assessment of vessel patency, direction of blood flow, flow velocity, and spectral waveforms.8 Three different Doppler displays are available: color, power, and spectral Doppler. Color Doppler provides information about the direction of motion and differences in flow velocity. Limitations of color Doppler imaging include dependence on angle of insonation, inability to display the entire Doppler spectrum in the image, and artifacts caused by aliasing and noise. Power (or amplitude) Doppler is a complementary technique that displays total amplitude of the echo signal but not flow direction. Power Doppler signal is more sensitive for flow detection than color Doppler and is less dependent on the angle of insonation. It is not subject to aliasing and is less sensitive to noise. Power Doppler is most useful in showing areas of low flow, depicting slow flow in an area of subtotal occlusion and demonstrating intralesional vascular patterns. In spectral

  Chapter 13  Cross-Sectional Imaging of Liver, Biliary, and Pancreatic Disease: Introduction and Basic Principles

209

FIGURE 13.1  Liver ultrasound. A, A liver mass in the right hepatic lobe is hyperechoic, or brighter, than the liver parenchyma. B, The gallbladder (*) is anechoic (black) and as a fluid-containing structure, shows through transmission of sound waves, making posterior soft tissues brighter. C, The liver is usually isoechoic or slightly hyperechoic to renal parenchyma. D, Doppler images demonstrate blood flow in the hepatic veins.

Doppler, a sample volume cursor is placed within the target vessel and displays a waveform of the entire range of velocities during time, rather than the mean velocity as in a color Doppler image. Arterial waveforms are characterized as high resistance by limited flow during diastole or low resistance by continuous flow during diastole. At sites of stenosis, flow is not laminar; instead, flow becomes turbulent, and the spectral Doppler waveform reflects the red blood cells moving at varying velocities.

COMPUTED TOMOGRAPHY CT excels as a cross-sectional imaging tool for hepatopancreatobiliary disease and provides high-resolution anatomic imaging that relies on differences in the ability of various tissues to attenuate x-ray beams. Relative to MRI, CT remains superior at in-plane and z-axis (interslice) resolution. Since its inception in the 1970s, the usage of CT has increased exponentially with key innovations such as helical scanning in the late 1980s and

multi-detector (MD) CT beginning in the late 1990s,9 both contributing to the speed of CT image acquisition. The reduction in scanning times (several seconds for the entire study) greatly decreased motion artifacts and allowed multiphasic evaluation (hepatic arterial, portal venous, and delayed phases) of the liver and pancreas (Fig. 13.2). Current CT scanners can obtain images with resolution below 1 mm in all planes (i.e., isotropic submillimeter voxels), yielding smoother images when the data acquired in the axial plane are reformatted in the coronal, sagittal, and oblique planes. With higher resolution data, many types of postprocessing10 aided by voxel isotropy and digital display, include maximum intensity projection (MIP), where processed images depict only the brightest structures within the specified data volume.10–15 Using portal venous phase source images, MIP images produce a more robust depiction of portal venous and hepatic venous anatomy (see Fig. 13.2; see also Chapter 5). Volume-rendered reconstructions provide a lifelike three-dimensional (3D) model of complex anatomy that can be rotated in any direction,11,12,14,15

210

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 13.2  Multiphasic computed tomography imaging. A, Noncontrast computed tomography (CT) images of the upper abdomen, showing the unenhanced liver (L) and spleen (S). B, Early arterial phase image shows enhancement of the aorta (A) and common hepatic artery (arrow). C, Portal venous phase image shows enhancement of the portal and hepatic veins. D, Maximum intensity projection (MIP) image depicting visceral arteries. E, MIP image of abdomen in the portal venous phase image. F, 3D reconstruction of the celiac, splenic, and hepatic arterial anatomy, including the gastroduodenal artery (arrowhead). Calcified plaques on the abdominal aorta appear brighter than the contrast within the arteries.

transforming the numerous axial images into an interactive 3D model that may be more intuitive to the surgeon. Hepatic arterial anatomy can be similarly displayed (see Fig. 13.2), and the relationship of tortuous vessels to the hepatic parenchyma and lobar anatomy can be depicted clearly. It is also possible to view a rotating model that depicts the relationship of a mass to the adjacent vessels from any angle to help the surgeon conceptualize

preoperatively what would be encountered at surgery (see Chapters 2 and 118–122). Although MRI offers superior tissue contrast and capability for functional imaging (and thus superior lesion characterization), the superior spatial resolution, ease of interpretation, greater availability, and lower cost of CT maintain it as the most frequently requested modality in evaluating the liver and

  Chapter 13  Cross-Sectional Imaging of Liver, Biliary, and Pancreatic Disease: Introduction and Basic Principles

pancreas. A major drawback remains usage of ionizing radiation, with a trend in past decades toward decreasing exposure of the patient population. Dose reduction in multiphasic CT studies of the liver and pancreas CT have been a priority.16 With a lower dose, however, CT images become noisier, requiring new reconstruction algorithms to “smooth out” the images, such as adaptive statistical iterative reconstruction (ASIR) and model-based iterative reconstruction.17–19 Lower-dose and new reconstruction algorithms are not without limitations because they may reduce the conspicuity of liver metastases.20 Dual-energy CT (DECT) is another recent development using either a single radiation source that alternates beam energies (“rapid switching” or rsDECT) or two radiation sources of differing energies (“dual source” or dsDECT) to produce CT images. For the liver, biliary system, and pancreas, applications include “material-specific imaging” and “virtual monochromatic imaging.”21 In the liver, “virtual iron images” may be used for quantitation of hepatic iron deposition without interference from coexisting steatosis,22 whereas “virtual non-iron images” can be created for fat quantitation independent of concomitant siderosis23 (see Chapter 69). “Virtual iodine mapping” may also aid in identifying tumor thrombus and distinguishing it from bland thrombus in the setting of hepatocellular carcinoma (HCC; see Chapter 89).24 In the pancreas, lower kilovolt peak images from “virtual monochromatic” dsDECT25 and lower kiloelectron volt images from virtual monochromatic rsDECT26 have been shown to improve conspicuity of hypovascular tumors, such as typical ductal adenocarcinoma. Lowerenergy virtual monochromatic images may also provide more robust surface-rendered 3D arterial images, whereas virtual higher-energy images have less apparent metallic artifact around biliary stents and clips.21

Computed Tomography in Liver Imaging State-of-the-art CT evaluation of the liver may include any combination of the following: precontrast, contrast-enhanced early arterial phase (CT angiography), late arterial phase, portal venous phase, and/or delayed phase. Routine CT is usually performed only in the portal venous phase because common liver metastases, such as those from colon cancer, are commonly hypovascular relative to adjacent normal liver parenchyma (see Chapter 90). On the other hand, hypervascular neoplasms such as hepatocellular adenomas and HCC and certain metastases (see Chapters 88, 89, and 91), including neuroendocrine tumors, renal cell carcinoma, melanoma, and thyroid cancer, are generally evaluated using a multiphasic protocol that includes precontrast, late arterial phase, and portal venous images, with the addition of delayed phase images for HCC.27,28 Early arterial phase high-resolution images (CT angiography) are obtained to assess tumor involvement of arteries and evaluate variant celiac axis anatomy.29 Identification of variant anatomy (see Chapter 2) is crucial to decisions regarding hepatic arterial embolization (see Chapter 94) and placement of hepatic arterial chemoinfusion pumps (see Chapter 97); gains in image resolution during the MDCT era have allowed CT angiography to largely supplant invasive direct catheter angiography for planning placement of intraarterial chemoinfusion pumps30 (see Chapter 21). Vascular mapping may now also be performed with CT. In planning for surgery and other locoregional therapy, portal and hepatic veins can be identified as anatomic landmarks

211

to localize tumors to specific hepatic segments (see Chapter 2) and to assess the proximity of lesions to the inflow and outflow vessels. This information determines the extent of potential hepatic resection required to achieve clear surgical margins. If a proposed operation will be extensive, postprocessing of CT images with 3D volume rendering can also identify segmental or lobar hepatic atrophy and compensatory hypertrophy.

Computed Tomography in Pancreatic Imaging CT imaging of the pancreas relies on the differential intravenous (IV) contrast enhancement between tumor tissue and normal pancreatic parenchyma. The use of IV contrast agent is mandatory for accurate diagnosis, and timing of the contrast injection and accurate delivery of the appropriate volume requires the use of a dedicated CT power injector.31 The precontrast scan permits evaluation of pancreatic calcifications and allows for localization of the gland and pertinent arteries in the z-axis for subsequent acquisition of contrast-enhanced phases. IV contrast medium is injected at a high flow rate of 4 to 6 mL per second. The late arterial or pancreatic parenchymal phase, acquired roughly 30 to 40 seconds after initiating contrast injection, is designed to maximize differences in contrast enhancement between pancreatic neoplasms and adjacent normal pancreatic tissue and is also useful in evaluating hypervascular liver metastases seen in patients with pancreatic endocrine neoplasms (see Chapter 91). Last, the portal venous phase acquired approximately 70 to 90 seconds from the start of IV contrast injection provides the best evaluation of hepatic metastases from pancreatic ductal adenocarcinoma32,32 (see Chapter 62) and, in some cases, offers the best contrast to identify the primary pancreatic lesions themselves. The dedicated pancreas protocol uses oral water as a negative contrast agent administered before the examination to aid distinction of enhanced vessels from the gastrointestinal tract33–35 and to facilitate identification of tumor invasion into the adjacent bowel.

MAGNETIC RESONANCE IMAGING MRI is a cross-sectional multiplanar imaging technique. MRI uses magnetic fields and radiofrequency pulses to generate images with outstanding tissue contrast and excellent spatial resolution. The principles of nuclear magnetic resonance were first described in the 1940s by Bloch et al.36 and Purcell et al.37 as a method for in vitro chemical analysis; these principles were later used by Damadian38 and Lauterbur39 to design MRI for in vivo imaging. Today, MRI is used extensively as a medical imaging tool throughout the body to visualize and distinguish normal and pathologic tissue.

Principles of Magnetic Resonance Imaging Liver MRI used in clinical practice consists of a combination of T1- and T2-weighted images (T1w and T2w), as well as diffusion-weighted imaging (DWI), obtained before or after IV contrast administration (Fig. 13.3). The variety of contrast available to MRI is a result of the signal available from the magnetic moment (or spin) present in hydrogen atoms (H1) because of its abundance in the human body in the form of water and fat. Other nuclei that may be imaged by MRI include phosphorus (P31), sodium (Na23), and carbon (C13), but these are used mostly in the research setting. A measurable signal is generated from the magnetic moment after excitation by a radiofrequency (RF) pulse; signal is generated as the excited

212

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 13.3  Magnetic resonance imaging of liver metastasis. A, Precontrast T1-weighted image with fat suppression shows a hypointense (dark) right hepatic metastasis (arrow). B, Perilesional hyperenhancement is seen on T1-weighted imaging in the arterial phase. C, The liver metastasis is hypovascular in the portal venous phase. D, Postcontrast delayed hepatobiliary phase shows a hypointense liver metastasis. Hyperintense hepatobiliary contrast (Gd-EOB-DTPA) is seen excreted into the gallbladder (*) and common hepatic duct. E, The right hepatic metastasis is hyperintense (bright) on T2-weighted imaging. F, Diffusion-weighted imaging shows hyperintense signal (or diffusion restriction) in the right hepatic metastasis. G, Contrast-enhanced CT image in the portal venous phase shows the same hypovascular right hepatic metastasis. H, Ultrasound image of the liver metastasis shows the expected hypoechoic appearance.

nuclei return to equilibrium, releasing energy in the form of an electromagnetic field that is captured by a receiver coil. The strength of this emitted signal determines the signal intensity (SI) of a tissue. The precise tissue SI depends on several factors, including its intrinsic longitudinal relaxation (T1), transverse relaxation (T2), proton density (the number of nuclei present), flow, and the coil itself. T1w and T2w images are created by manipulating the RF pulse and various electromagnetic fields during imaging. Differences in T1 and T2 relaxation times intrinsic to various soft tissues (e.g., fat, muscles, water) can be exploited to improve image contrast and diagnostic accuracy. For example, free water is low signal on standard T1w imaging and markedly high signal on T2w imaging. Thus so-called heavily T2w imaging sequences (e.g., used in magnetic resonance [MR] cholangiopancreatography) highlight high water content structures, such as bile and pancreatic ducts, while reducing the signals of other organs. DWI is used to highlight differences in water diffusion. The higher proportion of cell membranes in rapidly dividing cells contributes to restricted diffusion of cancer cells. DWI of the liver is thus used to help detect hepatic metastases and may also be used to assess changes in the liver parenchyma, such as liver fibrosis.40

Magnetic Resonance Imaging of the Liver MRI is routinely used to evaluate diffuse and focal liver abnormalities. Normal hepatic parenchyma is brighter (hyperintense) than the spleen on T1w images, whereas on T2w images, the spleen is relatively brighter than the liver (see Fig. 13.3). Although most hepatic lesions are low in signal intensity on T1w images, they have more variable intensity on T2w images, with cysts (see Chapter 73) and hemangiomas (see Chapter 88) having the highest T2 signal intensity in general. Precontrast and

postcontrast T1w imaging is also performed to assess enhancement patterns of the liver parenchyma and liver lesions, similar to a multiphasic CT. If a hepatobiliary contrast agent is used, additional transitional phase and delayed hepatobiliary phase images are acquired. MRI contrast agents for hepatobiliary imaging are divided into two categories: extracellular fluid (ECF) and hepatobiliary contrast agents. After IV injection, ECF agents, such as gadopentetate dimeglumine (gadolinium diethylenetriaminepentaacetic acid [Gd-DTPA]), distribute within the intravascular compartment and rapidly diffuse through the extravascular space, similar to the action of iodinated contrast agents in CT imaging. Hepatobiliary-specific contrast agents behave similar to traditional ECF contrast agents when first injected, but they are taken up to varying degrees by functioning hepatocellular tissue and are excreted in bile over time. Hepatobiliary specific agents include mangafodipir trisodium, gadobenate dimeglumine, and gadoxetic acid disodium (Gd-EOB-DTPA). Both gadobenate dimeglumine (MultiHance; Bracco Imaging, Cranbury Township, NJ) and gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Eovist/Primovist; Bayer Healthcare, Wayne, NJ) have been approved in the United States. Gd-EOB-DTPA has become the preferred hepatobiliary contrast agent given its rapid uptake by normal liver parenchyma that allows for hepatobiliary phase imaging at approximately 20 minutes after IV injection. These agents provide comprehensive information about the hepatic parenchyma, bile ducts, and liver vasculature.41,42

Magnetic Resonance Imaging Cholangiopancreatography MR cholangiopancreatography (MRCP) is an imaging technique used to evaluate the bile and pancreatic ducts and plays

  Chapter 13  Cross-Sectional Imaging of Liver, Biliary, and Pancreatic Disease: Introduction and Basic Principles

an important role in imaging benign disorders, as well as in comprehensive evaluation of malignancies of the biliary system.43–45 Heavily T2w images are used to provide an overview of biliary and pancreatic ductal anatomy, by reducing the signal of surrounding nonfluid structures. Cross-sectional images and maximum intensity projection images (see Fig. 13.2) are produced with current MRCP techniques, and projection images are similar to direct contrast-enhanced cholangiograms obtained with either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography. MRCP is a noninvasive imaging tool, eliminating the potential morbidity associated with ERCP or PTC.46 The basic principle of MRCP is to use T2w imaging to highlight stationary or slowly moving fluid, including bile, as high in signal intensity; surrounding tissues, including retroperitoneal fat and the solid visceral organs, with shorter T2 values, are markedly reduced in signal. In addition to heavily T2-weighted sequences, MRCP protocols also include routine T1w, T2w, and DWI sequences obtained during a liver MRI.

MAGNETIC RESONANCE IMAGING SAFETY CONSIDERATIONS MRI is an attractive alternative to CT imaging because of the lack of ionizing radiation and the higher safety profile of MR gadolinium contrast agents. However, physicians should be aware of some important considerations, including MR contrast deposition and the risk of interactions between the patient (including their implants) with the MR scanner. In a worst-case scenario, patients can die if placed in an MRI without proper implant screening, as some have after torsion of brain aneurysm clips.47 MRI facilities should all have screening programs in

213

place to address contraindicated devices, under new MRI safety guidelines proposed by the American College of Radiology.48 However, referring physicians should become familiar with their local imaging centers’ approach to MRI safety, and specifically their ability to scan patients with MR-conditional or MR-unsafe pacemakers and defibrillators. Unlike iodinated contrast used for CT imaging, MRI gadolinium-based contrast agents (GBCAs) have no association with contrast-induced nephropathy, and contrast-enhanced (CE) MRI is an alternative for patients with moderate to severe renal failure. Administration of GBCAs in patients with severe or end-stage renal insufficiency carries a small risk of nephrogenic systemic fibrosis (NSF). NSF is a serious and potentially fatal complication related to free gadolinium deposition within soft tissues and organs, with resulting scleroderma-like fibrosis. The exact causal mechanism of NSF remains unknown, but the risk of NSF increases in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min, and particularly in patients with end-stage disease (eGFR , 15 mL/min). Gadolinium contrast usage in these patients should only be performed if essential, after careful evaluation of risks versus benefits, and with consultation with a nephrologist, if available. Since NSF was initially described, the rapid international investigation, dissemination of information, and swift adjustment to policy have led to a precipitous drop in reported NSF cases. In multiple countries, NSF has essentially disappeared since 2009.49–51 In recent years, macrocyclic GBCAs have emerged as preferred contrast agents for patients undergoing MRI because of the lower risk of NSF and gadolinium deposition.52 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

213.e1

REFERENCES 1. Campbell SC, Cullinan JA, Rubens DJ. Slow flow or no flow? Color and power Doppler US pitfalls in the abdomen and pelvis [published correction appears in Radiographics. 2004;24(3):917]. Radiographics. 2004;24(2):497-506. 2. Feldman MK, Katyal S, Blackwood MS. US artifacts. Radiographics. 2009;29(4):1179-1189. 3. Rubens DJ, Bhatt S, Nedelka S, Cullinan J. Doppler artifacts and pitfalls. Radiol Clin North Am. 2006;44(6):805-835. 4. Gosink BB, Leymaster CE. Ultrasonic determination of hepatomegaly. J Clin Ultrasound. 1981;9(1):37-44. 5. Niederau C, Sonnenberg A, Müller JE, Erckenbrecht JF, Scholten T, Fritsch WP. Sonographic measurements of the normal liver, spleen, pancreas, and portal vein. Radiology. 1983;149(2):537-540. 6. Treece G, Prager R, Gee A, Berman L. 3D ultrasound measurement of large organ volume. Med Image Anal. 2001;5(1):41-54. 7. Wilson SR, Gupta C, Eliasziw M, Andrew A. Volume imaging in the abdomen with ultrasound: how we do it. AJR Am J Roentgenol. 2009;193(1):79-85. 8. McNaughton DA, Abu-Yousef MM. Doppler US of the liver made simple [published correction appears in Radiographics. 2011 MayJun;31(3):904]. Radiographics. 2011;31(1):161-188. 9. Goldman LW. Principles of CT: multislice CT. J Nucl Med Technol. 2008;36(2):57-76. 10. Salgado R, Mulkens T, Ozsarlak O, De Schepper AM, Parizel PA. CT angiography: basic principles and post-processing applications. JBR-BTR. 2003;86(6):336-340. 11. Johnson PT, Heath DG, Kuszyk BS, Fishman EK. CT angiography with volume rendering: advantages and applications in splanchnic vascular imaging. Radiology. 1996;200(2):564-568. 12. Johnson PT, Heath DG, Hofmann LV, Horton KM, Fishman EK. Multidetector-row computed tomography with three-dimensional volume rendering of pancreatic cancer: a complete preoperative staging tool using computed tomography angiography and volumerendered cholangiopancreatography. J Comput Assist Tomogr. 2003;27(3):347-353. 13. Magnusson M, Lenz R, Danielsson PE. Evaluation of methods for shaded surface display of CT volumes. Comput Med Imaging Graph. 1991;15(4):247-256. 14. Rubin GD. 3-D imaging with MDCT. Eur J Radiol. 2003;45(suppl 1): S37-S41. 15. Zeman RK, Davros WJ, Berman P, et al. Three-dimensional models of the abdominal vasculature based on helical CT: usefulness in patients with pancreatic neoplasms. AJR Am J Roentgenol. 1994;162(6):1425-1429. 16. Brenner DJ, Hall EJ. Computed tomography—An increasing source of radiation exposure. N Engl J Med. 2007;357(22):22772284. 17. Pickhardt PJ, Lubner MG, Kim DH, et al. Abdominal CT with model-based iterative reconstruction (MBIR): initial results of a prospective trial comparing ultralow-dose with standard-dose imaging. AJR Am J Roentgenol. 2012;199(6):1266-1274. 18. Shuman WP, Green DE, Busey JM, et al. Model-based iterative reconstruction versus adaptive statistical iterative reconstruction and filtered back projection in liver 64-MDCT: focal lesion detection, lesion conspicuity, and image noise. AJR Am J Roentgenol. 2013;200(5):1071-1076. 19. Shuman WP, Chan KT, Busey JM, et al. Standard and reduced radiation dose liver CT images: adaptive statistical iterative reconstruction versus model-based iterative reconstruction-comparison of findings and image quality. Radiology. 2014;273(3):793-800. 20. Jensen CT, Wagner-Bartak NA, Vu LN, et al. Detection of colorectal hepatic metastases is superior at standard radiation dose CT versus reduced dose CT. Radiology. 2019;290(2):400-409. 21. Morgan DE. Dual-energy CT of the abdomen. Abdom Imaging. 2014;39(1):108-134. 22. Joe E, Kim SH, Lee KB, et al. Feasibility and accuracy of dualsource dual-energy CT for noninvasive determination of hepatic iron accumulation. Radiology. 2012;262(1):126-135. 23. Zheng X, Ren Y, Phillips WT, et al. Assessment of hepatic fatty infiltration using spectral computed tomography imaging: a pilot study. J Comput Assist Tomogr. 2013;37(2):134-141. 24. Qian LJ, Zhu J, Zhuang ZG, et al. Differentiation of neoplastic from bland macroscopic portal vein thrombi using dual-energy spectral CT imaging: a pilot study. Eur Radiol. 2012;22(10):2178-2185.

25. Macari M, Spieler B, Kim D, et al. Dual-source dual-energy MDCT of pancreatic adenocarcinoma: initial observations with data generated at 80 kVp and at simulated weighted-average 120 kVp. AJR Am J Roentgenol. 2010;194(1):W27-W32. 26. Patel BN, Thomas JV, Lockhart ME, Berland LL, Morgan DE. Single-source dual-energy spectral multidetector CT of pancreatic adenocarcinoma: optimization of energy level viewing significantly increases lesion contrast. Clin Radiol. 2013;68(2):148-154. 27. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022. 28. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1): 52-60. 29. Michels N. Blood Supply and Anatomy of the Upper Abdominal Organs with a Descriptive Atlas. Lippincott; 1955. 30. Kapoor V, Brancatelli G, Federle MP, Katyal S, Marsh JW, Geller DA. Multidetector CT arteriography with volumetric three-dimensional rendering to evaluate patients with metastatic colorectal disease for placement of a floxuridine infusion pump. AJR Am J Roentgenol. 2003;181(2):455-463. 31. Tamm E, Charnsangavej C. Pancreatic cancer: current concepts in imaging for diagnosis and staging. Cancer J. 2001;7(4):298-311. 32. Bashir MR, Gupta RT. MDCT evaluation of the pancreas: nuts and bolts. Radiol Clin North Am. 2012;50(3):365-377. 33. Takeshita K, Furui S, Takada K. Multidetector row helical CT of the pancreas: value of three-dimensional images, two-dimensional reformations, and contrast-enhanced multiphasic imaging. J Hepatobiliary Pancreat Surg. 2002;9(5):576-582. 34. Lawler LP, Fishman EK. Three-dimensional CT angiography with multidetector CT data: study optimization, protocol design, and clinical applications in the abdomen. Crit Rev Comput Tomogr. 2002;43(2):77-141. 35. Soriano A, Castells A, Ayuso C, et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol. 2004;99(3):492-501. 36. Bloch F, Hansen WW, Packard M. The nuclear induction experiment. Phys Rev. 1946;70(7-8):474–485. 37. Purcell EM, Torrey HC, Pound RV. Resonance absorption by nuclear magnetic moments in a solid. Phys Rev. 1946;69(1-2):37-38. 38. Damadian R. Tumor detection by nuclear magnetic resonance. Science. 1971;171(3976):1151-1153. 39. Lauterbur PC. Image formation by induced local interactions. Examples employing nuclear magnetic resonance. 1973. Clin Orthop Relat Res. 1989;(244):3-6. 40. Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology. 2010;254(1):47-66. 41. Burke C, Alexander Grant L, Goh V, Griffin N. The role of hepatocyte-specific contrast agents in hepatobiliary magnetic resonance imaging. Semin Ultrasound CT MR. 2013;34(1):44-53. 42. Seale MK, Catalano OA, Saini S, Hahn PF, Sahani DV. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. Radiographics. 2009;29(6):1725-1748. 43. Mandelia A, Gupta AK, Verma DK, Sharma S. The value of magnetic resonance cholangio-pancreatography (MRCP) in the detection of choledocholithiasis. J Clin Diagn Res. 2013;7(9):19411945. 44. Singh A, Mann HS, Thukral CL, Singh NR. Diagnostic accuracy of MRCP as compared to ultrasound/CT in patients with obstructive jaundice. J Clin Diagn Res. 2014;8(3):103-107. 45. Vaishali MD, Agarwal AK, Upadhyaya DN, Chauhan VS, Sharma OP, Shukla VK. Magnetic resonance cholangiopancreatography in obstructive jaundice. J Clin Gastroenterol. 2004;38(10):887-890. 46. Zhong L, Xiao SD, Stoker J, Nj Tytgat G. Magnetic resonance cholangiopancreatography. Chin J Dig Dis. 2004;5(4):139-148. 47. Pride Jr GL, Kowal J, Mendelsohn DB, Chason DP, Fleckenstein JL. Safety of MR scanning in patients with nonferromagnetic aneurysm clips. J Magn Reson Imaging. 2000;12(1):198-200. 48. Expert Panel on MR Safety, Kanal E, Barkovich AJ, et al. ACR guidance document on MR safe practices: 2013. J Magn Reson Imaging. 2013;37(3):501-530. 49. Bennett CL, Qureshi ZP, Sartor AO, et al. Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease. Clin Kidney J. 2012;5(1):82-88.

213.e2 50. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? [published correction appears in Nephrol Dial Transplant. 2006;21(6):1745]. Nephrol Dial Transplant. 2006;21(4):1104-1108. 51. Idée JM, Fretellier N, Robic C, Corot C. The role of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: a critical update. Crit Rev Toxicol. 2014;44(10):895-913.

52. Gulani V, Calamante F, Shellock FG, Kanal E, Reeder SB, International Society for Magnetic Resonance in Medicine. Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol. 2017;16(7):564-570.

CHAPTER 14 Imaging features of benign and malignant liver tumors and cysts Kate Anne Harrington INTRODUCTION The increased frequency of cross-sectional imaging with improved imaging techniques has resulted in the increased detection of liver lesions. The majority of incidentally discovered liver lesions are benign, even in the oncologic population.1,2 Although ultrasound (US) can be useful in screening for and detecting liver lesions, lesion characterization is mostly performed using computed tomography (CT) or magnetic resonance imaging (MRI). Contrast-enhanced ultrasound (CEUS) provides real-time dynamic assessment capability, with high spatial and temporal resolution, making it a valuable component of multimodality imaging. This method is more widely used in Europe and Asia, with US Food and Drug Administration (FDA) approval of microbubble contrast agents for noncardiac use only granted since 2015. MRI has more advantages than CT in the evaluation of liver lesions, notwithstanding the avoidance of patient exposure to ionizing radiation that occurs with CT. The numerous sequences that are at the radiologist’s disposal with MRI means that many lesions can be accurately diagnosed on imaging.

BENIGN LIVER TUMORS For more information on benign liver tumors, see Chapter 88.

Hemangioma Hepatic hemangiomas are benign vascular tumors of the liver and have an estimated incidence of anywhere between 4% and 20%.3,4 Most hemangiomas are found incidentally on imaging studies such as ultrasound and CT. The most typical forms of hemangioma are cavernous and flash-filling hemangiomas. On US, hemangiomas are characteristically homogeneously hyperechoic, well-circumscribed masses with subtle posterior acoustic enhancement (Fig. 14.1A). A hyperechoic rim may also be seen in a portion of hemangiomas, particularly if the hemangioma was predominantly isoechoic to liver. Increased echogenicity is because of multiple vascular interfaces within hemangiomas. Although hemangiomas are vascular, flow is extremely slow, and usually no Doppler signal is evident.5 If a US shows a classic appearance of hemangioma and the patient has no risk factors, history of underlying liver disease (hepatitis, alcohol abuse, fatty liver, etc.), or malignancy, then no followup imaging needs to be performed.6,7 It should be noted that those with a history of malignancy and at an increased risk for hepatocellular carcinoma (HCC) should be further evaluated upon the identification of an echogenic liver lesion. In a study of 1,982 patients with cirrhosis, US depicted hemangioma-like lesions in 44 patients; on follow-up, half of these proved to be HCCs, and half were hemangiomas.8 Larger hemangiomas often lack characteristic features because of central fibrosis, necrosis, and myxomatous degeneration 214

and can appear heterogeneously hyperechoic (see Fig. 14.1B). When the background liver itself becomes hyperechoic as a result of steatosis, hemangiomas may appear hypoechoic to liver parenchyma.5,9 On CT, hemangiomas are typically hypoattenuating to surrounding liver on noncontrast imaging. In patients with hepatic steatosis, the liver is typically diffusely decreased in attenuation, thereby decreasing the conspicuity of hypoattenuating hemangiomas. However, fatty sparing around the rim of the hemangioma can occur, resulting in the presence of a hyperattenuating rim on noncontrast CT.10 MRI is ideal for characterizing hemangiomas and is the preferred modality for characterization with a high sensitivity and specificity.11 On T2-weighted imaging, hemangiomas are T2 bright, nearly similar in intensity to cerebrospinal fluid (CSF).3 On diffusion-weighted imaging (DWI), hemangiomas appear hyperintense on low b-values and remain hyperintense at higher b-values, similar to malignant lesions. Nevertheless, they will also have high apparent diffusion coefficient (ADC) values, a phenomenon known as T2 shine-through. This can be useful when differentiating from metastases, which have lower ADC values.12 The classical enhancement pattern of cavernous hemangiomas seen on multiphase contrast-enhanced imaging done on US, CT, and MRI is typically peripheral, nodular, discontinuous enhancement on arterial phase, with centripetal fill-in on portal venous phase and persistent homogenous enhancement on later postcontrast phases (Fig. 14.2). The peripheral areas of enhancement follow the same attenuation or signal intensity of blood vessels (such as the hepatic artery or portal vein).13–15 Caution must be used when assessing enhancement on MRI using a hepatocyte specific contrast agent such as gadoxetate disodium (Gd-EOB-DTPA). The overlapping extracellular phase and hepatobiliary excretion of this contrast may confound the typical hemangioma enhancement pattern and lead to the appearance of “pseudowashout” in the late dynamic phase.16 Because hemangiomas do not contain hepatocytes, they become gradually hypointense on the transitional and hepatobiliary phase. For this reason, we prefer not to use gadoxetate disodium as the contrast agent for initial liver lesion characterization and use a traditional extracellular fluid contrast (ECF) agent instead, such as one of the macrocyclic gadolinium agents (e.g., gadobenate dimeglumine, gadoterate meglumine, gadoteridol). Flash-filling hemangiomas are often small lesions (under 1 cm in diameter) and appear as diffusely hypervascular, homogenous lesions. Homogenous enhancement is seen in the arterial phase, and enhancement density/intensity follows that of the aorta in subsequent phases.15 Larger hemangiomas tend to follow the cavernous type enhancement pattern criteria, although giant hemangiomas

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

215

B

FIGURE 14.1  Hemangiomas. A, Longitudinal sonogram of the right lobe shows a brightly echogenic hemangioma (arrow) with a circumscribed border. B, Atypical hemangioma (arrow) with areas of internal heterogeneity, a result of fibrosis or myxomatous degeneration, and a thin echogenic rim (arrowhead).

(.6–10 cm) may also have variable signal intensity and a central scar.17 Giant hemangiomas often do not completely fill in with contrast on delayed phases. Calcification in hemangiomas is rare and is reported in 10% to 20% of cases,18 although our own experience is much lower than 10%. Calcifications may correspond to phleboliths and are most easily detected on CT. Sclerosed and sclerosing hemangiomas are a rare type of hemangioma where degeneration and intralesional fibrosis and hyalinization occurs (Fig. 14.3). These hemangiomas do not exhibit typical appearances on MRI because of loss of normal vascular channels. Markedly sclerosed hemangiomas lack the classic T2 hyperintense signal on MRI and may even become isointense to the liver parenchyma. Commonly, they demonstrate little or minimal arterial-phase enhancement and show variable progressive enhancement in portal venous and delayed phases.19 Some sclerosed hemangiomas may not achieve any enhancement on any phase, particularly if the lesion shows marked sclerosis on histopathologic evaluation.19 Additional features that may be seen in sclerosed hemangiomas include capsular retraction and peritumoral arterial enhancement.20 Thus, sclerosed hemangioma are easily mistaken for metastatic disease in the liver and may require biopsy for definitive diagnosis.

Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is the second most common solid benign liver lesion after hemangioma. Pathologically, FNH contains all the elements of normal liver, may have a central fibrous scar, and is surrounded by hepatocytes and small bile ducts. FNH has been associated with oral contraceptive

use, as well as chemotherapy in the pediatric age group, although the former association is not definitive.21 On US, FNH has a smooth lobulated contour and variable echogenicity. A key to US diagnosis of FNH is the characteristic Doppler appearance of a central feeding artery with tortuous spoke-wheel vascularity.22 A recognized feature of FNH is the presence of a central scar, yet this is usually better depicted on CT, MRI, or CEUS.14 On CT, FNH is isoattenuating or slightly hypoattenuating to adjacent liver on noncontrast imaging. If a central scar is present, it is hypointense on precontrast phase.23 Although described as a typical feature, a scar is usually only seen on CT in approximately 20% to 50% of cases.24,25 On MRI, most FNH are isointense to normal liver parenchyma and nearly invisible on T1- and T2-weighted images (Fig. 14.4). Occasionally, some lesions may be mildly T1 hypointense or minimally T2 hyperintense. When discussing relative T1 and T2 signal, a normal background liver parenchyma is assumed. In a liver with iron deposition, which diffusely lowers the signal intensity of the liver parenchyma, T1 and T2 relative hyperintensity can be expected.21 A central scar can be seen more frequently on MRI and is hypointense on T1-weighted images and hyperintense on T2-weighted images (see Fig. 14.4).24 After intravenous (IV) contrast administration, the typical enhancement pattern of FNH is diffuse homogenous hyperenhancement in the arterial phase, followed by fading to background hepatic attenuation/intensity by the portal venous phase (see Fig. 14.4).26–28 Fading to background hepatic parenchyma signal should be distinguished from “washout,” where a lesion becomes darker than background liver. When a central scar is

216

PART 2  DIAGNOSTIC TECHNIQUES

A

C

B

D

E

FIGURE 14.2  Cavernous hemangioma. A, Fat-saturated T2-weighted image shows a mass that is hyperintense to hepatic parenchyma, with well-defined margins. B, Precontrast T1-weighted fat saturation image at the same level shows the mass to be low in signal compared with background parenchyma. C–E, Multiphase T1-weighted postcontrast image in arterial, portal venous and equilibrium phases respectively shows progressive, peripheral nodular enhancement within this mass (arrows).

present, it enhances on delayed phases, beginning at approximately 3 minutes when using ECF contrast agents.29 When a hepatocyte-specific contrast agent is used, lesional enhancement similar to or higher-than-normal to background hepatic parenchyma during the delayed hepatobiliary phase is expected in the majority of FNHs (Fig. 14.5). Of note, with the use of a hepatobiliary-specific agent such as gadoxetate disodium, a central stellate scar, if present, does not progressively enhance on later dynamic phases and will appear relatively hypointense, reflecting the absence of hepatocytes and the presence of fibrous tissue within the scar.29

Hepatocellular Adenoma Hepatocellular adenoma (HCA) is a benign hepatocellular tumor; however, unlike FNH, it is a true neoplastic lesion with associated complications, such as abdominal pain, bleeding, and, rarely, malignant degeneration. HCAs have been traditionally associated with oral contraceptive use in women of childbearing age or anabolic steroid use in men. More recently, metabolic syndrome associations such as diabetes mellitus and obesity have also been recognized as risk factors.30 Adenomas are usually solitary, with multiple lesions seen in less than 30% of cases.31 Adenomatosis has been a term typically reserved for the presence of greater than 10 adenomas, first described in

1985.32 However, adenomatosis does not refer to a particular type of adenoma, and it has become apparent that clinical features and histologic subtype are more important than the number of adenomas present.31 Over the past decade, HCAs have been further characterized and subtyped by their specific morphologic and immunohistochemical phenotype, with the most recent classification in 2017 describing eight subtypes.33 Four additional subtypes were added to the already described hepatocyte nuclear factor (HNF)1a-inactivated HCA (H-HCA), inflammatory HCA (IHCA), b-catenin-activated HCA (b-HCA) and “unclassified” subtypes. The newly added subtypes were b-HCA exon 7/8, b-IHCA exon 3, b-IHCA exon 7/8, and sonic-hedgehog HCA (sh-HCA), some of which were previously lumped together in the “unclassified” section. When considering HCA diagnosis for a liver lesion on imaging, correlation with patient demographics is important because men with metabolic syndrome or anabolic steroid use and adenomas with b-catenin-activated mutations are at a much higher risk for malignant degeneration. On US, HCAs have variable echogenicity but are often hyperechoic because of intratumoral fat content. Internal hemorrhage within adenomas may produce cystic areas.23 Vascular flow is usually detected on Doppler imaging; however, the pattern of flow is nonspecific and may be seen as exclusively intralesional

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

217

m

A

D

B

E

C

F

FIGURE 14.3  Hepatic hemangioma undergoing sclerosis. A, Heavily T2-weighted image (echo time [TE] 150) shows a mass (m) that is hyperintense to hepatic parenchyma with well-defined margins. B, Precontrast T1-weighted fat saturation image at the same level shows the mass to be low signal compared with background parenchyma. C, T1-weighted postcontrast image in early portal venous phase shows peripheral nodular enhancement within this mass (arrows). Portions of the lesion fail to show enhancement during this phase. D, Equilibrium phase T1-weighted image postcontrast shows the lesion has partially filled in toward the central portion. This constellation of findings is typical for hepatic hemangioma. E–F, The same lesion 5 years later on T1-weighted postcontrast scans in portal venous and equilibrium phase imaging shows less avid enhancement and has shown slight size decrease, consistent with developing sclerosis. Sclerosing hemangiomas may show size decrease with less avid enhancement, associated capsular retraction, and lower T2 signal than nonsclerosed hemangiomas.

or perilesional or both perilesional and intralesional flow.34 On CEUS, HCAs demonstrate homogenous arterial hyperenhancement, with rapid and complete, usually centripetal, filling. On later phases of imaging contrast enhancement, characteristics are heterogenous, with some lesions demonstrating washout and others remaining iso- or hyperenhanced. It should be noted that washout in portal or later phases on postcontrast imaging on CT or MRI is not a typical feature of adenoma. It has been postulated that washout demonstrated on CEUS is because the microbubbles remain intravascular compared with the ECF contrast agents, which may see diffusion across the vascular endothelium into the tumor interstitium.34 The CT appearance of adenomas often overlaps with FNH and HCC. Adenomas tend to have similar attenuation to normal

liver on unenhanced images. Larger adenomas, however, are more heterogenous in appearance than smaller lesions, depending on their predilection to hemorrhage and/or the presence of fat. The characteristic pattern of contrast enhancement is variable degrees of arterial hyperenhancement and fading or persistent enhancement in later phases, depending on the HCA subtype. For example, strong arterial hyperenhancement with persistent enhancement in portal venous and subsequent delayed sequences is more typical for inflammatory HCA (Fig. 14.6).34 MRI is preferred to CT for identification of intracellular fat and for better characterization of HCA. Furthermore, certain imaging features on MRI have been shown to be associated with different subtypes to date.35–38

218

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D

FIGURE 14.4  Focal nodular hyperplasia (FNH). A, T2-weighted image shows a mass that is isointense to hepatic parenchyma (arrows). Centrally, within this mass is a hyperintense focus (arrowhead). B, A precontrast, T1-weighted gradient-echo image shows the mass (arrows) to be almost isointense to liver. C, Arterial dominant phase T1-weighted gradient-echo sequence shows that the mass enhances intensely with respect to hepatic parenchyma (arrows). The central focus, which was bright on the T2-weighted images, does not show enhancement on this phase of the injection (arrowhead). D, Postcontrast equilibrium phase image shows the mass to be isointense to background hepatic parenchyma. The central portion of scar shows delayed enhancement (arrowhead) characteristic of FNH.

H-HCAs are more likely to have diffuse, homogenous intratumoral fat deposition compared with other subtypes (Fig. 14.7). This can be demonstrated by diffuse signal drop-out on out-ofphase compared with in-phase T1-weighted imaging. They also typically enhance less avidly in the arterial phase and are heterogeneously low in signal in the delayed hepatobiliary phase. A specific feature of I-HCAs is the presence of marked sinusoidal dilatation, which manifests as moderate diffuse intralesional hyperintensity or a rim of hyperintensity (known as the “atoll sign”) on T2-weighted images and corresponding arterial hyperenhancement with persistent delayed enhancement on postcontrast imaging. A “crescent sign” has also been recently proposed, which is similar to the atoll sign, but the rim of T2 hyperintensity and hyperenhancement is incomplete or crescentshaped.36 Some I-HCAs may show focal or heterogenous fat deposition.37 I-HCAs also have a propensity for internal hemorrhage, which can manifest as T1 hyperintensity or hemosiderin deposition, as seen by signal drop-out on in-phase imaging.36 Intralesional hemorrhagic changes, however, are non-specific, with such changes also seen in other subtypes. For example shHCAs, which account for approximately 4% of HCAs, have also been noted to have a predilection to hemorrhage.39 b-HCAs

have no specific differentiating characteristics. They tend to show moderate, often heterogenous arterial-phase enhancement, which may persist but is variable in the late dynamic and delayed phases. These lesions show diffuse glutamine synthetase expression from upregulation, although they may be heterogenous. This is in contradistinction to FNH, which show map-like glutamine synthetase expression distribution adjacent to hepatic veins.38 Unclassified HCAs have no specific genetic or histopathologic abnormalities. Similarly, no specific imaging features have been identified for these lesions. Traditionally, HCAs are expected to be hypointense on the hepatobiliary phase when using hepatocyte-specific contrast agent, in contrast to FNHs, which retain the same contrast agent and appear iso- to hyperintense.40 Iso/hyperintense uptake by FNH has been shown to correlate to expression of hepatocyte proteins such as OATPB1/B3.41 Nevertheless, increasing studies have noted the retention of hepatocyte-specific contrast in a small proportion of adenomas, particularly the b-HCA subtype.42 This is thought to be explained by the expression of hepatocyte transport proteins such as OATPB1/B3 that can be seen in b-HCAs.41 The majority of adenomas do not display OATPB1/B3 expression, however, and the evaluation of

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

B

C

D

219

FIGURE 14.5  Focal nodular hyperplasia (FNH). A, Precontrast T1-weighted image demonstrates a mildly T1 hypointense lesion in the right lobe of liver (arrow). B, Arterial-phase T1-weighted sequence shows that the mass is diffusely hyperenhancing (arrow). C, Portal venous phase demonstrates mild persisting hyperenhancement of the FNH (arrow). D, Postcontrast hepatobiliary phase imaging shows retention of hepatocyte specific contrast, with mild hyperintensity of the FNH relative to the liver (arrow).

hepatocyte-specific contrast uptake in a lesion remains helpful in the differentiation of FNH from adenoma, when an HCA has low signal in the delayed hepatobiliary phase.40 Care should also be taken in the interpretation of perceived retention of hepatocyte-specific contrast in some lesions, which may instead be explained by inherent hyperintensity on precontrast T1 imaging because of the presence of blood products or relative to underlying hepatic parenchymal steatosis.42

Angiomyolipoma and Other Benign Fat-Containing Hepatic Tumors Angiomyolipoma Hepatic angiomyolipoma (HAML) is an uncommon tumor and is seen more frequently in women. HAML is generally considered a benign, solitary tumor made up of three elements: smooth muscle, thick-walled blood vessels, and mature adipose tissue.43 HAML imaging features may vary based on the relative proportions of the three elements within a lesion, which makes this lesion often challenging to diagnose on imaging.43 Although intralesional fat is typical in HAMLs, they can often show brisk, avidly enhancing soft tissue components with washout, which can overlap with other liver malignancies, such as HCC (see Chapter 89), and some lesions may present without

detectable fat (Fig. 14.8).44 Tortuous vessels and enlarged early draining veins to either portal veins or hepatic veins are features that have been associated with HAML.43–46 Intralesional hemorrhage may be seen in a small proportion of cases.44 At US, HAMLs are typically well-demarcated, echogenic lesions, similar in appearance to hemangiomas. On CT, intralesional fat is evidenced by fat density tissue (, 220 HU). On MRI, the signal characteristics of macroscopic lipid follow that of subcutaneous fat and demonstrate signal drop out on T1-weighted and T2-weighted fat-saturated sequences. Microscopic fat can also be seen in HAML, seen as signal drop-out on out-of-phase compared with in-phase T1-weighted images.46 Enhancement on multiphase CT and MRI is typically a heterogeneous pattern of hyperenhancement on arterial phase with washout on portal venous or delayed phase; however, gradual and prolonged enhancement may also be observed.43 Peripheral rim enhancement caused by peripheral tumor vessels may also be seen, a feature which the reader must be careful not to misdiagnose as a tumor capsule typically seen in a HCC.43,44 On contrast-enhanced images using gadoxetic acid, HAMLs typically appear hypointense on delayed hepatobiliary phase.46 In summary, if a well-demarcated, hypervascular, macroscopic fat-containing tumor is seen with peripheral enhancement, if it has no tumor capsule, and if there are early draining

220

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D

E

F

FIGURE 14.6  Adenoma. A–B, In- and out-of-phase T1-weighted imaging shows background hepatic steatosis with diffusely decreased signal intensity of the hepatic parenchyma on out of phase imaging. A mass in segment 4 is isointense to liver parenchyma on in phase imaging and relatively hyperintense on out of phase because of background steatosis (arrows). An adjacent smaller adenoma is also visualized (arrowhead). C, The mass is minimally hyperintense to hepatic parenchyma on fat saturated T2-weighted. D, Arterial-phase T1-weighted sequence demonstrates diffuse hyperenhancement. E, Portal venous phase image shows the mass fades to isointensity to background liver. F, Delayed-phase image using hepatobiliary contrast demonstrates the lesions do not retain contrast (arrows).

veins, an angiomyolipoma should be considered, particularly in patients without cirrhosis.

Myelolipoma Hepatic myelolipoma is a rare benign tumor containing mature adipose and myeloid tissue in varying degrees, with only a handful of published case reports in the medical literature.47 Imaging features reflect the tumor composition with heterogenous enhancement of myelogenous components and regions of macroscopic fat appearing as low attenuating fat density tissue on CT and signal intensity identical to subcutaneous fat on T1-weighted and T2-weighted sequences.

Lipoma Hepatic lipomas are composed entirely of mature adipose tissue with expected imaging features, including echogenic lesions on US, density values consistent with fat on CT, and following the signal intensity of subcutaneous fat on all sequences on MRI. Lipomas show minimal to no enhancement on CT or MRI, distinguishing them from other fat-containing lesions in the liver.48

Hepatic Peliosis Hepatic peliosis (also called peliosis hepatis) is a rare benign vascular disorder characterized by sinusoidal dilatation and numerous blood-filled spaces within the liver. The size of the lesions typically vary from 1 mm to several centimeters.49 Numerous etiologies have been associated with hepatic peliosis, such as drugs (ocular cicatricial pemphigoid [OCP], corticosteroids, chemotherapy), infection (leprosy, tuberculosis [TB]), underlying systemic disease (diabetes mellitus, hematologic disorders), immunocompromised status (acquired immunodeficiency syndrome [AIDS], post-transplant) and toxins (arsenic, thorium oxide).

Nevertheless, up to 50% of cases are idiopathic.49 US imaging may demonstrate hyperechoic lesions on a background of normal liver parenchyma or hypoechoic lesions in a steatotic liver. Posterior acoustic enhancement may be seen.50 On CEUS, a transient “fast surge” of central enhancement has been described.50 On nonenhanced CT, lesions are usually hypodense to liver and rarely hyperdense secondary to hemorrhage. Calcifications within peliotic lesions have also been described.49 On MRI, lesions are typically iso- or mildly hypointense on T1-weighted and hyperintense on T2-weighted imaging.51 T1-weighted hyperintense foci may also be seen, representing hemorrhage. Postcontrast multiphase imaging on CT and MRI typically shows arterial hyperenhancement with globular central enhancement, termed the “target sign,” and corresponds to the “fast surge” of central enhancement seen at CEUS.49,52 Enhancing lesions tend to demonstrate a centrifugal enhancement pattern on successive phases of postcontrast imaging, with persistent hyperenhancement.49 Some lesions may become isoattenuating or isointense on later phases of imaging, and small lesions may not be detected at all by CT because of their size.53 Other lesions may not show any enhancement because of the presence of thrombosis. On the hepatobiliary phase of imaging, lesions may have ill-defined margins and demonstrate low signal intensity.51 Lesions of hepatic peliosis typically do not demonstrate mass effect on adjacent hepatic vessels, unlike other liver tumors.53

Cystic Liver Lesions (see Chapters 72 and 73) Hepatic Cysts Simple hepatic or biliary cysts are common benign liver lesions and have no malignant potential. They are usually diagnosed incidentally and are almost always asymptomatic. Simple cysts

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

B

C

D

221

FIGURE 14.7  Adenoma. A–B, In- and out-of-phase imaging shows a mass that is isointense on in-phase imaging, which demonstrates diffuse loss of signal on out-of-phase imaging consistent with intratumoral fat content. C, Precontrast fat-saturated T1-weighted imaging shows the lesion to be hypointense relative to liver parenchyma because of fat content. D, Arterial-phase T1-weighted imaging demonstrates faint arterial enhancement (arrows).

increase in prevalence with age, with the majority of incidental cysts seen in those greater than 60 years of age.4 Certain diseases are associated with the presence of numerous hepatic cysts, such as autosomal dominant polycystic kidney disease, polycystic liver disease, and von Hippel-Lindau (Fig. 14.9).54 Simple cysts typically demonstrate imaging characteristics of an uncomplicated fluid-filled structure across all imaging modalities. On ultrasound, the cyst is typically anechoic and well-circumscribed, with either a round or slightly lobular contour, and has no perceptible wall.55 Cysts typically demonstrate posterior acoustic enhancement, which describes increased echoes of the structures seen distal to the cyst because of easier transmission of US waves through the fluid-filled cyst relative to adjacent organ tissue. Occasionally, thin internal septa may be seen. On CT, a cyst is homogenously hypoattenuating relative to background liver. At MRI, cysts are homogenously T1 hypointense and markedly T2 hyperintense, similar to CSF. Cysts do not enhance on postcontrast imaging.54 Complications such as cyst rupture, intracystic hemorrhage, or biliary obstruction are rare but may occur in large cysts.56 Intracystic hemorrhage is manifest by internal echoes and/or thickened septa on US, density higher than that of simple fluid on CT (.20 HU), and hyperintense signal on T1-weighted MR sequences.

Polycystic Liver Disease Polycystic liver disease (PLD) is characterized by the presence of multiple fluid-filled liver cysts, arbitrarily defined as greater than 20 cysts.57 Ultrasound is recommended in the initial evaluation and in the diagnosis of PLD, and the lesions will appear as simple or minimally complex cysts as previously described (see “Hepatic Cysts”). Cysts can vary in size from 1 mm to more than 12 cm. The role of CT or MRI is mostly to enable classification of disease severity or to evaluate for intracystic or volume-related complications. Volumetric studies can be performed using semi-automated software that allows for postprocessing and liver segmentation of acquired CT or MRI to estimate height-adjusted total liver volume (htTLV). The greater the htTLV, the greater the disease severity.58

Biliary Hamartoma Biliary hamartomas, also known as von Meyenburg complex, are benign tumors composed of small, dilated biliary structures lined by bland biliary epithelium and often containing inspissated bile. Tumors are usually small, measuring less than 1 cm in size.59 On US, hamartomas may be hyperechoic, hypoechoic, or mixed echogenicity, and a comet-tail artifact (linear, tapering

222

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D

FIGURE 14.8  Angiomyolipoma. A, T1-weighted in-phase image shows a high-signal right hepatic mass (arrow). B, T1-weighted out-of-phase image shows low signal at its margin because of chemical shift artifact between the mass and surrounding liver, confirming the presence of bulk fat. C, Axial T2-weighted image with fat saturation shows the mass is dark, similar to subcutaneous fat. D, Axial T1-weighted fat saturation image shows the mass is dark as well.

trail of echoes just distal to a strongly reflective surface) may be seen. On CT, multiple, small, hypoattenuating nodules are usually seen diffusely throughout the liver. These lesions typically have a more ill-defined margin, compared with simple liver cysts, which are well defined. These lesions typically do not demonstrate enhancement on CT,60 but they can be hard to distinguish from metastatic disease when small. On MRI, lesions are hypointense on T1-weighted imaging and markedly hyperintense on T2-weighted imaging. The appearance of these numerous lesions on heavily T2-weighted imaging, such as MR cholangiopancreatography (MRCP), has been likened to a “starry sky” (Fig. 14.10). Communication with the bile ducts is typically not seen.61 Endocystic mural nodules are also a feature, better seen on MRI than on CT, and are isointense on T1-weighted and intermediate signal on T2-weighted imaging, giving an irregular lesion contour.62 These nodules demonstrate enhancement on contrast-enhanced MRI.63 Thin, peripheral enhancement has also been described, although it was attributed to enhancement of adjacent, compressed liver parenchyma.63 Differential diagnoses for the presence of numerous

tiny cystic-appearing lesions include hepatic microabscesses, metastases, peribiliary cysts, and Caroli disease. The lack of communication with the biliary system helps differentiate biliary hamartomas from Caroli disease.

Caroli Disease Caroli disease is a congenital autosomal recessive disease that results in multifocal, saccular, or fusiform dilatation of large intrahepatic bile ducts, which may be diffuse or segmental. Caroli syndrome is the term used when Caroli disease and congenital hepatic fibrosis coexist. In the Todani classification of biliary cysts, Caroli disease is classified as Type V (see Chapter 46).64 The dilated ducts may measure up 5 cm in size and contain sludge or calculi.65 The lesions appear cystic on US, CT, and MRI. On contrast-enhanced imaging, Caroli disease often shows fibrovascular bundles with strong enhancement within focally dilated biliary ducts. This appearance has been termed the “central dot sign” and corresponds to a portal vein branch or portal radicle that protrudes into the lumen of the dilated duct.66 MRCP can demonstrate saccular or fusiform cystic foci

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

223

B

FIGURE 14.9  Hepatic cysts associated with polycystic kidney disease. A, Axial T2-weighted image at the level of the kidneys shows bilaterally enlarged kidneys with multiple hyperintense cysts. Little normal renal parenchyma is present at this level, and multiple small hepatic cysts (arrow) are seen. B, Coronal T2-weighted images through the kidneys show similar findings of enlarged kidneys containing multiple cysts (black arrows), and small hepatic cysts are identified (white arrow).

that are in communication with the biliary tree. Occasionally, filling defects may be seen that represent intraluminal calculi. Hepatocyte-specific MRI contrast agents can also be used to demonstrate communication with the biliary tree.55

Biliary Cystadenoma Biliary cyst adenoma (BCA) is a rare, slow-growing neoplasm arising from the bile ducts, with a strong predilection to occur in middle-aged women (see Chapter 88B).67 BCA was reclassified

FIGURE 14.10  Biliary hamartoma. Coronal magnetic resonance cholangiopancreatography (MRCP) maximum intensity projection (MIP) of the liver demonstrates numerous tiny T2 hyperintense bile duct hamartomas scattered throughout the hepatic parenchyma, resembling a “starry sky.”

as a mucinous cystic neoplasm (MCN) of the liver according to the 2010 World Health Organization (WHO) classification, but for the purposes of this chapter, it will be referred to as BCA because this term is still mostly in use. Although generally benign, these lesions are considered to be premalignant and have the potential to develop into biliary cystadenocarcinoma (BCAC) in up to 20% to 30% of cases.67 BCAs are more often solitary cystic lesions and seen within the left hepatic lobe.67 Sonographically, BCA may be multilocular, with cystic locules demonstrating different echogenicities, depending on cyst fluid content. They may have mural nodularity, nodular thickened septations, papillary excrescences, and mural or septal calcifications.67–69 CEUS typically demonstrates a honeycomb pattern of enhancement of the cyst septations and mural nodules, with hyperenhancement more likely to be seen in the arterial phase.70 Although CEUS is useful to demonstrate intratumoral vascularity, there are no significant differences in enhancement patterns between BCA and BCAC.71 US is more sensitive than CT in the detection of intracystic septations; however, CT offers a more accurate depiction of cyst size and anatomic location.69 On CT, BCAs are predominantly low attenuating, with density values measuring that of fluid (,20 HU) and tend to be multiloculated with internal septations or mural nodules. The density of loculated cyst fluid can vary, depending on its content, and may be hemorrhagic, mucinous, proteinaceous, or bilious. Rarely, they may be unilocular, and minimally complex lesions on CT may be difficult to differentiate from simple hepatic cysts. Occasionally, upstream or downstream biliary ductal dilatation may be seen in BCA, a feature that is rare in simple hepatic cysts.72 Mural calcification can occur rarely.73 On MRI, the lesions may be of low, intermediate, or increased signal on T1-weighted images, again depending on cyst fluid content. Proteinaceous or hemorrhagic material are typically hyperintense in signal on T1-weighted imaging and fluidfluid levels may be seen in the presence of internal hemorrhage.74 BCAs are usually hyperintense on T2-weighted sequences (Fig. 14.11).

224

PART 2  DIAGNOSTIC TECHNIQUES

m

A

B

m

C FIGURE 14.11  Biliary cystadenoma. A, Coronal T2-weighted image shows a lobulated mass (m) in close proximity to the left hepatic duct (arrowhead). B, Projection image in the coronal oblique plane shows the well-defined hyperintense mass to be in continuity with a mildly dilated left-sided biliary radicle (straight arrow). The normal right-sided biliary radicle (curved arrow) is easily seen with this technique. C, Postcontrast, T1-weighted gradient-echo image shows no enhancement within this mass (m).

Contrast-enhanced imaging typically demonstrates enhancement of septa and mural nodules. Intracystic debris in a hemorrhagic cyst can mimic mural nodules, and care should be taken to ensure true nodule enhancement has occurred by examining precontrast and postcontrast series.72 Communication with the biliary ductal system on delayed hepatobiliary phase imaging with hepatocyte-specific contrast agents has been reported, helping to differentiate these tumors from non-neoplastic, simple hepatic cysts.75 Infectious cysts may also communicate with the biliary tree, however.

Hepatic Abscess and Infection (see Chapters 11, 70, 71) A hepatic abscess is an inflammatory collection in the liver from a bacterial (pyogenic), parasitic, or fungal infection. CT is generally the modality of choice in recent postoperative or at-risk patients in whom there is a clinical suspicion of a hepatic pyogenic abscess. Patients with more atypical symptoms may present a diagnostic dilemma. Although some patients show symptoms suggesting abscesses, others do not. Abscesses are found more frequently in the right lobe of liver.76 On US, pyogenic abscesses can vary in appearance and may even appear solid, particularly if infected with Klebsiella pneumoniae. More

often, they appear cystic, with debris and thickened septations. There is typically absence of internal Doppler signal, but the abscess wall is usually vascular.77 The CT appearances of pyogenic abscesses can vary widely. They may appear as small, low-attenuating, well-defined masses and may be widely scattered or clustered with a tendency to coalesce (Fig. 14.12). The appearance of coalesced smaller abscesses into a larger multiloculated abscess has been called the “cluster sign.”78 Larger abscesses may range in appearance from unilocular cystic cavities with smooth outer margins to highly complex and septated structures with internal debris and irregular conforms. The attenuation value of the abscess cavity depends on the age of the abscess; it becomes lower as the abscess matures. Intralesional gas may be present, either in the form of gas bubbles or an air-fluid level, and can be a feature of up to 20% of abscesses.77 Other associated features include pneumobilia and thrombophlebitis.55 On MRI, pyogenic abscesses are hyperintense on T2-weighted images. A peripheral rim of signal hyperintensity indicating perilesional edema may also be seen surrounding the abscess wall. Pyogenic abscesses are generally hypointense on T1-weighted images, unless they have hemorrhagic or proteinaceous debris

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

225

B

FIGURE 14.12  Hepatic abscess. A–B, Postcontrast axial and coronal computed tomography (CT) demonstrating low attenuating, irregularly lobulated mass in the central right hepatic lobe (arrows). Smaller, discrete cystic lesions are seen within this region, which are tending to coalesce into adjacent larger lesions, a feature that can be seen in some hepatic abscesses called the “cluster sign.”

within them, in which case they will appear hyper- or isointense. If gas is present, it typically manifests as signal voids on all sequences, which is more pronounced on T1-weighted in-phase gradient echo sequences because of greater magnetic susceptibility.77 In the case of K. pneumoniae infection, the “turquoise sign” has been described, which refers to the presence of hypointense, thin, septal bands on T2-weighted images that resemble the turquoise mineral.77 Abscesses typically have thick walls that enhance after administration of contrast material on either CT or MRI. The central, pus-filled portion does not enhance. A “double target” sign may be seen, which describes the presence of hepatic parenchymal enhancement peripheral to the enhancing wall, secondary to increased capillary permeability.55 The imaging findings of abscesses can overlap with malignancies, although some features on postcontrast imaging can suggest abscess over tumor. On multiphase imaging, arterial rim enhancement that persists into portal venous or transitional phase is typical for abscesses, compared with arterially rim-enhancing malignant lesions that fade or wash out by the portal venous or transitional phase.79,80 Perilesional hyperemia and patchy liver parenchymal enhancement may also be frequently seen in abscesses.80 On the delayed hepatobiliary phase using hepatocyte-specific contrast, the periphery of the abscess is low in signal, corresponding to damaged hepatocytes.81 A significant size discrepancy between the measurable lesion on precontrast T1-weighted images and hepatobiliary phase images is therefore more frequently observed in abscesses than in tumors.79 DWI may be a valuable tool in differentiating hepatic abscesses from malignancy. The abscess periphery typically shows “T2-shine through” (i.e., high b-value on DWI and ADC) compared with malignant tumors, which typically demonstrate peripheral diffusion restriction.81 Conversely, central abscess pus-filled cavities demonstrate diffusion restriction.82 Hydatid or echinococcal cysts (EC) occur because of infection with a parasite called Echinococcus granulosus ingested through contaminated food (see Chapter 72). EC is most commonly seen in the right hepatic lobe and imaging appearances vary depending on the stage of the cyst.83 EC have a variable appearance on ultrasound and may appear as simple fluid-filled cysts. However, the cyst wall usually has a hypoechoic layer bordered by an echogenic line on each side, representing the

layers of the cyst membrane; inner germinal and acellular laminated layers (the endocyst) and outer, fibrous layer (the pericyst). Multiple floating, internal echoes may also be seen, especially on repositioning the patient, which are termed “hydatid sand” and represent parasite larva called protoscolices. Detachment of the endocyst from the pericyst can result in characteristic imaging appearances on US, CT, and MRI. A localized split resembles “floating membranes” within the cyst, and a complete membrane detachment has been called the “water lily” sign.84 The membrane is hyperattenuating relative to mother cyst fluid on CT and hypointense on T2-weighted imaging. Some cysts are multivesicular in appearance, containing daughter cysts or cysts-within-a-cyst. These clustered daughter cysts can also produce a “spoke-wheel” pattern. Numerous daughter cysts, along with detached membranes and hydatid sand, can make the cyst appear as a solid mass on US.83 On CT, daughter cysts are seen as small hypodense, peripheral foci within the mother cyst because they are usually lower in density than the mother cyst fluid.55 A proportion of EC may have partial or complete pericystic rim calcification and/or calcification of internal septa (Fig. 14.13).85 As healing progresses, all components within the cyst generally become more densely calcified. Partial calcification does not always indicate parasite death; however, it is implied when complete calcification occurs.85 Superinfection may complicate hydatid cysts, particularly if there has been membrane disruption and/or intrabiliary cyst rupture. The cysts appear less well-defined and may demonstrate air-fluid levels. Postcontrast imaging typically shows cyst rim-enhancement and perilesional hypervascularity.84 Other complications of EC include mass effect on adjacent structures and cyst rupture into the biliary tree or into adjacent viscera.84 Fungal microabscesses generally manifest in immunocompromised patients as numerous tiny abscesses disseminated throughout the liver. The classical imaging finding on US describes the “bull’s eye” appearance of a round hyperechoic lesion with a hypoechoic rim. An additional hypoechoic central focus can occasionally be present and give a “wheels-within-wheels” appearance.86 Most commonly, however, abscesses appear as small, nonspecific, hypoechoic nodules.77 On contrast-enhanced CT, fungal abscesses are small, hypodense lesions, ranging from several millimeters to 1.5 cm in size. The “bulls-eye” appearance

226

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 14.13  Echinococcal cyst. A, Postcontrast portal venous phase axial computed tomography (CT) demonstrating two complex cystic liver masses in the left and right lobes. The right lobe mass contains small daughter cysts, resulting in a cyst within a cyst appearance (asterisk). B, Postcontrast portal venous phase coronal CT of the same cyst demonstrating thin, partial rim calcification of the pericyst.

*

A

B

C

D

FIGURE 14.14  Fungal abscesses. A, Postcontrast portal venous phase axial computed tomography (CT) demonstrating only subtle hyperenhancement in the peripheral right lobe of liver (asterisk). No obvious lesion is discernable. B, Axial fat-saturated T2-weighted magnetic resonance imaging (MRI) at the same level reveals clustered, ill-defined T2 hyperintense lesions consistent with microabscesses with surrounding parenchymal edema (arrow). Also note the diffusely decreased signal of the hepatic and splenic parenchyma, consistent with transfusional hemosiderosis in this patient with a history of leukemia. C, Axial postcontrast T1-weighted images in the arterial phase demonstrating peri-abscess hyperemic change (arrowhead). D, Axial postcontrast T1-weighted images in portal venous phase shows persistent abscess and peri-abscess parenchymal enhancement (arrow).

on CT appears as a small, high-attenuation focus centrally surrounded by a low-attenuating zone. Authors have reported significant increase in sensitivity and lesion conspicuity using arterial-phase CT, compared with portal venous phase CT, when evaluating liver lesions in immunocompromised patients suspected to have hepatosplenic fungal infections (Fig. 14.14).

The addition of an arterial phase may also yield additional imaging findings that would support an infective etiology, such as transient hepatic parenchymal hyperemia.87 On MRI, the lesions are most conspicuous on T2-weighted sequences and are seen as hyperintense foci (see Fig. 14.14). Ring enhancement may be seen on early postcontrast phases, and the abscesses may also

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

227

A

B

C

FIGURE 14.15  Biloma. A, Postcontrast portal venous phase axial computed tomography (CT) in a patient with metastatic liver disease. In the right lobe, the patient has already undergone embolization, and a low attenuating fluid filled structure consistent with biloma is seen (asterisk). In the left lobe, an untreated low attenuating metastasis is also visualized (arrow). B, Postcontrast portal venous phase axial CT after left hepatic lobe embolization with a new fluid density lesion now seen at the site of the left lobe liver metastasis (arrow). C, Postcontrast portal venous phase coronal CT demonstrates communication of the cystic lesion with a mildly prominent bile duct (arrow) and is consistent with a biloma. Previously embolized right lobe metastasis is again seen on this image (asterisk).

show diffusion restriction.77 The MRI appearances of fungal abscesses varies as the infection evolves and with treatment. For example, in the early stages of infection and in the presence of neutropenia, the disease may be occult on MRI. The “dark ring” sign describes the emergence of susceptibility artifact (signal drop-out) at T1-weighted gradient echo imaging, such as inphase images, and corresponds to iron accumulation in macrophages at the periphery of the abscess in patients on antifungal treatment.55,88

Ciliated Hepatic Foregut Duplication Cyst A ciliated hepatic foregut duplication cyst (CHFC) is a rare congenital hepatic cystic lesion that develops secondary to embryonic foregut cell migration, and although it is considered a benign entity, it carries a risk for transformation into squamous cell carcinoma. CHFC is typically solitary, most commonly located in the subcapsular segment 4, and typically measures less than 3 cm in size.89,90 Imaging appearances are nonspecific. CHFC is typically hypoechoic or anechoic on US. It is usually hyperdense on CT because of its thick mucoid content. On MRI, hyperintensity on T2-weighted images is typical; however, T1-weighted signal intensity can vary depending on cyst fluid content. It does not demonstrate enhancement on contrast administration.90,91

be subtle in the acute setting, manifest by nonspecific small peri- or intrahepatic fluid collections or ascites. Follow-up imaging demonstrating an enlarging cystic fluid collection should increase suspicion for a biliary leak.92 In the postsurgical setting, distinguishing between a biliary leak and other postprocedural collections is not reliable by these modalities. Hepatobiliary scintigraphy using technetium-99m-labeled iminodiacetic acid demonstrates physiologic biliary excretion and, although it can be used to demonstrate the presence of an active biliary leak, its inherent poor spatial resolution limits the precise identification of the bile leak location. Although ERCP can be performed to identify the exact location of the biliary leak, it is nonetheless an invasive procedure with significant potential complications and is therefore usually reserved for nonsurgical therapeutic management (see Chapter 12). MRCP performed without contrast is useful in the diagnosis of bile leaks, and the addition of hepatobiliary-specific contrast material results in a reliable diagnostic technique that provides functional information on the biliary tree.92,93 The diagnosis of a biliary leak is achieved by demonstrating the presence of biliary contrast extravasation on delayed hepatobiliary phase postcontrast imaging.94

MALIGNANT TUMORS

Biloma

Hepatocellular Carcinoma (see Chapter 89)

A biloma is an encapsulated collection of bile outside of the biliary tree. It may occur secondary to trauma, spontaneously, or represent an iatrogenic complication after an interventional procedure or liver surgery (see Chapter 11; Fig. 14.15). Bilious fluid has the same density as water on imaging and both US and CT can reliably demonstrate the presence of loculated fluid within or around the liver. Post-traumatic bile duct injuries may

HCC is the most common primary hepatic malignancy worldwide. The most significant risk factors include the presence of cirrhosis and infection with hepatitis B and C viruses. Approximately 80% of HCC tumors develop in cirrhotic livers. The diffusely heterogenous, multinodular parenchyma in cirrhotic livers can increase the difficulty in distinguishing focal hepatic lesions on imaging (Fig. 14.16).95,96 These nodules represent a

228

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 14.16  Liver with cirrhotic configuration. A, T1-weighted spin-echo image at the level of the portal vein shows hypertrophy of the left lobe and caudate with atrophy of the right lobe of the liver. B, T2-weighted image of the liver at the same level shows mildly heterogeneous signal in the atrophied right lobe. Note also the focal hepatic scarring (arrow).

spectrum, from regenerative or dysplastic nodules to HCC. The American Association for the Study of Liver Diseases (AASLD) issued revised recommendations in 2018, recommending US imaging every 6 months, with or without serum a-fetoprotein (AFP), as the recommended modality used to screen for HCC in at-risk patients.97 When used as a surveillance test, US has a sensitivity of around 63%.98 On US, HCC tumors are often nonspecific in appearance and may be hypo- or hyperechoic.99 CEUS has been shown to be useful in the diagnosis of HCC, particularly in small HCCs less than 2 cm in size, where it has a sensitivity and specificity of 0.81 and 0.86, respectively.100 However, current AASLD guidelines do not recommend CEUS as a diagnostic tool. Subsequent diagnostic evaluation should be performed with multiphase CT or MRI, both demonstrating similar diagnostic cabilities.97,101 The additional advantage of MRI compared with CT in the evaluation of HCC is that malignancies show differences in signal intensity, diffusion, blood pool, and functional hepatocyte enhancement and growth, compared with regenerative or dysplastic nodules or background cirrhotic parenchyma. MRI also has an advantage over other modalities in assessing vascular invasion. The enhancement patterns at multiphasic CT and MRI using extracellular agents are essentially the same, and the hallmark pattern is that of arterial-phase hyperenhancement with washout appearance in the portal venous or delayed phase (Fig. 14.17). Washout refers to the reduction in enhancement of the tumor relative to background liver parenchyma.102 In addition to washout, peritumoral capsules, which are low in signal intensity on the arterial dominant phase and enhance later, are an important feature and their absence has been associated with microvascular invasion.103 If using hepatocyte-specific contrast agents, assessment of washout is confined to the portal venous phase and should not be characterized in the transitional or hepatobiliary phases.104 When using hepatocytespecific contrast agents, HCC tumors generally show hypointensity in the delayed hepatobiliary phase of imaging compared with surrounding liver in the majority of cases. Hepatocytespecific contrast agents have been shown to be more sensitive in the detection of small HCCs or premalignant lesions than extracellular agents.105,106 On other MRI sequences, HCC is generally hypointense on T1-weighted and mild to moderately hyperintense on

T2-weighted imaging.107 HCC with intracellular fat can be detected by signal loss on out-of-phase imaging (Fig. 14.18). Fat is associated with early HCC and can also be seen in dysplastic nodules.108 Intracellular lipid may be an important clue to small HCCs, especially those without typical enhancement patterns, because early HCC are sometimes hypovascular in the arterial phase.109,110 Larger lesions may be heterogenous because of areas of necrosis. An infiltrative appearance has been associated with more aggressive subtypes, as does the presence of macrovascular invasion.111 Because of the complexity of imaging features and overlap, as well as multimodality availability, there have been organized efforts to improve report standardization and communication regarding imaging findings in patients at risk for HCC. The Liver Imaging Reporting and Data System (LI-RADS), an initiative supported by the American College of Radiology, and the Liver and Intestinal Organ Transplant Committee (OPTN) have also issued guidelines regarding HCC classification. LI-RADS was revised in 2018 to facilitate integration of the diagnostic algorithm into the AASLD 2018 HCC clinical practice guidelines. The 2018 diagnostic algorithm describes a four-step approach to the assessment of liver lesions at multiphase CT or MRI in the untreated high-risk population for HCC.102 The algorithm is intended for use only in patients who are considered high risk for HCC and are without histologic diagnosis or have undergone previous treatment. As a result LI-RADS categories are designed to have high specificity but at the expense of sensitivity.112 Major features that are seen in HCC include non-rim arterial-phase hyperenhancement (the presence of this feature is mandatory for LR-5 categorization), non-peripheral “washout,” enhancing “capsule,” and threshold growth. Ancillary features favoring HCC include nodule-innodule or mosaic appearance, intralesional fat or blood products, and are also incorporated into the LI-RADS imaging interpretation algorithm (https://www.acr.org/Clinical-Resources/ Reporting-and-Data-Systems/LI-RADS/CT-MRI-LI-RADSv2018; Fig. 14.19). A separate category of LR-TIV (tumor in vein) is assigned for observations that are definitely malignant, with unequivocal enhancing soft tissue in vein. Although tumor in vein is most frequently associated with HCC, it is not exclusive to HCC, with macrovascular invasion also seen in other non-HCC liver tumors, such as intrahepatic cholangiocarcinoma (Fig. 14.20).113 Although continued revisions are inevitable,

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

B

C

D

229

FIGURE 14.17  Hepatocellular carcinoma. A, Precontrast axial computed tomography (CT) image demonstrating a lesion that is mildly hypointense to background liver containing scattered areas of hyperattenuation suggestive of blood products (arrowheads). B, Late arterial-phase enhancement demonstrates heterogenous non-rim arterial enhancement of the mass (arrows). C–D, Portal venous and delayed phase imaging respectively demonstrating progressive washout appearance with capsule, best appreciated on delayed phase (arrows).

A

B

FIGURE 14.18  Hepatocellular carcinoma containing intracellular lipid. A, T1-weighted in-phase gradient-echo image shows a mass in the liver that is darker than normal parenchyma, with a small internal area of brighter signal (arrow). B, T1-weighted out-of-phase gradient-echo image shows the same area (arrow) has lost signal, which is consistent with an admixture of fat and water-containing tissue.

230

PART 2  DIAGNOSTIC TECHNIQUES

m m

A

B

FIGURE 14.19  Large hepatocellular carcinoma showing a mosaic pattern. A, T1-weighted image shows a large heterogeneous mass (m) in the liver. Note the hypertrophied left hepatic lobe and caudate. B, T2-weighted image also shows the mass (m) to be heterogeneous, with islands of tissue that are hyperintense with respect to other portions of the same mass. This pattern is known as the mosaic pattern, and it can be seen in hepatocellular carcinoma, especially when the lesion is large.

consensus guidelines will encourage report standardization, improve communication, and ultimately improve decision making. Agreement among readers using newer algorithms tends to be moderate to substantial for expert readers but lower among novices, suggesting implementation of these criteria may require a learning curve.113–115

Intrahepatic Cholangiocarcinoma (see Chapter 50) Intrahepatic cholangiocarcinomas (IHCCs) account for approximately 10% of biliary duct cancers, and the majority of these are of the peripheral, mass-forming subtype.116 A less common intrahepatic subtype is the periductal-infiltrating type, which appears as thickened bile duct walls and longitudinal tumor extension along the bile ducts. Intrahepatic intraductalgrowth types are rare and usually present as a small intraluminal papillary tumor within a dilated bile duct.117 Increasingly, mass-forming IHCCs are seen to arise on a background of cirrhosis, making distinguishing these lesions from HCC difficult on imaging.118 On US, IHCC may present as a focal hepatic mass, which may be solitary or with satellite lesions, and may appear hypoor hyperechoic. The number of tumors present has been shown to be a significant prognostic indicator, with multiple lesions associated with a poorer outcome.119 Diagnostic workup and staging generally involves modalities such as CT and MRI. CT angiography with multiphase imaging offers improved spatial resolution and similar accuracy to MRI to assess vascular involvement and exceeds MRI accuracy when assessing for nodal and distant metastases.120 On CT, IHCC is usually low-attenuating on noncontrast imaging. The precontrast phase is useful for the detection of intraductal stones and differentiating stones from tumor.121 Capsular retraction and peripheral biliary ductal dilatation have also been described as features, but are not seen in every case.117 On MRI, IHCC generally have low T1-signal intensity, high heterogenous T2 signal, and lobulated margins. Enhancement patterns are similar on both multiphase contrast-enhanced CT and MRI using extracellular contrast agents, with tumors often showing peripheral enhancement in the arterial phase and

gradual centripetal fill-in on delayed phases because of the central abundant fibrous stroma.121,122 The initial rim of arterial enhancement, representing viable tumor cells histologically, is typically continuous and can demonstrate washout on later phases of imaging (Fig. 14.21).123 Non-rim arterial enhancement may be seen in smaller lesions, particularly in cirrhotic livers, and can therefore appear similar to small HCCs, making imaging diagnosis difficult.118 Caution should be used in the interpretation of images using hepatocyte-specific contrast, such as gadoxetic acid, since a “pseudo-washout” appearance can be seen on the later transitional phase of imaging because of the progressive enhancement of background liver, which can also mimic the appearance of HCC.124 The presence of washout should therefore be assessed only on the portal venous phase of hepatocyte-specific contrast agents to avoid misidentification of this feature. On hepatobiliary phase, a target appearance has also been described, which is represented by a rim of hypointensity and central “cloud-like” hyperintensity.121 The presence of a target sign on DWI has also been described in IHCC, which refers to a rim of hyperintensity and central low intensity on high b-value images and a rim of hypointensity on the corresponding ADC map, again reflecting peripheral hypercellular tumor cells and central fibrous stroma.125 A targetoid appearance of a liver lesion on DWI or postcontrast imaging in a patient at risk for HCC is sufficient to classify that lesion as LI-RADS M. Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary hepatic malignancy with both HCC and IHCC components and, accordingly, can mimic either HCC or IHCC, with imaging features more frequently overlapping with IHCC.126 One study showed that 6.5% of cHCC-CC can be misclassified as HCC, even when using LI-RADS criteria,127 and diagnosis is more challenging in smaller lesions.113

Fibrolamellar Carcinoma (see Chapter 89) Originally considered within the HCC spectrum and formerly termed “fibrolamellar HCC,” this malignant hepatocellular tumor’s distinct clinical, pathologic, and imaging features have led to the newer nomenclature. Fibrolamellar carcinoma (FLC)

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

TR LIVER RT

A

231

Long PV

B Long PV

.20

.20 PV

C

D

FIGURE 14.20  Hepatocellular carcinoma (HCC) with portal vein thrombosis. A, Transverse image shows a hypoechoic HCC in the right hepatic lobe (arrows). B, Transverse image of the main portal vein reveals only a trickle of blood flow (arrow). The lumen is nearly filled with echogenic thrombus. C, Longitudinal image of the main portal vein shows the extent of thrombus (arrow). D, Color Doppler image of the main portal vein confirms arterial flow (arrow) within the hypoechoic thrombus; this is pathognomonic for tumor thrombus. PV, Portal vein.

occurs in young adults, average age of presentation is 25 years, and it occurs in the absence of cirrhosis or risk factors for liver disease.128,129 It frequently presents as a large, well-demarcated, solitary mass with a mean diameter of greater than 11 cm, and a central scar can be seen in 46% to 73% of cases.130,131 A common diagnostic dilemma for radiologists is to distinguish FLC from either FNH or conventional HCC, both of which can present as a large solitary mass with a central scar. Metastatic disease is common at presentation in FLC, both in the abdomen and chest, with adenopathy being prominent in a majority of cases.129,130 On US, appearances are variable and nonspecific, occasionally showing calcifications and a central hyperechoic scar.132 There is little literature published on its appearance at CEUS. On unenhanced CT, FLH usually appears as a large, hypoattenuating, solitary mass with well-defined lobular margins and a central low-attenuating scar. Calcification, a finding that is used to help differentiate this lesion from FNH, can be seen

in 43% to 64% of cases, and when seen is typically associated with a central scar.129–131 On MRI, FLC is frequently low on T1-weighted and high on T2-weighted imaging.130,133 The central scar, if present, tends to be low in signal on T1-weighted and T2-weighted images because of fibrous changes. This is a distinguishing characteristic from FNH, in which if a central scar is present, it is typically increased in T2 signal. However, some FLC central scars can also show increased T2 signal. Therefore, the presence of increased T2 signal is not a reliable discriminator.130 A scar that is low in T2 signal, on the other hand, is seldom seen in FNH and should raise the suspicion for FLC (Fig. 14.22). FLCs usually show more heterogenous enhancement on arterial phase on either CT or MRI, compared with FNH. Imaging findings are more variable on later phases, with regions of washout sometimes demonstrated.131,133 The central scar tends not to enhance on portal venous and later phases of postcontrast imaging, in contrast to FNH scars, which typically do.

232

PART 2  DIAGNOSTIC TECHNIQUES

A

B

*

C

D

FIGURE 14.21  Mass forming intrahepatic cholangiocarcinoma. A, T1-weighted in-phase gradient-echo image shows a peripheral hypointense mass. B, T1-weighted fat saturation postcontrast-enhanced image in late arterial phase shows peripheral enhancement. C, T1-weighted postcontrastenhanced image in portal venous phase shows only partial filling of the mass. D, T1-weighted postcontrast-enhanced image in equilibrium phase shows progressive central filling of the mass representing central fibrous stroma (asterisk) and washout of the peripheral rim of viable tumor cells (arrow).

A

B

FIGURE 14.22  Fibrolamellar carcinoma. A, Precontrast axial CT image demonstrates a solitary mass in the right lobe of the liver (curved arrows). Clustered punctate foci of calcification is noted centrally (arrow). B, Portal venous phase postcontrast imaging demonstrates an enhancing mass (curved arrows). A central low attenuating scar (arrow) is visible and corresponds to the region of central punctate calcification, more easily apparent on precontrast imaging.

However, FLC scar enhancement on delayed phase has been described in a small proportion of cases.130,131 Partial uptake may be seen on hepatobiliary phase of imaging using hepatocytespecific contrast agents; FLC nonetheless typically remains hypointense relative to background liver.133

Epithelioid Hemangioendothelioma Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular origin and is considered to be a low-to-intermediate grade malignancy with variable clinical behavior (see Chapter 87). HEH tumors are typically multifocal and located in the peripheral, subcapsular regions of the liver.134 As the disease

progresses, these nodules tend to coalesce to appear as a large infiltrative, peripheral liver mass. Capsular retraction is also frequently observed in HEH.134,135 On US, discrete nodules of variable echogenicity may be seen or the liver may have a diffusely heterogenous echotexture in regions of coalesced tumor involvement.136 On noncontrast CT, central low density change and capsular retraction are frequently seen, with occasional central calcification also reported.137 Postcontrast features seen on both CT and MRI include arterial ring-like enhancement and target-like enhancement on portal venous phase.134,135,137 The target sign typically refers to the target appearance of the lesion on T2-weighted imaging, with a central core of high

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

A

C

233

B

D

E

FIGURE 14.23  Epithelioid hemangioendothelioma. A, Fat saturated T2-weighted axial image demonstrating multiple liver lesions in a peripheral, subcapsular distribution (arrows). The lesions are centrally T2 hyperintense (asterisk) with a surrounding halo of lower signal intensity, likened to a “target” appearance. B, Fat saturated T1-weighted axial image demonstrates a corresponding low T1 signal intensity (arrows). The surrounding halo is very slightly higher in intensity on T1-weighted imaging. C–E, Postcontrast images in the late arterial, portal venous, and equilibrium phases demonstrate arterial ring-like enhancement with more of a target-like enhancement pattern on later phases of imaging. A portal vein branch is seen extending towards the tumor with abrupt termination at the tumor margin, which has been likened to a “lollipop” in appearance. The vessel represents the lollipop stick (arrowhead).

signal, representing fibrosis stroma, surrounded by a rim of low-signal intensity, reflecting proliferating tumor cells. A mildly hyperintense halo may also be seen in the presence of an avascular rim because of invasion of hepatic sinusoids and small vessels by tumor cells. This target-like appearance may also be seen on DWI, on nonenhanced T1-weighted images, and on postcontrast hepatobiliary phase using hepatocytespecific contrast.134,135,138 Although usually diffusely low in signal on nonenhanced T1-weighted imaging, a small proportion of HEH lesions demonstrate low central signal intensity surrounded by a thin hyperintense ring and a peripheral low signal halo, which has also been called the “T1-weighted-darkbright-dark ring sign.”135 In the case of postcontrast hepatobiliary phase imaging, HEH may have a central hypointense core surrounded by a rim of mild signal intensity, also described as a “core pattern.”139 The “lollipop” sign refers to the presence of a hepatic vein or portal vein branch (the stick) extending towards the tumor (the candy of the lollipop) and then terminating at the margin or just within the lesion rim because of the vessel branch occlusion.140 It can be seen in up to half of cases of HEH and, when seen, is considered a characteristic finding (Fig. 14.23).137

Hepatic Angiosarcoma and Other Mesenchymal Tumors Primary hepatic angiosarcoma (HAS) is a rare but aggressive hepatic malignancy, with a median survival reported as less than 6 months. It has been associated with a variety of environmental exposures, most notably, thorium dioxide (Thorotrast), arsenic, and radiation exposure.45 When arising in the setting of thorium dioxide exposure, thorium deposition can be seen

as high-attenuating foci within the liver, perihepatic lymph nodes, and spleen. Underlying cirrhosis is often present (see Chapter 87).141 On US, HAS is usually heterogeneously hyperechoic, reflecting its vascular origin.141 On nonenhanced CT, HAS most commonly presents as either multiple, bilobar masses, one of which is usually dominant, or as a solitary mass.141,142 Because of the tumor’s vascular nature, tumor heterogeneity with multiple regions of mixed attenuation or foci with fluid-fluid levels may be seen, representing intratumoral hemorrhage.45,143 On MRI, HAS is typically high in T2 signal and low in T1 signal. Hemorrhagic foci within the lesion will demonstrate increased T1-weighted signal. On postcontrast imaging on either CT or MRI, HAS enhancement on multiphase imaging tends to follow that of blood pool, although the pattern of enhancement can be highly variable, including nodular, rim, branching, or diffuse patterns. Heterogenous arterial enhancement is typically seen, although regions of hyperenhancement are typically small relative to tumor size.141 Washout is typically not seen, and its absence can be a helpful factor in distinguishing HAS from HCC.141 In a proportion of cases, enhancement patterns resemble that of hemangiomas to a varying degree, such as the presence of centripetal fill-in (Fig 14.24).142,144 “Reverse hemangioma” centrifugal pattern has also been described in a number of cases.141 Splenic metastases are common and, if present, offer a clue to the diagnosis of HAS. A proportion of cases may present with capsular rupture and subcapsular hematoma and hemoperitoneum. Other rarer tumors of mesenchymal origin include leiomyosarcoma, fibrosarcoma, Kaposi sarcoma, and solitary fibrous

234

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

FIGURE 14.24  Hepatic angiosarcoma. A, Precontrast axial computed tomography (CT) image demonstrates scattered areas of vague liver heterogeneity (arrows). B–C, Postcontrast imaging in the arterial and portal venous phase respectively demonstrates the full extent of a dominant, heterogeneously enhancing mass replacing most the right the hepatic lobe (arrows). The irregular tumoral enhancement is similar to that of blood pool with progressive, centripetal enhancement on the later portal venous phase. A smaller mass is also seen in the left lobe of liver (arrowhead).

tumor (previous called “hemangiopericytoma”). The imaging features of these tumors are nonspecific on US, CT, and MRI. On MRI they are generally of low signal intensity on T1weighted images and hyperintense on T2-weighted images, with heterogenous enhancement.145,146 Undifferentiated embryonal sarcoma (UES) is usually seen in the pediatric population; however, cases have been reported in the adult population. These tumors tend to have extensive cystic and necrotic change and may be mistaken for hepatic abscesses or other cystic liver masses.147 Discrepancy between a predominantly solid appearance on US, and cystic appearance on CT has been described as a classical feature of UES.145

Primary Hepatic Lymphoma Primary hepatic lymphoma (PHL) is a rare hepatic tumor and refers to liver-confined lymphoma without involvement of lymph nodes, bone marrow, spleen, or other lymphomatous structures. In order of frequency, PHL may present as a solitary mass, multiple lesions, or a diffuse infiltrative process, with the most common imaging manifestation of a solitary mass seen in about 60% of cases.148,149 When multiple lesions are present, typically one of these lesions is dominant.150 In contrast, multiple lesions without a dominant mass or an infiltrative pattern are the main

A

imaging appearances seen in lymphoma with secondary involvement of the liver (SHL).150 SHL is relatively easier to diagnose because of concomitant involvement of other organs, especially spleen and generalized lymphadenopathy. On US, lesions are typically hypoechoic with case reports of lesions appearing anechoic and mimicking cysts. Nevertheless, absence of posterior acoustic enhancement should hint as to the presence of a solid lesion.149,151 PHL is typically hypoattenuating on CT.149 On MRI, an “insinuative” growth pattern has been described, which is shown by tumor growth without displacement of hepatic vessels or biliary ducts.148 This appearance has also been described as the “vessel penetration sign.”151 Lesions are typically homogenously T1 hypointense and T2 hyperintense; however, signal intensity may be heterogenous in the presence of blood products or necrosis.149 Postcontrast imaging on both CT and MRI demonstrate variable, nonspecific appearances, typically heterogeneously enhancing, but hypoattenuating or hypointense relative to background liver on multiphase imaging (Fig. 14.25). Arterial and portal venous rim enhancement can be seen in a proportion of cases.148,149 Restricted diffusion is typically seen, with one study noting that ADC values were significantly lower in PHL when compared with both benign liver lesions and other primary hepatic lesions.148

B

FIGURE 14.25  Primary hepatic lymphoma. A–B, Computed tomography (CT) axial and coronal contrast-enhanced images in the portal venous phase shows a large, solitary mass in the liver, with rather nonspecific features and demonstrating heterogeneous enhancement, hypoattenuating relative to background liver.

  Chapter 14  Imaging Features of Benign and Malignant Liver Tumors and Cysts

Imaging characteristics of lymphoma, however, are nonspecific and overlap with other malignant hepatic lesions.

Biliary Cystadenocarcinoma Biliary cystadenocarcinoma (BCAC) is a rare neoplasm arising from the bile ducts. BCAC is usually a result of malignant transformation of BCA; however, it can also arise de novo (see Chapter 88B).55 Imaging features of BCAC overlap with BCA and although the presence of “high-risk” features such

235

as mural nodularity, solid components, septations, and papillary excrescences have a high negative predictive value of 91%, the positive predictive value is low at 11%. Tumor size is also a poor discriminator of BCAC from BCA.67 Mural nodules greater than 1 cm in size are more likely to occur in BCAC, however.71 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

235.e1

REFERENCES 1. Khalil HI, Patterson SA, Panicek DM. Hepatic lesions deemed too small to characterize at CT: prevalence and importance in women with breast cancer. Radiology. 2005;235(3):872-878. 2. Wnorowski AM, Cook TS, Lalevic D, Langer JE, Zafar HM. Outcome of liver lesions indeterminate for malignancy on ultrasound: the role of patient age, risk status, and lesion echogenicity. Abdom Radiol (NY). 2018;43(11):2970-2979. 3. Albiin N. MRI of focal liver lesions. Curr Med Imaging Rev. 2012; 8(2):107-116. 4. Kaltenbach TE, Engler P, Kratzer W, et al. Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients. Abdom Radiol (NY). 2016;41(1):25-32. 5. Ito H, Tsujimoto F, Nakajima Y, et al. Sonographic characterization of 271 hepatic hemangiomas with typical appearance on CT imaging. J Med Ultrason (2001). 2012;39(2):61-68. 6. Marrero JA, Ahn J, Rajender Reddy K, Americal College of G. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014;109(9):1328-1347; quiz 1348. 7. Leifer DM, Middleton WD, Teefey SA, Menias CO, Leahy JR. Follow-up of patients at low risk for hepatic malignancy with a characteristic hemangioma at US. Radiology. 2000;214(1):167-172. 8. Caturelli E, Castellano L, Fusilli S, et al. Coarse nodular US pattern in hepatic cirrhosis: risk for hepatocellular carcinoma. Radiology. 2003;226(3):691-697. 9. Liu LP, Dong BW, Yu XL, Liang P, Zhang DK, An LC. Focal hypoechoic tumors of Fatty liver: characterization of conventional and contrast-enhanced ultrasonography. J Ultrasound Med. 2009;28(9): 1133-1142. 10. Kim KW, Kim MJ, Lee SS, et al. Sparing of fatty infiltration around focal hepatic lesions in patients with hepatic steatosis: sonographic appearance with CT and MRI correlation. AJR Am J Roentgenol. 2008;190(4):1018-1027. 11. Whitney WS, Herfkens RJ, Jeffrey RB, et al. Dynamic breath-hold multiplanar spoiled gradient-recalled MR imaging with gadolinium enhancement for differentiating hepatic hemangiomas from malignancies at 1.5 T. Radiology. 1993;189(3):863-870. 12. Miller FH, Hammond N, Siddiqi AJ, et al. Utility of diffusionweighted MRI in distinguishing benign and malignant hepatic lesions. J Magn Reson Imaging. 2010;32(1):138-147. 13. Caseiro-Alves F, Brito J, Araujo AE, et al. Liver haemangioma: common and uncommon findings and how to improve the differential diagnosis. Eur Radiol. 2007;17(6):1544-1554. 14. Wilson SR, Burns PN. Microbubble-enhanced US in body imaging: What role? Radiology. 2010;257(1):24-39. 15. Mamone G, Di Piazza A, Carollo V, et al. Imaging of hepatic hemangioma: from A to Z. Abdom Radiol (NY). 2020;45(3):672-691. 16. Kim B, Byun JH, Kim HJ, et al. Enhancement patterns and pseudowashout of hepatic haemangiomas on gadoxetate disodium-enhanced liver MRI. Eur Radiol. 2016;26(1):191-198. 17. Prasanna PM, Fredericks SE, Winn SS, Christman RA. Best cases from the AFIP: giant cavernous hemangioma. Radiographics. 2010; 30(4):1139-1144. 18. Stoupis C, Taylor HM, Paley MR, et al. The Rocky liver: radiologic-pathologic correlation of calcified hepatic masses. Radiographics. 1998;18(3):675-685; quiz 726. 19. Ridge CA, Shia J, Gerst SR, Do RK. Sclerosed hemangioma of the liver: concordance of MRI features with histologic characteristics. J Magn Reson Imaging. 2014;39(4):812-818. 20. Hwang JA, Kang TW, Cha DI, Kim SH, Ha SY, Kim SW. Differentiation of hepatic sclerosed hemangiomas from cavernous hemangiomas based on gadoxetic acid-enhanced magnetic resonance imaging features. J Comput Assist Tomogr. 2019;43(5):762-769. 21. Do RK, Shaylor SD, Shia J, et al. Variable MR imaging appearances of focal nodular hyperplasia in pediatric cancer patients. Pediatr Radiol. 2011;41(3):335-340. 22. Hussain SM, Terkivatan T, Zondervan PE, et al. Focal nodular hyperplasia: findings at state-of-the-art MR imaging, US, CT, and pathologic analysis. Radiographics. 2004;24(1):3-17; discussion 18-19. 23. Grazioli L, Ambrosini R, Frittoli B, Grazioli M, Morone M. Primary benign liver lesions. Eur J Radiol. 2017;95:378-398. 24. Mortele KJ, Praet M, Van Vlierberghe H, Kunnen M, Ros PR. CT and MR imaging findings in focal nodular hyperplasia of the liver:

radiologic-pathologic correlation. AJR Am J Roentgenol. 2000;175(3): 687-692. 25. Bioulac-Sage P, Balabaud C, Wanless IR. Diagnosis of focal nodular hyperplasia: not so easy. Am J Surg Pathol. 2001;25(10):1322-1325. 26. Rousseau C, Ronot M, Vilgrain V, Zins M. Optimal visualization of focal nodular hyperplasia: quantitative and qualitative evaluation of single and multiphasic arterial phase acquisition at 1.5 T MR imaging. Abdom Radiol (NY). 2016;41(5):990-1000. 27. Marin D, Brancatelli G, Federle MP, et al. Focal nodular hyperplasia: typical and atypical MRI findings with emphasis on the use of contrast media. Clin Radiol. 2008;63(5):577-585. 28. Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. AJR Am J Roentgenol. 2000;174(3):705-712. 29. Karam AR, Shankar S, Surapaneni P, Kim YH, Hussain S. Focal nodular hyperplasia: central scar enhancement pattern using Gadoxetate Disodium. J Magn Reson Imaging. 2010;32(2):341-344. 30. Bioulac-Sage P, Taouji S, Possenti L, Balabaud C. Hepatocellular adenoma subtypes: the impact of overweight and obesity. Liver Int. 2012;32(8):1217-1221. 31. Bioulac-Sage P, Laumonier H, Couchy G, et al. Hepatocellular adenoma management and phenotypic classification: The Bordeaux experience. Hepatology. 2009;50(2):481-489. 32. Flejou JF, Barge J, Menu Y, et al. Liver adenomatosis. An entity distinct from liver adenoma? Gastroenterology. 1985;89(5):1132-1138. 33. Bioulac-Sage P, Sempoux C, Balabaud C. Hepatocellular adenoma: classification, variants and clinical relevance. Semin Diagn Pathol. 2017;34(2):112-125. 34. Garcovich M, Faccia M, Meloni F, et al. Contrast-enhanced ultrasound patterns of hepatocellular adenoma: an Italian multicenter experience. J Ultrasound. 2019;22(2):157-165. 35. Katabathina VS, Menias CO, Shanbhogue AK, Jagirdar J, Paspulati RM, Prasad SR. Genetics and imaging of hepatocellular adenomas: 2011 update. Radiographics. 2011;31(6):1529-1543. 36. Bise S, Frulio N, Hocquelet A, et al. New MRI features improve subtype classification of hepatocellular adenoma. Eur Radiol. 2019; 29(5):2436-2447. 37. van Aalten SM, Thomeer MG, Terkivatan T, et al. Hepatocellular adenomas: correlation of MR imaging findings with pathologic subtype classification. Radiology. 2011;261(1):172-181. 38. Grazioli L, Olivetti L, Mazza G, Bondioni MP. MR imaging of hepatocellular adenomas and differential diagnosis dilemma. Int J Hepatol. 2013;2013:374170. 39. Nault JC, Couchy G, Balabaud C, et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology. 2017;152(4):880-894. e886. 40. Grieser C, Steffen IG, Kramme IB, et al. Gadoxetic acid enhanced MRI for differentiation of FNH and HCA: a single centre experience. Eur Radiol. 2014;24(6):1339-1348. 41. Sciarra A, Schmidt S, Pellegrinelli A, et al. OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy. Liver Int. 2019; 39(1):158-167. 42. Reizine E, Ronot M, Pigneur F, et al. Iso- or hyperintensity of hepatocellular adenomas on hepatobiliary phase does not always correspond to hepatospecific contrast-agent uptake: importance for tumor subtyping. Eur Radiol. 2019;29(7):3791-3801. 43. Cai PQ, Wu YP, Xie CM, Zhang WD, Han R, Wu PH. Hepatic angiomyolipoma: CT and MR imaging findings with clinicalpathologic comparison. Abdom Imaging. 2013;38(3):482-489. 44. Zhu Z, Yang L, Zhao XM, Luo DQ, Zhang HT, Zhou CW. Myomatous hepatic angiomyolipoma: imaging findings in 14 cases with radiological-pathological correlation and review of the literature. Br J Radiol. 2014;87(1038):20130712. 45. Choi HH, Manning MA, Mehrotra AK, Wagner S, Jha RC. Primary hepatic neoplasms of vascular origin: key imaging features and differential diagnoses with radiology-pathology correlation. AJR Am J Roentgenol. 2017;209(6):W350-W359. 46. Lee SJ, Kim SY, Kim KW, et al. Hepatic angiomyolipoma versus hepatocellular carcinoma in the noncirrhotic liver on gadoxetic acid-enhanced MRI: a diagnostic challenge. AJR Am J Roentgenol. 2016;207(3):562-570. 47. Xin H, Li H, Yu H, Zhang J, Peng W, Peng D. MR imaging to detect myelolipomas of the liver: a case report and literature review. Medicine. 2019;98(29):e16497.

235.e2 48. Costa AF, Thipphavong S, Arnason T, Stueck AE, Clarke SE. Fatcontaining liver lesions on imaging: detection and differential diagnosis. AJR Am J Roentgenol. 2018;210(1):68-77. 49. Iannaccone R, Federle MP, Brancatelli G, et al. Peliosis hepatis: spectrum of imaging findings. AJR Am J Roentgenol. 2006;187(1): W43-W52. 50. Kleinig P, Davies RP, Maddern G, Kew J. Peliosis hepatis: central “fast surge” ultrasound enhancement and multislice CT appearances. Clin Radiol. 2003;58(12):995-998. 51. Han NY, Park BJ, Sung DJ, et al. Chemotherapy-induced focal hepatopathy in patients with gastrointestinal malignancy: gadoxetic acid—enhanced and diffusion-weighted MR imaging with clinicalpathologic correlation. Radiology. 2014;271(2):416-425. 52. Iwata T, Adachi K, Takahashi M. Peliosis hepatis mimicking malignant hypervascular tumors. J Gastrointest Surg. 2017;21(6): 1095-1098. 53. Elsayes KM, Shaaban AM, Rothan SM, et al. A comprehensive approach to hepatic vascular disease. Radiographics. 2017;37(3): 813-836. 54. Anderson SW, Kruskal JB, Kane RA. Benign hepatic tumors and iatrogenic pseudotumors. Radiographics. 2009;29(1):211-229. 55. Borhani AA, Wiant A, Heller MT. Cystic hepatic lesions: a review and an algorithmic approach. AJR Am J Roentgenol. 2014;203(6): 1192-1204. 56. Lantinga MA, Gevers TJ, Drenth JP. Evaluation of hepatic cystic lesions. World J Gastroenterol. 2013;19(23):3543-3554. 57. Gevers TJ, Drenth JP. Diagnosis and management of polycystic liver disease. Nat Rev Gastroenterol Hepatol. 2013;10(2):101-108. 58. van Aerts RMM, van de Laarschot LFM, Banales JM, Drenth JPH. Clinical management of polycystic liver disease. J Hepatol. 2018; 68(4):827-837. 59. Torbenson MS. Hamartomas and malformations of the liver. Semin Diagn Pathol. 2019;36(1):39-47. 60. Luo TY, Itai Y, Eguchi N, et al. Von Meyenburg complexes of the liver: imaging findings. J Comput Assist Tomogr. 1998;22(3): 372-378. 61. Giambelluca D, Caruana G, Cannella R, Lo Re G, Midiri M. The starry sky liver: multiple biliary hamartomas on MR cholangiopancreatography. Abdom Radiol (NY). 2018;43(9):2529-2530. 62. Zheng RQ, Kudo M, Onda H, et al. Imaging findings of biliary hamartomas (von Meyenburg complexes). J Med Ultrason (2001). 2005;32(4):205. 63. Tohme-Noun C, Cazals D, Noun R, Menassa L, Valla D, Vilgrain V. Multiple biliary hamartomas: magnetic resonance features with histopathologic correlation. Eur Radiol. 2008;18(3):493-499. 64. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases, including cancer arising from choledochal cyst. Am J Surg. 1977;134(2):263-269. 65. Mamone G, Cortis K, Sarah A, Caruso S, Miraglia R. Hepatic morphology abnormalities: beyond cirrhosis. Abdom Radiol (NY). 2018;43(7):1612-1626. 66. Choi BI, Yeon KM, Kim SH, Han MC. Caroli disease: central dot sign in CT. Radiology. 1990;174(1):161-163. 67. Arnaoutakis DJ, Kim Y, Pulitano C, et al. Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor. Ann Surg. 2015;261(2):361-367. 68. Soares KC, Arnaoutakis DJ, Kamel I, et al. Cystic neoplasms of the liver: biliary cystadenoma and cystadenocarcinoma. J Am Coll Surg. 2014;218(1):119-128. 69. Choi BI, Lim JH, Han MC, et al. Biliary cystadenoma and cystadenocarcinoma: CT and sonographic findings. Radiology. 1989;171(1): 57-61. 70. Dong Y, Wang WP, Mao F, et al. Contrast enhanced ultrasound features of hepatic cystadenoma and hepatic cystadenocarcinoma. Scand J Gastroenterol. 2017;52(3):365-372. 71. Xu HX, Lu MD, Liu LN, et al. Imaging features of intrahepatic biliary cystadenoma and cystadenocarcinoma on B-mode and contrastenhanced ultrasound. Ultraschall Med. 2012;33(7):E241-E249. 72. Kim HJ, Yu ES, Byun JH, et al. CT differentiation of mucinproducing cystic neoplasms of the liver from solitary bile duct cysts. AJR Am J Roentgenol. 2014;202(1):83-91. 73. Patnana M, Menias CO, Pickhardt PJ, et al. Liver calcifications and calcified liver masses: pattern recognition approach on CT. AJR Am J Roentgenol. 2018;211(1):76-86.

74. Lewin M, Mourra N, Honigman I, et al. Assessment of MRI and MRCP in diagnosis of biliary cystadenoma and cystadenocarcinoma. Eur Radiol. 2006;16(2):407-413. 75. Billington PD, Prescott RJ, Lapsia S. Diagnosis of a biliary cystadenoma demonstrating communication with the biliary system by MRI using a hepatocyte-specific contrast agent. Br J Radiol. 2012; 85(1010):e35-e36. 76. Serraino C, Elia C, Bracco C, et al. Characteristics and management of pyogenic liver abscess: a European experience. Medicine. 2018;97(19):e0628. 77. Bachler P, Baladron MJ, Menias C, et al. Multimodality imaging of liver infections: differential diagnosis and potential pitfalls. Radiographics. 2016;36(4):1001-1023. 78. Jeffrey Jr RB, Tolentino CS, Chang FC, Federle MP. CT of small pyogenic hepatic abscesses: the cluster sign. AJR Am J Roentgenol. 1988;151(3):487-489. 79. Choi SY, Kim YK, Min JH, Cha DI, Jeong WK, Lee WJ. The value of gadoxetic acid-enhanced MRI for differentiation between hepatic microabscesses and metastases in patients with periampullary cancer. Eur Radiol. 2017;27(10):4383-4393. 80. Oh JG, Choi SY, Lee MH, et al. Differentiation of hepatic abscess from metastasis on contrast-enhanced dynamic computed tomography in patients with a history of extrahepatic malignancy: emphasis on dynamic change of arterial rim enhancement. Abdom Radiol (NY). 2019;44(2):529-538. 81. Park HJ, Kim SH, Jang KM, Lee SJ, Park MJ, Choi D. Differentiating hepatic abscess from malignant mimickers: value of diffusionweighted imaging with an emphasis on the periphery of the lesion. J Magn Reson Imaging. 2013;38(6):1333-1341. 82. Chan JH, Tsui EY, Luk SH, et al. Diffusion-weighted MR imaging of the liver: distinguishing hepatic abscess from cystic or necrotic tumor. Abdom Imaging. 2001;26(2):161-165. 83. Pakala T, Molina M, Wu GY. Hepatic echinococcal cysts: a review. J Clin Transl Hepatol. 2016;4(1):39-46. 84. Greco S, Cannella R, Giambelluca D, et al. Complications of hepatic echinococcosis: multimodality imaging approach. Insights Imaging. 2019;10(1):113. 85. Pedrosa I, Saiz A, Arrazola J, Ferreiros J, Pedrosa CS. Hydatid disease: radiologic and pathologic features and complications. Radiographics. 2000;20(3):795-817. 86. Pastakia B, Shawker TH, Thaler M, O’Leary T, Pizzo PA. Hepatosplenic candidiasis: wheels within wheels. Radiology. 1988;166(2): 417-421. 87. Metser U, Haider MA, Dill-Macky M, Atri M, Lockwood G, Minden M. Fungal liver infection in immunocompromised patients: depiction with multiphasic contrast-enhanced helical CT. Radiology. 2005;235(1):97-105. 88. Kelekis NL, Semelka RC, Jeon HJ, Sallah AS, Shea TC, Woosley JT. Dark ring sign: finding in patients with fungal liver lesions and transfusional hemosiderosis undergoing treatment with antifungal antibiotics. Magn Reson Imaging. 1996;14(6):615-618. 89. Ziogas IA, van der Windt DJ, Wilson GC, et al. Surgical management of ciliated hepatic foregut cyst. Hepatology. 2020;71(1):386-388. 90. Ambe C, Gonzales-Cuyar L, Farooqui S, Hanna N, Cunningham SC. Ciliated hepatic foregut cyst: 103 cases in the world literature. Open J Pathol. 2012;2:45-49. 91. Boumoud M, Daghfous A, Maghrebi H, et al. Imaging features of ciliated hepatic foregut cyst. Diagn Interv Imaging. 2015;96(3): 301-303. 92. Melamud K, LeBedis CA, Anderson SW, Soto JA. Biliary imaging: multimodality approach to imaging of biliary injuries and their complications. Radiographics. 2014;34(3):613-623. 93. Hoeffel C, Azizi L, Lewin M, et al. Normal and pathologic features of the postoperative biliary tract at 3D MR cholangiopancreatography and MR imaging. Radiographics. 2006;26(6):1603-1620. 94. Alegre Castellanos A, Molina Granados JF, Escribano Fernandez J, Gallardo Munoz I, Trivino Tarradas Fde A. Early phase detection of bile leak after hepatobiliary surgery: value of Gd-EOB-DTPAenhanced MR cholangiography. Abdom Imaging. 2012;37(5):795-802. 95. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022. 96. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2005; 19(1):3-23.

235.e3 97. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. 98. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37-47. 99. Caturelli E, Pompili M, Bartolucci F, et al. Hemangioma-like lesions in chronic liver disease: diagnostic evaluation in patients. Radiology. 2001;220(2):337-342. 100. Niu Y, Huang T, Lian F, Li F. Contrast-enhanced ultrasonography for the diagnosis of small hepatocellular carcinoma: a meta-analysis and meta-regression analysis. Tumour Biol. 2013;34(6):3667-3674. 101. Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology. 2018;67(1):401-421. 102. Elsayes KM, Kielar AZ, Elmohr MM, et al. White paper of the Society of Abdominal Radiology hepatocellular carcinoma diagnosis disease-focused panel on LI-RADS v2018 for CT and MRI. Abdom Radiol (NY). 2018;43(10):2625-2642. 103. Witjes CD, Willemssen FE, Verheij J, et al. Histological differentiation grade and microvascular invasion of hepatocellular carcinoma predicted by dynamic contrast-enhanced MRI. J Magn Reson Imaging. 2012;36(3):641-647. 104. Santillan C, Fowler K, Kono Y, Chernyak V. LI-RADS major features: CT, MRI with extracellular agents, and MRI with hepatobiliary agents. Abdom Radiol (NY). 2018;43(1):75-81. 105. Park MJ, Kim YK, Lee MW, et al. Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patterns. Radiology. 2012; 264(3):761-770. 106. Kobayashi S, Matsui O, Gabata T, et al. Relationship between signal intensity on hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging and prognosis of borderline lesions of hepatocellular carcinoma. Eur J Radiol. 2012;81(11):3002-3009. 107. Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part II. Extracellular agents, hepatobiliary agents, and ancillary imaging features. Radiology. 2014;273(1):30-50. 108. Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology. 2011;261(3):834-844. 109. Kutami R, Nakashima Y, Nakashima O, Shiota K, Kojiro M. Pathomorphologic study on the mechanism of fatty change in small hepatocellular carcinoma of humans. J Hepatol. 2000;33(2): 282-289. 110. Rhee H, Kim MJ, Park YN, Choi JS, Kim KS. Gadoxetic acidenhanced MRI findings of early hepatocellular carcinoma as defined by new histologic criteria. J Magn Reson Imaging. 2012; 35(2):393-398. 111. Taouli B, Hoshida Y, Kakite S, et al. Imaging-based surrogate markers of transcriptome subclasses and signatures in hepatocellular carcinoma: preliminary results. Eur Radiol. 2017;27(11): 4472-4481. 112. Ehman EC, Behr SC, Umetsu SE, et al. Rate of observation and inter-observer agreement for LI-RADS major features at CT and MRI in 184 pathology proven hepatocellular carcinomas. Abdom Radiol (NY). 2016;41(5):963-969. 113. Horvat N, Nikolovski I, Long N, et al. Imaging features of hepatocellular carcinoma compared to intrahepatic cholangiocarcinoma and combined tumor on MRI using liver imaging and data system (LI-RADS) version 2014. Abdom Radiol (NY). 2018;43(1):169-178. 114. Davenport MS, Khalatbari S, Liu PS, et al. Repeatability of diagnostic features and scoring systems for hepatocellular carcinoma by using MR imaging. Radiology. 2014;272(1):132-142. 115. Barth BK, Donati OF, Fischer MA, et al. Reliability, validity, and reader acceptance of LI-RADS-An in-depth analysis. Acad Radiol. 2016;23(9):1145-1153. 116. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755-762. 117. Seo N, Kim DY, Choi JY. Cross-sectional imaging of intrahepatic cholangiocarcinoma: development, growth, spread, and prognosis. AJR Am J Roentgenol. 2017;209(2):W64-W75.

118. Huang B, Wu L, Lu XY, et al. Small intrahepatic cholangiocarcinoma and hepatocellular carcinoma in cirrhotic livers may share similar enhancement patterns at multiphase dynamic MR imaging. Radiology. 2016;281(1):150-157. 119. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29(23):3140-3145. 120. Aljiffry M, Abdulelah A, Walsh M, Peltekian K, Alwayn I, Molinari M. Evidence-based approach to cholangiocarcinoma: a systematic review of the current literature. J Am Coll Surg. 2009;208(1): 134-147. 121. Joo I, Lee JM, Yoon JH. Imaging diagnosis of intrahepatic and perihilar cholangiocarcinoma: recent advances and challenges. Radiology. 2018;288(1):7-13. 122. Hennedige TP, Neo WT, Venkatesh SK. Imaging of malignancies of the biliary tract: an update. Cancer Imaging. 2014;14:14. 123. Fowler KJ, Brown JJ, Narra VR. Magnetic resonance imaging of focal liver lesions: approach to imaging diagnosis. Hepatology. 2011;54(6):2227-2237. 124. Kim R, Lee JM, Shin CI, et al. Differentiation of intrahepatic mass-forming cholangiocarcinoma from hepatocellular carcinoma on gadoxetic acid-enhanced liver MR imaging. Eur Radiol. 2016;26(6):1808-1817. 125. Park HJ, Kim YK, Park MJ, Lee WJ. Small intrahepatic massforming cholangiocarcinoma: target sign on diffusion-weighted imaging for differentiation from hepatocellular carcinoma. Abdom Imaging. 2013;38(4):793-801. 126. Fowler KJ, Sheybani A, Parker RA III, et al. Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI. AJR Am J Roentgenol. 2013;201(2):332-339. 127. Potretzke TA, Tan BR, Doyle MB, Brunt EM, Heiken JP, Fowler KJ. Imaging features of biphenotypic primary liver carcinoma (hepatocholangiocarcinoma) and the potential to mimic hepatocellular carcinoma: LI-RADS analysis of CT and MRI features in 61 cases. AJR Am J Roentgenol. 2016;207(1):25-31. 128. El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology. 2004;39(3):798-803. 129. Ganeshan D, Szklaruk J, Kundra V, Kaseb A, Rashid A, Elsayes KM. Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol. 2014;202(3):544-552. 130. Do RK, McErlean A, Ang CS, DeMatteo RP, Abou-Alfa GK. CT and MRI of primary and metastatic fibrolamellar carcinoma: a case series of 37 patients. Br J Radiol. 2014;87(1040):20140024. 131. Ganeshan D, Szklaruk J, Kaseb A, Kattan A, Elsayes KM. Fibrolamellar hepatocellular carcinoma: multiphasic CT features of the primary tumor on pre-therapy CT and pattern of distant metastases. Abdom Radiol (NY). 2018;43(12):3340-3348. 132. Durot I, Wilson SR, Willmann JK. Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 2018;43(4):819-847. 133. Palm V, Sheng R, Mayer P, et al. Imaging features of fibrolamellar hepatocellular carcinoma in gadoxetic acid-enhanced MRI. Cancer Imaging. 2018;18(1):9. 134. Ganeshan D, Pickhardt PJ, Morani AC, et al. Hepatic hemangioendothelioma: CT, MR, and FDG-PET-CT in 67 patients-a biinstitutional comprehensive cancer center review. Eur Radiol. 2020;30:2435-2442. 135. Paolantonio P, Laghi A, Vanzulli A, et al. MRI of hepatic epithelioid hemangioendothelioma (HEH). J Magn Reson Imaging. 2014;40(3):552-558. 136. Lyburn ID, Torreggiani WC, Harris AC, et al. Hepatic epithelioid hemangioendothelioma: sonographic, CT, and MR imaging appearances. AJR Am J Roentgenol. 2003;180(5):1359-1364. 137. Zhou L, Cui MY, Xiong J, et al. Spectrum of appearances on CT and MRI of hepatic epithelioid hemangioendothelioma. BMC Gastroenterol. 2015;15:69. 138. Mamone G, Miraglia R. The “Target sign” and the “Lollipop sign” in hepatic epithelioid hemangioendothelioma. Abdom Radiol (NY). 2019;44(4):1617-1620. 139. Lee JH, Jeong WK, Kim YK, et al. Magnetic resonance findings of hepatic epithelioid hemangioendothelioma: emphasis on hepatobiliary phase using Gd-EOB-DTPA. Abdom Radiol (NY). 2017; 42(9):2261-2271.

235.e4 140. Alomari AI. The lollipop sign: a new cross-sectional sign of hepatic epithelioid hemangioendothelioma. Eur J Radiol. 2006;59(3): 460-464. 141. Pickhardt PJ, Kitchin D, Lubner MG, Ganeshan DM, Bhalla S, Covey AM. Primary hepatic angiosarcoma: multi-institutional comprehensive cancer centre review of multiphasic CT and MR imaging in 35 patients. Eur Radiol. 2015;25(2):315-322. 142. Yi LL, Zhang JX, Zhou SG, et al. CT and MRI studies of hepatic angiosarcoma. Clin Radiol. 2019;74(5):406.e401-406.e408. 143. Thomas AJ, Menias CO, Pickhardt PJ, et al. Bleeding liver masses: imaging features with pathologic correlation and impact on management. AJR Am J Roentgenol. 2019;2013:8-16. 144. Koyama T, Fletcher JG, Johnson CD, Kuo MS, Notohara K, Burgart LJ. Primary hepatic angiosarcoma: findings at CT and MR imaging. Radiology. 2002;222(3):667-673. 145. Thampy R, Elsayes KM, Menias CO, et al. Imaging features of rare mesenychmal liver tumours: beyond haemangiomas. Br J Radiol. 2017;90(1079):20170373.

146. Ehman EC, Torbenson MS, Wells ML, et al. Hepatic tumors of vascular origin: imaging appearances. Abdom Radiol (NY). 2018;43(8):1978-1990. 147. Gabor F, Franchi-Abella S, Merli L, Adamsbaum C, Pariente D. Imaging features of undifferentiated embryonal sarcoma of the liver: a series of 15 children. Pediatr Radiol. 2016;46(12):16941704. 148. Colagrande S, Calistri L, Grazzini G, et al. MRI features of primary hepatic lymphoma. Abdom Radiol (NY). 2018;43(9):2277-2287. 149. Maher MM, McDermott SR, Fenlon HM, et al. Imaging of primary non-Hodgkin’s lymphoma of the liver. Clin Radiol. 2001;56(4):295-301. 150. Tomasian A, Sandrasegaran K, Elsayes KM, Shanbhogue A, Shaaban A, Menias CO. Hematologic malignancies of the liver: spectrum of disease. Radiographics. 2015;35(1):71-86. 151. Rajesh S, Bansal K, Sureka B, Patidar Y, Bihari C, Arora A. The imaging conundrum of hepatic lymphoma revisited. Insights Imaging. 2015;6(6):679-692.

CHAPTER 15 Imaging features of metastatic liver cancer Galina Levin and Richard Kinh Gian Do OVERVIEW Imaging plays a central role in the characterization of liver lesions and detection of liver metastases in patients at risk. As treatment options for patients with metastatic liver disease have proliferated over the past decade (see Chapters 90–92), timely and accurate characterization of liver lesions is increasingly important. Several imaging modalities, such as ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI), can be used in the detection of hepatic metastases. The choice of imaging tests may vary greatly between different institutions based on availability, expertise, preferences of the referring physicians and radiologists, and unique patient factors (for example, MRI-unsafe implanted devices, claustrophobia, impaired renal function, and contrast allergies). Conventional US is the most widely available technique, but its sensitivity is significantly affected by patient factors, such as obesity, bowel interposition between the liver and abdominal wall, and shadowing artifact from excessive bowel gas. Although new US contrast agents have significantly increased the sensitivity of hepatic lesion detection,1,2 contrast-enhanced US (CEUS) is not yet widely available in the United States. According to the current National Comprehensive Cancer Network guidelines, PET/CT (positron-emission tomography/ CT) is recommended for the initial staging of only some newly diagnosed tumors, such as lung, esophageal, head and neck, cervical cancers and lymphoma. In tumors that frequently metastasize to the liver such as colorectal, pancreatic, and gastric cancers, PET/CT is not routinely recommended for the initial staging in most cases (see Chapter 18).3 According to the American College of Radiology (ACR) Appropriateness Criteria for presurgical assessment of suspected hepatic metastases, traditional US carries a rating of 3 (on a scale of 1 to 9 with 1, 2, and 3 denoting “usually not appropriate” and 7, 8, and 9 denoting “usually appropriate”). In comparison, MRI, CT, and PET/CT carry ratings of 9, 8, and 6, respectively. CT and MRI are currently the most widely used modalities for the initial detection and surveillance of metastatic liver lesions and for presurgical planning.4 The goal of this chapter is to review the imaging characteristics of hepatic metastases, to compare the strengths and weaknesses of various imaging modalities, and to highlight important pearls and pitfalls of image interpretation.

ULTRASOUND Background US has been used since the 1970s, and conventional US has unique advantages, such as low cost, lack of radiation, and 236

widespread availability. However, US is less sensitive than other imaging modalities for liver metastases. Experience and technique of the doctor or technician acquiring US images may also vary significantly. Some studies report sensitivity of US in detection of liver metastases to be as low as 38%.1 Although US contrast agents were introduced and used worldwide since the 1990s, United States Food and Drug Administration (FDA) approval of the first contrast agent for liver lesions in children and adults took place in 2015.5 CEUS uses microbubbles that enable the demonstration of tissue perfusion similar to contrast enhancement in CT and MRI, but with subtle differences. Numerous studies demonstrate increased sensitivity and specificity of CEUS compared with conventional US, with sensitivities ranging between 72% and 96% and specificities between 93% and 98%.2 For example, in a prospective study that evaluated detection of hepatic metastases with US, CEUS, and contrastenhanced CT (CECT) in 253 patients with suspected hepatic metastases from various primary malignancies, CEUS improved sensitivity from approximately 40% to 83% and specificity from 63% to 84%. The sensitivity and specificity of CECT in the same study was demonstrated to be 89% and 89%, respectively.6 According to the latest guidelines and good clinical practice recommendations for CEUS in the liver from 2012 that involved collaboration of multiple leading ultrasound societies worldwide, the indications for liver CEUS are the following7: • Incidental findings on conventional US • Lesion(s) or suspected lesion(s) detected with US in patients with a known history of a cancer, as an alternative to CT or MRI • Patients with contraindications to CT and MRI contrast administration • Inconclusive MRI/CT findings • Inconclusive biopsy results US contrast agents are not nephrotoxic and are safe for use in patients with renal failure and even dialysis. These contrast agents are also safe in patients with iodine contrast allergies. The overall rate of severe allergic reactions is lower compared with iodinated CT contrast and is comparable to magnetic resonance (MR) contrast agents.5,8

Imaging Findings Although most metastases are hypoechoic (darker) with respect to the underlying liver parenchyma (Fig. 15.1A–B), some metastases can also be isoechoic (similar to) and hyperechoic (brighter) to adjacent liver (Fig. 15.2A–B). Echogenicity of liver metastases can vary, based on primary tumor and based on the composition of underlying liver parenchyma that can be affected by hepatic steatosis, prior chemotherapy treatments, and other forms of liver disease. Thus primary (benign or malignant neoplasms) and metastatic liver lesions may have

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

RT LOBE LIVER SAG

TR

B

LT LOBE LIVER SAG

TR

237

FIGURE 15.1  Hypoechoic hepatic metastasis and a cyst in the same patient with breast cancer. A, Sagittal and transverse grey scale ultrasound images demonstrate a hypoechoic lesion (arrow) with a poorly defined, slightly irregular wall. B, Sagittal and transverse ultrasound images in the same patient demonstrate a simple cyst (arrow). Note the difference in echogenicity when compared with the metastasis. The cyst is anechoic (completely black) and has a thin, sharp wall.

LEFT LIVER TRANS

A

B

FIGURE 15.2  Hyperechoic metastases in a patient with metastatic neuroendocrine tumor. A, Grey-scale ultrasound image demonstrates two adjacent metastases (arrows) with markedly echogenic periphery and relatively hypoechoic center. B, Another metastasis in the same patient (arrow) is completely hyperechoic.

238

PART 2  DIAGNOSTIC TECHNIQUES

B

A

FIGURE 15.3.  Hemangiomas. A, Longitudinal sonogram of the right lobe shows a brightly echogenic hemangioma (arrow) with a circumscribed border. B, Atypical hemangioma (arrow) with areas of internal heterogeneity, a result of fibrosis or myxomatous degeneration, and a thin echogenic rim (arrowhead).

A

B

FIGURE 15.4  Hypoechoic halo sign. A, Ultrasound image demonstrates metastatic neuroendocrine tumor in the liver with a subtle peripheral hypoechoic halo B, Ultrasound image demonstrates focal lymphomatous involvement of the liver with a prominent hypoechoic halo (arrow).

similar US characteristics (Compare Fig. 15.2B with Fig. 15.3); for example, metastases and hemangiomas (see Chapter 88A) may both demonstrate hyperechoic appearance with respect to adjacent liver. A hypoechoic halo sign (bull’s eye sign) is a helpful way to distinguish benign from malignant lesions. This is a sign of difference in acoustic impedance along the periphery compared with the center of the lesion, which reflects parenchymal compression and active growth on pathologic correlation. Therefore the halo sign is usually indicative of an expansile, malignant mass, such as a metastasis or a primary hepatic neoplasm (Fig. 15.4).9

Liver metastases demonstrate variable enhancement when evaluated with the CEUS technique. The arterial phase imaging characteristics vary between no enhancement, rim enhancement, and diffuse hyperenhancement. There is rapid, complete washout on the portal venous phase (Fig. 15.5). In contrast, hepatocellular carcinoma (HCC) demonstrates a later washout, and benign lesions demonstrate minimal or absent washout. Cholangiocarcinoma (see Chapter 50) demonstrates rapid washout on CEUS (unlike on CT and MRI where it demonstrates progressive delayed enhancement) and, therefore, cannot be reliably distinguished from a metastasis.10

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

239

B

C FIGURE 15.5  Hepatic metastases evaluated with contrast-enhanced ultrasound. A, Gray-scale image reveals a hypoechoic mass (arrow) representing a metastasis. B, In the arterial portal phase after contrast injection, the liver metastases (arrows) have peripheral rim enhancement, and an additional lesion is now evident. C, The metastases (arrows) show complete washout of contrast in less than a minute; image taken at 54 seconds. (Courtesy Stephanie R. Wilson.)

Limitations and Pitfalls The quality of images is highly dependent on the operator’s skill and patient’s body habitus, with both traditional US and CEUS. Small lesions, particularly less than 0.5 cm, are usually not adequately visualized and characterized. Liver lesions subjacent to interposed bowel may be completely obscured by the shadowing artifact from air contained within bowel loops. Specific anatomic location also plays a role. For example, lesions adjacent to the diaphragm (particularly in segments VII and VIII) or near the heart are technically challenging to image

because of motion and may be missed. Deep lesions in a setting of fatty liver are poorly visualized secondary to decreased acoustic penetration.5 Peribiliary metastases are particularly challenging to diagnose, even with CEUS. One study demonstrated that in a group of 35 patients with proven peribiliary metastases, only one was visualized with CEUS. In the same study, all peribiliary lesions were detected on MRI.11 Occasionally benign entities can mimic metastases on traditional US and CEUS. In the setting of hepatic steatosis, benign lesions, such as focal nodular hyperplasia (FNH), which is

240

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 15.6  Focal lesion in a patient with colon cancer. A, Ultrasound image demonstrates a small hypoechoic lesion seen on the background of hepatic steatosis. This raised a concern for metastatic disease. B, Magnetic resonance imaging (MRI) with Gd-EOB-DTPA obtained for further evaluation. Axial T1 postcontrast MRI image obtained during a hepatobiliary phase revealed peripheral hyperenhancement, consistent with focal nodular hyperplasia (FNH).

usually isoechoic to normal liver parenchyma, will appear hypoechoic (dark) relative to the liver (see Chapter 88A). A hypoechoic lesion is often interpreted as metastatic disease (Fig. 15.6). Focal fatty sparing or focal fat can mimic a mass lesion, particularly if it demonstrates an unusual shape or occurs in an atypical location. One study that looked at detection of metastases occult on conventional US with CEUS and MRI in cancer patients with hepatic steatosis demonstrated that in 1 out of 37 patients, CEUS misinterpreted geographic hepatic steatosis as metastases, which was correctly diagnosed with MRI.12 Abscesses can be isoechoic, hypoechoic, or hyperechoic relative to the hepatic parenchyma and can present as a solid, partially cystic, or a predominantly cystic lesion (see Chapter 70).13 Acoustic through transmission and lack of internal flow on Doppler interrogation favors an abscess rather than a neoplastic process. However, necrotic or cystic metastases may contain substantial cystic components and may not demonstrate appreciable internal vascularity, which makes it difficult to differentiate them from an abscess. Other benign entities, such as tuberculosis (TB), sarcoidosis, and inflammatory pseudotumors, may present as mass lesions and can mimic metastatic disease.14,15

COMPUTED TOMOGRAPHY Background CT is the most commonly used technique in the United States for the initial staging and surveillance for metastatic disease because this modality allows for assessment of the liver as well as other potential sites of metastatic disease in the lungs and pelvis. According to several meta-analyses performed between 2010 and 2019, the sensitivity of CECT in detection of hepatic metastases ranges between 74% and 83%.16–19 The sensitivity of CT is dependent on image acquisition technique and parameters, particularly slice thickness and phase of enhancement. Lower slice thickness improves the detection and characterization of liver metastases. For example, use of 2.5-mm slice thickness resulted in a 46% increase in lesion detection rate in one study when compared with 10-mm slice thickness and an 18% increase when compared with 5-mm slice thickness images.20 Use of intravenous (IV) iodinated contrast is necessary to optimize the sensitivity and specificity of CT. Noncontrast CT

images have limited utility in the evaluation of liver lesions with certain exceptions, such as hemorrhagic and calcified lesions that have higher density than underlying liver parenchyma. Previously embolized or ablated lesions are also frequently higher in density because of either postprocedural changes or embolization material, so the noncontrast phase is helpful in the post-treatment setting to accurately assess for the presence of enhancement.

Imaging Findings Metastases can be hypovascular, hypervascular, or isovascular (i.e., enhance less, similar, or greater) with respect to the background liver parenchyma. Most metastases (e.g., colorectal, pancreatic adenocarcinoma, and lung) are hypovascular relative to the liver and are best visualized on the portal venous phase of enhancement, which is acquired approximately 60 to 80 seconds after the injection of contrast (Fig. 15.7). The portal venous phase is usually sufficient for detection of most hypovascular metastases. However, 88% of hypovascular metastases demonstrate some degree of arterial hyperenhancement, most commonly either partial or complete peripheral ring hyperenhancement on the arterial phase of CT. This pattern of enhancement has been suggested to have a high positive predictive value for malignancy, near 98%.21 Utilization of the arterial phase for detection of hypovascular metastases remains controversial. Some studies report no added value with the addition of the arterial phase.22,23 However, there are studies that report improved sensitivity for lesion detection in the range of 8% to 13%. The most significant increase in the detection of metastases is observed with lesions less than 1 cm.24,25 The delayed phase is usually not helpful because both hypervascular and hypovascular metastases become less conspicuous a few minutes after the injection of contrast. Hypervascular liver metastases are less common and are most commonly observed with primary tumors, such as melanoma, neuroendocrine neoplasms, renal cell carcinoma, and thyroid cancer (see Chapters 91 and 92). Numerous studies have demonstrated advantages of multiphasic imaging in evaluation of hypervascular liver metastases (Fig. 15.8). For example, 14% of melanoma metastases are not seen on the portal venous phase images when the arterial phase of enhancement is not provided.26 Ten percent of hepatic metastases from renal cell carcinoma are missed if only the portal venous phase is used.27

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

241

B

FIGURE 15.7  A, Axial computed tomography (CT) image in a patient with colorectal cancer obtained during the portal venous phase. Hypovascular metastases with faint rim of peripheral hyperenhancement (arrows). B, Axial CT image in the same patient obtained a few months after initiation of chemotherapy demonstrates decreased metastases and new tiny calcifications along the posterior border of the residual metastasis.

A

B

FIGURE 15.8  Hypervascular metastases in a patient with a pancreatic neuroendocrine tumor best seen on the arterial phase. A. Axial computed tomography (CT) image obtained during an arterial phase demonstrates five hypervascular metastases (red arrows). Note primary pancreatic tumor in the left abdomen (green arrow) B. Axial CT images in the same patient obtained during the portal venous phase shows that only some metastases are visible (red arrows). Three additional metastases (green arrows) blend into background parenchyma.

Noncontrast images have been shown to add value in evaluation of a subset of lesions that are isodense on the portal venous and arterial phases. For example, a study of patients with primary hypervascular malignancies other than HCC demonstrated maximum sensitivity of 96% in detection of liver metastases when a combination of noncontrast and portal venous phases was used. Use of portal venous and arterial phases without the noncontrast phase resulted in sensitivity of 78%.28 Therefore multiphasic imaging that includes noncontrast, arterial, and portal venous phases is usually recommended for the evaluation of hypervascular liver metastases (Fig. 15.9). Liver metastases can also appear cystic with primary malignancies that are cystic in appearance, such as ovarian and mucinous cancers. Additionally, rapidly growing hypervascular tumors can produce cystic-appearing lesions because of central necrosis. Necrotic metastases usually retain irregular peripheral rim of hyperenhancing tissue while the center of the lesion shows absence or minimal enhancement (Fig. 15.10). “Peripheral washout sign,” a “targetoid” pattern of enhancement, can be seen in some metastases. This sign has a high specificity for malignancy. However, it is not specific for metastasis and may

be seen with primary liver malignancies as well (Fig. 15.11; see Chapter 14).8 Some metastases may demonstrate calcifications both at presentation and after chemotherapy treatment (see Fig. 15.7B). Mucinous gastrointestinal (GI) and ovarian tumors are considered common primaries to develop calcified liver metastases and calcifications within metastatic lymph nodes. A study from 2010 that evaluated for the presence of calcifications within liver metastases in different subtypes of colon cancer did not reveal any correlation between calcifications and the histologic subtype and differentiation degree of the primary malignancy (see Chapter 90).29 The appearance of hepatic metastases varies not only with the primary tumor type but also with changes in the underlying liver parenchyma and with treatment (see Chapters 69, 97, and 98). Hypovascular metastases may appear hyperdense or hypervascular on the background of hepatic steatosis or may become isodense on portal venous phase, limiting sensitivity of CT (Fig. 15.12). Colorectal liver metastases in patients with biopsy-proven hepatic steatosis were detected on CT only 65% of the time in one study, and only 11% of lesions measuring up

242

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

FIGURE 15.9  Neuroendocrine metastasis that is isodense on the arterial phase. A, Axial noncontrast computed tomography (CT) image demonstrates good visualization of the metastasis (red arrow). B, Axial arterial phase CT image. The same metastasis blends into the hepatic parenchyma. C, Axial CT image obtained during the portal venous phase shows washout of the lesion.

A

FIGURE 15.10  Cystic metastasis in a patient with endometrial sarcoma, initial presentation before treatment. Axial computed tomography (CT) image obtained during the portal venous phase demonstrates a large metastasis with a substantial low density/cystic central component reflecting necrosis (green arrow). A thick irregular peripheral rind represents remaining vascular tumor (red arrow).

A

B

B FIGURE 15.12  Hepatic metastases in a patient with hepatic steatosis and metastatic appendiceal neuroendocrine tumor. A, Coronal computed tomography (CT) image obtained during portal venous phase does not demonstrate metastases. B, Coronal magnetic resonance (MR) image obtained during a hepatobiliary phase with Gd-EOBDTPA reveals several small metastases (arrows).

to 1.0 cm were detected.30 Chemotherapy and liver-targeted therapies may change the morphology of metastases or the overall degree and pattern of enhancement or calcifications or may lead to the development of cystic components (Fig. 15.13; see Chapters 69, 97, and 98). For example, marked change in enhancement is seen for GI tumor metastases treated with imatinib.31 Occasionally, treated metastases may mimic cysts and hemangiomas. Therefore, careful review of prior imaging studies is critical for assessment of change in lesion size and enhancement characteristics before and after the initiation of treatment. FIGURE 15.11  Liver metastasis with a “peripheral washout sign” in a patient with breast cancer. Postcontrast coronal computed tomography (CT) image demonstrates a faint dark rim around the lesion (green arrow). Note low density center probably related to necrosis (red arrow) and a grey rim of intervening viable tumor (blue arrow).

Limitations and Pitfalls Multiple factors can affect lesion detection on CT, including patient imaging characteristics, imaging technique, and specific locations in the liver. Although CT modality offers superior

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

243

B

FIGURE 15.13  Change in density of metastases after chemotherapy. A, Hypovascular solid metastases in a patient with testicular germ cell tumor at presentation before treatment. B, Residual metastasis in segment 7 after chemotherapy demonstrates low density similar to a cyst.

resolution (with potential for submillimeter voxel resolution) compared with MRI, it has lower contrast resolution. Liver lesions that are smaller than 1.0 cm are not as accurately characterized by CT.32–35 A disadvantage associated with CT is the risk for ionizing radiation, which is proportional to the radiation dose. Although significant dose reduction for some protocols, such as lung cancer screening or renal colic, may provide sufficient diagnostic information, reducing dose in liver imaging results in decreased diagnostic accuracy. One prospective study that looked at accuracy of regular-dose CT and reduced-dose CT (approximately 60%–70% dose reduction) in the same patients with nonliver primary malignancies demonstrated a drop in sensitivity from 91% to 79%.36 Thus low contrast technique is not recommended for dedicated liver imaging. Liver metastases may be missed on CT for various reasons. A study that looked at characteristics of liver metastases from various primary tumors missed on CT noted that hepatic steatosis (see Chapter 69) and subcapsular location contributed to the highest fraction of missed lesions. For instance, 36 of 53 (67%) subcapsular lesions were missed, whereas 11 of 14 (78.6%) lesions in a setting of hepatic steatosis were missed.37 Decreased detection of subcapsular lesions when compared with more centrally located lesions is probably in part related to the fact that perceptual errors on imaging in general are more common with peripheral (“corner of film” phenomenon) rather than central locations of interest. Subcapsular lesions may also be mistaken for structures outside of the liver, for example, focal lobulation of the diaphragm. Detection of peribiliary lesions can also be challenging on CT. In a study evaluating detection of peribiliary metastases by different modalities, CT correctly identified only 22.8% of such metastases, whereas all peribiliary lesions were detected on MRI.11 Although most cases of high hepatic tumor burden are detected on CT, CT-occult extensive infiltrative pattern of tumor spread leading to liver failure has been described in the literature, most commonly with breast carcinoma.38 Effective chemotherapy can lead to complete resolution of metastases on CT images, a phenomenon referred to as radiologically disappearing liver metastases (DLM; see Chapters 90, 97, and 98). However, this does not always correlate with complete pathologic response. For example, radiologic-pathologic correlation of colorectal DLM demonstrated that only 66% that were subsequently resected represented a true complete response.39 This emphasizes the importance of evaluating prechemotherapy imaging in preoperative surgical planning.

FIGURE 15.14  Hepatic pseudolesion around the falciform ligament. Axial computed tomography (CT) image with intravenous contrast demonstrates a triangular area of hypoenhancement (arrow) abutting the falciform ligament that is related to either focal fat or perfusional anomaly and should not be misinterpreted as a metastasis.

Occasionally, benign processes can mimic metastatic disease. One of the most common pseudolesions in the liver is focal hypoenhancement around the falciform ligament, which may result either from focal fat deposition or anomalous venous supply (Fig. 15.14). It usually occurs in the left hepatic lobe, either along one side or both sides of the falciform ligament. Geographic shape and typical location are two of the most important key findings that help to distinguish this pseudolesion from a neoplastic process. Focal hepatic steatosis and areas of fatty sparing of an ovoid shape or in unusual locations can mimic metastases. If this is suspected, then further evaluation may be performed with liver MRI, which includes in- and opposed-phase T1-weighted imaging to confirm the presence of lipid (Fig. 15.15A–C). Other benign entities, such as sarcoidosis, TB, fibrosis, and infection, may have imaging characteristics that are similar to those of metastatic disease. Atypical hemangiomas can mimic metastases on both CT and MRI modalities. Atypical hemangiomas can demonstrate calcifications, central necrosis, adjacent capsular retraction, and hyalinization/fibrosis. Either all or some of the classic enhancement characteristic that include peripheral, discontinuous, nodular, and centripetal contrast pooling may be absent and preclude a definitive diagnosis on imaging. Therefore a biopsy is sometimes warranted in equivocal cases (see Chapter 88A).

244

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C FIGURE 15.15  Hepatic steatosis in a patient with pancreatic cancer after chemotherapy. A, Axial postcontrast computed tomography (CT) image obtained during restaging examination demonstrates a new hypodense lesion (arrow). B, Axial in-phase magnetic resonance (MR) image does not reveal a focal abnormality in the region of interest (arrow). C, Axial out-of-phase MR image shows an area of signal loss (darker focus) compared with in-phase reflect presence of microscopic fat (arrow). There is also mildly decreased signal throughout the entire right hepatic lobe as well. These findings are consistent with diffuse hepatic steatosis and more focal fat deposition.

PET/CT AND PET/MRI Background Fluorine-18-2-fluoro-2 deoxy-D-glucose (FDG) PET/CT is widely used in the evaluation of metastatic disease and provides both anatomic and metabolic information on the liver (see Chapter 18). According to the ACR Appropriateness Criteria for suspected liver metastases, PET/CT is not recommended as a first-line imaging modality.4 Early meta-analyses performed between 2002 and 2005 suggested that PET/CT is superior to other modalities in the detection of liver metastases,40,41 but more recent studies performed since 2010 in patients with colorectal and other primary tumors have highlighted superior sensitivity of MRI over PET/CT on a per patient as well as per lesion basis.42–45 One of the major strengths of PET/CT is its ability to diagnose extrahepatic metastatic disease, such as in nonenlarged lymph nodes or peritoneal disease. This can lead to change in management in 8% to 25% of patients with colorectal and other primary tumors.46–48 Another use of PET/CT is to assess treatment effect by demonstrating decreased FDG uptake within treated metastases. PET/MRI is a new hybrid technology that was approved by the FDA in 2011. Evaluation for hepatic metastases is the most common indication for PET/MRI of the liver. This test offers the advantages of high tissue contrast and physiologic information combined in one test. In a patient with hepatic metastases, a multiphasic contrast-enhanced MRI of the liver combined with PET images offers a comprehensive assessment of the presence and viability of hepatic and distant metastases. Because PET/MRI is a relatively new imaging technology, the research

data regarding specificity and sensitivity are more limited. Nevertheless, a recent meta-analysis from 2019 indicates increased sensitivity and specificity of PET/MRI compared with PET/CT with sensitivity and specificity of these modalities of 95.4%/99.3% and 68%/95.8%, respectively.49 Several studies have demonstrated superiority of PET/MRI over CECT and PET/CT. However, there are no data at this time to suggest that PET/ MRI is advantageous over hepatocyte-specific agent MRI for the detection of hepatic metastases. A retrospective study by Donati et al. that evaluated hepatic metastases from various malignancies with and without prior chemotherapy demonstrated the sensitivities of PET/MRI, gadoxetate disodium MRI, and PET/CT to be 93%, 91%, and 76%, respectively. For lesions up to 1 cm, the sensitivities of the same modalities were 70%, 80%, and 30%, respectively.50 Another retrospective study that looked at detection of colorectal cancer metastases in patients with PET/MRI, gadoxetate disodium MRI, CECT, and PET/CT also demonstrated superior sensitivity of PET/MRI compared with CECT and PET/CT but no significant difference between PET/MRI and MRI alone.51 In addition to F-18, other radiopharmaceutical agents that target specific tumors have emerged in recent years. For example, 68Ga-DOTA-TATE is used in the evaluation of neuroendocrine tumors and 68Ga-prostate specific membrane antigen (PSMA) is used for the evaluation of prostate cancer metastases. These agents can be used with either PET/CT or PET/MRI (see Chapter 18).

Imaging Findings Evaluation of PET images is usually performed qualitatively by assessing the tumor to background contrast ratio (Fig. 15.16A–B).

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

245

B

FIGURE 15.16  Hepatic metastasis in a patient with adenocarcinoma of unknown primary. A, Axial fused positron emission tomography (PET)/ computed tomography (CT) image demonstrates a hypermetabolic lesion in the left hepatic lobe (arrow). B, CT in the same patient does not a reveal a metastasis in the expected location (arrow). Moderate hepatic steatosis is present that probably limits visualization of that metastasis.

A

B

FIGURE 15.17  Hepatic metastases in a breast cancer patient. A, Axial contrast-enhanced computed tomography (CT) image demonstrates two metastases in the right hepatic lobe. B, Positron emission tomography (PET)/CT obtained on the same day demonstrates hypermetabolism within the larger lesion. However, the subcentimeter lesion adjacent to the gallbladder is not visualized.

Normal liver parenchyma demonstrates a relatively high baseline metabolic activity when compared with lung or muscle. Most hepatic metastases demonstrate hypermetabolism on PET/CT and typically have a standardized uptake value (SUV) of greater than 3.

Limitations and Pitfalls PET/CT has a limited role in the detection of subcentimeter lesions (Fig. 15.17A–B).52,53 False negatives may occur with tumors demonstrating low level metabolic activity, such as mucinous tumors.54 A retrospective study that looked at FDGPET/CT in the assessment of colorectal cancer metastases showed a significantly lower sensitivity with mucinous tumors. Sensitivity for mucinous cancers was 58%, and it was 92% for nonmucinous metastases.55 Sensitivity of FDG-PET/CT is significantly lower in patients with colorectal cancer after neoadjuvant chemotherapy.56 A prospective study that looked at accuracy of FDG-PET and triphasic CT in colorectal liver metastases demonstrated a drop in sensitivity of FDG-PET from 93.3% to 49% after neoadjuvant chemotherapy. For lesions less than 1 cm, sensitivity before and after chemotherapy was 33% and 17%, respectively. Thus lack of hypermetabolism within liver lesions in the setting of recent chemotherapy does not exclude the presence of viable metastases.57

False positives may occur with inflammatory and infectious processes, such as abscesses and postradiation changes. Although benign liver lesions usually demonstrate uptake similar to that of background liver parenchyma (see Chapter 88), focally increased uptake within hemangiomas, FNH, and hepatocellular adenomas has been reported.58,59 False positive uptake within either benign liver lesions or primary liver tumors have been described in the literature with 68Ga-DOTA-TATE and 68 Ga-PSMA as well (Fig. 15.18).60-62

MAGNETIC RESONANCE IMAGING Background Continuous improvements in MRI scanner hardware and software, in diffusion-weighted imaging (DWI), and increased use of hepatobiliary contrast agents have led to marked improvement in image quality and accuracy of MRI for liver imaging. MRI is considered superior to CT in hepatic lesion detection and characterization. Based on ACR Appropriateness Criteria for the initial staging of disease and surveillance after treatment of the primary malignancy, CT carries a higher rating than MRI because of its ability to evaluate the lungs and other sites of extrahepatic disease. However, MRI has a higher rating than CT when it comes to presurgical assessment of liver metastases.4

246

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 15.18  False positive with 68 Ga-PSMA positron emission tomography (PET). Axial fused images from a 68 Ga-PSMA PET in a patient with prostate cancer shows focal uptake in the liver (arrow). A metastasis was suspected. However, biopsy revealed a cholangiocarcinoma. This lesion was subsequently resected.

As hepatocyte-specific contrast agents (e.g., gadoxetate disodium, Gd-EOB-DTPA) have been increasingly used, metaanalyses published after 2010 have demonstrated the superiority of MRI in its sensitivity when compared with CT and PET/ CT with colorectal and other metastases, particularly with respect to subcentimeter liver lesions.16,35,63 For example, a prospective cohort study by Asato et al. from 2017 reports the overall sensitivity of MRI with DWI versus CT as 91.4% versus 80.9%. For lesions less than 1 cm, sensitivities for MRI with DWI versus CT were 73.3% and 56%, respectively.63 A metaanalysis by Choi et al. from 2018 that included patients with colorectal and other primary malignancies reports sensitivities for hepatocyte-specific MRI, CT, and PET as 93.1%, 82.1%, and 74.1%, respectively.19 A prospective study published by Sivesgaard et al. from 2018 evaluated diagnostic accuracy of CT, hepatocyte-specific MR, and PET/CT in 76 colon cancer patients with and without prior chemotherapy and/or ablative treatments. It demonstrated the highest per lesion sensitivity for MRI (85.9%–83.8%), followed by PET/CT (72.0%–72.1%) and CT (62.3%–69.1%). Sensitivities for lesions up to 1 cm sensitivities were as follows: MRI (91.5%–95.1%), PET/CT (86.5%–89.3%), and CT (79.2%–82.40%). MRI detected additional metastases in 18 patients compared with CT and 17 patients compared with PET/CT. Of note is that PET/CT was interpreted in combination with CECT in this study, which may account for the higher sensitivity of PET/CT compared with other studies. No significant per lesion specificity was found between modalities.64 A meta-analysis by Vilgrain et al. looked at sensitivities of DWI alone versus gadoxetic-enhanced (hepatocyte specific agent) MRI in 3,854 metastases from various primary tumors in 1,989 patients. Although a relatively small difference in sensitivities was found between DWI-MR and gadoxetic acid-enhanced MR (87.1% vs. 90.6%), the combination of two techniques was shown to have the highest sensitivity of 95.5%. Similar results were noted when limiting the analysis to colorectal liver metastases and metastases smaller than 1 cm.65 Although delayed hepatobiliary-phase imaging produces very high contrast between the tumor and the normal liver parenchyma, hypointense (dark) lesions on delayed phase could either be benign or malignant

(e.g., metastasis or a cyst). Thus it is importance to use all MR sequences to optimize lesion detection and characterization. Additional data have recently emerged with regard to costeffectiveness and improved mortality of patients imaged with hepatocyte-specific agents. A randomized multicenter trial (the VALUE study group) by Zech et al. published in 2014 reported a decreased need for additional imaging, higher diagnostic confidence, and a lower rate of intraoperative change of plans in patients with colorectal cancer who underwent initial imaging with hepatobiliary agent MRI compared with extracellularcontrast agent MRI and CECT.66 A study by Kim at al. in 2018 demonstrated increased 5-year survival rate in patients with colon cancer who underwent gadoxetic acid enhanced-MRI in addition to CT when compared with patients who underwent only CT (70.8% vs. 48.1%). In this study, MRI detected 39 additional synchronous liver metastases initially missed on CT in 26 patients.67

Imaging Findings Most liver metastases are hypovascular and hypervascular on multiphasic contrast-enhanced MRI, similar to CECT, but the superior contrast resolution of MRI enhances its sensitivity for liver metastases (see Chapters 90–92). In addition, the use of T1-weighted imaging, T2-weighted imaging, and DWI provides additional signal characteristics for liver lesions that improve the accuracy of MRI compared with other imaging modalities. Most metastases are hypointense (darker than liver parenchyma) on T1-weighted images and mildly hyperintense (slightly brighter than liver) on T2-weighted images (Fig. 15.19A–E). Notable exceptions to this rule are hemorrhagic and melanoma liver metastases because blood products and melanin both demonstrate high signal on T1-weighted images (Fig. 15.20). Other types of malignancies can also occasionally produce T1 hyperintense liver metastases because of high protein content. Most metastases are not as bright on T2-weighted images as hemangiomas and cysts, except when there is extensive necrosis or cystic components. Occasionally a target sign can be seen on T2-weighted images, where there is a markedly hyperintense center of the lesion (liquefactive necrosis) that is surrounded by a rim of more solid tissue. On T1-weighted images, there is usually a corresponding donut sign, a low signal intensity rim, and an even more hypointense (darker) center.68 DWI is a sequence that is wonderfully suited for detection of liver metastases. The signal in DWI is affected by the movement of water molecules in the tissues of interest. The signal intensity of liver lesions on DWI remains high in lesions with higher cellularity, such as liver metastases, compared with benign lesions. Numerous studies have demonstrated that DWI is more sensitive for the detection of liver lesions compared with CT.35 DWI, however, suffers from relatively low special resolution and is more susceptible to artifacts because of motion or field inhomogeneities (Fig. 15.21). T1-weighted imaging, T2-weighted imaging, and DWI sequences should be used in combination with contrast-enhanced sequences for a comprehensive evaluation of patients with liver metastases.

Limitations and Pitfalls Although MRI does not carry the risk associated with ionizing radiation or the risk of contrast-induced nephropathy, liver MRIs are lengthy examinations compared with CT (around 20–30 minutes compared with ,5 minutes) and is poorly

  Chapter 15  Imaging Features of Metastatic Liver Cancer

A

B

D

247

C

E

F

FIGURE 15.19  Usual magnetic resonance imaging (MRI) characteristic of hepatic metastases. Axial MRI images in a patient with colon cancer and prior right hepatectomy. A. T2-weighted image shows a subcentimeter lesion that is brighter than adjacent liver parenchyma (green arrow) but not as bright as cerebrospinal fluid in the spinal canal (red arrow). B, T1-weighted image with fat suppression. The lesion is slightly darker than the liver (arrow). C, Diffusion-weighted imaging (DWI). The lesion is markedly hyperintense (arrow). D. Postcontrast portal venous phase. The lesion is hypoenhancing with respect to adjacent liver (arrow). E. Delayed/ hepatobiliary phase. The metastasis is hypointense, but is more conspicuous because of increased contrast between the lesion and the enhancing hepatic parenchyma (arrow). F. Axial CT image from a follow-up examination showing subsequent ablation of the metastasis.

A

B

C FIGURE 15.20  Melanoma metastases. A. Axial two-weighted images demonstrates two adjacent metastases that are moderately brighter than adjacent liver (arrows). B. Axial T1-precontrast image shows that the larger metastasis is partially hyperintense, probably because of the presence of melanin (arrow). However, the second smaller metastasis is isointense and is not well seen. C. Axial subtraction image demonstrates a doughnut sign (arrow). Peripheral rim of enhancing viable tissue and central hypoenhancement probably due to necrosis.

248

PART 2  DIAGNOSTIC TECHNIQUES

may be less desirable than CT for the delineation of complex variant vascular anatomy in the upper abdomen. Imaging of disappearing colorectal metastases remains a challenge even when using hepatocyte-specific contrast agents (see Chapter 90). A retrospective review of resected colorectal liver metastases that were imaged with preoperative gadoxetateMRI revealed that 38.5% of lesions demonstrated “disappearance” on MRI. Fifty-five percent of those lesions demonstrated viability on pathology.69

SUMMARY

FIGURE 15.21  Axial magnetic resonance (MR) diffusion-weighted imaging (DWI) demonstrates an artifact from a hepatic arterial infusion pump (red arrows) that partially obscures the hepatic metastases (green arrows).

tolerated in a minority of patients. MRIs are susceptible to motion and other artifacts and, therefore, may not be ideal in patients who are unable to follow breath-holding instructions or who are unable to remain supine and still in the MRI scanner. Liver lesions in the left hepatic lobe, in proximity to the stomach and heart, may be obscured because of peristalsis or susceptibility artifact from intraluminal gas. Because of lower spatial resolution and susceptibility to motion, MRI technique

Multiple modalities can be used to image hepatic metastases. Traditional US is the least sensitive, least specific, most operator-depended modality and is most frequently affected by patient factors. CEUS is a rapidly evolving technique that shows much higher sensitivity and specificity than conventional US and approaches accuracy that is comparable to that of CT and MRI in some studies.2 However, CEUS is not yet widely available in the United States. Therefore the most frequently used modalities in the initial detection and surveillance of hepatic metastases in the United States are CECT and MRI, with PET/CT reserved for detection of extrahepatic disease. MRI shows superior sensitivity for presurgical assessment of liver metastases.4 PET-CT may play a complementary role in specific situations, such as in response assessment, or for specific tumors, such as neuroendocrine liver metastases with new radiotracers. PET-MRI is emerging as a technique for liver metastases detection that may play a larger role in the near future. References are available at expertconsult.com

248.e1

REFERENCES 1. Correas JM, Low G, Needleman L, et al. Contrast enhanced ultrasound in the detection of liver metastases: a prospective multi centre dose testing study using a perfluorobutane microbubble contrast agent (NC100100). Eur Radiol. 2011;21(8):1739-1746. 2. Cantisani V, Grazhdani H, Fioravanti C, et al. Liver metastases: contrast-enhanced ultrasound compared with computed tomography and magnetic resonance. World J Gastroenterol. 2014;20(29): 9998-10007. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Available at: https://www.nccn.org/. Accessed June 14, 2020. 4. Expert Panel on Gastrointestinal Imaging, Kaur H, Hindman NM, et al. ACR Appropriateness Criteria suspected liver metastases. J Am Coll Radiol. 2017;14(5S):S314-S325. 5. Erlichman DB, Weiss A, Koenigsberg M, Stein MW. Contrast enhanced ultrasound: a review of radiology applications. Clin Imaging. 2020;60(2):209-215. 6. Quaia E, D’Onofrio M, Palumbo A, Rossi S, Bruni S, Cova M. Comparison of contrast-enhanced ultrasonography versus baseline ultrasound and contrast-enhanced computed tomography in metastatic disease of the liver: diagnostic performance and confidence. Eur Radiol. 2006;16(7):1599-1609. 7. Claudon M, Dietrich CF, Choi BI, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall Med. 2013;34(1):11-29. 8. Lincke T, Zech CJ. Liver metastases: detection and staging. Eur J Radiol. 2017;97:76-82. 9. Wernecke K, Vassallo P, Bick U, Diederich S, Peters PE. The distinction between benign and malignant liver tumors on sonography: value of a hypoechoic halo. AJR Am J Roentgenol. 1992;159(5): 1005-1009. 10. Jang HJ, Kim TK, Wilson SR. Imaging of malignant liver masses: characterization and detection. Ultrasound Q. 2006;22(1):19-29. 11. Granata V, Fusco R, Catalano O, et al. Diagnostic accuracy of magnetic resonance, computed tomography and contrast enhanced ultrasound in radiological multimodality assessment of peribiliary liver metastases. PLoS One. 2017;12(6):e0179951. 1 2. Bartolotta TV, Taibbi A, Picone D, Anastasi A, Midiri M, Lagalla R. Detection of liver metastases in cancer patients with geographic fatty infiltration of the liver: the added value of contrast-enhanced sonography. Ultrasonography. 2017;36(2):160-169. 13. Shin DS, Jeffrey RB, Desser TS. Pearls and pitfalls in hepatic ultrasonography. Ultrasound Q. 2010;26(1):17-25. 14. Guarino B, Catalano O, Corvino A, Corvino F, Amore A, Petrillo A. Hepatic inflammatory pseudotumor: educational value of an incorrect diagnosis at contrast-enhanced ultrasound. J Med Ultrason (2001). 2015;42(4):547-552. 1 5. Warshauer DM, Molina PL, Hamman SM, et al. Nodular sarcoidosis of the liver and spleen: analysis of 32 cases. Radiology. 1995; 195(3):757. 1 6. Vreugdenburg TD, Ma N, Duncan JK, Riitano D, Cameron AL, Maddern GJ. Comparative diagnostic accuracy of hepatocytespecific gadoxetic acid (Gd-EOB-DTPA) enhanced MR imaging and contrast enhanced CT for the detection of liver metastases: a systematic review and meta-analysis. Int J Colorectal Dis. 2016; 31(11):1739-1749. 17. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/ CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology. 2010;257(3): 674-684. 18. Floriani I, Torri V, Rulli E, et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J Magn Reson Imaging. 2010;31(1):19-31. 19. Choi SH, Kim SY, Park SH, et al. Diagnostic performance of CT, gadoxetate disodium-enhanced MRI, and PET/CT for the diagnosis of colorectal liver metastasis: systematic review and meta-analysis. J Magn Reson Imaging. 2018;47(5):1237-1250. 2 0. Weg N, Scheer MR, Gabor MP. Liver lesions: improved detection with dual-detector-array CT and routine 2.5-mm thin collimation. Radiology. 1998;209(2):417-426.

21. Nino-Murcia M, Olcott EW, Jeffrey Jr RB, Lamm RL, Beaulieu CF, Jain KA. Focal liver lesions: pattern-based classification scheme for enhancement at arterial phase CT. Radiology. 2000;215(3):746-751. 22. Wicherts DA, de Haas RJ, van Kessel CS, et al. Incremental value of arterial and equilibrium phase compared to hepatic venous phase CT in the preoperative staging of colorectal liver metastases: an evaluation with different reference standards. Eur J Radiol. 2011;77(2):305-311. 23. Soyer P, Poccard M, Boudiaf M, et al. Detection of hypovascular hepatic metastases at triple-phase helical CT: sensitivity of phases and comparison with surgical and histopathologic findings. Radiology. 2004;231(2):413-420. 24. Honda Y, Higaki T, Higashihori H, et al. Re-evaluation of detectability of liver metastases by contrast-enhanced CT: added value of hepatic arterial phase imaging. Jpn J Radiol. 2014;32(8):467-475. 25. Silverman PM. Liver metastases: imaging considerations for protocol development with multislice CT (MSCT). Cancer Imaging. 2006;6(1):175-181. 26. Blake SP, Weisinger K, Atkins MB, Raptopoulos V. Liver metastases from melanoma: detection with multiphasic contrast-enhanced CT. Radiology. 1999;213(1):92-96. 27. Raptopoulos VD, Blake SP, Weisinger K, Atkins MB, Keogan MT, Kruskal JB. Multiphase contrast-enhanced helical CT of liver metastases from renal cell carcinoma. Eur Radiol. 2001;11(12):2504-2509. 28. Oliver JH III, Baron RL, Federle MP, Jones BC, Sheng R. Hypervascular liver metastases: do unenhanced and hepatic arterial phase CT images affect tumor detection? Radiology. 1997;205(3):709-715. 29. Xu L, Zhou Y, Qiu D. Correlation between calcified liver metastases and histopathology of primary colorectal carcinoma in Chinese. J Huazhong Univ Sci Technolog Med Sci. 2010;30(6):815-818. 30. Kulemann V, Schima W, Tamandl D, et al. Preoperative detection of colorectal liver metastases in fatty liver: MDCT or MRI? Eur J Radiol. 2011;79(2):e1-e6. 31. Werewka-Maczuga A, Stępień M, Urbanik A. Evaluation of alterations in tumor tissue of gastrointestinal stromal tumor (GIST) in computed tomography following treatment with imatinib. Pol J Radiol. 2017;82:817-826. 32. Motosugi U, Ichikawa T, Morisaka H, et al. Detection of pancreatic carcinoma and liver metastases with gadoxetic acid-enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT. Radiology. 2011;260(2):446-453. 33. Lee KH, Lee JM, Park JH, et al. MR imaging in patients with suspected liver metastases: value of liver-specific contrast agent gadoxetic acid. Korean J Radiol. 2013;14(6):894-904. 34. Berger-Kulemann V, Schima W, Baroud S, et al. Gadoxetic acidenhanced 3.0 T MR imaging versus multidetector-row CT in the detection of colorectal metastases in fatty liver using intraoperative ultrasound and histopathology as a standard of reference. Eur J Surg Oncol. 2012;38(8):670-676. 35. Kim HJ, Lee SS, Byun JH, et al. Incremental value of liver MR imaging in patients with potentially curable colorectal hepatic metastasis detected at CT: a prospective comparison of diffusionweighted imaging, gadoxetic acid-enhanced MR imaging, and a combination of both MR techniques. Radiology. 2015;274(3): 712-722. 36. Pooler BD, Lubner MG, Kim DH, et al. Prospective evaluation of reduced dose computed tomography for the detection of lowcontrast liver lesions: direct comparison with concurrent standard dose imaging. Eur Radiol. 2017;27(5):2055-2066. 37. Nakai H, Arizono S, Isoda H, Togashi K. Imaging characteristics of liver metastases overlooked at contrast-enhanced CT. AJR Am J Roentgenol. 2019;212(4):782-787. 38. Gulia S, Khurana S, Shet T, Gupta S. Radiographically occult intrasinusoidal liver metastases leading to hepatic failure in a case of breast cancer. BMJ Case Rep. 2016;2016:bcr2015214120. 39. Auer RC, White RR, Kemeny NE, et al. Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy. Cancer. 2010;116(6):1502-1509. 40. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT, MR imaging, and PET for diagnosis—meta-analysis. Radiology. 2005;237(1):123-131. 41. Kinkel K, Lu Y, Both M, Warren RS, Thoeni RF. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology. 2002;224(3):748-756.

248.e2 42. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/ CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology. 2010;257(3): 674-684. 43. Maegerlein C, Fingerle AA, Souvatzoglou M, Rummeny EJ, Holzapfel K. Detection of liver metastases in patients with adenocarcinomas of the gastrointestinal tract: comparison of (18)F-FDG PET/CT and MR imaging. Abdom Imaging. 2015;40(5):1213-1222. 44. Schulz A, Viktil E, Godt JC, et al. Diagnostic performance of CT, MRI and PET/CT in patients with suspected colorectal liver metastases: the superiority of MRI. Acta Radiol. 2016;57(9):1040 45. Sivesgaard K, Larsen LP, Sørensen M, et al. Diagnostic accuracy of CE-CT, MRI and FDG PET/CT for detecting colorectal cancer liver metastases in patients considered eligible for hepatic resection and/or local ablation. Eur Radiol. 2018;28(11):4735-4747. 46. Chua SC, Groves AM, Kayani I, et al. The impact of 18F-FDG PET/CT in patients with liver metastases. Eur J Nucl Med Mol Imaging. 2007;34(12):1906-1914. 47. Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014;311(18):1863-1869. 48. Truant S, Huglo D, Hebbar M, Ernst O, Steinling M, Pruvot FR. Prospective evaluation of the impact of [18F] fluoro-2-deoxy-Dglucose positron emission tomography of resectable colorectal liver metastases. Br J Surg. 2005;92(3):362-369. 49. Hong SB, Choi SH, Kim KW, et al. Diagnostic performance of [18F]FDG-PET/MRI for liver metastasis in patients with primary malignancy: a systematic review and meta-analysis. Eur Radiol. 2019;29(7):3553-3563. 50. Donati OF, Hany TF, Reiner CS, et al. Value of retrospective fusion of PET and MR images in detection of hepatic metastases: comparison with 18F-FDG PET/CT and Gd-EOB-DTPA-enhanced MRI. J Nucl Med. 2010;51(5):692-699. 51. Lee DH, Lee JM, Hur BY, et al. Colorectal cancer liver metastases: diagnostic performance and prognostic value of PET/MR imaging. Radiology. 2016;280(3):782-792. 52. Ruers TJ, Langenhoff BS, Neeleman N, et al. Value of positron emission tomography with [F-18] fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. J Clin Oncol. 2002;20(2):388-395. 53. Fong Y, Saldinger PF, Akhurst T, et al. Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases. Am J Surg. 1999;178(4):282-287. 54. Laurens ST, Oyen WJ. Impact of fluorodeoxyglucose PET/computed tomography on the management of patients with colorectal cancer. PET Clin. 2015;10(3):345-360. 55. Whiteford MH, Whiteford HM, Yee LF, et al. Usefulness of FDGPET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum. Dis Colon Rectum. 2000; 43(6):759-770. 56. Akhurst T, Kates TJ, Mazumdar M, et al. Recent chemotherapy reduces the sensitivity of [18F] fluorodeoxyglucose positron emission

tomography in the detection of colorectal metastases. J Clin Oncol. 2005;23(34):8713-8716. 57. Lubezky N, Metser U, Geva R, et al. The role and limitations of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings. J Gastrointest Surg. 2007;11(4):472-478. 58. Luk WH, Au-Yeung AW, Loke TK. Imaging patterns of liver uptakes on PET scan: pearls and pitfalls. Nucl Med Rev Cent East Eur. 2013;16(2):75-81. 59. Voncken FEM, Aleman BMP, van Dieren JM, et al. Radiationinduced liver injury mimicking liver metastases on FDG-PET-CT after chemoradiotherapy for esophageal cancer: a retrospective study and literature review. Strahlungsinduzierte Leberschäden ähneln Lebermetastasen im FDG-PET-CT nach Radiochemotherapie beim √ñsophaguskarzinom: eine retrospektive Studie und Literatursuche. Strahlenther Onkol. 2018;194(2):156-163. 60. Hod N, Levin D, Anconina R, Taragin BH, Dudnik J, Lantsberg S. 68Ga-DOTATATE PET/CT in focal fatty sparing of the liver. Clin Nucl Med. 2019;44(10):815-817. 61. Hofman MS, Lau WF, Hicks RJ. Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation. Radiographics. 2015;35(2): 500-516. 62. Shetty D, Patel D, Le K, Bui C, Mansberg R. Pitfalls in Gallium-68 PSMA PET/CT interpretation-a pictorial review. Tomography. 2018;4(4):182-193. 63. Asato N, Tsurusaki M, Sofue K, et al. Comparison of gadoxetic acid-enhanced dynamic MR imaging and contrast-enhanced computed tomography for preoperative evaluation of colorectal liver metastases. Jpn J Radiol. 2017;35(4):197-205. 64. Sivesgaard K, Larsen LP, Sørensen M, et al. Diagnostic accuracy of CE-CT, MRI and FDG PET/CT for detecting colorectal cancer liver metastases in patients considered eligible for hepatic resection and/or local ablation. Eur Radiol. 2018;28(11):4735-4747. 65. Vilgrain V, Esvan M, Ronot M, Caumont-Prim A, Aubé C, Chatellier G. A meta-analysis of diffusion-weighted and gadoxetic acidenhanced MR imaging for the detection of liver metastases. Eur Radiol. 2016;26(12):4595-4615. 66. Zech CJ, Korpraphong P, Huppertz A, et al. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus conventional MRI or CT in the staging of colorectal cancer liver metastases. Br J Surg. 2014;101(6):613-621. 67. Kim C, Kim SY, Kim MJ, et al. Clinical impact of preoperative liver MRI in the evaluation of synchronous liver metastasis of colon cancer. Eur Radiol. 2018;28(10):4234-4242. 68. Sica GT, Ji H, Ros PR. CT and MR imaging of hepatic metastases. AJR Am J Roentgenol. 2000;174(3):691-698. 69. Owen JW, Fowler KJ, Doyle MB, Saad NE, Linehan DC, Chapman WC. Colorectal liver metastases: disappearing lesions in the era of Eovist hepatobiliary magnetic resonance imaging. HPB (Oxford). 2016;18(3):296-303.

CHAPTER 16 Imaging features of gallbladder and biliary tract disease Scott R. Gerst and Richard K. Do In the past decade, the combination of increased computing processing power and technologic improvements in acquisition across all modalities have imparted significant advances in medical imaging, including imaging of the biliary tract and gallbladder. This chapter will review current methods of evaluating the most common abnormalities of the biliary system. As the gallbladder resides in a somewhat anterior right upper quadrant location, ultrasound is ideal for initial imaging (Fig. 16.1), with computed tomography (CT) and magnetic resonance imaging (MRI) utilized for more complex cases. The intrahepatic bile ducts closely follow the portal venous system, merging from the left and right hepatic lobe into the right and left hepatic ducts. The confluence of the right and left hepatic ducts forms the main bile duct, which is called the common hepatic duct superiorly, and becomes the common bile duct (CBD) once the cystic duct inserts. The CBD becomes retroperitoneal at the level of the pancreatic head, typically joining the pancreatic duct just before entering the ampulla of Vater (see Chapter 2). On axial CT, the CBD is a circular structure of fluid attenuation (0–20 Hounsfield units [HUs]) within the posterolateral aspect of the pancreatic head on a contrast-enhanced scan. It is normally less than or equal to a 9-mm caliber, although a diameter up to 10 mm may be observed in elderly patients or in patients post-cholecystectomy. Measurement of the extrahepatic duct is usually performed near the crossing of the hepatic artery, with measurement of the lumen from inner wall to inner wall. Intrahepatic bile ducts are best evaluated by MRI due to its superior tissue contrast, particularly on T2-weighted images. Contrast-enhanced CT also demonstrates intrahepatic bile ducts in normal subjects. Delineation of variant biliary anatomy is possible on CT or MRI, particularly if the biliary tree is dilated (Fig. 16.2; see Chapter 2). Dilated intrahepatic ducts should measure greater than 2 mm, or greater than 40% of the adjacent portal vein. The “double-track” sign, traditionally described on ultrasound, is caused by dilated bile ducts running parallel to portal vein branches (Fig. 16.3). The pattern of bile duct dilatation should be assessed to determine whether it is symmetric or localized to a portion of the liver. Imaging can usually differentiate intrahepatic from extrahepatic, as well as the etiology, of obstruction (Fig. 16.4). When evaluating biliary and gallbladder disorders, MRI with MR cholangiopancreatography (MRCP) is an excellent method.1,2 A combination of heavily T2-weighted images for ductal anatomy, intermediate T2-weighted and T1-weighted images for surrounding structures, and diffusion-weighted imaging (DWI) provide a comprehensive evaluation of benign and malignant biliary abnormalities. Hepatic lesions, diffuse liver disease, adenopathy, or other visceral abnormalities are also evaluated with the addition of dynamic T1weighted sequences acquired with intravenous gadolinium

contrast. MRCP offers high sensitivity and specificity in evaluating ductal dilatation, strictures, and intraductal abnormalities.3–7 MRCP is noninvasive, or minimally invasive with the addition of intravenous contrast, eliminating the added morbidity associated with endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC).7,8

BENIGN DISEASES OF THE BILIARY TRACT Biliary Hamartoma Bile duct hamartomas are common benign tumors composed of disorganized bile ducts and ductules surrounded by a fibrocollagenous stroma. The tumors are generally multiple, range from 1 to 15 mm, rarely communicate with the biliary tree, and are scattered throughout the liver.9 They are most often confused with cysts, although they may also be mistaken for metastases or microabscesses with delayed marginal enhancement on CT or MRI.10,11 On MRI, they appear cystic (Fig. 16.5), and may show a small internal mural nodule related to the fibrocollagenous component (see Chapters 47, 48, and 88).

Bile Duct Adenoma Bile duct adenomas are rare benign epithelial neoplasms, usually incidentally detected and asymptomatic. They are usually solitary and without specific imaging findings, although hyperenhancement has been reported in some series.12 Definitive diagnosis can be made only at histologic analysis. Internal heterogeneous enhancement has been reported on MRI, with reported hypointensity on delayed hepatobiliary phase imaging using hepatocyte contrast agents13 (see Chapters 47 and 48).

Cholelithiasis Ultrasound is usually the modality of choice in the evaluation of uncomplicated cholelithiasis or cholecystitis due to its high sensitivity and lower cost, but choledocholithiasis is more effectively imaged by MRI.14 On MRI, gallstones are wellcircumscribed, low-signal filling defects within a fluid-filled gallbladder or common duct on T2-weighted and MRCP images (Fig. 16.6). Coronal T2-weighted imaging, performed routinely with MRI, readily identifies common duct stones. MRCP can also be obtained to evaluate whether retained stones are present after cholecystectomy, although surgical clip artifact may limit visualization of the adjacent portion of the main bile duct. A negative MRCP may obviate the need for ERCP (see Chapters 33 and 34). Given that most gallstones in Western countries are mixed cholesterol stones and noncalcified, CT is limited for stone detection, but it may reveal unsuspected gallstones during studies performed for other reasons. On CT, gallstones are visible when either calcified or containing material of substantially lower attenuation than the surrounding bile (such as trapped 249

250

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 16.1  Gallbladder. A, Normal longitudinal gallbladder image with visualization of the gallbladder neck. B, Thickened gallbladder wall (arrows) resulting from inflammation. Sludge (arrowheads) layers posteriorly. C, Gallbladder polyps (arrows). Note the lack of acoustic shadowing.

C

ha

pv

A

B

FIGURE 16.2  Contrast-enhanced computed tomography in a patient with a minimally dilated biliary system. A, The intrahepatic bile ducts are seen as branching, low-attenuation structures adjacent to the portal veins. At the porta hepatis, the hepatic artery (arrow) is seen to pass between the main portal vein (pv) and the common hepatic duct. B, Scan caudal to the porta hepatis shows the common hepatic duct and the cystic duct running adjacent to each other in the hepatoduodenal ligament (arrows). The hepatic artery (ha) is in a more medial position.

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

251

nitrogen gas or high cholesterol content). Newer dual energy CT techniques have shown promise in detecting noncalcified cholesterol stones and acute cholecystitis.15,16 On ultrasound, gallstones are echogenic, mobile, and demonstrate posterior acoustic shadowing when imaging is optimized and when 3 mm or greater in size (Fig. 16.7). Ultrasound is technique and operator dependent. It is important to scan patients in different positions to differentiate gallstones from polyps, as polyps are fixed. Optimized Doppler analysis may also help, as stones are associated with “twinkle artifact” and polyps often show vascularity. Stones fixed in the gallbladder neck are frequently associated with cholecystitis. If large stones or multiple stones fill the entire gallbladder lumen, there may be little surrounding bile, limiting ultrasound evaluation due to acoustic shadowing. Identification of the “wall echo shadow” sign, produced by echoes from the anterior gallbladder wall, echogenic stones, and posterior acoustic shadowing produced by the stones, is helpful (Fig. 16.8). A porcelain gallbladder has echogenic calcification in the gallbladder wall. Gallbladder sludge is echogenic nonshadowing bile that sometimes takes on a rounded shape called “tumefactive” sludge. Sludge can

FIGURE 16.3  Biliary obstruction from choledocholithiasis. A, Transverse sonogram of the liver reveals the “double-track” sign (circled areas), consistent with intrahepatic biliary dilatation.

m m v v v m

ivc

B

A

a v

C

FIGURE 16.4  Biliary obstruction and vascular encasement from adenopathy at the porta hepatis. A, Mass (m) obstructs a mildly dilated common bile duct (arrows) and involves the main portal vein (v). B, Nodal masses (m) encase the portal vein (v) that is markedly narrowed (arrows). Ivc, Inferior vena cava. C, Color Doppler image shows narrowed hepatic artery (a; arrow) with dilatation proximal to the encased segment. v, Portal vein.

252

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 16.5  Adult male with multiple biliary hamartomas. A, T2-weighted axial magnetic resonance imaging (MRI) with fat saturation shows multiple (arrows) high-signal cysticappearing foci. B, Axial T1-weighted fat saturation image acquired in portal venous phase post intravenous gadolinium, with subtraction of precontract image, shows lack of significant enhancement within the structures (arrows), and no abnormal surrounding parenchymal enhancement. C, Coronal T2-weighted MRI again demonstrates multiple high T2 cysticappearing lesions (arrows).

C

A

B

FIGURE 16.6  Choledocholithiasis. A, Coronal T2-weighted single-shot fast spin-echo image through the common duct in a patient after cholecystectomy shows multiple stones within the common bile duct. Note the distal stone impacted at the level of the ampulla (arrow). B, Axial T2weighted image with the same technique also shows a stone, surrounded by bile, in the distal common bile duct (arrow).

obscure the interfaces of small stones. Sludge is avascular, and it usually changes with positional variation, albeit slowly.

Choledocholithiasis and Biliary Obstruction MRCP is the imaging modality of choice for choledocholithiasis, as it has the highest sensitivity and specificity.8,16 Intrahepatic calculi are rare in Western countries, but they most frequently occur in association with iatrogenic bile duct strictures

(Fig. 16.9). Bile duct calculi appear as intraluminal filling defects on MRCP, or echogenic foci on ultrasound (Fig. 16.10). Calculi may form or reflux into intrahepatic ducts, and small calculi can be mistaken for air. Because there is little bile surrounding intraductal calculi, and because the stones may be small, acoustic shadowing may not always be elicited on ultrasound, which has poor sensitivity in detecting choledocholithiasis. On CT, dense intraluminal calcification or a target sign

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

253

FIGURE 16.9  Intrahepatic cholelithiasis. Intrahepatic duct dilation is seen after recurrent anastomotic stricture formation at a hepaticojejunostomy. Several laminated, noncalcified calculi can be seen within the dilated ductal system.

FIGURE 16.7  Gallstones (curved arrow) layering in the gallbladder produce an acoustic shadow (straight arrows).

gb

cbd

v

W E S

FIGURE 16.10  Choledocholithiasis. Longitudinal view of the common bile duct (cbd) shows an echogenic stone (arrow) that produces acoustic shadowing (arrowheads). gb, Gallbladder; v, portal vein.

FIGURE 16.8  Gallstones. Gallstones fill the gallbladder lumen, producing a wall-echo-shadow (WES) sign from the anterior gallbladder wall, the echogenic anterior surface of gallstones, and posterior acoustic shadowing by the gallstones.

representing a halo of bile surrounding a higher attenuation stone are reliable indicators of intraductal calculi. Cholesterol stones may blend imperceptibly with surrounding bile, although dual-energy CT may have value in demonstrating these stones as either hypoattenuating or hyperattenuating relative to bile, depending on the energy level.16 In addition, a minority of patients with choledocholithiasis have no biliary ductal dilatation (see Chapters 37–39 and 44).

On ultrasound, debris or thick bile within the ducts may cause internal echoes within ducts or fluid levels, but they do not shadow and will shift with positional variation. Adherent intraductal clot as well as intraductal tumors often show no associated acoustic shadowing and will not shift with position.17,18 Obstruction as a result of biliary ascariasis is associated with tubular structures within the bile duct, and movement of the worms is pathognomonic19 (see Chapter 45). MRI and MRCP are superior to CT, which is of less value when stones are small and noncalcified and bile duct dilation is minimal or absent. Intrahepatic choledocholithiasis may have an unusual appearance, with segmental or subsegmental biliary radicles filled with calculi (see Chapter 44). In Asian patients with recurrent pyogenic cholangitis who subsequently form bile pigment stones, the debris filling the biliary system generally has higher

254

PART 2  DIAGNOSTIC TECHNIQUES

attenuation than normal bile on CT. Marked bile duct dilation is present, and often the larger intrahepatic ducts are dilated without side-branch dilation. Eccentric and diffuse extrahepatic bile duct wall thickening is usually seen.20 In biliary obstruction, both the pattern of obstruction and appearance of the duct wall are useful for diagnosis. A spectrum of chronic progressive, cholestatic disorders exists, with etiologies varying from recurrent infection to autoimmune disorders, and unknown. Recurrent pyogenic cholangitis is related to repeated bacterial infections and is evidenced by dilated ducts with intraductal calculi and segmental dilatation (Fig. 16.11) (see Chapter 44). Lobar atrophy may also be present. Of note, intraductal papillary mucinous tumor of the bile ducts may be confused with recurrent pyogenic cholangitis on imaging, because both diseases involve repeated episodes of incomplete

A

biliary obstruction and evident intraluminal masses or filling defects (see Chapters 47 and 51).21 Sclerosing cholangitis may be primary and of unknown etiology, or secondary and due, for example, to autoimmune disorders, infection, or ischemia (see Chapter 41). It causes a beaded appearance of the ducts with wall thickening and enhancement, strictures, and discontinuous areas of dilatation (Fig. 16.12); dilated ducts contain debris such as pus, sludge, or sloughed epithelium. Primary sclerosing cholangitis (PSC) carries an increased risk of cholangiocarcinoma, and MRCP remains the most sensitive and specific noninvasive imaging modality to assess these patients and to detect concomitant cholangiocarcinoma.22,23 Mural thickening of the ducts also is seen with HIV-associated cholangiopathy; however, HIV-associated cholangiopathy often shows added papillary stenosis, a finding not typically seen in PSC.24

B

C

D FIGURE 16.11  Recurrent pyogenic cholangitis. A, Axial computed tomography (CT) image post intravenous contrast shows dilated low attenuation intrahepatic ducts (arrows). B, Axial T1 weighted in phase magnetic resonating imaging (MRI) shows lower signal than expected for bile (arrow). C, Axial T2-weighted fat saturation image confirms there is no high signal bile corresponding to the area of dilatation. D, Ultrasound confirms echogenic calculus (arrow) with acoustic shadowing (arrowheads) in this location.

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

A

255

B

FIGURE 16.12  Primary sclerosing cholangitis in a patient with ulcerative colitis. A, Coronal reconstructed computed tomography (CT) image post intravenous contrast shows periductal high attenuation enhancement (arrows) consistent with inflamed, thickened duct walls, with scattered bilobar dilated ducts (*). B, Coronal T2-weighted three-dimensional magnetic resonance cholangiopancreatography (3D MRCP) shows intrahepatic duct beaded appearance with dilatation (arrows), and multiple strictures (arrowheads).

In patients with biliary obstruction who are being considered for surgical resection or palliative biliary drainage, the distribution of ductal dilatation should be carefully evaluated to determine management. Any isolated biliary ductal segments that do not communicate with the main ducts should be noted, because isolated segments may alter surgical approach, and biliary drainage may require placement of multiple catheters.25

Hyperplastic Cholecystoses and Gallbladder Polyps Hyperplastic cholecystoses, such as cholesterolosis and adenomyomatosis (ADM), can cause focal or polypoid gallbladder wall thickening. Cholesterolosis results from abnormal cholesterol deposits in the gallbladder wall creating wall irregularities or polypoid intraluminal masses. Cholesterolosis usually presents as multiple small (1–10 mm) nonshadowing polyps arising from the nondependent wall with echogenic speckles and lobular contour on ultrasound. Cholesterol polyps are benign with no malignant potential.26,27 ADM is a benign hyperplastic cholecystosis with no known inherent malignant potential that results from hyperplasia of both the mucosa and muscularis propria of the gallbladder wall (see Chapter 49). ADM has an association with chronic inflammation and calculi, as does gallbladder carcinoma, and may confound the diagnosis of an underlaying carcinoma on imaging, particularly when segmental.28 Intramural diverticula are called Rokitansky-Aschoff sinuses; they trap bile that accumulates cholesterol crystals appearing as cystic spaces in a thickened gallbladder wall with a characteristic comet tail artifact on ultrasound in ADM27 (Fig. 16.13). On MRI, the normally low T2 signal gallbladder wall may appear focally and diffusely thickened, with multiple punctate intramural high T2 signal foci throughout. Focal wall thickening is most common in the fundus; when it occurs in the gallbladder body, there may be annular constriction producing an hourglass-shaped gallbladder.

FIGURE 16.13  Gallbladder adenomyomatosis with bright reflectors in the gallbladder wall (arrows) producing comet tail artifact secondary to sound reverberation.

The majority of incidentally detected polypoid gallbladder lesions are nonneoplastic and represent cholesterol polyps or inflammatory polyps.29 Rarely, these may be neoplastic, such as adenomatous polyps, and malignant transformation to adenocarcinoma is a concern (see Chapter 49). Adenomatous polyps tend to be solitary and uniformly hyperechoic, yet they become more heterogeneous as they increase in size; they may either be pedunculated or sessile. Thickening or irregularity of the gallbladder wall adjacent to a polyp may represent malignancy.

256

PART 2  DIAGNOSTIC TECHNIQUES

In patients with polypoid gallbladder lesions, risk factors for malignancy include patient age (.60 years), coexistence of gallstones, and size of the polypoid lesion (.10 mm in diameter).30 Surgical consultation for asymptomatic polyps greater than 10 mm and for symptomatic gallbladder polyps irrespective of size has been proposed.31 Often, asymptomatic gallbladder polyps smaller than 10 mm are followed sonographically; those smaller than 6 mm may be followed at extended intervals.32

Cholecystitis For the diagnosis of cholecystitis, ultrasound has moderate to high sensitivity and specificity.33 Ultrasound findings of acute calculous cholecystitis include gallstones, gallbladder wall thickening greater than 3 mm, pericholecystic fluid, and a positive sonographic Murphy sign. Gallstones, wall thickening, and Murphy sign together have a positive predictive value of 92% to 95%33 (Fig. 16.14). Of note, gallbladder wall thickening is nonspecific, and diffuse thickening without primary gallbladder disease occurs in systemic processes such as hypoalbuminemia, congestive heart failure, ascites, hepatitis, and pancreatitis.34 CT and MRI are generally not used for initial detection of acute cholecystitis. Occasionally, patients with cholecystitis display a confusing clinical picture and may undergo CT examination before the precise nature of the disease is clear, with MRI used as a problem-solving alternative, to further evaluate for choledocholithiasis or complicated cholecystitis (see Chapter 34). In emphysematous cholecystitis, echogenic air within the gallbladder wall produces reverberation artifact on ultrasound. In this entity, there is the possibility of gallbladder necrosis, gangrene, and perforation. Gangrenous cholecystitis occurs more often in patients with diabetes mellitus or a white blood cell count greater than 15,000 cells/mL.35 Ultrasound features of gangrenous cholecystitis include floating intraluminal membranes from sloughed mucosa, shadowing foci from air in the

A

gallbladder wall, disrupted gallbladder wall, and pericholecystic abscess formation.36 CT is preferable when evaluating for complications such as pericholecystic abscess, emphysematous cholecystitis, or gallbladder perforation, and can identify patients in need of emergency surgery. CT findings most specific for acute gangrenous cholecystitis are gas in the gallbladder wall or lumen, intraluminal membranes, irregular gallbladder wall enhancement, and pericholecystic abscess.37 Although gallbladder distension, wall thickening, and gallstones are often present in acute cholecystitis, these are nonspecific signs that occur in most patients with chronic cholecystitis as well. Ill-defined pericholecystic lucency on CT, or heterogeneous increased T2 signal on MRI within the hepatic parenchyma adjacent to the gallbladder, suggests gallbladder inflammation (Fig. 16.15).

Mirizzi Syndrome Mirizzi syndrome is an uncommon condition in which the common hepatic duct is obstructed extrinsically by calculi impacted in or extruded from a Hartmann pouch or adjacent cystic duct. Cholecystobiliary and cholecystoenteric fistulae are common complications, and there is an increased risk of malignancy of the gallbladder (see Chapter 49). It is clinically important to recognize the diagnosis preoperatively to address the cause of obstruction. The typical CT features of Mirizzi syndrome are an impacted gallstone (eccentrically located relative to the bile duct) and associated dilation of the proximal biliary system with a normal-caliber downstream system. An irregular cavity with surrounding edema and inflammation may be seen adjacent to the gallbladder neck (Fig. 16.16). Although all typical findings may not be present on CT, direct cholangiography or MRCP can be obtained to further evaluate the nature of the obstruction and to search for the presence of a biliary fistula.

B

FIGURE 16.14  Acute cholecystitis. A, Longitudinal sonogram shows a distended gallbladder with thickened irregular wall (arrows) and layering sludge (arrowheads). B, Computed tomographic scan shows gallbladder wall thickening (arrows).

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

257

Choledochal Cysts

FIGURE 16.15  Acute cholecystitis. Computed tomography shows a distended, thick-walled gallbladder with pericholecystic fluid. No gallstones are seen.

Choledochal cysts, a rare congenital anomaly that usually presents before 10 years of age, manifest as dilatation of the extrahepatic bile ducts with possible associated intrahepatic duct dilatation (see Chapter 46). The presenting classic triad includes a palpable mass, abdominal pain, and jaundice (need ref). Cysts may be associated with chronic inflammation and increased risk for cholangiocarcinoma. Five types of cysts have been described38–40: type I fusiform extrahepatic duct dilatation (Fig. 16.17), type II extrahepatic duct diverticulum, type III choledochocele from a dilated terminal CBD, type IV multifocal dilatation, and type V cystic dilatation of the intrahepatic bile ducts that is synonymous with Caroli disease. Caroli disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD).41 The cysts may be large, and the connection with the bile duct is not always evident on ultrasound. On imaging, it is important to demonstrate the connection with the bile ducts to differentiate this condition from multiple cysts or biliary hamartomas. Arterial flow from the fibrovascular bundle at the margin of the saccules and central enhancing portal venous branch or “central dot sign” may also aid in diagnosis on CT or MRI. Types I and IV have been further subdivided, and recently, there have been advocates for dropping the numeric classification system for more descriptive, clinically meaningful nomenclature.42 MRI is well suited to diagnose and classify these cysts. Not only can three-dimensional (3D) MR cholangiograms depict the normal and abnormal anatomy, but direct coronal imaging and delayed scans post hepatocyte-specific gadolinium-based contrast agents can be obtained for further evaluation.9

MALIGNANT BILIARY TUMORS Gallbladder Carcinoma

A

B FIGURE 16.16  Mirizzi syndrome. A, Contrast-enhanced computed tomography reveals a large calcified gallstone associated with gallbladder wall thickening and extensive pericholecystic inflammatory change (arrowheads). B, Extensive inflammatory change surrounds the internal biliary stent (arrow).

In 2020 there will be nearly 12,000 new cases of gallbladder carcinoma within the United States, with risk factors including female gender, age, and gallstones43,44 (see Chapter 49). Porcelain gallbladder, a term used to describe calcification within the gallbladder wall, places a patient at some increased risk for gallbladder carcinoma. Older studies suggested that 10% to 25% of patients with a porcelain gallbladder develop gallbladder carcinoma, but more recent reports indicate that the risk may be lower, probably less than 10%, and related to the type of calcification (lower risk with complete calcification of the entire wall compared with selective calcification).45–47 Many patients with gallbladder carcinoma are diagnosed with advanced disease, but the majority have earlier stage gallbladder carcinoma detected incidentally after elective cholecystectomy for symptomatic gallstone disease. The CT imaging appearances of gallbladder carcinoma include a mass replacing the gallbladder (seen in 40%–65% of patients), focal or diffuse gallbladder wall thickening (seen in 20%–30%) (Figs. 16.18 and 16.19), and an intraluminal polypoid mass (seen in 15%–25%) (Fig. 16.20).48,49 When the mass occupies the gallbladder lumen, it can result in a displaced or “trapped” stone that is fixed in position due to intraluminal tumor. Additional imaging findings associated with gallbladder carcinoma reflect the pattern of disease spread. The most common mode by which gallbladder carcinoma spreads is direct invasion into the adjacent organs. The liver is the organ most

258

PART 2  DIAGNOSTIC TECHNIQUES

B A

D

C

frequently invaded, followed by the bile duct, adjacent bowel, or pancreas. Air may be seen within the gallbladder lumen if tumor results in an enteric fistula. Tumors involving the infundibulum or cystic duct may invade directly and obstruct the CBD or portal vein, precluding surgical resection. MRI offers improved characterization of gallbladder cancer compared with other modalities. However, differentiation from concurrent inflammatory conditions may be difficult with any modality. As opposed to inflammation-associated wall thickening with maintained mucosal and submucosal layers, gallbladder cancer typically shows irregular intermediate to high T2

FIGURE 16.17  Type I choledochal cyst in a patient with upper abdominal pain and loose stools. A, Heavily T2-weighted coronal magnetic resonance cholangiopancreatography (MRCP) three-dimensional volume acquired image showing extrahepatic main duct fusiform dilatation (arrows). B, Coronal intermediate T2-weighted image showing surrounding structures. C, Coronal T1-weighted image post intravenous gadolinium administration. Note low signal choledochal cyst (*) and enhanced high signal portal vein (arrow). D, Coronal contrast-enhanced computed tomography (CT), showing low attenuation dilated main bile duct (*) consistent with type I choledochal cyst.

signal thickening of the gallbladder wall, with early and prolonged heterogeneous enhancement, often in patients with multiple gallstones.50 Cholelithiasis is a predisposing condition. On ultrasound, in addition to a mass involving the gallbladder wall or replacing the gallbladder, secondary signs of gallbladder cancer include discontinuity of the echogenic mucosal lining, absence of echogenic specks seen in cholesterol crystals, and high-velocity arterial flow greater than 60 cm/s (Fig. 16.21). Gallbladder carcinoma often contiguously extends into hepatic segments IVB and V, or into the hepatic hilum, possibly directly involving the main bile duct with secondary

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

biliary obstruction. Adjacent adenopathy may also be present. CT or MRI are the preferred modalities to accurately determine tumor resectability (see Chapter 119A) and distant disease spread, including peritoneal metastases.51,52 Although CT remains the standard for initial imaging for gallbladder carcinomas, with reported overall accuracy of 85%, MRI offers similar accuracy for evaluating the primary tumor or hepatic metastases, with improved soft tissue contrast.53,54

259

DWI offers added sensitivity and specificity for extent of the primary tumor, and simultaneous ability to better assess for regional nodal or hepatic metastatic disease.50 Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may also provide improved sensitivity and specificity for nodal or distant metastatic disease.55 In the era of laparoscopic surgery for gallstone disease, it is important to assess the gallbladder carefully on preoperative ultrasound to exclude occult gallbladder cancer and to plan an appropriate surgical approach. Approximately 47% of gallbladder carcinomas are detected incidentally at laparoscopic cholecystectomy.56 A serious potential complication of laparoscopic cholecystectomy is the inadvertent dissemination of unsuspected gallbladder carcinoma including involvement along the port tracts and abdominal wall (Fig. 16.22).57 For patients with incidental discovery of carcinoma on laparoscopic cholecystectomy, re-exploration with definitive resection and re-excision of laparoscopic port sites is recommended.56,58

Extrahepatic Cholangiocarcinoma

FIGURE 16.18  Contrast-enhanced computed tomography reveals focal gallbladder wall thickening (arrows) in a patient with gallbladder cancer.

A

C

Cholangiocarcinoma is a relatively rare adenocarcinoma of the bile duct epithelium presenting mostly after the sixth decade of life (see Chapter 51). Although most patients have no known risk factors, conditions conferring increased risk include liver fluke infestation (see Chapter 45), PSC (see Chapter 41), choledochal cyst (including Caroli disease; see Chapter 46), hepatolithiasis (see Chapters 39 and 44), bile stasis, abnormal choledochopancreatic junction, hepatitis C viral infection, cirrhosis, alcoholic liver disease, ulcerative colitis, type 2 diabetes, thyrotoxicosis, and pancreatitis.59

B

FIGURE 16.19  Gallbladder carcinoma. A, Patient with fatty liver. Screening ultrasound revealed irregular nodular soft tissue involving the gallbladder fundus with poor delineation of surrounding wall (arrows). B, Axial computed tomography (CT) shows enhancement of the soft tissue (*) with infiltrated fat plane between gallbladder fundal wall and liver (arrow). C, Axial T2weighted magnetic resonance imaging (MRI) also shows poor delineation of the wall and obliteration of fat plane between gallbladder wall and liver (arrow). Pathology showed adenocarcinoma, with tumor invasion of the perimuscular connective tissue adjacent to liver.

260

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 16.20  Gallbladder carcinoma. The gallbladder is distended and contains calcified stones. Nodular soft tissue emanates from the gallbladder wall into the lumen (arrow).

A

B FIGURE 16.21  Gallbladder carcinoma. A, Gray scale longitudinal image of the gallbladder shows a solid irregular mass in the fundus. B, Transverse color Doppler image of this lesion demonstrates internal vascularity, suspicious for tumor. Pathology demonstrated gallbladder adenocarcinoma.

FIGURE 16.22  Contrast-enhanced computed tomography in a patient who had previously undergone laparoscopic cholecystectomy. The enhancing mass (arrow) within the anterior abdominal wall reflects recurrent gallbladder carcinoma within a laparoscopic port tract.

In 1997 the Liver Cancer Study Group of Japan categorized cholangiocarcinoma into three subtypes based on macroscopic appearance (mass forming, periductal infiltrating, and intraductal growing), corresponding in older literature to the terms “nodular,” “sclerosing/infiltrating,” and either “exophytic” or “papillary,” respectively (see Chapter 47). A combination of periductal infiltrating and mass-forming types is also common. Cholangiocarcinoma has also been divided by the seventh edition of the American Joint Committee on Cancer Staging Manual60 into perihilar, distal, and intrahepatic types, which are distinct clinical and radiologic entities61 (see Chapter 51). The perihilar location is most common at 60% to 70% and is generally associated with a component of biliary obstruction, whereas distal sites are less common at 20% to 30%, and intrahepatic is the least common at 5% to 15%.62,63 Preoperative high-resolution CT or MRI with MRC are typically used to address the following factors that determine resectability per the staging system for hilar cholangiocarcinoma developed by Jarnagin and colleagues25: level and extent of tumor, vascular invasion, hepatic lobar atrophy, and distant metastatic disease (Fig. 16.23) (see Chapters 51B and 119B). On MRI, bile duct tumors typically show intermediate, mildly increased T2 signal that is less bright than fluid in the dilated bile ducts. The level of obstruction and continuity of the tumor with the vasculature are well evaluated with MRI.64 CT angiography with multiphasic imaging offers improved spatial resolution to MRI, with similar accuracy to assess vascular involvement. Tumor extent along the portal veins and hepatic arteries can also be identified with multiphase CT angiography. CT is the preferred modality to assess for distant metastases.65 Focused assessment of ductal, portal venous, and hepatic arterial involvement is performed in staging and preoperative imaging. The portal vein and hepatic artery status and extent of ductal spread help determine surgical approach, because longterm survival is possible only with en bloc resection of the liver and the extrahepatic biliary ducts.66

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

261

pv

ivc

B

A

rpv

C

On CT, individual dilated bile ducts can be traced to the point(s) of obstruction (Fig. 16.24), and to evaluate the cause of biliary obstruction. On meta-analysis,67 multidetector row CT (MDCT) has a sensitivity and specificity of 89% and 92%, respectively, for portal venous involvement, and 84% and 93%, respectively, for hepatic arterial involvement (and 86% accuracy in assessing extent of ductal involvement). Moderate lobar atrophy is typically caused by long-standing obstruction of the ipsilateral bile duct; however, associated portal venous obstruction causes rapid and marked atrophy of the affected lobe (Fig. 16.25).66,68 Atrophy should also be recognized and reported when biliary decompression is under consideration, because drainage of an atrophic lobe does not relieve jaundice and is only indicated to relieve biliary sepsis.66

FIGURE 16.23  Klatskin tumor. A, Longitudinal view of the common hepatic duct shows a tapered segment (arrow) consistent with tumor stricture. ivc, Inferior vena cava; pv, portal vein. B, Transverse image at the biliary confluence reveals an echogenic mass (arrow) at the bifurcation and dilated bile ducts in both lobes. C, The left portal vein is narrowed and encased (arrows), as shown on color Doppler transverse image. rpv, Right portal vein.

Perihilar tumors of the periductal infiltrating morphologic subtype often appear as focal duct wall thickening with obliteration of the lumen,61 but may only manifest as ductal enhancement or merely narrowing. Although most biliary strictures are malignant, correlation with serum IgG4 levels may better assess for possible IgG4 sclerosing cholangitis (see Chapter 42). Malignant strictures tend to be longer ($18–22 mm) and have a thicker wall ($2 mm) than benign strictures, and they may show bile duct hyperenhancement.69 Mass-forming perihilar tumors, like their intrahepatic counterparts, are heterogeneous hypovascular masses with peripheral rim enhancement in the arterial and portal phase and central enhancement in delayed phases. In perihilar malignancies, hypoenhancing soft tissue infiltration of adjacent periductal fat may also be visible with delayed-phase

262

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 16.24  Cholangiocarcinoma. Contrast-enhanced computed tomography at two levels through the liver (left and right) reveals bilobar central intrahepatic biliary duct dilation as a result of an obstructing enhancing mass at the hepatic hilum (arrow).

FIGURE 16.25  Infiltrative hilar cholangiocarcinoma. Reformatted oblique axial image. The infiltrative mass (long arrow) in the left hepatic lobe causes left intrahepatic biliary ductal dilation (short arrows). Tumor extends along the central portion of the right portal vein with mild atrophy of the left lobe.

hyperenhancement, although this infiltration may sometimes be hypervascular (Fig. 16.26).59 Although operator dependent, ultrasound in expert hands may be helpful in the preoperative imaging evaluation of local tumor extent for hilar tumors but should be performed before intervention or stent placement to avoid pneumobilia and artifact, which may obscure both tumor and level of obstruction after biliary decompression. The majority of hilar cholangiocarcinomas are isoechoic, which renders their delineation challenging on ultrasound as well.

On ultrasound, extrahepatic cholangiocarcinoma may show infiltrative tumor spread along the duct walls, nodular mural thickening, or appear papillary. Intraductal papillary neoplasms of the bile duct (IPNBs) (see Chapter 60), including mucinous cystic neoplasm of the bile duct, may be intrahepatic or extrahepatic, typically manifest as a polypoid expansile intraductal mass, and have a better prognosis and surgical outcome (Fig. 16.27).70,71 Contrast-enhanced ultrasound (CEUS) in experienced hands may also aid the diagnosis and staging of cholangiocarcinoma.72,73 Ultrasound and CEUS are focused on local tumor extent and are preferably performed before any intervention. CT and MRI remain essential for evaluation of regional and distant disease, even if the tumor is visible on ultrasound. The least common intraductal-growing tumor subtype (8%–18%) predominantly shows multiple lesions along various segments of the bile ducts with papillary histologic features differentiating them from the other types of cholangiocarcinoma.74 The World Health Organization endorses the term “intraductal papillary neoplasm of the bile ducts” to encompass all variants of biliary intraductal neoplasia, which has been recognized as a biliary counterpart of pancreatic intraductal papillary mucinous neoplasm. These tumors, particularly the mucin-secreting subtype, are more often resectable with a more favorable prognosis.75 On CT, asymmetric biliary dilation is usually noted with enhancing, expansile, and well-defined intraductal soft tissue mass in the most dilated ducts. Unlike mass-forming or periductal-infiltrating subtypes, there is no invasion of adjacent liver parenchyma.59,61

DISTAL CHOLANGIOCARCINOMA The periductal infiltrating subtype is also the most common form involving the CBD. The radiologic and pathologic features are identical to those perihilar in location. The assessment and treatment of distal bile duct cancers is similar to that of pancreatic head carcinoma76 (see Chapters 59 and 117A). The less common intraductal subtype of cholangiocarcinoma is most often found involving the CBD. Imaging features are identical to its appearance in the perihilar region. Enhancement

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

A

C

of the mass is generally noted where tumor remains fixed along the duct wall, and there may be segmental asymmetric thickening and enhancement of the duct wall. The subset of intraductal mucinous tumors, considered a precursor to cholangiocarcinoma, may cause marked extra or intrahepatic duct dilatation, with low attenuation mucin on CT, high T2 signal on MRI, and hypoechoic or anechoic findings on ultrasound. The tumors may be small and not visible on imaging, or larger and fungating, with some tumors friable with sloughing resulting in intermittent or partial biliary obstruction.21,77

Biliary Cystic Tumors (Cystadenoma and Cystadenocarcinoma) Biliary cystadenomas (BCAs) are uncommon benign cystic lesions that occur predominantly (90%) in women between 42

263

B

FIGURE 16.26  Hilar cholangiocarcinoma in a patient with painless jaundice. A, Axial contrast-enhanced computed tomography (CT) shows hilar hypoenhancing biopsy–proven cholangiocarcinoma (*) inseparable from right hepatic artery (arrow). Note hyperattenuating biliary stent (arrowheads). B, Axial CT image at another level confirms tumor (*) abutting the portal vein at its bifurcation, with greater abutment of the right portal vein (arrow). C, Coronal reconstructed CT image shows periportal lymphadenopathy (*) suspicious for metastatic disease.

and 55 years of age and are more common within the left lobe (see Chapters 47 and 88B). Although benign, these lesions may recur after excision and have the potential to develop into biliary cystadenocarcinomas (BCACs). BCACs at presentation are more evenly distributed between men and women and generally occur a decade later.78 BCAs are most often intrahepatic (83%), but they may also occur within the extrahepatic bile ducts (13%) or gallbladder (0.02%). On CT, biliary cystic tumors (BCTs) tend to be multiloculated cystic lesions with internal septations; only rarely are they unilocular (Fig. 16.28). The attenuation of the cyst fluid depends on its content, which may be hemorrhagic, mucinous, proteinaceous, or bilious. Calcifications may be present within the wall of the cyst or within septa, and septa may enhance with intravenous contrast (Fig. 16.29). Although ultrasound and

264

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D

FIGURE 16.27  Intraductal papillary carcinoma. A, Axial T2-weighted magnetic resonance (MR) image shows expanded right intrahepatic bile duct (arrows) with heterogeneous filling defect (*). B, Axial T1-weighted fat saturated MR image shows marginal high T1 signal (arrow) along the filling defect (*). C, Coronal three-dimensional (3D) MR cholangiopancreatography volume acquired image also shows the expanded duct and intraductal mass (*). D, Axial ultrasound image in the region of interest shows marginal echogenic apparent calculus (arrow) with acoustic shadowing (arrowheads). Pathology revealed 1-cm intraductal papillary carcinoma, with marginal pigment stones accounting for the high T1 signal in (B).

FIGURE 16.28  Biliary cystadenoma. Contrast-enhanced computed tomography reveals a large cystic mass with a very subtle internal septation (curved arrows).

FIGURE 16.29  Recurrent biliary cystadenoma after resection. Multiloculated cystic lesion is seen at the resection margin containing enhancing septa and calcification.

  Chapter 16  Imaging Features of Gallbladder and Biliary Tract Disease

A

265

B

FIGURE 16.30  Afferent loop syndrome. A, Coronal T2-weighted sequence in a patient after pancreaticoduodenectomy for pancreatic carcinoma. The patient has a hepaticojejunostomy with a patent anastomosis (white arrow). The afferent loop is markedly dilated (black arrow) compared with other loops of bowel. No mechanical obstruction was noted. B, Axial T2-weighted image through the level of the anastomosis (arrow) shows the site to be patent without evidence of a stricture. The afferent loop is dilated.

MRI are considered more sensitive than CT for detection of septa and complexity, the accuracy of imaging in distinguishing the different types of complex and simple hepatic cystic lesions from BCA remains low.78,79 Multiple studies have also shown no reliable imaging features to predict BCAC over BCA in the absence of gross tumor.80,81

(MR) Postoperative Biliary Complications Complications from surgical procedures include bile leaks, abscess formation, and biliary strictures (see Chapters 28, 117A, 188, and 119). MRCP is uniquely suited for the assessment of the postoperative biliary tract, including the assessment of bile leaks and abscesses. Bile duct injuries after surgery can be multifactorial, but the result is commonly a stricture at the anastomotic site

(see Chapters 42 and 52). Surgical clips near the anastomosis may create streak artifacts during CT scanning, but contemporary clips are less problematic for MRI. MRI has multiplanar capabilities and superior tissue contrast, and MRCP sequences can minimize susceptibility to artifacts to allow improved visualization of the region of the anastomosis and improved diagnostic confidence (Fig. 16.30). More recently, hepatocyte contrast agents also allow delayed hepatobiliary phase scans by opacifying the biliary tree, which may improve diagnostic confidence to evaluate for active biliary leak, anatomic variants, and choledocholithiasis.9,82 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

265.e1

REFERENCES 1. Mandelia A, Gupta AK, Verma DK, Sharma S. The value of Magnetic Resonance Cholangio-Pancreatography (MRCP) in the detection of choledocholithiasis. J Clin Diagn Res. 2013;7(9):1941-1945. 2. Singh A, Mann HS, Thukral CL, Singh NR. Diagnostic accuracy of MRCP as compared to Ultrasound/CT in patients with obstructive jaundice. J Clin Diagn Res. 2014;8(3):103-107. 3. Hekimoglu K, Ustundag Y, Dusak A, et al. MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J Dig Dis. 2008;9(3):162-169. 4. Palmucci S, Mauro LA, Coppolino M, et al. Evaluation of the biliary and pancreatic system with 2D SSFSE, breathhold 3D FRFSE and respiratory-triggered 3D FRFSE sequences. Radiol Med. 2010; 115(3):467-482. 5. Palmucci S, Mauro LA, La Scola S, et al. Magnetic resonance cholangiopancreatography and contrast-enhanced magnetic resonance cholangiopancreatography versus endoscopic ultrasonography in the diagnosis of extrahepatic biliary pathology. Radiol Med. 2010;115(5):732-746. 6. Sandrasegaran K, Lin C, Akisik FM, Tann M. State-of-the-art pancreatic MRI. AJR Am J Roentgenol. 2010;195(1):42-53. 7. Xu YB. Magnetic resonance cholangiography in assessing biliary anatomy in living donors: a meta-analysis. World Journal of Gastroenterology. 2013;19(45):8427. 8. Chen W, Mo JJ, Lin L, Li CQ, Zhang JF. Diagnostic value of magnetic resonance cholangiopancreatography in choledocholithiasis. World J Gastroenterol. 2015;21(11):3351-3360. 9. Gupta RT, Brady CM, Lotz J, Boll DT, Merkle EM. Dynamic MR imaging of the biliary system using hepatocyte-specific contrast agents. Am J Roentgenol. 2010;195(2):405-413. 10. Lev-Toaff AS, Bach AM, Wechsler RJ, Hilpert PL, Gatalica Z, Rubin R. The radiologic and pathologic spectrum of biliary hamartomas. AJR Am J Roentgenol. 1995;165(2):309-313. 11. Nagano Y, Matsuo K, Gorai K, et al. Bile duct hamartomas (von Mayenburg complexes) mimicking liver metastases from bile duct cancer: MRC findings. World J Gastroenterol. 2006;12(8):1321-1323. 12. Chuy JA, Garg I, Graham RP, VanBuren WM, Venkatesh SK. Imaging features of bile duct adenoma: case series and review of literature. Diagn Interv Radiol. 2018;24(5):249-254. 13. Kim YS, Rha SE, Oh SN, et al. Imaging findings of intrahepatic bile duct adenoma (peribiliary gland hamartoma): a case report and literature review. Korean J Radiol. 2010;11(5):560-565. 14. Lee SL, Kim HK, Choi HH, et al. Diagnostic value of magnetic resonance cholangiopancreatography to detect bile duct stones in acute biliary pancreatitis. Pancreatology. 2018;18(1):22-28. 15. Yang CB, Zhang S, Jia YJ, et al. Clinical application of dual-energy spectral computed tomography in detecting cholesterol gallstones from surrounding bile. Acad Radiol. 2017;24(4):478-482. 16. Ratanaprasatporn L, Uyeda JW, Wortman JR, Richardson I, Sodickson AD. Multimodality Imaging, including Dual-Energy CT, in the evaluation of gallbladder disease. Radiographics. 2018;38(1): 75-89. 17. Ghittoni G, Caturelli E, Viera FT. Intrabile duct metastasis from colonic adenocarcinoma without liver parenchyma involvement: contrast enhanced ultrasonography detection. Abdom Imaging. 2010;35(3):346-348. 18. Jhaveri KS, Halankar J, Aguirre D, et al. Intrahepatic bile duct dilatation due to liver metastases from colorectal carcinoma. AJR Am J Roentgenol. 2009;193(3):752-756. 19. Lim JH. Radiologic findings of clonorchiasis. AJR Am J Roentgenol. 1990;155(5):1001-1008. 20. Schulte SJ, Baron RL, Teefey SA, et al. CT of the extrahepatic bile ducts: wall thickness and contrast enhancement in normal and abnormal ducts. AJR Am J Roentgenol. 1990;154(1):79-85. 21. Lim JH, Yoon KH, Kim SH, et al. Intraductal papillary mucinous tumor of the bile ducts. Radiographics. 2004;24(1):53-66; discussion 66-67. 22. Satiya J, Mousa OY, Gupta K, et al. Diagnostic yield of magnetic resonance imaging for cholangiocarcinoma in primary sclerosing cholangitis: a meta-analysis. Clin Exp Hepatol. 2020;6(1):35-41. 23. Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in patients with Primary Sclerosing Cholangitis (PSC): a comprehensive review. Clin Rev Allergy Immunol. 2020;58(1):134-149.

24. Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44(5):1063-1074. 25. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507-517; discussion 517–519. 26. Ito H, Hann LE, D’Angelica M, et al. Polypoid lesions of the gallbladder: diagnosis and followup. J Am Coll Surg. 2009;208(4): 570-575. 27. Levy AD, Murakata LA, Abbott RM, Rohrmann Jr CA. From the archives of the AFIP. Benign tumors and tumorlike lesions of the gallbladder and extrahepatic bile ducts: radiologic-pathologic correlation. Armed Forces Institute of Pathology. Radiographics. 2002; 22(2):387-413. 28. Morikawa T, Okabayashi T, Shima Y, et al. Adenomyomatosis concomitant with primary gallbladder carcinoma. Acta Med Okayama. 2017;71(2):113-118. 29. Corwin MT, Siewert B, Sheiman RG, Kane RA. Incidentally detected gallbladder polyps: is follow-up necessary?—Long-term clinical and US analysis of 346 patients. Radiology. 2011;258(1): 277-282. 30. Terzi C, Sokmen S, Seckin S, Albayrak L, Ugurlu M. Polypoid lesions of the gallbladder: report of 100 cases with special reference to operative indications. Surgery. 2000;127(6):622-627. 31. Wiles R, Varadpande M, Muly S, Webb J. Growth rate and malignant potential of small gallbladder polyps—systematic review of evidence. Surgeon. 2014;12(4):221-226. 32. Pedersen MR, Dam C, Rafaelsen SR. Ultrasound follow-up for gallbladder polyps less than 6 mm may not be necessary. Dan Med J. 2012;59(10):A4503. 33. Smith EA, Dillman JR, Elsayes KM, Menias CO, Bude RO. Crosssectional imaging of acute and chronic gallbladder inflammatory disease. AJR Am J Roentgenol. 2009;192(1):188-196. 34. van Breda Vriesman AC, Engelbrecht MR, Smithuis RH, Puylaert JB. Diffuse gallbladder wall thickening: differential diagnosis. AJR Am J Roentgenol. 2007;188(2):495-501. 35. Fagan SP, Awad SS, Rahwan K, et al. Prognostic factors for the development of gangrenous cholecystitis. Am J Surg. 2003;186(5): 481-485. 36. Schiappacasse G, Soffia P, Silva C, Villacres F. Computed tomography imaging of complications of acute cholecystitis. Indian J Radiol Imaging. 2018;28(2):195-199. 37. Bennett GL, Rusinek H, Lisi V, et al. CT findings in acute gangrenous cholecystitis. AJR Am J Roentgenol. 2002;178(2):275-281. 38. Lee HK, Park SJ, Yi BH, Lee AL, Moon JH, Chang YW. Imaging features of adult choledochal cysts: a pictorial review. Korean J Radiol. 2009;10(1):71-80. 39. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134(2):263-269. 40. Singham J, Yoshida EM, Scudamore CH. Choledochal cysts: part 1 of 3: classification and pathogenesis. Can J Surg. 2009;52(5): 434-440. 41. Sato Y, Ren XS, Nakanuma Y. Caroli’s disease: current knowledge of its biliary pathogenesis obtained from an orthologous rat model. Int J Hepatol. 2012;2012:107945. 42. Visser BC, Suh I, Way LW, Kang SM. Congenital choledochal cysts in adults. Arch Surg. 2004;139(8):855-860. 43. American Cancer Society. Cancer Statistics Center. Estimated New Cases, 2020 2020; http://cancerstatisticscenter.cancer.org. 44. Rustagi T, Dasanu CA. Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates. J Gastrointest Cancer. 2012;43(2):137-147. 45. Kim JH, Kim WH, Yoo BM, Kim JH, Kim MW. Should we perform surgical management in all patients with suspected porcelain gallbladder? Hepatogastroenterology. 2009;56(93):943-945. 46. Jones MW, Weir CB, Ferguson T. Porcelain gallbladder. In: StatPearls. Treasure Island, FL: 2020. 47. Khan ZS, Livingston EH, Huerta S. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg. 2011;146(10): 1143-1147. 48. Franquet T, Montes M, Ruiz de Azua Y, Jimenez FJ, Cozcolluela R. Primary gallbladder carcinoma: imaging findings in 50 patients with pathologic correlation. Gastrointest Radiol. 1991;16(2):143-148.

265.e2 49. Lane J, Buck JL, Zeman RK. Primary carcinoma of the gallbladder: a pictorial essay. Radiographics. 1989;9(2):209-228. 50. Tan CH, Lim KS. MRI of gallbladder cancer. Diagn Interv Radiol. 2013;19(4):312-319. 51. Bach AM, Loring LA, Hann LE, Illescas FF, Fong Y, Blumgart LH. Gallbladder cancer: can ultrasonography evaluate extent of disease? J Ultrasound Med. 1998;17(5):303-309. 52. Sandrasegaran K, Menias CO. Imaging and screening of cancer of the gallbladder and bile ducts. Radiol Clin North Am. 2017;55(6): 1211-1222. 53. Kalra N, Gupta P, Singhal M, et al. Cross-sectional imaging of gallbladder carcinoma: an update. J Clin Exp Hepatol. 2019;9(3): 334-344. 54. Dai MH, Fong YM, Lowy A. Treatment of T3 gallbladder cancer. J Gastrointest Surg. 2009;13(11):2040-2042. 55. Lee SW, Kim HJ, Park JH, et al. Clinical usefulness of 18F-FDG PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol. 2010;45(5):560-566. 56. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol Suppl. 2008;98(7):485-489. 57. Winston CB, Chen JW, Fong Y, Schwartz LH, Panicek DM. Recurrent gallbladder carcinoma along laparoscopic cholecystectomy port tracks: CT demonstration. Radiology. 1999;212(2): 439-444. 58. D’Angelica M, Dalal KM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Analysis of the extent of resection for adenocarcinoma of the gallbladder. Ann Surg Oncol. 2009;16(4):806-816. 59. Valls C, Ruiz S, Martinez L, Leiva D. Radiological diagnosis and staging of hilar cholangiocarcinoma. World J Gastrointest Oncol. 2013;5(7):115-126. 60. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471-1474. 61. Han JK, Choi BI, Kim AY, et al. Cholangiocarcinoma: pictorial essay of CT and cholangiographic findings. Radiographics. 2002; 22(1):173-187. 62. Matos C, Serrao E, Bali MA. Magnetic resonance imaging of biliary tumors. Magn Reson Imaging Clin N Am. 2010;18(3): 477-496, x. 63. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol. 2006;3(1):33-42. 64. Peporte AR, Sommer WH, Nikolaou K, Reiser MF, Zech CJ. Imaging features of intrahepatic cholangiocarcinoma in Gd-EOB-DTPAenhanced MRI. Eur J Radiol. 2013;82(3):e101-e106. 65. Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol. 2009;15(34):4240-4262. 66. Jarnagin W, Winston C. Hilar cholangiocarcinoma: diagnosis and staging. HPB (Oxford). 2005;7(4):244-251.

67. Ruys AT, van Beem BE, Engelbrecht MR, Bipat S, Stoker J, Van Gulik TM. Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis. Br J Radiol. 2012;85(1017):1255-1262. 68. Friesen BR, Gibson RN, Speer T, Vincent JM, Stella D, Collier NA. Lobar and segmental liver atrophy associated with hilar cholangiocarcinoma and the impact of hilar biliary anatomical variants: a pictorial essay. Insights Imaging. 2011;2(5):525-531. 69. Choi SH, Han JK, Lee JM, et al. Differentiating malignant from benign common bile duct stricture with multiphasic helical CT. Radiology. 2005;236(1):178-183. 70. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg. 2005;241(5):703-712; discussion 712-714. 71. Kendall T, Verheij J, Gaudio E, et al. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int. 2019;39(suppl 1):7-18. 72. Lim JH, Jang KT, Choi D, Lee WJ, Lim HK. Early bile duct carcinoma: comparison of imaging features with pathologic findings. Radiology. 2006;238(2):542-548. 73. Xu HX, Chen LD, Xie XY, et al. Enhancement pattern of hilar cholangiocarcinoma: contrast-enhanced ultrasound versus contrastenhanced computed tomography. Eur J Radiol. 2010;75(2):197-202. 74. Engelbrecht MR, Katz SS, van Gulik TM, Lameris JS, van Delden OM. Imaging of perihilar cholangiocarcinoma. AJR Am J Roentgenol. 2015;204(4):782-791. 75. Wang X, Cai YQ, Chen YH, Liu XB. Biliary tract intraductal papillary mucinous neoplasm: report of 19 cases. World J Gastroenterol. 2015;21(14):4261-4267. 76. Blumgart LH, Fong Y, Jarnagin WR, American Cancer Society. Hepatobiliary cancer. Hamilton, Ont. Lewiston, NY: B C Decker: Sales and distribution, US, B.C. Decker; 2001. 77. Lim JH, Kim MH, Kim TK, et al. Papillary neoplasms of the bile duct that mimic biliary stone disease. Radiographics. 2003;23(2):447-455. 78. Soares KC, Arnaoutakis DJ, Kamel I, et al. Cystic neoplasms of the liver: biliary cystadenoma and cystadenocarcinoma. J Am Coll Surg. 2014;218(1):119-128. 79. Doussot A, Gluskin J, Groot-Koerkamp B, et al. The accuracy of pre-operative imaging in the management of hepatic cysts. HPB (Oxford). 2015;17(10):889-895. 80. Arnaoutakis DJ, Kim Y, Pulitano C, et al. Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor. Ann Surg. 2015;261(2):361-367. 81. Buetow PC, Buck JL, Pantongrag-Brown L, et al. Biliary cystadenoma and cystadenocarcinoma: clinical-imaging-pathologic correlations with emphasis on the importance of ovarian stroma. Radiology. 1995;196(3):805-810. 82. Boraschi P, Donati F. Postoperative biliary adverse events following orthotopic liver transplantation: assessment with magnetic resonance cholangiography. World J Gastroenterol. 2014;20(32):11080-11094.

CHAPTER 17 Imaging features of benign and malignant pancreatic disease Shannan M. Dickinson and Seth S. Katz INTRODUCTION TO PANCREATIC IMAGING Transabdominal ultrasound (US) is a noninvasive, inexpensive, and rapid method of evaluating morphologic changes in the pancreas and may be used as an initial investigation in the setting of abdominal pain or suspected obstructive jaundice. However, considerable limitations reduce its diagnostic utility; these include overlying bowel gas obscuring the pancreas and limitations related to the patient’s body habitus.1 If a pancreatic mass or parenchymal abnormality is found at US, further assessment with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. If CT is performed in the workup of a pancreatic mass, particularly in suspected pancreatic ductal adenocarcinoma (PDAC), it should be performed as a multiphase pancreatic protocol study, with imaging in the pancreatic parenchymal/late arterial phase and the portal venous phase. MRI with Magnetic resonance cholangiopancreatography (MRCP) is also a mainstay of pancreatic imaging and can provide detailed assessment of the pancreatic and bile ducts. Secretin-enhanced MRCP is an advanced imaging technique, with limited availability. The technique can be used to improve visualization and assessment of the pancreatic ductal system and to assess exocrine gland function.2

CONGENITAL CONDITIONS, VARIANTS, AND BENIGN ALTERATIONS Pancreatic Divisum Pancreatic divisum is the most common congenital pancreatic ductal anatomic variant, resulting from failure of fusion of the ventral and dorsal pancreatic anlages (Fig. 17.1; see Chapters 1 and 53). This results in the majority of pancreatic parenchyma draining via the dorsal duct into the minor papilla.3 The ventral duct, which generally does not communicate with the dorsal duct,3 joins the common bile duct to empty into the major papilla. Pancreas divisum may be seen on high-spatial-resolution and thin-section multidetector CT4; however, MRI is generally superior in visualizing the pancreatic duct, with T2 sequences offering similar visualization to dedicated MRCP sequences.5 MRI will demonstrate the dominant dorsal duct emptying into the minor papilla, superior to the level of the bile duct, with the ventral duct sometimes too small to discretely visualize on MRI6 or even absent.3

Annular Pancreas Annular pancreas is present when a complete or incomplete ring of pancreatic tissue encircles the second portion of the duodenum (D2; Fig. 17.2; see Chapters 1 and 53).7 MRI will demonstrate the encircling, or partially encircling pancreatic 266

tissue, and sometimes the small associated annular duct that drains the annular portion.6 An incomplete ring is demonstrated by pancreatic tissue extending in both a posterolateral and anterolateral direction around the D2 or, in some cases, only in the posterolateral direction.7 Pancreatic tissue extending only in an anterolateral direction around the D2 is less specific for incomplete annular pancreas.7

Fatty Infiltration Fatty replacement of pancreatic tissue may be focal or diffuse and can occur in diabetic, obese, or elderly patients.6,8 Complete fatty replacement of the pancreas is seen most commonly in patients with cystic fibrosis or Schwachman-Diamond syndrome.6,8 In severe cases, the pancreas will be clearly visible and will have the same density (CT) or signal (MRI) to the mesenteric fat (Fig. 17.3).8 In this setting, the presence of the ductal system differentiates fatty replacement from agenesis.8 Fatty replacement may not be homogeneous, with the anterior pancreatic head more severely affected, compared with the posterior pancreatic head peribiliary tissue, which can be spared.8,9 This nonhomogeneous fatty replacement may mimic a mass or neoplasm on CT (Fig. 17.4); however, MRI can usually differentiate fatty replacement changes from neoplasm.6

PANCREATITIS Acute Pancreatitis The 2012 revised Atlanta classification provides standardized clinical and radiologic nomenclature for acute pancreatitis and associated complications.10 The classification defines two distinct types of acute pancreatitis: interstitial edematous pancreatitis (IEP) and necrotizing pancreatitis (NP), depending on the absence or presence of necrosis, respectively (see Chapters 55 and 56).10,11 Imaging of the pancreas is not necessarily required in the setting of mild cases of acute pancreatitis because the diagnosis can be based on clinical symptoms and serology.10,11 Nevertheless, imaging may be required to make the diagnosis if one of the aforementioned factors is negative or to assess for a causative factor, the most common being gallstones (see Chapter 33).11,12 Early US can be performed with a limited purpose of identifying gallstones or to demonstrate bile duct dilatation; however, stones in the distal duct may not be identified.13 Standard contrast-enhanced CT (CECT) abdomen is the most common modality used, and a multiphase pancreatic protocol is typically unnecessary.12 MRI/MRCP may also be used, particularly in the setting of iodinated contrast allergy, renal failure, or suspicion of choledocholithiasis.11,12 Nevertheless, MRI scan time is long compared with CT, and the availability of MRI should be

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

267

B

FIGURE 17.1  Pancreatic divisum. Three-dimensional (3D) Magnetic resonance cholangiopancreatography (MRCP) reconstruction (A) and an axial T2-weighted magnetic resonance image (MRI) (B) demonstrating the main pancreatic duct (long arrow) separately entering into the duodenum, superior to the common bile duct (short arrow). In image (A) the ducts cross, rather than coalesce to both empty into the duodenum at the ampulla.

FIGURE 17.2  Annular pancreas. Axial computed tomography (CT) in portal venous phase demonstrating annular pancreas (red circle) with pancreatic parenchyma completely encircling the proximal duodenum (arrow).

FIGURE 17.3  Axial computed tomography (CT) in portal venous phase demonstrating extensive fatty replacement of the pancreas, appearing isodense to the mesenteric fat. Minimal pancreatic acinar tissue is visible in the posterior aspect of the pancreatic head (arrow), where there can be peribiliary sparing.

FIGURE 17.4  Fatty infiltration with pseudomass. Axial computed tomography (CT) in portal venous phase. Diffuse fatty infiltration of the pancreas, most marked at the anterior pancreatic head (long arrows), mimicking a hypoenhancing pancreatic mass. This is demarcated by a region of fatty sparing at the posterior peribiliary pancreatic head (short arrow).

considered.12 Imaging in pancreatitis should ideally be performed five to seven days after pain onset, when necrosis is clearly definable and local complications have developed.10 Earlier imaging within the first few days after pain onset may miss or be equivocal for necrosis and correlates poorly with clinical severity.10,14 The CT Severity Index (CTSI)14 and later modified CT Severity Index (mCTSI)15 both define specific radiologic criteria for grading the severity of acute pancreatitis and complications. The CTSI score is based on pancreatic changes, the presence and amount of necrosis (none, #30%, 30%–50%, and .50%), and peripancreatic fluid collections.14 The mCTSI includes similar criteria, with a simplified definition of the amount of necrosis (none, #30%, and .30%), and includes extrapancreatic findings, such as pleural effusions and ascites.13,15 A study involving almost 400 patients demonstrated no significant difference between CTSI and mCTSI in evaluating the severity of acute pancreatitis.16

268

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 17.5  Axial computed tomography (CT) in portal venous phase demonstrating acute interstitial edematous pancreatitis with diffuse edematous enlargement of the pancreas with mild hypoenhancement (long arrows); note there are no nonenhancing parenchymal regions. Small amount of reactive fluid surrounding and adjacent to the pancreas (short arrows).

Interstitial Edematous Pancreatitis IEP is the more common form of acute pancreatitis and, at imaging, usually appears as diffuse or focal pancreatic enlargement with a small amount of peripancreatic fluid (Fig. 17.5). A 11 A The pancreatic parenchyma will generally enhance less than a normal pancreas because of the presence of interstitial edema.11 However, there should be no nonenhancing parenchymal regions or peripancreatic necrotic collections; if these are present, the diagnosis of NP should be made.11 According to the 2012 revised Atlanta criteria, any peripancreatic fluid collection occurring within the first 4 weeks of IEP is classified as an “acute peripancreatic fluid collection” (APFC; see Chapter 54). Because there is no necrosis in IEP, the APFC will contain only fluid and appear as homogeneous fluid attenuation (0–20 HU) at CT and fluid signal intensity on T2weighted MRI imaging, conforming to the retroperitoneal structures, and without a well-defined wall.10,11 These C usually resolve spontaneously without intervention and most APFC will remain sterile. In 10% of cases, the peripancreatic collections persist for more than four weeks,17 and these are termed pancreatic pseudocysts (see Chapter 54).10 Like APFC, pseudocysts should not include any solid components or debris. Pseudocysts will appear as homogeneous fluid attenuation CT and hyperintense on T2, with a well-defined enhancing capsule.11 A connection between the pseudocyst and the main pancreatic duct may be present, best visualized on MRI/MRCP (Fig. 17.6). On transabdominal US, pseudocysts typically appear as a circumscribed, smooth-walled spherical anechoic lesion with posterior acoustic enhancement.

Necrotizing Pancreatitis Necrotizing pancreatitis (NP) is defined by necrosis involving the pancreatic parenchyma and/or the peripancreatic soft tissues. Involvement of both parenchyma and peripancreatic soft tissues is the most common form, occurring in 75% of cases.10 Involvement of the peripancreatic tissues alone without

C B

B

C FIGURE 17.6  Pseudocyst communication with main duct. Axial T2-weighted magnetic resonance imaging (MRI) (A) demonstrates a pseudocyst adjacent to the pancreatic head. Coronal T2-weighted images (B) and maximum intensity projection (MIP) T2-weighted images (C) demonstrate communication between the pseudocyst and the main pancreatic duct (arrows).

parenchymal necrosis occurs in 25%, and pancreatic necrosis alone without peripancreatic collections is the least common, occurring in 5%.10 At early imaging within the first few days of pain onset, NP will appear as patchy enhancement, potentially indistinguishable from IEP, and with potential underestimation of the eventual extent of necrosis.10 At around five to seven days, the necrotic, nonenhancing parenchyma will become demarcated, and peripancreatic necrotic collections may develop (Fig. 17.7).10 If parenchymal necrosis is present, the amount of necrosis should be estimated according to either the CTSI or mCTSI

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

FIGURE 17.7  Axial computed tomography (CT) in the portal venous phase. Necrotizing pancreatitis with regions of nonenhancing pancreatic parenchyma at the pancreatic neck and body (long red arrows), with sparing of the pancreatic tail, with preserved normal enhancement (short red arrow). An acute necrotic collection (long white arrow) is present anterior to the pancreatic head.

systems.14,18 Parenchymal necrosis predominantly affects the neck and body, and the head and tail may be spared. If there is confluent necrosis extending over 2 cm at the head, neck, or body, the pancreatic duct may be disrupted and pancreatic fluid from the isolated non-necrotic distal body or tail will leak into soft tissues, causing fistulas and collections.19 The disrupted

A

269

duct may be best identified with ERCP or secretin MRCP. The isolated duct may not be dilated.19 Pancreatic and peripancreatic fluid collections occur in NP, and these have different and specific terms to the fluid collections found in IEP. A collection present within the first four weeks of NP is termed an “acute necrotic collection” (ANC). These can occur within the pancreas or peripancreatic tissue, are often multiple, loculated, and can extend into the pelvis.11 ANC contain a variable amount of fluid, debris, and necrotic tissue.10 At imaging, the debris and necrotic tissue will appear as nonenhancing solid components or fat globules.11 The term ANC is still used in NP to describe any fluid collection, even if the collection lacks debris.10 After four weeks, the collections will become encapsulated with a well-defined, thick enhancing wall, termed “walled off necrosis” (WON).10 These can occur in both the pancreatic parenchyma and peripancreatic tissues and may form coalescent collections.11 MRI is superior to CT in demonstrating the internal debris present with WON.20 The internal debris usually appears as dependant, nonenhancing T2 hypointense material on MRI,21 and as soft tissue or high attention on CT (Fig. 17.8). Infected necrosis does not have specific imaging findings; air within the necrotic areas can indicate infection but may also be secondary to fistula. Leaked pancreatic proteolytic enzymes can cause weakening of vessel walls and the formation of pseudoaneurysms, most commonly involving the splenic, gastroduodenal, and pancreaticoduodenal arteries, and may lead to life-threatening hemorrhage (see Chapter 115). If hemorrhage is clinically suspected, a multiphase CT with both arterial and portal venous phases should be performed.12 On imaging, pseudoaneurysms will show a connection to an adjacent vessel and enhance similar to arteries.22 Other local complications that may be evident on imaging include splenic or

B

C FIGURE 17.8  Walled off necrosis. A, Magnetic resonance imaging (MRI) demonstrates a T2 hyperintense focus at the pancreatic head with hypointense debris (arrow) exhibiting blooming artifact on (B) fat-saturated T1-weighted contrast images. C, Contrast-enhanced computed tomography (CT) 1 week later shows the fluid-attenuation and nonenhancing debris within the walled-off necrosis.

270

PART 2  DIAGNOSTIC TECHNIQUES

portal vein thrombosis, gastric outlet obstruction, and colonic necrosis.10

Chronic Pancreatitis Although transabdominal US may be the initial modality used in the assessment of chronic abdominal pain, a frequent symptom of chronic pancreatitis (CP), it has the lowest accuracy and is not recommended for initial assessment.1,23 CT and MRI/ MRCP are ideal first choices because they have comparable diagnostic performance and are noninvasive.23 CT is best for visualization of pancreatic calcification, whereas ductal and early parenchymal changes are better evaluated on MRI.1 The role of ERCP and EUS is discussed in Chapters 20 and 22, respectively (also see Chapters 57–58). Pancreatic calcification is commonly seen in CP and is the most specific CT imaging feature.24 Chronic alcoholic pancreatitis is the most common cause of pancreatic calcification in the United States, although CP related to other causes such as hyperparathyroidism and tropical pancreatitis may also cause calcifications.25 Importantly, pancreatic calcification is characteristically seen in other causes of pancreatitis, such as gallstones, drugs, viruses, and trauma.25 The calcifications are always present within the ductal system; however, this may be difficult to discern on imaging.24 The calcifications can vary widely in size, ranging from punctate to large coarse foci.24 The distribution may also vary from focal to diffuse involvement, with the pancreatic head usually more prominently affected than the tail.24,25 Coarse calcifications are a definite sign of CP,26 and innumerable punctate calcifications strongly suggest CP.27 The number and size of calculi are independent of disease duration and the degree of gland atrophy.28 Although calcifications are more frequently detected with increasing CP severity, the degree of calcification is not indicative of clinical severity or vice versa.28,29 Many patients with severe exocrine dysfunction may have a normal-appearing pancreas on CT.1 Although MRI/MRCP may be normal in early CP,1 it is an excellent modality to assess the pancreatic duct with strong correlation to ERCP findings.30 Dilatation of the main duct (.3.5 mm) is commonly seen and the duct may have a variable smooth, beaded, or irregular appearance with strictures.1,24 The dilatation of the main duct with alternating strictures and stenoses causes a classic “chain of lakes” appearance.31 Side branch dilatation can be seen predominantly in advanced cases on MRCP but may be missed in early disease.32 Intraductal calculi will be seen as filing defects in high signal pancreatic fluid.32 Features that favor ductal dilatation because of CP over PDACrelated ductal obstruction include the presence of intraductal or parenchymal calcifications, irregular ductal dilatation, relative limited gland atrophy, and, of course, the lack of a discrete mass.1 Secretin MRI can help in the diagnosis of early CP by assessing the exocrine parenchyma and ductal response to secretin.1 MRI is also very sensitive to detect parenchymal abnormalities associated with CP, and these may precede ductal abnormalities.1,33 Fat-suppressed T1 is best for evaluating the pancreatic parenchymal atrophy and fibrosis seen with CP. Early on, this will appear as subtle areas of decreased T1 signal within the pancreas1 and later as more diffuse parenchymal fibrosis and atrophy. On dynamic postcontrast MRI, the fibrotic parenchyma in CP will demonstrate delayed and reduced enhancement compared with a normal pancreas.1 The fibrotic parenchyma in CP can demonstrate restricted diffusion with low ADC compared with normal pancreas.1

FIGURE 17.9  Axial postcontrast T1 fat-saturated magnetic resonance imaging (MRI), chronic pancreatitis with an ill-defined hypoenhancing inflammatory mass at the pancreatic head (long arrows). Note normal enhancing parenchyma at the medial pancreatic head (short arrow). The common bile duct (short red arrow) is markedly hypointense because of pneumobilia.

Pseudocysts can be observed in CP without any clinical or biochemical evidence of acute pancreatitis.24 Some CP patients can experience superimposed episodes of acute pancreatitis, and therefore imaging features, such as fluid collections, peripancreatic stranding, and abscesses, may be present.24 Pseudotumors or focal benign inflammatory masses may occur in CP, with a small series reporting the presence in nearly 30% of patients.24 The masses most commonly occur in the pancreatic head and are often indistinguishable from PDAC; additionally patients with chronic pancreatitis are at increased risk for PDAC.34,35 On CT, calcification in the mass favors an inflammatory mass over PDAC.24 On MRI, ductal structures and the duct penetrating sign in the mass are indicative of an inflammatory mass, whereas these findings are absent in PDAC.36 On postcontrast T1 sequences, inflammatory masses are usually ill-defined and poorly demarcated, whereas PDAC will show relative demarcation to normal pancreas (Fig. 17.9).37 Both inflammatory masses and PDAC will usually have lower ADC values compared with normal pancreas, and PDAC has been demonstrated to have significant lower ADC values compared with inflammatory masses38; however, the ADC values in PDAC can be variable (as discussed later).

Groove Pancreatitis Groove pancreatitis is an inflammatory plate-like mass involving the groove between the pancreatic head, duodenum, and the common bile duct that may be partially cystic. The cystic change may be associated with duodenal stenosis and wall thickening, which may lead to abdominal pain and vomiting.39,40 Classic imaging features include loss of fat planes between the pancreatic head and the duodenum. Associated ill-defined sheetlike soft tissue will demonstrate arterial phase hypoenhancement and progressive patchy delayed enhancement because of fibrosis, often with small cysts or even a multilocular cystic mass.41 Coarse calcifications may be visible at CT (Fig. 17.10). At MRI, groove pancreatitis is typically hypointense to pancreatic parenchyma on T1-weighted images and is of variable signal intensity on T2-weighted images, depending on the acuity of the process, decreasing in signal with chronicity and increasing fibrosis.42 Decreased T1 signal can also be seen in the pancreatic head or diffusely. There is often narrowing of both the lower common

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

C

271

B

D

FIGURE 17.10  Groove pancreatitis in a 60-year-old woman with history of pancreatitis, alcohol, and tobacco use. A, Contrast-enhanced computed tomography (CT) demonstrates a multicystic lesion at the region of the pancreaticoduodenal groove, with several coarse calcifications (arrow) and sheet-like soft tissue effacing fat planes. B, Axial T2 hyperintense magnetic resonance imaging (MRI) demonstrates cystic components and hypointense surrounding tissue. C, Fat-saturated T1-weighted precontrast MRI demonstrates hemorrhage or proteinaceous material within some of the cystic components (arrow). D, T1 postcontrast subtraction imaging reveals no enhancement of the cystic foci, but some enhancement of surrounding tissue (arrow) in the portal venous phase.

bile duct and main pancreatic duct, with upstream ductal dilatation (more often of the bile duct) and widening of the space between the two. Cystic components of mixed size and complexity are often best seen on T2-weighted images along the thickened duodenal wall, a sign that carries some specificity.41 Because the entity can be extremely difficult to distinguish from necrotic PDAC, groove pancreatitis is often a diagnosis of exclusion.

Autoimmune Pancreatitis Two types of autoimmune pancreatitis (AIP) are recognized; type 1 is the most recognized type, which is a multi-organ disease that is associated with elevated immunoglobulin G4 (IgG4) levels.43,44 Type 2 AIP is a pancreatic specific disease not associated with an elevated IgG4.43,44 Both type 1 and type 2 AIP will appear similar on imaging; however, type 2 is more frequently focal (85% of cases) and will lack extrapancreatic disease (see Chapter 54).43 AIP causes enlargement of the pancreas in a focal, multifocal, or diffuse pattern.45 Focal AIP most commonly affects the pancreatic head.46 Diffuse AIP is characterized by sausage-shaped enlargement of the pancreas with loss of normal pancreatic contour lobulations and clefts (Fig. 17.11). A capsule-like rim or “halo”

FIGURE 17.11  Axial computed tomography (CT) in pancreatic parenchymal/late arterial phase. Diffuse autoimmune pancreatitis as evidence of diffuse enlargement of the pancreas with hypoenhancement. Note the lack of surrounding fluid.

272

PART 2  DIAGNOSTIC TECHNIQUES

CYSTIC PANCREATIC LESIONS

FIGURE 17.12  Focal autoimmune pancreatitis. Axial computed tomography (CT) in pancreatic parenchymal/late arterial phase with focal mass-like enlargement and hypoenhancement of the pancreatic tail (long arrow), with a small hypoenhancing halo (short arrow) partially surrounding the mass.

in the peripancreatic tissue is common and characteristic of AIP and is thought to correspond to inflammatory soft tissue (Fig. 17.12).47,48 On CT, the affected regions of the pancreas will demonstrate progressive enhancement, hypodense to normal pancreas in the pancreatic parenchymal phase, iso/hypodense in the portal venous phase, and hyperdense in the delayed phase.47–49 This is in contrast to PDAC, a frequent differential diagnosis in the case of focal disease, which is more commonly hypodense in both pancreatic parenchymal and portal venous phases.49 The characteristic capsule-like rim or “halo” will appear hypodense on CT, hypointense on T1 and T2 MRI, and demonstrate delayed postcontrast enhancement.47,50 On MRI, the affected area will appear hypointense on precontrast T1 and heterogeneously hyperintense on T2.47,50 On MRCP there is generally diffuse multifocal irregular narrowing of the pancreatic duct.51 The pancreatic duct may not be visualized at all in the affected regions.48,52 Upstream pancreatic duct dilatation and parenchymal atrophy is rare but has been reported.48 Tapered narrowing and enhancement of the distal common bile duct is commonly seen, and multiple biliary strictures may be evident.51,53 AIP will demonstrate restricted diffusion with low ADC; this generally normalizes with corticosteroid treatment.54 Extrapancreatic lesions are common in type 1 AIP, reported in 45% to 92% of patients.45,48,55,56 The lesions can involve numerous organs throughout the body. Common manifestations include hilar, peripancreatic, and para-aortic lymphadenopathy; biliary duct wall thickening; soft tissue masses in the kidneys, ureters, orbits, and retroperitoneum with retroperitoneal fibrosis; and swelling of the salivary and lachrymal glands.55 Renal involvement, demonstrated in up to 35% of patients, most commonly involves the renal cortex. These lesions are hypoenhancing and may manifest as diffuse patchy involvement, round or wedge-shaped lesions, or as small peripheral cortical nodules.57 Lesions will decrease with corticosteroid treatment.57

Cystic pancreatic lesions as a group include a large number of benign, premalignant, and malignant entities (see Chapter 60).58 The five most common constituents that include the vast majority of cases are: complications of pancreatitis, including pseudocyst (described previously), the mucinous entities of intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), and serous cystic neoplasms like serous cystadenoma (SCA). Pancreatic neuroendocrine tumors can also appear as predominately cystic lesions and are described later in this chapter. MRI and CT are the preferred modalities for the noninvasive characterization of cystic lesions.59,60 Both imaging modalities have similar utility with dedicated protocols,61–63 although a consensus of radiologists had traditionally deemed MRI to be the exam of choice—older iterations of current guidelines cite MRI’s superior contrast resolution facilitating recognition of septa, nodules, and duct communication, and the benefit of avoiding radiation exposure.64,65 Cystic lesions may also be detected by transabdominal US, but at a lower rate than MRI or CT66 and with limited ability to distinguish between cystic neoplasms and pseudocysts (40%–50% specificity).67 Therefore the role of US in the evaluation of cystic pancreatic lesions remains limited, in sharp contradistinction with EUS, which plays a major role in the diagnostic workup of these lesions (see Chapter 22).

Cystic Pancreatic Tumors Intraductal Papillary Mucinous Neoplasm IPMNs are mucin-producing neoplasms that arise from the main pancreatic duct or its branches and exhibit a spectrum of dysplasia from low-grade to high-grade to invasive carcinoma (see Chapter 60–62).68 They are the most common cystic neoplasms and may represent up to 30% of all cystic pancreatic lesions. As cross-sectional imaging, and particularly MRI, have become more common, IPMNs are now being discovered frequently as incidental small pancreatic cystic lesions on scans obtained for other indications.58,69 IPMNs can be classified into main duct, branch duct, and mixed type varieties, based either on imaging appearance or histopathology.70–75 The importance of this distinction is highlighted in an analysis of a group of studies from 2003 to 2010 demonstrating that, among main duct and mixed-type IPMN, prevalence of invasive carcinoma was 44% to 45% versus only 16.6% in the branch duct type (overall 30.8% prevalence in 3568 specimens).65 Among IPMNs without invasive carcinoma, actuarial risk of future carcinoma development is also much higher among main and mixed types.76 On CT or MRI, it is largely the mucin produced by the tumor that is identified rather than the neoplastic epithelium itself. When present, however, visible enhancing mural solid nodules may actually represent the cellular elements. Such nodules and main duct dilatation are associated with the presence of invasive cancer and high-grade dysplasia (Fig. 17.13)77– 80 ; therefore they are given considerable import in the revised 2017 international consensus Fukuoka guidelines (discussed later). Main duct IPMN is characterized on CT or MRI by diffuse or segmental dilatation of the main pancreatic duct to more than 5 mm caliber, without another identifiable cause of obstruction (Fig. 17.14). At MRI, this is best seen on

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

273

B

C

D

FIGURE 17.13  Coronal computed tomography (CT) in the portal venous phase demonstrates an intraductal papillary mucinous neoplasm (IPMN)-associated tumor. A, C, D, These show dilatation/expansion of the main (white arrows) and branch (black arrows) pancreatic ducts by invasive adenocarcinoma. B, Normal appearing portal vein (black arrows) with no evidence of tumor vascular encasement (no tumor vascular involvement was found at surgery or at pathologic examination).

A

B

C

FIGURE 17.14  Main duct intraductal papillary mucinous neoplasm (IPMN). A, Axial and (B) coronal contrast-enhanced computed tomography (CT) and (C) axial T2-weighted magnetic resonance imaging (MRI) demonstrates dilation of the main pancreatic duct to 9 mm caliber.

T2-weighted images where fluid in the duct has markedly hyperintense signal. Mural nodules, mucin globules, or a dilated major or minor papilla bulging into the duodenal lumen may be seen.81 Branch duct IPMN can occur anywhere in the gland, most commonly in the pancreatic head, and may be multifocal in approximately 30% of cases.82 They appear as a cluster of round or tubular lesions or a single lesion with fluid attenuation (0–20 HU) on CT or T2 hyperintense fluid signal on MRI with no or few septa (Fig. 17.15). A microcystic pattern has also been described, in which multiple thin septa separate numerous fluid-filled spaces.81,83 Communication with a nondilated main pancreatic duct is often seen, particularly at thin-section three-dimensional (3D) MRCP images.84 The presence of the lesion in the pancreatic head may compress the common bile duct, resulting in dilation of the intrahepatic bile ducts. As with the main duct type, mural nodules may be present. A mixedtype IPMN is designated when features of both branch and main duct types are present.

FIGURE 17.15  Axial computed tomography (CT) in the arterial phase of contrast enhancement shows a fluid-attenuation intraductal papillary mucinous neoplasm (IPMN) in the pancreatic head (arrow).

274

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C FIGURE 17.16  Mucinous cystic neoplasm in a 55-year-old woman. A, Computed tomography (CT) demonstrates an ovoid cystic lesion with a punctate mural calcification (arrow) in the pancreatic tail. The lesion is hyperintense on axial T2 hyperintense magnetic resonance imaging MRI (B). C, Post contrast fat-saturated T1-weighted MRI demonstrates a thickened pseudocapsule and a barely perceptible thin septation.

Mucinous Cystic Neoplasms Characterized histologically by the presence of progesterone and estrogen receptor-positive ovarian-type stroma, mucinous cystic neoplasms (MCNs) have been considered nearly exclusively tumors of perimenopausal women (see Chapter 60).58 Although there is a growing body of case reports of tumors considered by pathology to be MCN in males,85 a pathology review continues to describe the entity as nearly exclusively a lesion of women.86 MCNs are a pathologically heterogeneous group, including benign mucin-producing epithelium, dysplasia, carcinoma in situ, and invasive tumor (mucinous cyst adenocarcinoma). The typical appearance of MCN is a loculated cystic lesion occurring most commonly in the pancreatic body or tail (90%–95%). Morphologically, they appear as round or ovoid— “orange-like,” rather than the more “grape-like” clustered appearance of IPMN, with locules or pauciseptate individual cystic components, which are larger than the typical cystic components seen with serous cystadenoma (Fig. 17.16). Unlike IPMN, the lesions tend to be solitary and only rarely demonstrate communication with the main pancreatic duct if there is associated fistula formation. Mildly thickened, enhancing septa are common in MCN, and a delayed enhancing pseudocapsule may be seen.82 Peripheral calcification may be demonstrated on CT. On MRI, the lesions appear as simple fluid with T2 hyperintensity and usually T1 hypointensity, despite the mucinous contents, although occasionally lesions may have a more variable T1-weighted signal.87 Features that can be associated with malignancy (mucinous cystadenocarcinomas) are a thick wall (.2 mm), thick septations, and calcification within the wall or

septa (Fig. 17.17).88 In any case, the presence of internal enhancing soft tissue elements is indicative of carcinoma.

Serous Cystadenoma Pancreatic serous cystic neoplasms represent about 20% of all cystic pancreatic lesions and approximately 30% of cystic neoplasms (see Chapter 60).58 They are largely benign serous cystadenoma (SCA) with extremely rare instances of malignant serous cystadenocarcinoma,89 which can only be diagnosed on imaging in the presence of metastases.86 SCAs are indolent tumors with a slight female predilection, usually presenting in the 5th to 7th decades of life, often as an incidental radiographic finding in asymptomatic patients. Previously, these tumors had been called microcystic adenomas, a term that has fallen out of favor because of reported macrocystic and oligocystic variants.90 SCA tumors most commonly occur in the pancreatic body and tail and may vary in size from 1 mm to several centimeters; they may be large at the time of discovery because of their slowgrowing and potential asymptomatic nature. The lesions are generally lobulated and surrounded by a fibrous capsule. SCA tumors are typically comprised of numerous tiny cysts, which appear fluid-attenuation on CT and hyperintense on T2weighted MRI. The individual cysts may be variable in size, but are typically less than 1 cm.87 The cysts are sometimes so small that the cystic nature of the lesion becomes difficult to appreciate, with the appearance dominated by highly vascularized fibrous septa arranged in a honeycomb configuration radiating from a central nidus (Fig. 17.18). In this case, MRI is often superior to CT in demonstrating the tiny cystic regions.91–93 At

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

275

MRI, hemorrhage may be seen as higher T1-weighted signal, and the central nidus may enhance on delayed postcontrast imaging (Fig. 17.19). Stellate calcification of the central nidus strongly suggests the diagnosis of SCA; however, it is only seen in approximately 30% of cases.81 This feature may also be identified at US.94,95 Transabdominal US is otherwise not well suited as a characterization tool because numerous tiny cystic spaces may create multiple interfaces and not be resolved individually, causing the cystic component to appear echogenic or solid appearing. Nevertheless, internal architecture with honeycomb or spongy appearance can sometimes be delineated at higher frequency magnified US imaging (Fig. 17.20). In contrast to IPMN, SCA do not communicate with the pancreatic duct.86 In the absence of classic features suggesting SCA, such as multicystic morphology with a central nidus, differentiation from mucinous entities (particularly IPMN) may be challenging,96–99 and many cases are still diagnosed only upon resection.100

Differentiating Cystic Pancreatic Tumors

B FIGURE 17.17  Arterial phase axial computed tomography (CT) shows mucinous cystadenocarcinoma. A, Thick-walled cystic lesion with punctate mural calcification in the pancreatic body and tail. B, A different patient with mural ulceration in the anterolateral aspect of the thick-walled mucinous adenocarcinoma at the pancreatic tail.

FIGURE 17.18  Portal venous phase axial computed tomography (CT) shows a typical lobulated serous cystadenoma (SCA) with enhancing radiating septa in the pancreatic head.

One of the chief imaging challenges is distinguishing the mucinous lesions of IPMN and MCN, which have malignant potential, from other benign pancreatic cystic lesions (pseudocyst and SCA).63 To address this issue, several guidelines have been proposed within the past decade for imaging work-up and management of cystic lesions. The aforementioned revised 2017 international consensus Fukuoka guidelines,59 and a section of the white paper produced by the incidental findings committee of the American College of Radiology (ACR), also updated in 2017,60 are two of the more influential papers. Although there are differences in focus and recommendations, both guidelines support under certain circumstances a role for imaging surveillance that had been suggested by previous work.91,93 The 2017 ACR white paper proposes an algorithmic approach to all incidentally detected cystic lesions lacking solid elements in asymptomatic patients. The paper stratifies the approach with five separate algorithms based on patient age, lesion size, and presence of discernible communication with the main duct, with roles for imaging surveillance of varying frequency and length and further characterization by EUS.60 The 2017 international consensus Fukuoka guidelines, being aimed at already-suspected mucinous lesions (not restricted to asymptomatic patients), puts more emphasis on two groups of features: “high-risk stigmata,” including main duct caliber greater than 9 mm and enhancing mural nodule greater than 5 mm, and “worrisome features,” including main duct 5 to 9 mm caliber, abrupt caliber transition (more dilated upstream) with distal gland atrophy, nonenhancing mural nodules, size greater than 3 cm, associated lymphadenopathy, and change in size greater than 5 mm over two years. Imaging-only surveillance is recommended only for lesions without any of these imaging features in patients also without any of three specified clinical features (obstructive jaundice, elevated carbohydrate antigen [CA] 19-9, and pancreatitis).59 One potential problem in applying this approach has been that agreement on the presence of certain imaging features may not be repeatable among radiologists.101 Although the two guidelines have made a strong contribution to the management approach of these lesions, neither has gained universal acceptance as yet, and they may evolve with time. Challenging cases may be discussed at tumor boards using a combination of clinical judgment and imaging data to guide management decisions.

276

A

C

PART 2  DIAGNOSTIC TECHNIQUES

B

D

E FIGURE 17.19  Serous cystadenoma (SCA). A, Contrast-enhanced computed tomography (CT) demonstrates a lobulated cystic lesion radiating around a central nidus. B, Axial T2-weighted magnetic resonance imaging (MRI) demonstrates the T2 hypointense central nidus (arrow) that enhances on postcontrast fat-saturated T1-weighted MRI (C) (arrow). D, Precontrast fat-saturated T1-weighted MRI demonstrates hemorrhage or proteinaceous material in an anterior cystic component (arrow) that developed in the year after the CT image in A. E, CT of another patient demonstrates a SCA in the pancreatic head with calcification of the central nidus.

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

FIGURE 17.20  Serous cystadenoma of the pancreas. Magnified transverse intraoperative ultrasound images of the pancreatic tail demonstrate the typical honeycomb architecture of the lesion with anechoic areas bounded by echogenic septa.

Other Cystic Pancreatic Lesions Lymphangiomas are congenital malformations of the lymphatic system, which result from obstruction of the lymph flow and formation of multiloculated serous, serosanguineous, or chylous cystic lesions. They are indolent, often incidentally discovered, and tend to occur more commonly in women. They can be seen as peripancreatic or pancreatic lesions58 and may reach a large size up to 25 cm (average 12 cm).102 On CT, they appear as well-circumscribed, often multilocular fluid attenuation lesions with an enhancing capsule, thin septa, and, rarely, calcification. At MRI, they have the typical T2 hyperintense signal of fluid with T2 hypointense fibrous septa.103,104 On US, they appear complex because of internal septa and also may have internal echoes if they are secondarily infected. Rare calcifications can produce acoustic shadowing.

SOLID PANCREATIC LESIONS Pancreatic Ductal Adenocarcinoma Imaging is used in PDAC for initial diagnosis, assessment of resectability, and detection of metastatic disease (see Chapters 61 and 62). The National Comprehensive Cancer Network (NCCN) recommends that any patient with a clinical suspicion of PDAC and evidence of a dilated pancreatic or bile duct or stricture should undergo initial evaluation with a pancreatic protocol CT.105 NCCN endorses a dual-phase pancreatic protocol with imaging obtained in the pancreatic parenchymal and portal venous phases.106 The NCCN recommends CT as the preferred modality for preoperative assessment because it is widely available and can be extended to include both the chest and pelvis for staging purposes. MRI can be used if a CECT is contraindicated, or as a problem-solving tool, particularly if a suspected tumor is not visible on CT or for the characterization of indeterminate liver lesions.105 A 2016 meta-analysis found that CT and MRI were comparable in diagnosis and assessment

277

FIGURE 17.21  Axial computed tomography (CT) in portal venous phase shows abrupt cut off of the pancreatic duct with upstream dilatation (arrow) secondary to a small hypoenhancing pancreatic head/neck ductal adenocarcinoma.

of vascular involvement.107 Nevertheless, MRI is more sensitive in detecting hepatic metastases108 (see Chapter 15). In the setting of a known pancreatic tumor, high-quality imaging of the pancreas should be performed, even if standard portal venous phase CT imaging is available. This should be performed within four weeks of surgery, after the completion of neoadjuvant therapy (if applicable), and before stenting whenever possible.105 In addition, the NCCN recommends the use of the PDAC radiology reporting template,106 which is a consensus statement from the American Pancreatic Association and Society of Abdominal Radiology.105 This template facilitates a comprehensive and standardized approach in the reporting of PDAC to optimize treatment recommendations.106 In particular, the template standardizes terminology for tumor vascular involvement, with an at least 180-degree degree tumor vascular contact classified as abutment and a greater than 180-degree tumor vascular contact classified as encasement.106 On CT, PDAC typically appears as an ill-defined solid mass, hypoattenuating to normal pancreatic parenchyma in both the pancreatic parenchymal and portal venous phases.109 Tumors are often accompanied by secondary signs of abrupt pancreatic duct cut-off (Fig. 17.21), pancreatic or bile duct obstruction, upstream pancreatic atrophy, and/or contour abnormality.110 These secondary signs are important clues to the presence of PDAC and may be present on CT many months before patients becoming symptomatic with disease.111 Tumors located in the pancreatic head may cause dilatation of both the pancreatic and bile ducts, which is called the “doubleduct sign.”112 Pancreatic tail tumors generally present later, are larger, and are more infiltrative at the time of diagnosis.113 Approximately 5% of PDACs are isoattenuating to normal pancreas on both phases of dual-phase pancreatic protocol CT, and these have been shown to have increased survival compared with hypoattenuating tumors.114 Additionally small tumors (#20 mm) are more likely to be isoattenuating and difficult to discretely visualize; however, they are often accompanied by secondary signs.110 In the case of suspected PDAC

278

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D FIGURE 17.22  Pancreatic ductal adenocarcinoma with vascular encasement. A, Hypoenhancing tumor in the body and tail of the pancreas tracks posteriorly to encase the celiac axis, the proximal hepatic artery (black arrowhead), and the splenic artery (white arrowhead). B, Curved multiplanar reconstruction showing the tumor (arrow) in the body and tail of the pancreas. C, Coronal volume-rendered image shows the tumor occluding the splenic vein (arrowhead) and encasing celiac axis branches (arrows). D, Sagittal volume-rendered image shows tumor encasing the celiac axis (arrow).

without visible tumor on pancreatic protocol CT, further assessment should be considered with endoscopic US (EUS), MRI, or positron emission tomography (PET)/CT.105,110 Detailed assessment of tumor vascular involvement is required to ultimately determine the resectability of the tumor and should be described using the previously described standardized terms of abutment (#180 degrees) and encasement (.180 degrees).106 Vessel deformity, narrowing, or occlusion are specific signs of vascular invasion (Fig. 17.22).115–118 PDAC tumors are associated with peritumoral dense fibrotic reaction, which can abut or encase vessels.119 It is often impossible to differentiate between benign fibrous soft tissue or tumoral vascular involvement, a common scenario after neoadjuvant therapy where differentiation between active tumor, treated tumor, tumor fibrosis, and treatment-related fibrosis is challenging.120–123

On MRI, PDAC generally appears hypointense to normal pancreatic parenchyma on precontrast T1 imaging and remains predominantly hypointense in the arterial/parenchymal phases.112 The T2 signal is variable.124 The conspicuity of tumors may be affected by pancreatic parenchymal changes related to upstream obstructive pancreatitis, or CP, which causes decreased T1 and increased T2 parenchymal signal changes.110 Both the pancreatic and bile ducts are well visualised on MRCP, and tumor-related duct obstruction may be abrupt or gradual, with a smooth or beaded appearance of the dilated duct.112 Tumors can have variable restricted diffusion because this depends on both tumor differentiation and density of fibrosis.125

Pancreatic Neuroendocrine Neoplasms Pancreatic neuroendocrine neoplasms are a diverse group of tumors with varying clinical, functional, and histopathologic

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

features (see Chapter 65).126 They may be well-differentiated tumors (PNETs) or poorly differentiated carcinomas (PNECs). The 2017 revised World Health Organization (WHO) grading system127 further classifies PNETs into grades according to number of mitoses and Ki-67 index. Grade 1 (,2 mitoses/10 HPF, ,3% Ki-67) and grade 2 (2–20 mitoses/10 HPF, 3%–20% Ki-67) PNETs are considered low-grade tumors. Grade 3 PNETs are well-differentiated tumors, but have a higher mitotic rate (.20/10 HPF) or Ki-67 index (.20%) and have a worse prognosis compared with low-grade (grade 1 and grade 2) PNETs.128 Poorly differentiated neoplasms are classified as carcinomas (PNECs), with high mitotic rates (.20/10 HPF) and Ki-67 indices (.20%), and they demonstrate aggressive behavior.128 Well-differentiated neoplasm (PNETs) are usually solitary, except in the setting of familial syndromes, such as multiple endocrine neoplasia syndrome type 1 (MEN1), von HippelLindau disease (VHL), neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC).129 PNETs are considered functional or nonfunctional, depending on whether hormones secreted by the tumor cause systemic symptoms. Functional PNET manifest early because of clinical symptoms related to pathologic hormone secretion, with the most common being insulinoma. Functioning tumors tend to be small homogeneous masses without local invasion or distant metastases.129,130 Nonfunctional tumors are usually larger and present later with symptoms related to mass effect.129,131 These larger tumors demonstrate heterogeneous enhancement because of areas of cystic degeneration and necrosis.129 Local soft-tissue invasion, vascular invasion, and metastases are more commonly demonstrated in larger, nonfunctioning, clinically silent tumors.130 Calcification can occur in larger lesions and is more commonly associated with lymph node and liver metastases, compared with noncalcified tumors.130,132 CT is regarded as first-line imaging for PNET, and triphasic CT imaging protocol should be used; this not only aids in detection of the primary tumor but also helps to improve visualization of metastatic disease.133 A noncontrast scan before the multiphase CT is useful in demonstrating tumoral calcification; the tumor is typical isodense to normal pancreas on noncontrast CT.133 On MRI, PNETs will generally demonstrate nonspecific signal hypointensity on precontrast T1 and moderate hyperintensity on fat-suppressed T2 compared with normal pancreas, with smaller tumors appearing more homogenous and larger tumors appearing heterogeneous.134,135 PNET will generally demonstrate restricted diffusion because of high cellularity, and this feature may aid in the detection of nonhypervascular tumors.136 Additionally, lower ADC values were more commonly demonstrated in PNETs, with more aggressive behavior compared with PNETs that had benign features.137 Smaller tumors generally show homogeneous enhancement on both CT and MRI and are hypervascular to normal pancreas on arterial and pancreatic parenchymal phases (Fig. 17.23). Larger tumors usually demonstrate heterogeneous hypoenhancement on arterial phases and may be hypo or iso-enhancing to normal pancreas on portal venous and delayed phases.138 Obstruction of the pancreatic duct can occur in PNET, a feature that is often indicative of more aggressive behavior.137 The appearance of metastases is dependent on the vascularity of the primary PNET; hypervascular primary tumors will generally have hypervascular metastases.133,134 Well-differentiated PNETs

279

FIGURE 17.23  Axial computed tomography (CT) in pancreatic parenchymal/late arterial phase. A well-differentiated pancreatic neuroendocrine tumor (PNET) appearing as a hypervascular mass in the pancreatic head (arrows).

are usually avid on somatostatin receptor (SSTR) imaging (e.g., 68Ga-DOTATATE PET and 111In-octreotide), and these scans can be useful in demonstrating the extent of disease (see Chapter 18).131 A PNET may also appear as cystic neoplasm in 10% to 17% of cases,86 usually in nonfunctioning tumors, and these most commonly appear in the pancreatic body and tail. These appear as well-circumscribed unilocular or multilocular cystic lesions with an arterially enhancing, often slightly nodular rim.81,139 The rim may be somatostatin-receptor avid on SSTR imaging but will not typically be avid in the cystic component (Fig. 17.24).81,129 Patients with cystic PNET are 3.5 times more likely to have MEN1,139 and PNET should be a differential for a cystic pancreatic lesion in the setting of known MEN1.140 With regard to specific tumor types, almost all insulinomas arise in the pancreas, with no site predilection.129 Approximately half of somatostatinomas occur in the pancreas, most commonly in the pancreatic head with an average size of 5 to 6 cm.129,141,142 It is reported that up to half of patients have metastatic disease at the time of presentation, typically involving lymph nodes or liver.129,141 Most glucagonomas originate in the pancreatic body and tail and are often large tumors (5–6 cm) because of delayed presentation.129 Vasoactive intestinal peptide tumors (VIPomas) most frequently occur in the pancreatic tail, with a 5-cm average size at diagnosis.143 Most VIPomas are aggressive, with metastases present in 60% to 80% of cases at presentation.129 Gastrinoma tumors are more commonly extrapancreatic and multiple, occurring in the gastrinoma triangle; however, if they occur in the pancreas, they usually average 3 to 4 cm in size141 and can demonstrate rim enhancement.135 Poorly differentiated carcinomas (PNECs) occur most frequently in the pancreatic head and typically appear as ill-defined, heterogeneous masses with rim enhancement (Fig. 17.25). They are commonly associated with biliary obstruction, invasion of adjacent soft tissue, and nodal or hepatic metastatic disease.129 PNECs can demonstrate more restricted diffusion compared with well-differentiated PNETs.144 PNECs

280

PART 2  DIAGNOSTIC TECHNIQUES

A

C

B

D

E FIGURE 17.24  Cystic pancreatic neuroendocrine tumor (PNET). A, Contrast-enhanced computed tomography (CT) in the portal venous phase demonstrates a rounded pancreatic tail cystic lesion with slightly thick hyperenhancing rim. B, Magnetic resonance imaging (MRI) shows the T2 hyperintense cyst with hypointense rim. C, Postcontrast fat-saturated T1-weighted MRI in the arterial phase again demonstrates the hyperenhancing rim. D, CT in another patient with a larger PNET with cystic and solid components. E, Fusion imaging from a somatostatin receptor (68Ga-DOTATATE) positron emission tomography (PET)/CT demonstrates tracer uptake in the solid elements and physiologic uptake in the liver and right kidney.

are more typically FDG avid and usually demonstrate little or no uptake on SSTR imaging (see Chapter 18).

Pancreatic Lymphoma Lymphoma can occur in the pancreas in both primary and, more commonly, secondary forms. It may appear as solitary nodular, multinodular, or diffuse disease.50,145,146 On CT, the affected region will appear hypodense to normal pancreas, without cystic or necrotic areas.147,148 On MRI,

lymphoma is typically T1 hypointense and T2 hyperintense to normal pancreas.50,145 On postcontrast imaging, lymphomatous regions demonstrate homogenous hypoenhancement to pancreas in both arterial and delayed phase.50,145 Diffuse lymphomatous involvement of the pancreas is less common and may mimic acute pancreatitis.145 Features of acute pancreatitis, such as peripancreatic stranding, peripancreatic fluid collections, and fat necrosis are usually absent in pancreatic lymphoma.145 Vascular encasement can occur but

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

281

B

FIGURE 17.25  Pancreatic neuroendocrine carcinoma with liver metastases. A, Axial T1 postcontrast T1-weighted fat-saturated magnetic resonance imaging (MRI) in portal venous phase at the level of the pancreas demonstrating a hypovascular mass (long arrows) encasing the superior mesenteric vein (short arrow). B, Axial postcontrast T1-weighted fat-saturated MRI demonstrating multiple hypovascular liver metastases (long arrows) and a hypovascular peritoneal metastasis in the left upper quadrant (short arrow) abutting the left hepatic lobe.

FIGURE 17.26  Focal pancreatic lymphoma. Axial computed tomography (CT) in portal venous phase demonstrates a slight hypoenhancing mass in the pancreatic tail (white oval) encasing, but not occluding, the splenic vein (white arrow).

will generally lack features of vascular infiltration, such as vessel deformity (Fig. 17.26).145,147 Pancreatic duct obstruction can occur, but this is generally because of ductal displacement or compression rather than invasion. This is in contrast to PDAC where duct obstruction is more common and occurs because of tumoral invasion of the duct.147,148 Evaluation of the pancreatic duct with secretin MRI may be useful to distinguish between a patent but compressed duct (duct-penetrating sign) or an infiltrated duct; the latter suggests PDAC.149 Bile duct dilatation can reportedly occur in 42% of patients with primary pancreatic non-Hodgkin lymphoma.147,148 Lymph node involvement below the level of the renal veins can be seen with lymphoma, but is rare in PDAC cases.148 Differentiating pancreatic lymphoma and autoimmune pancreatitis can also be difficult because both have overlapping imaging appearances; however, lymphoma is more often bulky in appearance. Challenging with corticosteroid treatment is not recommended because enlargement in both pancreatic lymphoma and autoimmune pancreatitis can decrease with treatment.145

FIGURE 17.27  Acinar cell carcinoma. Axial computed tomography (CT) in portal venous phase demonstrating an encapsulated, partially exophytic heterogeneous pancreatic head mass (arrow).

Acinar Cell Carcinoma Acinar cell carcinoma (ACC) generally appears as a large, oval pancreatic mass, without site predilection, in older men.150–153 The tumors are typically well marginated, encapsulated, and partially or completely exophytic (Fig. 17.27).153,154 Intratumoral necrotic regions are common, particularly in larger tumors and may be because of local necrosis secondary to the release of pancreatic enzymes and impairment of blood supply.153,155 These cystic/necrotic regions are seen as heterogeneously hypodense areas on CT and T1-hypointense, T2-hyperintense areas on MRI.154,155 On MRI, the tumor has nonspecific signal hypointensity on precontrast T1 and iso/hypointensity on T2, relative to normal pancreas.151,155 Tumors commonly have an enhancing capsule and demonstrate hypoenhancement to pancreas on both arterial and portal venous phases.150,152,156 Intratumoral hemorrhage (T1-hyperintense areas on MRI) and calcification (best seen on CT) are less common reported features.151,153,155 Restricted diffusion may also be present.150 ACC rarely show biliary or pancreatic duct dilatation, which is thought to be because ACC originates in acinar cells of the

282

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 17.28  Solid pseudopapillary neoplasm (SPN). Axial computed tomography (CT) in portal venous phase demonstrating a large, heterogeneous but predominately hypoenhancing pancreatic head mass with some internal calcification.

pancreas rather than the ductal epithelium.151,155,156 ACC can be metastatic, with metastatic disease most commonly involving regional lymph nodes and the liver.155 A ACC from PDAC include Features helpful in differentiating presence of necrotic regions, well-defined margins, exophytic mass, large size, presence of enhancing capsule, and lack of biliary or pancreatic duct obstruction.154,156 Hypovascular PNET and solid pseudopapillary tumor may appear similar as large, well-marginated masses with internal calcification and cystic regions; however, solid pseudopapillary tumor almost exclusively occurs in young females and more commonly demonstrates intratumoral hemorrhage.157,158

Solid Pseudopapillary Neoplasm Solid pseudopapillary neoplasms (SPNs) are typical large solid tumors with cystic areas related to hemorrhage and necrosis; however, small tumors tend to be completely solid (Fig. 17.28).159 Tumors located in the pancreatic body and tail are generally larger, and pancreatic tail lesions may invade the spleen.159 The lesions typically appear sharply demarcated from pancreatic parenchyma and encapsulated,157,159 in contrast to PDAC. However, the tumor capsule can frequently show discontinuous areas160,161 and may not be seen at all in some lesions, particularly larger lesions.159,162 A common tumor feature is amorphous or scattered calcification,159,162 which is rare in PDAC.160 Pancreatic duct obstruction can occur with SPN,160 but this feature is inconsistently shown across small case series to be associated with malignant SPN over benign SPN.161,163 Vascular invasion can be seen in malignant SPN.163 On MRI, tumors frequently demonstrate internal hyperintensity on precontrast T1 imaging related to hemorrhagic necrosis (Fig. 17.29).157 Cystic or fluid regions with layering T1 hyperintense hemorrhagic debris may be seen.162 On multiphase postcontrast imaging, the tumor will typically show early peripheral heterogeneous enhancement of the solid portions, with progressive fill-in on the delayed phase.164 The fibrous tumor capsule may be evident as a T1/T2-hypointense rim, with some discontinuous regions, and commonly demonstrates early and more hyperintense enhancement compared with the tumor.164

B FIGURE 17.29  Solid pseudopapillary neoplasm (SPN). Axial precontrast T1 fat-saturated magnetic resonance imaging MRI (A) demonstrating a hypointense mass at the pancreatic head (long arrow) with internal T1 hyperintense foci (short arrows), which represent internal hemorrhagic or calcified components. Axial CT in pancreatic parenchymal/late arterial phase (B) showing the hypoenhancing mass (long arrow) with internal calcifications (short arrow).

Pancreatic Metastases In a Japanese autopsy series involving patients with malignant tumors, 15% had pancreatic metastases (excluding primary pancreatic cancer metastases), and approximately half of these were solitary (see Chapter 64).165 The most common tumors metastasizing to the pancreas vary across autopsy studies but are commonly from the kidney, gastrointestinal tract, lung, lymphoma, and breast.165–168 Pancreatic metastases may be solitary, multiple, or demonstrate diffuse involvement,169,170 with no known site predilection.171,172 Metastases are generally round or ovoid, with discrete margins.168,171 The imaging features of the pancreatic metastases are dependent on the imaging characteristics of the primary tumor. Metastases from renal cell carcinoma, hepatocellular carcinoma, and thyroid carcinomas are typically hypervascular, whereas those from the lung, breast, and gastrointestinal tract are generally hypovascular.170,173 Hypervascular metastases show avid enhancement in the arterial or pancreatic parenchymal phase, with wash-out on portal and delayed phase imaging (Fig. 17.30).171 Because of this feature, such metastases may not be appreciated unless arterial phase imaging is performed as part of a multiphase pancreatic protocol.174,175 Small hypervascular metastases more often show homogenous enhancement, whereas larger lesions may demonstrate heterogeneous or peripheral enhancement because of the presence of central necrosis.168,171,176

  Chapter 17  Imaging Features of Benign and Malignant Pancreatic Disease

A

283

B

FIGURE 17.30  Renal cell carcinoma metastatic to pancreas. A, Computed tomography (CT) in pancreatic parenchymal/late arterial phase shows hypervascular pancreatic metastases (arrows). The metastases become more inconspicuous/ isodense to pancreas on the portal venous phase (B).

On MRI, both hypo- and hypervascular metastases will typically demonstrate nonspecific hypointensity to pancreas on precontrast T1 imaging, show moderate or heterogeneous T2 hyperintensity, and may show restricted diffusion.171,175 Pancreatic metastases are usually found in the setting of widely metastatic disease. Nevertheless, pancreatic metastases from renal cell carcinoma (RCC) are commonly isolated or oligometastatic and may occur several years after the initial RCC diagnosis.170–172,177,178 Differentiating solitary RCC metastases from PNET is challenging because both could have an identical appearance on multiphase CT.170,171 Additionally, uptake on SSTR imaging is not pathognomonic of PNET because a number of case studies show somatostatin expression in RCC metastases.179–182 Ultimately biopsy may be required to differentiate between the two tumors. Solitary hypovascular metastases may be particularly difficult to differentiate from PDAC. Although metastases may obstruct the pancreatic duct,168,183,184 they may compress, rather than invade, the duct (as opposed to PDAC), and this is seen as a “duct-penetrating sign” on MRI.173 Metastases may be considered in the setting of a large pancreatic head tumor without biliary/pancreatic duct obstruction or infiltration of retropancreatic fat.185 An additional differentiating imaging feature favoring metastases is a lack of vascular invasion.186,187

Intrapancreatic Accessory Spleen Intrapancreatic accessory spleen (IPAS) is ectopic spleen tissue within the pancreas, which appears as a mass-like entity, and is reported to occur in 7% to 10% at an autopsy series.188,189 IPAS is generally small (1–3 cm) and commonly found in the pancreatic tail.190,191 This may occur by two mechanisms: via congenital presence of accessory spleen or via splenosis after splenectomy or splenic trauma.192 IPAS should be hyperattenuating (CT) and hyperintense (MRI) to normal pancreatic parenchyma on all postcontrast phases (Fig. 17.31).193,194 Further, IPAS should demonstrate identical precontrast T1 and T2 signal to normal spleen on MRI, which is hypointense and hyperintense to pancreas parenchyma, respectively.194 Rarely the IPAS T2 signal may be hyperintense to normal spleen because of the presence of a higher white to red pulp ratio.194

FIGURE 17.31  Intrapancreatic accessory spleen (IPAS). Axial computed tomography (CT) in pancreatic parenchymal/late arterial phase demonstrates a rounded hypervascular mass in the pancreatic tail (arrow).

On both CT and MRI, the enhancement pattern of IPAS will be similar, if not identical, to normal spleen.195 When large, the mass will show typical splenic heterogeneous arterial phase enhancement because of the different blood flow rates between splenic red and white pulp.195 When small, however, IPAS will be homogeneously enhancing. Thus the appearance of IPAS can be similar to other pancreatic tumors on multiphase CT and MRI, particularly hypervascular PNETs and metastases. Additionally, a small increase in the size of IPAS can occur because splenic size can be variable over time, affected by physiologic factors.196 If conventional CT or MRI are not definitive in the diagnosis of IPAS, then further confirmation is possible with either technetium-99m (99mTc) sulphur colloid or 99mTc heat damaged red blood cell scintigraphy (see Chapter 18). The references for this chapter can be found online by accessing the accompanying Expert Consult website.

283.e1

REFERENCES 1. Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162. 2. Boraschi P, Donati F, Cervelli R, Pacciardi F. Secretin-stimulated MR cholangiopancreatography: spectrum of findings in pancreatic diseases. Insights Imaging. 2016;7(6):819-829. 3. Yu J, Turner MA, Fulcher AS, Halvorsen RA. Congenital anomalies and normal variants of the pancreaticobiliary tract and the pancreas in adults: part 2, pancreatic duct and pancreas. Am J Roentgenol. 2006;187(6):1544-1553. 4. Soto JA, Lucey BC, Stuhlfaut JW. Pancreas divisum: depiction with multi-detector row CT. Radiology. 2005;235(2):503-508. 5. Bogveradze N, Hasse F, Mayer P, et al. Is MRCP necessary to diagnose pancreas divisum? BMC Med Imaging. 2019;19(1):33. 6. Borghei P, Sokhandon F, Shirkhoda A, Morgan DE. Anomalies, anatomic variants, and sources of diagnostic pitfalls in pancreatic imaging. Radiology. 2013;266(1):28-36. 7. Sandrasegaran K, Patel A, Fogel EL, Zyromski NJ, Pitt HA. Annular pancreas in adults. Am J Roentgenol. 2009;193(2):455-460. 8. Mortelé KJ, Rocha TC, Streeter JL, Taylor AJ. Multimodality imaging of pancreatic and biliary congenital anomalies. Radiographics. 2006;26(3):715-731. 9. Matsumoto S, Mori H, Miyake H, et al. Uneven fatty replacement of the pancreas: evaluation with CT. Radiology. 1995;194(2):453-458. 10. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-111. 11. Foster BR, Jensen KK, Bakis G, Shaaban AM, Coakley FV. Revised Atlanta classification for acute pancreatitis: a pictorial essay. Radiographics. 2016;36(3):675-687. 12. Porter KK, Zaheer A, Kamel IR, et al. ACR Appropriateness Criteria® acute pancreatitis. J Am Coll Radiol. 2019;16(11):S316-S330. 13. Baker ME, Nelson RC, Rosen MP, et al. ACR Appropriateness Criteria® acute pancreatitis. Ultrasound Q. 2014;30(4):267-273. 14. Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology. 2002;223(3):603-613. 15. Mortele KJ, Wiesner W, Intriere L, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome. Am J Roentgenol. 2004;183(5):1261-1265. 16. Bollen TL, Singh VK, Maurer R, et al. Comparative evaluation of the modified CT severity index and CT severity index in assessing severity of acute pancreatitis. Am J Roentgenol. 2011;197(2):386-392. 17. Lenhart DK, Balthazar EJ. MDCT of acute mild (nonnecrotizing) pancreatitis: abdominal complications and fate of fluid collections. Am J Roentgenol. 2008;190(3):643-649. 18. Mortele KJ, Wiesner W, Intriere L, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome. AJR Am J Roentgenol. 2004;183:1261-1265. 19. Sandrasegaran K, Tann M, Jennings SG, et al. Disconnection of the pancreatic duct: an important but overlooked complication of severe acute pancreatitis. Radiographics. 2007;27(5):1389-1400. 20. Kamal A, Singh VK, Akshintala VS, et al. CT and MRI assessment of symptomatic organized pancreatic fluid collections and pancreatic duct disruption: an interreader variability study using the revised Atlanta classification 2012. Abdom Imaging. 2015;40(6):1608-1616. 21. Macari M, Finn ME, Bennett GL, et al. Differentiating pancreatic cystic neoplasms from pancreatic pseudocysts at MR imaging: value of perceived internal debris. Radiology. 2009;251(1):77-84. 22. Miller FH, Keppke AL, Dalal K, Ly JN, Kamler VA, Sica GT. MRI of pancreatitis and its complications: part 1, acute pancreatitis. Am J Roentgenol. 2004;183(6):1637-1644. 23. Issa Y, Kempeneers MA, van Santvoort HC, Bollen TL, Bipat S, Boermeester MA. Diagnostic performance of imaging modalities in chronic pancreatitis: a systematic review and meta-analysis. Eur Radiol. 2017;27(9):3820-3844. 24. Luetmer PH, Stephens DH, Ward EM. Chronic pancreatitis: reassessment with current CT. Radiology. 1989;171(2):353-357. 25. Lesniak RJ, Hohenwalter MD, Taylor AJ. Spectrum of causes of pancreatic calcifications. Am J Roentgenol. 2002;178(1):79-86. 26. Klöppel G, Maillet B. Chronic pancreatitis: evolution of the disease. Hepatogastroenterology. 1991;38(5):408-412. 27. Tirkes T, Shah ZK, Takahashi N, et al. Reporting standards for chronic pancreatitis by using CT, MRI, and MR cholangiopancreatography:

the consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer. Radiology. 2019;290(1):207-215. 28. Andersen PL, Madzak A, Olesen SS, Drewes AM, Frøkjaer JB. Quantification of parenchymal calcifications in chronic pancreatitis: relation to atrophy, ductal changes, fibrosis and clinical parameters. Scand J Gastroenterol. 2018;53(2):218-224. 29. Lankisch PG, Otto J, Erkelenz I, Lembcke B. Pancreatic calcifications: no indicator of severe exocrine pancreatic insufficiency. Gastroenterology. 1986;90(3):617-621. 30. Sica GT, Braver J, Cooney MJ, Miller FH, Chai JL, Adams DF. Comparison of endoscopic retrograde cholangio-pancreatography with MR cholangiopancreatography in patients with pancreatitis. Radiology. 1999;210(3):605-610. 31. Griffin N, Charles-Edwards G, Grant LA. Magnetic resonance cholangiopancreatography: the ABC of MRCP. Insights Imaging. 2012;3(1):11-21. 32. Halefoglu AM. Magnetic resonance cholangiopancreatography: a useful tool in the evaluation of pancreatic and biliary disorders. World J Gastroenterol. 2007;13(18):2529-2534. 33. Tirkes T, Fogel EL, Sherman S, et al. Detection of exocrine dysfunction by MRI in patients with early chronic pancreatitis. Abdom Radiol. 2017;42(2):544-551. 34. Oto A, Eltorky MA, Dave A, et al. Mimicks of pancreatic malignancy in patients with chronic pancreatitis: correlation of computed tomography imaging features with histopathologic findings. Curr Probl Diagn Radiol. 2006;35(5):199-205. 35. Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis: aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010; 24(3):349-358. 36. Schima W. MRI of the pancreas: tumours and tumour-simulating processes. Cancer Imaging. 2006;6(1):199-203. 37. Kim JK, Altun E, Elias J, Pamuklar E, Rivero H, Semelka RC. Focal pancreatic mass: distinction of pancreatic cancer from chronic pancreatitis using gadolinium-enhanced 3D-gradient-echo MRI. J Magn Reson Imaging. 2007;26(2):313-322. 38. Huang WC, Sheng J, Chen SY, Lu JP. Differentiation between pancreatic carcinoma and mass-forming chronic pancreatitis: usefulness of high b value diffusion-weighted imaging. J Dig Dis. 2011;12(5):401-408. 39. Gabata T, Kadoya M, Terayama N, Sanada J, Kobayashi S, Matsui O. Groove pancreatic carcinomas: radiological and pathological findings. Eur Radiol. 2003;13(7):1679-1684. 40. Triantopoulou C, Dervenis C, Giannakou N, Papailiou J, Prassopoulos P. Groove pancreatitis: a diagnostic challenge. Eur Radiol. 2009;19(7):1736-1743. 41. Addeo G, Beccani D, Cozzi D, et al. Groove pancreatitis: a challenging imaging diagnosis. Gland Surg. 2019;8(suppl 3):S178-S187. 42. Blasbalg R, Baroni RH, Costa DN, Machado MCC. MRI features of groove pancreatitis. Am J Roentgenol. 2007;189(1):73-80. 43. Sah RP, Chari ST. Autoimmune pancreatitis: an update on classification, diagnosis, natural history and management. Curr Gastroenterol Rep. 2012;14(2):95-105. 44. Martins C, Lago P, Sousa P, et al. Type 2 autoimmune pancreatitis: a challenge in the differential diagnosis of a pancreatic mass. GE Port J Gastroenterol. 2017;24(6):296-300. 45. Vujasinovic M, Valente R, Maier P, et al. Diagnosis, treatment and long-term outcome of autoimmune pancreatitis in Sweden. Pancreatology. 2018;18(8):900-904. 46. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J Med. 2006;355(25):2670-2676. 47. Irie H, Honda H, Baba S, et al. Original report. Autoimmune pancreatitis: CT and MR characteristics. Am J Roentgenol. 1998; 170(5):1323-1327. 48. Suzuki K, Itoh S, Nagasaka T, Ogawa H, Ota T, Naganawa S. CT findings in autoimmune pancreatitis: assessment using multiphase contrast-enhanced multisection CT. Clin Radiol. 2010;65(9): 735-743. 49. Takahashi N, Fletcher JG, Hough DM, et al. Autoimmune pancreatitis: differentiation from pancreatic carcinoma and normal pancreas on the basis of enhancement characteristics at dual-phase CT. Am J Roentgenol. 2009;193(2):479-484. 50. Ishigami K, Tajima T, Nishie A, et al. MRI findings of pancreatic lymphoma and autoimmune pancreatitis: a comparative study. Eur J Radiol. 2010;74(3):e22-e28.

283.e2 51. Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis: imaging features. Radiology. 2004;233(2):345-352. 52. Takuma K, Kamisawa T, Tabata T, Inaba Y, Egawa N, Igarashi Y. Utility of pancreatography for diagnosing autoimmune pancreatitis. World J Gastroenterol. 2011;17(18):2332-2337. 53. Yang DH, Kim KW, Kim TK, et al. Autoimmune pancreatitis: radiologic findings in 20 patients. Abdom Imaging. 2006;31(1): 94-102. 54. Kamisawa T, Takuma K, Anjiki H, et al. Differentiation of autoimmune pancreatitis from pancreatic cancer by diffusion-weighted MRI. Am J Gastroenterol. 2010;105(8):1870-1875. 55. Fujinaga Y, Kadoya M, Kawa S, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol. 2010;76(2):228-238. 56. Takuma K, Kamisawa T, Gopalakrishna R, et al. Strategy to differentiate autoimmune pancreatitis from pancreas cancer. World J Gastroenterol. 2012;18(10):1015-1020. 57. Takahashi N, Kawashima A, Fletcher JG, Chari ST. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology. 2007;242(3):791-801. 58. Basturk O, Coban I, Adsay NV. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med. 2009;133(3):423-438. 59. Tanaka M, Fernández-del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17(5):738-753. 60. Megibow AJ, Baker ME, Morgan DE, et al. Management of incidental pancreatic cysts: a white paper of the ACR Incidental Findings Committee. J Am Coll Radiol. 2017;14(7):911-923. 61. Lee HJ, Kim MJ, Choi JY, Hong HS, Kim KA. Relative accuracy of CT and MRI in the differentiation of benign from malignant pancreatic cystic lesions. Clin Radiol. 2011;66(4):315-321. 62. Sainani NI, Saokar A, Deshpande V, Fernández-Del Castillo C, Hahn P, Sahani DV. Comparative performance of MDCT and MRI with MR cholangiopancreatography in characterizing small pancreatic cysts. Am J Roentgenol. 2009;193(3):722-731. 63. Visser BC, Yeh BM, Qayyum A, Way LW, McCulloch CE, Coakley FV. Characterization of cystic pancreatic masses: relative accuracy of CT and MRI. Am J Roentgenol. 2007;189(3):648-656. 64. Berland LL, Silverman SG, Gore RM, et al. Managing incidental findings on abdominal CT: white paper of the ACR incidental findings committee. J Am Coll Radiol. 2010;7(10):754-773. 65. Tanaka M, Fernández-Del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183-197. 66. Jeon JH, Kim JH, Joo I, Lee S, Choi SY, Han JK. Transabdominal ultrasound detection of pancreatic cysts incidentally detected at CT, MRI, or endoscopic ultrasound. Am J Roentgenol. 2018;210(3): 518-525. 67. Beyer-Enke SA, Hocke M, Ignee A, Braden B, Dietrich CF. Contrast enhanced transabdominal ultrasound in the characterisation of pancreatic lesions with cystic appearance. J Pancreas. 2010;11(5): 427-433. 68. Katabi N, Klimstra DS. Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach. J Clin Pathol. 2008;61(12):1303-1313. 69. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. Am J Roentgenol. 2008;191(3):802-807. 70. Bassi C, Procacci C, Zamboni G, Scarpa A, Cavallini G, Pederzoli P. Intraductal papillary mucinous tumors of the pancreas: where are we now? Int J Pancreatol. 2000;27(3):181-193. 71. Nakamura A, Horinouchi M, Goto M, et al. New classification of pancreatic intraductal papillary-mucinous tumour by mucin expression: its relationship with potential for malignancy. J Pathol. 2002;197(2):201-210. 72. Tan L, Zhao YE, Wang DB, et al. Imaging features of intraductal papillary mucinous neoplasms of the pancreas in multi-detector row computed tomography. World J Gastroenterol. 2009;15(32): 4037-4043. 73. Ogawa H, Itoh S, Ikeda M, Suzuki K, Naganawa S. Intraductal papillary mucinous neoplasm of the pancreas: assessment of the likelihood of invasiveness with multisection CT. Radiology. 2008; 248(3):876-886. 74. Freeman HJ. Intraductal papillary mucinous neoplasms and other pancreatic cystic lesions. World J Gastroenterol. 2008;14(19): 2977-2979.

75. Nagasaka T, Nakashima N. Problems in histological diagnosis of intraductal papillary-mucinous tumor (IPMT). Hepatogastroenterology. 2001;48(40):972-976. 76. Lévy P, Jouannaud V, O’Toole D, et al. Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy. Clin Gastroenterol Hepatol. 2006;4(4):460-468. 77. Anand N, Sampath K, Wu BU. Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11(8):913-921. 78. Kawamoto S, Horton KM, Lawler LP, Hruban RH, Fishman EK. Intraductal papillary mucinous neoplasm of the pancreas: can benign lesions be differentiated from malignant lesions with multidetector CT? Radiographics. 2005;25:1451-1468. 79. Kim KW, Park SH, Pyo J, et al. Imaging features to distinguish malignant and benign branch-duct type intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. Ann Surg. 2014; 259(1):72-81. 80. Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for malignancy in intraductal papillary-mucinous tumours of the pancreas. Br J Surg. 2003;90(10):1244-1249. 81. Kucera JN, Kucera S, Perrin SD, Caracciolo JT, Schmulewitz N, Kedar RP. Cystic lesions of the pancreas: radiologic-endosonographic correlation. Radiographics. 2012;32(7):E283-E301. 82. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17-32. 83. Procacci C, Megibow AJ, Carbognin G, et al. Intraductal papillary mucinous tumor of the pancreas: a pictorial essay. Radiographics. 1999;19(6):1447-1463. 84. Pedrosa I. Imaging considerations in intraductal papillary mucinous neoplasms of the pancreas. World J Gastrointest Surg. 2010; 2(10):324. 85. Tamura S, Yamamoto H, Ushida S, Suzuki K. Mucinous cystic neoplasms in male patients: two cases. Rare Tumors. 2017;9(3):93-95. 86. Abdelkader A, Hunt B, Hartley CP, Panarelli NC, Giorgadze T. Cystic lesions of the pancreas differential diagnosis and cytologichistologic correlation. Arch Pathol Lab Med. 2020;144(1):47-61. 87. Kalb B, Sarmiento JM, Kooby DA, Adsay NV, Martin DR. MR imaging of cystic lesions of the pancreas. Radiographics. 2009;29(6): 1749-1765. 88. Procacci C, Carbognin G, Accordini S, et al. CT features of malignant mucinous cystic tumors of the pancreas. Eur Radiol. 2001; 11(9):1626-1630. 89. Khashab MA, Shin EJ, Amateau S, et al. Tumor size and location correlate with behavior of pancreatic serous cystic neoplasms. Am J Gastroenterol. 2011;106(8):1521-1526. 90. Anderson MA, Scheiman JM. Nonmucinous cystic pancreatic neoplasms. Gastrointest Endosc Clin N Am. 2002;12(4):769-779. 91. Allen PJ, Jaques DP, D’Angelica M, Bowne WB, Conlon KC, Brennan MF. Cystic lesions of the pancreas: selection criteria for operative and nonoperative management in 209 patients. J Gastrointest Surg. 2003;7:970-977. 92. Sahani D, Prasad S, Saini S, Mueller P. Cystic pancreatic neoplasms evaluation by CT and magnetic resonance cholangiopancreatography. Gastrointest Endosc Clin N Am. 2002;12(4):657-672. 93. Visser BC, Muthusamay VR, Mulvihill SJ, Coakley F. Diagnostic imaging of cystic pancreatic neoplasms. Surg Oncol. 2004;13(1):27-39. 94. Hutchins GF, Draganov PV. Cystic neoplasms of the pancreas: a diagnostic challenge. World J Gastroenterol. 2009;15(1):48-54. 95. Yeh HC, Stancato-Pasik A, Shapiro RS. Microcystic features at US: a nonspecific sign for microcystic adenomas of the pancreas. Radiographics. 2001;21(6):1455-1461. 96. Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR. Cystic tumors of the pancreas: new clinical, radiologic, and pathologic observations in 67 patients. Ann Surg. 1990;212:432-445. 97. Visser BC, Muthusamy VR, Yeh BM, Coakley FV, Way LW. Diagnostic evaluation of cystic pancreatic lesions. HPB. 2008;10(1):63-69. 98. Chaudhari VV, Raman SS, Vuong NL, et al. Pancreatic cystic lesions: discrimination accuracy based on clinical data and high resolution CT features. J Comput Assist Tomogr. 2007;31(6): 860-867. 99. Kim SY, Lee JM, Kim SH, et al. Macrocystic neoplasms of the pancreas: CT differentiation of serous oligocystic adenoma from mucinous cystadenoma and intraductal papillary mucinous tumor. Am J Roentgenol. 2006;187(5):1192-1198.

283.e3 100. Chu LC, Singhi AD, Hruban RH, Fishman EK. Characterization of pancreatic serous cystadenoma on dual-phase multidetector computed tomography. J Comput Assist Tomogr. 2014;38(2):258-263. 101. Do RKG, Katz SS, Gollub MJ, et al. Interobserver agreement for detection of malignant features of intraductal papillary mucinous neoplasms of the pancreas on MDCT. Am J Roentgenol. 2014; 203(5):973-979. 102. Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, Sarr MG. Primary pancreatic cystic neoplasms of the pancreas revisited. Part IV: rare cystic neoplasms. Surg Oncol. 2012;21(3):153-163. 103. Macin G, Hekimoglu K, Uner H, Tarhan C. Pancreatic cystic lymphangioma: diagnostic approach with MDCT and MR imaging. JBR-BTR. 2014;97(2):97-99. 104. Manning MA, Srivastava A, Paal EE, Gould CF, Mortele KJ. Nonepithelial neoplasms of the pancreas: radiologic-pathologic correlation, part 1—benign tumors. Radiographics. 2016;36(1):123-141. 105. Tempero MA, Malafa MP, Chiorean EG, et al. Pancreatic adenocarcinoma, version 1.2019. J Natl Compr Canc Netw. 2019;17(3): 202-210. 106. Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the society of abdominal radiology and the American pancreatic association. Gastroenterology. 2014;146(1):248-260. 107. Treadwell JR, Zafar HM, Mitchell MD, Tipton K, Teitelbaum U, Jue J. Imaging tests for the diagnosis and staging of pancreatic adenocarcinoma: a meta-analysis. Pancreas. 2016;45(6):789-795. 108. Motosugi U, Ichikawa T, Morisaka H, et al. Detection of pancreatic carcinoma and liver metastases with gadoxetic acid-enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT. Radiology. 2011;260(2):446-453. 109. McNulty NJ, Francis IR, Platt JF, Cohan RH, Korobkin M, Gebremariam A. Multi-detector row helical CT of the pancreas: effect of contrast-enhanced multiphasic imaging on enhancement of the pancreas, peripancreatic vasculature, and pancreatic adenocarcinoma. Radiology. 2001;220(1):97-102. 110. Yoon SH, Lee JM, Cho JY, et al. Small (# 20 mm) pancreatic adenocarcinomas: analysis of enhancement patterns and secondary signs with multiphasic multidetector CT. Radiology. 2011;259 (2):442-452. 111. Gangi S, Fletcher JG, Nathan MA, et al. Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis. Am J Roentgenol. 2004;182(4):897-903. 112. Miller FH, Rini NJ, Keppke AL. MRI of adenocarcinoma of the pancreas. Am J Roentgenol. 2006;187(4):W365-W374. 113. Barreto S. Tumors of the pancreatic body and tail. World J Oncol. 2010;1(2):52. 114. Kim JH, Park SH, Yu ES, et al. Visually isoattenuating pancreatic adenocarcinoma at dynamic- enhanced CT: frequency, clinical and pathologic characteristics, and diagnosis at imaging examinations. Radiology. 2010;257(1):87-96. 115. Nakao A, Kanzaki A, Fujii T, et al. Correlation between radiographic classification and pathological grade of portal vein wall invasion in pancreatic head cancer. Ann Surg. 2012;255(1):103-108. 116. Hough TJ, Raptopoulos V, Siewert B, Matthews JB. Teardrop superior mesenteric vein: CT sign for unresectable carcinoma of the pancreas. Am J Roentgenol. 1999;173(6):1509-1512. 117. Buchs NC, Chilcott M, Poletti PA, Buhler LH, Morel P. Vascular invasion in pancreatic cancer: imaging modalities, preoperative diagnosis and surgical management. World J Gastroenterol. 2010; 16(7):818-831. 118. Tran Cao HS, Balachandran A, Wang H, et al. Radiographic tumor-vein interface as a predictor of intraoperative, pathologic, and oncologic outcomes in resectable and borderline resectable pancreatic cancer. J Gastrointest Surg. 2014;18(2):269-278. 119. Phillips P, Grippo PJ, Munshi HG, eds. Pancreatic stellate cells and fibrosis. In: Pancreatic Cancer and Tumor Microenvironment. Transworld Research Network; 2012. 120. Cassinotto C, Mouries A, Lafourcade JP, et al. Locally advanced pancreatic adenocarcinoma: reassessment of response with CT after neoadjuvant chemotherapy and radiation therapy. Radiology. 2014;273(1):108-116. 121. Cassinotto C, Cortade J, Belleannée G, et al. An evaluation of the accuracy of CT when determining resectability of pancreatic head adenocarcinoma after neoadjuvant treatment. Eur J Radiol. 2013; 82(4):589-593.

122. Beleù A, Calabrese A, Rizzo G, et al. Preoperative imaging evaluation after downstaging of pancreatic ductal adenocarcinoma: a multi-center study. Cancers (Basel). 2019;11(2):267. 123. Cassinotto C, Sa-Cunha A, Trillaud H. Radiological evaluation of response to neoadjuvant treatment in pancreatic cancer. Diagn Interv Imaging. 2016;97(12):1225-1232. 124. Tamm EP. Imaging of pancreatic ductal adenocarcinoma: state of the art. World J Radiol. 2013;5(3):98. 125. Wang Y, Chen ZE, Nikolaidis P, et al. Diffusion-weighted magnetic resonance imaging of pancreatic adenocarcinomas: association with histopathology and tumor grade. J Magn Reson Imaging. 2011;33(1):136-142. 126. Choe J, Kim KW, Kim HJ, et al. What is new in the 2017 World Health Organization Classification and 8th American Joint Committee on Cancer staging system for pancreatic neuroendocrine neoplasms? Korean J Radiol. 2019;20(1):5-17. 127. Lloyd RV, Osamura RY, Klöppel G, Rosai J, eds. World Health Organization Classification of Tumours of Endocrine Organs. 4th ed. International Agency for Research on Cancer; 2017. 128. Ueda Y, Toyama H, Fukumoto T, Ku Y. Prognosis of patients with neuroendocrine neoplasms of the pancreas according to the World Health Organization 2017 Classification. JOP J Pancreas. 2017; S(3):216-220. 129. Lewis RB, Lattin GE, Paal E. Pancreatic endocrine tumors: radiologic-clinicopathologic correlation. Radiographics. 2010;30(6): 1445-1464. 130. Buetow PC, Miller DL, Parrino TV, Buck JL. From the archives of the AFIP - Islet cell tumors of the pancreas: clinical, radiologic, and pathologic correlation in diagnosis and localization. Radiographics. 1997;17(2):453-472. 131. Tamm EP, Bhosale P, Lee JH, Rohren EM. State-of-the-art imaging of pancreatic neuroendocrine tumors. Surg Oncol Clin N Am. 2016; 25(2):375-400. 132. Poultsides GA, Huang LC, Chen Y, et al. Pancreatic neuroendocrine tumors: radiographic calcifications correlate with grade and metastasis. Ann Surg Oncol. 2012;19(7):2295-2303. 133. Tan EH. Imaging of gastroenteropancreatic neuroendocrine tumors. World J Clin Oncol. 2011;2(1):28. 134. Ciaravino V, De Robertis R, Tinazzi Martini P, et al. Imaging presentation of pancreatic neuroendocrine neoplasms. Insights Imaging. 2018;9(6):943-953. 135. Semelka RC, Custodio CM, Cem Balci N, Woosley JT. Neuroendocrine tumors of the pancreas: spectrum of appearances on MRI. J Magn Reson Imaging. 2000;11(2):141-148. 136. Sahani DV, Bonaffini PA, Fernández-Del Castillo C, Blake MA. Gastroenteropancreatic neuroendocrine tumors: role of imaging in diagnosis and management. Radiology. 2013;266(1):38-61. 137. Jang KM, Kim SH, Lee SJ, Choi D. The value of gadoxetic acidenhanced and diffusion-weighted MRI for prediction of grading of pancreatic neuroendocrine tumors. Acta Radiol. 2014;55(2): 140-148. 138. Jeon SK, Lee JM, Joo I, et al. Nonhypervascular pancreatic neuroendocrine tumors: differential diagnosis from pancreatic ductal adenocarcinomas at MR imaging—retrospective cross-sectional study. Radiology. 2017;284(1):77-87. 139. Bordeianou L, Vagefi PA, Sahani D, et al. Cystic pancreatic endocrine neoplasms: a distinct tumor type? J Am Coll Surg. 2008; 206(6):1154-1158. 140. Ligneau B, Lombard-Bohas C, Partensky C, et al. Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol. 2001;25(6): 752-760. 141. Horton KM, Hruban RH, Yeo C, Fishman EK. Multi-detector row CT of pancreatic islet cell tumors. Radiographics. 2006;26(2): 453-464. 142. Soga J, Yakuwa Y. Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. J Exp Clin Cancer Res. 1999;18(1): 13-22. 143. Ghaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008;12(2):382-393. 144. Wang Y, Chen ZE, Yaghmai V, et al. Diffusion-weighted MR imaging in pancreatic endocrine tumors correlated with histopathologic characteristics. J Magn Reson Imaging. 2011;33(5): 1071-1079.

283.e4 145. Fujinaga Y, Lall C, Patel A, Matsushita T, Sanyal R, Kadoya M. MR features of primary and secondary malignant lymphoma of the pancreas: a pictorial review. Insights Imaging. 2013;4(3): 321-329. 146. Rock J, Bloomston M, Lozanski G, Frankel WL. The spectrum of hematologic malignancies involving the pancreas. Am J Clin Pathol. 2012;137(3):414-422. 147. Boninsegna E, Zamboni GA, Facchinelli D, et al. CT imaging of primary pancreatic lymphoma: experience from three referral centres for pancreatic diseases. Insights Imaging. 2018;9(1):17-24. 148. Merkle EM, Bender GN, Brambs HJ. Imaging findings in pancreatic lymphoma: differential aspects. Am J Roentgenol. 2000;174(3): 671-675. 149. Boninsegna E, Manfredi R, Negrelli R, Avesani G, Mehrabi S, Pozzi Mucelli R. Pancreatic duct stenosis: differential diagnosis between malignant and benign conditions at secretin-enhanced MRCP. Clin Imaging. 2017;41:137-143. 150. Jornet D, Soyer P, Terris B, et al. MR imaging features of pancreatic acinar cell carcinoma. Diagn Interv Imaging. 2019;100(7-8): 427-435. 151. Hsu MY, Pan KT, Chu SY, Hung CF, Wu RC, Tseng JH. CT and MRI features of acinar cell carcinoma of the pancreas with pathological correlations. Clin Radiol. 2010;65(3):223-229. 152. Hu S, Hu S, Wang M, Wu Z, Miao F. Clinical and CT imaging features of pancreatic acinar cell carcinoma. Radiol Medica. 2013;118(5):723-731. 153. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell carcinoma of the pancreas in adults. Am J Roentgenol. 2005;184(2):511-519. 154. Mergo PJ, Helmberger TK, Buetow PC, Helmberger RC, Ros PR. Pancreatic neoplasms: MR imaging and pathologic correlation. Radiographics. 1997;17(2):281-301. 155. Tian L, Lv XF, Dong J, et al. Clinical features and CT/MRI findings of pancreatic acinar cell carcinoma. Int J Clin Exp Med. 2015;8(9):14846-14854. 156. Raman SP, Hruban RH, Cameron JL, Wolfgang CL, Kawamoto S, Fishman EK. Acinar cell carcinoma of the pancreas: computed tomography features - a study of 15 patients. Abdom Imaging. 2013;38(1):137-143. 157. Ohtomo K, Furui S, Onoue M, et al. Solid and papillary epithelial neoplasm of the pancreas: MR imaging and pathologic correlation. Radiology. 1992;184(2):567-570. 158. Buetow PC, Parrino TV, Buck JL, et al. Islet cell tumors of the pancreas: pathologic-imaging correlation among size, necrosis and cysts, calcification, malignant behavior, and functional status. Am J Roentgenol. 1995;165(5):1175-1179. 159. Anil G, Zhang J, Al-Hamar NE, Nga ME. Solid pseudopapillary neoplasm of the pancreas: CT imaging features and radiologicpathologic correlation. Diagnostic Interv Radiol. 2017;23(2):94-99. 160. Yin Q, Wang M, Wang C, et al. Differentiation between benign and malignant solid pseudopapillary tumor of the pancreas by MDCT. Eur J Radiol. 2012;81(11):3010-3018. 161. Huang YS, Chen JL, Chang CC, Liu KL. Solid pseudopapillary neoplasms of the pancreas: imaging differentiation between benignity and malignancy. Hepatogastroenterology. 2014;61(131): 809-813. 162. Buetow PC, Buck JL, Pantongrag-Brown L, Beck KG, Ros PR, Adair CF. Solid and papillary epithelial neoplasm of the pancreas: imaging-pathologic correlation in 56 cases. Radiology. 1996;199 (3):707-711. 163. Lee JH, Yu JS, Kim H, et al. Solid pseudopapillary carcinoma of the pancreas: differentiation from benign solid pseudopapillary tumour using CT and MRI. Clin Radiol. 2008;63(9):1006-1014. 164. Cantisani V, Mortele KJ, Levy A, et al. MR imaging features of solid pseudopapillary tumor of the pancreas in adult and pediatric patients. Am J Roentgenol. 2003;181(2):395-401. 165. Nakamura E, Shimizu M, Itoh T, Manabe T. Secondary tumors of the pancreas: clinicopathological study of 103 autopsy cases of japanese patients. Pathol Int. 2001;51(9):686-690. 166. Adsay NV, Andea A, Basturk O, Kilinc N, Nassar H, Cheng JD. Secondary tumors of the pancreas: an analysis of a surgical and autopsy database and review of the literature. Virchows Arch. 2004;444(6):527-535. 167. Rumancik WM, Megibow AJ, Bosniak MA, Hilton S. Metastatic disease to the pancreas: evaluation by computed tomography. J Comput Assist Tomogr. 1984;8(5):829-834.

168. Shi H, Zhao X, Miao F. Metastases to the pancreas. Medicine (Baltimore). 2015;94(23):e913. 169. Ferrozzi F, Bova D, Campodonico F, De Chiara F, Passari A, Bassi P. Pancreatic metastases: CT assessment. Eur Radiol. 1997;7(2):241-245. 170. Angelelli G, Mancini M, Pignataro P, Pedote P, Scardapane A. La tomografia computerizzata multidetettore nello studio delle metastasi pancreatiche. Radiol Medica. 2012;117(3):369-377. 171. Vincenzi M, Pasquotti G, Polverosi R, Pasquali C, Pomerri F. Imaging of pancreatic metastases from renal cell carcinoma. Cancer Imaging. 2014;14(1):5. 172. Sellner F, Tykalsky N, De Santis M, Pont J, Klimpfinger M. Solitary and multiple isolated metastases of clear cell renal carcinoma to the pancreas: an indication for pancreatic surgery. Ann Surg Oncol. 2006;13(1):75-85. 173. Triantopoulou C, Kolliakou E, Karoumpalis I, Yarmenitis S, Dervenis C. Metastatic disease to the pancreas: an imaging challenge. Insights Imaging. 2012;3(2):165-172. 174. Ng CS, Loyer EM, Iyer RB, David CL, DuBrow RA, Charnsangavej C. Metastases to the pancreas from renal cell carcinoma: findings on three- phase contrast-enhanced helical CT. Am J Roentgenol. 1999;172(6):1555-1559. 175. Ballarin R, Spaggiari M, Cautero N, et al. Pancreatic metastases from renal cell carcinoma: the state of the art. World J Gastroenterol. 2011;17(43):4747-4756. 176. Palmowski M, Hacke N, Satzl S, et al. Metastasis to the pancreas: characterization by morphology and contrast enhancement features on CT and MRI. Pancreatology. 2008;8(2):199-203. 177. Kassabian A, Stein J, Jabbour N, et al. Renal cell carcinoma metastatic to the pancreas: a single-institution series and review of the literature. Urology. 2000;56(2):211-215. 178. Wente MN, Kleeff J, Esposito I, et al. Renal cancer cell metastasis into the pancreas: a single-center experience and overview of the literature. Pancreas. 2005;30(3):218-222. 179. Kanthan GL, Schembri GP, Samra J, Roach P, Hsiao E. Metastatic renal cell carcinoma in the thyroid gland and pancreas showing uptake on 68Ga DOTATATE PET/CT scan. Clin Nucl Med. 2016;41(7):583-584. 180. Soydal C, Nak D, Araz M, Demirkazik A, Kucuk NO. 68GaDOTATATE uptake in pancreatic metastasis of renal cell carcinoma mimicking pancreatic neuroendocrine tumor. Clin Nucl Med. 2019;44(10):795-796. 181. Nadebaum D, Lee S, Nikfarjam M, Scott A. Metastatic clear cell renal cell carcinoma demonstrating intense uptake on 68 GaDOTATATE positron emission tomography: three case reports and a review of the literature. World J Nucl Med. 2018;17(3):195. 182. Edgren M, Westlin JE, Kälkner KM, Sundin A, Nilsson S. [ 111 In-DPTA-D-Phe 1 ] - octreotide scintigraphy in the management of patients with advanced renal cell carcinoma. Cancer Biother Radiopharm. 1999;14(1):59-64. 183. Tsitouridis I, Diamantopoulou A, Michaelides M, Arvanity M, Papaioannou S. Pancreatic metastases: CT and MRI findings. Diagnostic Interv Radiol. 2010;16(1):45-51. 184. Charnsangavej C, Whitley NO. Metastases to the pancreas and peripancreatic lymph nodes from carcinoma of the right side of the colon: CT findings in 12 patients. Am J Roentgenol. 1993; 160(1):49-52. 185. Boudghène FP, Deslandes PM, Leblanche AF, Bigot JMR, Boudghène FP. US and CT imaging features of intrapancreatic metastases. J Comput Assist Tomogr. 1994;18(6):905-910. 186. Klein KA, Stephens DH, Welch TJ. CT characteristics of metastatic disease of the pancreas. Radiographics. 1998;18(2):369-378. 187. Tan CH, Tamm EP, Marcal L, et al. Imaging features of hematogenous metastases to the pancreas: pictorial essay. Cancer Imaging. 2011;11(1):9-15. 188. Unver Dogan N, Uysal II, Demirci S, Dogan KH, Kolcu G. Accessory spleens at autopsy. Clin Anat. 2011;24(6):757-762. 189. Halpert B, Gyorkey F. Lesions observed in accessory spleens of 311 patients. Am J Clin Pathol. 1959;32(2):165-168. 190. Spencer LA, Williams TR. Imaging features of intrapancreatic accessory spleen. Br J Radiol. 2010;83:668-673. 191. Baugh KA, Villafane N, Farinas C, et al. Pancreatic incidentalomas: a management algorithm for identifying ectopic spleens. J Surg Res. 2019;236:144-152. 192. Movitz D. Accessory spleens and experimental splenosis. Principles of growth. Chic Med Sch Q. 1967;26(4):183-187.

283.e5 193. Se HK, Jeong ML, Joon KH, et al. Intrapancreatic accessory spleen: findings on MR imaging, CT, US and scintigraphy, and the pathologic analysis. Korean J Radiol. 2008;9(2):162-174. 194. Kim SH, Lee JM, Han JK, et al. MDCT and superparamagnetic iron oxide (SPIO)-enhanced MR findings of intrapancreatic accessory spleen in seven patients. Eur Radiol. 2006;16(9):18871897.

195. Vancauwenberghe T, Snoeckx A, Vanbeckevoort D, Dymarkowski S, Vanhoenacker FM. Imaging of the spleen: what the clinician needs to know. Singapore Med J. 2015;56(3):133-144. 196. Chow KU, Luxembourg B, Seifried E, Bonig H. Spleen size is significantly influenced by body height and sex: establishment of normal values for spleen size at US with a cohort of 1200 healthy individuals. Radiology. 2016;279(1):306-313.

CHAPTER 18 The role of nuclear medicine in diagnosis and management of hepatopancreatobiliary diseases Simone Krebs, Elisabeth O’Dwyer, and Mark Dunphy Nuclear medicine uses radioactive pharmaceuticals, or radiopharmaceuticals, for diagnostic imaging and internal radiotherapy of a variety of diseases. This chapter discusses clinical applications of diagnostic nuclear medicine imaging for the care of patients with hepatic, pancreatic, and biliary (hepatopancreatobiliary [HPB]) diseases. Radioembolization of liver tumors with radiolabeled microspheres is discussed more extensively in Chapter 94B. In general, the role of diagnostic nuclear medicine imaging (NMI), or scintigraphy, including positron emission tomography (PET), is to provide HPB clinicians with a noninvasive method to aid in detecting and localizing certain types of HPB disease and to evaluate HPB organ function and the effects of treatment. In general, NMI can be considered a clinical assay of cellular biology in the tissues of patients; the in vivo tissue accumulation, or uptake, of most radiopharmaceuticals depends on the biomolecular composition of living cells in body tissues, as well as tissue perfusion. The diagnostic accuracy of scintigraphy varies according to the specific scintigraphic study (including the specific radiopharmaceutical used and how it is assayed) and the specific disease or condition being studied. The HPB specialist must integrate diagnostic data from any scintigraphic study of a particular patient with signs, symptoms, and data from other relevant assays for optimal diagnostic accuracy and therapeutic decision making. NMI has a major positive impact on patient care, improving therapeutic strategy. This chapter discusses the published clinical evidence regarding the impact of nuclear medicine in HPB diseases and focuses on state-of-the-art nuclear medicine. As such, it concentrates predominantly on published medical literature from the past 15 years. In our experience, most clinical nuclear medicine research publications before then often employ methodology and technology that is no longer reflective of current state-of-the-art clinical practice in nuclear medicine. The stateof-the-art in nuclear medicine, in its diagnostic and therapeutic procedures, has improved rapidly in the past 15 years and continues to evolve and innovate, including major improvements in commercially available nuclear imaging camera systems (particularly the advent of hybrid “fusion imaging” camera systems), image data processing, new types of instrumentation, and clinical introduction of new radiopharmaceuticals, both for diagnostic imaging and nuclear therapy. Therefore we strongly advise the reader to note the dates of nuclear medicine references cited in HPB bibliographies and other guidelines, especially when these make judgments on the diagnostic accuracy or clinical impact of nuclear medicine; sometimes guidelines cite outdated nuclear medicine research from decades past. Such guidelines might be designed in recognition that nuclear medicine clinical practice varies worldwide, as reflected in the often widely varying diagnostic sensitivities 284

and specificities reported by different medical centers performing a particular NMI procedure and the variation of hardware (e.g., scanners) and techniques (e.g., administered tracer doses, software-based data-processing algorithms) employed in different centers. After an introduction to the pharmacology and technology of diagnostic imaging and therapy in radiopharmaceuticals and the general role of nuclear medicine in HPB diseases, we discuss current nuclear medicine procedures for specific HPB clinical indications. For diagnostic imaging procedures, discussion focuses on how well a particular clinical NMI study performs for a specific HPB indication, in terms of its diagnostic accuracy (sensitivity, specificity) and potential pitfalls, including necessary patient preparation, when applicable. The chapter also includes a concise look at select new, currently investigational radiopharmaceuticals relevant to HPB disease.

RADIOPHARMACEUTICALS Nuclear medicine specialists prescribe radiopharmaceuticals for diagnostic imaging and internal radiotherapy of a variety of diseases. Radiopharmaceuticals can be placed into three major categories of applications in HPB disease: detection and evaluation of cancerous HPB tumors, treatment of HPB cancers, and evaluation of HPB organ function (and indirectly for detection of disease entities causing HPB organ dysfunction). A radiopharmaceutical is a radioactive compound containing a radionuclide, also referred to as a “radioisotope” (radioactive isotope). A radioisotope is an energetically unstable atom that will achieve a stable or more stable, lower-energy state (transitioning from a parent to a daughter state) by releasing (radiating) energy (radiation) in some form (e.g., emitting a gamma ray, positron particle, or beta particle, as discussed later). The release of energy by the (parent) radioisotope atom may be called a physical decay, disintegration, or transition. The energy decay makes the elemental atom either become a different isotope of the same element (e.g., the radioisotope technetium 99m [99mTc] decays to the stable isotope technetium 99 [99Tc]) or become a different element by transmutation (e.g., the radioisotope 18F decays to become a stable form of the element oxygen, 18O). Other forms of nuclear decay are possible (e.g., transitions from a higher-energy unstable radioisotope to a lower-energy, but still unstable, daughter radioisotope). A radiopharmaceutical is administered in a trace amount (with no detectable radiobiologic effects) or therapeutic amount for use as a diagnostic imaging agent or therapeutic agent. A radiopharmaceutical also contains other active and inactive ingredients in the compound formulation. In the radiopharmaceutical, the elemental radioisotope atom typically is incorporated within a molecule by chemical bonding. The molecule is said to be radiolabeled.

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

As with any pharmaceutical, each type of radiopharmaceutical has in vivo pharmacokinetic (PK) properties specific to and determined by its molecular structure and associated physicochemical properties. PK properties include the radiopharmaceutical’s distribution in tissues throughout the body (biodistribution), metabolism, and bodily elimination (by hepatobiliary and urinary excretion for all relevant radiopharmaceuticals). The in vivo PK properties are also determined, to some degree, by the physicochemical properties of excipients (vehicles) in the radiopharmaceutical formulation (e.g., formulation of an orally administered radiopharmaceutical compound may affect its bioavailability and biodistribution), as well as by the route of administration (e.g., peripheral intravenous [IV] injection, hepatic arterial catheter infusion). The mass-amount of radioactive molecules in any prescribed radiopharmaceutical formulation is only a trace amount, typically in the picogram (pg) range. This tiny mass-dose of radioactive molecule is incapable of exerting detectable pharmacologic effects on body tissues in vivo, but the typical pg amounts of radioactive molecules emit radioactivity sufficient for diagnostic imaging and therapeutic applications. With exceptions, the nonradioactive constituents of radiopharmaceutical compounds typically used only for clinical diagnostic imaging are present in somewhat higher mass-amounts but are still scant, typically less than 100 micrograms (µg), and allergic reactions, other side effects, or pharmacodynamic effects are rarely reported. Nuclear medicine specialists may prescribe the radiopharmaceutical compound to be administered in conjunction with a relatively high and biologically effective massamount of a nonradioactive, or unlabeled, version of the same compound or a related compound, with therapeutic intent (relevant compounds are discussed later). The terms “radiotracer,” “tracer dose,” and “radiotracer dose” commonly refer to the use of trace amounts of a radiolabeled molecule to study molecular biology. The trace amount of radioactivity and the trace mass of the administered radiotracer are unable to affect (and therefore unable to interfere with measurements of) the biomolecular system or target being assayed. Following this common convention, in this chapter we use radiotracer to refer to radiopharmaceutical administered for diagnostic imaging. We use therapeutic radionuclide to refer to administration of a relatively high amount of radioactivity with the intent of inducing therapeutic radiobiologic effects in vivo, as discussed later. The radioactivity emitted by a therapeutic radiopharmaceutical may be useful for diagnostic imaging, as well as radiotherapy. The approach of combining diagnostic imaging and therapy using a same molecule or at least very similar molecules, which are either radiolabeled differently or given in different dosages, is known as theranostics.

Fluorodeoxyglucose Positron Emission Tomography In the past 25 years, fluorodeoxyglucose (FDG) PET has rapidly emerged as a revolutionary imaging modality in clinical oncology, demonstrating diagnostic efficacy in tumor staging and tumor-response evaluation for histologies across a variety of cancers. FDG, or 2-deoxy-2-(18F)fluoro-d-glucose, is an analogue of glucose; fluorine-18 occupies the molecular 29 position in which a hydroxyl group is found in glucose. The substitution affects the metabolism of FDG compared with glucose. In vivo, IV FDG extravasates into tissues, followed by its uptake into tissue cells by glucose transporter proteins. Once FDG enters the cell, hexokinase converts FDG to FDG-6-phosphate, which

285

cannot be metabolized further, thus trapping the tracer intracellularly. Blood FDG concentrations decrease to relatively low levels 45 to 90 minutes after injection; at this point, further FDG uptake in most tissues is relatively minor, and after that time, FDG concentrations in most tissues and tumors remain relatively stable. Acquiring a single FDG PET scan, beginning 45 to 90 minutes after injection, has become the standard clinical approach. Usually, as for HPB cancer imaging, the scan spans from “eyes to thighs,” including the entire head or extremities only if there is a patient-specific clinical reason. The basic rationale for using FDG PET for tumor detection is the observation that neoplastic cells typically accumulate FDG more than the non-neoplastic cells of origin and that the difference in FDG concentration between the tumor and surrounding normal tissues in an organ is detectable by PET. This avidity of tumors for FDG manifests on PET images as a “hot spot,” or a focus, of FDG accumulation that is of abnormally high concentration relative to other, healthy tissues. Why are some tumors FDG avid and other are not very avid? The physician-scientist and Nobel laureate Otto Warburg long ago observed in multiple tumor cell lines that he studied an abnormally high rate of glycolysis in cancer cells compared with their normal cellular counterparts, even in the presence of normal levels of oxygen. In normal cells with adequate environmental oxygen, glucose metabolism is typically directed into the mitochondrial tricarboxylic acid (TCA) cycle; glucose– TCA cycle metabolism yields the maximal amount of energy substrate (adenosine triphosphate [ATP]) from each glucose molecule metabolized for meeting the bioenergetic needs of the cell. The TCA cycle depends on oxygen to function; in normal cells, if environmental oxygen is low, glucose metabolism instead occurs in the cytosol by an oxygen-independent glycolytic process that yields much less ATP per glucose molecule. In cancer cells, however, Warburg observed that glucose metabolism occurred predominantly by glycolysis in the cytosol, regardless of whether or not the tumor cells were well oxygenated. This preference of tumor cells is the Warburg effect. According to the Warburg hypothesis, cancer cell metabolism of glucose was inefficient because it yielded fewer ATP molecules per glucose cell, and this inefficiency was caused by a defect in the mitochondrial metabolism of cancer cells. The Warburg effect remains a valid observation, although not a universal phenomenon among all cancer cell lines and types (i.e., glucose metabolism of some cancer cell lines is essentially the same as the glucose metabolism of normal cell counterparts). The Warburg hypothesis, however, is outdated; the shift of glucose metabolism from the mitochondrial TCA cycle to cytosolic glycolysis is not an inefficient use of glucose. Rather, it is a “repurposing” of glucose. In multiple cell lines, abnormal cytosolic glycolysis has become understood as advantageous to cancer cell proliferation. Cytosolic glycolysis yields fewer ATP molecules, but it yields glucose-derived metabolites during the multiple intermediate steps of glycolysis that the cell can use in other anabolic pathways as components for synthesizing macromolecules necessary for building cellular biomass before cell division and tumor growth. To meet the bioenergetic needs of these cells, instead of predominantly relying on glucose, these cells depend on other nutrient molecules, notably glutamine, to fuel the TCA cycle.1 The Warburg effect explains the avidity of tumors for FDG, the glucose analogue, when visualized by PET, but only in part. PET visualizes the FDG avidity of tumors at the macroscopic

286

PART 2  DIAGNOSTIC TECHNIQUES

tissue level (again, with spatial resolution of ~2 mm). The “FDG-avid tumor” visualized by PET and described in PET/ computed tomography (CT) reports represents a complex composite of FDG avidities of tumor cells and nonneoplastic cell constituents within the tumor internal microenvironment under the influence of complex biomolecular and other processes. Detected FDG avidity in a particular tumor often does primarily represent tumor cell FDG avidity (i.e., the sum of FDG uptake from all tumor cells within the tumor) more than the FDG avidity of other cells in the same tumor. However, the FDG avidity of other constituents of the tumor microenvironment sometimes contributes to a clinically significant degree, particularly in the posttreatment setting, potentially causing diagnostic confusion, as discussed. In certain cases, overall tumor FDG avidity can be caused, in relatively large part or even primarily, by tumor cellular constituents other than the neoplastic cells, such as infiltrating inflammatory cells, especially when the tumor cells do not have intrinsically high FDG avidity and when inflammatory cells are present in relatively high tissue concentrations. For example, inflammatory cells can accumulate around the necrotic cores of tumors before treatment and can infiltrate heavily throughout tumors after treatment. Standard FDG PET guidelines often advise that posttreatment PET be deferred for 6 to 8 weeks after chemotherapy and 2 to 3 months after radiotherapy. It was empirically observed in clinical PET trials that successfully treated tumors often demonstrate apparently suspicious residual FDG avidity in the first few weeks after treatment because of inflammatory cells infiltrating the treated tumors, presumably to clear the necrotic/apoptotic debris associated with successful treatment. Whenever using PET to characterize or localize tumors, the oncologist (and imaging specialist) should be aware of key factors that affect the apparent FDG avidity of a tumor and the diagnostic sensitivity of FDG PET: tumor size; cancer treatment(s); and background organ FDG avidity. As the Nyquist principle indicates, the apparent FDG avidity of subcentimeter tumors will be underestimated because such small lesions fall below the spatial resolution of PET technology. It is still possible for PET to detect a subcentimeter tumor if the tumor is so FDG avid that the FDG accumulation in tumor is detectably higher than that in background tissues of the organ involved, but many subcentimeter tumors lack apparent FDG avidity and may be reported as “too small to characterize by FDG PET.” Additionally, the specificity of FDG can vary in the setting of coexisting benign pathologies, leading to falsepositive results. For example, specificity of FDG PET is lower for patients who live in areas where tuberculosis (TB) is endemic. Furthermore, TB lesions absorb FDG and can mimic tumors on FDG PET. Cancer treatments, depending on action and efficacy, also affect apparent tumor FDG avidity.2 Tumor FDG avidity represents the sum of the FDG avidity of constituent tumor cells. Various studies indicate FDG PET is unable to detect microscopic residual disease; for example, a partially treated tumor containing FDG-avid cells may be of macroscopic size on CT or magnetic resonance imaging (MRI) but may contain a depleted cell population with a sum FDG avidity that appears minimal to nil on PET imagery. For staging, FDG PET is expected to be less accurate after therapy than before therapy.2 FDG PET can also be false positive, detecting FDG uptake at a former tumor site in the absence of residual disease. With systemic therapy, residual FDG uptake may indicate inflammatory cells (extremely FDG

avid, when active) infiltrating tissues to remove the debris of treated disease. Radiotherapy and surgery, for tumor treatment or resection, both evoke local tissue inflammation that can be greatly FDG avid, mimicking local residual or recurrent neoplastic disease on PET imagery. FDG PET is usually deferred for several weeks after surgery or radiotherapy, when evaluation for local disease is desired. Certain organs and organ systems have marked FDG avidity consistently or variably that may exceed that of primary tumors and metastases, obscuring tumor detection. For example, the brain is consistently FDG avid because it normally depends on glucose metabolism; FDG PET has limited sensitivity for detection of brain metastases. FDG is excreted through the urinary tract; the radioactive signal from excreted FDG in the collecting systems typically obscures PET evaluation of the kidneys and urinary bladder. The liver, lungs, and other tissues have lesser degrees of background FDG avidity that usually do not obscure tumor detection significantly. Besides tumor detection, for disease (re)staging, FDG PET may be used to evaluate tumor response to cancer therapy. Frequently, FDG PET is performed twice, before and after therapy, for comparison, using changes in tumor FDG avidity as an index of changes in tumor cell population size (i.e., tumor response). Marked decreases in tumor FDG avidity during therapy have frequently predicted favorable clinical outcomes, whereas stable or increasing FDG avidity portend worse outcomes across a variety of cancers. Evaluation of tumor FDG avidity after cytotoxic therapy without a pretreatment PET study for comparison can be performed but can yield potentially confusing findings; for example, reactive lymph nodes and partially treated metastatic adenopathy can have similar appearances on PET. Tumors may have marked residual FDG avidity after treatment, which may provoke concerns about tumor resistance. If a pretreatment FDG PET had been obtained, however, the residual FDG avidity might have been observed as a marked decrease from baseline tumor FDG avidity, suggesting a favorable tumor response. In other words, the change in tumor FDG avidity before versus after treatment can be more predictive of tumor response than merely the posttreatment FDG avidity alone. As mentioned, certain tumor histologies seem frequently to lack FDG avidity, despite the presence of viable, macroscopic neoplastic disease. A lack of tumor FDG avidity on a posttreatment PET scan can be potentially misleading as an indicator of tumor response, unless a pretreatment PET scan has demonstrated the tumor being treated was originally FDG avid.

DIAGNOSTIC IMAGING IN NUCLEAR MEDICINE In general, diagnostic NMI is a noninvasive procedure that uses scanning hardware to examine the distribution of a radiopharmaceutical within the internal environment of the body. As discussed, imaging the in vivo distribution of a radiopharmaceutical can be considered as an in vivo assay of radiopharmaceutical pharmacokinetics, not just in blood but also in tissues/ organs throughout the body. No radiopharmaceutical compound yet designed has been found to bind exclusively to one particular biologic molecule. Some compounds, however, such as radiolabeled antibodies, radiolabeled “small molecules,” and other types of agents, do bind with very high selectivity and affinity to relatively few biologic molecules and not at all to other types of molecules and are called “targeted agents.” Still, the

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

biophysiologic processes and biologic molecules targeted by such agents for diagnostic imaging (or “targeted therapy”) of a particular condition of interest can almost invariably be found in other physiologic or pathologic conditions, again precluding 100% specificity. For example, the biologic molecule prostatespecific membrane antigen (PSMA, now more properly referred to as glutamate carboxypeptidase II), once thought to be uniquely expressed by prostate tissues and thus a good biomarker for prostate cancer (e.g., for imaging by PSMA-targeted radiolabeled antibody), was later found to be expressed by certain other tissues in the body and in the neovasculature of most tumors. However, PSMA is highly expressed in only a few types of nonprostatic tissues and therefore still possesses high selectivity for prostatic tissues. Therefore “perfect” specificity should not be expected for diagnostic imaging agents, even radiolabeled antibodies, considering the underlying imperfect pharmacologic and biologic specificity, as well as potentially misleading imaging artifacts. In diagnostic NMI, the image is produced by the radiopharmaceutical administered to the patient. Once administered, the radioisotope physically decays with a characteristic radioactive emission pattern, producing energy or photons. These photons are detected by nuclear scanner (e.g., PET scanner or gamma camera) and an image is created. Does the biodistribution of the radioisotope atoms visualized by the nuclear scan represent the biodistribution of the administered radiopharmaceutical (molecules)? If the radiopharmaceutical does not undergo in vivo chemical transformation to another form (e.g., catabolite or metabolite) before imaging of the patient, the answer is yes. Otherwise, the radioisotope biodistribution imagery may represent a composite of biodistributions, including those of the (unmodified) administered radiopharmaceutical and the radioactive products of in vivo chemical reactions (i.e., reaction products that still incorporate the radioisotopic atom). Usually, in vivo metabolism of the radiopharmaceutical causes in vivo production of metabolites, one or more of which include the radioisotope; these are radiometabolites. Such metabolism may be the diagnostic imaging target of the nuclear scan (e.g., PET imaging with F-18 FDG to detect tumor concentrations of the FDG metabolite). Some radiometabolites may be radiolabeled molecules, or in vivo metabolism may yield radioisotope in free, unattached elemental form. These radiometabolites often have different in vivo PK properties from the intact parent radiopharmaceutical. Thus the radiotracer biodistribution visualized by nuclear imagery will represent a combination of biodistributions: that of the intact radiopharmaceutical and that of one or more radiometabolites. In vivo metabolism occurs but typically does not interfere with diagnostic interpretation. On the contrary, metabolism may yield a radiometabolite “trapped” in a tissue of interest, such as enzymatic trapping of the PET imaging FDG in tumor cells; the cytoplasmic enzyme hexokinase yields the radiometabolite FDG-6-phosphate, which is trapped intracellularly. This chapter discusses the meaning of each radiopharmaceutical scintigraphic biomarker scan relevant in HPB diseases. Once administered to a patient, the radioisotope used for diagnostic imaging emits radiation that can be detected by a nuclear scanner. Diagnostic imaging with radiopharmaceuticals, in standard clinical practice, may be referred to in various ways, including (1) using general terms such as nuclear imaging or scintigraphy, (2) referring to one of two general types of scintigraphic camera

287

technology (PET, single-photon emission computed tomography [SPECT]/single-photon emission tomography [SPET]), and (3) using the procedure involved (e.g., theranostic imaging). The term scintigraphy (Latin scintilla, “spark”) in medicine refers to the light produced by crystalline detectors in clinical scintigraphic cameras when those crystals are struck by gamma rays emitted from radiopharmaceuticals (e.g., as emitted from within a patient scanned after receiving a radiopharmaceutical injection). These scintillations produced in the crystalline detectors are recognized and processed by the camera system to yield nuclear imagery. Of the basic types of scans found in a radiology department (e.g., plain radiography, CT, MRI, ultrasound [US]), diagnostic NMI scans are typically of the longest duration, in terms of both the time the patient must physically spend with the scanner and the time required for the entire study (start to finish), often with necessary delays before scanning or between scanning (i.e., if the patient is scanned more than once after a single radiopharmaceutical administration) to allow the radiopharmaceutical time to undergo desired in vivo physiologic processes. The total duration of a diagnostic NMI study thus depends on a variety of technical, biologic, and typical clinical logistical variables. Most frequently, a radiopharmaceutical is administered intravenously by bolus injection. After the injection, a standard time-delay may be necessary before the patient undergoes scanning to allow the radiopharmaceutical to spread throughout the body and achieve a biodistribution considered optimal for imaging. To acquire data for a single image, the time that a patient spends “in front of the camera” must be of sufficient duration for the scanner to collect a statistically robust number of radioactive signals, or counts, to ensure that the derived imagery will be satisfactory for visual analysis. Low-count images are visually “noisy.” How long it takes for the camera to collect enough photons for a sufficient-quality diagnostic image depends primarily on the intrinsic properties of the radioisotope involved, how much radiopharmaceutical is administered, how well the radiopharmaceutical concentrates in tissues of interest (e.g., tumors) compared with surrounding tissues in vivo, how well the camera system detects photons, and how the photon data are constructed into imagery. Depending on the type of nuclear imaging study, before imaging even starts, there may be a standardized delay after the radiopharmaceutical administration to allow the radiopharmaceutical time to achieve an in vivo biodistribution considered optimal (i.e., one hour after FDG injection before PET scan acquisition). Lastly, the imaging specialist decides whether to have the patient undergo scanning at additional time points or using special techniques, if it is thought necessary to increase the diagnostic accuracy of the study. The referring clinician’s staff can help prepare patients mentally by advising them of the prolonged duration typical of diagnostic NMI. Nuclear scanners may be categorized into two general types: PET scanners and standard gamma cameras. Their designs are tailored to image two fundamentally different types of radiopharmaceuticals (radioisotopes): those that emit positrons (for PET cameras) and those that emit gamma rays (for standard gamma cameras). As mentioned previously, images are created from photons produced by decaying radioisotopes administered to the patient, which are detected by nuclear scanners. The scanner system processes the photon data and reconstructs it into an image that can be presented as a two-dimensional (2D), or planar, image or as a (virtual) three-dimensional (3D) image (e.g., allowing display of sections of data in conventional axial, coronal,

288

PART 2  DIAGNOSTIC TECHNIQUES

and sagittal views, similar to CT). Images may represent biodistribution at one or a few time points or can display time-dependent changes in biodistribution in cinematic fashion. Planar images of radiotracer biodistribution in the anteriorposterior plane will result in an image in which in vivo tracer accumulations in two or more organs or other tissues may overlap (in the 2D plane) and thus potentially obscure detection or evaluation of the radiotracer uptake of interest (e.g., tumor detection). Tomographic (SPECT and PET) nuclear imaging can help avoid this potential issue by permitting tracer biodistribution to be evaluated in three dimensions. However, the limited spatial resolution of scintigraphic imaging may make it difficult to localize a particular tracer accumulation in a small tissue structure (e.g., tracer uptake in a small tumor may be hidden if the tumor is located within or immediately adjacent to a normal organ that also accumulates tracer). Additionally, for single-photon imaging agents, SPECT often requires a significantly longer duration scan than a 2D planar scan using standard SPECT camera systems, and often 2D imaging may be sufficient for the clinical data desired. The necessity for SPECT imaging is guided by the reason for a particular examination, available clinical research, and the particular patient context. For PET, by definition, tomography (3D imaging) is always used, involving ring-type dedicated PET camera systems with sophisticated signal analysis algorithms. The advantage of PET imaging versus single-photon gamma imaging is that the PET permits a more precise determination of where the radiation originated, when using the coincidencedetection method. Thus the scan imagery reconstructed from PET data has a much better spatial resolution (typically 4–5 mm, vs. ,1 mm on CT) than that reconstructed from single-photon gamma data (typically 12–15 mm). According to the Nyquist principle, this superior resolution results in PET-acquired data providing superior quantification of radioactivity concentrations in imaging data analyses compared with single-photon imaging. As one potential advantage versus PET imaging, single-photon imaging can simultaneously detect and distinguish two or more different gamma-emitting radiopharmaceuticals in a single patient in vivo, whereas PET imaging cannot distinguish between different PET isotopes. Gamma rays emitted by non-PET isotopes for single-photon imaging can have a variety of signature energy levels, which can distinguish it and be separated by signal processing.

Fusion Imaging Scintigraphic imaging of PET and single-photon emission radiopharmaceuticals are often combined with CT imaging for fusion imaging: PET/CT and SPECT/CT, respectively. In fusion imaging, the 3D imagery of PET or SPECT is combined with CT data so that tracer biodistribution/localization is visualized within the internal anatomy. Clinical studies have, overall, demonstrated that fusion imaging can have a synergistic effect on the accuracy of scintigraphy and CT image analyses for various clinical applications. A notable general example is improved accuracy for detection of radiotracer-avid tumors; often, on fusion imagery, scintigraphy (PET or SPECT) highlights findings poorly detected or easily overlooked on CT, or vice versa. The CT information also serves as data for an important technical function, called attenuation correction, which improves the quantitative accuracy of measurements derived from PET or SPECT analyses. Fusion imaging has done much to rescue diagnostic nuclear medicine from its former moniker (deserved or not) of “unclear medicine.”

One important caveat remains regarding the CT scans involved in fusion PET/CT and SPECT/CT imaging: the companion CT scan. The quality of the companion CT image can vary considerably; it can be of standard diagnostic quality (i.e., exactly the same technical-quality CT scan as obtained from a separate, stand-alone, state-of-the-art CT scanner), or it can be of inferior diagnostic quality (e.g., if acquired with a lower current [mA], yielding relatively noisier images, with less detail and greater susceptibility to certain artifacts, such as beam hardening). Chest imaging may be acquired at pulmonary end expiration rather than the standard maximal pulmonary inspiration, limiting evaluation. The CT might be acquired with the patient’s upper extremities positioned along the torso if the patient cannot tolerate having the arms raised (the standard chest CT position) for the 15 to 25 minutes of a standard torso FDG PET/CT, often creating a beam hardening artifact. Additionally, oral and IV iodinated contrast material more routinely used in standard CT protocol are not always used. Nevertheless, a noncontrast low-dose companion CT performed typically is sufficient for the basic needs of the PET or SPECT scan, providing sufficient anatomic detail to identify what tissues are involved in radiotracer uptake within an organ and providing attenuation correction, a modification of the scintigraphic data based on tissue densities and depth measured by CT that improves scintigraphic image quality, especially for quantification (e.g., for PET quantitative measurements known as the standardized uptake value [SUV]). Decay photons emitted from within deeper or denser body tissues will lose more energy from tissue interactions than photons from superficial or less dense tissues. The attenuation correction attempts to account for that artifact to provide more accurate measurement of tissue tracer concentrations. Beyond CT, clinical PET/MRI systems are already available at a few major medical centers with increasing use in the setting of certain pathologies (e.g., prostate cancer and neuroimaging). The advantages of PET/MRI include simultaneous acquisition to improve registration of fusion images, lower radiation dose, superior soft-tissue contrast, and availability of multiparametric imaging. To date, the clinical use of PET/MRI has been limited by availability of accurate attenuation correction algorithms and problem of motion artifacts, including respiratory motion. With the advent of machine learning programs, however, these problems are being overcome and its use in clinical practice is expected to grow accordingly.

“Can I Order Two Nuclear Medicine Scans on the Same Day?” The distinction between positron-emitting (PET) and solely gamma photon–emitting (non-PET) isotopes is relevant for referring specialists primarily because of this question. Unlike positron-emitting radioisotopes, the gamma ray–emitting isotopes of radiopharmaceuticals used for single-photon imaging come in a variety of energy levels. Gamma cameras can distinguish and potentially use these energy levels to separate the biodistributions of one radioisotope from another if a patient were to receive two radiopharmaceuticals with different radioisotopes simultaneously (i.e.,, by having the camera only accept detected photons of the energy level characteristic of the particular radioisotope of interest, then doing the same for the other radioisotopes). However, the energy emissions of different single-photon imaging radioisotopes can overlap, particularly if one of the radioisotopes emits relatively high-energy emissions, because some emitted rays will lose energy and fall

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

into the energy (keV) range of the other radioisotope. The 511 keV coincidence gamma rays of PET radiopharmaceuticals are relatively high energy and will interfere with imaging of single-photon radiopharmaceuticals (whether to a significant degree depends on other technical factors). Thus, after a PET scan, some period of delay is necessary, to allow the PET radiopharmaceutical to undergo physical decay and biologic clearance from the patient, before performing another imaging study with a single-photon radiopharmaceutical or another PET radiopharmaceutical. Practically, if a patient receives 18F-FDG for FDG PET, the patient should wait more than 20 hours before a subsequent nuclear study is performed, based on the known half-life of 18F (~1.9 hours), the amount of tracer we administer to a patient (maximal tracer dose of 12 mCi), and a common rule of thumb of waiting 10 half-lives for a radioisotope to decay sufficiently before allowing imaging with another radiopharmaceutical. In general single-photon radiopharmaceutical imaging, however, studies can be performed immediately before PET scan as the photons of non-PET radioisotopes typically are relatively low energy and thus cannot interfere with detection of the relatively high-energy 511 keV photons of PET radiopharmaceuticals. A few non-PET radioisotopes do emit high-energy photons at or above the 511 keV range, but even the presence of these highenergy photons from a prior non-PET radiopharmaceutical injection do not necessarily preclude immediately performing a PET study. Because the high-energy photons of the non-PET radioisotope are not produced as pairs, these photons will strike PET detectors in random directions. The PET scanner, however, will ignore photons that are not detected in the coincidence pattern typical of annihilation photon pairs. As such, the PET scanner often can detect the desired PET radiopharmaceutical signal without significant interference from any residual non-PET radiopharmaceutical in the patient’s system.

289

Detection and Staging

NUCLEAR MEDICINE AND LIVER CANCER

HCC is detected and characterized by CT and MRI (see Chapter 14). Both 2020 National Comprehensive Cancer Network (NCCN) guidelines3 and 2018 European Association for the Study of the Liver (EASL) guidelines4 do not recommend PET/CT for detection of HCC because of its limited sensitivity. HCC is FDG avid in less than 40% of HCC cases, with the majority of well-differentiated HCC tumors not avid or demonstrating avidity close to background liver on 18F-FDG PET, thus limiting sensitivity of detection (Fig. 18.1). Inherently low FDG avidity is because of the (1) HCC lower levels of glucose transporter-1 expression and (2) overexpression of the enzyme glucose-6-phosphatase, which hydrolyzes FDG-6-phosphate to FDG, which can be transported out of the cell.5 However, increased glucose transporter expression has been demonstrated in poorly differentiated HCC, with increased FDG avidity on PET (Fig. 18.2); thus non-avid HCC appears to be associated with a less aggressive tumor and a more favorable patient prognosis.6 Tumor-to-liver uptake ratio (TLR) has been shown to correlate more closely with HCC doubling time and represents metabolic activity of HCC more precisely than SUV, with one study performed in 116 patients showing that a higher TLR (.1.62) was associated with poorer prognosis and presence of extrahepatic metastases.7,8 Additionally, FDG-avid portal vein thrombosis has been shown to be an independent predictor for progression-free survival (PFS) and overall survival (OS), irrespective of avidity of primary HCC.9 Thus PET/CT may be of potential prognostic value before surgical resection, liver transplantation, or locoregional therapy. Extrahepatic metastasis (most commonly lung, abdominal nodes, and bone) have been found in 37% of patients during staging with poorly differentiated HCC more frequently likely to metastasize.10 A positive statistical correlation between FDG avidity of primary HCCs and tendency of extrahepatic metastasis has been shown, suggesting that metastatic HCC lesions would also have increased FDG uptake. FDG PET has demonstrated high sensitivities of 77% to 100% for detecting extrahepatic metastasis, notably bone metastasis, with one study demonstrating superior diagnostic detection compared with bone scintigraphy.11–13 Thus PET may have a role in detecting extrahepatic disease, but current NCCN and EASL guidelines do not support routine use. NCCN recommends continued use of bone scintigraphy with 99mTc–radiolabeled bisphonates, such as methylenediphosphate (MDP), for staging of HCC patients with bone lesions. Additional PET tracers have been studied in HCC with Carbon 11 (11C) acetate14 and 11C choline15 and perform better than FDG PET for detection of well-differentiated HCC but are inferior compared with CT/MRI. Also, 11C has a physical half-life of 20 minutes, requiring an onsite cyclotron or nearby producer for manufacturing of tracer, thus further limiting its widespread routine clinical use. 68Ga-PSMA has recently been proposed as a potential tracer in HCC. PSMA plays a major role in regulating angiogenesis and endothelial cell recruitment, which occurs early in HCC and throughout hepatic tumorigenesis. Nearly 95% of HCCs stain positive for PSMA in the tumor vasculature and early prospective trials have shown that 68Ga-PSMA PET has outperformed 18F-FDG PET in the detection of HCC and extrahepatic disease.16

Hepatocellular Carcinoma

Tumor-Response Evaluation

For more information on hepatocellular carcinoma (HCC), see Chapter 89.

FDG PET/CT has become a tumor-response radiologic biomarker with a major clinical impact on the management of a growing

Radiation Dose in Nuclear Medicine When administered solely for diagnostic imaging, conventional radiopharmaceuticals expose the receiving patient to a low radiation dose, typically one or more orders of magnitude below the level of radiation exposure conventionally accepted as being associated with an increased risk for harmful radiation effects, based on decades of dosimetric research. Certain radiopharmaceuticals are administered at relatively high doses of radioactivity with therapeutic intent; the administered radioactivity is sufficiently high (and concentrates in body tissues at levels sufficient) to induce acute radiobiologic effects on diseased tissues and other organs within a patient, with potential therapeutic benefit as well as adverse side effects. The radiation dose absorbed by the patient from the radiopharmaceutical is determined by the specific type of radioactive isotope involved, the administered activity (amount) of radiopharmaceutical (quantified in becquerels, typically megabecquerels [MBq], or curies, typically millicuries [mCi]), and the pharmacokinetics and distribution of radiopharmaceutical throughout the body (biodistribution), which is again determined by the physicochemical characteristics of the radiopharmaceutical molecule (or element).

290

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 18.1  Well-differentiated hepatocellular carcinoma (HCC) on fluorodeoxyglucose (FDG) positron emission tomography (PET)/ computed tomography (CT). Multiphasic, contrast-enhanced CT of segment 8 lesion (arrow, top left image) contiguous with the inferior vena cava (IVC), which demonstrates with arterial phase hyperenhancement, washout, and enhancing capsule on delayed-phase imaging (arrow, top right image), diagnosed as HCC based on imaging characteristics. Corresponding fused axial 18F-FDG PET/CT (circle, bottom image) does not show uptake in lesion above background liver, suggestive of well-differentiated HCC.

FIGURE 18.2  Poorly differentiated hepatocellular carcinoma (HCC) on fluorodeoxyglucose (FDG) positron emission tomography (PET)/ computed tomography (CT). Maximum intensity projection (MIP) image from 18F-FDG PET/CT (left) shows multiple right hepatic lobe FDG-avid lesions (circled) in a patient with known multifocal HCC. Arterial phase MRI (top right image) shows dominant segment 7 lesion with arterial phase hyperenhancement (arrowhead), which demonstrates avidity above background liver on corresponding fused 18F-FDG PET/CT (arrow, bottom right image), typical of poorly differentiated HCC. Poorly differentiated HCCs are more frequently likely to metastasize, with metastatic lesions also more likely to demonstrate increased FDG uptake.

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

number of other cancers (e.g., it is standard of care in breast cancer, lymphoma, esophageal cancer, and gastric cancer). In these types of cancer, overall robust clinical literature demonstrates that a therapy-induced decrease in tumor FDG avidity, as a biomarker of a decrease in tumor metabolism and tumor cell mass, correlates with histopathologic response and is often prognostically powerful, especially when conventional changes in tumor volume (e.g., anatomic criteria such as RECIST) measured by CT or MRI failed to predict either pathologic response or prognosis.17 Nevertheless, unlike cancers such as invasive ductal breast cancer or high-grade lymphoma, which are frequently FDG avid, HCC frequently demonstrates minimal to no FDG avidity, therefore limiting the role of PET-response evaluation. As such, PET is not currently routinely recommended for HCC tumor response to therapy. Still, the role of PET/CT has been shown to be potentially useful in certain post-treatment scenarios. In previous studies of HCC patients who underwent curative surgical resection or liver transplantation, high FDG uptake in an HCC showed a significant association with tumor recurrence, especially early recurrence.18–20 Furthermore, retrospective studies have shown that when PET/CT is used in combination with Milan criteria (a solitary tumor #5 cm in diameter or 2 to 3 tumors # 3 cm in diameter) with or without serum alpha fetal protein (AFP) for selecting candidates for liver transplantation, patients who are beyond the Milan criteria but have a negative PET/CT had clinical outcomes comparable with those within Milan criteria.21 Furthermore, in candidates who met Milan criteria but had an FDG-avid HCC, higher rates of recurrence were seen than in those who had low FDG-avid HCC.22,23 Thus a FDG PET finding has been found to be an independent predictive factor for tumor recurrence. Along with Milan criteria and serum AFP and FDG PET, it could provide additional information for making decisions regarding liver transplantation for HCC patients. Locoregional therapy (e.g., ablation or transarterial chemoembolization [TACE]) is a preferred treatment option for patients with unresectable or nonoperable liver-confined disease (see Chapters 94 and 96). The prognostic value of FDG PET has been assessed in HCC patients treated with locoregional therapy, which suggests longer PFS and OS in patients with low FDG uptake of HCCs, again suggesting significant associations between FDG avidity of HCCs and clinical outcomes.24

Recurrence HCC recurrence typically manifests as tumor regrowth at a prior site of treatment (e.g., ablation) or as tumor appearing at a new site in the liver. PET/CT is not routinely recommended for surveillance in the post-treatment HCC patient. However, Hayakawa et al. evaluated FDG PET/CT for detecting recurrent HCC postoperatively in patients with either suspected recurrence on CT or MRI (group 1) or suspected recurrence because of abnormal serum tumor markers but with no disease evident on CT or MRI (group 2). FDG PET/CT had a 53% and 41% sensitivity and 100% specificity for recurrent tumor in both groups 1 and 2, respectively. The data from group 1 support the idea that FDG PET/CT cannot replace CT or MRI as the first-line imaging modality for detection of recurrence; the data from group 2 support the hypothesis that FDG PET/CT may be of value as second-line imaging if CT or MRI fails to detect recurrence.25 Wang et al. reported a remarkably high sensitivity of FDG PET/CT for HCC detection of 97%,

291

with a specificity of 83% (n 5 32).26 FDG PET/CT has reported sensitivity no greater than 90% (usually much lower) for HCC in the pretreatment setting.12

Colorectal Cancer Metastasis to Liver For more information on colorectal cancer (CRC) metastasis to liver, see Chapter 90. The most recent guidelines from the NCCN (2020),27 European Society of Medical Oncology (ESMO),28 and European Registration of Cancer Care (EURECCA)29 agree on the potential roles and limitations of FDG PET/CT in clinical management of CRC and only recommend PET/CT in certain clinical circumstances (e.g., potentially surgically curable metastatic disease). As such, this discussion focuses on the CRC patient with potentially resectable liver metastases. In CRC patients with liver metastases, but no extrahepatic metastases, complete resection of liver metastases improves long-term survival better than other treatments currently available. (see Chapters 90, 97, and 98). Before surgery, it is essential to confirm that liver metastases are likely resectable (based on CT and/or MRI imaging) and that no extrahepatic metastatic disease is present. CRC metastases occur most commonly in the liver, followed by the lungs, with metastases in the central nervous system, bones, adrenal glands, and spleen occurring in less than 10% of CRC patients.30 FDG PET/CT is extremely sensitive in detection of liver and lung metastases,31 the two most common viscera to be involved by metastatic disease at initial presentation.32 FDG PET/CT has long been recognized as superior to conventional CT for detecting hepatic metastases,33–35 with decreasing sensitivity for both modalities in characterizing subcentimeter hepatic lesions.36,37 FDG PET/CT and MRI are equivalent in diagnostic sensitivity for liver metastases, but MRI is more sensitive in identifying subcentimeter liver lesions than FDG PET/CT (i.e., with greater sensitivity). As such, PET/CT is not routinely indicated in primary staging of CRC in current NCCN guidelines. ESMO 2014 colorectal cancer guidelines agree with current NCCN guidelines regarding the role of FDG PET-CT.28 However, FDG PET/CT is considered a diagnostic adjunct to staging in patients with an equivocal finding on CT/MRI or in patients with potentially surgically curable metastatic disease (M1), as demonstrated on CT/MRI, but require evaluation for unrecognized metastatic disease that would preclude the possibility of surgical management. Patients planning to undergo hepatic resection based on conventional imaging will be found to have extrahepatic disease by FDG PET in 18% to 32% of cases (Fig. 18.3),37–39 changing management in 20% to 40% of cases in early clinical PET trials36,37 and changing management in curative-intent surgery in as many as 25% of patients in a later trial.40 Fernandez et al. found that patients with hepatic metastases who underwent FDG PET for preoperative staging had a much higher 5-year survival rate than historic controls.41 A randomized, controlled trial (RCT) of patients with resectable metachronous metastases assessed the role of PET/CT in the workup of potential curable disease.42 This study showed that while PET/CT did not impact survival, surgical management was changed in 8% of patients after PET/CT, with additional sites of metastatic disease detected in 2.7% of patients (bone, peritoneum/omentum, abdominal nodes), thus precluding surgical resection. In addition, 1.5% of patients had more extensive hepatic resections and 3.4% had additional organ surgery. However, 8.4% of patients in the PET/CT arm had

292

PART 2  DIAGNOSTIC TECHNIQUES

source after standard IV contrast CT or colonoscopy. A systematic review and meta-analysis of 11 trials (510 patients) reported pooled estimates of sensitivity and specificity for FDG PET/CT for detection of occult tumor recurrence (after conventional CT workup) of 94% (95% confidence interval [CI], 89%–97%) and 77% (95% CI, 66%–86%), respectively.45

THE ROLE OF NUCLEAR MEDICINE IN LOCOREGIONAL LIVER THERAPY Although surgical resection often provides the best patient outcomes for patients with HCC or metastatic liver lesion, some patients are not surgical candidates (e.g., because of the extent of tumor, underlying liver disease, or comorbid conditions). In these patients, locoregional therapies (e.g., ablation, transarterial chemoembolization, or radioembolization) can be offered typically as a palliative therapy, although it can offer curative extent in certain cases. Locoregional therapies will be discussed in more detail in Chapters 94 and 96, but we will briefly touch on the role of nuclear medicine in workup, therapy, and surveillance in this setting.

THE ROLE OF NUCLEAR MEDICINE IN HEPATIC ARTERIAL INFUSION THERAPY FIGURE 18.3  Role of fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in colon cancer. Maximum intensity projection (MIP) image from FDG PET/CT of a colon cancer patient on chemotherapy being considered for locoregional therapy of known liver metastases. The MIP image demonstrates FDG-avid liver metastases (arrowheads) and FDG-avid extrahepatic disease, a subcentimeter right adrenal metastases with intense hypermetabolic activity (arrow), new compared with a previous FDG PET scan and not appreciated on CT.

false-positive results, many of which required additional imaging with biopsies or other imaging modalities. Additionally, current NCCN guidelines for CRC do not advocate routine use of FDG PET/CT for post-treatment follow-up imaging of patients with no evidence of distant metastatic disease by contrast-enhanced CT/MRI because of the potential risk for false-negative (e.g., non-avid necrotic liver lesions after chemotherapy) or false-positive findings (e.g., post treatment or surgery tissue inflammation). NCCN guidelines also do not recommend PET/CT in long-term monitoring: a small RCT reported earlier detection of recurrences with PET and suggested improved clinical outcomes compared with conventional CE imaging,43 but larger trials are required to further investigate its utility. The utility of FDG PET/MRI in the follow-up of treated CRC patients has been investigated, with initial studies showing promising results. When compared with current standardof-care imaging, PET/MRI changed clinical management in 35.7% of cases: 21.5% upstaging cases and 14.2% downstaging cases (P , .001).44 However, larger multicenter prospective studies with larger patient numbers are required to confirm these preliminary results. NCCN guidelines also suggest clinicians consider FDG PET/ CT for evaluation of patients with serial elevations of serum carcinoembryonic antigen (CEA) levels without an identifiable

Hepatic arterial infusion therapy (HAIT) is direct infusion of a therapeutic compound (e.g., chemotherapeutic, embolic, or radioembolic agents) to treat malignant liver tumors (primary or secondary; see Chapters 94, 97, and 100). Clinical studies demonstrate that arterial infusion improves tumor uptake of certain chemotherapeutic agents compared with portal venous or systemic venous infusion.46 Cancerous liver tumors derive/ stimulate a nutrient blood supply from the arterial system by tumor neoangiogenesis as opposed to normal hepatic parenchyma, which receives blood supply mostly from the portal venous system. Hepatic arterial infusion scintigraphy (HAIS), also called hepatic arterial perfusion scintigraphy, is the imaging of the biodistribution of a radionuclide delivered directly into liver through an arterial catheter, typically in the (proper) hepatic artery, for delivery of chemotherapy, or potentially into hepatic lobar or segmental arterial branches, when HAIS is conducted associated with HAIT radioembolization (e.g., treatment with 90 Y-radiolabeled resin or glass microspheres or 131I-radiolabeled lipiodol). The role of HAIS is to: (1) predict that infused macroaggregated albumin (MAA) is properly distributed throughout the downstream liver or targeted hepatic subregion before HAIT, (2) ensure that no extrahepatic infusion caused by variant anatomy is present before HAIT, (3) calculate lung shunt volumes before radioembolic HAIT is performed, (4) predict or measure hepatic radiation dosimetry, before or after HAIT, and (5) ensure the integrity and function of an infusion system before administration of medication (e.g., post placement of a hepatic intraarterial pump reservoir-catheter system, which is used to deliver local chemotherapy). Placement of the arterial catheter used for HAIT and HAIS involves different possible techniques, most commonly placed intermittently into the hepatic artery during an interventional

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

radiology (IR) procedure. In certain institutions, catheters may connect to a subcutaneously implanted port or an infusion pump system to allow slow, continuous drug infusion of hepatic arterial chemotherapy (more commonly performed in the United States). The tracer used for HAIS for treatment planning is 99mTc MAA, a radiolabeled particulate, 25 to 50 mm in mean diameter, which physically occludes the first microvascular lumen it encounters. The infusate tracer, several hundred thousand MAA particles, labeled with a trace amount of radioactivity, are suspended in a small volume of saline (e.g., 2 cc) and injected into a transiently placed hepatic artery catheter or hepatic pump (see Chapter 97) by a trained operator (e.g., physician or nurse) and remain intact in vivo for several hours, allowing imaging of the distribution of tracer. Injection of an infusate can be slow (e.g., ,1 cc/min), which mimics somewhat the slow rate typical of pump-infusions in HAI chemotherapy. Fast injection of infusate (e.g., $1 cc/sec; bolus) allows rapid introduction of infusate into the hepatic artery, creating turbulence in the bloodstream that mixes infusate and blood more homogeneously and more rapidly and, as a result, bolus infusions of tracer infusate are typically not advised for HAIS because the bolus pressure may cause retrograde flow of tracer into other celiac branches and artifactual extrahepatic tracer accumulations.47 Extrahepatic tracer accumulations, when tracer is infused slowly, are usually because of variant hepatic arterial anatomy, such as branches supplying extrahepatic viscera (e.g., stomach, pancreas, gastrointestinal [GI] tract) and could lead to complications (e.g., GI ulceration) if not identified before HAIT. True aberrant arterial branches typically must be embolized before HAIT to avoid extrahepatic organ toxicity. SPECT/CT provides excellent anatomic localization of infused 99mTc MAA. Alternatively, 99mTc-labeled SC scintigraphy can immediately precede HAIS, to provide a gross outline of hepatic (and splenic) anatomic contours (Fig. 18.4). Because 99m Tc-MAA HAIS and 99mTc-SC scintigraphy use the same 99m Tc isotope, a larger amount (activity, MBq) of 99mTc MAA is administered than 99mTc sulphur colloid (SC), so that the

FIGURE 18.4  Normal appearance of technetium 99m (99mTc)– labeled sulfur colloid scintigraphy. An anterior projection of the abdomen is shown. The larger mass at left is the liver. The smaller mass is the spleen. Sulfur colloid tracer accumulation in vertebral marrow is sometimes faintly detectable, although not in this patient.

293

signal on the subsequent HAIS scan predominantly represents 99m Tc MAA. However, confusion can arise regarding overlap between 99mTc-SC and 99mTc-MAA signals, as in evaluation of the homogeneity of 99mTc-MAA hepatic distribution. Additionally, if any delay occurs after 99mTc SC is injected, before 99mTcMAA scintigraphy is performed, 99mTc-SC catabolic breakdown and release of free pertechnetate can yield gastric tracer-uptake, potentially mimicking extrahepatic infusion of the stomach on 99mTc-MAA scintigraphy. Obtaining dynamic images of 99mTc-MAA uptake as it is infused slowly for two minutes or more permits detection of increases in hepatic or extrahepatic tracer uptake indicative of true 99mTc-MAA signal, whereas any residual 99mTc-SC or free-pertechnetate signal will remain unchanged during dynamic imaging of the 99mTc-MAA infusion (Fig. 18.5). 99mTc-MAA SPECT/CT without 99mTc SC has the advantage of having SPECT imagery that solely represents 99mTc-MAA biodistribution, although CT typically is associated with a higher radiation dose to the patient than 99m Tc-SC scintigraphy. Abnormal HAIS findings include subtotal hepatic infusion (in nonselective angiography cases), extrahepatic organ infusion, catheter obstruction, and catheter leakage (Fig. 18.6) and typically require additional investigation (e.g., fluoroscopy or CT hepatic angiography) to guide subsequent management. In a clinical study of patients with implanted hepatic arterial pump-catheter systems, HAIS studies revealed abnormalities in 9% of patients after pump implantation; the abnormalities were predominantly extrahepatic infusion (63% of abnormal studies), but 12% demonstrated abnormal subtotal intrahepatic infusion (i.e., infusion distributed to only a portion of the liver, when infusion of the entire liver was expected). Abnormal subtotal intrahepatic infusion (i.e., regions of devoid of infusate

FIGURE 18.5  Normal appearance of hepatic arterial infusion scintigraphy. Serial anterior projection planar images were obtained during slow bolus injection of technetium 99m (99mTc) macroaggregated albumin (MAA) into the common hepatic artery via an implanted hepatic pump-catheter system at rate of five seconds/frame. On the first image, before the 99mTc MAA has reached the liver, faint activity is detectable in the liver (arrowhead); this faint activity is from 99mTc-labeled sulfur colloid tracer, used immediately before to obtain a gross anatomic outline. The 99m Tc MAA is visualized transiting through the pump catheter as it is slowly infused (arrow). Progressive accumulation of the 99mTc-MAA infusate throughout the liver is visualized as the infusion is completed. No abnormal extrahepatic accumulation of 99mTc-MAA infusate is evident.

294

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

FIGURE 18.6  Abnormal hepatic arterial infusion scintigraphy (HAIS). A 67-year-old woman with colon cancer with liver metastases after a recent hepatic arterial pump placement for intraarterial chemotherapy and HAIS performed to ensure patency of system before chemotherapy infusion. A, Two selected anterior abdominal images are shown from a series of five-second-per-frame images acquired during a one-minute infusion of technetium 99m (99mTc) macroaggregated albumin (MAA) into the common hepatic artery via a hepatic pump-catheter system. The top image was obtained at five seconds and the bottom image at 25 seconds into the infusion show abnormal progressive accumulation of 99mTc MAA only into the left lobe of liver (solid arrow) and in the gastropancreatic region (dashed arrow). B, Corresponding single-photon emission computed tomography (SPECT)/ computed tomography (CT) images from HAIS showing accumulation of 99mTc-MAA into the left lobe of liver (solid arrow) and in the gastropancreatic region (dashed arrow). C, Spot fluoroscopic image from angiography identifying celiac origin stenosis (arrowhead) with resultant reversal of arterial blood flow to the left hepatic artery. Additionally, the right hepatic artery was replaced to the superior mesenteric artery (not shown). These findings accounted for abnormal HAIS.

uptake) should be distinguished from heterogenous intrahepatic distribution of MAA infusate, which occurs probably in part because of laminar flow phenomenon. The laminar flow phenomenon can occur in the presence of a large hepatic tumor mass, which appears to draw hepatic arterial flow away from other hepatic regions. Heterogenous MAA infusate distribution throughout the liver has no clear clinical significance and in our experience is relatively common and not clearly associated with adverse outcomes. If MAA infusate is clearly, unexpectedly absent (not merely relatively low) in one or more hepatic subregions, however, the finding is potentially clinically significant because it suggests the possibly of aberrant intrahepatic arterial anatomy, a misplaced catheter, or an occluded arterial branch (e.g., stenotic or thrombosed). Anecdotal cases, including our own experiences, have found that abnormal subtotal hepatic infusion on HAIS can predict poor tumor response in those subregions without detectable receipt of infusate, whereas tumors in the same patient that appear well perfused on HAIS respond favorably.48 As such, abnormal subtotal hepatic infusion always warrants further investigation. In the setting of hepatic pump HAIS abnormalities, pump fluoroscopy evaluation fails to find corresponding abnormalities in approximately 25% of cases.49 In those cases, HAIS was repeated, and the previously identified HAIS abnormality was no longer evident scintigraphically in almost all cases. In the few cases in which the HAIS abnormality persisted, fluoroscopic or CT studies were again repeated, and a corresponding aberrant vessel was successfully identified. This study recommended evaluating abnormal HAIS findings by fluoroscopic correlative imaging initially; if radiographic correlation is found, HAIS is repeated in two to three weeks, seeking spontaneous normalization of HAIS.

Radioembolization therapy with yttrium 90 (90Y)–labeled glass or resin microspheres delivered by hepatic intraarterial catheter infusion is used for treatment of colorectal metastases or HCC (see Chapter 94B). Patients before therapy undergo HAIS to delineate hepatic perfusion and extrahepatic supply, as previously mentioned, but also dosimetry to calculate dose to tumor, and lung shunt fraction (LSF) needs to be calculated on 99mTc-MAA imaging before treatment because radiation-induced pneumonitis and sclerosis can occur because of hepatopulmonary shunting of radioembolic microspheres and is a potential major toxicity concern. Significant shunting is estimated at LSF greater than 15%, which requires treatment modification before HAIT to reduce complications or not treating if LSF is greater than 20%.50 Immediately after therapy, typically SPECT/CT is performed to evaluate technical success, although in certain centers, 90Y-PET/CT is used instead. After radioembolization dosimetry, SPECT or PET/CT, performed within 24 hours of treatment, has been employed in certain institutions because it enables rapid and precise prediction of efficacy on a per-lesion basis and allows for early treatment adaptation in case of undertreatment of the lesions. One study showed that in chemo-refractory mCRC, patients treated with radioembolization that absorbed dose determined on post radioembolization 90Y-PET/CT correlated with metabolic response, and higher lesion mean absorbed doses were associated with prolonged OS.51 There is no standard protocol for pre- and postradioembolization imaging, with CT being the most commonly used modality. The role of FDG PET/CT has been suggested as a promising radiologic assay for detecting a favorable liver tumor response to 90Y microsphere radioembolization.52 One study

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

showed that increased metabolic activity of the lesion pretherapy was associated with decreased liver PFS postradioembolization with authors recommending use of FDG PET/CT as part of work-up before therapy.53 Furthermore, the current data are heterogenous with regards to FDG PET/CT in the setting of evaluating postembolization treatment response of liver metastasis versus HCC because well-differentiated HCC does not typically accumulate FDG as previously discussed. As such, current guidelines do not recommend use of PET/CT routinely in pre- and postradioembolization imaging.

THE ROLE OF POSITRON EMISSION TOMOGRAPHY IN PERCUTANEOUS LIVER ABLATION Percutaneous ablation of hepatic malignancies, HCC or liver metastases, can be considered in patients who are not surgical candidates or as a bridging strategy before curative therapy (e.g., resection or transplantation27; see Chapter 96). As discussed previously, FDG PET/CT has been shown to be superior to CT or MRI alone in staging patients with hepatic metastases and can often lead to a change in the treatment plan in patients being considered for percutaneous ablation. In one study, preablation PET/CT led to a change in clinical management in 26% of patients in whom extrahepatic disease was identified and ablation was not performed.54 Another study found that PET/CT altered the clinical management in 25% of potential radiofrequency ablation (RFA) candidates with colorectal hepatic metastases in whom extrahepatic disease was missed by conventional imaging, and systemic chemotherapy was offered instead of performing ablation.55 PET/CT imaging can be used within the IR suite to guide ablation in PET-avid CT occult lesions. Additionally, periprocedural PET/CT can be used to determine technical success and permits immediate repeat tumor ablation as needed.56 Recurrence after percutaneous ablation of hepatic malignancy is, unfortunately, not uncommon. After ablation of HCC, local recurrence rates of 11% to 36% have been reported, with more frequent recurrence occurring after treatment of larger lesions and lesions close to large vessels. Metastatic colorectal cancer recurs even more frequently after ablation than in HCC, with reported rates over 50%. High quality post-ablation surveillance imaging is required to identify residual or recurrent tumor to allow early identification of recurrent or residual disease and retreatment. However, it can be challenging to distinguish recurrent or residual disease from normal treatment response. Immediately after thermal ablation of the liver, the central area of post-ablation necrosis is surrounded by a zone of hyperemia and a peripheral rim of mild reactive change, which appears as a central nonenhancing area of necrosis, with a rim of increased enhancement compared with normal liver tissue in the hyperemic zone on contrast enhanced CT or MRI (see Chapters 14 and 15). The rim of increased enhancement may mask residual viable tumor in the early post-ablation period. Cells destroyed by thermal ablation lose their ability to concentrate glucose within the cell; thus, on FDG PET/CT, there is a corresponding photopenic area.57 Glucose metabolism within the zone of hyperemia, however, is unaltered and normal FDG uptake or a rim of uniform, low-grade FDG uptake surrounding the ablation site may be present. If focal areas of increased FDG uptake are seen adjacent to the photopenic area of necrosis within 48 hours of ablation, residual macroscopic tumor is suspected. From 72 hours to 6 months after

295

ablation, a band of regenerative tissue containing neutrophils and fibroblasts develops surrounding the ablation zone that demonstrates variable degrees of both peripheral enhancement and also increased FDG uptake surrounding the ablation site because of inflammatory changes; however, FDG PET/CT seems more sensitive for determining the treatment effect and detecting local recurrence because of combined functional and anatomic information. Chen et al. retrospectively reviewed 33 lesions treated with RFA in 28 patients and reported that PET/CT demonstrated superior sensitivity and accuracy (94.1% and 87.9%, respectively) compared with MRI (66.7% and 75%, respectively) and multiphase contrast-enhanced CT (66.7% and 64.3%, respectively).58 To date, however, there are no established guidelines for when to perform post-ablation PET/CT, with some centers proposing intervals of 3 to 6 months for the first year after ablation, and over 95% of local recurrences identified within 1 year of treatment.59

NUCLEAR MEDICINE AND BILIARY TRACT CANCERS Intrahepatic and Extrahepatic Cholangiocarcinoma For more information on intrahepatic and extrahepatic cholangiocarcinoma, see Chapters 50 and 51. Cholangiocarcinomas include all tumors originating in the epithelium of the bile duct, with intrahepatic cholangiocarcinoma being more common than extrahepatic and the second most common primary hepatic tumor. Cholangiocarcinomas are typically FDG avid. A recent meta-analysis of 47 studies found that FDG PET/CT had an overall sensitivity of 91.7% and specificity of 51.3% for detection of cholangiocarcinoma with sensitivity of 88.4% and specificity of 69.1% for lymph node invasion.60 PET/CT performed better for the detection of distant metastases and local recurrence, with a sensitivity and specificity of 85.4% and 89.7% and 90.1% and 83.5%, respectively. A previous meta-analysis found PET/CT had higher diagnostic sensitivity for intrahepatic tumors than for perihilar and other extrahepatic tumors.61 As such, there is growing evidence that 18FDG-PET should be incorporated into the current standard of care for the staging (lymph node and distant metastases) and identification of relapse to guide treatment selection, especially if standard of care imaging MRI/CT are equivocal. Although the role of PET/CT for diagnosis of the primary tumor is not currently recommended by NCCN because of low sensitivity,3 emerging evidence indicates that it may be useful for the detection of regional lymph node metastases and distant metastatic disease in patients with otherwise potentially resectable disease.62,63 However, FDG-avid inflammation along the biliary tree (i.e., cholangitis) can mimic or obscure detection of FDG-avid biliary tumor.

Gallbladder Cancer For more information on gallbladder cancer, see Chapter 49. Gallbladder cancer is often diagnosed at an advanced stage because of the aggressive nature of the tumor; often its symptoms mimic benign conditions, including biliary colic or chronic cholecystitis. The role of PET has not been established in the evaluation of patients with gallbladder cancer, but evidence from retrospective studies indicates that it may be useful for the detection of radiologically occult regional lymph node and

296

PART 2  DIAGNOSTIC TECHNIQUES

distant metastatic disease in patients with otherwise potentially resectable disease.63,64 No prospective trials, however, have been performed to date to confirm the role of PET/CT. Additionally, false positives related to an inflamed gallbladder can make interpretation troublesome.

Pancreatic Adenocarcinoma For more information on pancreatic adenocarcinoma, see Chapters 61 and 62.

Detection and Staging The standard diagnostic workup for pancreatic cancer is highquality contrast-enhanced CT with pancreatic protocol.65 The role of PET/CT remains unclear, and current guidelines only recommend the role of PET/CT in certain circumstances (e.g., borderline resectable disease, markedly elevated CA 19-9, large primary tumors, or large regional lymph nodes) to detect extrapancreatic metastases. PET/CT has long been reported to be a highly sensitive method for detecting pancreatic cancer, with reported sensitivity of 85% to 97%; however, PET/CT lacks specificity with reported rates of 61% to 94%.66–68 A 2012 meta-analysis of 16 studies with 804 patients found FDG PET/CT offered a diagnostic sensitivity of 87% and specificity of 83%.69 A 2014 meta-analysis (including much of the same data as the 2012 analysis) obtained similar results: FDG PET/CT for evaluation of suspected pancreatic cancer was calculated to offer pooled sensitivity of 90% and specificity of 76%.70 Typically pancreatic adenocarcinoma presents as a focally hypermetabolic focus; however, benign conditions, such as focal acute pancreatitis and mass forming chronic pancreatitis can also present as hypermetabolic foci.62 One possible reason for the relatively low specificity of PET/ CT may be because of misdiagnosis of a benign condition, such as mass-forming pancreatitis, as a pancreatic adenocarcinoma. This is a challenging diagnosis on multiple imaging modalities because chronic inflammation in mass-forming pancreatitis leads to fibrosis of pancreatic parenchyma and thus demonstrates similar imaging characteristics to pancreatic adenocarcinoma on CT (a hypodense mass with mild or no enhancement; see Chapter 17). The reported sensitivity and specificity of CT for differentiating chronic pancreatitis from cancer were 82% to 94% and 83% to 90%, respectively,71 with similar results in MRI (sensitivity of 93% and specificity of 87%). Early studies suggested that FDG PET could reliably differentiate between mass-forming pancreatitis and pancreatic adenocarcinoma because overexpression of the glucose transporter 1 is increased in pancreatic cancer but not in chronic pancreatitis, which revealed the possibility of diagnosing pancreatic cancer from mass-forming pancreatitis.66,72 However, the value of FDGPET/CT in differentiating pancreatic cancer from chronic pancreatitis remains controversial because high FDG uptake caused by increased glycolytic activity in inflammatory cells such as neutrophils and activated macrophages has been seen in pancreatitis, including mass-forming pancreatitis,73 and its utility remains unclear in diagnosis. Another potential cause of low sensitivity of PET/CT in detection of pancreatic adenocarcinoma may be because of characteristics of the tumor. If the lesion is predominantly cystic then the lesion is typically FDG PET–negative, regardless of whether it is benign or malignant. However, some benign or low-grade malignant solid pancreatic lesions (e.g., solid pseudopapillary

tumors) can be as FDG avid as malignant solid pancreatic adenocarcinomas.74 In fact, if a solid tumor has activity close to blood pool activity (i.e., minimal FDG avidity), it is more likely to be a pancreatic adenocarcinoma or neuroendocrine tumor than a solid pseudopapillary tumor (which usually demonstrate FDG avid significantly above blood pool).75 The main potential utility of FDG PET/CT in pancreatic cancer is as an adjunct in staging. One study showed that sensitivity of detecting metastatic disease for PET/CT alone, standard CT alone, and the combination of PET/CT and standard CT were 61%, 57%, and 87%, respectively. Studies have shown that clinical management of 11% of patients with invasive pancreatic cancer and resectability status in at least 20% to 30% of patients were changed based on PET/CT findings because PET/CT detected metastatic lesions that were not identified by the standard staging protocol in these patients.76,77 Because of the low-dose noncontrast companion CT, however, PET/CT is limited in tumor(T) staging. Nonenhanced companion CT often fails to detect vascular invasion.78,79 Studies have shown that FDG PET/CT combined with contrastenhanced CT offers superior diagnostic accuracy compared with standard PET/CT (performed with a noncontrast, lowdose CT) with diagnostic sensitivity of 91% (95% CI, 86%– 96%) versus 88% (95% CI, 78%–100%), and specificity of 88% (95% CI, 73%–100%) versus 81% (95% CI, 69%–94%), respectively, although these were not statistically significant differences (P . .05).69 Also, contrast-enhanced PET/CT is not commonly performed in routine clinical practice because it does not replace the multiphase contrast-enhanced CT (pancreatic protocol) required for accurate diagnosis and staging (see Chapter 17). PET/CT utility in detecting nodal(N) metastasis is limited, with a reported sensitivity of 0% to 57%,26 perhaps because lymph node size is not a reliable parameter for the evaluation of metastatic involvement in pancreatic adenocarcinoma, and small nodes (,5 mm) are difficult to detect because of spatial resolution. Conversely, for detection of distant metastases, FDG PET/ CT appears to have relatively high specificity of 91% to 100%,26 especially for lung and bone metastases.78 However, detection of liver metastases with FDG PET/CT has a reported sensitivity of 22% to 88%; this wide variance is probably accounted for by the reduced sensitivity of PET in detection of subcentimeter lesions because of the partial volume averaging effect. Despite the variability in reported percentages, clinical studies predominantly report that FDG PET/CT seems to perform better than conventional CT for detection of liver metastases, although most studies were underpowered.26 MRI offers superior diagnostic sensitivity for liver metastases compared with FDG PET/CT on a per-lesion basis, particularly for detection of subcentimeter liver metastases. The sensitivity of FDG PET/CT for detection of bone metastases is superior to standard CT because bone metastases may only be associated with subtle osteolytic changes on CT or may be CT occult because they are predominantly bone marrow–based. MRI is at least as diagnostically accurate as FDG PET/CT for detection of osseous metastases. Other common metastatic sites include lungs and peritoneum, with the diagnostic accuracy of FDG PET/CT appearing similar to that of standard CT; a dedicated contrast-enhanced CT scan improves PET/CT detection of peritoneal metastases significantly compared with PET with a nondiagnostic companion CT.

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

PET/MRI has been shown to be equivalent to PET/CT for determination of resectability and staging tumors.80 The combination of diffusion-weighted imaging (DWI) and metabolic markers (metabolic tumor volume) appears to predict advanced stage tumor and is correlated with progression-free survival.81

Pancreatic Tumor Response and Recurrence FDG PET/CT for detecting pancreatic cancer response is superior in general to conventional CT or MRI for predicting favorable histopathologic response and for predicting patient outcomes.82 Multiple clinical trials have shown that changes in pancreatic tumor hypermetabolic activity, measured by comparing a pretreatment PET scan with a post-treatment or on-treatment PET scan, correlated with (predicted) histologic response, radiologic (CT or MRI) response, or patient response (e.g., overall survival or progression-free survival).26 Topkan et al. demonstrated that in patients with locally advanced unresectable pancreatic carcinoma treated with chemoradiotherapy (5-fluorouracil [5-FU] and gemcitabine), patients who demonstrated aboveaverage decreases in tumor hypermetabolic activity demonstrated superior median overall survival (17.0 vs. 9.8 months; P 5 .001), progression-free survival (8.4 vs. 3.8 months; P 5 .005), and locoregional progression-free survival (12.3 vs. 6.9 months; P 5 0.02) compared with poor responders.83 The predictive value of a favorable “metabolic response” on FDG PET/CT remained statistically significant for each of these three outcomes on multivariate analysis. Others have reported statistically significant correlations between favorable FDG PET/CT tumor metabolic response to chemoradiotherapy and favorable survival outcome in unresectable, locally advanced pancreatic cancer as well.76,77,84 One study showed similar predictive power of FDG PET/CT for treating unresectable disease treated with chemotherapy alone85 (see Chapter 66). For resectable pancreatic cancer, studies have shown FDG PET/CT can predict histologic response to neoadjuvant chemotherapy. Heinrich et al. initially showed in patients treated with neoadjuvant gemcitabine and cisplatin that although both PET responders and nonresponders had microscopic disease after surgery, the responders had less microscopic disease,86 and neither PET nor histologic response correlated with survival outcomes. Later studies compared metabolic response on PET/CT of other neoadjuvant regimes (namely, nab-paclitaxel plus gemcitabine vs. gemcitabine alone because the MAPCT trial proved that nab-paclitaxel and gemcitabine demonstrated superior efficacy versus gemcitabine alone for patients with metastatic pancreatic cancer). The nab-paclitaxel plus gemcitabine arm demonstrated an increased metabolic response compared with gemcitabine alone and its metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS; median 11.3 vs. 6.9 months). Also in both arms more patients experienced a metabolic response than a RECIST-defined size response.87 As a result of this study, the NCCN now recognizes the role of PET/CT in tumor response in the neoadjuvant chemotherapy setting. FDG PET/CT also has a role in detection of recurrence in pancreatic adenocarcinoma, although it is not recommended by guidelines currently. Pancreatic cancer recurrence can be detected by elevation of serum levels of the tumor marker with high diagnostic sensitivity, but serum assays do not distinguish the anatomic location of the disease recurrence (e.g., in a tumor resection bed or as new metastases). Small studies indicate that

297

FDG PET/CT after conventional CT in the setting of suspected recurrence will change therapeutic management in as many as 44% of patients,88 and FDG PET/CT identifies local pancreatic cancer recurrence in the surgical bed better than standard CT or MRI.88 FDG PET/CT detected local recurrence with 67% to 96% sensitivity versus 39% to 50% sensitivity for CT and/or MRI.26,89 FDG PET/CT appears superior to conventional CT for detection of recurrence in lymph nodes, peritoneal implants, and bones. Diagnostic sensitivity and specificity for FDG PET/CT are typically greater than 90% for suspicious FDG-avid lymph nodes, peritoneal lesions, and bone lesions compared with CT, which has a sensitivity of approximately 60% for nodal metastases, 50% for peritoneal recurrence, and less than 5% for recurrence as bone metastatic disease.89 As mentioned previously, MRI has superior sensitivity to FDG PET/CT for detection of liver lesions and thus detection of recurrent liver metastases.

Gastroenteropancreatic Neuroendocrine Tumors For more information on gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), see Chapters 65, 87, and 91. NETs are epithelial neoplasms with predominant neuroendocrine differentiation, which are classified according to their embryonic origin: foregut (bronchial, gastric, duodenal, pancreatic); midgut (ileal, jejunal, cecal); or hindgut (distal colonic, rectal). NET tumors are classified according to grade or Ki-67 expression: low grade (G1) indicates less than 3%, intermediate grade (G2) is 3% to 20%, and high grade (G3) is greater than 20%. NETs are variable in their presentation depending on whether the tumor is functioning or nonfunctioning. Although generally considered rare because of low incidence of 2.5 to 5 per 100,000 in the United States, NETs have a higher prevalence than more aggressive and common malignancies, such as pancreatic or gastric adenocarcinoma.90 For the purpose of this discussion, we will concentrate on GEP-NETs.

Imaging The somatostatin receptor (SSTR) family consists of different subtypes and belongs to the group of G-protein–coupled receptors. Approximately 70% to 90% of GEP-NETs express different SSTRs, predominantly subtype 2 and, to a lesser degree, subtypes 1 and 5 receptors.91,92  There have been major developments in diagnostic options available to patients in the last 5 years in the United States, thus allowing for the development of “personalized” therapeutic options. In June 2016, the Food and Drug Administration (FDA) approved the use of PET tracer 68Ga-radiolabeled SSTR analogue 68Ga-DOTATATE for the diagnosis of NET. Before this, there was a disparity in standards of practice for the diagnostic workup of NETs in the United States compared with Europe and the rest of world. In the United States, the FDA-approved radiotracers for NET imaging were planar and SPECT/CT imaging with the Indium-111 (111In) radiolabeled analogue of the SSTR-binding octapeptide, octreotide (111In pentetreotide). In Europe and elsewhere, however, PET tracers with 68Ga-SSTR analogues, notably 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE, were approved for workup of NETs.93 Octreotide was the first somatostatin analogue (SSA) introduced into clinical practice. In 1994, 111In–diethylenetriamine pentaacetic acid (DTPA)–octreotide (Octreoscan, Mallinckrodt, St. Louis, MO) was approved by the FDA as a clinical imaging agent because it demonstrates high affinity for SSTR2

298

PART 2  DIAGNOSTIC TECHNIQUES

with sensitivity of greater than 80% for diagnosis of well-differentiated (grades 1 and 2) tumors.94,95 Typically, planar and SPECT images are obtained 24 and 48 hours after tracer injection with SPECT/CT imaging, allowing for both functional and anatomic localization simultaneously. 68Ga-SSTR PET/ CT tracers have been repeatedly shown to offer significantly superior diagnostic sensitivity for SSTR-overexpressing NETs in multiple clinical trials, compared with 111In pentetreotide scintigraphy on a per-lesion and per-patient basis, and allow for earlier imaging time points (1–3 hours after tracer injection) for increased patient convenience.95 SSTR-targeted scintigraphy is often used to predict tumor response to SSTR-targeted therapy (e.g., with octreotide or other SSAs). Studies have showed that 68Ga-DOTATATE PET/CT changed treatment in 36% of patients compared with 111In pentetreotide96 and 41% of patients compared with conventional diagnostic imaging,97 mainly because of the detection of additional findings. 68Ga -DOTATATE PET/CT is also associated with no significant toxicity and lower radiation exposure compared with 111 In pentetreotide scintigraphy, and thus 68Ga -DOTATATE PET/CT should preferentially be used when available. Physiologic uptake of SSAs is seen in pituitary, thyroid, kidney, liver, and spleen. 68Ga -DOTATATE PET/CT tracers are most sensitive for low-grade NETs (low Ki-67 index). Highgrade NETs (high Ki-67 index) indicate a loss of SSTR expression and dedifferentiation and, therefore, FDG PET/ CT should be considered for characterization instead of 68GaSSTR PET/CT in these cases. Insulinomas, which predominantly express SSTR2 and SSTR5,98 are typically avid on 68 Ga-SSTR PET/CT imaging, with reported sensitivity up to 90%.99,100 As with other types of NET, higher-grade or poorly differentiated tumors are better assessed with FDG-PET/CT. 68 Ga-SSTR-PET/MRI has been used in imaging of NET and has been shown to improve the detection of liver metastases, particularly when hepatobiliary phase imaging is used.101 However, detection of bone and lung metastasis may be slightly limited compared with PET/CT.102 Although 68Ga-SSTR PET/CT has been shown to be both sensitive and specific for NET, false positives have been reported. Skoura et al. found 1.1% (14/1258) of false positives in 68 Ga-DOTATATE PET/CT performed in 728 patients with confirmed or suspected neuroendocrine tumors, with the majority of cases stemming from inflammatory causes (e.g., reactive nodes) or physiologic uptake in organs, which normally express SSTR2 (e.g., uncinate process of pancreas and adrenal glands).97 Additionally, osteoblasts have been shown to express SSTR2; thus osteoblastic processes, including degenerative change, fractures, or hemangiomas can be SSTR avid.103 There have also been case reports of non-neuroendocrine tumors, which are SSTR avid on 68Ga-SSTR PET/CT (e.g., medullary thyroid cancer).

Peptide Receptor Radionuclide Therapy If GEP-NETS are resectable, surgery is the primary approach (see Chapters 65 and 91). In patients with unresectable metastatic disease, however, multiple lines of therapy are used, including SSA therapy, targeted therapy (e.g., mTOR inhibitor everolimus or tyrosine kinase inhibitor sunitinib), or chemotherapy agents (e.g., capecitabine-temozolomide). In patients with metastatic SSTR expressing G1 and G2 NETs, who have failed first-line somatostatin treatment, peptide receptor radionuclide therapy (PRRT) is also an established treatment option.

PRRT exploits the molecular profile of NETs, which frequently overexpress SSTRs, allowing for the use of SSTR as a target for therapy (so-called theranostics). PRRT relies on the combination of the SSTR ligand and the selected radioisotope, preferentially a medium- to high-energy b emitter, which generates radiation-induced DNA damage, with 111In, 90 Y, and lutetium 177 (177Lu) being the most commonly studied radionuclides.94,104 When combining the SSTR ligand and radioisotopes other than 111In, however, a universal chelator molecule needs to be developed, which results in the introduction of 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA).105 Development of different ligands with higher affinity and preferential targeting of selected somatostatin subtypes can lead to the introduction of agents such as 177Lu and 90Y DOTA-TOC, DOTA-TATE, and DOTA-NOC. 90Y is a b emitter with a half-life of 2.7 days and maximal tissue penetration of 12 mm; 177Lu is a medium-energy b emitter with a half-life of 6.7 days and maximal tissue penetration of 2 mm, but which also emits low-energy gamma rays, which enables scintigraphy and subsequent dosimetry with the same therapeutic compound and thus is the current preferred radionuclide for clinical practice. 177 Lu-DOTATATE received FDA approval for treatment of metastatic, SSTR-positive, well-differentiated GEP-NET in January 2018 after the results of the Neuroendocrine Tumors Therapy (NETTER-1) and ERASMUS trials. The NETTER-1 trial was the first RCT to evaluate the efficacy and safety of 177Lu-DOTATATE in patients with advanced, progressive, SSTR-positive, grade 1 GEP NETs, demonstrating that patients that received PRRT with long-acting SSA had improved PFS compared with patients receiving long-acting SSA alone (at 20 months: 65.2% vs. 10.8%). The 177Lu-DOTATATE group also demonstrated an increased response rate of 18% versus 3% in the control group, and patients in the 177 Lu-DOTATATE arm reported an increased quality of life (Fig. 18.7). Nevertheless, OS has not yet been demonstrated in the 177Lu-DOTATATE arm, but preliminary data suggest a survival benefit.106 In the United States, 177Lu-DOTATATE (Luthathera, Advanced Accelerator Applications SA, SaintGenis-Pouilly, France) is administered in four cycles of 7.4 GBq (200 mCi) every 8 weeks. Long-term serious side effects of PRRT include renal failure and myelodysplastic syndrome (MDS)/leukemia, with the ERASMUS trial reporting rates of 2% and 3%, respectively, after more than four years of followup. Kidney protection using co-infusion of positively charged amino acids is mandatory in PRRT,107 as is vigilant monitoring of blood counts and renal function. Currently, the NETTER-2 trial is ongoing and looking at whether combination 177Lu-DOTATATE and long-acting SSA therapy prolongs PFS in patients with grade 2 and 3 GEPNET when given as a first-line therapy compared with longacting SSA alone (NCT03972488).108 Additional approaches to improve antitumoral efficacy include combination therapies (e.g., PRRT) and radio-sensitizing chemotherapeutic agents (e.g., capecitabine),109–111 PRRT and targeted therapy (e.g., everolimus)112 and combined radionuclide PRRT, including 177 Lu combined with a-emitters radionuclides. Applications of PRRT in the neoadjuvant setting to achieve tumor size reduction and thus allow curative surgery are also under investigation. Another approach in targeting somatostatin relies on the implementation of a binding-receptor antagonist instead of a receptor agonist, which may be of particular benefit

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

A

299

B

FIGURE 18.7  177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). A, Maximum intensity projection (MIP) image from 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in 75-year-old man with symptomatic well-differentiated insulin secreting neuroendocrine tumor with liver and bone metastases. Patient had been previously treated with octreotide therapy and hepatic arterial embolization but had increasing episodes of symptomatic hypoglycemia. Patient was referred for consideration of 177Lu-DOTATATE with pre-PRRT 68Ga-DOTATATE PET/ CT showing widespread somatostatin receptor expressing bone, nodal and liver metastases. B, MIP image from 68Ga-DOTATATE PET/CT after four cycles of 177Lu-DOTATATE PRRT in the same patient showing significant reduction in volume of somatostatin receptor expressing bone, nodal, and liver metastases, and the patient reported significant improvement in volume of hypoglycemia episodes.

in the setting of heavily pretreated NET patients. Whereas binding of SSTR agonists leads to receptor-mediated internalization, degradation, and intracellular trapping, the somatostatin antagonist is not internalized, offering the possibility to bind to more receptor sites and have a longer retention time.113–115 Radiolabeled SSTR antagonists, initially 111In-DOTA-BASS and more recently 177Lu-satoreotide tetraxetan (also known as 177LuDOTA-JR11,177Lu-IPN01072, and 177Lu-OPS201), have been investigated with early promising results.116–121

THE ROLE OF NUCLEAR MEDICINE IN NON­ ONCOLOGIC HEPATOBILIARY PATHOLOGIES Hepatobiliary Scintigraphy Hepatobiliary scintigraphy (or cholescintigraphy) refers to diagnostic imaging of radiotracers that assess hepatic perfusion, hepatocellular function, and hepatobiliary drainage. The most common clinical application of hepatobiliary scintigraphy is for detection of cholecystitis, including acute cholecystitis, typically induced by cystic duct obstruction, and chronic cholecystitis, typically associated with impaired gallbladder ability to contract normally (see Chapter 34). State-of-the-art hepatobiliary scintigraphy has high diagnostic sensitivity and specificity for detection of both acute and chronic cholecystitis, typically greater than 95%, when an optimal approach is used. Other notable but less common clinical indications for hepatobiliary scintigraphy are listed in Box 18.1; the diagnostic accuracy varies for each. Because information regarding hepatic function and biliary drainage can usually be diagnosed with clinical examination and

BOX 18.1  Clinical Indications for Hepatobiliary Scintigraphy

1. Functional biliary pain syndromes in adults 2. Functional biliary pain syndromes in pediatric patients 3. Acute cholecystitis 4. Right upper quadrant pain variants 5. Biliary system patency 6. Bile leak 7. Neonatal hyperbilirubinemia (biliary atresia versus neonatal hepatitis “syndrome”) 8. Assessment of biliary enteric bypass (e.g., Kasai procedure) 9. Assessment of liver transplant 10. Afferent loop syndrome 11. Assessment of biliary dilation (e.g., choledochal cyst) 12. Calculation of gallbladder ejection fraction 13. Functional assessment of the liver before partial hepatectomy 14. Demonstration of anomalous liver lobulation 15. Enterogastric (duodenogastric) reflux assessment 16. Esophageal bile reflux after gastrectomy 17. Sphincter of Oddi dysfunction 18. Differentiation of focal nodular hyperplasia from other hepatic neoplasms From Tulchinsky M, Ciak BR, Delbeke D, et al: SNM practice guideline for hepatobiliary scintigraphy 4.0. J Nucl Med Technol 38:210-218, 2010; and American College of Radiology, Society for Pediatric Radiology: ACR-SPR practice parameter for the performance of hepatobiliary scintigraphy. Amended 2017 (Resolution 40). www.acr.org.

blood tests, in general, most hepatobiliary medical society guidelines recommend diagnostic hepatobiliary scintigraphy in only a very few specific clinical indications and typically only as a second-line imaging modality. EASL Guidelines (2016) recommend abdominal US as the primary noninvasive imaging

300

PART 2  DIAGNOSTIC TECHNIQUES

procedure to distinguish intrahepatic from extrahepatic cholestasis, with MR cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) as potential next diagnostic imaging investigations for unexplained cholestasis122 (see Chapters 16 and 22). Hepatobiliary scintigraphy is not recommended for the investigation of cholestasis. Hepatobiliary scintigraphy uses an iminodiacetic acid (IDA)–derivative pharmaceutical radiolabeled with 99mTc. This has been colloquially known as “HIDA scan” because HIDA (or 99mTc-radiolabeled IDA compound, lidofenin) was the preeminent radiopharmaceutical in use at the time that hepatobiliary scintigraphy was introduced into clinical practice. Nevertheless, lidofenin is not commonly used in clinical practice because it has been replaced by 99mTc-radiolabeled disofenin or mebrofenin, which offer more favorable in vivo pharmacokinetics. The radiolabeled IDA compounds share common PK properties, differing predominantly in degrees or particular characteristics. All are injected intravenously and bind loosely to plasma proteins, mainly albumin; exiting the bloodstream, the IDA tracers dissociate from plasma proteins in the space of Disse and then undergo hepatic uptake by hepatocytes, followed by hepatic excretion into the intrahepatic biliary tree and subsequent clearance by biliary flow into the intestines via the sphincter of Oddi. These compounds also share PK properties with bilirubin. Bilirubin, the end-product of heme catabolism, is taken up from the blood circulation into hepatocytes by a high-affinity, sodium-independent, organic anion transport protein shared with IDA radiotracers. Inside hepatocytes, bilirubin is metabolized to a more water-soluble conjugated form; the IDA radiotracers, however, do not change form. Conjugated bilirubin and the IDA radiotracers both exit hepatocytes by energy-dependent active transport (particularly transporter ABCC2),123 then are excreted into the biliary tree, along with other components of bile (e.g., cholesterol, bile acids). In marked hyperbilirubinemia, the hepatic uptake of IDA radiotracers can be inhibited by competition in carriermediated transport of IDA radiotracers because of the high circulating levels of bilirubin, which uses the same transporters. In severe hyperbilirubinemia, a higher activity (MBq) of IDA radiotracer may be injected but not in hopes of reducing competitive inhibition by “mass effect,” because the higher radiotracer dose still involves only nanogram (trace) amounts of IDA compound. Rather, the liver will likely absorb the same percentage of the radiotracer dose, regardless of the activity. It is hoped, however, that this absorbed percentage, by using a higher administered activity (MBq), will yield more photons and more signal from the liver and biliary tree for better-quality scintigraphic image. In moderate to severe hyperbilirubinemia, 99mTc-radiolabeled mebrofenin is probably preferable to disofenin because mebrofenin has higher hepatic extraction.124 Hepatobiliary scintigraphy is first an assay of hepatic parenchymal function (see Chapter 4). Hepatic excretion of the radiolabeled IDA compounds is an energy-dependent, active transport process, dependent on intact hepatocellular function. An absent or abnormally low hepatic uptake of IDA radiotracer is indicative of hepatic parenchymal dysfunction, often a diffuse hepatic pathology (e.g., hepatitis). One proposed definition of “poor hepatic uptake” is hepatic tracer

uptake that is visually equivalent, in scintigraphic intensity, to that of tracer present in the cardiac blood pool 5 minutes after injection. Normally, hepatic tracer concentration should be greater than that of circulating tracer in the cardiac blood pool tracer by 5 minutes after injection.125 However, uptake of IDA radiotracers can remain relatively intact in the acute phase of hepatic injury, noting again that hepatocellular uptake of IDA radiotracers is not ATP dependent. In the early acute phase of hepatic injury, the cessation of ATP-mediated hepatocellular excretion of IDA radiotracers may precede any significant (i.e., scintigraphically detectable) decrease in overall hepatic uptake of IDA radiotracer. The differential analysis and clinical scenarios where this may be encountered are discussed later. Essentially, however, a marked decrease in IDA radiotracer and bile excretion and an associated lack of bile (tracer) flow through the biliary tree are signs of a severe hepatic dysfunction, which may be caused by a primary hepatic dysfunction (e.g., severe hepatitis) rather than a mechanical obstruction of biliary tree drainage (and thereby secondary hepatic dysfunction). Bile production depends on normal hepatocellular function (see Chapter 8). If hepatic parenchymal dysfunction is severe, bile production and bile flow will slow down, perhaps even stop, until hepatocellular recovery. Similarly, with severe hepatic parenchymal dysfunction and associated scant hepatic IDA radiotracer uptake, hepatic excretion of the IDA radiotracer and its drainage through the biliary tree will also be scant or undetectable on scintigraphy.

Normal Hepatobiliary IDA Radiotracer Scan This section discusses hepatobiliary scintigraphy with the commonly used 99mTc-labeled IDA tracers mebrofenin and disofenin, unless otherwise specified. Again, although colloquially called a “HIDA scan,” this, in fact, refers to imaging with lidofenin, which is not used in common routine practice. Scintigraphy with mebrofenin and disofenin yields similar findings in healthy individuals after standard preparation. Patient preparation varies, depending on the specific clinical indication, but usually includes fasting (unless the patient has no gallbladder; e.g., after cholecystectomy) and avoiding or counteracting recent use of opioids (Box 18.2).124 Current guidelines advise a fasting period of at least two hours, but preferably six hours, for adults, likely based on the normal gastric (and duodenal) clearance times after a typical solid meal. For infants, a fasting period of only two hours is typical, likely because the infant diet is liquid, and gastroduodenal

BOX 18.2  Hepatobiliary Scintigraphy: Key Points A “normal” hepatobiliary scan appearance is defined by the amount of tracer present in the blood pool, liver, biliary tree, and bowels, at different times after injection. Normal Patient Preparation Fasting (only if gallbladder present): • 2 hours for infants • 2–4 hours • $2–6 hours for adults • But not .24 hours fasting Opioids: wait $4 half-lives or use opioid antagonist (e.g., naloxone).

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

clearance of liquid meals is faster than that of solid meals. Physiologically during feeding, the gallbladder contracts, moving bile from gallbladder lumen out the cystic duct into the common bile duct (CBD) and the duodenum to aid digestion of food entering from the stomach. The duodenum, receiving a bolus of nutrients from the stomach, releases the hormone cholecystokinin (CCK); CCK causes contraction of the gallbladder and relaxes the sphincter of Oddi, allowing concentrated bile from the gallbladder stores to be pumped into the duodenal lumen. Thus, in the recently fed patient with relatively high levels of circulating CCK, the gallbladder often will be contracting, and excreted tracer may not enter the gallbladder lumen, potentially mimicking the appearance of a pathologic cystic duct obstruction and being misdiagnosed as consistent with acute cholecystitis on scintigraphy. In the fasting state, neural and hormonal impulses cause the sphincter of Oddi to be predominantly closed and the cystic duct of the gallbladder to remain predominantly open. This halts bile flow into the intestines (via sphincter of Oddi) and creates a pressure gradient directing bile (and IDA tracer) into the gallbladder. During fasting, some phasic contractions of gallbladder and relaxation of the sphincter of Oddi still occur, possibly to churn the bile and avoid precipitation of some bile constituents. Therefore a normal variability (i.e., range of normal values) occurs in the time required to observe excreted tracer in the gallbladder and bowels in well-prepared, healthy individuals. Prolonged fasting for longer than 24 hours (including during hyperalimentation) is also associated with excreted IDA tracer failing to enter the gallbladder lumen, creating a potentially misleading appearance scintigraphically. This is likely attributable to accumulation of biliary sludge in the gallbladder lumen, obstructing the cystic duct in a nonpathologic manner. Clinical research demonstrates that for patients who have undergone prolonged fasting, it is beneficial to administer a synthetic CCK octapeptide (sincalide) to “clean out” the gallbladder as part of patient preparation for hepatobiliary scintigraphy. Pretreatment with sincalide is typically 0.02 mg/kg intravenously during 30 to 60 minutes by slow infusion. One guideline suggests that hepatobiliary tracer injection can occur 15 to 30 minutes after slow sincalide infusion pretreatment.124 However, sincalide administration is associated with increased side effects, particularly crampy abdominal pain. Furthermore, sincalide can induce a contractile spasm of the gallbladder neck, especially if given as a bolus, creating a cystic duct obstruction lasting approximately one hour.126 Opioid medications (e.g., morphine) acutely induce strong, prolonged contraction of the sphincter of Oddi. If a patient has recently received opioid medications, passage of excreted radiotracer from the biliary tree into the duodenum can be delayed as a side effect. If biliary-to-bowel transit is delayed beyond three to four hours after injection from lingering opioid effects, this can mimic the appearance of CBD obstruction. To avoid this potential diagnostic pitfall, patients should avoid opioid medications before hepatobiliary scintigraphy; one guideline suggests waiting for four times the half-life of the particular opioid drug.124 Alternatively, naloxone may be administered to attempt to reverse the opioid effects.127 Additional forms of patient preparation for less common indications of hepatobiliary scintigraphy are discussed later. The in vivo hepatobiliary parameters typically assessed on scintigraphy are hepatic uptake and excretion of the administered IDA tracer and subsequent biliary drainage of the excreted

301

radiotracer through the biliary tree into the small bowel (Fig. 18.8). Typically, hepatobiliary scintigraphy begins with a series of consecutive planar images of the liver region (1 frame/ minute) for total acquisition of 60 minutes, starting at the time of radiotracer-injection. 99mTc-labeled IDA tracers clear rapidly from the bloodstream with elimination predominantly by hepatobiliary excretion. The tracers achieve maximal hepatic concentration approximately 10 minutes after injection and are detectable in the extrahepatic biliary tree within 30 to 60 minutes after injection. Excreted tracer passes from the biliary tree into the duodenum via the sphincter of Oddi and is detectable in the intestines in 80% of healthy people within one hour after injection. Biliary-to-bowel transit can take longer in some healthy individuals, especially if sincalide was administered before investigation (a paradoxical phenomenon).128 Excreted tracer that enters the intestines remains in the intestines, with no significant intestinal tracer reabsorption or enterohepatic recycling of radiotracer. Lastly, the gallbladder should be visualized within 30 to 60 minutes after injection, typically the endpoint of the study. Gallbladder nonvisualization after one hour in the proper clinical setting is highly suggestive of cystic duct obstruction, most commonly associated with acute cholecystitis. In these patients, additional imaging for 30 minutes after IV morphine administration or delayed imaging can be performed to confirm the diagnosis. As mentioned previously, the radiotracer 99mTclidofenin is now rarely used compared with current agents such as 99mTc-radiolabeled disofenin and mebrofenin, which have more favorable pharmaceutics with increased hepatic clearance (both with half-times of ,15–20 minutes vs, ,40 minutes with 99m Tc-lidofenin). However, older literature and certain guidelines often suggest obtaining delayed imaging at three to four hours after radiotracer injection, based on original 99mTc-lidofenin imaging. With increased hepatic clearance of 99mTc-disofenin and 99mTc-mebrofenin, however, delayed gallbladder imaging (.1 hours) is not typically possible because the liver is often essentially “empty” of radiotracer by two to four hours after injection. Nevertheless, with a severely ill patient, such as a patient with severe hepatocellular dysfunction, suspected CBD obstruction, or suspected biliary atresia, uptake and secretion of biliary tracer by dysfunctional hepatocytes may be abnormally delayed or biliary flow through the biliary tree may be greatly slowed, thus allowing for delayed imaging with 99mTc-disofenin and 99mTc-mebrofenin up to 24 hours after injection.129 Analysis of hepatobiliary scintigraphy is typically based on visual detection of tracer in expected locations at expected time points as previously discussed, with semiquantitative visual estimation of whether the amount of tracer present in the blood pool, liver, biliary tree, and bowels is appropriate for the time point after injection also employed. Quantitative analysis may be performed with region of interest (ROI) analysis, although it is not routinely performed in clinical practice. Nuclear medicine societies provide detailed guidance documents with technical protocols for image acquisition protocols.44 Pathology in hepatobiliary scintigraphy is thus indicated by one or more of the following: • An abnormally low amount of hepatic tracer uptake • An abnormally prolonged hepatic retention of tracer • An abnormally delayed appearance of excreted tracer in the biliary tree • An abnormally delayed appearance of excreted tracer in the intestines

302

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 18.8  Normal hepatobiliary iminodiacetic acid study. Serial images of the liver, in anterior projection, acquired beginning immediately after tracer injection; each image is five minutes in duration. The serial images show prompt systemic clearance of radiotracer (e.g., disappearing cardiac blood pool, gray arrowhead) via hepatic uptake, followed by prompt hepatobiliary excretion of tracer. Excreted tracer flows promptly through the extrahepatic biliary tree, including into the gallbladder lumen (large arrow). Excreted tracer passes from biliary tree into the duodenum, carried away into distal bowel loops by peristalsis (black arrowhead). One atypical incidental finding is enterogastric reflux of the biliary tracer (small arrow).

Augmented Hepatobiliary Scintigraphy Hepatobiliary scintigraphy can employ pharmacologic interventions, most notably with phenobarbital, morphine, and sincalide. Phenobarbital is used in cholescintigraphic evaluation of neonatal jaundice (see Chapters 1 and 40). Patient pretreatment with phenobarbital will stimulate bile production and biliary flow and increase the likelihood of visualizing hepatobiliary radiotracer excretion, if biliary atresia is absent. It reduces the likelihood of false-positive scintigraphic appearance of biliary flow obstruction. Morphine is used in cholescintigraphic evaluation of gallbladder cystic duct obstruction (see Chapter 34). If accumulation of excreted biliary tracer in gallbladder lumen is not observed in the expected time frame, morphine administration normally contracts the sphincter of Oddi and relaxes any physiologic gallbladder contraction; this increases the likelihood that biliary radiotracer can accumulate within the gallbladder, if no pathologic obstruction of the gallbladder cystic duct (e.g., associated with calculous or acalculous cholecystitis)

is present. It reduces the likelihood of false-positive scintigraphic appearance of gallbladder cystic duct obstruction. Because morphine contracts the sphincter of Oddi, scintigraphically, entry of biliary tracer into small intestines is typically confirmed visually before use of morphine, first to exclude CBD obstruction before attempting to exclude a cystic duct obstruction. If the decision to use morphine is made based on nonvisualization of the gallbladder but the injected biliary tracer has already essentially cleared from the liver and biliary tree into the bowels, it is often necessary for patients to receive a “booster” injection of biliary tracer before administration of morphine to renew a flow of radiotracer through the biliary tree. Sincalide is used in cholescintigraphy for evaluation of gallbladder cystic duct or CBD obstruction or gallbladder dyskinesia (see Chapters 34 and 37). Patient treatment with sincalide causes contraction of the gallbladder and relaxation of the sphincter of Oddi. Sincalide can be given before radiotracer to evacuate the gallbladder lumen if gallbladder accumulation of a biliary sludge is possible (e.g., from patient hyperalimentation

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

or prolonged fasting) or evident sonographically; such sludge can impede gallbladder accumulation of biliary tracer, creating a scintigraphic appearance mimicking a cystic duct obstruction (false positive). If the gallbladder lumen accumulates biliary tracer (i.e., there is no cystic duct obstruction) but gallbladder dyskinesia is suspected, sincalide can then be administered 30 to 60 minutes after tracer administration to assess gallbladder ejection fraction (normal .38%).

Gallbladder Ejection Fraction The scintigraphic hallmark of cholecystitis is gallbladder dyskinesia, defined as gallbladder ejection fraction (GBEF) less than 38%, on sincalide-stimulated cholescintigraphy.124,129 Gallbladder dyskinesia can be seen in both acute and chronic cholecystitis because both cause dysfunction of inflamed gallbladder smooth musculature. The GBEF study begins after the expected tracer accumulation in the gallbladder lumen has been visualized (see Chapter 34). Medications can interfere with interpretation of GBEF, most notably morphine. If morphine augmentation has been used, sincalide GBEF testing can still be performed with normal GBEF reliably excluding gallbladder dyskinesia; however, low GBEF results are nondiagnostic. Other medications associated with low GBEF include atropine, calcium channel blockers, octreotide, progesterone, indomethacin, theophylline, benzodiazepines, and histamine-2 receptor antagonists. As such, patient medications should be reviewed at the time of the study. Additionally, a variety of conditions other than cholecystitis have been associated with low GBEF results, including obesity, diabetes mellitus, celiac disease, cirrhosis, and myotonic dystrophy.

Clinical Uses of Hepatobiliary Scintigraphy ACUTE CHOLECYSTITIS. Acute cholecystitis is the most common clinical indication for cholescintigraphy, although abdominal US remains the first-line imaging modality (see Chapters 16 and 34). The reported sensitivity and specificity of cholescintigraphy for suspected acute calculous cholecystitis ranges from 87% to 98% and 81% to 100%, respectively.129 Kaoutzanis et al. retrospectively reviewed patients presenting to the emergency department with acute upper abdominal pain (n 5 406) who underwent investigation for acute cholecystitis, using abdominal US (n 5 132), scintigraphy (n 5 46), or both (n 5 228), as per the referrer wishes.130 The sensitivity for acute cholecystitis was 73% for US alone, 92% for scintigraphy alone, and 98% for both. Although this study is limited because of its retrospective nature and nonrandomization of imaging investigation performed, the findings indicate that hepatobiliary scintigraphy (1) continues to have a standard role in the evaluation of the patient with acute abdominal pain, especially if combined with abdominal US, and (2) offers high sensitivity for preoperative diagnosis of acute cholecystitis, alone or combined with US, in the correct clinical context. Acute cholecystitis in adults is almost always associated with a pathologic obstruction of the cystic duct, whether secondary to cholelithiasis impacted in the cystic duct or acalculous cholecystitis (i.e., inflammation and edema in the walls of the gallbladder neck, occluding the duct). Nonvisualization of the gallbladder at 60 minutes is suggestive of cystic duct obstruction and thus acute cholecystitis. As previously discussed, however, in a minority of healthy patients without pathologic obstruction of the cystic duct, the

303

gallbladder lumen does not accumulate excreted tracer within 1 hour because of a physiologic obstruction of inward biliary flow associated with physiologic contractions of the gallbladder. These contractions are typically stopped by adequate fasting; however, in a small percentage of patients, they persist. To increase the diagnostic specificity of gallbladder nonvisualization as a scintigraphic biomarker of cystic duct obstruction, guidelines suggest obtaining either delayed imaging 3 to 4 hours after injection or morphine administration to stimulate the sphincter of Oddi.42 If the gallbladder remains nonvisualized after these strategies, cystic duct obstruction can be diagnosed with greater specificity. The “cystic duct sign” is a nonelongated, spot-like focus of tracer accumulation in the expected location of the cystic duct along the common hepatic and bile duct course and can mimic gallbladder tracer accumulation. However, the cystic duct sign represents a focal accumulation of biliary radiotracer within the proximal cystic duct (closest to and communicating with the common duct), which can occur in cystic duct obstruction when cholelithiasis obstructing bile passage from the gallbladder is lodged more distally within the cystic duct. The cystic duct sign should be suspected when biliary tracer accumulation in the gallbladder region is not elongated but rather is more spot-like and smaller than usual. In cases of diagnostic uncertainty, a suspected cystic duct sign can be evaluated further by SPECT/CT to confirm an absence of excreted tracer in the gallbladder lumen. The “rim sign,” seen in 25% to 35% of patients with acute cholecystitis, describes an abnormal “blush” of activity around the gallbladder fossa, which can occur in flow phase imaging because of inflammation of the surrounding hepatic parenchyma. The rim sign has been associated with an increased risk for complicated cholecystitis, specifically gangrene and gallbladder perforation, and is sensitive but not specific for acute cholecystitis.129 Acalculous acute cholecystitis occurs in less than 10% of adult patients with acute cholecystitis but is associated with a high morbidity and mortality (see Chapter 34). Most patients with acute acalculous cholecystitis have cystic duct obstruction caused by multiple different etiologies, including fibrosis, anomalous vessels, and tumor, but most commonly because of inspissated bile, debris, and local edema. In most patients, the diagnosis can be made with cholescintigraphy; however, cholescintigraphy appears to have less diagnostic sensitivity for acalculous acute cholecystitis compared with calculous acute cholecystitis (70%–80% vs. 95%).124,129 Additionally, approximately 25% of patients with acute acalculous cholecystitis do not have cystic duct obstruction but rather direct inflammation of the gallbladder wall secondary to ischemia.129 Thus, gallbladder tracer accumulation can occur, a false-negative finding. In patients with gallbladder tracer accumulation, however, the presence of the rim sign or abnormally low GBEF can increase diagnostic sensitivity, although poor gallbladder contraction can also be seen in chronic cholecystitis.129 As mentioned previously, acalculous cholecystitis is relatively uncommon in adults; in pediatric patients, however, acute cholecystitis is more frequently acalculous. Cholescintigraphy remains the imaging examination of choice when acalculous cholecystitis is suspected. CHRONIC CHOLECYSTITIS. Patients with chronic cholecystitis typically present with recurrent biliary colic (typically chronic calculous cholelithiasis; see Chapter 34). If cholelithiasis is seen on US, then the patient is referred for cholecystectomy. As such,

304

PART 2  DIAGNOSTIC TECHNIQUES

cholescintigraphy is rarely indicated as part of a work-up, unless patients present with atypical symptoms, which the physician suspects are not attributed to chronic calculous cholecystitis, or chronic acalculous cholecystitis is suspected. Cholelithiasis is commonly seen, but one study showed that only 15% of patients developed biliary colic after 20-year follow-up.131 The cystic duct is typically patent in chronic cholecystitis; therefore, if tracer accumulates in the gallbladder during cholescintigraphy and a normal GBEF is seen, then symptomatic chronic cholecystitis is unlikely.132 Acalculous chronic cholecystitis is reported to occur in approximately 5% to 25% of patients, attributed to gallbladder lymphocyte infiltration and fibrosis similar to gallbladders with the calculous form of the disease but without stones and thus is associated with low GBEF and gallbladder dyskinesia. EXTRAHEPATIC BILE DUCT OBSTRUCTION. In cholescintigraphy performed in normal healthy volunteers, tracers undergo hepatobiliary drainage with detectable passage of excreted tracer into the duodenum within one hour after injection in a majority of cases, but can take up to two hours in approximately one-third

of people, probably because of transient/phasic physiologic contraction of the sphincter of Oddi. In healthy volunteers, with relatively delayed passage of tracer into the small bowel, excreted tracer is visible in the extrahepatic biliary tree, awaiting passage into the bowel once the sphincter of Oddi relaxes. Additionally, patients pretreated with sincalide before cholescintigraphy paradoxically seem to be more likely to demonstrate a nonpathologic delay in biliary transit into the bowel, especially if sincalide is infused relatively rapidly.128 Pathologic obstruction of the common hepatic duct or CBD can be diagnosed by cholescintigraphy (Fig. 18.9). Extrahepatic bile duct obstruction can be caused by cholelithiasis (choledocholithiasis or, rarely, Mirizzi syndrome; see Chapters 34 and 37) or tumor (e.g., pancreatic head mass compressing adjacent duct; see Chapters 49, 51, 62, 63, and 67). Tumor-associated biliary obstruction is usually identifiable by structural imaging (CT, US, or MRI) because biliary duct dilation is often already present at diagnosis. Obstructive choledocholithiasis, in contrast, often presents clinically as an acute biliary-type pain; in the first 24 to 72 hours after bile duct obstruction by choledocholithiasis, bile duct distension may not yet be marked enough to be

FIGURE 18.9  Complete biliary obstruction. Images were obtained immediately after injection and at 30 minutes, 60 minutes, and three hours. No severe hepatocellular dysfunction is evident; systemic tracer clearance is somewhat delayed (cardiac blood pool still detectable at 30 minutes), but the liver demonstrates prompt, visually distinct tracer uptake. No excreted tracer is detectable in the extrahepatic biliary tree at one hour after tracer injection. This constellation of scintigraphic findings is suspicious for an acute high-grade extrahepatic bile duct obstruction, in the proper clinical setting. If hepatocellular function is impaired, continued absence of detectable excreted extrahepatic tracer at three to four hours after injection increases diagnostic confidence.

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

suspicious on structural imaging. Cholescintigraphy can confirm a clinical suspicion of acute extrahepatic bile duct obstruction in patients with negative structural imaging. Additionally, patients with previously treated bile duct obstruction can have persistent bile duct dilation after treatment; if these patients return to the clinic with suspicious biliary colic, structural imaging may demonstrate a chronically distended bile duct of uncertain significance. Cholescintigraphy can confirm a clinical suspicion of acute recurrent extrahepatic bile duct obstruction in such patients. Acute extrahepatic bile duct obstruction has been described as having cholescintigraphic appearances that favor either a “high-grade” or a lesser, “partial” degree of biliary obstruction.129 An acute high-grade obstruction of the extrahepatic biliary tree can be diagnosed if the following findings are present: • The patient has good hepatic function, as indicated by blood tests and on cholescintigraphy by rapid hepatic tracer-uptake and rapid tracer clearance from the blood pool. • Excreted biliary tracer is not detectable or scantly present in the extrahepatic biliary tree by one hour after injection. If these two findings are present, extrahepatic bile duct obstruction is the likely diagnosis, and other etiologies are relatively rare.133 If hepatic function is poor, however, passage of

305

excreted tracer into the extrahepatic bile ducts can be delayed because hepatic bile production is slow (Fig. 18.10). Hepatic function may be poor because of a true bile duct obstruction (in which case it was more likely chronic than acute) or because of a separate nonobstructive etiology (e.g., hepatitis or cirrhosis). If hepatic function is poor, delayed imaging will improve test specificity (i.e., help avoid false diagnosis of bile duct obstruction).133 A partial obstruction of the extrahepatic bile ducts is associated with the following cholescintigraphic appearance: • Hepatic uptake is normally prompt (unless the patient also has hepatic dysfunction unrelated to biliary obstruction). • Excreted tracer appears promptly within the extrahepatic biliary tree. • Clearance of excreted tracer from the extrahepatic biliary tree is absent or scant during the first hour after injection. • Further clearance of excreted tracer from the extrahepatic biliary tree into the small bowel, after sincalide administration or at delayed time points, is less than expected. Normally, approximately half of biliary tracer has passed from the hepatobiliary tree into the small bowel by one hour after tracer injection, and a progressive decline in the net amount of tracer in the extrahepatic biliary tree is usually visibly evident

FIGURE 18.10  This study shows severe hepatocellular dysfunction, with the kidneys exhibiting increased clearance of the tracer. Note the parallel reduction in activity in the cardiac blood pool and the liver. The two bright foci beneath the liver are caused by activity in the pelvis of the right and left kidneys. The straight arrow points to the left renal pelvis; the curved arrow points to the right ureter. Images were acquired at two, 15, 25, and 60 minutes after injection.

306

PART 2  DIAGNOSTIC TECHNIQUES

scintigraphically within the first hour.134 However, an absence of bowel activity at one hour after tracer injection is sensitive for partial obstruction (~98%), but is not highly specific because of the normal variation in drainage of bile into bowel associated with phasic physiologic contractions of the sphincter of Oddi.135 Delayed imaging can be obtained to allow for detection of biliary passage into the bowel, allowing for the possibility of a physiologic contraction of the sphincter of Oddi. Alternatively, relaxation of the sphincter of Oddi can be induced by sincalide treatment to avoid delay and can be used in the setting of cholelithiasis. The gallbladder, if present, must accumulate excreted tracer normally, before use of sincalide, to exclude cystic duct obstruction. If clearance of excreted tracer from the extrahepatic biliary tree into the bowel remains less than expected after sincalide administration or at delayed time points, a partial bile duct obstruction can be diagnosed with a specificity of approximately 85%.129 POSTCHOLECYSTECTOMY SYNDROME AND SPHINCTER OF ODDI DYSFUNCTION. Postcholecystectomy syndrome refers to the recurrence of abdominal pain after cholecystectomy, which occurs in 10% to 40% of patients who have had cholecystectomy for symptomatic chronic cholecystitis and more commonly occurs in women136 (see Chapters 34 and 36). Onset of symptoms can occur from two days up to 25 years after surgery. Hepatobiliary causes for the recurrent pain include retained and recurrent stones, biliary stricture, tumors, a cystic duct remnant, and obstruction of the sphincter of Oddi. The explanation for presentation after cholecystectomy is that the biliary system no longer has a pressure-release mechanism, formerly served by the gallbladder, which increased pressure, producing the pain. In the majority of patients, however, other extrahepatic disorders (e.g., reflux esophagitis, gastritis, irritable bowel syndrome, chronic pancreatitis) are responsible for the postcholecystectomy pain syndrome.137 Sphincter of Oddi dysfunction is a poorly understood clinical entity that occurs weeks, months, or years after cholecystectomy in 1% to 14% of patients,138,139 presenting as either recurrent episodic biliary colic pain (stage I), recurrent pain associated with elevated liver enzymes or dilated ducts (stage II), or episodic pain with elevated liver enzymes and dilated biliary ducts (stage III).140 The dysfunction can be caused by true stenosis or secondary to spasm of the sphincter. The establishment of a diagnosis and treatment approaches is challenging. Sphincterotomy, advocated as effective therapy, can be associated with bleeding and pancreatitis. Cholescintigraphy and sphincter of Oddi manometry have been explored as assays to confirm diagnosis in support of therapeutic intervention. All biliary causes for the postcholecystectomy pain syndrome have a similar scintigraphic pattern on cholescintigraphy, that of a partial biliary obstruction. Various protocols assessing qualitative image analysis based on cholescintigraphy have been published recommending an infusion of sincalide during three to 10 minutes, completed 15 minutes before radiotracer injection.141 Another study, however, indicated that sphincter of Oddi manometry is superior to scintigraphy.142 Subsequently, another report indicated that although the sensitivity of scintigraphy is less compared with superior manometry, the higher accuracy in predicting treatment success compares favorably.143 Furthermore, manometry is rarely used anymore because of the frequent occurrence of serious side effects, particularly pancreatitis.

BILIARY TRACT COMPLICATIONS AFTER SURGERY. Cholescintigraphy can positively impact diagnostic evaluation of patients for biliary tract complications associated with a variety of procedures, such as laparoscopic cholecystectomy, partial hepatic resections, or liver transplantation (see Chapters 28, 32, and 42). Bile duct injuries may lead either to biliary duct obstruction or bile leakage but are generally rare, with a reported rate of 0.39% after laparoscopic cholecystectomy.144 CT and US are first-line imaging modalities to evaluate for suspected complications; nonspecific findings include fluid collection in the gallbladder fossa or peritoneal cavity. Cholescintigraphy allows for the noninvasive evaluation of the biliary tree for obstruction and leakage and can be used to characterize fluid collections detected by US or CT, particularly benefiting from the use of SPECT/ CT to visualize both the fluid collection (on CT) and the abnormal tracer accumulation within the collection on fusion SPECT/CT. Most leaks are observed at the cystic duct stump, and characteristic scintigraphy findings include tracer accumulation at the gallbladder fossa, near the porta hepatis or in the subphrenic space. SPECT/CT is also advantageous for patients with complicated postsurgical hepatobiliary anatomy (e.g., status after hepaticojejunostomy), to help clarify biliary flow patterns. LIVER TRANSPLANTATION. A biliary stricture is one of the most common biliary complications after liver transplantation, with incidence varying depending on the type of biliary reconstruction and with a higher incidence in patients undergoing duct-toduct anastomosis145 (see Chapter 111). Endoscopic retrograde cholangiopancreatography (ERCP), MRCP, and US are typically used for diagnosis of stricture; although the role of hepatobiliary scintigraphy has been studied in post-transplantation, it is not currently recommended in guidelines. Hepatobiliary scintigraphy with IDA-type tracers has been shown to provide accurate diagnosis of biliary complications in adult and pediatric patients.145–147 Nevertheless, hepatobiliary scintigraphy cannot reliably distinguish between cholestasis and rejection, which is typically diagnosed by liver biopsy.145,148 Hepatobiliary scintigraphy can have a role in diagnosis of biliary leaks after transplantation, especially Roux-en-Y choledochojejunostomy bile leaks, which can be difficult to diagnose on ERCP because of alternation of anatomy.

The Role of Hepatobiliary Scintigraphy in Pediatric Imaging NEONATAL JAUNDICE. The incidence of neonatal jaundice in the United States has been increasing, currently affecting approximately two-thirds of newborns149 (see Chapter 1). In most infants, the etiology of jaundice is physiologic; however, high concentrations of unconjugated bilirubin may cause permanent neurologic damage, known as chronic bilirubin encephalopathy or kernicterus. Even moderately elevated levels of bilirubin may induce permanent neurodevelopmental impairment (NDI) or bilirubin-induced neurologic dysfunction (BIND). The various etiologies include infections, isoimmunization, inherited disorders of bilirubin conjugation and transport, and biliary malformation. Biliary atresia, inspissated bile syndrome, and choledochal malformation are associated with a relatively good clinical outcome after surgery. Early establishment of the underlying cause is a key factor to improve associated morbidity and mortality rates. In pathologic jaundice, neonatal hepatitis and biliary atresia account for 70% to 80% of cases. Alagille syndrome and a1-antitrypsin deficiency account for 10% to

  Chapter 18  The Role of Nuclear Medicine in Diagnosis and Management of Hepatopancreatobiliary Diseases

15%.150 The clinical dilemma is that the diseases have similar clinical presentations and blood test findings, but biliary atresia, if present, requires urgent surgical intervention for optimal pediatric outcomes. 99mTc-IDA cholescintigraphy plays a valuable role in the evaluation of neonatal jaundice. Hepatobiliary scintigraphy is performed with 99mTc-labeled mebrofenin as the preferred agent because of its high hepatic extraction. BILIARY ATRESIA. Biliary atresia is a common cause of neonatal cholestasis jaundice and occurs in one in 10,000 to 15,000 newborns151 (see Chapters 1 and 40). Biliary atresia develops either during embryogenesis or the perinatal period, with progressive inflammatory sclerosis of the intrahepatic and extrahepatic biliary ducts. The cause of biliary atresia is unknown, although several mechanisms have been postulated, including viral etiologies.152,153 Early diagnosis within the first two months after birth is crucial to prevent irreversible liver damage. Treatment is based on palliative hepatoportoenterostomy (Kasai procedure) and often, ultimately, liver transplantation. Biliary atresia shows high-grade biliary obstruction with a persistent hepatogram and no biliary-to-bowel transit over 24 hours. The negative predictive value of the study is high (approximately 100%) and thus cholescintigraphy is typically used to exclude biliary atresia because the detection of excreted biliary tracer in the gallbladder or bowels effectively excludes biliary atresia.129 However, false-positive studies can be seen in biliary atresia or severe hepatocellular dysfunction (e.g., from hepatitis). Thus patient preparation for cholescintigraphy should include administration of phenobarbital (5 mg/kg/day) for up to five days before the test to activate liver excretory enzymes and increase bile flow, and cholescintigraphy imaging should continue at multiple time points up to 24 hours after tracer injection to allow for possible markedly slow biliary flow. A 2013 meta-analysis reported a pooled sensitivity and specificity of 98.7% (range, 98.1%–99.2%) and 70.4% (68.5%– 72.2%), respectively, for diagnosis of biliary atresia. Its nearperfect sensitivity for biliary atresia makes cholescintigraphy an effective assay for excluding biliary atresia. Its limited specificity demonstrates that a lack of biliary tracer transit into gallbladder or bowel, as a scintigraphic biomarker, has insufficient specificity to positively diagnose atresia and guide decision making on whether surgical intervention is necessary.154 If there is equivocal gallbladder filling on planar imaging, SPECT/CT imaging can be used to help diagnosis.155 Thus cholescintigraphy is diagnostically useful as a means to “rule out” biliary atresia.

Hepatobiliary Sulfur Colloid Imaging In the past, scintigraphy with radiolabeled SC provided a useful means for gross structural evaluation of liver and spleen; however, with the increased availability of CT and MRI, which provide far superior structural/anatomic delineation of organs, SC imaging has been almost entirely replaced for hepatobiliary imaging, except in a few very specific indications, most commonly as a diagnostic adjunct for hepatic arterial perfusion scintigraphy (as discussed previously), for detection of splenosis, and, rarely, for characterization of suspected focal nodular hyperplasia (FNH). Colloid scintigraphy is an umbrella term, because a variety of radiolabeled colloid particulates have been developed for human studies. In the United States, 99mTc-labeled SC is the only radiocolloid in common use for clinical hepatic scintigraphy. 99mTc-labeled SC is a particulate compound. 99mTc-labeled

307

SC particulates administered to humans range from 0.1 to 1.0 mm in size. After IV injection, 99mTc-labeled SC normally localizes at its highest concentration in the liver, followed by lesser uptake in the spleen and relatively low uptake in bone marrow (see Fig. 18.4). This liver-spleen-marrow biodistribution reflects the removal of 99mTc-labeled SC particulates from the bloodstream by phagocytes in the reticuloendothelial system (including hepatic Kupffer cells). Blood clearance is normally rapid (two to three minute half-life), allowing scintigraphy to begin 20 to 30 minutes after injection. In a few hours, catabolism of 99m Tc-labeled SC can become evident by scintigraphic signs of catabolic production of free 99mTc pertechnetate; signs of 99mTc pertechnetate include (delayed–time point) accumulation of radioisotope in stomach and thyroid and urinary radioisotope excretion. Splenic concentration of 99mTc-labeled SC normally is less than the scintigraphic intensity of hepatic concentration. Colloid shift is an abnormality in colloid biodistribution that occurs when hepatic 99mTc-labeled SC concentration is visually less than splenic concentration because of abnormally low hepatic uptake or abnormally high splenic uptake of 99mTc-labeled SC (e.g., in diffuse hepatic diseases such as advanced cirrhosis and severe hepatitis or causes of hypersplenism).156 It was hypothesized that hepatic colloid uptake could be a semiquantitative biomarker of hepatic function; however, this has not shown to be true, with one study showing no correlation between scintigraphic semiquantitative uptake measurements and Child-Pugh classification.157 Hepatic lesions can be colloid tracer “cold” or “hot” lesions; however, because of limited resolution of the planar and SPECT scans, only hepatic lesions greater than 1.5 to 2 cm can be reliably detected. The differential of cold or photopenic lesion, foci of absent or relatively low hepatic colloid uptake, is broad, but includes HCC, liver metastases, adenoma, and hepatic abscess.158 However, the only reported “hot” hepatic lesion is focal nodular hyperplasia because SC is taken up by Kupffer cells in the reticuloendothelial system, which are found in abundance in FNH. Intense focal uptake is thought to be quite specific for FNH but has relatively poor sensitivity of 60% to 70% for detection of FNH.159,160 The finding of diminished colloid uptake in the right and left liver lobes, with sparing of the caudate lobe, has been associated with Budd-Chiari syndrome (hepatic vein thrombosis). Splenosis, or ectopic splenic tissue, is an acquired condition (typically after trauma or splenectomy) where foci of splenic tissue is autoimplanted in various compartments of the body, which then recruits local blood supply and, as a result, can grow over time and present serious diagnostic problems because they can mimic malignant lesions (e.g., peritoneal metastases in pancreatic cancer). Although splenosis typically demonstrates similar imaging characteristics to the spleen on CT and MRI, it can be diagnostically challenging, especially in the postsplenectomy oncology patient. The diagnosis of splenosis can be confirmed with 99mTc-labeled SC scan, which will demonstrate increased uptake in lesions greater than 1.5 to 2.0 cm with sensitivity increased with SPECT imaging. If 99mTc-labeled SC scan fails to confirm the presence of splenic tissue, 99m Tc- tagged heat-damaged red blood cell (RBC) scan with autologous erythrocytes is the gold standard of imaging, being capable of specifically proving splenic tissue. Intrapancreatic accessory spleen (IPAS), a normal variant, can be a mimic of malignancy (e.g., pancreatic neuroendocrine tumors [PNET]). If conventional CT or MRI are not definitive in the diagnosis

308

PART 2  DIAGNOSTIC TECHNIQUES

of IPAS, then further confirmation is possible with 99mTc-labeled SC 1/2 99mTc- tagged heat-damaged RBC scan. These scans are both highly specific and best differentiate IPAS from PNET because the PNET will not show uptake.161,162 68Ga-SSR PET/ CT and octreotide scans are not reliable to differentiate between IPAS and PNET because false-positive IPAS tracer uptake has been reported.163–165

Incidental Liver Lesions The differential diagnosis of an incidental liver lesion is broad and includes benign lesions, such as hemangioma, FNH, hepatic adenoma, and regenerative nodules, and malignant lesions, including HCC or metastases (see Chapters 14, 15, and 87). Characterization and detection of liver lesions usually begins with US, CT, or MRI, which can be sufficient for diagnosis.166,167 The role of scintigraphy in characterizing liver lesions is typically limited and confined to second-line imaging, but it can be helpful in select cases when the differential diagnosis has been narrowed by initial evaluation of the liver lesion by CT/US/MRI, clinical history, and blood test findings. The American College of Radiology suggests a limited role for nuclear scintigraphy in characterization of incidentally discovered lesions, with CT or MRI always the preferred initial imaging modality.141 If a patient has a known extrahepatic malignancy and CT/MRI characterization is indeterminate, PET/CT, typically FDG, is potentially helpful for further characterization, especially if the patient had previously tracer-avid extrahepatic disease. Also, nuclear imaging may have a role in characterization of certain benign lesions if conventional imaging remains uncertain, as discussed later.

Focal Nodular Hyperplasia FNH is a regenerative mass lesion of the liver and the second most common benign liver lesion (see Chapters 14 and 88). It is commonly asymptomatic and requires no treatment. 99mTc SC imaging may be useful in characterizing FNH, especially when combined with SPECT imaging, if findings are equivocal on conventional imaging. SC is taken up by Kupffer cells in the reticuloendothelial system, which are found in abundance in FNH, thus appearing as a hot lesion. When present, intense focal uptake is thought to be quite specific for FNH but has quite poor sensitivity of approximately 60% to 70% for the detection of FNH.159,160,168 This, in part, may be because of the size of the lesion: SPECT sensitivity for detection is decreased in lesions less than 1.5 cm because of spatial resolution of SPECT camera and increased risk for partial volume–averaging effects that diminish the detectability of tracer uptake by colloid-avid FNH lesions and background hepatic uptake or because of the paucity of Kupffer cells in certain FNH, which then appear photopenic or with uptake similar to background liver. Additionally, hepatic adenomas may rarely contain Kupffer cells and be associated with uptake similar or slightly greater than background liver. Cholescintigraphy, using biliary tracers such as 99mTc-radiolabeled disofenin or mebrofenin, have been used in characterization of FNH. Hepatocytes in the FNH lesion produce bile; however, biliary canaliculi within the FNH are often characterized by disordered drainage connections with the remainder of the intrahepatic biliary tree and therefore, on cholescintigraphy, demonstrate abnormal focal accumulation and prolonged focal

retention of a biliary radiotracer. Early studies suggest cholescintigraphy had promising diagnostic sensitivity (e.g., 92%)169; however, with the advent of hepatobiliary contrast agents used in MRI, this technique is not used in modern clinical practice. Additionally, well-differentiated HCC are reported to demonstrate a similar cholescintigraphic phenotype, as an abnormal focal, prolonged retention of biliary tracer. The FDG PET appearance of FNH is variable, ranging from mild hypermetabolic, isointense to mild hypometabolic avidity compared with surrounding hepatic FDG uptake, but is rarely, if ever, intensely FDG avid.170

Hemangioma Hepatic hemangioma is the most common benign liver lesion (see Chapters 14 and 88). It is typically characterized on US or contrast-enhanced CT or MRI and is only incidentally seen on nuclear studies performed for other indications. On 99mTclabeled SC scintigraphy, hemangiomas appear as a photopenic or “cold” lesions, and on FDG PET, they typically demonstrate avidity equivalent or less than cardiac blood pool activity and also generally less than surrounding liver FDG uptake. There have been reported cases of hemangiomas that demonstrate intense avidity on 68Ga-PSMA PET/CT, used in prostate cancer imaging, probably because PSMA plays a major role in regulating angiogenesis and endothelial cell recruitment, and thus is expressed in hemangiomas. Hemangioma also demonstrates a scintigraphic hot-spot appearance on radiolabeled RBC) studies, with increased sensitivity in lesions at least 1.0 to 1.5 cm because smaller lesions tend to blend into surrounding hepatic tracer uptake because of partial volume averaging associated with the limited spatial resolutions of SPECT. The liver hot-spot appearance on 99mTc-labeled RBC scintigraphy has been described as pathognomonic for a hemangioma; however, there have been case reports with other pathologic entities (e.g., inflammatory adenoma demonstrating a liver hot-spot appearance).

Assessment of Pancreatic Function For more information, see Chapter 3. Clinical research into development of tracer-based PET assays of endocrine and exocrine pancreatic functional mass is ongoing. Diabetes mellitus (both type 1 and type 2) is associated with loss of insulin producing tissue or b-cell mass. Preservation of b-cell mass is being investigated to prevent diabetes progression, and thus a reliable noninvasive biomarker of b-cell mass would be an important aid to diabetes research. A candidate radiotracer of b-cell mass that has been studied includes dihydrotetrabenazine (DTBZ), a novel PET imaging agent,171 which appears promising, but further validation studies are needed before it can be considered for routine clinical practice. Pancreatic exocrine function, which can be impaired postoperatively or with certain diseases (e.g., chronic pancreatitis) is currently measured with invasive direct or noninvasive but lengthy indirect tests (e.g., requiring patient stool collection). Researchers have evaluated pancreatic uptake of the PET radiotracers, such as 11C methionine and 11C acetate, as noninvasive, real-time biomarkers of exocrine pancreatic function.172 These PET assays remain investigational, although preliminary data is encouraging. References are available at expertconsult.com.

308.e1

REFERENCES 1. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427-433. 2. Liu IJ, Lai YM, Espiritu JI, et al. Evaluation of fluorodeoxyglucose positron emission tomography imaging in metastatic transitional cell carcinoma with and without prior chemotherapy. Urol Int. 2006;77(1):69-75. 3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Colon Cancer. Version 3.2020. Available at: https://www.nccn.org/. Accessed June 5, 2020. 4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237-267. 5. Torizuka T, Tamaki N, Inokuma T et al. In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET. J Nucl Med. 1995;36(10)1811-1817. 6. Shiomi S, Nishiguchi S, Ishizu H, et al. Usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose for predicting outcome in patients with hepatocellular carcinoma. Am J Gastroenterol. 2001;96(6):1877-1880. 7. Lee M, Jeon JY, Neugent ML, Kim JW, Yun M. 18F-Fluorodeoxyglucose uptake on positron emission tomography/computed tomography is associated with metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma. Clin Exp Metastasis. 2017; 34(3-4):251-260. 8. Lee JD, Yun M, Lee JM, et al. Analysis of gene expression profiles of hepatocellular carcinomas with regard to 18F-fluorodeoxyglucose uptake pattern on positron emission tomography. Eur J Nucl Med Mol Imaging. 2004;31(12):1621-1630. 9. Lee JW, Hwang SH, Kim DY, Han KH, Yun M. Prognostic value of FDG uptake of portal vein tumor thrombosis in patients with locally advanced hepatocellular carcinoma. Clin Nucl Med. 2017; 42(1):e35-e40. 10. Katyal S, Oliver JH, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216(3):698-703. 11. Lee JE, Jang JY, Jeong SW, et al. Diagnostic value for extrahepatic metastases of hepatocellular carcinoma in positron emission tomography/computed tomography scan. World J Gastroenterol. 2012; 18(23):2979-2987. 12. Lee SM, Kim HS, Lee S, Lee S, Lee JW. Emerging role of 18Ffluorodeoxyglucose positron emission tomography for guiding management of hepatocellular carcinoma. World J Gastroenterol. 2019;25(11):1289-1306. 13. Sugiyama M, Sakahara H, Torizuka T, et al. 18F-FDG PET in the detection of extrahepatic metastases from hepatocellular carcinoma. J Gastroenterol. 2004;39(10):961-968. 14. Hwang KH, Choi DJ, Lee SY, Lee MK, Choe W. Evaluation of patients with hepatocellular carcinomas using [11C]acetate and [18F]FDG PET/CT: a preliminary study. Appl Radiat Isot. 2009; 67(7-8):1195-1198. 15. Yamamoto Y, Nishiyama Y, Kameyama R, et al. Detection of hepatocellular carcinoma using 11C-choline PET: comparison with 18F-FDG PET. J Nucl Med. 2008;49(8):1245-1248. 16. Kesler M, Levine C, Hershkovitz D, et al. 68 Ga-labeled prostatespecific membrane antigen is a novel PET/CT tracer for imaging of hepatocellular carcinoma: a prospective pilot study. J Nucl Med. 2019;60(2):185-191. 17. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(suppl 1):122S-150S. 18. Hatano E, Ikai I, Higashi T, et al. Preoperative positron emission tomography with fluorine-18- fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection. World J Surg. 2006;30:1736-1741. 19. Cho KJ, Choi NK, Shin MH, Chong AR. Clinical usefulness of FDG-PET in patients with hepatocellular carcinoma undergoing surgical resection. Ann Hepatobiliary Pancreat Surg. 2017;21(4):194. 20. Yoh T, Seo S, Ogiso S, et al. Proposal of a new preoperative prognostic model for solitary hepatocellular carcinoma incorporating 18 F-FDG-PET imaging with the ALBI grade. Ann Surg Oncol. 2018;25(2):542-549. 21. Takada Y, Kaido T, Shirabe K, et al. Significance of preoperative fluorodeoxyglucose-positron emission tomography in prediction of

tumor recurrence after liver transplantation for hepatocellular carcinoma patients: a Japanese multicenter study. J Hepatobiliary Pancreat Sci. 2017;24(1):49-57. 22. Yang SH, Suh KS, Lee HW, et al. The role of 18F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl. 2006;12(11): 1655-1660. 23. Lee JW, Paeng JC, Kang KW, et al. Prediction of tumor recurrence by18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med. 2009;50(5):682-687. 24. Song MJ, Bae SH, Lee SW, et al. 18F-Fluorodeoxyglucose PET/ CT predicts tumour progression after transarterial chemoembolization in hepatocellular carcinoma. Eur J Nucl Med Mol Imaging. 2013;40(6):865-873. 25. Hayakawa N, Nakamoto Y, Nakatani K, et al. Clinical utility and limitations of FDG PET in detecting recurrent hepatocellular carcinoma in postoperative patients. Int J Clin Oncol. 2014;19(6): 1020-1028. 26. Wang XY, Yang F, Jin C, Fu DL. Utility of PET/CT in diagnosis, staging, assessment of resectability and metabolic response of pancreatic cancer. World J Gastroenterol. 2014;20(42):15580-15589. 27. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. Version 2.2020. Available at: https://www.nccn.org/. Accessed June 5, 2020. 28. Van Cutsem E, Oliveira J, ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(suppl 4):61-63. 29. Van De Velde CJH, Boelens PG, Borras JM, et al. EURECCA colorectal: multidisciplinary management: European consensus conference colon & rectum. Eur J Cancer. 2014;50(1):1.e1-1.e34. 30. Kemeny NE, Chou JF, Capanu M, et al. KRAS mutation influences recurrence patterns in patients undergoing hepatic resection of colorectal metastases. Cancer. 2014;120(24):3965-3971. 31. Nahas CSR, Akhurst T, Yeung H, et al. Positron emission tomography detection of distant metastatic or synchronous disease in patients with locally advanced rectal cancer receiving preoperative chemoradiation. Ann Surg Oncol. 2008;15(3):704-711. 32. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. 33. Abdel-Nabi H, Doerr RJ, Lamonica DM, et al. Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucose whole-body PET: correlation with histopathologic and CT findings. Radiology. 1998;206(3):755-760. 34. Kinkel K, Lu Y, Both M, Warren RS, Thoeni RF. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology. 2002;224(3):748-756. 35. Even-Sapir E, Lerman H, Figer A, et al. Role of (18)F-FDG dualhead gamma-camera coincidence imaging in recurrent or metastatic colorectal carcinoma. J Nucl Med. 2002;43(5):603-609. 36. Fong Y, Saldinger PF, Akhurst T, et al. Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases. Am J Surg. 1999;178(4):282-287. 37. Ruers TJM, Langenhoff BS, Neeleman N, et al. Value of positron emission tomography with [F-18]fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. J Clin Oncol. 2002;20(2):388-395. 38. Boykin KN, Zibari GB, Lilien DL, McMillan RW, Aultman DF MJ. The use of FDG-positron emission tomography for the evaluation of colorectal metastases of the liver. Am Surg. 1999;65:1183-1185. 39. Lai DTM, Fulham M, Stephen MS, et al. The role of whole-body positron emission tomography with [18F]fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. Arch Surg. 1996;131(7):703-707. 40. Joyce DL, Wahl RL, Patel PV, Schulick RD, Gearhart SL, Choti MA. Preoperative positron emission tomography to evaluate potentially resectable hepatic colorectal metastases. Arch Surg. 2006; 141(12):1220-1226. 41. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg; 2004;240:438-450. 42. Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases a randomized clinical trial. JAMA. 2014;311(18):1863-1869.

308.e2 43. Sobhani I, Tiret E, Lebtahi R, et al. Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer. Br J Cancer. 2008;98(5):875-880. 44. Amorim BJ, Hong TS, Blaszkowsky LS, et al. Clinical impact of PET/MR in treated colorectal cancer patients. Eur J Nucl Med Mol Imaging. 2019;46(11):2260-2269. 45. Lu YY, Chen JH, Chien CR, et al. Use of FDG-PET or PET/CT to detect recurrent colorectal cancer in patients with elevated CEA: a systematic review and meta-analysis. Int J Colorectal Dis. 2013; 28(8):1039-1047. 46. Callahan MK, Kemeny NE. Implanted hepatic arterial infusion pumps. Cancer J. 2010;16(2):142-149. 47. Kaplan WD, D’Orsi CJ, Ensminger WD, Smith EH, Levin DC. Intra-arterial radionuclide infusion: a new technique to assess chemotherapy perfusion patterns. Cancer Treat Rep. 1978;62(5):699-703. 48. Borzutzky CA, Turbiner EH. The predictive value of hepatic artery perfusion scintigraphy. J Nucl Med. 1985;26(10):1153-1156. 49. Sofocleous CT, Schubert J, Kemeny N, et al. Arterial embolization for salvage of hepatic artery infusion pumps. J Vasc Interv Radiol. 2006;17(5):801-806. 50. Wright CL, Werner JD, Tran JM, et al. Radiation pneumonitis following yttrium-90 radioembolization: case report and literature review. J Vasc Interv Radiol. 2012;23(5):669-674. 51. Levillain H, Duran Derijckere I, Marin G, et al. 90Y-PET/CTbased dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer. EJNMMI Res. 2018;8:60. 52. Kennedy A, Coldwell D, Sangro B, Wasan H, Salem R. Radioembolization for the treatment of liver tumors: general principles. Am J Clin Oncol Cancer Clin Trials. 2012;35(1):91-99. 53. Kurilova I, Beets-Tan RGH, Flynn J, et al. Factors affecting oncologic outcomes of 90Y radioembolization of heavily pre-treated patients with colon cancer liver metastases. Clin Colorectal Cancer. 2019;18(1):8-18. 54. Kuehl H, Rosenbaum-Krumme S, Veit-Haibach P, et al. Impact of whole-body imaging on treatment decision to radio-frequency ablation in patients with malignant liver tumors: comparison of [F] fluorodeoxyglucose-PET/computed tomography, PET and computed tomography. Nucl Med Commun. 2008;29(7):599-606. 55. Georgakopoulos A, Pianou N, Kelekis N, Chatziioannou S. Impact of 18F-FDG PET/CT on therapeutic decisions in patients with colorectal cancer and liver metastases. Clin Imaging. 2013;37(3): 536-541. 56. Ryan ER, Sofocleous CT, Schöder H, et al. Split-dose technique for FDG PET/CT-guided percutaneous ablation: a method to facilitate lesion targeting and to provide immediate assessment of treatment effectiveness. Radiology. 2013;268(1):288-295. 57. Vogt FM, Antoch G, Veit P, et al. Morphologic and functional changes in nontumorous liver tissue after radiofrequency ablation in an in vivo model: comparison of18F-FDG PET/CT, MRI, ultrasound, and CT. J Nucl Med. 2007;48(11):1836-1844. 58. Chen W, Zhuang H, Cheng G, Torigian DA, Alavi A. Comparison of FDG-PET, MRI and CT for post radiofrequency ablation evaluation of hepatic tumors. Ann Nucl Med. 2013;27(1):58-64. 59. Nielsen K, Van Tilborg AA, Scheffer HJ, et al. PET-CT after radiofrequency ablation of colorectal liver metastases: suggestions for timing and image interpretation. Eur J Radiol. 2013;82(12):2169-2175. 60. Lamarca A, Barriuso J, Chander A, et al. 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: systematic review and meta-analysis. J Hepatol. 2019;71(1):115-129. 61. Annunziata S, Caldarella C, Pizzuto DA, et al. Diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography in the evaluation of the primary tumor in patients with cholangiocarcinoma: a meta-analysis. Biomed Res Int. 2014;2014:247693. 62. Santhosh S, Mittal BR, Rana SS, et al. Metabolic signatures of malignant and non-malignant mass-forming lesions in the periampulla and pancreas in FDG PET/CT scan: an atlas with pathologic correlation. Abdom Imaging. 2015;40(5):1285-1315. 63. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206(1):57-65. 64. Lee SW, Kim HJ, Park JH, et al. Clinical usefulness of 18F-FDG PET-CT for patients with gallbladder cancer and cholangiocarcinoma. J Gastroenterol. 2010;45(5):560-566.

65. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma. Version 1.2020. Available At: https://www.nccn.org/. Accessed June 5, 2020. 66. Van Kouwen MCA, Jansen JBMJ, Van Goor H, De Castro S, Oyen WJG, Drenth JPH. FDG-PET is able to detect pancreatic carcinoma in chronic pancreatitis. Eur J Nucl Med Mol Imaging. 2005;32(4):399-404. 67. Lemke AJ, Niehues SM, Hosten N et al. Retrospective digital image fusion of multidetector CT and 18F-FDG PET: clinical value in pancreatic lesions–a prospective study with 104 patients. J Nucl Med. 2004;45(8):1279-1286. 68. Lytras D, Connor S, Bosonnet L, et al. Positron emission tomography does not add to computed tomography for the diagnosis and staging of pancreatic cancer. Dig Surg. 2005;22(1-2):55-61. 69. Wu LM, Hu JN, Hua J, Liu MJ, Chen J, Xu JR. Diagnostic value of diffusion-weighted magnetic resonance imaging compared with fluorodeoxyglucose positron emission tomography/computed tomography for pancreatic malignancy: a meta-analysis using a hierarchical regression model. J Gastroenterol Hepatol. 2012;27(6): 1027-1035. 70. Rijkers AP, Valkema R, Duivenvoorden HJ, Van Eijck CHJ. Usefulness of F-18-fluorodeoxyglucose positron emission tomography to confirm suspected pancreatic cancer: a meta-analysis. Eur J Surg Oncol. 2014;40(7):794-804. 71. Yamada Y, Mori H, Matsumoto S, Kiyosue H, Hori Y, Hongo N. Pancreatic adenocarcinoma versus chronic pancreatitis: differentiation with triple-phase helical CT. Abdom Imaging. 2010;35(2): 163-171. 72. Reske SN, Grillenberger KG, Glatting G, et al. Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med. 1997;38(9):1344-1348. 73. Kato K, Nihashi T, Ikeda M, et al. Limited efficacy of 18F-FDG PET/CT for differentiation between metastasis-free pancreatic cancer and mass-forming pancreatitis. Clin Nucl Med. 2013;38(6): 417-421. 74. Kim Y Il, Kim SK, Paeng JC, Lee HY. Comparison of F-18-FDG PET/CT findings between pancreatic solid pseudopapillary tumor and pancreatic ductal adenocarcinoma. Eur J Radiol. 2014;83(1): 231-235. 75. Guan ZW, Xu BX, Wang RM, Sun L, Tian JH. Hyperaccumulation of18F-FDG in order to differentiate solid pseudopapillary tumors from adenocarcinomas and from neuroendocrine pancreatic tumors and review of the literature. Hell J Nucl Med. 2013;16(2): 97-102. 76. Bang S, Chung HW, Park SW, et al. The clinical usefulness of 18-fluorodeoxyglucose positron emission tomography in the differential diagnosis, staging, and response evaluation after concurrent chemoradiotherapy for pancreatic cancer. J Clin Gastroenterol. 2006;40(10):923-929. 77. Chang JS, Choi SE, Lee Y, et al. Clinical usefulness of (1)(8)F-fluorodeoxyglucose-positron emission tomography in patients with locally advanced pancreatic cancer planned to undergo concurrent chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2014;90:126-133. 78. Strobel K, Heinrich S, Bhure U, et al. Contrast-enhanced 18FFDG PET/CT: 1-Stop-shop imaging for assessing the resectability of pancreatic cancer. J Nucl Med. 2008;49(9):1408-1413. 79. Wakabayashi H, Nishiyama Y, Otani T, et al. Role of 18F-fluorodeoxyglucose positron emission tomography imaging in surgery for pancreatic cancer. World J Gastroenterol. 2008;14(1):64-69. 80. Joo I, Lee JM, Lee DH, et al. Preoperative assessment of pancreatic cancer with FDG PET/MR imaging versus FDG PET/CT plus contrast-enhanced multidetector CT: a prospective preliminary study. Radiology. 2017;282(1):149-159. 81. Chen BB, Tien YW, Chang MC, et al. PET/MRI in pancreatic and periampullary cancer: correlating diffusion-weighted imaging, MR spectroscopy and glucose metabolic activity with clinical stage and prognosis. Eur J Nucl Med Mol Imaging. 2016;43(10):1753-1764. 82. Jung W, Jang JY, Kang MJ, et al. The clinical usefulness of 18Ffluorodeoxyglucose positron emission tomography–computed tomography (PET–CT) in follow-up of curatively resected pancreatic cancer patients. HPB (Oxford). 2016;18(1):57-64. 83. Topkan E, Parlak C, Kotek A, Yapar AF, Pehlivan B. Predictive value of metabolic 18FDG-PET response on outcomes in patients with locally advanced pancreatic carcinoma treated with definitive concurrent chemoradiotherapy. BMC Gastroenterol. 2011;11:123.

308.e3 84. Schellenberg D, Quon A, Minn AY, et al. 18Fluorodeoxyglucose pet is prognostic of progression-free and overall survival in locally advanced pancreas cancer treated with stereotactic radiotherapy. Int J Radiat Oncol Biol Phys. 2010;77(5):1420-1425. 85. Maisey NR, Webb A, Flux GD, et al. FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study. Br J Cancer. 2000;83(3):287-293. 86. Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity results of a prospective phase II trial. Ann Surg. 2008;248(6):1014-1021. 87. Ramanathan RK, Goldstein D, Korn RL, et al. Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. Ann Oncol. 27(4):648-653. 88. Sperti C, Pasquali C, Bissoli S, Chierichetti F, Liessi G, Pedrazzoli S. Tumor relapse after pancreatic cancer resection is detected earlier by 18-FDG PET than by CT. J Gastrointest Surg. 2010; 14(1):131-140. 89. Kitajima K, Murakami K, Yamasaki E, et al. Performance of integrated FDG-PET/contrast-enhanced CT in the diagnosis of recurrent pancreatic cancer: comparison with integrated FDGPET/non-contrast-enhanced CT and enhanced CT. Mol Imaging Biol. 2010;12(4):452-459. 90. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4):934-959. 91. Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28(7):836-846. 92. Reubi JC, Landolt AM. High density of somatostatin receptors in pituitary tumors from acromegalic patients. J Clin Endocrinol Metab. 1984;59(6):1148-1151. 93. Virgolini I, Ambrosini V, Bomanji JB, et al. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA- conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTATATE. Eur J Nucl Med Mol Imaging. 2010;37(10):2004-2010. 94. Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB. Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours. Eur J Endocrinol. 2004;151(1):15-27. 95. Mukherjee JJ, Kaltsas GA, Islam N, et al. Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131i-meta-iodobenzylguanidine (131I-mIBG). Clin Endocrinol (Oxf). 2001;55(1):47-60. 96. Deppen SA, Liu E, Blume JD, et al. Safety and efficacy of 68GaDOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med. 2016;57(5): 708-714. 97. Skoura E, Michopoulou S, Mohmaduvesh M, et al. The impact of 68Ga-DOTATATE PET/CT imaging on management of patients with neuroendocrine tumors: experience from a national referral center in the United Kingdom. J Nucl Med. 2016;57(1):34-40. 98. Bertherat J, Tenenbaum F, Perlemoine K, et al. Somatostatin Receptors 2 and 5 are the major somatostatin receptors in insulinomas: an in Vivo and in Vitro study. J Clin Endocrinol Metab. 2003;88(11):5353-5360. 99. Nockel P, Babic B, Millo C, et al. Localization of insulinoma using 68Ga-DOTATATE PET/CT scan. J Clin Endocrinol Metab. 2017;102(1):195-199. 100. Tuzcu SA, Pekkolay Z, Kilin√ß F, Tuzcu AK. 68Ga-DOTATATE PET/CT can be an alternative imaging method in insulinoma patients. J Nucl Med Technol. 2017;45(3):198-200. 101. Hope TA, Pampaloni MH, Nakakura E, et al. Simultaneous 68Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor. Abdom Imaging. 2015;40(6): 1432-1440. 102. Beiderwellen KJ, Poeppel TD, Hartung-Knemeyer V, et al. Simultaneous 68Ga-DOTATOC PET/MRI in patients with gastroenteropancreatic neuroendocrine tumors: initial results. Invest Radiol. 2013;48(5):273-279. 103. Klinaki I, Al-Nahhas A, Soneji N, Win Z. 68Ga DOTATATE PET/CT uptake in spinal lesions and MRI correlation on a patient with neuroendocrine tumor: potential pitfalls. Clin Nucl Med. 2013;38(12):e449-e453.

104. Kwekkeboom DJ, Kam BL, Van Essen M, et al. Somatostatinreceptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17(1): R53-R73. 105. Wester HJ, Schottelius M, Scheidhauer K, Reubi JC, Wolf I, Schwaiger M. Comparison of radioiodinated TOC, TOCA and Mtr-TOCA: the effect of carbohydration on the pharmacokinetics. Eur J Nucl Med. 2002;29(1):28-38. 106. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177 Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. 107. Bodei L, Cremonesi M, Zoboli S, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. Eur J Nucl Med Mol Imaging. 2003;30(2):207-216. 108. Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET – Full Text View – ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/ NCT03972488. Accessed June 4, 2020. 109. Claringbold PG, Turner JH. Pancreatic neuroendocrine tumor control: durable objective response to combination 177Lu-octreotate-capecitabine-temozolomide radiopeptide chemotherapy. Neuroendocrinology. 2016;103(5):432-439. 110. Barber TW, Hofman MS, Thomson BNJ, Hicks RJ. The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable. Eur J Surg Oncol. 2012;38(1):64-71. 111. Ballal S, Yadav MP, Damle NA, Sahoo RK, Bal C. Concomitant 177Lu-DOTATATE and capecitabine therapy in patients with advanced neuroendocrine tumors: a long-term-outcome, toxicity, survival, and quality-of-life study. Clin Nucl Med. 2017;42(11): e457-e466. 112. Claringbold PG, Turner JH. Neuroendocrine tumor therapy with lutetium-177-octreotate and everolimus (NETTLE): a phase I study. Cancer Biother Radiopharm. 2015;30(6):261-269. 113. Ginj M, Zhang H, Waser B, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci USA. 2006;103(44): 16436-16441. 114. Hanyaloglu AC, von Zastrow M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol. 2008;48(1):537-568. 115. Wang X, Fani M, Schulz S, Rivier J, Reubi JC, Maecke HR. Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy. Eur J Nucl Med Mol Imaging. 2012;39(12):1876-1885. 116. Wild D, Fani M, Behe M, et al. First clinical evidence that imaging with somatostatin receptor antagonists is feasible. J Nucl Med. 2011;52(9):1412-1417. 117. Wild D, Fani M, Fischer R, et al. Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study. J Nucl Med. 2014;55(8):1248-1252. 118. Reidy-Lagunes D, Pandit-Taskar N, O’Donoghue JA, et al. Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist 177lu-satoreotide tetraxetan. Clin Cancer Res. 2019;25(23):6939-6947. 119. Krebs S, O’Donoghue JA, Biegel E, et al. Comparison of 68GaDOTA-JR11 PET/CT with dosimetric 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2020;47(13):3047-3057. 120. Fani M, Nicolas GP, Wild D. Somatostatin receptor antagonists for imaging and therapy. J Nucl Med. 2017;58(suppl 2):61S66S. 121. Nicolas GP, Morgenstern A, Schottelius M, Fani M. New developments in peptide receptor radionuclide therapy. J Nucl Med. 2019;60(2):167-171. 122. Hirschfield GM, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni MCS. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67:145-172. 123. Bhargava KK, Joseph B, Ananthanarayanan M, et al. Adenosine triphosphate-binding cassette subfamily C member 2 is the major transporter of the hepatobiliary imaging agent99mTc-mebrofenin. J Nucl Med. 2009;50(7):1140-1146.

308.e4 124. Tulchinsky M, Ciak BW, Delbeke D, et al. SNM practice guideline for hepatobiliary scintigraphy 4.0. J Nucl Med Technol. 2010; 38(4):210-218. 125. Kwatra N, Shalaby-Rana E, Narayanan S, Mohan P, Ghelani S, Majd M. Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center. Pediatr Radiol. 2013;43(10):1365-1375. 126. Mesgarzadeh M, Krishnamurthy GT, Bobba VR, Langrell K. Filling, postcholecystokinin emptying, and refilling of normal gallbladder: effects of two different doses of CCK on refilling: concise communication. J Nucl Med. 1983;24(8):666-671. 127. Patch GG, Morton KA, Arias JM, Datz FL. Naloxone reverses pattern of obstruction of the distal common bile duct induced by analgesic narcotics in hepatobiliary imaging. J Nucl Med. 1991; 32(6):1270-1272. 128. Kim CK, Palestro CJ, Solomon RW, Molinari DS, Lee SO, Goldsmith SJ. Delayed biliary-to-bowel transit in cholescintigraphy after cholecystokinin treatment. Radiology. 1990;176:553-556. 129. Ziessman HA. Hepatobiliary scintigraphy in 2014. J Nucl Med Technol. 2014;42(4):249-259. 130. Kaoutzanis C, Davies E, Leichtle SW, et al. Abdominal ultrasound versus hepato-imino diacetic acid scan in diagnosing acute cholecystitis – What is the real benefit? J Surg Res. 2014;188(1):44-52. 131. Gracie WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Engl J Med. 1982; 307(13):798-800. 132. Raymond F, Lepanto L, Rosenthall L, Fried GM. Tc-99m-IDA gallbladder kinetics and response to CCK in chronic cholecystitis. Eur J Nucl Med. 1988;14(7-8):378-381. 133. Ziessman HA. Acute cholecystitis, biliary obstruction, and biliary leakage. Semin Nucl Med. 2003;33(4):279-296. 134. Drane WE, Johnson DA. Sincalide-augmented quantitative hepatobiliary scintigraphy (QHBS): definition of normal parameters and preliminary relationship between QHBS and sphincter of Oddi (SO) manometry in patients suspected of having SO dysfunction. J Nucl Med. 1990;31(9):1462-1468. 135. Williams W, Krishnamurthy GT, Brar HS, Bobba VR. Scintigraphic variations of normal biliary physiology. J Nucl Med. 1984; 25(2):160-165. 136. Macaron C, Qadeer MA, Vargo JJ. Recurrent abdominal pain after laparoscopic cholecystectomy. Cleve Clin J Med. 2011;78(3): 171-178. 137. Jaunoo SS, Mohandas S, Almond LM. Postcholecystectomy syndrome (PCS). Int J Surg. 2010;8(1):15-17. 138. Bar-Meir S, Halpern Z, Bardan E, Gilat T. Frequency of papillary dysfunction among cholecystectomized patients. Hepatology. 1984; 4(2):328-330. 139. Baillie J. Sphincter of oddi dysfunction. Curr Gastroenterol Rep. 2010;12(2):130-134. 140. Hogan WJ, Geenen JE. Biliary dyskinesia. Endoscopy. 1988; 20(suppl 1):179-183. 141. Sostre S, Kalloo AN, Spiegler EJ, Camargo EE, Wagner Jr HN. A noninvasive test of sphincter of Oddi dysfunction in postcholecystectomy patients: the scintigraphic score. J Nucl Med. 1992; 33(6)1216-1222. 142. Cicala M, Scopinaro F, Corazziari E, et al. Quantitative cholescintigraphy in the assessment of choledochoduodenal bile flow. Gastroenterology. 1991;100(4):1106-1113. 143. Cicala M, Habib FI, Vavassori P, et al. Outcome of endoscopic sphincterotomy in post cholecystectomy patients with sphincter of Oddi dysfunction as predicted by manometry and quantitative choledochoscintigraphy. Gut. 2002;50(5):665-668. 144. Tantia O, Jain M, Khanna S, Sen B. Iatrogenic biliary injury: 13,305 Cholecystectomies experienced by a single surgical team over more than 13 years. Surg Endosc. 2008;22(4):1077-1086. 145. Kim J, Moon D, Lee S, et al. The usefulness of hepatobiliary scintigraphy in the diagnosis of complications after adult-to-adult living donor liver transplantation. Eur J Nucl Med. 2002;29(4):473-479. 146. Kurzawinski TR, Selves L, Farouk M, et al. Prospective study of hepatobiliary scintigraphy and endoscopic cholangiography for the detection of early biliary complications after orthotopic liver transplantation. Br J Surg. 1997;84(5):620-623. 147. Gelfand MJ, Smith HS, Ryckman FC, et al. Hepatobiliary scintigraphy in pediatric liver transplant recipients. Clin Nucl Med. 1992;17(7):542-549.

148. Brunot B, Petras S, Germain P, Vinee P, Constantinesco A. Biopsy and quantitative hepatobiliary scintigraphy in the evaluation of liver transplantation. J Nucl Med. 1994;35(8):1321-1327. 149. Schwartz HP, Haberman BE, Ruddy RM. Hyperbilirubinemia: current guidelines and emerging therapies. Pediatr Emerg Care. 2011;27(9):884-889. 150. Nadel HR. Hepatobiliary scintigraphy in children. Semin Nucl Med. 1996;26(1):25-42. 151. Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr. 2003;37(1):4-21. 152. Davenport M. A challenge on the use of the words embryonic and perinatal in the context of biliary atresia. Hepatology. 2005; 41(2):403-404. 153. Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res. 2005;57(5):87R-94R. 154. Kianifar HR, Tehranian S, Shojaei P, et al. Accuracy of hepatobiliary scintigraphy for differentiation of neonatal hepatitis from biliary atresia: systematic review and meta-analysis of the literature. Pediatr Radiol. 2013;43(8):905-919. 155. Sevilla A, Howman-Giles R, Saleh H, et al. Hepatobiliary scintigraphy with SPECT in infancy. Clin Nucl Med. 2007;32(1):16-23. 156. Rutland MD. Correlation of splenic function with the splenic uptake rate of Tc-colloids. Nucl Med Commun. 1992;13(11):843-847. 157. Esmaili J, Gholamrezanezhad A, Ebizadeh A. Correlation of liverspleen scan findings with modified Child-Pugh classification. Rev Esp Med Nucl. 2008;27(2):99-102. 158. Oppenheim BE, Wellman HN, Hoffer PB. Liver imaging. In: Gottschalk A, Hoffer PB, Potchen EJ, eds. Diagnostic Nuclear Medicine. Williams & Wilkins; 1988. 159. Herman P, Pugliese V, Machado MAC, et al. Hepatic adenoma and focal nodular hyperplasia: differential diagnosis and treatment. World J Surg. 2000;24(3):372-376. 160. Shamsi K, De Schepper A, Degryse H, Deckers F. Focal nodular hyperplasia of the liver: radiologic findings. Abdom Imaging. 1993;18(1):32-38. 161. Bhutiani N, Egger ME, Doughtie CA, et al. Intrapancreatic accessory spleen (IPAS): a single-institution experience and review of the literature. Am J Surg. 2017;213(4):816-820. 162. Kim SH, Lee JM, Han JK, et al. Intrapancreatic accessory spleen: findings on MR imaging, CT, US and scintigraphy, and the pathologic analysis. Korean J Radiol. 2008;9(2):162-174. 163. Lancellotti F, Sacco L, Cerasari S, et al. Intrapancreatic accessory spleen false positive to 68Ga-Dotatoc: case report and literature review. World J Surg Oncol. 2019;17(1):117. 164. Brasca LE, Zanello A, De Gaspari A, et al. Intrapancreatic accessory spleen mimicking a neuroendocrine tumor: magnetic resonance findings and possible diagnostic role of different nuclear medicine tests. Eur Radiol. 2004;14(7):1322-1323. 165. Collarino A, Del Ciello A, Perotti G, Rufini V. Intrapancreatic accessory spleen detected by 68Ga DOTANOC PET/CT and 99mTc-colloid SPECT/CT scintigraphy. Clin Nucl Med. 2015; 40(5):415-418. 166. Gore RM, Pickhardt PJ, Mortele KJ, et al. Management of incidental liver lesions on CT: a white paper of the ACR Incidental Findings Committee. J Am Coll Radiol. 2017;14(11):1429-1437. 167. American College of Radiology. ACR Appropriateness Criteria. Liver lesion-initial characterization. Available at: https://www.acr. org/Clinical-Resources/ACR-Appropriateness-Criteria. Accessed June 5, 2020. 168. Chung EM, Cube R, Lewis RB, Conran RM. From the archives of the AFIP: pediatric liver masses: radiologic-pathologic correlation part 1. Benign tumors. Radiographics. 2010;30(3):801-826. 169. Boulahdour H, Cherqui D, Charlotte F, et al. The hot spot hepatobiliary scan in focal nodular hyperplasia. J Nucl Med. 1993; 34(12):2105-2110. 170. Kurtaran A, Becherer A, Pfeffel F, et al. 18F-flurodeoxyglucose (FDG)-PET features of focal nodular hyperplasia (FNH) of the liver. Liver. 2000;20(6):487-490. 171. Blomberg BA, Eriksson O, Saboury B, Alavi A. b-cell mass imaging with dtbz positron emission tomography: Is it possible? Mol Imaging Biol. 2013;15(1):1-2. 172. Hyun O J, Lodge MA, Jagannath S, Buscaglia JM, Olagbemiro Y, Wahl RL. An exocrine pancreatic stress test with11C-acetate PET and secretin stimulation. J Nucl Med. 2014;55(7):1128-1131.

CHAPTER 19 Emerging techniques in diagnostic imaging Richard Kinh Gian Do The field of radiology has undergone tremendous growth over recent decades, with continuous advances in diagnostic imaging that include innovations in medical devices, such as the creation of dual energy–source multidetector computed tomography (CT); innovations in imaging agents, such as new hepatocyte-specific gadolinium (Gd)-binding contrast agents for magnetic resonance imaging (MRI); increases in use of functional imaging, such as for magnetic resonance (MR) diffusionweighted imaging, and innovations in image analysis tools, such as texture analysis, as well as the application of deep learning/ artificial intelligence. In this chapter, we will review a few emerging techniques in diagnostic imaging with relevance to hepatopancreatobiliary tumors.

DUAL-ENERGY COMPUTED TOMOGRAPHY Medical imaging with CT has benefited from the development of multidetector technology, leading to faster scanning of the abdomen with higher-resolution images, resulting in submillimeter isotropic image voxels that allow for multiplanar reformatting and three-dimensional volume rendering (see Chapter 13). New dose modulation techniques have also reduced the radiation dose exposure for patients. An exciting innovative technique in CT imaging relevant to hepatopancreatobiliary tumors is dual-energy CT (DECT).1,2 T   o understand the utility of DECT, a few physical principles underlying CT imaging are worth reviewing. CT is based on the application of x-rays, which represent electromagnetic waves (photons) of very high energy and very short wavelengths that can pass through most objects, allowing us to “see” through the body. The degree of x-ray attenuation by different elements in our body is proportional to the number of electrons present. The higher the atomic number of an element, the greater the number of electrons present that can interact with x-rays. Put simply, x-rays will be more frequently scattered or absorbed by the photoelectric effect when they travel through bones, which are high in calcium atoms (Ca20), than when traveling through other soft tissues made predominantly of hydrogen (H1), carbon (C6), nitrogen (N7), and oxygen (O8), which are lower in atomic number. The density of atoms present is another factor contributing to x-ray attenuation; lungs are radiolucent (dark) on plain film and CT because of the much lower density of atoms (and electrons) present in the air within the lungs. On the other hand, the use of iodinated contrast agents in contrast-enhanced CT (CECT) is partly based on the high attenuation of iodine (I53), which can more easily scatter and absorb x-rays because of the higher number of electrons, thereby making vessels and enhancing organs brighter than surrounding tissues. With single energy (or routine) CT, the x-rays are generated from accelerating electrons in a x-ray tube subject to a peak voltage, kVp, with a predictable energy spectrum of the emitted x-rays. The addition of a second x-ray beam with a different kVp allows us to create CT images based not only on electron

density but also on the concentration of distinct elements present in the body. DECT thus takes advantage of the “signature” x-ray interaction profile of distinct elements, such as calcium (Ca20) and iodine (I53). The potential applications of DECT are numerous but are primarily separated into two functions. The first is in changing the image contrast, such as by increasing the conspicuity of tumors that enhance using iodinated contrast. At lower x-ray energy, the attenuation of iodinated contrast is magnified compared with other elements in soft tissue, which can alter the conspicuity of subtle enhancing lesions. Potential applications include improving hepatocellular carcinoma (HCC) detection3 (see Chapter 89), liver metastasis detection4 (see Chapters 90–92), and pancreatic cancer or pancreatitis detection5,6 (Fig. 19.1; see Chapters 55–59, 62). A second application of DECT relies on the quantification of specific elements, such as calcium or iodine. Quantifying iodine can improve our ability to measure treatment response, such as in therapies in which tumor vascularization (and enhancement) is affected and changes in tumor attenuation are informative.7 Fat quantification, in patients at risk for hepatic steatosis, for example, is also another potential application of this technique.8 Although DECT is gaining in popularity as the applications multiply, a number of obstacles remain, including standardization and differences in hardware and software between vendors.9 Nevertheless, the potential quantification of certain elements by DECT, including iodine uptake, is attractive to radiologists who are increasingly exploring quantitative tools in medical imaging.

FUNCTIONAL IMAGING WITH MAGNETIC RESONANCE IMAGING The similarities between MRI and CT are evident: cross-sectional high-resolution imaging of abdominal organs, using intravenous (IV) contrast to highlight differences in enhancement. Analogous to advances in CT, progress in MRI technology has benefited from hardware upgrades generating more rapid and higher-resolution images. The added value for MRI over CT, however, comes from the ability to image patients without the risk of ionizing radiation and from exploiting new soft tissue contrast mechanisms (see Chapters 13–17). MRI is based on the principles of nuclear magnetic resonance (NMR), which harnesses the inherent magnetic properties of protons (H1) and their electromagnetic interactions. For example, tissue contrast can be generated from differences in chemical environment that affect tissue relaxivity (e.g., T1- vs. T2-weighted imaging), differences in microscopic and macroscopic motion (e.g., diffusion-weighted imaging [DWI] and vascular flow-sensitive imaging), electromagnetic environment (e.g., susceptibility imaging), and many others. The soft tissue contrast mechanisms generated by MRI are numerous and growing, with new sequences exploiting different biologic states 309

310

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C

D

FIGURE 19.1  Computed tomography (CT) images of a patient with infiltrative hepatocellular carcinoma obtained by dual-source dual-energy CT. Arterial phase (A and B) and portal venous phase images (C and D) on liver windows demonstrate an ill-defined right posterior hepatic mass with arterial phase hyper enhancement, better appreciated on the arterial phase of lower (60) KEV images (A) than traditional higher (77) KEV images (B). At a lower KEV (A and C), image noise is increased compared with higher KEV images (C and D).

(e.g., oxygenation of hemoglobin) being developed continuously. Two applications of MRI that emphasize function (and not just form) are dynamic contrast-enhanced MRI (DCEMRI) and diffusion-weighted MR imaging (DWI or DW-MRI). DCE-MRI is a technique that noninvasively characterizes the vasculature of organs and tumors and has the potential to provide predictive or prognostic response biomarkers in multiple cancers.10 Tumor response to chemotherapy has traditionally been assessed by measurements of tumor size, such as through guidelines from the Response Assessment Criteria in Solid Tumors. With cytotoxic therapies, response is measured by the magnitude of tumor reduction in size. Because new targeted therapies may inhibit vascularization or act as cytostatic agents, however, traditional response criteria based on tumor shrinkage may underestimate therapeutic effectiveness. With DCE-MRI,

calculations of tumor vascularity are used to better predict tumor response to antiangiogenic or targeted therapy. DCE-MRI is based on the repeated imaging of an organ or body part during several minutes, during which the initial uptake and subsequent distribution of IV administered contrast are recorded (Fig. 19.2). Although DCE-CT is also technically feasible, the increased ionizing radiation associated with obtaining multiple CT images has limited its development. With MRI, the arrival and distribution of Gd contrast throughout the vasculature and interstitial space is continuously imaged, and through pharmacokinetic modeling, the changes in signal intensity of an organ (or tumor) of interest are converted into perfusion parameters.11 Quantitative perfusion parameters obtained from DCEMRI reflect the rate of exchange of Gd from vessels to the interstitial space and include Ktrans, a volume transfer constant

  Chapter 19  Emerging Techniques in Diagnostic Imaging

311

FIGURE 19.2  Consecutive oblique coronal magnetic resonance images (MRI) were obtained of the abdomen every 5 seconds, before (first panel, top left) and immediately after intravenous contrast administration. Contrast can be seen arriving in the abdominal aorta (middle panel, top row), before enhancing the periphery of the right hepatic lobe peripheral cholangiocarcinoma, on subsequent frames. The entire tumor was imaged during this dynamic contrast-enhanced MRI sequence, with only a single representative slice through the middle of the tumor shown at various time points.

between blood plasma or vascular space (VS) and extracellular extravascular space (EES); kep, the rate constant between EES and VS; and ve, the fractional vascular volume. These perfusion parameters were initially applied for evaluation of antiangiogenic therapy, but their use has expanded to other targeted chemotherapy agents. Although there has been an increasing number of studies evaluating the utility of DCE-MRI in hepatobiliary tumors,12,13 the imaging protocols for DCE-MRI have differed among medical centers, limiting comparison of studies

and clinical adoption of this technique. Efforts are ongoing to reduce the variability and improve standardization of imaging parameters by the Quantitative Imaging Biomarker Alliance, formed by the Radiological Society of North America. An extension of DCE-MRI that is unique to liver imaging is the use of hepatobiliary contrast agents to simultaneously assess vascular supply (through both the hepatic artery and portal vein) as well as hepatic function.14 Although the majority of MR contrast agents containing Gd are excreted through the

312

PART 2  DIAGNOSTIC TECHNIQUES

kidneys and are predominantly limited to the vascular and extracellular space in distribution, gadoxetate disodium (GdEOB-DTPA) also undergoes uptake by hepatocytes and gets excreted through the biliary tree. Thus it is often referred to as a dual-function contrast agent, allowing the evaluation of both tumor and liver parenchymal enhancement in the same study.15 DWI is an alternative and complementary functional imaging technique to DCE-MRI that can help predict and monitor tumor response to therapy.16–18 With DWI, one can measure the apparent diffusion coefficients (ADCs), which provide an estimate of the magnitude of water diffusion in biologic tissues. When ADC is measured in tumors, it provides an indirect measure of tumor cellularity at baseline and necrosis after treatment. There is an inverse relationship between ADC and tumor cellularity, which is explained by the presence of cell membranes in proliferating tumors, which act as barriers to water motion. Thus rapidly growing tumors with smaller diving cells will be lower in ADC. Most treatments will lead to disruptions of cell membrane integrity, resulting in greater water diffusion and subsequent increases in ADC. In HCC19 and colorectal liver metastases,20,21 ADC can be used to assess response to chemoembolization and chemotherapy, respectively. A study using DWI to monitor HCC response to sorafenib is also promising.22 As an indirect measure of tumor cellularity and necrosis, DWI is ideally suited as a biomarker to assess therapy response. Similar to DCE-MRI, clinical adoption of DWI for hepatopancreatobiliary tumors will depend on further standardization of ADC measurements, a challenge that is not trivial because of field inhomogeneity and motion inherent to the upper abdomen, given its proximity to the lungs and heart, as well as from interspersed small and large bowel containing gas.

DIAGNOSTIC CRITERIA Although functional imaging techniques such as DCE-MRI and DWI are quantitative methods to measure tumor properties, the majority of diagnostic radiology still relies on the subjective interpretations of images. For example, CT and MRI have a critical role in the initial assessment of hepatobiliary lesions, such as in the characterization of a solitary liver mass that is incidentally discovered. A hypervascular solitary tumor may represent a benign neoplasm (e.g., focal nodular hyperplasia), a tumor with malignant potential (e.g., hepatocellular adenoma), or a primary malignancy, such as HCC. The temporal pattern of tumor enhancement, the heterogenous appearance of the tumor, and the conspicuity of the tumor with respect to the adjacent liver parenchyma on different MRI sequences are a few of the imaging features used by interpreting radiologists as diagnostic clues. Although CT and MRI techniques may be standardized across different medical centers, the variability in imaging interpretation between different radiologists can remain substantial. Thus an emerging body of research has focused on the diagnostic performance of radiologists. One of the criticisms of early retrospective studies that report on the accuracy of imaging modalities for different clinical questions has been the use of consensus interpretation among expert readers.23 Individual interpretation, rather than consensus interpretation, is the norm in routine clinical practice. The referring clinician is thus dependent on the training and expertise of the diagnostic radiologist who is assigned to interpret their patient’s imaging study at a particular point in time.

A method to reduce the potential variability among diagnostic radiologists is the establishment of diagnostic imaging criteria. For example, multiple criteria for the diagnosis of HCC have been published by various societies in different countries.24 The role of imaging diagnosis for HCC is unique in its potential impact in patient care, guiding the choice of treatment and even affecting the allocation of liver transplants. The American College of Radiology (ACR) first released a set of guidelines for the diagnosis of HCC termed the Liver Imaging Reporting and Data System (LI-RADS) in 201325 (see Chapter 89). LI-RADS has been regularly updated to incorporate new literature over time (http://www.acr.org/quality-safety/resources/LIRADS), and in 2018, LI-RADS was adopted into the American Association from the Study of Liver Diseases (AASLD) clinical practice guidance for HCC.26 At the core of the LI-RADS diagnostic criteria are the definitions of major imaging features, such as arterial phase hyperenhancement, washout appearance, and capsule, which are used to make a definitive diagnosis of HCC. The concept of washout on CT and MRI is straightforward, described as decreased enhancement in a lesion when compared with the liver parenchyma after initial enhancement on the arterial phase. With LI-RADS, the suggestion is to recognize this finding only when it is unequivocally present. The possibility that different radiologists may interpret “washout appearance” with some variability was well known.27 In fact, a large interobserver variability study since the first release of LIRADS demonstrated that there was only moderate agreement between radiologists for the detection of “washout appearance.”28 The agreement for the definitive diagnosis of HCC based on imaging criteria for LI-RADS, AASLD, and Organ Procurement and Transplantation Network (OPTN) guidelines was also moderate to substantial at best. Thus, despite efforts at standardization with the development of diagnostic guidelines, variability in the performance of diagnostic radiologists can remain substantial in specific clinical scenarios and a source of uncertainty for clinical management. Further efforts to reduce this variability may come in the form of accreditation programs, similar to that required for breast imagers through the ACR Mammography Accreditation Program and the federal Mammography Quality Standards Act. These studies are important acknowledgments of the variability inherent in diagnostic imaging that extend beyond the imaging techniques themselves.

RADIOMICS Variability in the interpretation of medical imaging partly stems from the inherent subjectivity of visual assessments performed by diagnostic radiologists. One method to reduce this variability will come from the use of computer software to aid in the interpretation of medical images and the quantification of imaging features. Radiomics is a growing field of study, with a focus on improving image analysis through the extraction of large amounts of advanced quantitative features of medical images, through automatic or semiautomatic software that can provide more and better information than a physician.29 The quantification of imaging features can include the description of tumor enhancement at the individual pixel level on CT or MRI, the measurement of tumor heterogeneity by texture analysis, the description of tumor border with respect to the surrounding organ, and many others. The features that are reproducible and most informative are then analyzed for their relationship with treatment outcomes or gene expression (i.e., radiogenomics). An underlying hypothesis for radiomics is that

  Chapter 19  Emerging Techniques in Diagnostic Imaging

A

313

B

FIGURE 19.3  Example of textural differences in liver parenchyma on computed tomography images from two patients (A and B). Sample with magnified rectangular regions of interest demonstrate greater heterogeneity in the second patient (B) than the first patient (A), which can be quantified by texture parameters.

genomic and proteomic data from malignancies can be represented in macroscopic image-based features and is correlated to tumor heterogeneity on medical images. Until recently, the heterogeneity of tumors on imaging was commonly observed but seldom assessed qualitatively by diagnostic radiologists or quantitatively by computer software. Tumor heterogeneity observed on imaging has the potential to reflect molecular and cellular dynamics that may be specific to individual patients and may be predictive of response to targeted therapies that are increasingly in use.30 Gatenby and colleagues propose that heterogeneity in tumor enhancement is based on perfusion deficits, which can generate significant microenvironmental selection pressures, and that adaptive response to heterogeneity can lead to the emergence of genetic variations within tumors. Quantifying tumor heterogeneity on imaging, to uncover differences in genetic background of individual tumors, can thus form the basis for patient-specific therapies in cancer treatment. Tumor heterogeneity in medical images can be investigated by texture analysis, defined as the measurement of variations in pixel intensity levels (i.e., gray-scale level) as a function of space. Thus, rather than subjective visual assessment of tumor heterogeneity, one can provide quantitative measures of heterogeneity based on accepted texture parameters, such as contrast, entropy, and other higher-order statistics (Fig. 19.3). Radiomics studies in multiple cancers and hepatopancreatobiliary tumors in particular have increased in recent years.31 In pancreas cancer, for example, tumor radiomics on CT images are associated with genotype and stromal content, which may help select patients for upfront surgery versus neoadjuvant therapy.32 Preoperative evaluation of HCC radiomics also shows potential in identifying microvascular invasion.33 Texture analysis is not limited to the analysis of tumors. During the development of liver cirrhosis, the liver acquires a characteristic nodular contour, and the liver parenchyma also

develops a heterogeneous appearance with an increasingly reticular enhancement pattern. A number of studies have investigated the potential of texture analysis to quantify liver fibrosis by MRI.34,35 Texture analysis of liver parenchyma also has the potential to predict liver failure after major hepatic resection and predict recurrence of liver metastases.36,37 A criticism of radiomics and texture analysis is the potential lack of reproducibility in texture features generated from computer algorithms.38,39 An alternative approach to analyzing medical imaging without relying on texture analysis is the use of machine learning (ML) techniques. This approach usually requires very large data sets of images, and early studies show potential applications in multiple settings, such as in the diagnosis of liver tumors40 or the application of LI-RADS categories for patients at risk for HCC.41 Further multi-institutional studies are needed to generate sufficiently large validation studies before clinical use.

SUMMARY The field of radiology has undergone tremendous progress in recent decades, with continual investments in imaging technologies to produce more rapid and higher-resolution scanning. Novel imaging devices, contrast agents, and functional techniques continue to emerge and provide improvements in biologic insight for medical decision making. Nevertheless, the variability inherent to imaging technique and diagnostic radiologists themselves can affect the diagnostic performance of an imaging study and is increasingly the subject of investigation. This acknowledgment is leading to the emergence of standardization in radiologic reports and image acquisition parameters, as well as greater interest in the use of computer-based image analyses. References are available at expertconsult.com

313.e1

REFERENCES 1. Coursey CA, Nelson RC, Boll DT, et al. Dual-energy multidetector CT: how does it work, what can it tell us, and when can we use it in abdominopelvic imaging? Radiographics. 2010;30(4):1037-1055. 2. Heye T, Nelson RC, Ho LM, Marin D, Boll DT. Dual-energy CT applications in the abdomen. AJR Am J Roentgenol. 2012;199 (suppl 5):S64-S70. 3. Altenbernd J, Heusner TA, Ringelstein A, Ladd SC, Forsting M, Antoch G. Dual-energy-CT of hypervascular liver lesions in patients with HCC: investigation of image quality and sensitivity. Eur Radiol. 2011;21(4):738-743. 4. Robinson E, Babb J, Chandarana H, Macari M. Dual source dual energy MDCT: comparison of 80 kVp and weighted average 120 kVp data for conspicuity of hypo-vascular liver metastases. Invest Radiol. 2010;45(7):413-418. 5. Macari M, Spieler B, Kim D, et al. Dual-source dual-energy MDCT of pancreatic adenocarcinoma: initial observations with data generated at 80 kVp and at simulated weighted-average 120 kVp. AJR Am J Roentgenol. 2010;194(1):W27-W32. 6. Martin SS, Trapp F, Wichmann JL, et al. Dual-energy CT in early acute pancreatitis: improved detection using iodine quantification. Eur Radiol. 2019;29(5):2226-2232. 7. Uhrig M, Sedlmair M, Schlemmer HP, Hassel JC, Ganten M. Monitoring targeted therapy using dual-energy CT: semi-automatic RECIST plus supplementary functional information by quantifying iodine uptake of melanoma metastases. Cancer Imaging. 2013;13(3):306-313. 8. Hur BY, Lee JM, Hyunsik W, et al. Quantification of the fat fraction in the liver using dual-energy computed tomography and multimaterial decomposition. J Comput Assist Tomogr. 2014;38(6):845-852. 9. Morgan DE. Dual-energy CT of the abdomen. Abdom Imaging. 2014;39(1):108-134. 10. Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol. 2006;24(20):3293-3298. 11. Do RK, Rusinek H, Taouli B. Dynamic contrast-enhanced MR imaging of the liver: current status and future directions. Magn Reson Imaging Clin N Am. 2009;17(2):339-349. 12. Konstantinidis IT, Do RK, Gultekin DH, et al. Regional chemotherapy for unresectable intrahepatic cholangiocarcinoma: a potential role for dynamic magnetic resonance imaging as an imaging biomarker and a survival update from two prospective clinical trials. Ann Surg Oncol. 2014;21(8):2675-2683. 13. Taouli B, Johnson RS, Hajdu CH, et al. Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI. AJR Am J Roentgenol. 2013;201(4):795-800. 14. Sourbron S, Sommer WH, Reiser MF, Zech CJ. Combined quantification of liver perfusion and function with dynamic gadoxetic acid-enhanced MR imaging [published correction appears in Radiology. 2012;264(3):920]. Radiology. 2012;263(3):874-883. 15. Sirlin CB, Hussain HK, Jonas E, et al. Consensus report from the 6th International forum for liver MRI using gadoxetic acid. J Magn Reson Imaging. 2014;40(3):516-529. 16. Hamstra DA, Rehemtulla A, Ross BD. Diffusion magnetic resonance imaging: a biomarker for treatment response in oncology. J Clin Oncol. 2007;25(26):4104-4109. 17. Padhani AR, Liu G, Koh DM, et al. Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia. 2009;11(2):102-125. 18. Thoeny HC, Ross BD. Predicting and monitoring cancer treatment response with diffusion-weighted MRI. J Magn Reson Imaging. 2010; 32(1):2-16. 19. Chapiro J, Wood LD, Lin M, et al. Radiologic-pathologic analysis of contrast-enhanced and diffusion-weighted MR imaging in patients with HCC after TACE: diagnostic accuracy of 3D quantitative image analysis. Radiology. 2014;273(3):746-758. 20. Cui Y, Zhang XP, Sun YS, Tang L, Shen L. Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. Radiology. 2008;248(3):894-900.

21. Koh DM, Scurr E, Collins D, et al. Predicting response of colorectal hepatic metastasis: value of pretreatment apparent diffusion coefficients. AJR Am J Roentgenol. 2007;188(4):1001-1008. 22. Schraml C, Schwenzer NF, Martirosian P, et al. Diffusionweighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009; 193(4):W301-W307. 23. Bankier AA, Levine D, Halpern EF, Kressel HY. Consensus interpretation in imaging research: Is there a better way? Radiology. 2010;257(1):14-17. 24. Cruite I, Tang A, Sirlin CB. Imaging-based diagnostic systems for hepatocellular carcinoma. AJR Am J Roentgenol. 2013;201(1): 41-55. 25. Mitchell DG, Bruix J, Sherman M, Sirlin CB. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology. 2015;61(3):1056-1065. 26. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1): 358-380. 27. Liu YI, Shin LK, Jeffrey RB, Kamaya A. Quantitatively defining washout in hepatocellular carcinoma. AJR Am J Roentgenol. 2013; 200(1):84-89. 28. Davenport MS, Khalatbari S, Liu PS, et al. Repeatability of diagnostic features and scoring systems for hepatocellular carcinoma by using MR imaging. Radiology. 2014;272(1):132-142. 29. Lambin P, Rios-Velazquez E, Leijenaar R, et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer. 2012;48(4):441-446. 30. Gatenby RA, Grove O, Gillies RJ. Quantitative imaging in cancer evolution and ecology. Radiology. 2013;269(1):8-15. 31. Wei J, Jiang H, Gu D, et al. Radiomics in liver diseases: current progress and future opportunities. Liver Int. 2020;40(9):2050-2063. 32. Attiyeh MA, Chakraborty J, McIntyre CA, et al. CT radiomics associations with genotype and stromal content in pancreatic ductal adenocarcinoma. Abdom Radiol (NY). 2019;44(9):3148-3157. 33. Zhang X, Ruan S, Xiao W, et al. Contrast-enhanced CT radiomics for preoperative evaluation of microvascular invasion in hepatocellular carcinoma: a two-center study. Clin Transl Med. 2020;10(2):e111. 34. Bahl G, Cruite I, Wolfson T, et al. Noninvasive classification of hepatic fibrosis based on texture parameters from double contrastenhanced magnetic resonance images. J Magn Reson Imaging. 2012;36(5):1154-1161. 35. House MJ, Bangma SJ, Thomas M, et al. Texture-based classification of liver fibrosis using MRI. J Magn Reson Imaging. 2015; 41(2):322-328. 36. Simpson AL, Doussot A, Creasy JM, et al. Computed tomography image texture: a noninvasive prognostic marker of hepatic recurrence after hepatectomy for metastatic colorectal cancer. Ann Surg Oncol. 2017;24(9):2482-2490. 37. Pak LM, Chakraborty J, Gonen M, et al. Quantitative imaging features and postoperative hepatic insufficiency: a multi-institutional expanded cohort. J Am Coll Surg. 2018;226(5):835-843. 38. Perrin T, Midya A, Yamashita R, et al. Short-term reproducibility of radiomic features in liver parenchyma and liver malignancies on contrast-enhanced CT imaging. Abdom Radiol (NY). 2018;43(12): 3271-3278. 39. Yamashita R, Perrin T, Chakraborty J, et al. Radiomic feature reproducibility in contrast-enhanced CT of the pancreas is affected by variabilities in scan parameters and manual segmentation. Eur Radiol. 2020;30(1):195-205. 40. Zhen SH, Cheng M, Tao YB, et al. Deep learning for accurate diagnosis of liver tumor based on magnetic resonance imaging and clinical data. Front Oncol. 2020;10:680. 41. Yamashita R, Mittendorf A, Zhu Z, et al. Deep convolutional neural network applied to the liver imaging reporting and data system (LI-RADS) version 2014 category classification: a pilot study. Abdom Radiol (NY). 2020;45(1):24-35.

CHAPTER 20 Direct cholangiography: Approaches, techniques, and current role Robert H. Siegelbaum and Robin B. Mendelsohn DIRECT CHOLANGIOGRAPHY OVERVIEW Direct cholangiography, the introduction of contrast medium into the biliary system, can be performed under fluoroscopic guidance percutaneously, endoscopically, or intraoperatively via surgically placed catheters. The nonoperative techniques are percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP). Magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CECT), however, have virtually eliminated the need for direct cholangiography (see Chapters 13 and 16).1–3 Currently, ERCP and PTC are typically performed only as part of a planned outpatient or inpatient interventional procedure, such as stone extraction, stent placement, biliary drainage, or stricture dilation (see Chapters 30, 31, and 37c). Magnetic resonance cholangiopancreatography (MRCP) and CECT are noninvasive imaging tests that do not require sedation and are generally considered to be safe. Imaging protocols with multiplanar reconstruction are standard and allow a large field of view, enabling visualization of the entire biliary tree and pancreatic duct (Fig. 20.1). Reconstructed three-dimensional data sets can be displayed in multiple projections, allowing for excellent visualization of the biliary tree and pancreatic duct. Injection of contrast dye under fluoroscopic guidance, on the other hand, is limited to visualization of structures in direct continuity with the opacified, nonisolated segments of the biliary tree (Fig. 20.2). While performing direct cholangiography with PTC, simultaneous crosssectional imaging may be required to ensure that the entire biliary tree has been opacified, even with multiple percutaneous puncture sites and injections. Cross-sectional imaging of the liver can be performed in a fluoroscopy room with rotational angiography or by direct CT imaging if available. Furthermore, MRCP and CECT provide superior diagnostic accuracy when compared with PTC or ERCP, allowing visualization of the bile duct wall, structures contiguous to the biliary tree (such as cysts and neoplasms), and structures adjacent to the liver.

PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY History Fluoroscopic imaging of the biliary tree was first reported by Burckhardt and Müller in 1921,4 who performed cholecystocholangiography via percutaneous puncture of the gallbladder. The first report of PTC was by Huard and Do-Xuan-Hop in 1937,5 who performed cholangiography with Lipiodol, a suboptimal contrast agent. Transhepatic cholangiography as a diagnostic tool gained popularity 15 years later, after Carter 314

and Saypol’s (1952)6 discussion of PTC with the use of a water-soluble contrast agent. In the ensuing years, many investigators7–12 described a variety of different techniques, including the use of sheathed or unsheathed needles of various sizes and different puncture sites. These procedures were associated with a significant risk of bile peritonitis, especially in obstructed biliary systems, and less frequently, bleeding. Fine-needle transhepatic access to the biliary tree was first developed at Chiba University and was presented by Ohto and Tsuchiya (1969),13 and later by Tsuchiya (1969).14 Numerous additional reports have also described decreased complications with fine-needle transhepatic access, and this technique has generally been accepted as the standard15–22 (see Chapter 31). Evaluation of the biliary tree by noninvasive imaging techniques have largely replaced transhepatic cholangiography (see Chapters 13 and 16). In 1985 Kadir23 reported that less than 5% of patients referred for evaluation of biliary disease required concomitant drainage procedures. With continued advancement of cross-sectional imaging techniques, in particular MRCP (see Chapters 13, 16 and 19),24–28 percutaneous fluoroscopic imaging of the biliary tree with contrast injection is typically performed only as part of a planned interventional procedure. Imaging evaluation of the biliary tree with MRCP or CECT is noninvasive, does not require sedation, and is generally regarded as safe (see Chapters 13 and 16). With direct needle puncture and contrast injection in the biliary tree, only bile ducts in continuity with the punctured duct are visualized. In the presence of bile duct isolation, multiple percutaneous needle punctures may be required to visualize the entire biliary tree (see Fig. 20.2). Even with multiple transhepatic bile duct needle punctures, CT imaging performed at the time of the procedure can be helpful to ensure that the biliary tree has been fully imaged. Alternatively, MRI and CECT can image the entire biliary system and can demonstrate the presence and severity of bile duct isolation (see Fig. 20.1). MRI or CECT can visualize the bile duct wall, liver, and surrounding structures, often providing more clinical information that could be relevant to patient care.

Preprocedural Preparation Patients should undergo cross-sectional imaging (CECT or MRI) before fluoroscopic imaging of the biliary tree. This is particularly so in patients who have undergone prior liver surgery or liver resection. MRI or CECT are the imaging modalities of choice because these studies depict the level of bile duct obstruction, patency of the portal venous system, the relationship of the liver and bile ducts to other structures, and the presence of tumors or lobar atrophy. Knowledge of this information could improve the chance of successful and safe bile duct puncture (see Chapter 31).

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

315

LOGIQ E9

21

–21 cm/s

A LOGIQ E9 FIGURE 20.1  Magnetic resonance cholangiopancreatography. Three-dimensional maximum intensity projection image showing marked dilatation of the intrahepatic and extrahepatic biliary tree, as well as the pancreatic duct, in a patient with a head of pancreas mass (see Chapters 16 and 17).

B FIGURE 20.3  Real-time ultrasound guidance can be helpful for the initial puncture in the presence of bile duct dilatation. A, Color Doppler image of the left liver revealing a dilated segment III bile duct. B, Static grayscale ultrasound image taken during puncture of the dilated bile duct with an echogenic 21-gauge needle.

Procedure Although typically not present in modern fluoroscopy suites, PTC is ideally performed on a tilting fluoroscopic table—another reason why these techniques have been largely supplanted by CECT and MRI. Because the specific gravity of contrast material is greater than that of bile, less contrast dye is typically required to fully delineate the biliary tree when the table is tilted.

Right-Sided Puncture FIGURE 20.2  Hilar cholangiocarcinoma involving first-order right and left hepatic ducts. Separate needle punctures were required to fill the right and left ducts.

Coagulation parameters and platelet count should be checked before the procedure and corrected if necessary. Informed consent is obtained in accordance with institutional policy, specifically including a discussion of the risks, benefits, and alternatives of the procedure. Patients generally receive moderate sedation or monitored anesthesia care. All patients should receive broad-spectrum intravenous (IV) antibiotic coverage according to institutional guidelines or preferences.

When performing a puncture of a right-sided bile duct, a site is selected in the right midaxillary line, typically one or two interspaces below the costophrenic angle. Needle puncture sites are ideally below the ninth intercostal space to avoid inadvertent crossing of the pleural space. The skin is prepped and draped using standard techniques and a subcutaneous anesthetic agent such as lidocaine is infused. A small dermatotomy is made with a No. 11 blade scalpel. A 21- or 22-gauge, 15- to 20-cm Chibastyle needle is advanced under fluoroscopic guidance superior to the closest rib to the target puncture site to avoid injury to an intercostal vessel or nerve. Real-time ultrasound guidance can be helpful for the initial puncture in the presence of bile duct dilatation.29 The puncture site and direction of puncture are chosen based on evaluation of the patient’s cross-sectional imaging studies (Fig. 20.3A–B). A small amount of water-soluble

316

PART 2  DIAGNOSTIC TECHNIQUES

contrast agent is injected while slowly withdrawing the needle until a bile duct is identified. Injection of contrast agent into a bile duct has the appearance of oil being dropped in water. Inadvertent opacification of a vascular structure is recognized by the rapid clearance of the contrast agent. If a bile duct is not entered during withdrawal of the needle, the needle is reintroduced in a slightly different direction. It is generally considered best practice not to withdraw the needle completely from the liver to minimize the number of punctures through the liver capsule. When opacification of the biliary tree is challenging, particularly in the case of a nondilated biliary tree, the same puncture site may be used multiple times before selecting a new percutaneous access site. If successful puncture of a bile duct is unlikely from that site after multiple attempts, a new site should be chosen. In patients with biliary obstruction, gentle injection of 10 mL of iodinated contrast is typically sufficient for bile duct opacification. A larger volume of contrast material is typically required in nonobstructed systems. When the bile ducts are visualized, fluoroscopic images should be acquired and stored in multiple projections to identify specific portions of the biliary tree and to completely delineate abnormal findings, if present. Of note, care should be taken to avoid puncture of the gallbladder or an extrahepatic bile duct.

Left-Sided Puncture Considerable variation is present in size and anatomic position of the left lateral segments of the liver. Careful review of preprocedural cross-sectional imaging is recommended to select an optimal puncture site. Although left-sided punctures can be performed through the right liver via an anterior axillary line approach to the segment IV bile ducts, a subxiphoid approach to a bile duct in segment II or segment III is generally preferred. As in punctures of right-sided bile ducts, percutaneous access to the biliary tree can be simplified by using real-time ultrasound guidance in the presence of dilated bile ducts.29

A

Success Rate and Accuracy Percutaneous opacification of the biliary tree is successful in 95% to 100% of patients with biliary obstruction.19,21,30 A success rate of 60% to 95% is reported for nondilated biliary systems. The likelihood of success in a nondilated system is increased by the number of needle passes performed.31 No current radiologic descriptions of obstructed bile ducts are pathognomonic for differentiation of benign and malignant disease.32,33 Bile cytology and review of cross-sectional imaging can be helpful in conjunction with fluoroscopic images in diagnosing the cause of the obstruction.

Pitfalls in Interpretation Lack of Opacification Failure to inject an adequate volume of contrast agent can result in incorrect interpretation of the level of obstruction. This pitfall can occur in the setting of complete obstruction and can be identified by the presence of a hazy margin at the level of the apparent (false) obstruction (Fig. 20.4).34 In high bile duct obstruction, especially when associated with variant anatomy, isolated segments of the biliary tree can be visualized only by direct puncture. If an incorrect bile duct is selected or if puncture of an additional bile duct is needed but not performed, the diagnosis of bile duct injuries and bile leaks can be missed. This is a clear limitation of direct cholangiography versus noninvasive imaging techniques.

Ductal Dilatation The absence of bile duct dilatation does not exclude the presence of clinically significant obstruction. Disorders such as sclerosing cholangitis, acquired immunodeficiency syndrome (AIDS), and chemotherapy-induced biliary sclerosis can present with bile duct fibrosis, impeding the ability of the bile ducts to become dilated. Conversely, bile duct dilatation does not always imply the presence of an obstructed biliary system. For

B

FIGURE 20.4  Ampullary carcinoma. A, With the patient supine, contrast pools proximally, giving a false impression of a high bile duct obstruction. The spurious nature of the level is suggested by the hazy inferior margin to the contrast column. B, With the patient sitting semierect, the contrast pools at the true point of obstruction, which is sharply defined.

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

example, dilatation that may be seen in patients with Caroli disease, or choledochal cysts, can have the radiographic appearance of bile duct dilation without the presence of obstruction.

Complications Significant complications of PTC are rare and occur in approximately 3% of patients.19 The most common major complications are bile leak (1%–2%), sepsis (2%–3%), and bleeding (0.2%– 0.4%). Other rare complications include pneumothorax, biliothorax, injury to the colon, and abscess formation. Puncture below the ninth intercostal space should decrease the incidence of chest complications. The risk for infectious complications, such as sepsis and abscess formation, can typically be decreased with proper antibiotic coverage. Care should be taken to not over-distend the bile ducts with contrast media because opacification and incomplete drainage of the biliary tree can be a source of cholangitis,29 particularly in the presence of bile duct isolation.

ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY History ERCP (see Chapter 30) was first described in 196835 and rapidly became accepted as an important diagnostic modality for patients with hepatobiliary and pancreatic diseases.36–39 Advances in technology and training over the last 50 years have enhanced and expanded the scope of ERCP. The addition of an elevator to the side-viewing duodenoscope helped facilitate cannulation of the papilla of Vater.40–42 The development of therapeutic applications through ERCP, including sphincterotomy43–45 and stenting,46,47 has transformed ERCP from a diagnostic into a therapeutic procedure. ERCP is considered to be an advanced procedure, requiring skills more difficult to learn than routine endoscopic procedures, and is offered as an additional year of training beyond the standard gastroenterology fellowship.

Indications Diagnostic ERCP has largely been replaced by noninvasive imaging techniques and is rarely performed without a therapeutic component. In 2002 the National Institutes of Health sponsored a consensus conference on ERCP and issued a statement proposing the indications for ERCP.48 They concluded that ERCP, MRCP, and endoscopic ultrasound have comparable sensitivity and specificity in the diagnosis of common bile duct (CBD) stones. They stated that avoidance of unnecessary ERCPs is the best way to reduce the number of complications and that endoscopists performing ERCPs should have appropriate training and expertise. In 2005 the American Society of Gastrointestinal Endoscopy published guidelines stating that, based on expert opinion, ERCP is primarily a therapeutic procedure for the management of pancreaticobiliary disorders.49 ERCP is currently rarely performed without a therapeutic component.

Technique Most ERCPs are performed as outpatient procedures in a hospital setting, although they can also be performed in ambulatory centers. Given that ERCP is a complex procedure, requiring special equipment and training, the risks and benefits of the procedure must be heavily considered before proceeding (see Chapter 30). Patients should be alert, oriented, and able to give informed consent. The next of kin can provide consent

317

in the rare cases where patients are unable to give informed consent. Patient age and clinical picture are important. Older age is not a risk factor for ERCP. Elderly patients have the same risks of bleeding and perforation as younger patients and actually have a lower risk of pancreatitis.50 After consent is obtained, the patient is brought into a room with a C-arm for availability of fluoroscopy during the procedure. IV sedation is given under monitored control. In the past, drug combinations of narcotics, such as meperidine and droperidol, and benzodiazepines, such as midazolam or diazepam, were used. More recently, this has been replaced by propofol, a short-acting sedative and amnestic with a rapid recovery profile. Studies have shown that propofol is more effective than sedation with midazolam, is safe, and is associated with a faster postprocedure recovery.51,52 In some centers, general anesthesia may be used if the endoscopic procedure is expected to be difficult, the patient has significant comorbid medical conditions, or there are any signs of functional or mechanical intestinal obstruction. Oxygen is administered by nasal cannula to avoid hypoxemia, which has been described in 40% of patients undergoing ERCP.53 The patient’s electrocardiogram, blood pressure, oxygen saturation, and overall condition are continually monitored throughout the procedure by a dedicated nurse. Antibiotics are not given routinely for diagnostic procedures. All endoscopic equipment used for this procedure, including the endoscopes, is either chemically disinfected or gas sterilized. The patient is usually placed in a semiprone position with special positioning of the arms to help optimize access to the ampulla of Vater. A side-viewing duodenoscope is used to afford excellent visualization of the ampulla of Vater. In patients with postoperative anatomy, a standard forward-viewing upper endoscope, pediatric colonoscope, or single balloon enteroscope may be needed to successfully approach the ampulla. An initial endoscopic evaluation of the stomach and duodenum is performed before cannulation of the ampulla. The ampulla is usually located in the second portion of the duodenum but, in rare instances, may be found more proximal or distal (see Chapter 2). It is usually easily identified, although in some cases, it may be distorted because of malignancy or edema from pancreatitis, hidden behind a fold, or within a diverticulum. The orifice of the CBD is usually located on the left upper corner of the ampulla. In most patients, the CBD and main pancreatic duct share a common channel. In a minority of patients, the orifices are separate. The minor papilla is located about 1 to 2 cm above the major papilla. The CBD is selectively cannulated with either a cannula or sphincterotome. Studies have shown that access to the biliary tree is easier and faster with a sphincterotome, compared with a cannula.54-56 Some endoscopists have been using guidewire-assisted cannulation. Whether insertion of a guidewire, as opposed to the more conventional technique of contrast injection, should be the preferred technique to access the bile ducts remains controversial. A guidewire does not produce the hydrostatic pressure associated with contrast injection and decreases the risk for trauma to the pancreatic duct, thereby theoretically decreasing the risk for post-ERCP pancreatitis. The data, however, are mixed. A meta-analysis looking at 12 randomized controlled trials (RCTs) with 3,450 patients concluded that wire-guided technique had a higher cannulation success rate (84% vs. 77%) and a lower risk of post-ERCP pancreatitis (3.5% vs. 6.7%).57 Nevertheless, a prospective trial with 1,249 patients showed no significant difference in post-ERCP pancreatitis in the guidewire group (5.2%) compared with the contrast injection group (4.4%).58

318

PART 2  DIAGNOSTIC TECHNIQUES

angle to approach cannulation (Fig. 20.6). The studies are limited, but a recent review concluded that the sole use of pancreatic guidewire does appear to be associated with an increased risk of pancreatitis.60 Other more invasive maneuvers, including precut sphincterotomy with or without pancreatic duct stent placement, may also improve success rate but are associated with an increased risk of complications, including bleeding, perforation, and pancreatitis, even in experienced hands.61 Duodenal diverticula are common and almost always are located near the papilla in the descending duodenum. Although

There are techniques to help facilitate access to the bile duct in difficult cannulations (see Chapter 30). Excess duodenal motility can be controlled by bolus injections of 0.25 to 1 mg of IV glucagon. If the pancreatic duct is inadvertently cannulated, placement of a pancreatic duct stent may help cannulation by both blocking the pancreatic duct orifice and providing more information to the endoscopist about the angle of the bile duct, especially in cases of distorted anatomy (Fig. 20.5).59 Another technique involves placing a guidewire into the pancreatic duct, which adds more information about the optimal

A

B

C

D

FIGURE 20.5  Pancreatic duct stent placement. A, Wire placement into the pancreatic duct. B, Contrast injection to confirm position in pancreatic duct. C, Placement of a 5 French (F) 3 5-cm pancreatic duct stent with a full external pigtail and a single internal flap. D, Endoscopic view of 5F pancreatic duct stent.

A

B

C

FIGURE 20.6  Guidewire placement in pancreatic duct to facilitate bile duct cannulation. A, Wire placement into pancreatic duct. B, This provided more information to the endoscopist about the angle of the bile duct, and the CannulaTome was adjusted under fluoroscopic guidance. C, Contrast injection confirmed position in common bile duct.

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

usually asymptomatic, diverticula have been shown to be associated with choledocholithiasis. Periampullary diverticula may make cannulation more difficult, but the data are mixed62,63 (see Chapter 30). In patients with surgically altered anatomy, ERCP may be quite challenging. In patients with a Billroth II gastrojejunostomy, success rates for bile duct cannulation are much lower.64 The papilla is found in the afferent limb, which may be difficult to traverse. In addition, the orientation of the ampulla is upside down compared with standard ERCP. In patients with Rouxen-Y gastrectomies, it is often difficult even to reach the papilla, given the long Roux limb. If the papilla is identified, cannulation may still be extremely difficult because of the location and position of the ampulla.65 Single balloon enteroscopy has been reported to have high procedural success rates and should be considered first-line intervention when biliary access is required after Roux-en-Y gastric bypass, Billroth II gastrojejunostomy, or hepaticojejunostomy66 (see Chapter 30). This is mostly only offered in tertiary care centers. Once the bile duct is selectively cannulated, a contrast agent is injected under fluoroscopic control, with subsequent radiographic images obtained of the duct anatomy. Choice of contrast agent differs among endoscopists. Many choose to use half strength contrast when looking for stones. Material for pathologic and cytologic evaluation can be obtained from either the biliary or pancreatic duct system, with a variety of dedicated endoscopic biopsy forceps and cytology brushes. Pathologic and cytologic material may be obtained from the ampulla of Vater, duodenum, and stomach for diagnostic purposes during the procedure as well.

Pancreatography Imaging the pancreatic duct can be an important adjunct to cholangiography during ERCP. Strictures, stones, and other obstructing lesions can be identified. Most recommend guidewire cannulation of the pancreatic duct over contrast injection because this produces less hydrostatic pressure in the duct, possibly decreasing the risk for post-ERCP pancreatitis. In general, the pancreatic duct is about 20 cm in length and variable in caliber. With increasing age comes progressive atrophy and fibrosis of the pancreas. The diameter of the main pancreatic duct also increases with age, although one study found no difference in pancreatic duct length among patients younger than 40 years compared with older patients. Duct diameter throughout the pancreas was significantly greater, however, in patients older than 40 years.67 Anatomic variations, such as pancreas divisum (Fig. 20.7), also may be identified on a pancreatogram (see Chapter 2). This abnormality has been described in 7.5% of ERCP procedures and can be confirmed by cannulation of the main pancreatic duct through the orifice in the minor papilla.68

Cholangioscopy and Pancreatoscopy Cholangioscopy and pancreatoscopy involve using miniature endoscopes through the channel of the duodenoscope, allowing for direct visualization of the bile and pancreatic ducts, respectively (see Chapters 30). A new skill set is necessary to perform these procedures, given that this technique uses two different endoscopes. Diagnostic cholangioscopy may be used to evaluate indeterminate biliary strictures and filling defects. Similarly, diagnostic pancreatoscopy may be used to evaluate pancreatic strictures and intraductal papillary mucinous neoplasms. Studies

319

FIGURE 20.7  Pancreas divisum. The cannula is in the major papillary orifice, and contrast injection opacifies the proximal portion of the major pancreatic duct (Wirsung). Injection through the minor papillae allows opacification of the duct of Santorini and the distal duct of Wirsung (see Chapter 53).

have shown that it is an accurate diagnostic tool for patients with pancreaticobiliary disorders.69–71 One prospective multicenter study of 87 patients reported that endoscopists were able to distinguish benign from malignant indeterminate biliary lesions 92.1% of the time with cholangioscopy with visualization alone.72 A recent systematic review and meta-analysis looking at 13 original articles concluded that cholangioscopy has very high diagnostic capability to diagnose malignant biliary obstruction.73 Complications of cholangiopancreatoscopy include bacteremia, bleeding, and pancreatitis. One retrospective study reported that complications of cholangiopancreatoscopy are increased compared with ERCP alone and are associated with a much higher risk of cholangitis.74

Complications Complications of ERCP include those associated with endoscopic procedures in general, as well as those specific to ERCP. Incidence rates of complications vary in the literature. A systematic survey of prospective studies reviewed 21 studies with 16,855 patients and reported a specific complication rate of 6.9% and a mortality rate of 0.33%.75 The experience of the endoscopist and case volume also has an impact on the complication rate. In a study conducted in Austria, endoscopists performing more that 50 ERCP procedures per year were compared with those performing fewer than 50 per year. Those in the higher case-volume group had a significantly higher success rate (86.9% vs. 80.3%; P , .001) and a lower overall complication rate (10.2% vs. 13.6%; P 5 .007).76

Pancreatitis The most common complication of ERCP is pancreatitis, with reported incidences ranging from 1% to 40% but most frequently

320

PART 2  DIAGNOSTIC TECHNIQUES

reported around 3% to 5%.75,77–80 The incidence of post-ERCP pancreatitis in children is quite low, about 2.5% in one study.81 The consensus classification defined post-ERCP pancreatitis as the clinical picture of new or worsened abdominal pain with amylase at least three times normal at 24 hours after the procedure and requiring hospitalization.82 They further defined it as mild if hospitalization is two to three days, moderate if hospitalization is four to 10 days, and severe if hospitalization is more than 10 days, if there is a pseudocyst or hemorrhagic pancreatitis, or if an intervention is required. Post-ERCP pancreatitis should be distinguished from transient asymptomatic hyperamylasemia, which occurs in 40% to 75% of cases and disappears within one to two days.43,83 Most cases of post-ERCP pancreatitis are mild and usually resolve in a few days with conservative measures of bowel rest and IV fluids. The management is the same as for pancreatitis from other causes. Multiple potential mechanisms have been proposed to explain the pathogenesis of post-ERCP pancreatitis. Mechanical injury to the pancreatic duct from manipulation of the papilla, instrumentation of the pancreatic duct, or injection of the pancreatic duct likely play a role.84 Similarly, thermal injury from electrocautery leading to edema and possible obstruction of the duct has been invoked.85 Hydrostatic pressure from contrast injection leading to injury is also likely a component. The contrast itself theoretically may cause a chemical or allergic injury. However, the use of nonionic contrast medium of low osmolarity has shown no advantage over the less expensive ionic contrast medium in preventing ERCP-related pancreatitis,86 and a meta-analysis showed no significant difference in post-ERCP pancreatitis among different contrast media.87 Although it remains unclear whether these mechanisms work independently or in conjunction, recent data have helped to elucidate both patient- and procedure-related risk factors that are independently associated with post-ERCP pancreatitis. These risk factors are additive.88 Patient-related factors include younger age, female sex, normal serum bilirubin, recurrent pancreatitis, history of post-ERCP pancreatitis, and sphincter of Oddi dysfunction. Procedure-related factors include difficult cannulation, pancreatic duct injection, precut sphincterotomy, pancreatic sphincterotomy, minor papilla sphincterotomy, balloon sphincteroplasty, ampullectomy, and sphincter of Oddi manometry. One study showed that trainee participation was an independent risk factor.77 Most studies, however, have not shown a correlation between case volume and rates of pancreatitis.80,88,89 Specific techniques and measures to decrease the risk of pancreatitis have been evaluated. The risk of pancreatitis is reduced by minimizing the number of attempts of cannulation, avoiding pancreatic duct cannulation if not necessary, and minimizing the volume of contrast injected into the pancreatic duct to avoid overdistension or “acinarization” of the pancreatic duct. Placement of a temporary pancreatic duct stent may also reduce the risk. One meta-analysis demonstrated that the use of pancreatic duct stents in high-risk patients decreased the rate of post-ERCP pancreatitis by about two-thirds.90 Their use is not routinely recommended but is reserved for high-risk patients. Studies have shown a benefit of pancreatic duct stents in biliary sphincterotomy for sphincter of Oddi dysfunction, precut sphincterotomy, balloon sphincteroplasty, endoscopic ampullectomy, and difficult cannulation.90–92 Many pharmacologic agents have been studied. A recent systematic review included 85 RCTs and 28 meta-analyses evaluating pharmacologic prevention of post-ERCP pancreatitis. They

concluded that rectal nonsteroidal antiinflammatory drugs (NSAIDs) were beneficial, especially in high-risk patients. Data on bolus-administered somatostatin, sublingual nitroglycerin, and some protease inhibitors were considered promising, but confirmatory studies are necessary.93 NSAIDs inhibit prostaglandin synthesis, phospholipase A2 activity, and neutrophil/endothelial cell attachment, which are all thought to play a major role in the pathogenesis of pancreatitis and thus may have a role in post-ERCP pancreatitis prevention. A meta-analysis that included 10 RCTs with a total of 2,269 patients concluded that NSAID use decreased the risk for post-ERCP pancreatitis (risk ratio [RR] 0.57; 95% confidence interval [CI], 0.38–0.86; P 5 .007).94 Nevertheless, these studies were extremely heterogeneous in regard to type of NSAID and to route and timing of administration. A placebocontrolled, double-blind RCT of high-risk patients showed that patients who received rectal indomethacin immediately after the procedure were less likely to develop post-ERCP pancreatitis than the control group (9.2% vs. 16.9%; P 5 .0005) and were less likely to develop moderate to severe pancreatitis (4.4% vs. 8.8%; P 5 .03).95 A meta-analysis that specifically looked at studies of rectal indomethacin and included four studies with 1,470 patients showed that the rate of pancreatitis was significantly lower using indomethacin compared with placebo (odds ratio [OR], 0.49; CI, 0.34–0.71; P 5 .0002).96 A network meta-analysis compared rectal indomethacin to pancreatic duct stenting and concluded that rectal indomethacin alone was superior to pancreatic duct stenting in post-ERCP prevention (OR, 0.48; 95% CI, 0.26–0.87).97 The European Society of Gastrointestinal Endoscopy guidelines recommend routine prophylactic use of rectal NSAIDs immediately before or after ERCP in all patients without a contraindication.98 Somatostatin and its analogue octreotide inhibit pancreatic secretions, decrease sphincter of Oddi pressure, modulate cytokines, and lead to apoptosis of pancreatic acinar cells, and therefore may be protective against post-ERCP pancreatitis. They have been studied extensively, with conflicting results. One meta-analysis included seven homogeneous high-quality studies involving 3,130 patients and concluded that somatostatin administered as a bolus was effective in prevention of post-ERCP pancreatitis.99 A different meta-analysis looked at 17 studies with a total of 3,818 patients and found that somatostatin and high-dose octreotide prevented post-ERCP pancreatitis if given over 12 hours or in bolus form.100 Subsequent RCTs have yielded mixed results. One double-blinded, placebo-controlled RCT involved 391 patients in three hospitals. Patients were randomized to receive 3 mg of somatostatin in 500 mL normal saline (NS) infused for 12 hours, starting 30 minutes before the ERCP or 500 mL NS infused for 12 hours, starting 30 minutes before the ERCP. They found a significantly lower risk for pancreatitis in the somatostatin group (3.6% vs. 9.6% in the placebo group; P 5 .02).101 Another study involved 133 patients who were randomized to a bolus of somatostatin infusion before ERCP, followed by continuous infusion for 12 hours, a bolus of somatostatin before ERCP only, and placebo alone; no significant differences were found among the three groups.102 A recent RCT of 510 patients randomized to an IV bolus of 250 µg of somatostatin before cannulation, followed by a four-hour continuous infusion of the drug at 250 mg/hr, or placebo with NS, showed no significant difference in rates of post-ERCP pancreatitis.103 Future research is necessary to elucidate the role of somatostatin in prevention of post-ERCP pancreatitis.

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

Nitroglycerin acts as a smooth muscle relaxant and subsequently may decrease sphincter of Oddi pressures, thereby decreasing the risk of post-ERCP pancreatitis. Only three out of seven RCTs showed that nitroglycerin was effective, but two of the three positive studies used sublingual nitroglycerin.93 One compared 2 mg sublingual nitroglycerin given five minutes before endoscopy with placebo in 186 patients and found a lower incidence of pancreatitis in the nitroglycerin group (7/90 vs. 17/96; P , .05).104 The second one enrolled 74 patients and randomly assigned them to 5 mg sublingual glyceryl trinitrate versus 100 mg vitamin C, five minutes before the ERCP. They found a significant difference in post-ERCP pancreatitis in the study group (7.9%) compared with placebo (25%; P 5 .012).105 In both studies, however, the consensus definition for pancreatitis was not used, which may account for the high rates of pancreatitis in the control groups. One RCT of 300 patients showed that the combination of rectal indomethacin and sublingual nitroglycerin was superior to rectal indomethacin alone at prevention of post-ERCP pancreatitis (6.7% vs. 15.3%; P 5 .016).106 More studies are needed to further clarify the benefit of nitroglycerin in post-ERCP pancreatitis. Protease inhibitors, such as gabexate mesylate, nafamostat mesylate, and ulinastatin, have been investigated, given that activation of proteolytic enzymes likely contributes to the pathogenesis of pancreatitis. A meta-analysis of 18 studies with a total of 4,966 patients showed a significant, yet small, risk reduction in postERCP pancreatitis with the protease inhibitors.107 They stated there was no solid evidence to support their use at this time. A pilot study investigated whether aggressive periprocedural hydration reduced the risk of post-ERCP pancreatitis and found that none of the patients in the aggressive hydration group developed pancreatitis compared with 17% of patients in the standard hydration group.108 A subsequent prospective multicenter RCT looked at 385 patients randomized to aggressive IV hydration (3 mL/kg/h during ERCP, a 20 mL/kg bolus and 3 mL/kg/h for eight hours after ERCP) with either lactated Ringer’s or NS or standard IV hydration with lactated Ringer’s (1.5 mL/kg/h during and hours after ERCP) and found that the rate of post-ERCP pancreatitis was significantly lower for the aggressive lactated Ringer’s group.109 A recent systematic review and meta-analysis reviewing 10 RCTs with 2,200 patients concluded that aggressive hydration with lactated Ringer’s during the perioperative ERCP period can prevent pancreatitis.110 Many other agents have been investigated, including secretin, corticosteroids, allopurinol, and topical epinephrine, with conflicting results, and are not recommended at this time.

Infection A serious complication of ERCP is the development of postprocedure infectious complications, most commonly cholangitis (see Chapter 43) and cholecystitis (see Chapter 34). In a systematic survey of 21 prospective studies with 16,855 patients, the incidence of infectious complications was 1.4%.75 Cholangitis most commonly occurs when there is failed or incomplete biliary drainage. The risk is increased in patients with hilar obstruction and sclerosing cholangitis, given the increased risk of incomplete drainage.80,111,112 Other risk factors include jaundice, small endoscopy center, and delay in performing ERCP.80,113 Treatment involves supportive care with antibiotics and decompression of the obstruction. Studies have shown that prophylactic antibiotics significantly reduce the frequency of procedure-related bacteremia but have not shown

321

a difference in rates of cholangitis.114 Two meta-analyses failed to demonstrate a benefit of giving routine prophylactic antibiotics.115,116 Antibiotics added to the injected radiographic contrast medium are also of no benefit.117 It has also been found that endoscopic instruments used in ERCP can be the source of serious infections In 2015 the US Food & Drug Administration (FDA) published a safety communication stating that the design of the duodenoscope may impede effective cleaning and lead to the transfer of multi-drug resistant organisms and subsequent infections, leading to outbreaks and deaths (https://www.fda.gov/medical-devices/medicaldevice-safety). A recent meta-analysis estimated the contamination rate of 15.25% in reprocessed duodenoscopes.118 Multiple societies released guidelines focusing on reprocessing techniques.119 In 2019 the FDA reported that the rate of transmitted infections decreased significantly. They recommended to transition to duodenoscopes with innovative designs to enhance safety (https://www.fda.gov/medical-devices/safety-communications/fda-recommending-transition-duodenoscopes-innovativedesigns-enhance-safety-fda-safety-communication#disposable). There are currently ongoing studies with multiple disposable devices.

Bleeding Bleeding is a rare complication of diagnostic ERCP and is most commonly seen with sphincterotomy. Risk factors for postsphincterotomy bleeding include bleeding during the procedure, concomitant thrombocytopenia or coagulopathy, anticoagulation started within three days of the sphincterotomy, and low case volume of the endoscopist.79 Rarely, there may be a Mallory-Weiss tear from scope trauma or submucosal hemorrhage from manipulation of the papilla.80 There have been case reports of intraperitoneal hemorrhage from injury to abdominal vessels, liver, and spleen.120,121

Perforation The most common type of perforation associated with ERCP is retroperitoneal perforation, which is usually associated with sphincterotomy, with an incidence ranging from 0.5% to 2.1%.82 In their systematic survey of 21 prospective studies with 16,855 patients, Loperfido and colleagues (1998)80 reported 101 perforations (0.6%) and 10 deaths from perforation (0.06%). Free bowel wall perforation is quite rare and is usually associated with a structural abnormality, such as a stricture or Billroth II gastrectomy.122 The management of the perforation depends on the size, location, and clinical picture. Free bowel wall perforations usually require surgery. Use of endoscopic clips for the treatment of duodenal perforations has also been reported.123,124

DIRECT CHOLANGIOGRAPHY AND PANCREATOGRAPHY BY PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY OR ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY The anatomy of the bile ducts is discussed in Chapter 2. Knowledge of the common variations of ductal branching is essential for accurate interpretations of cholangiograms, and these are shown in Figs. 20.8 and 20.9; segmental nomenclature is summarized in

322

PART 2  DIAGNOSTIC TECHNIQUES

RPSD VII

VIII II I

VI V

IV

III

LHD

RASD RHD

CHD FIGURE 20.8  Standard intrahepatic ductal anatomy. The segments are numbered according to Couinaud’s description (see Table 20.1). CHD, Common hepatic duct; LHD, left hepatic duct; RASD, right anterior sectoral duct; RHD, right hepatic duct; RPSD, right posterior sectoral duct. (See Chapter 2.)

Table 20.1. In the right lobe, the posterior segments lie more laterally than the anterior segments, so that the most lateral ducts on a cholangiogram are usually segments VI inferiorly and VII superiorly. The posterior sectoral duct is often recognizable by an arched course near the confluence (Figs. 20.10 and 20.11B). A right sectoral duct crosses to the left to join the left hepatic duct in 28% of cases, according to Healey and Schroy (1953)125; in 22%, this is the posterior sectoral duct (see Figs. 20.9B and 20.11B), and in 6%, this is the anterior duct (see Figs. 20.9C and 20.11D). Occasionally, a right sectoral or segmental duct, posterior more often than anterior, courses inferiorly and enters the common hepatic duct directly (Fig. 20.12). The confluence of the right and left ducts takes the form of a trifurcation rather than a bifurcation in 12% of cases according to Couinaud (1957; see Fig. 20.9A).126 In the left lobe, the superior and inferior lateral segment ducts, segments II and III, unite in the line of, or to the right of, the umbilical fissure in 92% of cases. In the latter instance, the quadrate lobe, segment IV, may drain wholly or partially into the segment II duct. Rarely, segment II and III ducts join at or close to the confluence (see Figs. 20.9E and 20.11C), and

TABLE 20.1  Segmental Nomenclature I II III IV V VI VII VIII

RPSD RHD LHD

LHD

CHD RASD

Sectoral duct

A

Caudate lobe Left lateral superior segment Left lateral inferior segment Left medial segment or quadrate lobe Right anterior inferior segment Right posterior inferior segment Right posterior superior segment Right anterior superior segment

D RPSD

RHD

II

LHD III RASD

IV

B

E

RHD

RPSD

II

IV

III

LHD

RASD

C

F

FIGURE 20.9  Variations of perihilar ductal anatomy. CHD, Common hepatic duct; LHD, left hepatic duct; RASD, right anterior sectoral duct; RHD, right hepatic duct; RPSD, right posterior sectoral duct. (See Chapter 2.)

FIGURE 20.10  Hilar cholangiocarcinoma involving first-order right hepatic duct, proximal common hepatic duct, and faintly opacified left hepatic duct (arrowhead). Note the characteristic arched course of the right posterior sectoral duct (arrow). (See Chapter 2.)

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

A

323

B

A L P

C

D

FIGURE 20.11  Postcholecystectomy strictures graded according to Bismuth. A, Grade I (.2 cm from the confluence of the right and left hepatic ducts; arrowheads): Calculi lie above and below the stricture (arrow). B, Grade II (,2 cm from the confluence): There has been a previous hepatojejunostomy; the right posterior sectoral duct (arrowhead) has an exaggerated arched course and enters the left hepatic duct as a normal variant. C, Grade III (the confluence is involved by stricture, but the right and left hepatic ducts are not completely separated): Ducts of segment II (white arrow) and segment III (black arrow) join the confluence independently as a normal variant. D, Grade IV (the right and left ducts are separated by the stricture): The right anterior sectoral duct (A) is draining into the left hepatic duct (L), which is separated from the right posterior sectoral duct (P) by the stricture (arrows). (See Chapter 42.)

segment IV drains directly into the common hepatic duct in 1% of cases (see Fig. 20.9F).125 The caudate ducts are often difficult to identify. Usually two or three ducts drain most commonly into the right posterior sectoral duct, right hepatic duct, or left hepatic duct.125 The recognizable caudate ducts are usually a few centimeters long and drain downward or to the right. The left hepatic duct (average length, 17 mm) is considerably longer than the right hepatic duct (average length, 9 mm) and has a longer extrahepatic course. The normal diameters of the main bile ducts as measured at PTC are shown in Table 20.2. These figures are greater than the true duct dimensions because of some distension produced by direct cholangiography,

together with considerable magnification occurring on any fluoroscopic “spot film.” The magnification is of the order of 40%127 and affects all structures in the image, including calculi, tubes, and strictures. The upper limits of normal for the diameter of the extrahepatic bile ducts as measured by ERCP vary between 9 and 14 mm.128 Combined radiologic and manometric studies129 have shown that even in the absence of extrahepatic cholestasis, the diameter of the bile ducts and the pressure difference therein increases with advancing age. The diameter of the bile ducts as measured by ultrasonography is less than those measurements obtained during ERCP.128 Anatomic abnormalities of the hepatobiliary system include cystic dilations (Fig. 20.13) of the bile duct or

324

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 20.12  Pancreatitis producing a typical, incomplete long stricture of the common bile duct. The right posterior sectoral duct has a low entrance into the common hepatic duct, an uncommon but important normal variant. (See Chapter 2.)

FIGURE 20.13  Choledochal cyst. (See Chapter 46.)

TABLE 20.2  Average Duct Diameters Measured Directly From 50 Normal Percutaneous Transhepatic Cholangiography Examinations DUCT DIAMETER (mm) Right hepatic 5 4.7 Left hepatic 5 5.2 Common hepatic 5 6.5 Common bile 5 7.6 From Okuda K, Musha H, Nakajima Y, et al. Frequency of intrahepatic arteriovenous fistula as a sequela to percutaneous needle puncture of the liver. Gastroenterology. 1978;74:1204–1207.

of the intrahepatic bile ducts (Caroli disease; see Chapter 46). There is a wide variation in where the cystic duct joins the common hepatic duct. A low junction with a correspondingly long cystic duct (Fig. 20.14) may result in difficulties if not recognized. This is especially true when a cholecystojejunostomy is performed as a palliative biliary bypass for carcinoma of the head of the pancreas, and the jaundice either is not relieved or recurs rapidly in the postoperative period.

Interpretations Because of its inherent weakness of only allowing visualization of the bile duct lumen, the main problem with the use of direct cholangiography is its lack of specificity. There are few, if any, pathognomonic radiologic findings. Many disease entities, from benign to malignant, overlap greatly in their cholangiographic appearances. The combination of history, blood markers, associated radiologic findings, and clinical scenario can often significantly narrow the differential diagnosis. However, it must be stressed strongly that because the cholangiographic appearance of many biliary diseases may be indistinguishable, biopsy is often required to rule out malignancy or to confirm suspected diagnosis.

FIGURE 20.14  Long cystic duct.

Bile Leaks Bile leaks are seen as sites of free extravasation of contrast agent at a site of bile duct injury. Injury may be secondary to trauma, but most commonly it is iatrogenic in nature. Associated bilomas may be seen at the point of bile leak. Diagnosis of bile leak can usually be made by noninvasive imaging techniques, such as

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

325

ultrasound, CT or MRI, but because the intrahepatic bile ducts are usually not dilated, a bile leak may not be evident on imaging. Cholescintography with technetium 99m–hepatic iminodiacetic acid (hepatobiliary iminodiacetic acid [HIDA] scan) may be useful for diagnosis when the other imaging modalities are inconclusive. ERCP can diagnose bile duct leaks effectively but is usually reserved for cases when a therapeutic intervention is anticipated.

Filling Defects Air Bubbles, Blood Clots, Calculi, Primary and Secondary Bile Duct Cancers, and Parasitic Diseases Air bubbles, although confusing, most commonly declare themselves by their perfectly circular shape and their distribution to nondependent structures. Blood clots in the bile duct are seen more frequently with PTC than with ERCP. Hemobilia can sometimes take more than 48 hours to resolve, and when it is more severe, it can be cast-like and may mask other filling defects (see Chapter 116). Calculous disease (see Chapter 37A, B and C) remains the most common filling defect in the biliary system. Distinguishing characteristics of gallstones and primary bile duct calculi include a faceted appearance and disposition to move to gravitydependent positions. Calculi may be seen as discrete filling defects (Figs. 20.15 and 20.16) or cast-like structures filling entire ducts, as occurs in recurrent pyogenic cholangitis, cystic diseases of the bile ducts, or even proximal to strictures of any etiology. Impacted calculi may be difficult to differentiate from strictures or tumors. Primary bile duct cancer (see Chapter 51A and B), specifically papillary cholangiocarcinomas, can also present as cholangiographic filling defects (Fig. 20.17). T-shaped filling defects may also be detected (Fig. 20.18),130 and papillary bile duct cancers may cause filling defects as a result of mucin

FIGURE 20.16  Benign stricture of the right hepatic duct (arrow) with multiple ductal calculi proximal to it. The hepatojejunostomy is partially strictured.

FIGURE 20.17  Papillary hilar cholangiocarcinoma (arrowheads). Only the right ducts are opacified. (See Chapter 51A and B.)

FIGURE 20.15  Choledocholithiasis.

production (Fig. 20.19). Other malignancies, including melanoma and intraductal metastases, such as colon cancer, are also more unusual causes of cholangiographic filling defects.131 Parasitic infections, such as hydatid disease (see Chapter 72) and infections with Ascaris lumbricoides or Clonorchis sinensis (see Chapter 45), are diseases with worldwide distribution that can also present cholangiographically as intraductal filling defects. A proportion of hepatic hydatid cysts (5%–10%) rupture into the bile ducts and may simulate choledocholithiasis. Calcified cysts are easy to recognize on radiographs, and daughter cysts can cause biliary obstruction. When the calcified cyst is not obvious,

326

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 20.18  “Golf tee” appearance of a papillary bile duct cancer (arrow) involving the common hepatic duct. (See Chapter 51A and B.)

FIGURE 20.19  Nasobiliary cholangiogram opacifying left hepatic ducts. Main left hepatic duct contains a small mucin-secreting papillary cholangiocarcinoma (arrow). The mucin results in expansion of the common bile duct below the tumor and appears as strand-like filling defects. (Courtesy Dr. A. Speer.)

biliary strictures with obstruction may be noted on cholangiogram. The biliary ducts can show considerable irregularities in caliber and extensive displacement of the intrahepatic branches secondary to the mass effect of a large hydatid cyst.132–134 A. lumbricoides is a commonly seen helminth with a prevalence of 90% in some parts of Africa and Asia (see Chapter 45). If the worm passes through the sphincter of Oddi, it may cause acute pancreatitis or a cholestasis syndrome.135 In the acute stage, the worm occasionally may be found and extracted from the ampulla, and it can be detected in the biliary tract by cholangiography. Eating raw meat has been associated with C. sinensis infestation. The prevalence of this disease has been estimated to be 60% of the general population of Hong Kong, based on stool ova examinations. This worm can penetrate through the papilla into the bile ducts. In an ERCP study of 31 consecutive patients, the typical filamentous, wavy, or elliptic appearance of the worm in the bile ducts was believed to be pathognomonic. Other common cholangiographic findings include widely dilated extrahepatic bile ducts, which are filled with biliary sludge and stones, and intrahepatic duct strictures, which are predominantly found in the branches of the left hepatic duct.136 The eggs of C. sinensis act as a nucleus for the development of the bile duct stones.137 Naval and colleagues (1984)138 reported successful endoscopic biliary lavage to eliminate the eggs. Invasion of Fasciola hepatica into the biliary tract also may cause serious lesions (see Chapter 45). In the chronic stage, F. hepatica infection can resemble sclerosing cholangitis.139 The appearance on ERCP is that of dilated bile ducts with unexplained sludge in the distal bile duct (Figs. 20.20 and 20.21).

FIGURE 20.20  Liver flukes in the distal bile duct presenting as “biliary sludge.” (See Chapter 45.)

  Chapter 20  Direct Cholangiography: Approaches, Techniques, and Current Role

327

CONCLUSION The role of direct cholangiography in the diagnosis of biliary disease has been largely supplanted by less invasive imaging modalities, such as MR cholangiography and CT with contrast. The ability to visualize the entire biliary tree, the bile duct wall, and other structures other than the bile duct lumen increases the diagnostic accuracy and clinical utility of these noninvasive techniques, which have become the gold standard for cholangiography. Direct cholangiography is generally reserved for clinical scenarios involving concomitantly planned therapeutic interventions. References are available at expertconsult.com.

FIGURE 20.21  Extracted liver flukes. (See Chapter 45.)

327.e1

REFERENCES 1. Stroszczynski C, Hünerbein M. Malignant biliary obstruction: value of imaging findings. Abdom Imaging. 2005;30(3):314-323. 2. Miller G, Schwartz LH, D’Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am. 2007;16(2):343-368. 3. Gakhal MS, Gheyi VK, Brock RE, Andrews GS. Multimodality imaging of biliary malignancies. Surg Oncol Clin N Am. 2009;2:225-239. 4. Burckhardt H, Müller W. Verusche über die Puncktion der Gallenblase und ihre Röntgendarstellung. Dtsch Chir. 1921;162:168. 5. Huard P, Do-Xuan-Hop. La ponction transhepatique des canaux biliares. Bull Soc Med Chir Indochine. 1937;15:1090. 6. Carter RF, Saypol GM. Transabdominal cholangiography. JAMA. 1952;148:253-255. 7. Flemma RJ, Shingleton WW. Clinical experience with percutaneous transhepatic cholangiography: experience from 107 cases. Am J Surg. 1966;111:13-22. 8. Glenn F, Evans JA, Mujahed Z, Thorbjarnason B. Percutaneous transhepatic cholangiography. Ann Surg. 1962;156:451. 9. Mujahed Z, Evans JA. Percutaneous transhepatic cholangiography. Radiol Clin North Am. 1966;4:535-545. 10. Seldinger SI. Percutaneous transhepatic cholangiography. Acta Radiol. 1966;253(suppl):1-134. 11. Shaldon S, Barber KM,Young WB. Percutaneous transhepatic cholangiography: a modified technique. Gastroenterology. 1962;42:371-379. 12. Weicher KL. Percutaneous transhepatic cholangiography: technique and application. Acta Chir Scand. 1964;11(suppl):330. 13. Ohto M, Tsuchiya Y. Non-surgically available percutaneous transhepatic cholangiography: technique and cases. Medicina (Tokyo). 1969;6:735-739. 14. Tsuchiya Y. A new safe method of percutaneous transhepatic cholangiography. Jpn J Gastroenterol. 1969;63:438. 15. Benjamin IS, Allison ME, Moule B, Blumgart LH. The early use of fine needle percutaneous transhepatic cholangiography in an approach to the diagnosis of jaundice in a surgical unit. Br J Surg. 1978;65:92-98. 16. Ferrucci JT, Wittenberg J, Sarno RA, Dreyfuss JR. Fine needle transhepatic cholangiography: a new approach to obstructive jaundice. AJR Am J Roentgenol. 1976;127:403-407. 17. Fraser GM, Cruikshank JG, Sumerling MD, Buist TA. Percutaneous transhepatic cholangiography with the Chiba needle. Clin Radiol. 1978;29:101-112. 18. Gold RP, Price JB. Thin needle cholangiography as the primary method for the evaluation of the biliary-enteric anastomosis. Radiology. 1980;136:309-316. 19. Harbin WP, Mueller PR, Ferrucci JT. Transhepatic cholangiography: complications and use patterns of the fine-needle technique: a multi-institution survey. Radiology. 1980;135:15-22. 20. Hinde GDB, Smith PM, Craven JL. Percutaneous cholangiography with the Okuda needle. Gut. 1977;18:610-614. 21. Jain S, Long RG, Scott J, Dick R, Sherlock S. Percutaneous transhepatic cholangiography using the “Chiba” needle: 80 cases. Br J Radiol. 1977;1950:175-180. 22. Pereiras R Jr, Chiprut RO, Greenwald RA, Schiff ER. Percutaneous transhepatic cholangiography with the “skinny” needle: a rapid, simple, and accurate method in the diagnosis of cholestasis. Ann Intern Med. 1977;86:562-568. 23. Kadir S. Diagnostic Angiography. Saunders: 1986. 24. Park DH, Kim MH, Lee SS, et al. Accuracy of magnetic resonance cholangiopancreatography for locating hepatolithiasis and detecting accompanying biliary strictures. Endoscopy. 2004;36:987-992. 25. Romagnuolo J, Bardou M, Rahme E, Joseph L, Reinhold C, Barkun AN. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med. 2003;139:547-557. 26. Simone M, Mutter D, Rubino F, et al. Three-dimensional virtual cholangioscopy: a reliable tool for the diagnosis of common bile duct stones. Ann Surg. 2004;240:82-88. 27. Vaishali MD, Agarwal AK, Upadhyaya DN, Chauhan VS, Sharma OP, Shukla VK. Magnetic resonance cholangiography in obstructive jaundice. J Clin Gastroenterol. 2004;38:887-890. 28. Zhong L, Yao QY, Li L, Xu JR. Imaging diagnosis of pancreaticobiliary diseases: a control study. World J Gastroenterol. 2003;9: 2824-2827.

29. Covey AM, Brown KB. Percutaneous transhepatic biliary drainage. Tech Vasc Interv Radiol. 2008;11:16-20. 30. Mueller PR, Harbin WP, Ferrucci Jr JT, Wittenberg J, Sonnenberg E. Fine needle cholangiography: reflections after 450 cases. AJR Am J Roentgenol. 1981;136:85-90. 31. Jaques PF, Mauro MA, Scatliff JH. The failed transhepatic cholangiogram. Radiology. 1980;134:33-35. 32. Hadjis NS, Collier NA, Blumgart LH. Malignant masquerade at the hilum of the liver. Br J Surg. 1985;72:659-661. 33. Wetter LA, Ring EJ, Pellegrini CA, Way LW. Differential diagnosis of sclerosing cholangitis of the common hepatic duct (Klatskin tumors). Am J Surg. 1991;161:57-63. 34. Kittredge RD, Baer JW. Percutaneous transhepatic cholangiography: problems in interpretation. AJR Am J Roentgenol. 1975;125:35-46. 35. McCune WS, Shorb PE, Moscovitz H. Endoscopic annulation of the ampulla of Vater: a preliminary report. Ann Surg. 1968;167: 752-756. 36. Cotton PB. Progress report ERCP. Gut. 1977;18:316-341. 37. Cotton PB, Blumgart LH, Davies GT, et al. Cannulation of the papilla of Vater via fiber-duodenoscope. Lancet. 1972;1:53-58. 38. Freeney PC. Radiology of the pancreas: two decades of progress in imaging and intervention. AJR Am J Roentgenol. 1988;150: 975-981. 39. Oi I, Kobayashi S, Kondo K. Endoscopic pancreatocholangiography. Endoscopy. 1970;2:103-106. 40. Kasugai T, Kuno N, Aoki I, Kizu M, Kobayashi S. Fiberduodenoscopy: analysis of 353 examinations. Gastrointest Endosc. 1971; 18:9-16. 41. Ogoshi K, Tobita Y, Hura Y. Endoscopic observation of the duodenum and pancreatocholedochography using duodenofiberscope under direct vision. Gastrointest Endosc. 1970;12:83-96. 42. Takagi K, Ikeda S, Nakagawa Y, Sakaguchi N, Takahashi T. Retrograde pancreatography and cholangiography by fiber-duodenoscope. Gastroenterology. 1970;59:445-452. 43. Classen M, Demling L. Hazards of endoscopic retrograde cholangiopancreatography. Acta Hepatogastroenterol. 1975;22:1-3. 44. Cotton PB, Chapman M, Whiteside CG, Le Quesne LP. Duodenoscopic papillotomy and gallstone removal. Br J Surg. 1976;63: 709-714. 45. Kawai K, Akasaka Y, Murakami K, Tada M, Koli Y. Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc. 1974; 20:148-151. 46. Laurence BH, Cotton PB. Decompression of malignant biliary obstruction by duodenoscope intubation of the bile duct. Br Med J. 1980;280(6213):522-523. 47. Soehendra N, Reijnders-Frederix V. Palliative bile duct drainage. A new endoscopic method of introducing a transpapillary drain. Endoscopy. 1980;12:8-11. 48. Cohen S, Bacon BR, Berlin JA. National Institutes of Health Stateof-the-Science Conference Statement: ERCP for diagnosis and therapy, January 14-16, 2002. Gastrointest Endosc. 2002;56(6): 803-809. 49. Adler DG, Baron TH, Davila RE, et al. ASGE guideline: the role of ERCP in diseases of the biliary tract and the pancreas. Gastrointest Endosc. 2005;62(1):1-8. 50. Badalov N, Tenner S, Baillie J. The prevention, recognition and treatment of post-ERCP pancreatitis. JOP. 2009;10(2):88-97. 51. Fanti L, Agostoni M, Casati A, et al. Target-controlled propofol infusion during monitored anesthesia in patients undergoing ERCP. Gastrointest Endosc. 2004;60:361-366. 52. Wehrman T, Kokabpick S, Lembcke B, Caspary WF, Seifert H. Efficacy and safety of intravenous propofol sedation during routine ERCP: a prospective, controlled study. Gastrointest Endosc. 1999; 49:677-683. 53. Woods SD, Chung SC, Leung JW, Chan AC, Li AK. Hypoxia and tachycardia during endoscopic retrograde cholangiopancreatography: detection by pulse oximetry. Gastrointest Endosc. 1989;35: 523-525. 54. Karamanolis G, Katsikani A, Viazis N, et al. A prospective crossover study using a sphincterotome and a guidewire to increase the success rate of common bile duct cannulation. World J Gastroenterol. 2005;11(11):1649-1652. 55. Laasch HU, Tringali A, Wilbraham L, et al. Comparison of standard and steerable catheters for bile duct cannulation in ERCP. Endoscopy. 2003;35(8):669-674.

327.e2 56. Rossos PG, Kortan P, Haber G. Selective common bile duct cannulation can be simplified by the use of a standard papillotome. Gastrointest Endosc. 1993;39(1):67-69. 57. Tse F, Yuan Y, Moayyedi P, Leontiadis GI. Guide wire-assisted cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. Endoscopy. 2013;45(8):605-618. 58. Mariani A, Giussani A, Di Leo M, Testoni S, Testoni PA. Guidewire biliary cannulation does not reduce post-ERCP pancreatitis compared with the contrast injection technique in low-risk and high-risk patients. Gastrointest Endosc. 2012;75:339-346. 59. Goldberg E, Titus M, Haluska O, Darwin P. Pancreatic-duct stent placement facilitates difficult common bile duct cannulation. Gastrointest Endosc. 2005;62(4):592-596. 60. Tse F. Pancreatic duct guidewire placement for biliary cannulation for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Cochrane Database Syst Rev. 2016;16(5):CD010571. 61. Harewood GC, Baron TH. An assessment of the learning curve for precut biliary sphincterotomy. Am J Gastroenterol. 2002;97: 1708-1712. 62. Rajnakova A, Goh PM, Ngoi SS, Lim SG. ERCP in patients with periampullary diverticulum. Hepatogastroenterology. 2003;50(51): 625-628. 63. Tham TCK, Kelly M. Periampullary duodenal diverticula, bile duct stones, and ERCP. Endoscopy. 2004;36:1050-1053. 64. Forbes A, Cotton PB. ERCP and sphincterotomy after Billroth II gastrectomy. Gut. 1984;25:971-974. 65. Wright BE, Cass OW, Freeman ML. ERCP in patients with longlimb Roux-en-Y gastrojejunostomy and intact papilla. Gastrointest Endosc. 2002;56:225-232. 66. Inamdar S, Slattery E, Sejpal DV, et al. Systematic review and meta-analysis of single-balloon enteroscopy–assisted ERCP in patients with surgically altered GI anatomy. Gastrointest Endosc. 2015; 82:9-19. 67. Anand BS, Vij JC, Mac HS, Chowdhury V, Kumar A. Effect of aging on the pancreatic ducts: a study based on endoscopic retrograde pancreatography. Gastrointest Endosc. 1989;35:210-231. 68. Bernard JP, Sahel J, Giovannini M, Sarles H. Pancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases. Pancreas. 1990;5:248-254. 69. Fukuda Y, Tsuyguchi T, Sakai Y, Tsuchiya S, Saisyo H. Diagnostic utility of peroral cholangioscopy for various bile-duct lesions. Gastrointest Endosc. 2005;62(3):374-382. 70. Itoi T, Osanai M, Igarashi Y, et al. Diagnostic peroral video cholangioscopy is an accurate diagnostic tool for patients with bile duct lesions. Clin Gastroenterol Hepatol. 2010;8(11):934-938. 71. Yamao K, Ohashi K, Nakamura T, et al. Efficacy of peroral pancreatoscopy in the diagnosis of pancreatic diseases. Gastrointest Endosc. 2003;57(2):205-209. 72. Osanai M, Itoi T, Igarashi Y, et al. Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study. Endoscopy. 2013;45(8):635-642. 73. Kulpatcharapong S, Pittayanon R, Kerr SJ, Rerknimitr R. Diagnostic performance of digital and video cholangioscopes in patients with suspected malignant biliary strictures: a systematic review and meta-analysis. Surg Onc. 2021. Online ahead of print. 74. Sethi A, Chen YK, Austin GL, et al. ERCP with cholangiopancreatoscopy may be associated with higher rates of complications than ERCP alone: a single-center experience. Gastrointest Endosc. 2011; 73:251-256. 75. Andriulli A, Loperfido S, Napolitano G, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastrotenterol. 2007;102(8):1781-1788. 76. Kapral C, Duller C, Wewalka F, Kerstan E, Vogel W, Schreiber F. Case volume and outcome of endoscopic retrograde cholangiopancreatography: results of a nationwide Austrian benchmarking project. Endoscopy. 2008;40(8):625-630. 77. Cheng C, Sherman S, Watkins JL, et al. Risk factors for post-ERCP pancreatitis: a prospective multicenter study. Am J Gastroenterol. 2006;101(1):139-147. 78. Christensen M, Matzen P, Schulze S, Rosenberg J. Complications of ERCP: a prospective study. Gastrointest Endosc. 2004;60:721-731. 79. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335:909-918.

80. Loperfido S, Angelini G, Benedetti G, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48:1-10. 81. Iqbal CW, Askegard-Giesmann JR, Pham TH, Ishitani MB, Moir CR. Pediatric endoscopic injuries: incidence, management and outcomes. J Pediatr Surg. 2008;43(5):911-915. 82. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc. 1991;37:383-391. 83. Okuno M, Himeno S, Kurokawa M, et al. Changes in serum levels of pancreatic isoamylase, lipase, trypsin, and elastase after endoscopic retrograde pancreatography. Hepatogastroenterology. 1985;32:87-90. 84. Johnson GK, Geenen JE, Johanson JF, Sherman S, Hogan WJ, Cass O. Evaluation of post-ERCP pancreatitis: potential causes noted during controlled study of differing contrast media. Midwest Pancreatidcobiliary Study Group. Gastrointest Endosc. 1997;46:217-222. 85. Ratani RS, Mills TN, Ainley CC, Swain CP. Electrophysical factors influencing endoscopic sphincterotomy. Gastrointest Endosc. 1999;49:43-52. 86. Hannigan BF, Keeling PW, Slavin B, Thompson RP. Hyperamylasemia after ERCP with ionic and non-ionic contrast media. Gastrointest Endosc. 1985;31:109-110. 87. George S, Kulkarni AA, Stevens G, Forsmark CE, Draganov P. Role of osmolarity of contrast media in the development of postERCP pancreatitis: a meta-analysis, Dig Dis Sci. 2004;49:503-508. 88. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for postERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc. 2001;54:425-434. 89. Testoni PA, Mariani A, Giussani A, et al. Risk factors for postERCP pancreatitis in high- and low-volume centers and among experts and non-expert operators, a prospective multicenter study. Am J Gastroenterol. 2010;105:1753-1761. 90. Singh P, Das A, Isenberg G, et al. Does prophylactic pancreatic stent placement reduce the risk of post-ERCP acute pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc. 2004;60: 544-550. 91. Fazel A, Quadri A, Catalano MF, Meyers SM, Geenen JE. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study. Gastrointest Endosc. 2003;57:291-294. 92. Freeman ML, Guda NM. Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc. 2004;59:830-834. 93. Kubiliun NM, Adams MA, Akshintala VS, et al. Evaluation of pharmacologic prevention of pancreatitis following endoscopic retrograde cholangiopancreatography: a systematic review. Clin Gastroenterol Hepatol. 2015;13(7):1231-1239. 94. Ding X, Chen M, Huang S, Zhang S, Zou X. Nonsteroidal antiinflammatory drugs for prevention of post-ERCP pancreatitis: a meta-analysis. Gastrointest Endosc. 2012;76:1152-1159. 95. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366:1414-1422. 96. Yaghoobi M, Rolland S, Waschke KA, et al. Meta-analysis: rectal indomethacin for the prevention of post-ERCP pancreatitis. Aliment Pharmacol Ther. 2013;38:995-1001. 97. Akbar A, Dayyeh BKA, Baron TH, et al. Rectal nonsteroidal antiinflammatory drugs are superior to pancreatic duct stents in preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a network meta-analysis. Clin Gastroenterol Hepatol. 2013;11:778-783. 98. Dumonceau JM, Andriulli A, Elmunzer BJ, et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline—updated June 2014. Endoscopy. 2014;46(9):799-815. 99. Rudin D, Kiss A, Wetz RV, Sottile VM. Somatostatin and gabexate for post-endoscopic retrograde cholangiopancreatography pancreatitis prevention: meta-analysis of randomized placebocontrolled trials. J Gastroenterol Hepatol. 2007;22(7):977-983. 100. Omata F, Deshpande G, Tokuda Y, et al. Meta-analysis: somatostatin or its long-acting analogue, octreotide, for prophylaxis against post-ERCP pancreatitis. J Gastroenterol. 2010;45(8):885-895. 101. Lee KT, Lee DH, Yoo BM. The prophylactic effect of somatostatin on post-therapeutic endoscopic retrograde cholangiopancreatography pancreatitis: a randomized, multicenter controlled trial. Pancreas. 2008;37(4):445-448.

327.e3 102. Chan HH, Lai KH, Lin CK, et al. Effect of somatostatin in the prevention of pancreatic complications after endoscopic retrograde cholangiopancreatography. J Chin Med Assoc. 2008; 71(12):605-609. 103. Concepcion MM, Gomez-Oliva C, Juanes A, et al. Somatostatin for prevention of post-ERCP pancreatitis: a randomized, doubleblind trial. Endoscopy. 2014;46(10):851-856. 104. Sudhindran S, Bromwich E, Edwards PR. Prospective randomized double-blind placebo-controlled trial of glyceryl trinitrate in endoscopic retrograde cholangiopancreatography-induced pancreatitis. Br J Surg. 2001;88(9):1178-1182. 105. Hao JY, Wu DF, Wang YZ, Gao YX, Lang HP, Zhou WZ. Prophylactic effect of glyceryl trinitrate on post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized placebocontrolled trial. World J Gastroenterol. 2009;15(3):366-368. 106. Sotoudehmanesh R, Eloubeidi MA, Asgari AA, Farsinejad M, Khatibian M. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol. 2014;109(6):903-909. 107. Seta T, Noguchi Y. Protease inhibitors for preventing complications associated with ERCP: an updated meta-analysis. Gastrointest Endosc. 2011;73(4):700-706. 108. Buxbaum J, Yan A, Yeh K, Lane C, Nguyen N, Laine L. Aggressive hydration with lactated ringer’s solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol. 2014;12(2):303-307. 109. Park CH, Paik WH, Park ET, et al. Aggressive intravenous hydration with lactated Ringer’s solution for prevention of post-ERCP pancreatitis: a prospective randomized multicenter clinical trial. Endoscopy. 2018;50(4):378-385. 110. Wu M, Jiang S, Lu X, et al. Aggressive hydration with lactated ringer solution in prevention of post-endoscopic retrograde cholangiography pancreatitis: a systematic review and meta-analysis. Medicine (Baltimore). 2021;100(16):e25598. 111. Bangarulingam SY, Gossard AA, Petersen BT, Ott BJ, Lindor KD. Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol. 2009;104(4):855-860. 112. Rerknimitr R, Kladcharoen N, Mahachai V, Kullavanijaya P. Result of endoscopic biliary drainage in hilar cholangiocarcinoma. J Clin Gastroenterol. 2004;38(6):518-523. 113. Navaneethan U, Gutierrez NG, Jegadeesan R, et al. Delay in performing ERCP and adverse events increase the 30-day readmission risk in patients with acute cholangitis. Gastrointest Endosc. 2013;78(1):81-90. 114. Sauter G, Grabein B, Huber G, Mannes GA, Ruckdeschel G, Sauerbruch T. Antibiotic prophylaxis of infectious complications with endoscopic retrograde cholangiopancreatography: a randomized controlled study. Endoscopy. 1990;22:164-167. 115. Bai Y, Gao F, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot prevent endoscopic retrograde cholangiopancreatography-induced cholangitis: a meta-analysis. Pancreas. 2009;38:126-130. 116. Harris A, Chan AC, Torres-Viera C, Hammett R, Carr-Locke D. Meta-analysis of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography (ERCP). Endoscopy. 1999;31:718-724. 117. Jendrzejewski JW, McAnally T, Jones SR, Katon RM. Antibiotics and ERCP: In vitro activity of amino-glycosides when added to iodinated contrast agents. Gastroenterology. 1980;78:745-748.

118. Larsen S, Russell RV, Ockert LK, et al. Rate and impact of duodenoscope contamination: a systematic review and meta-analysis. EClinicalMedicine. 2020;25:100451. 119. Petersen B, Cohen J, Hambrick RDH, et al. Multisociety guideline on reprocessing flexible GI endoscopes: 2016 update. Gastrointest Endosc. 2017;85(2):282-294. 120. Lo AY, Washington M, Fischer MG. Splenic trauma following endoscopic retrograde cholangiopancreatography (ERCP). Surg Endosc. 1994;8(6):692-693. 121. Wu WC, Katon RM. Injury to the liver and spleen after diagnostic ERCP. Gastrointest Endosc. 1993;39(6):824-827. 122. Wilkinson ML, Engelman JL, Hanson PJ. Intestinal perforation after ERCP in Billroth II partial gastrectomy. Gastrointest Endosc. 1994;40(3):389-390. 123. Katsinelos P, Paroutoglou G, Papaziogas B, et al. Treatment of a duodenal perforation secondary to an endoscopic sphincterotomy with clips. World J Gastroenterol. 2005;11:6232-6234. 124. Solomon M, Schlachterman A, Morgenstern R. Iatrogenic duodenal perforation treated with endoscopic placement of metallic clips: a case report. Case Rep Med. 2012;2012:609750. 125. Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver. AMA Arch Surg. 1953;66:599-616. 126. Couinaud C. Le Foie: Etudes Anatomiques et Chirurgicales. Paris: Masson; 1957. 127. Nichols DM, Burhenne HJ. Magnification in cholangiography. AJR Am J Roentgenol. 1984;141:947-949. 128. Niederau C, Sonnenberg A, Mueller J. Comparison of the extrahepatic bile duct size measured by ultrasound and by different radiographic methods. Gastroenterology. 1984;87:615-621. 129. Poralla T, Staritz M, Manns M, Klose K, Hommel G, Meyer zum Buschenfelde KH. Age and sex dependency of bile duct diameter and bile duct pressure: an ERC manometry study. Z Gastroenterol. 1985;23:235-239. 130. Torok N, Gores GJ. Cholangiocarcinoma. Semin Gastrointest Dis. 2001;12(2):125-132. 131. Riopel MA. Intrabiliary growth of metastatic colon adenocarcinoma: a pattern of intrahepatic spread easily confused with primary neoplasia of the biliary tract. Am J Surg Pathol. 1997;21(9):1030-1036. 132. Cottone M, Amuso M, Cotton PB. Endoscopic retrograde cholangiography in hepatic hydatid disease. Br J Surg. 1978;66:107. 133. Dyrszka H, Sanghavi B. Hepatic hydatid disease: findings on endoscopic retrograde cholangiography. Gastrointest Endosc. 1983;29:248-249. 134. Ibrahim MAH, Kawanishi H. Endoscopic retrograde cholangiography in the evaluation of complicated echinococcus of the liver. Gastrointest Endosc. 1981;27:20-22. 135. Winters C, Chobanian SJ, Benjamin SB, Ferguson RK, Cattau EL. Endoscopic documentation of Ascaris-induced acute pancreatitis. Gastrointest Endosc. 1984;30:83-84. 136. Yellin AE, Donovan AJ. Biliary lithiasis and helminthiasis. Am J Surg. 1981;142:128-135. 137. Lam SK, Wong KP, Chan PK, Ngan H, Ong GB. Recurrent pyogenic cholangitis: a study by endoscopic retrograde cholangiography. Gastroenterology. 1978;74:1196-1203. 138. Navab F, Diner WC, Westbrook KC, Kumpuris DD, Uthman UO. Endoscopic biliary lavage in a case of Clonorchis sinensis. Gastrointest Endosc. 1984;30:292-294. 139. Hauser SC, Bynum TE. Abnormalities on ERCP in a case of human fascioliasis. Gastrointest Endosc. 1984;30:80-81.

CHAPTER 21 Diagnostic angiography in hepatobiliary and pancreatic disease: Indications Aaron W.P. Maxwell and Hooman Yarmohammadi OVERVIEW Once a mainstay of diagnosis in hepatobiliary and pancreatic diseases, indications for catheter angiography have changed significantly in the past three decades. This is mainly because of the widespread adoption of noninvasive imaging modalities such as multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI). These imaging techniques can accurately demonstrate both vascular and nonvascular structures associated with the hepatobiliary and pancreatic systems without the risks of conventional diagnostic angiography (see Chapters 16 and 17). Historically, indications for catheter angiography have included the identification and characterization of focal liver lesions, the delineation of hepatic arterial anatomy before liver resection or transplantation, the assessment of vascular invasion by pancreatic cancer or cholangiocarcinoma, and the ascertainment of the organ of origin of an abdominal mass. Because of their improved sensitivity and specificity, however, computed tomography (CT) angiography and magnetic resonance angiography (MRA) have together all but replaced catheter angiography for these indications. Presently, catheter angiography is principally reserved for anatomic delineation before contemporaneous catheter-based interventions, including embolization of gastrointestinal (GI) bleeding (see Chapter 28), hepatic artery embolization (see Chapter 31), chemoembolization (see Chapter 94A), radioembolization (see Chapter 94B), and chemoperfusion (see Chapters 97 and 100). Contemporaneous with advances in CT and MRI, recent developments in imaging technology have enabled greater visualization of vascular anatomy during conventional catheter angiography. Cone beam CT (CBCT) is one such example, which allows the user to perform a three-dimensional (3D) rotational acquisition using the fluoroscope to generate a volumetric data set akin to helical CT within a smaller field of view. CBCT images can undergo multiplanar reformatting for improved visualization of vascular anatomy, as may be associated with a target lesion such as a liver tumor. In addition, many vendors offer software packages for automated vessel tracking, which serve to highlight tumor-feeding vessels to improve outcomes for embolization or infusion procedures. Hybrid imaging, or image fusion, techniques have further advanced the field of modern catheter angiography. Such techniques allow the operator to superimpose angiographic and cross-sectional imaging data in real-time to help facilitate improved visualization and targeting of lesions during therapeutic interventions. Data from both MDCT and MRI examinations obtained before the procedure can be used. The images can be post-processed and rendered in a 3D format to provide an anatomic depiction that would not be available by either technique alone. 328

In this chapter, we will discuss angiographic anatomy relevant to hepatobiliary and pancreatic surgery and discuss current indications for performing catheter angiography relevant to the hepatobiliary and pancreatic systems. Additionally, we will discuss localization of occult neuroendocrine tumors of the pancreas. Our discussion on splanchnic veins will include venographic anatomy, venous sampling, techniques of catheterbased venous imaging, and venous imaging before surgical or percutaneous venous interventions.

Angiography Technique In recent years, technologic advances have resulted in significant improvements in angiographic imaging. Cut-film angiography has been replaced with digital flat-panel detectors and biplane angiography units. Biplane angiography is capable of producing high-quality images in 3D views. These advances in technology allow for less contrast while minimizing radiation exposure to both patients and interventionalists. Depending on the procedure, catheter angiography may be performed under conscious sedation or general anesthesia. Most angiographic procedures are performed on an outpatient basis; however, some patients may require overnight stay primarily for pain control after embolization-based interventions or for symptoms related to recovery from anesthesia. All patients are seen in the clinic before the diagnostic or interventional catheter angiography procedure. During this visit, indications for performing the procedure are reviewed. Additionally, patients are assessed for any history of cardiopulmonary or renal disease. Prior history of angiography or other surgical interventions are also assessed. A thorough physical examination, which includes a detailed pulse examination and an assessment of the airway, lungs, and heart, is performed. Finally, patients’ performance status is evaluated. Most institutions either use Eastern Cooperation Oncology Group (ECOG) performance status or Karnofsky performance status. The procedure is explained to the patient in detail and after a discussion of the risks and benefits of the procedure, written informed consent is obtained. Relevant laboratory parameters reviewed before catheter angiography include serum creatinine and estimated glomerular filtration rate, hemoglobin and hematocrit levels, platelet count, and prothrombin time and international normalized ratio (INR). For liver-directed interventions such as embolization, serum bilirubin is also assessed. Additionally, a baseline 12-lead electrocardiogram (ECG) may be considered in patients with known or suspected cardiac disease. In patients with significant comorbidities, cardiology or geriatric consultation should be considered before the procedure to ensure the safety of conscious sedation or general anesthesia. In patients with a history of preexisting renal impairment, prophylactic measures may be considered to lower the risk of

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

further reductions in glomerular filtration rate related to the injection of iodinated contrast media during catheter angiography. Although multiple agents, including sodium bicarbonate and Nacetyl cysteine infusion, have been evaluated in randomized clinical trials (RCTs), intravenous (IV) hydration with normal saline (NS) solution before and/or subsequent to catheter angiography is the only measure currently recommended for this purpose. The risk of bleeding from the puncture site is low, and hematomas complicate 1% of femoral punctures and 3% of nonradial upper extremity punctures. An abnormal bleeding profile related to thrombocytopenia or an elevated INR increases the risk of hemorrhage, but there is only weak association between magnitude of INR elevation and procedure-related hemorrhage. The need to correct an underlying coagulopathy is dependent on the specific procedure to be performed and the preference of the angiographer. Based on the current recommendations from the Society of Interventional Radiology (SIR) consensus guideline, diagnostic catheter angiography (arterial intervention with access size up to 6 French [F]) is classified as a procedure with a low risk of bleeding. For this procedure, SIR recommends platelet count above 20,000 3 106 per liter and an INR of less than or equal to 1.8 for femoral access and 2.2 for radial access.1 Patients are advised to stop eating 6 hours before the procedure. IV hydration is recommended before, during, and after the arteriogram to diminish adverse effects of contrast media on renal function. The patient should also be encouraged to take ample fluids by mouth after the procedure. The right common femoral artery is the most common access site. The left common femoral artery, axillary artery, brachial artery, or radial artery may be used as alternatives when clinically appropriate. In the past few years, there has been growing interest and expertise with radial artery access, particularly with interventional cardiology procedures. With appropriate technique, including ultrasonographic guidance at the time of arterial puncture, the trans-radial approach is associated with low risk of bleeding or vessel injury and affords patients the advantage of immediate ambulation after catheter angiography. Additionally, recent studies have demonstrated comparable procedural and clinical outcomes with the trans-radial approach when compared with the trans-femoral approach.2 For all arterial access procedures, the desired puncture area is cleansed, and the patient is draped in a sterile fashion. In most centers, arterial entry is performed under real-time ultrasound guidance using a 21-gauge micropuncture set. The use of ultrasonography allows for assessment of the quality of the common femoral artery, depicts the position of the profunda femoris, and detects the presence of aberrant veins extending ventral to the puncture site. After entry into the vessel, the appropriate catheter is inserted for catheterization of the target vessel. After diagnostically adequate images are obtained, the catheter is removed, and one of a variety of closure devices is deployed to seal the arteriotomy; manual pressure may also be applied for 15 to 20 minutes, or until hemostasis is achieved. Patients are observed in a postprocedural area until they have recovered from sedation, and most can be discharged home 2 to 4 hours later.

329

encountered anatomy (Fig. 21.1) is the left gastric artery, splenic artery, and common hepatic artery (CHA) taking origin from the celiac axis. The CHA divides into the gastroduodenal artery (GDA) and proper hepatic artery, with the latter dividing into the right and left hepatic arteries (RHA and LHA, respectively). The right gastric artery most often originates from the base of the left hepatic artery, and the cystic artery most often originates from the right hepatic artery, but considerable variations in the origins of these arteries exist.3 Moreover, accessory duodenal arteries, either representing a supraduodenal or a retroduodenal artery, are frequently encountered; this is critical to recognize when planning embolization, chemoembolization, and radioembolization. The normal arterial supply to the liver is shown in Fig. 21.2, which shows the commonly recognized variations of the LHA,

RHA CyA

LHA LGA

RGEA

CHA

GDA

RGA CA

SA

FIGURE 21.1  Conventional celiac artery anatomy. CA, Celiac axis; CHA, common hepatic artery; CHA, cystic artery; GDA, gastroduodenal artery; LGA, left gastric artery; LHA, left hepatic artery; RGA, right gastric artery; RGEA, right gastroepiploic artery; RHA, right hepatic artery; SA, splenic artery. (See Chapter 2.)

II VIII

IV

III

V VII VI

RHA

LHA PHA

HEPATOBILIARY AND PANCREATIC ARTERIAL ANATOMY Arterial Anatomy Arterial anatomy has been discussed elsewhere (see Chapter 2) and will only be briefly reviewed here. The most frequently

FIGURE 21.2  Arterial anatomy of the liver. LHA, Left hepatic artery; PHA, proper hepatic artery; RHA, right hepatic artery. Additional vessels are labeled in accordance to the Couinaud segment they supply. (See Chapter 2.)

330

PART 2  DIAGNOSTIC TECHNIQUES

taking origin from the left gastric artery, and the RHA taking origin from the superior mesenteric artery (SMA). It is important to recognize that either a part or the entirety of the RHAs and LHAs may have these variant origins. When the entire vessel has a variant origin, it is termed replaced. If the entire trunk does not take a variant origin, the vessel is termed accessory. For example, if the right lobe is supplied by an RHA originating from the CHA, as well as an RHA taking origin from the SMA, the latter would be termed an accessory RHA. If the entire right lobe was supplied by an artery taking origin from the SMA, it would be called a replaced RHA (see Chapter 2). In most patients, the arteries to Couinaud segments I, II, III, and IV are branches of the LHA, and arteries to segments V, VI, VII, and VIII are branches of the RHA. The most variable segmental branch is to segment IV. Although most frequently arising as a branch vessel from the LHA, the segment IV artery may also take origin from the RHA, assuming the misnomer of a “middle hepatic artery” in older works. Separate origins of segment IVa, usually from the LHA, and segment IVb from the RHA are frequently identified. Also, a branch from the segment IV artery is often seen extending outside of the liver toward the abdominal wall along the midline, supplying the falciform ligament (Fig. 21.3). Recognition of this vessel is important when conducting embolization, chemoembolization, or radioembolization to avoid nontarget embolization, which may result in ischemia or radiation dermatitis to the periumbilical region. The RHA conventionally divides into an anterior (ventral) and a posterior (dorsal) branch. The anterior branch usually is more vertically oriented and supplies segments V and VIII. The posterior branch is usually more horizontally oriented and supplies segments VI and VII. More than one projection is usually required to ascertain with certainty which is the anterior branch

GDA

RGA PSPD

ASPD

FIGURE 21.4  Arterial anatomy of the pancreas. ASPD, Anterior superior pancreaticoduodenal artery; GDA, gastroduodenal artery; PSPD, posterior-superior pancreaticoduodenal artery; RGA, right gastric artery. (See Chapter 2.)

and which the posterior branch. In the right anterior oblique projection, the anterior branch moves medially, and the posterior branch moves laterally when compared with the posteroanterior (PA) projection. The entire segmental arterial supply to the liver should be accounted for before hepatic arterial therapy, major hepatic resection, partial hepatectomy (see Chapters 101 and 118), or living donor liver transplantation (LDLT, see Chapters 109 and 125). Adjunctive techniques such as CBCT may be used, as necessary, to achieve optimal delineation of hepatic vascular anatomy. The arterial supply to the pancreas is somewhat variable. The most consistent supply is to the pancreatic head, formed by a rich anastomotic arcade between the superior pancreaticoduodenal (SPD) artery arising from the GDA and the inferior pancreaticoduodenal (IPD) artery arising from the SMA (Fig. 21.4). There, variable arteries give rise to both anterior and posterior divisional branches. Additional pancreatic arterial supply includes the transverse pancreatic artery, which runs along the middle portion of the long axis of the pancreas and may take origin from the arterial arcade in the head of the pancreas, directly from the GDA, or as a branch of the dorsal pancreatic artery, which variably originates from the CHA or the splenic artery (Fig. 21.5). The transverse pancreatic artery may anastomose distal with the pancreatica magna artery, which typically arises from the splenic artery. A number of small branches from the splenic artery supply the pancreatic body and tail, but the number and location of these arteries vary and must be identified in each individual patient when clinically relevant (see Chapter 2).

Venous Anatomy

FIGURE 21.3  Subtracted angiography from celiac artery demonstrating the falciform artery (black arrow) arising from segment 4 hepatic artery branch (white arrow). This artery courses inferiorly with an inverted V-shaped distal branches and supplies the anterior abdominal wall, superior to the umbilicus.

The splenic vein and superior mesenteric vein (SMV) join to form the main portal vein (see Chapter 2). The inferior mesenteric vein (IMV) usually enters the splenic adjacent to the confluence, but it may also enter the SMV either at or just caudal to the confluence. The coronary vein most often drains into the cephalic aspect of the main portal vein just beyond the confluence of the SMV and splenic vein. The number and location of veins draining the pancreas is variable. Multiple small, unnamed veins drain directly into the splenic vein. Typically,

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

DP

TP

FIGURE 21.5  Arterial anatomy of the pancreas. DP, Dorsal pancreatic artery; TP, transverse pancreatic artery. (See Chapter 2.)

the anterior SPD vein drains directly into the portal vein, and the posterior SPD vein drains into the SMV. The IPD veins drain into the SMV at the caudal margin of the pancreas, and the portal vein courses obliquely cephalad from near the midline toward the liver, where it divides to supply the right and left lobes. This division, as well as the division into segmental branches, is variable and must be delineated when clinically relevant for each individual patient.

ANGIOGRAPHY INDICATIONS As mentioned earlier in this chapter, historical indications for performing diagnostic catheter angiography, including assessments of vascular invasion before potential pancreatic or biliary surgery, characterization of focal liver lesions, and preoperative arterial mapping before major hepatic resection, have been replaced by multidetector computed tomography angiography (MDCTA). MDCTA provides higher sensitivity and diagnostic accuracy for these indications. On rare occasion, there is a specific piece of critical anatomic information that cannot be ascertained with certainty by MDCTA, such as the origin and course of the artery to segment IV before a living donor partial hepatectomy. In these circumstances, catheter angiography can be a useful adjunctive technique. On extremely rare occasions, large tumors are identified on cross-sectional imaging, but the organ of origin cannot be determined. The majority of these are large sarcomas of the retroperitoneum but excluding a pancreatic source may be difficult. A similar situation can occur with large right adrenal or renal tumors blending with the hepatic parenchyma. In these highly selected cases, catheter angiography can be useful in delineating the organ of origin by demonstrating the primary arterial supply. Currently, the most common indication for arteriography is planning an arterial-based intervention such as embolization (see Chapter 94A), chemoembolization (see Chapter 94A), radioembolization (see Chapter 9B), or chemo-perfusion (see Chapters 97 and 100) to treat a primary or metastatic hepatic malignancy. These specific interventions will be discussed elsewhere in this book. Inadvertent administration of embolic particles, radiation particles, or chemotherapeutic agents into

331

arteries supplying the stomach or duodenum can lead to significant adverse outcomes, including death.4 Small anastomotic connections between intrahepatic branches to the lower esophagus, stomach, and diaphragm are of equal importance.5 As previously described, most modern angiography suites are equipped with CBCT imaging technology. This technology uses a fixed C-arm system equipped with a flat-panel detector and requires 3D CT volumetric images.6 CBCT has improved feasibility, effectiveness, and safety of many imageguided procedures by allowing the interventionalist to identify extrahepatic perfusion from aberrant hepatic arterial branches (Fig. 21.6). Other current indications of performing catheter angiography in the hepatobiliary and pancreatic system are as follows: 1. Treatment of bleeding/hemorrhage from liver, spleen and pancreas (see Chapters 113, 114, and 116) 2. Diagnosis of arterial occlusive diseases 3. Diagnosis and treatment of arterial stenosis 4. Treatment of visceral arterial aneurysms (see Chapter 115) 5. Diagnosis of vasculitis 6. Diagnosis of other visceral vascular disease 7. Localization of functional pancreatic neuroendocrine tumors (see Chapter 65) These indications will be discussed in the following sections.

Treatment of Bleeding/Hemorrhage Bleeding from the liver, spleen, or pancreas is most often secondary to iatrogenic or noniatrogenic trauma, but it may occur spontaneously in patients with mycotic aneurysms, pancreatitis, or collagen vascular diseases. Angiography is usually not used to ascertain whether arterial hemorrhage is present but rather to precisely localize and treat the offending vessel. Embolization of arterial bleeding will be discussed elsewhere in this book (see Chapters 28, 115, and 116), but salient features will be reviewed in this chapter.

Splenic Bleeding The most common cause of bleeding from the spleen is blunt trauma, and nonoperative management is currently the standard of practice. Splenic artery embolization has been established as a method to increase the success rate of nonoperative management of traumatic splenic injuries.7 A comparative study between two cohorts consisting of 625 patients over a 15-year period revealed an improved success rate of nonoperative management from 77% to 96% with the advent of splenic embolization.8 The indications for splenic arteriography and splenic arterial embolization are based on CT findings and include active contrast blush beyond or within the splenic parenchyma, pseudoaneurysm, an associated large hemoperitoneum, and a high-grade splenic injury.7 Moreover, the American Association for the Surgery of Trauma recommends angiography for grade III, IV, and V splenic injuries.9 Two techniques are used to perform splenic embolization. The first is occlusion of the proximal splenic artery with coils or Amplatzer plugs (AGA Medical, Plymouth, MN), and the second is selective small intrasplenic arterial embolization with a gelatin sponge or coils. Distal super-selective particle embolization has also been described. Collaterals through the short gastric arteries and the gastroepiploic arcade usually maintain splenic viability after proximal splenic artery occlusion, whereas distal intrasplenic embolization generally results in a variable degree of splenic infarction, depending on the size of the artery

332

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 21.6  Extrahepatic perfusion detected with C-arm computed tomography (CCT). A, Selective cystic arteriogram shows the gallbladder and several branches extending medially (arrow). B, CCT performed during contrast injection of the cystic artery confirms aberrant perfusion of the duodenum (arrowheads). (Courtesy Daniel Sze, Stanford University.)

occluded because intrasplenic arteries have no significant collateral routes. Both techniques have equivalent rates of major infarctions and infections requiring splenectomy.10 Distal splenic embolization is associated with higher rates of infarction; however, these infarctions are limited to the segments just distal to the site of embolization and are often of no clinical relevance. In summary, the current literature is inconclusive regarding whether the proximal or distal embolization should be used, although results from a recent systematic review and metaanalysis suggested proximal embolization may reduce the risk for postprocedure complications.11 Minor complications, including fever, pleural effusion, and partial splenic infarction, have been reported in up to 34% of patients using both techniques. Major complications, including splenic abscesses, splenic infarction, splenic atrophy, and postprocedure bleeding, have been observed in 14% of patients.10

Hepatic Bleeding Arterial hemorrhage from the liver may be encountered from blunt or penetrating trauma (see Chapter 113) but is most commonly because of an iatrogenic injury related to biopsy (see Chapter 23) or percutaneous transhepatic biliary drainage (PTBD; see Chapters 31 and 52). Arteriographic findings indicating a source of hemorrhage include extravasation, pseudoaneurysm formation, and arteriovenous fistula (see Chapter 115). In contrast to the spleen, a rich collateral network exists in the hepatic arterial bed, making proximal occlusion of the offending artery ineffective in many cases. Therefore super-selective catheterization using coaxial microcatheters to deposit coilspring emboli both distal and proximal to the area of injury is

the preferred technique for embolization when a discrete bleeding site can be identified (Fig. 21.7). The use of liquid embolic agents such as n-cyanoacrylate glue may also be considered since these agents may achieve rapid and focal hemostasis even in the setting of diminished thrombus formation because of coagulopathy or thrombocytopenia. For more diffuse injuries with multiple bleeding sites secondary to blunt trauma, using particulate embolization with a gelatin sponge may be a useful adjunct. As with blunt splenic injuries, nonoperative management has become the preferred method of management in hemodynamically stable patients. The success rate of this management exceeds 90%.12 Two main indications for hepatic angiography and embolization are primary hemostatic control in a hemodynamically stable patient that has radiographic evidence of active arterial hemorrhage and adjunctive hemostatic control after surgical exploration and packing of a hepatic parenchymal injury with evidence of continued bleeding or hemodynamic instability. Additionally, patients who present with hemodynamic instability can be successfully resuscitated with embolization.13 The yield of arteriography in identifying an arterial injury amenable to embolization is higher when the CT scan suggests a vascular injury. Complications after embolization of a hepatic arterial injury secondary to blunt trauma are relatively frequent.14 In a retrospective study, Letoublon et al. reported a 70% liver complication rate.14 These complications include hepatic ischemia, infarction, hepatic failure, gallbladder ischemia, bile leak, and abscess formation. The relative contribution of the embolization to these complications may be difficult to distinguish from sequelae of the underlying traumatic injury.

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

A

333

B

FIGURE 21.7  A, Digital subtracted angiography from celiac axis demonstrates active extravasation of contrast (black arrow) from the corresponding location of a liver biopsy consistent with post-liver biopsy bleeding. B, The injured/bleeding artery was embolized by coil embolization (black arrow). No further extravasation of contrast is detected on post-coil angiography.

Procedure-related iatrogenic injury to the hepatic artery may be suspected when a patient develops intracatheter or pericatheter hemorrhage after PTBD or when melena develops secondary to hemobilia after an intervention through the hepatic parenchyma. CT in these patients may or may not reveal an abnormality, and patients should undergo hepatic arteriography when a clinical suspicion of a hepatic arterial injury exists even in the absence of negative cross-sectional imaging. Patients with iatrogenic injuries usually have a single, discrete bleeding source that can be addressed with super-selective embolization techniques. Identification of a bleeding source may require provocation maneuvers, such as biliary catheter removal during the angiography. Complications related to the embolization procedure tend to be lower when compared with patients who have had blunt trauma because the traumatic injury to the liver is less extensive.

Pancreas Bleeding Bleeding from the pancreas is uncommon and usually encountered in patients with pancreatitis (see Chapters 56 and 58) or pancreatic surgery (see Chapters 28, 62, and 117). Posttraumatic bleeding from the pancreas is not frequently encountered in clinical practice. Pancreatic hemorrhage typically localizes to the retroperitoneum but may extend from the retroperitoneum into the peritoneal cavity or into the GI tract via communication with the pancreatic duct, a condition termed “hemosuccus pancreaticus.” Vascular complications are seen in 25% of patients suffering from pancreatitis and are usually arterial in origin. Proteolytic enzymes combined with intense inflammation can erode small arterial branches and create foci of extravasation or small pseudoaneurysms. Although this complication is encountered in only 2% to 5% of cases, it may be life threatening. Pseudocysts may erode into small arterial branches, leading to hemorrhage within the pseudocyst, or may erode into larger arterial branches and create a large pseudoaneurysm (Fig. 21.8; see Chapter 115). These pseudoaneurysms are most frequently identified in the splenic artery or its branches (60%–65%), followed by the GDA (20%–25%),

pancreaticoduodenal arteries (10%–15%), hepatic artery (5%–10%), and left gastric artery (2%–5%).15,16 The sensitivity of MDCT for the identification of pseudoaneurysms in patients with acute pancreatitis has been reported as high as 90%, obviating the need for angiography in most instances. However, small pseudoaneurysms arising from one or more intrapancreatic or peripancreatic arteries may not be visible using cross-sectional imaging.17 As with hepatic bleeding, conventional catheter angiography may be warranted in patients with clinical and/or laboratory evidence of significant active or recurrent hemorrhage of a pancreatic source despite unrevealing CT imaging. When the bleeding site is identified angiographically, it can be controlled with embolotherapy in up to 88% of patients.18 Angiography and embolization is also feasible and safe in treatment of hemorrhagic complications after pancreatic surgery19,20 (see Chapters 28, 62, and 117). Yekebas et al. reported significant hemorrhage in 5.7% of 1669 consecutive patients after partial or total pancreatectomy.19 In a more recent study, Casadei et al. reported significant hemorrhage in 9.8% of 182 patients after pancreatic resection for pancreatic and periampullary diseases.20 Bleeding may manifest clinically as GI hemorrhage, retroperitoneal or intraperitoneal hematoma, or bleeding through percutaneous or surgically placed drains. When a pancreaticojejunal anastomosis has been created, disruption of the anastomosis may lead to false localization of the bleeding site. Specifically, an extraluminal bleeding site may drain into the bowel through the dehisced anastomosis, or bleeding from the bowel at the anastomosis may extend outside the lumen to cause an intraperitoneal hematoma or hemorrhage through a drain. Angiography can be extremely useful in the diagnosis and treatment of these patients. In 25 of 43 patients undergoing angiography to diagnose and treat post-pancreatectomy hemorrhage, a bleeding site was located and embolized with an 80% success rate in controlling the hemorrhage.19 The relatively low rate of positive angiograms may be explained by the high incidence of venous bleeding encountered in the post-pancreatectomy patient. Many of these patients develop regional portal hypertension as a result of splenic, portal, or

334

PART 2  DIAGNOSTIC TECHNIQUES

A

C

SMV compression or occlusion secondary either to the underlying pathology or a surgical complication. Venous extravasation is rarely identified by arteriography but may be suggested by CT. If the underlying etiology is compression of the splenic or portal veins, percutaneous transvenous stenting may be potentially useful.

Diagnosis of Arterial Occlusive Disease Many arterial disorders that involve the primary branches of the celiac trunk, as well as the SMA, can be assessed adequately with MDCT or MRA. However, delineation of pathology in smaller branches, such as with vasculitis, may require the increased morphologic detail afforded by catheter angiography. Arterial occlusive disease as a result of atherosclerosis and compression of the celiac axis by a median arcuate ligament are common diseases that do not generally influence the conduct of hepatobiliary or pancreatic surgery. The principal exception

B

FIGURE 21.8  Pseudoaneurysm secondary to pancreatitis treated with coil embolization. A, Contrast-enhanced computed tomography reveals a pseudoaneurysm in the pancreatic head (arrow). B, Selective gastroduodenal arteriogram reveals the pseudoaneurysm (arrow) taking origin from a branch of the anterior-superior pancreaticoduodenal artery. C, The pseudoaneurysm is occluded with coils (arrowheads). (See Chapter 115.)

is in the performance of orthotopic liver transplantation (OLT), when preservation of brisk hepatic arterial flow is essential (see Chapter 111). In that circumstance, the inflow must be corrected either by surgical or endovascular interventions. Another potential area of concern is pancreaticoduodenectomy, particularly in jaundiced patients. In this situation, sacrifice of the GDA is required, which interrupts the retrograde arterial flow from the SMA to the liver and may uncommonly result in hepatic ischemia and necrosis. Likewise, fibromuscular dysplasia may rarely involve the SMA, but associated clinical sequelae are extremely uncommon. The SMA may also be compromised in very rare circumstances by a median arcuate ligament.

Diagnosis and Treatment of Arterial Stenosis Hepatic arterial anastomotic stenoses are observed in up to 11% to 12% of patients after OLT (see Chapter 11).21,22

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

FIGURE 21.9  Hepatic artery stenosis after orthotopic liver transplantation. Celiac arteriogram shows mild diffuse narrowing of the hepatic artery with two areas of critical stenosis (arrowheads). (See Chapter 111.)

335

and location of the aneurysm. Covered stent placement may be used to exclude the aneurysm sac from the parent vessel, resulting in aneurysm thrombosis, and coil embolization may be used in patients with large or tortuous vessels where stenting is not feasible.25 As with aneurysms elsewhere in the body, both proximal and distal coil embolization across the aneurysm neck is advised to prevent retrograde aneurysm sac perfusion, potentially resulting in postembolization aneurysm enlargement and rupture. Traditionally, surgical resection or ligation of visceral artery aneurysms was considered the standard of care; however, endovascular treatments have largely supplanted open resection. Large studies have reported technical success rates ranging from 89% to 98%.25,26,30 Endovascular treatments are associated with shorter hospital stay compared with surgical repair (3.8 vs. 12 days). Operative mortality and morbidity are both elevated relative to endovascular therapies for visceral aneurysms, particularly those that arise secondary to infection or inflammation (e.g., pancreatitis) or in the setting of prior surgical intervention.

Diagnosis of Vasculitis Vasculitis Although these stenoses are usually detected by surveillance duplex ultrasound and confirmed with MDCTA, catheter angiography is often performed to improve morphologic delineation and assess the degree of stenosis in preparation for endovascular treatment.23 Stenoses of the hepatic artery may also be more diffuse than suggested on noninvasive imaging studies such as ultrasound or CT (Fig. 21.9). Anastomotic stenoses of the hepatic artery anastomosis may lead to allograft dysfunction and biliary ischemia with the potential for diffuse biliary infarction if untreated. Severe stenosis may lead to hepatic artery thrombosis, which may yield irreversible allograft damage and necessitate re-transplantation. When a hepatic arterial stenosis is identified, endovascular therapy, including balloon angioplasty with or without stent placement, is warranted, with high published rates of technical success and few major complications.24

Vasculitides involving the hepatic arterial system may require catheter angiography for definitive diagnosis because of the technique’s increased spatial and temporal resolution since the characteristic microaneurysms and areas of arterial narrowing or irregularity may not be apparent by MDCT. The most common vasculitis with hepatic and pancreatic involvement is polyarteritis nodosa, which may not lead to symptoms despite involvement of the visceral arteries, although pancreatitis, cholecystitis, and hepatic dysfunction may be observed. Arterial abnormalities in the liver and pancreas have also been identified in patients with systemic lupus erythematosus and Wegener granulomatosus. In most patients, the underlying diagnosis is apparent, and the angiographic findings do not represent a diagnostic dilemma.

Treatment of Visceral Arterial Aneurysms

Segmental Arterial Mediolysis

Visceral artery aneurysms are rare entities that involve the celiac, splenic, superior mesenteric, or inferior mesenteric arteries and their branches (see Chapter 115). The prevalence of visceral artery aneurysm is 0.1% to 2%.25,26 True aneurysms involve all three vessel walls and are usually atherosclerotic or developmental in origin and differ from those encountered in pancreatic inflammatory disease, which are typically pseudoaneurysms. Depending on the size and location of the aneurysm, mortality from rupture ranges from 25% to 100%.27 The splenic artery is the most commonly affected artery (60%), followed by the hepatic artery (20%–50%). Splenic artery aneurysms in women of childbearing age are of particular concern because of their propensity to rupture during childbirth. Most splenic aneurysms are saccular and located in the mid to distal segment of the artery.28 The rate of rupture ranges from 3% to 20%.29 Size is the primary variable when considering intervention, with most societies and providers recommending definitive therapy for aneurysms greater than or equal to 2.0 cm in size. The endovascular treatment approach for splenic artery aneurysms depends on the tortuosity

Segmental arterial mediolysis (SAM) is a rare arteriopathy affecting vascular smooth muscle, resulting in the development of aneurysms, dissections, thrombosis, and, uncommonly, vessel rupture. SAM is most commonly seen in older adults and the cause remains unknown. Clinical manifestation are often nonspecific, and cross-sectional imaging may fail to identify or adequately delineate the true extent of the pathology, necessitating catheter angiography for reliable characterization of the relevant findings. Multifocal lesions with skip areas involving the superior mesenteric, hepatic, renal, and middle colic arteries in patients in their fourth to sixth decades are typical (Fig. 21.10). Medical treatment with immunosuppressants is not effective in patients with SAM, and endovascular interventions, including angioplasty, embolization, and stenting, represent the primary approach to therapy.31

Diagnosis of Other Visceral Vascular Disease

Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by telangiectasias of the skin and mucous

336

PART 2  DIAGNOSTIC TECHNIQUES

has previously been treated with transcatheter techniques, embolotherapy has currently fallen out of vogue because of the risk of precipitating hepatic failure. OLT is curative if the patient develops high-output cardiac failure.

Peliosis Hepatis Peliosis is a rare abnormality of the reticuloendothelial system that is most commonly encountered in the liver (peliosis hepatis). The name is derived from the Greek word “pelios,” which means “lead-colored,” referring to extravasated blood. Pathologically it is characterized by blood-filled cystic spaces that range in size from a few millimeters to multiple centimeters, distributed randomly in the liver. This abnormality has been associated with HIV infection and with the use of certain drugs, including immunosuppressives, antimetabolites, and oral contraceptives. Although usually benign, it has been associated with spontaneous massive hemorrhage and therefore may be encountered angiographically during the investigation of hepatic bleeding.33 Angiographically (Fig. 21.12), the lesions are easily visible as a disorganized collection of amorphous channels not dissimilar to those observed in HHT or hepatic hemangioma; however, the lack of shunting to the hepatic venous system distinguishes it from HHT, and the absence of sharp definition with persistence into the late venous phase distinguishes it from hemangioma. Peliosis hepatis should be among the differential diagnosis of multiple hypervascular lesions in a patient with long-standing history of oral contraceptive drug use and with no prior history of cancer.34

FIGURE 21.10  Segmental arterial mediolysis (SAM). Abdominal aortogram reveals a dissection with a small aneurysm in the celiac artery (arrow) as well as undulating irregularity of the common hepatic artery (arrowhead) typical of SAM.

membranes. HHT is also associated with arteriovenous malformations (AVMs) in the pulmonary and hepatic circulation, which may be life-threatening. Diagnosis is primarily clinical based on the Curacao criteria, which incorporates epistaxis, mucosal telangiectasia, visceral AVMS, and family history. Cross-sectional imaging, including ultrasound, CT, or MRI, plays a fundamental role in detecting visceral involvement in HHT. The hepatic arterial malformations that shunt blood into the hepatic venous system may be initially noted on a crosssectional imaging study, but the findings may be nonspecific. Catheter angiography can be diagnostic by depicting arteriovenous or arterioportal shunting (Fig. 21.11).32 Although HHT

A

Localization of Functional Pancreatic Neuroendocrine Tumors Calcium stimulation arteriography for the detection of pancreatic endocrine tumors was developed and described in 1991.35 Although unnecessary when imaging can confidently detect the offending pancreatic lesion, it is an extremely useful adjunct when the location of the lesion cannot be defined with confidence using noninvasive techniques (Fig. 21.13; see Chapter 65). To perform the localization, 1 mL of 10% calcium

B

FIGURE 21.11  Hereditary hemorrhagic telangiectasia (HHT). A, Selective hepatic arteriogram shows disorganized and dilated intrahepatic vessels typical of HHT. Coils are being placed preoperatively for impending liver transplantation. B, Slightly later in the sequence, early opacification of the hepatic vein is visible (arrowheads).

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

RIGHT

FIGURE 21.12  Peliosis hepatitis. Multiple small contrast collections can be seen within the hepatic parenchyma. This patient had spontaneous hemorrhage that created displacement of the hepatic parenchyma (arrowheads).

gluconate solution is selectively and sequentially injected via a microcatheter into small arteries supplying differing anatomic regions of the pancreatic parenchyma to provoke degranulation of hormone into the portal venous circulation. Serial blood samples taken from the hepatic vein and hormone level measurements are made. These measurements can then be

A

337

correlated with the anatomic location of injection, allowing for confident tumor localization. Given the heterogeneity of arterial supply to the pancreas, the operator must interrogate branches arising from the GDA, the SMA, and the splenic artery to ensure complete coverage of the pancreatic head, uncincate process, body, and tail. The origin of small branches supplying the pancreas from the splenic artery and CHA are important to note in determining the approximate areas of pancreatic arterial supply. In the aforementioned article by Guettier et al., calcium stimulation arteriography was the most sensitive technique for localizing surgically proven insulinomas with an accuracy of 84%, a false-negative rate of 11%, and a false-positive rate of 4%.36 Percutaneous transhepatic sampling of the splenic, superior, and portal venous system can also be performed to diagnose occult hormonally-active neuroendocrine tumors (NET) of the pancreas. This may be done in conjunction with calcium stimulation, as described, or it may be performed without stimulation because of the higher concentration of the hormone when obtained directly or adjacent to the venous tributary.

Insulinomas Insulinoma originates from b cells and is the most frequently hormonally active pancreatic NET. More than 90% of insulinomas are solitary, benign tumors for which surgical resection is curative. These tumors are the most common tumors originating from the islets of Langerhans (see Chapter 65). The most effective method of diagnosing insulinoma is a combination of dual-phase thin-section CT scan and endoscopic ultrasound (EUS; see Chapters 17 and 22).37 In a series of 75 surgicallyproven insulinomas, the sensitivities of CT and MRI were 28% and 35%, respectively.36 This series incorporated cross-sectional imaging dating back to the late 1980s that likely reduced the

B

FIGURE 21.13  Insulinoma. A, Selective gastroduodenal arteriogram shows no definite abnormality during the arterial phase. B, A subtle area of hypervascularity is identified during the capillary phase, possibly representing an insulinoma (arrowheads). This was confirmed as the region of tumor by calcium stimulation with venous sampling. (See Chapter 65.)

338

PART 2  DIAGNOSTIC TECHNIQUES

overall sensitivity. When cross-sectional imaging techniques were examined after 1994, the sensitivity of CT and MRI improved to 80% and 70%, respectively, because of improved imaging technology.38 More recent literature has shown even more favorable results, with 22 of 23 (96%) insulinomas identified before surgery using dual-energy CT technology.39 The sensitivity of EUS in detecting and localizing insulinomas ranges from 82% to 94%.40

Left portal vein

Gastrinomas Gastrin-secreting NET are the cause of Zollinger-Ellison syndrome, and in approximately one third of the cases are accosiated with multiple endocrine neoplasia (MEN) type 1. Fifty percent of gastrinomas occur in the pancreas, with the duodenum being the most common extrapancreatic location. Approximately 60% to 90% of gastrinomas are malignant. When a sporadic gastrinoma is identified, surgical resection is indicated. The role of surgery in patients with MEN type 1 is more controversial because of multiplicity of tumors and lack of an established survival benefit (see Chapter 65). The diagnosis and location of a gastrinoma can be established with a combination of somatostatin receptor scintigraphy (see Chapter 18) and EUS (see Chapter 22) in approximately 90% of patients. When an occult gastrinoma is encountered, angiography has been used for localization. The principles are identical to the localization of insulinomas; however, secretin has been used in addition to calcium gluconate as the stimulating agent. Sensitivities of arterial stimulation venous sampling (ASVS) in the detection of gastrinomas have ranged from 70% to 100%.41,42 Angiographically, gastrinomas are less hypervascular and more difficult to detect compared with insulinomas. Sensitivity of angiography alone without ASVS is less than 50%. Moreover, the 50% extrapancreatic location makes detection more difficult, often requiring superselective catheterization to evaluate the duodenum.

Glucagonoma Glucagonomas may occur sporadically or may be associated with MEN type 1. They originate from a cells of the pancreatic islets. These tumors are usually larger than gastrinomas or insulinomas at presentation, therefore localization can generally be achieved with cross-sectional imaging or EUS. Equchi et al. reported 8 patients with pancreatic hypervascular tumor and elevated serum glucagon level wherein glucagonomas were successfully localized using the ASVS technique.43

VENOGRAPHIC TECHNIQUES MDCT, magnetic resonance venography, and ultrasound are usually sufficient for depiction of the major visceral venous trunks and their primary branches in the vast majority of patients. Crosssectional imaging can accurately depict the relationship of a mass in the pancreas to both the splenic veins and SMVs. It also has the advantage of simultaneous opacification of all of the venous structures. However, in certain clinical situations, it is desirable to visualize the venous structures with a higher level of clarity. These situations include planning for percutaneous venous interventions in situations where occlusions are suspected or occasionally to plan a surgical portosystemic shunt. The most common technique to visualize the splanchnic vein is transarterial portography, in which selective splenic and

Right portal vein Main portal vein

Superior mesenteric vein

Inferior mesenteric vein

FIGURE 21.14  Arterial portography in a patient with hepatocellular carcinoma. During the venous phase of superior mesenteric arterial injection the inferior and superior mesenteric veins are opacified and join to form the main portal vein. The main then branches into left and right portal veins.

superior mesenteric arteriograms are performed with delayed imaging into the venous phase, depicting the splenic veins and SMVs, respectively (Fig. 21.14). When detailed visualization of the venous anatomy is required, a higher dose of contrast media can be used for the arterial injection, increasing the clarity of the venous opacification. When an extremely detailed evaluation is required, a combination of transarterial portography and MDCT can be performed (Fig. 21.15). The improved spatial and soft tissue contrast resolution of MDCT coupled with multiplanar and 3D reconstruction allows for visualization of venous anatomy that cannot be an-otherwise achieved by any other single technique. This is particularly useful in the presence of portal vein occlusion, when a complex venous reconstruction or bypass is being considered. Fig. 21.16 demonstrates a portovenography performed using a transsplenic access. The patient with unresectable pancreatic cancer presented with portal hypertension and ascites. Area of narrowing was treated with stent placement (see Fig. 21.16B). Direct venography of the splanchnic veins can be achieved by three routes: transjugular, transhepatic, and transsplenic. In the transjugular approach, a catheter is placed into the jugular vein and advanced into a hepatic vein. Free and wedged hepatic pressures can be obtained through this catheter to calculate corrected sinusoidal pressure in patients being assessed for portal hypertension. A biopsy of the hepatic parenchyma (trans­jugular liver biopsy) may also be performed during this procedure, when indicated. Injection of carbon dioxide through a catheter wedged in a hepatic vein or through a balloon catheter will often yield an image of the portal vein. If direct portography is warranted, one of several specially designed needles can be inserted to puncture the portal vein through the intervening hepatic parenchyma. A catheter is then advanced into the portal, splenic, or superior mesenteric venous system. This procedure is performed almost exclusively in patients

  Chapter 21  Diagnostic Angiography in Hepatobiliary and Pancreatic Disease: Indications

339

A

FIGURE 21.15  Multidetector computed tomography with three-dimensional reconstruction after superior mesenteric arterial injection. The superior mesenteric vein and cavernous transformation are easily visualized.

undergoing a transjugular intrahepatic portosystemic shunt (TIPS), but it is also used to manage selected patients with portal and SMV thrombosis.44 The portal venous system may also be accessed by a percutaneous transhepatic approach.45 After sterile preparation of the right upper quadrant, an intrahepatic portal venous radicle is punctured under real-time ultrasonographic guidance, permitting a vascular access sheath to be placed using a Seldinger technique. Standard guidewire and catheter manipulations are then used through the sheath for selectively catheterizing the splenic vein and the SMV or its branches. Once diagnostic images have been acquired or venous interventions have been performed, the catheter is removed. The transhepatic tract is then occluded by a variety of techniques including insertion of Gelfoam pledgets, deployment of coils, or injection of fibrin glue. The transhepatic venographic procedure is usually performed as part of a direct pancreatic venous sampling, lobar portal venous embolization to stimulate contralateral hypertrophy before major hepatic resection, assessment and management of an anastomotic portal venous stenosis after OLT, pharmacomechanical lysis of a splanchnic vein thrombosis, or rarely to control bleeding from a splanchnic vein. Percutaneous injection of the splenic parenchyma can also be used to delineate the anatomy of the splenic and portal veins and the draining tributaries. This examination is somewhat antiquated and has been generally replaced by MDCT or magnetic resonance venography. In infants, cross-sectional imaging may be inconclusive, and transarterial portography is

B FIGURE 21.16  A, Trans-splenic portovenography in a patient with unresectable pancreatic cancer causing narrowing in the main portal vein (black arrow). B, The area of narrowing was treated with stent placement (black arrow). The final run demonstrates free flow of contrast through the treated area consistent with successful treatment.

risky because of the diminutive size of the femoral arteries; however, it remains an alternative in planning a portosystemic shunt procedure. Percutaneous catheterization of the splanchnic veins is also possible from a transsplenic approach using a technique identical to that described for transhepatic catheterization.46 This procedure is usually done in conjunction with a percutaneous procedure to assess a portal vein stenosis or occlusion after OLT, but it may also be used in conjunction with the assessment and treatment of a splenorenal venous bypass, when access cannot be achieved from the systemic venous circulation. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

339.e1

REFERENCES 1. Patel IJ, Davidson JC, Nikolic B, et al. Addendum of newer anticoagulants to the SIR consensus guideline. J Vasc Interv Radiol. 2013;24(5):641-645. 2. Kiemeneij F, Laarman GJ, Odekerken D, Slagboom T, van der Wieken R. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: the access study. JACC. 1997;29(6):1269-1275. 3. Kobayashi S, Otsubo T, Koizumi S, et al. Anatomic variations of hepatic artery and new clinical classification based on abdominal angiographic images of 1200 cases. Hepatogastroenterology. 2014; 61(136):2345-2348. 4. Riaz A, Lewandowski RJ, Kulik LM, et al. Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J Vasc Interv Radiol. 2009;20(9):1121-1130; quiz 31. 5. Miyayama S, Yamashiro M, Okuda M, et al. Anastomosis between the hepatic artery and the extrahepatic collateral or between extrahepatic collaterals: observation on angiography. J Med Imaging Radiat Oncol. 2009;53(3):271-282. 6. Tacher V, Radaelli A, Lin M, Geschwind JF. How I do it: Conebeam CT during transarterial chemoembolization for liver cancer. Radiology. 2015;274(2):320-334. 7. Schnuriger B, Inaba K, Konstantinidis A, Lustenberger T, Chan LS, Demetriades D. Outcomes of proximal versus distal splenic artery embolization after trauma: a systematic review and metaanalysis. J Trauma. 2011;70(1):252-260. 8. Rajani RR, Claridge JA, Yowler CJ, et al. Improved outcome of adult blunt splenic injury: a cohort analysis. Surgery. 2006;140(4):625-631; discussion 31-32. 9. Raikhlin A, Baerlocher MO, Asch MR, Myers A. Imaging and transcatheter arterial embolization for traumatic splenic injuries: review of the literature. Can J Surg. 2008;51(6):464-472. 10. Ekeh AP, Khalaf S, Ilyas S, Kauffman S, Walusimbi M, McCarthy MC. Complications arising from splenic artery embolization: a review of an 11-year experience. Am J Surg. 2013;205(3):250-254; discussion 4. 11. Rong JJ, Liu D, Liang M, et al. The impacts of different embolization techniques on splenic artery embolization for blunt splenic injury: a systematic review and meta-analysis. Mil Med Res. 2017;4:17. 12. Christmas AB, Wilson AK, Manning B, et al. Selective management of blunt hepatic injuries including nonoperative management is a safe and effective strategy. Surgery. 2005;138(4):606-610; discussion 10-11. 13. Misselbeck TS, Teicher EJ, Cipolle MD, et al. Hepatic angioembolization in trauma patients: indications and complications. J Trauma. 2009;67(4):769-773. 14. Letoublon C, Morra I, Chen Y, Monnin V, Voirin D, Arvieux C. Hepatic arterial embolization in the management of blunt hepatic trauma: indications and complications. J Trauma. 2011;70(5): 1032-1036; discussion 6-7. 15. Kirby JM, Vora P, Midia M, Rawlinson J. Vascular complications of pancreatitis: imaging and intervention. Cardiovasc Intervent Radiol. 2008;31(5):957-970. 16. Aswani Y, Hira P. Venous complications of pancreatitis: a review. JOP. 2015;16(1):20-24. 17. Hyare H, Desigan S, Nicholl H, Guiney MJ, Brookes JA, Lees WR. Multi-section CT angiography compared with digital subtraction angiography in diagnosing major arterial hemorrhage in inflammatory pancreatic disease. Eur J Radiol. 2006;59(2):295-300. 18. Mansueto G, Cenzi D, D’Onofrio M, et al. Endovascular treatment of arterial bleeding in patients with pancreatitis. Pancreatology. 2007;7(4):360-369. 19. Yekebas EF, Wolfram L, Cataldegirmen G, et al. Postpancreatectomy hemorrhage: diagnosis and treatment: an analysis in 1669 consecutive pancreatic resections. Ann Surg. 2007;246(2):269-280. 20. Casadei R, Ricci C, Giampalma E, et al. Interventional radiology procedures after pancreatic resections for pancreatic and periampullary diseases. JOP. 2014;15(4):378-382. 21. Kim SJ, Na GH, Choi HJ, Yoo YK, Kim DG. Surgical outcome of right liver donors in living donor liver transplantation: single-center experience with 500 cases. J Gastrointest Surg. 2012;16(6):1160-1170. 22. Duffy JP, Hong JC, Farmer DG, et al. Vascular complications of orthotopic liver transplantation: experience in more than 4,200 patients. J Am Coll Surg. 2009;208(5):896-903; discussion 905.

23. Vaidya S, Dighe M, Kolokythas O, Dubinsky T. Liver transplantation: vascular complications. Ultrasound Q. 2007;23(4):239-253. 24. Gastaca M, Gomez J, Terreros I, et al. Endovascular therapy of arterial complications within the first week after liver transplant. Transplant Proc. 2020;52(5):1464-1467. 25. Hemp JH, Sabri SS. Endovascular management of visceral arterial aneurysms. Tech Vasc Interv Radiol. 2015;18(1):14-23. 26. Tulsyan N, Kashyap VS, Greenberg RK, et al. The endovascular management of visceral artery aneurysms and pseudoaneurysms. J Vasc Surg. 2007;45(2):276-283; discussion 283. 27. Cordova AC, Sumpio BE. Visceral artery aneurysms and pseudoaneurysms-should they all be managed by endovascular techniques? Ann Vasc Dis. 2013;6(4):687-693. 28. Nosher JL, Chung J, Brevetti LS, Graham AM, Siegel RL. Visceral and renal artery aneurysms: a pictorial essay on endovascular therapy. Radiographics. 2006;26(6):1687-1704; quiz 1687. 29. Lagana D, Carrafiello G, Mangini M, et al. Multimodal approach to endovascular treatment of visceral artery aneurysms and pseudoaneurysms. Eur J Radiol. 2006;59(1):104-111. 30. Sachdev U, Baril DT, Ellozy SH, et al. Management of aneurysms involving branches of the celiac and superior mesenteric arteries: a comparison of surgical and endovascular therapy. J Vasc Surg. 2006; 44(4):718-724. 31. Davran R, Cinar C, Parildar M, Oran I. Radiological findings and endovascular management of three cases with segmental arterial mediolysis. Cardiovasc Intervent Radiol. 2010;33(3):601-606. 32. Memeo M, Scardapane A, De Blasi R, Sabba C, Carella A, Angelelli G. Diagnostic imaging in the study of visceral involvement of hereditary haemorrhagic telangiectasia. Radiol Med. 2008;113(4): 547-566. 33. Choi SK, Jin JS, Cho SG, et al. Spontaneous liver rupture in a patient with peliosis hepatis: a case report. World J Gastroenterol. 2009;15(43):5493-5497. 34. Kootte AM, Siegel AM, Koorenhof M. Generalised peliosis hepatis mimicking metastases after long-term use of oral contraceptives. Neth J Med. 2015;73(1):41-43. 35. Doppman JL, Miller DL, Chang R, Shawker TH, Gorden P, Norton JA. Insulinomas: localization with selective intraarterial injection of calcium. Radiology. 1991;178(1):237-241. 36. Guettier JM, Kam A, Chang R, et al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94(4):1074-1080. 37. Jackson JE. Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2005;19(2):229-239. 38. Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247(1):165-172. 39. Lin XZ, Wu ZY, Tao R, et al. Dual energy spectral CT imaging of insulinoma-Value in preoperative diagnosis compared with conventional multi-detector CT. Eur J Radiol. 2012;81(10):2487-2494. 40. McLean A. Endoscopic ultrasound in the detection of pancreatic islet cell tumours. Cancer Imaging. 2004;4(2):84-91. 41. Cohen MS, Picus D, Lairmore TC, Strasberg SM, Doherty GM, Norton JA. Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas. Surgery. 1997;122(6): 1091-1100. 42. Turner JJ, Wren AM, Jackson JE, Thakker RV, Meeran K. Localization of gastrinomas by selective intra-arterial calcium injection. Clin Endocrinol (Oxf). 2002;57(6):821-825. 43. Eguchi H, Tanemura M, Marubashi S, et al. Arterial stimulation and venous sampling for glucagonomas of the pancreas. Hepatogastroenterology. 2012;59(113):276-279. 44. Liu FY, Wang MQ, Fan QS, Duan F, Wang ZJ, Song P. Interventional treatment for symptomatic acute-subacute portal and superior mesenteric vein thrombosis. World J Gastroenterol. 2009;15(40): 5028-5034. 45. Semiz-Oysu A, Keussen I, Cwikiel W. Interventional radiological management of prehepatic obstruction of [corrected] the splanchnic venous system. Cardiovasc Intervent Radiol. 2007;30(4):688695. 46. Tuite DJ, Rehman J, Davies MH, Patel JV, Nicholson AA, Kessel DO. Percutaneous transsplenic access in the management of bleeding varices from chronic portal vein thrombosis. J Vasc Interv Radiol. 2007;18(12):1571-1575.

CHAPTER 22 Endoscopic ultrasound of the biliary tract and pancreas Vineet Syan Rolston, Joseph Patrick Kingsbery, and Mark Andrew Schattner

IMAGING AND DIAGNOSIS The diagnosis of benign and malignant diseases of the pancreas and biliary tree historically have relied on a detailed history and complete physical examination, with correlation of the results of clinical chemistries. Imaging of the hepatic and pancreatic parenchyma and ductal anatomy has, however, evolved as critical for accurate diagnosis and for guiding therapy. Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) have become important noninvasive modalities in the routine investigation of pathologic conditions of the biliary tree or pancreas (see Chapters 12 and 13). Invasive procedures for imaging the biliary and pancreatic ductal systems, primarily percutaneous cholangiography (PTC) (see Chapter 20) or endoscopic retrograde cholangiopancreatography (ERCP) (see Chapter 31) remain important therapeutically, but diagnostically, these have been almost entirely replaced by less invasive modalities. Endoscopic ultrasonography (EUS) has become an essential tool for the diagnosis and treatment of pancreatic and biliary pathology. Its high-resolution images complement the more general findings of crosssectional imaging and result in a higher sensitivity for diagnosis of early-stage disease and detection of smaller lesions. Linear array echoendoscopes permit guided passage of needles and devices through the endoscope, allowing biopsies to be obtained and permitting therapeutic interventions. This chapter discusses the techniques of endosonography in the diagnosis, staging, and treatment of benign and malignant disease of the pancreas and biliary tree.

Endoscopic Ultrasound Technique The pancreas is located posterior to the stomach and is readily seen by EUS imaging through the wall of the stomach and duodenum. With the transducer in the duodenum, the pancreatic head and uncinate process, ampulla of Vater, pancreatic ducts, common bile duct (CBD), and the surrounding vascular and nodal structures can be visualized. With the transducer in the stomach, the pancreatic body and tail, gallbladder, and left lobe of the liver are seen. Additionally, the celiac, splenic, hepatic, and superior mesenteric arteries, as well as the splenic, superior mesenteric, and portal veins are all seen in detail (see Chapter 2). The normal pancreatic parenchyma has a homogeneous echogenic appearance (Fig. 22.1), and tumors usually appear hypoechoic, often with irregular borders, in sharp distinction from healthy tissue (Fig. 22.2). Small tumors of the pancreas that are often missed by CT or MRI are readily imaged by EUS. For example, islet cell tumors, which are often encapsulated and small, are more readily detected on EUS than cross-sectional imaging and appear as well-demarcated hypoechoic lesions (see Chapter 65). Other neuroendocrine tumors, such as gastrinomas, may be isoechoic within the pancreatic parenchyma and 340

difficult to identify without careful, tedious, real-time imaging (Fig. 22.3). Ampullary tumors are also often seen and staged on EUS because of their proximity to the duodenal wall, CBD, and pancreatic duct (Fig. 22.4) (see Chapter 59). Extrahepatic bile duct tumors can also be detected and described in detail with EUS imaging (Fig. 22.5). Cysts of the pancreas are generally anechoic and well demarcated and thus easily identified even when small (see Chapter 60). Some cysts may have internal echoes or solid nodules, which raise concern for a mucinous lesion or associated tumor (Figs. 22.6 and 22.7). Cysts can easily be distinguished from vascular structures using Doppler flow. Serous cystadenomas may also appear isoechoic with the pancreas and require careful imaging for proper identification (Fig. 22.8).

Endoscopic Ultrasound–Guided Fine-Needle Aspiration and Biopsy The development of linear array echoendoscopes, which scan an area orthogonally in line with the endoscope (thus in line with the biopsy channel), has allowed the development of EUSguided fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB). The indications for EUS-guided aspiration or biopsy include pathologic confirmation of a suspected pancreatic or periampullary cancer, evaluation of pancreatic masses, bile duct lesions or abnormal lymph nodes, and aspiration of pancreatic cysts. EUS-guided needle puncture has also provided the platform for therapeutic EUS-guided techniques (see Chapter 30).

Endoscopic Ultrasound Fine-Needle Aspiration Technique Within the duodenum or stomach, the EUS probe is positioned near the target lesion, typically less than 3 cm away. The area is then interrogated with Doppler flow to ensure the absence of significant vascular structures in the needle path. A 25-gauge, 22-gauge, or 19-gauge needle can then be directed into the target lesion. The tip and shaft of the needles used for FNA produce a bright, hyperechoic image. This allows the needle to be followed in real time to ensure precise positioning within the target lesion (Fig. 22.9). Ideally, a cytopathologist or cytotechnologist should be present at the time of the FNA to determine the cellular adequacy of the specimen, improve diagnostic yield, and reduce the need for additional pass of the biopsy needle.1 (Khoury et al, 2019). Alternatively, multiple punctures (six to seven) should be performed to ensure an adequate cytologic specimen.2 Cyst fluid can also be aspirated and sent for cytology, tumor markers, and chemical analysis (Fig. 22.10). More recently, the development of needles that can obtain core samples (FNB) allows tissue with preserved architecture to be acquired, as opposed to purely cytologic specimens.3 Several maneuvers have been described to improve diagnostic yield, including the use of a “fanning” technique, whereby multiple

  Chapter 22  Endoscopic Ultrasound of the Biliary Tract and Pancreas

341

SV

FIGURE 22.1  Normal endoscopic ultrasound image of the body of the pancreas with thin main pancreatic duct (arrow).

areas are sampled within a lesion, particularly the peripheral area of lesion to improve yield and reduce the number of passes required for diagnosis.4 The use of suction for FNA of lymph nodes or solid masses has been suggested to have improved cellularity; however, it may yield more bloody samples.5,6 The reinsertion of a stylet within the fine needle does not appear to increase yield, may increase the bloodiness of the sample, and can increase procedural time.7 However, the use of a stylet slowpull technique may confer some advantage for diagnostic yield.8

CBD

M

PV

FIGURE 22.3  Small, well-circumscribed, hypoechoic appearance of an insulinoma (arrow) in the body of the pancreas with splenic vein (SV) below.

SMV

DIAGNOSIS OF PANCREATIC CANCER FIGURE 22.2  Solid, irregular, hypoechoic mass (M) in the pancreatic head seen with abrupt termination of a dilated common bile duct (CBD) and contact with the portal confluence (portal vein [PV] and superior mesenteric vein [SMV]). Cytology obtained by endoscopic ultrasound– guided fine-needle aspiration proved to be adenocarcinoma.

A

Endoscopic Ultrasound Fine-Needle Aspiration and Biopsy of Solid Pancreatic Lesions Solid masses of the pancreas may represent a primary pancreatic cancer (see Chapter 62), neuroendocrine tumor (see Chapter 65), metastatic lesion (see Chapter 64), or focal pancreatitis (see Chapter 55). These masses may be difficult to visualize on

B FIGURE 22.4  Endoscopic (A) and endoscopic ultrasound (B) imaging of an ampullary tumor (arrow).

342

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 22.5  Hypoechoic mass appearance of cholangiocarcinoma of the common bile duct (solid arrow) with biliary stent visible (open arrow).

FIGURE 22.8  Typical microcystic appearance of a serous cystadenoma in the head of the pancreas (arrow).

FIGURE 22.6  Mucinous cystic lesion in the head of the pancreas with mural nodule (arrow).

FIGURE 22.9  Bright appearance of fine-needle aspiration of a solid mass in the head of the pancreas.

FIGURE 22.7  Multiseptated mucinous cystic lesion in the head of the pancreas (arrow).

FIGURE 22.10  Fine-needle aspiration of cyst fluid.

  Chapter 22  Endoscopic Ultrasound of the Biliary Tract and Pancreas

343

TABLE 22.1  Imaging Characteristics and Fluid Analysis of Pancreatic Cystic Lesions EUS MORPHOLOGY

COMMUNICATION WITH PANCREATIC DUCT FLUID AMYLASE FLUID CEA FLUID CYTOLOGY

Retention cysts

Unilocular, thin walled

No

Variable

Low

Pseudocyst

Unilocular, thick-walled with debris

Yes

Very high

Low

Serous cystadenoma

Microcystic with central calcification

No

Low

Low

Mucinous cystadenoma

Macrocystic with thick septations

Occasionally

Low

High

IPMN

Dilated, tortuous pancreatic duct and/or side branches

Yes

High

High

Normal duct or centroacinar cells Inflammatory cells, no epithelial cells Small cuboidal cells, positive glycogen stain Atypical ductal cells, positive mucin stain Atypical ductal cells, positive mucin stain

CEA, Carcinoembryonic antigen; EUS, endoscopic ultrasound; IPMN, intraductal papillary mucinous neoplasm.

noninvasive imaging when small. EUS allows high-resolution imaging of the pancreas as well as facilitating guidance of FNA and FNB. Some solid lesions in the pancreas may not need preoperative biopsy if the result of biopsy would not change the decision to resect the lesion. Current surgical guidelines recommend proceeding to surgery for resectable pancreatic lesions for which surgery is indicated without first obtaining a diagnostic biopsy.9 However, patients with locally advanced pancreatic lesions require histologic diagnosis before initiating chemotherapy or radiation. Biopsy is also indicated before surgical resection for those patients in whom there is suspicion for autoimmune pancreatitis (see Chapter 54). EUS-FNA has been shown to have superior diagnostic accuracy for pancreatic malignancy than percutaneous CT-guided and US-guided approaches, especially for small lesions.10 EUSFNB has a diagnostic accuracy similar to EUS-FNA; therefore either EUS-FNA or FNB is the preferred modality for diagnostic sampling of pancreatic lesions. Recent randomized controlled trials assessing EUS-FNA and FNB tissue acquisition reported diagnostic accuracies of 81% to 100% and 85% to 94% for FNA and FNB, respectively.6,11–14 In these studies, there was an equivalent complication rate of between 0% and 3% for both FNA and FNB, with bleeding, abdominal pain, and pancreatitis the most common complications cited. There is some suggestion that FNB produces a superior specimen with preserved tissue architecture over FNA samples. A retrospective study looking at EUS sampling of pancreatic lesions using a 22-gauge FNA needle and 25-gauge FNB needle in 76 patients found no difference in safety or technical success; however, the 25-gauge FNB needle produced a higher amount of diagnostic material and superior preservation of tissue architecture despite the smaller caliber needle.15 Additionally, a large retrospective study found that EUS-FNB was superior to EUS-FNA in obtaining tissue for genomic testing compared with FNA samples (90.9% vs. 66.6%, respectively). More research is needed in this area, as molecular testing is becoming more common and more directed therapies are becoming available.16

Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Cystic Lesions Cystic lesions of the pancreas remain a diagnostic and therapeutic challenge (see Chapter 60). The differential diagnosis

FIGURE 22.11  Large debris-filled pseudocyst adjacent to the tail of the pancreas.

includes retention/simple cysts, pseudocysts, cystic neoplasms, and cystic degeneration of solid masses (Table 22.1). EUS provides detailed imaging of the entire pancreas, including location and number of cysts; size; ductal dilatation or communication; signs of chronic pancreatitis; cyst wall thickness; mural nodules; papillary projections; and intracystic structures such as septations, debris, and mass components. Retention cysts are benign dilated segments of the pancreatic duct secondary to focal duct disruption. Under EUS they are generally small, thin-walled, and unilocular; they carry no malignant potential and can be left untreated Pseudocysts develop as a result of acute inflammation (see Chapters 55 and 56). On EUS, they are thick walled as they become chronic and may have debris within the cyst cavity (see Fig. 22.11). They can be seen in or adjacent to the pancreas and often communicate with the pancreatic duct. FNA will yield thick fluid with inflammatory cells, but there is an absence of epithelial cells. Tumor marker levels (carcinoembryonic antigen [CEA]) in the cyst fluid are low or undetectable; in contrast, fluid amylase is usually markedly elevated. Regarding cystic neoplasms, it is important to distinguish mucinous and papillary tumors from serous lesions (see Chapter 60). Serous tumors have no malignant potential and do not require resection unless symptoms occur or they encroach on vascular structures, specifically the portal and superior mesenteric and splenic veins. Typically, serous cystadenomas are

344

PART 2  DIAGNOSTIC TECHNIQUES

composed of a honeycomb of microcysts with no communication with the pancreatic duct (see Fig. 22.8). They can be large and exhibit central stellate calcification on imaging studies. Papillary lesions and solid pseudopapillary tumors carry the risk of malignant transformation and should be referred for resection. Mucinous lesions (mucinous cystic neoplasm [MCN] and intraductal papillary mucinous neoplasm [IPMN]) also harbor malignant potential. Mucinous cysts are generally composed of one or more large cystic spaces with thickened walls or septa (see Fig. 22.7). Features that may indicate malignant potential of MCNs include size 3 cm in size, rapid increase in cyst size during surveillance, mural nodules, mass-forming lesions, and peripheral egg-shell calcifications.17 In the case of IPMNs, distinguishing main-duct from side-branch types is important clinically because the former is associated with malignancy in as many as 62% of patients.18 Although crosssectional imaging may help in this regard by demonstrating a dilated pancreatic duct characteristic of main-duct IPMN, communication with the main pancreatic duct can also be demonstrated on EUS. Although these anatomic characteristics are helpful, EUS cyst morphology alone is insufficient to characterize the lesion.18–20 Aspiration of cyst fluid via EUS-FNA can further aid in the diagnosis. Cyst fluid can be analyzed for tumor markers, amylase, and molecular markers, and it provides material for cytopathologic assessment. Cyst fluid tends to be paucicellular; thus the sensitivity and negative predictive value of cytology is low.21,22 The presence of thick, viscous fluid and a positive mucin stain is suggestive of a mucinous lesion. The concentration of several tumor markers in pancreatic cyst fluid has been examined, and CEA has been found to be the most useful. Higher concentrations of CEA most accurately predict mucinous lesions, although the optimal cutoff is not universally agreed on, a cyst-fluid CEA concentration of more than 192 ng/mL predicts a mucinous lesion with a sensitivity of 73%, specificity of 84%, and an accuracy of 79%.19,23 Although helpful for diagnosing mucinous lesions, cyst-fluid CEA levels do not correlate with the presence of malignancy.24 Another limitation of cyst-fluid CEA analysis is that it requires aspiration of at least 1 mL of fluid, which can be difficult if the cavity is small or the fluid is very viscous, making it difficult to pull through a fine needle. More recently, cyst-fluid DNA analysis has shown promise in differentiating mucinous from nonmucinous cysts. This analysis can be done on as little as 200 mL of fluid. The presence of a KRAS mutation, high DNA content, and loss of polymorphic alleles are indicators of mucinous cysts. In a large validation study, early KRAS mutation followed by allelic loss was 96% specific and 37% sensitive for a malignant cyst.25 Interleukin-1b (IL-1b) has recently been identified as a potential biomarker for high-grade dysplasia or malignancy.26 Cyst fluid aspirated ahead of surgical resection was found to contain higher concentrations of IL-1b in specimens with evidence of high-grade dysplasia or carcinoma. Nonetheless, a reliable and sufficiently sensitive biomarker for malignancy is still lacking. The use of a EUS-guided through-the-needle biopsy forceps device has had promising results for further evaluation of cysts. A disposable needle is introduced through a standard 19-guage EUS-FNA needle to allow sampling of the cyst wall, mural nodules, or septae, and may provide greater sensitivity and specificity for both identification of cyst type and risk-stratification of mucinous cysts.27

Complications of Endoscopic Ultrasound Fine-Needle Aspiration and Biopsy EUS-FNA of the pancreas is a safe procedure. The reported rate of pancreatitis is 0% to 2%.28–31 (see Chapter 55) In a multicenter analysis of almost 5000 EUS-FNAs of solid pancreatic masses, the incidence of pancreatitis was 0.3%, and most cases were clinically mild.28 EUS-guided aspiration of pancreatic cysts is similarly safe, with a pancreatitis rate of less than 1% and an overall complication rate of about 2%.32 Bacteremia is uncommon following EUS-FNA of solid lesions, with a rate similar to that for diagnostic upper endoscopy; thus prophylactic antibiotic administration is unwarranted.33,34 However, early data evaluating EUS-guided cyst aspiration showed increased infectious complications leading to the recommendation of routine antibiotic prophylaxis for all patients undergoing this procedure.35 Major extraluminal hemorrhage is a rare complication and occurs at a rate of less than 1%.36

STAGING OF PANCREATIC CANCER The method of staging generally practiced in the United States is that published by the American Joint Committee on Cancer (see Chapter 62). It follows the tumor-node-metastasis (TNM) staging system and is outlined in Table 22.2.

TABLE 22.2  AJCC Staging of Pancreatic Cancer TNM DEFINITIONS Primary Tumor (T) TX Cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor confined to pancreas, #2 cm in diameter T2 Tumor confined to pancreas, .2 cm in diameter T3 Extrapancreatic extension, no celiac axis or SMA involvement T4 Involvement of celiac axis or SMA Regional Lymph Nodes (N) NX Cannot be assessed N0 Regional lymph node metastases absent N1 Regional lymph node metastases present Distant Metastases (M) MX Cannot be assessed M0 Distant metastases absent M1 Distant metastases present AJCC TNM Stage 0 Stage I IA IB Stage II IIA IIB Stage III Stage IV

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1-T3, N1, M0 T4, N0-N1, M0 T1-T4, N0-N1, M1

AJCC, American Joint Committee on Cancer; SMA, superior mesenteric artery; TNM, tumornode-metastasis. From Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.

  Chapter 22  Endoscopic Ultrasound of the Biliary Tract and Pancreas

Endoscopic Ultrasound Tumor-Node-Metastasis Staging Some of the first reports of EUS imaging of the pancreas described its ability to detect and diagnose pancreatic and periampullary tumors.37,38 However, subsequent studies evaluated the ability of EUS to stage tumors and assess appropriateness of resection.39,40 Although the general approach to the preoperative evaluation of pancreatic cancer has focused on the TNM stage, the usefulness of such staging is questionable, particularly because the T stage does not necessarily correlate with resectability. The role of EUS and CT scan for staging of pancreatic lesions is complementary in nature. EUS may offer a superior sensitivity for evaluating tumor invasion of the portal vein; however, it is lower than CT for tumor invasion in the celiac artery, superior mesenteric artery, and superior mesenteric vein.41–43 Perhaps the most useful application of EUS is the diagnosis of small pancreatic tumors (,3 cm) in patients with equivocal radiologic imaging. Several studies have demonstrated that EUS is superior to CT scanning for evaluation of pancreatic lesions smaller than 3 cm.44,45 In addition, EUS far exceeds CT and MRI in the diagnosis and staging of tumors of the ampulla of Vater to determine whether local or radical resection may be appropriate.46,47 EUS has also demonstrated greater sensitivity for detecting small pancreatic neuroendocrine tumors ,2 cm and insulinomas48 (see Chapter 65). Other reports, as well as our own experience, have shown the usefulness of EUS in evaluating patients with dilated pancreatic and/or bile ducts but no demonstrable cause. EUS in this setting has been useful in the identification of small tumors of the ampulla, pancreas, or bile duct and nonneoplastic causes, such as stone disease, chronic pancreatitis, or abnormal anatomy.49 Therefore, when a pancreatic mass is suspected but cannot be identified by standard imaging modalities, EUS should be considered if further clarification is clinically warranted. A large retrospective series reported a high specificity for EUS in predicting the absence of pancreatic cancer, with a negative predictive value of 100%, when the results of EUS showed a normal pancreas.49

Preoperative Reassessment After Neoadjuvant Chemoradiotherapy Studies on the treatment of pancreatic cancer have recently focused on neoadjuvant treatment with chemotherapy and radiation therapy, followed by attempted radical resection (see Chapter 66). Several studies have investigated the ability of EUS to reassess patients who have completed neoadjuvant therapy, with most suggesting that EUS is no better than CT for determining resectability. In one report, EUS correctly assessed residual tumor stage in 40% of patients and node status in 90%, but it incorrectly suggested venous invasion in 43%.50 These results suggest that inflammatory changes in the tumor bed, pancreas, and lymph nodes alter the anatomy and blur the distinction between normal tissue planes and between tumor and normal tissue.

DIAGNOSIS AND STAGING OF CHOLANGIOCARCINOMA Primary bile duct cancers (see Chapters 51 and 59) usually present with painless jaundice. Although transcutaneous US and CT scanning reliably show biliary dilatation, they are less accurate for delineating tumors, especially if tumors are smaller than 2 cm. ERCP is the dominant invasive modality used to

345

evaluate extrahepatic bile duct strictures. Diagnostic specimens can be obtained by deployment of a cytology brush against the stricture, but the sensitivity is low, with a yield of only 40% to 50%.51–53 EUS has now emerged as a useful diagnostic and staging technique in this regard using linear and radial echoendoscopes. If a biliary stricture is visualized, malignancy is suggested by the presence of an irregular, thickened (.3 mm) bile duct wall (see Fig. 22.5). Hypoechoic infiltration invading through the biliary wall layers or an adjacent pancreatic mass can also be seen. The accuracy of EUS-FNA in the diagnosis of bile duct strictures has a reported sensitivity ranging from 43% to 86%54–56 (Table 22.3). The results of a large single-center experience suggest that EUS can be very useful in the assessment of extrahepatic cholangiocarcinoma.57 Tumor detection was superior with EUS compared with triphasic CT scan and MRI. EUS-FNA added significant diagnostic yield, particularly with distal bile duct tumors, with an overall sensitivity of 73%. In addition, EUS determined resectability with a sensitivity and specificity of 53% and 97%, respectively. The disadvantage of EUS-FNA is the potential for transperitoneal seeding and is generally not recommended if the patient is a candidate for curative liver transplantation.58 The more recent development and use of per-oral cholangioscopy is a useful tool, allowing direct visualization of the biliary tree and targeted biopsies, with a reported sensitivity of 60% and specificity of 98% for diagnosis malignant biliary strictures.59

Endoscopic Ultrasound–Guided Intervention Tumor Localization Radiotherapy is increasingly important in the management of pancreatic cancer, but stereotactic radiation is limited by respiratory motion and accurate assessment of tumor size and location in real time. A role for EUS-guided intratumoral placement of gold fiducials in localizing pancreatic tumors for targeted radiation therapy has also been demonstrated, which limits radiotherapy toxicity to the surrounding.60–62 Gold fiducial markers can be backloaded into a 19-gauge or 22-gauge delivery system.63 Alternatively, multifiducial delivery systems have been developed to allow for placement of multiple markers, with

TABLE 22.3  Performance Characteristics for EUS in the Diagnosis and Staging of Pancreatic, Ampullary, and Extrahepatic Biliary Tumors SENSITIVITY

SPECIFICITY

ACCURACY

Pancreatic Tumors Diagnosisa Tumor .3 cm Tumor ,3 cm Tumor staging Nodal staging

86%–95% 85%–95% – –

94%–99% 87%–100% – –

86%–94% 93%–100% 72%–98% 44%–66%

Ampullary Tumors Diagnosis Resectability

– – –

– – –

93%–100% 61%–88%

Bile Duct Tumors Diagnosisa TN staging

– – –

– – –

43%–86% 60%–80%

a Includes the use of fine-needle aspiration to obtain cytology. EUS, Endoscopic ultrasound; TN, tumor node.

346

PART 2  DIAGNOSTIC TECHNIQUES

technical success of delivering at least three fiducials into the target area of 92%64 (see Chapter 67).

Celiac Plexus Neurolysis In patients with pain as a result of pancreatic cancer, EUSguided celiac plexus neurolysis (CPN) has been shown to be a safe and effective alternative to surgical or percutaneous approaches (see Chapters 62 and 67). The celiac axis is easily identified using a linear-array echoendoscope positioned in the stomach (Fig. 22.12), and it provides a quick method of palliating cancer-related pain in patients undergoing staging and diagnosis of pancreas cancer. Two large meta-analyses demonstrated improved sustained pain relief in 72% to 80% of patients at a follow-up range of 1 to 6 months.65,66 In addition, decreased analgesic requirements and fewer opioid-induced side effects can be expected after EUS-guided neurolysis. However, there is significant variation in the literature with regards to technique as well as assessments of pain score. Multiple iterations of the procedure (bilateral celiac trunk injection, 10 cc vs. 20 cc of ethanol, broad injection to include the superior mesenteric artery, direct injection into celiac ganglion) have been studied to optimize palliation.67–70 More recently, there has been interest in celiac ganglion radiofrequency ablation (RFA) for pancreatic cancer pain palliation. In a recent prospective randomized controlled trial, 26 patients with pain related to pancreatic cancer underwent EUS-CPN (12) or EUS-RFA (14). The authors found that EUS-RFA provided more pain relief and improved the quality of life for patients with pancreatic cancer at 2- and 4-weeks post-treatment more than EUS-CPN. This is a relatively new technique and deserves more investigation.71

Drainage of Pseudocysts and Peripancreatic Collections Pancreatic and peripancreatic fluid after pancreatic injury (see Chapter Classification of acute pancreatitis of these fluid collections and makes

collections are common 56) The revised Atlanta updates the definitions an important distinction

C

SMA

AO

between fluid collections due to interstitial edematous pancreatitis and those due to necrotizing pancreatitis.72 Fluid collections related to interstitial edematous pancreatitis are classified by the timing of their formation: acute peripancreatic fluid collections occur within the first 4 weeks of pancreatic injury and are characterized by nonencapsulated fluid-filled collections. Fluid collections that develop after the first 4 weeks of injury are referred to as pseudocysts and typically have a welldefined capsule surrounding them. Fluid collections that form as the result of necrotizing pancreatitis are similarly classified by their timing of formation: acute necrotic collections form in the first 4 weeks and are nonencapsulated, heterogeneous, nonliquefied material. Those that form after 4 weeks are referred to as walled-off necrosis and are made of encapsulated heterogeneous nonliquefied material. Although many pancreatic and peripancreatic fluid collections will resolve spontaneously over time, drainage is indicated in the setting of infection or if persistently symptomatic.73 The role for EUS is as a minimally invasive and effective technique for guiding drainage of pancreatic pseudocysts and walled-off necrosis74,75 (see Chapters 28, 30, and 56) or after pancreatic resection has been established. A fine needle is used to puncture the fluid collection, and a guidewire is used for transluminal stenting. Using real-time imaging and Doppler flow, intervening organs and vascular structures can be avoided. Thus there are fewer complications, such as bleeding and perforation, compared with the percutaneous approach. A randomized trial comparing surgical and endoscopic drainage showed equal efficacy of the surgical and endoscopic approach, but with a shorter length of hospital stay for endoscopic drainage. Currently, endoscopic drainage is generally considered the first-line of care for pancreatic and peripancreatic fluid collection management.75 Early experience with transluminal endoscopic drainage involved creating a fistula between the fluid collection and the luminal gastrointestinal (GI) tract with placement of plastic stents through the fistula to maintain patency. More recently, self-expanding metal stents and lumen-apposing metal stents have been used for this purpose, with a larger lumen allowing passage of semisolid and necrotic debris. A meta-analysis comparing metal and plastic stents for drainage of pancreatic fluid collections identified 7 studies with 681 patients (340 metal, 341 plastic) with metal stents superior in both clinical success (93.8% vs. 86.2%). Additionally, metal stents were associated with fewer adverse events compared with plastic (10.2% vs. 25%). Adverse events for transluminal drainage of pancreatic and peripancreatic fluid collections include bleeding, stent migration, infection, and perforation.76

EUS-Guided Biliary Drainage

FIGURE 22.12  Endoscopic ultrasound appearance of the longitudinal course of the aorta (AO) with celiac (C) and superior mesenteric artery (SMA) origins.

In patients with advanced abdominal malignancies, simultaneous duodenal and biliary obstruction can occur. Traditionally, these patients have required percutaneous or surgical biliary drainage because transpapillary decompression via ERCP is often not possible. EUS-guided transduodenal or transgastric biliary drainage is a novel approach that allows internal drainage.77–79 Like pseudocyst drainage, the dilated CBD or left hepatic duct is localized with EUS and punctured with an FNA needle. A cholangiogram is performed (Fig. 22.13A), followed by guidewire insertion, dilation of the tract, and deployment of a self-expandable metal stent across

  Chapter 22  Endoscopic Ultrasound of the Biliary Tract and Pancreas

A

347

B

FIGURE 22.13  A, Cholangiogram obtained by endoscopic ultrasound (EUS)-guided puncture of the common bile duct by fine-needle aspiration in preparation for EUS-guided biliary drainage. B, EUS image after deployment of self-expanding metal stent.

the choledochoduodenostomy or hepaticogastrostomy tract (see Fig. 22.13B). EUS-guided biliary drainage was compared with percutaneous drainage in patients who failed ERCP80 (see Chapter 30). EUS-guided biliary drainage was equally effective, with fewer adverse events, reduced need for reinterventions, and reduced cost (see Chapter 30). More recent studies have shown superiority of EUS-BD to ERCP in patients with duodenal stenosis, patients with altered anatomy, and in patients with indwelling duodenal stents.81–83

Novel Therapeutics EUS-guided ethanol ablation of cysts has been previously reported.84,85 Patients with asymptomatic, unilocular pancreatic cysts were treated by injection and lavage of the cyst with ethanol through an FNA needle, with complete cyst resolution documented in 30% to 35% of patients. More recently, ethanol has been combined with paclitaxel, with complete resolution achieved in 62% to 78% of patients.86 RFA of pancreatic cysts has also been described recently in a small series of patients.87 Despite these advances, concerns remain about residual epithelium, which could remain after ablation. In addition, evidence that ablation reduces the risk of malignancy, the need for resection, or continued surveillance is lacking. The use of lumen-apposing metal stents has allowed for the creation of EUS-guided gastroenterostomy (EUS-GE) for treatment of gastric outlet obstruction. By utilizing EUS to identify duodenum or jejunal loops adjacent to the gastric wall, and typically with the aid of a water-filling technique to distend the distal bowel, the electrocautery system of a lumen-apposing stent can be deployed. Khashab and colleagues demonstrated that while technical success for EUS-GE is lower than that of surgical gastrojejunostomy, EUS-GE has a similar clinical success rate and adverse event rate, offering a noninferior and less invasive option for treatment of gastric outlet obstruction.88

Mendelsohn and associates demonstrated good technical and clinical success in the presence of peritoneal carcinomatosis, encouraging the use of this therapy for palliative purposes.89 The use of a EUS-guided fine-needle injection (EUS-FNI) confers the ability to provide treatment to a targeted lesion. Therapies include the use of fiducial markers directly into malignant tissue as well as interstitial brachytherapy to general gamma rays and damaged local tissue.90 Other uses of FNI include direct delivery of antitumor agents to a lesion, including lymphocytic cultures to induce cytokine release, immature dendritic cells to generate T-cell immune responses, and viral vectors.91–93 Ongoing work for targeting the mutant KRAS oncogene in pancreatic cancer includes the use of loading platforms to deliver siRNA targeted against KRAS mutations for antitumor effects. Animal models have yielded promising results by impeding growth of pancreatic tumor cells and prolonged mouse survival.94 Clinical trials are underway to determine efficacy in humans.

SUMMARY EUS is an essential tool in the evaluation of patients with abnormalities that involve the pancreas and the biliary tree. It provides detailed images of the pancreas and bile ducts and complements the findings of noninvasive radiographic imaging. For patients seen initially with suspected pancreatic or bile duct cancer, multidetector CT scanning assists in identifying those with obvious masses, metastatic disease, and vascular involvement. The usefulness of EUS in this setting is limited, except to provide tissue diagnosis using EUS-guided FNA, in localizing lesions, or in management of the complications of metastatic disease. For patients with small tumors, ampullary lesions, or equivocal findings detected by CT or MRI, the high sensitivity of EUS helps provide a diagnosis, with a high accuracy for

348

PART 2  DIAGNOSTIC TECHNIQUES

tumor staging and determining resectability. Because EUS has poor sensitivity for identifying distant metastatic disease, CT scanning and laparoscopy will remain important tools in the evaluation of patients with pancreatic and bile duct cancer who are being considered for surgery. EUS-FNA and EUS-FNB are safe and valuable tools in the evaluation of patients with a suspected solid or cystic mass of the pancreas or extrahepatic bile

ducts. It has a higher diagnostic sensitivity and specificity than noninvasive imaging and allows tissue sampling and molecular testing as part of the same procedure. Similarly, EUS-FNA has evolved from a diagnostic to a therapeutic procedure in the management of biliary and pancreatic disease. References are available at expertconsult.com.

348.e1

REFERENCES 1. Khoury T, Kadah A, Farraj M, et al. The role of rapid on-site evaluation on diagnostic accuracy of endoscopic ultrasound fine needle aspiration for pancreatic, submucosal upper gastrointestinal tract and adjacent lesions. Cytopathology. 2019;30(5):499-503. 2. Crinò SF, Manfrin E, Scarpa A, et al. EUS-FNB with or without onsite evaluation for the diagnosis of solid pancreatic lesions (FROSENOR): Protocol for a multicenter randomized non-inferiority trial. Dig Liver Dis. 2019;51(6):901-906. 3. Khoury T, Sbeit W, Ludvik N, et al. Concise review on the comparative efficacy of endoscopic ultrasound-guided fine-needle aspiration vs core biopsy in pancreatic masses, upper and lower gastrointestinal submucosal tumors. World J Gastrointest Endosc. 2018;10(10):267-273. 4. Bang JY, Magee SH, Ramesh J, Trevino JM, Varadarajulu S. Randomized trial comparing fanning with standard technique for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic mass lesions. Endoscopy. 2013;45(6):445-450. 5. Puri R, Vilmann P, Sa˘ ftoiu A, et al. Randomized controlled trial of endoscopic ultrasound-guided fine-needle sampling with or without suction for better cytological diagnosis. Scand J Gastroenterol. 2009;44(4):499-504. 6. Lee JK, Choi JH, Lee KH, et al. A prospective, comparative trial to optimize sampling techniques in EUS-guided FNA of solid pancreatic masses. Gastrointest Endosc. 2013;77(5):745-751. 7. Sahai AV, Paquin SC, Gariépy G. A prospective comparison of endoscopic ultrasound-guided fine needle aspiration results obtained in the same lesion, with and without the needle stylet. Endoscopy. 2010;42(11):900-903. 8. Lee JM, Lee HS, Hyun JJ, et al. Slow-pull using a fanning technique is more useful than the standard suction technique in EUS-Guided fine needle aspiration in pancreatic masses. Gut Liver. 2018;12(3):360-366. 9. Evans DB, Farnell MB, Lillemoe KD, Vollmer Jr C, Strasberg SM, Schulick RD. Surgical treatment of resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg Oncol. 2009;16(7):1736-1744. 10. Brugge W, Dewitt J, Klapman JB, et al. Techniques for cytologic sampling of pancreatic and bile duct lesions. Diagn Cytopathol. 2014;42(4):333-337. 11. Noh DH, Choi K, Gu S, et al. Comparison of 22-gauge standard fine needle versus core biopsy needle for endoscopic ultrasoundguided sampling of suspected pancreatic cancer: a randomized crossover trial. Scand J Gastroenterol. 2018;53(1):94-99. 12. Hedenström P, Demir A, Khodakaram K, Nilsson O, Sadik R. EUS-guided reverse bevel fine-needle biopsy sampling and open tip fine-needle aspiration in solid pancreatic lesions - a prospective, comparative study. Scand J Gastroenterol. 2018;53(2):231-237. 13. Bang JY, Hebert-Magee S, Trevino J, Ramesh J, Varadarajulu S. Randomized trial comparing the 22-gauge aspiration and 22-gauge biopsy needles for EUS-guided sampling of solid pancreatic mass lesions. Gastrointest Endosc. 2012;76(2):321-327. 14. Vanbiervliet G, Napoléon B, Saint Paul MC, et al. Core needle versus standard needle for endoscopic ultrasound-guided biopsy of solid pancreatic masses: a randomized crossover study. Endoscopy. 2014;46(12):1063-1070. 15. Alatawi A, Beuvon F, Grabar S, et al. Comparison of 22G reversebeveled versus standard needle for endoscopic ultrasound-guided sampling of solid pancreatic lesions. United European Gastroenterol J. 2015;3(4):343-352. 16. Elhanafi S, Mahmud N, Vergara N, et al. Comparison of endoscopic ultrasound tissue acquisition methods for genomic analysis of pancreatic cancer. J Gastroenterol Hepatol. 2019;34(5):907-913. 17. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG Clinical Guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018;113(4):464-479. 18. Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12(3):183-197. 19. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126(5):1330-1336. 20. Ahmad NA, Kochman ML, Brensinger C, et al. Interobserver agreement among endosonographers for the diagnosis of neoplastic

versus non-neoplastic pancreatic cystic lesions. Gastrointest Endosc. 2003;58(1):59-64. 21. Centeno BA, Warshaw AL, Mayo-Smith W, Southern JF, Lewandrowski K. Cytologic diagnosis of pancreatic cystic lesions. A prospective study of 28 percutaneous aspirates. Acta Cytol. 1997; 41(4):972-980. 22. Sedlack R, Affi A, Vazquez-Sequeiros E, Norton ID, Clain JE, Wiersema MJ. Utility of EUS in the evaluation of cystic pancreatic lesions. Gastrointest Endosc. 2002;56(4):543-547. 23. Cizginer S, Turner BG, Bilge AR, Karaca C, Pitman MB, Brugge WR. Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas. 2011;40(7): 1024-1028. 24. Ngamruengphong S, Bartel MJ, Raimondo M. Cyst carcinoembryonic antigen in differentiating pancreatic cysts: a meta-analysis. Dig Liver Dis. 2013;45(11):920-926. 25. Khalid A, Zahid M, Finkelstein SD, et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009;69(6):1095-1102. 26. Maker AV, Katabi N, Qin LX, et al. Cyst fluid interleukin-1beta (IL1beta) levels predict the risk of carcinoma in intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res. 2011; 17(6):1502-1508. 27. Yang D, Samarasena JB, Jamil LH, et al. Endoscopic ultrasoundguided through-the-needle microforceps biopsy in the evaluation of pancreatic cystic lesions: a multicenter study. Endosc Int Open. 2018; 6(12):E1423-E1430. 28. Eloubeidi MA, Gress FG, Savides TJ, et al. Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States. Gastrointest Endosc. 2004; 60(3):385-389. 29. Gress F, Michael H, Gelrud D, et al. EUS-guided fine-needle aspiration of the pancreas: evaluation of pancreatitis as a complication. Gastrointest Endosc. 2002;56(6):864-867. 30. O’Toole D, Palazzo L, Arot√ßarena R, et al. Assessment of complications of EUS-guided fine-needle aspiration. Gastrointest Endosc. 2001;53(4):470-474. 31. Williams DB, Sahai AV, Aabakken L, et al. Endoscopic ultrasound guided fine needle aspiration biopsy: a large single centre experience. Gut. 1999;44(5):720-726. 32. Lee LS, Saltzman JR, Bounds BC, Poneros JM, Brugge WR, Thompson CC. EUS-guided fine needle aspiration of pancreatic cysts: a retrospective analysis of complications and their predictors. Clin Gastroenterol Hepatol. 2005;3(3):231-236. 33. Janssen J, König K, Knop-Hammad V, Johanns W, Greiner L. Frequency of bacteremia after linear EUS of the upper GI tract with and without FNA. Gastrointest Endosc. 2004;59(3):339-344. 34. Levy MJ, Norton ID, Wiersema MJ, et al. Prospective risk assessment of bacteremia and other infectious complications in patients undergoing EUS-guided FNA. Gastrointest Endosc. 2003;57(6):672-678. 35. Adler DG, Jacobson BC, Davila RE, et al. ASGE guideline: complications of EUS. Gastrointest Endosc. 2005;61(1):8-12. 36. Affi A, Vazquez-Sequeiros E, Norton ID, Clain JE, Wiersema MJ. Acute extraluminal hemorrhage associated with EUS-guided fine needle aspiration: frequency and clinical significance. Gastrointest Endosc. 2001;53(2):221-225. 37. Kaufman AR, Sivak Jr MV. Endoscopic ultrasonography in the differential diagnosis of pancreatic disease. Gastrointest Endosc. 1989; 35(3):214-219. 38. Yasuda K, Mukai H, Fujimoto S, Nakajima M, Kawai K. The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointest Endosc. 1988;34(1):1-8. 39. Rösch T, Braig C, Gain T, et al. Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonography, computed tomography, and angiography. Gastroenterology. 1992;102(1):188-199. 40. Tio TL, Tytgat GN. Endoscopic ultrasonography in staging local resectability of pancreatic and periampullary malignancy. Scand J Gastroenterol Suppl. 1986;123:135-142. 41. Rösch T, Dittler HJ, Strobel K, et al. Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes. Gastrointest Endosc. 2000;52(4):469-477. 42. Midwinter MJ, Beveridge CJ, Wilsdon JB, Bennett MK, Baudouin CJ, Charnley RM. Correlation between spiral computed tomography,

348.e2 endoscopic ultrasonography and findings at operation in pancreatic and ampullary tumours. Br J Surg. 1999;86(2):189-193. 43. Karmazanovsky G, Fedorov V, Kubyshkin V, Kotchatkov A. Pancreatic head cancer: accuracy of CT in determination of resectability. Abdom Imaging. 2005;30(4):488-500. 44. Lu X, Zhang S, Ma C, Peng C, Lv Y, Zou X. The diagnostic value of EUS in pancreatic cystic neoplasms compared with CT and MRI. Endosc Ultrasound. 2015;4(4):324-329. 45. Fusaroli P, Kypraios D, Caletti G, Eloubeidi MA. Pancreatico-biliary endoscopic ultrasound: a systematic review of the levels of evidence, performance and outcomes. World J Gastroenterol. 2012; 18(32):4243-4256. 46. Cannon ME, Carpenter SL, Elta GH, et al. EUS compared with CT, magnetic resonance imaging, and angiography and the influence of biliary stenting on staging accuracy of ampullary neoplasms. Gastrointest Endosc. 1999;50(1):27-33. 47. Maluf-Filho F, Sakai P, M Cunha JE, et al. Radial endoscopic ultrasound and spiral computed tomography in the diagnosis and staging of periampullary tumors. Pancreatology. 2004;4(2):122-128. 48. Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc. 2011;73(4):691-696. 49. Zylberberg H, Fontaine H, Corréas JM, Carnot F, Bréchot C, Pol S. Dilated bile duct in patients receiving narcotic substitution: an early report. J Clin Gastroenterol. 2000;31(2):159-161. 50. Bettini N, Moutardier V, Turrini O, et al. Preoperative locoregional re-evaluation by endoscopic ultrasound in pancreatic ductal adenocarcinoma after neoadjuvant chemoradiation. Gastroenterol Clin Biol. 2005;29(6-7):659-663. 51. Ponchon T, Gagnon P, Berger F, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995; 42(6):565-572. 52. Victor DW, Sherman S, Karakan T, Khashab MA. Current endoscopic approach to indeterminate biliary strictures. World J Gastroenterol. 2012;18(43):6197-6205. 53. Wakatsuki T, Irisawa A, Bhutani MS, et al. Comparative study of diagnostic value of cytologic sampling by endoscopic ultrasonography-guided fine-needle aspiration and that by endoscopic retrograde pancreatography for the management of pancreatic mass without biliary stricture. J Gastroenterol Hepatol. 2005;20(11): 1707-1711. 54. DeWitt J, Misra VL, Leblanc JK, McHenry L, Sherman S. EUSguided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointest Endosc. 2006;64(3):325-333. 55. Eloubeidi MA, Chen VK, Jhala NC, et al. Endoscopic ultrasoundguided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol. 2004;2(3):209-213. 56. Rösch T, Hofrichter K, Frimberger E, et al. ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study. Gastrointest Endosc. 2004;60(3):390-396. 57. Mohamadnejad M, DeWitt JM, Sherman S, et al. Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest Endosc. 2011;73(1):71-78. 58. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford). 2011;13(5): 356-360. 59. Navaneethan U, Hasan MK, Lourdusamy V, Njei B, Varadarajulu S, Hawes RH. Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointest Endosc. 2015;82(4):608-614.e2. 60. Pishvaian AC, Collins B, Gagnon G, Ahlawat S, Haddad NG. EUS-guided fiducial placement for CyberKnife radiotherapy of mediastinal and abdominal malignancies. Gastrointest Endosc. 2006;64(3):412-417. 61. Sanders MK, Moser AJ, Khalid A, et al. EUS-guided fiducial placement for stereotactic body radiotherapy in locally advanced and recurrent pancreatic cancer. Gastrointest Endosc. 2010;71(7): 1178-1184. 62. Yan BM, Dam JV. Endoscopic ultrasound-guided intratumoural therapy for pancreatic cancer. Can J Gastroenterol. 2008;22(4): 405-410. 63. Coronel E, Singh BS, Cazacu IM, et al. EUS-guided placement of fiducial markers for the treatment of pancreatic cancer. VideoGIE. 2019;4(9):403-406.

64. Nieto J, Abbas A, Wagh MS, Draganov PV. Tu1645 Prospective Evaluation of a New EUS-Guided Multi-Fiducial Delivery System. Gastrointest Endosc. 2015;81(5):Pg. AB543-AB543. 65. Kaufman M, Singh G, Das S, et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroenterol. 2010;44(2):127-134. 66. Puli SR, Reddy JBK, Bechtold ML, Antillon MR, Brugge WR. EUS-guided celiac plexus neurolysis for pain due to chronic pancreatitis or pancreatic cancer pain: a meta-analysis and systematic review. Dig Dis Sci. 2009;54(11):2330-2337. 67. Sahai AV, Lemelin V, Lam E, Paquin SC. Central vs. bilateral endoscopic ultrasound-guided celiac plexus block or neurolysis: a comparative study of short-term effectiveness. Am J Gastroenterol. 2009;104(2):326-329. 68. Leblanc JK, Rawl S, Juan M, et al. Endoscopic ultrasound-guided celiac plexus neurolysis in pancreatic cancer: a prospective pilot study of safety using 10 mL versus 20 mL Alcohol. Diagn Ther Endosc. 2013;2013:327036. 69. Sakamoto H, Kitano M, Kamata K, et al. EUS-guided broad plexus neurolysis over the superior mesenteric artery using a 25-gauge needle. Am J Gastroenterol. 2010;105(12):2599-2606. 70. Ascunce G, Ribeiro A, Reis I, et al. EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video). Gastrointest Endosc. 2011;73(2):267-274. 71. Bang JY, Sutton B, Hawes RH, Varadarajulu S. EUS-guided celiac ganglion radiofrequency ablation versus celiac plexus neurolysis for palliation of pain in pancreatic cancer: a randomized controlled trial (with videos). Gastrointest Endosc. 2019;89(1):58-66.e3. 72. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102-111. 73. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology. 2013;13(4 suppl 2):e1-e15. 74. Lopes CV, Pesenti C, Bories E, Caillol F, Giovannini M. Endoscopic-ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts and abscesses. Scand J Gastroenterol. 2007; 42(4):524-529. 75. Varadarajulu S, Trevino JM, Christein JD. EUS for the management of peripancreatic fluid collections after distal pancreatectomy. Gastrointest Endosc. 2009;70(6):1260-1265. 76. Saunders R, Ramesh J, Cicconi S, et al. A systematic review and meta-analysis of metal versus plastic stents for drainage of pancreatic fluid collections: metal stents are advantageous. Surg Endosc. 2019;33(5):1412-1425. 77. Will U, Thieme A, Fueldner F, Gerlach R, Wanzar I, Meyer F. Treatment of biliary obstruction in selected patients by endoscopic ultrasonography (EUS)-guided transluminal biliary drainage. Endoscopy. 2007;39(4):292-295. 78. Yamao K, Bhatia V, Mizuno N, et al. EUS-guided choledochoduodenostomy for palliative biliary drainage in patients with malignant biliary obstruction: results of long-term follow-up. Endoscopy. 2008; 40(4):340-342. 79. Park DH, Koo JE, Oh J, et al. EUS-guided biliary drainage with one-step placement of a fully covered metal stent for malignant biliary obstruction: a prospective feasibility study. Am J Gastroenterol. 2009;104(9):2168-2174. 80. Khashab MA, Valeshabad AK, Afghani E, et al. A comparative evaluation of EUS-guided biliary drainage and percutaneous drainage in patients with distal malignant biliary obstruction and failed ERCP. Dig Dis Sci. 2015;60(2):557-565. 81. Itoi T, Itokawa F, Tsuchiya T, Tsuji S, Tonozuka R. Endoscopic ultrasound-guided choledochoantrostomy as an alternative extrahepatic bile duct drainage method in pancreatic cancer with duodenal invasion. Dig Endosc. 2013;25(suppl 2):142-145. 82. Okuno N, Hara K, Mizuno N, et al. Efficacy of the 6-mm fully covered self-expandable metal stent during endoscopic ultrasoundguided hepaticogastrostomy as a primary biliary drainage for the cases estimated difficult endoscopic retrograde cholangiopancreatography: a prospective clinical study. J Gastroenterol Hepatol. 2018; 33(7):1413-1421. 83. Yamao K, Kitano M, Takenaka M, et al. Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan. Gastrointest Endosc. 2018;88(1):66-75.e2.

348.e3 84. DeWitt J, McGreevy K, Schmidt CM, Brugge WR. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc. 2009;70(4):710-723. 85. Gan SI, Thompson CC, Lauwers GY, Bounds BC, Brugge WR. Ethanol lavage of pancreatic cystic lesions: initial pilot study. Gastrointest Endosc. 2005;61(6):746-752. 86. Oh HC, Seo DW, Song TJ, et al. Endoscopic ultrasonographyguided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterology. 2011;140(1):172-179. 87. Pai M, Habib N, Senturk H, et al. Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors. World J Gastrointest Surg. 201527;7(4):52-59. 88. Khashab MA, Bukhari M, Baron TH, et al. International multicenter comparative trial of endoscopic ultrasonography-guided gastroenterostomy versus surgical gastrojejunostomy for the treatment of malignant gastric outlet obstruction. Endosc Int Open. 2017;5(4):E275-E281. 89. Mendelsohn RB, Gerdes H, Markowitz AJ, DiMaio CJ, Schattner MA. Carcinomatosis is not a contraindication to enteral stenting in

selected patients with malignant gastric outlet obstruction. Gastrointest Endosc. 2011;73(6):1135-1140. 90. Sun S, Xu H, Xin J, Liu J, Guo Q, Li S. Endoscopic ultrasoundguided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy. 2006;38(4):399-403. 91. Chang KJ, Nguyen PT, Thompson JA, et al. Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cancer. 2000;88(6):1325-1335. 92. Oh HC, Brugge WR. EUS-guided pancreatic cyst ablation: a critical review (with video). Gastrointest Endosc. 2013;77(4):526-533. 93. Hirooka Y, Kasuya H, Ishikawa T, et al. A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer. 2018 25;18(1):596. 94. Khvalevsky EZ, Gabai R, Rachmut IH, et al. Mutant KRAS is a druggable target for pancreatic cancer. Proc Natl Acad Sci USA. 2013;110(51):20723-207258.

CHAPTER 23 Image-guided liver biopsy Juan Camacho, Lynn A Brody, and Anne M Covey INTRODUCTION Percutaneous image-guided needle biopsy (PNB) is the cornerstone for diagnosis and treatment of many diseases involving the liver. Minimally invasive, PNB is an effective outpatient procedure with a low complication rate. The success of PNB requires proper patient selection, optimal procedural technique, and optimal postprocedure management. Interventional radiology (IR, which also stands for interventional radiologists) plays a central role in patient management because of the need for image-guided tissue sampling procedures. Several oncology trials have demonstrated that molecular and biomarker targeted therapies have a higher chance of clinical success,1 and such studies require tissue for analysis. PNB may also prevent unnecessary surgery for lesions with benign pathology.1 Finally, tissue obtained at PNB can allow for histologic grading that has both prognostic and treatment implications.2 The role of PNB has increased beyond simply obtaining a diagnosis, and tissue obtained from PNB can now predict disease susceptibility to treatment and provide prognostic information. In addition, tissue-based biomarkers can be used to prescribe a tumor-specific treatment regimen because they can predict response to targeted therapies and/or immunotherapy.3 As a result, an increased volume of tissue per biopsy and repeated sampling from the same target are often required. Because the results of PNB are so impactful for optimal care of patients with a liver mass or at risk for cirrhosis, obtaining adequate specimens is critically important. This also holds true for clinical trials in which inadequate specimens have been shown to be a cause of ineligibility for oncology patients.4 For example, in the National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH) trial, almost 15% of biopsy samples were inadequate for molecular analysis; this proved to be a major impediment in the treatment of patients for whom a trial was the last resort.5 Therefore, with PNB, IR can help improve patient outcomes through the study of biomarkers and optimization of specimen acquisition techniques. This chapter will explore the equipment and modalities used to perform PNB, the preprocedural and postprocedural patient care, sample adequacy concepts, and quality metrics, as well as future perspectives in the era of personalized medicine.

NEEDLE BIOPSY MODALITIES AND EQUIPMENT PNB involves advancing a needle under imaging guidance into a target to obtain tissue or cells for diagnosis. PNB can be performed using aspiration techniques with a thin hollow needle (18–25 gauge) for cytologic evaluation or by using a cutting tool (core needle biopsy [CNB]), which uses a larger needle (9–20 gauge) that has a capturing mechanism to allow for the extraction of a piece of tissue. Of the two, only CNB allows for gross histologic evaluation6 (Fig. 23.1). Both techniques can provide material for immunohistochemistry and molecular characterization.

Aspiration techniques include fine needle aspiration (FNA), fine needle capillary sampling (FNCS), and large needle aspiration (LNA). These techniques are generally considered safer and potentially less traumatic compared with CNB. During FNA, samples are acquired by using suction from a syringe until tissue/cells are collected. FNCS consists of placing a fine needle into the target, followed by rotating the tip within the target without aspiration until the sample ascends the needle by capillary action. An LNA is similar to an FNA but performed with a larger bore needle, is often useful to aspirate fluid for cytology, and may be preferred for thicker fluids/secretions. Ideally, an on-site cytopathologist or cytotechnologist can provide an immediate evaluation of the sample quality; this has been shown to increase the sensitivity of the biopsy, shorten the procedure time, and minimize the number of passes required to obtain a diagnostic specimen.7,8 A CNB is most commonly performed with 16- to 21-gauge needles that have an automated cutting mechanism and a variable throw or length of tissue sampled (5–30 mm). The specific needles are selected based on target size and presence of vascular structures or other organs in the path of or beyond the margins of the targeted lesion. The needle length is chosen after determining the depth of the target, based on the preprocedural imaging. Although FNA can provide excellent diagnostic information for metastatic disease, infection, and lymphoma, CNB samples are more likely to render definitive diagnosis for most primary liver tumors. To confirm adequacy of the specimen, a touch preparation can be prepared on a glass slide for immediate evaluation by a cytopathologist or cytotechnologist. Before placement in formalin or saline, the core of tissue is placed on a glass slide and gently moved over the slide to allow some cells to collect on the surface. Care should be taken to avoid excessive vigorous touch preparations because this has been shown to deplete the cellularity and DNA content of the specimen.9 Core samples are commonly placed in formalin. Occasionally, specimens may be sent “fresh” to pathology in saline or on saline-soaked gauze for special studies. Because cells placed in saline eventually undergo cell lysis related to osmotic shifts of saline into the cell, a specimen in saline needs to be fixed or frozen within a few hours to avoid deterioration of the tissue sample. Tissue also may be snap frozen for future studies. The preferred method for processing tissue may vary from institution to institution, and the preference of the pathologists reviewing the material should be ascertained before initiating a biopsy. For core biopsies obtained to evaluate organ parenchyma, end-cut rather than side-notch needles may yield more diagnostic samples in terms of number of portal triads.10 In the setting of organ dysfunction or failure, no touch preparation is required; specimens are sent in formalin or saline, depending on the indication and the preference of the pathologist. Many authors advocate performing both FNA and CNB to maximize the diagnostic yield of every biopsy.11–13 CNB is particularly useful in most solid primary liver lesions, such as 349

350

PART 2  DIAGNOSTIC TECHNIQUES

IMAGE GUIDANCE MODALITIES

A

C

B

D

FIGURE 23.1  Fine and core biopsy needles. A, Panoramic view of a semi-automatic core needle biopsy gun, demonstrating the finger notches and, in this case, a retracted plunger that conceals the specimen notch. B, Magnified lateral view of the tip of a semi-automatic core needle biopsy gun exposing the specimen notch when the plunger is deployed. C, Panoramic view of a fine needle for biopsy (in this case, a Westcott-style needle with the stylet in place). D, Magnified anterior view of the Westcott-style needle without the inner stylet, demonstrating the beveled tip and the notch in the sidewall of the needle just proximal to the tip, which facilitates the operator’s ability to choose more precisely the location from which the cells will be aspirated.

well-differentiated hepatocellular carcinoma (HCC) or nodular hyperplasia in the setting of cirrhosis and in confirmation of benign diagnoses, including hemangioma, adenoma, or focal nodular hyperplasia (FNH; see Chapter 87).14,15

For more information, see Chapter 13–17. Preprocedural target evaluation is crucial to adequately select the best imaging modality for a specific target lesion. Multiple imaging modalities are available. For a summary of advantages and disadvantages of each imaging modality, please refer to Table 23.1. For many lesions that can be seen with ultrasonography (US), ultrasound is ideal for PNB. Because it is located just under the diaphragm, the liver is susceptible to respiratory motion. Smaller lesions and lesions in proximity to critical structures benefit the most from US because of the ability to visualize the needle in real-time as it is advanced from the skin into the target. Another advantage of US is the ability to image in virtually any plane, which allows the operator to plan trajectories that might be impossible using computed tomography (CT) or magnetic resonance (MR) guidance. The fact that US does not use ionizing radiation is also relevant, especially for children and pregnant patients. US has been shown to result in a shorter procedure time and a lower cost when compared with CT-guided interventions.16 The ability to successfully and safely place a biopsy needle in a lesion is unfortunately operatordependent and has a relatively steep learning curve. Further, US imaging is limited or impossible in air-filled/gas-filled structures, such as the lung or bowel, and the sound waves cannot penetrate bone. CT is a common modality for guiding PNBs because it provides superb anatomic detail. IRs are very familiar with crosssectional imaging, making it the modality of choice for deep intra-abdominal structures or for those that cannot be adequately imaged with US (i.e., lung, pancreas, adrenal glands, retroperitoneal lymph nodes, bone). Many manufacturers offer CT fluoroscopy as an option on diagnostic scanners. This produces CT images in near real time. CT fluoroscopy can expose the operator to ionizing radiation, but some physicians prefer it because of the near immediacy between needle manipulation and image availability. Cone-beam CT (CBCT), also sometimes referred to as C-arm CT, uses a flat-panel x-ray detector that rotates around the patient; the x-rays are divergent, forming a cone. Images can be reconstructed in multiple planes, and three-dimensional reconstructions can be performed. The soft tissue resolution is not nearly as good as with conventional CT, but the resolution for lung and bone is adequate for biopsy guidance. Further, available biopsy path–planning and needle-navigation software may assist the operator with needle placement.17 MR imaging (MRI)–guided biopsy has been made possible by the advent of open-bore MRI systems that provide access to patients during imaging and the availability of nonferrous biopsy needles and monitoring equipment. The superior contrast resolution of MRI allows for the targeting of lesions that are difficult to visualize with US and noncontrast CT, and the ability of MRI to image in any plane enhances the safe targeting of lesions where access in the axial plane would be more dangerous or more difficult.18 However, there is a limited selection of MRI-safe biopsy needles and there is considerable artifact on the MRI images; this makes biopsy of small lesions challenging. Fluoroscopy is useful in the abdomen for guiding bile duct biopsies. Benign and malignant biliary strictures often have similar cholangiographic appearances and rarely can be distinguished based on imaging alone19,20 (see Chapter 16 and 20).

  Chapter 23  Image-Guided Liver Biopsy

351

TABLE 23.1  Commonly Used Imaging Modalities for Image-Guided Biopsy MODALITY

REAL TIME

COMMON TARGETS

LIMITATIONS

ADVANTAGES

Ultrasound

Yes

• Soft tissue lesions • Solid visceral organs • Omental and peritoneal lesions

• Operator dependent • Susceptible to artifacts • Unable to use in deeper lesions, some bone lesions, or gas-filled organs • Dense calcifications may obscure needle

• Multiplanar • Nonionizing radiation • Real time allows accurate targeting of mobile structures

CT

Nearly (CT fluoroscopy)

• • • • •

• Ionizing radiation • Metal artifacts • Positioning and patient motion • Targets can only be accessed in one plane and gantry angulation is not widely available

• Requires less operator skill than ultrasound • Allows in-plane visualization of the entire path to the lesion • Allows multiplanar reconstructions (not in real time) • High resolution and contrast

Fluoroscopy

Yes

• Endoluminal biopsies, commonly brush biopsies – bile ducts, ureter • Transjugular liver, renal biopsies • Selected bone lesions

• Ionizing radiation • Not cross sectional • Two-dimensional

• Widely available • Multiplanar

X-Ray

No

Stereotactic – breast

Ionizing radiation

Visualize and sample calcifications

MR

Nearly (MR Fluoroscopy)

• Breast • Prostate • Abdominal lesions

• High cost/infrastructure required • Requires special equipment

• Nonionizing • Multiplanar • Excellent contrast and spatial resolution • Ideal for “occult” lesions not well seen using other modalities

PET-CT

No, although often used in combination with CT

• Any FDG avid target

• Susceptible to miss-registration, particular in areas with significant respiratory motion • High cost • Additional radiation exposure

• Useful for lesions that may have different components (necrosis) • Very sensitive – can show malignant changes before morphologic changes on CT

Thoracic Pelvic Musculoskeletal Retroperitoneal Deep abdominal visceraliver, adrenal, pancreas, omentum

Lesions originating within the duct may be sampled by either an endoluminal or a direct percutaneous approach. Percutaneous transhepatic biliary drainage allows direct access to the biliary tract for endoluminal biopsy (see Chapter 31). Biopsy forceps or brush-biopsy catheters can be used through the existing tract to obtain tissue samples of suspicious areas. The sensitivity of forceps biopsy is in the range of 40% to 80%, higher than that of brush biopsy, which is in the range of 30% to 60%. Specificity for each approaches 98%.12,21,22 Combining forceps and brush biopsy of the bile duct may provide superior results to either alone. Studies have noted the sensitivity of brushing alone of 49%, forceps alone of 69%, and combined of 80%; with specificity for malignancy of 100%.23 However, a new percutaneous forceps biopsy technique cites sensitivity of 93.3%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 70%, with overall accuracy of 94.2%.24 Alternatively, after the biliary tree is opacified, a direct PNB of a bile duct lesion may be targeted with fluoroscopy, using a transhepatic approach.25,26 After contrast injection into the indwelling biliary drainage catheter to delineate the targeted bile duct abnormality, a fine needle is advanced through the abdomen to the target and a specimen is obtained. Confirmation of accurate needle position is made by obtaining oblique fluoroscopic images and by real-time fluoroscopy, when the needle is seen to move the duct or the indwelling catheter or both. Fluoroscopy can also be used to guide nontargeted transvenous biopsies of the liver.

Occasionally, a lesion is only well demonstrated by 18Ffluorodeoxyglucose (FDG) positron emission tomography (PET) imaging (see Chapter 18). In these cases, it is possible to use the combination of PET and CT to guide accurate needle placement. Certain lesions may also have varying FDG avidity; PET guidance allows the most hypermetabolic portion of a lesion to be targeted. Operators should be mindful of the patient as a source of radiation; the major source of radiation to the operator during PET-guided interventions was found to be the time spent in close proximity to the patient.27 New technology that requires further development into clinical practice allows for the fusion of multiple modalities. For example, CT and MRI scans can be overlaid with real-time US images to achieve the clarity of the CT or MR and the real-time visualization capabilities of US. PET images can also be fused. Additionally, robotic guidance systems have entered the market in an effort to optimize speed and accuracy for needle placement (Fig. 23.2).

PREPROCEDURE EVALUATION With the exception of nontarget liver biopsy, all patients undergoing PNB should have preprocedural imaging. Careful evaluation of the images by an IR is mandatory for the procedure to be successful because adequate imaging will determine the proper imaging modality for guidance, patient positioning, and

352

PART 2  DIAGNOSTIC TECHNIQUES

A

malignancy, pathologic staging of a malignancy, or molecular diagnostic testing. Absolute contraindications for a PNB are rare and are basically limited to lack of safe access. Relative contraindications are related to conditions that increase the risk for complications and include coagulopathy (depending on target location), inability to sedate or provide general anesthesia, and significant comorbidities.6 Table 23.2 lists the general approach to common medication classes that should be considered before any biopsy procedure.

Liver-Specific Considerations

B

C

The indication for liver biopsy can be broadly grouped into two categories: (1) Random (nontarget) liver biopsy for diagnosis of hepatocellular disease, and (2) targeted liver biopsy for tissue diagnosis of a liver mass. With refinements in abdominal imaging, benign diseases are often confidently diagnosed on imaging alone, obviating the need for a biopsy; this is particularly helpful in cases of suspected adenomas and hemangiomas because these highly vascular lesions have a higher risk for procedural complications. Certain locations in the liver can be more technically difficult in terms of visualizing and accessing the lesion, particularly with masses that are closer to the dome and/or more anterior. In these instances, patient cooperation with deep inspiration and/or decubitus or semirecumbent positioning can be helpful, although the need for deep inspiration in particular limits the ability to sedate the patient for the procedure, because sedated patients are typically not able to cooperate with breathing instructions. When multiple liver lesions with similar diagnostic imaging characteristics are present, the choice of which lesion to biopsy is made based on lesion visibility and location. A needle trajectory that passes through normal parenchyma before accessing the lesion is preferred to minimize the risk for hemorrhage and tract seeding.29–31

Focal Liver Lesions

D FIGURE 23.2  Image-guided liver biopsy. A, An 82-year-old male with a history of lymphoma was found to have a hypoechoic liver lesion not seen on computed tomography (CT; arrowheads). Ultrasoundguided biopsy was performed. Real-time ultrasound guidance allowed for placement of the needle (arrows) in a relatively avascular trajectory. B, A 27-year-old male with sarcoma and a solitary liver lesion (arrow). CT is useful for lesions high in the liver where ultrasound is limited by interposed air or bone. C, A 77-year-old man with cirrhosis, hepatopulmonary syndrome, and liver lesion suggestive of hepatocellular carcinoma. Magnetic resonance (MR) guidance allows for multiplanar planning of needle paths, as in this case in which coronal imaging was used. D, A 74-year-old with a remote history of lymphoma and smoldering myeloma. Areas of positron emission tomography (PET) avidity in the liver were seen without CT or ultrasound correlate. PET guidance was used to perform the biopsy and confirm the diagnosis of recurrent lymphoma.

preferred access/sampling technique.6 Main objectives for PNB may include diagnosis of the etiology of diffuse parenchymal diseases, microbiology diagnosis in infectious diseases, histologic diagnosis of a focal lesion, histologic classification of a

Focal liver lesions may be solitary or multiple. For a solitary lesion, several benign conditions—cyst, hemangioma, FNH, and adenoma—often can be diagnosed confidently by high-quality cross-sectional imaging, obviating the need for biopsy32–34 (see Chapter 14). These diagnoses should be considered in all solitary liver lesions, unless they are known to be new in the setting of a known cancer or in patients at risk for primary HCC. HCC may also be diagnosed based on imaging and clinical criteria (see Chapter 14 and 89). According to the integrated Liver Imaging Reporting and Data System (LI-RADS) and the American Association for the Study of Liver Diseases (AASLD) and National Comprehensive Cancer Network (NCCN) guidelines, liver lesions identified on screening US that are larger than 1 cm in patients with cirrhosis or chronic hepatitis can be diagnosed as HCC based on a single CT or MRI study demonstrating classic findings of arterial enhancement and portal venous or delayed-phase washout35,36 (see Chapter 14). When the diagnosis of HCC is considered and these criteria are not met or if patients are to be treated with systemic therapy, biopsy may be required. Smaller, encapsulated tumors are more likely to be well differentiated, and tissue cores are required to distinguish a well-differentiated tumor from normal or cirrhotic liver. Because of the risk for tumor seeding,30,31,37 when a curative treatment is possible, biopsy for HCC should be performed only after surgical consultation and after referencing the most

  Chapter 23  Image-Guided Liver Biopsy

353

TABLE 23.2  General Approach to Medications Addressed Before Percutaneous Image-Guided Needle Biopsy28 MEDICATION CLASS

LOW PROCEDURAL RISK

HIGH PROCEDURAL RISK

MEDICATION RESUME

Glycoprotein IIb/IIIa inhibitor

Withhold 24 hours before procedure

Direct thrombin inhibitors

Continue

Withhold 2–4 hours before procedure and check activated partial thromboplastin time (aPTT)

4–6 hours after procedure

Direct factor Xa inhibitors

Continue

eGFR $30 mL/min: withhold 4 doses eGFR ,30 mL/min: withhold 6 doses Emergent: Use reversal agents as appropriate (i.e., andexanet alfa).

24 hours

Nonsteroidal antiinflammatory drugs (NSAIDs)

Continue

Hold for five days if possible, minimum three days

24 hours after procedure

Parenteral direct P2Y12 inhibitors

Defer until patient is off medication. If emergent, withhold 1 hour before procedure, discuss with cardiology

Defer until patient is off medication. If emergent, withhold one hour before procedure, discuss with cardiology

4–6 hours after procedure

Intermediate-acting NSAID

Continue

Hold morning of procedure

24 hours after procedure

Reversible phosphodiesterase II inhibitor

Continue

Continue

4–6 hours after procedure

Thienopyridines (P2Y12 platelet inhibitors)

Continue

Withhold for five days before procedure

4–6 hours after procedure

Low molecular weight heparin

Continue

Prophylactic dose: withhold one dose Therapeutic dose: last dose 24 hours before the procedure Check anti-Xa level if renal function is impaired

12 hours after procedure

Heparin

Continue

Stop 4–6 hours before procedure.

6–8 hours after procedure

Phosphodiesterase (PDE) inhibitor

Continue

Hold morning of procedure

Resume day after procedure

Reversible adenosine diphosphate (ADP) receptor antagonist

Continue

Withhold five days before procedure

Day after procedure

Vitamin K antagonist

Do not withhold if preprocedure international normalized ratio (INR) ,3. For INR .3 (mechanical heart valves), consider bridging for cases that are high risk for thrombosis

Withhold for five days. Confirm INR ,1.8 preprocedure. Consider bridging for high thrombosis risk patients. If stat or emergent, use reversal agent.

Bridged patients: same day High risk for bleeding patients: resume day after procedure. High thrombosis risk cases may benefit from bridging

24 hours

Adapted from Patel IJ, Rahim S, Davidson JC, et al. Society of Interventional Radiology Consensus Guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions-part II: Recommendations: Endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol. 2019;30(8):1168–1184.e1

current imaging and clinical criteria. The AASLD position paper on liver biopsy reinforces caution based on concern for needle-track seeding, sampling error, and possible increased rate of recurrence post-transplant in Child B or C cirrhotic patients with stage I to III tumors greater than 3 cm and a-fetoprotein greater than 200 ng/mL.38 However, an accurate diagnosis of HCC is extremely important because confirmation of diagnosis alters the priority for liver transplantation.39 Multifocal solid liver lesions most commonly represent metastatic disease. In such cases, biopsy may be requested to (1) confirm the presence of metastatic disease in a patient with a known primary, (2) establish tumor type and stage simultaneously at initial presentation, (3) acquire tissue for genetic analysis, and (4) obtain required samples for patients undergoing experimental therapies.

and known or suspected cirrhosis (see Chapters 68, 69, and 74). Gastroenterologists have historically performed most liver biopsies without imaging guidance; however, unusual anatomy, obesity, and other exigencies occasionally make imaging-guided biopsy advisable. Adequate tissue cores can be obtained with needles that are 20 gauge and larger, although needles 18 gauge and larger provide a more generous specimen for analysis.40,41 It has been suggested that specimens of at least 1 cm in length are preferred.42 Biopsy may also be performed in transplanted livers and in living donors before transplant. Indications for this last group are controversial, and it is recommended to follow the recommendations of the Vancouver Forum43 in performing biopsy in potential donors who have a clinical or imaging-based reason to do so, but not as a matter of routine.44

Liver Parenchymal Biopsy

Transjugular liver biopsy is a useful alternative to PNB in patients with coagulopathy or significant ascites or when hepatic venous pressure measurements are required.45 Although transvenous

Core liver biopsy is used to grade and stage liver disease in patients with abnormal liver function studies, chronic hepatitis,

Transvenous Liver Biopsy

354

PART 2  DIAGNOSTIC TECHNIQUES

A

B

C FIGURE 23.3  Transjugular liver biopsy. A, A right hepatic venogram is shown via a catheter placed in the right internal jugular vein in a 29-year-old female with aplastic anemia and liver failure. B, The trough of an 18-gauge core biopsy needle is advanced into the liver parenchyma (arrow). C, Right hepatic venogram after biopsy shows contrast in the biopsy tract (arrow) and no evidence of extracapsular hemorrhage.

biopsy is seemingly more invasive than PNB, the risk for significant bleeding in patients with coagulopathy is minimized using a transvenous approach because bleeding from the biopsy site tracks back into the venous circulation and not into the abdominal cavity. Proper technique to avoid puncture of the liver capsule is crucial to optimize safety. In this technique, a venous sheath is introduced into a hepatic vein (most commonly the right hepatic vein from a right internal jugular approach; Fig. 23.3). Pressure measurements may be obtained to evaluate the source (presinusoidal, sinusoidal, or postsinusoidal) and degree of portal hypertension. A biopsy needle is introduced through the sheath into the liver parenchyma to obtain histologic samples. Care must be taken to avoid performing the biopsy too peripherally because this increases the risk for capsular puncture and secondary intraperitoneal hemorrhage. Transvenous biopsy is useful for nontargeted parenchymal biopsy and, in rare circumstances, for biopsy of focal lesions with or without the aid of additional imaging techniques like US.46,47 ASCITES. Historically, ascites has been considered a relative contraindication to liver biopsy. Some studies have suggested a higher complication rate in the presence of ascites, although

the validity of their results can be questioned because of the lack of image guidance and other co-existing confounding variables, such as coagulopathy or thrombocytopenia. Other studies have demonstrated that the presence of ascites did not result in a significant difference in the major complication rate.48,49 Many have advocated for ascites drainage before visceral interventions. The theoretical advantage of this approach is to allow a potential tamponade effect of the abdominal wall against the needle entry site in the liver. If a therapeutic paracentesis is being performed with a drain, some also advocate leaving the drain in place because this may help to identify a hemoperitoneum earlier, which may facilitate a prompt treatment. The utility of preprocedural drainage has not been demonstrated in the literature.

PROCEDURAL OUTCOMES AND COMPLICATIONS Diagnostic yield for percutaneous liver biopsy ranges from 83% to 100%.50,51 Outcomes are also influenced by size of the lesion, pathology, and the use of FNA or CNB. For example, accuracy for diagnosis of HCC has been reported to be greater than 86%, although nondiagnostic samples are more frequent in lesions smaller than 2 cm.52,53

  Chapter 23  Image-Guided Liver Biopsy

Complications Death after PNB is rare. Mortality in large series is under 0.01%, and it is more frequent in patients with cirrhosis or in those with underlying malignancy.54 Major hemorrhage requiring transfusion or intervention ranges from 0% to 3.4%48,55 (Fig. 23.4). Some authors advocate placing absorbable gelatin sponge (Gelfoam) pledgets in the biopsy tract, but this has not been shown definitively to decrease the risk of major bleeding.56 Additional risks include bleeding, pneumothorax, infection, bile leak, and needle-tract seeding of tumor. To minimize the risk of bleeding, patients should have relevant laboratory work before biopsy, including a complete blood count and coagulation profile. Although criteria differ from institution to institution and from physician to physician, a platelet count of greater than 50,000 μL and an international normalized ratio (INR) less than 1.5 are acceptable in most cases. Biopsy in thrombocytopenic patients can be performed with platelet coverage, although the decision to proceed with biopsy should be considered carefully. For patients with an elevated INR, transfusion of plasma or supplementation with vitamin K should be considered. One additional consideration is that patients with cirrhosis may have altered coagulation not accurately reflected by the INR. In these patients, measuring thromboelastography may more accurately predict the risk of bleeding and therefore inform judicious use of prophylactic blood products before biopsy. Elevated partial thromboplastin time (PTT) in patients not on heparin is usually because of circulating antiphospholipid cardiolipins and is not

A

D

B

355

typically clinically significant. A test of bleeding time may be performed to evaluate the significance of an elevated PTT in select patients. It is advisable to have patients stop antiplatelet medications, if possible, to minimize the risk of bleeding; however, the risk of stopping antiplatelet therapy must be weighed against the risk of bleeding from the biopsy. Occasionally, the balance favors performing the biopsy while the patient remains on regular medication(s). Pain out of proportion to imaging findings after liver biopsy may be because of bile peritonitis.57,58 Care should be taken to minimize needle passes through the gallbladder, cystic duct, or dilated bile ducts. If the gallbladder is inadvertently punctured, it should be aspirated as completely as possible before removing the needle. Bile leaks resulting in discernible collections are rare after liver biopsy in the absence of downstream biliary obstruction. Lesions in the dome of the liver sometimes require an approach for biopsy that crosses the lung base, putting patients at risk for pneumothorax. Pneumothorax occurs in approximately 30% of transthoracic procedures and requires placement of a chest tube in approximately 6% to 12% of cases. The risk of pneumothorax is typically related more to patient than technical factors, although depth of the target lesion, number of pleural surfaces transgressed, and patient positioning (e.g., prone positioning decreases the risk of pneumothorax) have been shown to affect the likelihood. Elderly patients and patients with underlying chronic obstructive pulmonary disease are more prone to pneumothorax that requires treatment.59–61

C

E

FIGURE 23.4  Liver biopsy complicated by hemorrhage. A, Positron emission tomography (PET) shows multiple 18F-fluorodeoxyglucose (FDG) avid liver lesions (arrow) in a 78-year-old male with gastric cancer. B, A 22-gauge FNA (arrow) was performed to confirm the presence of metastatic disease. The patient developed hypotension, pain, and tachycardia in the recovery room after the procedure, and C, a noncontrast computed tomography (CT) was performed showing acute hemoperitoneum. D, Celiac angiography was performed showing active extravasation from a right hepatic artery branch (arrows). E, The bleeding right hepatic artery branch was selectively catheterized and embolized with coils (arrowheads). Notice the gap between the liver edge and the abdominal wall because of hemoperitoneum.

356

PART 2  DIAGNOSTIC TECHNIQUES

A

B

FIGURE 23.5  Track seeding. A, Combination embolization and ethanol ablation was performed to treat an area of residual viable tumor in a 47-year-old male with hepatocellular carcinoma (HCC). Note the path of the 20-gauge needle (arrows) used for ethanol ablation. B, 20 months later, in addition to an intrahepatic recurrence (arrowheads) there is evidence of track seeding in the abdominal wall (arrow) that was not evident on 4 interval scans.

Another feared complication is tract seeding (Fig. 23.5). Multiple studies have found an incidence of seeding ranging from 0% to 6%. Two large meta-analyses demonstrated an incidence of 2.7% and median risk of 2.29%.29,30 High rates of tract seeding have also been suggested after liver biopsy in colorectal metastases.62 In other large surveys of percutaneous biopsy from all sites and malignancy types published in the literature, however, the reported overall seeding rate was 0.005% to 0.009%.63

TABLE 23.3  Common Mutations Found in Frequent Primary and Metastatic Malignancies to the Liver and Therapeutic Implication MALIGNANCY

MUTATIONS

TARGETED MEDICATION

Melanoma

BRAFV600E BRAFV600E or V600K BRAF V600X PD-L1

Vemurafenib Dabrafenib, Trametinib, Cobimetinib Nivolumab Pembrolizumab

Lung cancer

EGFR EGFR T790M EML4—ALK KRAS ROS1 PD-L1

Afatinib, Erlotinib, Gefitinib Osimertinib Ceritinib, Crizotinib, Alectinib Erlotinib, Gefitinib Crizotinib Pembrolizumab

Breast

ESR1 and HER2HER2

Everolimus Lapatinib Pertuzumab, Trastuzumab, Trastuzumab-emtansine Tamoxifen, Anastrozole, Exemestane, Letrozole

SAMPLE ADEQUACY AND CLINICAL IMPLICATIONS The evaluation of sample adequacy in the setting of parenchymal liver disease is considered when the total core sample measures 20 to 25 mm long and/or allows evaluation of more than 11 complete portal tracts. The specimen adequacy in oncologic samples refers to the availability of obtaining tissue for both histopathologic and biomarker analysis.64–67 For example, at least 50 viable cells per tissue section are needed for fluorescent in situ hybridization (FISH) testing, and a minimum of 200 ng of DNA (about 500 cells) is needed for genotyping. These numbers are changing rapidly because of improved sensitivity of multiple diagnostic platforms and current techniques allowing genotyping with less than 10 ng of DNA.68 Mutational analysis requires at least 10% malignancy cell content.68 From a practical standpoint, a 21-gauge needle aspirate can yield 100 cells and a CNB sample 500 cells.59,69 These pathologic biomarkers can have significant impact in diagnosis, prediction of response, and overall prognosis, allowing treatment monitoring and potentially screening of relatives. Most common pathologic biomarkers predictive of a potential response to a given intervention are further detailed in Table 23.3.

QUALITY ASSURANCE, BIOPSY LIMITATIONS, AND FUTURE DIRECTIONS IRs are the gatekeepers tasked with evaluating relative risks and potential rewards by selecting adequate targets for biopsy. This evaluation requires expertise in assessing safety, optimal sampling technique, potential complications, and image guidance to obtain the necessary specimens for pathologic analysis. To this end, the National Institutes of Health (NIH) has issued

ESR1 and PGR Gastric

HER2

Trastuzumab

GIST

c-KIT

Imatinib, Sunitinib

Pancreatic

EGFR and KRAS

Erlotinib

Colorectal

EGFR and KRASESR1 and PGR and HER2-

Cetuximab, Panitumumab Palbociclib Fulvestrant

Renal

ESR1 and HER2BRAF V600X

Everolimus Nivolumab

Ovarian

BRCA

Olaparib

several recommendations that can help improve the quality of the samples obtained for clinical trial purposes and that can be summarized under the following five premises70: 1. Include IR on any research proposal requiring tissue sampling. 2. Communicate with IR to establish the biopsy needs, including number of cores required, preferred tumor region to be sampled, and designated time points when sampling should be performed. 3. If safe and feasible, recommend collecting up to five cores per biopsy to allow molecular diagnostic testing.

  Chapter 23  Image-Guided Liver Biopsy

. Standardize the biopsy procedure as much as possible. 4 5. Review each case with an IR to ensure preprocedural successful planning.

Biopsy Limitations Although biopsy is the standard of care for many pathologies, innate limitations include sampling error, the subjective nature of the interpretation, the cost of the procedure in standard of care facilities, and the associated potential complications previously described. A biopsy is only able to evaluate a very small piece of parenchyma, which may or may not represent a diffuse process, leading to sampling error because it is well known that pathology may not affect the parenchyma uniformly.71,72 In addition, diagnostic accuracy and disease staging is directly related to specimen size, and small biopsy samples may be nondiagnostic or may not reveal cirrhosis, even when cirrhosis is present.73 Biopsy interpretation is subjective. Although pathologists have well-established criteria for diagnosis and staging of multiple liver diseases, there is interobserver and intraobserver variability. For example, in one study of pathologic staging of fibrosis, interobserver and intraobserver variability was approximately 80%; however, concordance for inflammatory activity and fat content was under 50%.74 Cost associated with percutaneous image-guided procedures should not and cannot be ignored. Every biopsy involves an expert IR and a pathologist in addition to technologists, nurses, and, in some cases, an anesthesiologist. The average direct costs of a percutaneous liver biopsy are $1,558 (in 2016 U.S. dollars),75,76 and this can be significantly higher for a transvenous procedure.

Future Directions Advances in diagnostic imaging and pathology will revolutionize PNBs in the near future. Radiogenomics is a field that studies the relationship between imaging phenotypes and the underlying genetic characteristics of a tumor. Radiogenomics has the potential of determining the ideal site to biopsy or even obviate the need for tissue diagnosis68 (see Chapters 13 and 19). Another field that is growing at an accelerated pace within diagnostic radiology is quantitative radiology, which measures the structural and biologic parameters of medical images to obtain metrics that can provide a “virtual biopsy.” These measurements can potentially determine not only disease status but also severity, treatment response, and future outcomes.77 Optical molecular imaging is also an emerging imaging modality that allows for characterization of tissue in real time. By using a molecular tracer in tissues, suspicious areas of any body part can potentially be biopsied or resected.68 These tracers include the development of theranostics, such as nanoparticles,

357

which combine both therapeutics and diagnostics in one package for image-guided therapy. This strategy has been explored in tumors, such as colorectal cancer, in which CEA, the folate receptor alpha (FRa), and the epidermal growth factor receptor (EGFR) present in tumor cells are actively being used as targets.78 The additional potential development of smart needles that can identify molecular characteristics of lesions confirming the ideal site for sampling is a revolutionary concept.68 Efforts are also underway to design steerable needles that allow for greater control and maneuverability to make the path to a lesion safer.68 All of these concepts align with the development of robotically assisted guided intervention programs.68 A parallel field to tissue sampling that has grown at an accelerated rate is the field of “liquid biopsy.” Liquid biopsy platforms can detect circulating tumor cells (CTCs), circulating tumor DNA (ct-DNA), and microvesicles containing RNA within a peripheral venous blood sample. Obtaining a peripheral blood sample is significantly safer than even a minimally invasive biopsy. Liquid biopsy may offer an alternative evaluation of tumor burden, as well as new biomarkers that can be followed over time at a potentially lower cost. More importantly, liquid biopsy may better reflect the spectrum of heterogeneity present in any given tumor.79,80

CONCLUSION PNB is a well-established and safe diagnostic tool, and it is an important instrument in the diagnosis of tumors, for determining the cause of organ dysfunction/staging, and for documenting recurrent or metastatic disease. Increasingly, needle biopsy is required to provide material for genetic analysis. Complications are infrequent, and most are easily treated or self-limiting. Tract seeding has been reported but occurs infrequently. It is important to remember that there is no such thing as a “negative” biopsy.81 If a diagnosis of malignancy is not made, a specific benign diagnosis needs to be confirmed. If nonspecific findings are evident on cytology, including inflammatory or reactive changes, fibrous tissue, or normal site tissue, or, if atypical cells are present, either another biopsy can be performed, or the lesion should be closely followed up with imaging depending on the pretest probability of disease. The role of biopsy in patient management is evolving in tandem with the development of associated fields, including functional and molecular imaging. Until biopsies are no longer necessary, every effort should be made to keep morbidity low and diagnostic rates high. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

357.e1

REFERENCES 1. Falconi A, Lopes G, Parker JL. Biomarkers and receptor targeted therapies reduce clinical trial risk in non-small-cell lung cancer. J Thorac Oncol. 2014;9(2):163-169. 2. Kim TH, Buonocore D, Petre EN, et al. Utility of core biopsy specimen to identify histologic subtype and predict outcome for lung adenocarcinoma. Ann Thorac Surg. 2019;108(2):392-398. 3. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89-95. 4. Lim C, Sung M, Shepherd FA, et al. Patients with advanced nonsmall cell lung cancer: are research biopsies a barrier to participation in clinical trials? J Thorac Oncol. 2016;11(1):79-84. 5. Flaherty KT, Gray R, Chen A, et al. The molecular analysis for therapy choice (NCI-MATCH) trial: lessons for genomic trial design. J Natl Cancer Inst. 2020;112(10):1021-1029. 6. Veltri A, Bargellini I, Giorgi L, Almeida P, Akhan O. CIRSE Guidelines on percutaneous needle biopsy (PNB). Cardiovasc Intervent Radiol. 2017;40:1501-1513. 7. Nasuti JF, Gupta PK, Baloch ZW. Diagnostic value and cost-effectiveness of on-site evaluation of fine-needle aspiration specimens: review of 5,688 cases. Diagn Cytopathol. 2002;27(1):1-4. 8. Tsou MH, Tsai SF, Chan KY, et al. CT-guided needle biopsy: value of on-site cytopathologic evaluation of core specimen touch preparations. J Vasc Interv Radiol. 2009;20(1):71-76. 9. Rekhtman N, Kazi S, Yao J, et al. Depletion of core needle biopsy cellularity and DNA content as a result of vigorous touch preparations. Arch Pathol Lab Med. 2015;139(7):907-912. 10. Constantin A, Brisson ML, Kwan J, Proulx F. Percutaneous USguided renal biopsy: a retrospective study comparing the 16-gauge end-cut and 14-gauge side-notch needles. J Vasc Interv Radiol. 2010;21(3):357-361. 11. Sigel CS, Moreira AL, Travis WD, et al. Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens. J Thorac Oncol. 2011;6(11):1849-1856. 12. Stewart CJ, Mills PR, Carter R, et al. Brush cytology in the assessment of pancreatico-biliary strictures: a review of 406 cases. J Clin Pathol. 2001;54(6):449-455. 13. Stewart CJ, Coldewey J, Stewart IS. Comparison of fine needle aspiration cytology and needle core biopsy in the diagnosis of radiologically detected abdominal lesions. J Clin Pathol. 2002; 55(2):93-97. 14. Kulesza P, Torbenson M, Sheth S, Erozan YS, Ali SZ. Cytopathologic grading of hepatocellular carcinoma on fine-needle aspiration. Cancer. 2004;102(4):247-258. 15. Kuo FY, Chen WJ, Lu SN, Wang JH, Eng HL. Fine needle aspiration cytodiagnosis of liver tumors. Acta Cytol. 2004;48(2): 142-148. 16. Sheafor DH, Paulson EK, Kliewer MA, DeLong DM, Nelson RC. Comparison of sonographic and CT guidance techniques: Does CT fluoroscopy decrease procedure time? AJR Am J Roentgenol. 2000;174(4):939-942. 17. Floridi C, Muollo A, Fontana F, et al. C-arm cone-beam computed tomography needle path overlay for percutaneous biopsy of pulmonary nodules. Radiol Med. 2014;119(11):820-827. 18. Stattaus J, Maderwald S, Forsting M, Barkhausen J, Ladd ME. MR-guided core biopsy with MR fluoroscopy using a short, widebore 1.5-Tesla scanner: feasibility and initial results. J Magn Reson Imaging. 2008;27(5):1181-1187. 19. Hadjis NS, Collier NA, Blumgart LH. Malignant masquerade at the hilum of the liver. Br J Surg. 1985;72(8):659-661. 20. Corvera CU, Blumgart LH, Darvishian F, et al. Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma. J Am Coll Surg. 2005;201(6):862-869. 21. Govil H, Reddy V, Kluskens L, et al. Brush cytology of the biliary tract: retrospective study of 278 cases with histopathologic correlation. Diagn Cytopathol. 2002;26(5):273-277. 22. Weber A, Schmid RM, Prinz C. Diagnostic approaches for cholangiocarcinoma. World J Gastroenterol. 2008;14(26):4131-4136. 23. Kulaksiz H, Strnad P, Römpp A, et al. A novel method of forceps biopsy improves the diagnosis of proximal biliary malignancies. Dig Dis Sci. 2011;56(2):596-601. 24. Patel P, Rangarajan B, Mangat K. Improved accuracy of percutaneous biopsy using “cross and push” technique for patients suspected

with malignant biliary strictures. Cardiovasc Intervent Radiol. 2015;38(4):1005-1010. 25. Chawla S, Malik N, Wig JD, Kochhar R, Gupta SK, Suri S. Cholangiographically guided aspiration cytology in the management of malignant biliary obstruction. Indian J Gastroenterol. 1989;8(2): 95-96. 26. Gonzalez-Aguirre A, Covey AM, Brown KT, et al. Comparison of biliary brush biopsy and fine needle biopsy in the diagnosis of biliary strictures. Minim Invasive Ther Allied Technol. 2018;27(5):278-283. 27. Ryan ER, Thornton R, Sofocleous CT, et al. PET/CT-guided interventions: personnel radiation dose. Cardiovasc Intervent Radiol. 2013;36(4):1063-1067. 28. Patel IJ, Rahim S, Davidson JC, et al. Society of Interventional Radiology Consensus Guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions-part II: recommendations: Endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol. 2019;30(8):1168-1184.e1. 29. Young AL, Lodge JP. Needle-track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2009;58(6):887-888. 30. Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK. Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev. 2007;33(5):437-447. 31. Perkins JD. Seeding risk following percutaneous approach to hepatocellular carcinoma. Liver Transpl. 2007;13(11):1603. 32. Kim J, Ahmad SA, Lowy AM, et al. An algorithm for the accurate identification of benign liver lesions. Am J Surg. 2004;187(2): 274-279. 33. Hussain SM, Terkivatan T, Zondervan PE, et al. Focal nodular hyperplasia: findings at state-of-the-art MR imaging, US, CT, and pathologic analysis. Radiographics. 2004;24(1):3-19. 34. Gibbs JF, Litwin AM, Kahlenberg MS. Contemporary management of benign liver tumors. Surg Clin North Am. 2004;84(2): 463-480. 35. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022. 36. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 5.2020. https://www.nccn.org/professionals/physician_ gls/pdf/hepatobiliary.pdf. 37. Durand F, Belghiti J, Paradis V. Liver transplantation for hepatocellular carcinoma: role of biopsy. Liver Transpl. 2007;13(11 suppl 2): S17-S23. 38. Saborido BP, Díaz JC, de Los Galanes SJ, et al. Does preoperative fine needle aspiration-biopsy produce tumor recurrence in patients following liver transplantation for hepatocellular carcinoma? Transplant Proc. 2005;37(9):3874-3877. 39. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044. 40. Guido M, Rugge M. Liver biopsy sampling in chronic viral hepatitis. Semin Liver Dis. 2004;24(1):89-97. 41. Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;1(8480):523-525. 42. Schiano TD, Azeem S, Bodian CA, et al. Importance of specimen size in accurate needle liver biopsy evaluation of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3(9):930-935. 43. Barr ML, Belghiti J, Villamil FG, et al. A report of the Vancouver Forum on the care of the live organ donor: lung, liver, pancreas, and intestine data and medical guidelines. Transplantation. 2006;81(10): 1373-1385. 44. Herrero JI, Rotellar F, Benito A, et al. Is liver biopsy necessary in the evaluation of a living donor for liver transplantation? Transplant Proc. 2014;46(9):3082-3083. 45. Behrens G, Ferral H. Transjugular liver biopsy. Semin Intervent Radiol. 2012;29(2):111-117. 46. Bodri D, Colodrón M, García D, Obradors A, Vernaeve V, Coll O. Transvaginal versus transabdominal ultrasound guidance for embryo transfer in donor oocyte recipients: a randomized clinical trial. Fertil Steril. 2011;95(7):2263-2268.e1.

357.e2 47. Middlebrook MR, Sickler GK, Wallace MJ, et al. Transabdominal ultrasound guidance for transvenous biopsy of focal hepatic masses. J Vasc Interv Radiol. 2000;11:365-368. 48. Little AF, Ferris JV, Dodd GD III, Baron RL. Image-guided percutaneous hepatic biopsy: effect of ascites on the complication rate. Radiology. 1996;199(1):79-83. 49. Murphy FB, Barefield KP, Steinberg HV, Bernardino ME. CT- or sonography-guided biopsy of the liver in the presence of ascites: frequency of complications. AJR Am J Roentgenol. 1988;151(3): 485-486. 50. Welch TJ, Sheedy PF II, Johnson CD, Johnson CM, Stephens DH. CT-guided biopsy: prospective analysis of 1,000 procedures. Radiology. 1989;171(2):493-496. 51. Gazelle GS, Haaga JR. Guided percutaneous biopsy of intraabdominal lesions. AJR Am J Roentgenol. 1989;153(5):929-935. 52. Caturelli E, Solmi L, Anti M, et al. Ultrasound guided fine needle biopsy of early hepatocellular carcinoma complicating liver cirrhosis: a multicentre study. Gut. 2004;53(9):1356-1362. 53. Huang GT, Sheu JC, Yang PM, Lee HS, Wang TH, Chen DS. Ultrasound-guided cutting biopsy for the diagnosis of hepatocellular carcinoma—a study based on 420 patients. J Hepatol. 1996;25(3): 334-338. 54. Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2(2):165-173. 55. Giorgio A, Tarantino L, de Stefano G, et al. Complications after interventional sonography of focal liver lesions: a 22-year singlecenter experience. J Ultrasound Med. 2003;22(2):193-205. 56. Hatfield MK, Beres RA, Sane SS, Zaleski GX. Percutaneous imaging-guided solid organ core needle biopsy: coaxial versus noncoaxial method. AJR Am J Roentgenol. 2008;190(2):413-417. 57. Ruben RA, Chopra S. Bile peritonitis after liver biopsy: nonsurgical management of a patient with an acute abdomen: a case report with review of the literature. Am J Gastroenterol. 1987;82(3):265-268. 58. Taylor JD, Carr-Locke DL, Fossard DP. Bile peritonitis and hemobilia after percutaneous liver biopsy: endoscopic retrograde cholangiopancreatography demonstration of bile leak. Am J Gastroenterol. 1987;82(3):262-264. 59. Covey AM, Gandhi R, Brody LA, Getrajdman G, Thaler HT, Brown KT. Factors associated with pneumothorax and pneumothorax requiring treatment after percutaneous lung biopsy in 443 consecutive patients. J Vasc Interv Radiol. 2004;15(5):479-483. 60. Hiraki T, Mimura H, Gobara H, et al. Incidence of and risk factors for pneumothorax and chest tube placement after CT fluoroscopyguided percutaneous lung biopsy: retrospective analysis of the procedures conducted over a 9-year period. AJR Am J Roentgenol. 2010;194(3):809-814. 61. Takeshita J, Masago K, Kato R, et al. CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan. AJR Am J Roentgenol. 2015; 204(1):29-34. 62. Jones OM, Rees M, John TG, Bygrave S, Plant G. Biopsy of resectable colorectal liver metastases causes tumour dissemination and adversely affects survival after liver resection. Br J Surg. 2005; 92(9):1165-1168. 63. Smith EH. Complications of percutaneous abdominal fine-needle biopsy. Review. Radiology. 1991;178(1):253-258. 64. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology [published correction appears in J Mol Diagn. 2013;15(5):730]. J Mol Diagn. 2013; 15(4):415-453.

65. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology [published correction appears in J Thorac Oncol. 2013;8(10):1343]. J Thorac Oncol. 2013; 8(7):823-859. 66. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. 67. Lim C, Tsao MS, Le LW, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol. 2015;26(7):1415-1421. 68. Tam AL, Lim HJ, Wistuba II, et al. Image-guided biopsy in the era of personalized cancer care: Proceedings from the Society of Interventional Radiology Research Consensus Panel. J Vasc Interv Radiol. 2016;27(1):8-19. 69. Pirker R, Herth FJ, Kerr KM, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol. 2010;5(10):1706-1713. 70. Ferry-Galow KV, Datta V, Makhlouf HR, et al. What can be done to improve research biopsy quality in oncology clinical trials? J Oncol Pract. 2018;14(11):JOP1800092. 71. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97(10):2614-2618. 72. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7): 1898-1906. 73. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol. 2003;39(2): 239-244. 74. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology. 1994;20(1 Pt 1):15-20. 75. Tapper EB, Hunink MG, Afdhal NH, Lai M, Sengupta N. Costeffectiveness analysis: risk stratification of nonalcoholic fatty liver disease (NAFLD) by the primary care physician using the NAFLD fibrosis score. PLoS One. 2016;11:e0147237. 76. Tapper EB, Sengupta N, Hunink MG, Afdhal NH, Lai M. CostEffective evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastography [published correction appears in Am J Gastroenterol. 2016;111(3):446]. Am J Gastroenterol. 2015;110(9):1298-1304. 77. Buckler AJ, Bresolin L, Dunnick NR, et al. Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities. Radiology. 2011;259(3):875-884. 78. Pereira I, Sousa F, Kennedy P, Sarmento B. Carcinoembryonic antigen-targeted nanoparticles potentiate the delivery of anticancer drugs to colorectal cancer cells. Int J Pharm. 2018;549(1-2):397403. 79. Alix-Panabières C, Pantel K. Real-time liquid biopsy: circulating tumor cells versus circulating tumor DNA. Ann Transl Med. 2013; 1(2):18. 80. Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579-586. 81. Phillips MD, Silverman SG, Cibas ES, Seltzer SE. Negative predictive value of imaging-guided abdominal biopsy results: cytologic classification and implications for patient management. AJR Am J Roentgenol. 1998;171(3):693-696.

CHAPTER 24 Intraoperative diagnostic techniques Ola Ahmed and M. B. Majella Doyle OVERVIEW The management of hepatobiliary and pancreatic disease has evolved greatly since the 1990s. Today’s operative surgeon has several valuable adjuncts to aid in accurate preoperative evaluation and planning for benign and malignant disease. Advances in contrast-enhanced computed tomography (CT), endoscopic ultrasound (EUS), magnetic resonance imaging (MRI; see Chapters 13–17), and endoscopic retrograde cholangiopancreatography (ERCP; see Chapters 20 and 30) have revolutionized the treatment of benign and malignant hepatobiliary and pancreatic disease. Despite these advances in the modern era, present-day management of these conditions relies on the appropriate use of intraoperative diagnostic modalities, particularly when confronted with challenging and unanticipated findings during surgical exploration. This chapter will review the intraoperative utility of ultrasound (US), cholangiography, and laparoscopy in hepatobiliary and pancreatic surgery.

INTRAOPERATIVE ULTRASONOGRAPHY Intraoperative US (IOUS) is commonly used during both open and laparoscopic procedures to provide accurate real-time imaging. It can be a valuable tool in the assessment of hepatic and biliary anatomy, evaluation of biliary calculi, localization of tumors, determination of the extent of and/or resectability of disease, and determination of the extent of mesenteric vascular involvement in the case of pancreatic tumors.1

Hepatic Disease Evaluation of the Liver IOUS of the liver was first introduced into clinical practice in the early 1980s and rapidly became routine practice for the management of malignant liver disease.2–4 Early reports demonstrated the advantages of IOUS, which in some cases altered the operative management of hepatic malignancy not only by delineating the proximity major vascular and biliary structures but also by detecting hepatic tumors not revealed on preoperative imaging (Fig. 24.1). In a study of 100 consecutive patients undergoing preoperative imaging for colorectal liver metastases, contrast-enhanced and unenhanced IOUS identified an additional 47 liver nodules that were not viewed using MRI, and these new findings resulted in the modification of a previously planned procedure.5 In a similar study of 102 patients with colorectal liver metastases, contrast-enhanced IOUS altered 22% of planned surgical procedures because of the additional diagnosis of nodules or more accurate visualization of vascular invasion.6 The yield of IOUS is highly dependent on the type and quality of preoperative imaging obtained and although additional intraoperative findings may not influence all planned resections, it remains an integral adjunct to parenchymal assessment and operative planning. 358

When evaluating the liver parenchyma, the sonographer must first evaluate the extent of intrahepatic disease and then assess for vascular occlusion or invasion. Sonographic features of liver tumors vary. The surgeon should anticipate the need for assistance in the case of ambiguous or challenging lesions and communicate with radiologists preoperatively so that personnel and equipment are readily available. The sonographer should be familiar with the characteristics of common parenchymal lesions (see Chapters 13–15). Hemangiomas are typically soft when palpated and either lack any visible flow or demonstrate minimal flow compared with the adjacent liver parenchyma. They typically appear hyperechoic with well-demarcated margins and may demonstrate posterior echo enhancement.7 In contrast, colorectal liver metastases are usually hyperechoic or isoechoic with adjacent liver parenchyma and are frequently surrounded by an illdefined hypoechoic rim that may give the lesion a bull’s-eye or target appearance. Mucinous variant colorectal cancer metastases may contain calcification that produces acoustic shadowing. Hepatocellular carcinoma (HCC) frequently invades major vascular structures and may be associated with portal lymphadenopathy.8

Technical Considerations Examination of the liver should always start with inspection of the organ and the entire peritoneal cavity followed by palpation. IOUS is then applied with increasing pressure to accurately delineate the spatial relationship of hepatic tumors to major vascular and biliary structures. Intraoperative transducers appropriate for liver surgery include high-frequency (6–10 MHz) T-shaped linear- or curvilinear-array transducers. These probes provide excellent high-resolution images and can identify lesions as small as approximately 1 to 2 mm in size at depths of penetration of approximately 10 to 12 cm. Transducers with color-flow Doppler imaging enable further discrimination of tumors and normal hepatic vasculature. Techniques for IOUS continue to evolve, with some units now routinely performing laparoscopic IOUS. Particular attention must be given to port placement in this scenario.9 Typically, no coupling gel is required because of the natural surface moisture of the liver. The transducer is initially held in a transverse position, and the survey of the liver begins by first identifying the confluence of the right and left portal pedicles. Next, all segmental pedicles on the right are visualized, followed by those on the left. Each hepatic vein is visualized by scanning peripherally and then by traversing toward the vena cava. Identifying the hepatic veins can be achieved by placing the transducer cranially in a midline position and angling towards the heart. The confluence of the left and middle vein has a characteristic appearance and should be observed in all sonographic examinations. Only light pressure should be applied to the liver. If the entire liver is to be scanned (e.g., to search for metastases), sequential overlapping sagittal strokes are made sweeping

  Chapter 24  Intraoperative Diagnostic Techniques

Tumor

LHD

359

some time to develop and has a longer learning curve, which may explain why it is not used more liberally for biliary disease. LUS is a useful adjunct for staging gallbladder carcinoma and cholangiocarcinoma (see Chapters 49–51). Sonographic findings not only reveal subtle liver metastases but also may help to define the local extent of these tumors and their relationship to the ductal system.13,14 Doppler and color flow images may help distinguish biliary sludge from polyps and other intraluminal tumors. Other applications of LUS include evaluating biliary strictures and malignant biliary obstructions in the planning of surgical reconstructions, such as biliary bypass procedures.

Technical Considerations PV

FIGURE 24.1  Intraoperative ultrasound view of a tumor (arrows) at the base of segment IV. The confluence of the right and left portal venous branches is shown (PV). Dilation of the left hepatic duct (LHD) is indicated and suggests possible involvement by tumor.

from superior to inferior, beginning at the most lateral margin of segment II and traveling toward the right. More focal scanning can be used to localize impalpable lesions situated deep within the liver parenchyma. Special care must be taken when imaging the superior portion of the right liver, the posterior subdiaphragmatic bare area, and surface lesions, such as hamartomas, because these areas are particularly challenging to completely visualize. Once the lesion has been delineated and measured, photographic documentation should be obtained and saved. The planned surgical margin of the lesion may be outlined using electrocauterization of the liver capsule because it will produce acoustic shadowing. The depth of the lesion can be estimated using its relationship to other structures or direct measurement.

Biliary Disease Evaluation of the Biliary Tree As laparoscopic cholecystectomy has become the standard of care for gallbladder disease, the use of laparoscopic US (LUS) during this procedure has emerged as an alternative to cholangiography (see Chapters 37 and 38). In this scenario, IOUS has a reported sensitivity and specificity over 90% for detecting choledocholithiasis and is recommended as the primary screening modality for evaluating bile duct calculi because of its safety, efficiency, and overall cost-effectiveness.10 IOUS is at least as good as cholangiography, if not better, at detecting stones during laparoscopic cholecystectomy.11 LUS in particular has the added advantage of reducing the risk for biliary and vascular injury. A recent systematic review compared LUS with intraoperative cholangiography (IOC) during laparoscopic cholecystectomy and found that routine LUS reduced bile duct injuries to almost 0% and resulted in a reduced procedure time when compared with IOC.12 However, proficiency with IOUS requires

The biliary tree and gallbladder are imaged best from a right subcostal port or from the periumbilical port. Sonographic examination of the gallbladder is approached through the liver by using a 5- or 7-MHz transducer. A nasogastric or orogastric tube should be placed for decompression. The bile ducts can be visualized through a compressed duodenum or gastric antrum using a 7-MHz transducer, but placing the transducer directly on the ducts should be avoided because reverberation artifact limits its sensitivity. Color flow images are helpful for distinguishing the common bile duct (CBD) from the portal vein, for identifying the insertion of cystic duct into the CBD, and for identifying any aberrant biliary anatomy during surgery.

Pancreatic Disease Evaluation of the Pancreas The principal application of IOUS for pancreatic disease is during staging laparoscopy (SL) in patients with pancreatic malignancy. In such cases, it can be used to further evaluate pancreatic lesions and their proximity to or invasion into vascular structures, concurrent liver metastases, and potential resectability. Approximately 20% to 35% of patients deemed initially resectable on preoperative imaging demonstrate occult metastases and/or locally invasive disease, which preclude curative resection (see Chapter 62). Other applications for US in pancreatic surgery include localizing islet cell tumors (see Chapter 65). These particularly small lesions may be difficult to visualize or palpate in the body or tail, and sonographic images may help delineate these and other malignant or premalignant tumors in the distal portions of the pancreas.15 In addition, US can help identify and characterize pancreatic ductal abnormalities and areas of necrosis in pancreatitis and may be useful during drainage procedures, such as cystogastrostomy (see Chapters 56 and 58).

Technical Considerations When IOUS is performed laparoscopically, a right upper or left upper quadrant port is used to orient the probe transversely along the long axis of the pancreas. Frequently, a periumbilical port is required to image the head, neck, and uncinate process. A range of probes, most commonly “I” or “T” shaped and convex, with different forms and frequencies can be used, ranging from 7.5 MHz to 10 MHz.16 The standard approach requires access into the retrocavity and direct contact between the probe and the pancreas. When this is difficult to achieve, the IOUS can be performed through the acoustic window of the left lobe of the liver or by pushing onto the gastric wall or overlying omentum.16

360

PART 2  DIAGNOSTIC TECHNIQUES

INTRAOPERATIVE CHOLANGIOGRAPHY IOC is most used during elective cholecystectomy to define biliary anatomy and to assess for choledocholithiasis. It is rarely necessary or helpful in assessing the extent of biliary tumors or during hepatic resection.

Choledocholithiasis In terms of diagnosing choledocholithiasis, IOC has a sensitivity ranging from 59% to 100% and specificity of 93% to 100%.17 The procedure itself is highly operator dependent, and there is ongoing debate regarding its routine use during laparoscopic cholecystectomy. Most cases of choledocholithiasis are suspected on clinical grounds with elevated liver enzymes and are often visualized during preoperative US, ERCP, or magnetic resonance cholangiopancreatography (MRCP; see Chapter 16). The incidence of clinically silent choledocholithiasis is low, occurring in roughly 1 in 25 cases of biliary colic.18,19 Even when missed during cholecystectomy, these residual stones rarely, if ever, cause symptoms or become clinically relevant. As a result, routine application of IOC for the evaluation of unsuspected choledocholithiasis may subject patients to unnecessary bile duct explorations or ERCP studies, with considerable cost to both patients and providers.20

Biliary Injuries Proponents of routine IOC argue that its use can help identify and prevent bile duct injuries, a rare but major complication during laparoscopic cholecystectomy (see Chapter 36). Iatrogenic injuries are typically because of either a technical error, in which the CBD is inadvertently transected or occluded with a surgical clip, or misidentification of the duct. The Stewart-Way classification categorizes bile duct and vascular injuries into four classes based on the mechanisms of injury.21 Class I injuries involve an incision (i.e., an incomplete transection) of the CBD without duct loss and typically occur when the CBD is mistaken for a cystic duct but the injury is recognized before complete transection. Class II injuries represent lateral injury to the common hepatic duct. Class III injuries are the most common and represent a CBD mistaken for a cystic duct, transected and partially excised before immediate intraoperative recognition. Finally, class IV injuries occur when a right hepatic duct is mistaken for a cystic duct. Ideally, if IOC is performed, it should be before dividing the presumed cystic duct. If cannulation of the CBD, rather than the cystic duct, occurs, the cholangiocatheter can be removed, and the ductotomy can be addressed by primary repair or by placing a T-tube, without the need for formal biliary reconstruction. A T-tube for large defects would allow the CBD to heal without stricture formation, and the tube can be removed nonoperatively several weeks after the cholecystectomy following cholangiography. The alternative scenario is complete transection of the CBD, a class III injury. In the absence of cholangiography, this transection is seldom recognized intraoperatively, typically presents postoperatively, and results in significant patient morbidity. Management requires an open bilioenteric anastomosis for repair; thus IOC has the potential to not only prevent bile duct injury but also mitigate its impact if injury does occur.

Controversies Critics of routine cholangiography suggest that such an approach increases the risk of ductal complications (i.e., stricture)

and pancreatitis, wastes time and money, and is seldom indicated if the critical view of safety is achieved (see Chapters 36 and 37). Proponents argue that routine cholangiography is a safe, accurate, quick, and cost-effective method for evaluating the bile duct.22,23 Although we favor a selective approach, we recognize that the success of either approach is highly variable and likely to depend on each surgeon’s familiarity with cholecystectomy and cholangiography. Whether selective or routine cholangiography is adopted, it is critical that surgeons develop a familiarity with the interpretation of the cholangiogram. Way et al. reported that out of 252 laparoscopic bile duct injuries, only 25% were recognized at the index operation.21

Technical Considerations The critical view of safety during laparoscopic cholecystectomy is an important first step before performing IOC.24 The gallbladder is retracted laterally, and the cystic duct and artery are dissected free and cleared of the fat and overlying peritoneum in Calot’s triangle. A clip can be applied to the infundibular junction to stop the flow of contrast into the gallbladder or bile from the gallbladder during the procedure. A small incision (,50% of the duct circumference) is made in the cystic duct adjacent to the gallbladder neck. Laparoscopically, the cystic duct is best approached from a right subcostal port or from the periumbilical port (we prefer the former). A 60-cm, tapered 5-Fr cholangiocatheter is then advanced directly into the cystic duct through the ductotomy. A specialized cholangiogram clamp, often termed an Olsen cholangiogram clamp, or clip secures the catheter in place. In the open setting, the cholangiocatheter can be secured using a silk ligature. Alternatively, a percutaneous method may be used, where access to the cystic duct is achieved via a separate puncture in the abdominal wall by using at least a 2-inch, 14-gauge needle. A 5-Fr cholangiocatheter is guided through this needle and directly into the cystic duct. Regardless of approach, the catheter is first flushed with saline to confirm its patency, then radiographic contrast is infused, and fluoroscopic images are obtained. A complete study demonstrates flow of contrast into the duodenum and shows opacification of both the right and left hepatic ducts.

STAGING LAPAROSCOPY Hepatobiliary and pancreatic malignancies are often very aggressive, and despite refinements in several preoperative diagnostic modalities, occult disease missed on imaging is discovered at the time of operative intervention in 20% to 25% of patients. In this setting, SL can clarify resectability, identify metastatic disease, and help specialty surgeons tailor curative and palliative operations for patients with hepatobiliary and pancreatic malignancies (Box 24.1). Controversy still exists,

BOX 24.1  Benefits of Laparoscopic Staging Avoids unnecessary exploratory laparotomy Excludes unnecessary chemotherapy/chemoradiation in patients with imaging occult metastatic disease Shorter time to initiation of adjuvant therapy Allows appropriate patient selection of those with locally advanced disease Decreased procedure-related morbidity Reduced hospital cost

  Chapter 24  Intraoperative Diagnostic Techniques

361

BOX 24.2  Potential Disadvantages of Staging Laparoscopy Potential for morbidity Risk of port-site recurrence Increased time of surgery and increased cost

however, and some critics may argue the procedure is of limited benefit in an era of more effective and high-quality preoperative imaging. The benefits of SL include shorter recovery, decreased hospital stay, decreased morbidity, improved quality of life, shorter time to initiation of adjuvant therapy, and reduced hospital costs. Disadvantages include increased potential morbidity, increased operating room times and costs, and potential port-site seeding (Box 24.2).

Surgical Technique

5 mm 10 mm

5 mm

Hasson

Technical Considerations SL is typically performed under general anesthesia. The patient is placed supine on the operating table and fully prepared as for laparotomy. The abdomen is marked for the intended open incision, which is traditionally a bilateral subcostal incision two to three fingerbreadths below the costal margin. In the case of pancreatic disease, access to the peritoneum is made through a 1-cm subumbilical incision; for hepatobiliary cases, a 1-cm incision is made along the midclavicular line. For both, the fascia and peritoneum are incised under direct vision, a blunt 5- or 10-mm port is placed, and insufflation is begun with the initial flow rate set at 2 L/min and gradually increased to 15 L/min to achieve an intra-abdominal pressure of 10 to 14 mm Hg. We use a 5- or 10-mm, 30-degree angled telescope to inspect the abdomen. Although we prefer a multiport technique to facilitate obtaining biopsy specimens and LUS, a single-port approach is also described. Two more ports are placed under direct vision, in the left and right upper quadrants. For pancreatic cases, another 5-mm port is inserted along the incision line to the right of the midline (Fig. 24.2). The peritoneal cavity is systematically assessed and adhesions are divided to facilitate adequate inspection of the abdominal viscera and peritoneum. All four quadrants are examined for evidence of peritoneal deposits; biopsies are taken of any suspicious lesions using standard biopsy forceps, and samples are sent for histologic examination (Fig. 24.3). If clinically indicated, peritoneal cytology can be sampled at this time by instilling 200 mL of warm normal saline into the peritoneal cavity followed by gentle agitation. The irrigant is aspirated from the right and left subhepatic spaces and from the pelvis, and a sample is sent for cytologic examination. Once the peritoneum is inspected, attention is turned to the anterior and posterior surfaces of the left lateral segment of the liver and the anterior and inferior surfaces of the right lobe (Fig. 24.4). Next, the hepatoduodenal ligament, the foramen of Winslow, and hilum of the liver are examined for lymphadenopathy (Fig. 24.5). Any suspicious nodes are excised and sent for pathology analysis. The patient is then placed in the 10-degree Trendelenburg position, and the omentum is retracted into the left upper quadrant. The ligament of Treitz and inferior surface of the transverse mesocolon are inspected for metastatic deposits and lymphadenopathy (Fig. 24.6). The operating table is then leveled and the left lateral segment of the liver is elevated superiorly with a retractor via the

FIGURE 24.2  Port placement for laparoscopic staging. For patients undergoing staging for hepatobiliary diseases, the camera may be placed along the line of a subcostal incision.

FIGURE 24.3  Peritoneal nodule. Arrow indicates a metastatic deposit, which can be sampled easily using a cup forceps to obtain a biopsy.

left upper quadrant port. The lesser omentum is opened to visualize the caudate lobe of the liver and the vena cava. Care should be taken to evaluate for, and avoid damage to, aberrant left hepatic arterial anatomy. From this vantage point, the anterior aspect of the head of the pancreas, posterior wall of the stomach, and “gastric pillar,” which contains the left gastric artery and vein, can be seen (Fig. 24.7). The left gastric artery can be followed to its origin to allow inspection of the celiac axis (Box 24.3).

362

PART 2  DIAGNOSTIC TECHNIQUES

FIGURE 24.7  Lesser sac. The “gastric pillar” (dashed arrow) and hepatic artery (solid arrow) are shown. FIGURE 24.4  Examination of the liver. A blunt 10-mm instrument is used in conjunction with a 5-mm grasper.

BOX 24.3  Steps for Staging Laparoscopy Examination of peritoneal cavity Placement of laparoscopic trocars Instillation of 200 mL of normal saline and aspiration of cytologic specimens Assessment of primary tumor Examination of the liver and porta hepatis Division of gastrohepatic omentum and examination of caudate lobe, vena cava, celiac axis, and lesser sac Identification of the ligament of Treitz and inspection of the mesocolon, duodenum, and jejunum Laparoscopic ultrasound From Conlon KC, Brennan MF. Laparoscopy for staging abdominal malignancies. Mosby: 2000.25

LAPAROSCOPIC ULTRASOUND FIGURE 24.5  The hepatoduodenal ligament can be examined from the left (shown) or right side. Periportal adenopathy (arrow) is shown.

US can be used as an adjunct in diagnostic laparoscopy. A systematic examination of the liver, biliary tree, and pancreas takes place as previously described. A 6- to 10-MHz T-shaped linearor curvilinear-array transducer is placed over the left lateral segment to assess segments I, II, and III. The probe is moved to the right liver and placed on the dome of the liver. The vena cava is visualized posteriorly, and the hepatic and portal veins are seen as the probe is moved anteriorly. Placement of the probe in the transverse direction over the hepatoduodenal ligament allows the common hepatic duct, CBD, hepatic arteries, and portal vein to be visualized (Fig. 24.8). Similarly, at the confluence of the portal vein, the splenic and superior mesenteric veins can be identified. Finally, the superior mesenteric artery is delineated, and its relationship to any pancreatic tumor is assessed. The probe is placed on the gastrocolic omentum and advanced first caudally and then through the window in the gastrohepatic omentum. LUS can help facilitate pathology biopsies and needle aspirations of any suspicious lesions (Fig. 24.9; Box 24.4).

Complications FIGURE 24.6  Examination of the ligament of Treitz. Proximal jejunum (solid arrow) and inferior mesenteric vein (dashed arrow) are shown.

Morbidity associated with SL is uncommon, occurring in only 1% to 2% of cases. Major complications are similar to those for other laparoscopic procedures and include hemorrhage, visceral perforation, and infection. A misconception is that

  Chapter 24  Intraoperative Diagnostic Techniques

363

of patients at a median 8.2 months postoperatively.27 The findings of this study further suggested that recurrence is a marker of more advanced disease rather than being an event resulting from the laparoscopy. Overall, Shoup et al. concluded that SL can be performed safely in the setting of presumed malignancy and others have demonstrated that the incidence of port-site recurrence (3%) is equivalent to that of open wound recurrence in patients who had an exploratory laparotomy alone (3.9%).28,29

STAGING LAPAROSCOPY FOR POTENTIALLY RESECTABLE DISEASE Hepatobiliary Malignancy FIGURE 24.8  Laparoscopic ultrasound of the hepatoduodenal ligament. Doppler capability facilitates identification of the hepatic artery.

FIGURE 24.9  Hepatic metastasis (arrow) in a patient with pancreatic adenocarcinoma.

BOX 24.4  Steps for Laparoscopic Ultrasound Insertion of laparoscopic ultrasound probe Examination of liver: left lateral segment, right lobe Transverse scan of hepatoduodenal ligament Identification of superior mesenteric artery, portal vein, splenic vein Examination of pancreas Assessment of tumor From Minnard EA, Conlon KC, Hoos A, et al. Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg. 1998;228:182–187.26

suspected malignancy precludes SL examination. An additional concern of laparoscopic intervention is port site tumor implantation. In an early study of 1650 laparoscopies for upper gastrointestinal malignancy, port site implantation occurred in 0.79%

Determining the resectability of hepatobiliary malignancy begins with CT or MRI; however, laparoscopy can play an effective role in detecting occult disease and spare open curative resections in the presence of advanced metastatic disease. In addition to the quality of preoperative imaging, the yield of laparoscopy depends on the underlying disease and can range from 16% to 57%.30 For example, hilar cholangiocarcinoma infrequently gives rise to peritoneal disease; however, it is often unresectable because of local tumor extension and/or vascular involvement, which is difficult to determine laparoscopically. The yield of laparoscopy is therefore lower than for other diagnoses, such as gallbladder cancer, which frequently results in peritoneal disease (see Chapter 51). In patients with HCC, laparoscopy can be used to evaluate for cirrhosis and aid in determining resectability (see Chapter 89). In a study of 60 patients with HCC who underwent SL, approximately 30% of patients were spared nontherapeutic laparotomy.31 In a prospective analysis of 401 patients with potentially resectable hepatobiliary malignancy, unresectable disease was discovered at the time of laparoscopy in 84 cases and 69 patients had unresectable disease identified during open exploration, for an overall false-negative rate of 22%.32 In total, SL spared 1 in 5 patients a laparotomy while also reducing hospital stay and morbidity. Laparoscopy is most accurate for identifying peritoneal deposits (80% accuracy) and hepatic disease (63% accuracy) and is least accurate for identifying nodal metastases (7% accuracy) and vascular invasion (18% accuracy).32 Factors that can improve the yield of laparoscopy include the surgeon’s preoperative judgment regarding the likelihood of resectability, the completeness of laparoscopic staging examinations, the addition of LUS, and the primary diagnosis. The yield was highest with gallbladder adenocarcinoma and cholangiocarcinoma and lowest with colorectal metastases. Laparoscopic staging can be used in the evaluation of colorectal metastases (see Chapter 90). Approximately one half of all patients with new diagnoses of colorectal cancer will subsequently develop liver metastases, yet only 20% are candidates for curative hepatic resection. Most authors agree that hepatic cirrhosis, extrahepatic tumor spread, and significant bilobar disease are relative contraindications for hepatic resection. However, in patients with known colorectal cancer and liver metastases, evidence for its routine use has not been conclusively established and is reported to add limited additional value.33,34 In a large series of 274 patients with colorectal metastases undergoing open hepatectomy, unresectable disease was found in 12 patients (4.4%) patients at the time of surgery. The authors suggest that unresectability could have been determined in

364

PART 2  DIAGNOSTIC TECHNIQUES

BOX 24.5  Criteria for the Clinical Risk Score to Determine Risks for Extrahepatic Disease Lymph node–positive tumor Disease-free interval between primary and detection of metastasis: ,12 months Number of hepatic tumors: .1 (based on preoperative imaging) Carcinoembryonic antigen: .200 ng/mL within 1 month of surgery Size of the largest hepatic tumor: .5 cm From Jarnagin WR, Conlon K, Bodniewicz P, et al. A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases, Cancer 2001b;91:1121–1128.

5 patients with laparoscopy; however, route SL is still not encouraged.35 In an effort to improve the yield of SL for hepatic colorectal metastases, a study used a clinical risk score (CRS) to try to determine which patients are more likely to have disease that is occult on preoperative imaging. The CRS uses five clinical parameters; each is shown as an independent predictor of outcome after resection and each criterion is assigned 1 point. Forty-two percent of patients with a CRS greater than 2 had unresectable disease detected at laparoscopy versus none of the patients with CRSs of 0 to 1 (Box 24.5)36. The score was later validated in a study of 200 patients with colorectal metastases who underwent SL and had the benefit of predicting the likelihood of finding incurable disease (P , .001) and determining curability (P , .001).37 Laparoscopy did not change the management of any patient with a CRS of 0 or 1; however, it did alter the course of patients with a score of 2 to 3 (18/129 patients affected) and a score of 4 to 5 (21/40 patients affected). Using such a risk scoring system to help guide the addition of laparoscopy to higherrisk patients could improve the overall yield from laparoscopy.

Pancreatic and Periampullary Malignancy Our approach for staging pancreatic adenocarcinoma is illustrated in Fig. 24.10. A minority of patients with pancreatic and

periampullary malignancies (see Chapter 62) are suitable candidates for curative resection. Similar to the management of other hepatobiliary malignancies, initial diagnostic evaluation begins with high-resolution contrast-enhanced CT. Imaging studies can predict resectability in 57% to 88% of cases.38 Other useful imaging modalities that may augment CT evaluations include MRI, ERCP, EUS, and positron-emission tomography (PET). However, sub-centimeter metastases on the surface of the liver or peritoneal cavity are not always evident on CT, MRI, or PET scanning and may be picked up laparoscopically. The Society of Surgical Oncology guidelines from the 2009 consensus statement regarding the pretreatment assessment of pancreatic cancer state the following regarding the use of laparoscopy: 1. For apparent resectable pancreatic cancer, SL should be used selectively on the basis of clinical parameters that optimize yield. These include pancreas head tumors of greater than 3 cm, tumors of the pancreas body and tail, equivocal findings on a CT scan, and high cancer antigen 19-9 levels (.100 U/mL). 2. For locally advanced unresectable pancreatic cancer without radiographic evidence of distant metastasis, SL may be used to rule out subclinical metastatic disease to optimize treatment selection. A recent Cochrane review included 16 studies and a total of 1146 patients in a meta-analysis to determine the role of SL after CT in pancreatic and periampullary cancers.39 The study concluded that laparoscopy may decrease the rate of unnecessary laparotomies in patients with resectable disease on CT scanning by avoiding 21 unnecessary laparotomies in 100 people for which a curative resection was planned. These findings demonstrate that, despite refinements in imaging techniques, peritoneal disease is not easily revealed on CT. As imaging has improved, the yield of laparoscopy has been challenged. In 1996, Conlon et al. reported the Memorial Sloan Kettering experience. In a review of 115 patients between the

Pancreatic mass on CT

Resectable

Unresectable

Laparoscopic staging ± LUS

Resectable

Unresectable

Open exploration

Appropriate therapy

Localized disease

Laparoscopy

Metastatic disease

Chemotherapy

No mets

Mets

Chemotherapy /radiotherapy

Chemotherapy

FIGURE 24.10  Use of laparoscopic staging in the management of adenocarcinoma of the pancreas. CT, Computed tomography; mets, metastases; LUS, laparoscopic ultrasound.

  Chapter 24  Intraoperative Diagnostic Techniques

TABLE 24.1  Reviews on Staging Laparoscopy for Pancreatic Cancer

BOX 24.6  Criteria for Unresectability in Pancreatic Cancer Histologically confirmed hepatic, serosal, peritoneal, or omental metastases Tumor extension outside pancreas Celiac or high portal node involvement confirmed by frozen section Extensive portal vein involvement by tumor or invasion/encasement of celiac axis, hepatic artery, or superior mesenteric artery Data from Conlon KC, Brennan MF. Laparoscopy for staging abdominal malignancies. Mosby: 2000; and Conlon KC, Minnard EA. The value of laparoscopic staging in upper gastrointestinal malignancy. Oncologist 1997;2:10–17.

years of 1992 and 1994 deemed resectable based on imaging, 38% had findings at the time of SL that precluded resection (Box 24.6).40 However, in an updated review of their experience, the yield of the procedure has decreased. In a review of 1045 patients with imaging-determined pancreatic and peripancreatic tumors, 12% of patients with pancreatic tumors had findings on diagnostic laparoscopy that precluded resection. The yield was greater for patients diagnosed with pancreatic adenocarcinoma and less for patients with tumors of the ampulla, distal bile duct, duodenum, and neuroendocrine tumors. The decrease in sensitivity between the time periods is likely in part because of the improvement in preoperative imaging with the addition of MDCT scanners and thin-slice imaging.41 In addition to the benefits related to recovery from laparoscopy, several authors have found that the laparoscopic approach to staging may be superior to open exploration for the detection of occult metastases. Contreras et al. determined that within a 4-year period, occult metastases among 52 patients with potentially resectable pancreatic tumors were more likely to be detected during SL when compared with open explorations (32% vs. 18%).42 Other centers have reported similar results, as detailed in Table 24.1. LUS may further increase the sensitivity of SL; however, it can be technically demanding, and it is unclear if many centers routinely use this adjunct. In an early study of pancreatic tumor staging with laparoscopy and LUS, John and colleagues demonstrated that additional staging information and a change to the initial decision of resectability was provided when LUS was utilized.49 A study of 50 patients similarly reported 96% specificity and 92% sensitivity when laparoscopic US was combined with SL.50 Vollmer et al. studied 72 patients with pancreatic head cancers and found that 22 patients had metastatic disease that precluded resection; laparoscopy alone identified 14 of these 22 patients; the remaining 8 patients had major vessel encasement or liver metastases revealed by LUS.45 Similarly, in a prospective study of 90 patients, LUS altered the planned surgical treatment in 14% of patients, whose SL procedures were equivocal.26 Sonography was particularly useful in identifying venous (42%) and arterial (38%) involvement, which precludes curative resection.

365

NO. RESECTABLE ON CT BUT UNRESECTABLE AT LAPAROSCOPY

LAPAROSCOPY CHANGED OPERATIVE PLAN (%)

REFERENCE

N

NO. RESECTABLE ON CT

Reddy et al., 199943

109

99

29

29

Jimenez et al., 200044

125

70

39

31

Conlon & Brennan, 200025

577

577

211

36

Vollmer et al., 2002a45

72

72

22

31

Doran et al., 200446

305

190

28

15

Contreras et al., 200942b

58

58

18

31

Mayo et al., 200947b

86

86

24

28

White et al., 200848

1045

1045

145

14

a

Excluding ampullary malignancies. Pancreatic adenocarcinoma only (including head and body/tail). CT, Computed tomography. b

Controversies Some critics of routine SL believe that unresectable disease caused by vascular involvement or local extension can only be confirmed during open explorations.51 Others suggest that the role for laparoscopy is limited only to those patients who do not require some form of palliation, either biliary or gastric bypass.52 This is determined in part by the type of malignancy.45 SL has not been shown to be useful among patients with ampullary or duodenal tumors because these cancers tend to present earlier and are less likely to have metastatic disease at the time of presentation. The relative yield of diagnostic laparoscopy may be lower at centers that have an aggressive palliative surgical approach, whereas even if a disease is unresectable, laparotomy is performed regardless for palliative intervention with bypass. Finally, some argue that SL is costly, time consuming, and of decreasing diagnostic yield because of improvements in radiologic imaging techniques.53,54 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

365.e1

REFERENCES 1. Novo Amado AM, Fraga Sánchez M, González Ramírez J, Calvo Arrojo G, Vidal Cameán C, Crespo Teijeiro JM. Valor de la ecografía intraoperatoria realizada con sondas convencionales y su utilidad en el manejo quirúrgico y terapéutico de los pacientes. Value of intraoperative ultrasound with conventional probes and its usefulness in surgical and therapeutic management of patients. Radiologia. 2017;59(6):516-522. 2. Bismuth H, Castaing D, Garden OJ. The use of operative ultrasound in surgery of primary liver tumors. World J Surg. 1987;11(5):610-614. 3. Belghiti J, Menu Y, Cherqui D, Nahum H, Fékété F. Traitement chirurgical des carcinomes hépato-cellulaires sur cirrhose. Intérêt de l’échotomographie per-opératoire. Gastroenterol Clin Biol. 1986; 10(3):244-247. 4. Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol. 1983;(suppl 2):493-497. 5. Arita J, Ono Y, Takahashi M, et al. Routine preoperative liver-specific magnetic resonance imaging does not exclude the necessity of contrast-enhanced intraoperative ultrasound in hepatic resection for colorectal liver metastasis. Ann Surg. 2015;262(6):1086-1091. 6. Takahashi M, Hasegawa K, Arita J, et al. Contrast-enhanced intraoperative ultrasonography using perfluorobutane microbubbles for the enumeration of colorectal liver metastases. Br J Surg. 2012;99(9):1271-1277. 7. Alzaraa A, Gravante G, Chung WY, et al. Contrast-enhanced ultrasound in the preoperative, intraoperative and postoperative assessment of liver lesions. Hepatol Res. 2013;43(8):809-819. 8. Santambrogio R, Cigala C, Barabino M, et al. Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: prospective comparison with pathology. Liver Int. 2018;38(2): 312-320. 9. Araki K, Conrad C, Ogiso S, Kuwano H, Gayet B. Intraoperative ultrasonography of laparoscopic hepatectomy: key technique for safe liver transection. J Am Coll Surg. 2014;218(2):e37-e41. 10. Dili A, Bertrand C. Laparoscopic ultrasonography as an alternative to intraoperative cholangiography during laparoscopic cholecystectomy. World J Gastroenterol. 2017;23(29):5438-5450. 11. Stiegmann GV, Soper NJ, Filipi CJ, McIntyre RC, Callery MP, Cordova JF. Laparoscopic ultrasonography as compared with static or dynamic cholangiography at laparoscopic cholecystectomy. A prospective multicenter trial. Surg Endosc. 1995;9(12):1269-1273. 12. Ishido K, Hakamada K, Machi J. Laparoscopic ultrasound during laparoscopic cholecystectomy – a systematic review. Ann Emerg Surg. 2017;2:1020. 13. Nadeem H, Jayakrishnan TT, Groeschl RT, Zacharias A, Clark Gamblin T, Turaga KK. Cost effectiveness of routine laparoscopic ultrasound for assessment of resectability of gallbladder cancer. Ann Surg Oncol. 2014;21(7):2413-2419. 14. Agarwal AK, Kalayarasan R, Javed A, Gupta N, Nag HH. The role of staging laparoscopy in primary gall bladder cancer—an analysis of 409 patients: a prospective study to evaluate the role of staging laparoscopy in the management of gallbladder cancer. Ann Surg. 2013;258(2):318-323. 15. Marcal LP, Patnana M, Bhosale P, Bedi DG. Intraoperative abdominal ultrasound in oncologic imaging. World J Radiol. 2013;5(3):51-60. 16. de Werra C, Quarto G, Aloia S, et al. The use of intraoperative ultrasound for diagnosis and stadiation in pancreatic head neoformations. Int J Surg. 2015;21(suppl 1):S55-S58. 17. Gurusamy KS, Giljaca V, Takwoingi Y, et al. Endoscopic retrograde cholangiopancreatography versus intraoperative cholangiography for diagnosis of common bile duct stones. Cochrane Database Syst Rev. 2015;2015(2):CD010339. 18. Nugent N, Doyle M, Mealy K. Low incidence of retained common bile duct stones using a selective policy of biliary imaging. Surgeon. 2005;3(5):352-356. 19. Metcalfe MS, Ong T, Bruening MH, Iswariah H, Wemyss-Holden SA, Maddern GJ. Is laparoscopic intraoperative cholangiogram a matter of routine? Am J Surg. 2004;187(4):475-481. 20. Ragulin-Coyne E, Witkowski ER, Chau Z, et al. Is routine intraoperative cholangiogram necessary in the twenty-first century? A national view. J Gastrointest Surg. 2013;17(3):434-442.

21. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and cognitive psychology perspective. Ann Surg. 2003;237(4):460-469. 22. Snow LL, Weinstein LS, Hannon JK, Lane DR. Evaluation of operative cholangiography in 2043 patients undergoing laparoscopic cholecystectomy: a case for the selective operative cholangiogram [published correction appears in Surg Endosc. 2001;15:532]. Surg Endosc. 2001;15(1):14-20. 23. Nickkholgh A, Soltaniyekta S, Kalbasi H. Routine versus selective intraoperative cholangiography during laparoscopic cholecystectomy: a survey of 2,130 patients undergoing laparoscopic cholecystectomy. Surg Endosc. 2006;20(6):868-874. 24. Hope WW, Fanelli R, Walsh DS, et al. SAGES clinical spotlight review: intraoperative cholangiography. Surg Endosc. 2017;31(5): 2007-2016. 25. Conlon KC, Brennan MF. Laparoscopy for staging abdominal malignancies. Adv Surg. 2000;34:331-350. 26. Minnard EA, Conlon KC, Hoos A, Dougherty EC, Hann LE, Brennan MF. Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg. 1998;228(2):182187. 27. Shoup M, Brennan MF, Karpeh MS, Gillern SM, McMahon RL, Conlon KC. Port site metastasis after diagnostic laparoscopy for upper gastrointestinal tract malignancies: an uncommon entity. Ann Surg Oncol. 2002;9(7):632-636. 28. Curet MJ. Port site metastases. Am J Surg. 2004;187(6):705-712. 29. Ziprin P, Ridgway PF, Peck DH, Darzi AW. The theories and realities of port-site metastases: a critical appraisal. J Am Coll Surg. 2002;195(3):395-408. 30. Gaujoux S, Allen PJ. Role of staging laparoscopy in peri-pancreatic and hepatobiliary malignancy. World J Gastrointest Surg. 2010;2(9): 283–290. 31. Weitz J, D’Angelica M, Jarnagin W, et al. Selective use of diagnostic laparoscopy prior to planned hepatectomy for patients with hepatocellular carcinoma. Surgery. 2004;135(3):273-281. 32. D’Angelica M, Fong Y, Weber S, et al. The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg Oncol. 2003;10(2):183-189. 33. Siriwardena AK, Mason JM, Mullamitha S, Hancock HC, Jegatheeswaran S. Management of colorectal cancer presenting with synchronous liver metastases. Nat Rev Clin Oncol. 2014;11(8):446459. 34. Hariharan D, Constantinides V, Kocher HM, Tekkis PP. The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of patients with resectable colorectal liver metastases: a metaanalysis. Am J Surg. 2012;204(1):84-92. 35. Dunne DF, Gaughran J, Jones RP, et al. Routine staging laparoscopy has no place in the management of colorectal liver metastases. Eur J Surg Oncol. 2013;39(7):721-725. 36. Grobmyer SR, Fong Y, D’Angelica M, Dematteo RP, Blumgart LH, Jarnagin WR. Diagnostic laparoscopy prior to planned hepatic resection for colorectal metastases. Arch Surg. 2004;139(12):1326-1330. 37. Mann CD, Neal CP, Metcalfe MS, Pattenden CJ, Dennison AR, Berry DP. Clinical Risk Score predicts yield of staging laparoscopy in patients with colorectal liver metastases. Br J Surg. 2007;94(7): 855-859. 38. Somers I, Bipat S. Contrast-enhanced CT in determining resectability in patients with pancreatic carcinoma: a meta-analysis of the positive predictive values of CT. Eur Radiol. 2017;27(8):3408-3435. 39. Allen VB, Gurusamy KS, Takwoingi Y, Kalia A, Davidson BR. Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer. Cochrane Database Syst Rev. 2016;7(7):CD009323. 40. Conlon KC, Dougherty E, Klimstra DS, Coit DG, Turnbull AD, Brennan MF. The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg. 1996;223(2):134-140. 41. White R, Winston C, Gonen M, et al. Current utility of staging laparoscopy for pancreatic and peripancreatic neoplasms. J Am Coll Surg. 2008;206(3):445-450. 42. Contreras CM, Stanelle EJ, Mansour J, et al. Staging laparoscopy enhances the detection of occult metastases in patients with pancreatic adenocarcinoma. J Surg Oncol. 2009;100(8):663-669.

365.e2 43. Reddy KR, Levi J, Livingstone A, et al. Experience with staging laparoscopy in pancreatic malignancy. Gastrointest Endosc. 1999;49(4 Pt 1):498-503. 44. Jimenez RE, Warshaw AL, Rattner DW, Willett CG, McGrath D, Fernandez-del Castillo C. Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg. 2000;135(4):409-415. 45. Vollmer CM, Drebin JA, Middleton WD, et al. Utility of staging laparoscopy in subsets of peripancreatic and biliary malignancies. Ann Surg. 2002;235(1):1-7. 46. Doran HE, Bosonnet L, Connor S, et al. Laparoscopy and laparoscopic ultrasound in the evaluation of pancreatic and periampullary tumours. Dig Surg. 2004;21(4):305-313. 47. Mayo SC, Austin DF, Sheppard BC, Mori M, Shipley DK, Billingsley KG. Evolving preoperative evaluation of patients with pancreatic cancer: does laparoscopy have a role in the current era? J Am Coll Surg. 2009;208(1):87-95. 48. White R, Winston C, Gonen M, et al. Current utility of staging laparoscopy for pancreatic and peripancreatic neoplasms. J Am Coll Surg. 2008;206(3):445-450. 49. John TG, Greig JD, Carter DC, Garden OJ. Carcinoma of the pancreatic head and periampullary region. Tumor staging with

laparoscopy and laparoscopic ultrasonography. Ann Surg. 1995;221(2):156-164. 50. Callery MP, Strasberg SM, Doherty GM, Soper NJ, Norton JA. Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg. 1997;185(1):33-39. 51. Friess H, Kleeff J, Silva JC, Sadowski C, Baer HU, Büchler MW. The role of diagnostic laparoscopy in pancreatic and periampullary malignancies. J Am Coll Surg. 1998;186(6):675-682. 52. Holzman MD, Reintgen KL, Tyler DS, Pappas TN. The role of laparoscopy in the management of suspected pancreatic and periampullary malignancies. J Gastrointest Surg. 1997;1(3):236-244. 53. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15(3):928-937. 54. Zamboni GA, Kruskal JB, Vollmer CM, Baptista J, Callery MP, Raptopoulos VD. Pancreatic adenocarcinoma: value of multidetector CT angiography in preoperative evaluation. Radiology. 2007;245(3):770-778.

PART 3

Anesthetic Management, Pre- and Postoperative Care

25 Liver and Pancreatic Surgery: Intraoperative Management



26 Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient



27 Enhanced Recovery Programs in Hepatobiliary Surgery



28 Postoperative Complications Requiring Intervention: Diagnosis and Management



29 The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

366

CHAPTER 25 Liver and pancreatic surgery: Intraoperative management Mary Fischer, Vittoria Arslan-Carlon, and Jose Melendez OVERVIEW Improvements in patient selection criteria, advances in hepatopancreatobiliary (HPB) surgical techniques, and perioperative care have enabled increasing numbers of older and previously deemed inoperable patients to undergo HPB surgery. Despite this increase in comorbidities, recent studies have documented the progressive safety of liver1–4 and pancreas surgery5–7; nonetheless, morbidity remains significant even at tertiary care centers.4,5,8–12 This chapter addresses the unique perioperative anesthetic considerations of patients undergoing HPB operations, with emphasis on the role of the anesthesia care provider (ACP) to improve morbidity.

PREOPERATIVE EVALUATION Risk and Outcome Improvement Components for the ACP to consider that influence postoperative morbidity include, but are not limited to, comorbid medical conditions, perioperative care to modify risk, and the ability to rescue should an adverse event occur. Identifying patients at increased risk of a poor outcome before surgery remains challenging, and what the anesthesiologist can do to improve perioperative outcome is not always obvious (see Chapter 27). There are several scoring systems to assist clinical risk assessment. By entering data into a multivariable prediction model, an individualized patient risk score for certain morbidities and mortality can be included to guide surgical planning and informed consent.13 Surgical risk prediction models, such as the Physiological and Severity Score for the Enumeration of Mortality and Morbidity (POSSUM), are not always based solely on preoperative data, nor are they procedure specific, and they are complex to use.14 Anesthesiologists prefer a less complicated risk score, such as the American Society of Anesthesiologists’ Physical Status Score (Table 25.1),15 which scores a patient on a scale that other patients may be compared, not the individualized risk prediction of an adverse outcome.16 However, even if the anesthesiologist knows the risk prediction or risk score, it may not be apparent which anesthesia management factors are independent risk factors for perioperative morbidity and amenable to preventive measures to improve outcome. Another option is to use a biomarker, such as plasma B-type natriuretic peptide concentrations, to predict complications; however, there is no biomarker specific to HPB surgery.17 No scoring system provides a clear identification of which elective surgery should proceed safely, and risk scores must be viewed in their clinical context. Anesthetic management can be a Sophie’s choice: modifying one component to prevent a complication that leads to

increasing risk by a different pathway. Anesthetic care, like all of life, has risk, and this risk is determined by the preoperative presence of one or more comorbidities that significantly augment the incidence of postoperative adverse events. A key component of complications after surgery is the failure to recognize the patients at risk so that appropriate assessments occur before surgery.18 Because anesthesia care is facilitative rather than therapeutic, the main outcome of anesthesia care has been traditionally measured in terms of absence of “complications.” Today it is rare for a patient to develop complications due directly to the act of anesthesia, yet anesthesia clinical decisions may impact the perioperative outcome. Given that anesthetic drugs are short-acting, it is not obvious that consequences of anesthetic management could last more than hours or days after surgery. There is arguably a shift toward avoiding anesthesia-related harm after surgery, such as the maintenance of normothermia, antibiotic dosing and glucose control (prevention of surgical site infection), thromboprophylaxis and b-blockade or prescribing target-controlled fluid management, opioid-sparing analgesia, or up-to-date intraoperative ventilation. The choices we make in the operating room may have an impact not only during the case, or in the immediate postoperative time, but long after the patient is discharged from the postanesthesia care unit (PACU).19 The occurrence of a 30-day postoperative complication is more important than the preoperative patient risk and intraoperative factors in determining the survival after surgery.20 Postoperative morbidity has been shown to adversely affect longterm outcome after HPB surgery; therefore efforts aimed at reducing perioperative morbidity will not only reduce usage of resources but will likely further enhance the therapeutic benefit of resection.21–24 Given the impact of anesthesia intervention on long-term postoperative outcomes and costs, a natural evolution of the Michigan Surgical Quality Collaborative has been to expand the data collection and collaboration efforts to include the anesthesiology provider and process. The Multicenter Perioperative Outcomes Group (MPOG) has built a comprehensive perioperative patient registry based on electronic healthcare data. Preoperative and intraoperative data are collected and used to identify variations in anesthetic care and optimal care patterns.25 The data collected are used as a foundation of collaboration between surgeons and anesthesiologists to establish process of care and outcome measures to recommend best practice clinical standards where prospective effectiveness trials may be absent. Although it is not possible to alter all risk factors, such as age, or avoid every potential consequence, such as pain, there are modifiable risk factors. Detailed evaluation and correction of all modifiable risk factors combined with best practice guidelines are our best choices to help avoid the most preventable 367

368

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

TABLE 25.1  American Society of Anesthesiologists’ Physical Status Score (ASA-PS) ASA CLASSIFICATION

EXAMPLES

ASA I

A normal healthy patient

Healthy; no smoking; no or very minimal drinking

ASA II

A patient with mild systemic disease

Smoker; more than minimal drinking; pregnancy; obesity; well-controlled diabetes; well-controlled hypertension; mild lung disease

ASA III

A patient with severe systemic disease, not incapacitating

Diabetes, poorly controlled hypertension; distant history of MI, CVA, TIA, cardiac stent; COPD; ESRD; dialysis; active hepatitis; implanted pacemaker; ejection fraction below 40%; congenital metabolic abnormalities

ASA IV

A patient with severe systemic disease that is a constant threat to life

Recent history of MI, CVA, TIA, cardiac stent; ongoing cardiac ischemia or severe valve dysfunction; implanted ICD; ejection fraction below 25%

ASA V

A moribund patient who is not expected to survive without the operation

Ruptured abdominal or thoracic aneurysm; intracranial bleed with mass effect; ischemic bowel in the face of significant cardiac pathology

ASA VI

A patient who has already been declared brain-dead and whose organs are being removed for transplant

Note: The addition of an “E” indicates emergency surgery. COPD, Chronic obstructive pulmonary disease; CVA, cerebrovascular accident; ESRD, end-stage renal disease; ICD, internal cardiac defibrillator; MI, myocardial infarction; TIA, transient ischemic attack.

complications. Before undergoing surgery, optimization of chronic medical conditions is of critical importance. Hyperglycemia should prompt evaluation of glycemic control including fasting glucose and HgbA1c levels. Uncontrolled diabetes has been associated with adverse postoperative outcomes including wound infections or organ space infection.26 Chronic cardiopulmonary comorbidities may require preoperative intervention and even modification of intraoperative approach. Functional status workup may identify correctable deficits that can be addressed preoperatively with physical conditioning, nutritional counseling, blood glucose control, and smoking cessation. To decrease patient anxiety, any complete preoperative evaluation of a patient undergoing HPB surgery should include extensive, preoperative education including education material and the opportunity to ask questions of the multidisciplinary team. Medical guidelines have rapid turnover, with medical reversal a reality, and staying current to apply evidence-based practice is recognizing that the correct “scientific answer” may shift over time.27,28 Not only is the patient population becoming older with ever-expanding comorbidities, but improvements in the medical management of some chronic illnesses mean that the implications of such illnesses may be quite different today than years past. Select patients might be better served having HPB surgery at a major medical center where the multidisciplinary care team provides optimum preparation of patients as well as the ability and availability to minimize the impact on patients when adverse events occur.29,30

Cardiac Evaluation Although the perioperative event rate has declined because of better anesthetic and surgical techniques, perioperative cardiac complications remain a significant problem. The first step in preoperative care is an adequate identification of patients at risk for perioperative cardiac events. Clinical history, physical examination, and review of a baseline electrocardiogram usually provide enough data to estimate cardiac risk. Estimation of a stable patient’s cardiac risk can be derived from the Lee Revised

Cardiac Risk Index (LRCRI), a simple index that identifies six independent risk factors to provide the risk of a cardiac complication in percentages.31 The risk of a perioperative major cardiac event (PMCE), defined as cardiac death, myocardial infarction (MI), or pulmonary edema within 30 days postoperatively, is the summation of an individual patient’s risk and functional capacity and the cardiac stress related to the surgery. There are active cardiac conditions that may lead to cancellation of the procedure, unless the surgery is emergent, but most PMCE risk is silent, and the LRCRI has shown only moderate predictive performance.32 The absence of coronary computed tomographic angiography findings of coronary artery disease confers low PMCE risk regardless of clinical risk, and some have suggested adding this noninvasive test to the LRCRI.33 The 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery are an excellent framework for evaluating cardiac risk in the perioperative period for patients with clinical risk factors.34 Cardiac functional status or capacity, as determined by doctors assessing patients with a brief set of questions, can be expressed in metabolic equivalents or simply the inability to perform various activities such as climbing two flights of stairs or walking four blocks.35,36 A patient’s cardiac functional status has been thought to be positively associated with postoperative outcomes.35,36 The Measurement of Exercise Tolerance before Surgery (METS) prospective cohort study concluded that subjectively assessed preoperative functional capacity did not accurately identify patients with poor cardiopulmonary fitness or predict morbidity or mortality.37 How this will affect the ACP’s choice for additional cardiac evaluation is unclear. Over the years, perioperative management has shifted from treating coronary obstruction with coronary revascularization toward medical therapy aiming at prevention of myocardial oxygen supply and demanding mismatch and coronary plaque stabilization. Today preoperative cardiac testing, cardiac stenting, and coronary revascularization are only performed for the same indications as the nonoperative setting.38,39

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

The risks and benefits of continuing perioperative medical management are complex. Perioperative b-blockade (PBB) has been shown to reduce the incidence of perioperative ischemic events and MI in patients with coronary artery disease but confers questionable benefit and possible harm in patients without coronary artery disease.40,41 The PeriOperative Ischemic Study Evaluation (POISE) trial completely transformed the premise of PBB, finding PBB stroke morbidity outweighed any PMCE prevention.42 POISE confirmed what clinical anesthesiologists had experienced: increased intraoperative hypotension and bradycardia in low-risk patients with newly initiated PBB. PBB guideline revisions followed rapidly in 2009. The guidelines recommended continuation of b-blockers for patients who are already on them and the initiation of PBB for high-risk patients, but not to initiate PBB in low-risk patients in the perioperative period. b-Blockers should still be used to manage acute hypertension and tachycardia perioperatively in patients at risk for myocardial supply and demand imbalance. Similarly, balancing the risk-to-benefit ratio of dual antiplatelet therapy (APT) or aspirin interruption and the risk of stent thrombosis versus continuation and the risk of bleeding is challenging. The POISE-2 trial showed that perioperative aspirin did not reduce PCME at 30 days but did increase perioperative bleeding.43 Only a small number of patients in this trial had coronary stenting, and patients with a bare-metal stent (BMS) for less than 6 weeks or a drug-eluting stent (DES) for less than 1 year were excluded. Contemporary data suggest that approximately one in five patients with coronary stent implantation will require noncardiac surgery within 2 years of their coronary intervention.44 Patients with freshly placed coronary stents presenting for liver surgery pose a significant challenge to anesthesiologists. It is no surprise that anesthesiologists must consistently stay current with rapidly evolving guidelines for the perioperative management of these patients. Some of the clinical questions that arise include the following: How soon can a stented patient undergo surgery? Should a patient continue APT during the perioperative period? What is the risk for surgical bleeding versus coronary thrombosis in this population? In 2016 the ACC/AHA guidelines recommended delaying noncardiac surgery 30 days after BMS implantation and 6 months after DES implantation. However, if the risk for delay for 6 months was greater that the risk for ischemia, elective surgery could be considered at 3 months.45 Communication among the patient’s cardiologist, surgeon, and anesthesiologist is essential for the management of patients with active or quiescent coronary artery disease. At the authors’ institution, the medical consult takes into account both the ACC/AHA patient’s number of clinical factors (does the patient have an active cardiac condition; planned surgery, low or high risk; good functional capacity; further testing required) and the LRCRI (high-risk type of surgery; history of ischemic heart disease; history of congestive heart failure; history of cerebrovascular disease; diabetes mellitus [insulin dependent]; renal insufficiency [creatinine . 2]), to determine whether the patient is at acceptable risk to proceed to the planned surgery or if there is the need for further testing before surgery or pharmacologic intervention perioperatively.38 In HPB patients with a history of alcohol abuse, cardiac assessment needs to stress the evaluation of myocontractile function. Two basic patterns of alcohol-induced cardiomyopathy have been shown: left ventricular dilation with impaired systolic function and left ventricular hypertrophy with

369

diminished compliance and normal or increased contractile performance.

Geriatric Evaluation Elderly patients with impaired functional status have been shown to have increased morbidity and mortality when undergoing HPB surgery.46,47 More than 80% of pancreatic cancers are diagnosed in patients older than 65 years old. Although age should not preclude surgery, at-risk elderly patients should have a comprehensive geriatric assessment and a multidimensional diagnostic tool used to test functional performance and mental status. Frailty has emerged as an important perioperative risk factor. Diagnosis of frailty is especially important in managing geriatric patients. It is a clinical syndrome in which three or more of the following criteria are met: unintentional weight loss of greater than 10 pounds within the previous year, self-reported exhaustion, weakness measured by grip strength, slow walking speed, and low levels of physical activity. Over 300 different types of frailty assessments have been created and used, but there is really no gold standard. Evidence of sarcopenia, which clinically manifests itself as a loss of skeletal mass, strength, and decreased physical performance, is often used to assess frailty. The most commonly used Fried phenotype looks at frailty as a syndrome, something with signs and symptoms that can be measured. In this case, 1 point is assigned to things like walking speed and weight loss, for a final score between 0 and 5.48 The frailty index is defined as the ratio of the number of deficits present in an individual to the total number of agerelated health variables considered. The key here is that the deficits are measured across multiple domains. One compares the number of deficits with the total number measured and ends up with a score between 0 and 1. The clinical frailty score uses a scale of 1 to 9 where each number is associated with a short vignette and an image. The electronic rapid fitness assessment (eRFA) is a questionnaire developed at our institution and used by all the doctors of the geriatrics service to gauge and understand an older patent’s level of fitness.49 At the authors’ institution, all patients over 65 deemed at increased risk are referred to a geriatric specialist. This service also advises on medications to be used with caution and nonpharmacologic strategies to reduce delirium and analgesics while the patient is in the hospital. Delirium (temporary inability to focus attention and think clearly) occurs in one of five older patients who undergo major surgery. Delirium is associated with a slower recovery and a poorer outcome, and a vicious circle may be initiated (delirium, physical restraint, and medication to treat delirium; postoperative complications; then more delirium). Korc-Grodzicki used comprehensive geriatric assessment components to predict the development of postoperative delirium and other comorbidities in patients undergoing varying abdominal surgeries. The study population included 416 patients, of which 20% of patients underwent HBP surgeries. Charleston comorbidity index score greater than 3, patients with a history of falls 6 months before surgery, instrumental activities of daily living scores of less than 8, and abnormal mini-cog test results were all predictive of postoperative delirium. In this study, patients who developed postoperative delirium had longer median length of hospital stays and greater likelihood of discharge to a skilled nursing facility.50 Randomized studies have shown that multicomponent interventions can reduce the incidence of delirium and/or related complications.51 We advocate a daily

370

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

protection and intervention program based on early-start and supporting treatment, with increased monitoring, better pain relief, avoidance of polypharmacy, and good nutrition, but from a prevention or therapeutic point of view, there is no one target for decreasing the incidence after surgery. It has been suggested by some studies that the routine use of perioperative medications, such as dexmedetomidine52 or ketamine53 can prevent postoperative delirium; however, available evidence does not support this. Gabapentin may reduce postoperative delirium, perhaps by reducing pain and opioid administration.

Pulmonary Evaluation Despite steady advances in care, patients with respiratory disease are still at increased risk for postoperative pulmonary complications (PPCs). PPCs continue to rival cardiovascular complications in frequency and severity after hepatic surgery.4 There are many limitations of studies that examine risk factors for PPCs, but there are some consistent patterns. Important risk factors for PPCs are the presence of pulmonary disease, cigarette smoking, low preoperative arterial oxygen saturation, acute respiratory infection during the previous month, age, preoperative anemia, site of surgery (with upper abdominal, especially near the diaphragm, or intrathoracic surgery being the highest risk), surgery duration of at least 2 hours, and emergency surgery.54,55 Despite the increased risk of PPCs in patients with preexisting pulmonary disease, no prohibitive level of pulmonary function has been established for which surgery is contraindicated. Neither abnormal pulmonary function testing nor arterial blood gas analysis are useful in predicting risk. Thus these tests are only justified as part of an effort to optimize preoperative pulmonary status, either with an immediate perioperative course of systemic corticosteroids or antibiotics, or to advise if surgery should be delayed.56 Poor functional capacity and especially low anaerobic threshold have been associated with a high risk of postoperative complications and death. Submaximal cardiopulmonary exercise testing is a noninvasive objective test that measures a patient’s anaerobic threshold and patients with low subjective functional capacity or dyspnea may benefit from this test of cardiopulmonary reserve to determine complication risk.57 Although it seems reasonable to assume that fitter patients will have better outcome, a recent study suggested that cardiopulmonary exercise testing should not be used as a barrier to patients undergoing liver surgery.58 Potential interventions to reduce PPCs include smoking cessation, preoperative exercise training, early mobilization, postoperative parental nutrition, and optimal treatment of pain.59 Although obesity presents the anesthesiologist with significant challenges, obesity per se is not a significant risk factor for PPCs and should not be used to deny a patient HPB surgery. There are two subsets of obese patients: one group is “the metabolically healthy but obese” and the other group is the “metabolically unhealthy but obese.”60 When an obese patient has three or more of the following criteria, abdominal obesity, increased triglycerides, decreased high-density lipoprotein, elevated cholesterol, hypertension, and glucose intolerance, the patient has a 2.5 increased incidence of PPCs.61 Obese patients are at risk of suffering from several respiratory derangements, including obstructive sleep apnea (OSA), obesity-hypoventilation syndrome, and restrictive impairment. The increase in body mass also results in increased oxygen consumption and carbon dioxide production. With these issues in mind, it is not surprising that acute PPCs are twice as likely in OSA patients.62 Many patients with OSA are undiagnosed,

but there is a strong relationship between obesity and OSA. The American Society of Anesthesiologists (ASA) addressed this issue with practice guidelines, including assessment of patients for possible OSA before surgery and careful postoperative monitoring for those suspected to be at risk.63 It is unclear whether screening for OSA will affect surgical morbidity, but it is reasonable to question obese patients about symptoms that may suggest sleep apnea before HPB surgery. At Memorial Sloan Kettering Cancer Center (MSKCC), all obese patients are given the STOP (Snoring, Tiredness, Observed apnea, high blood Pressure)-Bang (Body mass index, Age, Neck circumference, and gender) questionnaire.64 Given the association of obesity and OSA with multiple medical conditions (increased risk of venous stasis, pulmonary embolism, hypertension, cerebral vascular accidents, cardiomyopathy, arrythmias, and ischemic heart disease) the anesthesiologist is in a position to have an informed discussion with the patient about the increased risk of morbidity and mortality and work with other members of the patient’s care team to determine whether any interventions should be initiated before surgery in an effort to minimize the risk of complications.65 Polysomnography is the gold standard for diagnosis of OSA, but it is expensive and a limited resource. The most reasonable approach is to check room air-pulse oximetry. If the patient has an oxygen saturation level less than 96%, further evaluation is warranted. A 2-week period of continuous positive airway pressure (CPAP) therapy has been shown to be effective in correcting abnormal ventilatory drive and improving cardiac function.66

Venous Thromboembolism Prophylaxis In patients undergoing general surgery, the risk of venous thromboembolism (VTE) varies depending on both patient and procedure-specific factors.67 Patients having cancer surgery have a moderate risk for VTE.68–70 Guidelines recommend low-molecular-weight heparin (LWMH) for patients undergoing general surgery procedures with at least moderate (3%) risk of VTE, if the risk of bleeding does not negate the risk of VTE.67 After HPB surgery, the risk of VTE (deep vein thrombosis, pulmonary embolus) is not insignificant and is higher in the obese patient. After major hepatectomy, the concern for postoperative bleeding, combined with an erroneous presumption of protection because of the coagulopathy, often preclude the use of routine prophylaxis despite evidence to the contrary.71 In a recent retrospective review at our institution, postoperative VTE occurred in 2.6% of patients and was independently associated with higher postoperative international normalized ratio (INR) and LWMH had no relationship to VTE incidence or bleeding complications.72 Patients with more extensive liver resections and higher operative blood loss had a higher incidence of VTE. Despite an elevated INR and lower platelet count, a patient having major liver cancer surgery is in a normocoagulable or even a hypercoagulable state and at risk for VTE; yet there is no consensus of opinion for pharmacologic prophylaxis.73 The ACP and the surgeon should discuss risk versus benefit. Pancreatic cancer is among the most common malignancies associated with thrombosis, as it occurs in 50% of patients74 (see Chapter 62). Prophylaxis against postoperative VTE should be tailored to the patient’s level of risk. The Caprini score, which can be potentially used for such purposes, estimates VTE risk by adding various points for VTE risk factors.75 Current recommendations strongly advise effective and preventive strategies for all hospitalized patients who are defined as moderate to high risk for VTE and are awaiting pancreatic surgery. LMWHs

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

appear to be effective and are potentially associated with a lower risk of bleeding when the first dose is administered 12 hours preoperatively.67,76

Hepatic Evaluation Risk factors and symptoms of liver disease are not as well defined as in other organ systems. There is no single biomarker for liver dysfunction; instead, the diagnosis of liver disease requires a high degree of suspicion, with a careful probing of the clinical history to identify specific risk factors for liver disease, such as previous blood transfusions, jaundice, travel, tattoos, high-risk sexual behavior, illicit drug use, excessive alcohol intake, or chemotherapy77 (see Chapter 4). The goal of preoperative screening is to determine the presence of preexisting liver disease without the need for extensive or invasive monitoring. Liver function tests can measure different aspects of hepatic function, but as a group of tests, they lack specificity and are often affected by nonhepatic function. These biochemical markers cannot quantify hepatic cellular dysfunction. In contrast, anesthesiologists are often confronted with abnormal hepatic function tests in asymptomatic patients. In general, for asymptomatic patients with mildly elevated alanine and aspartate aminotransferase levels and a normal bilirubin concentration, cancellation of surgery is rarely indicated Most hepatic resections are performed for metastatic cancer. In these patients the quantity of hepatocyte dysfunction, whether induced by preoperative alcohol, chemotherapy, or metabolic syndrome, is more elusive to identify. In patients with significant abnormalities, additional investigation is warranted, given the higher risk to patients having HPB surgery to evaluate whether there is underlying cirrhosis or steatosis. Serologic testing to exclude viral hepatitis and human immunodeficiency virus should always be performed. The etiology of hyperbilirubinemia may have an obstructive or nonobstructive cause. No matter the root cause, jaundice adversely affects outcome. Unlike elevated bilirubin associated with hepatocyte disturbance, obstructive jaundice is typically seen in patients with bile duct obstruction and is not a contraindication for HPB surgery, if it is being performed to remove the cause of the obstruction. Biliary sepsis may contribute to the exacerbation of perioperative hemodynamic instability. In situations where there is clinical concern for the development of acute cholangitis, rapid biliary decompression and intravenous (IV) antibiotics should be administered preoperatively, and surgery should be delayed until the infection resolves. Patients with hyperbilirubinemia are a subset of patients with an increased risk of renal compromise after low central venous pressure (LCVP)-assisted hepatectomy.78 The surgeon and anesthesiologist must have a detailed discussion of risk versus benefit.

Alcohol Use Disorder Patients with unhealthy alcohol use face increased perioperative risks from the medical consequences associated with alcohol consumption as well as from physiologic dependence and withdrawal. Up to 50% of patients presenting for gastrointestinal (GI) cancer surgery have alcohol use disorder. Studies have found that many surgical patients have not had been appropriately assessed for alcohol use in the preoperative evaluation.79 Abstinence from drinking, as imposed by a hospital admission, places patients at risk for alcohol withdrawal syndrome (AWS). The preoperative evaluation of patients with unhealthy alcohol

371

use should include effective screening strategies to identify the presence of heavy alcohol use, detect end-organ damage secondary to alcohol consumption, and prompt intervention to address alcohol use before surgery. There are several screening tools to identify alcohol use disorder. The authors’ preference is to use the CAGE (cut down, annoyed, guilty, eye opener) questionnaire. AWS prophylaxis should begin on admission to the hospital. Evidence supports the use of benzodiazepines as firstline treatment.80 Two strategies are recommended: either a fixed-dosage or an as-needed regimen triggered by symptoms. These patients may have increased or decreased anesthesia requirements during induction and maintenance. The most common 90-day postoperative complications are infections, bleeding, and cardiopulmonary insufficiency; however, these complications are only increased if the patient has alcohol abuse at the time of surgery.81 For those patients with alcohol abuse at the time of surgery, the development of AWS is associated with a longer hospital stay and increased mortality.79

Blood Conservation Patient blood management is based on the three pillars: detecting and treating preoperative anemia, reducing the loss of red blood cells (RBCs) perioperatively, and optimizing the treatment of anemia.82 Thorough preoperative planning is essential to avoid perioperative allogeneic transfusion. Any history of bleeding disorders and management of anticoagulation must be evaluated, including discontinuation of drugs that adversely affect clotting (e.g., acetylsalicylic acid, nonsteroidal antiinflammatory drugs [NSAIDs], and anticoagulants). In patients with anemia, iron therapy may help optimize the starting operative hemoglobin. Preoperative autologous donation (PAD) also has been used to reduce the need for allogeneic RBC products.83 However, PAD may not avoid allogeneic blood because almost half of the patients who donate blood before surgery are anemic on the day of surgery, and preoperative strategies to augment the RBC mass require more time than is generally reasonable for optimal efficacy. Patients with low hemoglobin levels at the start of surgery are at an increased risk of receiving allogeneic blood.84 In addition, PAD is costly, it can be associated with clerical errors, and for every two units donated, usually only one unit gets transfused.85 If the patient is optimized and surgery is bloodless, the autologous units are discarded. Other blood conservation strategies, such as intraoperative blood salvage (cell saver) and acute normovolemic hemodilution (ANH), have been used successfully for patients having major liver resections and for Jehovah’s Witnesses.86 ANH has been shown in two prospective studies to reduce the number of RBCs transfused per patient in major liver resections.87,88 A score with good discriminatory ability to predict the necessity of RBC transfusion during liver resection was developed,89 and, subsequently, this score was incorporated into a nomogram to predict which patients would benefit from ANH to decrease transfusion during hepatic resection.90 At our institution a randomized controlled trial (RCT) of ANH in patients undergoing major pancreatic surgery showed no reduction in RBC transfusion.91

INTRAOPERATIVE STRATEGIES FOR HEPATOPANCREATOBILIARY SURGERY At tertiary care centers HPB surgery has evolved into a discrete specialty in which HPB surgeons manage the complexity of

372

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

both liver and pancreas surgery. Like HPB surgeons, anesthesiologists must master the intraoperative management of liver and pancreas surgery. Although many elements are similar between liver and pancreas anesthetic care for preoperative preparedness, i.e., “ready for surgery,” some intraoperative elements are procedure specific.

Fluid Management for Hepatopancreatobiliary Surgery: Pancreas One of the most common interventions made by ACPs is the administration of IV fluid. Many questions have arisen, and much controversy has emerged regarding how much fluid should be given perioperatively, which fluids should be given, when they should be given, and whether outcomes can be influenced. Because preoperative fluid status and perioperative fluid shifts are difficult to measure, and correct therapy remains uncertain, the assessment of intravascular volume status, the maintenance of hemodynamics, and the need for transfusion for patients undergoing HPB surgery remain an important clinical decision in the perioperative setting. Past research to identify the perfect recipe of fluid administration during abdominal surgery suffered from standardization of regimens and the goals chosen to influence the amount of fluid prescribed. Although liberal, standard, conservative or restrictive has been and still remains in the eye of the beholder, contemporary fluid therapists emphasize that administering more fluid (typically crystalloid) than is needed to patients undergoing surgery has been associated with harm.92 Preoperative volume loading and routine replacement of insensible and third space losses should be abandoned in favor of rational fluid therapy, zero-based fluid therapy or demand-related fluid protocols to avoid any collateral damage that may be caused by interstitial edema. There is evidence-based medicine to support this contemporary approach to fluid therapy. Mechanical bowel preparation and overnight fasting are less common and are no longer recommended before HPB surgeries.92 Intraoperative evaporated fluid losses during surgery are at most 1cc/kg/hr.93 Modern tracer studies do not support the existence of a third space.94 Therefore filling of this theoretical space is moot and the term should be abandoned; fluid is either intravascular or shifted into the interstitium. Focusing on intraoperative fluid management, the key question is whether administration of fluids will result in a clinically relevant increase in cardiac output, thereby enhancing tissue perfusion and oxygen delivery.95 Furthermore, a strategy that does not require an empiric fluid challenge to determine whether fluid administration would increase cardiac output has the obvious benefit of preventing fluid administration and volume overload–induced complications in patients who are fluid nonresponsive.96 Unfortunately, methods that have been used in the past to assess volume status and volume responsiveness are unreliable. There are many opinions regarding fluid management in the operating room; nonetheless, as a whole, fluid administration is based on textbook guidelines for surgery-specific replacement of blood loss and maintenance fluid requirements. The standard approach used to deliver these goals uses maintenance background fluid therapy that replenishes fluid lost by urinary output and perspiration then adding additional fluid boluses for blood loss or fluid shifts. It is accepted practice to adjust the dose of fluid in response to some form of end point. Conventional end points include urine output, blood pressure, and heart rate. For the higher risk patient or surgery, basic invasive

monitoring such as arterial pressure of CVP may be added. This traditional fluid management strategy is unreliable because the traditional static end point parameters, such as blood pressure, heart rate, urine output, and CVP, used to diagnose hypovolemia and the response to a fluid challenge are unreliable. Goal-directed individual fluid therapy (GDT) based on the optimization of cardiac output or using dynamic indices of blood flow and arterial pressure to guide fluid requirement has appeal and has become more common.96 The availability of minimally invasive hemodynamic monitoring techniques (esophageal Doppler, arterial waveform analysis) and the use of dynamic parameters of fluid responsiveness allow the use of protocolized GDT strategies. Functional hemodynamics parameters provide a numeric representation of the patient’s fluid responsiveness and are more reliable than using standard static parameters, such as blood pressure, heart rate, urine output, or even CVP.97 A recent meta-analysis supports GDT for patients having abdominal surgery to improve postoperative recovery and decrease complication rates, yet liver and pancreas surgeries were excluded.98 HPB surgery exposes patients to periods of cardiovascular insufficiency, either because of anesthesia-induced loss of vasomotor tone and baroreceptor responsiveness or because of blood loss and mechanical obstruction to blood flow. In all cases, stroke volume will fall as well as global oxygen delivery to the tissues. GDT is targeted to detect hypovolemia and hypoperfusion early (at or before anesthetic induction) to be proactive to avoid hypoperfusion.99 Because surgery also creates a cytokine storm, the combination of relative hypoperfusion and immune modulation will alter the microcirculation, causing subclinical damage. Whether GDT for HPB surgery can rescue patients from this insult is unknown. Based on the growing evidence supporting GDT, clinical societies have published guidelines for operative fluid management recommending that all ACPs should have a perioperative fluid plan using an algorithm guided by the most appropriate and accurate monitor. While acknowledging that the benefits of perioperative GDT have yet to be proven, experts believe the bulk of clinical research supports the implementation of a twostep GDT plan containing colloid and balanced solutions for major abdominal surgery. All ACPs should implement a twostep GDT plan, which begins immediately after induction of anesthesia. First, determine whether the patient requires hemodynamic support of augmentation of cardiovascular function. Second, if the need is apparent and the patient is fluid responsive, fluid bolus therapy should be considered and guided by appropriate changes in stroke volume.100

Pancreatic Anastomotic Leak The Whipple procedure, or pancreaticoduodenectomy (see Chapters 62 and 117) is an extensive and relatively long procedure with the potential for large fluid losses. Whether intraoperative fluid management influences outcome after pancreatic surgery is a controversial topic. Postoperative GI dysfunction is a frequent complication in these surgical patients. Although the pathogenesis of GI complications is multifactorial, gut hypoperfusion, secondary to hypovolemia or cardiac dysfunction, plays a key role.101 Although healthy patients may tolerate a 25% to 30% decrease in blood volume without changes in systemic arterial pressure or heart rate, splanchnic perfusion is compromised after 10% to 15%reduction in intravascular volume.102 Selective vasoconstriction of mesenteric arterioles,

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

mediated primarily by the renin-angiotensin system, contributes to the maintenance of systemic arterial pressure and the perfusion of nonmesenteric organs.103 This response occurs at the expense of splanchnic hypoperfusion that often outlasts the period of the hypovolemic insult or low-flow state, promoting abdominal damage. GI dysfunction presents with clinical signs and symptoms ranging from impaired motility101 and inability to tolerate enteral diet to ischemic injury.104 The type of surgery is important; for example, in abdominal surgery, poor oxygen delivery is significantly associated with anastomotic leak,102 especially in GI segments highly dependent on oxidative phosphorylation.105 Pancreaticoduodenectomy has a unique set of conditions, including three different anastomoses, giving rise to complications such as ileus, anastomotic leak, and pancreatic fistula formation. One of the postoperative GI complications of interest for pancreatic surgery, anastomotic leak, would seem to be the one most affected by excessive fluid administration. Hypervolemia (typically too much crystalloid) can damage the glycocalyx, a layer of membrane-bound proteoglycans and glycoproteins that coats healthy vascular endothelium and plays an important role in managing vascular permeability by acting as a second barrier to extravasation.106 The most common manifestation of hypervolemia is edema of the gut wall and prolonged ileus. A study in rats undergoing a bowel resection and anastomosis showed that excessive crystalloid results in submucosal intestinal edema, lower anastomotic bursting pressure, and a decrease in the structural stability of intestinal anastomosis in the early postoperative period.107 Retrospective single-center studies for pancreatectomies examining an association of anastomotic leak and higher amounts of perioperative fluid therapy report contradictory results.108–113 Two prospective RCT at MSKCC may be bringing us closer to identifying a safe range of intraoperative fluids that does not affect morbidity for patients undergoing pancreatectomy at high-volume centers. An RCT of hemodilution for patients undergoing pancreatectomy in which the hemodilution cohort received two more liters of intraoperative fluid than the liberal arm of our RCT of liberal versus restrictive fluid therapy114 showed an increased incidence of pancreaticoduodenectomy anastomotic leak (ANH 21% vs. standard deviation [STD] 7.7%).91 Both RCTs had fluid therapy guided by empiric end points. GDT has been advocated as the strategy to best maintain oxygen delivery and minimize splanchnic hypoperfusion, and a meta-analysis of major surgeries has shown it decreases major and minor GI complications in the perioperative period.115 The authors know of no trial that has looked at GDT and its effect on anastomotic leak for pancreatic surgery.

Fluid Management: Liver Surgery For hepatic resection, a relationship between extent of intraoperative blood loss and mortality and morbidity has been consistently shown. To minimize blood loss, it is common anesthesia practice to perform liver resections with the CVP less than 5 mm Hg. The blood loss resulting from a vascular injury is directly proportional to the pressure gradient across the vessel wall and the fourth power of the radius of the injury. If the CVP is lowered from 15 to 3 mm Hg, the blood loss through a vena caval injury consequently falls by a factor greater than 5. LCVP not only lessens the pressure component of the equation but also minimizes the radial component of flow by reducing vessel distention (Fig. 25.1). LCVP anesthesia is designed

373

to preclude vena caval and hepatic venous distention, facilitate mobilization of the liver and dissection of retrohepatic vena cava, minimize hepatic venous back bleeding during parenchymal transection, and facilitate control of inadvertent venous injury78 (see Chapter 118). LCVP anesthesia is often performed in combination with surgical inflow and outflow vascular control (Pringle technique) before parenchymal transection.116 In 1996 the authors developed and reported a simple, effective, and reproducible technique for decreasing the intraoperative blood loss in patients undergoing liver resection based on fluid restriction and the vasodilatory effects of anesthetic agents.78 Around the same time, a complex LCVP management technique was described117 that used epidural blockade and IV nitroglycerin. These patients often required intraoperative dopamine for systemic pressure support. The technique seemed cumbersome, adding an unnecessary level of complexity to an already challenging situation. Despite this, both approaches contributed to improved outcomes and continue to be practiced at major institutions.118–120 Over time several other techniques of LCVP have been advocated: administration of diuretics, low tidal volume (TV) ventilation with positive end-expiratory pressure (PEEP) reduction, hypovolemic hemodilution, and so forth. Recent comparison of fluid restriction or vasodilation to lower CVP concluded that either seemed equally effective.121 To reduce intraoperative blood loss the current practice of liver surgery in high-volume centers restricts the intraoperative fluid infusion to reduce CVP during parenchymal resection.122

Low Central Venous Pressure Technique: General Anesthesia LCVP-assisted hepatic resection at the authors’ institution has evolved over the years but is still true to the two original pillars: fluid restriction and pharmacologic vasodilation. This anesthetic technique was historically dependent on the presence of a central venous catheter to provide hemodynamic information and expeditious and reliable access in case rapid resuscitation

CVP A

CVP B FIGURE 25.1  Vena caval injury profile under various central venous pressure (CVP) conditions. A, High CVP. B, Low CVP. Increased CVP leads to distention of the vena cava, with ensuing enlargement in diameter of injury and increase in the bleeding driving pressure.

374

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

was required.78 However, in the modern era of bloodless hepatic resection, to avoid the morbidity associated with central vein cannulation, our clinical practice has abandoned the routine use of central venous lines. The authors have not adopted surrogate measures of CVP: external jugular venous pressure, peripheral venous pressure, inferior vena cava diameter using transesophageal echocardiography, inferior vena cava collapsibility using hand-carried ultrasound devices, or stroke-volume variation.119 Instead, the success of our LCVP is currently based on surgical visual inspection of the vena cava or the amount of venous back bleeding as reported by the surgeon.123 Patients should still be prepared for large-volume transfusion, although this is infrequently needed. Close cooperation between the anesthesiologist and the surgeon continues so that likely difficulties can be anticipated, and appropriate measures can be taken. Fluid management is an important aspect of the LCVP anesthesia. Intraoperative fluid management is divided into the following two phases.

Phase 1: Prehepatic Prehepatic resection starts at anesthesia induction and ends at the completion of parenchymal transection and hemostasis. During this phase, inflow control of the portal vein and hepatic artery are achieved, and the vena cava and hepatic veins are dissected. Sixty percent of the time hepatic parenchymal transection is performed with intermittent inflow occlusion (Pringle technique) applied.4 This phase avoids fluid excess and takes advantage of the vasodilatory effects of anesthetic drugs. Preoperative overnight fluid replacement is withheld, and maintenance fluid requirement at 1 mL/kg/hr of balanced crystalloid solution is infused until the liver resection is completed. Intermittently, small fluid boluses or vasoactive drugs may be given to maintain hemodynamic stability. Some extent of permissive oliguria caused by decreases in antidiuretic hormone or permissive relative hypotension while peripheral tone is decreased will allow for continued minimal fluid infusion until the specimen is delivered. Anesthesia is maintained with a combination of isoflurane or sevoflurane in oxygen and fentanyl. Isoflurane provides vasodilation with minimal myocardial depression.124 Consistent with its minimal effect on cardiac output and systemic pressure, fentanyl has no effect on liver blood flow and oxygen delivery and, given its lack of toxic metabolites, can be administered like any abdominal surgery without any dosing reduction.125 As tolerated, a background infusion of dexmedetomidine or ketamine may be added to minimize narcotic dosage. Shortly before transection of the liver, sublingual nitroglycerin is applied. This combination of inhalational agent, fentanyl, and sublingual nitroglycerin readily provides the favorable LCVP environment for hepatic resection.

Postresection: Phase 2 Posthepatic resection, the second phase, begins once the specimen has been delivered and hemostasis secured. During this phase, the goal of fluid prescription is to leave the operating room with a normovolemic patient. Early proactive GDT may compromise the effectiveness of LCVP on decreased blood loss. Although most liver surgery does not result in profound tissue hypoperfusion, some degree of hypoperfusion does occur with the Pringle technique, adding tissue perfusion injury before resuscitation. There is presently no approved treatment for

ischemia reperfusion injury (IRI), which is the inflammation that occurs when blood flow is returned to healthy liver tissue after diseased tissue has been surgically removed. IRI can harm the vascular barrier and the endothelial glycocalyx and results in part from the deposition of complement, a protein that kills liver cells and impairs regeneration.99 GDT has been shown to be effective when combined in an enhanced recovery after liver surgery (ERAS) program.120,126 (see Chapter 27). A recent randomized trial for hepatic surgery at our institution showed intraoperative GDT was a safe technique and allowed for less intraoperative fluid, but it did not influence overall 30-day morbidity.131 The optimal perioperative fluid resuscitation strategy for liver surgery remains undefined.

Renal Dysfunction The common assumption is that urine output must be maintained above a certain level to prevent acute kidney injury (AKI); therefore low urine output should be treated with crystalloid boluses.127,128 Yet, in the intraoperative period, oliguria defined as urine output less than 0.5mL/kg/hr is extremely common and often occurs as a neurohormonal response to surgical stress, rendering it an unreliable marker of volume status. In a large retrospective analysis, it was reported that 85% of postoperative patients not developing AKI had a urine output less than 0.5mL/kg/hr, surprisingly significantly more patients than those who developed AKI (75%).129 Recently, using a large national database, procedure-specific risk of perioperative AKI for patients undergoing intraabdominal surgery was evaluated.130 The results demonstrated that among patients undergoing intraabdominal surgery, the risk of severe AKI varies considerably, depending on the specific procedure. HPB procedures (liver and pancreas, elective and emergent) had a 1.8 % incidence of acute renal failure with an adjusted risk of 1%. The authors hypothesized that AKI may be a spectrum of diseases with different causes and consequences that depend on the clinical context in which it occurs. A retrospective review in a similar time period, as in the report by Kim and colleagues, evaluated severe clinical AKI following LCVPassisted liver resection.130 Clinically relevant AKI was rare (,1%) and resolved in half of these patients during a short follow-up period.118 These results are mirrored by analysis of postoperative morbidity after liver resections.132 Whereas Kim only had severe end points (creatinine .2, dialysis) to analyze, and may have underestimated the incidence of clinically significant AKI defined by the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, this review analyzed laboratory data and was able to apply the RIFLE criteria to the incidence of biochemical AKI118. Although biochemically defined renal dysfunction was a relatively common event (16%) in patients undergoing LCVP-assisted liver resection, it was a transient phenomenon, and its clinical significance was limited. The incidence of biochemical acute renal failure is not in and of itself an argument against the use of LCVP anesthesia for liver resections. Some permissive, clinically nonrelevant renal dysfunction is a very common event in this patient population, and it is consistent with published literature regarding other types of major operations.133 The evidence does not support LCVP-assisted liver surgery increasing the incidence of significant AKI. A retrospective review of a series of 1153 liver resections found that epidural anesthesia (EDA) and/or EDA

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

LCVP-assisted liver surgery significantly increases the incidence of AKI (defined by the Acute Kidney Injury Network [AKIN] criteria) following major resections but not minor liver resections.134

Blood Conservation, Transfusion The ACP not only has a pivotal role in reducing blood loss during hepatic surgery but also contributes to intraoperative blood conservation and controls transfusion protocol for all HPB surgery. Transfusion-free surgery, better known to the public as bloodless surgery, can only be achieved by the application of blood management techniques to decrease allogeneic transfusion. The three pillars of blood conservation are (1) build up the patient’s own blood volume, (2) reduce blood loss, and (3) recycle the patient’s own blood.82 The ACP should be familiar with recycling techniques, such as intraoperative RBC salvage and hemodilution, which are maneuvers that may contribute to reduced allogeneic RBC transfusion in major liver surgery. Autologous RBC salvage (intraoperative autotransfusion) involves recovery of the patient’s shed blood from a surgical wound, washing or filtering, and reinfusion of the blood into the patient. HPB operations often are performed for cancer. Cell salvage had been excluded in oncologic surgery because of the concern for potential dissemination of cancer cells, but the availability of leukocyte-depleting filters allows its use during cancer surgery. Another transfusion-sparing technique is ANH. This is a recycling technique that can be performed intraoperatively by the anesthesiologist. Blood is removed from the patient after induction and replaced with crystalloid or colloid fluid. The removed blood is stored at room temperature in the operating room and is returned to the patient at the conclusion of the operation. Two randomized studies of ANH in major hepatic resection showed a significant reduction in the percentage of patients requiring allogeneic RBC transfusion.87,88 An important factor in selection of patients who may benefit from ANH is predictably the likely operative blood loss. Studies have shown that the threshold for utilizing ANH is a predicted blood loss of 0.2 of the patient’s estimated total blood volume. Therefore utilizing ANH must be selective and reserved for those cases in which substantial blood losses are expected. In a randomized trial of 114 patients undergoing major liver resection and allocation of intraoperative management using a transfusion nomogram, low blood loss cases were more effectively identified with reduced ANH use in patients least likely to benefit.90 A similar trial showed no benefit of ANH in patients undergoing pancreatectomy.91 Tolerance of normovolemic anemia is important, and care must be taken not to confuse the momentary helpful effect of RBC transfusion on hypotension and hypovolemia with an outcome benefit. A restrictive approach to blood transfusion with a threshold of 7 g/dL has been shown to reduce blood use and not cause harm in critically ill patients,136 as well as in liver resection patients.137 In a recent review, Kingham and colleagues4 reported that transfusions have decreased by 50% over two decades, but perioperative blood loss and transfusion remain associated with morbidity. Cannon and colleagues138 specifically showed that transfusion with packed RBCs was associated with postoperative complications in patients undergoing hepatectomy. The correlation of transfusion with complications should not be interpreted as a direct cause-and-effect relationship; instead,

375

what is important is that patients undergoing liver surgery and receiving very few units of blood transfusion nevertheless have higher complication rates.139 There are increased infectious complications in those transfused: the more transfusions that are done, the higher the rate of total complications and infectious complications. The cause is not known, but one possible mechanism proposed is “transfusion-related immunomodulation.”140 In addition, patients who have received blood stored 29 days or more have twice the rate of infection. It has been suggested that the reason for this observation is that as stored RBCs break down they release cytokines that can lower immune function.141 One could hypothesize that by reducing transfusion, complications would also be reduced. A prospective trial of ANH reduced RBC transfusion but did not reduce morbidity.87 Most HPB surgery is performed for cancer, and studies have examined the association of cancer progression and RBC transfusion for primary and metastatic cancer. Because it was reported in the journal Anesthesiology that blood transfusion in rats promoted cancer progression,142 there has been a perception that an anesthesiologist’s choice to transfuse RBCs can influence long-term survival. Human studies have not supported animal data, however. A retrospective review of 1300 hepatectomy patients with metastatic colorectal cancer reported the major effect on survival is in the immediate postoperative period, but transfusion did not predict long-term survival.139 Patients receiving only autologous blood or spared-blood transfusion from ANH also did not have better disease-free survival.131,139 Postoperative complications, especially infectious and other tumor-related factors, such as tumor-infiltrating lymphocytes, are more dominant determinants of long-term cancer survival.143 The magnitude of operative blood loss during resection of hepatocellular carcinoma was found to be a predictor of recurrence and survival rates; however, the blood loss was found to be related to tumor characteristics and extent of surgery.144 RBC transfusions are indisputably associated with an increase in mortality and morbidity in liver surgery; however, transfusion may be a surrogate marker of one or more other variables that is more directly related to the complication. Abdominal infections are the most common complication of modern HPB surgery.4 Postoperative complications in cancer patients have been shown to reduce diseasefree survival and disease-specific survival.22,118 The mechanism is unknown, but perioperative inflammation and infection are a current theory.

CHOICE OF ANESTHESIA AND HEMODYNAMICS The impact of anesthesia and surgery on hepatic blood flow (HBF) has important implications for intraoperative management. The liver is unique in that it receives a dual afferent blood supply equivalent to about 20% of the cardiac output. The majority of HPF (70%) is via the portal vein and flows through the hepatic sinusoids, hepatic veins, vena cava, and back to the right atrium, and the remainder is derived from the hepatic artery. It is a low-resistance reservoir that can store blood during hypervolemia and a source of blood during times of hypovolemia. Although hepatic outflow may vary, hepatic inflow is constant by the reciprocal relationship of portal vein flow and hepatic artery flow.145 When portal venous flow increases, hepatic arterial flow decreases, and when

376

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

portal vein flow decreases, hepatic arterial flow increases. This is the hepatic arterial buffer response because the hepatic artery adjusts its tone to keep HBF at a steady state. The reverse is not true; hepatic arterial tone does not affect portal venous flow (see Chapter 5). Veins, particularly splanchnic veins, are much more compliant than arteries,146 and with a higher density of a-adrenergic receptors, are more sensitive to sympathetic activation than arteries.147 HBF is directly proportional to perfusion pressure (mean arterial or portal vein pressure minus hepatic vein pressure) across the liver and inversely related to splanchnic vascular resistance. Autoregulation of HPB is not prominent; therefore total HBF (arterial plus portal) can be modified by “surgery-related” factors, such as stimulation, retraction, or manipulation, and several “anesthesia-related” factors, such as positive pressure ventilation, anesthetic technique, or drug effect on perfusion pressure or splanchnic vascular resistance. Oxygen delivery to the liver may already be marginal because most of the blood flow is with desaturated hemoglobin delivered via the portal vein. A well-planned anesthetic maximizes the relationship between oxygen supply and demand, with the premise that reductions in systemic pressure will reduce HBF. A good rule of thumb is anything that could result in significant reductions of systemic pressure and/or blood flow (cardiac output–induced hypotension, hypovolemia, anesthetic overdoses) should be avoided. Volatile anesthetics reduce HBF in a dose-dependent fashion by affecting cardiac output and systemic pressure. Isoflurane has been considered the agent of choice in cases in which preservation of splanchnic blood flow is required. Liver blood flow and the hepatic artery buffer response are maintained better in the presence of isoflurane than with any other volatile anesthetic agent.148 In addition, isoflurane attenuates the increases in hepatic oxygen consumption associated with surgery and liver manipulation. Desflurane is shown to have no deleterious effects on liver function and hepatocyte integrity. Desflurane anesthesia is associated with significantly greater gut blood flow than equipotent isoflurane. This difference cannot be explained by systemic hemodynamics alone. There is no difference in total hepatic flow between isoflurane and desflurane groups, however, implying that an intact hepatic arterial supply buffers response with desflurane.149 Sevoflurane seems to be like isoflurane and desflurane with a few exceptions. Indocyanine green clearance is better preserved during sevoflurane anesthesia. Sevoflurane seems like isoflurane in its effect on regional HBF.150 Nitrous oxide is used extensively in patients with hepatic disease. It is not shown to contribute to hepatic disease exacerbation.151 The sympathomimetic effects of nitrous oxide decrease HBF.

Intravenous Anesthetics and Muscle Relaxants Inhaled anesthetics supply all the aspects needed for anesthesia in one package, but today most anesthesiologists choose multiple drugs to reach their goals: immobility, amnesia, suppression of autonomic reflexes, muscle relaxation, and analgesia. Over the last several decades, dramatic advances have been made in IV anesthesia, with the result that total IV anesthesia is now a workable alternative to the traditional inhalation anesthetic. Anesthesiologists using multiple drugs take advantage of the interactions of drugs with different mechanisms of action but similar therapeutic effects. The therapeutic goal of the

anesthetic can often be achieved with less toxicity and faster recovery than when the individual drugs are used alone in higher doses. The liver plays a major role in biotransformation, the process through which drugs are broken down into metabolites that can be more easily eliminated. The main mechanisms that affect hepatic elimination of a drug are changes in HBF and changes in the ability of the liver cells to biotransform a drug for excretion. These two mechanisms, hepatocyte function and HBF, have an important role in the choice of anesthetics for patients undergoing hepatobiliary surgery because even small changes in liver function or blood flow can change the concentrations of drugs and their metabolites. High-extraction drugs (ketamine, flumazenil, morphine, fentanyl, sufentanil, lidocaine) are directly related to liver blood flow and essentially cleared as they pass through the liver. Protein binding, enzymatic induction, intrahepatic shunting, and the effect of anesthetics on liver blood flow may affect the elimination of drugs with a high-extraction rate. Reductions in metabolic clearance result in increases of peak drug level with minimal change in the elimination half-life. Low-extraction drugs are those whose concentration is little changed after passage through the liver and depend on the intrinsic clearance (liver size, total enzyme capacity) of the liver. The elimination of drugs with a low-extraction rate (benzodiazepines) depends more on the metabolic capacity of the liver and less on the HBF. In patients with impaired liver function, such drugs experience a prolonged length of activity with no increase in peak levels. The safety of IV anesthetic agents and muscle relaxants is uncontested, yet, increasingly, anesthesiologists prefer agents that are not influenced by liver function or using multiple drugs for the same effect despite liver dysfunction. Although the use of opioids is appropriate during HPB surgery and the management is like other abdominal surgery, remifentanil, a short rapidly acting opioid, given by continual infusion and metabolized by plasma esterases, is gaining in popularity over fentanyl. The muscle relaxants atracurium and cisatracurium both undergo Hoffman degradation and ester hydrolysis, neither of which is dependent on liver function. Dexmedetomidine, an a2-agonist, and ketamine do depend on hepatic function; however, perioperatively, their weak analgesic effects decrease the minimum alveolar concentration of volatile vapors and the postoperative opioid requirements.152,153

Analgesia Strategies Effective analgesia in HPB surgery is important for postoperative respiratory function, compliance with physiotherapy, mobilization, and prevention of complications. Different analgesic strategies are needed for open and laparoscopic surgery. There is evidence supporting the use of wound catheters or transversus abdominis plane blocks. The POP-UP study demonstrated that continuous wound infiltration is noninferior to epidural analgesia in HPB surgery.154 Medial open transversus abdominis plane catheter analgesia conferred superior analgesia versus IV patient-controlled analgesia (PCA) following liver resection.155 Single-shot spinal opioid administration may provide adequate analgesia for both laparoscopic and open pancreatic surgery. Intrathecal morphine and PCA have been shown to provide acceptable postoperative outcomes in patients undergoing open liver resection.156 In a recent survey of HPB surgeons in Canada, IV PCA and epidural analgesia were used in

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

similar proportions, with very few surgeons reporting routine use of regional nerve blocks such as transversus abdominis plane catheters.157

Epidural Anesthesia and Analgesia In recent years HPB surgery, performed under general anesthesia and a thoracic epidural block, that may be used intraoperatively or solely to provide postoperative analgesia, has increased as providers have taken a growing interest in ERAS protocols (see Chapter 27). Guidelines for ERAS almost unanimously include the use of regional analgesia when appropriate. Level 1 evidence for the use of epidurals in open abdominal surgery stems from their ability to reduce PPCs158 and provide multimodal analgesia, thereby reducing opioid-related adverse effects. In contrast to pancreatic surgery, there remains an unclear role for EDA or analgesia in the setting of liver surgery. The most commonly used incisions are subcostal or midline, with significant cephalic retraction of the chest wall. Therefore the patient’s pain is more like a postthoracotomy patient’s pain. Although thoracic extrapleural analgesia (EPA) provides superior pain relief for thoracoabdominal operations159 and reduces PPCs,158 the risk versus benefit of an indwelling catheter with EDA for liver operations is controversial due to the role the liver plays in the postoperative coagulation cascade135 and the possibility that EDA may drive increased fluid therapy and transfusion160 or AKI.134 In addition, the number one complication following hepatectomy is abdominal infections, with PPCs, less common than thoracic surgery and resulting more from the act of surgery (pleural effusion or bile leak) than the patient’s comorbidity. The decision to consider the use of epidurals in liver surgery is further complicated by potential for perioperative hypotension, which may be exacerbated by management of patients using LCVP technique. EDA may be used to provide LCVP conditions during hepatic surgery.120,161 Despite many animal and human studies, the effects of thoracic EDA on HBF are not entirely clear. EDA can interfere with the numerous factors affecting HBF: hemodynamics, autonomic nervous system, circulating neurohumoral agents, and local metabolites (adenosine) either by sympathetic blockade, systemic hemodynamics, or even the circulating effects of local anesthetics.162 Splanchnic veins, with their higher density of a-adrenergic receptors, play the main role in maintaining a ratio between stressed (Vs) and unstressed blood volume (Vu).146 Vu is hemodynamically inactive, but when venoconstriction changes it, this is equivalent to a transfusion of a significant amount of blood. Controlled ventilation and EDA both decrease venous return (VR) and must be associated with an increase in Vs to maintain hemodynamics. Decreased Vs and VR can be restored by fluid infusion to fill up the increased venous capacity or by an a-agonist to increase sympathetic tone of the compliant veins, which robs from Vu to give to Vs. If fluid is infused to counteract the hemodynamic effects of EPA, this may lead to excessive hydration and increased packed RBC transfusion after hepatectomy. The clinical advantage of using a vasopressor is that it maintains tissue blood flow but avoids fluid infusion. However, a clinician who practices LCVP should realize that this approach might decrease the margin of safety. Low Vu per se is not harmful and up to 1000 mL of blood may be lost without change in standard hemodynamic parameters. However, beyond this point, when the mobilization of blood

377

from Vu to Vs is approximately complete, even minor reduced VR, whether by the Pringle technique, vena caval compression, or blood loss, can quickly lead to hemodynamic deterioration. Vasopressors during LCVP-assisted liver surgery are certainly justified; however, it may delay recognizing dangerous hypovolemia. Nonetheless, enthusiasts point out that there may be several other advantages to regional anesthesia, especially when combined with postoperative EPA: better pain control, attenuation of the stress response, decreased requirement of volatile anesthetics, and a reduction in the need for perioperative opioids. The avoidance of the need for perioperative opioid-based analgesia cannot be overstated. Aside from well-established immediate adverse effects attributed to opioids, perioperative opioids may have longer-lasting implications. The Centers for Disease Control and Prevention recently rated prescription opioid abuse among the top five health threats, and the so-called opioid crisis in the United States has been linked to the over prescription of opioids by well-intentioned providers. Perhaps the strongest arguments for the use of thoracic EDA for liver surgery is its possible modulation of the immune response and its possible effect on tissue microperfusion.162 Preclinical data, animal studies, and retrospective reviews demonstrate the potential for a decreased recurrence rate in some cancer types. Animal studies have shown that EDA could have an important role in modifying tissue microperfusion and protecting tissue from ischemic damage, regardless of the effects on hemodynamics. The notion that anesthesiologists may be able to impact the short-term and long-term outcome for a cancer patient simply by incorporating regional anesthesia is appealing, although unproven in human studies and more prospective randomized research is needed. Recently, basic science and retrospective reviews have suggested that the anesthetic management during cancer surgery may influence the patient’s long-term survival. There are several multicenter prospective trials underway to examine whether the use of regional anesthesia can truly decrease cancer recurrence. What is perhaps the most intriguing and an immediate hypothesis for HPB surgery is whether EDA can improve immune function and increase resistance to postoperative infection. Surgical stress and pain may induce lymphocyte depletion, which may be associated with the risk of postoperative infectious complications. Although circulating cytokines related to monocyte activation and phenotype alterations are not influenced by postoperative pain reduction compared with systemic opioid treatment, there has been evidence in animals that EPA influences lymphocyte distribution, increases the postoperative CD4/ CD8 ratio and B cells, and decreases natural killer cells. This preservation of immunity has not been shown in human studies.163 EDA combined with EPA has been shown to significantly reduce the amount of postoperative inflammatory response in patients by altering the circulating leukocyte surface molecules CD11b and CD62L (L-selectin), which are known to be more sensitive markers of the early detection of postoperative stress response inflammatory markers.164 If there is an attenuated neutrophil adhesive capability by EDA/EPA, and if this improves patient resistance to infection, this may be more important for HPB surgery than for other types of surgery because of the role that the liver plays in the immune and inflammatory process. An elevated INR or decreased platelet count can influence the timing of the removal of the catheter because of a theoretical risk of spinal hematoma.162 In recent years, bloodless hepatic

378

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

surgery, the known hypercoagulable state despite elevated INR and decreased platelet counts, and the safety of an indwelling catheter in other surgeries in patients who undergo anticoagulation postoperatively allows for re-evaluation of the modern age risk versus benefit in patients undergoing liver resection. There are no clinical guidelines as to the safety of epidural use solely for the patient undergoing liver surgery. The guidelines for the placement and removal of neuraxial analgesia in patients with coagulation defects outlined by the American Society of Regional Anesthesia (ASRA) apply to hepatic resection as well.165 Today, most ACPs believe that epidural use is safe in liver surgery. The vasodilatory effect of volatile anesthetics may safely be treated with vasopressor support and is expected to terminate at the end of surgery. The sympathetic blockage of epidural analgesic results in relative hypotension, which can be treated with temporary vasopressor support and does not require aggressive fluid resuscitation, but this treatment approach may need to be continued in the immediate postoperative time. At tertiary care centers, where an acute pain anesthesia service and ACP work closely with the surgeon to evaluate epidural function, volume status and potential complications, its benefits may outweigh its risks. There is a paucity of randomized trials examining this controversy, however. The ASA postoperative evidenced-based pain management guidelines are generalized and can be confusing when adapted to liver surgery. The web-based PROSPECT (Procedure-Specific Postoperative Pain Management) is a collaborative group of anesthesiologists, surgeons, and surgical scientists that recommend optimal postoperative pain management that is specific for different surgical procedures, as well as arguments for and against the invasiveness of the analgesic technique and the consequences of pain on outcome. Hepatic surgery is not represented, and what operation is transferable is unclear. Recent 2016 guidelines by the ERAS society specifically outline current evidence and recommendations for optimal postoperative pain management in liver surgery that support use of intrathecal or wound infusion catheters.166 Despite recognizing improved pain control, ERAS society recommendations are less enthusiastic regarding patient-controlled epidural anesthetic given potential delay in removal with elevated INR/prothrombin time and reported increased risk of kidney failure secondary to hypotension.167 After HPB surgery, most patients are extubated in the operating room. Until recently, it was tacitly assumed that postoperative pain was essentially the pain of inflammation plus, perhaps, some direct pain from cutting nerves. Subsequently, it has been demonstrated that there are important differences between pain from surgery and pain from inflammation.168 More important from a clinical perspective, some drugs are effective to treat either surgery pain or inflammation, such as opioids, whereas others are unique to the setting. A better understanding of the pain pathways and the concerted effort by ERAS to shorten and uncomplicate hospital stay, especially in the older patient, has drawn attention to the success of multimodality analgesia. Postoperative pain management has evolved considerably from the use of parental or neuraxial opioid monotherapy to multimodal opioid-sparing analgesia. The options include NSAIDs/cyclooxygenase-2 inhibitors, local anesthetics, N-methyl-d-aspartate antagonists, a2-antagonists, thoracic epidural catheters, singledose intrathecal, transverse abdominis plane blocks, IV PCA, and local analgesia including local wound injection catheters for the incisional wound.169 Although opioids have stood the test of

time to anchor postoperative pain, these drugs, whether infused epidurally or parentally, are not without adverse effects; consequently, targeted multimodality opioid-sparing analgesic algorithms are ubiquitous. These algorithms may not be safe for patients having hepatic surgery; instead, choices must be based on an individual basis, given the liver’s role in drug biotransformation and coagulation.

CARDIOPULMONARY Cardiopulmonary complications are no longer the major postoperative morbidity for HPB patients. This improvement parallels decreased blood loss, decreased transfusion rate, and improved perioperative fluid and hemodynamic management.

Cardiac Dysfunction The incidence of postoperative MI may be explained by better patient selection and optimization; however, the absence of benefit of preoperative revascularization in the face of known coronary artery disease may be explained, first, by the overall skill with which ACPs manage perioperative stressors, and second by the nature of perioperative MI. Ischemia can occur due to excess demand versus supply (type 2 MI)170 as triggered by hypertension, tachycardia, hypoxia, anemia, or hypotension. ACPs can and do manage these conditions both intraoperatively and postoperatively. Ischemia can also occur with acute plaque rupture and thrombosis formation.170 These events occur more often in the operative setting due to increased hypertension, tachycardia (shear forces), hypercoagulability, and surgery-associated inflammatory response. The perioperative period is particularly risky for patients with coronary stents who may already have a disrupted coronary endothelial lining and are predisposed to stent thrombosis. Fearful of the risk for surgical bleeding, well-meaning surgeons may inappropriately advise patients to discontinue their dual APT which not only reverses the antiplatelet effect but also leads to an exaggerated rebound thrombogenic effect. The POISE trials give credibility to a calculated strategy of decreasing heart rate while avoiding perioperative hypotension (avoid MI and stroke). The ACP should be able to manage these hemodynamic issues that can precipitate an MI, but the triggers to inflammation and hypercoagulation are poorly understood and not yet modifiable by an anesthetic method. The ACPs involved in nonpreventable events may have their clinical vigilance and ability to rescue the patient questioned, or they may feel as personally responsible as those involved in preventable events.171 Myocardial injury after noncardiac surgery is common and not necessarily revealed by ischemic features (symptoms or electrocardiographic findings). A large international study reported that an elevated troponin T, irrespective of ischemic features, independently predicted 30-day mortality.172

Pulmonary Dysfunction PPCs include pneumonia, respiratory failure, bronchospasm, pleural effusions, atelectasis, hypoxemia, and exacerbation of underlying chronic lung disease. Atelectasis and pleural effusion are common consequences of anesthesia and surgery after HPB surgery. With aggressive postoperative pulmonary toilet and early mobilization, these minor problems resolve without the need for further intervention. At least three mechanisms contribute to impaired pulmonary function in the postoperative period. First, respiratory

  Chapter 25  Liver and Pancreatic Surgery: Intraoperative Management

muscles disrupted by surgical transection (abdominal muscles) will not function normally. Second, patients may limit motion of respiratory muscles to minimize postoperative pain. Finally, stimulation of the visceral afferent nerves markedly changes the activation of respiratory muscles. For example, removal of the gallbladder activates vagal efferent, which produces a reflex inhibition of diaphragmatic activity. Of note, laparoscopic surgery may ameliorate the first two mechanisms but not the third, and significant decrements in pulmonary function may still be observed after laparoscopic surgery. ACPs play a key role in the prevention of PPCs. Preoperative preparation, intraoperative management, and immediate postoperative care can have a major impact on the occurrence of this morbidity. It has long been known that the induction of general anesthesia, both total IV anesthesia and inhaled anesthesia, decreases lung volume and promotes dependent zone atelectasis.173,174 To improve oxygenation, ACPs apply a high TV and high fraction of inspired oxygen (FiO2). High FiO2 via absorption atelectasis has also been linked to the development of atelectasis during the postoperative period.175 After HPB surgery, like all abdominal surgery, this impaired oxygenation caused by intraoperative atelectasis persists for days after the surgical procedure.176 An association, but not a causal effect, of atelectasis and PPC has been reported.177 There is experimental work that links atelectatic areas of the lung to translocation and increased bacterial growth, providing an optimal nidus for infection.178 Regardless of the etiology, PPCs increase 30-day mortality.54 The use of high TV (10–15 mL/kg) ventilation, encouraged to prevent atelectasis, results in high peak ventilatory airway pressure, which has been shown to be associated with acute lung injury.179 Low TV ventilation (TV 6–8 mL/kg ideal body weight) with PEEP (6–8 mm H2O) and recruitment maneuvers every 30 minutes (lung protective ventilation) has demonstrated reduced mortality in patients with acute respiratory distress syndrome and decreased PPCs in patients at risk of PPCs after abdominal surgery.180 Yet, most anesthesiologists decrease TVs without the addition of PEEP or respiratory maneuvers (likely because of their effects on hemodynamics), which in a large retrospective cohort may have led to increased mortality.181 The authors speculated that this resulted from increased atelectasis from lower intraoperative TV ventilation. Lung protective ventilation is being proposed as a standard of care to be bundled into ERAS or perioptimal care to further decrease the incidence of PPCs and serve as a measure of the quality and safety of care. Effective strategy during pancreatic surgery should involve the application of a protective ventilation strategy (lower TVs ,8 mL/kg, PEEP 5 6–12 mm Hg and recruitment maneuvers) to improve respiratory function during the postoperative period and to reduce the clinical signs of pulmonary infection.182 On the other hand, during liver surgery, the ACP must weigh the evidence for lung protective ventilation and the effect of high PEEP and respiratory maneuvers on decreased VR or liver congestion on a patient-by-patient basis. Postoperative respiratory failure is most commonly defined as the need for mechanical ventilation for more than 48 hours or unplanned postoperative reintubation. The nature and magnitude of the preexisting respiratory conditions determine the effect of a given standard anesthetic on respiratory function. The ACP plays a key role in the prevention of respiratory muscle-related PPCs. In patients with obstructive lung disease,

379

high airway resistance favors deep slow respiration, which may not be possible in patients with large abdominal incisions. The treatment of this pain with opioids will reduce minute ventilation and respiratory drive. A meta-analysis of patients undergoing thoracic and abdominal surgery showed that the odds of developing postoperative pneumonia was reduced nearly 50% in patients receiving epidural versus IV analgesia, fueling the controversy of this choice in patients after HPB resection.158 Particular attention must be paid to anesthetic elimination and residual drug effect, especially sedative, analgesic, and neuromuscular blockers, in posthepatectomy patients who have altered drug pharmacodynamics and pharmacokinetics. In a recent prospective cohort study, the use of intermediate-acting neuromuscular blocking agents was associated with postoperative desaturation (90%) and reintubation, regardless of train-offour monitoring and use of reversal agents.183 In a cohort of 33,769 surgical cases, planned reintubation within the first 3 days after surgery was associated with a 72-fold increased risk of in-hospital mortality.184 The findings of a recent systematic review and meta-analysis suggest that the use of early CPAP for the prevention of hypoxemia after abdominal surgery may reduce the incidence of PPCs compared with just supplemental oxygen.185 Anticipated respiratory compromise after HPB surgery in patients without an epidural may preclude early extubation, especially in combination with any baseline abnormality in gas exchange. If a patient must be placed on mechanical ventilation, diaphragmatic weakness, atrophy, and respiratory muscle fatigue can occur within hours. Like all muscles, complete rest can lead to diaphragm atrophy, and modes that allow patient triggering, such as assist-control ventilation, are necessary to maintain diaphragm muscle function.186

SPECIAL CONSIDERATION LIVER SURGERY: AIR EMBOLUS The goal of keeping a low central pressure to minimize back bleeding from the liver sinusoids during transection must be counterbalanced by a central pressure that minimizes the risk of air entrainment. The risk of intraoperative air emboli is likely to increase under LCVP anesthesia. Elimination of nitrogen from the anesthetic gas mixture is necessary to permit expiratory nitrogen monitoring for air emboli. Restriction of nitrous oxide in the gas mixture prevents the diffusion-mediated increase in the size of circulating air. Transesophageal echocardiography can be used to monitor air emboli, but this technology is sensitive and overdiagnoses clinically insignificant events. At our institution, during open hepatectomy, surgical and anesthesia vigilance and communication are the keys to detect and treat air emboli. With surgical watchfulness and rapid occlusion of open venous channels, and our monitoring of end-tidal carbon dioxide and hemodynamics, LCVP anesthesia results in a low incidence of clinically significant air emboli.

Minimally Invasive Liver Resection Anesthesiologists continually adjust strategies as innovative surgical techniques evolve. The benefits of laparoscopic liver resection (LLR) have been associated with less blood loss and earlier postoperative recovery,22 although all the comparisons reported are retrospective and therefore associated with a huge selection bias. Pneumoperitoneum induces predictable pulmonary and renal responses as well as phasic hemodynamic

380

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

changes. Intraperitoneal insufflation and head-up tilt result in impairment of HBF secondary to decreases in cardiac output.187,188 In well-selected patients, the consequences of these changes are not relevant. However, the challenges of the pneumoperitoneum, positioning, and mechanical ventilation on cardiopulmonary function in addition to longer surgical time may not be the correct choice for every patient. Before positioning, the patient should be prepared the same as for an open case, including the ability to do large-volume transfusion in case inadvertent major vessel bleeding occurs. A protocol should be in place as well as a fully open instrument tray and equipment available in case the robot must be undocked emergently to convert to open surgery. It is important that the anesthesiologist and surgeon have a discussion before the start of the laparoscopic or robotic liver case because the risk versus benefit of LCVP-assisted hepatic resection is less clear. The pneumoperitoneum compresses the portal vein, reduces portal blood flow, and seems to reduce hepatic back bleeding during transection. Decreasing blood loss for open resection is based on keeping the radius of an inadvertent venous injury small and the pressure head low so that less blood will be lost through the opening. However, retractions can distort vessels and stent them open during LLR. Fluid management is complicated by compromised hemodynamics resulting from positioning and decreased lung compliance. Renal parenchyma and venous compressions during pneumoperitoneum are the etiology of oliguria during LLR. The effects are reversible and usually cause no harm. Yet, many anesthesiologists prefer to optimize intravascular volume to minimize the effects of intraabdominal pressure (IAP) on renal and cardiac function. The issue of gas embolism (GE) during LLR is still debated. Some authors consider it little or no problem, and some consider it a real threat to patient safety.189 The debate centers on the theory that GE occurs when the IAP exceeds CVP.190 The opposite situation, when CVP exceeds IAP, does not prevent GE because it can occur irrespective of whether CVP is greater or less than IAP.191 Positive pressure ventilation causes rhythmic variations in VR for both pressure and flow. With an open vein because of entrainment during the phase with higher

flow, gas from the abdomen might reach the venous circulation. Both carbon dioxide and the argon beam coagulation (ABC) during liver surgery have been associated with GE.192

Ablation Major hepatectomies have decreased, whereas hepatectomy with concurrent surgery and repeat hepatectomies with or without simultaneous ablation have increased. The development of ablative techniques for tumor ablation has been one of the major advances for liver cancer (see Chapter 96). Ablation therapy for benign or malignant liver tumors is often used as an alternative to surgery, the principal aim being to ablate the undesirable areas without damaging the surrounding healthy tissue. At our institution, ablation is mostly used for parenchymalsparing procedures during a concurrent major hepatectomy or when comorbid conditions preclude major liver surgery. The treatments currently available, such as low-temperature cryosurgery, nonselective chemical ablation, focused ultrasound, radiofrequency ablation (RFA), microwave ablation (MWA), or electroporation, have their own specific advantages, disadvantages, and applications. At our institution, the ACP may care for patients undergoing an ablative procedure during open or laparoscopic surgery or percutaneous ablation in the interventional suite. Experience and rapidly changing technology have overcome many of the issues that challenged the ACP in the early years of RFA or cryotherapy and replaced them with newer concerns. RFA is by far the most frequently used procedure; however, for technical reasons, MWA and irreversible electroporation (IRE) are becoming common. MWA is faster and can be used for larger tumors, creating greater cell lysis.193 IRE requires the use of an electrocardiogram synchronizer to protect the patient from arrhythmias and dense muscle relaxation to prevent upper muscle body contraction.194 Despite synchronization, intraoperative cardiac events (hypertension; arrhythmias) as well as an increase in potassium levels are common during IRE but rarely impair completion of the procedure.167 References are available at expertconsult.com.

380.e1

REFERENCES 1. Mullen JT, Ribero S, Reddy SK, et al. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg. 2006;204(6):854–862. 2. Cescon M, Vetrone G, Grazi GL, et al. Trends in perioperative outcome after hepatic resection: analysis of 1500 consecutive unselected cases over 20 years. Ann Surg. 2009;249(6):995–1002. 3. Agrawal S, Belghiti J. Oncologic resection for malignant tumors of the liver. Ann Surg. 2011;253(4):656–665. 4. Kingham TP, Correa C, D’Angelica M. Hepatic parenchymal preservation surgery: decreasing morbidity and mortality rates in 4,152 resections for malignancy. J Am Coll Surg. 2015;220(4):471–479. 5. Cameron J, Riall T, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg. 2006;244:10–15. 6. Hill JS, Zhou Z, Simons JP, et al. A simple risk score to predict inhospital mortality after pancreatic resection for cancer. Ann Surg Oncol. 2010;17:1802–1807. 7. Vollmer C, Sanchez N, Gondek S, et al. A root-cause analysis of mortality following major pancreatectomy. J Gastrointest Surg. 2012;16(1):89–102. 8. Ho C, Kleef J, Friess H, Buchler MW. Complications of pancreatic surgery. HPB. 2005;7:99–108. 9. Aloia TA, Fahy BN, Fischer CP, et al. Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database. HPB (Oxford). 2009;11(6):510–515. 10. Kamiyama T, Nakanishi K, Yokoo H, et al. Perioperative management of hepatic resection toward zero mortality and morbidity: analysis of 793 consecutive cases in a single institution. J Am Coll Surg. 2010;211(4):443–449. 11. Kneuertz PJ, Pitt HA, Bilimoria KY, et al. Risk of morbidity and mortality following hepato-pancreato-biliary surgery. J Gastrointest Surg. 2012;16(9):1727–1735. 12. McMillan M, Sprys M, Malleo G, et al. Defining the practice of pancreatoduodenectomy around the world. HPB. 2015;17(12): 1145–1154. 13. Moonesinghe RM, Mythen MG, Das P, et al. Risk stratification tools for predicting morbidity and mortality in adult patients undergoing major surgery: qualitative systematic review. Anesthesiology. 2013;119(4):959–981. 14. Jones DR, Copeland GP, de Crossart. Comparison of POSSUM with APACHE II for prediction of outcome from a surgical high dependency unit. Br J Surg. 1992;79(12):1293–1296. 15. Saklad M. Grading of patients for surgical procedures. Anesthesiology. 1941;2:281–284. 16. Adams ST, Leveson SH. Methods of clinical prediction rules. BMJ. 2012;344(1):d8312. 17. Cuthbertson BH, Amiri AR, Croal BL, et al. Utility of B-type natriuretic peptide in predicting perioperative cardiac events in patients undergoing non-cardiac surgery. Br J Anaesth. 2007;99(2):170–176. 18. Jhanji S, Thomas B, Ely A, et al. Mortality and utilisation of critical care resources amongst high risk surgical patients in a large NHS trust. Anaesthesia. 2008;63(7):695–700. 19. Grocott MP, Pearse RM. Perioperative medicine: the future of anaesthesia? Br J Anaesth. 2012;108(5):723–726. 20. Khuri SF, Henderson WG, DePalma RG, et al. Determinant of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg. 2005;242(3):326–341. 21. Bottger T, Junginger T. Factors influencing morbidity and mortality after pancreaticoduodenectomy: critical analysis of 221 resections. World J Surg. 1999;231:164–172. 22. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-term survival after hepatic resection for metastatic colorectal cancer. Ann Surg. 2008;247(6):994–1002. 23. Aloia TA, Zimmitti G, Conrad C, et al. Return to intended oncologic treatment (RIOT): a novel metric for evaluating the quality of oncosurgical therapy for malignancy. J Surg Oncol. 2014;110(2): 107–114. 24. Correa-Gallego C, Gonen M, Fischer M, et al. Perioperative complications influence recurrence and survival after resection of hepatic colorectal metastases. Ann Surg Oncol. 2013;20(8)2477–2484. 25. Kheterpal S. Random clinical decisions: identifying variation in perioperative care. Anesthesiology. 2012;116(1):3–5. 26. Aw W, Fukuda S. Understanding the role of the gut ecosystem in diabetes mellitus. J Diabetes Investig. 2018;9(1):5–12.

27. Neuman MD, Bosk CL, Fleischer LA. Learning from mistakes in clinical practice guidelines: the case of perioperative b blockade. BMJ Qual Saf. 2014;23(11):957–964. 28. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc. 2013;88(8):790–798. 29. Fong Y, Gonen M, Rubin D, et al. Long-term survival is superior after resection for cancer in high volume centers. Ann Surg. 2005;242:540–544, discussion 544–547. 30. Nathan H, Cameron JL, Choti MA, et al. The volume-outcomes effect in hepato-pancreato-biliary surgery: hospital versus surgeon contributions and specialty relationship. J Am Coll Surg. 2009;208(4):528–538. 31. Lee TH. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100(10):1043–1049. 32. Ford MK, Beattie WS, Wijeysundera DN. Systematic review: prediction of perioperative cardiac complications and mortality by the revised cardiac risk index. Ann Intern Med. 2010;152(1):26–35. 33. Hwang JW, Kim EK, Yang JH, et al. Assessment of perioperative cardiac risk of patients undergoing noncardiac surgery using coronary computed tomographic angiography. Circ Cardiovasc Imaging. 2015;8(3):e002582. 34. Fleischer LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the ACC/AHA Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(22):e77–e137. 35. Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgeryexecutive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg. 2002;94(5):1052–1064. 36. Girish M, Trayner E, Damann O, et al. Symptom-limited stair climbing as a predictor of postoperative cardiopulmonary complications after high-risk surgery. Chest. 2001;120(4):1147–1151. 37. Wijeysundera DN, Pearse RM, Shulman MA, et al. Assessment of functional capacity before major non cardiac surgery: an international prospective cohort study. Lancet. 2018;391:2631. 38. Neuman MD, Goldstein JN, Cirullo MA, et al. Durability of class 1 American College of Cardiology/American Heart Association clinical practice guideline recommendations. JAMA. 2014;311(20): 2092–2100. 39. Levett DZ, Grocott MP. Cardiopulmonary exercise testing for risk prediction in major abdominal surgery. Anesthesiol Clin. 2015;33: 1–16. 40. Goldman L. Assessing and reducing cardiac risks of noncardiac surgery. Am J Med. 2001;110(4):320–323. 41. Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after noncardiac surgery. N Engl J Med. 2005;353(4):349–361. 42. Devereaux PJ, Yang H, Guyatt GH, et al. Rationale, design, and organization of the perioperative ischemic evaluation (POISE) trial; a randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery. Am Heart J. 2006;152(2):223–230. 43. Devereaux PJ, Mrkolrda M, Sessler DI. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370(16):1494–1503. 44. Hawn MT, Graham LA, Richman JR, et al. The incidence and timing of noncardiac surgery after cardiac stent implantation. J Am Coll Surg. 2012;214(4):658–666. 45. Levine GN, Bates ER, Bittl JA, et al. ACC/AHA guideline focused duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2016;68(10):1082–1115. 46. De La Fuente SG, Bennett KM, Scarborough JE. Functional status determines postoperative outcomes in elderly patients undergoing liver resections. J Surg Oncol. 2013;107(8):865–870. 47. La Torre M, Ziparo V, Nigri G, et al. Malnutrition and pancreatic surgery: prevalence and outcomes. J Surg Oncol. 2013;107: 702–708. 48. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3) M146–M156.

380.e2 49. Shahrokni A, Tin A, Downey R, et al. Electronic rapid fitness assessment: a novel tool for preoperative evaluation of the geriatric oncology patient. J Natl Compr Canc Netw. 2017;15(2):172–179. 50. Korc-Grodzicki B, Sun SW, Zhon Q, et al. Geriatric assessment as a predictor of delirium and other outcomes in elderly patients with cancer. Ann Surg. 2015;261(6):1085–1090. 51. Hshich TT, Yue J, Oh F, et al. Effectiveness of multicomponent, nonpharmacological delirium interventions: a meta-analysis. JAMA Intern Med. 2015;175:512. 52. Geng J, Qian J, Cheng H, et al. The influence of preoperative dexmedetomidine on patients undergoing cardiac surgery: a metaanalysis. PLoS One. 2016;11(4):e0152829. 53. Khan BA, Gutteridge D, Campbell NL, et al. Update on pharmacotherapy for prevention and treatment of post-operative delirium: a systematic evidence review. Curr Anesthesiol Rep. 2015;5(1):57–64. 54. Canet J, Gallart L, Gomar C, Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6):1338–1350. 55. Warner DO. Preventing postoperative pulmonary complications: the role of the anesthesiologist. Anesthesiology. 2000;92(5):1467–1472. 56. McAlister FA, Khan NA, Straus SE, et al. Accuracy of preoperative assessment in predicting pulmonary risk after nonthoracic surgery. Am J Respir Crit Care Med. 2003;167(5):741–744. 57. Snowden CP, Prentis JM, Anderson HL, et al. Submaximal cardiopulmonary exercise testing predicts complications and hospital length of stay in patients undergoing major elective surgery. Ann Surg. 2010;251(3):535–541. 58. Declan FJ, Dunne RP, Jones RP, et al. Cardiopulmonary exercise testing before liver surgery. J Surg Oncol. 2014;110(6):439–444. 59. Smetana GW, Lawrence VA, Cornell JE, American College of Physicians: preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med. 2006;144(8):581–595. 60. Glance LG, Wissler R, Mukanmel DB, et al. Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing noncardiac surgery. Anesthesiology. 2010;113(4): 859–872. 61. Neligan PJ, Fleischer LA. Obesity and diabetes: evidence of increased perioperative risk? Anesthesiology. 2006;104(3):398–400. 62. Dindo D, Muller MK, Weber M, Clavien PA. Obesity in general elective surgery. Lancet. 2003;361(9374):2032–2035. 63. Gross JB, Bachenberg KL, Benumoff JK, et al. Practice guidelines for the perioperative management of patients with sleep apnea: a report by the ASA Task Force on perioperative management of patients with sleep apnea. Anesthesiology. 2006;104(5):1081–1093. 64. Chung F, Subramanyam R, Liao P, et al. High STOP-Bang score indicates a high probability of obstructive sleep apnoea. Br J Anaesth. 2012;108(5):768–775. 65. Gupta RM, Parvizi J, Hanssen AD, Gay PC. Postoperative complications in patients with obstructive sleep apnea syndrome undergoing hip or knee replacement. Mayo Clin Proc. 2001;76(9):897–905. 66. Loadsman JA, Hillman DR. Anesthesia and sleep apnea. Br J Anaesth. 2001;86(2):254–266. 67. Gould MK, Cooke CR. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice guidelines. Chest. 2012;141(suppl 2):e227S–e277S. 68. Agnelli G, Bolis G, Capussotti L, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the89–95. 69. Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer incidence and effect on survival. J Clin Oncol. 2006;24(7):1112–1118. 70. Catheline JM, Capelluto E, Gaillard JL, et al. Thromboembolism prophylaxis and incidence of thromboembolic complications after laparoscopic surgery. Int J Surg Investig. 2000;2(1):41–47. 71. Tzeng CW, Katz MH, Fleming JB, et al. Risk of venous thromboembolism outweighs post-hepatectomy bleeding complications analysis of 5651 National Surgical Quality Improvement program patients. Ann Surg Oncol. 2012;20(2):482–490. 72. Nathan H, Weiss MJ, Soff GA, et al. Pharmacologic prophylaxis, postoperative INR, and risk of venous thromboembolism after hepatectomy. J Gastrointest Surg. 2013;218(2):295–302. 73. Barton JS, Riha GM, Differding JA, et al. Coagulopathy after a liver resection: is it over diagnosed and over treated? HPB (Oxford). 2013;15(11):865–871.

74. Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655–663. 75. Caprini JA, Aecelus JI, Hasty JH, et al. Clinical assessment of venous thromboembolic risk in surgical patients. Semin Thromb Hemost. 1991;17(suppl 3):304–312. 76. Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975–980. 77. Suman A, Carey WD. Assessing the risk of surgery in patients with liver disease. Cleve Clin J Med. 2006;73:398–404. 78. Melendez J, Arslan V, Fischer M, et al. Perioperative outcome of major hepatic resections under low central venous pressure anesthesia—blood loss, blood transfusion and the risk of post-operative renal dysfunction. J Am Coll Surg. 1998;178:620–625. 79. Chang PH, Steinberg MB. Alcohol withdrawal. Med Clin North Am. 2001;85(5):1191–1212. 80. Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med. 2014;371(22):2109–2113. 81. Rubinsky AD, Bishop MJ, Maynard C, et al. Postoperative risks associated with alcohol screening depend on documented drinking at the time of surgery. Drug Alcohol Depend. 2013;132(3): 21–27. 82. Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet. 2013;381(9880):1855–1865. 83. Brecker ME, Goodnough LT. The rise and fall of preoperative autologous blood transfusion. Transfusion. 2001;41:1459–1462. 84. Armas-Loughran B, Kalra R, Carson JL. Evaluation and management of anemia and bleeding disorders in surgical patients. Med Clin North Am. 2003;87:229–242. 85. Goldman M, Savard R, Long A, et al. Declining value of preoperative autologous donation. Transfusion. 2002;42:819–823. 86. Jabbour N, Gangandeep S, Mateo R, Transfusion free surgery: single institution experience of 27 consecutive liver transplants in Jehovah’s Witnesses. J Am Coll Surg. 2005;201(3):412–417. 87. Jarnagin WR, Gonen M, Maithel SK, et al. A prospective randomized trial of acute normovolemic hemodilution compared to standard intraoperative management in patients undergoing major hepatic resection. Ann Surg. 2008;248(3):360–369. 88. Matot I, Scheinin O, Jurim O, Eid A. Effectiveness of acute normovolemic hemodilution to minimize allogeneic blood transfusion in major liver resections. Anesthesiology. 2002;97:794–800. 89. Sima CS, Jarnagin WR, Fong Y, et al. Predicting risk of perioperative transfusion for patients undergoing elective hepatectomy. Ann Surg. 2009;250(6):914–921. 90. Frankel TL, Fischer M, Grant F, et al. Selecting patients for acute normovolemic hemodilution during hepatic resection: a prospective randomized evaluation of nomogram-based allocation. J Am Coll Surg. 2013;217(2):210–220. 91. Fischer M, Matsuo K, Gonen M, et al. A prospective randomized trial of acute normovolemic hemodilution compared to standard intraoperative management in patients undergoing pancreaticoduodenectomy. Ann Surg. 2010;(6):952–958. 92. Miller TE, Roche AM, Mythen M, et al. Fluid management and goal directed therapy as an adjunct to enhanced recovery after surgery (ERAS). Can J Anaesth. 2015;62(2):158–168. 93. Lamke LO, Nillson GE, Reither HL. Water loss by evaporation form the abdominalcavity during surgery. Acta Chir Scand. 1977;143(5):279–284. 94. Jacob M, Chappell D, Rehm M. The third space—fact or fiction? Best Pract Res Clin Anaesthesiol. 2009;23(2):145–157. 95. Grocott MP, Mythe MG, Gan TJ. Perioperative fluid management and clinical outcomes in adults. Anesth Analg. 2005;100(4): 1093–1106. 96. Cannesson M. Arterial pressure variability and goal directed therapy. J Cardiothorac Vasc Anesth. 2010;24(3):487–497. 97. Auler JO, Galas FR, Sundin MR, et al. Online monitoring of PPV to guide fluid therapy after cardiac surgery. Anesth Analg. 2008;106(4): 1201–1206. 98. Pearse RM, Harrison DA, MacDonald N, et al. Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA. 2014;311(21): 2181–2190. 99. Chappell D, Brettner F, Doerfler N, et al. Protection of glycolyx decrease platelet adhesion after ischaemia/reperfusion: an animal study. Eur J Anaesthesiol. 2014;9:474–481.

380.e3 100. Navarro LH, Bloomstone JA, Auler JO, et al. Perioperative fluid therpy: a statement from the international fluid optimization group. Periop Med. 2015;4:3. 101. Mythen MG. Postoperative gastrointestinal tract dysfunction. Anesth Analg. 2005;100(1):196–204. 102. Hamilton-Davies C, Mythen MG, Salmon J. Comparison of commonly used clinical indicators of hypovolaemia with gastrointestinal tonometry. Intensive Care Med. 1997;23(3):276–281. 103. Takala J. Determinants of splanchnic blood flow. Br J Anaesth. 1996;77(1):50–58. 104. Kusano C, Baba M, Takao S, et al. Oxygen delivery as a factor in the development of fatal postoperative complications after oesophagectomy. Br J Surg. 1997;84(2):252–257. 105. Testini M, Scacco S, Loiotila L, et al. Comparison of oxidative phosphorylation in the anastomosis of the small and large bowel. An experimental study in the rabbit. Euro Surg Res. 1998;30(1):1–7. 106. Becker Bf, Chappell D, Jacob M. Endothelial glycocalyx and coronary vascular permeability: the fringe benefit. Basic Res Cardiol. 2010;105(6):687–701. 107. Marjanovic G, Villain C, Juettner E, et al. Impact of different crystalloid volume regimes on intestinal anastomotic stability. Ann Surg. 2009;249(2):181–185. 108. Melis M, Marcon F, Masi A, et al. Effect of intraoperative fluid volume on perioperative outcomes after pancreaticoduodenectomy for pancreatic carcinoma. J Surg Oncol. 2012;105:81–84. 109. Eng O, Goswami J, Moore D, et al. Intraoperative fluid administration is associated with perioperative outcomes in pancreaticoduodenectomy: a single center retrospective analysis. J Surg Oncol. 2013;108:242–247. 110. Grant F, Protic M, Gonen M, et al. Intraoperative fluid management and complications following pancreatectomy. J Surg Oncol. 2013;107:529–535. 111. Wright G, Koehler A, Davis A, Chung MH. The drowning Whipple: perioperative fluid balance and outcomes following pancreaticoduodenectomy. J Surg Oncol. 2014;110:407–411. 112. Kulemann B, Fritz M, Glatz T, et al. Complications after pancreaticoduodenectomy are associated with higher amount of intraand postoperative fluid therapy: a single center retrospective cohort study. Ann Med Surg. 2017;16:23–29. 113. Behman R, Sherif H, Coburn N, et al. Impact of fluid resuscitation on major adverse events following pancreaticoduodenectomy. 2015;210(5):896–903. 114. Grant F, Brennan M, Allen P, et al. Prospective randomized controlled trial of liberal vs restricted perioperative fluid management in patients undergoing pancreatectomy. Ann Surg. 2016;264(4):591–598. 115. Giglio MT, Marucci M, Testini M, Brienza N. Goal-directed haemodynamic therapy and gastrointestinal complications in major surgery: a meta -analysis of randomized trials. Br J Anaeth. 2009;103(5):637–646. 116. Cunningham JD, Fong Y, Melendez J, et al. One hundred consecutive hepatic resections: blood loss, transfusion, and operative technique. Arch Surg. 1994;129:1050–1056. 117. Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: evolution of technique toward bloodless surgery. Br J Surg. 1996;83:1526–1529. 118. Correa-Gallego C, Berman A, Denis SC, Renal function after low central venous pressure-assisted liver resection: assessment of 2116 cases. HPB. 2015;17(3):258–264. 119. Dunki-Jacobs EM, Phillips P, Scoggins CR, et al. Stroke volume variation in hepatic resection: a replacement for standard central venous pressure monitoring. Ann Surg Oncol. 2013;21(3): 473–478. 120. Jones C, Kelliher L, Dickinson M, et al. Randomized clinical trial on enhanced recovery versus standard care following open liver resection. Br J Surg. 2013;100(8):1015–1024. 121. Zatloukal J, Pradl R, Kletecka J, et al. Comparison of absolute fluid restriction versus relative volume redistribution strategy in low central venous anesthesia in liver resection surgery: a randomized controlled trial. Minerva Anestesiol. 2017;83(10): 1051–1060. 122. Mise Y, Sakamoto Y, Ishizawa T, et al. A Worldwide survey of the current daily practice in liver surgery. Liver Cancer. 2013;2:55–66. 123. O’Connor DC, Seier K, Gonen M, et al. Invasive central venous monitoring during hepatic resection: unnecessary for most patients. HPB (Oxford). 2020;22:1732.

124. Schwinn DA, McIntyre RW, Reves JG. Isoflurane-induced vasodilation: role of the adrenergic nervous system. Anesth Analg. 1990;71:451–459. 125. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(suppl 2):S133–S153. 126. Hughes MJ, McNally S, Wigmore SJ. Enhanced recovery following liver surgery: a systematic surgery: a systematic review and meta-analysis. HPB (Oxford). 2014;16(8):699–706. 127. Nisanevich V, Felsenstein I, Almogy G, et al. Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology. 2005;103(1):25–32. 128. Sear JW. Kidney dysfunction in the postoperative period. Br J Anaesth. 2005;95(1):20–32. 129. Kheterpal S, Tremper KK, Englesbe MJ, et al. Predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function. Anesthesiology. 2007;107(6): 892–902. 130. Kim M, Henderson WG, DePalma RG, et al. Variations in acute renal failure in abdominal cases. Anesth Analg. 2014;119(5): 1121–1132. 131. Correa-Gallego C, Tan KS, Arslan-carlon V, et al. Goal-directed fluid therapy using stroke volume variation for resuscitation after low central venous pressure-assisted liver resection: a randomized clinical trial. J Am Coll Surg. 2015;221(2):591–601. 132. Virani S, Michaelson J, Hutter M, et al. Morbidity and mortality after liver resection: results of the patient safety in surgery study. J Am Coll Surg. 2007;204(6):1284–1292. 133. Bihorac A, Brennan M, Ozrazgat-Badenti T, et al. National surgical Quality improvement program underestimates the risk associated with mild and moderate postoperative acute kidney injury. Crit Care Med. 2013;41(11):2570–2583. 134. Kambakamba P, Slankamenac K, Tschuor C, et al. Epidural analgesia and perioperative kidney function after major liver resection. Br J Surg. 2015;102:805–812. 135. Matot I, Scheinin O, Eid A, Jurim O. Epidural anesthesia and analgesia in liver resection. Anesth Analg. 95(5):1179–1181. 136. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371(15):1381–1391. 137. Wehry J, Cannon R, Scoggins CR, et al. Restrictive blood transfusion protocol in liver resection patients reduces blood transfusions with no increase in patient morbidity. Am J Surg. 2015;209(2): 280–288. 138. Cannon RM, Brown RE, St Hill CR, et al. Negative effects of transfused blood components after hepatectomy for metastatic colorectal cancer. Am Surg. 2013;79(1):35–39. 139. Kooby DA, DA, Stockman J, Ben-Porat L, et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg. 2003;237(6):860–889. 140. Vamvakas EC. Allogeneic blood transfusion and cancer recurrence: 20 years later. Transfusion. 2014;54(9):2149–2153. 141. Vamvakas EC. Possible mechanisms of allogeneic blood transfusion associated postoperative infection. Transfus Med Rev. 2002;4:16(2):144–160. 142. Atzil S, Arad M, Glasner A, et al. Blood transfusion promotes cancer progression: a critical role for aged erythrocytes. Anesthesiology. 2008;109(6):989–997. 143. Khan H, Pillarisetty V, Katz SC. The prognostic value of liver tumor T cell infiltrates. J Surg Res. 2014;191(1):189–195. 144. Katz SC, Shia J, Liau KH, et al. Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma. Ann Surg. 2009;249(4): 617–623. 145. Lautt WW. Regulatory processes to maintain hepatic blood flow constancy: vascular compliance, hepatic arterial buffer response, hepatorenal reflex liver regeneration, escape from vasoconstriction. Hepatol Res. 2007;37(11):891–903. 146. Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology. 2008;108(4):735–774. 147. Birch DJ, Turmaine M, Boules PB, Burnstock G. Sympathetic innervation of human mesenteric artery and vein. J Vasc Res. 2008;45(4):323–332. 148. Berendes E, Lippert G, Loick HM, Brussel T. Effects of enflurane and isoflurane on splanchnic oxygenation in humans. J Clin Anesth. 1996;8:456–468.

380.e4 149. O’Riordan J, O’Beirne HA, Young Y, Bellamy MC. Effects of desflurane and isoflurane on splanchnic microcirculation during major surgery. Br J Anaesth. 1997;78:95–96. 150. Ebert TJ, Harkin CP, Muzi M. Cardiovascular responses to sevoflurane: a review. Anesth Analg. 1995;81(suppl 6):S11–S22. 151. Lampe GH, Wauk LZ, Whitendale P, et al. Nitrous oxide does not impair hepatic function in young or old surgical patients. Anesth Analg. 1990;71:606–609. 152. De Kock M, Lavand’homme P, Waterloos H. “Balanced analgesia” in the perioperative period: Is there a place for ketamine? Pain. 2001;92(3):373–380. 153. Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia. Br J Anaesth. 2009;102(1):117–122. 154. Mungroop T, Veelo D, Besselink M, et al. Continuous wound infiltration versus epidural analgesia after hepato-pancreato–biliary surgery (POP-UP): a randomized controlled, open label, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:105–113. 155. Karanicolas P, Cleary S, McHardy P, et al. Medial open transversus abdominis plane (MOTAP) catheters reduce opioid requirements and improve pain control following open liver resection. Ann Surg. 2018;268:233–240. 156. Kasivisvanathan R, Abbassi-Ghadi N, Mallett S, et al. A prospective cohort study of intrathecal versus epidural analgesia for patients undergoing hepatic resection. HPB (Oxford). 2014;16(8): 768–775. 157. Truong JL, Cyr DP, Lam-McCullough J, et al. Consensus and controversy in hepatic surgery: a survey of Canadian surgeons. J Surg Oncol. 2014;110:947–951. 158. Popping DM, Elia N, Marret E, et al. Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: a meta-analysis. Arch Surg. 2008;143(10):990–999. 159. Joshi GP, Bonnett F, Shah R, et al. A systematic review of randomized trials evaluating regional techniques for postthoracotomy analgesia. Anesth Analg. 2008;107(3):1026–1040. 160. Page A, Rostad B, Staley CA, et al. Epidural analgesia in hepatic resection. J Am Coll Surg. 2008;206(3):1184–1192. 161. Feltracco P, Brezzi ML, Barbieri S, et al. Epidural anesthesia and analgesia in liver resection and living donor hepatectomy. Transplant Proc. 2008;40(4):1165–1168. 162. Siniscalchi A, Gamberini L, Laici C, et al. Thoracic epidural anesthesia: effects on splanchnic circulation and implications in anesthesia and intensive care. World J Crit Care Med. 2015;4(1): 89–104. 163. Cata P, Bauer M, Sokari T, et al. Effects of surgery, general anesthesia, perioperative epidural analgesia on the immune function of patients with non -small cell lung cancer. J Clin Anesth. 2013;25(6):255–262. 164. Chloropoulou P, Iatrou C, Vagiatzake T, et al. Epidural anesthesia followed by epidural analgesia produces less inflammatory response than spinal anesthesia followed by intravenous morphine analgesia in patients with total knee arthroplasty. Med Sci Monit. 2013;19(1):73–80. 165. Apfelbaum JK, Ashburn MA, Connis RT, et al. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248–273. 166. Melloul E, Hubner M, Scott M, et al. Guidelines for perioperative care for liver surgery: Enhanced recovery after surgery (ERAS) society recommendations. World J Surg. 2016;40(10):2425–2440. 167. Kambakamba P, Bonvini J, Glenck M, et al. Intraoperative adverse events during irreversible electroporation—a call fraction. Am J Surg. 2016;212:715–721. 168. Brennan TJ. Incisional sensitivity and pain measurements: dissecting mechanisms for postoperative pain after surgery. Anesthesiology. 2005;103(1):3–4. 169. White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology. 2010;112(1): 220–225. 170. Landesberg G, Beattie WS, Mosseri M, et al. Perioperative myocardial infarction. Circulation. 2009;119(22):2936–2944. 171. Gazoni FM, Amato PE, Malik ZM, Durieux ME. The impact of perioperative catastrophes on an anesthesiologist: results of a national survey. Anesth Analg. 2012;114(3):596–603.

172. Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014;120(3):564–578. 173. Putensen C, Theuerkauf N, Zinserling J, et al. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009;151(8):566–576. 174. Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308:1651–1659. 175. Edmark L, Kostova-Aherdan K, Enlund M, Hedenstierna G. Optimal oxygen concentration during induction of general anesthesia. Anesthesiology. 2003;98:28–33. 176. Duggan M, Kavanagh BP. Pulmonary atelectasis: a pathogenic perioperative entity. Anesthesiology. 2005;102(4):838–854. 177. Milic-Emili J, Torchio R, D’Angelo E. Closing volume: a reappraisal (1967–2007). Eur J Appl Physiol. 2007;99(6):567–583. 178. Van Kaam AH, Lachmann RA, Herting E, et al. Reducing atelectasis attenuates bacterial growth and translocation in experimental pneumonia. Am J Respir Crit Care Med. 2004;169(9): 1046–1053. 179. Fernandez-Perez E, Sprung J, Afessa B, et al. Intraoperative ventilation for settings and acute lung injury after elective surgery: a nested case control study. Thorax. 2009;64(2):121–127. 180. Futier E, Constantin JM, Paugam-Brutz C, et al. A trial of intraoperative low tidal volume ventilation in abdominal surgery. N Engl J Med. 2013;369(5):428–437. 181. Levin MA, McCormick PJ, Lin HM, et al. Low intraoperative tidal volume ventilation with minimal PEEP is associated with increased mortality. Br J Anaesth. 2014;113(1):97–108. 182. Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology. 2013;118:1307–1321. 183. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e6329. 184. Brueckmann B, Villa-Uribe JL, Bateman BT, et al. Development and validation of a score for prediction of postoperative respiratory complications. Anesthesiology. 2013;118(6):1276–1285. 185. Ferreyra GP, Bausanno I, Squandrone V, et al. Continuous positive airway pressure for treatment of respiratory complications after abdominal surgery: a systematic review and meta-analysis. Ann Surg. 2008;247(4):617–626. 186. Powers SK, Decramer M, Gayan-Ramirez G, et al. Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm. Crit Care. 2008;12(6):191. 187. Berendes E, Lippert G, Loick HM, Brussel T. Effects of positive end-expiratory pressure ventilation on splanchnic oxygenation in humans. J Cardiothorac Vasc Anesth. 1996;10:598–602. 188. Eleftheriadis E. Splanchnic ischemia during laparoscopic cholecystectomy. Surg Endosc. 1996;10:324–326. 189. Min SK, Kim JH, Lee SY. Carbon dioxide and argon gas embolism during laparoscopic hepatic resection. Acta Anaesthesiol Scand. 2007;51(7):949–953. 190. Eriksson K, Fors D, Rubertson S, Arvidsson D. High intra-abdominal pressure during experimental laparoscopic liver resection reduces bleeding but increases the risk of gas embolism. Br J Surg. 2011;98(6):845–852. 191. Fors D, Eiriksson K, Arvidsson D, Rubertsson S. Elevated PEEP without effect upon gas embolism frequency or severity in experimental laparoscopic liver resection. Br J Anaesth. 2012;109(2): 272–278. 192. Vibert E, Perniceni T, Levard H, et al. Laparoscopic liver resection. Br J Surg. 2006;93(1):67–72. 193. Groeschl RT, Pilgrim CH, Hanna EM, et al. Microwave ablation for hepatic malignancies: a multiinstitutional analysis. Ann Surg. 2014;259:1195–1200. 194. Ball C, Thomson K, Kavnoudias H. Irreversible electroporation: a new challenge in out of operating theater anesthesia. Anesth Analg. 2010;110(5):1305–1309.

CHAPTER 26 Nutrition and perioperative critical care in the hepatopancreatobiliary surgery patient Russell C. Kirks Jr, R. Eliot Fagley, and Flavio G. Rocha Assessment of patient nutritional status and functional reserve allows surgeons to identify malnourishment and potential recovery before major abdominal surgery. Evolving nutritional and fluid management strategies, along with improving anesthesia, pain management, and hemodynamic monitoring, seek to minimize homeostatic alterations. Although specific surgical procedures, modalities, and disease states may each present specific challenges to perioperative management, these two efforts are now being understood to play a synergistic and cooperative role in patients’ physiology and recovery.

NUTRITIONAL AND FUNCTIONAL ASSESSMENT Gauging nutritional and functional status along with medical comorbidity portends a patient’s functional reserve. The ideal preoperative assessment should quantify the severity of malnutrition and depletion of lean body mass, estimate a patient’s physiologic reserve, and juxtapose these with the magnitude of metabolic stress induced by a surgical intervention.1 The idea that aspects of a patient’s nutritional status and functional reserve can be improved before a scheduled procedure is known as prehabilitation. A thorough nutritional assessment (NA) should include: (1) a clinical gastrointestinal (GI) and dietary history; (2) a physical and/or radiographic assessment of muscle mass; (3) a strength and functional assessment; (4) an evaluation of serum nutritional markers; and (4) a determination of nutrient requirements. Historical questions should identify the degree and rate of weight loss over the previous month and 6 months, use of alcohol, duration of jaundice, and altered stool pattern. Clinical or radiographic evidence of gastric emptying abnormality, severe gastroesophageal reflux disease, or intestinal obstruction may alter the method by which nutritional supplementation is delivered. Anthropometric tests incorporated into NA have the benefits of objectivity, rapidity, and reproducibility. A variety of anthropometric measurements, such as hand grip strength, may be used not only as a surrogate of muscle wasting but also to assess protein-energy malnutrition.2 Used in combination with assessment of objective clinical and laboratory parameters and patient-reported assessment of eating and nutrient intake, these assessments can be used to provide a more complete clinical picture of nutrition and as part of an estimation of immediate postoperative complications.3-5

SERUM BIOCHEMICAL MARKERS Although no single laboratory value is by itself indicative of nutritional sufficiency, many have the benefit of being easily obtainable through simple blood tests. Serum albumin has been extensively studied as a marker for nutritional status, and

low levels have been shown to be a sensitive predictor of adverse surgical outcomes.6–9 In the setting of liver disease, serum albumin may be more difficult to interpret as a nutritional marker because of its correlation with intrinsic liver function.10 Serum albumin should not be used as a sole prognosticator of nutritional status given its relationship as an acute phase reactant. Unlike albumin, prealbumin is thought to be a better indicator of nutritional status given its half-life of 48 hours. As such, short-term fluctuations in nutritional standing can be more accurately assessed using serum prealbumin.11 Unfortunately, like albumin, prealbumin levels can vary with chronic disease states. Given the limitations of anthropometric and biochemical assays, more accurate methods of NA have incorporated key features of both to create predictive nutritional scoring systems. A number of different schemas exist, including the Nutritional Risk Index (NRI), Nutritional Risk Score (NRS), Subjective Global Assessment (SGA), and Malnutrition Universal Screening Tool (MUST).

Sarcopenia Body mass index (BMI) is widely used in patient risk models but fails to account for the diversity of body composition. A relative dearth of lean muscle mass, called sarcopenia, is associated with functional impairments, physical disability, perioperative complications, prolonged hospital length of stay, and poorer long-term outcomes in cancer patients.12–16 Unlike cachexia, sarcopenia develops over a long period of time and is not necessarily associated with weight loss.17 Thus many patients who fall into a normal range for weight and BMI may have unrecognized sarcopenia. Patients who are both obese by BMI calculation and sarcopenic are categorized as having “sarcopenic obesity.” Sarcopenic obesity has been reported as one of the most powerful independent predictors of poor survival for patients with cancer and is associated with impaired functional status and decreased ability to tolerate chemotherapy, surgery, and other invasive therapies.18,19 The most clinically applicable method used to identify sarcopenia uses computed tomography (CT) imaging to estimate lean muscle mass of the psoas muscle of a single CT image at the L3 level normalized for height (total psoas area in mm2/ height in m2).12,20 Patients are sarcopenic if these values are less than 385 mm2/m2 in women or less than 545 mm2/m2 in men. In retrospective studies, sarcopenic patients who underwent liver transplantation, liver resection, and pancreatic resection had increased perioperative complications, increased postoperative mortality, and worse overall and recurrence-free survival.14,15,21–25 The pathophysiology of sarcopenia is not well understood but poor nutrition, alterations in hormonal and other signaling pathways, and inflammatory factors and cytokines are thought to be 381

382

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

TABLE 26.1  Comparison of Comorbidity Factors Assessed in Modified Frailty Indices MODIFIED 11-ITEM FRAILTY INDEX (mFI-11)

MODIFIED 5-ITEM FRAILTY INDEX (mFI-5)

History of diabetes mellitus History of congestive heart failure History of either COPD or pneumonia Functional status 2 (not independent) Hypertension requiring medication History of either transient ischemia attach or cerebrovascular accident History of myocardial infarction History of either peripheral vascular disease or rest pain History of cerebrovascular accident with neurologic deficit History of either PCI, PCS, or angina History of impaired sensorium

Diabetes mellitus (insulin- or noninsulin-dependent) Congestive heart failure (within 30 days of surgery) COPD or pneumonia Dependent functional health status (total or partial) at time of surgery Hypertension requiring medication

Scores calculated by assigning a 1 (for presence of comorbidity) or 0 (for absence of comorbidity). Higher scores suggest higher frailty and less physiologic reserve. COPD, Chronic obstructive pulmonary disease; PCI, percutaneous coronary intervention; PCS, prior cardiac surgery.

the principal mechanisms behind the development of sarcopenia in the chronically ill.26,27 Investigations seeking to mitigate the effects of sarcopenia have reported that exercise combined with supplemental protein or amino acids can reverse sarcopenia in the elderly.28,29 These observations support the practice of prescribing exercise and supplemental protein to sarcopenic patients before hepatopancreatobiliary (HPB) surgery.28

Frailty Whereas sarcopenia describes a specific and quantifiable finding, frailty comprises a more global assessment of physiology and resilience. Initially considered to be synonymous with age, frailty describes a depletion of physiologic reserves culminating in both a higher degree of vulnerability to physiologic stressors and a simultaneous decrement in the ability to recover from these physiologic challenges.30 Considering the physiologic challenges of HPB diseases and major abdominal surgery, the assessment of frailty and incorporation into perioperative planning and patient selection is gaining interest. With an aging population,31 a surgeon can expect to encounter more elderly and potentially more frail patients. Frailty is a risk factor for multiple adverse outcomes such as surgical complications, mortality, and loss of functional independence.32–34 In regards to postsurgical complications, the idea of diminished physiologic resilience contributes to increases in failure-to-rescue events, suggesting that these patients are less likely to recover from postsurgical complications even if they are managed appropriately.35,36 With increased postoperative complications, length of stay, disposition care requirements, and healthcare-associated costs due to frailty, modifying frailty could potentially alter costs associated with healthcare.37–39 Assessment and quantification of frailty is based on comorbidity and functional capability. Tools such as the 11-variable modified Frailty Index (mFI) are used to identify patients at higher risk for postoperative complications, disposition to facilities rather than home, and longer lengths of stay in oncologic surgical.40–42 A 5-factor modified frailty index has also been derived from American College of Surgeons National Quality Improvement Project (ACS-NSQIP) data. Comparing the 5- and 11-factor frailty indices across surgical subspecialties supports the predictive ability of the shorter 5-factor frailty

index for the prediction of mortality, postoperative complications, and 30-day readmission in general surgery procedures. This study did not specifically parse out HPB or surgical oncology patients43 (Table 26.1). Identifying frail patients allows for their enrollment in programs designed to improve modifiable risk factors when a surgery is planned or a period of observation, such as during or following neoadjuvant therapy, is included in a treatment plan. Degree of medical optimization, nutritional goals, and exercise prescription would be tailored to a patient’s specific needs.44,45 Prehabilitation of frail patients has not been studied extensively in a HPB surgery population. Prehabilitation efforts performed in non-HPB abdominal surgery population focus on smoking cessation, improving exercise tolerance, stress elimination, and nutritional improvement.46–48

NUTRITIONAL FOCUS: LIVER AND BILIARY DISEASE Patients with liver disease, biliary obstruction, bacterial or viral infection, or malnutrition have impaired antioxidant defenses coupled with increased oxidant stresses.49 Additional factors that deplete hepatic antioxidants include smoking, alcohol ingestion, general anesthesia, and surgery.50 Chronic liver disease further alters bile salt pools and enterohepatic circulation of bile salts, leading to impaired micelle formation and consequently malabsorption of fat and fat-soluble vitamins.

Obstructive Jaundice Approximately 45% to 70% of patients with obstructive jaundice present with malnutrition because of anorexia resulting in diminished oral intake.51 The primary nutritional deficit resulting from obstructive jaundice is malabsorption of fat and fat-soluble vitamins in addition to trace minerals. Biliary sepsis in patients with obstructive jaundice contributes to malnutrition by shifting protein synthesis from anabolic protein synthesis to acute-phase protein synthesis.52 Although some authors have advocated preoperative biliary drainage (PBD) in patients undergoing HPB surgery, multicenter trials and Cochrane analysis have demonstrated no evidence to support or refute routine biliary drainage and stenting in patients with malignant HPB diseases awaiting surgery.53,54 Conversely, PBD should probably be performed in

  Chapter 26  Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient

patients undergoing extended hepatectomy to improve the health of the planned remnant. To reverse the catabolic effects of chronic endotoxemia and restore hepatic protein synthesis, patients with cholangitis should be treated with biliary decompression for at least 4 weeks before major HPB surgery (see Chapter 43). For patients with pancreatic disease presenting with recentonset obstructive jaundice, PBD may not be required in the absence of profound malnourishment or deconditioning. Although routine PBD is discouraged in such patients because of substantial increases in the incidence of postoperative infectious complications,55 patients with long-standing obstructive jaundice, cholangitis, and those who are planned to receive neoadjuvant therapy before resection benefit from biliary decompression during this period. Such patients are best managed with internal biliary drainage as part of a comprehensive nutritional repletion program. Internal drainage can be accomplished by endoscopic drainage, percutaneous biliary access with internal stenting, or rendezvous procedure (see Chapters 30 and 31). For patients managed with external biliary drainage, bile refeeding may be a consideration: prolonged external drainage and discarding of bile occurring in the setting of biliary obstruction or disconnection culminates in dehydration, metabolic acidosis, progressive loss of biliary protein, and nutrient malabsorption. Most patients can tolerate bolus infusion of bile into their small bowel of 150 mL or less every 4 hours. If a patient has percutaneous jejunal feeding access, it is preferable to provide bile refeeding in a continuous manner. An alternative to enteric bile refeeding is to provide oral bile salts (ursodeoxycholic acid, 300 mg QID) to form micelles for fat absorption.56

Hepatic Steatosis The presence, degree, and evolution of hepatic steatosis may all be considerations in the operative assessment and planning for patients undergoing hepatic resection (see Chapter 69). Classically defined by the presence of 5% or greater of triglycerides in hepatic parenchyma based on biopsy, many studies characterize the degree of steatosis based on severity.57–60 Although the most common etiology of steatosis is because of nonalcoholic fatty liver disease (NAFLD), chemotherapy-associated steatosis (CAS) describes a change in intrahepatic fat (IHF) composition over time during chemotherapy administration. The degree of steatosis and presence of inflammation may alter the detection and tracking of hepatic lesions and size of the planned remnant when hepatectomy is planned. Cytotoxic chemotherapy administered in the treatment of colorectal liver metastases (CRCLM) may also contribute to hepatic steatosis or steatohepatitis. CAS has been described as a result of many current regimens used in the treatment of colorectal cancer and CRCLM including irinotecan and fluorouracil.61–63 An additional description of etiologic factors of steatosis and chemotherapy-associated changes is provided in Chapter 69. The degree of steatosis can contribute to the development of postoperative complications. Retrospective studies have found that patients undergoing hepatic resection were at significantly higher risk for infectious, wound-related, GI, and hepatobiliary complications when the background liver was characterized by at least 30% steatosis.64–66 Severe steatosis can also increase operative time and increase transfusion requirements.65 The degree of steatosis, with potential correlation to remnant function, also correlates with increasing overall

383

postoperative morbidity,67 post-hepatectomy liver failure (PHLF),68 increased intensive care unit (ICU) stay, and increased hospital length of stay.69 Liver parenchymal modification has been described in bariatric literature via low-calorie diets (800–1000 kCal/day for 4 weeks).70,71 Further dietary studies focusing on intrahepatic fat burden demonstrate that drastic changes in intrahepatic fat can be achieved in short periods of time.72,73 Pharmacologic interventions have also been investigated as measures to decrease intrahepatic fact and mitigate the inflammatory changes of steatohepatitis,74,75 but the duration of medication use in these studies may limit their practical use in the prior liver resection.

Cirrhosis and Liver Failure Cirrhosis causes multiple hormonal and metabolic alterations, yielding loss of fat and muscle mass, glucose intolerance, insulin resistance,76 increased plasma glucagon and catecholamines,77 elevated serum free fatty acids,78 hypoproteinemia, and hyperammonemia.79 These metabolic aberrations eventually lead to increased skeletal muscle proteolysis with muscle wasting and increased peripheral lipolysis, leading to hyperglycemia and hyperlipidemia.80 Added risk factors for malnutrition include protein-restricted diets used in an effort to prevent encephalopathy. The practice of routine protein restriction should be abandoned in an already malnourished patient because it exacerbates the problems inherently associated with malnutrition (see Chapters 77 and 78).

NUTRITIONAL FOCUS: PANCREATIC DISEASE Many factors contribute to perioperative nutritional deficits and malnutrition in patients with benign or malignant pancreatic disease. Patients with abdominal pain related to pancreatic disease may have profound malnutrition because of food avoidance, dietary restriction, exocrine or endocrine insufficiency, pancreatic and/or biliary duct obstruction, and chronic malabsorption. Patients with severe acute pancreatitis and particularly those with acute superimposed on chronic pancreatitis are at risk for profound malnutrition and metabolic derangement because of the catabolic effects of critical illness and sepsis.

Pancreatic Cancer Pancreatic cancer (PC) is associated with a severe metabolic derangement referred to as “cancer anorexia-cachexia syndrome”81,82 (see Chapter 62). This syndrome is associated with anorexia, tissue wasting, malnutrition, weight loss, and a loss of compensatory increase in feeding. The pathogenesis is dependent on disorders of carbohydrate, protein, lipid, and energy metabolism mediated by proinflammatory cytokine elaboration and an overall increase in leptin.83,84 PC patients have the highest incidence of cachexia among patients with cancer; up to 80% of such patients have cachexia at the time of initial diagnosis. Increasing severity of anorexia-cachexia in PC patients interferes with therapy and correlates with short survival.19,85 For this reason, patients with PC are perhaps the most likely of all patients undergoing HPB surgery to benefit from nutritional support strategies.

Pancreatic Exocrine Insufficiency Benign and malignant conditions of the pancreas can produce biliary and/or pancreatic duct obstruction resulting in maldigestion and malabsorption. The majority of patients with PC

384

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

present with malnutrition and weight loss, with 75% found to have pancreatic exocrine insufficiency (PEI) at presentation.86 The etiology of PEI in patients with PC is incompletely understood but likely related to main pancreatic duct obstruction, glandular atrophy, age- or cancer-related pancreatic exocrine senescence, and potentially reduced exocrine function because of previous pancreatitis. Because PEI is so common in patients with pancreatic cancer, an argument can be made to provide pancreatic enzymes to all symptomatic patients at the time of diagnosis. Asymptomatic patients, on the other hand, should be evaluated for PEI by fecal elastase 1 assay. The nutritional consequences of untreated or unrecognized steatorrhea can lead to significant weight loss, malnutrition, vitamin deficiencies, poor quality of life, and delays in therapy.87,88

NUTRITION SUPPORT OF HPB SURGERY PATIENTS The primary goal for nutritional support (NS) in patients before and after HPB surgery is to restore health and function as quickly as possible; this is facilitated by the support of normal digestion and intestinal absorption. Although no data support the routine use of NS in well-nourished patients undergoing HPB surgery, patients who are profoundly malnourished or deficient in specific vitamins probably benefit from NS.28,89,90 The majority of patients with HPB disease who are malnourished do not require specialized NS to correct their nutritional deficits because in most circumstances, their malnutrition is the consequence of inadequate caloric intake over prolonged periods of time. There are no consensus guidelines on a specific duration of nutritional repletion required to achieve a certain level of risk reduction of operative complications. Experts recommend at least 7 days and preferably 2 to 3 weeks of oral nutritional repletion in patients who have profound malnutrition or until such time that the serum prealbumin rises into a normal range.28,91

Routes of Feeding The most common and physiologic manner of NS is an oral diet tailored to the patient’s needs. If the patient is unable to consume an oral diet or meet their estimated caloric needs orally, enteral tube feeding access should be considered. Although nasoenteral feeding may be suitable for a short duration of feeding, jejunal, gastric, or gastrojejunostomy tubes should be considered for a longer duration of feeding. Supplementation with pancreatic enzymes, bile salts, and/or bile refeeding may enhance absorption in instances of PEI or biliary diversion, respectively. There is no clinical evidence to support the administration of supraphysiologic amounts of substrate (e.g., more than 5 mg/kg/min of glucose or more than 2 g protein/kg/day).89,92 If a patient fails to meet their total nutritional needs by combined oral and enteral routes, the addition of parenteral nutrition (PN) is appropriate. The increased infectious complications and costs associated with PN mandate that it is used only in patients with anatomic abnormalities of the GI tract in whom EN is not feasible or fails.93–97 The physiologic benefits of enteral nutrition (EN) over PN are maintenance of intestinal immunity and gut integrity, prevention of intestinal microbial translocation, reduced postoperative infections and sepsis, and lesser expense.98–100 Routine PN has not been found to

convey benefit to patients undergoing HPB operations in the first 2 weeks postoperatively.101 Prolonged PN can cause hepatocellular steatosis and cholestasis.102 It is important that, when PN is used, patients are not given excess calories (e.g., they should receive less than 30 kCal/kg/day) and glycemic control (serum glucose 100–150) is maintained with insulin.

Nutrition Support As Part of Enhanced Recovery After Surgery Programs Perioperative care regimens have changed substantially over the last decade with the advent of Enhanced Recovery After Surgery (ERAS) protocols103 (see Chapter 27). ERAS is a multimodal and multidisciplinary management pathway that’s goal is to maintain and more quickly restore health and function to patients by mitigating the catabolic stress response to operation. A central tenet of ERAS is to limit preoperative fasting and restore oral intake as soon as possible postoperatively. Current ERAS guidelines for pancreatic resection recommend the use of preoperative oral carbohydrate supplementation 2 to 3 hours before anesthesia.104–106 This practice has been shown to reduce psychological and physiologic stress, improve glycemic control during and after surgery, reduce skeletal muscle proteolysis and weakness, restore bowel motility, and reduce delayed gastric emptying after pancreaticoduodenectomy (PD).105,107 The feasibility, safety, and utility of ERAS in patients undergoing HPB operations has recently been established and leads to reduced morbidity and shorter hospital length of stay.104,108,109 The majority of patients treated within an ERAS protocol who do not experience a major complication have rapid return of bowel function and tolerate ingestion of a normal regular diet within 24 to 48 hours of surgery independent of the type of operation.110,111 Conversely, patients who deviate from postoperative recovery expectations usually have an underlying complication such as intraabdominal collection, fistula, or systemic infection. In a systematic review of the literature, Kagedan reported on 10 ERAS studies in patients undergoing PD. In the majority of studies, patients were allowed access to and tolerated solid food on the first or second postoperative day.110 A systematic review of five feeding routes after PD concluded that an oral diet is the preferred route of feeding and that there is no evidence to support routine EN or PN after PD.112 Current ERAS guidelines suggest most patients after hepatectomy can begin eating on day 1 after surgery,113 and a post-PD diet is resumed based on patient tolerance.106 Prolonged routine nasogastric decompression in patients undergoing PD and hepatectomy is not needed.111,114

PERIOPERATIVE CRITICAL CARE IN HEPATOBILIARY AND PANCREATIC SURGERY Intraoperative and perioperative management of patients undergoing HPB surgical procedures is affected by malnutrition, frailty, treatment-related physiologic changes, and diseaserelated physiologic disturbances related to chronic liver disease. Nutrition- and disease-related factors can predispose to postoperative complications or physiology, requiring postoperative management in an ICU setting. In addition to optimizing a patient’s nutrition and potentially improving stress tolerance before surgery, careful preoperative assessment, planning, and intraoperative monitoring may reduce the perioperative risks of morbidity and mortality of HPB surgery.

  Chapter 26  Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient

PREOPERATIVE ASSESSMENT AND CARE OF PATIENTS WITH LIVER DISEASE Patients with cirrhosis and portal hypertension have higher morbidity and mortality rates, not only after HPB surgical and nonsurgical procedures but also after major nonhepatic interventions115,116 (see Chapters 75, 101, and 102). When evaluating perioperative risks for patients with chronic liver diseases, three main factors should be considered: hepatic reserve, comorbid conditions, and the complexity of the planned surgical procedure. The development of splenomegaly and thrombocytopenia without documented portal hypertension has been noted in patients undergoing systemic chemotherapy, including those receiving chemotherapy before planned liver resection for metastatic disease.117–119 In the absence of cirrhosis as a causal agent, this may reflect underlying sinusoidal injury in the liver parenchyma.118,119 Mindfulness of potential portal hypertensive physiology should be considered in these patients with similar consideration given to the extent and timing of hepatectomy. Ascites, upper GI bleeding, poor nutritional state, anemia, thrombocytopenia, electrolyte disorders with or without acute kidney injury (AKI), and preoperative infection are additional risk factors for perioperative complications and mortality among cirrhotic patients undergoing surgery.120

Assessing Liver Function Several tools are available to assess hepatic reserve (see Chapter 4). The most frequently used are the Child-Turcotte-Pugh (CTP) and the Model for End-Stage Liver Disease (MELD) scores.121 The CTP score describes the degree of hepatic synthetic dysfunction and is based on the presence of hepatic encephalopathy, degree of ascites, prothrombin time, and serum levels of albumin and bilirubin. The score allows for categorization of cirrhosis into three classes: Class A (5–6 points) refers to well-compensated cirrhosis; class B (7–9 points) and class C (10–15 points) describe cases of cirrhosis that are in a state of mild and severe decompensation, respectively. The mortality rates for elective or emergent extrahepatic surgery range from 0% to 7.1% for class A, 50% for class B, and 84% to 100% for class C cirrhosis.122 Practical limitations of the CTP scoring system include variability and interobserver subjectivity in the estimation and detection of both ascites and encephalopathy.123 An additional limitation in surgical series is that many patients found to have hepatic encephalopathy would not be considered for hepatectomy; this has led certain groups to propose changes in the calculation of CTP scoring in which hepatic encephalopathy is replaced with platelet count to provide a more objective assessment of severity of portal hypertension.124 In 2000 the MELD score was developed as a prognostic index for 3-month mortality after a transjugular intrahepatic portosystemic shunt (TIPS) procedure.125 The MELD score is based on the international normalized ratio (INR), serum bilirubin, and creatinine levels.Because the calculation uses a natural logarithmic function, several application-based and internet calculators are available for ease of use. In 2016 the MELD score was updated by the incorporation of serum sodium level to yield the sodium-modified MELD, or MELDNa, based on accumulating evidence that hyponatremia was an additional powerful predictor of mortality in cirrhotic patients.126–128 The MELD score ranges from 6 to 40. Moderate MELD scores (.9) correspond to poor outcomes after hepatic resection

385

for HCC.129 The MELD score correlates well with the CTP score and is an accurate predictor of postoperative mortality in cirrhotic patients undergoing elective and emergent surgery.130,131 The predictive utility of the MELD-Na score has been studied in cirrhotic populations undergoing non-HPB surgical procedures with findings that support the idea that worsening liver function (as assessed by MELD-Na) increases the chances of postoperative complications, loss of independence, and mortality.132–134 In the setting of changing demographics related to the etiology of end-stage liver disease from hepatitis C virus to fatty liver disease, subtle changes in the predictive validity of the MELD score has are being explored.135,136

Portal Hypertension Portal hypertension confers a higher risk of in-hospital mortality.115 Ascites and varices related to portal hypertension are associated with increased risks for postoperative morbidity and complication, hospital mortality, and loss of independence at discharge in cirrhotic patients undergoing various surgical procedures.115,132,137 Although invasive measures such as hepatic venous gradient can predict clinical decompensation in patients with cirrhosis,138 incorporating predictive scales such as MELD-Na, noninvasive tools such as elastography, and simple factors such as platelet count124 may relegate invasive portal pressure measurements to equivocal cases in which diagnostic dilemma arises (see Chapters 77, 79, and 80). Cirrhotic patients undergoing preoperative multidisciplinary evaluation benefit from hepatology assessment and management to assess for the presence and degree of portal hypertension; this allows for diagnosis of esophageal varices as well as treatment, if needed, to control or minimize ascites. Although medical therapy such as octreotide or diuretics can lead to improvement in portal and systemic hemodynamics,139 this improvement may not extend to tolerance of liver resection. TIPS is indicated for patients with ascites refractory or intolerant to diuretics, but patients who undergo TIPS should be closely monitored for hepatic encephalopathy.140 b-Blockers are contraindicated in cirrhotic patients with refractory ascites, and these patients should avoid abdominal surgery because of the high rates of postoperative morbidity and death.141

Coagulopathy Coagulation abnormalities are frequent in cirrhotic patients and are the result of many causes, including decreased hepatic synthetic function, malnutrition, vitamin K deficiency, thrombocytopenia, and dysfibrinogenemia.142 There is no clear correlation between an increased risk for hemorrhage and a prolonged PT or activated partial thromboplastin time (aPTT).143 In the absence of bleeding, routine fresh frozen plasma (FFP) transfusions to correct prolonged PT-INR and aPTT are no longer advocated.144 Excessive FFP transfusions can lead to volume overload and may exacerbate ascites. Administration of cryoprecipitate is advocated when serum fibrinogen levels are less than 100 mg/dL in the presence of bleeding.145 Data on the benefits of fibrinogen concentrates are limited to trauma and massive hemorrhage.146 Transfusion of platelets is recommended before invasive procedures for moderate thrombocytopenia of less than 50,000/mL.147 Adjunctive desmopressin may be considered as rescue therapy for refractory hemorrhage, particularly when AKI is present, but conflicting results persist about its benefits in chronic liver disease.148

386

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

Cardiovascular and Respiratory Parameters Respiratory alkalosis tends to develop in patients with chronic liver disease. Increased abdominal girth in the setting of tense ascites can lead to a restrictive ventilatory defect with reduced functional residual capacity (FRC); therapeutic paracentesis may lead to improvement in respiratory parameters.149 Cirrhotic patients typically have a hyperdynamic hemodynamic profile because of low systemic vascular resistance, high cardiac output, and vasodilatation of the pulmonary, splanchnic, and peripheral beds.150,151 Patients with alcoholic liver disease and iron overload are predisposed to cardiomyopathy and cardiac arrhythmias.151 Hepatopulmonary syndrome (HPS) is relatively common in advanced cirrhosis and is often associated with portopulmonary hypertension. Signs and symptoms of HPS include hypoxemia, platypnea, orthodeoxia, clubbing, and spider angiomata.152 Transthoracic echocardiography with agitated saline or bubble contrast allows for the identification of intrapulmonary and right-to-left intracardiac shunts indicative of HPS.153 HPS signals an overall worse prognosis in patients with cirrhosis.154 General anesthesia in patients with HPS is associated with increased perioperative risk.155 Preoperative partial pressure of oxygen in arterial blood (PaO2) of 50 mm Hg or a macroaggregated albumin scan shunt fraction of 20% or higher are associated with prohibitive mortality rates from cardiorespiratory complications.156,157

Infection Patients with cirrhosis are at increased risk for infection, particularly spontaneous bacterial peritonitis (SBP).158 In patients with cirrhosis, infections increase mortality 4-fold with a median mortality rate of 38%,159 which can be accentuated by additional comorbidities.160 Risk factors for SBP include GI hemorrhage, metabolic alkalosis, dehydration, hyponatremia, and a high MELD score.161 SBP can be confirmed by a diagnostic paracentesis. If SBP is present, elective surgery should be deferred until the infection has been adequately controlled.

Assessment for Pancreatobiliary Surgery Nutritional and functional assessments play a role in patient selection before pancreatobiliary surgery, but other scoring systems seek to predict overall major complications or procedure-specific complications. The Preoperative Pancreatic Resection (PREPARE) score is based on several variables, including vital signs, laboratory values, comorbidity assessment via American Society of Anesthesiologists (ASA) category, and etiology of disease. The PREPARE score is accurate in identifying low- and high-risk patients for pancreatic surgery based on the projected occurrence of morbidity classified as grade III or above by the Clavien-Dindo classification.162,163 Additional perioperative risk calculators intended to enrich preoperative discussion and planning, such as those based on NSQIP data, may require additional disease-specific input to fully capture and describe potential risk associated with PD.164,165 Other predictors of PD-specific postoperative morbidity include pathology, texture of the pancreas, pancreatic duct diameter, and operative blood loss.166 Ongoing efforts seek to determine the most sensitive and specific data points to be used to produce highly predictive tools to predict PDspecific postoperative complications in open and minimally invasive PD populations.167,168

Additional Perioperative Considerations in HPB Surgical Patients Anemia Anemia is a common complication of chronic liver disease even in the absence of decompensation or esophageal varices.142 Anemia is caused by many factors, including bleeding, hemolysis, splenic sequestration, hepatic dysfunction, and malnutrition. Iron supplementation should be administered only in the presence of documented deficiency. Autologous blood transfusion and administration of erythropoietin have been used successfully to mitigate the need for red blood cell transfusions.169,170 The presence of chemotherapy-related anemia is identified in up to 75% of patients.171 The etiology of this anemia is multifactorial and includes treatment-associated myelosuppression and, in the HPB patient, potential nutritional, appetite-related, and disease-related contributions. Comparisons of parenteral iron administration alone172 and erythropoietin, along with parenteral iron,173 have not focused on HPB patients or on the recuperation of hemoglobin before surgical resection.

Electrolytes Hyponatremia in the setting of chronic liver disease is attributed to an impaired ability to excrete free water and can be found concurrently with other sequelae if it occurs in the setting of cirrhosis with portal hypertension.174 The causes of hyponatremia should be elucidated and addressed through various strategies, such as correction of fluid deficit or fluid restriction, and cautious and transient use of vasopressin-2 (V2)-receptor antagonists.175 Hypokalemia and hypomagnesemia can result from the use of loop diuretics, chronic respiratory alkalosis, or malnutrition in various HPB diseases and should be addressed before surgery to limit cardiac arrhythmias. Acute hypocalcemia can occur during hepatectomy or liver transplantation because of the massive citrate load associated with blood transfusion.176 Administration of intravenous (IV) calcium should be considered in the setting of intraoperative hemorrhage and hypotension because it helps maintain vascular muscle tone and may enhance hemostasis. Intraoperative and postoperative serum levels of potassium, calcium, magnesium, and phosphorus should be monitored, and abnormalities should be promptly corrected.177

INTRAOPERATIVE MANAGEMENT The core components of the intraoperative care of HPB surgical patients include careful selection of anesthetic, narcotic, and sedative agents; management of mechanical ventilation; maintenance of intravascular volume in the setting of hemorrhage and fluid shift/loss; glucose control and correction of electrolyte disorders; avoidance of hypothermia; and adjustment to blood losses in the setting of relative anemia and coagulopathy (see Chapter 25).

Selection of Anesthetic, Narcotic, and Sedative Agents The choices and doses of anesthetics, muscle relaxants, analgesics, and sedatives should account for the degree of impairment in hepatic synthetic function and clearance.178 Endotracheal intubation and induction are achieved in patients with liver disease similar to that in the general population. Presuming normal airway anatomy, atracurium, and cisatracurium are the

  Chapter 26  Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient

preferred neuromuscular blocking agents to facilitate intubation because they are not metabolized through the hepatic or renal system.178 If a rapid-sequence induction is required, the anesthesiologist is safe to use succinylcholine, a depolarizing neuromuscular blocking agent, or rocuronium, a steroid-based nondepolarizing neuromuscular blocking agent. Rocuronium has a reversal agent, sugammadex, which introduces an additional layer of safety, and makes poor hepatic clearance less problematic. Isoflurane, sevoflurane, and desfluorane remain the preferred inhalational anesthetic agents in patients with liver disease because they undergo less hepatic metabolism.179 Of the three agents, isoflurane is more frequently selected because of its minimal effects on hepatic blood flow, although the clinical applicability of this selection is somewhat theoretical. Enflurane and halothane are no longer used in clinical practice (see Chapter 25). Most narcotic, sedative, and analgesic agents are extensively metabolized in the liver, and their half-life is often altered in patients with chronic liver disease.180 Cirrhosis delays the elimination of alfentanil, whereas the metabolism of fentanyl, sufentanil, and remifentanil does not seem to be affected.181 Decreased protein binding and increased volumes of distribution hinder the clearance of midazolam in cirrhotic patients.182 Remifentanil is sometimes favored for induction because of rapid onset and elimination. Propofol is also preferred versus midazolam for sedation during surgical or endoscopic procedures because of shorter recovery time, more favorable pharmacokinetics, and less propensity to exacerbate subclinical encephalopathy.183

Management of Mechanical Ventilation From a ventilatory perspective, low to moderate tidal volume (Vt) is essential to mitigate effects of higher Vt including abdominal hypertension, respiratory alkalosis, potential barotrauma, and reduced ventricular preload.184 Patients with chronic liver disease are at increased risk for hypoxemia because of increased shunt fraction, diffusion abnormalities, ventilation-perfusion mismatch, and decreased FRC.185 Ventilatory changes during minimally invasive liver resection can be affected by institution of pneumoperitoneum, patient positioning, and strategies used to temper bleeding while operative control is obtained. Changes in mechanical ventilation rate and tidal volume may be requested during episodes of bleeding to decrease thoracic and resulting hepatic venous pressure while laparoscopic control of bleeding is obtained. Decreased respiratory rate or periods of apnea can contribute to respiratory acidosis. Therefore minute ventilation should be closely monitored, and consideration should be given to regular intraoperative arterial blood gas monitoring.

Fluid/Blood Loss and Hemodynamic Parameters Careful patient selection, attention to the volume of hepatic tissue resected, and reduction in intraoperative blood loss contribute to improved perioperative morbidity and mortality (see Chapters 25, 101, and 102). Decreased effective circulatory volume is frequently present in cirrhotic patients despite total body fluid overload.150 The initial periods of surgery are often associated with abdominal and thoracic pressure changes and fluid shifts resulting from the evacuation of ascites or when pneumoperitoneum is established. HPB surgery may also be marked by intraoperative hemorrhage, which is exacerbated by portal hypertension and coagulopathy.

387

The importance of minimization of intraoperative blood loss is highlighted in both hepatic and pancreatic surgery. Although blood loss can be an indicator of case complexity, intraoperative blood transfusion is a harbinger of morbidity and mortality in patients undergoing hepatic resections186 and is also associated with increased morbidity, mortality, and worsened oncologic outcomes in PD.187–189 Anesthetic techniques aimed at maintaining a low central venous pressure (CVP) during hepatic resection are associated with a reduction in blood loss, renal failure, and mortality.190 Strategies combining low CVP with pneumoperitoneum of 10 to 14 mm Hg are commonly used perioperative practices for minimally invasive hepatectomy191,192 (see Chapter 25). The physiologic challenges of maintaining low CVP under anesthesia include hemodynamic monitoring in the setting of low CVP, the contribution of pneumoperitoneum, and the technique chosen for maintenance of low CVP. Administering IV fluids in the immediate preoperative period may reduce hemodynamic alterations and prevent complications related to hypovolemia, such as postoperative AKI. Although a low CVP is a generally agreed-upon target, large volumes of blood products or IV fluids are sometimes necessary to maintain cerebral and cardiac perfusion. Once hepatic transection has been completed and bleeding is controlled, many protocols allow for a more liberal fluid or colloid administration to restore intravascular volume when low CVP anesthesia is used for liver resection (see Chapter 25). With technology allowing for indirect CVP assessment and calculation of stroke volume variation, routine central venous access for guidance of intraoperative resuscitation is being reevaluated. Stroke volume variation is a useful indicator of intraoperative blood loss and response to resuscitation and can safely guide the administration of IV fluid during hepatic resection.193,194 Studies comparing the use of stroke volume variation (SVV) monitoring against direct CVP monitoring show that SVV-based resuscitation allows for similar control of CVP and minimization of bleeding.193,195 Monitoring strategy does not seem to affect postoperative length of stay or postoperative morbidity.196 Intraoperative transesophageal echocardiography may also be employed in high-risk patient populations, although special expertise is required in employing this modality.

POSTOPERATIVE MANAGEMENT Despite careful planning, cautious patient selection, and judicious intraoperative monitoring and management, some patients experience AKI, infectious complications, ICU admission, postoperative hepatic insufficiency, and postoperative mortality. Cirrhosis increases the risk for AKI, sepsis, ICU admission, and postoperative mortality, particularly when associated with alcohol dependence, hepatic encephalopathy, and GI hemorrhage.197 High MELD score, admission to the ICU, and need for organ replacement therapy (pulmonary and/or renal) are predictors of increased length of stay and both short- and long-term mortality.198,199

Postoperative Hepatic Failure Hepatic failure, often manifested as encephalopathy, hyperbilirubinemia, development of ascites, and coagulopathy, can lead to acute respiratory failure, renal failure with/without hepatorenal syndrome, and bleeding complications. Whereas decompensation of cirrhosis can occur after abdominal procedures or

388

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

TABLE 26.2  Clinical Findings and Potential Additional Therapies Described by Grade of Posthepatectomy Liver Failure Definition

Location of Patient Care Additional Investigations that May Be Required

Liver Function

Pulmonary Renal Function

Potential Additional Therapies

PHLF GRADE A

PHLF GRADE B

PHLF GRADE C

Abnormal INR and bilirubin on POD 5 but no deviation in clinical management Surgical ward None

Deviation in regular postoperative care but without invasive intervention Intermediate level or ICU Liver/abdominal ultrasound with hepatic vascular evaluation; CXR; Blood, sputum, urine, potentially ascites cultures INR $1.5 but ,2; potentially some somnolence or confusion

Deviation from postoperative care, requiring invasive intervention

INR ,1.5; No symptoms of hyperammonemia SpO2 .90%, nasal cannula or simple face mask allowed Adequate UOP BUN ,150 mg/dL No symptoms of uremia Routine care

SpO2 ,90% despite use of nasal cannula or simple face mask UOP #0.5 mg/kg/h BUN ,150 mg/dL No symptoms of uremia Albumin, FFP, diuretics, noninvasive ventilation

ICU As grade B, but needs neurologic evaluation (CT head) to exclude stroke or structural disease INR $2; Hepatic encephalopathy Severe hypoxemia, SpO2 #85% despite high FiO2 Nonoliguric renal failure despite diuretics BUN $150 mg/dL Clinical uremia Intubation and mechanical ventilation, hemodialysis, extracorporeal liver support, liver transplantation

BUN, Blood urea nitrogen; CT, computed tomography; CXR, chest x-ray; FFP, fresh frozen plasma; FiO2, fraction of inspired oxygen; ICU, intensive care unit; INR, international normalized ratio; PHLF, posthepatectomy liver failure; POD, postoperative day; SpO2, arterial oxygen saturation; UOP, urine output.

illness, PHLF specifically describes a decrement in liver function after liver resection (see Chapter 77). The development of PHLF depends on the size and health of the liver remnant remaining after hepatectomy. Several postoperative criteria have been used in predicting PHLF and mortality. The 50-50 criteria, a combination of prothrombin time of less than 50% (or PT-INR . 1.7) and serum bilirubin greater than 50 mmol/L (or . 2.9 mg/dL), has been validated as an excellent predictor of death on days 3 and 5 for patients admitted to the ICU for PHLF.200,201 The Mullen criteria (bilirubin peak . 7 mg/dL on postoperative days 1–7) were found to be more accurate than the 50-50 criteria in predicting death from hepatic failure after liver resection.202 Although various methods exist to diagnose PHLF based on laboratory values, additional work has devised a classification system to describe the clinical impact of PHLF so that degree of morbidity can be described universally and independent of the differing systems used to diagnose PHLF. In this consensus statement, PHLF is determined by increased INR and hyperbilirubinemia on or after postoperative day 5; in cases of elevated values before surgery, the definition includes rising levels after surgery. The classification system bases its gradation of liver failure not on specific symptoms but on the impact on postoperative care, including location of care and additional measures used to treat symptoms (Table 26.2):203

Acute Renal Failure and Hepatorenal Syndrome AKI occurs in approximately 15% of patients who undergo liver resection and correlates to preexisting cardiovascular disease, preoperative serum alanine aminotransferase elevation, underlying renal disease, and diabetes mellitus204 (see Chapter 25). Postoperative AKI in patients with chronic liver disease may be caused by the administration of nephrotoxic drugs, intraoperative hypotension or hemorrhage, hypovolemia, intrinsic renal disease, and hepatorenal syndrome (HRS).205 Initial management of mild increase of serum

creatinine may be treated with volume expansion, withdrawal of diuretic therapy if it is being used, and search for nephrotoxic drugs. Further progression of renal dysfunction or failure to respond may require further assessment and exclusion of postoperative complications.206 HRS, an alarming postoperative renal complication in patients with advanced-stage liver disease, represents a functional renal failure caused by intrarenal vasoconstriction combined with splanchnic vasodilation; this may be precipitated by infection or intravascular volume depletion.207 There are two types of HRS: type 1 HRS is often associated with a rapid deterioration of renal function concomitant with deterioration in liver function. Type 2 HRS is characterized by a more gradual and less severe form of renal impairment often associated with refractory ascites174 (see Chapter 77). Vasoconstrictor agents, either alone or in combination with albumin or TIPS, are the main therapies for HRS208,209 (see Chapter 85). Continuous or intermittent renal replacement therapies should be offered to patients who do not respond to vasoconstrictors or TIPS and to prospective candidates for liver transplantation; recovery of renal function can be achieved in as many as 50% of patients.210 Terlipressin may be more effective for HRS related to sepsis or systemic inflammatory conditions.211,212 Its United States Food and Drug Administration (FDA) approval is pending (early 2020) for use in type 1 HRS. Noradrenaline has been compared with terlipressin without findings of significant outcome difference in randomized trials.206

Anemia and Hemorrhage Among patients with cirrhosis, postoperative anemia may warrant transfusion of red blood cells, particularly in the setting of surgical or GI hemorrhage. Hematocrit should be kept between 21% and 24% because excessive blood transfusions can lead to increased variceal rebleeding.213 In cirrhotic patients, the risk of postoperative variceal rupture and bleeding is increased by excessive blood transfusion, large-volume ascites, increased portal

  Chapter 26  Nutrition and Perioperative Critical Care in the Hepatopancreatobiliary Surgery Patient

pressure, and infection, particularly when coagulopathy and thrombocytopenia coexist.214 For patients with acute variceal hemorrhage, a MELD score greater than or equal to 18, transfusion requirement greater than or equal to 4 U of red blood cells within the first 24 hours of admission, and active bleeding at endoscopy are independent predictors of 6-week mortality and variceal rebleeding within the first 5 days.215 Variceal hemorrhage warrants transfusion of blood products and treatment aimed at modulating portal pressure216,217 (see Chapter 81). The traditional strategy of FFP transfusion to correct coagulopathy in patients who are not bleeding has been abandoned because of the absence of correlation between an increased risk for hemorrhage and a prolonged PT or aPTT. Moreover, FFP transfusion may lead to volume overload and does not decrease the risk for bleeding.143,218 Data on the successful use of four-factor prothrombin and fibrinogen complex in patients with liver cirrhosis and postoperative hemorrhage are lacking. Algorithms may include prothrombin concentrate in treatment of life-threatening hemorrhage in decompensated cirrhotic patients, but this may increase the risk for thromboembolic events.219–221

Sedative and Pain Management In patients with cirrhosis, sedative and narcotic agents undergo increased volume of distribution, slow hepatic metabolism, and prolonged elimination.181 Associated renal dysfunction should prompt adjustment of the doses of sedative and analgesic medications to prevent an exacerbation of hepatic encephalopathy and other complications.182 Narcotics can have unpredictable effects because of variable metabolism. In general, hydromorphone and fentanyl have cleaner side effect profiles, and so are often used judiciously, often in reduced doses, in patients with liver disease. Nonsteroidal antiinflammatory agents (NSAIDs) should be used sparingly because of the potential for peptic ulceration, fluid retention from inhibition of renal prostaglandin synthesis, precipitation of hepatorenal syndrome, and bleeding caused by antiplatelet activity, GI irritation, and renal failure.180 Optimal postsurgical analgesia is chosen based on several factors, including level of comfort provided, limitation of postoperative mobility, safety of use and potential complications, and patient satisfaction. Postoperative pain control strategies include intravenous patient-controlled analgesia (PCA), epidural catheters, and regional therapies, including wound/abdominal wall catheters or nerve blocks (see Chapter 25). Although epidural anesthesia has been used for decades, postoperative hypotension from alteration of sympathetic tone may limit return to mobilization and can raise concerns for other causes of hypotension (i.e., intraabdominal hemorrhage) after major HPB surgery. Theorized limitations in the use of epidural analgesia include concern for coagulopathy at the time of catheter removal, leading to a longer indwelling catheter time. A retrospective view of patients undergoing liver resection containing 15% cirrhotic (CPT A) patients found an 8% rate of postponement of catheter removal due to coagulopathy at the time when epidural would have been removed by clinical indication.222 Additional retrospective studies have found up to 32% of patients receiving FFP or vitamin K before epidural replacement to obtain a goal INR #1.3.223 Perioperative conditions may portend post-hepatectomy, such as cirrhosis, preoperative INR $1.3, preoperative platelet count #150,

389

major hepatectomy, and intraoperative estimated blood loss $1000 mL.224 Prediction of more severe postoperative coagulopathy could serve to influence the pain control strategy. Local anesthetic instillation in the transversus abdominis preperitoneal (TAP) and paravertebral locations may also be used to treat pain from abdominal incisions for HPB surgery. A randomized study comparing epidural against bilateral paravertebral block measuring visual pain scoring, incentive spirometry use, and use of opioid PCA (in both groups) found improved pain scores at 24 hours postoperatively in the epidural group, whereas incentive spirometer use and PCA use did not differ.225 Other regional blocks or infusion catheters are being explored as an alternative to epidural analgesia, both with and without concurrent use of PCA.226,227 Current ERAS Society guidelines for patients undergoing open hepatectomy as part of an ERAS protocol suggest consideration of wound catheters or intrathecal opiates rather than thoracic epidural analgesia113 (see Chapter 25).

Phosphate Metabolism After Hepatectomy Hypophosphatemia is a frequent occurrence in the early days after hepatectomy and should be corrected.228 Failure to develop hypophosphatemia is a marker of postoperative hepatic insufficiency and mortality and may be evident in the early postoperative period before the traditional markers defining PHLF become evident.229,230 In patients who develop PHLF, the later development of hypophosphatemia may signal the beginning of recovery.231

Postoperative Care after Pancreaticoduodenectomy Postoperative complications of PD, such as anastomotic leak, fistula, and abdominal collections, vary with the type of pancreatoenteric anastomosis, pancreatic texture, size of the main pancreatic duct, and intraoperative blood transfusion.168 As many as 18% of patients may require ICU admission for postoperative complications of PD. Delayed admission to the ICU for septic shock carries a mortality rate of close to 20%.232 Protocol-driven elimination of variation in perioperative care based on evidence from clinical trials has led to the development of ERAS recommendations for routine postoperative and perioperative management of patients undergoing PD106; these recommendations and their supporting evidence are further discussed elsewhere in this volume (see Chapters 27 and 117). In conclusion, evolutions in preoperative patient assessment including evaluation of sarcopenia, frailty, and comorbidity are allowing surgeons to identify and potentially intervene on patients at higher risk for perioperative morbidity and functional decline. Nutritional optimization, perioperative physiologic homeostasis, and consideration of disease-specific challenges are being increasingly employed in a cooperative manner in the care of HPB surgery patients with guidance from evidencebased multidisciplinary groups such as the ERAS Society. Although ongoing work explores the best ways to identify at-risk HPB surgery patients and the strategies most effective in preoperative physiologic and functional improvement, collaborative effort between surgeons, anesthesia staff, intensivists, rehabilitation or prehabilitation providers, and nursing embodies a global approach to perioperative care of this patient population. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

389.e1

REFERENCES 1. Schiesser M, Müller S, Kirchhoff P, Breitenstein S, Schäfer M, Clavien PA. Assessment of a novel screening score for nutritional risk in predicting complications in gastro-intestinal surgery. Clin Nutr. 2008;27:565-570. 2. Alvares-da-Silva MR, Reverbel da Silveira T. Comparison between handgrip strength, subjective global assessment, and prognostic nutritional index in assessing malnutrition and predicting clinical outcome in cirrhotic outpatients. Nutrition. 2005;21:113-117. 3. Hunt DR, Rowlands BJ, Johnston D. Hand grip strength—a simple prognostic indicator in surgical patients. JPEN J Parenter Enteral Nutr. 1985;9:701-704. 4. Norman K, Stobäus N, Gonzalez MC, Schulzke JD, Pirlich M. Hand grip strength: outcome predictor and marker of nutritional status. Clin Nutr. 2011;30:135-142. 5. Selakovic I, Dubljanin-Raspopovic E, Markovic-Denic L, et al. Can early assessment of hand grip strength in older hip fracture patients predict functional outcome? PloS One. 2019;14(8):e0213223. 6. Venkat R, Puhan MA, Schulick RD, et al. Predicting the risk of perioperative mortality in patients undergoing pancreaticoduodenectomy: a novel scoring system. Arch Surg. 2011;146:1277-1284. 7. Lai CC, You JF, Yeh CY, et al. Low preoperative serum albumin in colon cancer: a risk factor for poor outcome. Int J Colorectal Dis. 2011;26:473-481. 8. Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. 1999;134:36-42. 9. Billingsley KG, Hur K, Henderson WG, Daley J, Khuri SF, Bell Jr RH. Outcome after pancreaticoduodenectomy for periampullary cancer: an analysis from the Veterans Affairs National Surgical Quality Improvement Program. J Gastrointest Surg. 2003;7: 484-491. 10. Piquet MA, Ollivier I, Gloro R, Castel H, Tiengou LE, Dao T. Nutritional indices in cirrhotic patients. Nutrition. 2006;22:216217; author reply 218-219. 11. Beck FK, Rosenthal TC. Prealbumin: a marker for nutritional evaluation. Am Fam Physician. 2002;65:1575-1578. 12. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50:889-896. 13. Tan BH, Birdsell LA, Martin L, Baracos VE, Fearon KC. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res. 2009;15:6973-6979. 14. van Vledder MG, Levolger S, Ayez N, Verhoef C, Tran TC, Ijzermans JN. Body composition and outcome in patients undergoing resection of colorectal liver metastases. Br J Surg. 2012;99:550-557. 15. Harimoto N, Shirabe K, Yamashita YI, et al. Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma. Br J Surg. 2013;100:1523-1530. 16. Lieffers JR, Bathe OF, Fassbender K, Winget M, Baracos VE. Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery. Br J Surg. 2012; 107:931-936. 17. Walrand S, Guillet C, Salles J, Cano N, Boirie Y. Physiopathological mechanism of sarcopenia. Clin Geriatr Med. 2011;27:365-385. 18. Prado CM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9:629-635. 19. Martin HL, Ohara K, Kiberu A, Van Hagen T, Davidson A, Khattak MA. Prognostic value of systemic inflammation-based markers in advanced pancreatic cancer. Intern Med J. 2014;44:676-682. 20. Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008;33:997-1006. 21. Englesbe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg. 2010;211:271-278. 22. Valero V III, Amini N, Spolverato G, et al. Sarcopenia adversely impacts postoperative complications following resection or transplantation in patients with primary liver tumors. J Gastrointest Surg. 2015;19:272-281.

23. Itoh S, Shirabe K, Matsumoto Y, et al. Effect of body composition on outcomes after hepatic resection for hepatocellular carcinoma. Ann Surg Oncol. 2014;21:3063-3068. 24. Voron T, Tselikas L, Pietrasz D, et al. Sarcopenia impacts on shortand long-term results of hepatectomy for hepatocellular carcinoma. Ann Surg. 2015;261:1173-183. 25. Peng P, Hyder O, Firoozmand A, et al. Impact of sarcopenia on outcomes following resection of pancreatic adenocarcinoma. J Gastrointest Surg. 2012;16:1478-1486. 26. Kalyani RR, Corriere M, Ferrucci L. Age-related and diseaserelated muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol. 2014;2:819-829. 27. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12:223-226. 28. Evans DC, Martindale RG, Kiraly LN, Jones CM. Nutrition optimization prior to surgery. Nutr Clin Pract. 2014;29:10-21. 29. Yang Y, Breen L, Burd NA, et al. Resistance exercise enhances myofibrillar protein synthesis with graded intakes of whey protein in older men. Br J Nutr. 2012;108:1780-1788. 30. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149:766-772. 31. Ilinca S, Calciolari S. The patterns of health care utilization by elderly Europeans: frailty and its implications for health systems. Health Serv Res. 2015;50:305-320. 32. Sepehri A, Beggs T, Hassan A, et al. The impact of frailty on outcomes after cardiac surgery: a systematic review. J Thorac Cardiovasc Surg. 2014;148:3110-3117. 33. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol. 2012;13:e437-e444. 34. Handforth C, Clegg A, Young C, et al. The prevalence and outcomes of frailty in older cancer patients: a systematic review. Ann Oncol. 2015;26:1091-1101. 35. Khan M, Jehan F, Zeeshan M, et al. Failure to rescue after emergency general surgery in geriatric patients: does frailty matter? J Surg Res. 2019;233:397-402. 36. Joseph B, Zangbar B, Pandit V, et al. Emergency general surgery in the elderly: Too old or too frail? J Am Coll Surg. 2016;222:805-813. 37. Eamer GJ, Clement F, Holroyd-Leduc J, Wagg A, Padwal R, Khadaroo RG. Frailty predicts increased costs in emergent general surgery patients: a prospective cohort cost analysis. Surgery. 2019;166:82-87. 38. Fuertes-Guiró F, Viteri Velasco E. The impact of frailty on the economic evaluation of geriatric surgery: hospital costs and opportunity costs based on meta-analysis. J Med Econ. 2020:1-12. 39. Wilkes JG, Evans JL, Prato BS, Hess SA, MacGillivray DC, Fitzgerald TL. Frailty cost: economic impact of frailty in the elective surgical patient. J Am Coll Surg. 2019;228:861-870. 40. Tsiouris A, Hammoud ZT, Velanovich V, Hodari A, Borgi J, Rubinfeld I. A modified frailty index to assess morbidity and mortality after lobectomy. J Surg Res. 2013;183:40-46. 41. Hodari A, Hammoud ZT, Borgi JF, Tsiouris A, Rubinfeld IS. Assessment of morbidity and mortality after esophagectomy using a modified frailty index. Ann Thorac Surg. 2013;96:1240-1245. 42. Kristjansson SR, Nesbakken A, Jordhøy MS, et al. Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study. Crit Rev Oncol Hematol. 2010;76:208-217. 43. Subramaniam S, Aalberg JJ, Soriano RP, Divino CM. New 5-Factor modified frailty index using American College of Surgeons NSQIP data. J Am Coll Surg. 2018;226:173-181.e8. 44. Sousa-Santos AR, Amaral TF. Differences in handgrip strength protocols to identify sarcopenia and frailty – a systematic review. BMC Geriatr. 2017;17:238. 45. Aucoin SD, Hao M, Sohi R, et al. Accuracy and feasibility of clinically applied frailty instruments before surgery: a systematic review and meta-analysis. Anesthesiol. 2020;133(1):78-95. 46. Bruns ERJ, Argillander TE, Schuijt HJ, et al. Fit4SurgeryTV at-home prehabilitation for frail older patients planned for colorectal cancer surgery: a pilot study. Am J Phys Med Rehab. 2019;98:399-406. 47. Englesbe MJ, Grenda DR, Sullivan JA, et al. The Michigan Surgical Home and Optimization Program is a scalable model to improve care and reduce costs. Surgery. 2017;161:1659-1666.

389.e2 48. Gillis C, Li C, Lee L, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiol. 2014;121:937-947. 49. Bell H, Bjørneboe A, Eidsvoll B, et al. Reduced concentration of hepatic alpha-tocopherol in patients with alcoholic liver cirrhosis. Alcohol Alcohol. 1992;27:39-46. 50. Bulger EM, Helton WS. Nutrient antioxidants in gastrointestinal diseases. Gastroenterol Clin North Am. 1998;27:403-419. 51. Foschi D, Cavagna G, Callioni F, Morandi E, Rovati V. Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. Br J Surg. 1986;73:716-719. 52. O’Neil S, Hunt J, Filkins J, Gamelli R. Obstructive jaundice in rats results in exaggerated hepatic production of tumor necrosis factoralpha and systemic and tissue tumor necrosis factor-alpha levels after endotoxin. Surgery. 1997;122:281-286; Discussion 286-287. 53. Wang P, Li ZS, Liu F, et al. Risk factors for ERCP-related complications: a prospective multicenter study. Am J Gastroenterol. 2009; 104:31-40. 54. Mumtaz K, Hamid S, Jafri W. Endoscopic retrograde cholangiopancreaticography with or without stenting in patients with pancreaticobiliary malignancy, prior to surgery. Cochrane Database Syst Rev. 2007;2007:CD006001. 55. Mezhir JJ, Brennan MF, Baser RE, et al. A matched case-control study of preoperative biliary drainage in patients with pancreatic adenocarcinoma: routine drainage is not justified. J Gastrointest Surg. 2009;13:2163-2169. 56. Tripathy U, Dhiman RK, Attari A, et al. Preoperative bile salt administration versus bile refeeding in obstructive jaundice. Natl Med J India. 1996;9:66-69. 57. Puri P, Sanyal AJ. Nonalcoholic fatty liver disease: definitions, risk factors, and workup. Clin Liver Dis (Hoboken). 2012;1:99-103. 58. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg. 2007;245:923-930. 59. Pilgrim CH, Satgunaseelan L, Pham A, et al. Correlations between histopathological diagnosis of chemotherapy-induced hepatic injury, clinical features, and perioperative morbidity. HPB (Oxford). 2012;14:333-340. 60. Ramos E, Torras J, Lladó L, et al. The influence of steatosis on the short- and long-term results of resection of liver metastases from colorectal carcinoma. HPB (Oxford). 2016;18:389-396. 61. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065-2072. 62. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006; 24:4983-4990. 63. Nam SJ, Cho JY, Lee HS, et al. Chemotherapy-associated hepatopathy in korean colorectal cancer liver metastasis patients: oxaliplatin-based chemotherapy and sinusoidal injury. Korean J Pathol. 2012;46:22-29. 64. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7:1034-1044. 65. Behrns KE, Tsiotos GG, DeSouza NF, Krishna MK, Ludwig J, Nagorney DM. Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg. 1998;2:292-298. 66. de Meijer VE, Kalish BT, Puder M, Ijzermans JN. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;97:1331-1339. 67. Gomez D, Malik HZ, Bonney GK, et al. Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis. Br J Surg. 2007;94:1395-1402. 68. Sultana A, Brooke-Smith M, Ullah S, et al. Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study. HPB (Oxford). 2018;20:462-469. 69. Raptis DA, Fischer MA, Graf R, et al. MRI: the new reference standard in quantifying hepatic steatosis? Gut. 2012;61:117-127. 70. Edholm D, Kullberg J, Haenni A, et al. Preoperative 4-week lowcalorie diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in morbidly obese. Obes Surg. 2011; 21:345-350.

71. Colles SL, Dixon JB, Marks P, Strauss BJ, O’Brien PE. Preoperative weight loss with a very-low-energy diet: quantitation of changes in liver and abdominal fat by serial imaging. Am J Clin Nutr. 2006; 84:304-311. 72. Browning JD, Baker JA, Rogers T, Davis J, Satapati S, Burgess SC. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011;93:1048-1052. 73. Mardinoglu A, Wu H, Bjornson E, et al. An integrated understanding of the rapid metabolic benefits of a carbohydraterestricted diet on hepatic steatosis in humans. Cell Metab. 2018;27: 559-571.e5. 74. Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring). 2011;19:2310-2315. 75. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679-690. 76. Petrides AS, DeFronzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol. 1989;8:107-114. 77. Henriksen JH, Ring-Larsen H, Christensen NJ. Sympathetic nervous activity in cirrhosis. A survey of plasma catecholamine studies. J Hepatol. 1985;1:55-65. 78. Riggio O, Merli M, Cantafora A, et al. Total and individual free fatty acid concentrations in liver cirrhosis. Metabolism. 1984;33: 646-651. 79. Achord JL. Malnutrition and the role of nutritional support in alcoholic liver disease. Am J Gastroenterol. 1987;82:1-7. 80. Katz N. Metabolism of lipids. In: Thurman RG, Kauffman FC, Jungerman K, eds. Regulation of Hepatic Metabolism: Intra and Intercellular Compartmentation. Plenum Press; 1986:237-252. 81. Ryan DP, Grossbard ML. Pancreatic cancer: local success and distant failure. Oncologist 1998;3:178-188. 82. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002;52:72-91. 83. Bruera E, Sweeney C. Cachexia and asthenia in cancer patients. Lancet Oncol. 2000;1:138-147. 84. Tisdale MJ. Pathogenesis of cancer cachexia. J Support Oncol. 2003;1:159-168. 85. Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg. 2008;12:1193-1201. 86. Sikkens EC, Cahen DL, Kuipers EJ, Bruno MJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2010;24:337-347. 87. Ockenga J. Importance of nutritional management in diseases with exocrine pancreatic insufficiency. HPB (Oxford). 2009;11(suppl 3): 11-15. 88. Klapdor S, Richter E, Klapdor R. Vitamin D status and per-oral vitamin D supplementation in patients suffering from chronic pancreatitis and pancreatic cancer disease. Anticancer Res. 2012;32: 1991-1998. 89. Buzby GP. Veterans Affairs Total Parenteral Nutrition Cooperative Study Group: perioperative total parenteral nutrition in surgical patients. N Engl J Med. 1991;325:525-532. 90. Halliday AW, Benjamin IS, Blumgart LH. Nutritional risk factors in major hepatobiliary surgery. JPEN J Parenter Enteral Nutr. 1988; 12:43-48. 91. Jie B, Jiang ZM, Nolan MT, Zhu SN, Yu K, Kondrup J. Impact of preoperative nutritional support on clinical outcome in abdominal surgical patients at nutritional risk. Nutrition. 2012;28: 1022-1027. 92. Heidegger CP, Romand JA, Treggiari MM, Pichard C. Is it now time to promote mixed enteral and parenteral nutrition for the critically ill patient? Intensive Care Med. 2007;33:963-969. 93. Weimann A, Braga M, Harsanyi L, et al. ESPEN Guidelines on enteral nutrition: surgery including organ transplantation. Clin Nutr. 2006;25:224-244. 94. Plauth M, Cabré E, Riggio O, et al. ESPEN Guidelines on enteral nutrition: liver disease. Clin Nutr. 2006;25:285-294. 95. Meier R, Ockenga J, Pertkiewicz M, et al. ESPEN Guidelines on enteral nutrition: pancreas. Clin Nutr. 2006;25:275-284.

389.e3 96. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74:534-542. 97. Kreymann KG, Berger MM, Deutz NE, et al. ESPEN Guidelines on enteral nutrition: intensive care. Clin Nutr. 2006;25:210-223. 98. Zhu XH, Wu YF, Qiu YD, Jiang CP, Ding YT. Effect of early enteral combined with parenteral nutrition in patients undergoing pancreaticoduodenectomy. World J Gastroenterol. 2013;19: 5889-5896. 99. Kuboki S, Shimizu H, Yoshidome H, et al. Chylous ascites after hepatopancreatobiliary surgery. Br J Surg. 2013;100:522-527. 100. Abu Hilal M, Layfield DM, Di Fabio F, et al. Postoperative chyle leak after major pancreatic resections in patients who receive enteral feed: risk factors and management options. World J Surg. 2013;37:2918-2926. 101. Bengmark S. Nutrition of the critically ill – emphasis on liver and pancreas. Hepatobiliary Surg Nutr. 2012;1:25-52. 102. Bauer M, Kiehntopf M. Shades of yellow: monitoring nutritional needs and hepatobiliary function in the critically ill. Hepatology. 2014;60:26-29. 103. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth. 1997;78:606-617. 104. Lassen K, Coolsen MM, Slim K, et al. Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS®) Society recommendations. World J Surg. 2013; 37:240-258. 105. Viganò J, Cereda E, Caccialanza R, et al. Effects of preoperative oral carbohydrate supplementation on postoperative metabolic stress response of patients undergoing elective abdominal surgery. World J Surg. 2012;36:1738-1743. 106. Melloul E, Lassen K, Roulin D, et al. Guidelines for perioperative care for pancreatoduodenectomy: Enhanced Recovery After Surgery (ERAS) Recommendations 2019. World J Surg. 2020;44: 2056-2084. 107. Gianotti L, Biffi R, Sandini M, et al. Preoperative oral carbohydrate load versus placebo in major elective abdominal surgery (PROCY): a randomized, placebo-controlled, multicenter, phase III trial. Ann Surg. 2018;267:623-630. 108. Coolsen MM, van Dam RM, van der Wilt AA, Slim K, Lassen K, Dejong CH. Systematic review and meta-analysis of enhanced recovery after pancreatic surgery with particular emphasis on pancreaticoduodenectomies. World J Surg. 2013;37:1909-1918. 109. Jones C, Kelliher L, Dickinson M, et al. Randomized clinical trial on enhanced recovery versus standard care following open liver resection. Br J Surg. 2013;100:1015-1024. 110. Kagedan DJ, Ahmed M, Devitt KS, Wei AC. Enhanced recovery after pancreatic surgery: a systematic review of the evidence. HPB (Oxford). 2015;17:11-16. 111. Hughes MJ, McNally S, Wigmore SJ. Enhanced recovery following liver surgery: a systematic review and meta-analysis. HPB (Oxford). 2014;16:699-706. 112. Gerritsen A, Wennink RA, Besselink MG, et al. Early oral feeding after pancreatoduodenectomy enhances recovery without increasing morbidity. HPB (Oxford). 2014;16:656-664. 113. Melloul E, Hübner M, Scott M, et al. Guidelines for perioperative care for liver surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. World J Surg. 2016;40:2425-2440. 114. Dunne DF,Yip VS, Jones RP, et al. Enhanced recovery in the resection of colorectal liver metastases. J Surg Oncol. 2014;110:197-202. 115. Nguyen GC, Correia AJ, Thuluvath PJ. The impact of cirrhosis and portal hypertension on mortality following colorectal surgery: a nationwide, population-based study. Dis Colon Rectum. 2009; 52:1367-1374. 116. Kadry Z, Schaefer EW, Shah RA, et al. Portal hypertension: an underestimated entity? Ann Surg. 2016;263:986-991. 117. Jung EJ, Ryu CG, Kim G, et al. Splenomegaly during oxaliplatinbased chemotherapy for colorectal carcinoma. Anticancer Res. 2012; 32:3357-3362. 118. Overman MJ, Maru DM, Charnsangavej C, et al. Oxaliplatinmediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol. 2010;28:2549-2555. 119. Park S, Kim HY, Kim H, et al. Changes in noninvasive liver fibrosis indices and spleen size during chemotherapy: potential markers for oxaliplatin-induced sinusoidal obstruction syndrome. Medicine. 2016;95:e2454.

120. Ziser A, Plevak DJ, Wiesner RH, Rakela J, Offord KP, Brown DL. Morbidity and mortality in cirrhotic patients undergoing anesthesia and surgery. Anesthesiol. 1999;90:42-53. 121. Nicoll A. Surgical risk in patients with cirrhosis. J Gastroenterol Hepatol. 2012;27:1569-1575. 122. Franzetta M, Raimondo D, Giammanco M, et al. Prognostic factors of cirrhotic patients in extra-hepatic surgery. Minerva Chir. 2003; 58:541-544. 123. Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL. Model for End-Stage Liver Disease (MELD) predicts nontransplant surgical mortality in patients with cirrhosis. Ann Surg. 2005;242:244-251. 124. Maithel SK, Kneuertz PJ, Kooby DA, et al. Importance of low preoperative platelet count in selecting patients for resection of hepatocellular carcinoma: a multi-institutional analysis. J Am Coll Surg. 2011;212:638-648; discussion 648-650. 125. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000; 31:864-871. 126. Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl. 11:336-343. 127. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology. 2006;130:1652-1660. 128. Karapanagiotou A, Kydona C, Papadopoulos S, et al. The effect of hyponatremia on the outcome of patients after orthotopic liver transplantation. Transplant Proc. 2012;44:2724-2726. 129. Delis SG, Bakoyiannis A, Dervenis C, Tassopoulos N. Perioperative risk assessment for hepatocellular carcinoma by using the MELD score. J Gastrointest Surg. 2009;13:2268-2275. 130. Farnsworth N, Fagan SP, Berger DH, Awad SS. Child-TurcottePugh versus MELD score as a predictor of outcome after elective and emergent surgery in cirrhotic patients. Am J Surg. 2004;188:580-583. 131. Hoteit MA, Ghazale AH, Bain AJ, et al. Model for end-stage liver disease score versus Child score in predicting the outcome of surgical procedures in patients with cirrhosis. World J Gastroenterol. 2008;14:1774-1780. 132. Godfrey EL, Kueht ML, Rana A, Awad S. MELD-Na (the new MELD) and peri-operative outcomes in emergency surgery. Am J Surg. 2018;216:407-413. 133. Zielsdorf SM, Kubasiak JC, Janssen I, Myers JA, Luu MB. A NSQIP Analysis of MELD and perioperative outcomes in general surgery. Am Surgeon. 2015;81:755-759. 134. Causey MW, Nelson D, Johnson EK, et al. The impact of Model for End-Stage Liver Disease-Na in predicting morbidity and mortality following elective colon cancer surgery irrespective of underlying liver disease. Am J Surg. 2014;207:520-526. 135. Godfrey EL, Malik TH, Lai JC, et al. The decreasing predictive power of MELD in an era of changing etiology of liver disease. Am J Transplant. 2019;19:3299-3307. 136. Mahmud N, Goldberg DS. Declining predictive performance of the MELD: cause for concern or reflection of changes in clinical practice? Am J Transplant. 2019;19:3221-3222. 137. Csikesz NG, Nguyen LN, Tseng JF, Shah SA. Nationwide volume and mortality after elective surgery in cirrhotic patients. J Am Coll Surg. 2009;208:96-103. 138. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133:481-488. 139. Kalambokis G, Economou M, Kosta P, Papadimitriou K, Tsianos EV. The effects of treatment with octreotide, diuretics, or both on portal hemodynamics in nonazotemic cirrhotic patients with ascites. J Clin Gastroenterol. 2006;40:342-346. 140. Qi X, Jia J, Bai M, et al. Transjugular intrahepatic portosystemic shunt for acute variceal bleeding: a meta-analysis. J Clin Gastroenterol. 2015;49:495-505. 141. Sersté T, Melot C, Francoz C, et al. Deleterious effects of betablockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010;52:1017-1022. 142. Qamar AA, Grace ND, Groszmann RJ, et al. Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis. Clin Gastroenterol Hepatol. 2009;7:689-695.

389.e4 143. Tripodi A, Chantarangkul V, Primignani M, et al. Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med. 2012;7:139-144. 144. Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11:1064-1074. 145. Anderson MA, Glazebrook B, Cutts B, Stevenson L, Bielby L, Borosak M. When do we transfuse cryoprecipitate? Intern Med J. 2013;43:896-902. 146. Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth. 2008;101:769-773. 147. Johansson PI. Hemostatic strategies for minimizing mortality in surgery with major blood loss. Curr Opin Hematol. 2009;16:509-514. 148. Shah NL, Intagliata NM, Northup PG, Argo CK, Caldwell SH. Procoagulant therapeutics in liver disease: a critique and clinical rationale. Nat Rev Gastroenterol Hepatol. 2014;11:675-682. 149. Gupta D, Lalrothuama, Agrawal PN, et al. Pulmonary function changes after large volume paracentesis. Trop Gastroenterol. 2000; 21:68-70. 150. Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol. 2009;51:475-482. 151. Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut. 2008;57:268-278. 152. Singh C, Sager JS. Pulmonary complications of cirrhosis. Med Clin North Am. 2009;93:871-883, viii. 153. Rodríquez-Roisin R, Krowka MJ, Hervé P, Fallon MB. Highlights of the ERS Task Force on pulmonary-hepatic vascular disorders (PHD). J Hepatol. 2005;42:924-927. 154. Fauconnet P, Klopfenstein CE, Schiffer E. Hepatopulmonary syndrome: the anaesthetic considerations. Eur J Anaesth. 2013; 30:721-730. 155. Mazzeo AT, Lucanto T, Santamaria LB. Hepatopulmonary syndrome: A concern for the anesthetist? Pre-operative evaluation of hypoxemic patients with liver disease. Acta Anaesth. 2004; 48:178-186. 156. Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology. 2003;37:192-197. 157. Kawut SM, Taichman DB, Ahya VN, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transpl. 2005;11:1107-1111. 158. Khan J, Pikkarainen P, Karvonen AL, et al. Ascites: aetiology, mortality and the prevalence of spontaneous bacterial peritonitis. Scand J Gastroenterol. 2009;44:970-974. 159. Arvaniti V, D’Amico G, Fede G, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010;139:1246–1256, 1256.e1-e5. 160. Nobre SR, Cabral JE, Gomes JJ, Leitão MC. In-hospital mortality in spontaneous bacterial peritonitis: a new predictive model. Eur J Gastroenterol Hepatol. 2008;20:1176-1181. 161. Obstein KL, Campbell MS, Reddy KR, Yang YX. Association between model for end-stage liver disease and spontaneous bacterial peritonitis. Am J Gastroenterol. 2007;102:2732-2736. 162. Uzunoglu FG, Reeh M, Vettorazzi E, et al. Preoperative Pancreatic Resection (PREPARE) score: a prospective multicenter-based morbidity risk score. Ann Surg. 2014;260:857-863; discussion 863-864. 163. Rodriguez-Lopez M, Tejero-Pintor FJ, Perez-Saborido B, Barrera-Rebollo A, Bailon-Cuadrado M, Pacheco-Sanchez D. Severe morbidity after pancreatectomy is accurately predicted by preoperative pancreatic resection score (PREPARE): a prospective validation analysis from a medium-volume center. Hepatobiliary Pancreat Dis Int. 2018;17:559-565. 164. McMillan MT, Allegrini V, Asbun HJ, et al. Incorporation of procedure-specific risk into the ACS-NSQIP surgical risk calculator improves the prediction of morbidity and mortality after pancreatoduodenectomy. Ann Surg. 2017;265:978-986. 165. Epelboym I, Gawlas I, Lee JA, Schrope B, Chabot JA, Allendorf JD. Limitations of ACS-NSQIP in reporting complications for patients undergoing pancreatectomy: underscoring the need for a pancreas-specific module. World J Surg. 2014;38:1461-1467.

166. Braga M, Capretti G, Pecorelli N, et al. A prognostic score to predict major complications after pancreaticoduodenectomy. Ann Surg. 2011;254:702-707; discussion 707-708. 167. Mungroop TH, Klompmaker S, Wellner UF, et al. Updated alternative fistula risk score (ua-FRS) to include minimally invasive pancreatoduodenectomy: Pan-European validation. Ann Surg. 2021;273(2):334-340. 168. Mungroop TH, van Rijssen LB, van Klaveren D, et al. Alternative fistula risk score for pancreatoduodenectomy (a-FRS): design and international external validation. Ann Surg. 2019;269:937-943. 169. Kato K, Nomoto S, Sugimoto H, Kanazumi N, Takeda S, Nakao A. Autologous blood storage before hepatectomy for hepatocellular carcinoma. Hepatogastroenterology. 2009;56:802-807. 170. Silver M, Corwin MJ, Bazan A, Gettinger A, Enny C, Corwin HL. Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: a randomized, double-blind, placebo-controlled trial. Crit Care Med. 2006; 34:2310-2316. 171. Visweshwar N, Jaglal M, Sokol L, Zuckerman K. Chemotherapyrelated anemia. Ann Hematol. 2018;97:375-376. 172. Steinmetz T, Tschechne B, Harlin O, et al. Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapyassociated anaemia. Ann Oncol. 2013;24:475-482. 173. Gafter-Gvili A, Steensma DP, Auerbach M. Should the ASCO/ ASH Guidelines for the use of intravenous iron in cancer- and chemotherapy-induced anemia be updated? J Natl Compr Canc Netw. 2014;12:657-664. 174. Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol. 2008;48(suppl 1): S93-S103. 175. Kwo PY. Management of hyponatremia in clinical hepatology practice. Curr Gastroenterol Rep. 2014;16:382. 176. Chung HS, Cho SJ, Park CS. Effects of liver function on ionized hypocalcaemia following rapid blood transfusion. J Int Med Res. 2012;40:572-582. 177. Hayter MA, Pavenski K, Baker J. Massive transfusion in the trauma patient: Continuing Professional Development. Can J Anaesth. 2012;59:1130-1145. 178. Hoetzel A, Ryan H, Schmidt R. Anesthetic considerations for the patient with liver disease. Curr Opin Anaesth. 2012;25:340-347. 179. Nishiyama T, Fujimoto T, Hanaoka K. A comparison of liver function after hepatectomy in cirrhotic patients between sevoflurane and isoflurane in anesthesia with nitrous oxide and epidural block. Anesth Analg. 2004;98:990-993. 180. Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs. 2012;72:1645-1669. 181. Delcò F, Tchambaz L, Schlienger R, Drewe J, Krähenbühl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28: 529-545. 182. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64:1147-1161. 183. Khamaysi I, William N, Olga A, et al. Sub-clinical hepatic encephalopathy in cirrhotic patients is not aggravated by sedation with propofol compared to midazolam: a randomized controlled study. J Hepatol. 2011;54:72-77. 184. Determann RM, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14:R1. 185. Polverino F, Santoriello C, Andò F, et al. Recumbent deoxygenation in mild/moderate liver cirrhosis: the “clinodeoxia”. The orthoclino paradigm. Respir Med. 2014;108:1040-1048. 186. Neeff HP, Streule GC, Drognitz O, et al. Early mortality and long-term survival after abdominal surgery in patients with liver cirrhosis. Surgery. 2014;155:623-632. 187. Zhang L, Liao Q, Zhang T, Dai M, Zhao Y. Blood transfusion is an independent risk factor for postoperative serious infectious complications after pancreaticoduodenectomy. World J Surg. 2016;40:2507-2512. 188. Lopez-Aguiar AG, Ethun CG, Pawlik TM, et al. Association of perioperative transfusion with recurrence and survival after resection of distal cholangiocarcinoma: a 10-institution study from the US extrahepatic biliary malignancy consortium. Ann Surg Oncol. 2019;26:1814-1823.

389.e5 189. Kazanjian KK, Hines OJ, Duffy JP, Yoon DY, Cortina G, Reber HA. Improved survival following pancreaticoduodenectomy to treat adenocarcinoma of the pancreas: the influence of operative blood loss. Arch Surg. 2008;143:1166-1171. 190. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction. J Am Coll Surg. 1998;187:620-625. 191. Wakabayashi G, Cherqui D, Geller DA, et al. Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. Ann Surg. 2015; 261:619-629. 192. Tranchart H, O’Rourke N, Van Dam R, et al. Bleeding control during laparoscopic liver resection: a review of literature. J Hepatobiliary Pancreat Sci. 2015;22:371-378. 193. Dunki-Jacobs EM, Philips P, Scoggins CR, McMasters KM, Martin RC II. Stroke volume variation in hepatic resection: a replacement for standard central venous pressure monitoring. Ann Surg Oncol. 2014;21:473-478. 194. Harimoto N, Matsuyama H, Kajiyama K, et al. Significance of stroke volume variation during hepatic resection under infrahepatic inferior vena cava and portal triad clamping. Fukuoka Igaku Zasshi. 2013;104:362-369. 195. Shih TH, Tsou YH, Huang CJ, et al. The correlation between CVP and SVV and intraoperative minimal blood loss in living donor hepatectomy. Transplant Proc. 2018;50:2661-2663. 196. Ratti F, Cipriani F, Reineke R, et al. Intraoperative monitoring of stroke volume variation versus central venous pressure in laparoscopic liver surgery: a randomized prospective comparative trial. HPB (Oxford). 2016;18:136-144. 197. Lin CS, Lin SY, Chang CC, Wang HH, Liao CC, Chen TL. Postoperative adverse outcomes after non-hepatic surgery in patients with liver cirrhosis. Br J Surg. 2013;100:1784-1790. 198. Bahirwani R, Ghabril M, Forde KA, et al. Factors that predict short-term intensive care unit mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2013;11:1194-1200.e2. 199. Levesque E, Saliba F, Ichaï P, Samuel D. Outcome of patients with cirrhosis requiring mechanical ventilation in ICU. J Hepatol. 2014;60:570-578. 200. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg. 2005;242:824-828, discussion 828-829. 201. Paugam-Burtz C, Janny S, Delefosse D, et al. Prospective validation of the “fifty-fifty” criteria as an early and accurate predictor of death after liver resection in intensive care unit patients. Ann Surg. 2009;249:124-128. 202. Filicori F, Keutgen XM, Zanello M, et al. Prognostic criteria for postoperative mortality in 170 patients undergoing major right hepatectomy. Hepatobiliary Pancreat Dis Int. 2012;11:507-512. 203. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713-724. 204. Slankamenac K, Breitenstein S, Held U, Beck-Schimmer B, Puhan MA, Clavien PA. Development and validation of a prediction score for postoperative acute renal failure following liver resection. Ann Surg. 2009;250:720-728. 205. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279-1290. 206. Mattos ÂZ, Schacher FC, Mattos AA. Vasoconstrictors in hepatorenal syndrome – a critical review. Ann Hepatol. 2019;18:287-290. 207. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Postgrad Med J. 2008;84:662-670. 208. Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev. 2012: CD005162. 209. Nassar Junior AP, Farias AQ, LA DA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PloS One. 2014;9:e107466. 210. Fabrizi F, Aghemo A, Messa P. Hepatorenal syndrome and novel advances in its management. Kidney Blood Press Res. 2013;37: 588-601. 211. Boyer TD, Sanyal AJ, Wong F, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in

patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150:1579-1589.e2. 212. Rodríguez E, Elia C, Solà E, et al. Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis. J Hepatol. 2014;60:955-961. 213. de Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53:762-768. 214. García-Pagán JC, Villanueva C, Albillos A, et al. Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial. Gut. 2009;58:1144-1150. 215. Bambha K, Kim WR, Pedersen R, Bida JP, Kremers WK, Kamath PS. Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut. 2008;57: 814-820. 216. Abid S, Jafri W, Hamid S, et al. Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial. Am J Gastroenterol. 2009;104:617-623. 217. Martín-Llahí M, Pépin MN, Guevara M, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134:1352-1359. 218. Tinmouth A. Evidence for a rationale use of frozen plasma for the treatment and prevention of bleeding. Transfus Apher Sci. 2012; 46:293-298. 219. Pereira D, Liotta E, Mahmoud AA. The Use of Kcentra(®) in the reversal of coagulopathy of chronic liver disease. J Pharm Pract. 2018;31:120-125. 220. Tischendorf M, Fuchs A, Zeuzem S, Lange CM. Use of prothrombin complex concentrates in patients with decompensated liver cirrhosis is associated with thromboembolic events. J Hepatol. 2019;70:800-801. 221. O’Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA Clinical Practice Update: coagulation in cirrhosis. Gastroenterology. 2019;157:34-43.e1. 222. Esteve N, Ferrer A, Sansaloni C, Mariscal M, Torres M, Mora C. Epidural anesthesia and analgesia in liver resection: safety and effectiveness. Rev Esp Anestesiol Reanim. 2017;64:86-94. 223. Elterman KG, Xiong Z. Coagulation profile changes and safety of epidural analgesia after hepatectomy: a retrospective study. J Anesth. 2015;29:367-372. 224. Jacquenod P, Wallon G, Gazon M, et al. Incidence and risk factors of coagulation profile derangement after liver surgery: implications for the use of epidural analgesia-a retrospective cohort study. Anesth Analg. 2018;126:1142-1147. 225. Schreiber KL, Chelly JE, Lang RS, et al. Epidural versus paravertebral nerve block for postoperative analgesia in patients undergoing open liver resection: a randomized clinical trial. Reg Anesth Pain Med. 2016;41:460-468. 226. Serag Eldin M, Mahmoud F, El Hassan R, et al. Intravenous patient-controlled fentanyl with and without transversus abdominis plane block in cirrhotic patients post liver resection. Local Reg Anesth. 2014;7:27-37. 227. Yassen K, Lotfy M, Miligi A, Sallam A, Hegazi EAR, Afifi M. Patient-controlled analgesia with and without transverse abdominis plane and rectus sheath space block in cirrhotic patients undergoing liver resection. J Anaesthesiol Clin Pharmacol. 2019; 35:58-64. 228. George R, Shiu MH. Hypophosphatemia after major hepatic resection. Surgery. 1992;111:281-286. 229. Herbert GS, Prussing KB, Simpson AL, et al. Early trends in serum phosphate and creatinine levels are associated with mortality following major hepatectomy. HPB (Oxford). 2015;17:1058-1065. 230. Squires MH III, Dann GC, Lad NL, et al. Hypophosphataemia after major hepatectomy and the risk of post-operative hepatic insufficiency and mortality: an analysis of 719 patients. HPB (Oxford). 2014;16:884-891. 231. Hallet J, Karanicolas PJ, Zih FS, et al. Hypophosphatemia and recovery of post-hepatectomy liver insufficiency. Hepatobiliary Surg Nutr. 2016;5:217-224. 232. Welsch T, Degrate L, Zschäbitz S, Hofer S, Werner J, Schmidt J. The need for extended intensive care after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. Langenbecks Arch Surg. 2011;396:353-362.

CHAPTER 27 Enhanced recovery programs in hepatobiliary surgery Timothy E. Newhook and Thomas A. Aloia

INTRODUCTION In the 1990s, initial reports of fast-track surgical principles detailed their application to cardiac surgery patients with the goal of reducing intensive care unit (ICU) stay.1 Afterward, a novel multimodal approach to perioperative care was described by Kehlet and Mogensen, resulting in a dramatic reduction in length of hospital stay (LOS) after colectomy.2,3 After overcoming much skepticism and scrutiny, the ensuing paradigm shift in perioperative care of the surgical patient has resulted in their principles being applied across disciplines and in the formation of the Enhanced Recovery After Surgery (ERAS) Society (https://www.erassociety.org), which aims to disseminate and implement enhanced recovery best practices globally.4 Since the introduction of these practices, enhanced recovery program (ERP) principles have been successfully applied across the surgical spectrum and have now been adopted in other procedural (e.g., stem cell transplantation) and non-procedural (e.g., medical hospitalist) care. Principles of enhanced recovery have been increasingly incorporated into the care of hepatobiliary (HB) surgery patients, with clinical trials and individual reports documenting improved outcomes with these programs.5,6 Perhaps the earliest description of experience with ERPs and HB surgery came from Scotland, when Mackay and O’Dwyer published their small series of early discharge “fast-track” liver resection patients.7 In the same year, van Dam et al. described their initial experience with 61 patients who underwent hepatectomy under an ERP and compared outcomes with 100 consecutive hepatectomies before initiation of the protocol.8 Hepatectomy patients resumed oral intake earlier and had a decreased LOS compared with traditional pathway patients, along with similar rates of morbidity and mortality.8 Since that time, there has been an explosion of literature involving enhanced recovery after HB surgery, evaluating proposed pathways and operative strategies within an ERP framework. HB surgery is unique from other fields in gastrointestinal (GI) surgery because of differing patient comorbidities and underlying chronic diseases that may require intervention, and thus the perioperative care plans must be different. Recent advances in surgical planning, perioperative care, and operative techniques have resulted in decreased morbidity and mortality after HB surgery.9,10 Despite this, HB surgery remains difficult, with recognized rates of major complications as high as 30%, and mortality of up to 5% even at high-volume centers.11,12 Of particular concern are high rates of digestive and pulmonary complications associated with HB surgery. Therefore a shift toward perioperative care aimed at a reduction in these adverse outcomes via early intervention allows for a faster, more efficient recovery. Lastly, it is important to note that ERPs are management strategies predicated on safe, effective, and meticulous surgical technique to deliver optimal outcomes and 390

derive maximal benefit from these programs. In other words, an ERP cannot make up for substandard surgery. HB surgery remains complex, with perioperative variables not found in other surgical disciplines; it also requires significant contributions from many members of the HB surgery care team. These major operations can be incredibly complex, requiring a large multidisciplinary effort that may function more effectively with a standardized plan. Therefore implementation of such a protocol for patients undergoing HB surgery requires commitment from surgeons, trainees, anesthesiologists, nursing staff, and patients themselves to adhere to the common core principles discussed below.

THE “4 PILLARS” OF ENHANCED RECOVERY PROGRAMS Fundamental surgical principles, such as thromboembolic prophylaxis, prophylactic antibiosis, appropriate application of minimally-invasive approaches, and minimization of drains/ lines/tubes are critical to ERPs. In addition, modern ERP approaches consist of effective patient education and engagement, upon which stand “4 pillars” of enhanced recovery: early postoperative feeding, goal-directed fluid therapy, opioid-sparing analgesia, and early ambulation (Fig. 27.1).13,14 These core components occur at different phases of the ERP along the spectrum of care of an HB surgical patient and will be discussed later in this chapter. The foundation of all ERPs, patient engagement and education, is of critical importance. Much of enhanced recovery requires the participation of the patient (i.e., early ambulation) and thus all efforts within the pathway rest on a solid foundation of patient engagement. Effective education of both the patient and caregiver(s) in advance of and during recovery allows for a “team approach” that will lead to improved and enhanced outcomes. Along with the “4 pillars,” other critical aspects of a comprehensive ERP are detailed later along the phases of care for HB surgical patients (Table 27.1). Other aspects or program-specific elements exist; however, the following subjects remain most concordant with major published guidelines.

PREOPERATIVE PHASE Preoperative Patient Evaluation A thorough preoperative evaluation is imperative for any patient being considered for HB surgery. A complete history and physical examination should include a review of all comorbidities, surgical history, medications, and detailed oncologic history. Determination and quantification of receipt of any prior cytotoxic/targeted/immunologic therapies is paramount. Specific to HB surgery, any risk factors for hepatic dysfunction,

  Chapter 27  Enhanced Recovery Programs in Hepatobiliary Surgery

Ambulation

Non-narcotic analgesia

Early feeding

Goal directed fluid therapy

Enhanced recovery

Patient education and engagement FIGURE 27.1  The “4 pillars” and foundation of enhanced recovery programs (ERPs). (From Kim BJ, Aloia TA. What is “enhanced recovery,” and how can I do it? J Gastrointest Surg. 2018;22[1]:164–171.)

TABLE 27.1  Essential Elements of Enhanced Recovery Programs by Preoperative, Perioperative, and Postoperative Phases of Care for the HB Surgery Patient PREOPERATIVE PHASE

PERIOPERATIVE PHASE

POSTOPERATIVE PHASE

Patient Evaluation

Clear Liquids up to 2 hours pre-procedure

Early Mobilization

Medical Optimization

VTE prophylaxis

Goal-Directed Fluid Therapy

Prehabilitation

Antimicrobial prophylaxis

Prevention of PONV

Nutritional Assessment

Avoidance or early discontinuation of NGT or abdominal drains

Early Nutrition

Education and Engagement

Goal-Directed Fluid Therapy

Opioid-Sparing Analgesia

Neuraxial and Regional Anesthesia

Educate on Discharge Criteria

Opioid-Sparing Analgesia Minimally-invasive Surgical Approaches, if possible

portal hypertension, or cirrhosis should be ascertained by inquiring about prior HB surgical history, including endoscopic procedures and detailed social history. Physical examination should include detection of any signs of hepatic dysfunction, including jaundice, ascites, or prior surgical scars. Optimization of chronic comorbidities, both medically and with intervention, is critical to the quality of recovery after HB surgery (see Chapters 25 and 26). Borderline operability from a medical perspective must be uncovered because these patients (age .75 years, dependent function, lung disease, ascites/varices, myocardial infarction, stroke, steroids, weight loss .10%, and/or sepsis) have a threefold higher mortality after hepatectomy.15 Moreover, patients with more comorbidities are more likely to be discharged to a skilled nursing facility or nonroutine discharge after hepatopancreatic surgery.16 Optimization of

391

comorbidities before planned hepatectomy may greatly influence outcome and allow for adherence to ERP principles. Patient functional status must be evaluated thoroughly and potentially improved before planned HB surgery. Evaluation of functional status may be performed using reported grading tools (i.e., Eastern Cooperative Oncology Group Performance Status, Karnofsky Score, MD Anderson Symptom Inventory, Timed Up And Go).17–22 The concept of frailty as it applies to HB surgery is in evolution; however, objective tools such as these may identify patients that may be best suited for a coordinated “prehabilitation” program before surgical intervention. This allows for an improved “starting point” before physiologically stressful, complicated HB surgery. As it pertains to cardiopulmonary fitness, structured exercise programs have been shown to improve quality of life scores and exercise capacity before planned hepatectomy for colorectal liver metastases.23 Moreover, prehabilitation may be used as an opportunity to institute dietary and exercise programs aimed at reducing hepatic steatosis for patients deemed high risk and undergoing planned hepatectomy.24 Clearly, there are prime opportunities to potentially improve perioperative outcomes via preoperative optimization of HB surgical patients in the context of a comprehensive ERP (see Chapter 26). Determining a patient’s baseline use of pain medications, primarily opioids, can be critical to the success of an enhanced recovery approach. Preoperative opioid use has been reported in almost 25% of patients reporting for surgery, and preoperative opioid prescriptions are associated with higher postoperative opioid requirements and increased readmissions.25–27 Moreover, opioid tolerance is associated with decreased compliance with ERPs, particularly in the postoperative period.28 Therefore this information is imperative because it may inform regional anesthesia strategies and postoperative multimodal therapy.

Preoperative Education and Patient Engagement Patients being cared for along an ERP for HB surgery must be engaged and educated thoroughly on the goals of the program and the reasons behind care decisions. Educational materials on operative approaches and expectations for day-to-day care while in the hospital, including pain control, diet, and ambulation, should be provided in a format that is easy to comprehend. Patients will require detailed information regarding opioid-sparing analgesia, including the use of multimodal agents and the efficacy of initial and repeated regional anesthetic nerve blocks. Although no studies have evaluated education, there is a shared recognition that these educational efforts create excitement in patients about the potential for decreased LOS after their HB surgery and increase their willingness to work toward this enhanced recovery. Beyond allowing for understanding of expectations, these efforts reduce patient anxiety and lead to increased compliance.29 The ERAS Society recommendations for liver surgery are that “routine and dedicated preoperative counseling and education” be provided to patients before undergoing liver surgery.4

Preoperative Nutrition As with any elective surgical procedure, consideration of a patient’s baseline nutritional status and evaluation of potential nutritional deficits is critical during preparation for HB surgery (see Chapter 26). Important factors to consider include recent weight loss and obesity, body mass index (BMI), and laboratory

392

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

evaluation of nutritional indices, such as albumin, prealbumin, ferritin, and relevant vitamins and micronutrients.14,30 Beyond incorporation within the history and physical, several screening instruments are available, which may augment evaluation and have been shown to be useful in clinical practice.31,32 When possible, every attempt should be made to remediate nutritional deficiencies. The ERAS Society recommendations for liver surgery suggest that patients found to be “at risk” receive 7 days of oral nutritional supplementation before elective liver surgery. At-risk patients are defined as having greater than 10% to 15% weight loss within 6 months, BMI less than 18.5 kg/m2, and serum albumin less than 30 g/L without any signs of liver or renal dysfunction.4

PERIOPERATIVE PHASE Perioperative Nutrition and Carbohydrate Loading An integral aspect of ERPs is maintaining homeostasis and limiting the surgical stress response, as well as avoiding catabolism. Despite dogmatic guidelines of prolonged fasting before general anesthesia (nil per os after midnight), modern recommendations include the allowance of clear liquids up to 2 hours and solid food 6 hours before general anesthesia, as long as there are no concerns for gastroduodenal functional impairment.33,34 The role of preoperative carbohydrate loading is established for patients undergoing colorectal operations and is likely also applicable to HB surgical patients.4,35,36 Patients receiving preoperative carbohydrate loading before other interventions have been shown to have less anxiety, malaise, nausea, and perioperative insulin resistance in clinical trials.37 Although more evidence is required before strong recommendation for carbohydrate loading before HB surgery, data on the adverse effects of starvation are compelling enough that they should be considered.

Venous Thromboembolism Prophylaxis Perioperative venous thromboembolism (VTE) results in significant morbidity and mortality, and patients with malignancy are at higher risk for development of these complications. Concerns for bleeding after HB surgery has traditionally resulted in resistance to at least preoperative VTE chemoprophylaxis; however, a large percentage of patients undergoing hepatopancreatobiliary surgery have been shown to be hypercoagulable.38 Major hepatectomy itself is an independent risk factor for the development of VTE.39 Moreover, VTE rates increase with extent of hepatectomy and this risk exceeds that of major bleeding, strongly supporting the use of preoperative and early postoperative VTE chemoprophylaxis.40 Graded compression stockings and intermittent pneumatic compression/sequential compression devices (SCDs) can be placed before anesthesia induction and continued until ambulation, and this can further decrease the risk for VTE after HB surgery.36 Indeed, guidelines for liver surgery recommend administration of low-molecularweight heparin (LMWH) or unfractionated heparin 2 to 12 hours preoperatively and the use of SCDs.4

Antimicrobial Prophylaxis and Surgical Site Infection Prevention Routine use of antimicrobial prophylaxis for liver surgery remains inconsistent; however, national guidelines aimed at reducing complications after surgery recommend prophylaxis

within 1 hour before incision, appropriate re-dosing based on case duration, and continuation for 24 hours after surgery.13,41,42 Surgeons may choose to continue antibiotics for more than 24 hours for patients with previous or current biliary drainage; however, evidence supporting this practice is inconclusive. Similarly, skin preparations that include alcohol (e.g., chlorhexidine-alcohol 2%) are recognized as superior to povidone-iodine alone solutions in prevention of surgical site infection (SSI) for patients undergoing HB surgery.4,43

Nasogastric Tubes and Abdominal Drainage Routine use of nasogastric (NG) drainage after major abdominal surgery is largely being abandoned, and some major studies have revealed their prophylactic use to be detrimental.44 Specific to HB surgery, a randomized trial of 210 patients undergoing hepatectomy failed to reveal any difference in overall morbidity, pulmonary complications, frequency of postoperative emesis, or time to oral intake between patients with or without prophylactic NG tubes until flatus or bowel function.45 Moreover, a NG tube has been identified as independently associated with postoperative pulmonary complications after hepatectomy.46 Data for prophylactic abdominal drainage after HB surgery are mixed; however, supporters use them as potential indicators for biliary complications, such as bile leak and prevention of subdiaphragmatic abscesses. However, these drains may serve to impair patient mobilization postoperatively and may also result in increased pain and need for opioid medications. Therefore abdominal drains should be omitted if possible, particularly when intraoperative identification of bile leak tests (e.g., air-leak test) are performed and results are negative.30,47–49

Intraoperative Fluid Management Reduction in the volume of fluid administered after major abdominal surgeries has resulted in significantly decreased morbidity50 (see Chapter 25). Intraoperative fluid management for patients undergoing HB surgery within an ERP is unique compared with other major abdominal operations. This starts with avoidance of bowel preparations and prolonged preoperative fasting for HB operations, thus avoiding dehydration.30 Intraoperative fluid management should be goal-directed, focusing on maintaining euvolemia and avoiding excess crystalloid fluids. Goal-directed fluid therapy (GDFT) aims to optimize end-organ perfusion by monitoring various dynamic markers of resuscitation status, including central venous pressure (CVP), cardiac output/index (CO/CI), and noninvasive stroke volume variation (SVV) as examples. In place of invasive CVP monitoring, the SVV can guide GDFT and results in improved intraoperative fluid administration and decreased postoperative morbidity.51 However, this is more complex for HB operations because maintenance of a low CVP during hepatic transection results in reduced blood loss and lower rates of blood transfusion.52 This highlights the critical importance of establishing an individualized plan for fluid management with all team members to realize improved outcomes.

Neuraxial and Peripheral Regional Anesthesia Techniques The goal of a pain control regimen with ERPs is to limit the postoperative neuroendocrine stress response, allow for early ambulation, and maintain homeostasis. These goals are achieved by limiting opioid use as much as possible, while ensuring pain

  Chapter 27  Enhanced Recovery Programs in Hepatobiliary Surgery

control that facilitates full patient function and activity. To achieve this balance, liberal use of opioid-sparing analgesia and neuraxial blocks is advised. Opioid-sparing analgesia begins before the operating room and continues through a patient’s recovery, and regional anesthesia techniques augment pain control and thus reduce the need for opioids postoperatively. Neuraxial and peripheral regional anesthesia techniques (i.e., transversus abdominal plane [TAP], blocks, epidural catheters) are indispensable components of standardized multimodal analgesia strategies to limit opioid consumption while ensuring adequate acute pain control (see Chapter 25). Neuraxial blockade to cover the incisional area for HB surgery typically includes thoracic epidural anesthesia (TEA), which has been shown to be superior to analgesia and result in earlier return of GI tract function.53,54 Epidurals should be performed by experienced practitioners to cover the incisional area and are most beneficial for open surgery. TEA has resulted in superior pain control, patient experience, and decreased opioid consumption without increased length of stay as compared with intravenous (IV) patient-controlled analgesia (PCA) after HB surgery in randomized trials.55,56 Moreover, there may be oncologic benefit compared with IV analgesia, with TEA being associated with improved recurrence-free survival after resection of colorectal liver metastases.57 Use of TEA for HB surgery is the most supported by high-level evidence; however, trials comparing TEA with regional anesthesia techniques are ongoing. As alternatives to neuraxial blockade, peripheral techniques are emerging, such as the TAP and quadratus lumborum (QL) block. These approaches may result in decreased perioperative hypotension and urinary retention that may result from TEA, thus potentially allowing for more efficient return to homeostasis. In studies comparing these approaches with TEA, with some revealing similar pain control, there are conflicting data on opioid consumption being higher or lower than epidural.58,59 For example, epidural analgesia was associated with the lowest inpatient opioid use after pancreatectomy, likely because all patients with TAP blocks may get concomitant IV-PCA.27 Studies comparing peripheral and neuraxial analgesia techniques as they pertain to ERPs for HB surgery are clearly needed.

Operative Approach Most complex HB surgery is performed with an open approach; however, experienced centers have reported improved short-term and similar long-term outcomes with minimally invasive surgery (MIS) approaches60–62 (see Chapter 127). Application of MIS approaches to various aspects of HB surgery, particularly minor hepatectomy and left lateral sectionectomy, have become standard practice and recommended by international consensus guidelines.63,64 Despite this, few studies have evaluated the integration and impact of MIS into ERPs for HB surgery. A randomized trial resulted in decreased LOS for MIS liver surgery patients cared for under an ERP compared with traditional care; however, MIS compared with open HB surgery has not been shown to result in faster recovery within ERPs.65,66 Regardless, MIS HB surgical approaches dovetail with many of the core pillars of enhanced recovery, including resulting in decreased postoperative complications, lower intraoperative blood loss, faster time to oral intake, and decreased need for opioid pain medications.4,60,67–69 Application of MIS HB surgical techniques must be selected for patients with respect to safety and efficiency within the context of an ERP and be performed by surgeons experienced in these approaches.

393

POSTOPERATIVE PHASE Early Mobilization Enhanced recovery principles center on rapid return to homeostasis, and early postoperative mobilization and ambulation is critical to completing an ERP.70 As one of the four pillars of ERPs, it is imperative that patients and team members embrace this intervention. Early ambulation may have tremendous positive impacts on pulmonary function, VTE prevention, and resumption of GI function and is also associated with successful completion of an ERP.70 As previously mentioned, limiting abdominal drains, urinary catheters, invasive lines, and enteric tubes allows for more efficient mobility and prevents further barriers to this critical, simple intervention. Select patient populations will benefit from involvement of physical and occupational therapists.

Postoperative Fluid Resuscitation Once out of the operating room, GDFT remains important for HB surgical patients. Not only does over or under-resuscitation result in potential cardiopulmonary and renal complications, but it also overall impedes return to homeostasis. Postoperative trends in hemodynamics and urine output should guide fluid therapy. Moreover, certain serum laboratory values can help with assessment of intravascular volume, such as serum brain natriuretic peptide (BNP). According to a BNP-guided fluid management protocol, management of bolus fluids, diuresis, and fluid rate adjustments resulted in a fourfold reduction in cardiopulmonary and renal complications after hepatectomy.71 When integrated within ERPs, interventions such as this allow for more refined fluid management during recovery from HB surgery (see Chapters 25 and 26).

Postoperative Nausea and Vomiting Prophylaxis Nausea and emesis can be common after surgery, and efforts should be made to limit or prevent these debilitating symptoms. Team members must evaluate patients for known risk factors for postoperative nausea and vomiting (PONV), and a multimodal prevention approach is also recommended. The use of two antiemetic medications is advocated for by ERAS Society guidelines.4

Diet and Nutrition Rapid return to homeostasis and prevention of catabolism are facilitated by optimizing and maintaining cellular metabolism. Early postoperative nutrition, such as clear liquids on postoperative day 0 and regular diet on postoperative day 1, can shorten the interruption in cellular metabolism and is welltolerated within an ERP for HB surgery.13 It is our preference to avoid a full-liquid diet if possible because many patients may be lactose intolerant.30 Avoidance of NG tubes, encouragement of early ambulation, oral laxatives, and limitation of IV fluid replacement are all part of the multimodal approach to allow for early diet resumption after HB surgery (see Chapter 26).

Pain Control and Opioid-Sparing Analgesia Opioid-sparing analgesia is absolutely imperative to the success of ERPs and a pillar of these strategies. Opioids are helpful for treating acute pain after HB surgery; however, their adverse effects are counterproductive to recovery. These medications can decrease gastric emptying and increase pyloric sphincter tone,

394

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

thus potentiating or inducing PONV and can also cause paralytic ileus. Inability to initiate oral intake ensues, leading to a chain reaction that collapses the enhanced recovery effort. Therefore narcotic limitation, and sometimes omission, can exponentially hasten return of homeostasis. A multimodal approach to pain control supports the opioid-sparing theme, and this is a true perioperative approach. Many non-narcotic adjuncts can be started preoperatively, such as gabapentin, pregabalin, nonsteroidal antiinflammatory drugs (NSAIDs; i.e., Celecoxib), and acetaminophen. These medications form the basis of night of surgery analgesia, obviating the need for high-dose parenteral narcotics. Preoperative education, support, and continual discussion regarding the ability to avoid opioids with adequate analgesia will ensure the success of this approach (see Chapter 25). Benefits of neuraxial blockades initiated in the intraoperative setting continue postoperatively. For example, TEA has been shown to result in significant decrease in opioid use and improved patient reported outcomes, as compared with IVPCA in a randomized controlled trial of HB surgery patients.55 Moreover, regional anesthesia can be helpful as a “rescue” strategy within ERPs after HB surgery for patients struggling with acute pain control. For patients who did not receive neuraxial blockade or block preoperatively, these may be used in the postoperative setting to augment the opioid-sparing approach. Each institution may have particular aptitude in placing a particular type of block, so local preference is acceptable provided blocks are offered and widely applied. The benefits of opioid-sparing analgesia within ERPs can be seen across the entire patient surgical experience, from accelerating functional recovery to decreasing opioid need after discharge. After implementation of an HB-specific ERP at MD Anderson Cancer Center, patients were much less likely to require a prescription for traditional opioids at discharge or require opioids at their initial postoperative clinic visit.72 Although pain scores were similar between patients on ERP versus traditional care pathways, traditional care pathways were a predictor of requiring opioids at first follow-up.72 The efficacy of ERP management clearly extends beyond the traditional perioperative period.

FUTURE OF ENHANCED RECOVERY FOR HB SURGERY The field has made considerable progress since the initial introduction of ERP principles in surgery, particularly as applied to HB surgery patients. But what does the future hold as we move forward? Clearly, the future likely involves more minimally invasive approaches to HB surgical patients, including anesthesia techniques. Moreover, the application of ERP principles them-

selves are being increasingly applied before and longer after the initial perioperative period. With an aging population, more advanced tumors presenting for surgery, and more patients undergoing preoperative therapy, a multidisciplinary approach to preoperative optimization of patients is becoming critical. Prehabilitation programs and other medical optimization approaches have been garnering increasing attention in recent times because it is recognized that poor exercise capacity is strongly associated with worse outcomes after HB surgery.73–75 Therefore patients who are deconditioned by their underlying disease, physical condition, or treatment strategy should be advised to participate in a preoperative multidisciplinary conditioning program to optimize outcomes. Evaluation of these programs, including what interventions lead to improved outcomes, synergy within ERPs, and compliance are an important area of future research within enhanced recovery. Moreover, an organized enhanced recovery approach to HB surgery patients is important, and implementation, audit of consistent variables, and measured compliance are paramount to the program’s success and sustainability.76,77 Adherence to implementation science principles will help to push ERPs across practices. Since the explosion of literature early in the ERP journey, most studies have focused on individual program elements and outcomes, and the language of these variables is not consistent. Moreover, few studies include data on compliance of their program variables when communicating their results.77 Moving towards consistent language with consistent variables will allow cross-program comparisons and, ultimately, better outcomes for HB patients.

CONCLUSION Since the initial reports on enhanced recovery for patients after major abdominal surgery, great progress has been made to expand these principles to complex disciplines, such as HB surgery. By focusing on perioperative strategies for maintaining homeostasis and a rapid return to baseline, patients and members of their multidisciplinary care team have made tremendous improvements in short-term and long-term outcomes. Because HB surgery patients may have unique disease and management characteristics, this makes their ERPs distinct from other complex abdominal surgeries. Going forward, with technique refinements and the expansion of principles across the phases of HB surgical patient care, the multidisciplinary ERP approach will likely evolve to become the standard of care. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

394.e1

REFERENCES 1. Engelman RM, Rousou JA, Flack JE III, et al. Fast-track recovery of the coronary bypass patient. Ann Thor Surg. 1994;58(6):1742-1746. 2. Kehlet H, Mogensen T. Hospital stay of 2 days after open sigmoidectomy with a multimodal rehabilitation programme. Br J Surg. 1999;86(2):227-230. 3. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anesth. 1997;78(5):606-617. 4. Melloul E, Hubner M, Scott M, et al. Guidelines for perioperative care for liver surgery: Enhanced Recovery After Surgery (ERAS) society recommendations. World J Surg. 2016;40(10):2425-2440. 5. Ni TG, Yang HT, Zhang H, Meng HP, Li B. Enhanced recovery after surgery programs in patients undergoing hepatectomy: a meta-analysis. World J Gastroenterol. 2015;21(30):9209-9216. 6. Lei Q, Wang X, Tan S, Xia X, Zheng H, Wu C. Fast-track programs versus traditional care in hepatectomy: a meta-analysis of randomized controlled trials. Digestive Surg. 2014;31(4-5):392-399. 7. MacKay G, O’Dwyer PJ. Early discharge following liver resection for colorectal metastases. Scott Med J. 2008;53(2):22-24. 8. van Dam RM, Hendry PO, Coolsen MM, et al. Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection. Br J Surg. 2008;95(8):969-975. 9. Mizuno T, Cloyd JM, Omichi K, et al. Two-stage hepatectomy vs one-stage major hepatectomy with contralateral resection or ablation for advanced bilobar colorectal liver metastases. J Am Coll Surg. 226(5):825-834. 10. Cloyd JM, Mizuno T, Kawaguchi Y, et al. Comprehensive complication index validates improved outcomes over time despite increased complexity in 3707 consecutive hepatectomies. Ann Surg. 2020;271(4):724-731. 11. Dokmak S, Fteriche FS, Borscheid R, Cauchy F, Farges O, Belghiti J. 2012 Liver resections in the 21st century: we are far from zero mortality. HPB. 2013;15(11):908-915. 12. Farges O, Goutte N, Bendersky N, Falissard B, Group AC-FHS. Incidence and risks of liver resection: an all-inclusive French nationwide study. Ann Surg. 2012;256(5):697-704; discussion 704-705. 13. Kim BJ, Aloia TA. What is “enhanced recovery,” and how can i do it? J Gastrointest Surg. 2018;22(1):164-171. 14. Lillemoe HA, Aloia TA. Enhanced recovery after surgery: hepatobiliary. Surg Clin North Am. 2018;98(6):1251-1264. 15. Kim BJ, Tzeng CD, Cooper AB, Vauthey JN, Aloia TA. Borderline operability in hepatectomy patients is associated with higher rates of failure to rescue after severe complications. J Surg Oncol. 2017;115(3):337-343. 16. Paredes AZ, Hyer JM, Tsilimigras DI, et al. Predictors and outcomes of nonroutine discharge after hepatopancreatic surgery. Surgery. 2019;165(6):1128-1135. 17. Karnofsky DA. Cancer chemotherapeutic agents. CA Cancer J Clin. 1964;14:67-72. 18. Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: The M.D. Anderson Symptom Inventory. Cancer. 2000;89(7):1634-1646. 19. Carey EJ, Steidley DE, Aqel BA, et al. Six-minute walk distance predicts mortality in liver transplant candidates. Liver Transplant. 2010;16(12):1373-1378. 20. Hofheinz M, Mibs M. The Prognostic validity of the timed up and go test with a dual task for predicting the risk of falls in the elderly. Gerontol Geriatr Med. 2016;2:2333721416637798. 21. Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer. 1980;45(8):2220-2224. 22. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 23. Dunne DF, Jack S, Jones RP, et al. Randomized clinical trial of prehabilitation before planned liver resection. Br J Surg. 2016;103(5):504-512. 24. Doherty DT, Coe PO, Rimmer L, Lapsia S, Krige A, Subar DA. Hepatic steatosis in patients undergoing resection of colorectal liver metastases: A target for prehabilitation? A narrative review. Surg Oncol. 2019;30:147-158. 25. Hilliard PE, Waljee J, Moser S, et al. Prevalence of preoperative opioid use and characteristics associated with opioid use among patients presenting for surgery. JAMA Surg. 2018;153(10):929-937.

26. Tang R, Santosa KB, Vu JV, et al. Preoperative opioid use and readmissions following surgery. Ann Surg. 2022;275(1):e99-e106. 27. Newhook TE, Dewhurst WL, Vreeland TJ, et al. Inpatient opioid use after pancreatectomy: opportunities for reducing initial opioid exposure in cancer surgery patients. Ann Surg Oncol. 2019;26(11): 3428-3435. 28. Owodunni OP, Zaman MH, Ighani M, et al. Opioid tolerance impacts compliance with enhanced recovery pathway after major abdominal surgery. Surgery. 2019;166(6):1055-1060. 29. Granziera E, Guglieri I, Del Bianco P, et al. A multidisciplinary approach to improve preoperative understanding and reduce anxiety: a randomised study. Eur J Anaesthesiol. 2013;30(12):734-742. 30. Day RW, Aloia TA. Enhanced recovery in liver surgery. J Surg Oncol. 2019;119(5):660-666. 31. Weimann A, Braga M, Harsanyi L, et al. ESPEN guidelines on enteral nutrition: surgery including organ transplantation. Clin Nutr. 2006;25(2):224-244. 32. Schindler K, Pernicka E, Laviano A, et al. How nutritional risk is assessed and managed in European hospitals: a survey of 21,007 patients findings from the 2007-2008 cross-sectional nutritionDay survey. Clin Nutr. 2010;29(5):552-559. 33. Brady M, Kinn S, Stuart P. Preoperative fasting for adults to prevent perioperative complications. Cochrane Database Syst Rev. 2003(4):CD004423. 34. Gustafsson UO, Scott MJ, Schwenk W, et al. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations. World J Surg. 2013; 37(2):259-284. 35. Gustafsson UO, Hausel J, Thorell A, et al. Adherence to the enhanced recovery after surgery protocol and outcomes after colorectal cancer surgery. Arch Surg. 2011;146(5):571-577. 36. Nygren J, Thacker J, Carli F, et al. Guidelines for perioperative care in elective rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations. World J Surg. 2013;37(2): 285-305. 37. Bilku DK, Dennison AR, Hall TC, Metcalfe MS, Garcea G. Role of preoperative carbohydrate loading: a systematic review. Ann R Coll Surg Engl. 2014;96(1):15-22. 38. Le AT, Harris JW, Maynard E, Dineen SP, Tzeng CD. Thromboelastography demonstrates perioperative hypercoagulability in hepato-pancreato-biliary patients and supports routine administration of preoperative and early postoperative venous thromboembolism chemoprophylaxis. HPB. 2017;19(2):154-161. 39. Melloul E, Dondero F, Vilgrain V, Raptis DA, Paugam-Burtz C, Belghiti J. Pulmonary embolism after elective liver resection: a prospective analysis of risk factors. J Hepatol. 2012;57(6):1268-1275. 40. Tzeng CW, Katz MH, Fleming JB, et al. Risk of venous thromboembolism outweighs post-hepatectomy bleeding complications: analysis of 5651 National Surgical Quality Improvement Program patients. HPB. 2012;14(8):506-513. 41. Jones RS, Brown C, Opelka F. Surgeon compensation: “Pay for performance,” the American College of Surgeons National Surgical Quality Improvement Program, the Surgical Care Improvement Program, and other considerations. Surgery. 2005;138(5):829-836. 42. Bratzler DW, Houck PM, Surgical Infection Prevention Guideline Writers W. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Am J Surg. 2005;189(4):395-404. 43. Darouiche RO, Wall Jr MJ, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010;362(1):18-26. 44. Nelson R, Edwards S, Tse B. Prophylactic nasogastric decompression after abdominal surgery. Cochrane Database Syst Rev. 2007(3):CD004929. 45. Ichida H, Imamura H, Yoshimoto J, Sugo H, Ishizaki Y, Kawasaki S. Randomized controlled trial for evaluation of the routine use of nasogastric tube decompression after elective liver surgery. J Gastrointest Surg 2016;20(7):1324-1330. 46. Nobili C, Marzano E, Oussoultzoglou E, et al. Multivariate analysis of risk factors for pulmonary complications after hepatic resection. Ann Surg. 2012;255(3):540-550. 47. Vreeland TJ, Beaudry Simoneau E, Dewhurst WL, et al. Intraoperative air leak test to prevent bile leak after right posterior sectionectomy with en bloc diaphragm resection for metastatic teratoma. Ann Surg Oncol. 2019;26(8):2579.

394.e2 48. Tran Cao HS, Phuoc V, Ismael H, et al. Rate of organ space infection is reduced with the use of an air leak test during major hepatectomies. J Gastrointest Surg. 2017;21(1):85-93. 49. Zimmitti G, Vauthey JN, Shindoh J, et al. Systematic use of an intraoperative air leak test at the time of major liver resection reduces the rate of postoperative biliary complications. J Am Coll Surg. 2013;217(6):1028-1037. 50. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessorblinded multicenter trial. Ann Surg. 2003;238(5):641-648. 51. Correa-Gallego C, Tan KS, Arslan-Carlon V, et al. Goal-directed fluid therapy using stroke volume variation for resuscitation after low central venous pressure-assisted liver resection: a randomized clinical trial. J Am Coll Surg. 2015;221(2):591-601. 52. Hughes MJ, Ventham NT, Harrison EM, Wigmore SJ. Central venous pressure and liver resection: a systematic review and metaanalysis. HPB. 2015;17(10):863-871. 53. Hanna MN, Murphy JD, Kumar K, Wu CL. Regional techniques and outcome: what is the evidence? Curr Opin Anaesthesiol. 2009;22(5):672-677. 54. Popping DM, Elia N, Van Aken HK, et al. Impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. Ann Surg. 2014;259(6):1056-1067. 55. Aloia TA, Kim BJ, Segraves-Chun YS, et al. A randomized controlled trial of postoperative thoracic epidural analgesia versus intravenous patient-controlled analgesia after major hepatopancreatobiliary surgery. Ann Surg. 2017;266(3):545-554. 56. Revie EJ, McKeown DW, Wilson JA, Garden OJ, Wigmore SJ. Randomized clinical trial of local infiltration plus patient-controlled opiate analgesia vs. epidural analgesia following liver resection surgery. HPB. 2012;14(9):611-618. 57. Zimmitti G, Soliz J, Aloia TA, et al. Positive impact of epidural analgesia on oncologic outcomes in patients undergoing resection of colorectal liver metastases. Ann Surg Oncol. 2016;23(3):10031011. 58. Ayad S, Babazade R, Elsharkawy H, et al. Comparison of transversus abdominis plane infiltration with liposomal bupivacaine versus continuous epidural analgesia versus intravenous opioid analgesia. PloS One. 2016;11(4):e0153675. 59. Ganapathy S, Sondekoppam RV, Terlecki M, Brookes J, Das Adhikary S, Subramanian L. Comparison of efficacy and safety of lateral-to-medial continuous transversus abdominis plane block with thoracic epidural analgesia in patients undergoing abdominal surgery: a randomised, open-label feasibility study. Eur J Anaesthesiol. 2015;32(11):797-804. 60. Noba L, Rodgers S, Chandler C, Balfour A, Hariharan D, Yip VS. Enhanced recovery after surgery (ERAS) reduces hospital costs and improve clinical outcomes in liver surgery: a systematic review and meta-analysis. J Gastrointest Surg. 2020;24(4):918-932. 61. Coolsen MM, Wong-Lun-Hing EM, van Dam RM, et al. A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways. HPB. 2013;15(4): 245-251.

62. Zhao Y, Qin H, Wu Y, Xiang B. Enhanced recovery after surgery program reduces length of hospital stay and complications in liver resection: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017; 96(31):e7628. 63. Wakabayashi G, Cherqui D, Geller DA, et al. Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. Ann Surg. 2015; 261(4):619-629. 64. Abu Hilal M, Aldrighetti L, Dagher I, et al. The Southampton Consensus Guidelines for laparoscopic liver surgery: from indication to implementation. Ann Surg. 2018;268(1):11-18. 65. Liang X, Ying H, Wang H, et al. Enhanced recovery care versus traditional care after laparoscopic liver resections: a randomized controlled trial. Surg Endosc. 2018;32(6):2746-2757. 66. Ratti F, Cipriani F, Reineke R, et al. Impact of ERAS approach and minimally-invasive techniques on outcome of patients undergoing liver surgery for hepatocellular carcinoma. Dig Liver Dis. 2016; 48(10):1243-1248. 67. Xiong JJ, Altaf K, Javed MA, et al. Meta-analysis of laparoscopic vs open liver resection for hepatocellular carcinoma. World J Gastroenterol. 2012;18(45):6657-6668. 68. Mirnezami R, Mirnezami AH, Chandrakumaran K, et al. Short- and long-term outcomes after laparoscopic and open hepatic resection: systematic review and meta-analysis. HPB. 2011;13(5):295-308. 69. Bhojani FD, Fox A, Pitzul K, et al. Clinical and economic comparison of laparoscopic to open liver resections using a 2-to-1 matched pair analysis: an institutional experience. J Am Coll Surg. 2012;214(2):184-195. 70. Yip VS, Dunne DF, Samuels S, et al. Adherence to early mobilisation: key for successful enhanced recovery after liver resection. Eur J Surg Oncol. 2016;42(10):1561-1567. 71. Patel SH, Kim BJ, Tzeng CD, et al. Reduction of cardiopulmonary/ renal complications with serum BNP-guided volume status management in posthepatectomy patients. J Gastrointest Surg. 2018; 22(3):467-476. 72. Lillemoe HA, Marcus RK, Day RW, et al. Enhanced recovery in liver surgery decreases postoperative outpatient use of opioids. Surgery. 2019;166(1):22-27. 73. Junejo MA, Mason JM, Sheen AJ, et al. Cardiopulmonary exercise testing for preoperative risk assessment before hepatic resection. Br J Surg. 2012;99(8):1097-1104. 74. Snowden CP, Prentis J, Jacques B, et al. Cardiorespiratory fitness predicts mortality and hospital length of stay after major elective surgery in older people. Ann Surg. 2013;257(6):999-1004. 75. Ulyett S, Wiggans MG, Bowles MJ, et al. Clinical assessment before hepatectomy identifies high-risk patients. J Surg Res. 2015; 198(1):87-92. 76. Aloia TA, Keller DS, Kowalski RB, et al. Enhanced recovery program implementation: an evidence-based review of the art and the science. Surg Endosc. 2019;33(11):3833-3841. 77. Day RW, Fielder S, Calhoun J, Kehlet H, Gottumukkala V, Aloia TA. Incomplete reporting of enhanced recovery elements and its impact on achieving quality improvement. Br J Surg. 2015;102 (13):1594-1602.

CHAPTER 28 Postoperative complications requiring intervention: Diagnosis and management Franz Edward Boas and Stephen B. Solomon

IMAGING AND IMAGE-GUIDED THERAPY OF COMPLICATIONS AFTER PANCREATECTOMY Imaging After Pancreatectomy Computed tomography (CT) is the most common imaging modality for evaluation of the pancreas after surgery. Complications that can be detected on CT include anastomotic leak, abscess, fistula, and bleeding (see Chapters 62 and 117). Fluid collections, such as seromas, abscesses, and pancreatic pseudocysts, can be identified on CT (Fig. 28.1). Rim enhancement suggests abscess or pseudocyst. Gas within a collection suggests infection or enteric leak. Enteric leaks can have a thin tract containing gas and fluid, extending from an enteric anastomosis to an abscess. Oral contrast given before the CT can leak into the abscess, which is diagnostic of an enteric leak. Postoperative bleeding can be evaluated using a CT angiogram, which should include noncontrast and arterial phases. Hematomas are visible on noncontrast CT as high density (greater than 20 Hounsfield units) collections. Active arterial bleeding is seen as extravasation of contrast on arterial phase contrast-enhanced CT (CECT) scans. On delayed phase images (if obtained), the extravasated contrast continues to spread if there is active bleeding. On the other hand, a pseudoaneurysm (which can bleed intermittently) is an enhancing structure next to an artery, which maintains its shape on delayed CT images (Figs. 28.2 and 28.3). Magnetic resonance cholangiopancreatography (MRCP) is a fluid-sensitive magnetic resonance imaging (MRI) sequence that clearly shows the pancreatic duct, bile ducts, fistulas, and fluid collections. The MRCP is typically reconstructed into axial and coronal slices, as well as a three-dimensional (3D) images. The site of a pancreatic fistula can be identified in 75% of patients on CT, compared with 93% on MRCP.1

Interventional Radiology Procedures Postpancreatectomy Many postpancreatectomy complications are managed using image-guided percutaneous interventions, reducing the need for reoperation. After pancreaticoduodenectomy, 12% to 22% of patients require percutaneous intervention,2,3 including intra-abdominal abscess drainage (72%), percutaneous biliary drainage (PBD; 18%), and angiography with or without embolization (10%).4

Image-Guided Abdominal Drainage Postoperative abscesses can be drained percutaneously, using ultrasound or CT guidance (see Fig. 28.1). Small abscesses (,3 cm) can usually be treated with antibiotics alone, but larger collections require both antibiotics and drainage. Complications

of image-guided drainage of fluid collections are infrequent but include bleeding, sepsis, and peritonitis. Abscesses are typically drained using the Seldinger technique. A needle is advanced into the collection under ultrasound or CT guidance. After aspirating fluid, a stiff guide wire is placed through the needle into the collection. The needle is then removed, and a drain is placed over the wire into the collection. Typically, 8 to 10 French (Fr) drains are placed in thin, serous collections, and 10 to 12 Fr drains are placed in thick bloody or purulent collections.5 Larger drains are available for very thick collections, up to 20 Fr for locking loop drains and 36 Fr for straight drains. Biliary-type drains (which have additional side holes) may be helpful for long, multiloculated collections. After catheter placement, the abscess is emptied, and specimens are sent for gram stain and culture. The fluid can also be sent for amylase (to evaluate for pancreatic leak) and bilirubin (to evaluate for bile leak). Drain fluid to serum bilirubin ratio greater than five indicates a bile leak,6 and drain amylase to serum ratio greater than five indicates a pancreatic leak.7

Drain Management The drain should be flushed with normal saline two to three times per day to prevent clogging. Drainage from loculated collections can be improved by injecting tissue plasminogen activator (tPA) into the tube. One report showed an 89% success rate using tPA to drain abscesses refractory to simple catheter drainage.8 In a postsurgical patient, the benefit of tPA should be weighed against the risk of bleeding. If the drain output remains high, this suggests an ongoing pancreatic or enteric leak. The drain should be positioned adjacent to the leak for optimal drainage. When output from the drain decreases, the locking loop drain can be exchanged for a straight drain to collapse the abscess cavity adjacent to the leak. The straight drain can be slowly pulled back over days or weeks in an attempt to close the fistula. Occasionally, a persistent fistula is seen on abscessogram, even after the patient is doing well clinically, with no residual abscess cavity and no output from the drain. This is a one-way fistula, and the drain can usually be safely removed. Management of persistent pancreatic leaks is discussed later (see “Interventional Management of Pancreaticocutaneous Fistulas”). Minimal output from the drain indicates that the drainage is complete or that the drain is clogged or malpositioned. Pus leaking around a drain suggests that the drain is clogged and should be assessed with cross-sectional imaging or a tube study. Clogged drains can be exchanged over a guidewire. An abscess drain can typically be removed when the output is less than 20 mL a day, the patient has no fever or pericatheter leakage, and the drain flushes easily. An abscessogram or CT 395

396

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

A

B

FIGURE 28.1  A 77-year-old female patient after distal pancreatectomy for neuroendocrine tumor. A, Postoperative development of a large rim-enhancing fluid collection in the operative bed, suspicious for abscess or pseudocyst (asterisk). B, Computed tomography (CT)-guided drainage of the fluid collection with a 10-French (Fr) drainage catheter. Rust-colored fluid was aspirated and sent for analysis, which showed elevated amylase and negative culture, consistent with a pancreatic leak. The catheter was removed after the output had diminished. C, CT follow-up 10 months after drain removal showed resolution of the fluid collection (asterisk).

C

Extravasation

Pseudoaneurysm

Adventitia Media Intima Blood vessel

FIGURE 28.2  A pseudoaneurysm is a contained arterial rupture, which can bleed intermittently. On angiogram or computed tomography (CT) angiogram, it looks like a round enhancing structure. On the other hand, active extravasation of contrast looks like a jet of contrast on angiography, which continues to spread on delayed images.

scan can be performed before drain removal to ensure resolution of the cavity. An abscessogram shows if the tube is clogged or malpositioned, as well as the size of the residual collection and any fistulas. A CT scan shows the position of the tube and any undrained collections. On CT, a residual collection around an abscess drain indicates a clogged or poorly functioning drain. The median drainage time is 11 days for sterile fluid collections, 29 days for abscesses, and 30 days when there is a pancreatic leak.2

Interventional Management of Pancreaticocutaneous Fistulas Pancreatic leaks with pancreaticocutaneous fistulas can develop after pancreatic surgery. Most fistulas resolve after one month of conservative therapy, including jejunal feedings, somatostatin analogues, pseudocyst drains, and endoscopic stent placement in the pancreatic duct.9,10 The fistula is likely to persist if there is complete transection of the pancreatic duct, if there is a downstream ductal stricture, or if it is a high-output fistula.9 Several percutaneous approaches have been described for reconnecting the pancreas to the gastrointestinal (GI) tract to

  Chapter 28  Postoperative Complications Requiring Intervention: Diagnosis and Management

A

B

C

D

397

FIGURE 28.3  A 63-year-old female patient had clinical evidence of bleeding 3 weeks after pancreaticoduodenectomy for pancreatic adenocarcinoma. A, Computed tomography (CT) angiogram showed a large hematoma (arrowheads) in the subhepatic space, with highly enhancing components within this hematoma, consistent with a pseudoaneurysm (arrows) at the origin of the gastroduodenal artery. B, Catheter angiography confirmed a pseudoaneurysm (arrow) of the gastroduodenal artery, which was treated by occluding both the proper hepatic (outflow) and common hepatic arteries (inflow) with stainless steel coils. C, Postembolization angiogram showed coils in the hepatic arteries (arrows), with no enhancement of the hepatic arteries or the pseudoaneurysm of the gastroduodenal artery. D, A 46-year-old male had gastroduodenal artery stump bleeding after pancreaticoduodenectomy, which was treated by placement of a covered stent (between arrows) into the hepatic artery. Covered stent placement preserves hepatic arterial flow.

divert pancreatic fluid away from the fistula and allow it to heal. Cystogastrostomy (surgical, endoscopic, or percutaneous) can be performed if there is a pseudocyst associated with the fistula. If the pancreatic duct is dilated (.4 mm), then it can be punctured percutaneously, allowing for placement of a drain from the pancreatic duct to the stomach or bowel.11 However, the pancreatic duct is frequently nondilated because it is decompressed into the cutaneous tract. If the pancreatic duct is not dilated, then a snare can be placed into the duct via the cutaneous

fistula, providing a target for percutaneous puncture and drainage of the duct into the stomach.12

Management of Hemorrhage: Angiography, Embolization, and Covered Stent Placement (see Chapters 21, 31, and 115) Hemorrhage is seen in less than 10% of patients after pancreatectomy but is associated with high mortality.13 Major bleeding is seen on average 19 days after surgery and is usually preceded by a smaller sentinel bleed.14 Therefore even a small amount of

398

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

A

B

FIGURE 28.4  A 72-year-old female patient developed hemoperitoneum after pancreaticoduodenectomy. A, Angiogram showed a small pseudoaneurysm of the left hepatic artery (arrow). B, After coil embolization (arrow), the left hepatic artery is now supplied by the right hepatic artery, via intrahepatic collaterals (arrowhead).

increased bleeding from surgical drains or GI bleeding more than three days after pancreatic surgery should be evaluated immediately. Bleeding can be because of vessel injury during surgery or because of pancreatic fluid eroding the vessel wall. In hemodynamically stable patients, CT angiography can identify the bleeding vessel. CT angiogram is most likely to be positive if performed when the patient is actively bleeding. Hemodynamically unstable patients should proceed directly to catheter angiography and intervention or to the operating room. Pseudoaneurysms and arterial extravasation after pancreatic surgery occur in the gastroduodenal artery (GDA) most commonly, followed by the hepatic artery, superior mesenteric artery (SMA), and splenic artery15 (see Chapter 115). Selective coil embolization across the pseudoaneurysm is successful in approximately 85% of patients.16 In an otherwise normal liver, the right or left hepatic arteries can be safely coil embolized (Fig. 28.4) because the embolized lobe of the liver will be supplied by the portal vein and intrahepatic arterial collaterals.17 The proximal splenic artery can also be safely coil embolized without complete splenic infarction, because of collateral arterial supply to the spleen.18 Pseudoaneurysms and arterial extravasation can also be treated using a covered stent to exclude the pseudoaneurysm while preserving distal flow.19,20 Covered stents are particularly helpful for GDA stump blowouts (where coil embolization might not be technically possible), distal splenic artery pseudoaneurysms (where embolization has a higher risk of splenic infarction), common and proper hepatic artery pseudoaneurysms (to preserve arterial flow to the liver), and SMA pseudoaneurysms (to preserve flow to bowel). Examples of embolization and covered stent placement for bleeding after pancreatic surgery are shown in Figs. 28.3 and 28.4.

IMAGING AND IMAGE-GUIDED THERAPY OF COMPLICATIONS AFTER HEPATECTOMY

system. Postoperative bilomas, hematomas, and abscesses can be detected with these imaging modalities. The typical appearance of a biloma on imaging is that of an encapsulated fluid collection adjacent to the liver resection plane. Rim enhancement of a fluid collection suggests infection, but this is not a specific finding. In some cases, aspiration may be required to distinguish between infected and noninfected collections. A postoperative biloma, hematoma, or seroma might initially be sterile but can progress to become an abscess. Gas within a collection suggests infection or enteric leak. A HIDA scan, also known as hepatobiliary scintigraphy, is a nuclear medicine scan that can show biliary leaks.21 Although 99 Tc-HIDA has largely been replaced by other radiotracers (which have improved liver uptake), the term “HIDA scan” remains in common use. A normal HIDA scan initially shows radiotracer uptake in liver, followed by excretion of radiotracer into the bile ducts, gallbladder, and small bowel. Pooling of tracer elsewhere indicates a bile leak. HIDA scans are typically two-dimensional (2D) images acquired with a gamma camera, but fused 3D images can also be obtained, using a single photon emission computed tomography (SPECT)/CT scan. The 3D images can be helpful for more precise anatomic localization (see Chapter 18). MRCP is an MRI protocol optimized for seeing the bile ducts. It can show the anatomy of the biliary tree and any associated bilomas. MRCP can also show a biliary leak, when it is performed using an intravenous (IV) contrast agent that is excreted into the bile ducts, such as gadoxetate (Eovist).22 (Typically, MRCP is performed without IV contrast.) MRCP has higher resolution than a HIDA scan and can show the biliary tree more clearly than CT (see Chapter 16). Acute and subacute hematomas appear as high density collections on CT. In addition, active bleeding can be demonstrated by contrast media extravasation on CECT.

Interventional Radiology Procedures Posthepatectomy

Imaging After Hepatectomy

Intrahepatic Abscess Drainage

Ultrasound, CT, hepatobiliary iminodiacetic acid (HIDA) scan, and MRI/MRCP can be used to evaluate the liver and biliary

Small pyogenic liver abscesses can be successfully treated with antibiotics alone. Large (.3 cm) unilocular abscesses can be

  Chapter 28  Postoperative Complications Requiring Intervention: Diagnosis and Management

treated with percutaneous drainage and antibiotics. Large multiloculated abscesses have a lower success rate with percutaneous drainage and might require surgery.23 Intracavitary tPA can help drain multiloculated collections that are refractory to simple percutaneous drainage.8 When biliary obstruction is present, relief of the obstructed biliary tree is mandatory for successful abscess treatment. Abscesses located near the dome of the liver may be technically more difficult to drain without transgressing the pleura. Transpleural abscess drains carry a risk of empyema.

Interventional Management of Bilomas and Bile Leaks After liver resection, bile can leak from a bile duct injury, bilioenteric anastomosis, or the cut surface of the liver. Bile leakage can cause bile peritonitis and bilious fluid collections that can become infected. These fluid collections can be drained percutaneously, under CT, or using ultrasound guidance. When an infected biloma is drained, the fluid can initially appear purulent, then may turn bilious if there is a continued bile leak after the infection clears. Ideally, the drain should be placed near the bile leak to provide optimal drainage. The amount of drain output allows for monitoring of the amount of bile leak over time. Small bile leaks can resolve spontaneously.24 Persistent drainage greater than 100 mL a day (at 10 days posthepatectomy) should be treated with ERCP and placement of a plastic biliary stent or PBD placement, which decompresses the biliary system and diverts bile flow away from the defect in the bile ducts, allowing the leak to heal (Fig. 28.5). Complete transection of a bile duct at the hilum typically requires surgical repair. PBD is the preferred treatment for high bile duct injuries (at or above the bifurcation) and bilioenteric anastomotic leaks, both of which are difficult to access endoscopically. ERCP is less invasive than PBD and is the preferred treatment for leaks from the cut surface of the liver and for accessible common duct leaks (see Chapters 20, 30, and 31). PBD healed 88% to 100% of postoperative bile leaks, after an average of one to three months of drainage.25,26 Retrievable covered stents can be placed for common duct leaks.27 Intractable bile leaks can be managed with surgery, portal vein embolization,28 or bile duct embolization with N-butyl cyanoacrylate glue.29

A

B

399

Interventional Management of Biliary Strictures Postoperative biliary strictures can occur after hepatectomy, cholecystectomy, choledochojejunostomy, liver transplant, and other procedures. These strictures can be caused by direct biliary injury from surgery, ischemia, or recurrent tumor. Benign and malignant strictures can be difficult to distinguish on imaging, and biopsy may be required. Biliary strictures can cause jaundice, cholangitis, and pruritis (see Chapters 31 and 42). Low bile duct obstruction (common bile duct or common hepatic duct not involving the bifurcation) can be relieved via ERCP and placement of a plastic or metal biliary stent across the obstruction. High bile duct obstruction and bilioenteric anastomotic strictures (both of which are difficult to access endoscopically) can be treated with PBD or metal stent placement. Metal stents are typically only used for malignant obstruction because they have a limited patency rate (30 months on average when used for benign disease).30 However, retrievable covered stents can be used to treat benign biliary strictures31,32 (see Chapter 30). If the biliary stricture cannot be crossed percutaneously, an external biliary drain can be placed. If the biliary stricture can be crossed, an internal/external biliary drain is placed, which has side holes both above and below the obstruction. An internal/external biliary drain can be capped if there is no leak, infection, or significant blood in the bile and should be flushed daily with 10 mL normal saline to maintain patency. Biliary drains are typically exchanged every three months to prevent clogging, but are exchanged more frequently if cholangioplasty or other interventions are planned. An overthe-wire cholangiogram can be performed through a sheath that does not cross the bile duct injury to evaluate for persistent leak or stenosis. If the bile duct injury has resolved on the cholangiogram, then an external biliary drain can be placed to maintain access to the bile ducts. This external drain should be capped for two weeks without flushing. If the patient passes the capping trial (no fever, no significant leakage around the tube, no rise in bilirubin), then the drain can be safely removed. Benign biliary strictures are typically managed with endoscopic placement of a plastic biliary stent or percutaneous internal/external biliary drainage. Cholangioplasty can be performed

C

FIGURE 28.5  A 57-year-old male patient with metastatic colon cancer developed a bile leak after extended right hepatectomy. A biloma drain was placed, which was draining 700 mL of bile per day. A, Percutaneous cholangiogram shows a bile leak (arrow) into the biloma cavity (arrowhead). B, A left internal/external biliary drain (arrow) was placed to divert bile away from the biloma drain (arrowhead). C, After two months of biliary drainage, biloma drain output decreased to 15 mL per day. Follow-up cholangiogram shows resolution of the bile leak. The internal/external biliary drain was converted to an external biliary drain for a two-week capping trial before removal.

400

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

using a high pressure balloon during biliary drain placement or exchange. High pressures and prolonged cholangioplasty (up to 15 minutes) are typically required to overcome the dense fibrous tissue around biliary strictures. An 8-mm balloon can be used for intrahepatic strictures, and a 10- to 12-mm balloon for common duct strictures. Cholangioplasty can be repeated at two to 14 day intervals.33 For benign biliary strictures, cholangioplasty and internal/external biliary drainage have a long-term (25 years) primary success rate of 59% and a secondary success rate of 80%33 (see Chapter 31).

Malignant biliary obstruction can be relieved with a biliary drainage catheter to treat cholangitis or pruritis, or to lower bilirubin for chemotherapy. A metal biliary stent can be placed (percutaneously or endoscopically) for palliation of unresectable symptomatic biliary obstruction in patients with limited life expectancy. Metal biliary stents placed for malignant obstruction remain patent for an average of 11 months.34 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

400.e1

REFERENCES 1. O’Toole D, Vullierme MP, Ponsot P, et al. Diagnosis and management of pancreatic fistulae resulting in pancreatic ascites or pleural effusions in the era of helical CT and magnetic resonance imaging. Gastroenterol Clin Biol. 2007;31(8-9 Pt 1):686-693. 2. Zink SI, Soloff EV, White RR, et al. Pancreaticoduodenectomy: frequency and outcome of post-operative imaging-guided percutaneous drainage. Abdom Imaging. 2009;34(6):767-771. 3. Sohn TA, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy: role of interventional radiologists in managing patients and complications. J Gastrointest Surg. 2003;7(2):209-219. 4. Baker TA, Aaron JM, Borge M, Pierce K, Shoup M, Aranha GV. Role of interventional radiology in the management of complications after pancreaticoduodenectomy. Am J Surg. 2008;195(3):386-390; discussion 390. 5. Rotman JA, Getrajdman GI, Maybody M, et al. Effect of abdominopelvic abscess drain size on drainage time and probability of occlusion. Am J Surg. 2017;213(4):718-722. 6. Darwin P, Goldberg E, Uradomo L. Jackson Pratt drain fluid-toserum bilirubin concentration ratio for the diagnosis of bile leaks. Gastrointest Endosc. 2010;71(1):99-104. 7. Shinchi H, Wada K, Traverso LW. The usefulness of drain data to identify a clinically relevant pancreatic anastomotic leak after pancreaticoduodenectomy? J Gastrointest Surg. 2006;10(4):490-498. 8. Beland MD, Gervais DA, Levis DA, Hahn PF, Arellano RS, Mueller PR. Complex abdominal and pelvic abscesses: efficacy of adjunctive tissue-type plasminogen activator for drainage. Radiology. 2008;247(2):567-573. 9. Voss M, Pappas T. Pancreatic fistula. Curr Treat Options Gastroenterol. 2002;5(5):345-353. 10. Klek S, Sierzega M, Turczynowski L, Szybinski P, Szczepanek K, Kulig J. Enteral and parenteral nutrition in the conservative treatment of pancreatic fistula: a randomized clinical trial. Gastroenterology. 2011;141(1):157-163.e151. 11. Cope C, Tuite C, Burke DR, Long WB. Percutaneous management of chronic pancreatic duct strictures and external fistulas with longterm results. J Vasc Interv Radiol. 2001;12(1):104-110. 12. Boas FE, Kadivar F, Kelly PD, Drebin JA, Vollmer CM, ShlanskyGoldberg RD. Targeted transgastric drainage of isolated pancreatic duct segments to cure persistent pancreaticocutaneous fistulas from pancreatitis. J Vasc Interv Radiol. 2015;26(2):247-251. 13. Puppala S, Patel J, McPherson S, Nicholson A, Kessel D. Hemorrhagic complications after Whipple surgery: imaging and radiologic intervention. AJR Am J Roentgenol. 2011;196(1):192-197. 14. Otah E, Cushin BJ, Rozenblit GN, Neff R, Otah KE, Cooperman AM. Visceral artery pseudoaneurysms following pancreatoduodenectomy. Arch Surg. 2002;137(1):55-59. 15. Tien YW, Wu YM, Liu KL, Ho CM, Lee PH. Angiography is indicated for every sentinel bleed after pancreaticoduodenectomy. Ann Surg Oncol. 2008;15(7):1855-1861. 16. Tsai CC, Chiu KC, Mo LR, et al. Transcatheter arterial coil embolization of iatrogenic pseudoaneurysms after hepatobiliary and pancreatic interventions. Hepatogastroenterology. 2007;54(73): 41-46. 17. Nicholson T, Travis S, Ettles D, et al. Hepatic artery angiography and embolization for hemobilia following laparoscopic cholecystectomy. Cardiovasc Intervent Radiol. 1999;22(1):20-24.

18. Yamamoto S, Hirota S, Maeda H, et al. Transcatheter coil embolization of splenic artery aneurysm. Cardiovasc Intervent Radiol. 2008;31(3):527-534. 19. Heiss P, Bachthaler M, Hamer OW, et al. Delayed visceral arterial hemorrhage following Whipple’s procedure: minimally invasive treatment with covered stents. Ann Surg. 2008;15(3):824-832. 20. Suzuki K, Mori Y, Komada T, Matsushima M, Ota T, Naganawa S. Stent-graft treatment for bleeding superior mesenteric artery pseudoaneurysm after pancreaticoduodenectomy. Cardiovasc Intervent Radiol. 2009;32(4):762-766. 21. Arun S, Santhosh S, Sood A, Bhattacharya A, Mittal BR. Added value of SPECT/CT over planar Tc-99m mebrofenin hepatobiliary scintigraphy in the evaluation of bile leaks. Nucl Med Commun. 2013;34(5):459-466. 22. Aduna M, Larena JA, Martin D, Martinez-Guerenu B, Aguirre I, Astigarraga E. Bile duct leaks after laparoscopic cholecystectomy: value of contrast-enhanced MRCP. Abdom Imaging. 2005;30(4): 480-487. 23. Hope WW, Vrochides DV, Newcomb WL, Mayo-Smith WW, Iannitti DA. Optimal treatment of hepatic abscess. Am Surgeon. 2008;74(2): 178-182. 24. Vigano L, Ferrero A, Sgotto E, Tesoriere RL, Calgaro M, Capussotti L. Bile leak after hepatectomy: predictive factors of spontaneous healing. Am J Surg. 2008;196(2):195-200. 25. Cozzi G, Severini A, Civelli E, et al. Percutaneous transhepatic biliary drainage in the management of postsurgical biliary leaks in patients with nondilated intrahepatic bile ducts. Cardiovasc Intervent Radiol. 2006;29(3):380-388. 26. Ernst O, Sergent G, Mizrahi D, Delemazure O, L’Hermine C. Biliary leaks: treatment by means of percutaneous transhepatic biliary drainage. Radiology. 1999;211(2):345-348. 27. Gwon DI, Ko GY, Sung KB, Kim JH, Yoon HK. Percutaneous transhepatic treatment of postoperative bile leaks: prospective evaluation of retrievable covered stent. J Vasc Interv Radiol. 2011;22(1):75-83. 28. Hai S, Tanaka H, Takemura S, Sakabe K, Ichikawa T, Kubo S. Portal vein embolization for an intractable bile leakage after hepatectomy. Clin J Gastroenterol. 2012;5(4):287-291. 29. Vu DN, Strub WM, Nguyen PM. Biliary duct ablation with N-butyl cyanoacrylate. J Vasc Interv Radiol. 2006;17(1):63-69. 30. Tesdal IK, Roeren T, Weiss C, Jaschke W, Dueber C. Metallic stents for treatment of benign biliary obstruction: a long-term study comparing different stents. J Vasc Interv Radiol. 2005;16(11):1479-1487. 31. Gwon DI, Ko GY, Ko HK, Yoon HK, Sung KB. Percutaneous transhepatic treatment using retrievable covered stents in patients with benign biliary strictures: mid-term outcomes in 68 patients. Dig Dis Sci. 2013;58(11):3270-3279. 32. Cote GA, Slivka A, Tarnasky P, et al. Effect of covered metallic stents compared with plastic stents on benign biliary stricture resolution: a randomized clinical trial. JAMA. 2016;315(12):1250-1257. 33. Cantwell CP, Pena CS, Gervais DA, Hahn PF, Dawson SL, Mueller PR. Thirty years’ experience with balloon dilation of benign postoperative biliary strictures: long-term outcomes. Radiology. 2008;249(3):1050-1057. 34. Dahlstrand U, Sandblom G, Eriksson LG, Nyman R, Rasmussen IC. Primary patency of percutaneously inserted self-expanding metallic stents in patients with malignant biliary obstruction. HPB. 2009;11(4):358-363.

CHAPTER 29 The impact of hepatobiliary interventions on health and quality of life and health Piera Marie Cote Robson THE CONCEPTS OF HEALTH AND QUALITY OF LIFE Promotion of health and restoration of quality of life is central to the delivery of healthcare. There is limited value in engaging in a medical intervention if there is no anticipated impact on health or improvement in quality of life. This chapter will explore the concepts and tools used to measure health and quality of life and will summarize current research on how hepatobiliary interventions impact patients’ perceptions of their health and quality of life.

Health The Constitution of the World Health Organization (WHO) defines health as a “state of complete physical, mental, and social well-being, not merely the absence of disease.”1 This definition integrates three components of well-being (physical, mental and social) into a holistic view of health. Physical health reflects the physiologic and biologic components of health and the maintenance of homeostasis.2 Mental health is the aspect of health that relates to a person’s mental status or their psychological and emotional state.2 Social health is the ability of a person to engage in the social aspects of life and fill roles within society.2 The WHO takes the position that the measurement of health is as important as evaluating the severity of disease. Over time, the perception of disease has evolved from the biomedical concept of disease to the broader biopsychosocial model of disease. The biomedical concept restricts the focus of disease to one of “organic malfunction.”3 This narrow view was broadened in the biopsychological model, which was first proposed by George Engel in 1977. “To provide a basis for understanding the determinants of disease and arriving at rational treatments and patterns of healthcare, a medical model must also take into account the patient, the social context in which he [sic] lives, and the complementary system devised by society to deal with the disruptive effects of illness, that is, the physician role and the health care system.”4 The biopsychological model encourages healthcare professionals to incorporate all aspects of health into their clinical care and decision making, weighing various aspects of health, as needed, to optimally address the patient’s clinical presentation.3 The attention to the effect of a person’s social situation on health has gained increased attention in this century, particularly with regard to how societal differences impact health and health equality.5 Social determinants of health (SDH) are the “conditions in the environments in which people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks.”6

The key areas of SDH are “economic stability, education, social and community context, health and health care, neighborhood and built environment.”6 To achieve population health, the WHO has called for the evaluation of SDH in clinical care and the incorporation of SDH into research so that the effect of SDH on a person’s health can be recognized, addressed, and measured. As the biopsychological model has gained acceptance, the question turns from whether health should be assessed to how best evaluate it. The evaluation of health necessarily includes the biomedical aspects provided by objective clinical data. Incorporated into this evaluation are assessments of psychological health including depression, delirium, and suicide screening.7–9 Social aspects of health are incorporated into patient assessment by exploring social determinants of health such as by assessing financial toxicity and food and housing insecurity.10 A patient’s well-being is evaluated using a measure of quality of life (QOL).11

Quality of Life QOL has been frequently defined as the “individual’s perception of their position in life in the context of their culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns.”11 The concept of QOL reflects the experience of an individual and is an evaluation of their own life.12 It is built on culture, experience, values, goals, expectations, and standards.11 In the very broadest of terms, QOL is multidimensional and influenced by many factors outside the realm of health/disease, including self-esteem, spirituality, financial security, job satisfaction, and personal freedom.13 The WHO Quality of Life Group (1998) offered a succinct definition of QOL as “a subjective evaluation that is embedded in a cultural, social and environmental context.”13 QOL was first discussed in the literature in the 1960s when it was realized that the extension of life through a medical intervention did not always result in the improvement of QOL.14 It was also recognized that medical interventions, at times, resulted in a cost to QOL.14,15 The term “health-related quality of life” (HRQOL) is often use to describe QOL related to healthcare experiences. HRQOL does not consider factors that affect QOL that are outside of the purview of the healthcare system including cultural, economic, and political factors.16 Excluding factors that are not managed by clinicians offers an incomplete view of the person by excluding social well-being from assessment, and it devalues the impact of SDH on the health of individuals. It undermines the holistic approach of the biopsychosocial model and takes a narrow view of QOL similar to the narrow view of the biomedical model of disease.17 The assessment of QOL is an assessment of a patientreported outcome (PRO) measure. PRO is “used as an umbrella 401

402

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

term for different concepts for measuring subjectively perceived health status.”18 PRO includes any direct report by a patient of their health condition that has not been interpreted by a clinician or anyone else.19 PRO measures can assess a single value at one point in time or measure change in that value over time.18 The psychometrical approach to PRO measures is used most commonly in healthcare. This approach refers to the individual reporting of the presence and quality of perceived symptoms, the functional state, QOL, health behaviors, satisfaction, and emotional and mental status.18 How the individual reports these measures is their prerogative; however, consensus has not been achieved regarding the definition of concepts measured by PROs. As such, there is an opportunity for additional research in this field.18 The interrelationships between different PROs have not been clearly defined. Wilson and Cleary developed a conceptual framework to describe the relationships between five different measures of health.16 The five measures of health are physiologic and biologic factors, symptoms, functioning, general health perceptions, and overall QOL. This linear model depicts the relationships on a continuum from biologic and physiologic processes to symptoms to function followed by health perceptions, which result in QOL. The framework depicts characteristics of the individual and environment as moderators of health measures. This is a parsimonious model that describes and explains health and can be used to evaluate health outcomes and their relationships with QOL. Patient report is the key feature of PRO measures. For practical reasons, initial investigations of QOL and other PRO measures used the external judgment of observers, typically nurses or clinicians, to evaluate treatment impact. Examples of this are the commonly used measures of performance such as the Karnofsky Performance Scale (KPS) Index20 and the Eastern Cooperative Oncology Group (ECOG) Performance Index.21 These are measures of function and performance, but they are not PROs because they provide the clinician’s perception of the patient’s status, not the patient’s report of their function and performance. This method of evaluating patient outcomes is inherently biased by the observer’s own internal standards. Multiple studies evaluating the degree of agreement between the proxy ratings of QOL by observers to patient assessments have consistently found very little correlation between the two measures.22–27 In clinical trial research, up to 76% of cases with severe symptoms are underreported by providers.28–30 The validity of QOL instruments and rigor of results is contingent on patients’ reporting. Unfortunately, this requisite self-reporting can become an issue when patients are followed over time because disease status and symptoms worsen, making completion more challenging. With time, patients are less likely to fill out instruments, leading to nonrandom missing data, which is a significant challenge in QOL research.31,32 Feinstein33 coined the term “sensibility” of QOL instruments to denote the practical issues related to implementation of QOL measurements. All PRO measures must be evaluated before use from the perspective of the patient. The number of items in a measure, the thought required to complete the measure, and the time required to complete a measure can lead to “questionnaire burn-out” and subsequent patient noncompletion. Other issues, such as literacy and preferred language, may prohibit patients from completing instruments independently.

Measurement of Quality of Life Essential to the assessment of QOL are instruments developed specifically to measure the construct of QOL. As with the conceptual evolution, assessment of QOL in the clinical setting has been progressive. In the field of oncology, there was a need to assess the “quality of survival” since early chemotherapeutic treatments were severely toxic and there were few options to mitigate the adverse effects.34 In 1982 the Eastern Cooperative Oncology Group published criteria to measure the toxicity from treatment. All included measures were objective clinical parameters except for their novel performance status scale.21 In the absence of specific measures of QOL, some researchers reported the ECOG scale and the KPS as surrogates for QOL despite being single unidimensional parameters of performance. With time, the void of valid and reliable instruments for QOL assessment has been filled with multidimensional instruments of QOL with well-established psychometric properties. The availability of QOL instruments has led to increasing acceptance of their importance as a necessary outcome measure in oncology and surgery. The WHO lists benefits of QOL assessment in clinical practice, including improved decision making, enhanced physician and patient relationship, and better evaluation of treatments.35 Through the assessment of QOL, a physician learns which patient’s domains are most impacted, and this understanding can drive clinical decisions.36 The assessment of QOL improves the physician and patient relationship by increasing the physician’s understanding of the patient’s experience.36 Lastly, QOL assessment allows the physician to evaluate the relative merits and effectiveness of treatment options from a patient’s perspective.35,36 The acceptance of QOL as an important parameter to assess does not overcome the challenges of implementing assessment into routine clinical practice. There are inherent limitations in the assessment and measurement of QOL. As a subjective measurement, individual benefit may go unrecognized within the results of the entire sample.37 In many cases, specific detected numeric differences in two assessments (e.g., presurgery to postsurgery) have not been correlated with the clinical implication of the findings.38 Finally, patients may not be able to adequately reflect their experience within the context of an instrument.39 These limitations need to be acknowledged and present opportunities for additional research and instrument development.

QUALITY OF LIFE AS AN OUTCOME MEASURE IN SURGERY: WHY AND WHEN? Surgery, as a specialty, is unique in the immediateness of the intervention and its largely irreversible effects. The goal of the surgeon is to repair, remove, or revise pathologic processes and initiate healing. The ultimate goal is evaluation of the impact of surgery on QOL with preoperative and postoperative assessment of QOL. Presurgical QOL information should be integrated into the informed consent process and postsurgical QOL information should guide clinical decision making and be used as a marker of surgical success. A recent review of 33 randomized surgical oncology trials, in which QOL data were collected, indicated that in two-thirds of trials, the QOL information influenced clinical decision making and/or facilitated the surgical consent process.40 Integration of the QOL data was more common among later trials included in the systematic

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

review, reflecting the progressively increased value attached to these outcomes by surgeons.40 On a similar note, it has been shown that communicating both technical procedural–related information and QoL information to the patient and their family facilitates an improved physician-patient relationship, reconciles patient expectations, and improves patient satisfaction.41–45 Furthermore, although QOL measurement tools have evolved

403

from generic to disease/site specific, and subsequently have become more sensitive, focus on QOL as a predictive/prognostic variable of outcomes such as morbidity, mortality, and survival has increased. Meta-analysis of 30 randomized clinical trials with QOL data from the European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ)-C30 (core 30 items; Fig. 29.1) revealed

ENGLISH

EORTC QLQ-C30 (version 3) We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential. Please fill in your initials: Your birthdate (Day, Month, Year): Today's date (Day, Month, Year):

31 Not at All

A Little

Quite a Bit

Very Much

1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase?

1

2

3

4

2. Do you have any trouble taking a long walk?

1

2

3

4

3. Do you have any trouble taking a short walk outside of the house?

1

2

3

4

4. Do you need to stay in bed or a chair during the day?

1

2

3

4

5. Do you need help with eating, dressing, washing yourself or using the toilet?

1

2

3

4

Not at All

A Little

Quite a Bit

Very Much

6. Were you limited in doing either your work or other daily activities?

1

2

3

4

7. Were you limited in pursuing your hobbies or other leisure time activities?

1

2

3

4

8. Were you short of breath?

1

2

3

4

9. Have you had pain?

1

2

3

4

10. Did you need to rest?

1

2

3

4

11. Have you had trouble sleeping?

1

2

3

4

12. Have you felt weak?

1

2

3

4

13. Have you lacked appetite?

1

2

3

4

14. Have you felt nauseated?

1

2

3

4

15. Have you vomited?

1

2

3

4

16. Have you been constipated?

1

2

3

4

During the past week:

Please go on to the next page FIGURE 29.1  European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30). A user’s agreement is required to use this scale and can be accessed through the website at: https://qol.eortc.org/questionnaire/eortc-qlq-c30/ Continued

404

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

ENGLISH

Not at All

A Little

Quite a Bit

Very Much

17. Have you had diarrhea?

1

2

3

4

18. Were you tired?

1

2

3

4

19. Did pain interfere with your daily activities?

1

2

3

4

20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television?

1

2

3

4

21. Did you feel tense?

1

2

3

4

22. Did you worry?

1

2

3

4

23. Did you feel irritable?

1

2

3

4

24. Did you feel depressed?

1

2

3

4

25. Have you had difficulty remembering things?

1

2

3

4

26. Has your physical condition or medical treatment interfered with your family life?

1

2

3

4

27. Has your physical condition or medical treatment interfered with your social activities?

1

2

3

4

28. Has your physical condition or medical treatment caused you financial difficulties?

1

2

3

4

During the past week:

For the following questions please circle the number between 1 and 7 that best applies to you 29. How would you rate your overall health during the past week? 1

2

3

4

5

6

Very poor

7 Excellent

30. How would you rate your overall quality of life during the past week? 1

2

3

4

5

6

Very poor

7 Excellent

© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0

FIGURE 29.1 cont’d

that the addition of QOL parameters (physical functioning, pain, anorexia) to sociodemographic and clinical variables provides prognostic value and significantly improves the predictive accuracy of models of survival.46 Moreover, patient scores within the physical functioning domain have been shown to be an independent predictor of survival for multiple different cancers.47–49 More specific to hepatobiliary surgery, global QOL, social well-being, and physical functioning have all been shown to independently predict survival outcomes in patients with colorectal liver metastases (CRLMs) and to add to the prognostic value

of survival models, including standard biomedical data.50–52 Similar findings have been observed among patients with hepatocellular carcinoma (HCC).53 Whether QOL simply reflects a highly sensitive instrument of patients’ overall health status not evaluated elsewhere, or whether QOL impacts other important areas, such as self-care/treatment adherence and thus survival, is unknown. What is clear is that measurement of QOL to aid informed consent and clinical decision making, to facilitate physician-patient relationship and manage expectations, and to help improve prognostication is requisite to optimize care of surgical patients.

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

As with any outcome measure, it is essential to identify the clinical scenarios in which assessment is appropriate. Consequently, it is incumbent on surgeons to define these relevant settings where QOL endpoints will result in clinically meaningful/actionable outcomes. It is suggested that the most pertinent scenarios for surgical patients include evaluation of palliative interventions or procedures in which survival outcomes are thought to be equivocal and/or survival outcomes similar, but morbidity/side-effect profiles differ significantly.40,54–58 In fact, the intention of palliative surgery is to mitigate physical symptoms in patients with noncurable disease, with the primary goal of improving or maintaining QOL.59 Inclusion of QOL measurements in studies in which these specific scenarios are encountered will maximize the clinical applicability of the QOL outcomes observed.

Psychometric Properties of Quality of Life Instruments Before using an instrument for clinical or research purposes, the psychometric properties of the instrument must be evaluated and understood. These properties should guide the selection of the instrument. For QOL results to be respected on the same level as other measured clinical variables, established rigor of measurement tool is essential and depends on three primary concepts: reliability, validity, and responsiveness/sensitivity, which are described in this section. Reliability is the degree to which a method of measurement consistently assigns scores to individuals or measures the attribute of interest.60 A measure’s reliability reflects the ability to identify the true score as opposed to measurement error. Therefore a measure that has perfect reliability would only identify the true score; however, perfect measures do not exist.60,61 There are two key types of reliability: stability reliability and equivalence reliability.61 Stability reliability is evaluated when the attributes are expected to be stable. Equivalence reliability evaluates whether all items consistently measure the attributes of the tool and whether individuals obtain similar scores on similar measures.61 Within these two types of reliability are the different ways reliability can be measured. Test-retest reliability, which is a type of stability reliability, is the evaluation of score when the same test is given to the same group of individuals at different times. The degree to which the two overall scores, as well as individual items, are correlated is an indicator of stability reliability. A reliability coefficient of the comparison is generated.62 Internal consistency reliability is an indicator of equivalence reliability and is an indicator of the degree to which the items of a measure covary, or hang together, conceptually. Internal consistency often uses the Cronbach alpha statistic (ranging from 0.00 to 1.00), which can be generated after only one administration of the test (an advantage of this method of assessing reliability). Nevertheless, this means it is specific to the population using the instrument and should be repeated with each test administration. Alternate forms (or parallel forms) reliability is a means of demonstrating equivalence reliability by using different versions of an instrument to determine whether the scores remain constant. Questions are pulled from a question bank and should test the same concept. The means, variances, and Cronbach alphas of both tests should be approximately equivalent. The researcher makes a decision regarding the

405

approach to establish reliability based on the concept or attribute being measured.60,61,63,64 Validity is the degree to which an instrument successfully measures the attribute/construct that it is intended to measure. There are multiple types of validity. • Content validity is the degree or extent to which the content of the measure encompasses the domain or concept that is being addressed in the measure. Content validity exists if, out of all possible items that might be used to identify the domain/construct, the items selected are representative of the concept or domain.60,61,63,64 • Criterion validity is the degree to which a measure’s scores correlate with another measure’s scores. Criterion validity is the correlation between the measure and the “gold standard” for assessment of that attribute.60,61,63,64 There are two types of criterion validity: predictive and concurrent. • Predictive validity provides a predictive indicator of the extent to which future performance on a criterion can be predicted based on performance on a prior measure.60 • Concurrent validity is the degree to which a measure can be used to determine an individual’s current position or standing on the criterion being measured.60 • Construct validity is the degree to which an instrument measures the attribute/construct under investigation.60 • Convergent validity is the degree to which two measures that measure the same construct/attribute are related to each other.60 • Discriminant validity is the degree to which two measures that measure different constructs/attributes should not be related to each other.60 A key aspect of validity is that it is not a property of the measure. Validity is a property of the scores obtained from a population with a purpose for the measurement.61,64 Therefore the evidence for validity must be provided each time a measure or an instrument is used. This means that different sources of evidence must be woven into the argument that the use of the specific measure was appropriate to evaluate the construct/attribute in the designated population. Additionally, the interpretation of scores must be supported using evidence from the current study and past studies, and the evidence gathered during the current study can inform future use of the measure/instrument. Responsiveness is the ability of an instrument to detect and measure changes during time and treatments. A good instrument is stable when nothing has changed and capable of detecting even small changes when they occur. Responsiveness is dependent on the number of items in a questionnaire as well as the number of potential responses. From a practical standpoint, the number of items and associated responses must be optimized to ensure sufficient responsiveness without creating overly cumbersome questionnaires in which respondents experience “question fatigue,” leading to increased rates of nonresponse and missing data. The content of QOL instruments typically includes multiple domains containing information on a specific area of health/disease, such as physical, social, emotional, role, and global functioning. In turn, each domain contains a number of items (questions or statements) for which respondents must provide an answer, either on a Likert scale or in visual analogue form. Each item is individually scored, and scores from all items in a given domain are summed to give each domain a specific score.65

406

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

QUALITY OF LIFE INSTRUMENTS AND INTERPRETATION Early in the history of QOL assessment in cancer clinical trials, no standard instrument was used, and the default was simply ad hoc trial-specific questionnaires that prohibited comparison across trials and often even among patients with the same disease.66 These findings prompted a new era in QOL research heralded by the development of multiple standardized tools/instruments to measure QOL. There are now more than 600 QOL PRO measures, of varying quality, and the sheer number of measures highlights the expansion of the QOL field.67 There is a need to carefully select measures of QOL for strong psychometric properties and established use in similar populations. The former ensures that the instrument will accurately measure the concept of QOL and the latter supports comparability of the findings. To date, no “gold-standard” instrument exists for the evaluation of QOL. Generic instruments are used in many surgical trials such as the Medical Outcomes Survey 36-Item Short Form (SF-36). Although these instruments provide a broad overview

of the patient’s QOL, care must be taken to choose an instrument that is intended to measure QOL and is not simply a PRO measure of another related construct. The advantage of a generic instrument is that it permits comparison across disease states and treatment types. Patient burden must also be considered since these surveys can be time consuming to complete and, in the end, the effort invested may not result in data with adequate sensitivity to identify changes in QOL specifically related to different diseases and/or treatments. Two commonly used generic instruments used in the oncologic setting are the EORTC, presented in Table 29.1A, and the Functional Assessment of Cancer Therapy-General (FACT-G). These types of instruments focus more on expected changes specifically related to cancer and its treatment. Consequently, they are more sensitive to QOL changes and are good for comparisons across different cancer diagnoses but are not generalizable to other disease states. Disease-specific tools focus on a single disease state. There are only six validated and reliable instruments that were designed for disease specific assessment of hepatobiliary or pancreatic cancers.80 Three are disease-specific instruments of the EORTC,77–79,81–83 two are disease specific scales of the

TABLE 29.1A  Generic and Disease-Specific Health-Related Quality-of Life-Measurement Instruments AUTHOR, YEAR, COUNTRY

TYPE OF INSTRUMENT

Medical Outcomes Study 36-Item Short Form (SF-36)

Ware, 1992, US68

Generic profile based

EuroQoL EQ 5D-5L

EuroQoL Group, 1990, UK69

Generic value/ preference based

Spitzer Quality-ofLife Index (QLI)

Spitzer, 1981, Australia70

Generic index

INSTRUMENT

DESCRIPTION OF QUALITY-OF-LIFE MEASURES

INTERPRETATION

HPBSPECIFIC MODULES COMMENTS

36 items 8 health-status scales: General health perceptions Physical functioning Role limitations due to physical problems Role limitations due to emotional problems Social functioning Bodily pain Vitality (energy/fatigue) General mental health EQ-5D-5L (descriptive system): 5 dimensions, 5 levels of severity: Mobility, selfcare, usual activities, pain/discomfort, anxiety/depression

8 health-status scale No scores Items in each scale are summed and averaged to give a single score (0-100) for each health status Higher scores 5 better quality of life (QOL)

Comparison across broad range of disease states and treatments Less sensitive to changes in disease/health status

No

Self-administered with minimal responder bias Revision of EQ5D-3L, increased levels of severity from 3-5 to improve sensitivity and reduce ceiling effect

EQ-VAS (visual analogue scale) 5 items: Activity Daily living Health Support Outlook

Each dimension given a 1-digit number expressing the level selected Numbers from each dimension are combined to give 5-digit number corresponding to a specific health state; preference value is then assigned based on empirically derived valuations (0-1) VAS: quantitative measure of overall health perceived by respondent (self-rated) Higher score 5 better QOL

No

3 types of data produced: 1. Profile indicating extent of the problems in each domain 2. Populationweighted health index 3. Self-rated assessment of health status

407

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

TABLE 29.1A  Generic and Disease-Specific Health-Related Quality-of Life-Measurement Instruments—cont’d

INSTRUMENT FACT-G (Functional Assessment of Cancer Treatment– General)

EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer-Core Quality-of-Life Questionnaire)

Gastrointestinal Quality-of-Life Index (GQLI)

AUTHOR, YEAR, COUNTRY

TYPE OF INSTRUMENT

Cella, 1993, US71

Disease specific: cancer

DESCRIPTION OF QUALITY-OF-LIFE MEASURES

INTERPRETATION

HPBSPECIFIC MODULES COMMENTS

27 items, 4 domains: Physical (7) Social/family (7) Emotional (6) Functional (7)

Each item scored 0-4 on Yes Likert scale; items in given domain are summed to give overall score for each domain Scores for each domain summed to give overall score Higher score 5 worse QOL Aaronson, 1993, Disease 30 items; 9 multiitem Each item in a scale is Yes Netherlands72 specific: scales 1 6 single items: scored, and an overall cancer 5 functional scales: scale score from 0-100 Physical is reported Role Higher-score functional/ Social global scales 5 better Cognitive QOL Emotional 1 Global Health/QOL Scale 3 symptom scales: Pain Fatigue Nausea/vomiting Eypasch, 1995, Disease 36 items, 5 response Scores from all questions No Germany and specific: any categories (recall over are summed and a Canada73 GI disease 2 wk): single score is reported Core symptoms items Higher score 5 better QOL Physical items Scores from all items are Psychological items summed, and a single Social items score is reported Disease-specific items Higher score 5 better QOL

Comparable across different cancers Moderate sensitivity to changes over time Published data exists regarding clinically important changes over time, allowing improved interpretation Comparable across different cancers Sensitive to cancerrelated changes overtime Published data exists regarding clinically important changes during time, allowing for improved interpretation

Assesses QOL pertaining to a variety of diseases of the liver, pancreas, and biliary system Single score lacks sensitivity to change

TABLE 29.1B  Disease Specific Health Related Quality of Life Measurement Instruments AUTHOR, YEAR, COUNTRY

DESCRIPTION OF QUALITY-OFLIFE MEASUREMENT

Hepatobiliary subscale (HS) FACT 1 HS 5 FACTHep

Heffernan et al, 2002, US74

FACT Hepatobiliary Symptom Index-8 (FHSI-8)

Yount et al, 2002, US75

Specific disease: Metastatic or primary liver cancer, pancreatic cancer, CCA, GBCA FACT-G 1 18-item subscale, including HPB-specific concerns related to: Jaundice GI obstruction Fatigue/energy Each item scored (0-4) and summed to give overall subscale score Specific disease: Metastatic or primary liver cancer, pancreatic cancer, CCA, GBCA 8 key symptoms from 18-item HS scale including: Pain Nausea Fatigue (3 2 items) Jaundice Weight loss Back Pain Stomach Pain/discomfort * Developed in response to clinician concern regarding the time and resources required to complete and interpret multidimensional QOL assessments

CORE QUESTIONNAIRE

MODULE

Functional Assessment of Cancer Therapy (FACT)

COMMENTS HS can be combined with physical and functional domain scores of FACT-G to give Trial Outcome Index (TOI) 7 additional questions (nonscored) at end of HS, addressing HAIP and biliary drainage

Brief index with good correlation with scores on FACT-G and FACT-Hep Capacity to discriminate patients based on performance status/ treatment; status adequate but not as good as FACT-G subscales or HS Developed primarily based on pancreatic cancer

Continued

408

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

TABLE 29.1B  Disease Specific Health Related Quality of Life Measurement Instruments—cont’d CORE QUESTIONNAIRE

MODULE

AUTHOR, YEAR, COUNTRY

DESCRIPTION OF QUALITY-OFLIFE MEASUREMENT

European Organization for Research and Treatment of Cancer–Quality-ofLife Questionnaire– Core 30 (EORTC QLQ-C30)

Pancreatic carcinoma (QLQ-PAN26)

Fitzsimmons et al, 1998, UK76

Specific disease: Diseases of the pancreas, not oncology specific 26-item subscale, including items concerning pancreas: Symptoms Treatments Emotional issues

Colorectal liver metastases (QLQ-LMC21)

Kavadas et al,77 2003, UK

Specific disease: CRLM 21-item subscale. including items concerning CRLM-specific: Symptoms Treatment Emotional issues

Hepatocellular carcinoma (QLQ-HCC18)

Blazeby et al, 2004, UK78

Specific disease: HCC 18-item subscale, including items concerning HCC-specific: Symptoms Treatments Emotional Issues

Cholangiocarcinoma, Gallbladder Carcinoma (QLQ-BIL21)

Friend et al, 2011, UK79

Specific disease: CCA and GBCA 21-item subscale, including items concerning CCA/GBCA-specific: Symptoms Treatments Emotional issues

COMMENTS Commonly used although no information on psychometric properties in oncology population Examples: Pain (abdominal, back, positional, night) Dietary restrictions GI symptoms Cachexia Weight loss Jaundice Pruritus Ascites Examples: Pain (abdominal, back) Eating problems (early satiety) Fatigue Lethargy Jaundice Taste Tingling hands/feet Stress Loss of enjoyment Examples: Fatigue Body image Jaundice Nutrition Pain Fevers Examples: Eating Satiety Jaundice Fatigue Anxiety Pain Stress Worry

CCA, Cholangiocarcinoma; CRLM, colorectal liver metastases; GBCA, gallbladder carcinoma; GI, gastrointestinal; HAIP, hepatic arterial infusion pump; HCC, hepatocellular carcinoma; HPB, hepatopancreatobiliary; QOL, health-related quality of life; UK, United Kingdom; US, United States.

FACT,74,75 and one is the QOL for patients with Liver Cancer Treatment (QOL-LC).84 These instruments use the modular approach, which is specific to patients with cancer. It refers to the use of a core cancer questionnaire in conjunction with validated modules for specific disease sites (i.e., pancreas, liver, biliary modules).56 This approach is based on the premise that, although there are similar effects of disease/treatment across cancers, each primary tumor site is also associated with a unique set of QOL concerns. Use of a modular approach increases the sensitivity to detect small, yet clinically relevant, changes in QOL. This method has been popularized by the EORTC, in which the core EORTC QLQ-C30 questionnaire is paired/supplemented with a site- and/or symptom-specific instrument. The FACT hepatobiliary subscale (FACT-Hep) is an example of a modular instrument (Fig. 29.2). The comprehensive nature of these tools provides increased sensitivity; however, practicality, in terms of time

and resources required to complete, may be prohibitive in some settings. Based on this, attempts to develop brief scales that adequately correlate with the more extensive evaluations have been attempted. Yount et al.75 developed and tested an eight-item symptom scale from the FACT-Hep that correlated well with overall FACT-G scores; however, the ability to discriminate patients based on performance status/treatment status was limited. Overall, these simplified indices are not as sensitive or reliable as longer multidimensional evaluations of QOL; however, their practicality makes them attractive alternatives. QOL is more than the sum of its parts, and it is likely that a global assessment in the form of an index is complementary to, rather than an alternative to, individual domain evaluation. It is generally accepted that a single assessment of patients’ perceptions of overall QOL is improved over aggregation of individual domain scores, where each domain is given equal importance and

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

a “mean” QoL is estimated.85,86 Ideally, optimal QOL assessment strategies should include both global- and domain-specific measurements. The vast array and potential combinations of available measurement tools can be overwhelming and make interpretation/ evaluation of QOL literature difficult. To critically appraise QOL literature, it is essential to understand the psychometric

409

properties so that judgment as to the robustness of the results can be made. Table 29.2 outlines QOL levels of evidence based on the psychometric properties of the measurement tool(s) used.44 Guyatt et al.87 and Wu et al.88 have published review articles that present a standardized approach to critical appraisal and provide a means by which QOL can be integrated into evidence-based medicine.

FACT-Hep (Version 4) Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.

PHYSICAL WELL-BEING

Not A little Some- Quite Very at all bit what a bit much

GP1

I have a lack of energy................................................... 0

1

2

3

4

GP2

I have nausea................................................................

0

1

2

3

4

GP3

Because of my physical condition, I have trouble meeting the needs of my family.....................................

0

1

2

3

4

GP4

I have pain.....................................................................

0

1

2

3

4

GP5

I am bothered by side effects of treatment....................

0

1

2

3

4

GP6

I feel ill............................................................................ 0

1

2

3

4

GP7

I am forced to spend time in bed.................................... 0

1

2

3

4

SOCIAL/FAMILY WELL-BEING

Not A little Some- Quite Very at all bit what a bit much

GS1

I feel close to my friends................................................

0

1

2

3

4

GS2

I get emotional support from my family.......................... 0

1

2

3

4

GS3

I get support from my friends.........................................

0

1

2

3

4

GS4

My family has accepted my illness................................. 0

1

2

3

4

GS5

I am satisfied with family communication about my illness............................................................................. 0

1

2

3

4

I feel close to my partner (or the person who is my main support) ................................................................ 0

1

2

3

4

1

2

3

4

GS6

Q1

Regardless of your current level of sexual activity, please answer the following question. If you prefer not to answer it, please mark this box and go to the next section.

GS7

I am satisfied with my sex life........................................

English (Universal) Copyright 1987, 1997

0

16 November 2007 Page 1 of 3

FIGURE 29.2  Functional assessment of cancer treatment–hepatobiliary questionnaire (FACT-Hep). (Courtesy Dr. David Cella copyright 1987, 1997. Permission for use must be obtained by contacting Dr. David Cella at www.FACIT.org or [email protected].) Continued

410

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

FACT-Hep (Version 4) Please circle or mark one number per line to indicate your response as it applies to the past 7 days.

Not A little Some- Quite Very at all bit what a bit much

EMOTIONAL WELL-BEING

GE1

I feel sad........................................................................... 0

1

2

3

4

GE2

I am satisfied with how I am coping with my illness.........

0

1

2

3

4

GE3

I am losing hope in the fight against my illness................

0

1

2

3

4

GE4

I feel nervous.................................................................... 0

1

2

3

4

GE5

I worry about dying...........................................................

0

1

2

3

4

GE6

I worry that my condition will get worse............................ 0

1

2

3

4

Not at all

FUNCTIONAL WELL-BEING

A little Some- Quite Very bit what a bit much

GF1

I am able to work (include work at home)......................... 0

1

2

3

4

GF2

My work (include work at home) is fulfilling......................

0

1

2

3

4

GF3

I am able to enjoy life........................................................ 0

1

2

3

4

GF4

I have accepted my illness................................................ 0

1

2

3

4

GF5

I am sleeping well............................................................. 0

1

2

3

4

GF6

I am enjoying the things I usually do for fun.....................

0

1

2

3

4

GF7

I am content with the quality of my life right now.............. 0

1

2

3

4

English (Universal) Copyright 1987, 1997

16 November 2007 Page 2 of 3

FIGURE 29.2 cont’d

TABLE 29.2  Levels of Evidence in Health-Related Quality-of-Life Evaluation LEVEL OF EVIDENCE

METHODOLOGY/APPROACH

EXPLANATION

Low

Single items (symptoms/performance/VAS)

Middle (A)

Conversion of preexisting tools

Middle (B)

Assessment of a single QOL domain

High

Multidimensional assessments

Often developed for a single study Typically not psychometrically validated Adaptation of tools from traditional psychology and psychiatry Assumes measures are reliable and valid in cancer patients (example: Beck Depression Inventory) Measurement of multiple single items within a single domain of QOL Typically focused on physical well-being and/or measurement of treatment toxicities/side effects (example: performance scores) Highest level of QOL evidence Multiple subscales evaluating multiple domains (physical, social, emotional, role, spiritual, etc.) Disease specific (example: FACT, EORTC QLQ-C30, FLIC)

EORTC-QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; FACT, Functional Assessment of Cancer Therapy; FLIC, Functional Living IndexCancer; QOL, health-related quality of life; VAS, visual analogue scale. From Table 1 in Passik SD, Kirsh KL. The importance of quality-of-life endpoints in clinical trials to the practicing oncologist. Hematol Oncol Clin North Am. 2000;14(4):877–886.

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

411

FACT-Hep (Version 4) Please circle or mark one number per line to indicate your response as it applies to the past 7 days. Not at A little Some- Quite all bit what a bit

ADDITIONAL CONCERNS

Very much

C1

I have swelling or cramps in my stomach area ..................

0

1

2

3

4

C2

I am losing weight............................................................... 0

1

2

3

4

C3

I have control of my bowels................................................

0

1

2

3

4

C4

I can digest my food well ....................................................

0

1

2

3

4

C5

I have diarrhea (diarrhoea) .................................................

0

1

2

3

4

C6

I have a good appetite ........................................................ 0

1

2

3

4

Hep 1

I am unhappy about a change in my appearance............... 0

1

2

3

4

CNS 7

I have pain in my back .......................................................

0

1

2

3

4

Cx6

I am bothered by constipation ............................................

0

1

2

3

4

H17

I feel fatigued .....................................................................

0

1

2

3

4

An7

I am able to do my usual activities.....................................

0

1

2

3

4

Hep 2

I am bothered by jaundice or yellow color to my skin.........

0

1

2

3

4

Hep 3

I have had fevers (episodes of high body temperature) ..... 0

1

2

3

4

Hep 4

I have had itching ...............................................................

0

1

2

3

4

Hep 5

I have had a change in the way food tastes .......................

0

1

2

3

4

Hep 6

I have had chills .................................................................

0

1

2

3

4

HN 2

My mouth is dry ..................................................................

0

1

2

3

4

Hep 8

I have discomfort or pain in my stomach area .................... 0

1

2

3

4

English (Universal) Copyright 1987, 1997

16 November 2007 Page 3 of 3

FIGURE 29.2 cont’d

QUALITY OF LIFE STUDIES IN HEPATOBILIARY CANCER The development of reliable, valid, and sensitive measurement tools for use in cancer patients and, more specifically, in patients with hepatobiliary malignancy, has led to an increase in the number and quality of studies assessing QOL in patients with hepatopancreatobiliary (HPB)-related malignancy. The following sections highlight the current status of QOL as it pertains to definitive surgical management as well as palliative interventions in patients with advanced HPB malignancies.

Tables 29.3 to 29.7 summarize the most recent reports in the literature as well as landmark studies on QOL in the setting of HPB malignancy.

Pancreatic Resection Despite advances in surgical technique and perioperative care after pancreatic resection, morbidity remains common (20%– 30%; see Chapters 27, 62, and 66). Furthermore, in the setting of pancreatic cancer, even with complete resection, long-term survival is rare. It is therefore not surprising that with high morbidity and less than optimal survival outcomes, the impetus

412

TABLE 29.3  Studies of Pancreatic Surgery and Health-Related Quality of Life

Pancreatic Resection Nguyen, Journal of Gastrointestinal Surgery, 200389

POPULATION (PATIENT WITH) Periampullary cancer randomized to PD or a RPD (PD 1 retroperitoneal lymph node dissection)

STUDY PURPOSE/ QUALITY-OF-LIFE ENDPOINT

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

Primary outcome: Cross-sectional, postoperative QOL N 5 105 (55 PD and 50 RPD); QOL assessed at a single, nonstandard postoperative time point

Van Heek, Annals of Surgery, 200390

Unresectable periampul- Primary outcome: Prospective randomized lary cancer randomized development of trial, N 5 65 (36 HJ 1 to undergo a double GOO GJ, 29 HJ alone) QOL bypass (HJ 1 GJ) or a Secondary end point: assessed preoperasingle bypass (HJ) QOL tively, at discharge, and q1mo for 6 mo

Billings, J Gastrointestinal Surgery, 200591

Periampullary disease (benign and malignant) requiring TP

Primary outcome: longitudinal QOL

Cross-sectional matched design, N 5 27 TP; TP cohort age/gender matched 1:1 with IDDM cohort; QOL assessed at a single, nonstandard, postoperative time point

Nieveen van Dijkum, British Journal of Surgery, 200592

Resectable pancreatic tumors (benign and malignant) undergoing PD compared with unresectable pancreatic tumors undergoing double bypass (HJ 1 GJ) Pancreatic tumors (benign and malignant) undergoing PD with PG or PJ reconstruction

Primary outcome: longitudinal QOL

Prospective longitudinal, N 5 114 (PD 5 72, HJ 1 GJ 5 42); assessed preoperatively, postoperatively, and at 1.5-, 3-, 6-, 9-, and 12-mo follow-up

Primary outcome: QOL and longterm morbidity

Cross-sectional, N 5 104 (PG 5 63, PJ 5 41); QOL assessed at a single, nonstandardized, postoperative time point

Schmidt, Annals of Surgical Oncology, 200593

QUALITY-OF-LIFE INSTRUMENT

QUALITY-OF-LIFE RESULTS

COMMENTS

FACT-Hep

Assessments were completed at mean 2.1 yr after surgery. No differences at long-term follow-up in QOL and GI functional status between PD and RPD. RPD patients had a statistically significantly higher postoperative complication rates (43% to 29%, P 5 .01) EORTC 2/36 HJ 1 GJ and 12/29 HJ paCompletion rates were QLQ-C30 1 tients developed GOO (P , .01). .90% in both groups PAN26 module After an initial decline with surfor the first 4 mo postgery, QOL returned to baseline operatively and 75% in by 4 mo postoperatively and the last 2 mo was not different between groups SF-36 Health Mean follow-up time: 7.5 yrs Only evaluated TP patients Survey, Audit postoperatively. TP cohort had alive with no disease at of Diabeteslower SF-36 role, and physical time of survey adminisDependent QOL and general health scores tration (mean, 7.5 yr), (ADD QOL), (P , .05). ADD QOL scores “healthy-survivor” bias EORTC Pan26, were decreased but not different nonvalidated from IDDM controls institutional survey Medical outcomes After an initial decline, QOL scores study (MSO-24), returned to baseline at 3 mo gastrointestinal postoperatively in both groups. QOL index Rapid decline in QOL was ob(GIQLI) served in both groups in the 8th wk before death

EORTC QLQ-C30 104/133 surviving patients reOnly evaluated subset of 1 PAN26 modsponded to questionnaires patients alive at the ule, nonvali(mean assessment time, 6.4 yr time of survey adminisdated institupostoperatively). Global QOL tration (mean, 6.5 yr), tional evaluation was the same between PJ and “healthy-survivor” bias of GI symptoms PG groups. PG group had significant decrease in multiple GI symptoms but increase in steatorrhea, early satiety, and food aversion. PJ patients had no change in GI symptoms but did report reduced jaundice-related symptoms

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

FIRST AUTHOR, JOURNAL, YEAR

Pancreatic tumors (benign and malignant) undergoing PD

Primary outcome: longitudinal QOL

Cross-sectional matched design, N 5 49 PD; PD cohort age/gender matched 1:1 with patients undergoing open cholecystectomy for benign disease; QOL assessed at a single, nonstandardized postoperative time point

EORTC QLQC30 1 PAN26 module

Wehrmann, European Journal of Gastroenterology and Hepatology, 200595

Unresectable pancreatic head cancer with pancreatic duct obstruction and postprandial epigastric pain undergoing endoscopic pancreatic duct stenting Consecutive patients admitted to hospital with various stages of pancreatic cancer

Primary outcome: QOL and pain control

Prospective longitudinal, N 5 20; QOL assessed preprocedure and 4 and 12 wk postprocedure

Spitzer QLI

Primary outcome: QOL in patients with pancreatic cancer Secondary outcome: relation of symptoms to QOL Primary outcome: longitudinal QOL

Cross sectional matched design, N 5 45 (44% stage 4) QOL assessed at a single time point following admission to hospital

EORTC QLQ-C30 and EuroQol (EQ-5D-3L)

Global QOL as well as all subscale measures were decreased among patients with pancreatic cancer. Fatigue and pain were significantly associated with worse QOL

Prospective longitudinal, N 5 91 (PPD 5 34, PPPD 5 57); QOL assessed preoperatively and at 3, 6, 12, and 24 mo postoperatively Cross-sectional, N 5 67 (23 PD and 44 PPPD); QOL assessed at a single, nonstandardized postoperative time point

EORTC QLQC30 1 PAN26 module

Cross-sectional, N 5 28; QOL assessed at a single, nonstandard postoperative time point

EORTC QLQ-C30 and a unique symptom index

QOL, global as well as all subCompletion rates: preopscales, declined postoperative erative 56%, 3 mo, but returned to baseline by 72% of survivors; 24 3-6 mo in both groups. Among mo, 56% of survivors survivors, no differences were observed in QOL PD patients reported less steatorrhea and diabetic symptoms but reported more flatus, diarrhea, and fatigue compared with PPPD patients. Mean scores on global QOL subscales were higher in the PPPD group than the PD group (P . .05). Assessed QOL at mean 5.4 yr postoperatively. Global measures of QOL among the treated group were no different than those of the general population; however, symptoms of nausea/ vomiting, diarrhea, and appetite loss were greater (P # .02). Compared with asymptomatic patients, symptomatic patients reported a significantly lower QOL (P 5 .05)

Muller-Nordhorn, Digestion, 200696

Schniewind, British Journal of Surgery, 200697

Pancreatic head cancer undergoing PD or PPPD

Han, Hepatogastroenterology, 200798

Pancreatic mass (benign and malignant) treated with PD or PPPD and alive without at $3 yr

Primary outcome: long-term gastrointestinal functional outcomes and QOL

You, Surgery, 200799

Patients with MEN-1 undergoing PD for pancreaticoduodenal neoplasm

Primary outcome: perioperative outcomes and survival Secondary outcome: QOL

EORTC QLQ-C30

Mean assessment at 42 mo postprocedure. Global health status was similar between PD and matched controls. Patients with malignant indication for PD had decreased physical and role functioning as well as more symptoms of fatigue, muscle weakness, and failure to gain weight compared with patients undergoing PD for benign disease Successful procedure in 19/20 paCompletion rates: preoptients. Patients reported a signifierative 100%, 4 wk cant improvement in pain and QOL 100%, 12 wk 16/19 at 4 wk (P , .01) but decreased (84%) again at 12 wk to preprocedure values

413

Continued

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Shaw, Hepaticogastroenterology, 200594

414

TABLE 29.3  Studies of Pancreatic Surgery and Health-Related Quality of Life—cont’d STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

Various stages of newly diagnosed pancreatic cancer (treatment course at enrollment unknown)

Primary outcome: QOL and survival by stage/treatment

Kostro, Acta Chirugica Belgica, 2008101

Potentially resectable pancreatic cancer, subsequently undergoing curative PD or palliative double bypass (HJ 1 GJ) or laparotomy alone

Primary outcome: longitudinal QOL

Prospective longitudinal, N 5 92 divided into 3 groups: Group 1: localized disease treated surgically (28, 30.5%) Group 2: locally advanced disease (34, 37%) Group 3: metastatic disease (30, 32.5%) QOL assessed at enrollment, then 3and 6-mo follow-up Prospective longitudinal, N 5 54 (26 PD, 17 DBP, 11 laparotomy); QOL assessed preoperatively and at 1, 2, 3, and 6 mo postoperatively

Halloran, Pancreatology, 2011102

Patients undergoing partial pancreatectomy for pancreatic cancer

Primary outcome: pancreatic exocrine insufficiency Secondary outcome: QOL, nutrition, symptoms

Prospective longitudinal, N 5 40; QOL assessed only postoperatively at 1.5, 3, 6, and 12 mo

Ljungman, World Journal of Surgery, 2011103

Resectable periampullary cancer

Primary outcome: cost utility of curative treatment for pancreatic cancer Secondary outcome: QOL

Walter, European Journal of Surgical Oncology, 2011104

Advanced pancreatic cancer undergoing palliative resection (PR) or double bypass (HJ 1 GJ)

Primary outcome: longitudinal QOL between PR and HJ 1 GJ

Retrospective cohort, N 5 119; QOL assessed preoperatively, early postoperatively (,1 yr), or late postoperatively (1-5 yr), compared with age-matched healthy controls Prospective longitudinal, N 5 86 (61 HJ 1 GJ, 25 PR); QOL assessed preoperatively, at discharge, and 3 and 6 mo postoperatively

POPULATION (PATIENT WITH)

Crippa, Journal of Gastrointestinal Surgery, 2008100

QUALITY-OF-LIFE INSTRUMENT FACT-Hep

EORTC QLQ-C30 1 PAN26

QUALITY-OF-LIFE RESULTS

COMMENTS

Median OS for the entire cohort, 9.8 mo. In group 1 (resected), QOL was significantly improved (P 5 .03). Group 2 (locally advanced, various treatments) experienced no change, and group 3 (metastatic disease, various treatments) experienced a persistent decline over time

Survival poor overall, but QOL improved with surgery

No differences in global QOL Completion rates: between the patient groups. preoperatively 100%, Palliative HJ 1 GJ was associ1 mo 46/54 (85%), ated with increased symptoms 2 mo 42/54 (78%), immediately postoperatively 3 mo 31/54 (57%), but acceptable QOL. Eight 6 mo 22/54 (41%) wks before death, all subscales and global QOL declined rapidly EORTC QLQ-C30 Overall, QOL increased at 6 QOL was not measured (P 5 .03) and 12 mo (P , .01) preoperatively; basePhysical and role functioning were line 5 postoperative increased at 3 mo (P 5 .03); (6 wk); improvements social functioning was improved in QOL may be inflated at 6 and 12 mo (P 5 .03 and P , .01, respectively) Trend toward worse QOL in patients who experienced exocrine insufficiency SF-36 Health Sur- QOL index lower in study patients QOL data available for vey and Utility compared with controls at all time only 58 patients (37 Index (SF-36-6D points (P , .05) early and 27 late); late preferenceQOL index (0.69) at long-term data subject to based utility follow-up was not different from “healthy-survivor bias” index, scored index scores preoperatively (0.65) 0 5 death to or early postoperatively (0.63) in 1 5 perfect the treated group health) EORTC QLQ-C30 Outside of worse scores on Completion rates: basephysical functioning subscales line 100%, discharge at 6 mo, the HJ 1 GJ group 78/86 (91%), 3 mo had significantly better QOL and 58/86 (67%), 6 mo improved symptoms compared 41/86 (48%) with PR group

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

STUDY PURPOSE/ QUALITY-OF-LIFE ENDPOINT

FIRST AUTHOR, JOURNAL, YEAR

Periampullary cancer undergoing PD

Primary outcome: longitudinal QOL

Prospective longitudinal, N 5 37; QOL assessed preoperatively, 1, 3, 6, and 12 mo postoperatively

SF-36 Health Survey

Mbah, Journal of the Pancreas, 2012106

Pancreatic cancer undergoing pancreatectomy

Primary outcome: QOL following pancreatectomy in patients with and without complication

Prospective longitudinal, N 5 34 QOL assessed preoperatively and at 2-3 wk, 6 wk, 3, and 6 mo postoperatively

EORTC QLQ-C30 and FACTAnemia

Belyaev, Langenbecks Archives of Surgery, 2013107

Pancreatic disease (benign and malignant) undergoing pancreatic resection

Primary outcome: longitudinal QOL comparison by procedure and diagnosis

Retrospective cohort, N 5 174 (105 malignant, 69 benign); QOL assessed preoperatively and at 3 and 24 mo postoperatively, included comparison to age-matched population norms

SF-36 Health Survey

Roberts, HPB (Oxford), 2014108

Pancreatic tumors (benign or malignant) treated with TP

Primary outcome: Cross sectional matched overall QOL and design, N 5 28 TP; diabetes-specific TP cohort age/gender problems between matched to IDDM TP and matched group; QOL assessed IDDM at a single, nonstandardized postoperative time point

Epelboym, Journal of Surgical Research, 2014109

Pancreatic tumors treated Primary outcome: Cross sectional matched with TP morbidity/mortality design, N 5 17 TP; TP post-TP cohort matched on age/ Secondary outcome: gender/operative indicaoverall, pancreastion to patients who unspecific and diabederwent PD and had or tes-specific QOL developed diabetes following TP postoperatively (PD 1 DM); QOL assessed at a single, nonstandardized postoperative time point

EORTC QLQC30 1PAN26 module and Problem Areas in Diabetes Scale

EORTC QLQ-C30 1 PAN26 module and Audit of Diabetes- Dependent Quality of Life (ADDQOL)

One mo postprocedure, significant decline in physical function (P , .01) and emotional role (P , .03). At 3 mo, mental health increased significantly (P 5 .02); 6 mo, physical role (P , .01), physical pain (P 5 .01), social function (P 5 .01) improved significantly. At 12 mo, these changes were sustained as well as significant improvement in vitality (P 5 .02) and emotional role (P , .01) After an initial postoperative decline, QOL returned to baseline at 6 wk. Overall, complication rate was 21%, with no difference in QOL scores among those who did and did not have complications (P 5 .11). At 6 mo, scores on cognitive functioning significantly declined (P 5 .02). QOL was worse compared with population norms at all time points, P 5 .03. Early postoperative QOL was best in patients undergoing distal pancreatectomy and worst with TP. Patients with cancer, as opposed to benign diagnosis, had lower postoperative QOL and persistent decline to 24 mo. Patients with benign tumors/pancreatitis had initial drop, followed by slow trend toward recovery at 24 months. Physical (P , .01), cognitive (P , .01), and social functioning (P 5 .02), as well as working ability (P 5 .01), were worse in TP compared with IDDM groups. Symptoms of fatigue, nausea/vomiting, and insomnia were also worse (P # .01); however, no differences in diabetesspecific problems were observed QOL assessed at median 45 mo postoperatively. Overall and pancreasspecific measures of QOL were not different between TP and PD 1 DM groups. Diabetes negatively impacted QOL and was not different between TP and PD 1 DM groups.

Completion rates: preoperative 100%, 1 mo 29/37 (78%), 3 mo 26/37 (70%), 6 mo 28/34 survivors (82%), 12 mo 28/28 survivors (100%)

QOL data collected as part of a prospective trial examining the safety of intraoperative autotransfusion during oncologic resections; QOL stratified by anemia at discharge was also evaluated Completion rates: preoperatively 100%, 3 mo 133/174 (76%), 24 mo 83/174 (48%)

88/123 TP were dead at time of survey administration; 28 of the remaining 33 returned surveys

TP patients had more hypoglycemic events (2 requiring hospitalization), but given small numbers, this was not statistically significant

415

Continued

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Chan, Journal of Gastrointestinal Surgery, 2012105

416

TABLE 29.3  Studies of Pancreatic Surgery and Health-Related Quality of Life—cont’d STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

Resectable or borderline resectable pancreatic cancer undergoing neoadjuvant chemoradiation

Primary outcome: QOL during and after chemoradiation and surgery

Prospective multiinstitutional Phase II clinical trial, N 5 55; QOL assessed at baseline, after 2 cycles of neoadjuvant therapy, after surgery, at 6 mo from initiation of therapy, and 6-mo intervals for 2 yr

Eshuis, British Journal of Surgery, 2015111

Scheduled for PD for oncologically indicated disease

Primary outcome: Single institution RCT, Compare QOL N 5 73 (38 retrocolic, between retrocolic 35 antecolic), QOL and antecolic gasassessed at baseline, troenteric recon2, 4, and 12 weeks struction after postoperatively PD and correlate findings with DGE

EORTC QLQ-C30 and PAN 26; GIQLI

Hartwig, Annals of Surgery, 2015112

Locally advanced or centrally located pancreatic tumors undergoing TP

Primary outcome: perioperative morbidity/mortality and survival Secondary outcome: longitudinal QOL overall and compared with healthy controls

EORTC QLQC30 1 PAN26

POPULATION (PATIENT WITH)

Serrano, International Journal of Radiation Oncology Biology Physics, 2014110

Prospective longitudinal, N 5 81 (25 benign disease, 56 malignant disease), TP cohort age/gender matched to healthy controls; QOL assessed preoperatively and 1, 2, 3, 4, and 5 yr

QUALITY-OF-LIFE INSTRUMENT EORTC QLQC30 1 PAN26 module and FACT-Hep

QUALITY-OF-LIFE RESULTS

COMMENTS

After 2 cycles of chemoradiation, QOL assessed as part of QOL was not different from a Phase II clinical trial baseline. Global QOL was not of neoadjuvant chemostatistically (EORTC QLQ-C30) radiation (gemcitabine or clinically (FACT-G) different 1 oxaliplatin 1 radiafrom baseline at the conclusion tion) in patients with of chemoradiation; however, resectable or borderpancreatic pain was improved, line resectable pancrescores of physical function deatic cancer; compliclined, and diarrhea symptoms ance in nonoperated increased significantly. Among group poor and not inpatients who underwent reseccluded in longer-term tion global, QoL and most analysis subscales returned to baseline measures by 6 mo Statistically significant differences Response rate 88% for any QOL outcomes between across time points study groups were not found. QOL declined for both groups at 2 and 4 weeks and improved by 12 weeks. QOL outcomes in were statistically significantly worse in DGE group in QLQC30 global health status and all functional scales except cognitive (Cohen’s d 5 0.53-0.96, P , .0450) at two weeks postoperatively. In GIQLI scores were statistically significantly worse in DGE group in total score, physical well-being, and mental wellbeing (Cohen’s d 50.65-0.98, P , .023) at 2 weeks postoperatively. The group differences resolved by 12 weeks. No difference in global QOL scores 596 TP or completion between TP patients and matched pancreatectomy were controls; however, all functional included in primary scale scores (physical, emotional, analysis; QOL assesssocial, role, cognitive) were signifiment was available in cantly lower at all time points in only 81 patients who the TP group. Global QOL and had follow-up at study functional scales were not different center based on indication for operation (benign vs. malignant), but symptoms were greater among patients undergoing TP for malignant disease at yr 1 and 2 (P , .01)

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

STUDY PURPOSE/ QUALITY-OF-LIFE ENDPOINT

FIRST AUTHOR, JOURNAL, YEAR

Pancreatic resection for pancreatic or periampullary malignancy or premalignancy

Primary outcome: Describe QOL after pancreatic resection

Prospective longitudinal quasi experimental single institution study, N 5 68, assessed QOL at baseline, 1, 3, 6, 12 months except if hospitalized at time of assessment.

EORTC-QLQC30; SF-36

Williamsson et al., British Journal of Surgery, 2015

PD for malignant and benign disease

Evaluate safety, outcomes, and patient experience after PD before and after implementation of fasttrack recovery program.

EORTC QLQC30 and EORTC QLQ-PAN26

De Rooij et al., Annals of Surgery, 2018115

Left-sided, confined Primary outcome: (Yonsei criteria116) compare time pancreatic tumors to functional re(benign, pre-malignant, covery between malignant) undergoing MIDP ODP. SecMIDP or ODP ondary outcome: compare QOL

Retrospective study of control group (retrospective chart review) and fast-track group (prospectively entered database); N 5 100 (50 fast-track, 50 control); QOL assessed 2 weeks before and 4 weeks after PD Patient-blinded, multicenter RCT, N 5 108 (51 MIDP, 57 ODP), assessed QOL at 14, 30, 90 days postoperatively.

Shin et al, HPB, 2019117

PD with duct to mucosa PJ

Van Hilst, British Journal of Surgery, 2019118

Describe outcome differences in those with and without external and internal pancreatic stents

Prospective, single institution longitudinal study, N 5 185 (97 external stenting, 88 internal stenting), QOL assessed at 1-2 weeks and 1 year. Pancreatic tumors Describe cost-effec- Patient-blinded, multi(benign, pre-malignant, tiveness and QOL center RCT, N 5 104 malignant) undergoing after distal pancre(48 MIDP, 56 ODP), MIDP or ODP atectomy QOL assessed at baseline and 365 days post resection (first 90 days reported by de Rooij et al.115)

EORTC-QLQC30

EORTC QLQC30 and EORTC QLQ-PAN26

EORTC QLQC30

Follow-up instrument QLQ-C30 Global Health had a clinically relevant worsening at completion 57%-94% 1 month in 50% of subjects across assessments. (P 5 .010). Scores were equal to Study limited to those or improved from baseline levels well enough to be at 6 months in 88% and 79%, outpatients at time of respectively. At 12 months, 87% assessment. Mean and 97% returned to baseline or scores were not evalubetter, respectively. Similar trends ated; instead clinical were seen in the physical and relevance, defined as social scales. a greater than 10% change from baseline, were used. 70% completion rate of instruments. In both groups, QOL deteriorated in most aspects after surgery. There were no group differences noted.

Overall global health score was higher for MIDP than ODP mean difference 4.97 (95% CI -1.22 to 11.16, P 5 .12, corrected for baseline scores). MIDP had higher rate of grade B and C postoperative fistulas (RR 1.72 (95% CI 0.96-3.09, P 5 .07), whereas ODP had higher rate of DGE (RR 0.30 (95% CI 0.09-1.03, P 5 .04) There was no statistically significant differences between groups at 1-2 week and 1 year in the global health status, functional scales, or the pancreatic cancer-specific scales (all P . .170).

Completion rates of 65% of the 97 patients who were alive at 1 year. The global health score and seven categories of the PAN-26 were comparable at 1 year between groups (all P . .153)

DBP, Double bypass; DGE, delayed gastric emptying; DM, diabetes mellitus; DP, distal pancreatectomy; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; FACT, Functional Assessment of Cancer Therapy; GI, gastrointestinal; GJ, gastrojejunostomy; GOO, gastric outlet obstruction; HJ, hepaticojejunostomy; IDDM, insulin-dependent diabetes mellitus; MEN-1, multiple endocrine neoplasia-1; MIDP, minimally invasive ductal pancreatectomy; MSO, Medical Outcomes Study; ODP, open distal pancreatectomy; OS, overall survival; QOL, quality of life; PAN26, pancreatic cancer module; PD, pancreaticoduodenectomy; PG, pancreaticogastrostomy; PJ, pancreaticojejunostomy; PPPD, pylorus-preserving pancreaticoduodenectomy; QLI, Quality-of-Life Index; RCT, randomized controlled trial; RPD, radical pancreaticoduodenectomy; RR Relative riskSF-36, 36-item Short Form; TP, total pancreatectomy.

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Heerkens, British Journal of Surgery, 2015113

417

418

TABLE 29.4  Studies of Hepatic Resection and Health-Related Quality of Life STUDY DESIGN, N, AND ASSESSMENT TIME POINTS

HCC undergoing HR

Primary outcome: longitudinal QOL

Prospective longitudinal N 5 76 (66 HR, 10 controls—unresectable HCC treated with TACE); QOL assessed every 3 months for 2 years

Chen, Hepatobiliary and Pancreatic Disease International, 2004120

Primary hepatic cancer undergoing HR

Primary outcome: short-term and longitudinal QOL

Prospective longitudinal, Gastrointestinal N 5 36; QOL assessed QOL Index preoperatively; at 2, 5, (GQLI) and 10 wk; 4, 6, and 9 mo; and 1, 1.5, and 2 yr postoperatively

Langenhoff, British Journal of Surgery, 2006121

Hepatic malignancy undergoing HR (CRLM, CCA, HCC, and other hepatic metastases)

Primary outcome: short-term and longitudinal QOL

Prospective cohort, EORTC QLQN 5 97 (group 1 5 C30 and HR [n 5 60], group EQ-5D-3L 2 5 unresectable at 1 EQ-VAS laparotomy [n 5 19], group 3 5 unresectable at presentation [n 5 20]); QOL assessed at baseline and 0.5-, 3-, 6-, and 12-mo follow-up

Eid, Cancer, 2006122

Hepatic malignancy undergoing HR or surgical RFA (CRLM, CCA, HCC, other metastases)

Primary outcome: comparison of QOL based on type of surgical intervention

Prospective longitudinal, FACT-Hep, N 5 40 (24 major FHSI-8, POMS, hepatectomy, 8 minor EORTC QLQhepatectomy, 8 surgical C30 1 PAN26 RFA); QOL assessed at module; global baseline, discharge, rating of first postoperative visit, change scales 6 wk, 3 mo, and 6 mo (6 domains, scales 27 to 17)

POPULATION (PATIENT WITH:)

Hepatic Resection Poon, Archives of Surgery, 2001119

QUALITY-OF-LIFE INSTRUMENT FACT-G, translated into Chinese

QUALITY-OF-LIFE RESULTS

COMMENTS

At 3 mo, global QOL, PWB, EWB, Disease recurrence was and SWB significantly improved treated with TACE, over baseline and were mainsystemic chemothertained out to 2 yr among the HR apy, and/or BSC group; no changes were observed in QOL measures among unresected controls at 3 mo, and decline was observed starting at 9 mo. Disease recurrence was associated with a significant decline in mean QOL (P , .001) Mean GQLI was decreased at 2-10 47% (17/36) patients died wk postoperatively, followed by a by 9-mo follow-up gradual return to baseline by 4 mo, and at 9 mo. Mean GQLI scores were increased above baseline measures. Disease recurrence was associated with a steady decline in QOL. Group 1: decrease in global and functional QOL domains; decrease in EQ-VAS and symptoms at 2 wk, with return to baseline at 3 mo; stable or improved out to 12 mo Group 2: decrease in global and functional QOL domains; decrease in EQ-VAS and increased symptoms at 2 wk, with continued decline and ongoing symptoms Group 3: no change in global, functional, or symptoms, QOL domains, or EQ-VAS at 2 wk or 3 mo, decrease in global and functional domain-specific QOL at 6 mo Major hepatectomy associated with decrease in physical and functional domain scores on FACT-Hep at 6 wk compared with minor resection or RFA. No differences in QOL measures at 3 and 6 mo were observed between interventions. A similar trend was observed for all QOL measures (POMS, EORTC QLQC30/PAN36, FHSI-8, global rating scales)

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

STUDY PURPOSE/ QUALITY-OF-LIFE ENDPOINT

FIRST AUTHOR, JOURNAL, YEAR

HCC

Primary outcome: QOL in HCC compared with population norms and between treatment type

Cross-sectional cohort, WHOQOL-BREF N 5 161 (121 HR, 31 and EORTC TACE, 8 PEI, 1 BSC) QLQ-C30 QOL assessed at single (Taiwanese time point translation)

Martin, Surgery, 2007124

CRLM, CCA, or HCC undergoing HR

Primary outcome: time to return to baseline QOL

Prospective longitudinal N 5 32 (24 major hepatectomy, 8 minor hepatectomy); QOL assessed at consent, discharge, first postoperative visit, 6 wk, then 3, 6, and 12 mo

FACT-HEP, FHSI8, EORTC QLQ-C30 1 PAN26 module, POMS; global rating scale (6 domains, scales 27 to 17)

Dasgupta, British Journal of Surgery, 2008125

Hepatic malignancy undergoing HR (CRLM, CCA, HCC, other metastases)

Primary outcome: longitudinal QOL

Prospective longitudinal, N 5 103 (74 CRLM, 9 CCA, 8 HCC, 12 other); QOL assessed at baseline, 6, 12, and 36-48 mo

EORTC QLQ-C30

Banz, World Journal of Surgery, 2009126

HR for benign or malignant disease at least 6 mo before analysis

Primary outcome: impact of postoperative diagnosis (benign/malignant) on QOL

Cross-sectional cohort, N 5 135 (89 malignant disease, 46 benign disease); QOL assessed at a single, nonstandardized postoperative time point

EORTC QLQC30 1 LM21 module

Bruns, World Journal of Gastroenterology, 2010127

HR for benign or malignant disease at least 3 mo before analysis

Primary outcome: QOL and identification of variables associated with/ predictive of decrease QOL

Cross-sectional cohort, SF-12 (mental N 5 96 (76 malignant component [21 primary, 55 metasscale [MCS] 1 tases], 20 benign); QOL physical comassessed at a single, ponent scale nonstandardized post[PCS]), ad hoc operative time point symptom and pain scale

Compared with population norms, HCC was associated with decrease in social and psychological domains and improved environment domains; HR was associated with improved QOL compared with TACE/PEI/ BSC Major hepatectomy associated with decline in all measures of QOL postoperatively; QOL nadir scores observed at 6 wk, with return to baseline values by 3 mo. Minor resection was associated with decrements in all measures at discharge; nadir QOL scores observed at initial postoperative visit and returned to baseline by 6 wk postoperatively Decrease from baseline to 6 mo in physical functioning domain and increase in dyspnea/ fatigue. At 12 mo, physical function and fatigue return to baseline but dyspnea persistent. Survivors with no recurrence at 36-48 mo had improved global QOL over patients with disease recurrence Patients who underwent hepatic resection for malignant disease had similar general, global, and self-assessed QOL relative to those with benign diagnoses. However, physical function scores and pain, fatigue, and social function scores were worse in the malignant group MCS significantly lower among patients with benign vs. malignant diagnosis as well as primary vs. metastatic cancers (P , .05). No difference in QOL based on sex, age, or postoperative complications. Increase in symptoms/ pain and decreases in daily activities were associated with worse PCS/MCS

70% Hepatitis B

Major hepatectomy 5 $3 Couinaud segments

44/103 (43%) alive at last follow-up

QOL assessment at a mean of 27 mo postoperatively

QOL assessed once between 3-36 mo postoperatively

Continued

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Lee, Journal of Surgical Oncology, 2007123

419

420

TABLE 29.4  Studies of Hepatic Resection and Health-Related Quality of Life—cont’d STUDY DESIGN, N, AND ASSESSMENT TIME POINTS

#4 CRLM with no EHD undergoing HR

Primary outcome: short-term and longitudinal QOL

Prospective longitudinal, EQ-5D-3L 1 EQN 5 138 (117 curative VAS HR, 19 unresectable at laparotomy); QOL assessed at baseline, then 3 wk, 6 wk, and every 3 months for 3 yr

Rees, Journal of Clinical Oncology, 2012129

CRLM undergoing HR

Primary outcome: longitudinal QOL

Prospective longitudinal, EORTC QLQN 5 232; QOL asC30 1 LM21 sessed preoperatively module and at 3, 6, and 12 mo postoperatively

Miller, American Journal of Surgery, 2013130

Hepatic malignancy undergoing HR of . 2 segments (CRLM, CCA, HCC, other metastases)

Primary outcome: impact of anemia and postoperative complications on short term QOL

Mise, World Journal of Surgery, 2014131

HCC undergoing HR

Primary outcome: longitudinal QOL Secondary outcome: identification of perioperative predictors of QOL

Prospective longitudinal, N 5 41 (16 CRLM, 9 HCC, 4 CCA, 12 other); QOL assessed preoperatively, at first postoperative visit, then 1.5, 3, and 6 mo postoperatively Prospective longitudinal, N 5 69; QOL assessed preoperatively and every 3 months for a year.

POPULATION (PATIENT WITH:)

Wiering, British Journal of Surgery, 2011128

QUALITY-OF-LIFE INSTRUMENT

EORTC QLQC30, FACTAnemia, global change rating scale (27 to 17)

SF-36 Health Survey

QUALITY-OF-LIFE RESULTS

COMMENTS

Overall, decline in global QOL at 3 and 6 wk postoperatively. Curative HR was associated with return of global QOL to baseline at 3 mo and stabilization to 3 yr. Patients found to be unresectable at laparotomy had persistent decline in QOL during the study period. Disease recurrence associated with decline in QOL during time. Patients with recurrence amenable to re-resection had global QOL scores similar to patients never experiencing recurrence Twenty percent of patients had severe symptoms at baseline. At 3 mo postoperatively, all functional scales decreased, proportion with severe symptoms increased, and functional scales returned to baseline at 6 mo and stabilized thereafter. Ten percent of patients continued to have severe problems with pain and sexual function 1 yr postoperatively Social and functional domains Anemia defined at scores lower in anemic group discharge as ,10 g/ at all time points. Major dL; 34% overall complications associated with complication rate, increased pain at 6 wk and 25% major 6 mo but no difference in any complication rate domain-specific QOL scales PCS did not change after surgery. At 9 mo, MCS were significantly improved versus baseline and population norms; female sex, age . 70 yr, thoracoabdominal incisions, tumors . 5 cm, and ICGR-15 , 10% were associated with worse PCS at 3 mo; no clinical variables were predictive of MCS at 3 mo

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

STUDY PURPOSE/ QUALITY-OF-LIFE ENDPOINT

FIRST AUTHOR, JOURNAL, YEAR

CRLM treated with HR $ 5 yr before assessment

Primary outcome: long-term QOL

Long-term follow-up of EORTC QLQprospective cohort, C30 1 LM21 N 5 68; QOL assessed module at single, nonstandardized time point $ 5 yr postoperatively

Studer et al., British Journal of Surgery, 2018133

Malignant and benign tumors requiring liver resection

Evaluate long-term QOL after liver resection

Prospective, single institution, longitudinal study, N 5 188 (130 malignant, 58 benign), QOL assessed at baseline, 1, 3, 6 and 12 months.

EORTC QLQC30, LMC21

Wang et al., Medicine, 2019134

HCC undergoing resection

Compare effect of intervention on depression, anxiety, QOL, and survival

Single-institution RCT, N 5 136 (68 comprehensive education and care program group, 68 control group); QOL assessed at baseline, 3, 6, 9 and 12 months after resection.

EORTC QLQ-C30

Overall, scores in all domains excellent at long-term follow-up and were significantly improved from baseline; ,5% of patients reported severe symptoms; persistent symptoms included peripheral neuropathy, sexual dysfunction, constipation, and diarrhea There was no difference in global health status between baseline and 1 month assessment. At 3, 6, 12 months, global health status improved, with benign tumors having a statistically significantly better score than malignant tumors (P # 0.006 at all time points). The intervention group had statistically significantly higher global health status scores at 12 months compared with the control group (P , .05). Still, there was no statistically significant difference in global health status at time points before 12 months (P . .05). There was no statistically significant group differences in symptom scores at any time point (P . .05).

QOL assessment at median of 8 (6.9-9.2) yr postoperatively

Data on instrument completion rates not provided, limited data on scores provided.

BSC, Best supportive care; CCA, cholangiocarcinoma; CRLM, colorectal liver metastases; EHD, extrahepatic disease; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; EWB, emotional well-being; FACT-G, Functional Assessment of Cancer Therapy–General; FHSI-8, FACT-Hepatobiliary Symptom Index-8; HCC, hepatocellular carcinoma; HR, hepatic resection; QOL, health-related quality of life; ICGR-15, indocyanine green retention rate at 15 minutes; LM21, colorectal liver metastases module; PAN26, pancreatic cancer module; PEI, percutaneous ethanol injection; POMS, profile of mood states; PWB, physical well-being; RFA, radiofrequency ablation; SF-12, 12-item Short Form; SWB, social well-being; TACE, transarterial chemoembolization; VAS, visual analogue scale; WHOQoL-BREF, World Health Organization Quality-of-Life–BREF (abbreviated) assessment.

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Rees, British Journal of Surgery, 2014132

421

Locoregional Treatments Steel, Psychooncology, 2004135

POPULATION (PATIENT WITH) HCC treated with TACE (cisplatin) or 90 Y radioembolization

STUDY PURPOSE/ QUALITY-OF-LIFE END POINT

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

Primary outcome: QOL and survival

Prospective cohort, FACT-Hep N 5 28; QOL assessed preprocedure and 3, 6, and 12 mo postprocedure

QUALITY-OF-LIFE INSTRUMENT

EuroQoL-5D-3L Prospective longitudinal, and EORTC N 5 201 (117 HR, QLQ-C30 45 surgical ablation, 39 CTX) survival data; QOL assessed preprocedure and at 3, 6, 9, and 12 mo for randomly selected members of the cohort; N 5 109 (53 HR, 29 surgical ablation, 27 CTX) Prospective longitudinal, FACT-G (Chinese N 5 83 (43 TACE, translation) 40 TACE 1 RFA); QOL assessed preprocedure and 3 mo postprocedure Retrospective evaluation Spitzer QLI of 2 randomized clinical trials, N 5 489; QOL assessed at baseline only

Ruers, Annals of Surgical Oncology, 2006136

Nonresectable CRLM Primary outcome: treated with surgical comparison of ablation ± resection vs. longitudinal QOL systemic chemotherand survival apy (CTX)

Wang, Quality of Life Research, 2007137

HCC treated with TACE or TACE1 percutaneous RFA

Primary outcome: short-term postprocedure QOL

Bonnetain, Quality of Life Research, 2008138

Advanced HCC treated with tamoxifen, TACE, or BSC in the palliative setting (primarily alcohol-related cirrhosis)

Primary outcome: determine the value of baseline QOL scores in predicting overall survival

Kalinowski, Digestion, 2009139

Unresectable liver; only neuroendocrine tumor metastases treated with 90Y

Primary outcome: Prospective longitudinal, EORTC QLQsafety and N 5 9; QOL assessed C30 1 LMC21 90 efficacy of Y preprocedure, and 3, module Secondary outcome: 6, 9, 12 mo postprocelongitudinal QOL dure

Kuroda, Journal of Gastroenterology and Hepatology, 2010140

HCC treated with percu- Primary outcome: Prospective cohort, N 5 SF-36 Health taneous RFA with and comparison of he49; QOL assessed preSurvey without postprocedure patic function and procedure and 1 yr BCAA supplementation nutritional status following RFA with and without BCAA supplementation Secondary outcome: QOL

QUALITY-OF-LIFE RESULTS

COMMENTS

Overall, QOL and scores on all Overall, survival at 6 mo subscales declined from baseline not different between to 6 mo for both groups. At 3 groups; only 14 pamo, FWB and overall QOL scores tients evaluable at are higher in 90Y group (P , .01). 6 mo At 6 mo, FWB remains significantly improved over TACE, but overall QOL was not different Baseline QOL similar between All patients underwent groups. All groups experienced initial laparotomy; no an initial decline in QOL and difference in median physical function at 3 wk postOS between ablation procedure. Ablation and HR and CTX groups groups return to baseline at 3 (31 and 26 mo, mo, whereas CTX did not. HR respectively) was associated with higher QOL than both ablation and CTX; however, QOL in ablation group was significantly higher than CTX group from 3-12 mo TACE 1 RFA group higher overall FACT-G, SWB, and FWB scores at 3 mo postprocedure (P , .01). Predictors of QOL were ChildPugh class and tumor recurrence Higher Spitzer QLI at baseline asso- Combined QOL data ciated with increased median OS from 2 RCTs of palliative (P , .01). In addition to common treatment for HCC: (1) variables used in classification tamoxifen to best supsystems (Okuda/CLIP/BCLC), portive care (N 5 416), QOL was the single best prog(2) TACE to tamoxifen nostic factor for survival only (N 5 122) Overall, an initial decrease in mean Late decline in QOL was QOL scores occurred after 90Y. associated with tumor At 6 mo, the majority of patients recurrence/disease had improvement in QOL scores, progression followed by a trend toward decline QOL at 12 mo. BCAA group experienced improve- Hepatitis C patients only ment in overall health as well as physical and social functioning (P , .05 for all subsets); QOL did not change in no-BCAA group following RFA

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

FIRST AUTHOR, JOURNAL, YEAR

422

TABLE 29.5  Studies of Locoregional Therapy for Hepatic Tumors and Health-Related Quality of Life

Previously untreated HCC undergoing TACE

Primary outcome: Prospective longitudinal, QOL N 5 73 ($3 TACE Secondary outcome: N 5 23); QOL asQOL in patients sessed preprocedure treated with $3 and 4, 8, and 12 mo TACE procedures postprocedure

Eltawil, HPB (Oxford), 2012142

Unresectable, nonablatable primary hepatic tumors (HCC and ICC) undergoing TACE

Primary outcome: QOL and treatment efficacy

Shun, Oncologist, 2012143

HCC treated with TACE

Primary outcome: Prospective cohort, short-term QOL N 5 89; QOL following single assessed within TACE procedure 3 days before disSecondary outcome: charge, and 4 and variables associ8 wk ated with changes in postprocedure QOL

Toro, Surgical Oncology, 2012144

HCC undergoing HR, TACE, percutaneous RFA, or NT

Primary outcome: Prospective longitudinal, QOL in all patients N 5 51 (14 HR, 15 with HCC regardTACE, 9 RFA, 13 NT); less of treatment QOL assessed preprocedure and 3, 6, 12, and 24 mo postprocedure

Salem, Clinical Gastroenterology and Hepatology, 2013145

HCC treated with TACE or 90Y

Primary outcome: short-term postprocedure QOL

Prospective longitudinal, N 5 48 patients; QOL assessed before first TACE and before each subsequent procedure (3-4 mo)

Prospective cohort, N 5 56 (27 TACE, 29 90Y); assessed preprocedure and 2 and 4 wk postprocedure

Completion rates: 4 mo Baseline QOL significantly lower 48/73 (66%), 8 mo compared with population norms. 38/73 (52%), 12 mo Mental health score at 4 mo 28/73 (38%) postprocedure, but not at 8 or 12 mo, was improved (P 5 .05). No other changes in QOL were observed in study cohort over time. The subset of patients undergoing $3 TACE procedures with improved mental health after first and second procedures, whereas bodily pain improved (P , .01, P 5 .05, respectively), and vitality scores declined (P 5 .04) after first procedure only WHOQoL-BREF Overall QOL did not decline in the 12 mo after TACE. After third TACE procedure (,1 yr), a trend toward a decline in the physical health domain was observed (P 5 .08) and coincided with increasing AFP and tumor size. SF-12 Health Mean QOL was improved from Survey, Sympdischarge to 8 wk postprocetom distress dure. At all timepoints, physical Scale (SDS), component scores were lower Hospital Anxiety than mental component scores. and Depression Factors associated with lower Scale (HADS) physical component scores: age, new diagnosis, higher levels of symptom distress, and depression. Factors associated with lower mental component scores: male sex, recurrent disease, higher levels of anxiety, and depression FACT-Hep (Italian Postoperatively, all domains of Percentage change in translation) QOL significantly improved in QOL from baseline was the HR group and were significalculated at each time cantly higher compared with all point. The average perother treatments. Mean PWB centage change in and EWB after RFA was imeach group was used proved compared with TACE for comparison and NT 90 FACT-Hep No difference in overall QOL beY patients had greater tween treatment groups. At 4 wk, tumor burden and more 90 Y had a greater improvement in advanced disease; ESS SWB, FWB, embolotherapy-speconsists of the following cific score (ESS), and a trend toitems: pain, bothered ward better overall QOL and TOI by treatment side compared with TACE group effects, ability to work, diarrhea, and appetite Continued SF-36 Health Survey

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Wible, Journal of Vascular and Interventional Radiology, 2010141

423

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

HCC treated with percutaneous RFA or TACE

Primary outcome: short-term postprocedural QOL

Prospective cohort SF-36 Health design, N 5 120 (40 Survey TACE, 40 RFA, 40 HCV without HCC [controls]); QOL assessed preprocedure and 1 mo postprocedure

Huang, British Journal of Surgery, 2014147

Small HCC (,3 cm) treated with HR or percutaneous RFA

Primary outcome: longitudinal QOL and survival

Prospective longitudinal, N 5 389 (HR, RFA); QOL assessed preprocedure, and 3, 6, 12, 24, and 36 mo postprocedure

FACT-Hep

Kolligs et al, Liver International, 2015148

Unresectable liver: only HCC, with preserved hepatic function treated with SIRT or TACE

Primary outcome: safety and shortterm postprocedure QOL

Pilot randomized controlled trial, N 5 18 (8 SIRT, 10 TACE) QOL assesses preprocedure and 1, 6, and 12 wk postprocedure

FACT-Hep

Anota et al., BMJ Open, 2016149

HCC ineligible for curative treatments

Xu et al., Integrative Cancer Therapies, 2016150

HCC undergoing TACE

Explore associations Prospective, three EORTC between QOL and group design; N 5 21; QLQ-C30 Phase II dose in Groups: 5 mg, 10 mg, Phase I trial of 15 mg; QOL assessed idarubicin-loaded at baseline, 15, 30, 60 TACE beads by days post TACE evaluating time to deterioration in at least one QOL domain Evaluate effect of de- Double blind, placebo MDASI-GI coction treatment controlled RCT, on post-embolizaN 5140 (50 neither tion syndrome placebo or decoction, 40 placebo, 50 Jian Pi Li Qi decoction administered day of procedure and for 3 days after), QOL assessed at baseline and daily for 3 days after the procedure.

POPULATION (PATIENT WITH)

Hamdy, Journal of the Egyptian Society of Parasitology, 2013146

QUALITY-OF-LIFE INSTRUMENT

QUALITY-OF-LIFE RESULTS

COMMENTS

At baseline, RFA and TACE groups had significantly worse physical function, energy/fatigue, pain, and general health compared with controls. Significant improvements in all QOL domains were observed at 1 mo in the RFA group (P , .05) but not the TACE group Baseline QOL was similar between groups. For both groups, following an initial postprocedural decline, QOL consistently improved and exceeded baseline values at 6-12 mo. Compared with HR, RFA group had significantly higher overall QOL scores at all time points. On multivariate analysis, HR was independently associated with worse QOL Efficacy of treatment for local tumor control was similar between groups (73% disease control TACE vs. 77% disease control SIRT). At baseline, SIRT patients had significantly worse PWB scores; however, no differences were observed between groups in overall QOL or subscales at 6 or 12 wk postprocedure Completion rates 81%-100% across time points. 90% of patients developed a deterioration in one or more QOL score. Patients at 10 mg dose had longer times to deterioration for global scores and physical and pain domains.

Hepatitis C patients only

The Jian Pi Li Qi decoction group demonstrated a statistically significant improvement on day 2 in the following symptoms of pain, fatigue lack of appetite, drowsiness dry mouth and constipation (p , .005).

Excluded patients who could not tolerate placebo or decoction (n 5 5)

Hepatitis B patients only; no difference in DFS and OS between groups; survey completion rates .95% at all time points

SIRTACE was an openlabel multicenter randomized control pilot study; TACE at 6-wk intervals until fully treated or disease progression (gold standard) vs. single session SIRT Design highlights novel method of incorporating QOL assessment into phase I clinical trials.

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

STUDY PURPOSE/ QUALITY-OF-LIFE END POINT

FIRST AUTHOR, JOURNAL, YEAR

424

TABLE 29.5  Studies of Locoregional Therapy for Hepatic Tumors and Health-Related Quality of Life—cont’d

Unresectable hepatic metastases from ocular melanoma treated with DEB loaded with doxorubicin

Describe QOL following treatment with DEB loaded with doxorubicin

Prospective, longitudinal, multi-center trial; N 5 20 receiving 3 treatments; baseline, 3-7 days after each treatment

FACT-Hep

Vilgrain et al., The Lancet, 2017152

Locally advanced, inoperable HCC

Compare efficacy and safety of sorafenib treatment with SIRT with 90Y

EORTC-C30, EORTC QLQ-HCC18

Prince et al., The Journal of Nuclear Medicine, 2018153

Multi-institution, openlabel, phase 3 RTC, N 5 459 (237 SIRT, 222 sorafenib), QOL assessed at baseline and every 3 months. Prospective, single institution, longitudinal study, N 5 37, QOL assessed at baseline, 1 and 6 weeks, and every 3 months.

Inoperable liver metastases Evaluate efficacy refractory to systemic of 166Ho-microtreatment undergoing spheres. Demonembolization stration of change in QOL after the procedure was a secondary outcome. Advanced unresectable Evaluate effect of Prospective, single 90 HCC with infiltrative Y radioembolizainstitution, longitudinal characteristics and tion on QOL and study, N 5 30, QOL portal vein thrombosis survival assessed at baseline, treated with 90Y 1, 3, 6 months post radioembolization procedure

Xing et al., BMC Cancer, 2018154

EORTC

SF-36

Completion rates were 90%. No statistically significant differences were found between baseline and 3rd treatment in SWB, EWB, FWB, or FACT-G score (p. .127). PWB and FACT-Hep total scores were statistically significantly different between baseline and the 2nd treatment assessment (p , .025). There was a statistically significant decrease in FACT-Hep TOI after each treatment in pairwise analysis (P 5 .003). QOL global health status subscore was statistically significantly better in the SIRT group than the sorafenib group (group effect P 5 .005, time effect P , .001) Global QOL declined from baseline to 1 week (83 (IQR 67-83) to 42 (IQR 56-86) and recovered at 6 weeks to 67 (IQR 56-83). The worst symptoms peaked at 1 week post-procedure (fatigue, eating, pain, and emotional problems). Completion rates declined with time (1 month 100%, 3 months 87%, 6 months 67%). No statistically significant change in 8 domains of SF-36 at any time point compared with baseline.

AFP, a-Fetoprotein; BCAA, branched-chain amino acids; BCLC, Barcelona Clinic Liver Cancer Classification; BSC, best supportive care; CLIP, Cancer of the Liver Italian Program HCC (hepatocellular carcinoma) classification system; CRLM, colorectal liver metastases; CTX, systemic chemotherapy; DEB, drug-eluting beads; DFS, disease-free survival; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; EWB, emotional well-being; FACT, Functional Assessment of Cancer Therapy; FACT-G, FACT-General; FWB, functional well-being; HAE, hepatic artery embolization; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; Hep, hepatobiliary; HR, hepatic resection; QOL, health-related quality of life; ICC, intrahepatic cholangiocarcinoma; MDASI-GI, MD Anderson Symptom Inventory-Gastrointestinal Module; NT, no treatment; Okuda, Okuda Prognostic Classification; OS, overall survival; PWB, physical well-being (FACT); QLI, Quality-of-Life Index; RCTs, randomized controlled trials; RFA, radiofrequency ablation; SF-36, 36-item Short Form; SIRT, selective internal radiotherapy; SWB, social well-being (FACT); TACE, transarterial chemoembolization; TOI, Trial Outcome Index; WHOQoL-BREF, World Health Organization Quality-of-Life project (short form of WHOQoL-100); 90Y, yttrium-90 radioembolization.

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

Rostas et al, The American Journal of Surgery, 2017151

425

POPULATION (PATIENT WITH)

Gastric Outlet Obstruction Mehta, Surgical Malignant GOO Endoscopy, 2006155 randomly assigned to DS or LGJ (56% pancreatic cancer)

STUDY PURPOSE/ QUALITY-OF-LIFE END POINT

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

Primary outcome: morbidity, pain and short-term QOL

Randomized clinical trial, N 5 27 (14 LGJ, 13 DS); QOL assessed preprocedure and 1 mo postprocedure

Schmidt, American Journal of Surgery, 2009156

Malignant GOO Primary outcome: undergoing palliative short-term QOL intervention: surgical bypass, PEG, PEJ, or ES

Van Hooft, Gastrointestinal Endoscopy, 2009157

Malignant GOO undergoing palliative ES

Van Hooft, Scandinavian Journal of Gastroenterology, 2010158

Malignant GOO undergoing palliative ES

Dolz, Gastroenterology Hepatology, 2011159

Malignant GOO undergoing palliative ES

Van den Berg, Endoscopy, 2013160

Malignant GOO undergoing palliative ES (54% pancreatic cancer)

Prospective cohort, N 5 47 (16 surgical bypass, 7 PEJ/PEG, 24 ES); QOL assessed preprocedure and 1 and 3 mo postprocedure

Primary outcome: Multicenter single-arm symptom palliaprospective trial, tion (GOO-SS) N 5 51; QOL assessed Secondary outcome: preprocedure, at 4 wk, safety, efficacy, and bimonthly and global QOL Primary outcome: Combined data from identify predictors 2 multicenter singleof survival from arm prospective trials, baseline N 5 101; baseline QOL evaluation assessment only

Primary outcome: Multicenter, single-arm prospecprocedural tive trial N 5 71 (38 duodenal technical success, tumors, 15 recurrent tumors clinical efficacy, localized to GJ anastomosis, and short-term 18 antral tumors); QOL asQOL sessed preprocedure and 1 mo postprocedure Primary outcome: Multicenter, single-arm, proprocedural technispective trial, N 5 46; QOL cal success and assessed preprocedure and clinical efficacy bimonthly until death Secondary outcome: QOL

QUALITY-OF-LIFE INSTRUMENT

QUALITY-OF-LIFE RESULTS

COMMENTS

SF-36 Health Survey

13/14 successful LGJ vs. 10/13 In-hospital mortality, rates successful DS. LGJ had more posthigh for both groups: procedure complications and longer 23% (3/13) LGJ and LOS. Mean physical health score in 17% (2/12) DS the DS group was improved at 1 mo (P , .01), whereas no changes in QOL were observed in the LGJ group EORTC QLQAt 3 mo, both ES and surgery groups Median OS 5 64 days; C30 1 STO22 had improved global QOL, physical only 10 patients commodule and role functioning, with decreased pleted QOL questionGOO symptoms compared with naires at all time points baseline (statistically significant only (5 ES and 5 surgery); in ES group). In the surgical group, initial procedural sucthere was a significant decline in cess rates: 70% ES physical functioning at 1 mo; vs. 100% surgical byhowever, this rebounded by 3 mo. pass No changes were observed in the PEG/PEJ group EORTC QLQGOO symptoms (GOO-SS) consisMedian OS 5 62 days; C30, EQ-5Dtently improved postprocedure, technical success ES 3L1VAS whereas global QOL (QL2 subscale 98%. Clinically, stent and EQ-VAS) was unchanged dysfunction occurred in following ES 7 patients (14%), migration in 1 patient (2%) EORTC QLQWHO performance status (HR, 2.63; Median OS 5 82 days, C30, EQ-5D95% CI, 1.68 to 4.12, P , .01), prealthough statistically 3L 1 EQ-VAS scription narcotic use (HR, 2.42; 95% significant the HR for CI, 1.38 to 4.25, P , .01), and pain EORTC pain score 5 score of the EORTC (HR, 1.01; 95% 1.01, clinical relevance CI, 1.00 to 1.01, P 5 .04) indepenquestionable dently associated with worse OS EuroQoL - 5D-3L Symptoms of GOO were significantly Median OS 5 91 days, improved postprocedure, whereas 29/71 (40%) comno change in QOL was observed. pleted both preproceStent efficacy was dependent on tudure and postprocemor location (GJ anastomosis [87%] dure assessments . duodenal [70%] . antral [29%]) EORTC QLQC30 and EQ5D-3L 1 EQVAS

Global QoL reflected by health status (QL2) and EQ-VAS demonstrated significant improvement between baseline and the mean scores during total follow-up. Data from EORTC scales not presented

Median OS 5 87 days, technical success 5 89%, clinical success 5 72%, periprocedural complication 5 57% (one or more complications)

CI, Confidence interval; DS, Duodenal stent; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; EQ-VAS, EuroQoL Visual Analogue Scale; ES, endoscopic stent; GOO-SS, gastric outlet obstruction symptom scale; HR, hazard ratio; LGJ, laparoscopic gastrojejunostomy; LOS, length of stay; OS, overall survival; PEG, percutaneous endoscopic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; QOL, health-related quality of life; QL, quality of life; SF-36, 36-item Short Form; STO22, EORTC gastric specific QoL Module.

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

FIRST AUTHOR, JOURNAL, YEAR

426

TABLE 29.6  Studies of Palliative Intervention for Malignant Gastric Outlet Obstruction (GOO) and Health-Related Quality of Life

TABLE 29.7  Studies of Malignant Biliary Obstruction and Health-Related Quality of Life FIRST AUTHOR, JOURNAL, YEAR

POPULATION (PATIENT WITH)

Malignant Biliary Obstruction Abraham, MBO undergoing Gastrointestinal palliative intent ES Endoscopy, 2002161 (66% distal obstruction, 12.5% mid-CBD obstruction, 21.5% hilar or intrahepatic obstruction) Chan, Journal of MBO undergoing ES Gastrointestinal as initial drainage Surgery, 2005162 procedure

STUDY PURPOSE/ QUALITY-OF-LIFE END POINT

QUALITY-OF-LIFE INSTRUMENT

Primary outcome: short-term QOL

Prospective cohort, N 5 50; QOL assessed preprocedure and at 1 mo postprocedure

SF-36 Health Survey

Primary outcome: stent patency Secondary outcome: morbidity, mortality, and short-term QOL

Randomized double-blinded controlled trial of ciprofloxacin vs. placebo before ES for MBO, N 5 94 (50 placebo, 44 ciprofloxacin); QOL assessed preprocedure and 1 mo postprocedure

SF-36 Health Survey

Artifon, American Journal of Gastroenterology, 2006163

Metastatic pancreatic cancer with MBO undergoing surgical bypass (choledochojejunostomy or cholecystojejunostomy) or ES

Primary outcome: cost of care Secondary outcome: shortterm QOL

Prospective randomized trial, N 5 30 (15 surgery, 15 ES); QOL assessed preprocedure and 30, 60, and 120 days postprocedure

SF-36 Health Survey

Saluja, Clinical Gastroenterology and Hepatology, 2008164

Unresectable gallbladder carcinoma with hilar obstruction undergoing ES or PTBD with plastic stent

Primary outcome: short-term QOL and clinical effectiveness of biliary drainage

Prospective randomized trial, N 5 54 (27 ES, 27 PTBD); QOL assessed preprocedure and 1 and 3 mo postprocedure

WHOQoL– BREF-26 and EORTC QLQ-C30

Robson, Annals of Surgical Oncology, 2010165

MBO undergoing PTBD

Primary outcome: short-term QOL, symptom control, morbidity/mortality and procedural efficacy

Prospective cohort, N 5 109; QOL assessed preprocedure and 1 and 4 wk postprocedure

FACT-Hep and VASP

QUALITY-OF-LIFE RESULTS

COMMENTS

Overall, decrease in T-bili from baseline to 1 mo postprocedure was associated with significant improvements in social function and mental health; however, if baseline T-bili was very high (14 mg/dL), no improvement in social function was observed Baseline QOL was similar between groups. Compared with baseline, at 1-mo follow-up, social functioning scores improved in the ciprofloxacin group and were significantly different from placebo (P 5 .05). All other subscales and summative QOL measures were not different between groups For the entire cohort, QOL scores improved at 30 and 60 days postprocedure, followed by decline to preprocedure levels at 120 days. ES was associated with significantly higher QOL than surgery at 30 days (P 5 .04) and 60 days (P 5 .05)

84% of patients experienced at least a 33% reduction in T-bili postprocedure; 25% mortality at 1 mo

At 1 mo postprocedure, no change was observed in global QOL for either group; however, symptom scale scores were improved in both PTBD and ES. At 3 mo, both groups showed a trend toward improvement in all domains of QOL assessed. PTBD was associated with improved physical and psychological scores compared with ES (P 5 .02) as well as greater improvement in symptom scores at 3 mo VASP scores (pruritus symptoms) significantly improved during time; however, overall QOL as measured by mean FACT-Hep scores were significantly decreased at 1 and 4 wk postprocedure

Median OS and stent patency were not different between groups; however, cholangitis was less common in the ciprofloxacin group

Median OS and postprocedural morbidity were not different between groups; overall cost of care from treatment to death was significantly reduced with ES ($4270 USD) vs. HJ ($8320 USD) Median OS was not different between groups. Clinical procedural success was higher in the PTBD group (89%) vs. ES (41%), and cholangitis was less common with PTBD (11%) compared with ES (48%)

Median OS 5 4.7 mo, mortality 10% at 1 wk, 28% by 8 wk; 100% technical procedural success but 50% major complications Continued

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

427

POPULATION (PATIENT WITH)

Larssen, Surgical Endoscopy, 2011166

Malignant GI obstruction undergoing ES SEMS

Artifon, Journal of Clinical Gastroenterology, 2012167

MBO with history of a failed ERCP undergoing PTBD or EUS-CD

Aggarwal, Brachytherapy, 2013168

MBO undergoing palliative ILBT with access via PTBD

Barkay, Journal of Clinical Gastroenterology, 2013168

STUDY PURPOSE/ QUALITY-OF-LIFE END POINT

STUDY DESIGN, N, AND QOL ASSESSMENT TIME POINTS

QUALITY-OF-LIFE INSTRUMENT

Primary outcome: short-term QOL Secondary outcome: comparison of physicianand patient-rated treatment effect

Prospective cohort, N 5 162 (40 [25%] biliary); QOL assessed preprocedure and 2 wk postprocedure

EORTC QLQC30 ± STO22 ± PAN26

Primary outcome: clinical and technical procedural success Secondary outcome: cost, morbidity, and QOL Primary outcome: symptom control, QOL, and survival

Prospective randomized trial, N 5 25 (13 EUS-CD, 12 PTBD); QOL assessed preprocedure and 7 and 30 days postprocedure

SF-36 Health Survey

Prospective longitudinal, N 5 18; QOL assessed pre-PTBD, post-PTBD, pre-ILBT, post-ILBT, and follow-up

EORTC QLQ-C30

MBO undergoing ES

Primary outcome: longitudinal QOL

Prospective longitudinal, N 5 164; QOL assessed preprocedure, at 30 and 180 days postprocedure

FACT-G

Moses, World Journal of Gastroenterology, 2013169

Infrahilar MBO undergoing ES randomly assigned to pcSEMS or PS

Primary outcome: time to stent failure Secondary outcome: morbidity, mortality, KPS, QOL

Multicentered prospective randomized trial, N 5 85 enrolled: 74 with QOL data (36 PS, 38 pcSEMS); QOL assessed preprocedure at baseline and 1, 3, 6, 9, 12, and 15 mo

SF-36 Health Survey

Castiglione et al., Abdominal Radiology, 2020170

Malignant obstructive jaundice undergoing PTBD

Compare QOL between right and left drainage approaches to PTBD

Prospective, single institution RCT, N 5 64 (31 right access, 33 left access), QOL assessed daily postoperatively for 7 days

EORTC QLQ-BIL21

QUALITY-OF-LIFE RESULTS

COMMENTS

Global QOL as well as nausea/vomiting, and appetite loss, and pruritus symptoms were significantly improved in patients with biliary obstruction treated with SEMS. Both patients and physicians reported symptom improvement; however, degree of improvement reported by physicians was higher than that of patients. No difference in QOL measured at 7 or 30 days postprocedure for either group

In addition to biliary obstruction, study cohort included patients undergoing esophageal, duodenal, and colonic SEMS

One hundred percent clinical and technical success in both groups; complication rates and procedural costs not different between groups Median OS 5 8.7 mo

Significant improvement in overall QOL post-PTBD, post-ILBT, and at last follow-up. Physical and social functioning scores were improved at all time points, as was insomnia symptom scale. The percentage of patients who reported pruritus and icterus declined at each time point Significant improvement in global QOL and PWB, EWB, and FWB subscales at 30 and 180 days. Weight loss, appetite, pruritus, and pain improved significantly at both time points At baseline, SEMS group had signifiTime to stent failure cantly worse physical functioning significantly longer scores; no differences were observed among the pcSEMS between groups thereafter. At 1 mo, group, and cholangitis vitality was improved, and at 6 mo was less common; no physical functioning was improved in difference in OS the pcSEMS group. PS was associated with significant improvement in subscales of bodily pain, social functioning, and mental health at 1 mo Jaundice, tiredness, anxiety, and pain The ability to randomize scales was worse in right sided to right or left suggests drainage group (p , .03). There was there was clinical no difference between groups in treat equivalence to the and weight loss scales (P . .38) approaches.

BMS, Bare metal stent; CBD, common bile duct; EWB, emotional well-being; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30; EORTC QLQ-BIL21, European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire–Biliary 21; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic stenting; EUS-CD, endoscopic ultrasound-guided cyst drainage; FACT, Functional Assessment of Cancer Therapy; FWB, functional well-being; GI, gastrointestinal; LBT, intraluminal brachytherapy; KPS, Karnosfsky Performance Score; MBO, malignant biliary obstruction; OS, overall survival; pcSEMS, partially covered self-expanding metallic stent; PAN26, pancreatic cancer module-26; PTBD, percutaneous transhepatic biliary drainage; PS, performance score; PWB, physical well-being; QOL, health-related quality of life; SEMS, self-expanding metallic stent; SF-36, 36-item Short Form; STO22, EORTC gastric specific QoL Module; T-bili, total bilirubin; WHOQoL– BREF-22, World Health Organization Quality-of-Life assessment (abbreviated version, 22 items); VASP, visual analogue scale for pruritus assessment.

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

FIRST AUTHOR, JOURNAL, YEAR

428

TABLE 29.7  Studies of Malignant Biliary Obstruction and Health-Related Quality of Life—cont’d

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

for robust QOL evaluation among patients undergoing pancreatic resection has gained significant momentum. As a consequence of this increased interest, study design and methodology have improved greatly and appreciably enhanced the quality of this expanding body of knowledge (see Table 29.3). Patients with pancreatic cancer often experience considerable symptoms and are at increased risk for impaired QOL compared with population norms.103,105,107 Results of QOL evaluation after pancreatic surgery are divergent and heavily dependent on the cohort studied and the timing of evaluation relative to surgery. Among well-selected patients with localized, resectable disease, QOL at 3 months after surgery was reportedly improved.100,171 Unfortunately, the beneficial findings reported in these studies appear to be the exception, with the great majority of investigations reporting stability and/or a decline in QOL scores after pancreatic resection.92,96,97,100,103,105–107,118,172 The heterogeneity observed in these studies is likely multifactorial and related, but not limited, to differences in disease stage, the QOL instrument used, timing/frequency of measurement, and length of follow-up. Early postoperative evaluation of QOL typically represents a transient state, primarily reflective of a patient’s recovery from the acute effects of surgery. These findings certainly allow surgeons to better inform patients, improve the consent process, and help tailor expectations. However, longer-term follow-up post-pancreatectomy is requisite to unveil the true clinical impact of surgical resection on QOL outcomes. In a recent prospective longitudinal study, QOL 12 months after pancreaticoduodenectomy (PD) for periampullary malignancies was evaluated using the SF-36 survey. Despite the heterogeneity in cancer subtypes included, and initial decrements, significant improvements were observed in the majority of subscales when measured at 12 months.105 Similarly, significant improvements in QOL domains assessed with the EORTC QLQ-C30 were observed among a group of patients undergoing partial pancreatectomies for pancreatic adenocarcinoma at 6 and 12 months postoperatively. Although baseline measurements were obtained postoperatively, and absolute QOL improvement is most certainly overestimated in this later study, the overall conclusions remain the same.102 After pancreatectomy, patients tend to experience surgery-related decline in QOL, although the overwhelming majority of data support a gradual improvement/ return to baseline within the first postoperative year. To date, several studies have compared QOL of patients undergoing different types of partial pancreatomy—classic PD versus radical pancreaticoduodenectomy (RPD) versus pylorus-preserving pancreaticoduodenectomy (PPPD) versus parenchyma-preservation/-sparing pancreatectomy (PSP), with different reconstruction techniques—pancreaticogastrostomy (PG) versus pancreaticojejunostomy (PJ), for a mix of benign and malignant indications.89,94,98,99,102,109,115,117,118,173 In general, patients undergoing partial pancreatectomy for benign disease, regardless of the type (PD, RPD, PPPD, and PSP) had similar long-term global ratings of QOL as well as comparable social, functional, and role scores on the EORTC QLQ-C30. Furthermore, studies of long-term QOL among patients with completely resected malignant tumors also suggest that QOL trends follow the same postoperative trajectory independent of the type of resection and/or reconstruction. Total pancreatectomy (TP) is a procedure associated with substantial and irreversible long-term consequences related to pancreatic insufficiency. Patients undergoing TP are dependent

429

on orally administered exogenous pancreatic enzymes to prevent malabsorptive syndromes/chronic diarrhea as well as strict insulin administration regimens to balance blood sugars and mitigate long-term diabetic complications. Not surprisingly, TP has the potential to substantially influence many QOL domains. In a longitudinal study of 32 patients undergoing TP for locally advanced central tumors (benign and malignant), QOL was assessed postoperatively and annually for 4 years thereafter. Interestingly, no difference in the mean global QOL scores between healthy norms and the entire TP population was observed; however, physical functioning among the TP group was significantly lower. Compared with benign counterparts, patients undergoing TP for malignant disease had higher symptom scale scores, suggesting a greater negative impact on QOL among this group. The number of patients evaluable at each time point in this study was low, and longer-term outcomes are subject to the “health survivor” bias.112 Billings and colleagues91 compared QOL outcomes of 27 long-term survivors (mean, 7.5 years) treated with TP for malignancy with age- and gender-matched controls. TP patients experienced a negative impact on their QOL and health status compared with the general population; however, compared with patients with insulin-dependent diabetes mellitus (IDDM) from other causes, the differences were no longer observed. Similarly, Epelboym and colleagues109 compared QOL between patients treated with TP versus PD with IDDM. Patients in the TP group had a slightly higher number of hypoglycemic events, but no significant differences were observed in global QOL scores. A subsequent study matched TP patients to IDDM patients and compared global QOL scores using the EORTCQLQ-C30 plus the PAN26 module and diabetes-specific QOL scores. Overall, TP patients reported worse global QOL compared with matched IDDM patients; however, when using the diabetes-specific measurement tool, there were no significant differences.174 These findings suggest that although TP impacts QOL, the changes observed are comparable to those seen in patients with IDDM alone and/or other types of pancreatic resection. This suggests that if TP is indicated, concerns regarding the impact of pancreatic insufficiency on QOL should not obviate intervention in well-selected patients. Many patients with pancreatic cancer are seen late with disease that is not amenable to curative resection. Although less common in the era of percutaneous and endoscopic interventions, some patients may require or may be best served with surgical palliation of gastric and/or biliary obstructions (see Chapter 69). In a randomized study, Van Heek et al. compared QOL after prophylactic double bypass with hepaticojejunostomy (HJ) plus gastrojejunostomy (GJ) to single biliary bypass (HJ) alone. In terms of QOL measures, no differences were observed between groups. However, an 18% reduction in the risk of gastric outlet obstruction and need for repeat intervention was observed in the HJ-plus-GJ group. QOL was not reassessed or compared among those who did and did not develop obstructive symptoms requiring secondary intervention. This is unfortunate because this may have influenced longer-term QOL.90 Palliative resection for advanced carcinoma of the pancreatic head has been suggested as an alternative to prophylactic surgical bypass (HJ plus GJ), with the potential added benefit of reducing pain associated with advanced pancreatic malignancy. When directly compared, no differences have been shown in terms of operative morbidity/mortality and/or overall survival between palliative resection and bypass. Furthermore,

430

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

despite the idea that resection improves pain control, and potentially QOL, it has been observed that patients treated with palliative resection actually experience significantly greater declines in emotional, cognitive, and social-functioning scales as assessed by the EORTC QLQ-C30 compared with surgical bypass alone.104 In combination, these findings suggest that resection provides no advantage in terms of survival or QOL. Consequently, use of resection as a means of palliation for advanced pancreatic head tumors should be used sparingly. To reiterate, the primary goal of palliative care is symptom management and maintenance of QOL. To this end, pancreatic stenting for the relief of intractable malignant pain has been evaluated. Wehrmann et al. assessed overall QOL using the Spitzer Quality-of-life Index (QLI), as well as pain control and opioid analgesic use, at baseline and every 4 weeks after intervention in patients with unresectable pancreatic carcinoma. Stenting was associated with significantly improved pain control at 4 weeks, which persisted out to 12 weeks. QLI scores paralleled pain scores and were improved versus baseline at the 4-week time point, with return to baseline levels at 12 weeks.95 Stenting of the pancreatic duct in select patients with advanced pancreatic malignancy and significant pain transiently improves pain control and QOL and is most certainly a reasonable option for palliation of these patients (see Chapter 69).

Hepatic Resection In the early eras of hepatic surgery, mortality ranged from 30% to 60%, and elective intervention was rare. Similar to pancreatic resection, however, improvement in surgical technique, perioperative care, and multidisciplinary team management has led to significant decreases in morbidity and mortality (from .50% down to 2%–3%) associated with hepatic resection (Jarnagin et al. 2002; see Chapter 103).175 As a consequence, hepatic resection has become the standard of care for definitive management of many hepatic tumors. The increased use of hepatectomy for both primary and metastatic hepatic cancers has undoubtedly improved survival outcomes; however, questions regarding the impact of hepatic resection on QOL remain. At present, there are a number of studies that address QOL as it pertains to hepatic resection and treatment of hepatic tumors (see Table 29.4). QOL in the early postoperative period primarily reflects procedure-related factors (e.g., incisional pain, mobility limitations, complications). To date, multiple studies have evaluated the short-term impact of hepatic resection on QOL.120–122,124,128,130 Among patients undergoing hepatectomy for primary hepatic cancer (HCC/intrahepatic cholangiocarcinoma [ICC]), a significant decline in mean scores on the Gastrointestinal QOL Index (GQLI) was observed 2 to 10 weeks postoperatively.120 The initial decline was followed by a gradual return to baseline by 4 months, and in patients without recurrence, mean GQLI was greater than baseline assessment by 9 months. This postoperative trend in QOL after hepatic resection has been observed in multiple studies121,122,124,128,130,133 and appears similar regardless of underlying tumor type (primary/metastatic) or QOL measurement tool used (e.g., EORTC QLQ-C30, FACT-G, FACT-Hep, GQLI). Although the extent of resection may alter the degree/duration of QOL decline postoperatively, in the absence of disease recurrence, the overall trend remains the same.120,122,124,126 In direct contrast to patients undergoing curative resection, patients found to have unresectable disease at the time of laparotomy experience a steady decline in global

QOL and all functional subscales, with persistence of symptoms throughout follow-up.121,136 Laparotomy for hepatic malignancy, without resection of disease, negatively impacts both early and longer-term QOL outcomes. As such, meticulous preoperative evaluation is essential to avoid subjecting patients to futile intervention. Compared with short-term postoperative QOL, longitudinal evaluation (3 to 6 months) after hepatic resection is less reflective of the technical procedure and more likely related to patient- and disease-specific factors.126,127,133 Overall, patients with HCC have worse psychological and social functioning compared with population norms,123 and not surprisingly, patients amenable to complete resection have improved QOL compared with HCC treated with transarterial chemoembolization (TACE), percutaneous ethanol injection, and/or best supportive care144 (see Chapters 91, 96, and 98). In a long-term evaluation of hepatic resection for HCC in patients with persevered hepatic function, significant improvements in mean QOL and subscale scores were observed at 3 months and persisted out to 2 years follow-up.119 Similar improvement was not observed in a control group with HCC undergoing TACE. Chen and colleagues120 also observed similar long-term trends in patients undergoing hepatic resection for HCC. However, findings from these studies contrast with those of Mise and colleagues,131 in which no change in the physical component scale on SF-36 and minimal change on the mental component scale were observed after hepatectomy for HCC. The measurement tools used in these studies differed (disease-specific FACT-G vs. generic SF-36) in terms of sensitivity to change and may account for the observed differences. It is likely that longerterm QOL assessment in patients with HCC is heavily dependent on the type and severity of underlying hepatic disease as well as other associated comorbidities. Future studies stratifying for these potential confounders are necessary. CRLMs are the most common indication for hepatic resection, and multiple studies have assessed longer-term QOL outcomes among these patients50,121,126,127,132,176 (see Chapter 92). Based on the literature, there is general consensus that after an initial postoperative decline, global QOL tends to return to baseline and at times exceeds baseline scores during longerterm follow-up. Likewise, disease-specific symptoms and symptom scales tend to follow a similar trajectory after hepatectomy for CRLMs. However, a recent study by Rees and colleagues177 using the EORTC QLQ-C30 in conjunction with the liverspecific module found that as many as 10% of patients had persistent severe symptoms of pain and decrements in sexual function at 1 year after resection of CRLMs. Longer-term follow-up of this study cohort suggests that, even at a median of 8 years follow-up, 5% of patients still have significant symptoms.132 This study did not account for the use of preoperative or postoperative chemotherapy or further treatments. Consequently, it is difficult to discern if the reported persistent symptoms are related to CRLMs, hepatic resection, previous surgery for primary tumor, or ongoing oncologic therapy. Overall survival is increased among patients with resectable CRLMs. Unfortunately, disease recurrence requiring further oncologic therapy is the norm and may influence QOL. In a well-designed prospective study by Wiering and colleagues,128 patients undergoing hepatic resection and having less than or equal to four CRLMs were followed for 3 years, and QOL was assessed at predefined time points. Overall, disease recurrence was associated with a decline in QOL as measured by the

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

EQ-5D-3L plus EQ-VAS (visual analogue scale). This decline in QOL, however, was mitigated by the ability to undergo repeat curative resection of recurrent disease. QOL scores of patients who underwent complete re-resection were similar to those of patients who never experienced a recurrence. Dasgupta and colleagues125 also report a decrement in global QOL on the EORTC QLQ-C30 in the setting of recurrence. Similar decrements in QOL have been observed after recurrence of HCC119,120 and after repeat resection of recurrent HCC, QOL trends parallel to what is seen with CRLMs.178 At present, it is reasonable to suggest that recurrence of disease after hepatic resection for malignancy portends worse QOL; however, this decrement may be transient if complete surgical re-excision can be achieved.

Locoregional Treatment of Hepatic Tumors Locoregional therapy (LRT), including hepatic arterial embolization, selective internal radiotherapy (SIRT), and ablation, may be used with curative and/or palliative intent for both primary and metastatic tumors of the liver (see Chapters 96–98). These therapies treat disease/symptoms using percutaneous methods, thereby avoiding the morbidity of an open or laparoscopic surgical procedure. In addition to bland hepatic artery embolization (embolization with particles alone), chemotherapy and radiotherapy may be delivered to the liver locally via TACE and yttrium-90 (90Y) microsphere radioembolization (see Chapter 96). Ablative therapies vary by the agent/energy source used to induce cell damage/death and include thermal (radiofrequency, microwave, or cryotherapy; see Chapters 98B and 98C), electrical (irreversible electroporation; see Chapter 98C), and chemical (alcohol injection; see Chapter 98D) techniques. The use of LRT to treat hepatic tumors has increased substantially, and the impact on morbidity/mortality and survival has been well documented. In general, these types of “hard” clinical outcomes are similar across LRTs; as such, studies evaluating QOL and LRT for primary and metastatic hepatic tumors are rapidly emerging (see Table 29.5). HCC is the most common primary hepatic tumor (see Chapter 91). Because HCC typically arises in the setting of underlying cirrhosis, treatment decisions are dependent on tumor characteristics/disease burden, hepatic function, and performance status. Transplant and hepatic resection are the primary curative therapies; however, these are limited to a minority of patients (see Chapters 103 and 115). As a consequence, LRT has emerged as the mainstay of treatment for many patients with HCC. Although some patients may be rendered disease free, LRT in the setting of HCC is typically noncurative and offered to provide local disease control and ameliorate symptoms. As a consequence, interest in QOL associated with LRT has focused primarily on this population of patients. Although LRT is used in the treatment of hepatic metastases from neuroendocrine tumors (NET) and CRLMs, limited data are available regarding the impact of LRT on QOL in these populations.136,139 Compared with published population norms, patients with HCC have lower overall QOL.146,154 Multiple studies have evaluated short-term (0–3 months) postprocedural QOL among patients with HCC treated with LRT.137,143,145,146,148–150 In general, regardless of modality (TACE/90Y radioembolization/radiofrequency ablation [RFA]) and/or QOL instrument used, most patients experience a transient decrement in overall QOL very early (1–3 weeks) after intervention. This is typically

431

followed by an improvement in most subscales/domains (physical, emotional, social, mental/psychological), global QOL, and symptoms. The impact of LRT on longer-term QOL has also been extensively evaluated.135,140–142,144,147,152,154 Similar to short-term evaluations, most longitudinal studies report an initial early decline in QOL regardless of LRT modality. Nevertheless, because the natural history of HCC differs based on the etiology of underlying hepatic disease (i.e., hepatitis C virus cirrhosis vs. hepatitis B virus cirrhosis), it is not surprising that reported longitudinal QOL outcomes with LRT treatment of HCC vary (see Chapters 70 and 76). Steel and colleagues135 found a persistent decrease in global QOL and all subscales from baseline to 6 months after TACE (cisplatin) or 90Y radioembolization. Interestingly, in this study, despite having greater disease burden and lower reported QOL at treatment initiation, patients undergoing 90Y radioembolization had better functional wellbeing at 3- and 6-month follow-up when compared with those treated with TACE. Vilgrain et al.152 reported statistically significant differences in the two randomized treatments (sorafenib arm vs. SIRT arm). The QOL global health status subscore of the EORTC was statistically significantly better in the SIRT group than the sorafenib group. Other studies of TACE141,142 and RFA140 for unresectable HCC have reported no significant changes in QOL parameters during longer-term follow-up. Toro and colleagues144 evaluated longitudinal QOL among patients undergoing hepatic resection, RFA, TACE, or no treatment (NT). With the exception of the NT group, all patients (resection, RFA, TACE) reported persistent improvements in QOL from 3 to 24 months. In this study, compared with TACE and NT groups, patients treated with RFA had significantly better physical and emotional well-being. Improved longerterm QOL after LRT was also observed in a recent study comparing hepatic resection with RFA in patients with small (,3 cm) HCC.147 QOL is not only important as a clinical outcome, but correlational studies have also shown that among patients undergoing transarterial embolic therapy for HCC, baseline QOL is actually one of the strongest predictors of overall survival.138 The studies are nonrandomized and thus subject to inherent disease- and patient-related selection bias. Apart from the earlier discussed RCT comparing chemotherapy regimen with SIRT,152 the only other known RCT evaluating QOL explored the impact of a herbal extract on reducing postembolization syndrome.150 The Jian Pi Li Qi decoction arm demonstrated statistically significant improvement on day 2 postembolization in the following symptoms of pain, fatigue, lack of appetite, drowsiness, dry mouth, and constipation (P , .005). To date, no single LRT modality has consistently been shown to be superior to others in terms of QOL outcomes. Review of the literature suggests that, in general, 90Y radioembolization and RFA are associated with better QOL compared with TACE135,137,144–146 and TACE in combination with RFA yields better outcomes than TACE alone.137 TACE and 90Y radioembolization are typically used to treat multifocal unilobar/ segmental disease, whereas RFA is indicated for small solitary lesions or low-volume multifocal disease; as such, comparison between treatments without randomization or matching for extent of disease/hepatic function is limited. A single, small, randomized pilot study of TACE versus selective internal radiotherapy was recently completed. QOL was a secondary endpoint of the trial, and when using the FACT-Hep scale, no

432

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

significant differences were observed between the treatments arms at 6 or 12 weeks of follow-up. Despite the limitations of the available literature, small sample sizes, heterogenous patient populations, and lack of randomization, it is reasonable to conclude that QOL after LRT for HCC is improved in the short term, whereas longerterm outcomes vary and are likely strongly influenced by patient- and disease-specific variables. Furthermore, the clinical indications and patient populations amenable to TACE versus RFA versus 90Y radioembolization are inherently different. At present, no one form of LRT has consistently been associated with superior QOL. Overall, in patients with unresectable, nontransplantable liver, only HCC treatment with LRT provides local disease control and likely improves the overall QOL for patients during the first 6 to 12 months after intervention.

Palliative Treatments Surgery for tumors of the pancreas, liver, and bile ducts has improved over time; however, as many as 85% of patients with HPB malignancies are seen late with advanced-stage disease that is not amenable to surgical intervention. In this setting, significant complications related to the precarious location of these tumors are common and often require intervention to ameliorate associated symptoms. The goal of treatment in this setting is palliative. It is therefore critical that interventions minimize morbidity and improve symptoms to maintain or improve QOL.

Gastric Outlet Obstruction Malignant gastric outlet obstruction (GOO) occurs when the pyloric channel or duodenum is externally compressed by tumor and/or internally obstructed because of local tumor invasion (see Chapter 69). It is a debilitating complication of advanced malignancies, occurring in 10% to 20% of periampullary cancers.90,179 The predominant symptoms associated with GOO include early satiety, bloating, nausea, vomiting, reflux, and abdominal pain, often leading to anorexia, weight loss, and cachexia. Treatment of GOO is essential not only to improve symptoms but also to allow suitable candidates to return to or initiate other oncologic therapy. Before the development of endoscopic and minimally invasive techniques, treatment of GOO required laparotomy and open surgical bypass (GJ). More recently, advancements in both laparoscopic and endoscopic techniques have led to the development of less invasive means of treating GOO, including laparoscopic GJ (LGJ), percutaneous endoscopic gastrostomy/jejunostomy (PEG/PEJ), or endoscopic/radiologic duodenal stenting (DS). At present, determining which intervention to use requires a balanced assessment of life expectancy, risks and benefits of each intervention, the potential need for repeat intervention, and the overall impact on QOL. In the context of palliative interventions for GOO, QOL has only been assessed as the primary outcome in one study; however, it has been assessed extensively as a secondary outcome (see Table 29.6). It should be noted that many studies of QOL related to treatment of GOO have used a tool designed specifically for this patient population called the Gastric Outlet Obstruction Scoring Scale (GOO-SS).157,159,160 Although the scale only evaluates a single domain (physical), it is often reported as a surrogate for QOL. There remains a paucity of research on QOL in this population. There is a single randomized trial of 27 patients with malignant GOO (56% pancreatic cancer) treated with DS (n 5 13) versus LGJ (n 5 14) that has been completed.155 The underlying

fragility of this group of patients is highlighted by the high rate of hospital mortality (DS at 17% and LGJ at 23%). Not surprisingly, LGJ was associated with longer hospital stay (LOS) and greater postprocedural complications compared with DS. However, the procedural success rate in the DS group (77%) was lower than in the LGJ group (100%). Physical and mental QOL scores on the SF-36 at baseline were similar between groups. Among evaluable patients at 1 month follow-up (n 5 13, 6 LGJ and 7 DS), patients treated with DS had improved physical QOL scores, whereas no changes in QOL were observed in the LGJ group. The authors concluded that DS provided improved palliation versus LGJ based on decreased LOS, morbidity, and increased physical QOL at 1 month; however, this must be viewed in light of the decreased procedural success rates of DS and need for potential repeat intervention. Similarly, Schmidt et al.156 observed improvements in global QOL, physical and role functioning, and a decrease in symptoms after palliative intervention (endoscopic stenting [ES] and surgical bypass) among 50 patients with malignant GOO at 3 months post-procedure. DS is the most recent addition to the armamentarium of procedures available to palliate GOO, and prospective trials evaluating safety and efficacy have also included an evaluation of QOL outcomes and/or symptom relief.157,159,160 In terms of symptom relief, evaluated with GOO-SS, placement of ES was consistently associated with symptom improvement and increased oral intake across studies. In two of three studies reporting QOL outcomes, no changes in global measures of QOL were observed at 1 month follow-up.157,159 Although no untreated GOO control group was included, and the QOL in this population was not documented, it is likely that QOL would decline with progressive/untreated GOO and that stability of global measures represents a positive QOL outcome. Conversely, the most recent study by van den Berg and colleagues160 reported significant improvements in global QOL after ES. This study compared preprocedural QOL measure with the mean QOL for the entire follow-up period (not standardized post-procedure time point); as such, the conclusions regarding QOL outcomes are difficult to interpret. Overall, studies reporting on QOL after palliative procedures for GOO are limited in size, follow-up, and, most importantly, response rates.179 Reported median overall survival of patients with advanced/end-stage malignancy and GOO ranges from 3 to 4 months; therefore even short-term follow-up can be difficult, and results are inherently biased in that patients returning questionnaires/surveys represent a “healthy survivor” subgroup.179,180,181 Furthermore, QOL is most commonly reported as a secondary outcome of safety and efficacy trials; as such, established QOL instruments were not used and full data are not reported (e.g., single global measures reported as means, little evaluation of subscales), and the robustness of analysis and methodology is suboptimal. Despite this, available literature would suggest that relief of obstruction obviates the main symptoms associated with GOO, leading to a stabilization of QOL. The palliative nature of intervention for GOO demands assessment of QOL. At present, additional prospective studies with QOL as a primary outcome measure are necessary to define the true relationship between treatment of malignant GOO and QOL.

Malignant Biliary Obstruction Malignant biliary obstruction (MBO) is common in the setting of pancreaticobiliary cancers (see Chapters 49, 51, and 65). In

  Chapter 29  The Impact of Hepatobiliary Interventions on Health and Quality of Life and Health

fact, jaundice is often the initial clinical presentation of these tumors. Hyperbilirubinemia is associated with increased perioperative risk in certain situations and is a contraindication to many chemotherapy regimens. Furthermore, biliary obstruction may be associated with symptoms of anorexia, weight loss, pruritus, and malabsorption, leading to significant functional impairment. As such, intervention to alleviate MBO is undertaken for two primary reasons: to allow initiation of definitive oncologic therapy (surgery and/or chemotherapy) and/or to palliate associated symptoms. In the past, surgical bypass with HJ was the mainstay of treatment for MBO. In the current era, however, ES and image-guided percutaneous transhepatic biliary drainage (PTBD) are the most common procedures used to relieve jaundice (see Chapters 29 and 30).167,182–185 Intraluminal brachytherapy (ILBT) has also been proposed as a mechanism to treat MBO. Initial reports regarding ILBT for MBO suggest an improvement in QOL; however, research in this area is limited.168 Decisions regarding the type of intervention for MBO are complex and must take into account not only anatomic location but also life expectancy, intended future oncologic therapy, safety/efficacy, and QOL. To date, multiple studies have evaluated management strategies for MBO, which have included analysis of QOL outcomes (see Table 29.7). Several studies have assessed different methods of achieving decompression of the biliary tree and compared subsequent impact on QOL. Surgical bypass for MBO is uncommon in developed countries and data pertaining to its impact on QOL are limited. In a study from Brazil, where surgical bypass remains common, a comparison was made between ES and surgical bypass (choledochojejunostomy or cholecystojejunostomy) in patients with metastatic pancreatic cancer.163 Regardless of treatment type, global QOL improved from baseline at the 30- and 60-day follow-up, respectively, but returned to preprocedure values by 120 days. However, global QOL scores in patient treated with ES were significantly higher at all time points compared with the surgery group. No differences in procedural complications or survival were observed between groups. The equivalence in morbidity and mortality between procedures with improved QOL suggests ES may be superior to surgical bypass in select patients. Techniques of ES and PTBD for MBO continue to evolve. Similarly, studies evaluating not only safety/efficacy of these interventions, but also QOL, continue to increase. ES for MBO is associated with reasonable clinical and technical success. Reduction in total bilirubin levels by at least one-third of preprocedural values with ES has been associated with improved social and mental functioning as measured by SF-36; however, these QOL improvements appear to be mitigated by the absolute preprocedure bilirubin (preprocedure total bilirubin  14 mg/ dL; no change in QOL parameters).161 Furthermore, in an assessment of 40 patients undergoing ES with self-expanding metal stents (SEMS), global QOL on the EORTC QLQ-C30 was improved, as were symptoms of nausea/vomiting, appetite, and pruritus at 2 weeks after the procedure.166 Using the FACT-G questionnaire, Barkay et al.186 also evaluated ES for MBO and found improvement in global QOL and physical, emotional, and functional well-being at both 1 and 6 months follow-up. Likewise, a recent study comparing partially covered self-expandable metal stents with plastic stents revealed no difference between treatments in terms of QOL but a general trend in both arms toward an improvement in global QOL and subscales.169 Taken in concert, these findings suggest that ES

433

for MBO improves short-term QOL and symptoms; however, conclusions regarding longer-term QOL outcomes are limited by the substantial decrements in survey completion with prolonged follow-up. In a prospective evaluation of 109 patients with MBO presenting for PTBD, significant improvements in pruritus symptoms were observed, but overall QOL, as assessed by FACTHep, significantly declined during the 4-week period after PBD.165 The mortality rate was extremely high (28% at 8 weeks post-PBD), highlighting the degree of illness and frailty among this patient population.165 A recent study randomized patients to either the right or left access approach before PTBD and assessed QOL in the 7 days after the procedure.170 Although the study found the right access group had worse scores in jaundice, tiredness, drain care, and anxiety scales, the study was limited by duration of follow-up and assumption of equivalence in drainage approaches.170 PTBD followed by ILBT has recently been touted to reduce localized tumor burden and result in improved biliary drainage and symptom relief. In a study of high-dose ILBT, 18 patients with advanced pancreaticobiliary or metastatic cancer underwent PTBD, followed by two ILBT sessions 1 week apart.168 In conjunction with significant improvement in symptoms (100% resolution of pruritus), global QOL, as well as physical and social functional scores, were improved at all assessment points.168 It appears that PTBD alone significantly improves biliary obstructive symptoms; however, in the absence of further treatments, QOL seems to decline in a fashion expected of end-stage pancreaticobiliary cancers. ES was initially preferred to PTBD because drainage was internal and thought to be more readily achievable. However, advances in image-guided interventions and the development of internal stents for percutaneous delivery mean adequate internal drainage can be achieved with both PTBD and ES. The growing number of techniques and methods for ES and PTBD has led to multiple comparative evaluations of the two procedures. Saluja et al.164 randomly assigned patients with unresectable gallbladder carcinoma and hilar obstruction to undergo either PTBD or ES. At the 1-month follow-up, no significant change in overall QOL was observed between the groups; however, at 3 months, a trend toward improvement was noted in both. Compared with ES, PTBD was associated with significantly greater improvement in the physical and psychological domains of QOL. Both groups experienced improvement in symptoms, but PBD was associated with significantly greater improvements in fatigue compared with ES. Conversely, evaluation of patients randomly assigned to PBD or endoscopic ultrasound-guided choledochoduodenostomy (EUS-CD) revealed no significant change in QOL in the 30 days after intervention.167 Furthermore, there were no significant differences between the PBD and EUS-CD groups. It appears that, regardless of procedure performed, relief of obstruction per se provides symptom relief and at best stabilizes QOL, which among this fragile cohort likely represents a positive outcome.

CHALLENGES IN HEALTH-RELATED QUALITYOF-LIFE RESEARCH AND FUTURE DIRECTIONS Despite the widespread implementation of QOL assessment, interpretation of findings and implementation at the clinical practice level is a significant challenge. Merely stating a P value, indicating a statistical difference, is the standard; however,

434

PART 3  ANESTHETIC MANAGEMENT, PRE- AND POSTOPERATIVE CARE

determining how this is to be interpreted clinically is a challenge and is one of the major criticisms of QOL research. To date, this has significantly limited the clinical applicability of QOL research outcomes. As of 2005, only 25% of QOL studies reported on the clinical significance, and thus applicability, of their findings.187 Several methods have been suggested to rectify this issue, including establishment of a minimal important difference (MID)—the smallest difference in a score in the domain of interest that a patient perceived as beneficial and that would mandate a change in patient management.188 Two primary methods for determining a MID for QOL outcomes exist: distribution based (estimate based on observed scores in a sample) and anchor based (compare, or anchor, QOL differences/changes to other clinical variables or patient’s subjective assessment). Although imperfect, a MID provides a means by which to place QOL into a clinical context. Proponents for both forms of measurement of MID exist; however, a combination of both methods, where feasible, likely yields the most clinically useful and accurate information.189 Longitudinal studies of QOL are essential in the current era, where disease treatments are becoming more and more complex and survival “with” disease is common. However, this assessment is subject to several biases, including “response shift,” whereby patients recalibrate their internal standards regarding QOL during the course of treatment/follow-up and “healthy survivor”; as time passes, sicker patients are less likely to complete surveys, and therefore longer-term results are heavily biased toward patients who are faring the best. Although methods exist to attempt combating these issues, their use is rare and the approaches lack validation. Furthermore, long-term studies are often limited by the logistics of survey administration and practicality. Missing data is a common and critical concern when interpreting QOL data. The consequences of missing QOL information depends on both the amount and the cause of missing data. It is to be expected that some information will be missing at random; the real concern comes when “missingness” is not a random event. There are multiple mechanisms by which to assess the importance of missing data, including comparison of statistical means from patients with complete follow-up to those with incomplete follow-up, to see if there is a difference between groups in QOL indices. If this is indeed the fact, data

are nonignorable missing data and must be accounted for or explained. Given the significant impact of missing data in QOL assessment, especially in studies during time, the best method to deal with it is, in fact, preventive. Trials assessing QOL should be designed in a fashion such that implementation strategies and rigorous follow-up are in place at the outset. Future directions in QOL are based on item response theory and include computerized adaptive testing in which patients’ responses to a given question will prompt the subsequent line of questions, thus individualizing surveys. Furthermore, the use of electronic surveys is increasingly become part of standard clinical care such that questionnaires are completed before each clinic visit, immediate feedback is generated for the patient and treating physician, and important patient-centered concerns may be addressed and decisions made. Likewise, in response to increasing fervor surrounding personalized medicine, QOL researchers have developed GENEQoL, an initiative assessing potential links between QOL outcomes and genetics. Given that QOL may be predictive of clinical outcomes, the ultimate goal of such investigations would be the development of a QOL genetic signature to be used as a predictor of patient outcomes.190,191 QOL research in surgery is in its infancy and, as such, faces many challenges, from study design and implementation to clinical application. However, it is encouraging that enthusiasm surrounding development of this field continues to rise among surgeons and institutions alike. In the future, collaboration between surgeons, statisticians, qualitative researchers, and most importantly, patients will be essential to further the development and clinical application of QOL outcomes in surgery. Furthermore, as the landscape of medicine continues to evolve, become more complex, and offer more life-saving/prolonging treatments, there is no doubt that QOL measurement and understanding will become increasingly valuable and essential for optimal patient care.

Acknowledgments This chapter was fully reviewed and revised for this edition. The foundation was laid by past authors of the 4th and 5th editions, Michael D’Angelica, Sofija Pitka, Steven D. Passik, and Julie Leal. There is grateful acknowledgement for their past contribution. References are available at expertconsult.com.

434.e1

REFERENCES 1. International Health Conference. Constitution of the World Health Organization. 1946. Bull World Health Organ. 2002;80(12):983-984. 2. Alslman ET, Ahmad MM, Bani Hani MA, Atiyeh HM. Health: a developing concept in nursing. Int J Nurs Knowl. 2017;28(2):64-69. 3. Farre A, Rapley T. The new old (and old new) medical model: four decades navigating the biomedical and psychosocial understandings of health and illness. Healthcare. 2017;5(4):88. 4. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196(4286):129-136. 5. CSDH. Closing the gap in a generation: health equity through action on the social determinants of health. Final Report of the Commission on Social Determinants of Health. 2008. https://apps.who.int/iris/bitstream/handle/ 10665/43943/9789241563703_eng.pdf;jsess. Accessed May 22, 2020. 6. Office of Disease Prevention and Health Promotion. Social Determinants of Health. US Department of Health and Human Services. 2020. https://www.healthypeople.gov/2020/topics-objectives/topic/ social-determinants-of-health. Accessed May 22, 2020. 7. Smith K. Mental health: a world of depression. Nature. 2014; 515(7526):181. 8. O’Mahony R, Murthy L, Akunne A,Young J, Guideline Development Group. Synopsis of the National Institute for Health and Clinical Excellence guideline for prevention of delirium. Ann Intern Med. 2011;154(11):746-751. 9. Jayakrishnan TT, Sekigami Y, Rajeev R, Gamblin TC, Turaga KK. Morbidity of curative cancer surgery and suicide risk. Psychooncology. 2017;26(11):1792-1798. 10. Ward PR, Mamerow L, Meyer SB. Identifying vulnerable populations using a social determinants of health framework: analysis of national survey data across six Asia-Pacific countries. PloS One. 2013;8(12):e83000. 11. World Health Organization. WHOQOL Measuring Quality of Life. WHO; 1997. 12. Pinto S, Fumincelli L, Mazzo A, Caldeira S, Martins JC. Comfort, well-being and quality of life: discussion of the differences and similarities among the concepts. Porto Biomed J. 2017;2(1):6-12. 13. WHOQOL Group. Development of the World Health Organization WHOQOL-BREF Quality of Life Assessment. Psych Med. 1998; 28:551-558. 14. Elkinton JR. Medicine and the quality of life. Ann Intern Med. 1966;64(3):711-714. 15. Spitzer WO. State of science 1986: quality of life and functional status as target variables for research. J Chronic Dis. 1987;40(6): 465-471. 16. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA. 1995;273(1):59-65. 17. Karimi M, Brazier J. Health, health-related quality of life, and quality of life: what is the difference? Pharmacoeconomics. 2016;34(7): 645-649. 18. Brettschneider C, Luhmann D, Raspe H. Informative value of patient reported outcomes (PRO) in health technology assessment (HTA). GMS Health Technol Assess. 2011;7:Doc01. 19. US Department of Health and Human Services Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. https://www.fda.gov/media/77832/download. Accessed December 2, 2020. 20. Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984; 2(3):187-193. 21. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 22. Choiniere M, Melzack R, Girard N, Rondeau J, Paquin MJ. Comparisons between patients’ and nurses’ assessment of pain and medication efficacy in severe burn injuries. Pain. 1990;40(2): 143-152. 23. Kahn SB, Houts PS, Harding SP. Quality of life and patients with cancer: a comparative study of patient versus physician perceptions and its implications for cancer education. J Cancer Educ. 1992; 7(3):241-249. 24. Presant CA. Quality of life in cancer patients. Who measures what? Am J Clin Oncol. 1984;7(5):571-573.

25. Slevin ML, Plant H, Lynch D, Drinkwater J, Gregory WM. Who should measure quality of life, the doctor or the patient? Br J Cancer. 1988;57(1):109-112. 26. Sprangers MA, Aaronson NK. The role of health care providers and significant others in evaluating the quality of life of patients with chronic disease: a review. J Clin Epidemiol. 1992;45(7): 743-760. 27. Stephens RJ, Hopwood P, Girling DJ, Machin D. Randomized trials with quality of life endpoints: are doctors’ ratings of patients’ physical symptoms interchangeable with patients’ self-ratings? Qual Life Res. 1997;6(3):225-236. 28. Fromme EK, Eilers KM, Mori M, Hsieh YC, Beer TM. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Qualityof-Life Questionnaire C30. J Clin Oncol. 2004;22(17):3485-3490. 29. Jim HSL, Hoogland AI, Brownstein NC, et al. Innovations in research and clinical care using patient-generated health data. CA Cancer J Clin. 2020;70(3):182-199. 30. Di Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol. 2015;33(8):910-915. 31. Bernhard J, Cella DF, Coates AS, et al. Missing quality of life data in cancer clinical trials: serious problems and challenges. Stat Med. 1998;17(5-7):517-532. 32. Hahn EA, Webster KA, Cella D, Fairclough DL. Missing data in quality of life research in Eastern Cooperative Oncology Group (ECOG) clinical trials: problems and solutions. Stat Med. 1998; 17(5-7):547-559. 33. Feinstein AR. Clinimetric perspectives. J Chronic Dis. 1987;40(6): 635-640. 34. Izsak FC, Medalie JH. Comprehensive follow-up of carcinoma patients. J Chronic Dis. 1971;24(2):179-191. 35. Division of Mental Health and Prevention of Substance Abuse. WHOQOL User Manual. 1998. Available at: https://www.who.int/ tools/whoqolbla. Accessed January 2, 2021. 36. World Health Organization. WHOQOL: Measuring Quality of Life. Available at: https://www.who.int/healthinfo/survey/whoqolqualityoflife/en/index3.html. Accessed October 12, 2020. 37. Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: the past, present, and future. Lancet Oncol. 2015;16(1):e32-e42. 38. Whalen GF, Ferrans CE. Quality of life as an outcome in clinical trials and cancer care: a primer for surgeons. J Surg Oncol. 2001; 77(4):270-276. 39. Roy UB, King-Kallimanis BL, Kluetz PG, Selig W, Ferris A. Learning from patients: reflections on use of patient-reported outcomes in lung cancer trials. J Thorac Oncol. 2018;13(12):1815-1817. 40. Blazeby JM, Avery K, Sprangers M, Pikhart H, Fayers P, Donovan J. Health-related quality of life measurement in randomized clinical trials in surgical oncology. J Clin Oncol. 2006;24(19):3178-3186. 41. Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013;13:211. 42. D’Angelica M, Hirsch K, Ross H, Passik S, Brennan MF. Surgeonpatient communication in the treatment of pancreatic cancer. Arch Surg. 1998;133(9):962-966. 43. Detmar SB, Muller MJ, Schornagel JH, Wever LD, Aaronson NK. Health-related quality-of-life assessments and patient-physician communication: a randomized controlled trial. JAMA. 2002; 288(23):3027-3034. 44. Passik SD, Kirsh KL. The importance of quality-of-life endpoints in clinical trials to the practicing oncologist. Hematol Oncol Clin North Am. 2000;14(4):877-886. 45. Velikova G. Use of electronic quality of life applications in cancer research and clinical practice. Expert Rev Pharmacoecon Outcomes Res. 2004;4(4):403-411. 46. Quinten C, Coens C, Mauer M, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol. 2009;10(9): 865-871. 47. Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol. 2008;26(8):1355-1363.

434.e2 48. Quinten C, Maringwa J, Gotay CC, et al. Patient self-reports of symptoms and clinician ratings as predictors of overall cancer survival. J Natl Cancer Inst. 2011;103(24):1851-1858. 49. Quinten C, Martinelli F, Coens C, et al. A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites. Cancer. 2014;120(2): 302-311. 50. Earlam S, Glover C, Fordy C, Burke D, Allen-Mersh TG. Relation between tumor size, quality of life, and survival in patients with colorectal liver metastases. J Clin Oncol. 1996;14(1):171-175. 51. Efficace F, Bottomley A, Coens C, et al. Does a patient’s self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer? Eur J Cancer. 2006; 42(1):42-49. 52. Maisey NR, Norman A, Watson M, Allen MJ, Hill ME, Cunningham D. Baseline quality of life predicts survival in patients with advanced colorectal cancer. Eur J Cancer. 2002;38(10):1351-1357. 53. Yeo W, Mo FK, Koh J, et al. Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol. 2006;17(7):1083-1089. 54. Bruner DW, Movsas B, Konski A, et al. Outcomes research in cancer clinical trial cooperative groups: the RTOG model. Qual Life Res. 2004;13(6):1025-1041. 55. Byrne C, Griffin A, Blazeby J, Conroy T, Efficace F. Health-related quality of life as a valid outcome in the treatment of advanced colorectal cancer. Eur J Surg Oncol. 2007;33(suppl 2):S95-S104. 56. Langenhoff BS, Krabbe PF, Wobbes T, Ruers TJ. Quality of life as an outcome measure in surgical oncology. Br J Surg. 2001;88(5): 643-652. 57. Sajid MS, Iftikhar M, Rimple J, Baig MK. Use of health-related quality of life tools in hepatobiliary surgery. Hepatobiliary Pancreat Dis Int. 2008;7(2):135-137. 58. Velanovich V. The quality of quality of life studies in general surgical journals. J Am Coll Surg. 2001;193(3):288-296. 59. Hofmann B, Haheim LL, Soreide JA. Ethics of palliative surgery in patients with cancer. Br J Surg. 2005;92(7):802-809. 60. Switzer GE, Wisniewski SR, Belle SH, Dew MA, Schultz R. Selecting, developing, and evaluating research instruments. Soc Psychiatry Psychiatr Epidemiol. 1999;34(8):399-409. 61. DeVon HA, Block ME, Moyle-Wright P, et al. A psychometric toolbox for testing validity and reliability. J Nurs Scholarsh. 2007; 39(2):155-164. 62. Polit D, beck CT. Nursing Research Principles and Methods. 7th ed. Lippincott Williams & Wilkins; 2004. 63. Polit DF, Beck CT. Nursing Research: Principles and Methods. 7th ed. Lippincott, Williams, & Wilkins; 2004. 64. Waltz CF, Strickland OL, Lenz ER. Measurement in Nursing and Health Research. 5th ed. Springer; 2017. 65. Fraser SC. Quality-of-life measurement in surgical practice. Br J Surg. 1993;80(2):163-169. 66. de Haes JC, van Knippenberg FC. The quality of life of cancer patients: a review of the literature. Soc Sci Med. 1985;20(8):809-817. 67. Emery MP, Perrier LL, Acquadro C. Patient-reported outcome and quality of life instruments database (PROQOLID): frequently asked questions. Health Qual Life Outcomes. 2005;3:12. 68. Ware Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care. 1992;30(6):473-483. 69. EuroQol G. EuroQol—a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199-208. 70. Spitzer WO, Dobson AJ, Hall J, et al. Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis. 1981;34(12):585-597. 71. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570-579. 72. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376. 73. Eypasch E, Williams JI, Wood-Dauphinee S, et al. Gastrointestinal Quality of Life Index: development, validation and application of a new instrument. Br J Surg. 1995;82(2):216-222. 74. Heffernan N, Cella D, Webster K, et al. Measuring health-related quality of life in patients with hepatobiliary cancers: the functional

assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol. 2002;20(9):2229-2239. 75. Yount S, Cella D, Webster K, et al. Assessment of patient-reported clinical outcome in pancreatic and other hepatobiliary cancers: the FACT Hepatobiliary Symptom Index. J Pain Symptom Manage. 2002;24(1):32-44. 76. Fitzsimmons D, Johnson CD. Quality of life after treatment of pancreatic cancer. Langenbecks Arch Surg. 1998;383(2):145-151. 77. Kavadas V, Blazeby JM, Conroy T, et al. Development of an EORTC disease-specific quality of life questionnaire for use in patients with liver metastases from colorectal cancer. Eur J Cancer. 2003;39(9):1259-1263. 78. Blazeby JM, Currie E, Zee BC, et al. Development of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur J Cancer. 2004;40(16):2439-2444. 79. Friend E, Yadegarfar G, Byrne C, et al. Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQBIL21. Br J Cancer. 2011;104(4):587-592. 80. Tian L, Cao XY. Systematic review of the psychometric properties of disease-specific, quality-of-life questionnaires for patients with hepatobiliary or pancreatic cancers. Jpn J Nurs Sci. 2018;15(2): 99-112. 81. Blazeby JM, Fayers P, Conroy T, et al. Validation of the European Organization for Research and Treatment of Cancer QLQ-LMC21 questionnaire for assessment of patient-reported outcomes during treatment of colorectal liver metastases. Br J Surg. 2009;96(3): 291-298. 82. Chie WC, Blazeby JM, Hsiao CF, et al. International cross-cultural field validation of an European Organization for Research and Treatment of Cancer questionnaire module for patients with primary liver cancer, the European Organization for Research and Treatment of Cancer quality-of-life questionnaire HCC18. Hepatology. 2012; 55(4):1122-1129. 83. Mikoshiba N, Tateishi R, Tanaka M, et al. Validation of the Japanese version of the EORTC hepatocellular carcinoma-specific quality of life questionnaire module (QLQ-HCC18). Health Qual Life Outcomes. 2012;10:58. 84. Wan C, Fang J, Yang Z, et al. Development and validation of a quality of life instrument for patients with liver cancer QOL-LC. Am J Clin Oncol. 2010;33(5):448-455. 85. Aaronson NK. Quality of life: what is it? How should it be measured? Oncology. 1988;2(5):69-76, 64. 86. Osoba D. Lessons learned from measuring health-related quality of life in oncology. J Clin Oncol. 1994;12(3):608-616. 87. Guyatt GH, Naylor CD, Juniper E, Heyland DK, Jaeschke R, Cook DJ. Users’ guides to the medical literature. XII. How to use articles about health-related quality of life. Evidence-Based Medicine Working Group. JAMA. 1997;277(15):1232-1237. 88. Wu AW, Bradford AN, Velanovich V, Sprangers MA, Brundage M, Snyder C. Clinician’s checklist for reading and using an article about patient-reported outcomes. Mayo Clin Proc. 2014;89(5): 653-661. 89. Nguyen TC, Sohn TA, Cameron JL, et al. Standard vs. radical pancreaticoduodenectomy for periampullary adenocarcinoma: a prospective, randomized trial evaluating quality of life in pancreaticoduodenectomy survivors. J Gastrointest Surg. 2003;7(1):1-9; discussion 9-11. 90. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophylactic gastrojejunostomy for unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on assessment of quality of life. Ann Surg. 2003;238(6): 894-902; discussion 902-905. 91. Billings BJ, Christein JD, Harmsen WS, et al. Quality-of-life after total pancreatectomy: is it really that bad on long-term follow-up? J Gastrointest Surg. 2005;9(8):1059-1066; discussion 1066-1067. 92. Nieveen van Dijkum EJ, Kuhlmann KF, Terwee CB, Obertop H, de Haes JC, Gouma DJ. Quality of life after curative or palliative surgical treatment of pancreatic and periampullary carcinoma. Br J Surg. 2005;92(4):471-477. 93. Schmidt CE, Bestmann B, Kuchler T, Longo WE, Kremer B. Prospective evaluation of quality of life of patients receiving either abdominoperineal resection or sphincter-preserving procedure for rectal cancer. Ann Surg Oncol. 2005;12(2):117-123.

434.e3 94. Shaw CM, O’Hanlon DM, McEntee GP. Long-term quality of life following pancreaticoduodenectomy. Hepatogastroenterology. 2005;52(63):927-932. 95. Wehrmann T, Riphaus A, Frenz MB, Martchenko K, Stergiou N. Endoscopic pancreatic duct stenting for relief of pancreatic cancer pain. Eur J Gastroenterol Hepatol. 2005;17(12):1395-1400. 96. Muller-Nordhorn J, Roll S, Bohmig M, et al. Health-related quality of life in patients with pancreatic cancer. Digestion. 2006;74(2): 118-125. 97. Schniewind B, Bestmann B, Henne-Bruns D, Faendrich F, Kremer B, Kuechler T. Quality of life after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head. Br J Surg. 2006;93(9):1099-1107. 98. Han SS, Kim SW, Jang JY, Park YH. A comparison of the longterm functional outcomes of standard pancreatoduodenectomy and pylorus-preserving pancreatoduodenectomy. Hepatogastroenterology. 2007;54(78):1831-1835. 99. You YN, Thompson GB, Young Jr WF, et al. Pancreatoduodenal surgery in patients with multiple endocrine neoplasia type 1: Operative outcomes, long-term function, and quality of life. Surgery. 2007;142(6):829-836; discussion 836.e821. 100. Crippa S, Dominguez I, Rodriguez JR, et al. Quality of life in pancreatic cancer: analysis by stage and treatment. J Gastrointest Surg. 2008;12(5):783-793; discussion 793-794. 101.Kostro J, Sledzinski Z. Quality of life after surgical treatment of pancreatic cancer. Acta Chir Belg. 2008;108(6):679-684. 102. Halloran CM, Cox TF, Chauhan S, et al. Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study. Pancreatology. 2011;11(6):535-545. 103. Ljungman D, Lundholm K, Hyltander A. Cost-utility estimation of surgical treatment of pancreatic carcinoma aimed at cure. World J Surg. 2011;35(3):662-670. 104. Walter J, Nier A, Rose T, et al. Palliative partial pancreaticoduodenectomy impairs quality of life compared to bypass surgery in patients with advanced adenocarcinoma of the pancreatic head. Eur J Surg Oncol. 2011;37(9):798-804. 105. Chan C, Franssen B, Dominguez I, Ramirez-Del Val A, Uscanga LF, Campuzano M. Impact on quality of life after pancreatoduodenectomy: a prospective study comparing preoperative and postoperative scores. J Gastrointest Surg. 2012;16(7):1341-1346. 106. Mbah N, Brown RE, St Hill CR, et al. Impact of post-operative complications on quality of life after pancreatectomy. JOP. 2012; 13(4):387-393. 107. Belyaev O, Herzog T, Chromik AM, Meurer K, Uhl W. Early and late postoperative changes in the quality of life after pancreatic surgery. Langenbecks Arch Surg. 2013;398(4):547-555. 108. Roberts KJ, Blanco G, Webber J, et al. How severe is diabetes after total pancreatectomy? A case-matched analysis. HPB (Oxford). 2014;16(9):814-821. 109. Epelboym I, Winner M, DiNorcia J, et al. Quality of life in patients after total pancreatectomy is comparable with quality of life in patients who undergo a partial pancreatic resection. J Surg Res. 2014;187(1):189-196. 110. Serrano PE, Herman JM, Griffith KA, et al. Quality of life in a prospective, multicenter phase 2 trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;90(2):270-277. 111. Eshuis WJ, de Bree K, Sprangers MA, et al. Gastric emptying and quality of life after pancreatoduodenectomy with retrocolic or antecolic gastroenteric anastomosis. Br J Surg. 2015;102(9): 1123-1132. 112. Hartwig W, Gluth A, Hinz U, et al. Total pancreatectomy for primary pancreatic neoplasms: renaissance of an unpopular operation. Ann Surg. 2015;261(3):537-546. 113. Heerkens HD, Tseng DS, Lips IM, et al. Health-related quality of life after pancreatic resection for malignancy. Br J Surg. 2016; 103(3):257-266. 114. Williamsson C, Karlsson N, Sturesson C, Lindell G, Andersson R, Tingstedt B. Impact of a fast-track surgery programme for pancreaticoduodenectomy. Br J Surg. 2015;102(9):1133-1141. 115. de Rooij T, van Hilst J, Bosscha K, et al. Minimally invasive versus open pancreatoduodenectomy (LEOPARD-2): study protocol for a randomized controlled trial. Trials. 2018;19(1):1.

116. Lee SH, Kang CM, Hwang HK, Choi SH, Lee WJ, Chi HS. Minimally invasive RAMPS in well-selected left-sided pancreatic cancer within Yonsei criteria: long-term (.median 3 years) oncologic outcomes. Surg Endosc. 2014;28(10):2848-2855. 117. Shin YC, Jang JY, Chang YR, et al. Comparison of long-term clinical outcomes of external and internal pancreatic stents in pancreaticoduodenectomy: randomized controlled study. HPB (Oxford). 2019;21(1):51-59. 118. van Hilst J, Strating EA, de Rooij T, et al. Costs and quality of life in a randomized trial comparing minimally invasive and open distal pancreatectomy (LEOPARD trial). Br J Surg. 2019;106(7):910-921. 119. Poon RT, Fan ST, Yu WC, Lam BK, Chan FY, Wong J. A prospective longitudinal study of quality of life after resection of hepatocellular carcinoma. Arch Surg. 2001;136(6):693-699. 120. Chen L, Liu Y, Li GG, Tao SF, Xu Y, Tian H. Quality of life in patients with liver cancer after operation: a 2-year follow-up study. Hepatobiliary Pancreat Dis Int. 2004;3(4):530-533. 121. Langenhoff BS, Krabbe PF, Peerenboom L, Wobbes T, Ruers TJ. Quality of life after surgical treatment of colorectal liver metastases. Br J Surg. 2006;93(8):1007-1014. 122. Eid S, Stromberg AJ, Ames S, Ellis S, McMasters KM, Martin RC. Assessment of symptom experience in patients undergoing hepatic resection or ablation. Cancer. 2006;107(11):2715-2722. 123. Lee LJ, Chen CH, Yao G, et al. Quality of life in patients with hepatocellular carcinoma received surgical resection. J Surg Oncol. 2007;95(1):34-39. 124. Martin RC, Eid S, Scoggins CR, McMasters KM. Health-related quality of life: return to baseline after major and minor liver resection. Surgery. 2007;142(5):676-684. 125. Dasgupta D, Smith AB, Hamilton-Burke W, et al. Quality of life after liver resection for hepatobiliary malignancies. Br J Surg. 2008;95(7):845-854. 126. Banz VM, Inderbitzin D, Fankhauser R, Studer P, Candinas D. Long-term quality of life after hepatic resection: health is not simply the absence of disease. World J Surg. 2009;33(7):1473-1480. 127. Bruns H, Kratschmer K, Hinz U, et al. Quality of life after curative liver resection: a single center analysis. World J Gastroenterol. 2010;16(19):2388-2395. 128. Wiering B, Oyen WJ, Adang EM, et al. Long-term global quality of life in patients treated for colorectal liver metastases. Br J Surg. 2011;98(4):565-571; discussion 571-572. 129. Rees JR, Blazeby JM, Fayers P, et al. Patient-reported outcomes after hepatic resection of colorectal cancer metastases. J Clin Oncol. 2012;30(12):1364-1370. 130. Miller AR, St Hill CR, Ellis SF, Martin RC. Health-related quality of life changes following major and minor hepatic resection: the impact of complications and postoperative anemia. Am J Surg. 2013;206(4):443-450. 131. Mise Y, Satou S, Ishizawa T, et al. Impact of surgery on quality of life in patients with hepatocellular carcinoma. World J Surg. 2014; 38(4):958-967. 132. Rees JR, Blazeby JM, Brookes ST, John T, Welsh FK, Rees M. Patient-reported outcomes in long-term survivors of metastatic colorectal cancer needing liver resection. Br J Surg. 2014;101(11): 1468-1474. 133. Studer P, Horn T, Haynes A, Candinas D, Banz VM. Quality of life after hepatic resection. Br J Surg. 2018;105(3):237-243. 134. Wang J, Yan C, Fu A. A randomized clinical trial of comprehensive education and care program compared to basic care for reducing anxiety and depression and improving quality of life and survival in patients with hepatocellular carcinoma who underwent surgery. Medicine. 2019;98(44):e17552. 135. Steel J, Baum A, Carr B. Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic arterial infusion of Cisplatin versus 90-Yttrium microspheres (Therasphere). Psychooncology. 2004;13(2):73-79. 136. Ruers TJ, Joosten JJ, Wiering B, et al. Comparison between local ablative therapy and chemotherapy for non-resectable colorectal liver metastases: a prospective study. Ann Surg Oncol. 2007;14(3): 1161-1169. 137. Wang YB, Chen MH, Yan K, Yang W, Dai Y, Yin SS. Quality of life after radiofrequency ablation combined with transcatheter arterial chemoembolization for hepatocellular carcinoma: comparison with transcatheter arterial chemoembolization alone. Qual Life Res. 2007;16(3):389-397.

434.e4 138. Bonnetain F, Paoletti X, Collette S, et al. Quality of life as a prognostic factor of overall survival in patients with advanced hepatocellular carcinoma: results from two French clinical trials. Qual Life Res. 2008;17(6):831-843. 139. Kalinowski M, Dressler M, Konig A, et al. Selective internal radiotherapy with Yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: a prospective single center study. Digestion. 2009;79(3):137-142. 140. Kuroda H, Ushio A, Miyamoto Y, et al. Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial. J Gastroenterol Hepatol. 2010;25(9):1550-1555. 141. Wible BC, Rilling WS, Drescher P, et al. Longitudinal quality of life assessment of patients with hepatocellular carcinoma after primary transarterial chemoembolization. J Vasc Interv Radiol. 2010;21(7):1024-1030. 142. Eltawil KM, Berry R, Abdolell M, Molinari M. Quality of life and survival analysis of patients undergoing transarterial chemoembolization for primary hepatic malignancies: a prospective cohort study. HPB (Oxford). 2012;14(5):341-350. 143. Shun SC, Chen CH, Sheu JC, Liang JD, Yang JC, Lai YH. Quality of life and its associated factors in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization treatment: a longitudinal study. Oncologist. 2012;17(5):732-739. 144. Toro A, Pulvirenti E, Palermo F, Di Carlo I. Health-related quality of life in patients with hepatocellular carcinoma after hepatic resection, transcatheter arterial chemoembolization, radiofrequency ablation or no treatment. Surg Oncol. 2012;21(1):e23-e30. 145. Salem R, Gilbertsen M, Butt Z, et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol. 2013;11(10):1358-1365.e1. 146. Hamdy H, Fathy Barakat EM, El Folly RF. Impact of hepatocellular carcinoma on health related quality of life in Egyptian patients: a single centre study. J Egypt Soc Parasitol. 2013;43(1):183-194. 147. Huang G, Chen X, Lau WY, et al. Quality of life after surgical resection compared with radiofrequency ablation for small hepatocellular carcinomas. Br J Surg. 2014;101(8):1006-1015. 148. Kolligs FT, Bilbao JI, Jakobs T, et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int. 2015;35(6):1715-1721. 149. Anota A, Boulin M, Dabakuyo-Yonli S, et al. An explorative study to assess the association between health-related quality of life and the recommended phase II dose in a phase I trial: Idarubicinloaded beads for chemoembolisation of hepatocellular carcinoma. BMJ Open. 2016;6(6):e010696. 150. Xu L, Wang S, Zhuang L, et al. Jian Pi Li Qi decoction alleviated postembolization syndrome following transcatheter arterial chemoembolization for hepatocellular carcinoma: a randomized, double-blind, placebo-controlled trial. Integr Cancer Ther. 2016; 15(3):349-357. 151. Rostas JW, Tam AL, Sato T, Scoggins CR, McMasters KM, Martin RCG II. Health-related quality of life during trans-arterial chemoembolization with drug-eluting beads loaded with doxorubicin (DEBDOX) for unresectable hepatic metastases from ocular melanoma. Am J Surg. 2017;214(5):884-890. 152. Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636. 153. Prince JF, van den Bosch M, Nijsen JFW, et al. Efficacy of radioembolization with (166)Ho-microspheres in salvage patients with liver metastases: a phase 2 study. J Nucl Med. 2018;59(4):582-588. 154. Xing M, Kokabi N, Camacho JC, Kim HS. Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization. BMC Cancer. 2018;18(1):75. 155. Mehta S, Hindmarsh A, Cheong E, et al. Prospective randomized trial of laparoscopic gastrojejunostomy versus duodenal stenting for malignant gastric outflow obstruction. Surg Endosc. 2006;20(2): 239-242. 156. Schmidt C, Gerdes H, Hawkins W, et al. A prospective observational study examining quality of life in patients with malignant gastric outlet obstruction. Am J Surg. 2009;198(1):92-99.

157. van Hooft JE, Uitdehaag MJ, Bruno MJ, et al. Efficacy and safety of the new WallFlex enteral stent in palliative treatment of malignant gastric outlet obstruction (DUOFLEX study): a prospective multicenter study. Gastrointest Endosc. 2009;69(6):1059-1066. 158. van Hooft JE, Dijkgraaf MG, Timmer R, Siersema PD, Fockens P. Independent predictors of survival in patients with incurable malignant gastric outlet obstruction: a multicenter prospective observational study. Scand J Gastroenterol. 2010;45(10):1217-1222. 159. Dolz C, Vilella A, Gonzalez Carro P, et al. Antral localization worsens the efficacy of enteral stents in malignant digestive tumors. Gastroenterol Hepatol. 2011;34(2):63-68. 160. van den Berg MW, Haijtink S, Fockens P, et al. First data on the Evolution duodenal stent for palliation of malignant gastric outlet obstruction (DUOLUTION study): a prospective multicenter study. Endoscopy. 2013;45(3):174-181. 161. Abraham NS, Barkun JS, Barkun AN. Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life. Gastrointest Endosc. 2002;56(6):835-841. 162. Chan G, Barkun J, Barkun AN, et al. The role of ciprofloxacin in prolonging polyethylene biliary stent patency: a multicenter, double-blinded effectiveness study. J Gastrointest Surg. 2005;9(4): 481-488. 163. Artifon EL, Sakai P, Cunha JE, et al. Surgery or endoscopy for palliation of biliary obstruction due to metastatic pancreatic cancer. Am J Gastroenterol. 2006;101(9):2031-2037. 164. Saluja SS, Gulati M, Garg PK, et al. Endoscopic or percutaneous biliary drainage for gallbladder cancer: a randomized trial and quality of life assessment. Clin Gastroenterol Hepatol. 2008;6(8): 944-950.e3. 165. Robson PC, Heffernan N, Gonen M, et al. Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction. Ann Surg Oncol. 2010;17(9):2303-2311. 166. Larssen L, Medhus AW, Hjermstad MJ, et al. Patient-reported outcomes in palliative gastrointestinal stenting: a Norwegian multicenter study. Surg Endosc. 2011;25(10):3162-3169. 167. Artifon EL, Aparicio D, Paione JB, et al. Biliary drainage in patients with unresectable, malignant obstruction where ERCP fails: endoscopic ultrasonography-guided choledochoduodenostomy versus percutaneous drainage. J Clin Gastroenterol. 2012;46(9): 768-774. 168. Aggarwal R, Patel FD, Kapoor R, Kang M, Kumar P, Chander Sharma S. Evaluation of high-dose-rate intraluminal brachytherapy by percutaneous transhepatic biliary drainage in the palliative management of malignant biliary obstruction—a pilot study. Brachytherapy. 2013;12(2):162-170. 169. Moses PL, Alnaamani KM, Barkun AN, et al. Randomized trial in malignant biliary obstruction: plastic vs partially covered metal stents. World J Gastroenterol. 2013;19(46):8638-8646. 170. Castiglione D, Gozzo C, Mammino L, Failla G, Palmucci S, Basile A. Health-Related Quality of Life evaluation in “left” versus “right” access for percutaneous transhepatic biliary drainage using EORTC QLQBIL-21 questionnaire: a randomized controlled trial. Abdom Radiol (NY). 2020;45(4):1162-1173. 171. Yeo TP, Burrell SA, Sauter PK, et al. A progressive postresection walking program significantly improves fatigue and health-related quality of life in pancreas and periampullary cancer patients. J Am Coll Surg. 2012;214(4):463-475; discussion 475-477. 172. Williamson S, Chalmers K, Beaver K. Patient experiences of nurse-led telephone follow-up following treatment for colorectal cancer. Eur J Oncol Nurs. 2015;19(3):237-243. 173. Schmidt U, Simunec D, Piso P, Klempnauer J, Schlitt HJ. Quality of life and functional long-term outcome after partial pancreatoduodenectomy: pancreatogastrostomy versus pancreatojejunostomy. Ann Surg Oncol. 2005;12(6):467-472. 174. Roberts KJ, Hodson J, Mehrzad H, et al. A preoperative predictive score of pancreatic fistula following pancreatoduodenectomy. HPB (Oxford). 2014;16(7):620-628. 175. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg. 2002;236(4):397-406; discussion 406-407. 176. Diouf M, Chibaudel B, Filleron T, et al. Could baseline healthrelated quality of life (QoL) predict overall survival in metastatic colorectal cancer? the results of the GERCOR OPTIMOX 1 study. Health Qual Life Outcomes. 2014;12:69.

434.e5 177. Aiken LH, Shang J, Xue Y, Sloane DM. Hospital use of agencyemployed supplemental nurses and patient mortality and failure to rescue. Health Serv Res. 2013;48(3):931-948. 178. Tanabe G, Ueno S, Maemura M, et al. Favorable quality of life after repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology. 2001;48(38):506-510. 179. Upchurch E, Ragusa M, Cirocchi R. Stent placement versus surgical palliation for adults with malignant gastric outlet obstruction. Cochrane Database Syst Rev. 2018;5:CD012506. 180. Jeurnink SM, Steyerberg EW, Hof G, van Eijck CH, Kuipers EJ, Siersema PD. Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients. J Surg Oncol. 2007;96(5):389-396. 181. Jeurnink SM, van Eijck CH, Steyerberg EW, Kuipers EJ, Siersema PD. Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review. BMC Gastroenterol. 2007;7:18. 182. Mihalache F, Tantau M, Diaconu B, Acalovschi M. Survival and quality of life of cholangiocarcinoma patients: a prospective study over a 4 year period. J Gastrointestin Liver Dis. 2010;19(3):285-290. 183. Covey AM, Brown KT. Palliative percutaneous drainage in malignant biliary obstruction. Part 1: indications and preprocedure evaluation. J Support Oncol. 2006;4(6):269-273. 184. Perez-Johnston R, Deipolyi AR, Covey AM. Percutaneous biliary interventions. Gastroenterol Clin North Am. 2018;47(3):621-641.

185. Yarmohammadi H, Covey AM. Percutaneous biliary interventions and complications in malignant bile duct obstruction. Chin Clin Oncol. 2016;5(5):68. 186. Barkay O, Mosler P, Schmitt CM, et al. Effect of endoscopic stenting of malignant bile duct obstruction on quality of life. J Clin Gastroenterol. 2013;47(6):526-531. 187. Efficace F, Osoba D, Gotay C, Sprangers M, Coens C, Bottomley A. Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making. Ann Oncol. 2007;18(4): 775-781. 188. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10(4):407-415. 189. Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol. 2008;61(2): 102-109. 190. Sloan JA, Zhao CX. Genetics and quality of life. Curr Probl Cancer. 2006;30(6):255-260. 191. Sprangers MA, Sloan JA, Veenhoven R, et al. The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes. Twin Res Hum Genet. 2009;12(3):301-311.

PART 4

Techniques of Biliary Tract Intervention: Radiologic, Endoscopic, and Surgical

30 Interventional Endoscopy for Biliary Tract Disease: Technical Aspects



31 Radiologic Hepatobiliary Interventions



32 Bile Duct Exploration and Biliary-Enteric Anastomosis

435

CHAPTER 30 Interventional endoscopy for biliary tract disease: Technical aspects Yakira David, Dennis Yang, and Christopher DiMaio

EQUIPMENT NEEDED FOR STANDARD ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY CANNULATION

ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY STANDARD CANNULATION TECHNIQUE

Before attempting cannulation of the biliary tree for standard endoscopic retrograde cholangiopancreatography (ERCP), the appropriate equipment must be assembled (see Chapter 20). At baseline that equipment should include1: • Side-viewing duodenoscope with biopsy channel of at least 3.2 mm to 4.2 mm • Guidewire2,3: • Hydrophilic or Hydrophilic tipped • Diameter: 0.018, 0.025, and 0.035 inches. The 0.035 inch is most commonly used, but the 0.025 size can be useful in smaller papillae and the 0.018 inch in the pancreatic duct. Although these have the advantage of being able to access narrower orifices, their smaller size makes them more pliable and more difficult to control. • Tip: angled or straight-tipped • Length: • Long-wire (420–480 cm) – This allows for universal exchange capabilities across all devices and brands and is also needed for complex rendezvous endoscopic ultrasound (EUS)–assisted cholangiopancreatography and single-operator cholangioscopy. It, however, does not allow for control by the endoscopist and instead relies heavily on excellent coordination with communication with a trained endoscopy assistant. • Short-wire system (184–270 cm) – Allows exclusive control of the guidewire by the endoscopist because it can be locked in place both at the level of the elevator and externally at the biopsy port to allow for easy exchange of devices over the wire. • Standard cannulation catheters (typically have two to three lumens to facilitate concurrent passage of a guidewire and contrast injection) OR: • Sphincterotome – This includes an electrosurgical cutting wire at the distal end of the catheter. This is used primarily to perform a sphincterotomy. Additionally, applying tension on the cutting wire results in bowing of the sphincterotome which aligns its axis to facilitate cannulation. • Access (pre-cut) papillotomy catheters – These are used for precut sphincterotomies or biliary fistulotomies. The most commonly used of these catheters is the needle-knife (NK), which has a retractable electrosurgical cutting wire.

There are two main techniques that can be used to cannulate the biliary system: traditional contrast-assisted biliary cannulation and guidewire-assisted biliary cannulation.4

436

Traditional Contrast-Assisted Biliary Cannulation In traditional contrast-assisted biliary cannulation, the catheter is engaged with the papillary orifice and contrast is injected to delineate the trajectory and pathway of the bile duct. Afterwards, the catheter and/or a guidewire can be inserted directly into the bile duct. One of the main risks of this is inadvertent injection of contrast into the pancreatic duct, which increases the risk for post-ERCP pancreatitis (PEP; see Chapter 55).

Guidewire-Assisted Biliary Cannulation This involves confirmed cannulation of the bile duct with a guidewire before the injection of any contrast. There are two methods to achieve this: • Touch guidewire technique: The tip of the catheter can be engaged with the biliary orifice and then the guidewire can be advanced into the common bile duct under fluoroscopic guidance. This technique may be associated with higher cannulation rates.5 • No-touch technique: Alternatively, the guidewire can be advanced one to two mm beyond the tip of the catheter and then advanced directly through the papillary orifice oriented towards the bile duct under fluoroscopy. Guidewire-assisted biliary cannulation has been found to be superior to the contrast-assisted biliary cannulation technique because it results in higher rates of primary biliary cannulation, less need for precut sphincterotomy, and a lower risk of PEP.6

DIFFICULT BILIARY CANNULATION Difficult biliary access is defined as the inability to achieve selective biliary cannulation by standard ERCP techniques within 10 minutes or five cannulation attempts or failure of access to the major papilla.7 Repeated attempts at biliary cannulation are independently associated with an increased risk of PEP. There are a few strategies that have been established to facilitate biliary cannulation in such instances.

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

Pancreatic Duct Wire or Stent Placement to Facilitate Biliary Access In the “double-wire technique,” a guidewire is deliberately placed in the pancreatic duct while the biliary cannulation device is preloaded with a second guidewire to reattempt biliary cannulation. Theoretically, the pancreatic guidewire assists by straightening the common channel and common bile duct (CBD), thus facilitating biliary cannulation. Furthermore, the direction of the pancreatic wire exiting the papilla on endoscopy may provide anatomic cues regarding the optimal axis for biliary cannulation. Although this technique has been associated with high rates of cannulation in difficult situations, it has not been conclusively shown to be superior to standard cannulation and may be associated with an increased risk of PEP.8,9 Placement of a pancreatic duct stent facilitates biliary duct cannulation and also reduces the risk of PEP by ensuring pancreatic duct drainage and by minimizing further inadvertent entry into the pancreatic duct on repeated attempts at biliary cannulation.8,9

Access “Precut” Sphincterotomy for Biliary Access Access “precut” sphincterotomy refers to the technique of incising the papilla before obtaining biliary access. Precutting can be a useful technique to achieve selective bile duct cannulation when standard approaches fail. The needle-knife (NK) catheter is typically used for this procedure. The NK catheters have a retractable bare electrosurgical cutting wire that extends from the tip of the catheter. The exposed needle can then be inserted into the papillary orifice, and the cut is directed upward in the axis of the bile duct, generally in the 11 to 12 o’clock position. Another variation of this technique involves using the NK to begin an incision above the ampullary orifice to directly access the CBD by creating a biliary fistula (“fistulotomy”). Precut sphincterotomy has been associated with biliary cannulation rates exceeding 90%.10,11 Nevertheless, precutting is not without risk because the incision is performed without the guidance of a wire within the duct. Earlier experience with precut sphincterotomy demonstrated an increased risk of complications such as PEP, bleeding, and perforation.12,13 Nevertheless, given that precut sphincterotomy has traditionally been used as a second option or last resort during difficult cannulation, it has been suggested that precut sphincterotomy may be a surrogate marker of difficult cannulation and not an independent predictor of PEP.14,15 More recent data have indicated no overall increased risk of complications when compared with persistent attempts at cannulation and may even be associated with a lower risk of PEP compared with repeated attempts at cannulation.10,11,16,17,18 Some centers have modified this technique and perform a “shallow” precut sphincterotomy, which uses only three mm of the NK, which has demonstrated overall lower complication rates.19 These centers have even advocated for this to be used as the first-line approach for all ERCPs.20 Overall, there is good evidence to recommend early precut sphincterotomy in cases of challenging biliary cannulation but not enough to recommend this universally as the first-line approach for all ERCPs. It is important to emphasize that this approach should be performed by an experienced biliary endoscopist familiar with the nuances and technical aspects of this approach.4

437

Transpancreatic Precut Sphincterotomy Transpancreatic precut (transeptal) sphincterotomy (TPS) for biliary access was first described by Goff and is thus sometimes known as the Goff technique.21 In this technique, after selective cannulation of the pancreatic duct, precut sphincterotomy is performed by cutting the septum between the pancreatic and bile duct with the standard sphincterotome directed cephalad toward the bile duct. Since its introduction, several studies have demonstrated high rates of bile duct cannulation without increased complication rates compared with other precut techniques used for difficult biliary cannulation, when used in expert hands.22,23 To reduce the risk of PEP after TPS, it is further recommended that a pancreatic stent be left in situ.4 The decision on the type of precut technique used can be determined based on papilla morphology (e.g., for protuberant papilla where NK fistulotomy may be preferential) or based on the presence of inadvertent pancreatic duct cannulation (where transpancreatic precut sphincterotomy may be preferred).24 It is again crucial that any of these precut techniques be performed by an expert endoscopist.4

TECHNIQUES FOR BILIARY ACCESS IN PATIENTS WITH SURGICALLY ALTERED ANATOMY ERCP in patients with surgically altered anatomy can be technically difficult. There are two main challenges that need to be overcome to successfully complete the procedure. The first challenge is to reach the papilla or bilioenteric anastomosis in altered luminal anatomy. The second challenge is to be able to cannulate and perform the intended intervention from an altered position with the available endoscopes and accessories.

Endoscopic Retrograde Cholangiopancreatography in Patients With a Bilroth II Gastrojejunostomy In Bilroth II anatomy, the distal stomach is resected and an end-to-side gastrojejunostomy has been created. From the gastrojejunal anastomosis, an afferent limb leads toward the proximal duodenum, whereas the efferent limb leads to the distal small bowel. In the Braun variation, there is additionally a sideto-side jejuno-jejunostomy between the afferent and efferent limbs. ERCP is performed by intubating the afferent limb and cannulating the papilla from a caudal angle. Although the afferent limb may be short, identification of the limb and navigating through the sharp angulation of this limb can be challenging with the conventional side-viewing duodenoscope, and even more so with the Braun variation. An alternative is to perform the entire procedure with a forward-viewing gastroscope or pediatric colonoscope. This can be further aided by placing a transparent cap on the tip of the endoscope, which facilitates navigation through the tortuous afferent limb and stabilizes the scope position for selective biliary cannulation. Other options for afferent limb intubation and biliary cannulation include use of balloon-assisted enteroscopy, spiral enteroscopy, or use of an anterior oblique-viewing endoscope.25,26 There are limitations, however, to using these endoscopes because they lack elevators, which aid with biliary cannulation, and there are less ERCPdirected accessories available.

438

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

When using a duodenoscope, the papilla is usually visible en face upon reaching the second portion of the duodenum. From this position, the papilla appears rotated by 180 degrees, and as such biliary cannulation generally proceeds toward the five o’clock position instead of the 11 o’clock position used for standard ERCP. Hence standard straight cannulas may be preferable for selective bile duct cannulation compared with the upward-curved papillotomes. Alternative devices that have been explored to facilitate bile duct access in these patients include the Bilroth II sphincterotome with a downward “reversed bow” curved wire, rotatable sphincterotomes, pull-type sphincterotomes, or triple-lumen needle-knives. In expert hands these have success rates of over 90%.27,28,29 Despite the inherent challenges of Bilroth II anatomy, the success rates for ERCP are similar amongst the different techniques used. In a large single-center series of 713 patients, the success rate for afferent limb intubation and biliary or pancreatic duct cannulation using the duodenoscope was 87% and 94%, respectively.30 Similarly, ERCP success rates with overtube-assisted enteroscopy (single-balloon [SBE], double- balloon [DBE], spiral enteroscopy) exceeded 90% in patients with Bilroth II anatomy.25,31 A systematic review comparing the different techniques has reported rates of access and selective biliary cannulation exceeding 95% for both side-viewing and forward-viewing endoscopy.32 In additional to the potential risks associated with conventional ERCP, Bilroth II anatomy increases the risk of adverse events, including perforations at the gastrojejunal anastomosis or within the afferent limb itself.30 The risk of this has been noted to be marginally higher with side-viewing endoscopy.32,33 At this time, some society guidelines recommend the sideviewing endoscope as a first option with forward-viewing endoscopes (gastroscope, pediatric colonoscope, and balloon enteroscope) as the second choice in cases of failure.4 Given that there are pros and cons to both side-viewing conventional endoscopes and forward-viewing scopes, the endoscopist should be familiar with multiple techniques and be prepared to change strategies on a case-by-case basis, depending on the intraprocedural findings.

Transoral Endoscopic Retrograde Cholangiopancreato­ graphy in Patients with a Roux-en-Y Anatomy Roux-en-Y reconstruction has been used in bariatric gastric bypass, gastric resections, pancreaticoduodenectomy (Whipple procedure), resection of biliary malignancies, reconstruction of benign biliary strictures, and in some cases of liver transplant (see Chapters 42, 117A, and 119A). Briefly, in patients with Roux-en-Y anatomy, the jejunum is divided into two segments close to the ligament of Treitz. The distal segment of this is anastomosed to the stomach or gastric remnant and forms the “Roux” limb. A jejunojejunal anastomosis is then formed by anastomosing the proximal segment further down on the distal segment. Proximally, this connects to the duodenum and the biliary system and forms the “biliopancreatic” limb. Before attempting ERCP, a comprehensive review of the patient’s operative reports, imaging, and prior procedures are necessary, and a discussion with their surgeon would be ideal to develop a strategic approach.34 Emphasis should be placed on the type of resection and anastomosis, length of both limbs, and whether there is a native papilla or other type of bilioenteric anastomosis.

Roux-en-Y anatomy poses a major challenge for ERCP, given the length of bowel that must be traversed to reach the papilla or bilioenteric anastomosis. This is often prohibitive for duodenoscopes, and again the altered orientation makes cannulation difficult. To improve success rates, various combinations and adaptations of forward-viewing and side-viewing scopes have been employed. Push enteroscopy (using a forward-viewing enteroscope or push colonoscope) can be an alternative when the biliopancreatic limb cannot be reached with the duodenoscope.35,34 Deep enteroscopy platforms, including SBE, DBE, and spiral enteroscopy, were developed to allow access to the distal small bowel and have quoted success rates of reaching the papilla of up to 86%.25,31,36–39 Although the longer enteroscopes may facilitate navigation through the surgically altered anatomy compared with the duodenoscope, this advantage comes with several limitations. First, the lack of a side-viewing perspective and an elevator can potentially make cannulation more difficult. Second, there are limited accessories specifically designed to use with the longer endoscopes to perform diagnostic and therapeutic interventions. The use of larger-diameter biliary stents can be limited by the size of the working channel of the endoscope, and even smaller-caliber accessories may be difficult to advance through the channel when the longer endoscope is torqued or looped in the surgically altered bowel. Lastly, these procedures can be long (median ranging from one to three hours), with the increased risk of prolonged general anesthesia.25 Success rates of device-assisted enteroscopy range from 70% to 86% across multiple studies, with the main limiting factor being the enteroscopy, as cannulation rates are upwards of 85% once the papilla or bilioenteric anastomosis is reached.36–40

Alternatives to Transoral Access for ERCP in Surgically Altered Anatomy Transoral ERCP in patients with Roux-en-Y gastric bypass (RYGB) can be challenging given the relatively longer Roux and biliopancreatic limbs that must be traversed. Hence, alternative access routes through the remnant stomach directly to the native papilla have been explored. Percutaneous Transgastric ERCP – This involves creation of a gastrostomy to the excluded stomach and can be done via open surgery or via a percutaneous gastrostomy placed by interventional radiology, but is most commonly performed laparoscopically.41 In laparoscopic-assisted transgastric ERCP, a 15-mm trocar is inserted into the excluded stomach is used to pull it adjacent to the abdominal wall, and is secured with a purse-string suture. The duodenoscope can then be inserted through the trocar into the excluded stomach and advanced in an anterograde manner to the papilla. If subsequent ERCPs are anticipated, a gastrostomy tube may be inserted to maintain and allow for maturity of the gastrostomy tract over two to four weeks.34 This technique has quoted success rates of up to 100% and low rates of severe adverse events, even in lower volume community hospitals.41–48 It has the advantage of facilitating use of standard side-viewing duodenoscopes and ERCP accessories, which improves success rates of cannulation and interventions when compared with enteroscopy-assisted ERCP.49,50 Additionally, laparoscopy allows for diagnosis and management of internal hernias, adhesions, and cholecystectomy if

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

indicated in the same setting (see Chapter 24). Coordination between gastroenterology and surgical teams and maintenance of a sterile field are the main challenges with this approach.42 As an alternative to this multidisciplinary approach, a technique using percutaneous- assisted transprosthetic endoscopic therapy has been described.51,52 In this technique, an enteroscope is advanced transorally into the excluded stomach, followed by the creation of a percutaneous endoscopic gastrostomy. The gastrostomy tract is then dilated to allow for the placement of a fully covered esophageal self-expanding metal stent (SEMS). A duodenoscope can then be advanced through the stent to perform antegrade ERCP. This has just been described in a single-center case series, however, and has not been widely adopted.52 EUS-Directed Transgastric ERCP (EDGE) – This is another option for patients with RYGB (see Chapter 22). It involves the creation of a fistula between the gastric pouch or proximal Roux limb and the excluded stomach under EUS guidance, using a lumen-apposing metal stent (LAMS). A duodenoscope is then inserted orally and advanced through this fistula to the excluded stomach, and the ERCP is completed in the standard manner. There is a risk of acute stent migration when attempting ERCP in the same session that the LAMS is placed, which can lead to a free perforation of both the gastric pouch/roux limb or the excluded stomach. Because of this risk, some centers perform a “staged EDGE” whereby the ERCP is performed in a separate session after placement of the LAMS.53,54 However, if a single-stage EDGE is desired, such as in cases of acute cholangitis, some investigators have reported success with anchoring the LAMS in place using either an over-the-scope clip (OTSC) or with endoscopic suturing.55,56 This procedure has technical and clinical success rates ranging from 91% to 100%, with main adverse events being related to bleeding, perforation, and stent dislodgement.53,57–60 There is also concern for weight regain because of the creation of the gastro-gastric fistula, although weight loss has actually been more common in the short term.58,61 The fistula often closes spontaneously after removal of the LAMS or can be closed by endosuturing or by using an OVESCO if necessary53,54. The EDGE procedure has higher clinical and technical success when compared with enteroscopy-assisted ERCP but does have more adverse events.62 When compared with the laparoscopic transgastric approach, the EDGE procedure has similar success and adverse event rates but has shortened procedure times and shorter hospital stays.54,61 EUS-Directed Transenteric ERCP (EDEE) – This technique has been recently described and involves the creation of an enteroenteric anastomosis to facilitate ERCP in non– RYGB surgical anatomy (e.g., Whipple, hepaticojejunostomy, Bilroth II, and duodenal switch).63 The pancreaticobiliary limb is first identified either by enteroscopy or via direct EUS puncture from the stomach, duodenum, or jejunum and filled with a solution of contrast, saline, and methylene blue. A target is then identified where the distance between the two luminal walls is less than 1 cm and there are no intervening vascular structures on Doppler. EDEE is then performed using either a 15 mm or 20 mm LAMS. A standard duodenoscope can then be passed through the LAMS to facilitate completion of the ERCP. In

439

this study, 22% of ERCPs were done in the same session as the LAMS placement but did not demonstrate any increased risk of adverse events compared with those that were done in a separate session. Additionally, despite no stent fixation being done for any of the procedures, there were no occurrences of stent migration. This procedure has technical and clinical success rates of up to 100% and 94.4%, respectively, with an adverse event rate of 5.6%. This procedure provides an additional option to access the pancreaticobiliary region in patients with complicated surgically anatomy in institutions where this expertise is available. In summary, selection of the appropriate technique for biliary access in patients with surgically altered anatomy should be individualized and would likely involve a combination of methods and endoscopic tools based on patient factors and operator’s expertise.

EUS-GUIDED BILIARY ACCESS/DRAINAGE ERCP success rates for biliary and pancreatic duct decompression can be anywhere from 76% to 98% depending on operator expertise, alterations in anatomy, and the etiology of biliary obstruction (see Chapter 20).64 Alternative methods of biliary decompression have traditionally included percutaneous transhepatic drainage or surgery (see Chapters 20, 31, 42, and 52). With the advancement of curvilinear-array echoendoscopes and peripheral devices, EUS-guided biliary drainage (EUSBD) has become increasingly reported either via an intrahepatic (hepaticogastrostomy) or extrahepatic (choledocho-duodenostomy) approach (Fig 30.1A). This approach has been found to have better clinical success outcomes and less adverse events when compared with percutaneous drainage.65 EUS-BD has conventionally been used as a second-line therapy when ERCP is unsuccessful.4,66 Nevertheless, there are increasing reports, including two randomized controlled trials (RCTs), of EUS-BD being used as the primary procedure for biliary decompression with comparable success rates and decreased adverse event rates compared with ERCP.67,68 In cases of malignant biliary obstruction, these techniques have a pooled technical and clinical success rate of 95% and 97%, respectively, and adverse event rates (mainly biliary peritonitis and cholangitis) of 19%.69 At this time, given inter-institution variations in access to EUS, it cannot be universally recommended as the initial procedure for biliary decompression. There are three main EUS-guided techniques: rendezvous, anterograde stenting, and direct transluminal drainage, which are described in detail in the following sections.

Rendezvous Technique The EUS rendezvous technique was first described by Mallery et al. in 2004 and involves EUS-guided wire placement into the bile duct in an antegrade fashion to facilitate subsequent retrograde biliary cannulation (see Chapter 20).70 The point of biliary duct entry (intrahepatic vs. extrahepatic) depends on accessibility and which route facilitates wire manipulation. Nevertheless, accessing the extrahepatic bile ducts from the second portion of the duodenum has been associated with a higher success rate.71 Whether it is through an intrahepatic or extrahepatic approach, a therapeutic linear echoendoscope is used to visualize the bile duct from the stomach or small intestine. Once an avascular plane has been identified using

440

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

A

C

B

D

FIGURE 30.1  Endoscopic ultrasound (EUS)–guided biliary drainage. A, Cholangiogram showing complete distal bile duct obstruction with diffuse upstream dilation. B, The common bile duct is accessed by using an EUS needle. C, A guidewire is left across the choledochoduodenostomy. D, After dilating the tract, a stent is successfully deployed.

Doppler ultrasonography, an EUS needle is advanced into the bile duct (see Fig 30.1B). Bile is aspirated, and contrast is injected to confirm position inside the bile system. A hydrophilic guidewire is then advanced antegrade through the EUS needle and into the bile duct and manipulated across the papilla. The needle is first exchanged out over the wire, followed by an exchange of the echoendoscope over the wire. The duodenoscope is then inserted transorally adjacent to the indwelling wire and advanced to the duodenum, with visualization of the wire traversing the papilla. The distal end of the indwelling guidewire can be grasped with forceps or snare and withdrawn through the accessory channel, and a cannulation catheter can be backloaded over the guidewire and re-advanced to the papilla. Alternatively, biliary cannulation can be accomplished in the standard retrograde fashion adjacent to the indwelling wire. Overall success and complication rates of the EUS-guided rendezvous technique are quoted as 80% to 86% and 10% to 15%, respectively.72,73

Antegrade Biliary Drainage This technique is useful in cases where conventional or even rendezvous ERCP cannot be performed because of inaccessibility of the papilla (e.g., because of proximal luminal obstruction or altered surgical anatomy, such as in RYGB). Similar to

the previously detailed rendezvous technique, the bile duct is identified and accessed from the stomach or small intestine. The transmural tract is then dilated over the guidewire with either a balloon catheter or bougie to allow anterograde advancement of a stent into the bile system with subsequent deployment across the biliary obstruction and through the papilla. Success rates from various case series range from 57% to 100%, and complication rates range from 0% to 6%.74,75

Transluminal Biliary Drainage In cases where anterograde or rendezvous techniques for transpapillary drainage cannot be accomplished (e.g., impacted biliary calculi, papillary stenosis, and tumor infiltration), an EUS-guided transluminal approach can facilitate biliary decompression. In the original variations of this procedure, the bile duct was accessed under EUS guidance, with placement of a guidewire similar to described above. The fistula tract was then dilated, and a stent was deployed over the guidewire (see Fig 30.1C and D). This technique was initially performed with plastic stents.76 It was subsequently performed with SEMS77 and then LAMS,78 in an attempt to improve patency and reduce leakage and migration. More recently, with the introduction of electrocauteryenhanced LAMS (ECE-LAMS), this procedure can be reduced to a single step wherein the biliary duct is punctured

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

with the ECE-LAMS system and the stent is deployed without the need for guidewire placement or fistula tract dilation. This procedure has been associated with technical and clinical success rates of 88% to 93% and 97% to 100%, respectively, with overall adverse event rates (mostly mild) of up to 36%.79-81

TECHNIQUES FOR THE MANAGEMENT OF CHOLEDOCHOLITHIASIS Complications of cholelithiasis accounts for over 300,000 hospital admissions annually at a cost of over four billion dollars.82 Choledocholithiasis is present in 10% to 15% of patients with symptomatic gallstones and can result in significant morbidity and mortality related to biliary obstruction, ascending cholangitis, and pancreatitis.83 Up to one-third of CBD stones may pass spontaneously, but for those that do not, ERCP with biliary sphincterotomy and stone extraction is considered the first-line management (Fig 30.2A; see Chapter 37).83–85

Biliary Sphincterotomy Endoscopic sphincterotomy (EST) aims at opening the terminal part of the CBD by cutting the papilla and sphincter

441

muscles. The basic technique of sphincterotomy has not changed significantly since its initial description. The standard sphincterotome, the Erlangen “pull-type” model, consists of a catheter containing an electrosurgical cutting wire exposed 20 to 25 mm near the tip of the sphincterotome. The leading tip distal to the wire, the “nose,” is five to ten mm in diameter. Once deep biliary cannulation has been achieved, the sphincterotome is retracted slowly, until one-fourth to one-half of the wire length is exposed outside the papilla. The sphincterotome is slightly bowed so the cutting wire is in contact with the roof of the papilla. The incision is made by upward lifting of the sphincterotome with pressure against the papillary roof, but not excessively, to avoid a rapid large incision (“zipper”; see Fig 30.2B). It is recommended that a current mode with alternating cutting and coagulating phases (e.g., Endocut) be used because this reduces the rates of uncontrolled cutting (“zipper”), PEP, and postsphincterotomy bleeding.4,86 The size of the sphincterotomy varies on a case-by-case basis and can be limited by the length of the intraduodenal portion of the CBD. In general, the sphincterotomy should be of adequate size to allow the passage of the stone in the CBD. The size of sphincterotomy can be

A

B

C

D

FIGURE 30.2  Endoscopic management of choledocholithiasis. A, Cholangiogram showing diffusely dilated biliary system with stone in the common bile duct (arrow). Biliary sphincterotomy (B), followed by sphincteroplasty (C). D, Extraction of large stone.

442

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

gauged by the ability to move the bowed sphincterotome across the opening, by passing an inflated balloon catheter through the site, and/or by eliminating the tapering or “pinch” of the intraampullary bile duct seen on fluoroscopy.

Endoscopic Balloon Papillary Dilation Endoscopic balloon dilation (EBPD; also known as sphincteroplasty) of the biliary sphincter muscle can be used as an alternative or adjunct to sphincterotomy. The main advantage of sphincteroplasty is that it results in transient widening of the biliary sphincter such that it remains intact and functional after the procedure. This reduces duodenobiliary reflux, which, in turn, reduces cholangitis and stone recurrence. Additionally, because there is no cutting involved, there is a lower risk of procedure-related bleeding. Thus, use of this technique may be preferred to sphincterotomy in patients who are at increased risk of bleeding because of medications or underlying coagulopathy. It can also be helpful in facilitating biliary cannulation in patients with surgically altered anatomy in whom standard sphincterotomy cannot be performed safely or is technically difficult. Standard EBPD can be used for calculi less than 8 mm in size and involves the dilation of the papilla with a balloon diameter up to 10 mm.4,87 In this procedure, after selective biliary cannulation and placement of a guidewire in the bile duct, a balloon-tipped catheter (i.e., CRE balloon or Hurricane RX dilation balloon; Boston Scientific, MA) is advanced over the guidewire. The deflated balloon is positioned across the papilla and inflated with radiopaque contrast medium under both endoscopic and fluoroscopic visualization (see Fig. 30.2C). The inflated balloon is maintained until the “waist” corresponding with the biliary sphincter disappears. The optimum time for balloon inflation has not been defined, but longer inflation times (five minutes vs. 1 min) have been associated with increased rates of stone clearance and a decreased risk of PEP.88,89 It is recommended that this technique be performed with an 8 mm balloon irrespective of the size of the CBD.4 Earlier approaches to this technique selected balloon sizes that were less than the size of the CBD because of concern for bile duct injury90; however, it has been demonstrated that using a standard 8 mm balloon size irrespective of the size of the CBD did not result in any increased risk of perforation. Additionally, use of smaller size balloons has been associated with increased risk of PEP, compared with either larger balloons or ESR.4 Endoscopic papillary large balloon dilation (EPLBD) is a modification of this technique for removal of large bile duct stones in which the papilla is dilated with a balloon greater than 10 mm with or without EST.91,92 For this technique, it is recommended that the balloon size not exceed the size of the distal bile duct because of the risk of perforation.93 Overall EPLBD has been associated with comparable and even higher rates of stone clearance, with less additional interventions for stone clearance and comparable rates of adverse events compared with EST.87,94–97 It is recommended that, for large stones, EPLBD should be done after EST because this has been found to have higher rates of complete stone clearance compared with EST alone.83,85,98,99 Additionally, ELBD has been found to be an effective alternative to and reduces the need for mechanical lithotripsy for large bile duct stone removal.96,99

Stone Extraction Bile duct stone extraction after sphincterotomy or sphincteroplasty can be performed using either extraction balloon catheters

or wire baskets, which are equally effective (.80%–92.3% clinical success rates) and safe (6.6%–11.8% adverse event rates; see Fig. 30.2D).100–102 Extraction balloon catheters are available in different sizes (8.5–20 mm) and in most centers are the standard first-line approach for stone extraction, given their ease of use and lack of risk of becoming entrapped within the duct. The extraction balloon is inflated (to the diameter of the bile duct) above the stone and pulled back gently to the level of the papilla. In the setting of multiple stones, it is important to remove the stones individually, starting with the most distal one, to avoid stone impaction. Similarly, there are also a variety of wire baskets in different sizes and configurations. The stone is entrapped between the wires when the basket is closed, and subsequent removal is achieved by traction removal of the basket in the axis of the bile duct. The effective traction of the wire basket often allows for effective removal of medium to large stones within the CBD or stones that are “floating” within a dilated bile duct and thus easily slip around a balloon.103 Conversely, the extraction balloon may be more suitable for the removal of small stones/ fragments that are difficult to entrap between the wires or when opening of the basket is constrained by duct caliber and has been found to be more efficacious than wire baskets in achieving complete clearance if there are more than four bile duct stones or if they are less than 6 mm.101,102

Biliary Stenting In difficult cases of choledocholithiasis in which the bile duct cannot be completely cleared with the previous techniques, plastic or fully covered SEMS should be placed as a temporizing measure.83,100 This strategy maintains biliary drainage and is found to reduce the stone burden at subsequent ERCP. This is thought to be because of direct mechanical friction between the stent and the stones, which results in their disintegration, and papillary dilation, which results in their passage.83,100 It is recommended that these stents be removed or exchanged after two to six months to reduce the risk of cholangitis. These stents inevitably become occluded and as such should not be used as destination therapy for management of bile duct stones.83,100

Lithotripsy Standard stone extraction techniques may fail when a stone is large, impacted, or proximal to a stricture or when stones are multiple. A variety of modalities are currently available to fragment these difficult stones before extraction, including mechanical lithotripsy, endoscopic intraductal lithotripsy, and extracorporeal shock-wave lithotripsy.

Mechanical Lithotripsy Mechanical lithotripsy has been the most frequently used lithotripsy approach, given its ease of use and availability. It is recommended for difficult stones that have not been able to be cleared with sphincterotomy and EPLBD.100 Success rates range from 63% to over 90%, depending on CBD size relative to the size of the stone.97 More than one procedure may be necessary to achieve complete duct clearance. There are two variations to the technique of mechanical lithotripsy: an external-type lithotripter/out-of-the-scope (OTS) method and an integrated through-the-scope (TTS) method. The TTS method is recommended for elective cases.100 Here, a special lithotripsy basket contained within a metal

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

sheath is inserted through the accessory channel of the endoscope. Once the stone is captured within the basket, forceful traction on the wires against the metal sheath results in stone fragmentation.104 The OTS method is used as a “salvage” method when a standard basket engages a large stone and becomes lodged at the papilla.100 In this method, the stone is captured within a standard Dormia basket, the basket handle is cut off, and the endoscope is removed. A coiled metal sheath is inserted over the wire until its tip is in contact with the stone, and mechanical lithotripsy is performed by turning the crank handle, crushing the stone between the basket wires and the metal tip of the sheath.104 The most common adverse events include PEP, hemorrhage, basket entrapment, basket wire rupture, traction wire fracture, or a broken handle and can occur in up to 13% of cases.105 Other types of lithotripsy, sphincterotomy extension, or stenting are options for management of these complications. The most common reason for failure is large stones exceeding 3 cm in size.105

Endoscopic Intraductal Lithotripsy Intraductal shock-wave lithotripsy is an alternative modality for the fragmentation of refractory calculi. It can be performed with fluoroscopic guidance only but is preferably performed under direct visualization via cholangioscopy. The two methods used to accomplish this are electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL). They both involve irrigation of the bile duct with a saline solution and the generation of shock waves through this fluid medium, which shatter the calculi. The fragments are then removed by standard methods.104 In electrohydraulic lithotripsy (EHL), a bipolar electrode probe is positioned about one to two mm from the stone. A charge is transmitted across the electrodes, which creates a spark. This, in turn, causes expansion of the surrounding fluid, which generates a shock wave, which shatters the intraductal stones.104 Laser lithotripsy (LL) is based on the principle of transforming optical energy into mechanical energy. In LL, focusing the high-power density laser light on the surface of the calculi results in the transformation of matter into a plasma state, which is a gaseous collection of ions and free electrons. Subsequently, the plasma expands, inducing an oscillation wave with tensile/compressive forces that create cavitation of the stone surface and ultimately shatter the stone.104 Intraductal lithotripsy is associated with better rates of duct clearance compared with conventional therapies, including mechanical lithotripsy, with success rates upwards of 90%.105–110 Although both modalities are efficacious and head-to-head RCTs are lacking, LL may be more successful at duct clearance than EHL.108 Adverse events occurred in up to 11.3% of cases and were mainly because of cholangitis, pancreatitis, and hemorrhage and may be higher in EHL than LL.105,107–109

Extracorporeal Shock-Wave Lithotripsy Extracorporeal shock-wave lithotripsy (ESWL) can be considered when conventional techniques have failed and intraductal lithotripsy is not feasible.100 It involves initial placement of a nasobiliary tube by interventional radiology to aid with stone visualization. Under ultrasound or fluoroscopic guidance, high pressure electrohydraulic or electromagnetic energy is delivered to the liquid medium in the bile duct, which generate shock

443

waves and results in stone fragmentation.84,104 Multiple ESWL sessions are generally required and final duct clearance rates range from 60% to 90%.84,111 ERCP may have to be performed after ESWL for stone fragment removal. Adverse events, including hemobilia, cholangitis, pancreatitis, and cardiac arrhythmias, have been reported in 9% to 35% of cases.100 Additionally, recurrence of bile duct stones have occurred in up to 20% of patients.112 The need for ESWL has decreased as the effectiveness of intraductal lithotripsy has improved, with several studies suggesting superior ductal clearance and fewer treatment sessions with LL compared with ESWL.100,108

TECHNIQUES FOR THE MANAGEMENT OF BILIARY STRICTURES ERCP with stenting is a well-standardized technique commonly used to relieve biliary obstruction secondary to both benign and malignant disease. The goal is to relieve the biliary obstruction that can potentially lead to complications, such as jaundice, pruritus, cholangitis, chronic liver disease, and liver failure. Biliary stricture characterization can be a diagnostic challenge that requires a multidisciplinary approach with the integration of laboratory testing, noninvasive, and invasive imaging, and tissue sampling methods. This section focuses on the technical aspects and outcomes associated with endoscopic management of benign and malignant biliary strictures. Advances in endoscopic imaging and tissue sampling for the diagnosis of biliary strictures will be covered later in this chapter.

Types of Biliary Stents Plastic Stents Plastic biliary stents are composed of polyethylene, polyurethane, or Teflon. Stent diameter and length range from 5Fr to 12Fr and 5 to 18 cm, respectively.113 Plastic stents are available in a variety of configurations: straight, angled, curved, with flaps (flanged), or coiled at one or both ends (single or double pigtail) for anchorage. All plastic stents are radiopaque, some with additional markers at the proximal and distal end of the stents to facilitate visualization under fluoroscopy. Insertion is via a push catheter over a guidewire. Duration of stent patency is largely dependent on the size of the inner diameter, with 10Fr and larger stents remaining patent, on average, for approximately three months, and stent occlusion developing secondary to bacterial colonization, sludge, tissue debris, or bilioduodenal reflux.114 Shorter patency times may be observed in patients undergoing chemotherapy for pancreatic adenocarcinoma.114

Self-Expandable Metal Stents SEMS are composed of stainless steel or a variety of metal alloys, such as nitinol (nickel and titanium combination) or platinol (platinum core with nitinol encasement). This material is malleable, which allows the SEMS to adapt to many configurations without compromising radial expansile force. SEMS are configured into a cylinder by interwoven wires and are deployed from a constrained position within a delivery catheter. Stent diameter and length vary from 6 mm to 10 mm and 4 to 12 cm, respectively.113 The larger stent diameter compared with plastic stents results in increased duration of stent patency (on average, six–12 months). SEMS can be covered, partially covered, or uncovered. The covering consists of a silicone, polycaprolactone, polyether polyurethane, polyurethane,

444

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

A

B

C

FIGURE 30.3  A, Cholangiogram showing a benign biliary anastomotic stricture (arrow) after orthotopic liver transplantation. Balloon dilation across the stricture (B), followed by placement of three plastic biliary stents (C).

TABLE 30.1  Etiologies of Biliary Strictures BENIGN ETIOLOGIES

MALIGNANT ETIOLOGIES

Iatrogenic (postoperative) Cholecystectomy Biliary anastomosis Chronic pancreatitis Autoimmune pancreatitis Primary sclerosing cholangitis Autoimmune sclerosing cholangiopathy Ischemic Vasculitis Infectious (viral, parasitic, HIV cholangiopathy, tuberculosis) Radiation therapy Postsphincterotomy Portal biliopathy Abdominal trauma

Pancreas carcinoma Cholangiocarcinoma Ampullary carcinoma Gallbladder carcinoma Hepatocellular carcinoma Metastasis

HIV, Human immunodeficiency virus.

or expanded polytetra-fluoroethylene fluorinated ethylene propylene lining.113 Covering reduces tumor or hyperplastic tissue ingrowth but is associated with a higher migration rate compared with uncovered metal stents because of decreased tissue anchoring.114 Partial or fully covered SEMS can typically be removed or repositioned, whereas uncovered stents are difficult to remove because of tumor ingrowth or benign tissue hyperplasia.113

Endoscopic Management of Benign Biliary Strictures There are numerous etiologies of benign biliary strictures. Many cases of benign biliary strictures are secondary to postoperative iatrogenic injury, after cholecystectomy or at the site of a biliary anastomosis after biliary surgery or liver transplantation (Fig 30.3A). Benign biliary strictures may also result from ischemic injury and/or inflammatory processes such as primary sclerosing cholangitis or chronic pancreatitis (Table 30.1; see Chapter 42). Comprehensive evaluation of a biliary stricture and its etiology should always be sought before any therapeutic endoscopic intervention so as to rule out any underlying malignant etiology. Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive imaging modality that can accurately delineate the biliary anatomy, site, and length of the

biliary stricture and thus provide useful information for ERCP planning115 (see Chapter 16).

Endoscopic Technique ERCP with stricture dilation and biliary stenting is currently recommended as the first-line intervention for the management of biliary strictures116,117 (see Chapter 39B). It is performed after a detailed assessment of the type and site of the biliary stricture. The key technical step is to negotiate the stricture and achieve biliary access with the use of a guidewire. This process can be challenging, and the use of different sizes and types of hydrophilic guidewires in addition to guidewire manipulation with steerable catheters or sphincterotomes is often necessary. Although not required in all cases, biliary sphincterotomy may need to be performed to facilitate subsequent therapy, including stricture dilation and stent placement.

Stricture Dilation Stricture dilation can be performed using push-type dilation catheters (bougies) or hydrostatic balloons (range, 4–10 mm in diameter) when the stricture is not amenable to mechanical dilation. The balloon is inflated with diluted contrast material to the maximum atmospheric pressure allowable and is kept inflated until the stricture “waist” is obliterated, generally after 30 to 60 seconds (see Fig. 30.3B). Dilation can be safely performed to a diameter 1 to 2 mm larger than the downstream bile duct diameter, but caution must be exercised in anastomotic strictures that are less than four weeks old.117 Depending on the etiology, stricture dilation alone is associated with high restricturing rates, and thus stent placement is often pivotal in maintaining patency.117,118 One exception is for primary sclerosing cholangitis (PSC), where serial dilation alone may provide adequate therapeutic benefit.119,120

Biliary Stenting Two types of stents can be used: plastic and covered SEMS (cSEMS). For plastic stents, placement of a single plastic stent has poor outcomes for resolving benign biliary strictures. Instead, it is recommended that multiple side-by-side plastic stents be placed during the index ERCP (number and caliber of stents limited by size of the bile duct and stricture; see Fig. 30.3C).121 These can be sequentially exchanged with additional stents placed each time, usually at three month intervals for up to 12 months.

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

Alternatively, a single cSEMS can be placed and exchanged periodically until stricture resolution is achieved (see Fig. 30.2C).116 It is important to highlight that placement of a fully covered SEMS (FCSEMS) may potentially block drainage of a neighboring duct (including the cystic duct); thus these stents are preferably restricted to distal bile duct strictures and must be used cautiously in patients with an in situ gallbladder because mechanical obstruction of the cystic duct and resultant cholecystitis may ensue.122–124 It must be noted, however, that concomitant obstruction of the cystic duct by tumor or the presence of gallstones may be stronger predictors of cholecystitis than stent type alone.122,125 Both stents have demonstrated similar efficacy with stricture resolution rates of up to 95% in plastic and 100% for cSEMS and recurrence rates of up to 20% across multiple etiologies of benign strictures.56,126–133 Nevertheless, cSEMS have the ability to exert greater radial force, which results in more sustained stricture dilation, and require fewer stent exchanges when compared with plastic stents.56,127,128,134 Recurrence rates may be higher in chronic pancreatitis than in anastomosis or surgical strictures.135 Adverse events occurred in up to 23% and were mainly because of stent migration or occlusion. The importance of compliance with stent exchanges must be emphasized to patients to reduce the risk of stent occlusion and resulting cholangitis.121 To date, the ideal number of stents, the type of stent, and the duration of stent placement for benign stricture resolution remain highly debated and often vary on a case-by-case basis.

Endoscopic Management of Malignant Biliary Strictures Malignant biliary obstruction is most frequently seen in the setting of pancreaticobiliary malignancy, but it can also be because of many other etiologies (see Table 30.1). When indicated, endoscopic therapy is considered the mainstay therapy for biliary decompression. A careful multidisciplinary review of the indication and appropriateness of any endoscopic intervention should be sought before any procedure.

Preoperative Biliary Drainage The routine need for preoperative biliary decompression in patients with resectable pancreaticobiliary disease remains controversial (see Chapters 50–51B and 62). From a technical standpoint, the placement of a short plastic or metal biliary stent does not appear to interfere with subsequent pancreaticoduodenectomy.136,137 However, meta-analyses of the current literature indicate that routine preoperative biliary drainage may be associated with increased postoperative complications (in particular, wound infection) when compared with patients who proceed directly to surgery.138,139 As such, routine preoperative biliary drainage in patients with resectable malignant obstruction is not recommended and should be reserved for cholangitis, severe symptomatic jaundice, and pre-neoadjuvant chemotherapy and in cases of delayed surgery.140–143 If stenting is required for these reasons, the shortest-length FCSEMS has been recommended because these were associated with better patency rates and lower infection rates and did not interfere with subsequent pancreaticoduodenectomy if indicated.136,141,144 A more recent prospective multicenter RCT, however, suggests that uncovered SEMS (UCSEMS) and FCSEMS have similar success rates despite prior concerns of tumor in growth in UCSEMS. Stent lengths of 6 and 8 cm were found to have longer patency times than 4 cm.143 Additional multicenter trials are

445

needed to further validate these findings. It must be noted that if the definitive diagnosis and/or staging of the biliary stricture is not certain, an UCSEMS should not be placed because it has poor long-term patency and removal is difficult.140 Plastic biliary stents or a FCSEMS can be placed for biliary decompression while workup is completed.

Palliative Biliary Drainage of Distal Bile Duct Obstruction Distal malignant biliary obstructions are typically defined as those distal to the cystic duct insertion, although this definition is suboptimal, given the substantial anatomic variability of the cystic duct insertion site. Therapeutic options include surgical bypass, percutaneous decompression, and endoscopic stenting. A large meta-analysis of 2,436 patients demonstrated that endoscopic stenting was associated with a lower risk of procedural complications than traditional surgical bypass.145 A large metaanalysis of 20 RCTs, which included 1,713 patients, demonstrated improved stent patency for distal biliary obstruction with SEMS versus plastic stents.146 In light of this, SEMS are recommended over plastic stents for the treatment of distal malignant bile duct obstruction.140 In terms of what type of SEMS is superior, a meta-analysis of 11 RCTs demonstrated no difference in stent failure or mortality between cSEMS and UCSEMS. There was a higher rate of migration and sludge with cSEMS, whereas tumor ingrowth was more likely with UCSEMS.147 Ultimately, the optimal stent choice depends on various factors, including establishment of diagnosis, need for reinterventions, operator’s expertise, cost analysis, and the patient’s life expectancy.143

Palliative Biliary Drainage of Proximal Bile Duct Obstruction (Hilar) Malignant biliary obstructions at the biliary confluence can be technically challenging (see Chapter 51B). The extent of the biliary obstruction is commonly classified based on the modified Bismuth-Corlette classification and can be summarized as follows: Bismuth type I strictures involve the proximal common hepatic duct (CHD) but not the confluence of the left and right ductal systems, type II involves the confluence but spares the segmental hepatic ducts, type IIIa and IIIb involve either the right or left segmental hepatic ducts, respectively, whereas both segmental hepatic ducts are involved in type IV.148 Biliary drainage with stent placement can be particularly difficult in those with advanced complex strictures (Bismuth type II and above). Evaluation with noninvasive imaging (i.e., MRCP) to delineate the anatomy is mandatory for preprocedural planning and helps limit contrast injection during the ERCP and the risk of contaminating undrainable segments. Furthermore, evaluation of the side of the liver (i.e., lack of atrophy, patent portal vein branch, and lack of extensive segmental biliary involvement) that will provide biliary drainage to the most functional parenchyma is critical. It is of utmost importance that the best approach (including percutaneous approaches) be evaluated in a multidisciplinary review. In patients with strictures that do not involve the confluence of the right and left hepatic ducts (Bismuth type I), adequate biliary drainage is often achieved by placing a single biliary stent. Controversy exists as to whether both lobes of the liver need to be drained when a bifurcation lesion obstructs both lobes. The main determining factor associated with effective drainage is the liver volume to be drained. Drainage of 50% of the liver volume has been found to represent effective biliary

446

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

drainage and is associated with improved median survival.149–151 Thus the goal of endoscopic therapy should be directed at achieving drainage volume greater than 50%, irrespective of whether unilateral or multisegmental stenting is performed.140 Both unilateral and bilateral stents may have similar technical success rates, although bilateral metal stent placement has been found to have decreased need for reintervention and improved symptom-free stent patency.152–154 However, a recent multicenter retrospective study found a higher rate of adverse events (PEP, bleeding, perforation, and cholangitis) and death with bilateral compared with unilateral stent placement.155 Given these potential benefits and risks, it is important to individualize the decision on stent placement based on the patient’s anatomy and clinical scenario. Several studies have suggested that an SEMS is preferable to a plastic stent, based on higher rates of successful drainage, prolonged patency, and prolonged survival and lower rates of complications.156,157 The use of UCSEMS is preferred for proximal malignant biliary strictures because placement of a covered stent can potentially obstruct drainage of adjacent ducts.140 For stent implantation, a guidewire is advanced across the malignant stricture into the duct preselected for drainage (Fig 30.4A). After wire placement, if necessary, dilation of a tight stricture can be performed with a balloon catheter or bougie (see Fig 30.4B). A sphincterotomy is not necessary when the distal ends of the stents are positioned within the duct, which may reduce the risk of poststenting cholangitis. On the other hand, stent revision is technically less demanding and more accessible when the distal end of the stents protrude out of the papilla (see Fig 30.4C). Regardless of stent positioning, all patients who undergo endoscopic therapy for these complex strictures should receive prophylactic antibiotics. In summary, endoscopic stenting of proximal biliary obstruction is challenging. Preprocedural cross-sectional imaging and multidisciplinary review is essential in the selection of the target parenchyma for drainage and the optimal approach (percutaneous vs. endoscopic). If endoscopic approaches are favored, this planning will, in turn, help maximize biliary drainage by targeting the dominant biliary systems, limit the use of contrast during the procedure, and avoid intubating atrophic segments or areas that cannot be effectively drained.

A

B

Adjunctive Therapies for Biliary Strictures In addition to stenting, a few adjunctive therapies are available to remodel and treat the stricture, which can have implications on stent patency, quality of life, and survival.

Photodynamic Therapy Photodynamic therapy (PDT) is based on the ability of photosensitizers to generate cytotoxic oxygen species in the target tissue upon exposure to light of an appropriate wavelength. Photosensitizing agents (sodium porfimer or aminolaevulinic acid) are injected intravenously preprocedurally, and ERCP is subsequently performed two to four days thereafter. A catheter with a quartz fiber coupled with a diode laser emitting a wavelength of 630 nm is inserted into the bile duct through the accessory channel of the endoscope. The catheter is directed against the photosensitized malignant cells, causing tumor cell death by the generation of oxygen-free radicals. This procedure can also be done under direct visualization via cholangioscopy.158 A meta-analysis of six studies, which included 170 patients, as well as subsequent retrospective studies have demonstrated improved survival (Weighted mean difference [WMD] 265 days; 95% confidence interval [CI]: 154–376; P 5 .01; I(2) 5 65%) and improved quality of life as measured by Karnofsky scores (WMD 7.74; 95% CI: 3.73–11.76; P 5 .01; I(2)5 14%) with PDT with stenting compared with stenting alone.159,160 The main adverse effects of PDT are cholangitis, which can be seen in up to 50% of patients, and photosensitivity.159,160

Radiofrequency Ablation Radiofrequency ablation (RFA) relies on the generation of high-frequency alternating electromagnetic energy resulting in thermal injury to the target tissue. A variety of RFA probes designed to be used with an ERCP scope are commercially available. The probe is inserted into the working channel of the duodenoscope and advanced into the bile duct over a guidewire. Unlike PDT, ERCP-guided RFA requires direct contact of the probe with the malignant stricture. Upon correct positioning of the probe under fluoroscopy, the probe is activated and the ablative energy is delivered directly to the target tissue, resulting in local coagulative necrosis.161

C

FIGURE 30.4  A, Cholangiogram showing a type IIIb malignant hilar obstruction with upstream dilation of the right and left hepatic ducts. Balloon dilation across the stricture (B) and placement of bilateral uncovered metal biliary stents to drain both lobes of the liver (C).

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

Recent studies have confirmed the safety and efficacy of RFA as an adjunct to SEMS in patients with a malignant biliary stricture. A meta-analysis of nine observational studies, including 505 patients, demonstrated that the addition of RFA to biliary stenting was safe and resulted in longer stent patency times with pooled WMD in stent patency of 50.6 days (95% CI, 32.83–68.48) favoring patients receiving RFA and improved survival (hazard ratio [HR] 1.395; 95% CI, 1.145–1.7; P , .001).162 RFA was also found to have similar survival to patients treated with PDT with a median survival of 9.6 versus 7.5 months, respectively (P 5 .799).163 Further studies, including RCTs, over a longer period are needed to validate these preliminary findings.

TECHNIQUES FOR THE MANAGEMENT OF BILE LEAKS Bile leak is a well-known complication from injury to the biliary tree, either secondary to trauma or iatrogenic after laparoscopic cholecystectomy, liver resection, or transplantation (see Chapter 28). Bile leaks can be classified as either high grade or low grade. High-grade leaks demonstrate rapid extravasation of contrast during cholangiogram, whereas low-grade leaks exhibit contrast extravasation only after near complete intraductal filling has occurred (Fig 30.5A). The aim of endoscopic therapy is to decrease the transpapillary pressure gradient, thus favoring transpapillary bile flow rather than extravasation at the site of the leak. This can be achieved by performing a biliary sphincterotomy, placing a transpapillary biliary stent, or both. In most instances, placement of a plastic biliary stent (7Fr or 10Fr) is sufficient without the need of a sphincterotomy and its potential associated risks164 (see Fig. 30.5B). Nevertheless, both stenting alone and stenting with sphincterotomy demonstrated superior outcomes when compared with sphincterotomy alone.165,166 It is not necessary to place the proximal end of the stent beyond the site of the leak because reduction of the pressure inside the duct alone is generally sufficient. Typically, the stent is left in place for approximately four to six weeks. Various studies have reported endoscopic success rates for the management of bile leaks between 70% to 100%, with high-grade

A

447

leaks being associated with lower success rates.167,168 In the minority of cases in which the bile leak is refractory to endoscopic therapy with plastic stent placement and/or sphincterotomy, upsizing the stent or placing multiple plastic stents (MPS) can be performed in subsequent sessions until resolution is documented.167 An alternative to this is to temporarily place a single FCSEMS, which has been shown to be an effective rescue therapy for refractory bile leaks and may be superior to MPS.140,169,170 It should be noted that, in the presence of a perihepatic bile collection, endoscopic stenting alone does not result in the reabsorption of the established biloma. Thus symptomatic bilomas will need to be drained percutaneously. An output of less than 10 mL per day through a percutaneous drain is associated with bile leak resolution and can be used as a surrogate indicator for stent removal. Successful EUS-guided transenteric/ transgastric drainage of bilomas with SEMS has been described, but additional prospective studies are required for validation.171

ENDOSCOPIC MANAGEMENT OF AMPULLARY ADENOMAS Ampullary adenomas are dysplastic glandular lesions that arise from either the major or minor duodenal papilla (see Chapter 63). These lesions can occur sporadically or arise in the context of genetic syndromes, such as familial adenomatous polyposis (FAP). If not removed, ampullary adenomas can undergo malignant transformation to ampullary cancer, with a reported incidence from 25% to 85%.172 With advances in therapeutic endoscopy, endoscopic ampullectomy/papillectomy has become an acceptable alternative therapy to surgery for ampullary adenomas.173

Diagnosis and Local Staging Before endoscopic ampullectomy, preoperative assessment with both a forward- and side-viewing endoscope is routinely performed to further characterize the lesion. Endoscopic findings, including spontaneous bleeding, friability, ulceration, and induration, are often associated with malignant lesions. Biopsies obtained during endoscopy can assess for dysplasia or unsuspected

B

FIGURE 30.5  A, Cholangiogram showing contrast extravasation (arrow) at the biliary anastomosis in a patient after liver transplantation, consistent with bile leak. B, Bile leak treated by placing a plastic stent across the biliary anastomosis.

448

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

carcinoma, although malignancy may be missed in up to 30% of tumors when forceps biopsy specimens are obtained.174,175 Hence, other advanced imaging modalities, including narrow-band imaging, confocal laser endomicroscopy, and high-definition white light endoscopy, have been proposed as complementary techniques to help predict histologic characteristics of ampullary lesions, but further multicenter trials are needed to validate these techniques.176 EUS has been shown to be superior to computed tomography (CT), angiography, and magnetic resonance imaging (MRI) for local tumor staging, including assessment of the size of lesion and involvement/infiltration of the periampullary wall layers, the CBD, and the pancreatic duct, in addition to identification of malignant periampullary lymph nodes.177 When performed, EUS can help stratify which lesions are amenable to endoscopic ampullectomy. ERCP with both biliary and pancreatic duct evaluation, and intraductal ultrasound (IDUS) can also aid in the detection of tumor extension into either ductal system. Many experts agree that smaller lesions (,1 cm) without suspicious signs of malignancy (ulceration, spontaneous bleeding, biopsies positive for high-grade dysplasia or carcinoma) may not require EUS evaluation before endoscopic resection.177

Endoscopic Therapy Endoscopic ampullectomy (papillectomy) can be considered once malignancy has been reasonably excluded. This procedure is performed with the standard monopolar diathermic snare used for colon polypectomy. The aim of endoscopic excision is to obtain complete removal of the ampullary lesion, preferably en bloc (Fig. 30.6A and B). When performing this technique, it is common for the intra-ampullary portions of the CBD and pancreatic duct to be removed as well. Submucosal injection is not routinely recommended because the center of the ampullary lesion is generally tethered down by the bile and pancreatic duct. Thus submucosal injection may actually raise the surrounding mucosa, create a depressed center (“valley effect”), and interfere with en bloc excision and subsequent attempts at bile and pancreatic duct access.177 For most ampullary lesions, the tip of the snare is positioned against the wall of the duodenum at the superior aspect of the mass. The snare is then slowly opened, and the snare

A

B

catheter advanced slowly to allow the open snare to drape downward over the lesion encircling it. Once achieved, the snare is slowly closed while simultaneously advancing the snare catheter toward the base of the lesion, followed by polypectomy. Thermal therapy (i.e., argon plasma coagulation, monopolar and bipolar coagulation, neodymium:yttrium-aluminum-garnet laser) can be used to fulgurate any residual tissue after piecemeal or incomplete resection, with caution to avoid excessive tissue destruction around the biliary and pancreatic duct orifices.177 Additionally, in cases where there is intraductal extension, intraductal RFA or ablation with a cystotome has demonstrated high therapeutic success rates, even in malignant neoplasms.178,179 A meta-analysis of 29 studies including 1,751 patients demonstrated a pooled complete resection rate of 94.2%. Adverse events occurred in 24.9% of them, with the majority being because of PEP (11.9%). Follow-up ranged from 9.6 to 84.5 months and demonstrated recurrence in 11.8% of patients.180 Prophylactic pancreatic stenting is recommended after an ampullectomy because it has been found to reduce the risk of PEP.177,180 Whether ERCP with pancreatic and biliary sphincterotomy/stent placement is performed preresection or postresection often depends on the endoscopist’s preference (see Fig 30.6C). Because identification of the pancreatic orifice after ampullectomy can be challenging, some endoscopists favor performing pancreatography with iodinated contrast diluted with methylene blue or indigo carmine before resection. The blue-stained pancreatic orifice can theoretically be more readily identified adjacent to the bile-stained biliary orifice, and thus facilitate postresection cannulation.177 Prophylactic biliary sphincterotomy and/or stenting is neither widely performed nor uniformly recommended unless there is concern for inadequate biliary drainage after ampullectomy.177 Patients who have undergone endoscopic ampullectomy should undergo routine surveillance, given the risk of recurrence.177 Endoscopic surveillance should be performed with a side-viewing duodenoscope; the timing interval and duration of surveillance is dependent on several factors, including histology and margin status of resected specimen, history of FAP, and the patient’s age and comorbidities. Furthermore, any specimen with unexpected malignancy should be referred for surgical consultation.

C

FIGURE 30.6  Endoscopic ampullectomy. A, Ampullary adenoma. Ampullectomy with en bloc resection (B), followed by biliary and pancreatic duct stenting (C).

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

Endoscopic Biliary Tissue Acquisition and Advanced Imaging Techniques The role of ERCP as a diagnostic tool has significantly diminished with the advent of multiple noninvasive imaging tests of the biliary system, including high-resolution CT and MRCP. One notable exception to this trend is the need for ERCP with tissue sampling in suspected malignant biliary obstruction.

Biliary Tissue Acquisition and Analysis Intraductal Brushings Intraductal brushing during ERCP is the standard first-line approach for tissue acquisition of biliary strictures, primarily because of wide availability and technical feasibility. The technique involves advancing the sheathed cytology brush over a guidewire into the bile duct to the proximal end of the stricture. The brush is then advanced out the catheter, and multiple to and fro movements are performed with the brush across the stricture for approximately 10 passes. The brush is then withdrawn into the catheter and removed as a unit, which has been shown to improve diagnosis.173 Repeated brushing with consecutive brushes may increase diagnostic yield.181 The diagnostic yield of brush cytology for biliary strictures is low, with a meta-analysis of 16 studies demonstrating sensitivities ranging from 6% to 64%.173 The poor sensitivity of brush cytology has often been attributed to sampling error and low cellular yield because of the scirrhous nature of cholangiocarcinoma and because pancreatic adenocarcinomas frequently cause only extrinsic compression of the distal bile duct, rather than frank invasion.

Biliary Intraductal Biopsies Endobiliary forceps biopsy during ERCP is an alternate technique routinely used for tissue sampling of biliary strictures. A variety of flexible forceps are available in adult (7Fr) and pediatric (5Fr to 6Fr) calibers. Similar to other accessories, the forceps can be advanced into the bile duct. A prior sphincterotomy may facilitate this process but is not essential in the presence of an indwelling guidewire in the biliary system.182,183 Although previous studies have suggested that tissue sampling with forceps provided the highest yield for detection of malignancy, a recent meta-analysis indicates that both brushings and biopsy are comparable and have limited sensitivity (pooled sensitivity of 45% and 48%, respectively).184 A combination of both of these techniques leads to only a moderate improvement in sensitivity of 59.4%.184 A major advancement in the ability to evaluate and sample biliary strictures is the development of digital cholangioscopy devices that allow for direct visualization of the stricture and targeted cholangioscopy-guided tissue biopsies. This modality is currently the most high yield in the evaluation of indeterminate biliary strictures. A detailed discussion is included in the following section of this chapter.

Molecular Analysis of Tissue Samples Chromosomal abnormalities are typically seen in malignant biliary strictures, and there are various techniques to assess this, with the goal of improving diagnostic sensitivity when compared with conventional histocytopathology. Flow cytometry has been commonly used to identify aneuploidy in tissue specimens. Older data have shown that flow

449

cytometry for DNA evaluation yields improved sensitivity (42%) but at the expense of lower specificity of 70% and 77% for the diagnosis of malignant biliary strictures.185 Furthermore, flow cytometric analysis requires large cellular samples, which can be challenging with current endoscopic tissue sampling techniques. As a result of these limitations, flow cytometry is less frequently used in the analysis of biliary specimens.186 Digital image analysis (DIA) is another technique that had been investigated to increase the diagnostic yield of routine cytology. DIA uses a computer assessment to quantify DNA content, chromatin distribution, and nuclear morphology to assess for aneuploidy. In a single-center prospective study, DIA had a higher sensitivity (39%) compared with routine cytology (18%), albeit with a significantly lower specificity (77% vs. 98%, respectively).187 For patients with negative cytology and histology who were later proven to have malignancy, however, DIA identifies the diagnosis of malignancy in only 14% of cases.188 With these shortcomings in diagnosis and improvements in other techniques such as FISH (fluorescent in-situ hybridization), DIA is used less commonly.186 FISH is a cytogenetic technique that uses fluorescent probes that selectively bind to specific portions of selected chromosomes, allowing assessment of polysomy via fluoroscopic microscopy. The presence of multifocal polysomy in particular is a strong predictor of cholangiocarcinoma.189 A potential advantage of FISH is that it requires fewer cells for analysis compared with routine cytology or flow cytometry. A meta-analysis of six studies on 828 patients with PSC demonstrated a sensitivity and specificity for the diagnosis of cholangiocarcinoma of 68% and 70%, respectively.190 Another study of biliary strictures of varying etiologies noted that, compared with brush cytology alone, FISH resulted in an increase in sensitivity from 39.5% to 63.9% with a similar specificity of 94.3%.191 Sensitivity can be further improved by using a combination of FISH probes 1q21, 7p12, 8q24, and 9p21, which, in a single center study, was found to have a sensitivity of 93% and a specificity of 100%.192 Because of the improved sensitivity of FISH when cytology is negative for malignancy, it is currently recommended for the diagnosis of cholangiocarcinoma in PSC patients (see Chapter 41).193 Next-generation sequencing has been recently applied to biliary strictures and has resulted in an increased sensitivity of diagnosis of cholangiocarcinoma of 77% in brushing and 83% in biopsy specimens.194 Overall, ERCP with brush cytology and/or intraductal biopsies should be performed in the initial evaluation of indeterminate biliary strictures. Advanced cytologic methods, such as FISH and next-generation sequencing, can potentially improve sensitivity, especially in the setting of negative cytology and histology. It should be stressed that a multidisciplinary review of the indication for biliary tissue sampling is of critical importance. Some strictures do not require biopsy if surgery is indicated on clinical and radiologic grounds, and other biopsy approaches may be more appropriate.

Advanced Endoscopic Biliary Imaging Peroral Cholangioscopy Peroral cholangioscopy is a technique that permits direct endoscopic visualization of the bile ducts by using miniature endoscopes and catheters inserted through the accessory port of a duodenoscope. In the endoscope-based (“mother-daughter”)

450

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

system, a small, thin endoscope (daughter) is inserted through the accessory channel of the duodenoscope (mother). The main limitation of this system is the requirement of two separate endoscopists to operate each scope during the procedure. Single-operator cholangioscopy has also been developed and involves advancement of the digital cholangioscope over a guidewire through the working channel of a therapeutic duodenoscope. These initially consisted of fiberoptic probes but have since evolved to use high-resolution digital technology. The digital SpyGlass system (Boston Scientific Corp) has been available since 2015. It has two dedicated irrigation channels and four-way tip deflection. A biliary sphincterotomy is often required to allow passage of the catheter into the duct. In addition to the channel for the optical probe, the catheter includes a 1.2-mm accessory channel and two 0.6-mm irrigation channels.195 Alternatively, direct cholangioscopy can also be performed using ultraslim endoscopes originally designed for pediatric or transnasal esophagogastroduodenoscopy. This requires a previous ERCP with a large sphincterotomy or sphincteroplasty. Direct cholangioscopy can be performed with the tandem technique, which involves placing a guidewire into the bile duct via a duodenoscope, which is then withdrawn, and then advancing the ultraslim endoscope over the guidewire. The alternative is the freehand intubation technique in which the ultraslim endoscope is advanced independently to the papilla. The bile duct is then cannulated with a guidewire over which the endoscope is advanced. Although this has the advantage of needing a single operator and having a larger working channel (2 mm), which permits use of a wider range of accessories, it does carry a risk of air embolism. To reduce this risk, it is recommended to use only carbon dioxide insufflation or water irrigation to clear the bile duct.195 Peroral cholangioscopy has been primarily used for the management of refractory choledocholithiasis (discussed earlier in this chapter) and for the evaluation of indeterminate biliary strictures. Cholangioscopy allows direct visualization and inspection of mucosal abnormalities of the biliary epithelium (Fig 30.7A–C). Various classification systems that include

A

B

features such as vessel and pit pattern, papillary projections, and ulceration have been found to improve diagnostic accuracy and interobserver agreement for diagnosis of cholangiocarcinoma in indeterminate biliary strictures.98,196 Despite a definitive consensus on criteria for diagnosis of cholangiocarcinoma, a meta-analysis of six studies demonstrated that direct single-operator cholangioscopy had a pooled sensitivity and specificity of 94% and 95%, respectively, for diagnosing malignancy among indeterminate strictures by visual interpretation alone.197 Furthermore, direct visualization during cholangioscopy also permits selective targeted tissue sampling and results in adequate biopsies in more than 90% of cases.198 A meta-analysis of 10 studies demonstrated a sensitivity of 60.1% for cholangioscopy-guided biopsies in the diagnosis of malignant biliary strictures.199 In a prospective randomized study, it was found that three biopsies resulted in a sensitivity of 76.9%.200 When combined with visualization assessment, the overall sensitivity of digital single-operator cholangioscopy (DSOC) guided biopsies can increase to 87%.197 In a recent international multicenter prospective RCT, first-pass sensitivity of DSOC-guided biopsy samples was significantly higher than ERCP-guided brushing (68.2% vs. 21.4%; P , .01). The overall accuracy of DSOC was also significantly better that ERCP-guided brushings ( 87.1% vs. 65.5%; P 5 .05).201 Overall, there was no difference in adverse events with DSOC compared with ERCP intraductal biopsies or brushings.201 Overall, cholangioscopy represents an evolving novel technology for the evaluation of indeterminate biliary strictures, exclusion of occult malignancy, and management of biliary stones.

Endoscopic Ultrasound Transduodenal endoscopic ultrasound with fine-needle aspiration (FNA) has also been used for the evaluation and tissue diagnosis of extrahepatic biliary strictures (see Chapter 22). A meta-analysis of 20 studies including 957 patients demonstrated a specificity of 100% for both proximal and distal biliary strictures. Nevertheless, the sensitivity for distal strictures was

C

FIGURE 30.7  Evaluation of a dominant common bile duct stricture (CBD) in primary sclerosing cholangitis (PSC). A, Magnetic resonance cholangiopancreatography revealing a long-segment distal CBD stricture (arrow) with upstream biliary dilation. B, Cholangiogram showing long CBD stricture, upstream extrahepatic dilation, and intrahepatic ducts with beading consistent with PSC. C, Direct visualization of the bile duct with peroral cholangioscopy reveals a smooth, scarred stricture.

  Chapter 30  Interventional Endoscopy for Biliary Tract Disease: Technical Aspects

83% compared with 76% for proximal strictures.202 This is likely because of the proximity of the distal segment of the CBD to the duodenal wall rather than the proximal perihilar segments, which impacts visualization and tissue acquisition. The pooled adverse event rate was 1%, with the main event being self-controlled bleeding. When combined with ERCP, diagnostic sensitivity increases to 85.8%, with a specificity of 87.1%.203 There is a theoretical risk of tumor seeding with EUS-FNA. One study of 191 patients who were planned for liver transplantation for cholangiocarcinoma reported rates of seeding of up to 83% in patients who had undergone transperitoneal FNA (either percutaneously or via EUS) of hilar strictures compared with 8% in those who did not undergo FNA.204 This study, however, only had three out of 16 FNAs that were performed via EUS as opposed to percutaneously, and separate analysis of tumor seeding in each group was not performed. Additionally, more recent studies seem to temper this concern and have not demonstrated any difference in overall (HR 1.36; 95% CI, 0.93, 1.99, P 5 .112) or progression-free survival (HR 0.98, 95% CI 0.63–1.53, P 5 .944) or the development of tumor seeding in patients who underwent EUS FNA compared with those who did not.205,206 Because of potential risk of tumor seeding, however, EUS-FNA can disqualify patients from liver transplantation for perihilar cholangiocarcinoma in some centers and as such should be performed cautiously and after multidisciplinary discussion on patients who are otherwise potential transplant candidates.207–209

Endoscopic Intraductal Ultrasound The evolution of EUS has led to the development of smallcaliber ultrasound probes (2.9 mm or less in diameter) for biliary endosonography. These IDUS mini probes are introduced through the accessory channel of the duodenoscope over a guidewire and advanced into the bile duct. IDUS operates at higher frequencies (12–30 Mhz), with penetration of 2 cm at higher image resolution (0.07–0.18 mm) compared with standard EUS.210 The bile duct appears as three layers on IDUS. The innermost hyperechoic layer corresponds to the mucosa and bile interface. The middle hypoechoic layer corresponds to the discontinuous fibromuscular layer, whereas the outermost hyperechoic layer represents the subserosal fat plane.210 IDUS has been used for the evaluation of suspected choledocholithiasis. It has been found to have a sensitivity for detecting choledocholithiasis of 95%, which is superior to either MRCP (80%) or ERCP (90%).211 IDUS was additionally more sensitive at detecting stones less than 8 mm in size in the setting of CBD greater than 12 mm compared with ERCP. As such, it has been suggested that IDUS may be most useful in patients who have a high likelihood of choledocholithiasis but a negative ERCP.212 With the high diagnostic accuracy of EUS (sensitivity of 89% and specificity of 94%) for detecting choledocholithiasis in patients with suspected choledocholithiasis, however, the role of IDUS in the diagnostic algorithm of biliary stone disease remains to be determined.83,210 Several studies have reported IDUS findings in strictures concerning for biliary malignancy. These criteria include the presence of localized wall thickening, polypoid lesions, sessile lesions, intraductal infiltrating lesions, and size greater than 10 mm.213–215 The sensitivity of predicting malignancy in bile duct strictures has been found to be greater than 90%

451

and can be more sensitive than EUS, especially in more proximal strictures.210,214,216 Furthermore, IDUS has been shown to improve local tumor staging for cholangiocarcinomas in various studies, even compared with standard EUS.217 Conversely, the restricted depth of penetration with IDUS and the inability to perform FNA significantly limits its utility for assessing advanced tumor extension and nodal and metastatic staging. IDUS is a promising advanced endoscopic imaging modality that permits high-resolution images of the bile system. This advantage is hindered by the limited depth of penetration and ability to examine more distal sites. Further studies are needed to validate its place as an adjunct imaging tool to ERCP and EUS.195

Confocal Laser Endomicroscopy Confocal endomicroscopy (CLE) allows real-time highresolution evaluation of gastrointestinal mucosal histology in vivo. Imaging is achieved by the projection of a low-power laser light passed through a confocal aperture. The focused beam targeted on a specific layer of tissue is then captured by a photodetection device and transformed into electrical signals processed into grayscale images.218 Because CLE relies on tissue fluorescence, intravenous fluorescein dye (5–10 mL of 10% fluorescein) is administered to highlight tissue structures (individual cell structures, vasculature) before imaging. The lack of contrast uptake by neoplastic tissue results in a contrasted dark appearance compared with adjacent normal structures.195 There are two currently available CLE systems: endoscopebased CLE (eCLE) and probe-based CLE (pCLE). The former is too large because the CLE is integrated in the tip of the endoscope, and thus biliary examination is generally performed with pCLE probes that can be inserted through the accessory channel of the duodenoscope. The laser (488 nm, blue light) is transmitted through thousands of optimal fibers within the probe (the cholangioflex probe is 9 mm in diameter), and subsequent confocal image data is collected at a frame rate of 12 frames/ second, with a limited field of vision of 325 mm. pCLE can be challenging because optimal imaging requires significant probe and patient stability. The indications for pCLE in biliary disease have not been established, but studies have suggested a potential role in the evaluation of biliary strictures suspicious for malignancy. CLE has been found to have a pooled sensitivity of 90% and specificity of 72% to decipher between benign and malignant strictures in the evaluation of indeterminate biliary stenosis in a metaanalysis of eight prospective studies.219 The Miami criteria has been developed to identify malignant strictures and include findings of thick white (.20 mm) and dark bands (.40 mm), epithelial structures, and dark clumps. A combination of two of these findings was found to have a sensitivity of 97% and specificity of 33% for diagnosing malignancy.220 Additionally, the Paris criteria was developed and validated for identification of inflammatory strictures. The criteria for this includes multiple thin white bands, dark granular pattern with scales, increased space between scales, and thickened reticular structures. When the Paris criteria was retrospectively applied to videos of the same strictures used to previously validate the Miami criteria, it was found to have a sensitivity of 81% and specificity of 83.3% for diagnosing malignant strictures, thereby

452

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

reducing false positives.221 A more recent randomized prospective trial found that when using a combined Miami and Paris classification, real-time pCLE had a sensitivity of 89% and specificity of 71% when compared with ERCP alone. When combined with tissue sampling, the sensitivity of pCLE was 89% with a specificity of 88%.222 Despite these promising preliminary results, there have been discrepancies in the interpretation of pCLE findings between

endoscopists for both benign and malignant pancreaticobiliary lesions, which indicates the need for dedicated training.223 Overall, pCLE is a promising technique for evaluating indeterminate biliary strictures, but further studies are needed to improve accuracy and interobserver agreement. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

452.e1

REFERENCES 1. Kethu SR, Adler DG, Conway JD, et al. ERCP cannulation and sphincterotomy devices. Gastrointest Endosc. 2010;71(3):435-445. 2. Somogyi L, Chuttani R, Croffie J, et al. Guidewires for use in GI endoscopy. Gastrointest Endosc. 2007;65(4):571-576. 3. Singhvi G, Dea SK. Guidewires in ERCP. Gastrointest Endosc. 2013;77(6):938-940. 4. Testoni PA, Mariani A, Aabakken L, et al. Papillary cannulation and sphincterotomy techniques at ERCP: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. 2016;48(7):657-683. 5. Bassi M, Luigiano C, Ghersi S, et al. A multicenter randomized trial comparing the use of touch versus no-touch guidewire technique for deep biliary cannulation: the TNT study. Gastrointest Endosc. 2018;87(1):196-201. 6. Tse F,Yuan Y, Moayyedi P, Leontiadis GI. Guidewire-assisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Cochrane Database Syst Rev. 2012;12(12):CD009662. 7. Liao WC, Angsuwatcharakon P, Isayama H, et al. International consensus recommendations for difficult biliary access. Gastrointest Endosc. 2017;85(2):295-304. 8. Sasahira N, Kawakami H, Isayama H, et al. Early use of doubleguidewire technique to facilitate selective bile duct cannulation: the multicenter randomized controlled EDUCATION trial. Endoscopy. 2015;47(5):421-429. 9. Tse F, Yuan Y, Bukhari M, Leontiadis GI, Moayyedi P, Barkun A. Pancreatic duct guidewire placement for biliary cannulation for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Cochrane Database Syst Rev. 2016;16(5): CD010571. 10. Navaneethan U, Konjeti R, Venkatesh PG, Sanaka MR, Parsi MA. Early precut sphincterotomy and the risk of endoscopic retrograde cholangiopancreatography related complications: an updated metaanalysis. World J Gastrointest Endosc. 2014;6(5):200-208. 11. Saritas U, Ustundag Y, Harmandar F. Precut sphincterotomy: a reliable salvage for difficult biliary cannulation. World J Gastroenterol. 2013;19(1):1-7. 12. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for postercp pancreatitis: a prospective, multicenter study. Gastrointest Endosc. 2001;54(4):425-434. 13. Masci E, Toti G, Mariani A, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96(2):417-423. 14. Bailey AA, Bourke MJ, Kaffes AJ, Byth K, Lee EY, Williams SJ. Needle-knife sphincterotomy: factors predicting its use and the relationship with post-ERCP pancreatitis (with video). Gastrointest Endosc. 2010;71(2):266-271. 15. Manes G, Di Giorgio P, Repici A, MacArri G, Ardizzone S, Porro GB. An analysis of the factors associated with the development of complications in patients undergoing precut sphincterotomy: a prospective, controlled, randomized, multicenter study. Am J Gastroenterol. 2009;104(10):2412-2417. 16. Sundaralingam P, Masson P, Bourke MJ. Early precut sphincterotomy does not increase risk during endoscopic retrograde cholangiopancreatography in patients with difficult biliary access: a metaanalysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2015;13(10):1722-1729.e2. 17. Mariani A, Di Leo M, Giardullo N, et al. Early precut sphincterotomy for difficult biliary access to reduce post-ERCP pancreatitis: a randomized trial. Endoscopy. 2016;48(6):530-555. 18. Choudhary A, Winn J, Siddique S, et al. Effect of precut sphincterotomy on post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and meta-analysis. World J Gastroenterol. 2014;20(14):4093-4101. 19. Fiocca F, Cereatti F, Maselli R, Ceci V, Donatelli G, Fanello G. Early ‘shallow’ needle-knife papillotomy and guidewire cannulation: an effective and safe approach to difficult papilla. Therap Adv Gastroenterol. 2015;8(3):114-120. 20. Kalayci MU, Altintas T. Can early “shallow” needle-knife papillotomy be the first choice in ERCP? Surg Laparosc Endosc Percutan Tech. 2020;30(2):180-182. 21. Goff JS. Common bile duct pre-cut sphincterotomy: transpancreatic sphincter approach. Gastrointest Endosc. 1995;41(5):502-505.

22. Pécsi D, Farkas N, Hegyi P, et al. Transpancreatic sphincterotomy has a higher cannulation success rate than needle-knife precut papillotomy – a meta-analysis. Endoscopy. 2017;49(9):874-887. 23. Pécsi D, Farkas N, Hegyi P, et al. Transpancreatic sphincterotomy is effective and safe in expert hands on the short term. Dig Dis Sci. 2019;64(9):2429-2444. 24. Wen J, Li T, Lu Y, Bie LK, Gong B. Comparison of efficacy and safety of transpancreatic septotomy, needle-knife fistulotomy or both based on biliary cannulation unintentional pancreatic access and papillary morphology. Hepatobiliary Pancreat Dis Int. 2019;18(1):73-78. 25. Skinner M, Popa D, Neumann H, Wilcox CM, Mönkemüller K. ERCP with the overtube-assisted enteroscopy technique: a systematic review. Endoscopy. 2014;46(7):560-572. 26. Nakahara K, Okuse C, Suetani K, et al. Endoscopic retrograde cholangiography using an anterior oblique-viewing endoscope in patients with altered gastrointestinal anatomy. Dig Dis Sci. 2015; 60(4):944-950. 27. Fujita K, Myojo S, Yoshida S, Kawase Y. Endoscopic sphincterotomy using a pull-type sphincterotome with an attached stabilizer in patients with Billroth II gastrectomy. Endoscopy. 2011;43(suppl 2): E47-E48. 28. Park SB, Kim HW, Kang DH, et al. Sphincterotomy by triple lumen needle knife using guide wire in patients with Billroth II gastrectomy. World J Gastroenterol. 2013;19(48):9405-9409. 29. Maluf-Filho F, Kumar A, Ferreria de Souza T, et al. Rotatable sphincterotome facilitates bile duct cannulation in patients with altered ampullary anatomy. Gastroenterol Hepatol (N Y). 2008;4(1): 59-62. 30. Bove V, Tringali A, Familiari P, et al. ERCP in patients with prior Billroth II gastrectomy: report of 30 years’ experience. Endoscopy. 2015;47(7):611-616. 31. Chauhan SS, Manfredi MA, Abu Dayyeh BK, et al. Enteroscopy. Gastrointest Endosc. 2015;82(6):975-990. 32. Park TY, Kang JS, Song TJ, et al. Outcomes of ERCP in Billroth II gastrectomy patients. Gastrointest Endosc. 2016;83(6):1193-1201. 33. Park TY, Bang CS, Choi SH, et al. Forward-viewing endoscope for ERCP in patients with Billroth II gastrectomy: a systematic review and meta-analysis. Surg Endosc. 2018;32(11):4598-4613. 34. Enestvedt BK, Kothari S, Pannala R, et al. Devices and techniques for ERCP in the surgically altered GI tract. Gastrointest Endosc. 2016;83(6):1061-1075. 35. Wright BE, Cass OW, Freeman ML. ERCP in patients with longlimb Roux-en-Y gastrojejunostomy and intact papilla. Gastrointest Endosc. 2002;56(2):225-232. 36. Ali MF, Modayil R, Gurram KC, Brathwaite CEM, Friedel D, Stavropoulos SN. Spiral enteroscopy–assisted ERCP in bariatriclength Roux-en-Y anatomy: a large single-center series and review of the literature (with video). Gastrointest Endosc. 2018;87(5): 1241–1247. 37. Shah RJ, Smolkin M, Yen R, et al. A multicenter, U.S. experience of single-balloon, double-balloon, and rotational overtube-assisted enteroscopy ERCP in patients with surgically altered pancreaticobiliary anatomy (with video). Gastrointest Endosc. 2013;77(4):593-600. 38. Inamdar S, Slattery E, Sejpal DV, et al. Systematic review and meta-analysis of single-balloon enteroscopy-assisted ERCP in patients with surgically altered GI anatomy. Gastrointest Endosc. 2015; 82(1):9-19. 39. Liu K, Joshi V, Saxena P, Kaffes AJ. Predictors of success for double balloon-assisted endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y anastomosis. Dig Endosc. 2017;29(2): 190-197. 40. De Koning M, Moreels TG. Comparison of double-balloon and single-balloon enteroscope for therapeutic endoscopic retrograde cholangiography after Roux-en-Y small bowel surgery. BMC Gastroenterol. 2016;16(1):98. 41. Aiolfi A, Asti E, Rausa E, Bernardi D, Bonitta G, Bonavina L. Trans-Gastric ERCP after Roux-en-Y gastric bypass: systematic review and meta-analysis. Obes Surg. 2018;28(9):2836-2843. 42. Abbas AM, Strong AT, Diehl DL, et al. Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Rouxen-Y gastric bypass. Gastrointest Endosc. 2018;87(4):1031-1039. 43. Mohammad B, Richard MN, Pandit A, Zuccala K, Brandwein S. Outcomes of laparoscopic-assisted ERCP in gastric bypass patients at a community hospital center. Surg Endosc. 2020;34(12): 5259-5264.

452.e2 44. Banerjee N, Parepally M, Byrne TK, Pullatt RC, Coté GA, Elmunzer BJ. Systematic review of transgastric ERCP in Roux-en-Y gastric bypass patients. Surg Obes Relat Dis. 2017;13(7):1236-1242. 45. Bowman E, Greenberg J, Garren M, et al. Laparoscopic-assisted ERCP and EUS in patients with prior Roux-en-Y gastric bypass surgery: a dual-center case series experience. Surg Endosc. 2016; 30(10):4647-4652. 46. Grimes KL, Maciel VH, Mata W, Arevalo G, Singh K, Arregui ME. Complications of laparoscopic transgastric ERCP in patients with Roux-en-Y gastric bypass. Surg Endosc. 2015;29(7):1753-1759. 47. Habenicht Yancey K, McCormack LK, McNatt SS, Powell MS, Fernandez AZ, Westcott CJ. Laparoscopic-assisted transgastric ERCP: a single-institution experience. J Obes. 2018;2018:8275965. 48. Frederiksen NA, Tveskov L, Helgstrand F, Naver L, Floyd A. Treatment of common bile duct stones in gastric bypass patients with laparoscopic transgastric endoscopic retrograde cholangiopancreatography. Obes Surg. 2017;27(6):1409-1413. 49. Schreiner MA, Chang L, Gluck M, et al. Laparoscopy-assisted versus balloon enteroscopy-assisted ERCP in bariatric post-Roux-en-Y gastric bypass patients. Gastrointest Endosc. 2012;75(4):748-756. 50. Choi EK, Chiorean MV, Coté GA, et al. ERCP via gastrostomy vs. double balloon enteroscopy in patients with prior bariatric Rouxen-Y gastric bypass surgery. Surg Endosc. 2013;27(8):2894-2899. 51. Baron TH, Song LM, Ferreira LE, Smyrk TC. Novel approach to therapeutic ERCP after long-limb Roux-en-Y gastric bypass surgery using transgastric self-expandable metal stents: experimental outcomes and first human case study (with videos). Gastrointest Endosc. 2012;75(6):1258-1263. 52. Law R, Wong Kee Song LM, Petersen BT, Baron TH. Singlesession ERCP in patients with previous Roux-en-Y gastric bypass using percutaneous-assisted transprosthetic endoscopic therapy: a case series. Endoscopy. 2013;45(8):671-675. 53. Ngamruengphong S, Nieto J, Kunda R, et al. Endoscopic ultrasound-guided creation of a transgastric fistula for the management of hepatobiliary disease in patients with Roux-en-Y gastric bypass. Endoscopy. 2017;49(6):549-552. 54. Dhindsa BS, Dhaliwal A, Mohan BP, et al. EDGE in Roux-en-Y gastric bypass: How does it compare to laparoscopy-assisted and balloon enteroscopy ERCP: a systematic review and meta-analysis. Endosc Int Open. 2020;8(2):E163-E171. 55. Irani S, Yang J, Khashab MA. Mitigating lumen-apposing metal stent dislodgment and allowing safe, single-stage EUS-directed transgastric ERCP. VideoGIE. 2018;3(10):322-324. 56. Khan MA, Baron TH, Kamal F, et al. Efficacy of self-expandable metal stents in management of benign biliary strictures and comparison with multiple plastic stents: a meta-analysis. Endoscopy. 2017;49(7):682-694. 57. Kedia P, Tyberg A, Kumta NA, et al. EUS-directed transgastric ERCP for Roux-en-Y gastric bypass anatomy: a minimally invasive approach. Gastrointest Endosc. 2015;82(3):560-565. 58. Tyberg A, Nieto J, Salgado S, et al. Endoscopic ultrasound (EUS)directed transgastric endoscopic retrograde cholangiopancreatography or EUS: mid-term analysis of an emerging procedure. Clin Endosc. 2017;50(2):185-190. 59. James TW, Baron TH. Endoscopic ultrasound-directed transgastric ERCP (EDGE): a single-center US experience with follow-up data on fistula closure. Obes Surg. 2019;29(2):451-456. 60. Wang TJ, Thompson CC, Ryou M. Gastric access temporary for endoscopy (GATE): a proposed algorithm for EUS-directed transgastric ERCP in gastric bypass patients. Surg Endosc. 2019;33(6): 2024-2033. 61. Kedia P, Tarnasky PR, Nieto J, et al. EUS-directed Transgastric ERCP (EDGE) versus Laparoscopy-assisted ERCP (LA-ERCP) for Roux-en-Y Gastric Bypass (RYGB) Anatomy. J Clin Gastroenterol. 2019;53(4):304-308. 62. Bukhari M, Kowalski T, Nieto J, et al. An international, multicenter, comparative trial of EUS-guided gastrogastrostomy-assisted ERCP versus enteroscopy-assisted ERCP in patients with Rouxen-Y gastric bypass anatomy. Gastrointest Endosc. 2018;88(3): 486-494. 63. Ichkhanian Y, Yang J, James TW, et al. EUS-directed transenteric ERCP in non–Roux-en-Y gastric bypass surgical anatomy patients (with video). Gastrointest Endosc. 2020;91(5):1188-1194.e2. 64. Keswani RN, Qumseya BJ, O’Dwyer LC, Wani S. Association between endoscopist and center endoscopic retrograde cholangiopancreatography volume with procedure success and adverse outcomes:

a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2017;15(12):1866-1875.e3. 65. Sharaiha RZ, Khan MA, Kamal F, et al. Efficacy and safety of EUS-guided biliary drainage in comparison with percutaneous biliary drainage when ERCP fails: a systematic review and metaanalysis. Gastrointest Endosc. 2017;85(5):904-914. 66. Guo J, Giovannini M, Sahai AV, et al. A multi-institution consensus on how to perform EUS-guided biliary drainage for malignant biliary obstruction. Endosc Ultrasound. 2018;7(6):356-365. 67. Paik WH, Lee TH, Park DH, et al. EUS-guided biliary drainage versus ERCP for the primary palliation of malignant biliary obstruction: a multicenter randomized clinical trial. Am J Gastroenterol. 2018;113(7):987-997. 68. Park JK, Woo YS, Noh DH, et al. Efficacy of EUS-guided and ERCP-guided biliary drainage for malignant biliary obstruction: prospective randomized controlled study. Gastrointest Endosc. 2018;88(2):277-282. 69. Hathorn KE, Bazarbashi AN, Sack JS, et al. EUS-guided biliary drainage is equivalent to ERCP for primary treatment of malignant distal biliary obstruction: a systematic review and meta-analysis. Endosc Int Open. 2019;7(11):E1432-E1441. 70. Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage of obstructed biliary and pancreatic ducts: report of 6 cases. Gastrointest Endosc. 2004;59(1):100-107. 71. Iwashita T, Yasuda I, Mukai T, et al. EUS-guided rendezvous for difficult biliary cannulation using a standardized algorithm: a multicenter prospective pilot study (with videos). Gastrointest Endosc. 2016;83(2):394-400. 72. Shiomi H, Yamao K, Hoki N, et al. Endoscopic ultrasound-guided rendezvous technique for failed biliary cannulation in benign and resectable malignant biliary disorders. Dig Dis Sci. 2018;63(3):787-796. 73. Martínez B, Martínez J, Casellas JA, Aparicio JR. Endoscopic ultrasound-guided rendezvous in benign biliary or pancreatic disorders with a 22-gauge needle and a 0.018-inch guidewire. Endosc Int Open. 2019;7(8):E1038-E1043. 74. Ardengh JC, Lopes CV, Kemp R, Dos Santos JS. Different options of endosonography-guided biliary drainage after endoscopic retrograde cholangio-pancreatography failure. World J Gastrointest Endosc. 2018;10(5):99-108. 75. Iwashita T, Doi S, Yasuda I. Endoscopic ultrasound-guided biliary drainage: a review. Clin J Gastroenterol. 2014;7(2):94-102. 76. Giovannini M, Moutardier V, Pesenti C, Bories E, Lelong B, Delpero JR. Endoscopic ultrasound-guided bilioduodenal anastomosis: a new technique for biliary drainage. Endoscopy. 2001; 33(10):898-900. 77. Park DH, Moon SH, Lee SS, Seo DW, Lee SK, Kim MH. EUSguided biliary drainage with one-step placement of newly designed fully covered metal stent for malignant biliary obstruction: a prospective feasibility study. Gastrointest Endosc. 2009;104(9): 2168-2174. 78. Itoi T, Binmoeller KF. EUS-guided choledochoduodenostomy by using a biflanged lumen-apposing metal stent. Gastrointest Endosc. 2014;79(5):715. 79. Jacques J, Privat J, Pinard F, et al. Endoscopic ultrasound-guided choledochoduodenostomy with electrocautery-enhanced lumenapposing stents: a retrospective analysis. Endoscopy. 2019;51(6):540-547. 80. Anderloni A, Fugazza A, Troncone E, et al. Single-stage EUSguided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction. Gastrointest Endosc. 2019;89(1):69-76. 81. Tsuchiya T, Teoh AYB, Itoi T, et al. Long-term outcomes of EUSguided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction: a prospective multicenter study. Gastrointest Endosc. 2018;87(4):1138-1146. 82. Peery AF, Crockett SD, Murphy CC, et al. Burden and Cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019;156(1):254-272.e11. 83. Buxbaum JL, Abbas Fehmi SM, Sultan S, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89(6):1075-1105.e15. 84. Narula VK, Fung EC, Overby DW, Richardson W, Stefanidis D, SAGES Guidelines Committee. Clinical spotlight review for the management of choledocholithiasis. Surg Endosc. 2020;34(4):1482-1491. 85. Williams E, Beckingham I, El Sayed G, et al. Updated guideline on the management of common bile duct stones (CBDS). Gut. 2017;66(5):765-782.

452.e3 86. Li DF, Yang MF, Chang X, et al. Endocut versus conventional blended electrosurgical current for endoscopic biliary sphincterotomy: a meta-analysis of complications. Dig Dis Sci. 2019;64(8): 2088-2094. 87. Haseeb A, Freeman ML. Endoscopic papillary large balloon dilation versus endoscopic sphincterotomy for treatment of bile duct stones. Curr Treat Options Gastroenterol. 2019;17(2):221-230. 88. Shen YH, Yang LQ, Yao YL, et al. Dilation time in endoscopic papillary balloon dilation for common bile duct stones. Surg Laparosc Endosc Percutan Tech. 2017;27(5):351-355. 89. Liao WC, Lee CT, Chang CY, et al. Randomized trial of 1-minute versus 5-minute endoscopic balloon dilation for extraction of bile duct stones. Gastrointest Endosc. 2010;72(6):1154-1162. 90. Aiura K, Kitagawa Y. Current status of endoscopic papillary balloon dilation for the treatment of bile duct stones. J Hepatobiliary Pancreat Sci. 2011;18(3):339-345. 91. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc. 2003;57(2):156-159. 92. Jeong S, Ki SH, Lee DH, et al. Endoscopic large-balloon sphincteroplasty without preceding sphincterotomy for the removal of large bile duct stones: a preliminary study. Gastrointest Endosc. 2009;70(5):915-922. 93. Kim TH, Kim JH, Seo DW, et al. International consensus guidelines for endoscopic papillary large-balloon dilation. Gastrointest Endosc. 2016;83(1):37-47. 94. Park TY, Song TJ. Recent advances in endoscopic retrograde cholangiopancreatography in Billroth II gastrectomy patients: a systematic review. World J Gastroenterol. 2019;25(24):3091-3107. 95. Matsubayashi CO, Ribeiro IB, De Moura DTH, et al. Is endoscopic balloon dilation still associated with higher rates of pancreatitis?: A systematic review and meta-analysis. Pancreas. 2020; 49(2):158-174. 96. Tringali A, Rota M, Rossi M, Hassan C, Adler DG, Mutignani M. A cumulative meta-analysis of endoscopic papillary balloon dilation versus endoscopic sphincterotomy for removal of common bile duct stones. Endoscopy. 2019;51(6):548-559. 97. Kogure H, Kawahata S, Mukai T, et al. Multicenter randomized trial of endoscopic papillary large balloon dilation without sphincterotomy versus endoscopic sphincterotomy for removal of bile duct stones: MARVELOUS trial. Endoscopy. 2020;52(9): 736-744. 98. Sethi A, Tyberg A, Slivka A, Adler DG, Desai AP, Sejpal DV, Pleskow DK, Bertani H, Gan SI, Shah R, Arnelo U, Tarnasky PR, Banerjee S, Itoi T, Moon JH, Kim DC, Gaidhane M, Raijman I, Peterson BT, Gress FG, Kahaleh M. Digital Single-operator Cholangioscopy (DSOC) Improves Interobserver Agreement (IOA) and Accuracy for Evaluation of Indeterminate Biliary Strictures: The Monaco Classification. J Clin Gastroenterol. 2022 Feb 1;56(2):e94-e97. doi: 10.1097/ MCG.0000000000001321. 99. Dong SQ, Singh TP, Zhao Q, Li JJ, Wang HL. Sphincterotomy plus balloon dilation versus sphincterotomy alone for choledocholithiasis: a meta-analysis. Endoscopy. 2019;51(8):763-771. 100. Manes G, Paspatis G, Aabakken L, et al. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2019;51(5):472-491. 101. Ishiwatari H, Kawakami H, Hisai H, et al. Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy. 2016;48(4):350-357. 102. Ozawa N, Yasuda I, Doi S, et al. Prospective randomized study of endoscopic biliary stone extraction using either a basket or a balloon catheter: the BasketBall study. J Gastroenterol. 2017; 52(5):623-630. 103. Doshi B, Yasuda I, Ryozawa S, Lee GH. Current endoscopic strategies for managing large bile duct stones. Dig Endosc. 2018; 30(S1):59-66. 104. ASGE Technology Committee, Watson RR, Parsi MA, et al. Biliary and pancreatic lithotripsy devices. VideoGIE. 2018;3(11):329-338. 105. Angsuwatcharakon P, Kulpatcharapong S, Ridtitid W, et al. Digital cholangioscopy-guided laser versus mechanical lithotripsy for large bile duct stone removal after failed papillary large-balloon dilation: a randomized study. Endoscopy. 2019; 51(11):1066-1073. 106. Maydeo AP, Rerknimitr R, Lau JY, et al. Cholangioscopy-guided lithotripsy for difficult bile duct stone clearance in a single session

of ERCP: results from a large multinational registry demonstrate high success rates. Endoscopy. 2019;51(10):922-929. 107. Buxbaum J, Sahakian A, Ko C, et al. Randomized trial of cholangioscopy-guided laser lithotripsy versus conventional therapy for large bile duct stones (with videos). Gastrointest Endosc. 2018; 87(4):1050-1060. 108. Veld JV, Van Huijgevoort NCM, Boermeester MA, et al. A systematic review of advanced endoscopy-assisted lithotripsy for retained biliary tract stones: laser, electrohydraulic or extracorporeal shock wave. Endoscopy. 2018;50(9):896-909. 109. Brewer Gutierrez OI, Bekkali NLH, Raijman I, et al. Efficacy and safety of digital single-operator cholangioscopy for difficult biliary stones. Clin Gastroenterol Hepatol. 2018;16(6):918-926. 110. Bang JY, Sutton B, Navaneethan U, Hawes R, Varadarajulu S. Efficacy of single-operator cholangioscopy-guided lithotripsy compared with large balloon sphincteroplasty in management of difficult bile duct stones in a randomized trial. Clin Gastroenterol Hepatol. 2020;18(10):2349-2356.e3. 111. Cecinato P, Fuccio L, Azzaroli F, et al. Extracorporeal shock wave lithotripsy for difficult common bile duct stones: a comparison between 2 different lithotripters in a large cohort of patients. Gastrointest Endosc. 2015;81(2):402-409. 112. Muratori R, Mandolesi D, Pierantoni C, Festi D, Colecchia A, Mazzella G, Bazzoli F, Azzaroli F. Ductal stones recurrence after extracorporeal shock wave lithotripsy for difficult common bile duct stones: Predictive factors. Dig Liver Dis. 2017 Oct;49(10):11281132. doi: 10.1016/j.dld.2017.05.010. Epub 2017 May 23. 113. Pfau PR, Pleskow DK, Banerjee S, et al. Pancreatic and biliary stents. Gastrointest Endosc. 2013;77(3):319-327. 114. Kwon CI, Lehman GA. Mechanisms of biliary plastic stent occlusion and efforts at prevention. Clin Endosc. 2016;49(2):139146. 115. Costamagna G, Boškoski I. Current treatment of benign biliary strictures. Ann Gastroenterol. 2013;26(1):37-40. 116. Chathadi KV, Chandrasekhara V, Acosta RD, et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015;81(4):795-803. 117. Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc. 2017;86(1):44-58. 118. Tomoda T, Kato H, Miyamoto K, et al. Comparison between endoscopic biliary stenting combined with balloon dilation and balloon dilation alone for the treatment of benign hepaticojejunostomy anastomotic stricture. J Gastrointest Surg. 2019;24(6): 1352-1358. 119. Rupp C, Hippchen T, Bruckner T, et al. Effect of scheduled endoscopic dilatation of dominant strictures on outcome in patients with primary sclerosing cholangitis. Gut. 2019;68(12):2170-2178. 120. Ponsioen CY, Arnelo U, Bergquist A, et al. No superiority of stents vs balloon dilatation for dominant strictures in patients with primary sclerosing cholangitis. Gastroenterology. 2018;155(3): 752-759. 121. Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – updated august 2018. Endoscopy. 2019;51(2):179-193. 122. Suk KT, Kim HS, Kim JW, et al. Risk factors for cholecystitis after metal stent placement in malignant biliary obstruction. Gastrointest Endosc. 2006;64(4):522-529. 123. Fumex F, Coumaros D, Napoleon B, et al. Similar performance but higher cholecystitis rate with covered biliary stents: results from a prospective multicenter evaluation. Endoscopy. 2006; 38(8):787-792. 124. Jang S, Stevens T, Parsi M, et al. Association of covered metallic stents with cholecystitis and stent migration in malignant biliary stricture. Gastrointest Endosc. 2018;87(4):1061-1070. 125. Park DH, Kim M, Choi JS, et al. Covered versus uncovered wallstent for malignant extrahepatic biliary obstruction: a cohort comparative analysis. Clin Gastroenterol Hepatol. 2006;4(6): 790-796. 126. Kahaleh M, Brijbassie A, Sethi A, et al. Multicenter trial evaluating the use of covered self-expanding metal stents in benign biliary strictures: Time to revisit our therapeutic options? J Clin Gastroenterol. 2013;47(8):695-699. 127. Haapamäki C, Kylänpää L, Udd M, et al. Randomized multicenter study of multiple plastic stents vscovered self-expandable

452.e4 metallic stent in the treatment of biliary stricture in chronic pancreatitis. Endoscopy. 2015;47(7):605-610. 128. Coté GA, Slivka A, Tarnasky P, et al. Effect of covered metallic stents compared with plastic stents on benign biliary stricture resolution: a randomized clinical trial. JAMA. 2016;315(12):1250-1257. 129. Devière J, Reddy DN, Püspök A, et al. Successful management of benign biliary strictures with fully covered self-expanding metal stents. Gastroenterology. 2014;147(2):385-395. 130. Saxena P, Diehl DL, Kumbhari V, et al. A US multicenter study of safety and efficacy of fully covered self-expandable metallic stents in benign extrahepatic biliary strictures. Dig Dis Sci. 2015; 60(11):3442-3448. 131. Larghi A, Tringali A, Rimbas¸ M, et al. Endoscopic management of benign biliary strictures after liver transplantation. Liver Transplant. 2019;25(2):323-335. 132. Martins FP, De Paulo GA, Contini MLC, Ferrari AP. Metal versus plastic stents for anastomotic biliary strictures after liver transplantation: a randomized controlled trial. Gastrointest Endosc. 2018;87(1):131.e1-131.e13. 133. Tal AO, Finkelmeier F, Filmann N, et al. Multiple plastic stents versus covered metal stent for treatment of anastomotic biliary strictures after liver transplantation: a prospective, randomized, multicenter trial. Gastrointest Endosc. 2017;86(6):1038-1045. 134. Zhang X, Wang X, Wang L, Tang R, Dong J. Effect of covered self-expanding metal stents compared with multiple plastic stents on benign biliary stricture: a meta-analysis. Medicine (Baltimore). 2018;97(36):e12039. 135. Park JS, Lee SS, Song TJ, et al. Long-term outcomes of covered self-expandable metal stents for treating benign biliary strictures. Endoscopy. 2016;48(5):447. 136. Tol JAMG, Van Hooft JE, Timmer R, et al. Metal or plastic stents for preoperative biliary drainage in resectable pancreatic cancer. Gut. 2016;65(12):1981-1987. 137. Shaib Y, Rahal MA, Rammal MO, Mailhac A, Tamim H. Preoperative biliary drainage for malignant biliary obstruction: results from a national database. J Hepatobiliary Pancreat Sci. 2017;24(11):637-642. 138. Lee PJ, Podugu A, Wu D, Lee AC, Stevens T, Windsor JA. Preoperative biliary drainage in resectable pancreatic cancer: a systematic review and network meta-analysis. HPB. 2018;20(6):477-486. 139. Scheufele F, Schorn S, Demir IE, et al. Preoperative biliary stenting versus operation first in jaundiced patients due to malignant lesions in the pancreatic head: a meta-analysis of current literature. Surgery. 2017;161(4):939-950. 140. Dumonceau JM, Tringali A, Papanikolaou IS, et al. Endoscopic biliary stenting: Indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline – updated october 2017. Endoscopy. 2018;50(9):910-930. 141. Lutz MP, Zalcberg JR, Ducreux M, et al. 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. Eur J Cancer. 2017;79:41-49. 142. Kubota K, Sato T, Watanabe S, et al. Covered self-expandable metal stent deployment promises safe neoadjuvant chemoradiation therapy in patients with borderline resectable pancreatic head cancer. Dig Endosc. 2014;26(1):77-86. 143. Seo DW, Sherman S, Dua KS, et al. Covered and uncovered biliary metal stents provide similar relief of biliary obstruction during neoadjuvant therapy in pancreatic cancer: a randomized trial. Gastrointest Endosc. 2019;90(4):602-612.e4. 144. Nakamura K, Sho M, Akahori T, et al. A comparison between plastic and metallic biliary stent placement in patients receiving preoperative neoadjuvant chemoradiotherapy for resectable pancreatic cancer. World J Surg. 2019;43(2):642-648. 145. Moss AC, Morris E, Leyden J, MacMathuna P. Malignant distal biliary obstruction: a systematic review and meta-analysis of endoscopic and surgical bypass results. Cancer Treat Rev. 2007;33(2):213-221. 146. Almadi MA, Barkun A, Martel M. Plastic vs. self-expandable metal stents for palliation in malignant biliary obstruction: a series of meta-analyses. Am J Gastroenterol. 2017;112(2):260-273. 147. Tringali A, Hassan C, Rota M, Rossi M, Mutignani M, Aabakken L. Covered vsuncovered self-expandable metal stents for malignant distal biliary strictures: a systematic review and meta-analysis. Endoscopy. 2018;50(6):631-641. 148. Bismuth H, Majno PE. Biliary Strictures: classification based on the principles of surgical treatment. World J Surg. 2001;25(10): 1241-1244.

149. Vienne A, Hobeika E, Gouya H, et al. Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment. Gastrointest Endosc. 2010; 72(4):728-735. 150. Kerdsirichairat T, Arain MA, Attam R, et al. Endoscopic drainage of .50% of liver in malignant hilar biliary obstruction using metallic or fenestrated plastic stents. Clin Transl Gastroenterol. 2017;8(8):e115. 151. Takahashi E, Fukasawa M, Sato T, et al. Biliary drainage strategy of unresectable malignant hilar strictures by computed tomography volumetry. World J Gastroenterol. 2015;21(16):4946-4953. 152. Xia MX, Cai XB, Pan YL, et al. Optimal stent placement strategy for malignant hilar biliary obstruction: a large multicenter parallel study. Gastrointest Endosc. 2020;91(5):1117-1128.e9. 153. Lee TH, Kim TH, Moon JH, et al. Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video). Gastrointest Endosc. 2017;86(5):817-827. 154. Ashat M, Arora S, Klair JS, Childs CA, Murali AR, Johlin FC. Bilateral vs unilateral placement of metal stents for inoperable high-grade hilar biliary strictures: a systemic review and metaanalysis. World J Gastroenterol. 2019;25(34):5210-5219. 155. Staub J, Siddiqui A, Murphy M, et al. Unilateral versus bilateral hilar stents for the treatment of cholangiocarcinoma: a multicenter international study. Ann Gastroenterol. 2020;33(2): 202-209. 156. Sangchan A, Kongkasame W, Pugkhem A, Jenwitheesuk K, Mairiang P. Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial. Gastrointest Endosc. 2012;76(1):93-99. 157. Mukai T, Yasuda I, Nakashima M, et al. Metallic stents are more efficacious than plastic stents in unresectable malignant hilar biliary strictures: a randomized controlled trial. J Hepatobiliary Pancreat Sci. 2013;20(2):214-222. 158. Talreja JP, DeGaetani M, Sauer BG, Kahaleh M. Photodynamic therapy for unresectable cholangiocarcinoma: contribution of single operator cholangioscopy for targeted treatment. Photochem Photobiol Sci. 2011;10(7):1233-1238. 159. Leggett CL, Gorospe EC, Murad MH, Montori VM, Baron TH, Wang KK. Photodynamic therapy for unresectable cholangiocarcinoma: a comparative effectiveness systematic review and metaanalyses. Photodiagnosis Photodyn Ther. 2012;9(3):189-195. 160. Talreja JP, Degaetani M, Ellen K, Schmitt T, Gaidhane M, Kahaleh M. Photodynamic therapy in unresectable cholangiocarcinoma: not for the uncommitted. Clin Endosc. 2013;46(4): 390-394. 161. Webb K, Saunders M. Endoscopic management of malignant bile duct strictures. Gastrointest Endosc Clin N Am. 2013;23(2): 313-331. 162. Sofi AA, Khan MA, Das A, et al. Radiofrequency ablation combined with biliary stent placement versus stent placement alone for malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc. 2018;87(4):944-951.e1. 163. Strand DS, Cosgrove ND, Patrie JT, et al. ERCP-directed radiofrequency ablation and photodynamic therapy are associated with comparable survival in the treatment of unresectable cholangiocarcinoma. Gastrointest Endosc. 2014;80(5):794-804. 164. Sendino O, Fernández-Simon A, Law R, et al. Endoscopic management of bile leaks after liver transplantation: an analysis of two high-volume transplant centers. United European Gastroenterol J. 2018;6(1):89-96. 165. Abbas A, Sethi S, Brady P, Taunk P. Endoscopic management of postcholecystectomy biliary leak: when and how? A nationwide study. Gastrointest Endosc. 2019;90(2):233-241.e1. 166. Tewani SK, Turner BG, Chuttani R, Pleskow DK, Sawhney MS. Location of bile leak predicts the success of ERCP performed for postoperative bile leaks. Gastrointest Endosc. 2013;77(4):601-608. 167. Canena J, Horta D, Coimbra J, et al. Outcomes of endoscopic management of primary and refractory postcholecystectomy biliary leaks in a multicentre review of 178 patients. BMC Gastroenterol. 2015;15:105. 168. Dechêne A, Jochum C, Fingas C, et al. Endoscopic management is the treatment of choice for bile leaks after liver resection. Gastrointest Endosc. 2014;80(4):626-633.e1. 169. Canena J, Liberato M, Horta D, Romão C, Coutinho A. Shortterm stenting using fully covered self-expandable metal stents for

452.e5 treatment of refractory biliary leaks, postsphincterotomy bleeding, and perforations. Surg Endosc. 2013;27(1):313-324. 170. Canena J, Liberato M, Meireles L, et al. A non-randomized study in consecutive patients with postcholecystectomy refractory biliary leaks who were managed endoscopically with the use of multiple plastic stents or fully covered self-expandable metal stents (with videos). Gastrointest Endosc. 2015;82(1):70-78. 171. Tonozuka R, Itoi T, Tsuchiya T, et al. EUS-guided drainage of hepatic abscess and infected biloma using short and long metal stents (with videos). Gastrointest Endosc. 2015;81(6):1463-1469. 172. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc. 2006;63(4):570-580. 173. Angsuwatcharakan P, Ahmed O, Lynch PM, et al. Management of ampullary adenomas in familial adenomatous polyposis syndrome: 16 years of experience from a tertiary cancer center. Gastrointest Endosc. 2020;92(2):323-330. 174. Kang SH, Kim KH, Kim TN, et al. Therapeutic outcomes of endoscopic papillectomy for ampullary neoplasms: retrospective analysis of a multicenter study. BMC Gastroenterol. 2017;17(1):69. 175. Elek G, Gyôri S, Tóth B, Pap Á. Histological evaluation of preoperative biopsies from ampulla Vateri. Pathol Oncol Res. 2003; 9(1):32-41. 176. Pittayanon R, Imraporn B, Rerknimitr R, Kullavanijaya P. Advances in diagnostic endoscopy for duodenal, including ampullary, adenoma. Dig Endosc. 2014;26(suppl 2):10-15. 177. Chathadi KV, Khashab MA, Acosta RD, et al. The role of endoscopy in ampullary and duodenal adenomas. Gastrointest Endosc. 2015;82(5):773-781. 1 78. Pérez-Cuadrado-Robles E, Piessevaux H, Moreels TG, et al. Combined excision and ablation of ampullary tumors with biliary or pancreatic intraductal extension is effective even in malignant neoplasms. United European Gastroenterol J. 2019;7(3):369-376. 1 79. Rustagi T, Irani S, Reddy DN, et al. Radiofrequency ablation for intraductal extension of ampullary neoplasms. Gastrointest Endosc. 2017;86(1):170-176. 1 80. Spadaccini M, Fugazza A, Frazzoni L, et al. Endoscopic papillectomy for neoplastic ampullary lesions: a systematic review with pooled analysis. United European Gastroenterol J. 2020;8(1):44-51. 1 81. Barkun A, Liu J, Carpenter S, et al. Update on endoscopic tissue sampling devices. Gastrointest Endosc. 2006;63(6):741-745. 182. Yamashita Y, Ueda K, Kawaji Y, et al. The wire-grasping method as a new technique for forceps biopsy of biliary strictures: a prospective randomized controlled study of effectiveness. Gut Liver. 2016;10(4):642-648. 1 83. Lin LF, Siauw CP, Ho KS, Tung JN. Guidewire technique for endoscopic transpapillary procurement of bile duct biopsy specimens without endoscopic sphincterotomy. Gastrointest Endosc. 2003;58(2):272-274. 1 84. Navaneethan U, Njei B, Lourdusamy V, Konjeti R, Vargo JJ, Parsi MA. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc. 2015; 81(1):168-176. 1 85. Ryan ME, Baldauf MC. Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc. 1994;40(2 Pt 1): 133-139. 1 86. Korc P, Sherman S. ERCP tissue sampling. Gastrointest Endosc. 2016;84(4):557-571. 187. Baron TH, Harewood GC, Rumalla A, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2004;2(3):214-219. 1 88. Levy MJ, Baron TH, Clayton AC, et al. Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol. 2008; 103(5):1263-1273. 1 89. Eaton JE, Barr Fritcher EG, Gores GJ, Atkinson EJ, Tabibian JH, Topazian MD, Gossard AA, Halling KC, Kipp BR, Lazaridis KN. Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2015 Feb;110(2):299-309. doi: 10.1038/ajg.2014.433. Epub 2015 Jan 27. 1 90. Navaneethan U, Njei B, Venkatesh PGK, Vargo JJ, Parsi MA. Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma

in primary sclerosing cholangitis: a systematic review and metaanalysis. Gastrointest Endosc. 2014;79(6):943-950.e3. 191. Salomao M, Gonda TA, Margolskee E, et al. Strategies for improving diagnostic accuracy of biliary strictures. Cancer Cytopathol. 2015;123(4):244-252. 192. Barr Fritcher EG, Voss JS, Brankley SM, et al. An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples. Gastroenterology. 2015;149(7):1813-1824.e1. 193. Bowlus CL, Lim JK, Lindor KD. AGA clinical practice update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: expert review. Clin Gastroenterol Hepatol. 2019;17(12):2416-2422. 194. Singhi AD, Nikiforova MN, Chennat J, et al. Integrating nextgeneration sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. Gut. 2020;69(1):52-61. 195. Tringali A, Lemmers A, Meves V, et al. Intraductal biliopancreatic imaging: European Society of Gastrointestinal Endoscopy (ESGE) technology review. Endoscopy. 2015;47(8):739-753. 196. Robles-Medranda C, Valero M, Soria-Alcivar M, et al. Reliability and accuracy of a novel classification system using peroral cholangioscopy for the diagnosis of bile duct lesions. Endoscopy. 2018; 50(11):1059-1070. 197. de Oliveira PVAG, de Moura DTH, Ribeiro IB, et al. Efficacy of digital single-operator cholangioscopy in the visual interpretation of indeterminate biliary strictures: a systematic review and metaanalysis. Surg Endosc. 2020;34(8):3321-3329. 198. Almadi MA, Itoi T, Moon JH, et al. Using single-operator cholangioscopy for endoscopic evaluation of indeterminate biliary strictures: results from a large multinational registry. Endoscopy. 2020; 52(7):574-582. 199. Navaneethan U, Hasan MK, Lourdusamy V, Njei B, Varadarajulu S, Hawes RH. Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointest Endosc. 2015;82(4):608-614.e2. 200. Bang JY, Navaneethan U, Hasan M, Sutton B, Hawes R, Varadarajulu S. Optimizing outcomes of single-operator cholangioscopy– guided biopsies based on a randomized trial. Clin Gastroenterol Hepatol. 2020;18(2):441-448.e1. 201. Gerges C, Beyna T, Tang RSY, et al. Digital single-operator peroral cholangioscopy-guided biopsy sampling versus ERCP-guided brushing for indeterminate biliary strictures: a prospective, randomized, multicenter trial (with video). Gastrointest Endosc. 2020; 91(5):1105-1113. 202. Sadeghi A, Mohamadnejad M, Islami F, et al. Diagnostic yield of EUS-guided FNA for malignant biliary stricture: a systematic review and meta-analysis. Gastrointest Endosc. 2016;83(2):290-298.e1. 203. Jo JH, Cho CM, Jun JH, et al. Same-session endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography-based tissue sampling in suspected malignant biliary obstruction: a multicenter experience. J Gastroenterol Hepatol. 2019;34(4):799-805. 204. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB. 2011;13(5):356-360. 205. Chafic AH El, Dewitt J, LeBlanc JK, et al. Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients. Endoscopy. 2013;45(11):883-889. 206. Onoyama T, Matsumoto K, Takeda Y, et al. Endoscopic ultrasonography-guided fine needle aspiration for extrahepatic cholangiocarcinoma: a safe tissue sampling modality. J Clin Med. 2019;8(4):417. 207. Gleeson FC, Lee JH, Dewitt JM. Tumor seeding associated with selected gastrointestinal endoscopic interventions. Clin Gastroenterol Hepatol. 2018;16(9):1385-1388. 208. Strongin A, Singh H, Eloubeidi MA, Siddiqui AA. Role of endoscopic ultrasonography in the evaluation of extrahepatic cholangiocarcinoma. Endosc Ultrasound. 2013;2(2):71-76. 209. Levy MJ, Heimbach JK, Gores GJ. Endoscopic ultrasound staging of cholangiocarcinoma. Curr Opin Gastroenterol. 2012;23(3):244-252. 210. Gabbert C, Warndorf M, Easler J, Chennat J. Advanced techniques for endoscopic biliary imaging: cholangioscopy, endoscopic ultrasonography, confocal, and beyond. Gastrointest Endosc Clin N Am. 2013;23(3):625-646.

452.e6 211. Moon JH, Cho YD, Cha SW, et al. The detection of bile duct stones in suspected biliary pancreatitis: comparison of MRCP, ERCP, and intraductal US. Am J Gastroenterol. 2005;100(5):1051-1057. 212. Endo T, Ito K, Fujita N, et al. Intraductal ultrasonography in the diagnosis of bile duct stones: when and whom? Dig Endosc. 2011; 23(2):173-175. 213. Tamada K, Tomiyama T, Wada S, et al. Endoscopic transpapillary bile duct biopsy with the combination of intraductal ultrasonography in the diagnosis of biliary strictures. Gut. 2002;50(3):326-331. 214. Kim HS, Moon JH, Lee YN, et al. Prospective comparison of intraductal ultrasonography-guided transpapillary biopsy and conventional biopsy on fluoroscopy in suspected malignant biliary strictures. Gut Liver. 2018;12(4):463-470. 215. Ito Y, Shibutani S, Egawa T, Hayashi S, Nagashima A, Kitagawa Y. Utility of intraductal ultrasonography as a diagnostic tool in patients with early distal cholangiocarcinoma. Hepatogastroenterology. 2015;62(140):782-786. 216. Chen L, Lu Y, Wu J, Bie L, Xia L, Gong B. Diagnostic utility of endoscopic retrograde cholangiography/intraductal ultrasound (ERC/IDUS) in distinguishing malignant from benign bile duct obstruction. Dig Dis Sci. 2016;61(2):610-617. 217. Meister T, Heinzow HS, Woestmeyer C, et al. Intraductal ultrasound substantiates diagnostics of bile duct strictures of uncertain etiology. World J Gastroenterol. 2013;19(6):874-881.

218. Nakai Y, Isayama H, Shinoura S, et al. Confocal laser endomicroscopy in gastrointestinal and pancreatobiliary diseases. Dig Endosc. 2014;26(suppl 1):86-94. 219. Fugazza A, Gaiani F, Carra MC, et al. Confocal laser endomicroscopy in gastrointestinal and pancreatobiliary diseases: a systematic review and meta-analysis. Biomed Res Int. 2016;2016: 4638683. 220. Meining A, Shah RJ, Slivka A, et al. Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures. Endoscopy. 2012;44(3):251-257. 221. Kahaleh M, Giovannini M, Jamidar P, et al. Probe-based confocal laser endomicroscopy for indeterminate biliary strictures: refinement of the image interpretation classification. Gastroenterol Res Pract. 2015;2015:675210. 222. Slivka A, Gan I, Jamidar P, et al. Validation of the diagnostic accuracy of probe-based confocal laser endomicroscopy for the characterization of indeterminate biliary strictures: results of a prospective multicenter international study. Gastrointest Endosc. 2015;81(2):282-290. 223. Talreja JP, Turner BG, Gress FG, et al. Pre- and post-training session evaluation for interobserver agreement and diagnostic accuracy of probe-based confocal laser endomicroscopy for biliary strictures. Dig Endosc. 2014;26(4):577-580.

CHAPTER 31 Radiologic hepatobiliary interventions Karen T. Brown and Anne M. Covey RADIOLOGIC HEPATOBILIARY INTERVENTIONS Minimally invasive hepatic intervention is indicated in a wide range of pathologic conditions and can be generally divided into vascular, biliary, and hepatic parenchymal procedures. The objective of this chapter is to provide a broad overview of the spectrum of interventions that can be performed percutaneously using imaging guidance. Greater detail will be found in individual chapters devoted to each topic.

Vascular Procedures The liver is an extremely vascular organ with nutrient supply from both the portal vein and hepatic artery and drainage via the hepatic veins. These vessels are common targets for the interventional radiologist.

Portal Vein The majority of the nutrient blood flow to the liver is via the portal vein, which drains the splanchnic circulation and spleen. The most common abnormality involving the portal vein is portal hypertension, typically as a sequela of cirrhosis (see Chapters 74, 79, 81, and 85). Clinical manifestations of portal hypertension include splenomegaly, thrombocytopenia, varices, ascites, and liver failure. In 1969 Rosch and colleagues1 reported the first case of transjugular intrahepatic portosystemic shunt (TIPSS) in dogs (see Chapter 85). Thirteen year later, Colapinto and colleagues (1982)2 reported the first human application of TIPSS. In this procedure, a path is created from the hepatic vein to the portal vein through the liver parenchyma, thereby decreasing portal pressure and relieving patients from intractable ascites or acute variceal bleeding. Initially the tract was formed with serial dilators or balloon dilation, with limited success. When the Palmaz metallic balloon expandable stents became available in the mid-1980s,3 procedural success improved, and the technique gained widespread acceptance. Further refinement using covered self-expanding stents has improved long-term patency, making this a viable option not only for patients with life-threatening hemorrhage but also as a means to control intractable ascites.4,5 The most significant complication of TIPSS is hepatic encephalopathy because of the volume of blood shunted past the liver parenchyma (see Chapter 77). As a result, the presence of hepatic encephalopathy is a relative contraindication to the procedure. Other contraindications include right heart failure, hepatic vein occlusion, and sepsis. The risk of cardiac decompensation after TIPSS can be predicted noninvasively.6 In patients with hepatic encephalopathy and portal hypertension or patients with “left-sided (sinistral) portal hypertension” (gastric varices because of splenic vein occlusion), balloonoccluded retrograde transvenous obliteration (BRTO) or balloonoccluded antegrade transvenous obliteration (BATO) may be preferable to TIPSS. BRTO and BATO refer to procedures in which a high-risk or bleeding gastric varix is catheterized and

sclerosed, typically with a mixture of Ethiodol, Sotradechol, and air agitated through a three-way stopcock.7 In patients with isolated sinistral portal hypertension because of occlusion of the splenic vein, recanalization of the occluded splenic vein or embolization of the splenic artery may be considered.8 In some cases, portal vein narrowing or occlusion because of extrinsic compression by tumor may cause symptoms similar to those seen in cirrhotic portal hypertension. In such cases, placement of a self-expanding stent can relieve varices and ascites. This is most commonly seen in patients with locally advanced pancreaticobiliary cancer, where portal vein stenting may also improve thrombocytopenia, broadening chemotherapy options. Another procedure that has gained widespread acceptance is portal vein embolization (PVE) as an adjunctive procedure before hepatic resection (see Chapter 102C). Patients with a suboptimal future liver remnant (FLR), which can be assessed volumetrically (i.e., with computed tomography [CT] or magnetic resonance imaging [MRI]) or functionally (e.g., indocyanine green clearance), may undergo contralateral PVE to induce preoperative hypertrophy of the FLR9 (see Chapter 102C). In patients with cirrhosis, most surgeons believe that a FLR of greater than 40% of the total liver volume (TLV) is optimal. For patients without underlying liver disease, a FLR of greater than 25% is thought to be acceptable. Other risk factors for impaired liver function include diabetes, prior chemotherapy, and steatosis, and therefore the desired volume of the FLR is best assessed on a case-by-case basis. PVE to improve the safety of hepatic resection was first proposed by Makuuchi and colleagues in 1990.10 Initially, this procedure was performed via a transileocolic approach that required laparotomy and general anesthesia. Although ligation of a portal vein branch can be carried out during a laparotomy, today this procedure is most commonly performed percutaneously, typically as an outpatient procedure. A wide range of agents have been used to perform the procedure, including ethanol, Gelfoam, thrombin, polyvinyl alcohol, glue, spherical embolic agents, coils, and sclerosing agents. No agent has proven superior; each is expected to increase the absolute FLR/TLV in the range of 8% to 10%. Complications are uncommon, the most significant being nontarget embolization to the main portal vein or portal vein supplying the FLR, which could preclude operation. This occurs in less than 1% of patients.11 Liver hepatic venous deprivation is another technique to improve contralateral hepatic hypertrophy before major hepatic resection. In this procedure, both the portal and hepatic veins in the hemiliver to be resected are embolized to maximize growth of the FLR and allow major hepatic resection.12

Hepatic Artery Unlike portal vein interventions, which are most commonly undertaken to treat the sequela of portal hypertension or, in the 453

454

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

case of PVE, as adjunct to hepatic resection, most transarterial interventions in the liver are done to effect treatment of unresectable malignancy or for control of bleeding in the setting of trauma (see Chapters 21, 94, 113, 115, and 116). Both primary and metastatic liver tumors derive the majority of trophic blood supply from the hepatic artery, unlike the non– tumor-bearing parenchyma, which receives the majority of nutrient flow from the portal vein (see chapter 5). Therefore administering a treatment to the artery can affect tumor regression while minimizing collateral damage to the underlying parenchyma. In the mid-1970s, it was recognized that the unusual dual vascular supply to the liver might allow effective transarterial treatment for hypervascular metastases from neuroendocrine tumors, as well as primary hepatocellular carcinoma (HCC). Subsequently, transarterial treatments have been applied to a wide variety of hypervascular tumors, including sarcoma and breast cancers, as well as some tumors that are not particularly hypervascular by imaging, such as colon cancer or cholangiocarcinoma (see Chapter 94). Different forms of treatment have been administered via the hepatic artery to treat such tumors, including chemotherapy infusion, bland (particle) embolization (transcatheter arterial embolization [TAE]), transarterial chemoembolization with lipiodol (TACE), embolization with drug-eluting beads (DEBTACE), and radioembolization (RAE; see Chapter 94). Two randomized trials have demonstrated improvement in overall survival in patients with HCC treated with TACE compared with patients who received best supportive care.13,14 To date, there has been no study demonstrating a significant difference in overall survival among any method of embolization, including TACE, DEB-TACE, TAE, or RAE.15,16 Indications for arterially directed therapy include control of symptoms (e.g., pain or hormonal-related symptoms because of neuroendocrine liver metastases; see Chapter 91), control of tumor in the liver to prolong survival, progression of disease after systemic treatment, and local tumor control to maintain eligibility for liver transplant in select patients with HCC (see Chapter 89). Transarterial therapies are rarely, if ever, curative and instead are intended to be repeated upon disease progression. In cases of minimal disease burden, ablation may be performed in conjunction with embolization as a potentially curative therapy (see Chapter 96). In this instance, performing the embolization immediately before ablation has the advantage of depositing contrast-laden particles within the tumor to assist in targeting with the ablation device and also decreasing the “heat sink” effect, whereby flowing blood continues to “cool” the tumor margin, potentially increasing the risk of local recurrence. Occluding arterial blood flow may increase the zone of ablation.17 In some cases, the angiogram may identify additional sites of disease undetected on preprocedure imaging, changing the treatment plan. Selection criteria differ slightly with each treatment option. Broadly speaking, patients with unresectable disease involving less than 50% of the liver without underlying liver disease or with well-compensated (Childs-Pugh score A–B7) cirrhosis may be candidates. In the past, portal vein occlusion was considered an absolute contraindication because of the reported higher complication rate and risk of death. More recently, series of patients with portal vein occlusion treated with TAE, TACE, and RAE have been shown to respond to treatment without a significant increase in complications, thus supporting its use in this group of patients with limited treatment options.18-22

The complication profiles differ slightly between the various transarterial therapies. TACE is infrequently associated with bone marrow suppression and alopecia. Radiation-induced liver failure occurs in 1% to 2% of patients who undergo RAE; however, radiologic findings of cirrhosis and portal hypertension are seen in greater than 50% of patients with neuroendocrine tumor treated with whole liver RAE at a mean of 4.1 years after treatment.23 With varying frequency, intra-arterial therapy is associated with arterial sclerosis and arterial occlusion, which can make future intervention more difficult.24 This is more commonly seen with TACE and DEB-TACE than with TAE.25,26 The clinical relevance of this angiographic finding is that over time tumors can derive arterial supply from nonhepatic collateral vessels, making treatment more challenging and creating a higher risk of nontarget embolization. Branches that commonly give rise to extrahepatic tumor supply include the right phrenic, internal mammary, gastroduodenal, intercostal, and renal capsular arteries. Complications include nontarget embolization, liver failure, vessel injury, and postembolization syndrome. Postembolization syndrome occurs in the majority of patients, other than those treated with RAE, and consists of some degree of pain, fever, and/or nausea that can last for several days. Prolonged pain may suggest nontarget embolization to the pancreas, resulting in pancreatitis, or to the gallbladder or upper gastrointestinal (GI) tract, resulting in cholecystitis or gastric or duodenal ulceration. The hepatic artery is also a vessel that may require intervention after liver transplant. After primary graft malfunction, hepatic artery thrombosis (HAT) is the second leading cause of graft failure after liver transplant and is a major cause of transplant-related mortality (see Chapter 111). This complication can result from technical issues with the anastomosis, including disparate diameters of donor and recipient vessels, and tension on, or kinking of, the anastomosis. In most cases, HAT occurs within the first 100 days and manifests as fulminant hepatic necrosis and/or biliary tract ischemia and necrosis, resulting in sepsis. Because these patients are immunosuppressed to prevent graft rejection, the gramnegative sepsis resulting from biliary necrosis can be very difficult to treat (see Chapter 111). Early posttransplant screening Doppler ultrasound (US) can be used to detect abnormal flow in the hepatic artery. If this test is abnormal, a contrast study (US, CT, or angiography) should be considered. To salvage the organ, a precious resource, revascularization is often attempted after documentation of abnormal flow, even in asymptomatic patients.27 Other hepatic artery complications may develop post-transplant, including stenosis and pseudoaneurysm. As with occlusion, revascularization with catheter-directed thrombolysis, angioplasty, and/or stent placement is effective in the majority of cases with hepatic artery stenosis. Pseudoaneurysm is a rare but potentially fatal complication that may be treated with a covered stent graft (see Chapters 111 and 115). After blunt abdominal trauma, the liver is the second most commonly injured abdominal organ after the spleen (see Chapter 113). The American Association for the Surgery of Trauma Injury Scoring Scale was developed to help guide management of these patients.28 Injuries to the hepatic artery include pseudoaneurysms, which can be unifocal or multiple, resulting in a “starry sky” appearance of multiple sites of extravasation/ injury on angiography. Focal extravasation or pseudoaneurysm

  Chapter 31  Radiologic Hepatobiliary Interventions

is usually treated with coil embolization of the affected vessel distal and proximal to the injury, or with a covered stent. In the case of multifocal injury, particle embolization of the hepatic artery may be performed. Because of the dual blood supply to the liver discussed earlier, embolization of the hepatic artery in the presence of a patent portal vein is rarely of clinical consequence. Hepatic artery injury may occur after iatrogenic hepatic interventions, either surgical or percutaneous, such as biliary drainage or TIPSS, and is treated similarly with coil embolization or covered stent placement.

Hepatic Vein The least common vascular target of endovascular intervention in the liver is the hepatic vein. Budd-Chiari is a potentially lifethreatening disease of heterogeneous etiology, resulting in obstruction of hepatic venous outflow that occurs in less than one per million persons (see Chapter 86). Acutely, patients are symptomatic with abdominal pain and ascites, and over time, centrilobular fibrosis and cirrhosis may develop. Initial therapy includes systemic anticoagulation, but the benefit of anticoagulation alone is debatable. Patients with ongoing symptoms may benefit from thrombolysis, venoplasty, and/or stent placement and, in some cases, TIPSS29 (see Chapter 85). Stenosis of the intrahepatic or suprahepatic inferior vena cava may occur as a complication after orthotopic liver transplantation, and symptomatology mimicking Budd-Chiari may ensue. Elevated velocities by Doppler US suggest the diagnosis, and a pressure gradient of greater than 6 mm Hg across the stenosis at venography is diagnostic.30 Venoplasty or, in select cases, stent placement can alleviate symptoms and preserve graft function.

Biliary Intervention Noninvasive imaging of the biliary tree with contrast-enhanced CT (CECT) and MRI have virtually eliminated the need for invasive percutaneous transhepatic cholangiography to diagnose biliary tract disorders (see Chapters 16 and 20). As a result, percutaneous transhepatic cholangiography is rarely performed for diagnostic purposes alone but rather at the time of planned biliary intervention. Percutaneous transhepatic biliary drainage or stent placement can be performed to relieve symptoms caused by obstructive jaundice, including pruritus, anorexia, and cholangitis. Biliary drainage can also be performed to lower the bilirubin preoperatively, to allow for chemotherapy or, in the setting of bile leak, to divert bile.31 Less common indications include access to treat biliary stone disease or to facilitate intraductal therapies, such as brachytherapy. In general, bile duct obstruction below the common hepatic duct (i.e., “low” bile duct obstruction)32 is best treated endoscopically because placement of a plastic or self-expanding metal stent (SEMS) can drain the entire biliary tree through the normal orifice of the sphincter of Oddi. In cases of high bile duct obstruction, (at or above the cystic duct insertion) percutaneous drainage is preferred because this allows a specific duct to be targeted for drainage without contamination of potentially isolated, undrained ducts (see Chapters 20 and 52). Ideally, the need for drainage and optimal plan for a given patient is made by multidisciplinary consensus involving hepatobiliary surgeons, gastroenterologists, and interventional radiologists. Preprocedure planning must include high-quality imaging of the liver and biliary tree. CECT and MRI are extremely useful to show biliary anatomy and pathology (see

455

Chapter 16). In some cases, US may add additional information about the level of obstruction and patency of portal vein branches, but US alone is not sufficient for preprocedure planning. A dose of prophylactic broad-spectrum antibiotic to cover enterococci, streptococci, and aerobic and anaerobic gram-negative bacilli is recommended before biliary intervention. This is particularly important when there has been bile duct reconstruction or biliary instrumentation because, in this setting, the incidence of colonized bile is high. With malignant biliary obstruction in the absence of signs or symptoms of cholangitis, placement of a primary SEMS may be performed. Compared with plastic stents, metal stents have a longer median patency (3–9.1 months vs. 1.8–5.5 months), but there is no difference in overall patient survival.33 When feasible, primary stent placement is preferred because it does not require an exteriorized device. Additionally, if there are incompletely drained ducts, having a catheter may put patients at risk for developing cholangitis because bile colonization occurs within 48 hours, and when a primary stent is placed, there is less opportunity for contaminating incompletely drained ducts. Finally, in high bile duct obstruction, stents can often be placed above the papilla. Without reflux of bowel contents or an exteriorized device, the sterility of the biliary tree is maintained so that if or when patients present with occluded stents, the likelihood of presenting with cholangitis is diminished. Metal stents also may be covered with polyurethane, with the goal of preventing tumor ingrowth, resulting in improved patency. Unfortunately, this has not been shown to be the case, and increased complications of acute cholecystitis34 and stent migration have been seen.35 Covered stents are not generally indicated in high bile duct obstruction because of the risk of occluding undrained segmental bile ducts. Further studies are needed to establish the indications for covered versus bare metal stents.

Bile Duct Biopsy In some cases, the etiology of biliary obstruction may not be evident at the time of drainage. Bile obtained at the time of drainage may be sent for cytology, but diagnostic sensitivity is relatively low. Bile duct biopsy may be helpful in establishing a diagnosis of intraductal pathology (e.g., cholangiocarcinoma) and in differentiating recurrent tumor from ischemic/postoperative stricture (see Chapters 22 and 51). At the time of biliary drainage, endoluminal brush or forceps biopsy of the stricture depicted by cholangiography can be used to obtain a sample. These techniques are most useful for intraductal pathology (e.g., cholangiocarcinoma) in contradistinction to extrinsic masses that may cause biliary obstruction (e.g., hilar adenopathy or parenchymal liver mass). In cases in which establishing a diagnosis is difficult, the biliary tree can be opacified through an indwelling drainage catheter, and the stricture targeted with a percutaneous fine needle.36 Cholangiographic-guided needle biopsy can be used to diagnose both intraductal and extraductal causes of obstruction.

Percutaneous Cholecystostomy Percutaneous cholecystostomy is most commonly indicated for the treatment of acute acalculous cholecystitis in severely ill hospitalized patients but may also be used to treat calculous cholecystitis in patients who are too sick for, or in whom comorbidities preclude, definitive cholecystectomy (see Chapters 34 and 35). It may also be performed to provide access to the

456

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

gallbladder or biliary tree for stone removal or, in rare instances, to provide biliary drainage in patients with common bile duct (CBD) obstruction distal to the insertion of the cystic duct. When performed in the setting of gallstones, it is often used as a temporizing measure to allow the resolution of sepsis and optimization of the patient’s medical conditions for subsequent cholecystectomy. In cancer patients with bile duct obstruction, it is not uncommon to see cholecystitis complicating SEMS placement when gallstones are present and the stent covers the cystic duct orifice, particularly when contrast is seen within the cystic duct or gallbladder. Some of these patients undergo subsequent cholecystectomy but, in palliative situations, the patients may live with a cholecystostomy catheter. Cholecystostomy has been reported effective as definitive therapy in very-high-risk patients with calculous cholecystitis who have remained asymptomatic after catheter placement.37 After cholecystostomy, clinical resolution of infection occurs within 24 to 48 hours in the vast majority of cases. When performed for acalculous cholecystitis, the catheter can be capped once it begins to drain bile, a clear sign that the cystic duct is patent, but the catheter should not be removed until tract maturation has occurred. In general, this occurs within two to three weeks.38 Tract maturation may happen earlier when a transhepatic rather than transperitoneal route to the gallbladder has been employed. If stone removal from the gallbladder is to be undertaken, this should also be performed after tract maturation.

Biliary Stone Disease Stones can be removed from the gallbladder or biliary tree using a variety of approaches and methods (see Chapters 30, 36, and 37). When there is a retained CBD stone after cholecystectomy and a T-tube has been left in place, this is accomplished via the T-tube tract following tract maturation. When choledocholithiasis occurs in a patient with remote cholecystectomy, it can be performed through a transhepatic approach if endoscopy is unsuccessful. Choledocholithiasis may present with cholangitis or be asymptomatic. The first step in stone removal is placement of a percutaneous biliary drainage catheter. After a period of two to three weeks of drainage, during which a mature tract forms, the biliary catheter is exchanged for a large diameter sheath. The first order of business then is balloon sphincterotomy, followed by pushing smaller calculi into the duodenum using a balloon. If the stones are too large to pass through the dilated ampulla, they can be broken up using baskets, snares, or even lithotripsy. Once the duct is thought to be clear, the internal external drainage catheter is replaced. The patient returns in one to two weeks, and sheath cholangiography is performed to look for retained stones. If the ducts are clear, the internal external catheter is replaced with an external drain above the ampulla and then capped. If the patient does well with the catheter capped, it can be removed without further imaging.

Bile Duct Injury The bile duct can be injured from blunt or penetrating trauma but is probably most commonly injured at the time of surgery (see Chapters 28, 32, 42, and 113). There was a fairly high rate of bile duct injury when laparoscopic cholecystectomy was initially introduced, at least in part related to lack of operator experience, now mostly related to unrecognized bile duct anomalies (see Chapters 2 and 36). When the bile duct is

clipped or transected, there is little that can be done percutaneously other than draining the obstructed duct or diverting the transected one. When postoperative strictures occur, patients may present with cholangitis, pruritus, or jaundice. Percutaneous access to the biliary tree is established first, and then the stricture is crossed. An internal external catheter is left across the stricture for a couple of weeks as tract maturation occurs. The patient returns, and the stricture is dilated with a balloon.39 When applied to bilioenteric anastomoses, success is likely in the majority of patients, with stricture recurrence in as few as 5% of patients on long-term follow-up.40 Dilation of the CBD is not likely to be successful using a balloon of less than 10 mm. If an acceptable result is not seen when the patient returns for a repeat study after their first dilation, the stricture can be redilated, sometimes with a larger balloon. Strictures particularly resistant to dilation have been treated by some operators by using cutting balloons with good, durable results.41

Hepatic Cysts Liver cysts occur in up to 5% of the population and are incidentally seen on cross-sectional imaging (see Chapters 73 and 88B). They can enlarge slowly and rarely become symptomatic, although symptoms from mass effect may develop if they impinge on adjacent structures. In addition, bleeding may occur into the cyst, causing pain. A simple liver cyst should be differentiated from a cystic tumor. The most common mimic of the simple cyst is a cystadenoma that has the potential to become a cystadenocarcinoma (see Chapter 88B). Unfortunately, cross-sectional imaging studies do not reliably distinguish between these two entities. Metastases that become necrotic can also appear cystic; however, history and previous imaging will usually make the distinction. Treatment of simple liver cysts is not typically indicated unless the patient is symptomatic and the symptoms are clearly related to the cyst. Simple aspiration can provide temporary relief, and, when the symptoms are relieved, serves as proof of association, but recurrence after aspiration is very high. Drainage and sclerosis have been reported, but have generally been replaced by laparoscopic unroofing of the cyst, which is typically well tolerated by the patient and avoids problems associated with an indwelling catheter (see Chapter 73). Cystadenomas, because of the risk of malignancy, require surgical resection.

Hepatic Abscess Most liver abscesses in the United States are pyogenic, caused by bacteria (see Chapter 70). Amebic abscesses caused by Entamoeba histolytica and fungal abscesses each account for about 10% of liver abscesses (see Chapter 71). Pyogenic liver abscesses are usually polymicrobial, and an etiology can often be discovered. Ascending hematogenous infection from the GI tract is a common etiology, and patients with diverticulitis or appendicitis may present with a liver abscess. Appearance on cross-sectional imaging is usually that of a complex collection with many internal septa, resembling a cauliflower. Despite this appearance, these can be successfully treated percutaneously in combination with antibiotics, although catheter drainage may be prolonged.42 Imaging should include the pelvis, with careful evaluation for a potential source. Patients who develop bile duct obstruction, particularly in the setting of bactibilia related to previous biliary-enteric

  Chapter 31  Radiologic Hepatobiliary Interventions

bypass, transampullary stent placement, or a preexisting percutaneous drain, also may present with a liver abscess, although in this situation it is often better classified as an infected biloma and is usually less complex in appearance. Causes of infected biloma include stent obstruction, recurrent tumor, or anastomotic stricture, and a catheter placed into a biloma for drainage will continue to drain bile until the causative obstruction is eliminated. Liver abscess can also occur as a complication after embolization of liver tumors in the patient group with compromised sphincter of Oddi and bactibilia43 (see Chapter 94). This should always be considered in the preprocedure evaluation of patients undergoing hepatic artery embolization that have had a previous pancreatoduodenectomy or colonized bile for any reason. True liver abscesses should be distinguished from “perihepatic” collections that occur postoperatively, are not in the parenchyma of the liver, and are usually much easier to treat (see Chapters 28 and 101).

Amebic Abscess Unlike pyogenic hepatic abscess, amebic abscesses are typically associated with travel history to an endemic region (see Chapter 71). At presentation, patients almost universally have fever and abdominal pain. Hepatomegaly occurs often, particularly with large cysts. When cysts are small, aspiration may be necessary to differentiate amebic from pyogenic abscess because amebic antibodies may not be detected at presentation, although they typically appear later. Symptoms resolve quickly with administration of metronidazole, and intervention beyond that is rarely needed unless there has been rupture. A randomized trial of 57 patients with abscesses 5 to 10 cm in size found that although fever and pain resolved sooner in the group treated with aspiration and metronidazole, compared with metronidazole alone, the difference was not statistically significant, and there was no difference in morbidity, mortality, treatment failure, days to normalization of leukocytosis, or duration of hospital stay between the two groups.44

Echinococcal Cysts Hydatid cystic disease is a parasitic disease caused by Echinococcus granulosa (see Chapter 72). The larvae of this parasite cause the disease, which is endemic in Mediterranean, Middle Eastern, and South American countries and in New Zealand and Turkey, where people are in close contact with sheep and dogs. The most common site of disease is in the liver (50%– 80%), followed by the lung (5%–30%). Surgery is the primary method of treatment; however, percutaneous approaches have been investigated in recent years. In 2005 Paksoy and colleagues45 reported on 59 patients with 109 hydatid cysts that were treated percutaneously, injecting either hypertonic saline or albendazole sodium as the scolicidal agent. All patients were given 10 mg/kg/day of albendazole, beginning 48 hours before their procedure, and this was continued for two months after the procedure. Directly before the procedure, they received diphenhydramine and hydrocortisone to prevent anaphylactic reactions. Treatment was safe and effective in both groups, with only one recurrence in the group treated with hypertonic saline. This compares well with a reported 4% incidence of recurrence after surgery. Although all cysts returned to their initial size directly after aspiration and injection, successful treatment was associated with decrease in size over time.

457

Hepatic Ablation Tumors Small primary and metastatic tumors in the liver may be completely eradicated by chemical or thermal ablation (see Chapter 96). The most common tumors treated with ablation include HCC and colorectal liver metastases. Improved screening of patients with risk factors for HCC has resulted in detection of small tumors amenable to curative resection or ablation. Colorectal cancer is the third most common malignancy in the United States, and most disease-related deaths are secondary to metastatic disease. Up to 50% of patients with colorectal cancer will develop liver metastases during the course of their disease (see Chapter 90). In almost half of these patients, disease is limited to the liver, and up to 25% of these patients have resectable disease. More effective systemic chemotherapy (see Chapters 97 and 98) and advances in techniques of hepatic resection (see Chapter 101) have combined to improve survival and increase rates of hepatic resection. Concomitantly, there have been advances in interventional radiologic techniques of percutaneous thermal ablation, including radiofrequency, microwave, laser, and cryoablation, as well as irreversible electroporation (see Chapter 96). All of these techniques are less costly, safer, and result in shorter hospital stays than hepatic resection and can be applied in place of surgical resection in well-selected cases, although the risk of local recurrence is higher.46–51 There are other tumors that might be treated with ablation, assuming they meet number, size, and location criteria for successful treatment.

Criteria for Treatment Even the most advanced ablative techniques are limited with regard to the tumor size that can be successfully treated. It has recently been shown that an ablative margin is critical to a successful ablation, with a margin of at least 5 and ideally 10 mm on CT four to eight weeks after ablation associated with the best local tumor control.52 Most commercially available ablation systems result in an elliptic volume of coagulative necrosis, with a maximum long axis of 5 cm, limited by properties of the local tumor/tissue environment. For this reason, successful ablation, with a low rate of local tumor recurrence is seen most often in tumors less than 3 cm in size, and the best results are obtained in tumors 2.5 cm or smaller. Larger tumors, or those with complex geometry, are unlikely to be effectively treated by attempting to extend the thermal effect by using multiple overlapping applications. The location of the tumor may also limit effectiveness of ablation or ability to use the technique safely. Tumors that are adjacent to high-flow blood vessels (portal vein, hepatic vein, inferior vena cava) will be cooled where they are in contact with the blood vessel so that the application of heat will be less effective at that margin and the risk of recurrence higher. Subcapsular tumors can be difficult to treat effectively. Structures that may be injured by heat or cold, such as bile ducts and other adjacent organs, might preclude safe treatment, although irreversible electroporation has been developed, in part, to address that issue. Ideal patients for percutaneous ablation should have oligometastatic disease with three or fewer tumors, all less than 3 cm in size, that are not adjacent to a major bile duct or bile duct branch or in contact with any high-flow vessel, especially one greater than 5 mm in size. Local tumor recurrence and survival rates are both related to the number of tumors treated, and the best outcome is found in patients with a solitary tumor.

458

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

Size criteria can be extended in HCC or other vascular tumors that can be embolized first. In this instance, addition of ablation to embolization provides several theoretical advantages. In the first instance, it provides a method of “double kill,” whereby the tumor is exposed to two tumoricidal events: ischemia and lethal temperature.53 Because embolization results in cessation of flowing arterial blood, the primary blood supply to hepatic tumors, heat resulting from ablation does not need to overcome the cooling effects of flowing blood in the tumor or immediate environment, theoretically increasing efficiency of the process, resulting in more effective heating of the tissue. Second, when ablation is

performed directly after embolization, it becomes much easier to radiologically target small tumors in the 1- to 2-cm range because they retain dense contrast. Finally, it is possible to target areas within the tumor that may show less deposition of embolic material and in which recurrence is likely.54 The following chapters will provide a more detailed discussion of these techniques, as well as more in-depth consideration of indications, outcomes, and potential complications of radiologic hepatic interventions. References are available at expertconsult.com.

458.e1

REFERENCES 1. Rosch J, et al. Transjugular portal venography and radiologic portocaval shunt: an experimental study. Radiology. 1969;92(5): 1112-1114. 2. Colapinto RF, et al. Creation of an intrahepatic portosystemic shunt with a Grüntzig balloon catheter. Can Med Assoc J. 1982;126(3):267-268. 3. Palmaz JC, et al. Expandable intrahepatic portacaval shunt stents in dogs with chronic portal hypertension. AJR Am J Roentgenol. 1986;147(6):1251-1254. 4. Boyer TD, Haskal ZJ. The role of TIPS in the management of portal hypertension. Hepatology. 2005;41(2):386-400. 5. Saad WE. The history and future of TIPS: food for thought. Semin Intervent Radiol. 2014;31(3):258-261. 6. Billey C, Billet S, Robic MA, et al. A prospective study identifying predictive factors of cardiac decompensation after transjugular intrahepatic portosystemic shunt: The Toulouse algorithm. Hepatology. 2019;70(6):1928-1941. 7. Saad WE, et al. BATO with or without BRTO for the management of gastric varices: concept and technical applications. TechVasc Interv Radiol. 2012;15(3):203-225. 8. Ghelfi J, Thony F, Frandon J, Rodiere M, Leroy V, Vendrell A. Gastrointestinal bleeding due to pancreatitis-induced splenic vein thrombosis: treatment with percutaneous splenic vein recanalization. Diagn Interv Imaging. 2016;97(6):677-679. 9. May BJ, et al. Update on portal vein embolisation: evidence-based outcomes, controversies, and novel strategies. J Vasc Interv Radiol. 2013;24(2):241-254. 10. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527. 11. van Lienden KP, et al. Portal vein embolisation before liver resection: a systematic review. Cardiovasc Intervent Radiol. 2013;36(1):25-34. 12. Guiu B, et al. Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique. Eur Radiol. 2016;26(12):4259-4267. 13. Llovet JM, et al. Arterial embolisation or chaemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359(9319):1734-1739. 14. Lo CM, et al. Randomized controlled trail of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164-1171. 15. Brown DB, et al. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol. 2012;23(3): 287-294. 16. Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046-2053. 17. Tanaka T, et al. Superselective particle embolisation enhances efficacy of radiofrequency ablation: effects of particle size and sequence of action. Cardiovasc Intervent Radiol. 2013;36(3):773-782. 18. Kim KM, et al. Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion. J Gastroenterol Hepatol. 2009;24(5):806-814. 19. Lau WY, et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology. 2013;84(5):311-318. 20. Maluccio MA, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19(6):862-869. 21. Borgheresi A, Covey A, Yarmohammadi H, et al. Embolization with microspheres alone for hepatocellular carcinoma with portal vein tumor: analysis of outcome and liver function at disease progression. HPB (Oxford). 2020;22(4):588-594. 22. Abouchaleh N, Gabr A, Ali R, et al. 90Y radioembolization for locally advanced hepatocellular carcinoma with portal vein thrombosis: long-term outcomes in a 185-patient cohort. J Nucl Med. 2018;59(7):1042-1048. 23. Su YK, Mackey RV, Riaz A, et al. Long-term hepatotoxicity of yttrium-90 radioembolization as treatment of metastatic neuroendocrine tumor to the liver. J Vasc Interv Radiol. 2017;28(11):1520-1526.

24. Miyayama S, et al. Extrahepatic blood supply to hepatocellular carcinoma: angiographic demonstration and transcatheter arterial chemoembolization. Cardiovasc Intervent Radiol. 2006;29(1):39-48. 25. Erinjeri JP, et al. Arterial patency after repeated hepatic artery bland particle embolization. J Vasc Interv Radiol. 2010;21(4):522-526. 26. Geschwind JF, et al. Transcatheter arterial chemoembolization of liver tumors: effects of embolization protocol on injectable volume of chemotherapy and subsequent arterial patency. Cardiovasc Intervent Radiol. 2003;26(2):111-117. 27. Pareja E, et al. Vascular complications after orthotopic liver transplantation: Hepatic artery thrombosis. Transplant Proc. 2010;42(8): 2970-2972. 28. Kozar RA, Crandall M, Shanmuganathan K, et al. Organ injury scaling 2018 update: Spleen, liver, and kidney [published correction appears in J Trauma Acute Care Surg. 2019;87(2):512]. J Trauma Acute Care Surg. 2018;85(6):1119-1122. 29. Copelan A, et al. Diagnosis and management of Budd-Chiari syndrome: an update. Cardiovasc Intervent Radiol. 2015;38(1):1-12. 30. Kubo T, et al. Outcome of percutaneous transhepatic venoplasty for hepatic venous outflow obstruction after living donor liver transplantation. Radiology. 2006;239(1):285-290. 31. Perez-Johnston R, Deipolyi AR, Covey AM. Percutaneous biliary interventions. Gastroenterol Clin North Am. 2018;47(3):621-641. 32. Bismuth H, et al. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 1992;215(1):31-38. 33. Levy MJ, et al. Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: an evidence-based approach. Clin Gastroenterol Hepatol. 2004;2(4):273-285. 34. Isayama H, et al. A prospective randomised study of “covered” versus “uncovered” diamond stents for the management of distal malignant biliary obstruction. Gut. 2004;53(5):729-734. 35. Yoon WJ, et al. A comparison of covered and uncovered Wallstents for the management of distal malignant biliary obstruction. Gastrointest Endosc. 2006;63(7):996-1000. 36. Gonzalez-Aguirre A, Covey AM, Brown KT, et al. Comparison of biliary brush biopsy and fine needle biopsy in the diagnosis of biliary strictures. Minim Invasive Ther Allied Technol. 2018;27(5): 278-283. 37. Nasim S, et al. Emerging indications for percutaneous cholecystostomy for the management of acute cholecystitis—A retrospective review. Int J Surg. 2011;9:456-459. 38. Hatjidakis AA, et al. Maturation of the tract after percutaneous cholecystostomy with regard to access route. Cardiovasc Intervent Radiol. 1998;21:36-40. 39. Lee AY, et al. Percutaneous transhepatic balloon dilation of biliary enteric anastomotic strictures after surgical repair of iatrogenic bile duct injuries. PLoS One. 2012;7(10):e46478. 40. Janssen JJ, et al. Percutaneous balloon dilatation and long-term drainage as treatment of anastomotic and nonanastomotic benign biliary strictures. Cardiovasc Intervent Radiol. 2014;37(6):1559-1567. 41. Murkund A, et al. Percutaneous management of resistant biliaryenteric anastomotic strictures with use of a combined cutting and conventional balloon cholangioplasty protocol: A single-center experience. J Vasc Interv Radiol. 2015;26:560-565. 42. Mezhir JJ, et al. Current management of pyogenic liver abscess: surgery is now second line treatment. J Am Coll Surg. 2010; 2010(6):975-983. 43. Mezhir JJ, et al. Pyogenic liver abscess after hepatic artery embolisation: a rare but potentially lethal complication. J Vasc Interv Radiol. 2011;22(2):177-182. 44. Bammigatti C, et al. Percutaneous needle aspiration in uncomplicated amebic liver abscess: a randomized trial. Trop Doct. 2013; 43(1):19-22. 45. Paksoy Y, et al. Percutaneous treatment of liver hydatid cysts: comparison of direct injection of albendazole and hypertonic saline solution. AJR Am J Roentgenol. 2005;185(3):727-734. 46. Chen MS, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243(3):321-328. 47. Cucchetti A, et al. Systematic review of surgical resection vs. radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol. 2013;19(26):4106-4118. 48. Feng K, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012;57(4):794-802.

458.e2 49 . Gervais DA, et al. Society of Interventional Radiology position statement on percutaneous radiofrequency ablation for the treatment of liver tumors. J Vasc Interv Radiol. 2009;20:S342-S347. 50. Huang J, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010;252(6):903-912. 51. Xu XL, Liu XD, Liang M, Luo BM. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with metaanalysis and trial sequential analysis. Radiology. 2018;287(2): 461-472.

52. Shady W, Petre EN, Do KG, et al. Percutaneous microwave versus radiofrequency ablation of colorectal liver metastases: ablation with clear margins (A0) provides the best local tumor control. J Vasc Interv Radiol. 2018;29(2):268-275. 53. Elnekave E, et al. Long-term outcomes comparing surgery to embolization-ablation for treatment of solitary HCC ,7cm. Ann Surg Oncol. 2013;20(9):2881-2886. 54. Wang X, et al. Patterns of retained contrast on immediate postprocedure computed tomography (CT) after particle embolisation of liver tumors predicts subsequent treatment response. Cardiovasc Intervent Radiol. 2013;36(4):1030-1038.

CHAPTER 32 Bile duct exploration and biliary-enteric anastomosis Brooke C. Bredbeck and Clifford S. Cho OVERVIEW Minimally invasive techniques to manage biliary pathology have reduced the need for open operative intervention. Although open exploration for biliary disease has become less common, specific situations like obstructive common duct stones not amenable to endoscopic therapy or restoration of biliary-enteric continuity following resection of bile duct tumors remain indications for surgical approaches. It is important to have a thorough understanding of biliary anatomy (see Chapter 2) and a familiarity with various options for operative exposure and management (see Chapter 42). Operative techniques encompassing bile duct exploration and biliary-enteric bypass will be the focus of this chapter.

ANATOMY Knowledge of extrahepatic biliary anatomy and an appreciation of anatomic variants are essential for safe operative conduct (see Chapter 2). The intrahepatic bile ducts draining the various sections ultimately coalesce into the right hepatic duct draining the right hemiliver and the left hepatic duct draining the left hemiliver. These converge at the liver hilum to form the common hepatic duct, which is generally the most anterior structure and lies along the right border of the porta hepatis at this location. In approximately 80% to 90% of cases, the right hepatic artery courses posterior to the common hepatic duct toward the right liver; however, in a minority of cases, it can be found anterior to the duct. The right hepatic duct has a short extrahepatic segment (approximately 1.5–2 cm) in contrast to the left hepatic duct, which traverses beneath segment IVB for approximately 3 to 4 cm after exiting the liver parenchyma. When segment IVB is broad, the left hepatic duct assumes a longer extrahepatic course with a transverse orientation, as opposed to a shorter and more oblique orientation when segment IVB is narrow (Fig. 32.1). The left hepatic duct and left portal vein travel within a peritoneal reflection of the gastrohepatic ligament; exposure of these structures is facilitated by lowering the hilar plate at the base of segment IVB (Fig. 32.2). As the left hepatic duct and left portal vein enter the umbilical fissure, they are joined by the left hepatic artery, and vascular branches to segments II, III, and IV travel with biliary drainage from these segments. To maximize access to these structures, a bridge of hepatic tissue at the base of the umbilical fissure (bridging segments III and IV) must often be divided (Fig. 32.3). The ligamentum teres (obliterated umbilical vein) at the base of the falciform ligament runs across the umbilical fissure, separating segment IV from segments II and III. Segment I hepatic ducts flow into both the right and left biliary systems, with the majority of drainage entering the left hepatic duct just proximal to common hepatic duct. Safe operative conduct requires a close familiarity with anatomic variations of biliary drainage, as they occur in up to 25%

of patients.1 There are a number of ductal anomalies related to the convergence of the left and right hepatic ducts and the insertion of the cystic duct. Although the left biliary system is fairly consistent, the right biliary system is prone to anatomic variation; the most common variants include the right anterior or posterior section ducts traversing a longer extrahepatic course before joining the left biliary system2 (see Chapters 2 and 42).

BILE DUCT EXPLORATION Overview It is estimated that approximately 10% of the US adult population is affected by cholelithiasis, with nearly one-third of these patients requiring cholecystectomy over their lifetime (see Chapter 33). Approximately 10% to 15% of patients undergoing cholecystectomy have choledocholithiasis, and common bile duct stones remain the most common indication for biliary exploration3 (see Chapters 32 and 37). There are a number of techniques available for evaluation and clearance of the common bile duct, including percutaneous, endoscopic, laparoscopic, and open methods (see Chapters 30, 31, and 37). Although open common bile duct exploration (CBDE) is only necessary in a small subset of patients, it is performed at a similar rate to the laparoscopic approach: a review of the NSQIP database between 2008 and 2013 revealed that just over half of 2,635 CBDEs were performed in an open manner.4 This subset includes patients undergoing an open cholecystectomy (or a laparoscopic cholecystectomy converted to open) in which choledocholithiasis is suspected, patients with large or multiple stones, and patients requiring transduodenal sphincteroplasty (see Chapter 117D). Because percutaneous, endoscopic, and laparoscopic modalities are discussed in alternate chapters, OBDE will be the focus of the following section.

Incision and Exposure A right subcostal incision affords satisfactory exposure of the gallbladder, portal structures, and duodenum. Division of the lateral peritoneal attachments of the right colon, followed by mobilization of transverse colon mesentery off of the duodenum, provides visualization of the duodenum (see Chapters 37 and 117). A generous Kocher maneuver facilitates access to the common bile duct located in the lateral border of the hepatoduodenal ligament. Cephalad retraction of the undersurface of the liver at the base of segment IVB will optimize visualization of the extrahepatic biliary system (Fig. 32.4) (see Chapter 119). Additionally, cholecystectomy can enhance exposure of the hepatoduodenal ligament and facilitate intraoperative transcystic cholangiography, which can help to delineate biliary anatomy. Dissection of the gallbladder and cystic duct also identifies the confluence of the cystic duct and common bile duct. Once the common bile duct has been successfully identified, 459

460

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

II

VIII I

VII

III

VI

Segment III pedicle

V

IV

Umbilical fissure

Left hepatic pedicle Right hepatic pedicle FIGURE 32.1  Diagrammatic expanded view of the liver showing its segmental structure (see Chapter 2). Elements of the portal triad are distributed to the right and left liver on a segmental basis. The left hepatic duct always pursues an extrahepatic course beneath the base of segment IV in the groove separating segment IV from the caudate lobe (segment I; see Fig. 32.2). The ligamentum teres marks the umbilical fissure and runs to join the umbilical portion of the left branch of the portal vein. Each portal triad is composed of the hepatic artery, portal vein, and biliary duct. Note the distribution of the left portal triad in the umbilical fissure; major branches recur to segment IV medially, and two major branches pursue a lateral course to segments II and III of the left lobe.

FIGURE 32.3  The bridge of liver tissue frequently present between the base of segment IV and the left lobe of the liver can be divided (see Chapter 2), as illustrated in this approach to a patient with hilar cholangiocarcinoma. This is conveniently done by passing a curved director beneath it and cutting it with diathermy. Such division can be useful in aiding an approach to the left hepatic duct, particularly if the course of the duct is vertical and the base of segment IV is short. If the bridge of tissue is present, the maneuver is always necessary to allow dissection of the segment III duct (see Fig. 32.8).

Segment IV

Anterior

CL

A

B

C

FIGURE 32.2  Sagittal section showing the relationship of segment IV and caudate lobe to the left portal triad, which is encased within a reflection of the lesser omentum that fuses with the Glisson capsule at the base of segment IV. The arrow indicates the point of incision for the dissection to lower the hilar plate (see also Fig. 32.5). A, Left hepatic duct. B, Left branch, portal vein. Note the left hepatic artery (C) joins the left duct and left branch of the portal vein at the umbilical fissure (see Chapter 2).

the overlying peritoneal tissue can be dissected free to allow access to the anterior portion of the duct (see Chapters 37, 42, and 117D).

Supraduodenal Exploration The anterior aspect of the common bile duct is exposed, and two stay sutures are placed on either side of the midpoint of the planned longitudinal incision (see Chapter 37). The choledochotomy should be located anteriorly to avoid compromising

FIGURE 32.4  To optimize exposure of the extrahepatic biliary system, the undersurface of the liver at segment IVB is retracted cephalad. Also depicted here is the initial line of incision for an approach to the left hepatic duct by lowering of the hilar plate. The incision is made at precisely the point at which the Glisson capsule reflects to the lesser omentum (see Fig. 32.2).

blood vessels that typically run along the medial and lateral aspects of the common bile duct and common hepatic duct. To avoid injury to the cystic duct, the site of cystic duct insertion should be identified, as this may occur in a medial or posterior location. During the incision, caution should be taken to avoid injuring the posterior wall of the duct. The length of the choledochotomy will depend on the diameter of the duct and size of stones present with the lumen, but is generally 1 to 2 cm. Another consideration regarding the location of this incision is

  Chapter 32  Bile Duct Exploration and Biliary-Enteric Anastomosis

461

proximity to the duodenum; in the event that a choledochoduodenostomy may be required for appropriate drainage, every effort should be made to position the incision distally enough to permit a tension-free anastomosis to the proximal duodenum. After choledochotomy, flushing of the duct (distally toward ampulla) with saline irrigation can result in expulsion of stones. Following this, a deflated Fogarty balloon catheter is passed distally through the ampulla into the duodenum. Once the tip of the catheter is palpated within the duodenal lumen, the balloon is inflated, and the catheter is withdrawn until resistance is encountered, indicating that the balloon is positioned against the sphincter of Oddi. The balloon is slowly and partially deflated while applying continuous tension, allowing passage into the distal common bile duct. At this point, the balloon is carefully reinflated, and the catheter is swept proximally, sweeping retained stones up toward the cholodochotomy. This process is repeated until no stones return. The catheter is then passed proximally to retrieve any stones within the common hepatic duct and intrahepatic biliary tree. Rigid instruments such as clamps or stone forceps can cause injury to the bile duct and should therefore be used with caution. A choledochoscope can be utilized to visualize remnant stones, which can be captured with basket retrieval in which the basket is passed beyond the stone, opened, and pulled back to ensnare the stone. The choledochoscope and associated basket with stone are then withdrawn. At the conclusion of duct exploration, confirmation of proximal and distal duct clearance is performed either by choledochoscopy or completion cholangiography.5

closure.6 Another meta-analysis found primary closure superior to T-tube closure in laparoscopic CBDE when comparing rates of postoperative biliary peritonitis, operative time, length of hospital stay, and hospital expenses.7 If a T-tube is employed, use of a 14-French (Fr) or larger size will permit cholangiography and choledochoscopy. The T-tube is prepared by cutting two limbs at lengths that will not traverse into the left or right hepatic duct proximally or into the duodenum distally, and excising the back wall of the horizontal portion of the T (to minimize the risk of tube occlusion and to facilitate eventual tube removal). The tube is inserted through the choledochotomy, and the remainder of the duct is closed with fine absorbable sutures around the tube. Care should be taken to leave enough redundancy in the intraperitoneal portion of the tube to avoid tension (and possible tube dislodgement) in the event of significant postoperative abdominal distension. Postoperatively, the T-tube is placed to dependent drainage until resolution of postoperative papillary edema allows physiologic flow of bile into the duodenum. If persistently elevated output or drainage around the tube occurs, investigation via cholangiography can identify malfunction, dislodgement, or distal obstruction secondary to retained stone. If the results of a repeat cholangiogram at approximately 2 to 3 weeks are normal, the T-tube may be removed. If choledocholithiasis persists, the T-tube can be clamped to promote stone passage. If signs or symptoms of cholangitis occur, the tube can be unclamped and repeat imaging is obtained. Residual obstruction may be amenable to stone extraction via T-tube or endoscopic or percutaneous access (see Chapter 37A).

Transduodenal Exploration

Outcomes

When an impacted stone at the distal common bile duct cannot be cleared via choledochotomy, a transduodenal approach can be employed. A 2- to 4-cm longitudinal incision on the lateral aspect of the second portion of the duodenum allows visualization of the ampulla. Stay sutures are placed on either side of the incision to maximize exposure (see Chapters 37 and 117D). If there is difficulty visualizing the ampulla, a small catheter can be passed through the choledochotomy into the duodenum. A sphincterotomy is performed at the 11 o’clock position to follow the direction of the bile duct, and the sphincter is incised to the level of the impacted stone or probe. This location minimizes the chance of pancreatic duct injury, which is generally located opposite the planned sphincterotomy site. The stone is then extracted, and the common bile duct mucosa is approximated to the duodenal mucosa with absorbable sutures (sphincteroplasty) to avoid postoperative papillary stenosis. Once again, a catheter is passed to ensure resolution of obstruction, and choledochoscopy or cholangiography is used to confirm the absence of residual stones. The duodenotomy is typically closed in one layer.5 If sphincteroplasty is not successful, the obstruction can be bypassed with a choledochoduodenostomy (discussed later).

Open CBDE is safe and effective, although endoscopic and laparoscopic modalities may now have more favorable risk profiles as these techniques have matured (see Chapters 30, 37B, and 37C). The most recent Cochrane review primarily reflects outcomes from the early endoscopic and laparoscopic era, with 10 of 16 trials published before 2000. Within this analysis, open CBDE and endoscopic retrograde cholangiopancreatography (ERCP) had similar rates of mortality (1% vs. 3%) and morbidity (20% vs. 19%), respectively.8 A recent prospective randomized trial demonstrated lower morbidity and shorter length of stay for laparoscopic versus open CBDE.9 Compared with laparoscopic CBDE, a recent meta-analysis found that endoscopic retrograde cholangiogram and sphincterotomy was associated with a higher common bile duct stone clearance rate and lower postoperative bile leakage rate, but a higher rate of pancreatitis.10 Although it may incur greater morbidity compared with less invasive techniques, open CBDE overall remains a highly effective and safe way to clear common bile duct stones, especially when other modalities are not an option (see Chapter 38).

T-Tubes T-tube insertion for choledochotomy closure has historically been used to drain bile in the setting of common bile duct or papillary edema and to facilitate postoperative duct access. Disadvantages include tube migration, obstruction, and bile leak. A meta-analysis of open CBDEs found that primary closure is equivalent in morbidity and mortality and decreases both operative time and hospital stay compared with T-tube

BILIARY-ENTERIC ANASTOMOSIS Overview There are three key aspects to consider when planning a biliaryenteric anastomosis: identification of a healthy segment of bile duct tissue proximal to the site of obstruction; preparation of a segment of alimentary tract such as duodenum or, more commonly, Roux-en-Y jejunal limb; and construction of a mucosato-mucosa anastomosis (see Chapter 42). It is important

462

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

to use preoperative imaging to clearly delineate the biliary anatomy before undertaking operative intervention for biliary decompression, but invasive cholangiography is no longer necessary to delineate biliary anatomy in the great majority of cases. Cross-sectional imaging with magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) (or high-resolution computed tomography [CT]) can accurately characterize the anatomy of the biliary tree and underlying pathology (see Chapter 16). Instrumentation of the biliary tree introduces bacterial contamination that, in a setting of biliary stasis, can result in cholangitis, periductal inflammation, and a higher risk of postoperative infections. Likewise, insertion of a percutaneous drain into an excluded biliary segment will result in bacterial colonization of static bile. If that hepatic segment cannot be decompressed by a subsequent operative intervention, it will not be possible to remove the external drain without risking refractory cholangitis. These complexities underscore the critical importance of an experienced multidisciplinary team reviewing and treating complex biliary obstruction, particularly at the biliary confluence. Depending on the underlying pathology, there are a number of options for restoring biliary continuity with the alimentary tract. For instance, benign etiologies such as iatrogenic bile duct injury, strictures from previous biliary-enteric operations, choledochal cysts, or inflammatory strictures may require restoration with Roux-en-Y choledochojejunostomy or hepaticojejunostomy. Additionally, benign proximal biliary strictures as well as malignancy (cholangiocarcinoma) may require anastomosis between intrahepatic ducts and jejunum (see Chapters 42, 51, and 119B). Choledocholithiasis refractory to local exploration may require choledochoduodenostomy. Benign ampullary adenomas and papillary stenosis that fail endoscopic management may be treated with transduodenal surgical ampullectomy. Finally, the gallbladder may also be utilized to facilitate drainage (cholecystoduodenostomy and cholecystojejunostomy). Although nonoperative measures can be utilized in most situations, familiarity with the various surgical techniques enables appropriate restoration of biliary-enteric continuity when the situation demands.

Incision and Exposure A right subcostal incision with or without an upper midline extension or a left subcostal extension followed by upward elevation and cephalad retraction of the costal margin provides adequate exposure for construction of any biliary-enteric anastomosis (see Chapters 37 and 42). The ligamentum teres is ligated and divided, and the falciform ligament is divided to its most cephalad extent on the diaphragm. Retraction of the ligamentum teres is helpful for optimal visualization of the vascular inflow and biliary drainage of segments II, III, and IV. If direct decompression of the gallbladder is not to be undertaken, cholecystectomy can be advantageous for identification of the cystic duct, which can be dissected to its point of insertion onto the common hepatic duct. Cholecystectomy will also expose the cystic plate, which runs in continuity with the hilar plate. By lowering the hilar plate, the left hepatic duct may be exposed as it runs against the base of segment IVB.11 Mobilization of the right colon with caudal retraction, followed by a generous Kocher maneuver, will further enhance exposure for biliary-enteric bypass. Caution must be exercised in the setting of long-standing biliary obstruction or conditions associated with ipsilateral hepatic atrophy and contralateral hypertrophy. In the scenario of marked right hemiliver atrophy, the liver hilum and portal

structures will become rotated in a counterclockwise manner. Consequently, the portal vein will assume a more anterior location and the common bile duct or common hepatic duct will be posteriorly displaced. Hypertrophy of segment IV protrudes over the porta hepatis and may provide additional complexity for access to the hilum and left biliary system.12

Hepaticojejunostomy Roux-en-Y hepaticojejunostomy is used to create a large tension-free anastomosis to healthy hepatic ducts that drain all biliary segments. The proximal jejunum should reach easily to the hepatic duct confluence in the right upper quadrant, where the biliary anastomosis will take place. If this approach is not feasible due to tumor infiltration or a high stricture, drainage can be obtained via the right hepatic duct or left hepatic duct (discussed later). Moreover, ducts draining segments II and III can be utilized when the left hepatic duct is not accessible.2 Disadvantages include the necessity for two anastomoses and exclusion of bile from the duodenum (see Chapters 37 and 42).

Approach to Right Hepatic Duct As the portal pedicles enter the liver parenchyma, they remain enclosed within a fibrous sheath derived from Glisson capsule (see Chapter 2). Access to the right portal pedicle containing the right hepatic duct can be achieved by isolating the pedicle in an extrahepatic location or by exposing the pedicle via intrahepatic dissection (see Chapter 42). The extrahepatic approach begins by lowering the hilar plate; the peritoneum along the posterior aspect of segment IV is divided, allowing separation of Glisson capsule from the peritoneal reflection enveloping the porta hepatis. By reflecting the base of segment IV in a cephalad direction, this dissection effectively exposes the confluence of the right and left hepatic duct. By continuing this plane of dissection to the right (onto the cystic plate), the right hepatic duct may be exposed.13 If the extrahepatic portion of the right hepatic duct is too short to be visualized in this way (as is often the case), the intrahepatic approach may be used. This requires hepatotomies in the caudate process just posterior to the porta hepatis and along the base of the gallbladder fossa. A blunt right angle clamp may be passed between these hepatotomies to encircle the right pedicle, which can then be delivered for further dissection to identify the right hepatic duct, or the anterior or posterior sectional ducts (Fig. 32.5).14

Approach to Left Hepatic Duct The left hepatic duct traverses an extrahepatic course below segment IVB from the umbilical fissure to the porta hepatis. After ligation of the ligamentum teres with a firm tie, retraction is applied to elevate the left hemiliver. The bridge of tissue at the base of the umbilical fissure contains no large vessels and can be divided to provide mobility of the base of segment IVB, and to enhance exposure of the left portal pedicle (see Fig. 32.3). The left hepatic duct runs with the left portal vein and is exposed by lowering the hilar plate (Fig. 32.6). Dissection toward the hepatic confluence to expose an adequate segment of the left hepatic duct is facilitated by retracting segment IVB anteriorly2 (see Chapter 42).

Approach to Segment III Duct The presence of a bulky unresectable tumor at the hepatic hilus may require construction of a more proximal anastomosis. This can be achieved by exposing the biliary drainage of the left

  Chapter 32  Bile Duct Exploration and Biliary-Enteric Anastomosis

A

463

B

FIGURE 32.5  A, Exposure of the right hepatic pedicle in the setting of a cholangiocarcinoma extending into the left hepatic duct. Intrahepatic exposure of the right hepatic duct is accomplished initially by controlling the right portal pedicle. After performing hepatotomies in the caudate process just posterior to the porta hepatis and along the base of the gallbladder fossa, a blunt right angle can be used to facilitate encircling and delivery of the right pedicle. The overlying hepatic parenchyma is further dissected, which allows identification of the right hepatic duct and the anterior or posterior sectional ducts. B, The relevant duct, usually the anterior sectoral duct, is opened, and anastomosis is carried out.

biliary obstruction, patients experienced durable relief of jaundice and pruritis, with an 80% patency rate at one year.15 After ligation and retraction of the ligamentum teres, the band of liver parenchyma at the base of the ligamentum teres joining segment III and IVB (if present) is divided to enhance exposure of the segment III duct (which, if dilated, may be more readily apparent). This exposure can be facilitated by fashioning a superficial hepatotomy along the left of the ligamentum teres, through which the segment III duct may be exposed and opened without risk of injury to the vascular pedicle to segment III (Fig. 32.7). In circumstances in which identification is difficult, localization can be confirmed by aspiration with a small gauge needle. On occasion, a wedge resection of a portion of segment III can also be performed to provide exposure of the segment III duct (Fig. 32.8).11 To prepare for biliaryenteric anastomosis, the duct should be dissected free for 1.5 cm but should not be cleared circumferentially (to minimize devascularization injury). A defunctionalized jejunal loop is then brought up in a retrocolic fashion and prepared for anastomosis (see Chapter 42).

Construction of Anastomosis

FIGURE 32.6  The hilar plate is lowered, and the left hepatic duct is exposed for dissection. The exposure is carried medially and to the right to expose the confluence and the right hepatic duct.

hemiliver within the umbilical fissure.11,15,16 If the left hemiliver has not atrophied from long-standing biliary obstruction, unilateral left-sided biliary decompression will effectively relieve obstructive jaundice and restore hepatic function, even when the biliary drainage of the excluded right hemiliver remains obstructed. In a series evaluating segment III bypass for malignant

For the purposes of Roux-en-Y reconstruction, the most proximal loop of jejunum that can be brought to lie against the planned site of anastomosis without tension is selected. The jejunum is transected and a Roux limb of 50 to 70 cm is passed in a retrocolic fashion through the avascular portion of the transverse mesocolon to the right of the middle colic artery. The jejunojejunostomy may be fashioned in a sutured or stapled manner. We do not typically employ a transanastomotic stent; however, if a stent is to be used, it is preferable to pass the stent through the cut hepatic duct before construction of the anastomosis. The stent may be affixed against the duct wall with a single 4-0 or 5-0 absorbable catgut suture, which is tied on the outside of the duct wall (Fig. 32.9); this maneuver helps to avoid inadvertent dislodgment of the tube during placement of the anastomotic sutures. When more than one biliary duct

464

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

A

B

C

D

FIGURE 32.7  A, The liver is held up so that its inferior surface is seen. The bridge of liver between segment IV and the left lobe of the liver has been divided. The base of the ligamentum teres is seen. B, The ligamentum teres is then pulled downward. The peritoneum of its upper surface on the left side is incised, and the extensions passing into the liver are exposed. The left sides of these extensions are divided between ligatures, which must be passed carefully using aneurysm needles. This part of the dissection is tedious and should be carried out meticulously because hemorrhage within the recess adjacent to the segment III duct can be difficult to control. C, The segment III duct is exposed. D, The duct is opened longitudinally for anastomosis, which is carried out by the technique illustrated in Fig. 32.13.

orifice is present, it is preferable to create a single duct orifice by approximating the two ducts with a single row of 4-0 or 5-0 absorbable sutures (Fig. 32.10). The hepaticojejunostomy may be performed using an endto-side or side-to-side anastomosis. Side-to-side anastomosis usually requires less dissection (preserving vascular supply) and allows for a wider anastomosis, which may decrease risk of stricture.17 A study examining the two anastomoses in a series of 125 type 1a choledochal cysts found that about 10% of the end-to-side group experienced stricture after two years followup, compared with none in the end-to-side group.18 A side-to-side anastomosis is especially useful in the setting of left hepatic duct or segment III duct hepaticojejunostomy (see Fig. 32.6). Additionally, benign strictures (e.g., iatrogenic) can be approached in this fashion. When decompression is undertaken at the level of the proximal hepatic duct, increased length may be achieved by extending the incision onto the left hepatic duct. A longitudinal ductotomy of approximately 2.5 to 3.0 cm is performed, with a corresponding jejunotomy on the

antimesenteric border, 2 cm from the staple line. An anterior row of full-thickness, single interrupted 4-0 or 5-0 absorbable sutures passed from outside to inside are retracted to allow exposure for placement of the posterior row. Full-thickness, single interrupted 4-0 or 5-0 absorbable sutures approximate the inferior edge of the duct to the superior edge of jejunum. Following placement, the posterior row of sutures is tied. Subsequently, the preplaced anterior row of sutures is used to complete the anastomosis; they are passed from inside to outside on the jejunum, and the knots are tied.17 For an end-to-side hepaticojejunostomy, the bile duct segment is transected, and an adjacent jejunotomy is fashioned at a safe distance from the mesenteric margin of the bowel approximately 2 cm from the staple line. The jejunotomy length should be shorter than the ductotomy, as the bowel is more pliable than the duct. An anterior row of full-thickness, single interrupted 4-0 or 5-0 absorbable sutures is placed in the bile duct passed from inside to outside and working from the patient’s left to right. This row of sutures, with needles intact, is

  Chapter 32  Bile Duct Exploration and Biliary-Enteric Anastomosis

465

A

A

B

FIGURE 32.8  A, The liver is split to the left of the ligamentum teres in the umbilical fissure, and it may be necessary to remove a small wedge of liver tissue. B, The segment III duct is exposed at the base of the liver split above and behind its accompanying vein and is ready for anastomosis.

FIGURE 32.10  Adjacent ductal orifices may be approximated before anastomosis.

FIGURE 32.9  Manner of fixation of transanastomotic tubes. Note the introduction of the absorbable suture in a mattress fashion across the ductal wall, proximal to the future site of anastomosis. This secures the tube conveniently during anastomosis.

retracted and elevated; this maneuver effectively pulls the anterior aspect of the duct away, facilitating exposure and placement of the posterior row of sutures (Fig. 32.11). A single, full-thickness posterior row of interrupted 4-0 or 5-0 absorbable sutures is used to approximate the inferior edge of the biliary duct to the superior edge of jejunum, also working from patient’s left to right. These sutures are tied and cut short except for the two corner sutures, which are secured with clamps.

The previously placed row of anterior sutures is then used to complete the anastomosis. Each needle is passed through the jejunum, tied, and cut short; the corner stay sutures are then cut (see Chapters 42 and 119B).

Choledochojejunostomy In cases of distal obstruction, a choledochojejunostomy decompresses the biliary tree, using the common hepatic or common bile duct. Causes of distal obstruction include ampullary stone(s), iatrogenic injuries, benign strictures not amenable to endoscopic management, and unresectable periampullary tumors in which biliary stenting is not effective. Advantages of a surgical approach versus nonoperative decompressive modalities are long-term patency and durability without the need for repeat stent placement or revision. Choledochojejunostomy can be performed as an end-to-side or side-to-side anastomosis. For the end-to-side technique, a cholecystectomy with cystic duct ligation is performed followed

466

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

wall of the duct is sutured to the jejunum with a running 3-0 or 4-0 absorbable suture. The tail of the suture and needle are left intact. A jejunotomy is fashioned along the duct, and single interrupted 3-0 or 4-0 absorbable sutures are used to approximate the jejunal mucosa to the duct mucosa, with the knots tied on the inside of the lumen. The anterior portion of the anastomosis is then completed using the running suture used to construct the posterior row (Fig. 32.12). Because of the small lumen, the anastomosis is generally completed with a single layer to avoid narrowing. Placement of a sponge circumferentially around the anastomosis allows for an intraoperative test to confirm absence of a large bile leak. The alternative approach of constructing a side-to-side anastomosis offers the advantages of less devascularization with the use of a nontransected duct, and preservation of biliary-duodenal continuity (in case future ERCP should be desirable).17 To perform this anastomosis, the anterior surface of the duct is exposed and opened longitudinally for a distance of 2.5 to 3.0 cm, avoiding the medial and lateral locations of periductal vasculature. The biliary-enteric anastomosis can then be completed in a similar manner as described for side-to-side hepaticojejunostomy (see previous discussion). A single, interrupted anterior (or right) row of sutures allows exposure for placement of the posterior (or left) row approximating duct to jejunum, followed by completion of the anterior row17 (see Chapters 42 and 119B).

A

Choledochoduodenostomy

B FIGURE 32.11  A, The initial step in the creation of hepaticojejunostomy Roux-en-Y. The anterior layer of suture (3-0 Vicryl) on the bile duct is inserted first, and the sutures are passed from the inside out, starting from the patient’s left and working toward the right. The needles are retained, and the sutures are kept in order. B, The anterior layer of sutures is elevated. This displays the posterior ductal wall, and the posterior row of sutures is now placed, again from left to right.

by ligation of the common bile duct or common hepatic duct (hepaticojejunostomy) at the level of planned transection. The duct is opened at the level of the planned anastomosis, and the endobiliary stent (if present) is removed. If desired, bile cultures may also be collected at this time. The remainder of the common bile duct is transected, and the distal stump is oversewn with 3-0 absorbable suture. It is important to identify a healthy, well-vascularized duct proximal to the level of injury or pathology to avoid ischemic stricture. Similarly, care should be taken to avoid excessive circumferential dissection of the duct, as this can compromise its blood supply. A 50- to 70-cm Roux-en-Y limb of jejunum is passed in a retrocolic position to the right of the middle colic vessels, and positioned to reside adjacent to the proximal bile duct in a tension-free manner. The posterior

While choledochoduodenostomy has the physiologic advantage of enabling bile flow into the duodenum, this procedure is effective only for distal strictures or impacted stone(s) in the distal common bile duct. After mobilization of the hepatic flexure of the colon, a generous Kocher maneuver is performed to allow sufficient mobility of the duodenum to enable construction of a tension-free anastomosis. The gallbladder is removed and the cystic duct is ligated. A 2.5- to 3.0-cm longitudinal incision is made on the anterior surface of the supraduodenal common bile duct. Correspondingly, the duodenum adjacent to the common bile duct is incised longitudinally along its superolateral border (Fig. 32.13). This produces incisions that are perpendicular to one another (unlike the parallel configuration used during hepaticojejunostomy). As with the hepaticojejunostomy, the duodenotomy is generally shorter in length than the ductotomy. The anastomosis is then constructed in a manner that anastomoses the bile duct transversely to the longitudinally oriented duodenotomy. Three corner 4-0 or 5-0 absorbable sutures are placed: the first two are positioned between the midpoints of the ductotomy and proximal and distal aspects of the duodenotomy, and the third is placed between the distal aspect of the common bile duct incision and midpoint of the superior lip of the duodenotomy. Traction on the three corner sutures reorients the distal portion of the ductotomy transversely, facilitating placement of the posterior row of absorbable sutures between the superior edge of the duodenotomy and the distal half of the common bile duct. Full-thickness sutures are used to approximate the ductal mucosa to duodenal mucosa. A fourth corner suture can then be placed between the proximal end of the ductotomy and the midpoint of the anterior duodenal wall. Retraction of this fourth corner suture tents the remaining anterior wall of the anastomosis forward, facilitating placement of the remaining anterior row of sutures (Fig. 32.14). As before, use of a single row of sutures minimizes the risk of anastomotic narrowing (see Chapter 42).

  Chapter 32  Bile Duct Exploration and Biliary-Enteric Anastomosis

467

II I A

III

IV

B

FIGURE 32.12  A, Technique for end-to-side anastomosis of the bile duct below the hilus to jejunum. I, A 3-0 Vicryl suture is used, and the serosa of the jejunum is sutured to the full thickness of the bile duct. II, This suture is developed as the posterior wall of the bile duct is attached to the jejunal serosa. The dotted line marks the point of incision in the jejunum, which is made after the posterior layer is attached. III, The suture is now developed either as a continuous or an interrupted suture on the anterior layer. The posterior layer of the jejunal mucosa is not sutured directly to the bile duct mucosa. Several interrupted sutures may be inserted before completing the anterior layer, however, to approximate the mucosa (inset). IV, The anastomosis is completed. The inset shows the posterior layer with mucosal apposition. B, Alternatively, the jejunum may be opened, and a mucosato-mucosa anastomosis may be performed with a continuous polydioxanone suture as illustrated.

468

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

FIGURE 32.13  After the gallbladder is removed, the common bile duct is removed through a conventional longitudinal incision following a Kocher incision (1) freeing the lateral duodenum around the common duct. Routine common duct exploration is carried out. If indications for a choledochoduodenostomy exist, the anastomosis is performed. The incision in the common duct (2) is extended to 2.5 cm by direct measurement. In almost all instances, the incision in the duct carries into the common hepatic duct. The incision in the postbulbar duodenum (3) is slightly smaller because the stoma in the duodenum stretches to approximate the choledochal incision. 2

3

1

D

C B B

A

A

A

B

D

A

E B

C

D

FIGURE 32.14  A, Each side of the choledochoduodenostomy is bisected by suture (A and B) of absorbable material (Vicryl or PDS) that passes from the end of the duodenal incision through the midpoint of the choledochal incision. Likewise, the duodenal incision is bisected by a suture through the posterior wall of the duodenal incision and the lower apex of the choledochal incision (C). These stitches convert part of the longitudinal choledochotomy incision into a transverse ostium. The lax approximation of the duodenal and choledochal incisions occurs, with the duodenum mobilized, by placing tension on a lateral stay suture (A or B) and the middle stay suture (C). B, Sutures may be placed to complete the posterior suture line approximating the common bile duct to the posterior duodenal incision. After placement of the sutures, they are tied so that the knots are within the lumen. The anterior wall is similarly approximated using a suture bisecting the anterior duodenal incision (D) and through the original apex of the bile duct incision. C, With this bisecting suture (D) tented forward, each of the segments between the tied lateral stay suture and this anterior suture is similarly approximated using interrupted sutures with the knots tied on the outside. The anastomosis is completed by completing the third segment of this triangle with sutures placed between the remaining lateral stay suture and the bisecting, anterior suture (D). It is important in the placement of these last sutures that they do not catch the posterior suture line. The benefit of placing all the sutures in one line of the triangular closure and tying them all after placement is that it allows an internal inspection before the lumen of the choledochoduodenostomy is obscured. A single row of sutures is all that is used. A second row does nothing but decrease the choledochoduodenostomy orifice size and should be avoided. The sutures should be placed close enough for a bile-tight approximation. Digital pressure on the duodenum or the common duct should give no evidence of leakage. D, The completed anastomosis allows a thumb-sized defect to be palpated through the duodenal tongue that has been brought on to the common bile duct and common hepatic duct. The anastomosis may be drained or not, according to preference (the leak rate is 1%). The presence of a closed-suction drain (Jackson-Pratt type) obviates the need for a subsequent percutaneous drainage catheter if this uncommon complication occurs.

  Chapter 32  Bile Duct Exploration and Biliary-Enteric Anastomosis

decompress the extrahepatic biliary ducts. As a result, use of cholecystoduodenostomy or cholecystojejunostomy is limited to circumstances of advanced malignancy that require simple operative interventions and only short-term palliation.20 Cholecystoenterostomy may be suitable in situations where major tumoral obstruction obscures access to the porta hepatis; however, the obstruction must not extend to the level of the cystic duct insertion. The presence of cholelithiasis is another consideration, as significant stone burden within the gallbladder makes this operative strategy less attractive. Operatively, the gallbladder and cystic duct are evaluated to ensure their suitability for biliary decompression. To construct a cholecystoduodenostomy, a Kocher maneuver is used to provide enough duodenal mobility for a tension-free anastomosis. If cholecystojejunostomy is performed, the most proximal loop of jejunum that will easily lie adjacent to the gallbladder is selected; a Roux-en-Y is not routinely performed. The gallbladder fundus is secured to the antimesenteric border of duodenum or jejunum with interrupted 3-0 absorbable sutures. A cholecystotomy is performed and the gallbladder evacuated of stones and bile; a bile specimen can be sent for analysis. Continuity with the common hepatic duct is confirmed, and a corresponding enterotomy mirroring the cholecystotomy is fashioned. An anterior row of sutures is then placed to complete the anastomosis (Fig. 32.16) (see Chapter 37).

Transduodenal ampullectomy Transduodenal ampullectomy is used for benign ampullary tumors and strictures not amenable to endoscopic therapy, as well as symptomatic pancreas divisum. It is substantially less morbid than the alternative of pancreaticoduodenectomy and generally well tolerated, with success rates of over 80%.19 After adequate exposure, a longitudinal duodenotomy on the anterior surface of D2 is made to gain access to the ampulla. It can be helpful to place stay sutures of 3-0 PDS along the duodenal mucosa circumferentially around the ampullary mass, as retraction of these sutures can help to visualize the area surrounding the ampulla. As the ampullary mass is excised, stay sutures of 4-0 or 5-0 PDS can be placed along the cut edges of the biliary and pancreatic ducts to facilitate their identification. After excision of the ampulla, the biliary and pancreatic ducts are joined with sutures to create a common ostium. Reinsertion of the duct is accomplished with interrupted duct-tomucosa sutures of 4-0 or 5-0 PDS, and the duodenotomy is closed in one layer (Fig. 32.15) (see Chapter 117D).

Cholecystoduodenostomy and Cholecystojejunostomy Less common approaches to biliary bypass are cholecystoduodenostomy or cholecystojejunostomy. The cholecystoenteric bypass is relatively easy to construct, but long-term patency rates are suboptimal compared with maneuvers that directly

A

469

B

C FIGURE 32.15  Technique of transduodenal ampullectomy. A, Stay sutures of 3-0 PDS are placed along the duodenal mucosa circumferentially about the ampullary mass to facilitate exposure of the periampullary space. B, On removal of the ampullary mass, the luminal openings of the distal common bile duct and pancreatic duct are visible (the instrument is indicating the pancreatic duct orifice). C, The anastomosis is completed with a series of interrupted 4-0 PDS sutures between the common bile duct and pancreatic duct wall and the surrounding duodenal mucosa (see Chapter 117D).

470

PART 4  TECHNIQUES OF BILIARY TRACT INTERVENTION: RADIOLOGIC, ENDOSCOPIC, AND SURGICAL

B

A

C FIGURE 32.16  Technique of cholecystojejunostomy. A, The cystic duct should join the common bile duct above the tumor. If it enters at the level of the tumor (dashed line), the procedure is contraindicated. B, The posterior layer of the anastomosis is performed with a running suture between the openings at the fundus of the gallbladder and the jejunum. C, The anterior layer of the side-to-side anastomosis is completed.

Outcomes A recent single institution retrospective analysis of 45 patients undergoing reconstruction after biliary injury measured a postoperative biliary fistula rate of 3%, and a biliary stricture rate of less than 5% over four years.17 Other analyses have also confirmed the safety and longevity of biliary decompression, with low rates of fistula and stricture formation necessitating subsequent operative intervention.15,21–23 Although the limited number of patients requiring biliary-enteric bypass prohibits comparative analysis of the various techniques, the larger series demonstrate low perioperative morbidity and mortality and adequate long-term patency.

In patients undergoing bypass for benign disease, consideration should be given to prolonged clinical monitoring, as there appears to be both a risk of delayed stricture and an elevated risk of cholangiocarcinoma. In a review of 1,003 patients undergoing biliary decompression, cholangiocarcinoma developed in 5.8% of patients after transduodenal sphincteroplasty, 7.6% of patients after choledochoduodenostomy, and 1.9% of patients after hepaticojejunostomy after an interval of 132 to 218 months.24 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

470.e1

REFERENCES 1. Babel N, Sakpal SV, Paragi P, Wellen J, Feldman S, Chamberlain RS. Iatrogenic bile duct injury associated with anomalies of the right hepatic sectoral ducts: a misunderstood and underappreciated problem. HPB Surg. 2009;2009:153269. 2. Blumgart LH, Kelley CJ. Hepaticojejunostomy in benign and malignant high bile duct stricture: approaches to the left hepatic ducts. Br J Surg. 1984;71:257-261. 3. Chen H, Jorissen R, Walcott J, Nikfarjam M. Incidence and predictors of common bile duct stones in patients with acute cholecystitis: a systematic literature review and meta-analysis. ANZ J Surg. 2020;90:1598-1603. 4. Halawani HM, Tamim H, Khalifeh F, et al. Outcomes of laparoscopic vs open common bile duct exploration: analysis of the NSQIP database. J Am Coll Surg. 2017;224:833. 5. Verbesey JE, Birkett DH. Common bile duct exploration for choledocholithiasis. Surg Clin North Am. 2008;88:1315-1328. 6. Gurusamy KS, Koti R, Davidson BR. T-tube drainage versus primary closure after open common bile duct exploration. Cochrane Database Syst Rev. 2013;2013(6):CD005640. 7. Podda M, Polignano FM, Luhmann A, Wilson MS, Kulli C, Tait IS. Systematic review with meta-analysis of studies comparing primary duct closure and T-tube drainage after laparoscopic common bile duct exploration for choledocholithiasis. Surg Endosc. 2016;30:845-861. 8. Dasari BVM, Tan CJ, Gurusamy KS, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013;2013(12):CD003327. 9. Grubnik VV, Tkachenko AI, Ilyashenko VV, Vorotyntseva KO. Laparoscopic common bile duct exploration versus open surgery: comparative prospective randomized trial. Surg Endosc. 2012;26: 2165-2171. 10. Lyu Y, Cheng Y, Li T, Cheng B, Jin X. Laparoscopic common bile duct exploration plus cholecystectomy versus endoscopic retrograde cholangiopancreatography plus laparoscopic cholecystectomy for cholecystocholedocholithiasis: a meta-analysis. Surg Endosc. 2019;33:3275-3286. 11. Blumgart LH. Surgical approaches to the left hepatic duct. Langenbecks Arch Chir. 1987;370:235-249. 12. Pottakkat B, Vijayahari R, Prasad KV, et al. Surgical management of patients with post-cholecystectomy benign biliary stricture

complicated by atrophy-hypertrophy complex of the liver. HPB 2009;11:125-129. 13. Strasberg SM, Linehan DC, Hawkins WG. Isolation of right main and right sectional portal pedicles for liver resection without hepatotomy or inflow occlusion. J Am Coll Surg. 2008;206:390-396. 14. Launois B, Jamieson GG. The posterior intrahepatic approach for hepatectomy or removal of segments of the liver. Surg Gynecol Obstet. 1992;174:155-158. 15. Jarnagin WR, Burk E, Powers C, Fong Y, Blumgart LH. Intrahepatic biliary enteric bypass provides effective palliation in selected patients with malignant obstruction at the hepatic duct confluence. Am J Surg. 1998;175:453-460. 16. Voyles CR, Bowley NJ, Allison DJ, Benjamin IS, Blumgart LH. Carcinoma of the proximal extrahepatic biliary tree radiologic assessment and therapeutic alternatives. Ann Surg. 1983;197:188-194. 17. Winslow ER, Fialkowski EA, Linehan DC, Hawkins WG, Picus DD, Strasberg SM. “Sideways”: results of repair of biliary injuries using a policy of side-to-side hepatico-jejunostomy. Ann Surg. 2009; 249:426-434. 18. Xia HT, Liu Y, Yang T, Liang B, Wang J, Dong JH. Better long-term outcomes with hilar ductoplasty and a side-to-side Roux-en-Y hepaticojejunostomy. J Surg Res. 2017;215:21-27. 19. Schneider L, Contin P, Fritz S, Strobel O, Büchler MW, Hackert T. Surgical ampullectomy: an underestimated operation in the era of endoscopy. HPB (Oxford). 2016;18:65-71. 20. Dayton MT, Traverso W, Longmire Jr WP. Efficacy of the gallbladder for drainage in biliary obstruction. Arch Surg. 1980;115:1086-1089. 21. Murr MM, Jean-Francois G, Nagorney DM, Harmsen WS, Ilstrup DM, Farnell MB. Long-term results of biliary reconstruction after laparoscopic bile duct injuries. Arch Surg. 1999;134:604-610. 22. Chapman WC, Halevy A, Blumgart LH, Benjamin IS. Postcholecystectomy bile duct strictures: management and outcome in 130 patients. Arch Surg. 1995;130:597-604. 23. Tocchi A, Costa G, Lepre L, Liotta G, Mazzoni G, Sita A. The long-term outcome of hepaticojejunostomy in the treatment of benign bile duct strictures. Ann Surg. 1996;224:162-167. 24. Tocchi A, Mazzoni G, Liotta G, Lepre L, Cassini D, Miccini M. Late development of bile duct cancer in patients who had biliaryenteric drainage for benign disease: a follow-up study of more than 1000 patients. Ann Surg. 2001;234:210-214.

PART 5

Biliary Tract Disease I. Inflammatory, Infective, and Congenital

A. Gallstones and Gallbladder



33 The Natural History of Symptomatic and Asymptomatic Gallstones



34 Cholecystitis



35 Percutaneous Treatment of Gallbladder Disease



36 Cholecystectomy Techniques and Postoperative Problems



37A Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques



37B Stones in the Bile Duct: Minimally Invasive Surgical Approaches



37C Stones in the Bile Duct: Endoscopic and Percutaneous Approaches



38 Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?



39 Intrahepatic Stone Disease



B. Biliary Stricture and Fistula



40 Extrahepatic Biliary Atresia



41 Primary Sclerosing Cholangitis



42 Benign Biliary Strictures and Biliary Fistulae



C. Biliary Infection and Infestation



43 Cholangitis



44 Recurrent Pyogenic Cholangitis



45 Biliary Parasitic Disease



D. Cystic Disease of the Biliary Tract 46 Bile Duct Cysts in Adults

II Neoplastic



A. General 47 Tumors of the Bile Ducts: Pathologic Features

B. Benign Tumors 48 Benign Tumors and Pseudotumors of the Biliary Tract

471



C. Malignant Tumors



49 Tumors of the Gallbladder



50 Intrahepatic Cholangiocarcinoma



51A Extrahepatic Biliary Tumors



51B Perihilar Cholangiocarcinoma: Presurgical Management



472

52 Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

PART 5  Biliary Tract Disease

SECTION I.  Inflammatory, Infective, and Congenital A. Gallstones and Gallbladder

CHAPTER 33 The natural history of symptomatic and asymptomatic gallstones Sean J. Judge and Sepideh Gholami INTRODUCTION The aim of this chapter is to describe established and novel findings on the natural history of gallstones. Gallstones have been a scourge of humankind for millennia. Each year surgeons perform over 700,000 cholecystectomies in the United States alone, with an estimated annual cost of approximately $6.2 billion USD.1,2 The annual rate of hospital admissions for acute cholecystitis and the associated hospital charges continue to increase,3 highlighting the great burden gallstone disease places on the American healthcare system. Despite these increasing trends, a substantial proportion of the population have asymptomatic gallstones that will likely never come to the attention of the individual or medical provider. In this chapter we focus on the epidemiology and natural history of symptomatic and asymptomatic gallstones and the evolving understanding of the many factors that may influence development of complications. The implications of these findings for the diagnosis and treatment of gallstones disease and directions for future research are also discussed.

HISTORICAL PERSPECTIVE Humans have recorded gallstone disease since the beginning of written medical communication. Indeed, it is documented that ancient Greeks and Egyptians suffered from the disease.4 In that time and for the following years, treatment consisted of various herbal remedies. The first recorded operation for gallstone disease was performed by Jean-Louis Petit in 1743. When exploring a patient with abdominal pain and an erythematous abdomen, Petit lanced the abdominal wall, opened the gallbladder, and removed the stones. He then allowed the gallbladder to fistulize, thus performing the first cholecystostomy5 (see Chapter 35). Over a century later, the American surgeon John Stough Bobbs performed the first deliberate cholecystostomy after identifying an inflamed and stone-filled gallbladder in a young woman undergoing laparotomy. He proceeded to incise the gallbladder, remove the stones, and close the organ without extirpation or drainage.6 It was Carl Langenbuch, a pioneering German surgeon, who

ushered in the modern era of gallbladder surgery by proposing removing the gallbladder as opposed to removing stones alone.7 An additional century passed before another pioneering German surgeon, Erich Mühe, performed the first laparoscopic cholecystectomy in 19858 and set the stage for the minimally invasive approach to gallbladder disease (see Chapter 36). Dr. Mühe presented his work to the Congress of the German Surgical Society in 1986.9 The lecture was not the success he had hoped and was only published as a brief abstract in the proceedings.9 At the 1990 meeting of the Society of American Gastrointestinal Surgeons (SAGES), several French surgeons were recognized for their early work in laparoscopic cholecystectomy, but Dr. Mühe was not acknowledged. It was not until 1999 when he was recognized by SAGES for performing the first laparoscopic cholecystectomy.10

CLASSIFICATION AND NOMENCLATURE Gallstones are firm masses formed within the biliary tract as precipitations of cholesterol or bilirubin and have distinct etiologies (see Chapter 8). Gallstones are categorized by their color or primary chemical component, notably cholesterol (yellow), black pigment, or brown pigment stones. The location of the mass dictates the terminology used (i.e., cholelithiasis is within the gallbladder, choledocholithiasis is within an extrahepatic bile duct, and hepatolithiasis is within an intrahepatic bile duct; Fig. 33.1).11 In the United States, the most common form of gallstones is cholesterol stones formed within the gallbladder, and as such, this will be the major focus of this chapter. Further clarification should be made regarding the term “gallstone disease,” which represents the manifestation of gallstones and ensuing signs or symptoms. Therefore patients with gallstones may be asymptomatic (stones discovered incidentally) or symptomatic (presence of gallstone disease). Gallstone disease can be separated into uncomplicated disease (biliary colic, chronic cholecystitis) or complicated disease (acute cholecystitis, obstructive jaundice, gallstone ileus, acute gallstone pancreatitis) based on the manifestation (see Chapters 37 and 38).

473

474

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

A

B

C

FIGURE 33.1  Common sites for stone formation and obstruction within the biliary system. A, Cholelithiasis, B, choledocholithiasis, and C, hepatolithiasis determined by stones (green spheres) located in the gallbladder, common bile duct, and intrahepatic bile duct, respectively. (Images courtesy Dr. Thomas W. Loehfelm, Department of Radiology, University of California, Davis.)

Sweden 11–25% Canadian Indians 62% American Indians 64–73% Mexican Americans 27%

Norway 22%

Denmark 22–30% Poland 20%

White Americans 17% Black Americans 14%

Rumania 13%

China 5%

Italy 14%

Japan 5% Taiwan 5–12%

India 10–22%

Thailand 4%

Sub-Saharan Black Africans 5%

Malpuche Indians 49% Maoris (Easter Island) 29%

FIGURE 33.2  Worldwide prevalence of gallstones in women based on ultrasonographic studies. (With permission from Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: Cholelithiasis and cancer. Gut and Liver. 2012;6[2]:172–187.)

PREVALENCE AND EPIDEMIOLOGY OF GALLSTONES The prevalence of gallstones in a given population is multifactorial and primarily driven by gender, age, diet, ethnicity, and genetics. In 1993 the NIH estimated that approximately 10% to 15% of the US adult population had gallstones.12 Since that time, expanded data on the global prevalence of gallstones have revealed the broad ranges of gallstone prevalence observed across various countries and ethnicities, including the United States,13–15 South America,16–20 Europe,21–30 Asia,31–35 and Africa.36–38 The estimated global prevalence of gallstones in women is shown in Fig. 33.2. Research from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has provided some of the best insight into the prevalence of gallstones within US populations. Implemented through the National Health and Nutrition Examination

Survey (NHANES) III by the US Centers for Disease Control and Prevention (CDC) from 1988 until 1994, 14,294 people aged 20 to 74 years underwent screening and completed ultrasound examinations of the gallbladder for detection of stones.14 The overall prevalence of gallstones was 5.5% in men and 8.6% in women. Gallstone prevalence increased with age, with reported 17.2% in men and 16.4% in women by age 60 to 74 years. The NHANES III study revealed substantial variation in gallstone prevalence according to race and ethnicity with the lowest prevalence in non-Hispanic Black men (3.9%) and highest in Mexican-American women (12.8%). American Indians are estimated to have the highest rates of gallstones and gallbladder disease in the world.39 Prevalence of gallstones in separate American Indian communities in four states—Arizona, Oklahoma, North Dakota, and South Dakota— were 18% in women and 17% in men.13 When using a composite score of the presence of stones and prior cholecystectomy, the

A. Gallstones and Gallbladder  Chapter 33  The Natural History of Symptomatic and Asymptomatic Gallstones

overall prevalence in this population was 64% in women and 30% in men.13

NATURAL HISTORY OF SYMPTOMATIC GALLSTONES For uncomplicated disease, most typically biliary colic, current treatment recommendations include elective cholecystectomy in patients fit for surgery. This is based on results from older studies showing a high prevalence of continued symptoms, an eventual need for cholecystectomy, and a significant rate of complications (Table 33.1). Thistle et al. published a report evaluating patients from the National Cooperative Gallstone Study, which investigated the efficacy of chenodeoxycholic acid in patients with gallstones.40 Using the placebo group to determine the natural history of gallstones in symptomatic patients over 2 years, the authors detected a 69% cumulative incidence of biliary symptoms. This was corroborated in a larger study following 556 symptomatic patients in the Health Insurance Plan of Greater New York where nearly 65% of patients described either unchanged or increased symptoms.41 During a median follow-up of 5.7 years, 44% of symptomatic patients underwent cholecystectomy and 8% of the symptomatic patients developed complications from their gallstone disease, including acute cholecystitis and obstructive jaundice. Friedman et al. followed 298 mildly symptomatic patients over 25 years within the Kaiser Northern California System.42 In this extensive follow-up period, 9% experienced severe (acute cholecystitis, obstructive jaundice, biliary pancreatitis) gallstone disease, 25% experienced nonsevere (biliary colic) gallstone disease, and 31% of patients underwent cholecystectomy. Results from a more recent Italian study showed a relatively benign natural history for symptomatic gallstones by following 213 patients for nearly 10 years.43 The authors reported that 64% of individuals experienced decreased symptoms, 25% reported unchanged symptoms, and only 11% reported an increase in symptoms. Even for those individuals initially reporting severe symptoms, complete resolution was obtained in 52%.43 Despite this high rate of resolution, the authors reported a 9% complication rate, similar to prior publications. With the likelihood of persistent or worsening symptoms (~30%–70%) and risk of complications (~6%–9%), cholecystectomy for symptomatic

475

patients remains the appropriate treatment given the relatively low risk of the operation in patients fit for surgery. Additional large studies on this topic appear unlikely because there is uniform consensus among clinicians.

NATURAL HISTORY OF ASYMPTOMATIC GALLSTONES In contrast to symptomatic gallstones, the debate over the natural history and treatment of asymptomatic gallstones is rooted within the medical and surgical giants of America. Sir William Osler wrote, “The gall-bladder will tolerate the presence of large numbers [of stones] for an indefinite period of time” and concluded that the presence of gallstones in asymptomatic patients is not an indication for surgery.44 Concurrently, in 1911 William Mayo stated that the “innocent” gallstone is a myth and early cholecystectomy decreased the mortality and morbidity associated with prolonged gallbladder disease.45 As larger cohorts with more diverse patients were published, the consensus has become a watchful waiting strategy for most patients with asymptomatic gallstones because the cumulative rate of symptom development appears to be around 10% to 30%, with an even lower rate of complications (0%–8%; Table 33.2). The earliest evaluation of the natural history comes from Comfort et al. who published their experience with incidental gallstones at the Mayo Clinic in 1948.46 The authors identified 112 patients with incidental gallstones found during abdominal surgery, and over 10 to 20 years, biliary colic developed in 19% of these patients.46 Nearly 40 years later, Gracie and Ransohoff published one of the most cited articles describing the natural history of stones in asymptomatic male and female faculty members from the University of Michigan.47 During the follow-up period of approximately 24 years, biliary symptoms developed in 13% of patients and 40% of the total cohort underwent cholecystectomy (cholecystectomy rate of 88% in those who developed symptoms). With a reported complication rate of 2%, they concluded that the “the innocent gallstone is not a myth.” In the last twenty years, further comprehensive studies have set out to gain a better understanding of these rates and elucidate risk factors for the development of symptoms or complications. Halldestam et al. prospectively identified Swedish citizens

TABLE 33.1  Reports and Details on the Natural History of Symptomatic Gallstones INCIDENCE RATE

NO. OF SYMPTOMATIC PATIENTS

YEARS OF FOLLOW-UP

BILIARY SYMPTOMS (%)

Thistle et al. (1984)40 McSherry et al. (1985)41

112 556

2 5.7, median

Friedman et al. (1989)42

298

25

69 36 decreased 39 unchanged 25 increased 9 severe 25 non-severe

Attili et al. (1995)21 Festi et al. (2010)43

  38 213

10 9, mean

STUDY

a

Includes six choledochoduodenostomies and two cholecystostomies.

6 acute cholecystitis 64 were decreased 25 were unchanged 11 were increased

CHOLECYSTECTOMY (%)

COMPLICATIONS (%)

6 44a

— 8

31 overall 85 for severe 95 for non-severe 45 —

9

6 9

476

INCIDENCE RATE

STUDY

NO. OF ASYMPTOMATIC PATIENTS

YEARS OF FOLLOW-UP

BILIARY SYMPTOMS (%)

CHOLECYSTECTOMY (%)

COMPLICATIONS (%)

Comfort et al. (1948)46

112

10–20

19

21

—

Gracie and Ransohoff (1982)47

123

24

13

40

2

Thistle et al. (1984)40 McSherry et al. (1985)41

193 135

2 4

31 10

3 7

— 2

Friedman et al. (1989)42

123

25

19 overall 6 severe 13 non-severe

16 71 for severe 94 for non-severe

6

Cucchiaro et al. (1990)48

139

5

11

6

1

Wada et al.a (1990)49 Juhasz et al. (1994)50

680 110

13, median 6, median

20 15

— 18

— 5

Attili et al. (1995)21

118

10

24

3

Angelico et al. (1997)51 Halldestam et al. (2004)52 Festi et al. (2010)43 Sood et al. (2015)53

47 120b 580 213

10 7, median 9, mean 4, mean

12, 16, 26, 15, 12 22 11, 14,

51 patients developed symptoms. Dyspepsia, n 5 30 (27%) Biliary colic, n 5 21 (19%) Cholecystectomy rates: Remained asymptomatic, 39% Developed symptoms, 88% — An additional 5 patients had incidental cholecystectomies Cumulative probability of any event after diagnosis: 0.18, 5 yr 0.30, 10 yr 0.34, 15 yr 0.41, 20 yr 9 cholecystectomies Incidental, n 5 3 Elective, n 5 4 Emergency, n 5 2 — 8-yr median follow-up on subset of cohort shows 27% developed symptoms and 33% underwent cholecystectomy 1 death from gallbladder adenocarcinoma

23 8c 14 Not reported

0 4 ,1 —

— 1 death from gallbladder adenocarcinoma — —

Shabanzadeh et al. (2016)54

664

17, median

7 in patients without complications

8

Noted increased rates of biliary colic in patients who were aware of gallstones

a

20

2 yr 4 yr 10 yr 10 yr

4 years 10 years

Abstract only. Article in Japanese

b

Includes gallstones, sludge, and cholesterolosis

c

10 of 14 patients with symptoms underwent cholecystectomy. Study does not report prophylactic cholecystectomy rate in patients who remained asymptomatic.

COMMENTS

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

TABLE 33.2  Reports and Details on the Natural History of Asymptomatic Patients

A. Gallstones and Gallbladder  Chapter 33  The Natural History of Symptomatic and Asymptomatic Gallstones

aged 35 to 85 years for the presence of asymptomatic gallstones.52 During a median follow-up of 7 years, 12% of the cohort developed biliary symptoms, 8% underwent cholecystectomy, and 4% experienced gallstone-related complications (acute cholecystitis, obstructive jaundice, and gallstone pancreatitis). The authors only identified younger age as a risk factor for the development of gallstone-related events.52 The most current and comprehensive analysis on this topic was published by Shabanzadeh et al. in 201654 and determined prediction rules for risk stratification in asymptomatic individuals. The authors followed 664 people with asymptomatic gallstones from the general population of urban Copenhagen, Denmark and during a median follow-up of 17 years, 20% of individuals developed symptoms of gallstone disease, and 8% experienced gallstonerelated complications.54 A unique component of this study involved nondisclosure of ultrasound results creating cohorts of patients who were either aware or unaware of their asymptomatic gallstones. Interestingly, the most significant predictor of gallstone-related events was awareness of gallstones, but as the authors note, this may be secondary to the protopathic bias or may reflect a confounding variable in which those who were aware of their stones before enrollment likely had symptoms that prompted evaluation and may not have been truly asymptomatic.54 Extensive studies over the course of nearly 80 years have provided significant evidence for the relatively benign natural history of asymptomatic gallstones. In contrast to symptomatic stones, most patients with asymptomatic gallstones (~70%–90%) will never experience gallstone-related symptoms, and even more (90%–99%) will never experience complications of their gallstones. As such, prophylactic cholecystectomy is not appropriate in asymptomatic patients within the general population.

RISK FACTORS FOR GALLSTONE DISEASE (SEE CHAPTER 8) As identified in the recent work from Shabanzadeh54 and Sood,53 there appear to be factors that increase the risk of gallstone-related events in patients with asymptomatic stones. Ignoring the confounding factor of gallstone awareness, the authors identified large stones greater than 10 mm, female gender, and two or more stones as independent predictors of all gallstone-related events. Female gender was determined as a risk factor for gallstone disease in asymptomatic Malaysian citizens.53 Apart from these observations in the general public, specific populations and clinical scenarios require further discussion because of increased rates of either stone formation or complications.

Bariatric and Metabolic Surgery Patients Obesity55,56 and rapid weight loss57–59 are both considered risk factors for gallstone formation, but the magnitude of the risk of developing gallstone disease in these populations remains controversial. Specifically, in patients undergoing weight loss surgery (sleeve gastrectomy or Roux-en-Y gastric bypass), practice has changed from a concurrent prophylactic cholecystectomy to intervening only in patients with preoperative biliary symptoms. A prior report in patients undergoing gastric exclusion surgery showed nearly 30% of patients developed gallstone disease after bariatric surgery, with most occurring in the first 24 months postoperative.60 These results were followed by work from Swartz et al. evaluating 692 patients undergoing

477

Roux-en-Y gastric bypass (96% laparoscopic) from 2003 to 2004 at a single center using a protocol of postoperative ursodeoxycholic acid therapy. Approximately 15% of patients required subsequent cholecystectomy during a mean follow-up of 7.5 months.61 Authors also discovered an indirect relationship between the duration of ursodeoxycholic acid therapy and the rate of cholecystectomy; specifically, patients who did not use therapy had a 25% rate of cholecystectomy compared with 10% in those that were adherent to therapy for 6 months.61 The authors concluded that bariatric surgery patients can be managed like the general population, with significant benefit from ursodeoxycholic acid therapy.61 These results support the Choosing Wisely guidelines, which states that during weight loss surgery the gallbladder should not be routinely removed unless clinically indicated because of the associated risk of surgery without clear evidence showing benefit of removing a normal or asymptomatic gallbladder.62

Hemolytic Disorders Hematologic disorders resulting in increased red blood cell (RBC) hemolysis are associated with increased rates of pigment gallstones because of elevated efflux of bilirubin. Most commonly, these disorders include sickle cell anemia (SS) and hereditary spherocytosis (HS). The rates of gallstones and gallstone disease in SS were investigated through The Jamaican Cohort Study evaluating 100,000 consecutive infants from 1973 until 1981.63 Three hundred fifteen infants with homozygous SS were identified, and gallstones developed in 31% of patients and were present in almost 10% of SS patients by the time of their first ultrasound (5 patients were , 6 years of age); 7 individuals underwent cholecystectomy for gallstone-related events (~2%).63 This study suggests that gallstones are a common manifestation of SS, but rates of complications necessitating surgery are low. Incidence and complication rates for adults with SS were investigated by researchers at King’s College Hospital tracking all SS patients between 2003 and 2013.64 Gallstones were identified in 44% of patients and gallstone-related complications occurred in 26% during the 11-year follow-up period. Authors identified a perioperative complication rate of approximately 10% in SS patients undergoing cholecystectomy.64 Given the increased risk for surgical complications, there is a limited role for prophylactic cholecystectomy in this population. Similar to SS disease, patients with HS show high rates of pigment gallstones. In a retrospective study from the Johns Hopkins Hospital analyzing 58 patients who underwent splenectomy for HS between 1960 and 1979,65 gallstones were present in 21% of all patients. Since many of these patients eventually undergo splenectomy to remove the site of RBC hemolysis, there has been controversy regarding performing concomitant cholecystectomy. After splenectomy, the risk of pigment stone formation is markedly reduced and some surgeons have performed cholecystolithotomy at the time of splenectomy to remove the stones and preserve the gallbladder.66 Current guidelines from the British Society of Hematology support cholecystectomy only in patients with symptomatic gallstone disease undergoing splenectomy.67

Transplant Patients Solid organ transplant patients may be at increased risk for gallstone formation and increased complications from gallstone disease (see Chapter 111). Kilic et al. evaluated the Nationwide

478

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

Inpatient Sample (NIS) database to identify heart transplant recipients who underwent cholecystectomy between 1998 and 2008.68 The authors identified 1,687 patients (75% laparoscopic) who underwent post-transplant cholecystectomy and found increased mortality in open cases compared with laparoscopic, as well as in urgent or emergent cases compared with elective cases. On multivariate analysis, urgent or emergent admission, open operation, and complicated gallstone disease were independent predictors of inpatient mortality, supporting the use of prophylactic cholecystectomy in heart transplant patients with asymptomatic gallstones or mildly symptomatic gallstone disease.68 Kao et al. arrived at a similar conclusion through use of a decision analysis algorithm based on the option for pre-transplant cholecystectomy, post-transplant cholecystectomy, or expectant management.69 For heart transplantation, the authors determined post-transplant prophylactic cholecystectomy to have the lowest mortality, whereas the preferred strategy in kidney/pancreas transplant patients was expectant management.69 Although there are no guidelines mandating prophylactic cholecystectomy in heart transplant candidates or recipients, patients may benefit from elective operations for asymptomatic gallstones.

Immunotherapy Patients Immune checkpoint inhibition (ICI) and other systemic immunotherapies (e.g., interleukin [IL]-2, IL-15) have been associated with extensive side effects and toxicities,70–72 but to date, there does not appear to be a correlation with increased gallstone formation or gallstone disease. Notably, both IL-273 and ICI74 have been associated with acalculous gallbladder

pathology mimicking acute cholecystitis, and differentiating the etiologies is critical to avoid inappropriate surgical management in patients often requiring cessation of immunotherapy and initiation of systemic steroids.

GALLSTONES AND THE MICROBIOME The influence of the gut microbiome on health and disease has been extensively explored in the last few decades. There have been recent advances in the understanding of the impact of intestinal microbiome on bile acids and subsequent role in both gallstone formation75 and other gastrointestinal (GI) diseases.76 Recently, this was explored further in a study evaluating the microbiome profile of feces, bile, and gallstones in patients undergoing cholecystectomy that compared this profile with the feces of healthy individuals.77 The authors found significant differences in feces microbiome diversity between gallstone patients and healthy individuals and noted higher microbiome diversity in the bile compared with the feces in patients with gallstones.77 These observations have been investigated in animal models, using a diet-induced cholesterol gallstone mouse model.78 Notably, germ-free mice had increased cholesterol gallstone formation, which normalized after fecal microbiota transfer with known commensal organisms.78 As this field continues to expand, further details regarding the interconnectedness of the gut-microbiome-liver axis will be elucidated with potential for predictive biomarkers, preventive measures, and therapeutics. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

478.e1

REFERENCES 1. Shaffer EA. Epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol. 2006;20(6):981-996. 2. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas. Gastroenterology. 2009;136(4):1134-1144. 3. Wadhwa V, Jobanputra Y, Garg SK, Patwardhan S, Mehta D, Sanaka MR. Nationwide trends of hospital admissions for acute cholecystitis in the United States. Gastroenterol Rep (Oxf). 2016; 5(1):36-42. 4. Yannos S, Athanasios P, Christos C, Evangelos F. History of biliary surgery. World J Surg. 2013;37(5):1006-1012. 5. Petit JL. On tumors formed by bile retained in the gallbladder which have often been mistaken for abscesses in the liver. Memoires de l’Academie Royale de Chirurgie. 1743;(1):155-187. 6. Bobbs JS. Case of lithotomy of the gallbladder. Trans Indiana State Med Soc. 1868:68-73. 7. Langenbuch C. A case of extirpation of the gallbladder for chronic cholecystitis. Cure. Berlin Klinische Wochenschrift. 1882;19(48): 725-727. 8. Mühe E. Die erste Cholecystektomie durch das Laparoskop. Langenbecks Arch Chir. 1986;369(1):804. 9. Litynski GS. Erich Mühe and the rejection of laparoscopic cholecystectomy (1985): a surgeon ahead of his time. JSLS. 1998;2(4): 341-346. 10. Reynolds Jr W. The first laparoscopic cholecystectomy. JSLS. 2001; 5(1):89-94. 11. Lammert F, Gurusamy K, Ko CW, et al. Gallstones. Nat Rev Dis Primers. 2016;2(1):16024. 12. Gollan JL, Bulkley GB, Diehl AM, et al. Gallstones and laparoscopic cholecystectomy. JAMA. 1993;269(8):1018-1024. 13. Everhart JE, Yeh F, Lee ET, et al. Prevalence of gallbladder disease in American Indian populations: Findings from the Strong Heart Study. Hepatology. 2002;35(6):1507-1512. 14. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117(3):632-639. 15. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in Pima Indians. N Engl J Med. 1970;283(25): 1358-1364. 16. Coelho J, Bonilha R, Pitaki S, et al. Prevalence of gallstones in a Brazilian population. Int Surg. 1999;84(1):25-28. 17. Cohen H, Antoniello L, Bak M, et al. Prevalence of gallbladder lithiasis in a Uruguayan population. Acta Gastroenterol Latinoam. 1992;22(2):107-114. 18. Covarrubias C, Miquel JF, Puglielle L, et al. The role of ethnicity and other risk factors for cholelithiasis in a highly prevalent area: cross-sectional and cohort studies in Chileans and Amerindian Araucanos. Gastroenterology. 1995;108(4):A1053. 19. Moro PL, Checkley W, Gilman RH, et al. Gallstone disease in Peruvian coastal natives and highland migrants. Gut. 2000;46(4):569. 20. Palermo M, Berkowski DE, C√≥rdoba JP, Verde JM, Giménez ME. Prevalence of cholelithiasis in Buenos Aires, Argentina. Acta Gastroenterol Latinoam. 2013;(46):98-105. 21. Attili AF, de Santis A, Capri R, Repice AM, Maselli S. The natural history of gallstones: the GREPCO experience. The GREPCO Group. Hepatology. 1995;21(3):656-660. 22. Barbara L, Sama C, Labate AMM, et al. A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology. 1987;7(5):913-917. 23. Caroli-Bosc FX, Deveau C, Harris A, et al. Prevalence of cholelithiasis (results of an epidemiologic investigation in Vidauban, Southeast France). Dig Dis Sci. 1999;44(7):1322-1329. 24. de Pancorbo CM, Carballo F, Horcajo P, et al. Prevalence and associated factors for gallstone disease: results of a population survey in Spain. J Clin Epidemiol. 1997;50(12):1347-1355. 25. Heaton KW, Braddon FE, Mountford RA, Hughes AO, Emmett PM. Symptomatic and silent gall stones in the community. Gut. 1991;32(3):316-320. 26. Borch K, Jönsson KA, Zdolsek JM, Halldestam I, Kullman E. Prevalence of gallstone disease in a Swedish population sample: relations to occupation, childbirth, health status, life style, medications, and blood lipids. Scand J Gastroenterol. 1998;33(11): 1219-1225.

27. Kratzer W, Kachele V, Mason RA, et al. Gallstone prevalence in Germany: the Ulm gallbladder stone study. Dig Dis Sci. 1998; 43(6):1285-1291. 28. Reshetnikov OV, Ryabikov AN, Shakhmatov SG, Malyutina SK. Gallstone disease prevalence in Western Siberia: cross-sectional ultrasound study versus autopsy. J Gastroenterol Hepatol. 2002;17(6): 702-707. 29. Shabanzadeh DM, Sørensen LT, Jørgensen T. Association between screen-detected gallstone disease and cancer in a cohort study. Gastroenterology. 2017;152(8):1965-1974.e1. 30. Völzke H, Baumeister SE, Alte D, et al. Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence. Digestion. 2005;71(2):97-105. 31. Chen CH, Huang MH, Yang JC, et al. Prevalence and risk factors of gallstone disease in an adult population of Taiwan: an epidemiological survey. J Gastroenterol Hepatol. 2006;21(11):1737-1743. 32. Chung YJ, Park YD, Lee HC, et al. Prevalence and risk factors of gallstones in a general health screened population. Korean J Med. 2007;72(5):480-490. 33. Nomura H, Ksahiwagi S, Hayashi J, et al. Prevalence of gallstone disease in a general population of Okinawa, Japan. Am J Epidemiol. 1988;128(3):598-605. 34. Unisa S, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK. Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural Gangetic basin of North India. HPB. 2011;13(2):117-125. 35. Zeng Q, He Y, Qiang D, Wu L. Prevalence and epidemiological pattern of gallstones in urban residents in China. Eur J Gastroenterol Hepatol. 2012;24(12)1459-1460. 36. Akute O, Obajimi M. Cholelithiasis in Ibadan: an update. West Afr J Med. 2002;21(2):128-131. 37. Gyedu A, Adae-Aboagye K, Badu-Peprah A. Prevalence of cholelithiasis among persons undergoing abdominal ultrasound at the Komfo Anokye Teaching Hospital, Kumasi, Ghana. Afr Health Sci. 2015;15(1):246-252. 38. Safer L, Bdioui F, Braham A, et al. Epidemiology of cholelithiasis in central Tunisia. Prevalence and associated factors in a nonselected population. Gastroenterol Clin Biol. 2000;24(10):883-887. 39. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver. 2012;6(2):172-187. 40. Thistle JL, Cleary PA, Lachin JM, Tyor MP, Hersh T. The natural history of cholelithiasis: The National Cooperative Gallstone Study. Ann Intern Med. 1984;101(2):171-175. 41. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg. 1985;202(1):59-63. 42. Friedman GD, Raviola CA, Fireman B. Prognosis of gallstones with mild or no symptoms: 25 years of follow-up in a health maintenance organization. J Clin Epidemiol. 1989;42(2):127-136. 43. Festi D, Reggiani MLB, Attili AF, et al. Natural history of gallstone disease: expectant management or active treatment? Results from a population-based cohort study. J Gastroenterol Hepatol. 2010;25(4): 719-724. 44. Osler W. The Principles and Practice of Medicine. 8th ed. D. Appleton and Company; 1912. 45. Mayo WJ. “Innocent” gall-stones a myth. JAMA 1911;LVI(14): 1021-1024. 46. Comfort MW, Gray HK, Wilson JM. The silent gallstone: a ten to twenty year follow-up study of 112 Cases. Ann Surg. 1948;128(5): 931-937. 47. Gracie WA, Ransohoff DF. The natural history of silent gallstones. N Engl J Med. 1982;307(13):798-800. 48. Cucchiaro G, Rossitch JC, Bowie J, et al. Clinical significance of ultrasonographically detected coincidental gallstones. Dig Dis Sci. 1990;35(4):417-421. 49. Wada K. Natural course of asymptomatic gallstone disease. Nihon Rinsho. 1993;51(7):1737-1743. 50. Juhasz ES, Wolff BG, Meagher AP, Kluiber RM, Weaver AL, van Heerden JA. Incidental cholecystectomy during colorectal surgery. Ann Surg. 1994;219(5):467-474. 51. Angelico F, Del Ben M, Barbato A, Conti R, Urbinati G. Ten-year incidence and natural history of gallstone disease in a rural population of women in central Italy. The Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). Ital J Gastroenterol Hepatol. 1997;29(3):249-254.

478.e2 52. Halldestam I, Enell EL, Kullman E, Borch K. Development of symptoms and complications in individuals with asymptomatic gallstones. Br J Surg. 2004;91(6):734-738. 53. Sood S. Natural history of asymptomatic gallstones: differential behaviour in male and female subjects. Med J Malaysia. 2015;70(6): 341-345. 54. Shabanzadeh DM, Sørensen LT, Jørgensen T. A prediction rule for risk stratification of incidentally discovered gallstones: results from a large cohort study. Gastroenterology. 2016;150(1):156-167.e1. 55. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham study. J Chronic Dis. 1966;19(3):273-292. 56. Stampfer MJ, Maclure KM, Colditz GA, Manson JE, Willett WC. Risk of symptomatic gallstones in women with severe obesity. Am J Clin Nutr. 1992;55(3):652-658. 57. Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight-reduction dieting. Arch Intern Med. 1989;149(8):1750-1753. 58. Broomfield PH, Chopra R, Sheinbaum RC, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N Engl J Med. 1988;319(24): 1567-1572. 59. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995;122(12):899-905. 60. Amaral JF, Thompson WR. Gallbladder disease in the morbidly obese. Am J Surg. 1985;149(4):551-557. 61. Swartz DE, Felix EL. Elective cholecystectomy after Roux-en-Y gastric bypass: why should asymptomatic gallstones be treated differently in morbidly obese patients? Surg Obes Relat Dis. 2005;1(6): 555-560. 62. American Society for Metabolic and Bariatric Surgery Routine Gallbladder Removal. Choosing Wisely, An Initiative of the ABIM; Published June 25, 2015. Available at: https://www.choosingwisely.org/ clinician-lists/american-society-metabolic-bariatric-surgery-routinegallbladder-removal/. Accessed May 18, 2020. 63. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: observations from The Jamaican Cohort Study. J Pediatr. 2000;136(1):80-85. 64. Coats T, Gardner K, Thein SL. Gallstones in sickle cell disease: a single institution experience. Blood. 2014;124(21):4939.

65. Rutkow IM. Twenty years of splenectomy for hereditary spherocytosis. Arch Surg. 1981;116(3):306-308. 66. Yamada Y, Sekioka A, Nomura A, et al. Simultaneous gallbladderpreserving cholecystolithotomy and laparoscopic splenectomy as a surgical option for hereditary spherocytosis in a child: a case report. J Pediatr Surg Case Rep. 2017;23:37-39. 67. Bolton-Maggs PHB, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis – 2011 update. Br J Haematol. 2012;156(1):37-49. 68. Kilic A, Sheer A, Shah AS, Russell SD, Gourin CG, Lidor AO. Outcomes of cholecystectomy in US heart transplant recipients. Ann Surg. 2013;258(2). 69. Kao LS, Flowers C, Flum DR. Prophylactic cholecystectomy in transplant patients: a decision analysis. J Gastrointest Surg. 2005; 9(7):965-972. 70. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. 71. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol. 1991;9(4): 694-704. 72. Conlon KC, Lugli E, Welles HC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2015;33(1):74-82. 73. Kuppler K, Jeong D, Choi JW. Non-infectious cholecystopathy secondary to high-dose IL-2 cancer immunotherapy. Acta Radiol Open. 2015;4(10):2058460115579458. 74. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J Immunother Cancer. 2019;7(1):118. 75. Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014;30(3):332-338. 76. Søreide K. Gallstone disease and cancer risk: finding the bug in the system. Gastroenterology. 2017;152(8):1825-1828. 77. Wu T, Zhang Z, Liu B, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics. 2013;14(1):669. 78. Fremont-Rahl JJ, Ge Z, Umana C, et al. An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis. PLoS One. 2013;8(7):e70657.

CHAPTER 34 Cholecystitis Alexandra W. Acher, Kaitlyn J. Kelly, and Sharon M. Weber OVERVIEW Cholecystitis, a common condition usually resulting from complications of cholelithiasis, occurs in two forms: acute and chronic. Acute cholecystitis requires urgent intervention, typically with antibiotics and cholecystectomy. In the setting of acute cholecystitis, cholecystectomy is optimally performed within 72 hours of symptom onset. If urgent cholecystectomy is not feasible, cholecystectomy can be performed electively, provided symptoms have resolved with medical management. Chronic cholecystitis is the manifestation of ongoing, intermittent inflammation and biliary colic. Patients with this condition benefit from elective cholecystectomy. A less common version of cholecystitis is acute acalculous cholecystitis, which occurs most often in critically ill patients. Although gallstones are, by definition, absent in this condition, cholecystectomy specimens in patients with acute acalculous cholecystitis often reveal biliary sludge (see Chapter 33).

ACUTE CHOLECYSTITIS Pathogenesis The cause of acute calculous cholecystitis is an impacted gallstone in the outlet of the gallbladder, either in the infundibulum or in the cystic duct.1 The impacted gallstone results in gallbladder distension and edema with acute inflammation, which eventually can result in venous stasis and obstruction, followed by thrombosis of the cystic artery. Ultimately, ischemia and necrosis of the gallbladder can occur. Because the fundus of the gallbladder is the greatest distance from the cystic arterial blood supply, it is more sensitive to ischemia and is the most common location for necrosis of the gallbladder. The acute inflammation of cholecystitis may be complicated by secondary biliary infection. Positive bile cultures are found in approximately 20% of patients with acute cholecystitis,2 the most common of which are gram-negative bacteria of gastrointestinal origin, such as Klebsiella spp. and Escherichia coli. The incidence of bactobilia has been reported to be as high as 60% in patients who have had endoscopic sphincterotomy or other biliary instrumentation3 (see Chapters 30 and 31).

Clinical Manifestations Most patients with acute cholecystitis are seen with severe, constant, right upper quadrant abdominal or epigastric pain, sometimes with radiation to the subscapular area. This pain may be preceded by intermittent, self-limited bouts of abdominal pain from episodes of biliary colic. Acute cholecystitis is frequently associated with fever and leukocytosis, findings that are not present in cases of uncomplicated biliary colic. Patients also may have a Murphy’s sign (inspiratory arrest on palpation of the right upper quadrant of the abdomen). Other presenting symptoms include nausea, vomiting, and anorexia.

Differential Diagnosis Several disease processes can present similarly to cholecystitis and should be considered in the differential diagnosis. These include peptic ulcer disease, gastritis and gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, right lower lobe pneumonia, and biliary dyskinesia. An initial chest radiograph is generally sufficient to assess for a right lower lobe infiltrate. The other diagnoses should be entertained and worked up appropriately in symptomatic patients without gallstones on ultrasound (US). The Tokyo Guidelines are also a useful tool to assess the likelihood of acute cholecystitis and can be used to assist in diagnosis.4 These guidelines are based on three clinical and diagnostic categories: local signs of inflammation (Murphy’s sign or right upper quadrant mass or right upper quadrant tenderness), systemic signs of inflammation (fever, elevated C-reactive protein, elevated white blood cell [WBC] count), and imaging findings suggestive of cholecystitis (pericholecystic fluid, gallbladder wall edema, luminal debris and stone impaction). For patients who present with one item from each category, validation studies demonstrate a guideline sensitivity and specificity of 91% and 97%, respectively.5 Additionally, the Tokyo Guidelines stratify presentations of acute cholecystitis according to risk of 30-day mortality: 1.1% for mild acute cholecystitis (Grade I), 0.8% for moderate acute cholecystitis (Grade II), and 5.4% for severe acute cholecystitis (Grade III; P , .0001).4 Online calculators allow for easy access and use of this tool.

Diagnostic Evaluation and Imaging Abdominal US (see Chapter 16) is useful for assessing patients suspected to have acute cholecystitis. Typical findings include gallstones, gallbladder wall thickening (.4 mm), and pericholecystic fluid (Fig. 34.1). In addition, the sonographer can assess for pain and inspiratory arrest when the gallbladder is directly compressed by the US probe (sonographic Murphy’s sign). Typically, conventional grayscale imaging is used, which, together with clinical picture and sonographic Murphy’s sign, is sensitive and specific for diagnosing acute cholecystitis, with an overall accuracy of greater than 90% (Pinto et al., 2013). Other ultrasound techniques that assess blood flow, such as Doppler and color velocity imaging, may improve accuracy in selected cases. Hepatobiliary scintigraphy (see Chapter 18) is a useful study in selected patients when the diagnosis is uncertain. This nuclear medicine study is performed with derivatives of aminodiacetic acid (hepatoiminodiacetic acid, isopropylacetanilido iminodiacetic acid, or diisopropylacetanilido iminodiacetic acid), which are taken up by hepatocytes and secreted in bile. When the tracer is labeled with technetium, scintigraphy allows for visualization of the extrahepatic biliary system. A normal scan delineates the biliary tree, including the gallbladder, and shows prompt emptying of the agent into the duodenum. Nonvisualization of the gallbladder on scintigraphy implies obstruction of the cystic duct and is 479

480

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

TRANS RT GB

FIGURE 34.1  Transverse view of the gallbladder on ultrasound in a patient with calculous cholecystitis, revealing gallstones and gallbladder wall thickening.

consistent with acute cholecystitis (Fig. 34.2). Hepatobiliary scintigraphy is not useful in patients with reduced hepatic function because it depends on hepatic excretion of bile, but it is accurate in approximately 90% of patients with acute cholecystitis and may be more accurate than US alone in some presentations.6 An added utility of scintigraphy is that in addition to gallbladder filling or nonfilling, it can also be used to quantify gallbladder emptying. Abnormal emptying is defined as an ejection fraction (EF) of 35% or less on scintigraphy, although cutoff values of between 35% and 40% have been reported.6 The evaluation of EF is potentially useful for patients with symptoms suggestive of biliary dyskinesia or chronic acalculous cholecystitis but usually unnecessary in cases of acute cholecystitis because 90% of acute cholecystitis is secondary to cholelithiasis obstruction of the cystic duct.6 Consensus on the utility of scintigraphy EF in diagnosing biliary dyskinesia or chronic cholecystitis remains debated. This is in part because of reliance on retrospective data limited by selection bias and because

A

of inconsistent indications and variability in EF cutoff values.6 In a study of 141 symptomatic patients with normal US and scintigraphy demonstrating normal gallbladder filling and an EF of 35% or less who underwent cholecystectomy, 95% had symptom relief and 41% had cholecystitis on histologic evaluation of the gallbladder.7 A recent meta-analysis of studies from 1980 to 2016 (n 5 29 studies) examining the use of scintigraphy EF in the diagnosis of biliary dyskinesia or cholecystitis found only two randomized controlled trials (RCTs) and 27 observational studies.8 This meta-analysis demonstrated that of the patients who underwent cholecystectomy, the chance of symptom improvement was similar in patients with a low EF versus those with a normal EF (risk ratio [RR] 1.09, P 5 .07). However, they also found that in patients managed medically, symptom improvement was more likely in patients with normal EF than those with a low EF (RR 2.37, P , .0005). Because of the heterogeneity of studies and bias inherent in retrospective data, no definitive conclusions could be drawn regarding how to interpret a normal EF in the setting of biliary symptoms and unclear imaging findings.8 In the setting of biliary pain with unclear US findings, however, a low EF is considered a reliable indicator of a biliary etiology.6,8 Hepatobiliary scintigraphy is more involved, more expensive, and requires a longer time than US; however, it should be considered in certain cases.9–11 Guidelines have suggested a diagnostic approach that starts with US for patients with biliary symptoms. If no gallstones are definitively identified, this should be followed by esophagogastroduodenoscopy to exclude alternative causes of symptoms, such as peptic ulcer disease or gastritis. If the endoscopy is negative, hepatobiliary scintigraphy should follow. Computed tomography (CT; see Chapter 16) can also help diagnose acute cholecystitis and provides more detailed anatomic information than US. CT is particularly useful in patients whose symptoms suggest a complication such as pericholecystic abscess or an alternative diagnosis. The CT findings of acute cholecystitis are the same as those seen on US and include wall thickening, pericholecystic stranding or fluid, distension of the gallbladder, high-attenuation bile, and subserosal edema. CT is generally less sensitive than US for diagnosing

B

FIGURE 34.2  A, Normal hepatoiminodiacetic acid (HIDA) scan demonstrating contrast-filled gallbladder (arrow). B, Abnormal HIDA scan demonstrating nonfilling of the gallbladder consistent with cystic duct obstruction. (Courtesy Dr. Scott Perlman, University of Wisconsin Hospital and Clinics)

A. Gallstones and Gallbladder  Chapter 34  Cholecystitis

acute cholecystitis, particularly early in the course, when the imaging findings may be subtle.12,13

Treatment Initial treatment with antibiotics active against enteric bacteria should begin as soon as the patient is diagnosed with acute cholecystitis. Additionally, oral intake should be held, and appropriate intravenous (IV) fluid resuscitation should be started in preparation for surgery. Parenteral analgesics should be administered as needed. The definitive treatment for acute cholecystitis is cholecystectomy (see Chapter 36). From the time this operation was first performed in 1882 by Langenbuch, open cholecystectomy has been the standard of care for patients with acute cholecystitis. With the advent of laparoscopic cholecystectomy in the 1980s, the standard approach has changed such that cholecystectomy is now routinely performed laparoscopically. The benefits of laparoscopic cholecystectomy are discussed in Chapter 36, but they include a shorter postoperative stay and decreased analgesia requirements.14 Although the laparoscopic approach is now standard for most cases, it is interesting to note that two prospective randomized studies suggested little or no difference in intraoperative or postoperative complications or length of stay between laparoscopic versus small-incision open cholecystectomy15,16; however, most of these patients underwent elective rather than urgent cholecystectomy. Early analysis of the results of laparoscopic cholecystectomy in patients with acute versus chronic cholecystitis showed increased morbidity and mortality rates for patients with simple or complicated acute cholecystitis. Because of the increased morbidity and mortality, acute cholecystitis initially was considered a relative contraindication to laparoscopic cholecystectomy.17 Subsequent reports, however, have shown improved safety of this technique in the acute setting.18–21 The conversion rate to an open procedure is higher for patients with acute cholecystitis compared with patients undergoing elective cholecystectomy,22

481

but most patients with acute cholecystitis (.80%) can undergo successful laparoscopic cholecystectomy.23 Retrospective series have reported that risk factors for conversion to open cholecystectomy include obesity,24 elevated WBC count and elevated bilirubin,25,26 previous surgery,26 and male gender.26 Other novel surgical approaches to cholecystectomy have been proposed to treat patients with symptomatic gallstones, including mini-laparoscopic cholecystectomy (see Chapter 36), which uses 2- to 3-mm ports27; mini-cholecystectomy,28 in which a small (mean, 5.5 cm) incision is used to remove the gallbladder; single-incision laparoscopic cholecystectomy; and natural orifice transluminal endoscopic (NOTES) cholecystectomy with transvaginal extraction. Prospective randomized studies evaluating the safety of these techniques are lacking, but existing data suggest decreased postoperative pain and improved cosmesis at the expense of slightly longer operating times with these techniques. Laparoscopic subtotal cholecystectomy (LSC) has also been evaluated as a means of decreasing the conversion rate to open procedure in patients with acute cholecystitis29,30 (see Chapter 36). Subtotal cholecystectomy can be of two types: fenestrating or reconstituting31 (see Figs. 34.3 and 34.4). A subtotal fenestrating cholecystectomy involves excising the peritonealized gallbladder (anterior surface) and leaving the posterior wall of the gallbladder in situ. The remnant mucosa may be cauterized, any stone burden is evacuated, and the cut edge of the gallbladder can then be oversewn or cauterized. The cystic duct can also be sutured closed from the luminal/ mucosal side to avoid injury to the common bile duct31 (see Chapter 36). In contrast, a reconstituting subtotal cholecystectomy involves excising the peritonealized gallbladder, extracting any stones, and closing (sewing or stapling) the inferior gallbladder in a way that preserves a small lumen and patent biliary drainage through the cystic duct.31 Drains are typically left after either approach. Each subtotal cholecystectomy technique has different advantages and disadvantages, and their feasibility depends on

Liver

Mucosa

Bare liver Cut edge of gallbladder

Cystic duct orifice

“Shield” of McElmoyle Hepatocystic triangle (obscured)

A

B

FIGURE 34.3  Schematic of a subtotal fenestrating cholecystectomy. (From Strasberg SM, Pucci MJ, Brunt LM, Deziel DJ. Subtotal cholecystectomy“fenestrating” vs “reconstituting” subtypes and the prevention of bile duct injury: Definition of the optimal procedure in difficult operative conditions. J Am Coll Surg. 2016;222:89–96.)

482

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

Liver

Liver

Bare liver Cut edge of gallbladder Bare liver Mucose

Suture line Hepatocystic triangle (obscured)

Gallbladder remnant

A

B

FIGURE 34.4  Schematic of a subtotal reconstituting cholecystectomy. (From Strasberg SM, Pucci MJ, Brunt LM, Deziel DJ. Subtotal cholecystectomy“fenestrating” vs “reconstituting” subtypes and the prevention of bile duct injury: Definition of the optimal procedure in difficult operative conditions. J Am Coll Surg. 2016;222:89–96.)

patient presentation and anatomy. In a retrospective multiinstitutional study32 comparing outcomes after subtotal fenestration versus reconstituting cholecystectomy (median follow-up of six years, interquartile range [IQR] 5–10 years), fenestration was associated with a higher risk of bile leak (18% vs. 7%, P , .02), wound infection (11% vs. 3%, P , .02) and longer hospitalization (median 5 days, IQR 3–17 days vs. three days, IQR 2–6 days, P 5 .005). However, reconstitution was associated with an increased risk of recurrent biliary pathology (18% vs. 9%, P , .02). Interestingly, in this study patients who underwent subtotal fenestrating cholecystectomy had an increased risk of subsequent completion cholecystectomy (9% vs. 4%, P , .02) despite a lower risk of recurrent cholecystitis. This may be reflective of the fact that patients underwent completion cholecystectomy for various indications such as choledocholithiasis and biliary colic, in addition to recurrent cholecystitis. There was, however, no difference in reintervention rate (endoscopic retrograde cholangiopancreatography [ERCP] or completion cholecystectomy) between those patients who underwent subtotal fenestrating versus reconstituting cholecystectomy (32% vs. 26%, P 5 .21). Laparoscopic cholecystectomy remains the standard therapy for definitive treatment of patients with acute cholecystitis. Conversion to an open approach or performing either type of subtotal cholecystectomy is appropriate for highrisk cases where a laparoscopic approach may be unsafe. In patients with a high perioperative risk related to sepsis, duration of presenting symptoms, or underlying medical comorbidities, initial treatment of acute cholecystitis with percutaneous cholecystostomy tube placement is preferred (see Chapter 35). The standard of care for this high-risk patient cohort is percutaneous cholecystostomy tube followed by interval cholecystectomy, which is typically performed at least six to eight weeks after tube placement. Percutaneous cholecystostomy is placed under US or CT guidance33 and decompresses the gallbladder by evacuating the infected bile and relieving the pain associated with gallbladder distension from outlet obstruction.

Most patients (.80%) have immediate clinical improvement after biliary decompression.33–35 The incidence and severity of complications after percutaneous cholecystostomy tube placement is low and relatively benign.34,36–38 Approximately 33% of patients who undergo cholecystostomy tube for acute cholecystitis will experience tube-related complications.39 The most common complications include tube displacement, tube site skin infection, and tube site pain.39,40 After resolution of the acute inflammatory process, the standard of care includes interval cholecystectomy in patients without contraindications to surgery. Laparoscopic cholecystectomy can often be performed successfully,37 but the conversion from a laparoscopic to open approach is relatively increased in this population. In patients with previous percutaneous cholecystostomy, the rate of conversion from a laparoscopic to open approach ranges from 14% to 32%.37,41 This is in contrast to the relatively low conversion rates for elective cholecystectomy (5%)42 and emergent cholecystectomy performed for acute cholecystitis (6%).43 Overall, compared with patients who were treated with antibiotics and delayed cholecystectomy, patients who underwent percutaneous cholecystostomy tube followed by interval cholecystectomy had shorter overall hospital stay and decreased cost,36 although there is clearly selection bias, which can make these differences difficult to evaluate. There is a subset of patients who are unable to undergo interval cholecystectomy, either because of prohibitive anticipated surgical morbidity and mortality or because of other considerations (i.e., noncurative cancer). These patients have two options for tube management: tube removal or indefinite tube continuation (sometimes referred to as a destination tube). The criteria for cholecystostomy tube removal include resolution of the obstructive inflammatory process and patency of the cystic and common bile ducts. Biliary patency can be assessed via a clamp trial where the cholecystostomy tube is clamped and the patient self-monitors for any recurrent

A. Gallstones and Gallbladder  Chapter 34  Cholecystitis

symptoms or via cholecystography to confirm tube position and duct patency. The most concerning complication after cholecystostomy tube removal in nonsurgical patients is recurrent cholecystitis. Recurrent cholecystitis after cholecystostomy tube removal is reported to be between 10% to 21%, although these numbers are skewed by the selection bias of retrospective research and the high mortality (43%) of nonsurgical patients.39,44 Risk factors for recurrent cholecystitis after cholecystostomy tube removal include tube removal within 44 days of percutaneous placement (OR 5.6; 95% confidence interval [CI]: 1.25–23.2; P 5 .02) and history of choledocholithiasis (OR 24.4; 95% CI: 2.7–220.7; P 5 .005). Patients who underwent a successful clamping trial before tube removal had lower rates of recurrent cholecystitis (OR 0.10; 95% CI 0.01–0.8; P 5 .03).44 Advancements in endoscopic technologies and techniques have led to expanded options for definitive nonoperative management of acute cholecystitis. Lumen-apposing self-expandable metallic stents (LASEMS) have historically been used for transgastric drainage of pancreatic pseudocyst or walled off necrosis45 (see Chapter 56). They have more recently, however, been adapted to offer transduodenal or transgastric gallbladder drainage in patients unfit for cholecystectomy. One such stent is the AXIOS stent (AXIOS; Xlumena Inc, Mountain View, CA), a fully covered self-expandable nitinol-based stent with anchoring flanges on opposing ends that inhibit post-placement migration. Its use in cholecystitis as a means of achieving biliary decompression has only been described in case reports of anywhere from one to 30 patients. A systematic review45 of 11 studies (78 patients total) found that AXIOS/LASEMS placement from duodenum or stomach to the gallbladder was successfully achieved in 97% of patients and relieved symptoms in 99.6% of patients. Minor procedure-associated complications included transient fever (n 5 1), hematochezia (n 5 1), and pain (n 5 1). There were no procedure-associated major complications and no reports of stent migration. Stents were removed within one to two weeks in 10 out of the 11 studies, after establishment of a fistulous tract between the gallbladder and either duodenum or stomach. Only one study (n 5 27 patients) examined long-term outcomes (three months): three patients developed mucosal ingrowth and two patients developed recurrent cholecystitis from an obstructed stent.45 Any consideration of LASEMS should occur at initial diagnosis and treatment planning as LASEMS are not compatible with other biliary drainage approaches (i.e., percutaneous cholecystostomy tube). LASEMS could offer a nonoperative management strategy for acute cholecystitis in patients unfit for surgery; however, multiinstitutional RCTs are needed to definitively understand the short- and long-term risks and benefits of this approach and the most appropriate population for its application.

Timing of Surgery The optimal interval of time between the diagnosis of acute cholecystitis and definitive treatment with cholecystectomy has been the subject of many prospective randomized trials, with nine evaluating open cholecystectomy and five evaluating laparoscopic cholecystectomy.23,46 The concern in operating on patients with early cholecystitis (typically defined as ,72 hours) is the fear of increased operative complications, including common bile duct injury (see Chapter 36). The downside of performing delayed cholecystectomy (weeks after the diagnosis of cholecystitis) is that a subset of patients will develop recurrence

483

cholecystitis before cholecystectomy, leading to readmission and urgent surgery.23 In multiple randomized prospective trials evaluating the timing of open cholecystectomy, patients undergoing early operation did not experience any increase in perioperative morbidity or mortality and had a shorter total length of hospital stay compared with patients undergoing delayed operation.47,48 In addition, a meta-analysis of these trials demonstrated that more than 20% of patients did not respond to medical management while awaiting definitive treatment, and approximately half of these patients required urgent surgical treatment as a result.23 Additionally, no increase in morbidity was seen in patients undergoing early (,72 hours from symptom onset) versus late (.72 hours from symptom onset) cholecystectomy with either laparoscopic (P 5 .6) or open (P 5 .2) approach. However, patients undergoing delayed cholecystectomy had significantly prolonged total hospitalization and higher cost of care compared with patients who underwent early cholecystectomy.23 Injury to the common bile duct (see Chapters 36 and 42) is a feared complication of any cholecystectomy but particularly for those performed in the setting of acute cholecystitis. Acute severe inflammation can obscure biliary anatomy and predispose to biliary injuries and complications. Multiple prospective randomized trials have demonstrated (Table 34.1) that although early cholecystectomy is associated with a significant increase in operation time compared with delayed cholecystectomy (P 5 .002), there is no significant difference in postoperative morbidity or mortality, including the incidence of common bile duct injury.46 No significant difference has been found in the conversion rate (laparoscopic to open approach) in early versus delayed cholecystectomy. Nevertheless, conversion to open surgery was higher (20%–30%) in patients with acute cholecystitis compared with patients undergoing elective laparoscopic cholecystectomy in the nonacute setting. Perhaps the most important finding was that in all but one study, patients randomly assigned to delayed cholecystectomy did not respond to medical management (supportive care and antibiotics) in 15% to 30% of cases. Although patients in the early surgery group generally experienced a longer postoperative hospital stay (P 5 .004), most of these trials demonstrated a decrease in overall length of hospital stay (surgical admission plus readmission) in the early compared with the delayed group (cumulative P , .001).18–21,53 Early cholecystectomy has also been demonstrated to be more cost effective than delayed cholecystectomy. This was illustrated in a meta-analysis of studies of various designs performed by Lau and colleagues,54 which concluded that early surgery was more cost effective because of its associated reduced overall length of hospital stay and avoidance of readmissions for recurrent symptoms. Early laparoscopic cholecystectomy is therefore the preferred surgical technique for patients with acute cholecystitis. Catena and colleagues55 have proposed the use of a harmonic scalpel for improved hemostasis and biliostasis in laparoscopic cholecystectomy, and preliminary data suggested it may decrease the conversion rate to open procedure in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. A prospective RCT subsequently confirmed these findings.55 The majority of trials examining early versus delayed laparoscopic cholecystectomy define “early” as within 72 hours of symptom onset, but the impact of the time from symptom

484

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

TABLE 34.1  Results of Prospective Randomized Trials Comparing Early Versus Delayed Laparoscopic Cholecystectomy for Acute Cholecystitis REFERENCE

N

DEFINITION

Ozkardes et al., 201449

60

Saber & Hokkam, 201450

120

Gutt et al., 201351

618

Early: ,24 hours Late: 6–8 weeks Early: ,72 hours Late: 6–8 weeks Early: ,24 hours Late: 7–45 days Early: ,72 hours Late: 3 months Early: ,4 days Late: 6–12 weeks Early: ,7 days Late: 6–8 weeks Early: ,24 hours Late: 6–8 weeks Early: ,3 days Late: 6–8 weeks

Macafee et al., 200952

72

Kolla et al., 200453

40

Johansson et al., 200319

145

Lai et al., 199820

104

Lo et al., 199821

99

MORBIDITY RATE

LENGTH OF STAY (DAYS)

CONVERSION TO OPEN CHOLECYSTECTOMY

27% 0 NR NR 12% 34% 22% 11% 20% 15% 18% 10% 9% 8% 29% 13%

 5  8  2  6  5 10  6  6  4 10  5  8  8 12  6 11

13%   0%   5%   2% 10% 12%   3%   3% 25% 25% 31% 21% 24%   8% 11% 23%

NR, Not recorded.

onset to cholecystectomy on outcomes has also been examined in more detail. A nonrandomized prospective study by Tzovaras and colleagues56 assessed 129 patients undergoing laparoscopic cholecystectomy for acute cholecystitis. Patients were divided into three groups according to the time from symptom onset to cholecystectomy: less than three days, between four and seven days, and greater than seven days. This study found no significant difference in conversion rate (laparoscopic to open), morbidity, or postoperative hospital stay among these groups and suggested that cholecystectomy may be safe even if performed up to or after seven days from symptom onset. The results of this study, however, should be interpreted in the context of its inherent selection bias because the timing of surgery was determined by surgeon discretion rather than randomization of clinically similar groups.

CHRONIC CHOLECYSTITIS Pathogenesis and Clinical Manifestations Chronic cholecystitis may result after one or more episodes of acute cholecystitis, or it may evolve, initially without symptoms, merely from the presence of gallstones. In most cases, patients describe at least one episode of abdominal pain that is clinically consistent with biliary colic. The term colic is a misnomer because the pain from chronic cholecystitis is usually constant in nature and is similar to that seen initially with acute cholecystitis, although it is self-limited and often less severe. The pain associated with chronic cholecystitis seems to be the result of intermittent obstruction of the gallbladder outflow. There are numerous well-described risk factors for the development of gallstones and subsequent chronic cholecystitis. Patients at particularly high risk include obese women, in whom pathologic changes of chronic inflammation are found even in the absence of gallstones57,58; this may be because of an increase in the cholesterol saturation of bile in obese patients59 (see Chapter 8). These patients are often asymptomatic.

Xanthogranulomatous cholecystitis is a subtype of chronic cholecystitis that can appear similar to gallbladder cancer on imaging studies60 (see Chapter 49). It is characterized by the presence of destructive inflammation of the gallbladder wall, often accompanied by proliferative fibrosis. The histologic appearance is that of foamy histiocytes in a background of acute and chronic inflammatory cells. This process can result in the appearance of asymmetric gallbladder wall thickening and/or mass formation in the gallbladder wall and can be difficult or impossible to distinguish from gallbladder cancer (Fig. 34.5). Further confusing this picture, serum cancer antigen 19-9 levels can be elevated in xanthogranulomatous cholecystitis.61

Diagnostic Imaging US examination of the gallbladder most often reveals circumferential thickening of the gallbladder wall with cholelithiasis (see Chapter 16). In advanced cases, a small, shrunken gallbladder with a thickened wall and multiple gallstones are seen. Discomfort may be reproduced with direct pressure on the gallbladder with the US probe. Commonly, particularly in obese patients and in those with mild symptoms, the US examination shows no particular gallbladder wall abnormalities.57

Treatment Elective cholecystectomy is the treatment of choice for patients with symptoms of chronic cholecystitis (see Chapter 36). In most ($90%) cases, cholecystectomy can be accomplished laparoscopically. Patients occasionally are seen with atypical pain (left hypochondrium) or with minimal or no pain but, rather, intermittent nausea or bloating. In such cases, evaluation for other possible causes of symptoms should be undertaken, particularly if the US shows gallstones but no sequelae of chronic cholecystitis. In cases where there is asymmetric gallbladder wall thickening or mass formation concerning for malignancy, a laparoscopic exploration is reasonable, but with a low threshold for conversion to an open operation. The surgeon should be prepared to perform a definitive gallbladder cancer operation, including liver resection

A. Gallstones and Gallbladder  Chapter 34  Cholecystitis

A

485

B

FIGURE 34.5  A, Coronal image of a patient seen with chronic right upper quadrant pain and a distended gallbladder with asymmetric wall thickening concerning for malignancy. B, Gross image of the resected gallbladder, which was firm and markedly abnormal. Final pathology demonstrated xanthogranulomatous cholecystitis.

and regional lymphadenectomy. In these cases, it is critical to avoid gallbladder perforation or spillage intraoperatively. Frozen-section analysis of any grossly abnormal tissue can be considered, but it is often appropriate to proceed with a cancer operation if gross findings are suspicious for malignancy (see Chapter 49).

ACUTE ACALCULOUS CHOLECYSTITIS Pathogenesis Acalculous cholecystitis usually occurs in patients with coexisting acute major illnesses, such as generalized sepsis, major trauma, or burns, or in those undergoing a prolonged recovery from major operations who are unable to tolerate oral intake.62 It has been speculated that in such situations, there is no stimulus for gallbladder contraction, the bile becomes inspissated, and biliary sludge forms. The exact pathogenesis is unknown but likely involves some combination of ischemia, biliary stasis, and sepsis.63,64 Inspissated bile and sludge seem to play some causative role as well. Although this condition traditionally has been described in the patient groups mentioned earlier, several reports suggest an increase in the de novo presentation of acalculous cholecystitis in the outpatient population, including patients with atherosclerotic vascular disease, as is seen in hypertension and diabetes.65–67 Overall, acalculous cholecystitis represents approximately 5% to 15% of all cases of acute cholecystitis. A male predominance is seen in cases of acalculous cholecystitis, in contrast to acute calculous cholecystitis, which occurs more commonly in women.66,68,69 A prospective study evaluating trauma patients with serial US examinations found that the incidence of acalculous cholecystitis in severely injured patients (injury severity score $ 12, requiring intensive care for . four days) was 11%,70 which is similar to other reports.71 In addition, three factors were correlated with an increased risk for acalculous cholecystitis in this high-risk population: (1) high injury-severity score, (2) increased heart rate, and (3) transfusion requirement at the time of admission. This study suggests that more acutely injured patients, who are

expected to require prolonged ventilatory and nutritional support, are at higher risk for acalculous cholecystitis.70

Clinical Manifestations Part of the difficulty in making the diagnosis of acalculous cholecystitis is that many patients seen with this condition are critically ill and require ventilatory support and sedation. The symptoms and signs are often masked by the patient’s underlying condition or the interventions used to treat it.68 In the outpatient population seen with acalculous cholecystitis, the diagnosis is more straightforward, mimicking the signs and symptoms of acute calculous cholecystitis.66 The most frequent physical and laboratory findings are fever, right upper quadrant pain, leukocytosis, and hyperbilirubinemia. These findings are often nonspecific, however, in the setting of sepsis and critical illness.68 The incidence of gangrene and perforation seems to be increased in patients with acalculous cholecystitis compared with acute calculous cholecystitis, likely because of the delay in diagnosis that is common with this disease. Severe gallbladder complications such as gangrene, perforation, and empyema occur more commonly in older patients with elevated WBC counts.66,69 In many series, the risk of severe gallbladder complications was found to be 50% to 60%.68,69,72 This high risk may be the result of the disturbance in capillary microcirculation, which has been shown in pathologic studies on gallbladder specimens after cholecystectomy for acalculous cholecystitis.63,64 In addition, partly as a result of the severity of the patient’s underlying condition, the mortality rates are as high as 15% in some series.69

Diagnostic Evaluation and Imaging Imaging algorithms for patients with suspected acalculous cholecystitis are similar to algorithms for patients with acute cholecystitis. The initial imaging test is usually US, which classically reveals gallbladder distension, a thickened gallbladder wall, and biliary sludge without stones69 (Fig. 34.6; see Chapter 16). The difficulty with interpreting these findings is that many critically ill, parenteral nutrition–dependent patients have these findings.

486

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

of this modality has shown improved accuracy in diagnosing acalculous cholecystitis.66,68 In some series, scintigraphy has been found to be more sensitive than CT or US in diagnosing acalculous cholecystitis.66,68,75,76 The specificity of hepatobiliary scintigraphy can be improved by administering morphine to cause constriction of the sphincter of Oddi and improve gallbladder filling (see Chapter 16). This maneuver decreases the incidence of false-positive studies and improves specificity, but it does not result in improvements in sensitivity compared with conventional scintigraphy.68,77,78 As discussed previously, evaluation of gallbladder EF with scintigraphy can aid in diagnosis of acalculous cholecystitis and chronic cholecystitis. However, caution should be exhibited in interpreting a normal EF in the setting of clinical symptoms, as various studies have reported symptom relief with either surgery or medical management in this population6,8. FIGURE 34.6  Ultrasound of a patient with acalculous cholecystitis reveals marked thickening of the gallbladder wall (arrows).

Partly because of this difficulty, the accuracy of US to diagnose acalculous cholecystitis has been highly institution dependent, with some series showing it to be highly sensitive and specific70 and others showing it to be less accurate.68 US is widely available and easy to use, even in critically ill patients, because it can be performed at the bedside, and it is inexpensive. US should be performed as the initial imaging modality for suspected acalculous cholecystitis. The natural history of abnormalities visualized on US in critically ill patients is unclear; a prospective trial assessed 255 critically ill trauma patients with serial US examinations. In this trial, all patients with US findings consistent with acalculous cholecystitis also had significant clinical symptoms of abdominal pain and/or distension, hemodynamic instability, or organ failure. All patients with US findings suggestive of acalculous cholecystitis underwent cholecystectomy and all had acalculous cholecystitis on final pathology. A subset of patients had positive US findings without significant clinical symptoms and within this subset, US findings normalized within three weeks. In addition, 15% of patients experienced hydrops of the gallbladder without clinical symptoms with eventual normalization of US findings observed in all.70 These findings suggest that although many critically ill patients may develop US abnormalities consistent with acalculous cholecystitis, the combination of clinical symptoms and positive imaging findings is crucial in distinguishing patients who may benefit from intervention. Because of the difficulty establishing a diagnosis in these critically ill patients, CT has been used as an additional diagnostic adjunct. The advantage of CT is that imaging of the entire chest, abdomen, and pelvis can be obtained; this is particularly important in this patient cohort, in whom clinical signs and symptoms may be misleading or may result from other causes. CT may be more sensitive and specific than US,73,74 but it has the disadvantage of requiring transport of the patient outside of the intensive care unit. When a patient’s diagnosis is questionable based on physical findings or US evaluation or both, hepatobiliary scintigraphy may also be employed (see Chapter 18). In past reports, a high rate of false-positive scintigraphy results were seen in patients with acalculous cholecystitis74, but more recent evaluation

Treatment The definitive treatment for acalculous cholecystitis is cholecystectomy, which can be performed laparoscopically in most cases. In patients who are critically ill, placement of a percutaneous cholecystostomy tube allows decompression of the gallbladder and drainage of contained, infected bile (see Chapter 35); this allows time for the patient to recover from the acute illness before considering proceeding with cholecystectomy.36,79 Percutaneous cholecystostomy may be the definitive treatment for acalculous cholecystitis because there is no chronic obstruction of the gallbladder outlet as in acute cholecystitis.35,80

COMPLICATIONS OF CHOLECYSTITIS Gangrenous Cholecystitis Gangrenous cholecystitis is a more common finding in diabetic patients with acute cholecystitis who present with a leukocytosis.81 In addition, the risk of gangrenous cholecystitis is higher in patients with acalculous cholecystitis, likely owing to the delay in diagnosis that commonly occurs in this disease.68,69,72 As previously mentioned, the most common site for necrosis to occur is in the fundus. Full-thickness necrosis is by definition always present in patients with gangrenous cholecystitis, but this condition may or may not result in free perforation of the gallbladder. In patients with free perforation, bile-stained abdominal fluid is present. Because these patients are generally ill, imaging with CT scan is often performed. Findings most specific for acute gangrenous cholecystitis on CT scan include air in the wall or lumen, intraluminal membranes, an irregular wall, or pericholecystic abscess. As expected, a contrast-enhanced CT scan may show a lack of mural enhancement in patients with gangrenous cholecystitis.82

Empyema In cases of empyema, the gallbladder is filled with purulent bile. This condition usually is associated with acute cholecystitis and occurs in the setting of infected bile and an obstructed cystic duct. Most patients with empyema have calculous cholecystitis, but empyema also can occur in patients with acalculous disease.83 The clinical course can mimic that of an intra-abdominal abscess from other causes, and patients are often seen initially with clinical manifestations of sepsis. Patients with gallbladder

A. Gallstones and Gallbladder  Chapter 34  Cholecystitis

empyema require urgent cholecystectomy or percutaneous cholecystostomy, depending on the severity of illness at the time of presentation.83 Critically ill patients may be best served by a temporary cholecystostomy tube followed by elective cholecystectomy.

Emphysematous Cholecystitis Emphysematous cholecystitis is a rare entity that results from the presence of gas-forming bacteria in the bile. Emphysematous cholecystitis may be seen in association with acute or gangrenous cholecystitis, and it is more common in men and patients with diabetes.84 The diagnosis occasionally can be made by simple abdominal radiographs, but more often it is diagnosed on US (Fig. 34.7) or CT scan82,85,86 (Fig. 34.8). Patients should receive IV antibiotics to include coverage for Clostridium species, followed by emergent cholecystectomy.

487

Mirizzi Syndrome Mirizzi syndrome is defined as biliary obstruction secondary to cholecystitis related to large gallstones. It occurs in 0.3% to 3% of patients undergoing cholecystectomy87 (see Chapter 37–38). An impacted stone in the gallbladder infundibulum or cystic duct can compress the bile duct, usually at the level of the common hepatic duct (type I), or a stone can erode from the gallbladder or cystic duct into the common hepatic duct, resulting in a cholecystocholedochal fistula (type II). Patients are seen with symptoms of acute cholecystitis but with the additional finding of hyperbilirubinemia and elevated alkaline phosphatase. A laparoscopic approach to this condition has been shown to result in high conversion and complication rates and is generally not recommended.87,88 Open cholecystectomy is the gold standard for treatment when this condition is identified preoperatively. If inflammation has obliterated the triangle of Calot, a partial cholecystectomy with removal of any stones may be all that is possible and usually resolves the condition. In the acute setting, the biliary obstruction often resolves after cholecystectomy and resolution of the inflammatory process. In some cases, however, the chronic inflammation leads to fistulation from the gallbladder to the bile duct, or a biliary stricture results, both of which will complicate the operative procedure and may require biliary reconstruction (see Chapter 42).

Cholecystoenteric Fistula

FIGURE 34.7  Ultrasound of the gallbladder revealing air within the gallbladder wall (arrows) consistent with emphysematous cholecystitis.

R 2 2 2

L 2 7 7

Cholecystoenteric fistula, or perforation of the gallbladder into an adjacent hollow organ, is a rare complication of acute cholecystitis. The duodenum and the transverse colon are the most common sites of fistulation, which results in decompression of the gallbladder and may result in brief symptomatic improvement. This complication occurs most frequently in women in their sixth to seventh decades and has been shown to be associated with Mirizzi syndrome or an additional hepatobiliary abnormality such as gallbladder cancer89–91 (see Chapters 3738, 42, 49). Contamination of the biliary tree by enteric organisms may result, and patients may be seen with cholangitis and pneumobilia. Approximately 10% to 15% of patients with cholecystoenteric fistulae will pass gallstones into the small intestine and be seen with small bowel obstruction, termed gallstone ileus. In patients with cholecystocolonic fistula, chronic diarrhea is the most common presenting symptom in nonemergent cases.91 Patients with cholecystoenteric fistula require cholecystectomy with takedown and closure of the fistula. When cholecystoenteric fistula is encountered at the time of surgery, concomitant Mirizzi syndrome should be considered. Patients with gallstone ileus require removal of the obstructing stone via enterotomy,90 and it is important to perform a thorough examination of the bowel for any other stones. Fistula takedown and cholecystectomy can be performed at the same procedure or at a second, delayed procedure if the patient is too unstable to tolerate a prolonged initial operation, or if the pericholecystic inflammation is so severe as to make initial cholecystectomy unsafe.

Bouveret Syndrome

FIGURE 34.8  Computed tomography scan (noncontrast) in a patient with emphysematous cholecystitis showing gallbladder filled with air.

Bouveret syndrome is defined as gastric outlet obstruction secondary to gallstone impaction facilitated by a bilioenteric fistula92 (Fig. 34.9). Gallstone ileus is estimated to occur in less than 0.5% of patients with clinically relevant cholelithiasis.92 Bouveret syndrome represents only 1% to 3% of all cases of

488

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

FIGURE 34.9  Coronal and axial cuts from a computed tomography scan in a patient presenting with Bouveret syndrome, demonstrating a large hyperlucent stone (arrows) obstructing the first portion of the duodenum with associated gastric distension and outlet obstruction.

gallstone ileus. It is hypothesized to occur secondary to inflammatory remodeling and stone-associated pressure necrosis after acute cholecystitis. Risk factors include female gender, older age, and stones greater than 2.5 cm in diameter. The presenting symptoms can range from nonspecific (nausea, abdominal pain) to complete foregut outlet obstruction. Because of its rarity and potential for vague presenting symptoms, its inclusion on the differential for foregut symptoms is often overlooked. Diagnosis is facilitated by abdominal imaging. The pathopneumonic findings on abdominal plain films are Rigler’s triad (dilated stomach, pneumobilia, and a radio-opaque duodenal shadow), but abdominal films are only diagnostic in about 30% of presentations. US offers more anatomic detail of the bilioenteric fistula and can also characterize the gallbladder; however, sensitivity is variable and user-dependent. A more sensitive modality is contrast-enhanced multi-detector CT, which allows for simultaneous evaluation of the bilioenteric fistula, the gallbladder, and the anatomic relationship between inflammatory change and surrounding structures (i.e., porta hepatis, pancreas). Esophagoduodenoscopy is the most sensitive diagnostic modality and is potentially therapeutic.92 Treatment can be facilitated from either endoscopic or surgical approaches. Endoscopic removal can be achieved through

direct mechanical removal, mechanical lithotripsy, laser lithotripsy, extracorporeal shockwave lithotripsy, or intracorporeal electrohydraulic lithotripsy. A described complication from lithotripsy is distal enteric obstruction from stone fragmentation. Unfortunately, endoscopic stone extraction is only successful in about 10% of cases. However, because of its less invasive nature, it is generally recommended before any surgical approach. Surgical approach must consider both patient comorbidity and the anatomy of the bilioenteric fistula as it relates to surrounding structures. Surgery can include enterolithotomy with or without closure of the bilioenteric fistula and cholecystectomy (usually done in a multi-stage operation) but depending on the degree of inflammation and location of the impacted stone can also include more invasive approaches. Although the optimal surgical approach is a topic of continued debate, many argue for enterolithotomy alone because it minimizes risk in a typically older population. Although difficult to study because of its rarity, the risk of recurrent biliary symptoms or enteric obstruction after enterolithotomy alone is estimated to be less than 10%.92 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

488.e1

REFERENCES 1. Sjodahl R, Tagesson C, Wetterfors J. On the pathogenesis of acute cholecystitis. Surg Gynecol Obstet. 1978;146:199-202. 2. den Hoed PT, Boelhouwer RU, Veen HF, Hop WC, Bruining HA. Infections and bacteriological data after laparoscopic and open gallbladder surgery. J Hosp Infect. 1998;39:27-37. 3. Reinders JS, Kortram K, Vlaminckx B, van Ramshorst B, Gouma DJ, Boerma D. Incidence of bactobilia increases over time after endoscopic sphincterotomy. Dig Surg. 2011;28:288-292. 4. Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25:41-54. 5. Yokoe M, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo Guidelines. J Hepatobiliary Pancreat Sci. 2012;19:578-585. 6. Ziessman HA. Hepatobiliary scintigraphy in 2014. J Nucl Med Technol. 2014;42:249-259. 7. Middleton GW, Williams JH. Diagnostic accuracy of 99Tcm-HIDA with cholecystokinin and gallbladder ejection fraction in acalculous gallbladder disease. Nucl Med Commun. 2001;22:657-661. 8. Gudsoorkar VS, Oglat A, Jain A, Raza A, Quigley EMM. Systematic review with meta-analysis: cholecystectomy for biliary dyskinesia-what can the gallbladder ejection fraction tell us? Aliment Pharmacol Ther. 2019;49:654-663. 9. Chatziioannou SN, Moore WH, Ford PV, Dhekne RD. Hepatobiliary scintigraphy is superior to abdominal ultrasonography in suspected acute cholecystitis. Surgery. 2000;127:609-613. 10. Kalimi R, Gecelter GR, Caplin D, et al. Diagnosis of acute cholecystitis: sensitivity of sonography, cholescintigraphy, and combined sonography-cholescintigraphy. J Am Coll Surg. 2001;193:609-613. 11. Mahid SS, Jafri NS, Brangers BC, Minor KS, Hornung CA, Galandiuk S. Meta-analysis of cholecystectomy in symptomatic patients with positive hepatobiliary iminodiacetic acid scan results without gallstones. Arch Surg. 2009;144:180-187. 12. Fidler J, Paulson EK, Layfield L. CT evaluation of acute cholecystitis: findings and usefulness in diagnosis. AJR Am J Roentgenol. 1996;166:1085-1088. 13. Harvey RT, Miller Jr WT. Acute biliary disease: initial CT and follow-up US versus initial US and follow-up CT. Radiology. 1999;213: 831-836. 14. Cox MR, Wilson TG, Luck AJ, Jeans PL, Padbury RT, Toouli J. Laparoscopic cholecystectomy for acute inflammation of the gallbladder. Ann Surg. 1993;218:630-634. 15. Keus F, Werner JE, Gooszen HG, Oostvogel HJ, van Laarhoven CJ. Randomized clinical trial of small-incision and laparoscopic cholecystectomy in patients with symptomatic cholecystolithiasis: primary and clinical outcomes. Arch Surg. 2008;143:371-377; discussion 7-8. 16. Majeed AW, Troy G, Nicholl JP, et al. Randomised, prospective, single-blind comparison of laparoscopic versus small-incision cholecystectomy. Lancet. 1996;347:989-994. 17. Flowers JL, Bailey RW, Scovill WA, Zucker KA. The Baltimore experience with laparoscopic management of acute cholecystitis. Am J Surg. 1991;161:388-392. 18. Chandler CF, Lane JS, Ferguson P, Thompson JE, Ashley SW. Prospective evaluation of early versus delayed laparoscopic cholecystectomy for treatment of acute cholecystitis. Am Surg. 2000;66: 896-900. 19. Johansson M, Thune A, Blomqvist A, Nelvin L, Lundell L. Management of acute cholecystitis in the laparoscopic era: results of a prospective, randomized clinical trial. J Gastrointest Surg. 2003;7: 642-645. 20. Lai PB, Kwong KH, Leung KL, et al. Randomized trial of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Br J Surg. 1998;85:764-767. 21. Lo CM, Liu CL, Fan ST, Lai EC, Wong J. Prospective randomized study of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Ann Surg. 1998;227:461-467. 22. Schirmer BD, Edge SB, Dix J, Hyser MJ, Hanks JB, Jones RS. Laparoscopic cholecystectomy. Treatment of choice for symptomatic cholelithiasis. Ann Surg. 1991;213:665-676; discussion 77. 23. Papi C, Catarci M, D’Ambrosio L, et al. Timing of cholecystectomy for acute calculous cholecystitis: a meta-analysis. Am J Gastroenterol. 2004;99:147-155.

24. Rosen M, Brody F, Ponsky J. Predictive factors for conversion of laparoscopic cholecystectomy. Am J Surg. 2002;184:254-258. 25. Alponat A, Kum CK, Koh BC, Rajnakova A, Goh PM. Predictive factors for conversion of laparoscopic cholecystectomy. World J Surg. 1997;21:629-633. 26. Kanaan SA, Murayama KM, Merriam LT, et al. Risk factors for conversion of laparoscopic to open cholecystectomy. J Surg Res. 2002;106:20-24. 27. Hsieh CH. Early minilaparoscopic cholecystectomy in patients with acute cholecystitis. Am J Surg. 2003;185:344-348. 28. Assalia A, Kopelman D, Hashmonai M. Emergency minilaparotomy cholecystectomy for acute cholecystitis: prospective randomized trial—implications for the laparoscopic era. World J Surg. 1997;21: 534-539. 29. Horiuchi A, Watanabe Y, Doi T, et al. Delayed laparoscopic subtotal cholecystectomy in acute cholecystitis with severe fibrotic adhesions. Surg Endosc. 2008;22:2720-2273. 30. Singhal T, Balakrishnan S, Hussain A, Nicholls J, Grandy-Smith S, El-Hasani S. Laparoscopic subtotal cholecystectomy: initial experience with laparoscopic management of difficult cholecystitis. Surgeon. 2009;7:263-268. 31. Strasberg SM, Pucci MJ, Brunt LM, Deziel DJ. Subtotal cholecystectomy-“fenestrating” vs “reconstituting” subtypes and the prevention of bile duct injury: Definition of the optimal procedure in difficult operative conditions. J Am Coll Surg. 2016;222:89-96. 32. van Dijk AH, Donkervoort SC, Lameris W, et al. Short- and longterm outcomes after a reconstituting and fenestrating subtotal cholecystectomy. J Am Coll Surg. 2017;225:371-379. 33. Hatzidakis AA, Prassopoulos P, Petinarakis I, et al. Acute cholecystitis in high-risk patients: percutaneous cholecystostomy vs conservative treatment. Eur Radiol. 2002;12:1778-1784. 34. Byrne MF, Suhocki P, Mitchell RM, et al. Percutaneous cholecystostomy in patients with acute cholecystitis: experience of 45 patients at a US referral center. J Am Coll Surg. 2003;197:206-211. 35. Vauthey JN, Lerut J, Martini M, Becker C, Gertsch P, Blumgart LH. Indications and limitations of percutaneous cholecystostomy for acute cholecystitis. Surg Gynecol Obstet. 1993;176:49-54. 36. Akyurek N, Salman B, Yuksel O, et al. Management of acute calculous cholecystitis in high-risk patients: percutaneous cholecystotomy followed by early laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2005;15:315-320. 37. Spira RM, Nissan A, Zamir O, Cohen T, Fields SI, Freund HR. Percutaneous transhepatic cholecystostomy and delayed laparoscopic cholecystectomy in critically ill patients with acute calculus cholecystitis. Am J Surg. 2002;183:62-66. 38. Werbel GB, Nahrwold DL, Joehl RJ, Vogelzang RL, Rege RV. Percutaneous cholecystostomy in the diagnosis and treatment of acute cholecystitis in the high-risk patient. Arch Surg. 1989;124:782-785; discussion 5-6. 39. Colonna AL, Griffiths TM, Robison DC, et al. Cholecystostomy: are we using it correctly? Am J Surg. 2019;217:1010-1015. 40. Beland MD, Patel L, Ahn SH, Grand DJ. Image-guided cholecystostomy tube placement: short- and long-term outcomes of transhepatic versus transperitoneal placement. AJR Am J Roentgenol. 2019;212:201-204. 41. Suzuki K, Bower M, Cassaro S, Patel RI, Karpeh MS, Leitman IM. Tube cholecystostomy before cholecystectomy for the treatment of acute cholecystitis. JSLS. 2015;19:e201400200. 42. Ercan M, Bostanci EB, Teke Z, et al. Predictive factors for conversion to open surgery in patients undergoing elective laparoscopic cholecystectomy. J Laparoendosc Adv Surg Tech A. 2010;20:427-434. 43. Sippey M, Grzybowski M, Manwaring ML, et al. Acute cholecystitis: risk factors for conversion to an open procedure. J Surg Res. 2015;199:357-361. 44. Park JK, Yang JI, Wi JW, et al. Long-term outcome and recurrence factors after percutaneous cholecystostomy as a definitive treatment for acute cholecystitis. J Gastroenterol Hepatol. 2019;34: 784-790. 45. Patil R, Ona MA, Papafragkakis C, Anand S, Duddempudi S. Endoscopic ultrasound-guided placement of the lumen-apposing selfexpandable metallic stent for gallbladder drainage: a promising technique. Ann Gastroenterol. 2016;29:162-167. 46. Siddiqui T, MacDonald A, Chong PS, Jenkins JT. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a metaanalysis of randomized clinical trials. Am J Surg. 2008;195:40-47.

488.e2 47. Norrby S, Herlin P, Holmin T, Sjodahl R, Tagesson C. Early or delayed cholecystectomy in acute cholecystitis? A clinical trial. Br J Surg. 1983;70:163-165. 48. Van der Linden W, Edlund G. Early versus delayed cholecystectomy: the effect of a change in management. Br J Surg. 1981;68:753-757. 49. Ozkardes AB, Tokac M, Dumlu EG, et al. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a prospective, randomized study. Int Surg. 2014;99:56-61. 50. Saber A, Hokkam EN. Operative outcome and patient satisfaction in early and delayed laparoscopic cholecystectomy for acute cholecystitis. Minim Invasive Surg. 2014;2014:162643. 51. Gutt CN, Encke J, Koninger J, et al. Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304). Ann Surg. 2013;258:385-393. 52. Macafee DA, Humes DJ, Bouliotis G, Beckingham IJ, Whynes DK, Lobo DN. Prospective randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy for acute gallbladder disease. Br J Surg. 2009;96:1031-1040. 53. Kolla SB, Aggarwal S, Kumar A, et al. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a prospective randomized trial. Surg Endosc. 2004;18:1323-1327. 54. Lau H, Lo CY, Patil NG, Yuen WK. Early versus delayed-interval laparoscopic cholecystectomy for acute cholecystitis: a metaanalysis. Surg Endosc. 2006;20:82-87. 55. Catena F, Ansaloni L, Di Saverio S, Gazzotti F, Coccolini F, Pinna AD. The HAC Trial (Harmonic for Acute Cholecystitis) Study. Randomized, double-blind, controlled trial of harmonic(H) versus monopolar diathermy (M) for laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) in adults. Trials. 2009;10:34. 56. Tzovaras G, Zacharoulis D, Liakou P, Theodoropoulos T, Paroutoglou G, Hatzitheofilou C. Timing of laparoscopic cholecystectomy for acute cholecystitis: a prospective non randomized study. World J Gastroenterol. 2006;12:5528-5531. 57. Calhoun R, Willbanks O. Coexistence of gallbladder disease and morbid obesity. Am J Surg. 1987;154:655-658. 58. Csendes A, Burdiles P, Smok G, Csendes P, Burgos A, Recio M. Histologic findings of gallbladder mucosa in 87 patients with morbid obesity without gallstones compared to 87 control subjects. J Gastrointest Surg. 2003;7:547-551. 59. St George CM, Shaffer EA. Spontaneous obesity and increased bile saturation in the ground squirrel. J Surg Res. 1993;55:314-316. 60. Agarwal AK, Kalayarasan R, Javed A, Sakhuja P. Mass-forming xanthogranulomatous cholecystitis masquerading as gallbladder cancer. J Gastrointest Surg. 2013;17:1257-1264. 61. Clarke T, Matsuoka L, Jabbour N, et al. Gallbladder mass with a carbohydrate antigen 19-9 level in the thousands: malignant or benign pathology? Report of a case. Surg Today. 2007;37:342-344. 62. Gu MG, Kim TN, Song J, Nam YJ, Lee JY, Park JS. Risk factors and therapeutic outcomes of acute acalculous cholecystitis. Digestion. 2014;90:75-80. 63. Hakala T, Nuutinen PJ, Ruokonen ET, Alhava E. Microangiopathy in acute acalculous cholecystitis. Br J Surg. 1997;84:1249-1252. 64. Warren BL. Small vessel occlusion in acute acalculous cholecystitis. Surgery. 1992;111:163-168. 65. Parithivel VS, Gerst PH, Banerjee S, Parikh V, Albu E. Acute acalculous cholecystitis in young patients without predisposing factors. Am Surg. 1999;65:366-368. 66. Ryu JK, Ryu KH, Kim KH. Clinical features of acute acalculous cholecystitis. J Clin Gastroenterol. 2003;36:166-169. 67. Savoca PE, Longo WE, Zucker KA, McMillen MM, Modlin IM. The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year study. Ann Surg. 1990;211:433-437. 68. Kalliafas S, Ziegler DW, Flancbaum L, Choban PS. Acute acalculous cholecystitis: incidence, risk factors, diagnosis, and outcome. Am Surg. 1998;64:471-475. 69. Wang AJ, Wang TE, Lin CC, Lin SC, Shih SC. Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis. World J Gastroenterol. 2003;9:2821-2823.

70. Pelinka LE, Schmidhammer R, Hamid L, Mauritz W, Redl H. Acute acalculous cholecystitis after trauma: a prospective study. J Trauma. 2003;55:323-329. 71. Imhof M, Raunest J, Rauen U, Ohmann C. Acute acalculous cholecystitis in severely traumatized patients: a prospective sonographic study. Surg Endosc. 1992;6:68-71. 72. Swayne LC. Acute acalculous cholecystitis: sensitivity in detection using technetium-99m iminodiacetic acid cholescintigraphy. Radiology. 1986;160:33-38. 73. Blankenberg F, Wirth R, Jeffrey Jr RB, Mindelzun R, Francis I. Computed tomography as an adjunct to ultrasound in the diagnosis of acute acalculous cholecystitis. Gastrointest Radiol. 1991;16: 149-153. 74. Mirvis SE, Vainright JR, Nelson AW, et al. The diagnosis of acute acalculous cholecystitis: a comparison of sonography, scintigraphy, and CT. Am J Roentgenol. 1986;147:1171-1175. 75. Prevot N, Mariat G, Mahul P, et al. Contribution of cholescintigraphy to the early diagnosis of acute acalculous cholecystitis in intensive-care-unit patients. Eur J Nucl Med. 1999;26:1317-1325. 76. Puc MM, Tran HS, Wry PW, Ross SE. Ultrasound is not a useful screening tool for acute acalculous cholecystitis in critically ill trauma patients. Am Surg. 2002;68:65-69. 77. Cabana MD, Alavi A, Berlin JA, Shea JA, Kim CK, Williams SV. Morphine-augmented hepatobiliary scintigraphy: a meta-analysis. Nucl Med Commun. 1995;16:1068-1071. 78. Flancbaum L, Alden SM, Trooskin SZ. Use of cholescintigraphy with morphine in critically ill patients with suspected cholecystitis. Surgery. 1989;106:668-673; discussion 73-74. 79. McClain T, Gilmore BT, Peetz M. Laparoscopic cholecystectomy in the treatment of acalculus cholecystitis in patients after thermal injury. J Burn Care Rehabil. 1997;18:141-146. 80. Davis CA, Landercasper J, Gundersen LH, Lambert PJ. Effective use of percutaneous cholecystostomy in high-risk surgical patients: techniques, tube management, and results. Arch Surg. 1999;134: 727-731; discussion 31-32. 81. Fagan SP, Awad SS, Rahwan K, et al. Prognostic factors for the development of gangrenous cholecystitis. Am J Surg. 2003;186: 481-485. 82. Bennett GL, Balthazar EJ. Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin North Am. 2003;41: 1203-1216. 83. Tseng LJ, Tsai CC, Mo LR, et al. Palliative percutaneous transhepatic gallbladder drainage of gallbladder empyema before laparoscopic cholecystectomy. Hepatogastroenterology. 2000;47:932-936. 84. Garcia-Sancho Tellez L, Rodriguez-Montes JA, Fernandez de Lis S, Garcia-Sancho Martin L. Acute emphysematous cholecystitis. Report of twenty cases. Hepatogastroenterology. 1999;46:2144-2148. 85. Gill KS, Chapman AH, Weston MJ. The changing face of emphysematous cholecystitis. Br J Radiol. 1997;70:986-991. 86. Konno K, Ishida H, Naganuma H, et al. Emphysematous cholecystitis: sonographic findings. Abdom Imaging. 2002;27:191-195. 87. Lai EC, Lau WY. Mirizzi syndrome: history, present and future development. ANZ J Surg. 2006;76:251-257. 88. Antoniou SA, Antoniou GA, Makridis C. Laparoscopic treatment of Mirizzi syndrome: a systematic review. Surg Endosc. 2010;24: 33-39. 89. Beltran MA, Csendes A, Cruces KS. The relationship of Mirizzi syndrome and cholecystoenteric fistula: validation of a modified classification. World J Surg. 2008;32:2237-2243. 90. Chowbey PK, Bandyopadhyay SK, Sharma A, Khullar R, Soni V, Baijal M. Laparoscopic management of cholecystoenteric fistulas. J Laparoendosc Adv Surg Tech A. 2006;16:467-472. 91. Costi R, Randone B, Violi V, et al. Cholecystocolonic fistula: Facts and myths. A review of the 231 published cases. J Hepatobiliary Pancreat Surg. 2009;16:8-18. 92. Qasaimeh GR, Bakkar S, Jadallah K. Bouveret’s syndrome: an overlooked diagnosis. A case report and review of literature. Int Surg. 2014;99:819-823.

CHAPTER 35 Percutaneous treatment of gallbladder disease Jad Abou Khalil, George Zogopoulos, and Jeffrey S. Barkun OVERVIEW The first reports of an operative cholecystostomy are attributable to Johannes Fabricius (1618) and Stalpert Von Der Wiel (1667) who described the procedure as occurring almost by happenstance upon the incision of an abdominal wall abcess.1 The following two centuries revealed further sporadic reports, until Marion Sims, an American surgeon in Paris, performed a clearly intentional cholecystostomy in 1878. Kocher and Tait2 formalized the procedure in 1878, many months after and independently of Sims’ efforts. At a time when cholecystectomy had become the gold standard for the management of most acute gallbladder diseases, operative cholecystostomy remained an attractive alternative in situations of significant patient comorbidity or intraoperative risk, often as a bridge to cholecystectomy3,4 (see Chapters 33 and 36). The first description of an ultrasound-guided percutaneous cholecystostomy (PC) for acute cholecystitis followed the development of percutaneous biliary drainage for the management of obstructive jaundice and dates back to 1980.5,6 Early case series showed encouraging results in patients who were not candidates for cholecystectomy,7 and ensuing cohort studies popularized its use in circumstances in which cholecystectomy was not feasible (see Chapter 36). The popularity of this procedure has persisted into the laparoscopic era. In the absence of comparative data, PC has supplanted open and laparoscopic alternatives to cholecystostomy and become widely accepted as a treatment for cholecystitis in situations in which surgical intervention is not feasible or deemed too risky. A review of nationwide medical administrative data confirms that the number of PCs performed in the United States for all indications increased 6-fold between 1994 and 2004. The vast majority of PCs, 97% in that time period, have been performed by interventional radiologists.8 An examination of the National Inpatient Sample database demonstrated that between 1998 and 2010, 1.5% of calculous and 7.5% of acalculous cholecystitis cases in the United States were treated with PC.9 In addition to its use for the management of acute cholecystitis, PC also provided its early practitioners with the opportunity to investigate the management of gallstone disease nonsurgically by chemical dissolution, mechanical extraction, or lithotripsy of gallbladder calculi.6,10 However, these approaches are not curative and have largely been abandoned because of the high rates of recurrence of cholelithiasis and cholecystitis. Furthermore, the logistical hurdles required for their safe administration and the superiority of laparoscopic cholecystectomy (LC; see later) have made these treatments impractical. In this chapter, we will examine the indications and contraindications for PC and illustrate some of its technical aspects and potential complications. We will place a particular emphasis on the quality of the evidence available in the literature and propose guidelines for the management of patients considered for PC.

INDICATIONS AND CONTRAINDICATIONS FOR PERCUTANEOUS CHOLECYSTECTOMY Acute Calculous Cholecystitis in High-Risk Patients Despite the dearth of high-quality data, the use of PC in patients with acute calculous cholecystitis (ACC) at high risk for surgery has become commonplace. In reviews of surgical databases, patients who receive PC are demonstrably older and have greater medical comorbidity than those receiving LC.9,11 A systematic review of cohort studies examining PC for ACC identified 53 studies examining the question; however, differences in outcome reporting, biases in control selection, and the significant heterogeneity of study populations made it impossible to draw conclusive recommendations on clear indications in high-risk surgical patients.12 The review confirmed that mortality rates after PC are high (15.4% vs. 4.5% with cholecystectomy), likely indicating selection biases favoring the use of PC in patients with higher comorbidity. Although the high mortality rate is likely inflated by the higher mortality in early cohorts, it remains elevated in contemporary cohorts, reflecting the high-risk population in whom PC is performed. Only three randomized studies examining the use of PC in acute cholecystitis have been published; however, they ask different questions, and have significant methodologic limitations. Hatzidakis and colleagues13 randomly assigned 123 high-risk patients (Acute Physiology and Chronic Health Evaluation [APACHE] score . 12) with ultrasound-proven ACC or acute acalculous cholecystitis (AAC) to ultrasound-guided PC versus conservative medical therapy (63 and 60 patients, respectively; see Chapter 34). In this trial, ultrasound-guided PC was unsuccessful in 5% of patients who had to undergo computed tomography (CT)-guided PC. The authors were unable to demonstrate a difference in symptom resolution after 3 days or in 30-day mortality and concluded that PC was indicated if symptoms failed to resolve after 3 days of conservative medical management. The study, however, had significant methodologic flaws. There was no pre-planned power analysis, no measures taken to conceal allocation, and no attempt to blind the investigators, the patients, or the care providers. Moreover, an evolving procedural learning curve within the study period made PC appear more morbid than it likely is in more experienced hands. The conclusion of this trial (i.e., that PC should be delayed until more conservative measures have failed to improve symptoms within 3 days) is counter to the current thinking, which promotes the use of early PC if it is to be used at all. This early use of PC is supported by observational cohorts where delayed PC is associated with more bleeding complications and an increased length of stay.14 The second randomized trial by Akyürek et al.15 randomly assigned 70 patients with ultrasound-proven AAC to PC followed by early LC 3 to 4 days later or to conservative management with delayed LC 8 weeks after recovery (33 patients). 489

490

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

In this study, PC followed by early LC decreased hospital length of stay and costs compared with conservative management with delayed LC. There was no difference in the proportions of conversion to open cholecystectomy at operation. The authors did not define inclusion or exclusion criteria, and no definition was provided for “a high-risk” surgical patient. The study was also not adequately powered to detect meaningful differences in the outcomes it compared. Furthermore, the trial did not state how randomization was performed and lacked blinding or allocation concealment. Of note, the analysis was performed strictly per-protocol and there was a notable 13% drop-out rate. Such methodologic shortcomings make it difficult to make recommendations based on this study. A Cochrane Collaboration Systematic Review16 on the use of PC in high-risk patients with ACC identified the aforementioned two randomized trials,13,15 grading their quality as very low and their risk of bias as very high. The group was unable to generate any recommendation on the usefulness of PC compared with conservative therapy, calling for higher-quality randomized trials. The largest multicenter randomized trial to date, the CHOCOLATE (Acute Cholecystitis in High-Risk Surgical Patients: Percutaneous Cholecystostomy Versus Laparoscopic Cholecystectomy) trial provides us with the highest-level evidence.17 It randomized high-risk patients with ACC, defined as patients with an APACHE II score between 7 and 15, to PC versus LC. The trial excluded critically ill patients (APACHE II score . 15), those not considered to be surgical candidates, and patients with delayed presentations (.7 days from symptom onset). In this population, as in the literature at large, patients undergoing PC had a rapid improvement in their symptoms, but the incidence of major complications was greater in the PC group at an interim analysis (12% vs. 65%, respectively; P , .001). Healthcare utilization and cost were also greater in the PC group. The major morbidity increase in the PC group was driven by reinterventions. Importantly, the 65% morbidity rate far exceeds what would be considered standard for PC. Nevertheless, it is clear from this study that patients who are physiologically able to tolerate a cholecystectomy should be offered surgery rather than PC. As a result of this trial and other data, the 2018 Tokyo Guidelines on the management of cholecystitis now recommends a cholecystectomy even in patients with a Tokyo grade II or III acute cholecystitis if they have a Charlson Comorbidity Index less than 6 , American Society of Anesthesiologists (ASA) class of 2 or less, good functional status, favorable organ system failure (defined as cardiovascular or renal organ system failure rapidly reversible during admission and before laparoscopic cholecystectomy for acute cholecystitis), and no negative predictive factors. This is in contrast to the 2013 guidelines, which recommended PC more liberally for acute cholecystitis grades II and III.18 In conclusion, despite the absence of convincing high-level evidence, and based mainly on retrospective unmatched cohorts, PC is frequently performed in patients with ACC who do not respond to medical therapy and who are deemed unfit for surgery because of age or medical comorbidity. The evidence suggests that LC should be offered to patients with acute cholecystitis who can tolerate surgery.

Acute Calculous Cholecystitis With Delayed Presentation PC, followed by interval LC, has been used in the specific context of ACC late in the course of the disease, hoping that conversion to open cholecystectomy would be less than during

LC at the index presentation. This was the subject of a retrospective cohort study of patients with an ASA score of 1 or 2 presenting with ACC after more than 72 hours of symptoms who did not respond to nonoperative treatment for 48 hours. It compared early PC with PC and delayed LC 4 weeks later (48 patients) to LC (43 patients). The authors found a lower frequency of conversion to open surgery, shorter hospital stay, and fewer total complications with PC and delayed LC (40% vs. 19%; P 5 .029 in the early LC vs. early PC and delayed LC group).19 The main methodologic limitation of the study was selection bias: It is unclear how patients in the early cholecystectomy group were selected, and no attempt was made to adjust for baseline differences between the groups. Zehetner and colleagues20 analyzed patients with ultrasound-confirmed ACC presenting more than 72 hours after symptom onset. They compared 23 patients treated with PC with those treated by LC. The authors pair-matched patients for age, sex, race, body mass index, diabetes, and sepsis. Contrary to the previous study, the authors demonstrated increased length of hospital stay (LOS) with PC and no difference in major morbidity; however, there was a significant proportion of conversion to open surgery in the non-PC group (17%) and a trend toward higher 30-day mortality in the PC group (13%). The deaths in the PC group were because of advanced cancer, illustrating the significant selection bias that went into treatment attribution, a bias that was not accounted for by matching on basic demographic characteristics in a very small sample.

Acute Acalculous Cholecystitis The use of PC in high-risk patients with AAC is supported by many cohort studies demonstrating decreased morbidity and mortality when compared with LC or open cholecystectomy21,22 (Fig. 35.1). However, when compared with conservative medical therapy, different studies reach different conclusions, with some large studies showing no benefit attributable to PC. An examination of 43,341 patients with AAC and severe sepsis or shock within the California Office of Statewide Health Planning and Development Patient Discharge Database (1995–2009) demonstrated that patients undergoing PC had the greatest number of comorbidities and were the sickest. No difference in survival, however, was found between PC and medical management after extensive multivariate adjustment.23 This remained true in the subgroup of patients with severe sepsis or shock and those dependent on mechanical ventilation. In fact, patients seemed to fare best when they could undergo cholecystectomy alone or were treated with PC followed by cholecystectomy. The study did not consider short-term outcomes, LOS, symptom control, and quality-of-life measures. This large study of medico-administrative data is the strongest evidence that PC might not offer a mortality benefit over medical management in patients with AAC who are deemed unfit for surgery, but this conclusion is clouded by significant residual confounders that cannot be adjusted for in a medico-administrative database. An analysis of 58,518 patients with AAC from another medico-administrative database, the National Inpatient Sample,9 demonstrated that, after multivariate adjustment (for sex, age, race, Charlson index, and hospital teaching status), PC remained associated with increased odds of death, increased LOS, and decreased odds of gallbladder-specific and total complications compared with surgery, indicating that in both ACC and AAC, its use was reserved for select sicker patients. The study did not compare PC with nonoperative management, and there is no doubt that residual

A. Gallstones and Gallbladder  Chapter 35  Percutaneous Treatment of Gallbladder Disease

A

C

statistical confounding is a concern in such large retrospective databases. Therefore whether or not PC in critically ill patients with AAC offers a survival advantage over medical treatment alone remains unclear because our knowledge is derived from retrospective cohort studies with varying degrees of risk adjustment and significant residual confounding.24 Some data exist that indicate that in patients with AAC, a PC can constitute a definitive treatment without the need for a delayed cholecystectomy. Calculous etiology and presence of pus in the gallbladder are independent predictors of recurrence of cholecystitis after PC.25 Most patients with AAC treated with PC will not experience a recurrence of the cholecystitis26 (in one series of PC for AAC, 21% of patients died in hospital, and 18% of patients treated with PC died from unrelated causes in the months after discharge).27

491

B

FIGURE 35.1  Percutaneous transhepatic cholecystostomy for acute acalculous hemorrhagic cholecystitis. After an initial gallbladder puncture under ultrasound guidance with a 22-gauge needle, the procedure was continued under fluoroscopic control. A, Direct cholecystography showed a large filling defect in the infundibulum of the gallbladder. B, The 22-gauge access was converted to a larger caliber, and a guidewire was introduced into the gallbladder. A 6.5-French self-retaining pigtail catheter was placed in the gallbladder lumen. There was no opacification of the cystic duct at the time of the initial procedure. C, Repeat cholangiography was done 1 week after emergency cholecystostomy. The cystic duct was patent, and there was unimpeded flow of contrast material into the duodenum. Most of the debris within the gallbladder had disappeared. The cholecystostomy catheter was removed 1 week after cholecystostomy; elective cholecystectomy was not required.

Special Populations Pregnancy Although the safety of LC is well established in the second trimester of pregnancy,28,29 most surgeons are reluctant to operate in the first and third trimesters out of fear of spontaneous abortion and preterm labor. PC may thus provide a safe temporizing measure for pregnant patients seen with severe biliary colic or cholecystitis in the first and third trimester who fail conservative medical therapy. The evidence to support this approach is scarce, and no large cohort or controlled trial has examined this question. Two small studies have reported the feasibility and safety of PC in pregnancy for acute cholecystitis and biliary colic in a limited number of patients. Allmendinger et al.30 published a case report of two pregnant patients who underwent PC for cholecystitis at 30 and 32 weeks of gestation, respectively,

492

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

followed by elective cholecystectomy in the postpartum phase. Chiappetta Porras et al.31 described a cohort of 122 patients treated for symptomatic cholelithiasis in the first trimester, among which four cholecystostomies in the first trimester for cholecystitis and four gallbladder aspirations in the third trimester (three for biliary colic and one for cholecystitis) are described. These case reports and case series suggest that PC is feasible during pregnancy and may be used as a safe alternative to operative intervention after failure of medical management, but its use should be limited when a safe laparoscopic cholecystectomy can be performed.

Sepsis of Unknown Origin in the Intensive Care In the critically ill patient with persistent sepsis of unknown origin, PC affords a safe and rapid therapeutic intervention in the event of suspected AAC or ACC, and it can be used to exclude the gallbladder as the septic focus. Two case series describe such an approach: In 2432 and 82 patients,33 PC resulted in resolution of sepsis in 58% and 51% of patients, respectively. These case series were, however, not followed by controlled trials. Moreover, it is possible that the incidence of AAC was higher compared with contemporary practice because of different intensive care practices, such as prolonged enteric starvation. We postulate that “diagnostic PC” has less utility in the modern intensive care setting.

Conclusion PC should be reserved for patients who are not medically fit to undergo open cholecystectomy or LC.34 It may be used as a bridge to cholecystectomy in patients failing medical therapy for ACC who are not fit for surgery at the time of presentation, and it could be used as definitive therapy in patients with AAC.

TECHNICAL ASPECTS AND COMPLICATIONS Insertion Technique 1. Drainage versus aspiration: Drainage has been demonstrated to be superior to simple aspiration of the acutely inflamed gallbladder in a single randomized trial35 and is currently the most widely used approach. 2. Operator: Most commonly, PC is performed by radiologists8 (see Chapter 30) under ultrasonographic guidance, but a single publication reports on a series performed by surgeons,36 with acceptable results and improved access times, although this experience may not be generalizable to most institutions. Regardless of who performs the procedure, it is advisable that only individuals highly facile with ultrasonographic or CT-guided interventional techniques perform PC and that there be regular institutional quality monitoring, according to proposed procedure-specific quality-control benchmarks.37 3. Approach: Patient preparation consists of skin disinfection and standard sterile precautions, procedural sedation, and either prophylactic administration or ready availability of atropine because vagal reactions have been documented.38 PC is performed under direct ultrasound or computed tomography (CT) guidance, with equivalent success and complication rates.39 After the planned anatomic course is identified, the gallbladder is entered using a finder needle, and a guidewire is inserted into it, with a size 7- to 10-French

pigtail catheter inserted over the guidewire using a Seldinger technique. Other catheters, such as a central venous catheter, can be used in lieu of a pigtail catheter and may be of use in certain institutional settings, but data on catheter displacement and patency times with these other options are limited.40 A catheter placed by transhepatic access is preferred to the transperitoneal route. The transhepatic tract matures faster than the transperitoneal tract (2 weeks vs. 3 weeks, respectively), allowing faster removal of the catheter as well as less bile leaks and bile peritonitis.41 The transhepatic approach is safer because it avoids the peritoneum in patients with significant ascites or bowel interposition.42 However, it is associated with the potential for pneumothorax, bleeding, and hemobilia.10

Complications In experienced hands, PC has both a high technical success rate (.98.9%)12 and a low complication rate. Documented complications include hemorrhage (2.5%), pneumothorax (0.5%), and postprocedural catheter dislodgement (,1%).37 After catheter withdrawal, 3% of patients experience severe bile peritonitis and another 3% experience a mild symptomatic biliary leak.43 Bile leaks are associated with transperitoneal access44 and may require operative therapy or repeat PC. In a systematic review of 35 papers, displacement of the PC catheter was reported in 8.6%; however, this may be an underestimation in an outpatient population.12 In a cohort described by Smith et al.,11 catheter-related complications occurred in 14.5% of patients, including tube dislodgement in 10 of 143 (7%), extra-abdominal peritube bile leak in 7 of 143 (5%), pain in 4 of 143 (3%), and occlusion in 4 of 143 (3%). These complications were managed mostly with tube repositioning or upsizing, and none required operation.

Management of the Percutaneous Cholecystectomy Catheter and the Gallbladder As already stated, the catheter tract usually matures after 2 weeks for transhepatic catheters and after 3 weeks for transperitoneal drains. A cholecystogram can be obtained before removal of the catheter 3 to 6 weeks after insertion, but imaging is not necessary in cases where a small-bore catheter was placed and where the cystic duct was patent at insertion. In AAC, assuming the resolution of precipitating factors, PC is considered curative, and LC is not mandatory because 70% of patients may not experience a recurrence.26 There remains a debate as to whether PC can be considered curative after ACC.45 Recurrence rates of cholecystitis after PC in ACC without interval cholecystectomy vary between studies: from 4.1% at 1 year in one study46 to 11.7% at 38 months in another.47 A cohort from the United Kingdom shows a recurrence rate as high as 22% at 1 year but also a 1-year mortality of 37% after index admission, mainly from medical causes unrelated to gallstone disease.44 Although cholecystectomy may be desirable after PC for ACC, a review of a large medico-administrative database demonstrates that PC is, in fact, only followed by elective cholecystectomy in 40% of patients at 1 year, whereas an additional 18% die without undergoing cholecystectomy.48 It is therefore prudent to weigh the risk of interval LC with the patient’s concurrent medical comorbidities, evolving surgical risks, and life expectancy against the risk of recurrence and ensuing morbidity and mortality.

A. Gallstones and Gallbladder  Chapter 35  Percutaneous Treatment of Gallbladder Disease

PERCUTANEOUS TREATMENT OF GALLSTONES: TECHNIQUES OF HISTORIC INTEREST Many techniques have been developed in an attempt to avoid the need for elective cholecystectomy. The 1980s saw the rise in popularity of extracorporeal shock-wave lithotripsy (ESWL), which in association with oral bile salt therapy, promised to clear the gallbladder of gallstones without resorting to surgery. Its use, however, was limited to patients with less than three cholesterol stones of 2 cm or less in size, and it required multiple treatments over months. The proportion of patients with recurrent cholelithiasis at 6 years was 69%, making ESWL an unacceptable option for most patients.49 Moreover, it has been proven to not be a costeffective approach,50 and its use has been largely abandoned. Methyl tert-butyl ether (MTBE), a cholesterol solvent, has been used to dissolve gallbladder calculi after the placement of

493

a PC. Its use, however, is cumbersome, requires specialized equipment and tubing that will not be destroyed by MTBE, and involves bothersome, prolonged administration over many days.51 Its use is mainly of historic interest. A publication has suggested the use of PC as an adjunct to cystic duct stenting in patients deemed unfit for LC.52 Only four patients were described in this study, and no information on long-term patency of this technique was described. A small series has described the feasibility of endoscopic ultrasoundguided transduodenal drainage of the gallbladder; however, this experience has not been reproduced to date.53 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

493.e1

REFERENCES 1. Hardy KJ. Carl Langenbuch and the Lazarus Hospital: events and circumstances surrounding the first cholecystectomy. Aust N Z J Surg. 1993;63(1):56-64. 2. Traverso LW. Carl Langenbuch and the first cholecystectomy. Am J Surg. 1976;132(1):81-82. 3. Glenn F. Cholecystostomy in the high risk patient with biliary tract disease. Ann Surg. 1977;185(2):185-191. 4. Skillings JC, Kumai C, Hinshaw JR. Cholecystostomy: a place in modern biliary surgery? Am J Surg. 1980;139(6):865-869. 5. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49(6):330-333. 6. vanSonnenberg E, D’Agostino HB, Goodacre BW, Sanchez RB, Casola G. Percutaneous gallbladder puncture and cholecystostomy: results, complications, and caveats for safety. Radiology. 1992;183(1): 167-170. 7. Eggermont AM, Laméris JS, Jeekel J. Ultrasound-guided percutaneous transhepatic cholecystostomy for acute acalculous cholecystitis. Arch Surg. 1985;120(12):1354-1356. 8. Duszak Jr R, Behrman SW. National trends in percutaneous cholecystostomy between 1994 and 2009: perspectives from Medicare provider claims. J Am Coll Radiol. 2012;9(7):474-479. 9. Anderson JE, Chang DC, Talamini MA. A nationwide examination of outcomes of percutaneous cholecystostomy compared with cholecystectomy for acute cholecystitis, 1998-2010. Surg Endosc. 2013; 27(9):3406-3411. 10. van Sonnenberg E, D’Agostino H, Casola G. Interventional gallbladder procedures. Radiol Clin North Am. 1990;28(6):1185-1190. 11. Smith TJ, Manske JG, Mathiason MA, Kallies KJ, Kothari SN. Changing trends and outcomes in the use of percutaneous cholecystostomy tubes for acute cholecystitis. Ann Surg. 2013;257(6): 1112-1115. 12. Winbladh A, Gullstrand P, Svanvik J, Sandström P. Systematic review of cholecystostomy as a treatment option in acute cholecystitis. HPB (Oxford). 2009;11(3):183-193. 13. Hatzidakis AA, Prassopoulos P, Petinarakis I, et al. Acute cholecystitis in high-risk patients: percutaneous cholecystostomy vs conservative treatment. Eur Radiol. 2002;12(7):1778-1784. 14. Chou CK, Lee KC, Chan CC, et al. Early percutaneous cholecystostomy in severe acute cholecystitis reduces the complication rate and duration of hospital stay. Medicine (Baltimore). 2015;94(27):e1096. 15. Akyürek N, Salman B, Yüksel O, et al. Management of acute calculous cholecystitis in high-risk patients: percutaneous cholecystostomy followed by early laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2005;15(6):315-320. 16. Gurusamy KS, Rossi M, Davidson BR. Percutaneous cholecystostomy for high-risk surgical patients with acute calculous cholecystitis. Cochrane Database Syst Rev. 2013;(8):CD007088. 17. Kortram K, van Ramshorst B, Bollen TL, et al. Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): study protocol for a randomized controlled trial. Trials. 2012;13:7. 18. Okamoto K, Suzuki K, Takada T, et al. Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis [published correction appears in J Hepatobiliary Pancreat Sci. 2019;26(11):534]. J Hepatobiliary Pancreat Sci. 2018;25(1):55-72. 19. Karakayali FY, Akdur A, Kirnap M, Harman A, Ekici Y, Moray G. Emergency cholecystectomy vs percutaneous cholecystostomy plus delayed cholecystectomy for patients with acute cholecystitis. Hepatobiliary Pancreat Dis Int. 2014;13(3):316-322. 20. Zehetner J, Degnera E, Olasky J, et al. Percutaneous cholecystostomy versus laparoscopic cholecystectomy in patients with acute cholecystitis and failed conservative management: a matched-pair analysis. Surg Laparosc Endosc Percutan Tech. 2014;24(6):523-527. 21. Byrne MF, Suhocki P, Mitchell RM, et al. Percutaneous cholecystostomy in patients with acute cholecystitis: experience of 45 patients at a US referral center. J Am Coll Surg. 2003;197(2):206-211. 22. Simorov A, Ranade A, Parcells J, et al. Emergent cholecystostomy is superior to open cholecystectomy in extremely ill patients with acalculous cholecystitis: a large multicenter outcome study. Am J Surg. 2013;206(6):935-941. 23. Anderson JE, Inui T, Talamini MA, Chang DC. Cholecystostomy offers no survival benefit in patients with acute acalculous cholecystitis and severe sepsis and shock. J Surg Res. 2014;190(2):517-521.

24. Mansour JC, Yopp AC. Percutaneous cholecystostomy: the challenges of cohort analysis. J Surg Res. 2014;190(2):417-418. 25. Bhatt MN, Ghio M, Sadri L, et al. Percutaneous cholecystostomy in acute cholecystitis-Predictors of recurrence and interval cholecystectomy. J Surg Res. 2018;232:539-546. 26. Peters R, Kolderman S, Peters B, Simoens M, Braak S. Percutaneous cholecystostomy: single centre experience in 111 patients with an acute cholecystitis. JBR-BTR. 2014;97(4):197-201. 27. Mc Cormack L, Pekolj J, de Santibañes E, Sívori J. Enfoque terapéutico actual en colecistitis aguda alitiásica [Current therapeutic approach to acute acalculous cholecystitis]. Acta Gastroenterol Latinoam. 1996; 26(1):7-13. 28. Lu EJ, Curet MJ, El-Sayed YY, Kirkwood KS. Medical versus surgical management of biliary tract disease in pregnancy. Am J Surg. 2004;188(6):755-759. 29. Swisher SG, Schmit PJ, Hunt KK, et al. Biliary disease during pregnancy. Am J Surg. 1994;168(6):576-581. 30. Allmendinger N, Hallisey MJ, Ohki SK, Straub JJ. Percutaneous cholecystostomy treatment of acute cholecystitis in pregnancy. Obstet Gynecol. 1995;86(4 Pt 2):653-654. 31. Chiappetta Porras LT, Nápoli ED, Canullán CM, et al. Minimally invasive management of acute biliary tract disease during pregnancy. HPB Surg. 2009;2009:829020. 32. Lee MJ, Saini S, Brink JA, et al. Treatment of critically ill patients with sepsis of unknown cause: value of percutaneous cholecystostomy. Am J Roentgenol. 1991;156(6):1163-1166. 33. Boland GW, Lee MJ, Leung J, Mueller PR. Percutaneous cholecystostomy in critically ill patients: early response and final outcome in 82 patients. Am J Roentgenol. 1994;163(2):339-342. 34. Abi-Haidar Y, Sanchez V, Williams SA, Itani KM. Revisiting percutaneous cholecystostomy for acute cholecystitis based on a 10-year experience. Arch Surg. 2012;147(5):416-422. 35. Ito K, Fujita N, Noda Y, et al. Percutaneous cholecystostomy versus gallbladder aspiration for acute cholecystitis: a prospective randomized controlled trial. Am J Roentgenol. 2004;183(1):193-196. 36. Silberfein EJ, Zhou W, Kougias P, et al. Percutaneous cholecystostomy for acute cholecystitis in high-risk patients: experience of a surgeon-initiated interventional program. Am J Surg. 2007;194(5): 672-677. 37. Saad WE, Wallace MJ, Wojak JC, Kundu S, Cardella JF. Quality improvement guidelines for percutaneous transhepatic cholangiography, biliary drainage, and percutaneous cholecystostomy. J Vasc Interv Radiol. 2010;21(6):789-795. 38. Little MW, Briggs JH, Tapping CR, et al. Percutaneous cholecystostomy: the radiologist’s role in treating acute cholecystitis. Clin Radiol. 2013;68(7):654-660. 39. Loberant N, Notes Y, Eitan A, Yakir O, Bickel A. Comparison of early outcome from transperitoneal versus transhepatic percutaneous cholecystostomy. Hepatogastroenterology. 2010;57(97):12-17. 40. Park SH, Kang CM, Chae YS, et al. Percutaneous cholecystostomy using a central venous catheter is effective for treating high-risk patients with acute cholecystitis. Surg Laparosc Endosc Percutan Tech. 2005;15(4):202-208. 41. Hatjidakis AA, Karampekios S, Prassopoulos P, et al. Maturation of the tract after percutaneous cholecystostomy with regard to the access route. Cardiovasc Intervent Radiol. 1998;20(1):36-40. 42. Ginat D, Saad WE. Cholecystostomy and transcholecystic biliary access. Tech Vasc Interv Radiol. 2008;11(1):2-13. 43. Wise JN, Gervais DA, Akman A, Harisinghani M, Hahn PF, Mueller PR. Percutaneous cholecystostomy catheter removal and incidence of clinically significant bile leaks: a clinical approach to catheter management. Am J Roentgenol. 2005;184(5):1647-1651. 44. Sanjay P, Mittapalli D, Marioud A, White RD, Ram R, Alijani A. Clinical outcomes of a percutaneous cholecystostomy for acute cholecystitis: a multicentre analysis. HPB (Oxford). 2013;15(7): 511-516. 45. Chung YH, Choi ER, Kim KM, et al. Can percutaneous cholecystostomy be a definitive management for acute acalculous cholecystitis? J Clin Gastroenterol. 2012;46(3):216-219. 46. Li M, Li N, Ji W, et al. Percutaneous cholecystostomy is a definitive treatment for acute cholecystitis in elderly high-risk patients. Am Surg. 2013;79(5):524-527. 47. Chang YR, Ahn YJ, Jang JY, et al. Percutaneous cholecystostomy for acute cholecystitis in patients with high comorbidity and re-evaluation of treatment efficacy. Surgery. 2014;155(4):615-622.

493.e2 48. de Mestral C, Gomez D, Haas B, Zagorski B, Rotstein OD, Nathens AB. Cholecystostomy: a bridge to hospital discharge but not delayed cholecystectomy. J Trauma Acute Care Surg. 2013;74(1):175-180. 49. Cesmeli E, Elewaut AE, Kerre T, De Buyzere M, Afschrift M, Elewaut A. Gallstone recurrence after successful shock wave therapy: the magnitude of the problem and the predictive factors. Am J Gastroenterol. 1999;94(2):474-479. 50. Barkun AN, Barkun JS, Sampalis JS, et al. Costs and effectiveness of extracorporeal gallbladder stone shock wave lithotripsy versus laparoscopic cholecystectomy. A randomized clinical trial. McGill Gallstone Treatment Group. Int J Technol Assess Health Care. 1997; 13(4):589-601.

51. Thistle JL, May GR, Bender CE, et al. Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med. 1989;320(10): 633-639. 52. Elmunzer BJ, Novelli PM, Taylor JR, Piraka CR, Shields JJ. Percutaneous cholecystostomy as a bridge to definitive endoscopic gallbladder stent placement. Clin Gastroenterol Hepatol. 2011;9(1): 18-20. 53. Lee SS, Park DH, Hwang CY, et al. EUS-guided transmural cholecystostomy as rescue management for acute cholecystitis in elderly or high-risk patients: a prospective feasibility study. Gastrointest Endosc. 2007;66(5):1008-1012.

CHAPTER 36 Cholecystectomy techniques and postoperative problems Morgan Bonds and Flavio Rocha OVERVIEW Cholecystectomy is one of the most frequently performed general surgery procedures in the United States (US) with over 500,000 being performed annually.1 There are many reasons for this, including the frequency of gallbladder disease and indications for intervention in the US population. The advent of laparoscopic cholecystectomy in the 1980s also resulted in a rapid rise in the number of cholecystectomies because of the reduced postoperative recovery, reduced pain, and ability to complete the procedure in the outpatient setting.2,3 As familiarity with laparoscopy has increased, the incidence of open cholecystectomy has steadily decreased. This chapter will address techniques of open cholecystectomy because this approach is still used when laparoscopy is contraindicated or technically impossible. Appropriate laparoscopic cholecystectomy techniques will also be discussed, including strategies to prevent common bile duct injuries (CBDI), which are an avoidable source of severe morbidity with this procedure. Alternative minimally invasive approaches and common complications will also be addressed.

INDICATIONS Symptomatic gallstones are the primary reason a patient requires cholecystectomy (see Chapters 33 and 34). In the US, approximately 5% to 22% of the population has cholelithiasis.4 Cholelithiasis can lead to several pathologic conditions including biliary colic, acute cholecystitis, gallstone pancreatitis, or choledocholithiasis, but the majority of patients with cholelithiasis will remain asymptomatic (see Chapter 33). As such, prophylactic cholecystectomy in asymptomatic patients is typically not warranted. Nevertheless, cholecystectomy may be indicated for certain populations with asymptomatic cholelithiasis. An example is sickle cell anemia where hepatic and vaso-occlusive disease can be indistinguishable from acute cholecystitis.5 Gallbladder polyps without cholelithiasis can be an indication for cholecystectomy (see Chapter 49). Resection is recommended for gallbladder polyps greater than or equal to 10 mm and in patients with biliary symptoms in the setting of gallbladder polyps of any size.6 Cholecystectomy is also often performed concomitantly with other procedures. Examples include pancreaticoduodenectomy and major anatomic liver resections. Cholecystectomy at the time of bariatric surgery is controversial. It is thought that biliary symptoms increase after extreme weight loss. Nevertheless, a systematic review and meta-analysis reported that concomitant cholecystectomy increases postoperative morbidity and operative time7 (see Chapter 34). Timing of cholecystectomy can vary by indication. Acute cholecystitis cases should proceed to the operating room as 494

early as possible. A recent study using a Swedish registry found that adverse events, mortality, and CBDIs were higher in patients who underwent cholecystectomy more than 4 days after admission.8 These data suggest the optimal timing for cholecystectomy is within 48 hours of admission for acute cholecystitis.

LAPAROSCOPIC CHOLECYSTECTOMY TECHNIQUES Laparoscopy has become the standard access for removing the gallbladder. Multiple studies have shown a decrease in postoperative pain, an earlier return to normal activity, a decrease in hospital length of stay (LOS), and a reduction in incisional hernia development for laparoscopic cholecystectomy when compared with open cholecystectomy.9–12 Familiarity with the anatomy of the porta hepatis, including common biliary and vascular variations, can reduce complication rates for both laparoscopic and open cholecystectomy, particularly for challenging cases presenting with significant inflammation.

Operating Room Setup Before beginning any procedure, the surgeon must ensure that all equipment is present and functional, which includes equipment for potentially necessary procedures such as cholangiography or need for conversion to laparotomy (Box 36.1).

Port Placement and Exposure Once pneumoperitoneum is obtained, a 5- or 10-mm port is placed in the periumbilical region. A 30-degree laparoscope is inserted, and the abdominal cavity is inspected. One 5-mm trocar is placed along the right anterior axillary line 2 centimeters below the costal margin. The other 5-mm port is placed at the midclavicular line on the right at the edge of the liver. A fourth port (5- or 10-mm) is placed in the subxiphoid region and should be placed 2 to 4 centimeters below the xiphoid depending on the location of the gallbladder and falciform ligament (Fig. 36.1). A fifth port can be placed in the location deemed most appropriate for additional retraction, if necessary.

Dissection and Critical View of Safety An atraumatic grasper is placed through the most lateral port and grasps the fundus of the gallbladder to retract it cephalad and laterally. This raises the liver edge and exposes the neck of the gallbladder and the porta. With the gallbladder retracted cephalad, a second atraumatic grasper is placed through the midclavicular port to manipulate the infundibulum of the gallbladder. Adhesions should be taken down until the gallbladder infundibulum can be seen. Retraction of the infundibulum caudally and to the right exposes the triangle of Calot. A cautery instrument placed through the xiphoid port opens the

A. Gallstones and Gallbladder  Chapter 36  Cholecystectomy Techniques and Postoperative Problems

495

Attention is next turned to obtaining the critical view of safety (CVS).13 This technique has been shown to reduce the rates of iatrogenic bile duct injuries14 (see Chapters 32 and 42). In fact, a recent multisociety consensus statement recommended CVS for identification of the cystic duct and cystic artery during laparoscopic cholecystectomy, and when CVS was not attainable, a subtotal cholecystectomy should be performed rather than attempting a fundus-first approach15 (see Chapter 34). Attachments at the neck of the gallbladder are dissected using a combination of blunt and cautery assisted dissection. It is useful to serially retract the infundibulum medially and laterally to fully dissect the triangle of Calot. Carrying dissection to the level of the common bile duct (CBD) is not indicated because this only increases the risk for iatrogenic injury. Blunt dissection with a Maryland grasper or right-angle grasper can help create a window behind the cystic duct by spreading in the avascular tissue. The gallbladder is dissected off the liver edge, exposing the cystic plate. The criteria for CVS have been met when (1) there are only two structures seen entering the gallbladder, the cystic duct and cystic artery; (2) the lower third of the cystic plate is exposed; and (3) tissue has been cleared from the hepatocystic triangle so that all structures can be clearly identified anteriorly and posteriorly (Box 36.2).16 These views are demonstrated in Fig. 36.3. If any question or doubt about the anatomy is encountered, a cholangiogram should be performed to reorient the surgeon (see Chapter 24). Most surgeons attempt the CVS during laparoscopic cholecystectomy, but in practice it is rarely achieved. An evaluation of 160 online videos of laparoscopic cholecystectomy found only one video accomplished a passing CVS score.17 The safe cholecystectomy curriculum can be found free of charge at the

BOX 36.1  Equipment for Laparoscopic Cholecystectomy Laparoscopic Viewing Equipment • Camera light source • Laparoscope (5-mm and 10 mm, 30 degree) • Monitors (one over each shoulder) • Insufflator and tubing • Trocars (multiple 5-mm trocars and at least one 10-mm) Instruments for Dissection and Removal of Gallbladder • Clips (5-mm and 10-mm variety) • Electrocautery • Suction • Irrigation • Atraumatic graspers • Maryland grasper (or laparoscopic right angle grasper) • Endoscopic retrieval bag Instruments for Unusual Circumstances • Endoloop • Laparoscopic needle driver • Absorbable hemostatic agent • Staplers • Argon laser • Cholangiography equipment (catheter, injectable contrast, c-arm for fluoroscopy) • Open cholecystectomy tray and instruments

peritoneum in the triangle of Calot (Fig. 36.2). This should be started at the edge of the gallbladder neck to avoid iatrogenic injury to aberrant hepatic vasculature or bile ducts. Dissection of the peritoneum is continued on both sides of the gallbladder 1 to 2 mm from the liver edge.

D

C

Gallbladder Liver

Laparoscope

B

A

A

B

FIGURE 36.1  Positions for insertion of trocars during laparoscopic cholecystectomy. The laparoscope (A) is positioned in the periumbilical region, the graspers for gallbladder retraction (B) and manipulation (C) are positioned in the right upper quadrant (RUQ) along the subcostal region, and the subxyphoid region (D) is used for the dissector, diathermy, and clip appliers.

496

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital A. Triangle of cholecystectomy

B. Triangle of Calot FIGURE 36.2  A, Triangle of cholecystectomy limited by the common hepatic duct, right hepatic duct, cystic duct, and inferior liver edge. B, The triangle of Calot limited by the common hepatic duct, cystic duct, and cystic artery.

BOX 36.2  Doublet Scoring for Critical View of Safety Criteria for Achieving Critical View of Safety Two structures connected to gallbladder: • Only two structures clearly seen entering the gallbladder. Cystic plate: • Approximately 1/3 of cystic plate is clearly visible. Clearance of hepatocystic triangle: • Hepatocystic triangle is cleared of tissue so visibility of cystic structures and plate is unimpeded and the surgeon is certain no other structures are in the hepatocystic triangle.

tenting the CBD with clips placed too distally on the cystic duct. The tips of the clip should be directly visualized to be free before closing to avoid inadvertent injury to other structures and ensure the clip completely occludes the artery or duct. If it is not possible to secure a clip completely across a structure, an Endoloop device can be used to ligate it. Scissors are used to divide the cystic artery and duct. In rare cases with a large inflamed cystic duct that cannot accommodate clips, endovascular staplers can be used to divide and secure the duct. These situations, however, should raise the level of concern regarding possible injury to the CBD, and the surgeon should consider intraoperative cholangiography if there is any concern whatsoever regarding the anatomy. Cautery is avoided for division because of the increased risk for necrosis resulting in clip slippage. The gallbladder is dissected off the cystic plate from the infundibulum to the fundus with electrocautery. Blindly placing clips, clamps, or cauterizing at this time risks causing hemorrhage or inadvertent injury to the hepatic blood supply, superficial biliary pedicles, or middle hepatic vein branches and should be avoided (Fig. 36.4). Before completely freeing the gallbladder from the liver, the gallbladder is used for retraction to inspect the cystic plate for hemostasis and inspect that clips are still securely placed on the cystic duct and artery. Specimen removal is performed through the periumbilical incision because it is easy to enlarge this incision to extract large gallstones. Bag extraction is performed with videoscopic visualization to ensure the bag does not rip and specimen contents are not lost. Spilled bile or debris should be completely irrigated and cleared with suction to prevent subsequent migration or abscess formation. The fascia of port sites greater than 10 mm are closed to prevent development of incisional hernias although some surgeons elect not to close the epigastric site because herniation is unlikely in that location.

Three-Port and Two-Port Techniques Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) website.18

Completion of Cholecystectomy Once all critical anatomy is confirmed, the cystic artery and duct are clipped and divided. Care should be taken to avoid

Anterior view

Attempts to improve on the traditional four-port laparoscopic cholecystectomy by decreasing the number of port sites have been introduced. The series reporting these techniques are small but suggest that these techniques are feasible and safe. Proponents cite the reduced cost related to fewer trocars, fewer scars, and reduced cost.19,20 Typically, the right upper quadrant ports are eliminated by using suture to retract the gallbladder

Posterior view

FIGURE 36.3  A, Critical view. Hepatocystic triangle is dissected free of all tissue except for the cystic duct and artery, and one-third of the cystic plate on the liver bed is exposed. When this view is achieved, the two structures entering the gallbladder can only be the cystic duct and artery. B, Critical view of safety during laparoscopic cholecystectomy.

A. Gallstones and Gallbladder  Chapter 36  Cholecystectomy Techniques and Postoperative Problems

497

SILC.24 Careful patient selection is necessary to optimize the use of this technique. It is critical to understand that the CVS should be obtained regardless of the number of laparoscopic ports used to reduce the risk of vasculobiliary injury during minimally invasive cholecystectomy.

Robotic-Assisted Laparoscopic Cholecystectomy The use of robotic assisted laparoscopic surgery has significantly increased in recent years. This upswing in robotic surgery is because of a combination of aggressive marketing resulting in patient demand. This platform is attractive to surgeons as well because it offers the benefits of 3-dimensional (3D) visualization, improved ergonomics, and an easier learning curve compared with laparoscopy. Robotic laparoscopic cholecystectomy has been proposed as an ideal tool to improve skill and confidence using the robotic platform25 (see Chapter 127A). Despite similar outcomes, robotic surgery is associated with significantly higher costs than laparoscopy. The upfront cost of purchasing a robotic console is approximately 2 million dollars. In addition, there is the cost of maintenance and replacement of disposable instruments. A single institution analysis reported lower readmission rates with robotic cholecystectomy in propensity matched patients, but the overall hospital costs and operative time were significantly larger.26 These cost discrepancies must be considered when deciding on the optimal minimally invasive approach to cholecystectomy. FIGURE 36.4  Blind placement of clips or clamps for hemostasis can result in injury to the hepatic artery or bile duct.

in their stead.21 A small randomized controlled trial (RCT) with 217 patients compared four-port with three-port cholecystectomy and found no difference in length of operation or morbidity, including iatrogenic bile duct injuries; however, there was also no difference in pain medication required between groups.22 Currently, there are no obvious advantages that these techniques offer over the four-port technique.

Single-Incision Laparoscopic Cholecystectomy Single-incision laparoscopic cholecystectomy (SILC) is the extreme attempt at reducing the number of ports for laparoscopic cholecystectomy. SILC is performed through a single transabdominal incision, usually at the umbilicus. There are specifically designed single-port systems and instruments available that have been approved by the US Food and Drug Administration (FDA). Several RCTs comparing SILC with standard laparoscopic cholecystectomy have been performed, although most are hampered by low accrual. A 2017 trial from Egypt enrolled 187 patients. SILC had a statistically significant longer operating time and conversion rate compared with three-port laparoscopic cholecystectomy; the only advantage to SILC in this study was the aesthetic score.23 In addition to the absence of benefit to the patient, SILC induces significantly more stress on the surgeon. A double-blind RCT measured surgeon heart rate and salivary cortisol before being randomized to either SILC or traditional laparoscopic cholecystectomy, after clipping the cystic duct and while closing skin. SILC was associated with higher heart rates and cortisol levels. Surgeons also reported the surgical workload was more demanding with

CONTRAINDICATIONS Contraindications to this procedure are divided into two categories: (1) contraindications to cholecystectomy and (2) contraindications to laparoscopy. Absolute contraindications to operative cholecystectomy include refractory coagulopathy and intolerance of general anesthesia (see Chapter 35). The 2018 Tokyo Guidelines do not discourage cholecystectomy for patients with severe sepsis and end-organ failure (Grade III cholecystitis) if supportive care is available and the operating surgeon feels the patient can withstand the procedure.27 Relative contraindications include severe cardiopulmonary disease, pregnancy, and cirrhosis with portal hypertension, but ultimately the decision is made based on clinical judgment (see Chapter 75). The presence of cirrhosis can complicate many abdominal surgical interventions. Laparoscopic cholecystectomy in cirrhotic patients is especially challenging because it can be difficult to retract the stiff, friable liver and avoid the potential for bleeding from the associated coagulopathy. Outcomes between Childs-Pugh A/B cirrhotic patients undergoing laparoscopic cholecystectomy and those with normal liver function are similar with the exception that operative times are longer and there is a trend towards increased rates of conversion to open cholecystectomy28 in the former. Laparoscopic cholecystectomy is also feasible in cirrhotics with portal hypertension.29 When performing laparoscopic cholecystectomy in a cirrhotic patient, the surgeon must be aware of aberrant portosystemic venous collateralization in the liver bed, porta hepatis, and abdominal wall. It is recommended that an energy-sealing device be available to limit blood loss during dissection. Hemostatic agents and argon beam should be readily available to assist with hemostasis. The procedure should be converted to an open procedure for significant bleeding.

498

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

CONVERSION TO OPEN Although laparoscopy is the preferred approach for cholecystectomy, there are many situations that may necessitate conversion to open procedure. The decision and timing of intraoperative conversion to laparotomy depends on the surgeon’s experience, comfort with laparoscopic and open techniques, and patient factors (anatomy and pathology). There is no consensus on when conversion is necessary as long as patient safety is the ultimate priority. Contemporary conversion rates are reported to be between 5% to 15%.30,31 Reasons to consider conversion include unclear anatomy despite cholangiography, intraoperative complication, failure to progress, and pathology not amenable to laparoscopic or postoperative endoscopic techniques. Independent factors associated with conversion to open cholecystectomy include prior upper abdominal surgery, pericholecystic fluid, acute cholecystitis, and emergent cholecystectomy.32 Conversion has been described as a “complication” of laparoscopy by some; however, this view is untenable and conversion should be regarded as mature judgment because it can prevent disastrous complications in challenging cases.

OPEN TECHNIQUE Incision The traditional incision used for an open cholecystectomy is a right subcostal or Kocher incision. This incision is created 2 centimeters below the right costal margin and extends from the midline to the lateral edge of the right rectus muscle. This incision can be extended superiorly along the midline if further exposure is needed.

Dissection Retrograde Cholecystectomy When performing a retrograde cholecystectomy, the critical view of safety must be identified before removing the gallbladder from the liver. Although this is the usual approach during laparoscopic cholecystectomy, it can be more difficult for an unexperienced surgeon without the magnification of laparoscopy and difference in exposure. The same principles must be maintained to prevent inadvertent biliary injury. The fundus of the gallbladder is grasped with a Kelly or similar clamp. Peritoneum overlying the infundibulum is incised. The incision is extended along the anterior and posterior gallbladder, being careful to stay close to the edge of the gallbladder. Once the cystic duct is identified, a suture ligature is passed around it and used to place tension on the duct for better exposure and to prevent stone migration into the CBD. The CVS has been achieved once all fibroadipose tissue is cleared from the hepatocystic triangle, only two structures are seen clearly entering the gallbladder, and a third of the cystic plate is seen (see Box 36.2). Any stones palpated within the cystic duct are “milked” back into the gallbladder. The cystic artery can be ligated with either clips or sutures then divided. If cholangiography is indicated, it is performed at this time. Ligation and division of the cystic duct occurs next. To complete the retrograde cholecystectomy, the gallbladder is dissected off the cystic plate using cautery. The dissection plane is kept close to the gallbladder to avoid entering the cystic

plate and deeper liver parenchyma. Brisk bleeding from liver parenchyma lacerations tend to be venous in nature because distal branches of the middle hepatic vein can be located immediately deep to the cystic plate (see Chapter 2). These can usually be treated by holding constant pressure over the area for 5 to 10 minutes. Hemostatic agents may be beneficial in these instances as well. If these techniques fail, deep hemostatic sutures can be placed. Nevertheless, one must be aware of the location of the right portal pedicle and its anterior branch, which can be close to the base of the gallbladder fossa.

Antegrade, or Fundus-Down Cholecystectomy Antegrade cholecystectomy is an alternate technique for cholecystectomy, but this technique should not be used in the presence of severe inflammation that obstructs visualization of the cystic duct. As with the fundus-down laparoscopic technique, there is still significant risk of biliary injury in these cases without proper visualization of the cystic duct and artery. A clamp is used to grasp the fundus of the gallbladder; another clamp is used to grasp the peritoneum on the liver edge to provide countertraction. An incision is made in the gallbladder serosa approximately 5 millimeters from the liver edge with cautery. A dissection plane is developed between the superior gallbladder wall and the cystic plate. Again, care is taken to avoid entering the cystic plate and lacerating the liver parenchyma. This plane is continued medially and laterally toward the gallbladder neck. An energy-sealing device can be used on edematous or vascularized peritoneum. Dissection is performed posterior and lateral to fully free the gallbladder from the cystic plate. This best exposes the cystic artery and duct. The cystic artery is ligated and transected as it enters the gallbladder wall. The infundibulum is dissected free to expose the cystic duct. One should not dissect more than 1 centimeter of the cystic duct because this increases risk of CBDI. Once the cystic duct is visualized, it can be ligated with suture or clips and divided. The gallbladder is removed, and the abdomen is closed.

PARTIAL OR SUBTOTAL CHOLECYSTECTOMY Subtotal cholecystectomy is the recommended technique for treating severely inflamed gallbladders when the CVS cannot be safely obtained16 (see Chapter 34). Fibrosis and inflammation can cause the cystic duct to shorten and fuse with the CBD; this can lead to the surgeon mistaking the CBD for the cystic duct (Fig. 36.5). In these cases, it is best to err on the side of caution and avoid dissecting in the hepatocystic triangle. Cholecystitis can be managed safely until inflammation has subsided, but CBDIs have significant long-term morbidity. In these cases, a partial or subtotal cholecystectomy, in which a portion of the gallbladder is removed and gallstones are extracted while leaving the posterior wall of the gallbladder in place, is the procedure of choice for source control and surgical management. This technique can be used either open or laparoscopically, and the technique is similar for both. To perform a safe subtotal cholecystectomy, all dissection should be performed above the “the line of safety,” which runs between the sulcus of Rouviere.33 These landmarks are seen in Fig. 36.6. The gallbladder is drained and opened with cautery at the fundus. Bile, stones, and debris are suctioned or set aside for future extraction in a specimen bag in a laparoscopic approach. This incision is

A. Gallstones and Gallbladder  Chapter 36  Cholecystectomy Techniques and Postoperative Problems

499

A

FIGURE 36.5  The common hepatic duct can be mistaken for the cystic duct when the region of the infundibulum cannot be delineated because of fibrosis and inflammation.

B FIGURE 36.7  A–B, Laparoscopic subtotal cholecystectomy and open subtotal cholecystectomy demonstrating the anterior wall excised and a small strip of the posterior wall left attached to the liver. The remnant mucosa can then be either removed or coagulated with cautery or argon laser. Line of safety Hilar plate Sulcus of rouviere

FIGURE 36.6  The limit of proximal dissection for subtotal cholecystectomy is the “line of safety” between the sulcus of Rouviere and hilar plate. The ensures dissection occurs away from the common bile duct in the setting of severe inflammation. (From Purzner RH, Ho KB, Al-Sukhni E, Jayaraman S. Safe laparoscopic subtotal cholecystectomy in the face of severe inflammation in the cystohepatic triangle: A retrospective review and proposed management strategy for the difficult gallbladder. J Can Chir. 2019;62:402–411.)

extended to the gallbladder neck without dissecting the cystic duct or artery. The anterior wall of the gallbladder is then completely removed, and the posterior wall is left on the cystic plate (Fig. 36.7). The remnant mucosa is then coagulated with either cautery or argon beam. A drain should be placed near the gallbladder stump to drain potential bile collection. Subtotal cholecystectomies, both open and laparoscopic, are being performed more frequently, and conversion to open procedure is becoming less common.34 As one may expect, there is a higher risk of bile leaks and subphrenic collection with subtotal cholecystectomy compared with standard cholecystectomy.

One study found the relative risk of bile leak after subtotal cholecystectomy was as high as 3-fold; these were more common if the gallbladder remnant was left open.33

ANATOMIC VARIATIONS An intimate knowledge of gallbladder and biliary anatomy, as well as common variations, is essential to perform a safe cholecystectomy (see Chapter 2). Variations in gallbladder anatomy such as duplicated, left-sided, bilobed, or congenitally absent gallbladder are rare, and they are typically identified preoperatively. As such, this section will focus on relevant biliary anatomy and variations that can potentially lead to inadvertent injury (see Chapter 42). Significant variations of the cystic duct and hepatic duct junction exist (Fig. 36.8; see Chapter 2). The common hepatic duct can range in length from 1 to 7.5 centimeters. A large series of magnetic resonance cholangiopancreatographies demonstrated that 40.7% of patients had some variant in biliary tree anatomy. In this study, 5% of subjects had medial cystic duct insertion.35 Anomalous extrahepatic bile ducts occur in up to 12% of patients, with the most common being an anomalous right sectoral duct that empties into either the common hepatic or cystic duct.36 Fig. 36.9 demonstrates common anatomic biliary variation of the right sectoral ducts. When these variations occur, they often represent the only biliary drainage for the corresponding segment(s) of the liver. Thus injury or obstruction of these ducts results in liver atrophy or obstructive cholangitis in that segment. It should be noted that true duplication of the

500

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

A

B

FIGURE 36.8  A, Variations in the confluence of the cystic duct and common hepatic duct. B, High insertion of the cystic duct demonstrated on endoscopic retrograde cholangiopancreatography.

A

B

FIGURE 36.9  A, Variations in the confluence of the extrahepatic bile ducts and cystic duct. B, Cholangiogram demonstrating a cystic duct inserting into the right anterior section bile duct.

cystic duct is exceedingly rare, and cholangiography should be performed if the surgeon believes such an anomaly has been encountered (see Chapter 24). Arterial anatomic variations are also common and can contribute to morbidity after cholecystectomy (see Chapter 2). Typically, the cystic artery originates from the right hepatic artery (76%) but may also branch off the left, common, or proper hepatic arteries.37 Arterial injury may accompany a bile duct injury resulting in a combined vasculobiliary injury. The right hepatic artery is involved in 92% of these injuries because of its proximity to the CBD and can significantly add to the difficulty of bile duct repair38 (see Chapter 42).

POSTOPERATIVE MANAGEMENT Most patients undergoing elective laparoscopic cholecystectomy are discharged the same day because of the decreased pain profile associated with this minimally invasive technique. A patient admitted with acute cholecystitis is often observed in the hospital overnight postoperatively because of infectious concerns. Elderly patients, comorbid patients, patients requiring significant analgesia postoperatively, and patients with complicated procedures may also benefit from postoperative admission. The patient is allowed a diet shortly after surgery. Oral narcotics for postoperative incisional pain can be prescribed for pain control,

A. Gallstones and Gallbladder  Chapter 36  Cholecystectomy Techniques and Postoperative Problems

501

but many patients recover with only over-the-counter pain medications, including nonsteroidal antiinflammatories and acetaminophen. Routine follow-up by the surgeon in clinic can occur between 1 and 4 weeks after surgery.

IMMEDIATE POSTOPERATIVE COMPLICATIONS Biliary Injury Biliary injury remains the most feared complication of cholecystectomy (see Chapters 28 and 34). It has been shown that bile duct injuries have a 30-day mortality rate of 2% in a large database study.39 Another prospective cohort of 800 patients with CBDI referred to a single center reported the mean survival after iatrogenic biliary injury was 17.6 years, and patients also had a worse physical quality of life and loss of productivity; at long-term follow-up, 34.9% were receiving disability benefits.40 Although these injuries are rare, occurring at a rate of 0.08% and 0.25%, the impact on patients is significant. Intraoperative cholangiography has been proposed to reduce iatrogenic bile duct injury during laparoscopic cholecystectomy41 (see Chapter 24). Nevertheless, recent retrospective studies show a higher incidence of CBDI when intraoperative cholangiogram is performed (0.25% vs. 0.12%). This is likely because cholangiography is used more frequently during challenging cases.42 Proper biliary anatomy identification and interpretation of the cholangiography images are required for it to aid in prevention of CBDI. The CVS, as described earlier, remains the current standard technique to reduce the incidence of CBDI during cholecystectomy. Inflammation of the gallbladder increases the risk of CBDI. As the grade of cholecystitis severity increases, the risk of CBDI rises.43 The “classic injury” occurs when the CBD is mistaken for the cystic duct and ligated. This is thought to occur when the gallbladder is retracted too aggressively to the right, causing the cystic duct to lie parallel and adjacent to the CBD. Dissection is then continued along the CBD superiorly until an “aberrant” or “duplicated” duct is encountered. If this duct is subsequently divided, a more proximal bile duct injury will occur (Fig. 36.10). If a CBDI is identified at the time of surgery, the surgeon must assess the extent of the injury, their own experience repairing these injuries, the patient’s condition, and the hospital resources. A hepatobiliary surgeon should be called to assess the situation if one is available. When a specialist is not available, the best course of action is to place a drain near the porta hepatis, close the patient, and initiate transfer to a center with hepatobiliary expertise. Proceeding with gallbladder extraction after identifying a biliary injury is not recommended because it risks amplifying the injury38 (see Chapter 42). CBDIs are often not discovered during the index procedure. Patients with ongoing abdominal pain, fevers, or ileus should alert the surgeon to a potential complication. The initial diagnostic test should start with abdominal ultrasound followed by computed tomography (CT) of the abdomen if a complication is suspected. If excessive peritoneal fluid is present, percutaneous drainage should be performed. The type of injury should be determined next and this can be done with magnetic resonance cholangiopancreatography (MRCP), percutaneous transhepatic cholangiography, and/or endoscopic retrograde cholangiopancreatography (ERCP). Simple postoperative leaks can be managed with drainage alone or drainage and ERCP placement of

3 2

1

FIGURE 36.10  Pathogenesis of the “classic” injury. 1. The common bile duct is mistaken as the cystic duct and is clipped and divided. 2. The dissection is carried up along the left side of the common hepatic duct in the belief that this is the underside of the gallbladder. 3. The common hepatic duct is transected while the surgeon tries to dissect what they believe is the gallbladder from the liver bed. If the structure is recognized as a bile duct at this point, it is often thought to be a second cystic duct or an accessory duct. While the common hepatic duct is divided, the right hepatic artery is often injured. (From Strasberg SM, Helton WS. An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy. HPB (Oxford). 2011;13:1–14.)

biliary stents.44 Several centers with advanced gastroenterologists are beginning to manage selected patients with complex injuries with percutaneous-endoscopic rendezvous procedures with promising long-term results.45 Further details regarding repair of biliary injuries are discussed elsewhere in this textbook (see Chapter 42).

Bleeding Clinically significant bleeding occurs in 0.1% to 1.9% of laparoscopic cholecystectomies. Bleeding can arise from (1) the liver, (2) an abdominal arterial source, or (3) port sites. Significant bleeding from the liver bed tends to be from the terminal branches of the middle hepatic vein. Bleeding from the gallbladder fossa that appears venous in nature can be controlled laparoscopically with hemostatic agents and applied pressure. Visualization can be improved by lifting the liver and increasing the pressure of pneumoperitoneum. Clips or sutures can be placed in the cystic plate for hemostasis if all landmarks are identified to avoid injury to underlying portal structures. If visualization is lost, pressure should be applied to the area with sponge and grasper while converting to laparotomy. During laparotomy, one should keep pressure on the venous injury because air embolus is possible and can be severe. Acute hemodynamic decline in the postoperative period should raise concern for significant bleeding, which is likely because of a dislodged clip. As with any laparoscopic procedure, bleeding can occur from trocar insertion.

Retained Common Bile Duct Stones Common bile duct stones are present in approximately 5% to 15% of patients presenting for cholecystectomy.46–48 Those

502

PART 5  BILIARY TRACT DISEASE  SECTION I  Inflammatory, Infective, and Congenital

suspected of having choledocholithiasis should undergo preoperative diagnostic MRCP or ERCP, especially if the surgeon is not comfortable exploring the CBD laparoscopically. Choledocholithiasis is not an indication for laparotomy in the modern era. Laparoscopic bile duct exploration at the time of cholecystectomy has been shown to reduce hospital LOS and overall cost compared with endoscopic treatment followed by cholecystectomy49 (see Chapter 37). Retained common duct stones after cholecystectomy are rare. In one single center study, the incidence of postoperative ERCP for suspected retained stones was 1.8%.50 As with patients with presumed choledocholithiasis, those suspected of having a retained CBD stone should be studied with either MRCP or ERCP depending on facility capabilities. Endoscopic sphincteroplasty with stone extraction is the most widely accepted treatment for this condition in the current era. The details of CBD stone management are discussed in other chapters (see Chapters 37 and 38).

These strictures arise from an injury to the bile duct that was unidentified in the immediate postoperative period. Causes include incomplete transection, clipping or ligation, thermal injury, or ischemic devascularization of the bile duct. Commonly, patients with benign biliary strictures present with symptoms consistent with obstructive jaundice (see Chapter 42). Options for management of biliary strictures are varied. Endoscopic treatment is typically the first approach, with surgery reserved for those who do not respond to endoscopic therapy.60 Endoscopic stenting has been shown to result in 67% of patients being symptom-free for 28 months, and having a normal ERCP after stenting was predictive of not reforming a stricture.61 Nevertheless, surgery remains the mainstay of therapy for benign biliary strictures after cholecystectomy. A recent meta-analysis showed that a surgical approach had an 84% long-term patency rate.62 Further description of the management of benign and malignant biliary strictures will be addressed elsewhere in the book (see Chapters 30 and 31).

Gallbladder Perforation

Postcholecystecomy Diarrhea

Entering the gallbladder during cholecystectomy is a common event, particularly during the learning phase of the procedure. Careful retraction is essential because spillage of bile and stones can result in serious complications. Intraperitoneal spillage of stones can lead to abscess and fistula formation.51 In patients with incidental gallbladder carcinoma, bile spillage at the time of cholecystectomy resulted in higher rates of carcinomatosis (24% vs. 4%) compared with those without spillage, as well as poorer disease-free survival52 (see Chapter 49).

Postcholecystectomy diarrhea is defined as three or more loose stools per day after removal of the gallbladder. It is difficult to assess the prevalence of this disorder. Etiology is likely multifactorial in nature. One factor may be the increased number of bile salts in the colon because of continuous bile flow into the gut, which leads to secretory diarrhea.63 Recent evidence showed that the gut microbiome of patients with postcholecystectomy diarrhea is altered. Compared with healthy patients, patients with diarrhea after cholecystectomy had significantly higher levels of Proteobacteria, which may be pathogenic in this process.64 Currently, the recommended therapy is the administration of bile-acid binding agents and antidiarrheals; however, these have variable results.63

DELAYED COMPLICATIONS OF CHOLECYSTECTOMY Remnant Gallbladder and Cystic Duct Stones Recurrent stone formation in a remnant gallbladder or cystic duct is rare. Most patients present with pain similar to their precholecystectomy symptoms, and it can occur at any time from 4 months to 25 years after surgery. Remnant gallbladder stones are usually associated with subtotal cholecystectomy. Diagnosis requires a study that delineates the biliary anatomy, such as MRCP or ERCP. Endoscopic ultrasound, intraoperative cholangiogram, and percutaneous transhepatic cholangiogram can also be useful in obtaining a diagnosis of retained stones.53 Treatment of cystic duct stones can be managed in a variety of ways. Some stones are amendable to endoscopic retrieval or lithotripsy, whereas others require a surgical intervention to extract the stone and ligate the cystic duct closer to the common duct.54 Treatment of a remnant gallbladder typically requires resection to prevent further stone formation. Depending on the situation and surgeon skill set, completion cholecystectomy can be performed either open or laparoscopically with low morbidity.55–57

Biliary Strictures Benign strictures of the CBD occur in up to 2.7% of laparoscopic cholecystectomies and 0.5% of open cholecystectomies.58,59

CONCLUSION Cholecystectomy remains the gold standard for the management of gallbladder disease in the developed world, with the vast majority now performed minimally invasively with excellent results. Most patients now undergo this operation in an ambulatory setting. Attempts at improving outcomes from laparoscopic cholecystectomy will continue to drive the development of novel surgical tools and techniques. Although relatively safe, there is room to reduce the number of CBDIs because these have a significant impact on patient quality of life and overall survival. These gains will be achieved with improved outreach and education regarding the CVS and when to pursue alternative procedures instead of forging ahead with total cholecystectomy. As new technology arises, surgeons must always keep in mind the safety of the patient alongside the development of new techniques. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

502.e1

REFERENCES 1. Wier LM, Steiner CA, Owens PL. Surgeries in hospital-owned outpatient facilities, 2012. HCUP Statistical Brief #188. February 2015. Agency for Healthcare Research and Quality, Rockville, MD. Available at: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb188Surgeries-HospitalOutpatient-Facilities-2012.pdf. Accessed April 27, 2020. 2. Legorreta AP, Silber JH, Costantino GN. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy. JAMA. 1993;270(12):1429-1432. 3. Al-Mulhim AA, Al-Ali AA, Albar AA, et al. Increased rate of cholecystectomy after introduction of laparoscopic cholecystectomy in Saudi Arabia. World J Surg. 1999;23:458-462. 4. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas. Gastroenterology. 2009;136(4):1134-1144. 5. Tagge EP, Othersen HB, Jackson SM, et al. Impact of laparoscopic cholecystectomy on the management of cholelithiasis in children with sickle cell disease. J Pediatr Surg. 1994;29:209-212. 6. Wiles R, Thoeni RF, Barbu ST, et al. Management and follow-up of gallbladder polyps. Eur Radiol. 2017;27:3856-3866. 7. Tustumi F, Bernardo WM, Santo MA, Cecconello I. Cholecystectomy in patients submitted to bariatric procedure: a systemic review and meta-analysis. Obes Surg. 2018;28:3312-3320. 8. Blohm M, Osterberg J, Sandblom G, Lundell L, Hedberg M, Enochsson L. The sooner, the better? The importance of optimal timing of cholecystectomy in acute cholecystitis: data from the National Swedish Registry for Gallstone Surgery, GallRiks. J Gastrointest Surg. 2017;21:33-40. 9. Barkun JS, Sampalls JS, Fried G, et al. Randomised controlled trial of laparoscopic versus mini cholecystectomy. Lancet. 1992;340: 1116-1119. 10. Bass EB, Pitt HA, Lillemoe KD. Cost-effectiveness of laparoscopic cholecystectomy versus open cholecystectomy. Am J Surg. 1993;165(4):466-471. 11. McMahon AJ, Baxter JN, Anderson JR, et al. Laparoscopic versus minilaparotomy cholecystectomy: a randomised trial. Lancet. 1994;343:135-138. 12. Soper NJ, Barteau JA, Clayman RV, Ashley SW, Dunnegan DL. Comparison of early postoperative results for laparoscopic versus standard open cholecystectomy. Surg Gynecol Obstet. 1992:174(2):114-118. 13. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125. 14. Strasberg SM, Brunt LM. Rationale and use of the critical view of safety in laparoscopic cholecystectomy. J Am Coll Surg. 2010:211(1): 132-138. 15. Brunt LM, Deziel DJ, Telem DA, et al. Safe cholecystectomy multisociety practice guideline and state-of-the-art consensus conference on prevention of bile duct injury during cholecystectomy. Surg Endosc. 2020;272(1):3-23. 16. Sanford DE, Strasberg SM. A simple effective method for generation of a permanent record of the critical view of safety during laparoscopic cholecystectomy by intraoperative “doublet” photography. J Am Coll Surg. 2014;218(2):170-178. 17. Deal SB, Alseidi AA. Concerns of quality and safety in public domain surgical education videos: an assessment of the critical view of safety in frequently used laparoscopic cholecystectomy videos. J Am Coll Surg. 2017;225(6):725-730. 18. Society of American Gastrointestinal and Endoscopic Surgeons. The SAGES Safe Cholecystectomy Program. Available at: https:// sages.org/safe-cholecystectomy-program/. Accessed May 30, 2020. 19. Sun S, Yang K, Gao M, He X, Tian J, Ma B. Three-Port versus four-port laparoscopic cholecystectomy: meta-analysis of randomized clinical trials. World J Surg. 2009;33:1904-1908. 20. Tuveri M, Tuveri A. Laparoscopic cholecystectomy: complications and conversions with the 3-trocar technique: a 10-year review. Surg Laparosc Endosc Percutan Tech. 2007;17(5):380-384. 21. Taha M, Sallam AN, Zakaria HM, Nassar A. Modified technique for two ports laparoscopic cholecystectomy: combined safety and economic value. Egypt J Surgery. 2019;38:511-516. 22. Koirala R, Gurung TM, Rajbhandari A, Rai P. Three-port versus four-port laparoscopic cholecystectomy: a randomized controlled trial. Nepal Med Coll J. 2019;21(1):40-43.

23. Omar MA, Redwan AA, Mahmoud AG. Single-incision versus 3-port laparoscopic cholecystectomy in symptomatic gallstones: a prospective randomized study. Surgery. 2017;162:96-103. 24. Abdelrahman AM, Bingener J, Yu D, et al. Impact of single-incision laparoscopic cholecystectomy (SILC) versus conventional laparoscopic cholecystectomy (CLC) procedures on surgeon stress and workload: a randomized controlled trial. Surg Endosc. 2016;30: 1205-1211. 25. Jayaraman S, Davies W, Schlachta CM. Getting started with robotics in general surgery with cholecystectomy: the Canadian experience. Can J Surg. 2009;52(5):374-378. 26. Kane WJ, Charles EJ, Mehaffey JH, et al. Robotic compared with laparoscopic cholecystectomy: a propensity matched analysis. Surgery. 2020;167(2):432-435. 27. Okamoto K, Suzuki K, Takada T, et al. Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25:55-72. 28. Okamuro K, Cui B, Moazzez A, et al. Laparoscopic cholecystectomy is safe in emergency general surgery patient with cirrhosis. Am Surg. 2019;85(10):1146-1149. 29. Tan HY, Gong JF, Tang WH, Li P, Yang K. Risk assessment of laparoscopic cholecystectomy in liver cirrhotic patients with clinically significant portal hypertension: a retrospective cohort study. J Laparoendosc Adv Surg Tech A. 2019;29(9):1116-1121. 30. Coffin SJ, Wrenn SM, Callas PW, Abu-Jaish W. Three decades later: investigating the rate of and risks for conversion from laparoscopic to open cholecystectomy. Surg Endosc. 2018;32:923-929. 31. Hu AS, Menon R, Gunnarsson R, de Costa A. Risk factors for conversion of laparoscopic cholecystectomy to open surgery: a systemic literature review of 30 studies. Am J Surg. 2017;214(5):920-930. 32. Utsumi M, Aoki H, Kunitomo T, et al. Preoperative risk factors for conversion of laparoscopic cholecystectomy to open cholecystectomy and the usefulness of the 2013 Tokyo Guidelines. Acta Med Okayama. 2017;71(5):419-425. 33. Purzner RH, Ho KB, Al-Sukhni E, Jayaraman S. Safe laparoscopic subtotal cholecystectomy in the face of severe inflammation in the cystohepatic triangle: a retrospective review and proposed management strategy for the difficult gallbladder. Can J Surg. 2019;62(6): 402-411. 34. Sabour AF, Matsushima K, Love BE, et al. Nationwide trends in the use of subtotal cholecystectomy for acute cholecystitis. Surgery. 2020;167(3):569-574. 35. Adatepe M, Adibelli ZH, Esen OS, Imamoglu C, Yildirim M, Erkan N. Anatomic variations of biliary ducts: magnetic resonance cholangiopancreatography findings of 1041 consecutive patients. Eur Surg. 2016;48:296-303. 36. Berci G, Hamlin JA. Operative Biliary Radiology. Williams & Wilkins; 1981:110-116. 37. Chen TH, Shyu JF, Chen CH, et al. Variations of the cystic artery in Chinese adults. Surg Laparosc Endosc Percutan Tech. 2000;10(3): 154-157. 38. Strasberg SM, Helton WS. An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy. HPB. 2011;13(1): 1-14. 39. Ismael HN, Cox S, Cooper A, Narula N, Aloia T. The morbidity and mortality of hepaticojejunostomies for complex bile duct injuries: a multi-institutional analysis of risk factors and outcomes using NSQIP. HPB. 2017;19(4):352-358. 40. Booij K, de Reuver PR, van Dieren S, et al. Long-term impact of bile duct injury on morbidity, mortality, quality of life, and workrelated limitations. Ann Surg. 2018;268(1):143-150. 41. Flum DR, Dellinger EP, Cheadle A. Intraoperative cholangiography and risk of common bile duct injury during cholecystectomy. JAMA. 2003;289(13):1639-1644. 42. Altieri MS,Yang J, Obeid N, Zhu C, Talamini M, Pryor A. Increasing bile duct injury and decreasing utilization of intraoperative cholangiogram and common bile duct exploration over 14 years: an analysis of outcomes in New York state. Surg Endosc. 2018;32:667-674. 43. Tornqvist B, Waage A, Zheng Z, Ye W, Nilsson M. Severity of acute cholecystitis and risk of iatrogenic bile duct injury during cholecystectomy, a population-based case-cohort study. World J Surg. 2016;40:1060-1067. 44. Kozarek RA, Ball TJ, Patterson DJ, Brandabur JJ, Raltz S, Traverso LW. Endoscopic treatment of biliary injury in the era of laparoscopic cholecystectomy. Gastrointest Endosc. 1994;40(1):10-16.

502.e2 45. Schreuder AM, Booij K, de Reuver PR, et al. Percutaneous-endoscopic rendezvous procedure for the management of bile duct injuries after cholecystectomy: short- and long-term outcomes. Endoscopy. 2018; 50(6):577-587. 46. Clayton E, Connor S, Alexakis N, Leandros E. Meta-analysis of endoscopy and surgery versus surgery alone for common bile duct stones with the gallbladder in situ. Br J Surg. 2006;93(10): 1185-1191. 47. Ebner S, Rechner J, Beller S, Erhart K, Riegler FM, Szinicz G. Laparoscopic management of common bile duct stones. Surg Endosc. 2004;18:762-765. 48. Chen H, Jorissen R, Walcott J, Nikfarjam M. Incidence and predictors of common bile duct stones in patients with acute cholecystitis: a systemic literature review and meta-analysis. ANZ J Surg. 2020;90(9): 1598-1603. 49. Bansal VK, Misra MC, Rajan K, et al. Single-stage laparoscopic common bile duct exploration and cholecystectomy versus twostage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with concomitant gallbladder stones and common bile duct stones: a randomized controlled trial. Surg Endosc. 2014;28:875-885. 50. Lee D, Ahn YJ, Lee HW, Chung JK, Jung IM. Prevalence and characteristics of clinically significant retained common bile duct stones after laparoscopic cholecystectomy for symptomatic cholelithiasis. Ann Surg Treat Res. 2016;91(5):239-246. 51. Jabbari Nooghabi A, Hassanpour M, Jangjoo A. Consequences of lost gallstones during laparoscopic cholecystectomy: a review article. Surg Laparosc Endosc Percutan Tech. 2016;26(3):183-192. 52. Horkoff MJ, Ahmed Z, Xu Y, et al. Adverse outcomes after bile spillage in incidental gallbladder cancers: a population based study. Ann Surg. 2021;273(1):139-144. 53. Chowbey P, Sharma A, Goswami A, et al. Residual gallbladder stones after cholecystectomy: a literature review. J Minim Access Surg. 2015;11(4):223-230. 54. Phillips MR, Joseph M, Dellon ES, Grimm I, Farrell TM, Rupp CC. Surgical and endoscopic management of remnant cystic duct

lithiasis after cholecystectomy: a case series. J Gastrointest Surg. 2014;18:1278-1283. 55. Dikmen K, Buyukkasap AC, Bostanci H, Sare M. Clinical characteristics and treatment approaches in patients with post-cholecystectomy syndrome due to remnant gallbladder. Ann Med Res. 2019;26(7): 1172-1177. 56. Saroj SK, Kumar S, Afaque Y, Bhartia A, Bhartia VK. The laparoscopic re-exploration in the management of the gallbladder remnant and the cystic duct stump calculi. J Clin Diagn Res. 2016;10(8): PC06-PC08. 57. Zhu J, Zhang Z. Laparoscopic remnant cholecystectomy and transcystic common bile duct exploration for gallbladder/cystic duct remnant with stones and choledocholithiasis after cholecystectomy. J Laparoendosc Adv Surg Tech A. 2015;25(1):7-11. 58. Strasberg SM, Callery MP, Soper NJ. Laparoscopic surgery of the bile ducts. Gastrointest Endosc Clin N Am. 1996;6(1):81-105. 59. Deziel DJ, Millikan KW, Economou SG, Doolas A, Ko ST, Airan MC. Complications of laparoscopic cholecystectomy: a national survey of 4292 hospitals and an analysis of 77604 cases. Am J Surg. 1993;165(1):9-14. 60. Ma MX, Jayasekeran V, Chong AK. Benign biliary strictures: prevalence, impact, and management strategies. Clin Exp Gastroenterol. 2019;12:83-92. 61. Kassab C, Prat F, Liguory C, et al. Endoscopic management of postlaparoscopic cholecystectomy biliary strictures: long-term outcome in a multicenter study. Gastroenterol Clin Biol. 2006;30(1):124-129. 62. Huszar O, Kokas B, Matrai P, et al. Meta-analysis of the long term success rate of different interventions in benign biliary strictures. PLoS One. 2017;12(1):e0169618. 63. Arlow FL, Dekovich AA, Priest RJ, Beher WT. Bile acid-mediated postcholecystectomy diarrhea. Arch Intern Med. 1987;147(7): 1327-1329. 64. Kang Z, Lu M, Jiang M, Zhou D, Huang H. Proteobacteria acts as a pathogenic risk-factor for chronic abdominal pain and diarrhea in post-cholecystectomy syndrome patients: a gut microbiome metabolomics study. Med Sci Monit. 2019;25:7312-7320.

CHAPTER 37A Stones in the bile duct: Clinical features and open surgical approaches and techniques Bryan Clary and Gabriel T. Schnickel OVERVIEW The first successful common bile duct exploration (CBDE) by Thornton in 1889 and the introduction of catheter-based biliary decompression by Courvoisier and Kehr marked the initial efforts in treating choledocholithiasis. Open cholecystectomy and bile duct exploration were performed commonly as the standard treatment for patients with choledocholithiasis for many years with good success and low rates of morbidity and mortality (Table 37A.1). During this era of open operative interventions, the percentage of retained stones was only 1% to 3%, and long-term follow-up revealed that revisional surgery was necessary in about 10% of the patients.1–4 In the last several decades, however, there has been a shift away from open cholecystectomy and CBDE with improvements in noninvasive imaging and increasing sophistication of percutaneous and endoscopic interventions (see Chapters 19, 29, 30, and 36C). Beyond the widespread availability of endoscopic retrograde cholangiopancreatography (ERCP), the increased use of laparoscopy and minimally invasive techniques has made open CBDE an infrequently used tool. The significant trend toward laparoscopic surgery including cholecystectomy, intraoperative cholangiogram (IOC), and CBDE over the last several decades has impacted the experience of surgical trainees. This has resulted in limited experience in open biliary surgery, specifically open cholecystectomy and open CBDE. Chief residents complete training with an average of a single CBDE, open or laparoscopic.5 Although the majority of cholecystectomies are now performed laparoscopically (see Chapter 35), laparoscopic CBDE (LCBDE; see Chapter 36B) has not been similarly embraced. This is in part because of the wide availability of ERCP but also in part because the technical demands of LCBDE do not lend themselves to routine use by most general surgeons. Surveys of general surgeons practicing in a rural area of the United States demonstrated that the preferred approach to choledocholithiasis was ERCP (75%), followed by laparoscopic (21%) or open (4%) exploration.6 Analysis of practice patterns in large hospital systems more than a decade later found a similar underutilization of LCBDE with less than 30% of patients undergoing a single-stage laparoscopic cholecystectomy with LCBDE.7 There is also broad variability in terms of evaluation and treatment of choledocholithiasis across geographic regions. A multicenter trial found that when choledocholithiasis was suspected, laparoscopic cholecystectomy with IOC was the most common initial procedure in seven institutions followed by ERCP in four and magnetic resonance cholangiopancreatography (MRCP) in one.8 Despite these considerations, there remain indications for open CBDE. This chapter presents a review of the clinical

features of choledocholithiasis with an emphasis on the technical aspects of open CBDE.

ORIGIN OF CHOLEDOCHOLITHIASIS CBD stones are broadly classified by their location of origin (see Chapter 32). Secondary stones, those that originate in the gallbladder and migrate into the bile duct, are the most common. Chemically, these stones tend to be cholesterol or blackpigment stones. Primary CBD stones, in contrast, originate within the CBD and are predominantly brown-pigment (calcium bilirubin) stones. Primary stones occur in patients with congenital absence of the gallbladder and in those whose CBD had been cleared at the time of prior cholecystectomy. CBD stones that occur in the immediate postcholecystectomy period should be assumed to be secondary stones that are the result of an incompletely cleared CBD. Secondary stones are the most commonly observed CBD stones, particularly in Europe and North America. Primary stones are encountered more commonly in Asia and are associated with a high incidence of intrahepatic bile duct stones seen in Southeast Asian countries such as Taiwan, Hong Kong, and Singapore9 (see Chapter 39). The relative prevalence of intrahepatic bile duct stones in all gallstone cases in Taiwan is extremely high (.50%) and coexisting intrahepatic and extrahepatic bile duct stones are found in approximately 70% of these patients. Typical presentations for inflammatory, infective, and congenital choledocholithiasis include biliary colic, jaundice, cholangitis (see Chapter 43), and pancreatitis (see Chapter 55). Of these, pain from biliary colic tends to be the most common symptomatic manifestation of CBD stones. In many cases, the intermittent obstruction and passage of CBD stones will result in fluctuating elevation of bilirubin and hepatocellular enzymes. If untreated for a long period of time, these recurrent episodes may lead to secondary biliary cirrhosis. In contrast to the intermittent obstruction that results in biliary colic, persistent CBD obstruction can result in cholangitis, which may display the Charcot’s classic triad (fever/rigors, jaundice, and right upper quadrant pain) or the Reynold’s pentad (Charcot’s triad plus hypotension and altered mental status) (see Chapter 43). Pancreatitis is the second most frequent symptomatic presentation of CBD stones (see Chapter 55), and depending on the timing of cholangiography, CBD stones can be identified in up to 50% of these patients. Patients who have symptomatic bile duct stones are at risk of experiencing further symptoms or complications if left untreated. More than one-half of patients who had retained bile duct stones experienced recurrent symptoms during a follow-up period of 6 months to 13 years,10 and 25% developed serious complications.11 The potential for serious sequelae related to CBD stones makes the identification and 503

504

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

TABLE 37A.1  Mortality Rates of Biliary Reoperation for Retained or Recurrent Bile Duct Stones REFERENCE

NUMBER OF OPERATIONS

NUMBER OF DEATHS (%)

Saharia et al. (1977)76

30

0

Jones (1978)96

22

0

McSherry & Glenn (1980)

341

7 (2%)

Allen et al. (1981)

47

1 (2%)

22

1 (5%)

DenBesten & Berci (1986)

86

2 (2.3%)

Girard (2000)

88

0

TOTAL

920

15 (1.6%)

18

78

De Almeida et al. (1982) 13

definitive treatment of patients with CBD stones of great importance. The potential long-term sequelae of untreated clinically significant stones have led some to advocate for routine intraoperative cholangiography at the time of cholecystectomy so that clearance of the duct at the time of surgery can be ensured. The clinical significance and natural history of asymptomatic CBD stones, however, is unpredictable, as many small stones will pass spontaneously without incident. During the era of open cholecystectomy, the practice of routine cholangiography was common, and studies from this period demonstrated an incidence of choledocholithiasis approaching 10% to 15% in patients without any clinically evident common duct involvement.12–18 Proponents of a more selective approach to cholangiography, however, note that the percentage of clinically significant stones is far lower than the 10% to 15% of patients who will have cholangiographic findings of CBD stones when routine cholangiography is used. The use of selective intraoperative cholangiography in laparoscopic cholecystectomy series demonstrates similar findings.19 Collins and colleagues identified filling defects consistent with stones in 4.6% of patients on IOC.20 In these patients, access was maintained for the performance of postoperative cholangiograms. At 48 hours, 26% of patients had a normal cholangiogram, and an additional 26% had evidence for passage of the stones by 6 weeks. Only 22 patients (2.2%) had persistent CBD stones at 6 weeks after laparoscopic cholecystectomy and underwent ERCP for retrieval.20

PREOPERATIVE DIAGNOSIS In the absence of clinical signs such as cholangitis or pancreatitis, preoperative identification of choledocholithiasis typically relies on serum liver function tests (LFTs) and imaging studies. The utility of LFTs in predicting the presence of CBD stones has been demonstrated by a number of groups.21,22 Serum bilirubin and alkaline phosphatase are typically the most commonly used laboratory values; however, a raised g-glutamyltransferase (GGT) level has been suggested to be the most sensitive and specific laboratory indicator of CBD stones. A GGT value greater than 90 U/L has been proposed to indicate a high risk of choledocholithiasis, with sensitivity and specificity of 86% and 75%, respectively.21

Transabdominal ultrasound (TUS) alone has a low sensitivity (25%–60%) for detection of CBD stones and is highly operator dependent.23,24 When used in conjunction, clinical examination, laboratory studies, and ultrasonography (typically the first-line imaging modality) (see Chapter 15) are sensitive in 96% to 98% and specific in 40% to 75% for identification of patients with choledocholithiasis.25–28 Liu and colleagues stratified precholecystectomy patients into four groups of descending risk of choledocholithiasis based on guidelines incorporating clinical evaluation, serum chemistry analysis, and TUS. The occurrence of choledocholithiasis in these groups (group 1, extremely high risk; group 2, high risk; group 3, moderate risk; group 4, low risk) was 92.6%, 32.4%, 3.8%, and 0.9%, respectively. Triaging patients in this manner resulted in preoperative identification of choledocholithiasis by ERCP in 92.3% of the patients who were subsequently referred for endoscopic clearance.28 Similarly, the American Society of Gastrointestinal Endoscopy (ASGE) identified several predictors of choledocholithiasis in their guidelines for the use of endoscopy in the evaluation of CBD stones.29 CBD stones seen on TUS or crosssectional imaging, clinical evidence of ascending cholangitis, and bilirubin greater than 4 mg/dL were identified as high-risk criteria for choledocholithiasis and patients should move directly to ERCP. They suggest that any other risk factors, such as those mentioned previously, should prompt additional investigation with MRCP, endoscopic ultrasonography (EUS), or IOC at the time of cholecystectomy. ERCP requires cannulation of the papilla and is associated with a significant risk of adverse events in up to 15% of patients and severe adverse events including death or prolonged hospital stay in approximately 2%. For this reason, ERCP should be reserved for individuals in the high-risk category or with CBD stones confirmed by MRCP or EUS. When taken in sum, these data suggest that the ERCP is best reserved as a therapeutic measure for patients with a high probability of CBD stones, rather than as an initial diagnostic test. Like TUS, standard computed tomography (CT) scanning has a low sensitivity for the detection of bile duct stones and is most useful in documenting biliary dilation or excluding mass lesions as a cause of biliary obstruction (see Chapter 18). Newer techniques of CT cholangiography use contrast agents excreted in the biliary tree, which when combined with highresolution helical scans and three-dimensional reconstructions can give accurate and detailed information about the biliary tree.30,31 The sensitivity of this technique can be as high as 97%, and the specificity is 75% to 96%.30–38 Although these data suggest accuracy comparable to MRCP (see Chapter 19), helical CT cholangiography is limited by several issues: (1) possible allergic reactions to the contrast agents (as high as 15% in one series using intravenous iotroxate),33 (2) suboptimal ductal contrast opacification in the presence of significant jaundice,36,37 and (3) limited visualization of intrahepatic duct branches.33,39 MRCP has become the gold standard for noninvasive biliary imaging since its introduction in 1991 and has been recommended by some as the preoperative noninvasive modality of choice for the detection of CBD stones40–44 (see Chapter 17). MRCP provides precise anatomic detail of the biliary tract and has a sensitivity of 81% to 100% and a specificity of 92% to 100% in detecting choledocholithiasis.41,45 The accuracy of MRCP in diagnosing CBD stones is comparable with that of ERCP (see Chapters 19 and 20) and IOC (see Chapter 23).41,46

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

As a diagnostic test, MRCP has largely replaced ERCP, once considered the gold standard of preoperative bile duct imaging, because the nonselective use of ERCP in all patients with suspected choledocholithiasis detects CBD stones in less than 50%.47,48 Although both MRCP and ERCP are effective at detecting choledocholithiasis, a randomized trial looking at an MRCP first versus ERCP first approach to patients with suspected CBD stone disease found equivalent patient outcomes. Importantly, those in the MRCP arm were 50% less likely to have a subsequent ERCP.49 Indiscriminate use of ERCP exposes over half of patients to unnecessary procedure-related morbidity and mortality50; thus ERCP is better used as therapeutic intervention rather than a diagnostic one. Although MRCP is currently the most accurate noninvasive imaging modality for choledocholithiasis, it may miss stones smaller than 5 mm in diameter and can underestimate the number of stones detected.46 Furthermore, it is expensive when compared with TUS or CT, not readily available at smaller facilities, and may not be technically feasible in obese patients or those with significant claustrophobia. EUS has also emerged as an alternative to ERCP and MRCP for preoperative assessment of bile duct stones and was initially described in 199051,52 (see Chapter 16). EUS and MRCP are both highly accurate in detecting choledocholithiasis, with EUS having a slight edge because of its increased sensitivity at detecting small stones (97% vs. 90%).53 EUS may be particularly useful in patients in which MRCP may be limited such as patients with obesity, claustrophobia, metal clips, cardiac pacemaker, or inability for breath holding. EUS also provides the advantage of immediate transition to therapeutic ERCP if diagnostic findings warrant. A systematic Cochrane review of the literature, including 18 studies involving 2532 participants, found both EUS and MRCP to be highly accurate at diagnosing CBD stones and found no difference in sensitivity or specificity between the two modalities.54 Randomized controlled trials (RCTs) have also demonstrated that EUSguided ERCP can avoid unnecessary ERCP in up to two-thirds of patients when compared with using ERCP alone for diagnosis of choledocholithiasis.55 Furthermore, selective use of ERCP based on EUS findings resulted in reduced risk of overall complications and post-ERCP pancreatitis (PEP).

TIMING AND SEQUENCE OF INTERVENTIONS Suspected Choledocholithiasis Before Cholecystectomy In patients with suspected choledocholithiasis, selecting and sequencing the laparoscopic, open, and endoscopic therapeutic modalities can be challenging. Before the popularization of therapeutic laparoscopy, precholecystectomy endoscopic clearance of the CBD was uncommon. Several studies did not reveal any morbidity or mortality advantage with preoperative endoscopic sphincterotomy (ES)56–58 and one actually showed an increased rate of morbidity in patients who underwent preoperative ERCP, followed by open cholecystectomy, compared with the group that was treated with single-stage open cholecystectomy and CBDE.58 A systematic review of the literature, including eight trials with 737 participants, comparing open CBDE versus ERCP for clearance of CBD stones found no significant difference in morbidity or mortality. However, open CBDE was more effective at clearing CBD stones than ERCP.59

505

The expansion of therapeutic laparoscopy saw a rise in the popularity of preoperative ERCP CBD clearance for patients with suspected choledocholithiasis, in part because laparoscopic CBDE is more technically challenging than laparoscopic cholecystectomy alone (see Chapters 36B and 36C). For surgeons who are comfortable with LCBDE, the data support single-stage laparoscopic management (laparoscopic cholecystectomy and IOC with CBDE in those with CBD stones) over preoperative ERCP, followed by laparoscopic cholecystectomy. Several prospective RCTs compared these two treatment strategies (Cuschieri et al., 1999; Rogers et al., 2010; Sgourakis et al., 2005) and found that the two groups had equivalent success rates of duct clearance and patient morbidity, but a significantly shorter hospital stay was reported with the singlestage laparoscopic treatment.22,60,61 Single-stage laparoscopic cholecystectomy with LC 1 CBDE results in fewer procedures, the shortest length of stay and most cost-effective treatment for patients with CBD stones. Despite these findings it continues to be underutilized in measures of current practice patterns with less than one-third of patients received single-stage LC 1 LCCBDE versus laparoscopic cholecystectomy with preoperative or postoperative ERCP.7 When LCBDE is not part of the surgeon’s armamentarium, the decision to perform a precholecystectomy ERCP should be weighed carefully because it is not without complications. Although most post-ERCP complications are mild to moderate in severity,62 the risk of severe complications, such as pancreatitis, bleeding, infection, and perforation, need to be weighed against the likelihood that ERCP will find clinically relevant CBD stones. ERCP has an overall complication rate of 10% and a mortality rate less than 0.5%.63–66 In a systematic review of 108 RCTs with 13,296 participants the incidence of PEP was 9.7% and up to 14.7% in the high-risk population. Most cases are mild to moderate and the mortality rate associated with PEP was 0.7%. Despite advances in equipment and techniques the rate of PEP has not decreased in the modern experience with a rate of 10% in studies since 2000.67 Additionally, the increased financial cost of preoperative ERCP should be considered when evaluating its role in the treatment of suspected stones. Accurately predicting which patients will have clinically relevant choledocholithiasis can be challenging. Several studies have shown that a “negative” ERCP is performed in 40% to 70% of patients because most of these biochemical and radiographic abnormalities were the result of transient biliary obstruction secondary to stones that passed preprocedurally into the duodenum.58,63,65,66,68 As mentioned earlier in this chapter, the 2019 ASGE guidelines suggest immediate ERCP for patients in the high-risk category: (1) CBD stone on ultrasound or cross-sectional imaging, (2) total bilirubin .4 mg/dL and dilated CBD, and (3) ascending cholangitis. EUS or MRCP are recommended for intermediate-risk patients, whereas low-risk patients may proceed to cholecystectomy. Treatment strategies for patients stratified to the low- and high-likelihood groups are generally agreed on. Patients who are in the low risk for choledocholithiasis group should go directly to laparoscopic cholecystectomy (with or without IOC) because CBD clearance is unlikely to be necessary. For patients in the high-risk group, particularly those needing biliary decompression for treatment of acute cholangitis and in patients with severe gallstone pancreatitis and evidence of persistent choledocholithiasis, precholecystectomy ERCP is warranted. Patients with multiple medical comorbidities,

506

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

limited life expectancy, or other issues that would make them poor surgical candidates, ERCP with ES and biliary decompression can sometimes be used as the definitive management without cholecystectomy60,69 (see Chapter 29). This strategy is not ideal for patients who are acceptable surgical candidates, however, because there is a risk of recurrent biliary symptoms if cholecystectomy is not performed. In a prospective randomized trial published in 1995 by Hammarström and colleagues, an expectant policy after ES was compared with open cholecystectomy combined with CBDE. It was reported that 20% of the patients after ES alone needed cholecystectomy during followup.2 A prospective randomized trial of high-risk patients performed by Targarona and colleagues (1996) comparing ES and subsequent open cholecystectomy to ES alone resulted in similar findings.4 They noted patients who underwent elective open cholecystectomy had significantly fewer recurrent biliary symptoms (6% vs. 21%) and needed fewer readmissions (4% vs. 23%) than patients who did not undergo surgery after ES. In contrast to the general consensus of how to treat highand low-likelihood patients, the question of how to treat intermediate-risk patients has been the subject of some debate. A recent RCT examined an up-front cholecystectomy and IOC strategy against preoperative ERCP and subsequent cholecystectomy for intermediate-risk patients.70 Fifty patients were randomized to each group, and differences in length of stay, number of subsequent CBD interventions, morbidity, mortality, and quality of life were analyzed. No significant difference was found in morbidity or quality of life; however, patients who underwent cholecystectomy as the initial procedure had a significantly shorter length of stay (median, 5 days vs. 8 days; P , .001) and fewer common duct investigations. A systematic review of seven trials including 746 participants compared single-stage LC 1 LCBDE versus two-stage preoperative ERCP 1 LC or LC 1 postoperative ERCP.71 The authors found no difference in morbidity or mortality but a lower rate of retained stones in the single-stage group. Together a singlestage LC 1 CBDE provides the best clearance of the bile duct, the shortest length of stay, and is more cost-effective with equivalent morbidity and mortality.

Common Bile Duct Exploration at Time of Open Cholecystectomy Therapeutic laparoscopy has become routine in much of the world, and as laparoscopic experience has grown, surgeons have become increasingly more comfortable using LCBDE when choledocholithiasis is noted intraoperatively. In areas of the developing world, however, where access to endoscopic, radiologic, and laparoscopic expertise is limited, open cholecystectomy and bile duct exploration remains a mainstay of treatment. Even in settings where laparoscopy and endoscopy are readily available, however, there will still be some patients in whom an open approach to CBDE may be required (see Chapters 36B and 36C). Principal among these include patients with (1) large or impacted CBD stones and who have failed previous endoscopic interventions; (2) a need for biliary enteric drainage; (3) anatomic considerations that preclude endoscopic treatment, such as prior gastric resection, gastric bypass or duodenal diverticula; and (4) complex situations requiring an open approach for cholecystectomy, including those with Mirizzi syndrome, biliary-enteric fistula, severe cholecystitis, or a high index of suspicion for cancer.

Postcholecystectomy Choledocholithiasis (See Chapter 38) Incidence The majority of initial operations for gallstone disease, with or without demonstrated choledocholithiasis, are curative, but some patients will develop sequelae of choledocholithiasis postcholecystectomy. Approximately 1% to 2% of all patients who undergo cholecystectomy have stones left in the CBD that require further intervention.72 Retained calculi occur rarely after open cholecystectomy without CBDE (Bergdahl & Holmlund, 1976), whereas the incidence in those who undergo open cholecystectomy with concomitant CBDE is slightly higher but still reported to be less than 5%.73–75 Retained CBD stones occur with higher frequency after positive CBDE than after a negative one. The rate of recurrence increases to approximately 20% after a second operation on the biliary tract for choledocholithiasis,76,77 and this rate increases after subsequent reoperation.78

Treatment Endoscopic and percutaneous methods remain the preferred modalities when managing recurrent or retained CBD stones (see Chapters 30 and 36C). The open surgical approach is reserved for patients who have failed nonoperative treatments. Decision making is further influenced by clinical presentation, condition of the patient, institutional expertise, and presence or absence of a T-tube. RETAINED STONES IN THE PRESENCE OF A T-TUBE. Along with the rise in popularity of laparoscopic biliary surgery decreasing use of T-tube biliary drainage has also occurred. When LCBDE is performed, primary closure has been shown to be safe, and routine use of postexploration T-tubes is no longer common79–81 (see Chapters 31 and 42). If a T-tube is present, it provides nonsurgical options for accessing the biliary tree postoperatively. In the presence of a T-tube, retained CBD stones in the immediate postoperative period can be managed with observation, mechanical extraction, or ES. In the initial weeks after CBDE, 10% to 25% of retained stones found on postoperative cholangiography will pass spontaneously into the duodenum, and as such interventions are not undertaken, assuming there is no evidence of obstruction or cholangitis. If calculi persist after 4 to 6 weeks, treatment options include radiologic approach through the T-tube tract (see Chapter 30) or ERCP (see Chapter 29). Because of its high success rate and low morbidity and mortality, nonoperative mechanical extraction through the T-tube tract is an attractive treatment choice. A success rate of 95% has been reported with a morbidity rate of only 4%,82 Burhenne reported no deaths in a series of 661consecutive patients.83 When complications do occur, they can be treated medically in most instances, and only 0.2% of cases have required surgery.82 ES also has been shown to be effective in the management of retained stones in the early postoperative period after exploration of the CBD with a T-tube still in place.2,84 Although ES has the considerable advantage that it can be carried out as soon as retained stones are discovered, treatment may be unnecessary in some patients because stones may pass spontaneously. Some authors have suggested that mechanical stone extraction through the T-tube tract is superior to ES because of its high success rate and lower morbidity profile, although modern

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

endoscopic equipment may mitigate some of the post-ERCP hemorrhagic complications seen in earlier series.85,86 Regardless, the safety and efficacy of percutaneous intervention through the T-tube makes it an ideal choice for initial postoperative interventions, and ES is best used in the early postoperative period before a T-tube tract is well formed, if the patient is clinically unstable, the T-tube is inappropriate in size and position, or mechanical extraction through the T-tube has failed. If these techniques fail, operative management can be undertaken with the expectation of a high success rate and acceptable morbidity and mortality.16,87 RETAINED OR RECURRENT STONES IN THE ABSENCE OF A T-TUBE. ES is the procedure of choice and should be attempted first in patients without a T-tube in place87,88 (see Chapters 29 and 36C). Most reports of ES indicate a success rate in achieving overall clearance of stones from the CBD of more than 85%.63,71,89 Although early complication rates for ES range from 5% to 15%, emergency surgery is uncommonly required and most complications can be managed conservatively. Hemorrhage, pancreatitis, cholangitis, and perforation are the most frequent complications, and mortality usually is reported at 0.5% to 2%.85,88 Long-term complication rates, mainly from stenosis or new stones or both, are low (,10%), and most complications can be managed endoscopically.2,63,88,89 Although initial ES has a success rate of 80% to 90% stents may be placed when the duct cannot be completely cleared of stones for biliary drainage and subsequent attempts at clearance. The success rate of subsequent attempts varies widely in the literature from 44% to 96% and success depends on size, shape, and number of residual stones. The 2019 ASGE guidelines recommend ES with large balloon dilation in patients with difficult or large CBD stones. A meta-analysis of nine RCTs found ES 1 large balloon dilation more effective at stone clearance than ES alone (odds ratio [OR] 2.8). Lithotripsy, either mechanical or cholangioscopy assisted, is an effective technique to address difficult or refractory stone disease. Success rates also vary widely in the literature and frequently require multiple attempts with a complication rate up to 25%. The most common complication being cholangitis.53 Additionally, percutaneous transhepatic rendezvous techniques can sometimes aid in duct clearance, particularly if there is difficulty cannulating the ampulla. Often, however, failures of endoscopic management will be the result of large impacted stones or anatomic issues that are not ameliorated by a percutaneous approach. Definitive stenting with metal stents in uncleared ducts carries a high rate of morbidity and mortality and should be approached with caution. In such settings, operative management is the most reasonable alternative.87 Reoperation for retained stones can be performed safely, with operative mortality less than 2%.16 Miller and colleagues reported 237 patients with CBD stones treated by CBDE or ES.90 Success was higher and mortality was lower for the operatively managed group. The complication rate was similar, but the complications tended to be more serious and more apt to require surgery in the ES group.90 A systematic review performed by Dasari and colleagues found that duct clearance in patients undergoing open bile duct exploration was superior to ES, but it should be noted that most series that compare open cholecystectomy/CBDE to ES are from the era of open surgery, which also corresponds to the early days of ERCP and ES.71 Therefore caution should be used in extrapolating these data to the modern endoscopic

507

experience. Nevertheless, these findings reinforce that surgery can be a valuable, effective, and safe tool in the treatment of recurrent/retained CBD stones, even if confined to the subset of patients who fail ES. In patients with anatomy that is unfavorable for conventional ERCP and ES such as those with history of gastric resection or gastric bypass, laparoscopic-assisted ERCP provides an alternative approach for CBD clearance. Laparoscopic-assisted ERCP utilizes a laparoscopic approach to the remnant stomach, which is accessed via trocar for introduction of the duodenoscope for conventional ERCP. A multicenter study of 579 patients looking at laparoscopic-assisted ERCP in patients with previous Roux-en-Y gastric bypass found a procedure success rate of 98% with an adverse event rate of 18%.91 Adverse events were related to laparoscopy in 10% and ERCP in 7% and both in 1%. The gastrostomy can be closed surgically at the end of the procedure or a G-tube left in place for subsequent access if indicated. Together this is a viable alternative for certain patients, although it carries a higher complication profile than conventional ERCP 1 ES alone. When reoperation is required for retained CBD stones, the optimal procedure is complete removal of all stones via choledocholithotomy, choledochoscopy, placement of a T-tube (in many cases), and completion cholangiography. This procedure is adequate for most patients, and the overall failure rate has been reported as low as 3%.16 Others, however, have reported significantly higher failure rates,76,78 which has prompted some authors to recommend biliary-enteric drainage in all patients with previous choledocholithotomy.78,92 Tompkins and Pitt (1982) and Cameron (1989) emphasized, however, that concomitant biliary drainage should not be regarded as mandatory procedure in all patients with retained or recurrent stones.87,93 In general, biliary-enteric drainage at reoperation is appropriate in the following scenarios: (1) stricture or stenosis of the distal bile duct or sphincter of Oddi, (2) marked dilation of the duct of 2 cm or more, (3) multiple or primary bile duct stones, (4) inability to remove all stones from the duct, and (5) a third operation. Transduodenal sphincteroplasty, choledochoduodenostomy, and choledochojejunostomy are effective methods of biliary enteric drainage94–96 (see Chapter 31). With the wide availability of ERCP, operative sphincteroplasty is rarely required because ES is sufficient in most cases. In the presence of a long distal CBD stricture, ES is not an appropriate choice because it does not address the primary obstructive issue. For ducts smaller than 1 to 1.5 cm in diameter, sphincteroplasty is the preferred operative approach as this avoids possible anastomotic stricture formation, but it does carry a greater risk of postoperative pancreatitis. Occasionally, recurrent or primary stones will be seen in patients with dilated ducts and a widely patent sphincter after sphincteroplasty or sphincterotomy. In such cases, choledochoduodenostomy or Roux-en-Y choledochojejunostomy is necessary. Side-to-side or end-to-side choledochoduodenostomy and end-to-side Roux-en-Y choledochojejunostomy are excellent drainage options for CBDs larger than 1.5 cm and offer better decompression of an extremely large duct. CDD can be performed end to side or side to side depending on the situation. Although side to side has been reported to have a higher rate of sump syndrome more recent reviews have not found this to be the case.97 In the context of previous biliary pancreatitis, patients who present for reoperation with multiple stones and an incompletely cleared proximal

508

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

biliary system may be better served with an end-to-side choledochoduodenostomy as opposed to a side-to-side technique because it minimizes the chance of stones dropping distally and causing recurrent pancreatitis. Sump syndrome, the development of cholangitis, hepatic abscess, or pancreatitis caused by stones, sludge, or debris or food lodged in the CBD obstructing normal biliary drainage, is an uncommonly observed complication of choledochoduodenostomy and should be managed initially by endoscopic modalities. If ERCP fails to improve symptoms, the choledochoduodenostomy can be converted to a Roux-en-Y choledochojejunostomy. Laparoscopic or open approaches to choledochoduodenostomy are options with a low complication rate that allow easier subsequent endoscopic access to the biliary tree and more physiologic biliary drainage and do not require an entero-enteric anastomosis.98

Clinical Experience With Reoperation Girard reviewed all patients who underwent reoperation for retained or recurrent choledocholithiasis at the MaisonneuveRosemont Hospital between 1969 and 1990. Eighty-five patients with preoperatively confirmed choledocholithiasis underwent a total of 88 operations. Eighty-five of these operations were second procedures, and three patients required a third operation. Three types of bile duct reoperation were performed: choledocholithotomy with T-tube drainage (64 patients), choledocholithotomy with side-to-side choledochoduodenostomy (15 patients), and choledocholithotomy with transduodenal sphincteroplasty (6 patients). Choledocholithotomy with Ttube drainage in one patient and choledocholithotomy with side-to-side choledochoduodenostomy in two patients were performed at a third operation. The average hospital stay was 9.3 days. There were no deaths in the series despite the fact that 43 of 85 patients were older than 60 years and 44 patients had associated risk factors. Six minor complications were observed, none of which necessitated urgent surgery. Two patients (3%) of the 64 who had choledocholithotomy with T-tube drainage developed recurrent bile duct stones 4 and 5 years after a second operation, and side-to-side choledochoduodenostomy was performed.99 To summarize, ES has become the first-line therapy for retained or recurrent bile duct stones, but surgery can be performed safely with low mortality and morbidity when required. Surgery remains a critical component of the armamentarium that can be used to treat recurrent bile duct stones. As with most things in modern medicine, a multidisciplinary approach to recurrent CBD stones is important to properly select and sequence the numerous options now available. Gastroenterologists, radiologists, and surgeons should work together closely to assess the most appropriate intervention for an individual patient. In making the choice between open surgery, laparoscopic surgery, percutaneous therapies, and ES, the surgeon must consider not only the published data but institutional expertise and experience. In a patient with a retained stone and a T-tube in place, percutaneous extraction through the T-tube tract or ES should be attempted first. In the absence of a T-tube, ES should be attempted first. If unsuccessful or contraindicated, operative management is a reasonable alternative. Surgical intervention has a high success rate and acceptable rates of mortality and morbidity. Before operation, the surgeon must make an accurate diagnosis of retained stones by using a combination of MRCP, ERCP, and EUS. These findings should be confirmed via intraoperative cholangiography and complete clearance of

the biliary tree documented with completion cholangiography and choledochoscopy. Not all patients require biliary-enteric drainage, but certain patients, particularly those with multiple or incompletely cleared calculi, large ducts (.2 cm), and distal CBD strictures will benefit from drainage procedure.

SURGICAL TECHNIQUES FOR EXPLORATION OF THE COMMON BILE DUCT The principal techniques for open exploration of the CBD will be detailed in this section. Broadly, the goals of CBDE include complete clearance of calculi from the biliary system and establishment of free flow of bile into the gut. The preferred approach to CBDE is typically through a supraduodenal choledochotomy, with the transduodenal/transampullary route reserved for patients with impacted stones that cannot be removed readily from above. Stones impacted at the ampulla can be broken down and removed through a supraduodenal approach; however, a transduodenal sphincteroplasty is generally less traumatic. Clearance of the biliary tree should be confirmed by performing postexploratory choledochoscopy and cholangiography. The value of choledochoscopy has been confirmed by many authors.74,75,100 Postexploratory cholangiography should also be performed before closure of the abdomen, not only because it can locate missed stones, but also because it may reveal unsuspected disruption of the biliary ductal system. If the cholangiography technique is meticulous, issues with false positives from air bubbles and poor opacification of the entire system can be largely eliminated to provide consistent and reliable cholangiograms. The selective use of biliary-enteric drainage procedures is another method to decrease the incidence of subsequently symptomatic retained stones. Although we do not recommend routine biliary-enteric decompression at initial operation, it should be considered carefully in patients with multiple stones, large stones, dilated duct, distal bile duct stricture, and in selected elderly patients. If these conditions pertain to an elderly or poor-risk patient, choledochoduodenostomy may obviate reexploration. Other indications include (1) the presence of irretrievable intrahepatic stones, (2) proven ampullary stenosis, or (3) an impacted ampullary stone.

Supraduodenal Choledochotomy and Exploration of the Common Bile Duct Exposure The liver is retracted superiorly with a broad-bladed, slightly curved retractor, such as a Hartmann (“sweetheart”) retractor. This retractor should be deep enough to displace the liver but not so curved as to traumatize it. A pack should be put over the hepatic flexure of the colon down to the hepatorenal pouch and the medial part of the duodenum. This pack is retracted by a similar, broad-bladed retractor to prevent the colon or duodenum from obscuring vision (Fig. 37A.1). The lesser omentum and stomach are retracted to the left after placement of another pack. The gallbladder is usually removed before exploration of the CBD and the cystic duct ligated with a suture that can be left long and used for retraction if necessary. Palpation of the CBD and handling of its lower part during exploration and subsequent choledochoscopy is best facilitated by mobilizing the duodenum and head of pancreas with the performance of a Kocher maneuver (Fig. 37A.2).

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

509

A FIGURE 37A.1  Exposure of the common bile duct by packs and retractors.

Choledochotomy A distal vertical supraduodenal choledochotomy is generally preferred for several reasons. First, because a choledochoduodenostomy may be required (see Chapter 31), the opening should be positioned in the lowest part of the supraduodenal CBD such that an anastomosis can be created easily and without tension (Figs. 37A.3 and 37A.4). Second, a distal choledochotomy leaves the maximal amount of bile duct proximally so that it may be used in the future for an additional procedure (e.g., repair of a stricture). Third, the usual distance from this point to the papilla measures 7 cm or more, which is the exact length of the rigid choledochoscope sometimes used for CBDE; this is less of an issue when using a flexible scope, which is typically much longer. The anatomy of the cystic duct is highly variable, and care must be exercised to open the correct duct (see Chapter 2). A cystic duct lying anterior or closely applied to the CBD can be easily opened in error, particularly if dilated. Bile is aspirated by gentle suction, and a specimen should be sent for culture (Fig. 37A.5).

Exploration of the Duct All efforts must be made to minimize trauma related to the exploration, and rigid instruments should be avoided if possible, as false passages into the duodenum and pancreas can be created.101 Grasping forceps of any type can catch the duct wall and result in delayed stricture formation. Use of the Fogarty balloon catheter (5- to 6-Fr) can avoid these issues and has been found to be suitable for CBDE.102,103 The Fogarty catheter is held in long forceps with the surgeon’s dominant hand, introduced into the CBD (Fig. 37A.6), and passed into the duodenum. The balloon is inflated, and the catheter is withdrawn until it impinges against the papilla (Fig. 37A.7). The balloon is identified in the second part of the

B FIGURE 37A.2  A, The gallbladder has been removed. The dotted line indicates the incision in the retroperitoneum to allow mobilization of the duodenum by the Kocher maneuver (B).

duodenum by palpation, and the location is noted as the site of duodenotomy should a sphincteroplasty become necessary. Stones can usually be felt against the shaft of the catheter within the duct. The balloon is deflated and gently withdrawn through the papilla, and then the balloon is reinflated immediately. Passage back through the ampulla can be detected by a sudden easing of the pull on the catheter. At this point, the syringe is held in the surgeon’s nondominant hand, and the degree of balloon inflation is controlled by the thumb and the plunger. With gentle traction superiorly from long forceps held in the surgeon’s dominant hand, the catheter is gradually pulled up to the choledochotomy site (Fig. 37A.8), with care being taken to prevent any stone slipping into the proximal biliary tree. If the traction is anterior rather than superior, there is the risk of lacerating the opening into the duct (Fig. 37A.9), and the risk is increased when the opening in the duct is longitudinal. The procedure is repeated until the distal duct is considered to be clear.

510

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

FIGURE 37A.3  The common bile duct is opened just above the duodenum to leave room for a choledochoduodenostomy if necessary.

A

FIGURE 37A.4  Two fine absorbable stay sutures are used to lift and render the common bile duct (CBD) tense for an incision about 1 to 2 cm long, depending on the size of the duct and the size of the stones. If the CBD is not made tense, damage can be done to the posterior wall, or an irregular incision can be made.

B

FIGURE 37A.5  A, The cystic duct may lie anterior to the common bile duct (CBD) and may be opened in error. B, The cystic duct may run parallel to the CBD with a low entrance, mimicking a dilated duct.

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

A

B

C

D

511

FIGURE 37A.6  A Fogarty catheter is fed into the duct with forceps by using the dominant hand. The operator’s nondominant hand is used to grasp the mobilized duodenum, which allows palpation of the passage of the catheter and of any stones within the intrapancreatic portion of the common bile duct.

Next, this procedure is repeated for the proximal ducts by reinserting the catheter upward into each of the main hepatic ducts. The degree of balloon inflation is of great importance here, as overinflation will result in damage to the ducts and underinflation risks missing stones. Correct inflation can be achieved by inflating the balloon until the tension of the syringe plunger can be felt in the fingers. This tension is maintained as the catheter is withdrawn into the gradually widening duct. It is important to remove the stone when it appears at the choledochotomy opening and to avoid letting it fall into another part of the duct. The next step in CBDE is to irrigate the duct generously with saline. Small stones, sludge, and debris can be flushed into the duodenum or back into the choledochotomy opening by irrigating the ductal system. Finally, the Fogarty catheter is passed again into the duodenum, and the balloon is inflated and retracted against the papilla. Although the catheter is held in the surgeon’s dominant hand, the index and middle fingers of the other hand are placed posterior to the duodenum with the thumb anterior; this allows palpation of the duct against the wall of the catheter for any residual stones.

Postexploratory Investigations Following exploration, the surgeon must make every effort to ensure that the duct system is normal using choledochoscopy or cholangiography (see Chapter 23).

FIGURE 37A.7  A, The Fogarty catheter is attached to a syringe, and the balloon is inflated in the duodenum. B, The Fogarty catheter is retracted with the balloon against the papilla. C and D, The balloon is deflated and gently withdrawn until it slips through the papilla; the balloon is then reinflated.

Choledochoscopy Choledochoscopy is a well-established method to ensure that the duct system is normal. Modern instruments are small enough to allow visualization of the major right and left hepatic ducts and intermediate hepatic ducts and to allow visualization of the orifices of the smaller biliary radicles. Although flexible scopes carry a higher cost and are more difficult to maintain compared with rigid scopes, they allow for less traumatic choledochoscopy and are more versatile because of their increased

512

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

A

B

FIGURE 37A.8  A, The balloon is withdrawn gently, revealing the stone. B, Long forceps can be used to obstruct the common hepatic duct to prevent the stone from slipping upward.

choledochoscope.99 This can be facilitated by use of a stone basket through the working port of a flexible choledochoscope. The use of grasping or biopsy forceps should be avoided if possible because these instruments can damage the bile duct.

T-Tube Cholangiography After insertion of a T-tube and closure of the choledochotomy, T-tube cholangiography should be performed to ensure adequate clearance of the biliary system. With proper technique and use of fluoroscopy, T-tube cholangiography is an excellent tool for detecting residual stones after CBDE (Fig. 37A.10). The cystic duct stump, a possible location of residual stones, can be delineated, and incorrect placement of the T-tube can be detected to prevent complications after the operation. In case of residual stones, the T-tube has to be removed, and the duct needs to be explored again; this necessitates a second suture of the CBD, which is a disadvantage of T-tube cholangiography.

FIGURE 37A.9  Angled traction on the Fogarty catheter can result in tearing of the lower end of the choledochotomy.

length. Flexible scopes also allow the introduction of therapeutic instruments through the working channel. Some surgeons experienced in choledochoscopy recommend exploration of the CBD and removal of stones under direct vision by using the

T-TUBE DRAINAGE. The standard practice is to use a T-tube to allow spasm or edema of the sphincter to settle after the trauma of the exploration. Failure to drain the duct might theoretically result in a buildup of pressure in the extrahepatic ductal system and cause leakage at the disruption of the closure of the duct, along with biliary peritonitis. As noted earlier in this chapter, several series have not found any decreased risk for bile leak with placement of a T-tube and have in fact noted increased operative times and length of stay.81 Routine use of a T-tube has, therefore, been questioned. The main role of T-tube placement, therefore, is not to prevent a bile leak but rather to allow an avenue for subsequent treatment of retained stones in highrisk patients. In the event of a retained stone, the T-tube can be useful later for interventional radiologic techniques through the tract created by the tube (Fig. 37A.11) or even direct choledochoscopy. The size of the T-tube should be adapted to the

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

513

diameter of the CBD, and 14-Fr is the smallest size that should be used. Use of a smaller tube will not result in a satisfactory tract for subsequent interventional radiology procedures. T-TUBE PLACEMENT. First, the limbs of the T-tube must be shortened (Fig. 37A.12A). T-tubes can become obstructed, particularly if they are tight fitting, and they can be difficult to extract. This situation can be avoided by cutting off a strip of the wall (see Fig. 37A.12B). The practice of dividing the back wall of the T-tube makes subsequent interventional radiology more difficult because the guidewire lodges in the posterior defect. This problem can be avoided by making the length of the T-tube appropriate or by limiting the division of the T-tube. The modified T-tube is held in Desjardin forceps, which conveniently grasps the T-junction of the tube, allowing it to be slipped into the choledochotomy (Fig. 37A.13). The long limb of the tube is placed at the lower end of the opening, and repair is begun just above the upper apex of the incision by using continuous or interrupted absorbable fine sutures. The final stitch should close the opening against the T-tube (Fig. 37A.14).

FIGURE 37A.10  A postexploration T-tube cholangiogram identifies a residual stone (arrow) in the intrahepatic bile ducts that was missed during operative exploration of the bile duct.

A

AVOIDING PROBLEMS IN THE CLOSURE OF THE CHOLEDOCHOTOMY. When closing the choledochotomy over a T-tube, care must be taken to ensure that the wall of the T-tube is not caught in one of the sutures or accidentally affixed to the CBD wall. If this occurs, there is a risk of laceration of the CBD when the T-tube is eventually removed. The proximal limb of the T-tube should be shortened so that it does not enter and obstruct one of the hepatic ducts (Fig. 37A.15). The distal limb should be similarly shortened so that it does not enter the duodenum because, if

B

FIGURE 37A.11  A, Faceted retained distal common bile duct (CBD) stone on T-tube cholangiography 1 week after operation. The T-tube is inserted in the common hepatic duct above the confluence of the cystic duct. B, The retained CBD stone is ensnared in the wire basket before extraction. This stone measured 5 mm in diameter and was extracted intact through the sinus tract of a 14-Fr T-tube.

514

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

6 cm

A

B

FIGURE 37A.12  A, The T-tube is modified by shortening the limbs to prevent proximal obstruction and distal entry into the duodenum. B, A T-tube is modified by removing half the diameter to prevent obstruction and enable easy removal.

FIGURE 37A.13  The T-tube is introduced by Desjardin forceps.

FIGURE 37A.14  The choledochotomy closure is begun above, with the T-tube emerging at the lower end of the repair.

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

A

B

515

C

FIGURE 37A.15  A, The suture must not catch the tube as shown here. B, The T-tube limb should not enter the hepatic duct, as shown here. C, The distal end of the T-tube should not enter the duodenum, as shown here.

FIGURE 37A.16  The T-tube should be brought out lateral to the wound, and a closed-suction drain should be placed in the hepatorenal space beneath the liver.

the tube does, it can act as a siphon. Furthermore, a tube extending through the papillary orifice may incite pancreatitis. The correct position of the T-tube is with the long limb emerging under the costal margin laterally (Fig. 37A.16). This position facilitates radiologic techniques for later postoperative removal of stones should this be necessary. A suction drain is placed on the right, within the abdomen as high as possible in the hepatorenal pouch. POSTOPERATIVE MANAGEMENT. Initially, bile is allowed to drain freely into a bile bag to allow any spasm or edema of the sphincter to settle before testing the suture line of the choledochotomy. The volume drained externally should decrease as the bile flow through the ampulla improves. Persistently elevated

volume of externally drained bile should raise concerns for continued distal obstruction or to the distal T-tube limb lying within the duodenum. Similarly, there is a problem if there is no external drainage of the bile or if bile drains around the Ttube, and may indicate that the tube is blocked or dislodged from the duct. Issues with T-tube drainage should be evaluated by T-tube cholangiography. If cholangiography does not reveal any issues, management is aimed at waiting for the bile to flow easily through the papilla into the duodenum. The T-tube should be left to external gravity drainage until this occurs. Once it appears that bile is flowing into the duodenum, a T-tube cholangiogram can be taken about 5 to 7 days postoperatively. If it appears normal, the tube is removed on day 7 or 8 by gentle traction. If there are residual stones or unclear findings on T-tube cholangiography in the first 1 to 2 weeks after surgery, intervention does not necessarily need to be undertaken unless the patient has signs of cholangitis or rising bilirubin. A repeat cholangiogram several days later will often show spontaneous passage of the stone. If a stone is still seen in an otherwise well patient, the patient can safely be sent home with a sealed drainage system and instructions to open the drain to a bag in the event of any problems. After about 5 weeks, further cholangiography is carried out. If the stone is still present, it is extracted via interventional radiology or endoscopic papillotomy (Fig. 37A.17).

Transduodenal Sphincteroplasty The role of transduodenal sphincteroplasty in the treatment of choledocholithiasis centers predominantly around management of impacted stones at the ampulla. It also has a role in treating patients with anatomy that prevents ES (e.g., Billroth II gastrectomy), failures of ES, and sometimes in patients with pancreatitis where a drainage procedure of the duct of Wirsung is indicated.104 Similarly, hydatid cyst remnants and membranes can be readily extracted from the CBD. Exploration may extend to the left and right hepatic ducts, and angled Randall forceps are useful for this purpose.

516

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

FIGURE 37A.17  Balloon extraction of a single stone (arrow).

Sphincteroplasty consists of suturing the outer edge or both edges of a surgical sphincterotomy to avoid possible future stenosis of the incision. The stitches achieve hemostasis of the incision margins and help to avoid possible leakage of the duodenal contents should the excision extend beyond the common portion of the sphincter, incurring the risk of retroduodenal perforation. Transduodenal sphincteroplasty is contraindicated in the presence of a large CBD (.2 cm) or where there is a long suprasphincteric stricture. It also should not be attempted in the presence of a duodenal diverticulum or where there is severe periampullary inflammation.

Indications The most common indications for transduodenal sphincteroplasty relate to bile duct stones and cholangitis (see Chapter 43). STONES IMPACTED IN THE DISTAL AMPULLARY REGION. An impacted stone is often readily palpable, and the incision may be made safely using the stone as a guide. In such cases, extraction through a supraduodenal choledochotomy is often impossible without undue risk of creating a false passage and without significant risk of postoperative pancreatitis. MULTIPLE AND RECURRENT COMMON BILE DUCT STONES. In cases of multiple and recurrent CBD stones, sphincteroplasty should provide long-term biliary drainage. When 20 or more stones are removed from the CBD, it is probable that one or more stones are still present.58 In this situation, choledochoduodenostomy or sphincteroplasty yields excellent results. PAPILLARY STENOSIS. Papillary stenosis is encountered less frequently than in the past. When it is found at operation, transduodenal sphincteroplasty ensures good biliary drainage and prevents

FIGURE 37A.18  A section of the sphincter of Oddi. Note the distinction between the papilla, the common portion of the sphincter, and the sphincters of the common bile duct and duct of Wirsung.

restenosis.105 ES is technically successful in only 60% to 80% of cases, and the mortality rate exceeds 1%.106 In addition, sphincterotomy for papillary stenosis is five times more likely to lead to restenosis than if the same procedure is performed for calculi.107 PYOGENIC CHOLANGITIS (SEE CHAPTER 43). If papillary stenosis or CBD stones or both exist together with cholangitis, transduodenal sphincteroplasty can be an excellent procedure for definitive biliary drainage. CHRONIC PANCREATITIS AND ACUTE GALLSTONE PANCREATITIS (SEE CHAPTERS 55–58). In chronic pancreatitis, some authors report good long-term results with transduodenal sphincteroplasty alone108 or in addition to transpapillary septectomy109 or with other drainage procedures of the duct of Wirsung.110 The presence of a stone at the lower end of the CBD or pancreatic duct may cause biliary pancreatitis, and transduodenal sphincteroplasty with clearance of the CBD is a treatment option.

Technique Sphincteroplasty consists of the incision of the common portion of the sphincter of Oddi (Fig. 37A.18) with partial suture of the incision margin. Using this procedure, the sphincters of the CBD and the duct of Wirsung are not involved, and their functions are not impaired. The procedure also can be called a subtotal lower sphincteroplasty (Fig. 37A.19).111 The approach to the sphincter of Oddi is through a minimal duodenotomy in the second part of the duodenum.

Preparation, Position of the Patient, and Incision Preoperative preparation is routine. The patient is placed in a supine position on a radiotransparent operating table. A transverse incision below the right costal margin is preferred.112 This

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

FIGURE 37A.19  Subtotal lower sphincteroplasty involves only the papilla, whereas the common bile duct and the duct of Wirsung are preserved.

517

FIGURE 37A.20  Transverse subcostal incision offers excellent exposure with a low incidence of postoperative incisional hernia.

incision allows optimal light and excellent access; it is particularly suitable in obese patients, and the incidence of postoperative incisional hernia is probably lower than with vertical and oblique incisions. The incision of the abdominal wall follows a transverse line, from the midaxillary to the median line at the level of the 11th and 12th ribs (Fig. 37A.20).

Preparation of the Operative Field and Exposure The abdomen is opened, and a large retractor is positioned at the upper margin of the wound. The hepatic flexure of the colon is displaced inferiorly, and the stomach is displaced to the left by means of two surgical pads. Viscera are maintained in this position with two large, curved retractors. For the performance of the sphincteroplasty, extended mobilization of the duodenum and pancreas (Kocher maneuver) is mandatory.109 The assistant surgeon displaces the second portion medially and forward, and the peritoneum is incised posteriorly along the curved lateral margin of the duodenum. The mesocolon of the right colic flexure is mobilized and retracted inferiorly. At this point, the assistant surgeon also should displace the duodenum superiorly (Fig. 37A.21). Access is provided to the avascular space between the posterior aspect of the head of the pancreas anteriorly and the perinephric fat and inferior vena cava posteriorly; elevation of the structures should reach the left margin of the inferior vena cava. It is important to expose and mobilize the third portion of the duodenum to allow easy access to the papilla and for closure of the duodenotomy without tension (see Fig. 37A.21).

Duodenotomy Duodenotomy is performed in the lateral duodenal wall by surgical diathermy. The cut is 10 to 15 mm long immediately above

FIGURE 37A.21  It is important to expose and mobilize the third portion of the duodenum to easily identify and operate on the papilla and allow facile closure of the duodenotomy.

518

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

2

3

15 mm 1

3

FIGURE 37A.22  The duodenotomy is performed above the junction of the second and third portions of the duodenum; the surgeon takes into account that the papilla usually is located at the junction of the upper two-thirds and lower third of the second part of the duodenum.

FIGURE 37A.23  If the papilla is not easily seen, it can often be palpated as a small elevation in the medial duodenal wall. If the papilla is still not easily seen, a small Nélaton catheter is introduced through the cystic duct stump until it is seen to protrude from the papillary orifice. The forefinger, introduced through the duodenotomy, detects the papilla as a small, thick elevation.

the inferior knee of the duodenum, with the surgeon taking account of the fact that the papilla usually is located at the junction of the lower third with the upper two-thirds of the second portion of the duodenum (Fig. 37A.22). The duodenal incision may be longitudinal or transverse; both types are suitable, provided that the suture of such incisions is always transverse. We prefer a longitudinal incision, because if the retractor on the duodenum widens the duodenotomy, this occurs longitudinally. In the case of a transverse duodenotomy, any inadvertent extension would cause a transverse enlargement of the wound.

Identification of the Papilla After the duodenal incision, the papilla is readily shown on the medial duodenal wall in 15% to 20% of patients. It appears as a roundish elevation with a central orifice. When the papilla is not readily visible, it should be detected by displacement and flattening of the mucosal folds. This should be done with great care to avoid tearing of the mucosa, which would hinder good exposure. Identification of the papilla under direct vision is possible in 80% of patients. If this is not the case, digital palpation can be used running the forefinger, introduced through the duodenotomy, across the medial duodenal wall. The papilla is identified as a small elevation. If digital palpation fails, a small (5- to 6-Fr) Nélaton catheter can be introduced via the cystic duct stump and advanced downward to emerge at the papilla (Fig. 37A.23). This maneuver should never be performed with rigid catheters because this may result in the formation of false passages. Sometimes a very small papilla is detected, and its catheterization is difficult or impossible. In such cases, the orifice is probably that of the duct of Santorini. The major papilla should be searched for in a lower position.

Sphincteroplasty After the papilla has been identified, it is exposed by gentle extraction with an Allis or similar clamp. This clamp is applied

FIGURE 37A.24  The duodenotomy is kept open by a suitable retractor placed in the upper margin of the duodenal incision. The papilla is exposed by gentle traction with an Allis clamp placed laterally, never medially, to avoid trauma to the duct of Wirsung.

laterally, never medially, to avoid trauma to the duct of Wirsung (Fig. 37A.24).113 A Nélaton catheter (4- to 5-Fr) is introduced from the outside or via the cystic duct. Following the line of the catheter and avoiding plastic catheters, which melt when surgical

A. Gallstones and Gallbladder  Chapter 37A  Stones in the Bile Duct: Clinical Features and Open Surgical Approaches and Techniques

FIGURE 37A.25  With a Nélaton catheter as a guide, a cut is made using surgical diathermy on the medial wall of the duodenum extending superiorly and slightly externally (11 o’clock position). With diathermy, good hemostasis is achieved.

diathermy is applied, the surgeon makes a cut using surgical diathermy. This cut is made superiorly (at the 11 o’clock position) for 4 to 5 mm (Fig. 37A.25). We prefer surgical diathermy because the instrument ensures good hemostasis. When a sample for biopsy is required, it should be obtained with a scalpel and be taken only from the outer margin of the incision. Possible bleeding from the cut, usually modest, can be arrested with a stitch. After sphincterotomy, two or three stitches are placed between the duodenal mucosa and the wall of the CBD on the outer margin by using an atraumatic needle and fine sutures. Traction is applied to these sutures, and incision of the sphincter is extended for another 6 to 7 mm with sutures placed every 2 to 3 mm, all laterally, until the entire common tract of the sphincter of Oddi has been incised (Fig. 37A.26). The incision is complete when it is 10 to 12 mm long and an appropriate forceps can be easily introduced (Fig. 37A.27). Its entry into the CBD allows an abundant flow of bile because of distension of its sphincter. Sutures should be placed only on the outer margin of the sphincterotomy to prevent the risk of damage to the duct of Wirsung. The opening of the duct of Wirsung usually is identified as a small orifice from which clear, colorless pancreatic juice flows.

Instrumental Exploration of the Common Bile Duct After sphincteroplasty, instrumental exploration of the CBD and extraction of stones is performed.114 An angled Randall forceps is introduced into the CBD, and the bile duct is carefully explored. The maneuver should be repeated several times to extract all stones. The next step is to rinse with saline solution, introduced under slight pressure with a Nélaton catheter (8- to 9-Fr) and abruptly withdrawn so that small fragments flow downstream with the siphoning (Fig. 37A.28). Other means to extract stones from the CBD are with a Fogarty catheter and Dormia basket. The problem of residual stones is best

519

FIGURE 37A.26  After sphincterectomy is performed, several stitches are placed between the duodenal mucosa and the wall of the common bile duct (CBD) by using an atraumatic needle and 3-0 suture. Sutures should be placed only on the outer margin of the sphincterotomy to avoid the risk of damaging the duct of Wirsung, which in its distal portion runs inferiorly and medially along the length of the CBD.

FIGURE 37A.27  Sphincteroplasty is completed when the incision is 10 to 21 mm long, and a Randall forceps can be introduced easily into the common bile duct to extract stones or other foreign bodies.

prevented with choledochoscopy; the endoscope is introduced via the sphincteroplasty.

Duodenal Closure As already emphasized, initial longitudinal duodenotomy should be closed transversely to avoid stenosis of the duodenum. A number of approaches to the closure exist including linear stapling, a running inverting suture line, and interrupted single

520

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

layer closure. The suture should not be under tension, and for this reason, preliminary extended mobilization of the duodenum and pancreas is mandatory. The operation is now complete, and the wound is closed without abdominal drains.

Comment It is not necessary to perform transduodenal sphincteroplasty combined with supraduodenal choledochotomy, which has a higher associated mortality rate.115 The cystic duct remnant may be used to introduce a Nélaton catheter to assist recognition of the papilla. There is no need to insert a T-tube, which lengthens the hospital stay and may predispose the patient to stenosis and infection of the CBD.115,116

Review of Reported Results

50 mL FIGURE 37A.28  After the extraction of stones, the common bile duct is rinsed with saline solution introduced under slight pressure with a Nélaton catheter and with subsequent siphoning so that small fragments can run downstream.

A

B

In a retrospective analysis of 25,541 transduodenal sphincteroplasties performed by 130 surgeons in different countries, early transduodenal sphincteroplasty–related complications were bleeding (0.65%), acute pancreatitis (0.60%), dehiscence of the duodenal closure (0.55%), and cholangitis (0.50%), for an overall morbidity rate of 2.3% and a mortality rate of 0.8%.117 A retrospective study found that the factors affecting mortality in 2.1% of 333 patients (but only in 0.9% for sphincterectomyrelated complications) were older than 70 years of age, and had a bilirubin level greater than 85 mmol/L, diabetes, renal failure, and coagulopathy. The mortality rate increased when supraduodenal choledochotomy was combined with transduodenal sphincteroplasty and when a T-tube was used.118 Transduodenal sphincteroplasty alone108 or associated with transampullary septectomy119 has led to good long-term results in patients with chronic and acute recurrent pancreatitis, even in cases with pancreas divisum and in selected patients with abdominal pain of hepatobiliary origin. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

C

FIGURE 37A.29  The duodenotomy always should be closed transversely to avoid stenosis of the duodenum. A, The superior and inferior angles are approximated. B, The resulting lateral gaps are sutured with two extramucosal nonabsorbable purse-string sutures. C, Three to four nonabsorbable seromuscular stitches are added as a second layer. The sutures should not be under tension.

520.e1

REFERENCES 1. Gonzalez JJ, Sanz L, Grana JL, Bermejo G, Navarrete F, Martinez E. Biliary lithiasis in the elderly patient: morbidity and mortality due to biliary surgery. Hepatogastroenterology. 1997;44(18):1565-1568. 2. Hammarstrom LE, Holmin T, Stridbeck H, Ihse I. Long-term follow-up of a prospective randomized study of endoscopic versus surgical treatment of bile duct calculi in patients with gallbladder in situ. Br J Surg. 1995;82(11):1516-1521. 3. Neoptolemos JP, Carr-Locke DL, Fossard DP. Prospective randomised study of preoperative endoscopic sphincterotomy versus surgery alone for common bile duct stones. Br Med J (Clin Res Ed). 1987;294(6570):470-474. 4. Targarona EM, Ayuso RM, Bordas JM, et al. Randomised trial of endoscopic sphincterotomy with gallbladder left in situ versus open surgery for common bileduct calculi in high-risk patients. Lancet. 1996;347(9006):926-929. 5. Sirinek KR, Willis R, Schwesinger WH. Who will be able to perform open biliary surgery in 2025? J Am Coll Surg. 2016;223(1):110-115. 6. Bingener J, Schwesinger WH. Management of common bile duct stones in a rural area of the United States: results of a survey. Surg Endosc. 2006;20(4):577-579. 7. Gilsdorf D, Henrichsen J, Liljestrand K, et al. Laparoscopic common bile duct exploration for choledocholithiasis: analysis of practice patterns of Intermountain HealthCare. J Am Coll Surg. 2018;226(6):1160-1165. 8. Frazee R, Regner J, Truitt MS, et al. The southwestern surgical congress multi-center trial on suspected common duct stones. Am J Surg. 2019;217(6):1006-1009. 9. Kim MH, Sekijima J, Lee SP. Primary intrahepatic stones. Am J Gastroenterol. 1995;90(4):540-548. 10. Johnson AG, Hosking SW. Appraisal of the management of bile duct stones. Br J Surg. 1987;74(7):555-560. 11. Caddy GR, Tham TC. Gallstone disease: symptoms, diagnosis and endoscopic management of common bile duct stones. Best Pract Res Clin Gastroenterol. 2006;20(6):1085-1101. 12. Coelho JC, Buffara M, Pozzobon CE, Altenburg FL, Artigas GV. Incidence of common bile duct stones in patients with acute and chronic cholecystitis. Surg Gynecol Obstet. 1984;158(1):76-80. 13. DenBesten L, Berci G. The current status of biliary tract surgery: an international study of 1072 consecutive patients. World J Surg. 1986;10(1):116-122. 14. Doyle PJ, Ward-McQuaid JN, Smith AM. The value of routine peroperative cholangiography—a report of 4000 cholecystectomies. Br J Surg. 1982;69(10):617-619. 15. Ganey JB, Johnson Jr PA, Prillaman PE, McSwain GR. Cholecystectomy: clinical experience with a large series. Am J Surg. 1986; 151(3):352-357. 16. Girard RM, Legros G. Retained and recurrent bile duct stones. Surgical or nonsurgical removal? Ann Surg. 1981;193(2):150-154. 17. Lygidakis NJ. Incidence and significance of primary stones of the common bile duct in choledocholithiasis. Surg Gynecol Obstet. 1983;157(5):434-436. 18. McSherry CK, Glenn F. The incidence and causes of death following surgery for nonmalignant biliary tract disease. Ann Surg. 1980; 191(3):271-275. 19. Fogli L, Boschi S, Patrizi P, et al. Laparoscopic cholecystectomy without intraoperative cholangiography: audit of long-term results. J Laparoendosc Adv Surg Tech A. 2009;19(2):191-193. 20. Collins C, Maguire D, Ireland A, Fitzgerald E, O’Sullivan GC. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: natural history of choledocholithiasis revisited. Ann Surg. 2004;239(1):28-33. 21. Peng WK, Sheikh Z, Paterson-Brown S, Nixon SJ. Role of liver function tests in predicting common bile duct stones in acute calculous cholecystitis. Br J Surg. 2005;92(10):1241-1247. 22. Sgourakis G, Dedemadi G, Stamatelopoulos A, Leandros E, Voros D, Karaliotas K. Predictors of common bile duct lithiasis in laparoscopic era. World J Gastroenterol. 2005;11(21):3267-3272. 23. Amouyal P, Amouyal G, Levy P, et al. Diagnosis of choledocholithiasis by endoscopic ultrasonography. Gastroenterology. 1994; 106(4):1062-1067. 24. Sugiyama M, Atomi Y. Endoscopic ultrasonography for diagnosing choledocholithiasis: a prospective comparative study with ultrasonography and computed tomography. Gastrointest Endosc. 1997; 45(2):143-146.

25. Alponat A, Kum CK, Rajnakova A, Koh BC, Goh PM. Predictive factors for synchronous common bile duct stones in patients with cholelithiasis. Surg Endosc. 1997;11(9):928-932. 26. Koo KP, Traverso LW. Do preoperative indicators predict the presence of common bile duct stones during laparoscopic cholecystectomy? Am J Surg. 1996;171(5):495-499. 27. Trondsen E, Edwin B, Reiertsen O, Faerden AE, Fagertun H, Rosseland AR. Prediction of common bile duct stones prior to cholecystectomy: a prospective validation of a discriminant analysis function. Arch Surg. 1998;133(2):162-166. 28. Liu TH, Consorti ET, Kawashima A, et al. Patient evaluation and management with selective use of magnetic resonance cholangiography and endoscopic retrograde cholangiopancreatography before laparoscopic cholecystectomy. Ann Surg. 2001;234(1):33-40. 29. Committee ASoP, Buxbaum JL, Abbas Fehmi SM, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89(6): 1075-1105.e15. 30. Cabada Giadas T, Sarria Octavio de Toledo L, Martinez-Berganza Asensio MT, et al. Helical CT cholangiography in the evaluation of the biliary tract: application to the diagnosis of choledocholithiasis. Abdom Imaging. 2002;27(1):61-70. 31. Maniatis P, Triantopoulou C, Sofianou E, et al. Virtual CT cholangiography in patients with choledocholithiasis. Abdom Imaging. 2003;28(4):536-544. 32. Anderson SW, Rho E, Soto JA. Detection of biliary duct narrowing and choledocholithiasis: accuracy of portal venous phase multidetector CT. Radiology. 2008;247(2):418-427. 33. Gibson RN, Vincent JM, Speer T, Collier NA, Noack K. Accuracy of computed tomographic intravenous cholangiography (CT-IVC) with iotroxate in the detection of choledocholithiasis. Eur Radiol. 2005;15(8):1634-1642. 34. Kim HJ, Park DI, Park JH, et al. Multidetector computed tomography cholangiography with multiplanar reformation for the assessment of patients with biliary obstruction. J Gastroenterol Hepatol. 2007;22(3):400-405. 35. Kondo S, Isayama H, Akahane M, et al. Detection of common bile duct stones: comparison between endoscopic ultrasonography, magnetic resonance cholangiography, and helical-computed-tomographic cholangiography. Eur J Radiol. 2005;54(2):271-275. 36. Polkowski M, Palucki J, Regula J, Tilszer A, Butruk E. Helical computed tomographic cholangiography versus endosonography for suspected bile duct stones: a prospective blinded study in nonjaundiced patients. Gut. 1999;45(5):744-749. 37. Soto JA, Alvarez O, Munera F, Velez SM, Valencia J, Ramirez N. Diagnosing bile duct stones: comparison of unenhanced helical CT, oral contrast-enhanced CT cholangiography, and MR cholangiography. AJR Am J Roentgenol. 2000;175(4):1127-1134. 38. Zandrino F, Curone P, Benzi L, Ferretti ML, Musante F. MR versus multislice CT cholangiography in evaluating patients with obstruction of the biliary tract. Abdom Imaging. 2005;30(1):77-85. 39. Chopra S, Chintapalli KN, Ramakrishna K, Rhim H, Dodd GD III. Helical CT cholangiography with oral cholecystographic contrast material. Radiology. 2000;214(2):596-601. 40. Wallner BK, Schumacher KA, Weidenmaier W, Friedrich JM. Dilated biliary tract: evaluation with MR cholangiography with a T2-weighted contrast-enhanced fast sequence. Radiology. 1991;181(3):805-808. 41. Hallal AH, Amortegui JD, Jeroukhimov IM, et al. Magnetic resonance cholangiopancreatography accurately detects common bile duct stones in resolving gallstone pancreatitis. J Am Coll Surg. 2005;200(6):869-875. 42. Shanmugam V, Beattie GC, Yule SR, Reid W, Loudon MA. Is magnetic resonance cholangiopancreatography the new gold standard in biliary imaging? Br J Radiol. 2005;78(934):888-893. 43. Taylor AC, Little AF, Hennessy OF, Banting SW, Smith PJ, Desmond PV. Prospective assessment of magnetic resonance cholangiopancreatography for noninvasive imaging of the biliary tree. Gastrointest Endosc. 2002;55(1):17-22. 44. Topal B, Van de Moortel M, Fieuws S, et al. The value of magnetic resonance cholangiopancreatography in predicting common bile duct stones in patients with gallstone disease. Br J Surg. 2003;90(1):42-47. 45. Verma D, Kapadia A, Eisen GM, Adler DG. EUS vs MRCP for detection of choledocholithiasis. Gastrointest Endosc. 2006;64(2): 248-254.

520.e2 46. Varghese JC, Liddell RP, Farrell MA, Murray FE, Osborne DH, Lee MJ. Diagnostic accuracy of magnetic resonance cholangiopancreatography and ultrasound compared with direct cholangiography in the detection of choledocholithiasis. Clin Radiol. 2000; 55(1):25-35. 47. Behrns KE, Ashley SW, Hunter JG, Carr-Locke D. Early ERCP for gallstone pancreatitis: for whom and when? J Gastrointest Surg. 2008;12(4):629-633. 48. Petrov MS, van Santvoort HC, Besselink MG, van der Heijden GJ, van Erpecum KJ, Gooszen HG. Early versus conservative management in acute biliary pancreatitis without cholangitis: a metaanalysis of randomized trials. Ann Surg. 2008;247(2):250-257. 49. Bhat M, Romagnuolo J, da Silveira E, et al. Randomised clinical trial: MRCP-first vs. ERCP-first approach in patients with suspected biliary obstruction due to bile duct stones. Aliment Pharmacol Ther. 2013;38(9):1045-1053. 50. Demartines N, Eisner L, Schnabel K, Fried R, Zuber M, Harder F. Evaluation of magnetic resonance cholangiography in the management of bile duct stones. Arch Surg. 2000;135(2):148-152. 51. Amouyal P, Palazzo L, Amouyal G, et al. Endosonography: promising method for diagnosis of extrahepatic cholestasis. Lancet. 1989;2(8673):1195-1198. 52. Edmundowicz SA, Aliperti G, Middleton WD. Preliminary experience using endoscopic ultrasonography in the diagnosis of choledocholithiasis. Endoscopy. 1992;24(9):774-778. 53. Manes G, Paspatis G, Aabakken L, et al. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2019;51(5):472-491. 54. Giljaca V, Gurusamy KS, Takwoingi Y, et al. Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. Cochrane Database Syst Rev. 2015(2):CD011549. 55. Petrov MS, Savides TJ. Systematic review of endoscopic ultrasonography versus endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis. Br J Surg. 2009;96(9):967-974. 56. Heinerman PM, Boeckl O, Pimpl W. Selective ERCP and preoperative stone removal in bile duct surgery. Ann Surg. 1989;209(3): 267-272. 57. Neoptolemos JP, Carr-Locke DL, London NJ, Bailey IA, James D, Fossard DP. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet. 1988;2(8618):979-983. 58. Stain SC, Cohen H, Tsuishoysha M, Donovan AJ. Choledocholithiasis. Endoscopic sphincterotomy or common bile duct exploration. Ann Surg. 1991;213(6):627-633; discussion 633-634. 59. Dasari BV, Tan CJ, Gurusamy KS, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013(12): CD003327. 60. Cuschieri A, Lezoche E, Morino M, et al. E.A.E.S. multicenter prospective randomized trial comparing two-stage vs single-stage management of patients with gallstone disease and ductal calculi. Surg Endosc. 1999;13(10):952-957. 61. Rogers SJ, Cello JP, Horn JK, et al. Prospective randomized trial of LC1LCBDE vs ERCP/S1LC for common bile duct stone disease. Arch Surg. 2010;145(1):28-33. 62. Andriulli A, Loperfido S, Napolitano G, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol. 2007;102(8):1781-1788. 63. Cotton PB. Endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy. Am J Surg. 1993;165(4):474-478. 64. Davis WZ, Cotton PB, Arias R, Williams D, Onken JE. ERCP and sphincterotomy in the context of laparoscopic cholecystectomy: academic and community practice patterns and results. Am J Gastroenterol. 1997;92(4):597-601. 65. DeIorio Jr AV, Vitale GC, Reynolds M, Larson GM. Acute biliary pancreatitis. The roles of laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography. Surg Endosc. 1995; 9(4):392-396. 66. Ponsky JL. Endoscopic management of common bile duct stones. World J Surg. 1992;16(6):1060-1065. 67. Kochar B, Akshintala VS, Afghani E, et al. Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials. Gastrointest Endosc. 2015;81(1): 143-149.e9. 68. Cuschieri A, Croce E, Faggioni A, et al. EAES ductal stone study. Preliminary findings of multi-center prospective randomized trial

comparing two-stage vs single-stage management. Surg Endosc. 1996;10(12):1130-1135. 69. Leung JW. Does the addition of endoscopic sphincterotomy to stent insertion improve drainage of the bile duct in acute suppurative cholangitis? Gastrointest Endosc. 2003;58(4):570-572. 70. Iranmanesh P, Frossard JL, Mugnier-Konrad B, et al. Initial cholecystectomy vs sequential common duct endoscopic assessment and subsequent cholecystectomy for suspected gallstone migration: a randomized clinical trial. JAMA. 2014;312(2):137-144. 71. Dasari BV, Tan CJ, Gurusamy KS, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013(9): CD003327. 72. Roslyn JJ, Binns GS, Hughes EF, Saunders-Kirkwood K, Zinner MJ, Cates JA. Open cholecystectomy. A contemporary analysis of 42,474 patients. Ann Surg. 1993;218(2):129-137. 73. Bergdahl L, Holmlund DE. Retained bile duct stones. Acta Chir Scand. 1976;142(2):145-149. 74. Dayton MT, Conter R, Tompkins RK. Incidence of complications with operative choledochoscopy. Am J Surg. 1984;147(1):139-145. 75. Kappes SK, Adams MB, Wilson SD. Intraoperative biliary endoscopy. Arch Surg. 1982;117(5):603-607. 76. Saharia PC, Zuidema GD, Cameron JL. Primary common duct stones. Ann Surg. 1977;185(5):598-604. 77. Way LW. Retained common duct stones. Surg Clin North Am. 1973;53(5):1139-1147. 78. Allen B, Shapiro H, Way LW. Management of recurrent and residual common duct stones. Am J Surg. 1981;142(1):41-47. 79. Dong ZT, Wu GZ, Luo KL, Li JM. Primary closure after laparoscopic common bile duct exploration versus T-tube. J Surg Res. 2014;189(2):249-254. 80. El-Geidie AA. Is the use of T-tube necessary after laparoscopic choledochotomy? J Gastrointest Surg. 2010;14(5):844-848. 81. Gurusamy KS, Koti R, Davidson BR. T-tube drainage versus primary closure after open common bile duct exploration. Cochrane Database Syst Rev. 2013(6):CD005640. 82. Mazzariello RM. A fourteen-year experience with nonoperative instrument extraction of retained bile duct stones. World J Surg. 1978;2(4):447-455. 83. Burhenne HJ. Garland lecture. Percutaneous extraction of retained biliary tract stones: 661 patients. AJR Am J Roentgenol. 1980; 134(5):889-898. 84. O’Doherty DP, Neoptolemos JP, Carr-Locke DL. Endoscopic sphincterotomy for retained common bile duct stones in patients with T-tube in situ in the early postoperative period. Br J Surg. 1986;73(6): 454-456. 85. Lambert ME, Martin DF, Tweedle DE. Endoscopic removal of retained stones after biliary surgery. Br J Surg. 1988;75(9):896-898. 86. Christoforidis E, Vasiliadis K, Goulimaris I, Botsios D, Tsorlini H, Betsis D. Endoscopic management of retained bile stones with an indwelling T-tube. Surg Endosc. 2004;18(11):1582-1586. 87. Cameron JL. Retained and recurrent bile duct stones: operative management. Am J Surg. 1989;158(3):218-221. 88. Sivak Jr MV. Endoscopic management of bile duct stones. Am J Surg. 1989;158(3):228-240. 89. Escourrou J, Cordova JA, Lazorthes F, Frexinos J, Ribet A. Early and late complications after endoscopic sphincterotomy for biliary lithiasis with and without the gall bladder “in situ.” Gut. 1984;25(6):598-602. 90. Miller BM, Kozarek RA, Ryan Jr JA, Ball TJ, Traverso LW. Surgical versus endoscopic management of common bile duct stones. Ann Surg. 1988;207(2):135-141. 91. Abbas AM, Strong AT, Diehl DL, et al. Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Rouxen-Y gastric bypass. Gastrointest Endosc. 2018;87(4):1031-1039. 92. Lygidakis NJ. A prospective randomized study of recurrent choledocholithiasis. Surg Gynecol Obstet. 1982;155(5):679-684. 93. Tompkins RK, Pitt HA. Surgical management of benign lesions of the bile ducts. Curr Probl Surg. 1982;19(7):321-398. 94. Braasch JW, Fender HR, Bonneval MM. Refractory primary common bile duct stone disease. Am J Surg. 1980;139(4):526-530. 95. Johnson AG, Rains AJ. Prevention and treatment of recurrent bile duct stones by choledochoduodenostomy. World J Surg. 1978;2(4): 487-496. 96. Jones SA. The prevention and treatment of recurrent bile duct stones by transduodenal sphincteroplasty. World J Surg. 1978;2(4): 473-485.

520.e3 97. Okamoto H, Miura K, Itakura J, Fujii H. Current assessment of choledochoduodenostomy: 130 consecutive series. Ann R Coll Surg Engl. 2017;99(7):545-549. 98. Kays JK, Koniaris LG, Milgrom DP, Nakeeb A. Biliary bypass with laparoscopic choledochoduodenostomy. J Gastrointest Surg. 2018; 22(5):928-933. 99. Blumgart LH. Surgery of the liver and biliary tract. New York: Churchill Livingstone; 1988. 100. Nora PF, Berci G, Dorazio RA, et al. Operative choledochoscopy. Results of a prospective study in several institutions. Am J Surg. 1977;133(1):105-110. 101. Orloff MJ. Importance of surgical technique in prevention of retained and recurrent bile duct stones. World J Surg. 1978;2(4):403-410. 102. Fogarty TJ, Krippaehine WM, Dennis DL, Fletcher WS. Evaluation of an improved operative technic in common duct surgery. Am J Surg. 1968;116(2):177-183. 103. Fox JN, Gunn AA. Common bile duct exploration by a balloon catheter. J R Coll Surg Edinb. 1984;29(2):81-84. 104. Lehman GA, Sherman S. Diagnosis and therapy of pancreas divisum. Gastrointest Endosc Clin N Am. 1998;8(1):55-77. 105. Ramirez P, Parrilla P, Bueno FS, et al. Choledochoduodenostomy and sphincterotomy in the treatment of choledocholithiasis. Br J Surg. 1994;81(1):121-123. 106. Seifert E, Gail K, Weismuller J. [Long term results after endoscopic sphincterotomy]. Dtsch Med Wochenschr. 1982;107(16):610-614. 107. Tzovaras G, Rowlands BJ. Diagnosis and treatment of sphincter of Oddi dysfunction. Br J Surg. 1998;85(5):588-595. 108. Hakaim AG, Broughan TA, Vogt DP, Hermann RE. Long-term results of the surgical management of chronic pancreatitis. Am Surg. 1994;60(5):306-308. 109. Moody FG, Becker JM, Potts JR. Transduodenal sphincteroplasty and transampullary septectomy for postcholecystectomy pain. Ann Surg. 1983;197(5):627-636.

110. Kestens PJ, Gigot JF, Foxius A, Collard A, Gianello P. [Surgical treatment of chronic pancreatitis with predominant cephalic involvement by double Wirsung duct diversion and restoration of permeability of the cephalic duct]. Ann Chir. 1996;50(10): 853-860; discussion 861-864. 111. Stefanini P, Carboni M, De Bernardinis G, Negro P. Transduodenal sphincteroplasty. Int Surg. 1977;62(8):414-417. 112. Vogt DP, Hermann RE. Choledochoduodenostomy, choledochojejunostomy or sphincteroplasty for biliary and pancreatic disease. Ann Surg. 1981;193(2):161-168. 113. Partington PF. Twenty-three years of experience with sphincterotomy and sphincteroplasty for stenosis of the sphincter of Oddi. Surg Gynecol Obstet. 1977;145(2):161-168. 114. Speranza V, Lezoche E, Minervini S, Carlei F, Basso N, Simi M. Transduodenal papillostomy as a routine procedure in managing choledocholithiasis. Arch Surg. 1982;117(7):875-877. 115. Sheridan WG, Williams HO, Lewis MH. Morbidity and mortality of common bile duct exploration. Br J Surg. 1987;74(12): 1095-1099. 116. Ratych RE, Sitzmann JV, Lillemoe KD, Yeo CJ, Cameron JL. Transduodenal exploration of the common bile duct in patients with nondilated ducts. Surg Gynecol Obstet. 1991;173(1):49-53. 117. Negro P, Tuscano D, Flati D, Flati G, Carboni M. [Surgical risk of the Oddi sphincterotomy. Results of an international survey (25541 cases)]. J Chir (Paris). 1984;121(2):133-139. 118. Sellner FJ, Wimberger M, Jelinek R. Factors affecting mortality in transduodenal sphincteroplasty. Surg Gynecol Obstet. 1988;167(1): 23-27. 119. Kelly SB, Rowlands BJ. Transduodenal sphincteroplasty and transampullary septectomy for papillary stenosis. HPB Surg. 1996; 9(4):199-207.

CHAPTER 37B Stones in the bile duct: Minimally invasive surgical approaches Michele L. Babicky and Paul D. Hansen INTRODUCTION Epidemiology of Choledocholithiasis The prevalence of cholelithiasis is approximately 15% in the general population, with up to 10% of patients having concomitant choledocholithiasis (CDL; for more information, see Chapter 33). The prevalence of gallstones is increased in the elderly population over 65 years of age, reaching up to 35% in women.1 Risk factors for gallstones include: obesity, type 2 diabetes and insulin resistance, genetic defects in cholesterol metabolism, female gender, rapid weight gain or loss (as seen with bariatric surgery and pregnancy), systemic inflammatory diseases (such as Crohn disease and rheumatoid arthritis2), hemolytic disorders, and conditions leading to biliary stasis (cystic fibrosis, chronic total parenteral nutrition [TPN], estrogen hormonal supplementation).3 The majority of common bile duct (CBD) stones in Western countries are secondary to gallstone formation within the gallbladder, with an extraordinarily higher prevalence in Native American (73%) and Hispanic (27%) populations.4 In Eastern countries, the incidence of primary hepatolithiasis and CDL is higher (see Chapter 39), with reported prevalence ranging from 2% to 25%, related to endemic infectious organisms that colonize the liver and biliary tree (e.g., Clonorchis sinensis, liver fluke; see Chapter 45) and cause a predisposition to recurrent pyogenic cholangitis5,6 (see Chapter 44). CDL is identified in up to 18% of patients undergoing cholecystectomy.7 Additionally, some patients may be asymptomatic with intra- and extrahepatic biliary dilation and/or CBD stones incidentally identified on cross-sectional imaging performed for other clinical indications. These clinical scenarios can vary significantly in presentation and morbidity, ranging from minimal symptoms to critical illness caused by septic cholangitis. If left untreated, chronic CDL can also cause inflammatory strictures, recurrent infections, or biliary cirrhosis.

Clinical Presentation The index of suspicion for the presence of CBD stones should be high in patients presenting with gallstone pancreatitis (see Chapters 54 and 55), ascending cholangitis (see Chapter 43), or obstructive jaundice in the setting of acute or chronic cholecystitis with a history of biliary colic (see Chapter 34). Hyperbilirubinemia, defined as elevation of the total bilirubin level greater than 1.3 mg/dL with a predominant unconjugated (direct) component, is most suggestive of biliary obstruction in a patient with otherwise no evidence or history of underlying liver disease (see Chapter 4). Elevation of the alkaline phosphatase (AP) levels (.150 IU/L) out of proportion to changes in the aminotransferase enzyme levels can be seen in the presence of nonobstructing stones or sludge, and an upward trend can be

indicative of ongoing cholestasis and/or inflammation of the biliary tree. Elevated gamma-glutamyl transferase levels (.50 IU/L) can confirm a hepatobiliary source of the elevated AP in complex or asymptomatic patients. Depending on the clinical presentation, first-line imaging modalities include abdominal ultrasound (most sensitive test for identifying gallstones and ductal dilation) and/or single phase abdominal CT scan (most sensitive for identifying acute cholecystitis).8,9 Intra- or extrahepatic biliary dilation, dilation of the CBD more than 8 mm, or the presence of a filling defect can be informative and guide the treatment algorithm. The caliber, number, and location of the stones combined with the clinical status of the patient will also influence treatment decisions (see Chapter 13). In patients where the diagnosis of CDL is unclear, either magnetic resonance cholangiopancreatography (MRCP; see Chapter 13) or endoscopic ultrasound (EUS; see Chapter 22) with or without endoscopic retrograde cholangiopancreatography (ERCP; see Chapter 20) can be considered. Recent metaanalyses demonstrate that both EUS and MRCP have high specificity for identifying CDL, with a slightly higher sensitivity for EUS and the added therapeutic benefit of performing ERCP if stones are identified.10–12 MRCP can be useful when ERCP is not available and may provide anatomic delineation before surgery. Some centers advocate MRCP to avoid the risk of unnecessary ERCP; however, this is associated with an increased cost. The choice of modality may depend on clinical factors of the patient. For example, a patient with a history of Roux-en-Y gastric bypass (RNYGB) surgery complicates the ability to perform routine EUS/ERCP without the use of single or double balloon enteroscopy via the Roux limb. In contrast, a patient with a pacemaker, severe claustrophobia, or inability to hold their breath may preclude MRCP as an option in the diagnostic work-up.

Historical Management of Choledocholithiasis The management of CDL has evolved dramatically over the last four decades (see Chapter 38). Before the advent of laparoscopy in the 1980s, stones in the CBD were identified and removed at the time of open surgical exploration for cholecystectomy. Even after the introduction of ERCP in the 1970s, laparotomy remained the mainstay for CBD exploration (CBDE; see Chapter 37A).13 At that time, the tools and techniques used for surgical clearance of the CBD were superior to those available via ERCP, and as long as a laparotomy was used to perform the cholecystectomy, minimally invasive treatment of CDL was unnecessary. It was not until the introduction of the laparoscopic cholecystectomy (LC) in the late 1980s that finding an associated less invasive method of treating CDL became a priority. 521

522

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

During the initial adoption of LC, most general surgeons did not have the skill set, experience, or equipment to facilitate a laparoscopic CBDE. As the skills, experience, and tools have developed, the advantages and disadvantages of laparoscopic CBDE versus ERCP have been a frequent source of debate (see Chapter 37C). This chapter will discuss laparoscopic techniques for managing CDL, including indications and technical aspects of laparoscopic transcystic, transcholedochal, and transduodenal CBDE, as well as laparoscopic biliary-enteric bypass procedures and laparoscopic-assisted ERCP.

CLINICAL SCENARIOS Indications for Intervention The standard of care for the management of most CBD stones is minimally invasive, whether laparoscopic, endoscopic, or percutaneous. The minimally invasive techniques used and the sequence in which they are used depends on the specific clinical scenario. In addition, the capability and experience of the available personnel at each institution will affect the treatment algorithm. The most common clinical scenarios encountered by surgeons include known or suspected stones before cholecystectomy, the diagnosis of stones intraoperatively, and stones identified subsequent to cholecystectomy.

Preoperative Choledocholithiasis Ascending cholangitis, gallstone pancreatitis, and symptomatic cholelithiasis or acute cholecystitis with evidence of CDL on imaging or liver function tests require evaluation for the presence of CDL (see Chapter 33). For CBD stones confirmed at the time of initial clinical presentation, the decision making is often based on surgeon preference and institutional capabilities. The two primary strategies include ERCP followed by LC or LC with intraoperative cholangiogram (IOC). In the latter case, laparoscopic CBDE can be performed simultaneously or postoperative ERCP is performed if CBD stones are identified on the cholangiogram. ERCP has become widely available in urban settings within the United States with more than 150,000 procedures performed annually (see Chapters 20, 30, and 37C). In general, ERCP is more accessible than laparoscopic CBDE and is also highly effective with successful clearance of the CBD in more than 95% of cases.14 In most centers, CBD stones up to 1.5 cm can be extracted and centers that use lithotripsy can treat stones as large as 3 cm in diameter.15 Therefore, in settings where laparoscopic CBDE is not available, the debate centers on preoperative versus postoperative ERCP. The central argument against an ERCP-first strategy is that 80% of known or suspected CBD stones will have passed before the intervention, making the risks and cost of the intervention unnecessary.16 The risks of ERCP include acute pancreatitis (3%–7%), bleeding (0.3%–1.4%), ascending cholangitis (1.4%), and perforation (0.6%). The mortality associated with ERCP is 0.2% to 0.9%.17 Proponents of performing preoperative ERCP argue that if ERCP is unsuccessful a CBDE can be performed at the time of cholecystectomy without requiring a third procedure. A randomized controlled trial (RCT) of 100 patients undergoing either preoperative ERCP followed by LC or LC with CBDE demonstrated comparable outcomes with similar rates of stone clearance (98% vs. 88%, respectively, not significant),

with slightly shorter hospital length of stay (LOS) and decreased professional fees in the LC1CBDE group.18 Our preferred strategy in most patients is to proceed straight to LC with selective intraoperative cholangiogram. Laparoscopic CBDE or postoperative ERCP are used when CBD stones are identified (see later). In patients with cholangitis (see Chapters 43, 55, and 56; severe pancreatitis) with hemodynamic instability and persistent hyperbilirubinemia, we recommend preoperative ERCP.19 This allows for both clearance of the duct and assessment for additional or alternative pathologies such as impacted stones, strictures, or malignancy. In the case of ascending cholangitis, broad-spectrum antibiotics and urgent biliary decompression with ERCP is typically the best option because it is the least invasive and both diagnostic and therapeutic20 (see Chapters 20, 30, and 43). If ERCP is unavailable or not possible (e.g., history of RNYGB), percutaneous transhepatic biliary decompression (PTC) should be considered (see Chapters 20 and 31). Surgical options, laparoscopic or open, are indicated when less invasive methods are not immediately available, and the patient’s condition warrants immediate biliary decompression (see Chapter 37A). In both cholangitis and pancreatitis, once the patient has sufficiently recovered, cholecystectomy should be completed during the same hospitalization because recurrent symptoms are common and can lead to significant morbidity.21,22

Intraoperative Choledocholithiasis When CDL is diagnosed on IOC, and the surgeon experience and diameter of cystic duct are favorable (greater than 8 mm), our preference is to proceed with laparoscopic transcystic CBDE (Fig. 37B.1). If clearance cannot be achieved via the transcystic route, the options are to proceed with transcholedochal CBDE or a postoperative ERCP. Intraoperative ERCP, although uncommon, is also available at some institutions.23,24 Our preference is to proceed with postoperative ERCP if the stones are less than 2 cm and do not appear to be impacted.

FIGURE 37B.1  Intraoperative cholangiogram demonstrating retained common bile duct stone impacted just above ampulla.

A. Gallstones and Gallbladder  Chapter 37B  Stones in the Bile Duct: Minimally Invasive Surgical Approaches

ERCP avoids complications associated with a transcholedochal exploration, including biliary strictures and bile leaks.25 When the probability of endoscopic clearance is questionable or low, we proceed with a transcholedochal exploration. A number of retrospective studies have shown that LC with CBDE as a single operative procedure is more cost effective and results in shorter hospital LOS than LC and ERCP.18,26,27 A recent prospective RCT showed that both options were highly effective and equivalent in overall cost, although the hospital LOS was shorter for laparoscopic CBDE.18

Postoperative Choledocholithiasis CDL identified after a cholecystectomy or when there is not a plan to perform a cholecystectomy is typically managed with ERCP; however, occasionally endoscopy is unsuccessful or cannot be performed because of altered anatomy. ERCP fails to cannulate the CBD in 1% to 2% of cases. In this situation we proceed with laparoscopic CBDE. Similarly, if stone extraction fails because of the size of the stones, then laparoscopic exploration is a reasonable next step. In the case of impacted or large stones that cannot be removed endoscopically or surgically, biliary-enteric bypass with either a choledochoduodenostomy (CD) or Roux-en-Y hepaticojejunostomy (RNY-HJ) should be considered (see Chapter 37A).

TECHNIQUES Laparoscopic Transcystic Common Bile Duct Exploration The primary method for performing laparoscopic CBDE with minimal morbidity is via the cystic duct. Transcystic exploration is typically performed using standard LC trocar placement, with the cholangiogram catheter placed through the epigastric port into the cystic duct. An additional trocar may be placed in the right midclavicular line to facilitate access to the cystic duct, if necessary (Fig. 37B.2A). The gallbladder is left in situ to provide retraction and counter-traction on the cystic duct, allowing easier passage of wires, catheters, and the choledochoscope. First, an intraoperative cholangiogram is performed. The cystic duct should be dissected along its length from the insertion

523

into the gallbladder to its origin from the CBD. This allows for adequate exposure and assessment of the caliber of the cystic duct. The cystic duct is clipped distally and partially transected, allowing enough room for final ligation with clips but close enough to the CBD so that a tortuous cystic duct does not need to be navigated for stone extraction. A cholangiogram is performed with 1:1 dilution of saline and contrast to lessen the viscosity of the contrast solution and better visualize filling defects. Care should be taken not to introduce air bubbles into the biliary tree because these can be confused for filling defects on fluoroscopy. This approach works best for stones less than 1 cm and when the cystic duct is short and dilated. If the cystic duct is diminutive, cholangiogram and stone extraction will prove difficult. At times, the cystic duct can be serially dilated with balloon catheters to facilitate access to the CBD. The first and easiest step in facilitating passage of stones through the ampulla is pharmacologic relaxation of the Sphincter of Oddi using intravenous glucagon (1 mg).28 Next, the duct is vigorously irrigated with saline or contrast to flush the stones through the ampulla. This technique is most successful for sludge and stones less than 4 mm.29 If flushing is unsuccessful, two additional techniques are used: dilation of the ampulla and choledochoscopy. Ampullary dilation is performed by passing a wire through the cystic duct and into the duodenum under fluoroscopic guidance. A 4- to 6-mm diameter, 4-cm long ureteral balloon is advanced over the wire and positioned across the ampulla. After fluoroscopic confirmation of the balloon’s position, it is inflated, dilating the ampulla (Fig. 37B.3A). After dilation, the balloon is removed, and the duct is again vigorously irrigated. Finally, a cholangiogram is performed to assess for residual stones. If ampullary dilation is unsuccessful, choledochoscopy is the next step. Some surgeons prefer to proceed straight to choledochoscopy without attempting ampullary dilation because it allows for direct visualization of the duct and stones. A cholangioscope or ureteroscope is passed transcystically into the common duct. If the cystic duct is too small, the same balloon used for ampullary dilation can be used to gently dilate the cystic duct until it is large enough to allow the cholangioscope to pass. Once the stones are identified, they can be gently

Cholangio scope port 5 5 5 5

10 mm

5

5 If needed

5 10

A

10

B

FIGURE 37B.2  A, Illustration demonstrating trocar placement for performing laparoscopic transcystic or transcholedochal common bile duct exploration. An additional trocar may be placed in the right midclavicular line for access to the cystic duct, if necessary. B, Illustration demonstrating trocar placement for performing laparoscopic transduodenal common bile duct exploration and sphincterotomy. The trocar position is slightly lower to facilitate mobilization of the duodenum. An additional camera trocar in the right lower quadrant allows for easier visualization of the ampulla.

524

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

can make accessing the proximal CBD challenging. Large stones, impacted stones, and significant inflammation can all increase the difficulty of clearing the duct transcystically. In such cases, the surgeon must decide whether to proceed with a transcholedochal exploration or defer to postoperative ERCP. If the CBD is less than 1 cm in diameter and in the absence of large impacted stones, our preference is to proceed with postoperative ERCP because it has a high rate of success and less potential morbidity.

Laparoscopic Transcholedochal Common Bile Duct Exploration

A

B

FIGURE 37B.3  A, Illustration demonstrating advancement of a ureteral balloon catheter across the ampulla with dilation. B, Illustration demonstrating dislodgement of common bile ducts stones with a cholangioscope. The stones can then be pushed across the ampulla with the scope.

pushed through the ampulla with the tip of the cholangioscope (see Fig. 37B.3B) or they can be snared. To snare the stones, we recommend a helical stone retrieval basket, which is passed through the working channel of the cholangioscope. Under direct visualization the basket is then passed beyond the stone. Once the basket is distal to the stone, it is opened and withdrawn until the stone is captured. The snare is then closed, and the stone is removed through the cystic duct. Care must be taken to avoid causing injury with the snare. It is a stiff instrument and ductal perforation or penetration into the pancreas is possible, particularly with snares that have a blunt tip. Some authors recommend blind or fluoroscopically guided wire basket stone capture and extraction. In our experience, this has proven less successful and the risk for injury is higher. There are two options to deal with large stones that cannot be extracted through the cystic duct. Large stones that are soft can often be crushed by tightening the snare around them. The debris can then be snared individually or pushed through the ampulla and into the duodenum. For large stones that are too hard to crush, a laser or mechanical lithotripsy catheter can be passed through the cholangioscope allowing the stone to be fractured under direct visualization.30 Finally, in ducts with significant inflammation or strictures, biopsy should be considered. Malignancy may be an inciting event in the development of ductal debris or ductal obstruction. Complications of transcystic CBDE, as observed by Paganini et al., include bile leak (1%), acute pancreatitis (0.5%), and rupture of the cystic duct (6.8%).31 The success rate of a laparoscopic transcystic approach to CDL by experienced surgical teams is 80% to 90%.29 There are a number of reasons a transcystic CBDE can fail. In some cases, the cystic duct is too small, tortuous, or even obliterated and passage of a catheter into the CBD is difficult or impossible. It can be difficult to pull stones retrograde into the cystic duct from the CBD because the tendency is for stones to slip upward into the common hepatic duct. Occasionally the cystic duct inserts into the very distal CBD or at an acute angle. This

As discussed, laparoscopic choledochotomy is indicated when the transcystic approach fails or in the presence of multiple, large, or impacted stones (Fig. 37B.4A). Choledochotomy should be avoided if the CBD is less than 1 cm in diameter.25 The CBD is accessed by exposing the second portion of the duodenum and mobilizing the duodenum down to the level of the pancreas. Excessive mobilization and skeletonization of the CBD should be avoided to preserve blood supply to the proximal duct. Stay sutures may be placed anteriorly on either side of the choledochotomy (preserving the 3 o’clock and 9 o’clock blood supply) to allow for traction on the CBD. A longitudinal choledochotomy is then made on the distal CBD. The choledochotomy should be long enough for removal of the largest stone and passage of the choledochoscope. Typically, a 1 cm incision is sufficient to meet both of these goals (see Fig. 37B.4B–C). A cholangioscope is passed directly into the duct and a thorough exploration of the proximal and distal duct is performed. Stones may be flushed out of the ductotomy, removed directly with atraumatic graspers (see Fig. 37B.4D–E), or extracted using a snare passed through the cholangioscope as described in the transcystic approach. There is a mechanical advantage to removing impacted stones directly through a choledochotomy, although stones impacted in the head of the pancreas may require a transduodenal approach. After clearance of the duct and completion of the exploration, the ductotomy is closed primarily or over a T-tube. Historically, T-tubes were used to decompress the biliary tree and were thought to minimize bile leaks (see Chapter 37A). They also allow postoperative percutaneous access to the CBD. Ttubes, however, have potential morbidity including inadvertent displacement, erosion, cholangitis, and nutritional deficiencies from bile loss.32 In addition, T-tubes can be painful and problematic to manage. Several RCTs have concluded that primary closure of the duct does not result in a higher rate of bile leaks.33 These studies have uniformly shown a decreased hospital LOS, shorter operative time, lower hospital expenses, and earlier return to normal activity in patients who did not have a T-tube.34 In addition, because of the high success rates of duct clearance by choledochotomy, the need for T-tubes to provide percutaneous access for retained stones is unlikely.33 A recent meta-analysis of 16 studies and 1770 patients concluded that primary duct closure is feasible after laparoscopic CBDE and is associated with fewer postoperative complications, decreased operative time, shorter LOS, and lower median hospital expenses.35 If clearance of the duct has been achieved with confidence and there are no concerns of distal obstruction, our preference is to primarily close the choledochotomy, without a T-tube, with simple interrupted sutures spaced evenly to avoid duct ischemia. We generally use 5-0 monofilament slowly absorbable

A. Gallstones and Gallbladder  Chapter 37B  Stones in the Bile Duct: Minimally Invasive Surgical Approaches

A

C

525

B

D

E

F FIGURE 37B.4  A, Preoperative magnetic resonance cholangiopancreatogram (MRCP) demonstrating a significant burden of common bile duct stones refractory to endoscopic lithotripsy. B, Illustration demonstrating an anterior choledochotomy made to accommodate the cholangioscope. Two stay stitches are placed at 3 o’clock and 9 o’clock to allow for traction on the common bile duct. C, Intraoperative photograph of anterior ductotomy at the time of laparoscopic transcholedochal common bile duct exploration. D, Intraoperative photograph demonstrating transcholedochal stone extraction. E, Intraoperative photograph demonstrating the residual ductotomy and endoscopically placed stent after stone extraction. This defect was repaired with a choledochoduodenostomy. F, Endoscopic image of choledochoduodenal anastomosis 3 months postoperatively.

526

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

suture. T-tubes may be used if there is concern for residual stones or if the caliber or quality of the tissue of the CBD is friable and inadequate for primary closure. In these cases, biliary-enteric bypass should be considered for definitive management (see Chapter 37A). If a T-tube is used, once in place, the ductotomy is closed around the base of the tube using a few sutures adjacent to the side of the T-tube and the tube is exteriorized through a lateral trocar site. A final cholangiogram through the T-tube is performed at the conclusion of the case. Tubes are left in place for 3 weeks to promote formation of an inflammatory tract around the tube. The T-tube can then be gently removed, and the tract will collapse and seal spontaneously. If stones are discovered postoperatively, percutaneous stone extraction via the T-tube is successful in 95% of cases.36 Surgical drains are not placed routinely unless there is an increased risk for bile leak or a T-tube is used. We clamp the Ttube once the patient is tolerating a diet if there is no evidence of obstruction. The surgical drain is removed if there is no evidence of a bile leak after the T-tube is has been clamped. The overall success rate of laparoscopic choledochotomy is 83% to 96%, with a morbidity rate of 5% to 10% and mortality rate of 1%.25 As mentioned previously, this procedure is not without complications. Bile leak (reported as high as 14%) and postoperative CBD strictures are the most feared complications.27 Choledochotomy has similar rates of pancreatitis (7.3% vs. 8.8%), retained stones (2.4% vs. 4.4%), reoperation (7.3% vs. 6.6%), and overall morbidity (17% vs. 13%) as ERCP.27 Major advantages of the transcholedochal approach include easier access to both upper and lower ductal system and extraction of any size stone. Conversion to an open procedure must always be considered in difficult cases, although challenging laparoscopic cases are frequently also challenging open cases, and referral to a specialty center should always be considered before converting to a laparotomy. In patients with a high risk of recurrent stone disease or formation of a biliary stricture, usually because of inflammation or a small duct, a definitive bypass should be considered (see Fig. 37B.4F).

Laparoscopic Transduodenal Sphincterotomy and Common Bile Duct Exploration For impacted stones refractory to clearance by endoscopy or CBDE, laparoscopic transduodenal exploration with sphincterotomy is an alternative modality for duct clearance. Nevertheless, this procedure is technically challenging and should be reserved for unique circumstances and only attempted by experienced laparoscopic surgeons. This procedure can typically be performed with a 4 or 5 trocar technique. We have found it useful to place the trocars lower than the typical approach to cholecystectomy. An additional camera trocar in the right lower quadrant will also provide a better angle for visualization of the ampullary reconstruction (see Fig. 37B.2B). To gain access to the duodenum, the right colon is mobilized and a Kocher maneuver is completed. With the duodenum elevated, it may be useful to place a surgical sponge posterior to the head of the pancreas. This will elevate the duodenum and absorb enteric fluids leaked into the field once the duodenotomy is created. A longitudinal incision is made in the antimesenteric wall of the second portion of the duodenum using electrocautery or ultrasonic shears to expose the major duodenal papilla. If the papilla is not easily located and the cystic and CBD are patent, a cholangiogram catheter or wire can be inserted via the cystic duct and passed through the

A

B

FIGURE 37B.5  A, Illustration of transduodenal sphincterotomy made at the 11 o’clock position of the ampulla with a cautery device. B, Illustration of laparoscopic interrupted suture repair of the ampulla re-approximating the bile duct mucosa to the duodenum.

ampulla to aid in identification. Once the papilla is identified, the CBD is intubated using a wire or silicone tube. Electrocautery or ultrasonic shears are then used to create a sphincterotomy at the 11 o’clock position on the papilla (Fig. 37B.5A).37 This facilitates a transduodenal CBDE using cholangiocatheters, balloons, or a cholangioscope. Once clearance of the CBD is achieved, the mucosa of the bile duct is sutured to the duodenum with interrupted 5-0 monofilament slowly absorbable sutures (see Fig. 37B.5B).37 The duodenotomy is then closed to complete the case. The risk of complications from transduodenal sphincterotomy is reported to be similar to ERCP.38 We use surgical drains selectively and, if used, they are removed within a few days of the operation if there is no evidence of bile leak.

Laparoscopic Biliary-Enteric Bypass In patients at moderate to high risk for recurrent CBD stones, or in patients with distal inflammatory strictures, biliary-enteric bypass may provide the most durable result (see Chapters 37A and 42). The two primary options for bypass are CD or RNY-HJ. Currently there is inadequate comparative data to recommend one technique over another. There are a number of retrospective studies comparing the two anastomoses that show equivalent outcomes and morbidity, and selection of the appropriate technique depends on intraoperative technical factors, clinical findings, and patient anatomy.39–41 CD has been criticized in the past because of concern for reflux of enteric contents into the CBD leading to chronic inflammation and recurring bouts of cholangitis, referred to as sump syndrome.42,43 Results of analyses by several authors suggest that symptoms associated with sump syndrome may actually be because of a mechanical problem associated with a narrow anastomosis and/or stricture.44–46 Our current preference is laparoscopic CD because it is technically easier, leads to a more physiologic reconstruction, and allows direct access to the biliary system should further evaluation or manipulation of the duct prove necessary.47,48 Nevertheless, CD can be difficult in the setting of significant duodenal inflammation or inadequate duodenal mobility after Kocherization. In these cases, we proceed with laparoscopic RNY-HJ. To perform a laparoscopic CD, we use a trocar placement similar to that described for the transduodenal sphincterotomy

A. Gallstones and Gallbladder  Chapter 37B  Stones in the Bile Duct: Minimally Invasive Surgical Approaches

(see Fig. 37B.1B). A Kocher maneuver is performed, and the duodenum is mobilized to perform a tension-free anastomosis to the CBD. The degree of Kocherization ultimately depends on individual anatomy and mobility of the duodenum. Next, approximately 2 cm of the inferior and anterior surface of the distal CBD is exposed. The dissection plane should remain anterior to the duct to avoid injury of the blood supply to the proximal duct. A thorough laparoscopic ultrasound examination should be performed to identity the CBD and verify the location of any stones. A 1.5 cm supraduodenal longitudinal choledochotomy is made in the anterior wall of the duct using electrocautery or ultrasonic shears. A choledochoscope is then inserted through the choledochotomy and a thorough examination both proximal and distally is performed. The appearance of any stricture should raise concern for underlying malignancy, and biopsies should be performed at this point if there are any concerns for a neoplastic process. A 1 cm longitudinal duodenotomy is made in the adjacent post bulbar duodenum. The duodenotomy is made slightly shorter than the ductotomy because of the inevitable stretching of the duodenotomy (Fig. 37B.6A). With the advent of the absorbable barbed suture,49 we now perform a single layer running CD with two 3-0 absorbable

A

B FIGURE 37B.6  A, Illustration demonstrating the setup of a choledochoduodenostomy anastomosis. Stay sutures can be placed to ensure appropriate alignment. B, Illustration demonstrating completion of the choledochoduodenostomy with the final sutures placed in the superior apex.

527

barbed sutures. We place two to three interrupted posterior 3-0 Vicryl sutures to secure the inferior apex of the anastomosis. The posterior sutures are tied internally. The lateral and medial sides are then run sequentially from the inferior apex, rolling the duodenum up to complete the anastomosis (see Fig. 37B.6B). To complete the anastomosis, two to three additional buttressing stitches can be placed in the duodenum to secure it to bile duct, before cutting the suture and removing the needle. No knots are required in the barbed suture. Alternatively, an interrupted anastomosis can be performed with multiple 3-0 Vicryl sutures. Tying the sutures as they are placed can limit access during placement of the subsequent sutures, but leaving too many sutures untied makes it difficult to identify the appropriate sutures and frequently leads to tangling of the sutures. To avoid these problems, we typically place two to three sutures at a time, tying the deeper sutures after the shallower sutures are placed. Alternating dyed and undyed sutures and clipping the suture tails also helps in identification of the sutures and prevents tangling. Final inspection of the anastomosis should confirm that there is no leakage of bile from the anastomosis and no tension on the duodenum or duct. Similar to laparoscopic sphincterotomy, drains are used selectively and removed early. We also use upper gastrointestinal contrast studies selectively before starting a diet in patients who are at high risk of an anastomotic leak. Trocar placement for laparoscopic RNY-HJ is similar to that used for sphincterotomy and CD, although a slightly lower placement may facilitate access to and division of the jejunum. Access to the common hepatic duct may require mobilization of the right colon and more extensive Kocherization of the duodenum. Laparoscopic ultrasound examination is again used to facilitate identification of the portal structures. We typically prefer an end-to-side hepaticojejunostomy (Fig. 37B.7A), although this requires circumferential dissection and division of the duct distally. In some cases, significant periportal inflammation makes circumferential dissection of the CBD near impossible and fraught with potential iatrogenic injury to the portal vein or right hepatic artery. In these cases, a side-to-side hepaticojejunostomy should be considered (see Fig. 37B.7B). To create the Roux limb, the jejunum is divided using an endostapler approximately 20 cm distal to the ligament of Trietz. The mesentery is then divided to allow the Roux limb to reach the bile duct without tension. The limb is preferentially passed antecolic; however, if this results in too much tension, it can be passed retrocolic through the transverse mesocolon just to the right of the middle colic vessels. The jejunojejunostomy is created in the infracolic position 30 to 40 cm distal to the future bilioenteric anastomosis. The hepaticojejunostomy is created in a single layer using 3-0 absorbable barbed suture or 4-0 or 5-0 interrupted absorbable sutures (Vicryl or PDS). Depending on the size of the duct, this anastomosis may be created using interrupted sutures (ducts less than 1 cm), in a fashion similar to that described for the CD, or running sutures (ducts greater than 1 cm). Again, drains are used selectively.

SPECIAL CIRCUMSTANCES Choledocholithiasis after Roux-en-Y Gastric Bypass Laparoscopic CBDE or laparoscopic-assisted ERCP may be the only options in patients with a history of gastrointestinal surgery. With the introduction and rapid expansion of RNYGB

528

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

single-balloon endoscopes can facilitate successful performance of ERCP in nearly 80% of patients53 (see Chapter 30). Nevertheless, the majority of centers do not currently have access to these technologies, and the procedures are time consuming and technically difficult to perform.54 Some studies have suggested that EUS-guided gastrogastrostomy formation to facilitate ERCP may be an alternative to double- or single-balloon endoscopy.55 In these cases, laparoscopic access to the distal gastric remnant may be a straightforward solution to allow performance of an intraoperative ERCP and/or EUS, minimizing time, cost, and potential postprocedure complications. One study has even shown this technique to be more cost-effective than double-balloon enteroscopy.23

Laparoscopic-Assisted Endoscopic Retrograde Cholangiopancreatography A

B FIGURE 37B.7  A, Illustration demonstrating an end-side hepaticojejunostomy. B, Illustration demonstrating a side-side hepaticojejunostomy.

procedures, it is becoming increasingly common to have patients present in whom an ERCP is either not possible or extremely challenging. A recent review of the National Inpatient Sample demonstrated that nearly 2 million bariatric surgeries were performed between 1993 and 2016, with substantial improvements in complication rates.50 Approximately 160,000 procedures are performed annually, with more than 98% of procedures now performed laparoscopically, 28% of which are RNYGB. Approximately 40% of patients undergoing bariatric procedures will develop gallstones or biliary sludge within six months of surgery, with less than 50% of patients becoming symptomatic.51 The performance of LC at the time of gastric bypass surgery remains controversial, with some studies demonstrating increased operative times and hospital LOS. Prophylactic ursodiol has been shown in an RCT to reduce the incidence of gallstone formation after gastric bypass surgery.52 Because of these factors, late presentation of gallstone disease and CDL will continue to be a persistent clinical challenge. In patients who have undergone a previous RNYGB procedure, access to the ampulla of Vater using double- and

At laparoscopy, the gastric remnant is identified, and the front wall of the stomach is exposed. The gastric remnant may need to be mobilized from surrounding adhesions to adequately reach the anterior abdominal wall, with care being taken to avoid injury to the mesentery of the gastrojejunal limb. We place two 0 sutures through the abdominal wall and through the anterior wall of the stomach adjacent to the future gastrotomy site with a Keith needle or suture passer. These sutures are used to retract and stabilize the stomach to the anterior abdominal wall. Hardy sutures should be used because they can snap from torque on the trocar site during ERCP causing the stomach to fall away from the abdominal wall and subsequent loss of access. A gastrotomy is then made in the location that will allow easy passage of the endoscope through the pylorus. A 15-mm, radially dilating trocar with a balloon tip or a single port device is inserted through the abdominal wall and directly into the gastrotomy. A sterile drape with Ioban is placed around the trocar and used to preserve the sterile field. The endoscope can then be placed through the trocar or single port device into the stomach to perform the ERCP. After the conclusion of the ERCP, the gastrotomy is sutured closed with 3-0 absorbable suture in either a single or double layer. Surgical drains are rarely indicated after this procedure.

CONCLUSION The first laparoscopic biliary surgery was performed more than 35 years ago. During the last three decades, substantial progress has been made in surgical skill sets, experience, and technology. Our understanding of how and when to apply these minimally invasive tools has greatly reduced the suffering of patients with CDL. We now have the ability to diagnose biliary stone disease, differentiate it from neoplastic processes, and treat it with very high levels of success and decreasing levels of morbidity. We have reviewed a wide range of approaches to the management of patients with CBD stones. In managing these patients, surgeons must assess their own skill set and the capabilities of their hospital and team. They must understand the tools and talent available within their institutions. Finally, they must apply this knowledge to the particular clinical scenario of their patient. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

528.e1

REFERENCES 1. Irojah B, Bell T, Grim R, Martin J, Ahuja V. Are they too old for surgery? Safety of cholecystectomy in superelderly patients (./5 Age 90). Perm J. 2017;21:16-013. 2. Garcia-Gomez MC, de Lama E, Ordonez-Palau S, Nolla JM, Corbella E, Pinto X. High prevalence of gallstone disease in rheumatoid arthritis: a new comorbidity related to dyslipidemia? Reumatol Clin. 2019;15(2):84-89. 3. Di Ciaula A, Wang DQ, Portincasa P. Gallbladder and gastric motility in obese newborns, pre-adolescents and adults. J Gastroenterol Hepatol. 2012;27(8):1298-1305. 4. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver. 2012;6(2):172-187. 5. Li C, Wen T. Surgical management of hepatolithiasis: a minireview. Intractable Rare Dis Res. 2017;6(2):102-105. 6. Kim HJ, Kim JS, Joo MK, et al. Hepatolithiasis and intrahepatic cholangiocarcinoma: a review. World J Gastroenterol. 2015;21(48): 13418-13431. 7. Dasari BV, Tan CJ, Gurusamy KS, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013;12: CD003327. 8. Fagenholz PJ, Fuentes E, Kaafarani H, et al. Computed tomography is more sensitive than ultrasound for the diagnosis of acute cholecystitis. Surg Infect (Larchmt). 2015;16(5):509-512. 9. Benarroch-Gampel J, Boyd CA, Sheffield KM, Townsend Jr CM, Riall TS. Overuse of CT in patients with complicated gallstone disease. J Am Coll Surg. 2011;213(4):524-530. 10. Meeralam Y, Al-Shammari K, Yaghoobi M. Diagnostic accuracy of EUS compared with MRCP in detecting choledocholithiasis: a meta-analysis of diagnostic test accuracy in head-to-head studies. Gastrointest Endosc. 2017;86(6):986-993. 11. Giljaca V, Gurusamy KS, Takwoingi Y, et al. Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. Cochrane Database Syst Rev. 2015(2):CD011549. 12. Artifon EL, Kumar A, Eloubeidi MA, et al. Prospective randomized trial of EUS versus ERCP-guided common bile duct stone removal: an interim report (with video). Gastrointest Endosc. 2009;69(2): 238-243. 13. Kroger W, Arendt R, Teichmann W, Leithauser W. [First experiences with endoscopic retrograde cholangiopancreaticography (ERCP) (author’s transl)]. Radiol Diagn. 1975;16(3):315-324. 14. Kum CK, Goh PM. Preoperative ERCP in the management of common bile duct stones before laparoscopic cholecystectomy. Eur J Surg. 1996;162(3):205-210. 15. Lenze F, Heinzow HS, Herrmann E, et al. Clearance of refractory bile duct stones with extracorporeal shockwave lithotripsy: higher failure rate in obese patients. Scand J Gastroenterol. 2014;49(2):209-214. 16. Urbach DR, Khajanchee YS, Jobe BA, Standage BA, Hansen PD, Swanstrom LL. Cost-effective management of common bile duct stones: a decision analysis of the use of endoscopic retrograde cholangiopancreatography (ERCP), intraoperative cholangiography, and laparoscopic bile duct exploration. Surg Endosc. 2001;15(1):4-13. 17. Orenstein SB, Marks JM, Hardacre JM. Technical aspects of bile duct evaluation and exploration. Surg Clin North Am. 2014;94(2): 281-296. 18. Rogers SJ, Cello JP, Horn JK, et al. Prospective randomized trial of LC1LCBDE vs ERCP/S1LC for common bile duct stone disease. Arch Surg. 2010;145(1):28-33. 19. Chan T, Yaghoubian A, Rosing D, et al. Total bilirubin is a useful predictor of persisting common bile duct stone in gallstone pancreatitis. Am Surg. 2008;74(10):977-980. 20. Hui CK, Lai KC, Yuen MF, Ng M, Lai CL, Lam SK. Acute cholangitis—predictive factors for emergency ERCP. Aliment Pharmacol Ther. 2001;15(10):1633-1637. 21. Chang L, Lo S, Stabile BE, Lewis RJ, Toosie K, de Virgilio C. Preoperative versus postoperative endoscopic retrograde cholangiopancreatography in mild to moderate gallstone pancreatitis: a prospective randomized trial. Ann Surg. 2000;231(1):82-87. 22. Li VK, Yum JL, Yeung YP. Optimal timing of elective laparoscopic cholecystectomy after acute cholangitis and subsequent clearance of choledocholithiasis. Am J Surg. 2010;200(4):483-488. 23. Schreiner MA, Chang L, Gluck M, et al. Laparoscopy-assisted versus balloon enteroscopy-assisted ERCP in bariatric post-Roux-en-Y gastric bypass patients. Gastrointest Endosc. 2012;75(4):748-756.

24. Moreels TG. Endoscopic retrograde cholangiopancreatography in patients with altered anatomy: how to deal with the challenges? World J Gastrointest Endosc. 2014;6(8):345-351. 25. Verbesey JE, Birkett DH. Common bile duct exploration for choledocholithiasis. Surg Clin North Am. 2008;88(6):1315-1328, ix. 26. Cuschieri A, Lezoche E, Morino M, et al. E.A.E.S. multicenter prospective randomized trial comparing two-stage vs single-stage management of patients with gallstone disease and ductal calculi. Surg Endosc. 1999;13(10):952-957. 27. Nathanson LK, O’Rourke NA, Martin IJ, et al. Postoperative ERCP versus laparoscopic choledochotomy for clearance of selected bile duct calculi: a randomized trial. Ann Surg. 2005;242(2): 188-192. 28. Petelin JB. Laparoscopic approach to common duct pathology. Am J Surg. 1993;165(4):487-491. 29. Kroh M, Chand B. Choledocholithiasis, endoscopic retrograde cholangiopancreatography, and laparoscopic common bile duct exploration. Surg Clin North Am. 2008;88(5):1019-1031, vii. 30. Jones T, Al Musawi J, Navaratne L, Martinez-Isla A. Holmium laser lithotripsy improves the rate of successful transcystic laparoscopic common bile duct exploration. Langenbecks Arch Surg. 2019;404(8): 985-992. 31. Paganini AM, Guerrieri M, Sarnari J, et al. Thirteen years’ experience with laparoscopic transcystic common bile duct exploration for stones. Effectiveness and long-term results. Surg Endosc. 2007; 21(1):34-40. 32. Gurusamy KS, Koti R, Davidson BR. T-tube drainage versus primary closure after laparoscopic common bile duct exploration. Cochrane Database Syst Rev. 2013;6:CD005641. 33. Zhang WJ, Xu GF, Wu GZ, Li JM, Dong ZT, Mo XD. Laparoscopic exploration of common bile duct with primary closure versus T-tube drainage: a randomized clinical trial. J Surg Res. 2009; 157(1):e1-e5. 34. Mangla V, Chander J, Vindal A, Lal P, Ramteke VK. A randomized trial comparing the use of endobiliary stent and T-tube for biliary decompression after laparoscopic common bile duct exploration. Surg Laparosc Endosc Percutan Tech. 2012;22(4):345-348. 35. Podda M, Polignano FM, Luhmann A, Wilson MS, Kulli C, Tait IS. Systematic review with meta-analysis of studies comparing primary duct closure and T-tube drainage after laparoscopic common bile duct exploration for choledocholithiasis. Surg Endosc. 2016;30(3): 845-861. 36. Burhenne HJ. Garland lecture. Percutaneous extraction of retained biliary tract stones: 661 patients. AJR Am J Roentgenol. 1980;134(5): 889-898. 37. Makary MA, Elariny HA. Laparoscopic transduodenal sphincteroplasty. J Laparoendosc Adv Surg Tech A. 2006;16(6):629-632. 38. Carboni M, Negro P, D’Amore L, Proposito D. Transduodenal sphincterotomy in laparoscopic era. World J Surg. 2001;25(10): 1357-1359. 39. Narayanan SK, Chen Y, Narasimhan KL, Cohen RC. Hepaticoduodenostomy versus hepaticojejunostomy after resection of choledochal cyst: a systematic review and meta-analysis. J Pediatr Surg. 2013;48(11):2336-2342. 40. Santore MT, Behar BJ, Blinman TA, et al. Hepaticoduodenostomy vs hepaticojejunostomy for reconstruction after resection of choledochal cyst. J Pediatr Surg. 2011;46(1):209-213. 41. Luu C, Lee B, Stabile BE. Choledochoduodenostomy as the biliary-enteric bypass of choice for benign and malignant distal common bile duct strictures. Am Surg. 2013;79(10):1054-1057. 42. Khajanchee YS, Cassera MA, Hammill CW, Swanstrom LL, Hansen PD. Outcomes following laparoscopic choledochoduodenostomy in the management of benign biliary obstruction. J Gastrointest Surg. 2012;16(4):801-805. 43. Tang CN, Siu WT, Ha JP, Li MK. Laparoscopic choledochoduodenostomy: an effective drainage procedure for recurrent pyogenic cholangitis. Surg Endosc. 2003;17(10):1590-1594. 44. Degenshein GA. Choledochoduodenostomy: an 18 year study of 175 consecutive cases. Surgery. 1974;76(2):319-324. 45. Madden JL, Chun JY, Kandalaft S, Parekh M. Choledochoduodenostomy: an unjustly maligned surgical procedure? Am J Surg. 1970;119(1):45-54. 46. de Almeida AC, dos Santos NM, Aldeia FJ. Choledochoduodenostomy in the management of common duct stones or associated pathology—an obsolete method? HPB Surg. 1996;10(1):27-33.

528.e2 47. O’Rourke RW, Lee NN, Cheng J, Swanstrom LL, Hansen PD. Laparoscopic biliary reconstruction. Am J Surg. 2004;187(5):621-624. 48. Moraca RJ, Lee FT, Ryan Jr JA, Traverso LW. Long-term biliary function after reconstruction of major bile duct injuries with hepaticoduodenostomy or hepaticojejunostomy. Arch Surg. 2002;137(8): 889-893; discussion 893-894. 49. Fernandez LC, Toriz A, Hernandez J, et al. Knotless choledochorraphy with barbed suture, safe and feasible. Surg Endosc. 2016;30(8): 3630-3635. 50. Campos GM, Khoraki J, Browning MG, Pessoa BM, Mazzini GS, Wolfe L. Changes in utilization of bariatric surgery in the United States From 1993 to 2016. Ann Surg. 2020;271(2):201-209. 51. Shiffman ML, Sugerman HJ, Kellum JH, Brewer WH, Moore EW. Gallstones in patients with morbid obesity. Relationship to body weight, weight loss and gallbladder bile cholesterol solubility. Int J Obes Relat Metab Disord. 1993;17(3):153-158.

52. Sugerman HJ, Brewer WH, Shiffman ML, et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg. 1995; 169(1):91-96; discussion 96-97. 53. Moreels TG. ERCP in the patient with surgically altered anatomy. Curr Gastroenterol Rep. 2013;15(9):343. 54. Lopes TL, Clements RH, Wilcox CM. Laparoscopy-assisted ERCP: experience of a high-volume bariatric surgery center (with video). Gastrointest Endosc. 2009;70(6):1254-1259. 55. Bukhari M, Kowalski T, Nieto J, et al. An international, multicenter, comparative trial of EUS-guided gastrogastrostomy-assisted ERCP versus enteroscopy-assisted ERCP in patients with Rouxen-Y gastric bypass anatomy. Gastrointest Endosc. 2018;88(3): 486-494.

CHAPTER 37C Stones in the bile duct: Endoscopic and percutaneous approaches Satish Nagula HISTORICAL OVERVIEW

ENDOSCOPIC TECHNIQUES

In the 1970s and 1980s, endoscopic retrograde cholangiopancreatography (ERCP) transformed the diagnostic approach to suspected biliary disease and jaundice (see Chapters 20 and 30). Similarly, in the years since it was first performed in humans,1,2 endoscopic sphincterotomy (ES) has had a dramatic impact on the management of biliary disease, specifically in the treatment of common bile duct (CBD) stones. The widespread availability of ES has made endoscopic stone extraction the primary modality for the management of choledocholithiasis. Interest in ERCP and endoscopic sphincterotomy as definitive therapy for CBD stones grew in the 1990s after the introduction of laparoscopic cholecystectomy (see Chapter 36). Patient-related factors, clinical judgment, availability of expertise, and current evidence from clinical trials must be combined to decide on an endoscopic, percutaneous, or surgical approach. Although ERCP as a diagnostic modality has been replaced by noninvasive imaging modalities such as magnetic resonance cholangiopancreatography (MRCP) (see Chapter 13), it remains the major nonoperative tool for the management of biliary diseases such as choledocholithiasis and obstructive jaundice.

An endoscopy service that treats CBD stones must have access to an appropriate endoscopy facility and high-quality fluoroscopy. The endoscopy team must be fully cognizant of all basic ERCP maneuvers, less frequently used techniques, and potential complications and their management. It is essential to explain the nature of the procedure to the patient and to outline the purpose, benefits, advantages, alternatives, and potential hazards (see Chapters 20 and 30). On successful deep biliary cannulation with a sphinctertome, a cholangiogram is initially performed, which defines the ductal anatomy and the extent of the stone burden. ES is usually the first therapeutic step in stone extraction. Balloon dilation of the biliary sphincter is an alternative to ES, but this has fallen out of favor due to increased risks of severe post-ERCP pancreatitis.6–8 Standard pull-type sphincterotomes allow a vertical incision to be made from the papillary orifice in a cephalad direction along the intramural course of the CBD for a variable length (average, 10 to 15 mm), depending on local anatomy, the degree of CBD dilation, and the size of the stone to be removed (Fig. 37C.1). The incision is produced by the controlled application of monopolar electrocautery delivered by a generator specifically designed for endoscopic use. It is fundamental to ES technique that complete control of wire tension and electrocautery be maintained at all times. “Smart” generators incorporate a pulsed generator (Erbe, Tubingen, Germany; ConMed Endoscopic Technologies, Billerica, MA) with feedback-controlled power output, thus avoiding a “zipper effect” and reducing pancreatitis and bleeding. Occasionally, a precut sphincterotomy, also referred to as an access papillotomy, is needed to initiate ES when the standard instrument cannot be inserted deeply. This incision is often needed when cannulation has been prevented by an impacted stone. The needle-knife is more useful in this situation because the intramural CBD is usually grossly distended and easily incised, starting from the papilla and extending cephalad. Needle-knife fistulotomy is a variant of this technique; the incision is begun above the papilla to form a choledochoduodenal fistulotomy. This technique is similar in efficacy to precut sphincterotomy, but more often it requires mechanical lithotripsy (ML) and may have a lower rate of pancreatitis.9 Patients with Billroth II partial gastrectomy (Fig. 37C.2) and Roux-en-Y bypass operations present special problems to the endosco­ pist, and numerous methods have been described to obtain successful cannulation10,11 and removal of CBD stones12 (see Chapter 37B). It is standard practice to attempt stone extraction from the CBD immediately after ES. The two accessory instruments used most commonly for this are the Dormia-type basket (Fig. 37C.3) and the Fogarty-type balloon (Figs. 37C.4 and 37C.5), which

INDICATIONS FOR ENDOSCOPIC THERAPY Patients with choledocholithiasis may present with asymptomatic stones on noninvasive imaging or direct cholangiography or with a variety of clinical symptoms (see Chapter 33), such as cholestasis, pain, cholangitis (see Chapter 43), and pancreatitis (see Chapter 55). In the early days of ES—at a time when few endoscopy centers could offer the technique and criticisms by surgical experts were common—it was considered justifiable only in elderly postcholecystectomy patients with recurrent or retained bile duct stones who were at high risk of serious complications from open surgical CBD exploration or reexploration.3 The impressive success of ES in this group, combined with expanded availability, a low rate of complications, and strong patient preference, has led to ERCP becoming the primary modality for the management of CBD stones. The endoscopist now must consider several clearly defined conditions for which endoscopic management may be indicated in patients with definite or suspected bile duct stones4,5: 1. Acute cholangitis 2. Visualized CBD stone on abdominal ultrasound, endoscopic ultrasound (EUS), computed tomography (CT), MRCP, or intraoperative cholangiogram 3. High suspicion of CBD stones: cholelithiasis, dilated CBD, and abnormal liver biochemical tests 4. Worsening gallstone pancreatitis 5. Recurrent CBD stones or gallstone pancreatitis, nonsurgical candidate for cholecystectomy

529

530

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

FIGURE 37C.1  Endoscopic retrograde cholangiopancreatography showing a dilated bile duct, a single duct stone just below the endoscope, a guidewire, and a sphincterotome in position during sphincterotomy (arrows).

A

B

FIGURE 37C.2  Endoscopic retrograde cholangiopancreatography in a patient with Billroth II partial gastrectomy showing insertion of a catheter (curved arrow) (A) and placement of a guidewire and short biliary endoprosthesis (solid arrow) (B) immediately before needle-knife sphincterotomy and demonstration of common bile duct stones (open arrows).

FIGURE 37C.3  Endoscopic retrograde cholangiopancreatography showing large stone in the proximal bile duct (arrows) and basket extraction of a distal bile duct stone (chevrons) after endoscopic sphincterotomy.

A

B

FIGURE 37C.4  Endoscopic retrograde cholangiopancreatography showing a nondilated bile duct containing a single distal stone (white arrow) (A) and extraction balloon (black arrow, right) (B) placed above the stone immediately before its removal after endoscopic sphincterotomy.

A. Gallstones and Gallbladder  Chapter 37C  Stones in the Bile Duct: Endoscopic and Percutaneous Approaches

A

531

B

FIGURE 37C.5  Endoscopic retrograde cholangiopancreatography series showing technique of balloon dilation of the papilla for extraction of small stones. A, Initial cholangiography with demonstration of three small stones (long arrows, left) and placement of a guidewire and insertion of an 8-mm dilating balloon located between two radiopaque markers (small arrows, right). B, Inflation of the dilating balloon (left) followed by insertion of an extraction basket for stone removal (right).

are greater than 90% successful in clearing the CBD. Occlusion cholangiography is performed after stone extraction to confirm complete ductal clearance.

Difficult Stones Difficulties in extraction of CBD stones are either related to anatomic factors affecting the ability to perform an adequate ES or related to complex morphology of the stones themselves (see Chapters 30 and 37B). An inaccessible papilla may be related to aberrant anatomy or unfavorable duodenal or papillary structures, such as a periampullary diverticulum, or prior surgery, such as Billroth II or Roux-en-Y reconstruction. Techniques have been described for the unique challenge of selective bile duct cannulation in a patient with a Billroth II partial gastrectomy.10 The performance of ES in Billroth II or Roux-en-Y anatomy is also a challenge because the visualized anatomy is inverted. In especially difficult cases, needle-knife sphincterotomy with a stentor guidewire used as a guide may be an option, or specially designed reverse-direction accessories. Roux-en-Y gastric bypass patients pose an extra challenge for the endoscopist due to the long pancreaticobiliary limb. ERCP using overtube-assisted enteroscopy has been performed successfully in patients with Roux-en-Y gastric bypass, with a recent meta-analysis demonstrating a 75% technical success rate and an 8% adverse event rate.13 When ES has been successfully performed, extraction may be hindered by a variety of stone factors, including size, number, consistency, shape, and location of stones, as well as ductal factors such as contour and diameter at the level of and distal to the stones, and the presence of coexisting pathology (e.g., stricture or tumor). Stones that are likely to be more difficult to extract and may require adjuvant techniques to remove them are those that appear larger than the endoscope on radiographic imaging (usually .15 mm); stones that are numerous or hard in consistency; stones that are square, piston shaped, or faceted that tightly fit the bile duct or that are packed against each

other; intrahepatic stones; or stones located proximal to a stricture or narrowed distal bile duct or in a sigmoid-shaped duct. Methods that have been developed to dilate the papillary orifice, reduce stone size, and facilitate endoscopic removal include endoscopic papillary large balloon dilation (EPLBD), ML, intracorporeal lithotripsy with laser or electrohydraulic probes, extracorporeal shockwave lithotripsy (ESWL), and chemical contact dissolution therapy. Treatment options must be discussed jointly by the endoscopist, surgeon, and interventional radiologist when difficulties are encountered (Fig. 37C.6).

Extracorporeal Shockwave Lithotripsy ESWL with a variety of lithotripsy machines is now an alternative to endoscopic management of difficult bile duct stones. In contrast to intracorporeal techniques, direct contact with the stone is unnecessary. Most centers localize stones with fluoroscopic focusing during contrast perfusion of the bile duct through an endoscopically placed nasobiliary catheter or percutaneous drain.14,15 Ponchon et al.16 reported ESWL success with an ultrasound localization system, although it was less effective when multiple stones were present. Several large series indicated success rates for ESWL stone fragmentation of 53% to 91% and duct clearance in 58% to 90%.17–20 Minor complications are common and include biliary pain, hemobilia, transient liver function test elevations, and cutaneous petechiae. Overall, with the use of endoscopic techniques such as ML, EHL, laser lithotripsy, and ESWL, one report showed successful stone removal in 98% of 217 patients, with only 5 patients requiring surgery.21 However, given the high efficacy of newer endoscopic techniques, ESWL is currently rarely used for bile duct stones.

Mechanical Lithotripsy Removal of large CBD stones is a challenge for the most skilled endoscopists (see Chapter 30).22,23 ML remains an excellent option for stones that cannot be removed by conventional

532

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

This procedure can be performed through the endoscope instrumentation channel, or it can be done after the endoscope has been removed from the patient and a metal sheath has been extended over the inner Teflon catheter. The end of the metal sheath is attached to a winding mechanism, which retracts the basket when cranked and impales the stone against the rigid distal end of the metal sheath leading to stone fracturing. The stone fragments can be removed with the same basket or a standard retrieval basket or balloon. In experienced centers, this technique allows removal of more than 90% of difficult bile stones that are refractory to standard extraction techniques, but multiple procedures may be required to achieve complete ductal clearance.24–27

Endoscopic Papillary Large Balloon Dilation

FIGURE 37C.6  Endoscopic retrograde cholangiopancreatography showing a dilated bile duct containing multiple faceted stones in a postcholecystectomy patient positioned such that standard extraction techniques might be difficult.

techniques because it can be used safely and effectively during the initial endoscopic procedure. Mechanical lithotripters are modifications of standard Dormia baskets and possess great tensile strength (Fig. 37C.7). The reinforced basket is opened in the CBD, and the stone is entrapped within the braided wires.

A

EPLBD in conjunction with ES has greatly improved the rates of ductal clearance of difficult stones without the need for advanced ERCP lithotripsy techniques. The first report of EPLBD (12–20 mm) with ES was described in 2003, when a retrospective review demonstrated that 38 out of 40 patients with large stones previously unable to be removed with standard techniques had successful ductal clearance with acceptable complication rates.28 Further research has shown that endoscopic sphincterotomy with EPLBD can obviate the need for ML. A review of seven studies included 902 patients and compared ES with EPBLD versus ES with standard techniques.29 The authors found no differences in ductal clearance between the EPLBD and standard-techniques groups (98% vs. 95%, P 5 .6), but patients in the EPLBD group needed less ML. The use of EPLBD had a relative risk reduction of 0.58 (0.32–0.74) in terms of adverse events. For large bile duct stones (.13 mm), EPLBD results in improved ductal clearance (96% vs. 74%, P , 0.001) with reduced need for ML (3.9% vs. 35.6%, P , 0.001) compared with ES alone.30 Although the studies mentioned in the previous sections demonstrate the safety of EPLBD, there has been concern for the rare but serious complications, such as bleeding, perforation,

B

FIGURE 37C.7  Endoscopic retrograde cholangiopancreatography sequence showing use of transendoscopic mechanical lithotripsy. A, Positioning of the mechanical lithotripsy basket with its metallic sheath in the proximal bile duct (left) and its slow withdrawal toward the distally placed stone to entrap it (right). B, Process of lithotripsy after stone entrapment within the basket (left) as the basket wires cut through the stone (right) to produce stone fragmentation.

A. Gallstones and Gallbladder  Chapter 37C  Stones in the Bile Duct: Endoscopic and Percutaneous Approaches

and pancreatitis related to stretching the ampullary orifice to such a large size. A review of 33 publications including 2924 total procedures compared the complication rates of EPLBD with a large ES, with limited ES, and without ES.31 The rate of adverse events was less than 10% in each group and not significantly different. The rates of severe complications such as pancreatitis (all ,4%) and perforation (all ,0.5%) were acceptable and also not significantly different among the three groups. The rate of bleeding, however, was highest in the large ES group, at 4.1%, which was significantly higher than the limited-ES and no-ES groups (1.3% vs. 1.9%, respectively). A multicenter retrospective study that included 946 patients who underwent EPBLD for CBD stones greater than 10 mm in size sought to determine the predictive factors of adverse events in EPLBD.32 Based on their findings, the authors made the following recommendations: (1) Indication should be patients with a dilated CBD without distal CBD strictures. (2) Avoid full-ES immediately before LBD to prevent perforation and bleeding. (3) Inflate the balloon gradually to recognize an occult stricture. (4) Discontinue balloon inflation if resistance is met in the presence of a persistent balloon waist. (5) Do not inflate the balloon beyond the maximal size of the upstream dilated CBD. (6) Do not hesitate to convert into alternative stone removal methods, such as ML or electrohydraulic lithotripsy (EHL), if there is difficulty in removing stones. If performed correctly (with an incomplete ES and then EPLBD to the size of the CBD), ES with EPLBD is a safe and effective method for removal of multiple or large stones in the CBD, which leads to shorter procedure times with decreased use of lithotripsy techniques.

Electrohydraulic Lithotripsy Since its development during the 1950s in the former Soviet Union as a method to fragment rocks during mining, EHL has been adapted for medical use in the treatment of nephrolithiasis and biliary tract calculi. The electrohydraulic probe consists of two coaxially isolated electrodes at the tip of a flexible catheter, which is capable of delivering electric sparks in short, rapid pulses leading to sudden expansion of the surrounding liquid environment and generating pressure waves that result in stone fragmentation.33 Direct cholangioscopy with either mother-daughter cholangioscopes34 or single-operator cholangioscopy (SOC) systems, such as the SpyGlass DS (Boston Scientific, Natick, MA), are used to directly target stones for fragmentation while avoiding ductal trauma or perforation.35,36 Continuous saline irrigation is used with the bipolar electrode placed near the surface of the stone to provide a medium for shockwave energy transmission, to flush away debris, and to maintain adequate visualization.36 Reports document complete stone clearance after multiple sessions in 86% of patients,34,37–39 and in a prospective nonrandomized trial, EHL was comparable to ESWL in stone clearance.37 The largest study of EHL performed to date is a retrospective review of 407 patients with difficult biliary stones who underwent ERCP with SOC, using either EHL (75.2%) or laser lithotripsy (24.8%). On subgroup analysis, 74.5% of patients who underwent EHL achieved complete stone fragmentation and ductal clearance in a single procedure. Adverse events across the entire study population occurred in 15 patients (3.7%), including 6 with cholangitis and 1 with pancreatitis. The adverse events were classified as mild in 10 of 15 patients (66.7%).40

533

Laser Lithotripsy Reports of the use of a holmium:yttrium-aluminum-garnet (holmium:YAG) laser lithotripsy for choledocholithiasis were first published in 1998.41,42 During holmium laser therapy, continuous ductal irrigation with normal saline is needed to provide a medium for the transfer of energy and to help clear stone fragments.43 Despite the fragmentation of stones, standard techniques such as balloon sweep or mechanical lithotripsy may still be required to completely clear the duct of all debris. A study published in 2007 described how the holmium laser can fragment stones regardless of their composition, whether they are cholesterol, pigment, or calcium stones.44 The holmium laser has a high absorption coefficient in water and therefore has a better safety margin and has more than 100 times the energy absorption than the neodymium laser.45 Despite the safety profile, to prevent bile duct injury, it is necessary to use direct visual control while performing holmium laser lithotripsy, which also allows real-time assessment of any biliary injuries.46,47 Cholangioscopy was classically performed using motherdaughter scopes with two endoscopists, but several recent studies demonstrate the safety and efficacy of the SpyGlass SOC for laser lithotripsy with the holmium:YAG laser. A prospective study in 2011 examined 60 patients with choledocholithiasis who either failed therapy with conventional methods or were referred for management of potentially difficult stone removal.45 Complete ductal clearance using the Spyglass SOC system with the holmium:YAG laser was achieved in 50 patients (83.3%) in one session, and the remaining patients achieved ductal clearance after one additional session. Complications included fever in 3 patients (although these patients were already admitted with cholangitis), postprocedure pain requiring hospital admission in 4 patients, and a biliary stricture in 1 patient who developed a stricture proximal to the stone, which was successfully treated with dilation using a 10-Fr biliary stent for 3 months. The authors were not sure if the stricture was caused by the laser therapy or the stone itself. A multicenter retrospective study demonstrated even higher rates of complete ductal clearance in a single procedure (97%), with a low adverse event rate (4.1%; 2 with minor bleeding of the bile duct wall, 1 patient with mild pancreatitis).48

Endoprosthesis Placement In the few situations in which stone extraction is incomplete or impossible, a nasobiliary tube or an endoprosthesis (Fig. 37C.8) should be inserted to provide biliary decompression and prevent stone impaction in the distal CBD. This is a temporizing therapy to allow the patient’s clinical condition to improve, until complete stone clearance is achieved via additional endoscopic maneuvers or surgery (see Chapters 30 and 37). Nasobiliary tubes are rarely tolerated beyond a few days. Furthermore, problems with tube placement, such as accidental dislodgment, have led to the alternative therapy of temporary biliary endoprosthesis placement.49,50 In a poor-risk surgical patient, ES and long-term placement of a plastic biliary endoprosthesis has been proposed as a nonsurgical alternative.51–54 Of 84 patients intentionally treated with permanent plastic stents for endoscopically irretrievable stones and followed for a mean of 3 years, 49 (58%) developed biliary complications, and 9 died as a result of complications. Most of the patients had a long, symptom-free interval, however, before complications developed, supporting stenting alone as a short-term treatment.55,56 In a randomized study with a short mean follow-up (1.5 years)

534

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

stent removal. Complete ductal clearance was achieved in 15 of 16 (93.7%) patients after the second ERCP. The 13 patients who refused repeat ERCP were followed for more than 6 months without any complications related to stent placement. In patients in whom complete ductal clearance is not feasible on the index ERCP, FC-SEMS placement can greatly improve the chances of success on the subsequent ERCP while also minimizing the need for advanced lithotripsy techniques.

Dissolution Therapy

FIGURE 37C.8  Endoscopic retrograde cholangiopancreatography showing placement of a 10-Fr diameter endoprosthesis for the temporary management of cholangitis caused by several bile duct stones.

that compared placement of a plastic biliary stent with ES as definitive therapy with stone clearance by means of the basket, balloon, or mechanical lithotripter, the patients with stents had a significantly greater rate of cholangitis (36%) than the patients managed by a conventional endoscopic duct clearance approach (14%). The high risk of long-term complications does not support the concept of permanent plastic stent therapy except for patients with severe comorbidity and a short life expectancy. The fully covered self-expanding metal stent (FC-SEMS) was designed to improve patency of traditional self-expanding metal stents by preventing tissue ingrowth in malignant bile duct obstruction. However, the silicone covering on the stent has allowed for delayed stent removal and thus has subsequently been successfully used in an off-label fashion for benign biliary diseases, such as benign biliary strictures and complex bile duct stones.57,58 It has been postulated that the friction between the stones and the stent reduces the stone size, and that the radial dilating force of the stent across the papilla further assists in the clearance of choledocholithiasis.59,60 A retrospective review studied 36 patients with complex biliary stones who had incomplete ductal clearance despite the use of advanced extraction techniques.61 All patients had successful biliary drainage after the initial SEMS was placed. Thirty-three patients (94%) had complete ductal clearance after a mean of 2.2 ERCP sessions. There were no immediate or delayed complications related to FCSEMS placement or removal, and only 4 patients had spontaneous migration of stents that were deemed clinically insignificant. Another retrospective review evaluated 29 patients with longterm FC-SEMS placement for the management of difficult CBD stones that could not be removed by standard or advanced techniques.59 All patients had successful procedures in terms of biliary drainage, and the stents were left in place for a median of 200 days. After ERCP, 13 of the patients refused repeat procedures, and therefore only 16 patients returned for successful

Contact chemical dissolution of stones has been attempted by perfusing the CBD with solvents administered via an indwelling nasobiliary tube, percutaneous transhepatic catheter, cholecystostomy tube, or an existing T-tube. The initial results with these agents were disappointing because of incomplete stone dissolution and complications. A semisynthetic vegetable oil, monooctanoin, composed of 70% glycerol-1-monooctanoate and 30% glycerol-1,2-dioctanoate, was used experimentally for the dissolution of CBD stones beginning in 1977. Results collected from 222 clinicians treating 343 patients with CBD stones between 1977 and 1983 reported a success rate for complete stone dissolution of only 25.6% and an additional partial success rate of 28%.62 Serious adverse events leading to discontinuation of treatment occurred in 5% of patients, including hemorrhage from duodenal ulceration, acute pancreatitis, jaundice, pulmonary edema, acidosis, anaphylaxis, septicemia, and leukopenia, but no deaths were reported. The use of organic solvents, such as the aliphatic ether methyl tert-butyl ether,63 also has been disappointing, with complete stone dissolution achieved in only 30% to 45% and an unacceptable complication rate related to systemic absorption from spillover of solvent into the duodenum and intrahepatic bile ducts.64–68 Expectations of developing a solvent-chelating agent (ethylenediaminetetraacetic acid) for pigment stones have not been realized. As a result of its low efficacy and morbidity, contact dissolution therapy has not assumed an important role in patients with refractory CBD stones, and newer agents with better methods for instillation are awaited.

RESULTS OF ENDOSCOPIC THERAPY (SEE CHAPTER 30) Successful endoscopic treatment of CBD stones requires an adequate ES, which is now achieved in greater than 90% of attempts in most reported series, with noticeable improvement as experience increases.3,21,69–74 Most experts now would expect to extract stones in at least 90% of successful sphincterotomies. Reported success rates should be interpreted with caution because centers with greater expertise are more likely to be referred difficult cases that may be failures from attempts elsewhere, biasing results. Patient characteristics also vary considerably from unit to unit and country to country, reflecting different referral patterns, patient selection, and attitudes toward endoscopic therapy. Results from centers around the world with individual and collected series of 430 to 9041 patients range from 75% to 96% for duct clearance, with a median value of 91%.21,69–80

Complications of Endoscopic Therapy (see Chapter 30) Despite the disparate indications and selection of patients among centers, the overall incidence of ERCP-related complications seems to be remarkably consistent and ranges between 5% and 10%.69–75,81–83 A comprehensive review of all major prospective ERCP trials (16,855 patients) revealed the following

A. Gallstones and Gallbladder  Chapter 37C  Stones in the Bile Duct: Endoscopic and Percutaneous Approaches

specific complication rates: acute pancreatitis, 3.5% (range, 1.0%–8.7%); cholecystitis or cholangitis, 1.4% (range, 0%–5%); acute hemorrhage from sphincterotomy site, 1.3% (range, 0.3%–6.2%); perforation, 0.6% (range, 0%–6.2%); and small numbers of other rare complications, such as impacted basket and gallstone ileus. Complication rates must be interpreted with caution because definitions of hemorrhage, acute pancreatitis, cholangitis, and perforation often differ, although many studies use consensus definitions.84 Post-ERCP pancreatitis is defined as a rise in serum amylase to at least three times the upper limit of normal with accompanying typical pain of pancreatitis, leading to either a hospital admission or prolongation of current hospitalization (see Chapter 55). It is important to recognize that isolated asymptomatic hyperamylasemia after ERCP is a common and expected finding. Post-ERCP pancreatitis is managed like any typical bout of acute pancreatitis (see Chapter 56), and although most attacks are mild and self-limited, clinicians must remain vigilant in diagnosing severe pancreatitis. Wire-guided cannulation decreases the rate of post-ERCP pancreatitis by approximately 50% compared with conventional contrast-guided approaches.85 Risk factors for post-ERCP pancreatitis include suspected sphincter of Oddi dysfunction, prior history of post-ERCP pancreatitis, female patients, young age, difficult cannulation, and contrast injections into the pancreatic duct.75,86–88 Prophylactic pancreatic ductal stent placement and periprocedural administration of rectal nonsteroidal antiinflammatory drugs, such as diclofenac and indomethacin, each reduce the risk of post-ERCP pancreatitis by 50%.89 The combined protective effect of pancreatic stents and rectal nonsteroidal antiinflammatory drugs is the subject of ongoing study. A new, highly potent protease inhibitor, nafamostat mesylate, has shown significant efficacy in early trials; however, larger clinical studies are needed.90 Postsphincterotomy bleeding is often recognized immediately after the sphincterotomy, but some patients may have delayed bleeding. Although there is a paucity of data, use of antiplatelet agents does not appear to increase the risk of bleeding. Controlled sphincterotomy technique with the use of blended current, while avoiding the “zipper” cut, is a recommended method to prevent bleeding. In patients with delayed bleeding, symptoms are similar to any routine upper gastrointestinal bleed, including hemodynamic changes and melena. Mild cholestasis may be evident due occlusion of the biliary orifice with blood clots. Mild to moderate bleeding can often be controlled with endoscopic techniques, including balloon tamponade of the sphincterotomy site, injection of dilute epinephrine (1:10,000), bipolar cautery, and placement of hemostatic clips.91–93 Temporary placement of FC-SEMS can provide durable hemostasis through long-term tamponade of the bleeding site, with efficacy demonstrated in a small case series.94 In rare cases of major arterial hemorrhage, the endoscopic view of the papillary area is obscured by blood, precluding any further endoscopic therapies. In these patients, angiography with superselective embolization of the active bleeding site has been shown to be highly effective.95 Accordingly, surgical management for post-ERCP bleeding has become very uncommon in hospitals with interventional radiology services. Duodenal perforation is relatively rare and is either a small retroperitoneal perforation related to the sphincterotomy or a large duodenal perforation from the shaft of the scope. The perforation may be asymptomatic and noticed only as retroperitoneal gas (Fig. 37C.9) or extravasation of radiographic contrast material, but even in a symptomatic patient conservative

535

FIGURE 37C.9  Computed tomography scan of the stomach, with oral contrast administration showing extensive retroperitoneal, intraperitoneal, and subcutaneous air caused by a perforation from endoscopic sphincterotomy. The patient made an uneventful recovery on conservative treatment.

treatment is often effective, with spontaneous resolution and avoidance of potentially difficult surgery. Occasionally, this complication presents late after ES with a retroperitoneal collection of bile or pus in the flank or inguinal region72,96 and requires percutaneous or surgical drainage. Post-ERCP cholangitis is confined almost completely to patients in whom CBD clearance has not been achieved, and measures should be directed at providing adequate biliary drainage (e.g., by nasobiliary catheter or endoprosthesis) and administering parenteral antibiotics. Gallstone ileus is a rare complication, but its recognition needs to be emphasized because symptoms may be obscure in elderly patients, and they occur many days after ERCP and stone release; treatment is along standard surgical lines (see Chapter 43). The impaction of an extraction basket within the bile duct during stone extraction occurs rarely in experienced hands because many endoscopic maneuvers have been learned to prevent or salvage this situation. These maneuvers include (1) avoiding basket closure during initial attempts to extract a large stone to prevent impaling the basket wires in the stone surface, (2) converting the standard basket into a crushing type by replacing the handle with a mechanical lithotripter, and (3) extending the ES incision by removing the duodenoscope over the impacted basket catheter and reintroducing it alongside the catheter, introducing a second duodenoscope, or passing a sphincterotome along the same instrument channel as the impacted basket catheter when using large-channel (3.7 mm or 4.2 mm) endoscopes. Death after ERCP is a rare event, with a mortality rate directly attributable to the procedure ranging between 0% and 0.94%, with an average of 0.3%,81 with roughly equal distribution of causes between hemorrhage, pancreatitis, cholangitis, and perforation.

Long-Term Morbidity Reports on long-term follow-up ranging from 1 to 15 years after ERCP with ES in postcholecystectomy patients have demonstrated that more than 90% of patients are well on symptomatic

536

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

review, and 7% to 11% have significant symptoms secondary to recurrent stones (5%), with or without stenosis of the ES site (1.5%–3%) and cholangitis (2%).69,73,97–101 Most of these long-term complications are amenable to further endoscopic treatment.

LAPAROSCOPIC AND PERCUTANEOUS APPROACHES TO BILE DUCT STONES Laparoscopic Common Bile Duct Exploration (see Chapter 37B) Laparoscopic CBD exploration was first performed in the early 1990s and typically performed at experienced tertiary referral centers.102–104 Ductal exploration may be accomplished through the cystic duct or directly through a choledochotomy. The transcystic route is the least invasive and generally does not require any direct ductal manipulation or drainage procedure, whereas choledochotomy requires either closure of the duct over a Ttube or primary closure of the choledochotomy with or without a biliary stent placed in an antegrade fashion without need for a T-tube.104,105 Bile duct clearance rates average 90%, with a median rate of conversion to open operation of 4%.106 Complication rate is 2.5%, with a median mortality rate of 1%.107 Multiple randomized clinical trials have been performed comparing single-stage laparoscopic CBD exploration at the time of cholecystectomy versus a two-stage approach with ERCP preceding or following laparoscopic cholecystectomy.108–111 The results of these trials have been strikingly similar, demonstrating similar ductal clearance rates for both groups with comparable rates of complications and mortality. Recent meta-analyses have conflicting results, with one meta-analysis favoring the singlestage surgical approach and the other meta-analysis favoring preoperative ERCP followed by cholecystectomy.112,113 These conflicting conclusions reflect the similarity in outcomes between these two approaches. In studies that examined hospital parameters, the single-stage surgical approach was associated with a shorter length of stay and reduced hospital costs. Length of stay and associated hospital costs can be reduced with improved coordination between the surgeon and the endoscopist. Although the single-stage approach appears at least equivalent to the two-stage approach, implementation of this strategy is restricted to centers with significant expertise in laparoscopic bile duct exploration. Conversely, most facilities have ready access to ERCP services, and thus a two-stage approach is the most common strategy in the United States.

Percutaneous Approach (see Chapters 31 and 35) In the 5% to 10% of patients for whom the endoscopic approach is unsuccessful at clearing the CBD of stones, two nonsurgical approaches are available: a rendezvous procedure and a complete percutaneous procedure. If the papillary region can be reached endoscopically and deep biliary cannulation is unable to be achieved, a rendezvous procedure may be used. Although typically used for patients with obstructive jaundice from pancreaticobiliary malignancy, this technique can be used for choledocholithiasis in patients with surgically altered anatomy, such as a Billroth II, or in patients with challenging papillary anatomy, such as a large periampullary diverticulum. This involves a two-stage procedure with the introduction of a percutaneous guidewire through the bile ducts and papilla into the duodenum in the first stage, followed by an ERCP.114–117 In one report of

rendezvous procedures for choledocholithiasis, 0.9% (15/1753) of ERCPs were unsuccessful at biliary cannulation, usually owing to duodenal diverticula or Billroth II anatomy.118 Three patients underwent surgery, and 93% of the remaining patients underwent a successful rendezvous procedure. There was one complication with a retroperitoneal perforation that required surgical management, and during follow-up, only one patient developed recurrent choledocholithiasis, requiring a repeat rendezvous procedure. In a multicenter prospective trial of endoscopic biliary sphincterotomy complications,75 the combined endoscopic-percutaneous approach was a risk factor for the development of complications, with a high rate of complications at 22.6% (6.5% classified as severe). EUS-guided rendezvous procedures have emerged as a viable alternative to percutaneous rendezvous approaches for bile duct access in patients with unsuccessful biliary cannulation119 (see Chapters 30 and 35). The complete percutaneous approach has been established as treatment for hepatolithiasis120 (see Chapters 39 and 44), but it may also be used for choledocholithiasis. Historically, the procedure involves initial establishment of a transhepatic fistula, followed by stone extraction under fluoroscopy or cholangioscopy 7 to 8 days after the fistula forms. In a series of 31 patients with failed endoscopic procedures, percutaneous biliary access was achieved in all patients, and stone clearance was complete in 87% after a mean of 5.6 sessions.121 All patients underwent balloon dilation of the papilla, and most patients required additional means of stone fragmentation, including ML, EHL, and ESWL. Complications including pancreatitis and bacteremia occurred in 9.7% and did not require surgical intervention. The 4 patients who did not respond to percutaneous management underwent surgery. Recent advances in the percutaneous approach to bile duct stones have focused on antegrade expulsion of the stones into the duodenum using a Fogarty-type balloon after dilation of the biliary sphincter (sphincteroplasty). This requires a much smaller bore tract as compared with percutaneous extraction of biliary stones. Large series have demonstrated high clinical success with the percutaneous approach (95%) with a 7% major complication rate, including cholangitis, subcapsular hematoma, subcapsular abscess, and arterial injury.122 In most centers, the percutaneous approach to bile duct stones is limited to patients where ERCP is not feasible due to anatomic considerations.

SPECIFIC CLINICAL SCENARIOS Pregnancy Symptomatic choledocholithiasis during pregnancy poses a diagnostic and therapeutic challenge. Biliary tract stone disease occurs in approximately 1.5% of pregnancies.123 Endoscopic treatment can be performed safely in pregnant patients using techniques to minimize fluoroscopy.124–127 A recent retrospective study using the Nationwide Inpatient Sample demonstrated a higher risk of post-ERCP pancreatitis in pregnant patients (12%) compared with control patients (5%); multivariable analysis confirmed pregnancy was an independent risk factor for post-ERCP pancreatitis.128

Patients With Gallbladder in Situ (see Chapters 37 and 38) In elderly patients or in patients with significant comorbidity, a deliberate decision often is made to leave the gallbladder in situ after ERCP and CBD stone removal. The short- and long-term

A. Gallstones and Gallbladder  Chapter 37C  Stones in the Bile Duct: Endoscopic and Percutaneous Approaches

results and complications of ERCP with ES in patients with gallbladders do not differ from those in postcholecystectomy patients.129 The risk of deferring cholecystectomy was examined in a study of 120 patients with known gallstones who underwent successful ERCP with bile duct clearance. The study excluded patients who were not surgical candidates, and patients were randomized to laparoscopic cholecystectomy within 6 weeks after ERCP or a wait-and-see policy with median 2.5-year followup. Nearly half the patients in the wait-and-see group developed biliary-related problems, including biliary pain and cholecystitis, which led to cholecystectomy or repeat ERCP or both, whereas none of the patients in the cholecystectomy group experienced biliary-related problems. The wait-and-see group also had a higher rate of conversion to an open procedure at the time of surgery.130 A meta-analysis of randomized trials comparing the wait-and-see approach with elective cholecystectomy confirmed these findings, with a higher risk of biliary pain (relative risk, 14.6) and cholangitis (relative risk, 2.5) in patients who deferred cholecystectomy.131 The risk of these future biliary complications needs to be balanced with operative risk in patients with significant underlying comorbidity.

Suspected Choledocholithiasis (see Chapters 33, 34, and 37) In patients with suspected choledocholithiasis, it is imperative to perform a risk assessment for the presence of CBD stones before cholecystectomy. The following algorithm accounts for the relative efficacy, safety, and cost-effectiveness of each procedure and imaging study.132 Patients with any very strong predictor of CBD stones (visualized CBD stone on imaging, cholangitis, or bilirubin .4) or two strong predictors of CBD stones (dilated CBD .6 mm, bilirubin between 1.8 and 4) should undergo preoperative ERCP. Moderate predictors are any other abnormal liver function tests, age older than 55 years, and gallstone pancreatitis. Patients without any very strong, strong, or moderate predictors are deemed low risk for CBD stones and should proceed directly to cholecystectomy. All remaining patients are at intermediate risk for CBD stones and should either undergo preoperative MRCP or EUS, followed by ERCP if CBD stones are visualized. Alternatively, depending on local expertise, these intermediate-risk patients can proceed with laparoscopic cholecystectomy with intraoperative cholangiogram; patients can then proceed with laparoscopic bile duct exploration or undergo postoperative ERCP. In patients who undergo preoperative ERCP, it is important to minimize the time between the ERCP and cholecystectomy, to reduce the risk of recurrent CBD stones before surgery. Subsequent studies have found this algorithm to be moderately accurate (60%–70%) for predicting the presence of CBD stones; the remaining patients did not have CBD stones on ERCP despite having criteria suggestive of choledocholithiasis.133,134

Acute Cholangitis (see Chapter 43) Acute cholangitis resulting from CBD stones traditionally was managed by supportive measures and parenteral antibiotics, followed by early surgery if improvement was slow or absent. In early reports, the mortality from emergency surgery ranged from 12% to 16%, with higher rates for elderly patients.69,135,136 The only randomized trial of emergency endoscopic versus surgical management of severe calculous cholangitis137 showed a 3-fold difference in mortality rate (10% vs. 32%; P , .03) in favor of ERCP. In patients who are hemodynamically stable, it is reasonable

537

to proceed with ES during ERCP with removal of all calculi. Care must be taken to minimize aggressive contrast injection (particularly during balloon-occluded cholangiography) to reduce the potential risk of bacteremia from the procedure. In patients with hemodynamic compromise, procedure duration can be minimized using a two-stage approach, placing a plastic biliary stent without sphincterotomy to achieve biliary decompression, which leads to resolution of cholangitis.138 After the patient’s clinical status has improved, a second ERCP can be performed with ES, allowing complete ductal clearance of CBD stones.

Gallstone Pancreatitis (see Chapters 55 and 56) Acute pancreatitis resulting from gallstones in the ampulla of Vater was first reported by Opie in 1901.139 From his observations in this study, an “obstructive theory” was derived to explain the mechanism responsible for gallstone pancreatitis. Current evidence suggests that transient stone impaction in the common channel of the pancreatic duct and CBD causes increased pancreatic ductal pressure with associated inappropriate activation of pancreatic enzymes.140 In support of the obstructive theory, gallstones can be recovered from the feces of 85% to 95% of patients,141–143 and the incidence of CBD stones is 80% in patients undergoing urgent operative or endoscopic intervention compared with a 5% to 30% incidence when the procedure is delayed.142–146 The Ranson, Imrie, Glasgow, and Acute Physiology, Age, and Chronic Health Evaluation (APACHE II) assessments provide well-established criteria for assessing the severity of pancreatitis and predicting local adverse events—such as necrosis, hemorrhage, infection, and pseudocyst formation—and systemic complications of acute respiratory distress syndrome, disseminated intravascular coagulation, distant fat necrosis, and renal failure.147 Stratifying patients by severity based on these criteria has been helpful in directing appropriate management. Most patients experience mild pancreatitis resulting from transient impaction of a stone in the ampulla, followed by spontaneous migration into the duodenum. These patients do well with conservative therapy alone and are unlikely to benefit from urgent intervention. In contrast, it has been proposed that more severe cases of pancreatitis result from persistent stone impaction or choledocholithiasis with infected bile, suggesting the possibility that early stone extraction by surgical or endoscopic techniques would halt progression of the acute event and prevent the development of future attacks in the short term. Early surgical therapy in cases of acute biliary pancreatitis (ABP) has been challenged owing to the high operative morbidity and mortality. Results and conclusions from numerous series comparing early and late surgical therapy in gallstone pancreatitis are difficult to interpret. The mortality rates range from 2% to 67%, studies are retrospective with frequent comparisons to historical controls, and stratification for severity of illness has not been used.144,145,148,149 In one study, Kelly and Wagner150 prospectively randomized 165 patients with gallstone pancreatitis to early or delayed surgery. In the group with severe pancreatitis, mortality was 48% after urgent operative intervention compared with 11% mortality rate in patients in whom surgery for gallstones was delayed for more than 48 hours. In contrast, patients with mild pancreatitis had mortality rates of 3.3% and 0%, respectively. Another study of moderate to severe gallstone pancreatitis with peripancreatic fluid collections confirmed these results, with complications in 44% of patients in the early surgery group compared with 6% in the delayed surgery group.151

538

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

The results of these aforementioned studies favor avoidance of early operative intervention in the acute phase of biliary pancreatitis, as the previous surgical dictum was that inflammation and edema from pancreatitis can distort biliary anatomy, which would complicate surgery and predispose patients to bile duct injury.152 However, recent robust clinical data have challenged this thought process, leading to a paradigm shift favoring cholecystectomy during the initial hospitalization for ABP, once the acute inflammatory process has improved (see Chapters 34 and 36). A UK study retrospectively reviewed admissions to the hospital while awaiting an elective outpatient cholecystectomy after an episode of biliary pancreatitis.153 Of the 58 patients awaiting laparoscopic cholecystectomy, 21% had unplanned readmissions if waiting for more than 28 days. No patients who had cholecystectomy within 28 days had recurrent admissions. The presence of a sphincterotomy did not affect readmission rates despite the fact that no patients with ES returned with ABP, as they instead returned with cholecystitis or biliary colic. These results were echoed by another European study that retrospectively analyzed 80 patients with ABP who had ERCP with ES.154 The authors found a 60% rate of recurrent biliary complications (pancreatitis, symptomatic choledocholithiasis, colic) in patients who delayed cholecystectomy versus 2% in the group who underwent early cholecystectomy (P , .0001). A multicenter randomized control trial of 266 patients with mild gallstone pancreatitis has been performed. In this study, 129 patients were randomly assigned to same-admission cholecystectomy within 3 days, whereas 137 were randomized to interval cholecystectomy within 25 to 30 days.152 Readmission for gallstone-related complications (pancreatitis, cholecystitis, cholangitis, jaundice, colic) was significantly more common in the interval group than the same-admission group (17% vs. 5%, P 5 .002). These results remained significant when comparing patients with endoscopic sphincterotomy in a subgroup analysis. As with the previous retrospective studies, there was no difference in length of stay, difficulty of surgery, conversions from laparoscopic to open surgery, or healthcare use between the two groups. Because of this paradigm shift in the surgical management of biliary pancreatitis, along with the change in guidelines recommending cholecystectomy on the index admission, a retrospective review studied how the implementation of an acute care surgery (ACS) service for biliary disease affected outcomes in biliary pancreatitis.155,156 The rate of index cholecystectomy increased from 2.4% to 67% (P , .001) after the implementation of the ACS service, which correlated with a decrease in readmission rate for biliary-related disease from 16.8% to 7.3% (P 5 .04). Although an ACS service is not a new concept, the study demonstrates the importance of inpatient consultation and prompt evaluation by a surgical service that adheres to the current management guidelines. The data regarding cholecystectomy in patients with severe ABP with complications such as multiorgan failure or necrosis are not as robust, and a Cochrane Review states that there is currently no evidence to support or refute early laparoscopic cholecystectomy for patients with severe acute pancreatitis.157 Usually, a delay in surgery in these patients is secondary to critical illness or while awaiting other surgical or endoscopic treatments for complications of pancreatitis such as symptomatic pseudocysts or walled-off pancreatic necrosis. In patients who are too ill or have limiting comorbidities (severe coronary artery disease, cirrhosis) to tolerate any type of surgery, there is

a potentially protective effect of an endoscopic sphincterotomy in preventing further biliary complications, although the data for the role of ES in lieu of a cholecystectomy for a high-risk patient in the absence of choledocholithiasis are limited.158 In the acute setting, an endoscopic approach to biliary pancreatitis offers the theoretical advantage of immediate relief of biliary obstruction and ductal clearance without the risks of surgery. As animal models and human studies have suggested that the duration of biliary obstruction is a critical factor in determining the severity of pancreatitis, early resolution of obstruction with ERCP would theoretically ameliorate the course of the disease.159 The timing of ERCP in ABP has been controversial, and until recently, many studies did suggest a role for early ERCP.160 Three often-quoted studies in previous guidelines and reviews gave the antecedent evidence that early ERCP (within 72 hours) and sphincterotomy reduced complications in ABP.161–163 These studies included patients with conditions that necessarily required ERCP (cholangitis, jaundice), and therefore the question of a biliary sphincterotomy in all patients with ABP was not adequately addressed. A randomized multicenter European study avoided these confounding variables by examining the role of early ERCP with sphincterotomy in patients with ABP without cholangitis or jaundice.164 Two hundred thirty-eight patients were randomly assigned to early ERCP (within 72 hours) or conservative treatment. The overall mortality and complication rates were similar between the two groups regardless of the severity of pancreatitis, but the rate of serious respiratory failure was higher in the invasive group (P 5 .03). A meta-analysis published in 2009 of the seven known well-designed, randomized, controlled trials on this topic confirms these same findings.165 According to the published data, the current practice management guidelines state that early ERCP is not needed in patients with ABP who lack the laboratory or clinical evidence of ongoing biliary obstruction or cholangitis. In the absence of jaundice or cholangitis, noninvasive methods such as MRCP and EUS should be used to screen for choledocholithiasis.156,160

CONCLUSIONS Endoscopic management of choledocholithiasis is widely accepted as a highly effective therapy for CBD stones. Endoscopic techniques are well established, and accessories have been developed to enhance success and safety. ERCP with ES is the standard of care in the management of CBD stones in most clinical situations, regardless of the presence or absence of the gallbladder. Improvements in endoscopic techniques allow for the management of complex bile duct stone disease. The endoscopic removal of stones in the perioperative period has been shown to be effective, minimizing the need for surgical CBD exploration. Patients with acute cholangitis should be considered for urgent endoscopic management. ERCP is generally not indicated in the management of gallstone pancreatitis in the absence of associated obstructive jaundice or cholangitis. Integrated, multidisciplinary therapy where surgeons, interventional radiologists, and endoscopists collaborate closely together allows for the development and evaluation of new procedural techniques, as well as the optimal management of patients with both routine and complex biliary stone disease. References are available at expertconsult.com.

538.e1

REFERENCES 1. Classen M, Demling L. Endoskopische Sphinkterotomie der Papilla Vateri und Steinextraktion aus dem Ductus choledochus [Endoscopic sphincterotomy of the papilla of vater and extraction of stones from the choledochal duct (author’s transl)]. Dtsch Med Wochenschr. 1974;99(11):496-497. doi:10.1055/s-0028-1107790. 2. Kawai K, Akasaka Y, Murakami K, Tada M, Koli Y. Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc. 1974;20(4):148-151. doi:10.1016/s0016-5107(74)73914-1. 3. Blumgart LH, Wood CB. Endoscopic treatment of biliary-tract diseases. Lancet. 1978;2(8102):1249. doi:10.1016/s0140-6736(78) 92115-3. 4. ASGE Standards of Practice Committee, Early DS, Ben-Menachem T, et al. Appropriate use of GI endoscopy. Gastrointest Endosc. 2012;75(6):1127-1131. doi:10.1016/j.gie.2012.01.011. 5. ASGE Standards of Practice Committee, Maple JT, Ikenberry SO, et al. The role of endoscopy in the management of choledocholithiasis [published correction appears in Gastrointest Endosc. 2012 Jan;75(1):230-230.e14]. Gastrointest Endosc. 2011;74(4):731-744. doi:10.1016/j.gie.2011.04.012. 6. Baron TH, Harewood GC. Endoscopic balloon dilation of the biliary sphincter compared to endoscopic biliary sphincterotomy for removal of common bile duct stones during ERCP: a metaanalysis of randomized, controlled trials. Am J Gastroenterol. 2004;99(8): 1455-1460. doi:10.1111/j.1572-0241.2004.30151.x. 7. Bergman JJ, Rauws EA, Fockens P, et al. Randomised trial of endoscopic balloon dilation versus endoscopic sphincterotomy for removal of bileduct stones. Lancet. 1997;349(9059):1124-1129. doi:10.1016/S0140-6736(96)11026-6. 8. Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology. 2004;127(5):1291-1299. doi:10.1053/j. gastro.2004.07.017. 9. Mavrogiannis C, Liatsos C, Romanos A, Petoumenos C, Nakos A, Karvountzis G. Needle-knife fistulotomy versus needle-knife precut papillotomy for the treatment of common bile duct stones. Gastrointest Endosc. 1999;50(3):334-339. doi:10.1053/ge.1999.v50. 98593. 10. Lin LF, Siauw CP, Ho KS, Tung JC. ERCP in post-Billroth II gastrectomy patients: emphasis on technique. Am J Gastroenterol. 1999;94(1):144-148. doi:10.1111/j.1572-0241.1999.00785.x. 11. Wright BE, Cass OW, Freeman ML. ERCP in patients with longlimb Roux-en-Y gastrojejunostomy and intact papilla. Gastrointest Endosc. 2002;56(2):225-232. doi:10.1016/s0016-5107(02)70182-x. 12. Bergman JJ, van Berkel AM, Bruno MJ, et al. A randomized trial of endoscopic balloon dilation and endoscopic sphincterotomy for removal of bile duct stones in patients with a prior Billroth II gastrectomy. Gastrointest Endosc. 2001;53(1):19-26. doi:10.1067/mge. 2001.110454. 13. Klair JS, Jayaraj M, Chandrasekar VT, et al. ERCP with overtubeassisted enteroscopy in patients with Roux-en-Y gastric bypass anatomy: a systematic review and meta-analysis. Endoscopy. 2020;52(10):824-832. doi:10.1055/a-1178-9741. 14. Gordon SJ, Stampfl DA, Grimm IS, Dahnert W, Goldberg BB, Taglienti G. Successful shock-wave lithotripsy of bile duct stones using ultrasound guidance. Dig Dis Sci. 1991;36(8):1102-1109. doi:10.1007/BF01297454. 15. White DM, Correa RJ, Gibbons RP, Ball TJ, Kozarek RJ, Thirlby RC. Extracorporeal shock-wave lithotripsy for bile duct calculi. Am J Surg. 1998;175(1):10-13. doi: 10.1016/s0002-9610(97) 00234-1. 16. Ponchon T, Martin X, Barkun A, Mestas JL, Chavaillon A, Boustière C. Extracorporeal lithotripsy of bile duct stones using ultrasonography for stone localization. Gastroenterology. 1990;98(3): 726-732. doi:10.1016/0016-5085(90)90295-c. 17. Bland KI, Jones RS, Maher JW, et al. Extracorporeal shock-wave lithotripsy of bile duct calculi. An interim report of the Dornier U.S. Bile Duct Lithotripsy Prospective Study. Ann Surg. 1989; 209(6):743-755. doi:10.1097/00000658-198906000-00012. 18. Gilchrist AM, Ross B, Thomas WE. Extracorporeal shockwave lithotripsy for common bile duct stones. Br J Surg. 1997;84(1): 29-32. 19. Sackmann M, Holl J, Sauter GH, Pauletzki J, von Ritter C, Paumgartner G. Extracorporeal shock wave lithotripsy for clearance

of bile duct stones resistant to endoscopic extraction. Gastrointest Endosc. 2001;53(1):27-32. doi:10.1067/mge.2001.111042. 20. Sauerbruch T, Stern M. Fragmentation of bile duct stones by extracorporeal shock waves. A new approach to biliary calculi after failure of routine endoscopic measures. Gastroenterology. 1989; 96(1):146-152. doi:10.1016/0016-5085(89)90775-0. 21. Schumacher B, Frieling T, Haussinger D, Niederau C. Endoscopic treatment of symptomatic choledocholithiasis. Hepatogastroenterology. 1998;45(21):672-676. 22. Leung JW, Tu R. Mechanical lithotripsy for large bile duct stones. Gastrointest Endosc. 2004;59(6):688-690. doi:10.1016/s0016-5107 (04)00174-9. 23. Leung JW, Neuhaus H, Chopita N. Mechanical lithotripsy in the common bile duct. Endoscopy. 2001;33(9):800-804. 24. Akcakaya A, Ozkan OV, Bas G, et al. Mechanical lithotripsy and/or stenting in management of difficult common bile duct stones. Hepatobiliary Pancreat Dis Int. 2009;8(5):524-528. 25. Chang WH, Chu CH, Wang TE, Chen MJ, Lin CC. Outcome of simple use of mechanical lithotripsy of difficult common bile duct stones. World J Gastroenterol. 2005;11(4):593-596. doi:10.3748/ wjg.v11.i4.593. 26. Shaw MJ, Mackie RD, Moore JP, et al. Results of a multicenter trial using a mechanical lithotripter for the treatment of large bile duct stones. Am J Gastroenterol. 1993;88(5):730-733. 27. Van Dam J, Sivak Jr MV. Mechanical lithotripsy of large common bile duct stones. Cleve Clin J Med. 1993;60(1):38-42. doi:10.3949/ ccjm.60.1.38. 28. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc. 2003;57(2):156-159. doi:10.1067/mge.2003.52. 29. Madhoun MF, Wani S, Hong S, Tierney WM, Maple JT. Endoscopic papillary large balloon dilation reduces the need for mechanical lithotripsy in patients with large bile duct stones: a systematic review and meta-analysis. DiagnTher Endosc. 2014;2014:309618. doi:10.1155/2014/309618. 30. Karsenti D, Coron E, Vanbiervliet G, et al. Complete endoscopic sphincterotomy with vs. without large-balloon dilation for the removal of large bile duct stones: randomized multicenter study. Endoscopy. 2017;49(10):968-976. doi:10.1055/s-0043-114411. 31. Kim JH, Yang MJ, Hwang JC, Yoo BM. Endoscopic papillary large balloon dilation for the removal of bile duct stones. World J Gastroenterol. 2013;19(46):8580-8594. doi:10.3748/wjg.v19.i46.8580. 32. Park SJ, Kim JH, Hwang JC, et al. Factors predictive of adverse events following endoscopic papillary large balloon dilation: results from a multicenter series. Dig Dis Sci. 2013;58(4):1100-1109. doi:10.1007/s10620-012-2494-8. 33. Picus D. Intracorporeal biliary lithotripsy. Radiol Clin North Am. 1990;28(6):1241-1249. 34. Hixson LJ, Fennerty MB, Jaffee PE, Pulju JH, Palley SL. Peroral cholangioscopy with intracorporeal electrohydraulic lithotripsy for choledocholithiasis. Am J Gastroenterol. 1992;87(3):296-299. 35. Aljebreen AM, Alharbi OR, Azzam N, Almadi MA. Efficacy of spyglass-guided electrohydraulic lithotripsy in difficult bile duct stones. Saudi J Gastroenterol. 2014;20(6):366-370. doi:10.4103/ 1319-3767.145329. 36. DiSario J, Chuttani R, Croffie J, et al. Biliary and pancreatic lithotripsy devices. Gastrointest Endosc. 2007;65(6):750-756. doi:10. 1016/j.gie.2006.10.002. 37. Adamek HE, Maier M, Jakobs R, Wessbecher FR, Neuhauser T, Riemann JF. Management of retained bile duct stones: a prospective open trial comparing extracorporeal and intracorporeal lithotripsy. Gastrointest Endosc. 1996;44(1):40-47. doi:10.1016/s00165107(96)70227-4. 38. Arya N, Nelles SE, Haber GB, Kim YI, Kortan PK. Electrohydraulic lithotripsy in 111 patients: a safe and effective therapy for difficult bile duct stones. Am J Gastroenterol. 2004;99(12):2330-2334. doi:10.1111/j.1572-0241.2004.40251.x. 39. Siegel JH, Ben-Zvi JS, Pullano WE. Endoscopic electrohydraulic lithotripsy. Gastrointest Endosc. 1990;36(2):134-136. doi:10.1016/ s0016-5107(90)70967-4. 40. Brewer Gutierrez OI, Bekkali NLH, Raijman I, et al. Efficacy and safety of digital single-operator cholangioscopy for difficult biliary stones. Clin Gastroenterol Hepatol. 2018;16(6):918-926.e1. doi:10. 1016/j.cgh.2017.10.017.

538.e2 41. Burdick JS, Magee DJ, Hernandez EJ, Clark PJ, Miller G. Holmium laser for treatment of left hepatic duct stone. Gastrointest Endosc. 1998;48(5):523-526. doi:10.1016/s0016-5107(98)70098-7. 42. Das AK, Chiura A, Conlin MJ, Eschelman D, Bagley DH. Treatment of biliary calculi using holmium: yttrium aluminum garnet laser. Gastrointest Endosc. 1998;48(2):207-209. doi:10.1016/s00165107(98)70167-1. 43. Lee TY, Cheon YK, Choe WH, Shim CS. Direct cholangioscopybased holmium laser lithotripsy of difficult bile duct stones by using an ultrathin upper endoscope without a separate biliary irrigating catheter. Photomed Laser Surg. 2012;30(1):31-36. doi:10. 1089/pho.2011.3094. 44. Yates J, Zabbo A, Pareek G. A comparison of the FREDDY and holmium lasers during ureteroscopic lithotripsy. Lasers Surg Med. 2007;39(8):637-640. doi:10.1002/lsm.20545. 45. Maydeo A, Kwek BE, Bhandari S, Bapat M, Dhir V. Single-operator cholangioscopy-guided laser lithotripsy in patients with difficult biliary and pancreatic ductal stones (with videos). Gastrointest Endosc. 2011;74(6):1308-1314. doi:10.1016/j.gie.2011.08.047. 46. Hochberger J, Tex S, Maiss J, Hahn EG. Management of difficult common bile duct stones. Gastrointest Endosc Clin N Am. 2003; 13(4):623-634. doi:10.1016/s1052-5157(03)00102-8. 47. Sauer BG, Cerefice M, Swartz DC, et al. Safety and efficacy of laser lithotripsy for complicated biliary stones using direct choledochoscopy. Dig Dis Sci. 2013;58(1):253-256. doi:10.1007/s10620012-2359-1. 48. Patel SN, Rosenkranz L, Hooks B, et al. Holmium-yttrium aluminum garnet laser lithotripsy in the treatment of biliary calculi using single-operator cholangioscopy: a multicenter experience (with video). Gastrointest Endosc. 2014;79(2):344-348. doi:10.1016/j.gie. 2013.07.054. 49. Kiil J, Kruse A, Rokkjaer M. Large bile duct stones treated by endoscopic biliary drainage. Surgery. 1989;105(1):51-56. 50. Rustgi AK, Schapiro RH. Biliary stents for common bile duct stones. Gastrointest Endosc Clin N Am 1991;1:79-91. 51. Cotton PB, Forbes A, Leung JW, Dineen L. Endoscopic stenting for long-term treatment of large bile duct stones: 2- to 5-year follow-up. Gastrointest Endosc. 1987;33(6):411-412. doi:10.1016/s0016-5107(87) 71675-7. 52. Foutch PG, Harlan J, Sanowski RA. Endoscopic placement of biliary stents for treatment of high risk geriatric patients with common duct stones. Am J Gastroenterol. 1989;84(5):527-529. 53. Nordback I. Management of unextractable bile duct stones by endoscopic stenting. Ann Chir Gynaecol. 1989;78(4):290-292. 54. Soomers AJ, Nagengast FM, Yap SH. Endoscopic placement of biliary endoprostheses in patients with endoscopically unextractable common bile duct stones. A long-term follow up study of 26 patients. Endoscopy. 1990;22(1):24-26. doi:10.1055/s-2007-1012781. 55. Bergman JJ, Rauws EA, Tijssen JG, Tytgat GN, Huibregtse K. Biliary endoprostheses in elderly patients with endoscopically irretrievable common bile duct stones: report on 117 patients. Gastrointest Endosc. 1995;42(3):195-201. doi:10.1016/s0016-5107(95)70091-9. 56. Maxton DG, Tweedle DE, Martin DF. Retained common bile duct stones after endoscopic sphincterotomy: temporary and longterm treatment with biliary stenting. Gut. 1995;36(3):446-449. doi:10. 1136/gut.36.3.446. 57. Devière J, Nageshwar Reddy D, Püspök A, et al. Successful management of benign biliary strictures with fully covered self-expanding metal stents. Gastroenterology. 2014;147(2):385-395; quiz e15. doi: 10.1053/j.gastro.2014.04.043. 58. Tarantino I, Mangiavillano B, Di Mitri R, et al. Fully covered selfexpandable metallic stents in benign biliary strictures: a multicenter study on efficacy and safety. Endoscopy. 2012;44(10): 923-927. doi:10.1055/s-0032-1310011. 59. García-Cano J, Reyes-Guevara AK, Martínez-Pérez T, et al. Fully covered self-expanding metal stents in the management of difficult common bile duct stones. Rev Esp Enferm Dig. 2013;105(1):7-12. doi:10.4321/s1130-01082013000100003. 60. Katsinelos P, Galanis I, Pilpilidis I, et al. The effect of indwelling endoprosthesis on stone size or fragmentation after long-term treatment with biliary stenting for large stones. Surg Endosc. 2003;17(10):1552-1555. doi:10.1007/s00464-002-9240-9. 61. Cerefice M, Sauer B, Javaid M, et al. Complex biliary stones: treatment with removable self-expandable metal stents: a new approach (with videos). Gastrointest Endosc. 2011;74(3):520-526. doi:10.1016/ j.gie.2011.05.026.

62. Palmer KR, Hofmann AF. Intraductal mono-octanoin for the direct dissolution of bile duct stones: experience in 343 patients. Gut. 1986;27(2):196-202. doi:10.1136/gut.27.2.196. 63. Allen MJ, Borody TJ, Bugliosi TF, May GR, LaRusso NF, Thistle JL. Rapid dissolution of gallstones by methyl tert-butyl ether. Preliminary observations. N Engl J Med. 1985;312(4):217-220. doi:10. 1056/NEJM198501243120406. 64. Brandon JC, Teplick SK, Haskin PH, Sammon JK, Muhr WF, Hofmann AF, et al. Common bile duct calculi: updated experience with dissolution with methyl tertiary butyl ether. Radiology. 1988;166(3):665-667. doi:10.1148/radiology.166.3.3340760. 65. Diaz D, Bories P, Ampelas M, Larrey D, Michel H. Methyl tertbutyl ether in the endoscopic treatment of common bile duct radiolucent stones in elderly patients with nasobiliary tube. Dig Dis Sci. 1992;37(1):97-100. doi:10.1007/BF01308349. 66. Kaye GL, Summerfield JA, McIntyre N, Dooley JS. Methyl tert butyl ether dissolution therapy for common bile duct stones. J Hepatol. 1990;10(3):337-340. doi:10.1016/0168-8278(90)90142-e. 67. Murray WR, LaFerla G, Fullarton GM. Choledocholithiasis—in vivo stone dissolution using methyl tertiary butyl ether (MTBE). Gut. 1988;29(2):143-145. doi:10.1136/gut.29.2.143. 68. Neoptolemos JP, Hall C, O’Connor HJ, Murray WR, Carr-Locke DL. Methyl-tert-butyl-ether for treating bile duct stones: the British experience. Br J Surg. 1990;77(1):32-35. doi:10.1002/bjs. 1800770111. 69. Cotton PB. Endoscopic management of bile duct stones; (apples and oranges). Gut. 1984;25(6):587-597. doi:10.1136/gut.25.6.587. 70. Cotton PB, Vallon AG. British experience with duodenoscopic sphincterotomy for removal of bile duct stones. Br J Surg. 1981;68(6):373-375. doi:10.1002/bjs.1800680602. 71. Geenen JE, Vennes JA, Silvis SE. Résumé of a seminar on endoscopic retrograde sphincterotomy (ERS). Gastrointest Endosc. 1981; 27(1):31-38. doi:10.1016/s0016-5107(81)73140-7. 72. Leese T, Neoptolemos JP, Carr-Locke DL. Successes, failures, early complications and their management following endoscopic sphincterotomy: results in 394 consecutive patients from a single centre. Br J Surg. 1985;72(3):215-219. doi:10.1002/bjs. 1800720325. 73. Seifert E, Gail K, Weismüller J. Langzeitresultate nach endoskopischer Sphinkterotomie [Long term results after endoscopic sphincterotomy]. Dtsch Med Wochenschr. 1982;107(16):610-614. doi:10.1055/s-2008-1069987. 74. Siegel JH. Endoscopic papillotomy in the treatment of biliary tract disease: 258 procedures and results. Dig Dis Sci. 1981;26(12):10571064. doi:10.1007/BF01295968. 75. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335(13):909918. doi:10.1056/NEJM199609263351301. 76. Nakajima M, Kizu M, Akasaka Y, Kawai K. Five years experience of endoscopic sphincterotomy in Japan: a collective study from 25 centres. Endoscopy. 1979;11(2):138-141. doi:10.1055/s-0028-1098339. 77. Reiter JJ, Bayer HP, Mennicken C, Manegold BC. Results of endoscopic papillotomy: a collective experience from nine endoscopic centers in West Germany. World J Surg. 1978;2(4):505-511. doi:10.1007/BF01563686. 78. Safrany L. Endoscopic treatment of biliary-tract diseases. An international study. Lancet. 1978;2(8097):983-985. doi:10.1016/s01406736(78)92543-6. 79. Sherman S, Ruffolo TA, Hawes RH, Lehman GA. Complications of endoscopic sphincterotomy. A prospective series with emphasis on the increased risk associated with sphincter of Oddi dysfunction and nondilated bile ducts. Gastroenterology. 1991;101(4):10681075. 80. Vaira D, D’Anna L, Ainley C, et al. Endoscopic sphincterotomy in 1000 consecutive patients. Lancet. 1989;2(8660):431-434. doi:10.1016/s0140-6736(89)90602-8. 81. Andriulli A, Loperfido S, Napolitano G, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol. 2007;102(8):1781-1788. doi:10.1111/j. 1572-0241.2007.01279.x. 82. Masci E, Toti G, Mariani A, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96(2):417-423. doi:10.1111/j.1572-0241.2001.03594.x. 83. Vandervoort J, Tham TCK, Wong RCK, et al. Prospective analysis of risk factors for pancreatitis after diagnostic and therapeutic ERCP. Gastrointest Endosc. 1996;43:400.

538.e3 84. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc. 1991;37(3):383-393. doi:10.1016/s00165107(91)70740-2. 85. Tse F, Yuan Y, Moayyedi P, Leontiadis GI. Guide wire-assisted cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. Endoscopy. 2013;45(8):605618. doi:10.1055/s-0032-1326640. 86. Freeman ML, DiSario JA, Nelson DB, et al. Risk factors for postERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc. 2001;54(4):425-434. doi:10.1067/mge.2001.117550. 87. Neoptolemos JP, Shaw DE, Carr-Locke DL. A multivariate analysis of preoperative risk factors in patients with common bile duct stones. Implications for treatment. Ann Surg. 1989;209(2):157-161. doi:10.1097/00000658-198902000-00004. 88. Vandervoort J, Soetikno RM, Tham TC, et al. Risk factors for complications after performance of ERCP. Gastrointest Endosc. 2002;56(5):652-656. doi:10.1067/mge.2002.129086. 89. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366(15):1414-1422. doi:10.1056/NEJMoa1111103. 90. Park KT, Kang DH, Choi CW, et al. Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients? Pancreas. 2011;40(8):1215-1219. doi:10.1097/MPA.0b013e31822116d5. 91. Grimm H, Soehendra N. Unterspritzung zur Behandlung der Papillotomie-Blutung [Infiltrating injection in the management of post-papillotomy hemorrhages]. Dtsch Med Wochenschr. 1983;108(40):1512-1514. doi:10.1055/s-2008-1069776. 92. Leung JW, Chan FK, Sung JJ, Chung SC. Endoscopic sphincterotomy-induced hemorrhage: a study of risk factors and the role of epinephrine injection. Gastrointest Endosc. 1995;42(6):550-554. doi:10.1016/S0016-5107(95)70009-9. 93. Wilcox CM, Canakis J, Mönkemüller KE, Bondora AW, Geels W. Patterns of bleeding after endoscopic sphincterotomy, the subsequent risk of bleeding, and the role of epinephrine injection. Am J Gastroenterol. 2004;99(2):244-248. doi:10.1111/j.1572-0241.2004.04058.x. 94. Debenedet AT, Elta GH. Post-sphincterotomy bleeding: fullycovered metal stents for hemostasis. F1000Res. 2013;2:171. doi:10. 12688/f1000research.2-171.v1. 95. Maleux G, Bielen J, Laenen A, et al. Embolization of post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy: technical results, clinical efficacy and predictors of outcome. Eur Radiol. 2014;24(11):2779-2786. doi:10.1007/s00330014-3332-5. 96. Neoptolemos JP, Harvey MH, Slater ND, Carr-Locke DL. Abdominal wall bile staining and ‘biliscrotum’ after retroperitoneal perforation following endoscopic sphincterotomy. Br J Surg. 1984;71(9):684. doi:10.1002/bjs.1800710912. 97. Escourrou J, Cordova JA, Lazorthes F, Frexinos J, Ribet A. Early and late complications after endoscopic sphincterotomy for biliary lithiasis with and without the gall bladder ‘in situ’. Gut. 1984;25(6):598-602. doi:10.1136/gut.25.6.598. 98. Hawes RH, Cotton PB, Vallon AG. Follow-up 6 to 11 years after duodenoscopic sphincterotomy for stones in patients with prior cholecystectomy. Gastroenterology. 1990;98(4):1008-1012. doi:10. 1016/0016-5085(90)90026-w. 99. Ikeda S, Tanaka M, Matsumoto S, Yoshimoto H, Itoh H. Endoscopic sphincterotomy: long-term results in 408 patients with complete follow-up. Endoscopy. 1988;20(1):13-17. doi:10.1055/s2007-1018117. 100. Rösch W, Riemann JF, Lux G, Lindner HG. Long-term follow-up after endoscopic sphincterotomy. Endoscopy. 1981;13(4):152-153. doi:10.1055/s-2007-1021671. 101. Sivak Jr MV. Endoscopic management of bile duct stones. Am J Surg. 1989;158(3):228-240. doi:10.1016/0002-9610(89)90256-0. 102. Khoo DE, Walsh CJ, Cox MR, Murphy CA, Motson RW. Laparoscopic common bile duct exploration: evolution of a new technique. Br J Surg. 1996;83(3):341-346. doi:10.1002/bjs.1800830314. 103. Martin IJ, Bailey IS, Rhodes M, O’Rourke N, Nathanson L, Fielding G. Towards T-tube free laparoscopic bile duct exploration: a methodologic evolution during 300 consecutive procedures. Ann Surg. 1998;228(1):29-34. doi:10.1097/00000658199807000-00005. 104. Rhodes M, Nathanson L, O’Rourke N, Fielding G. Laparoscopic exploration of the common bile duct: lessons learned from 129

consecutive cases. Br J Surg. 1995;82(5):666-668. doi:10.1002/ bjs.1800820533. 105. Huang SM, Wu CW, Chau GY, Jwo SC, Lui WY, P’eng FK. An alternative approach of choledocholithotomy via laparoscopic choledochotomy. Arch Surg. 1996;131(4):407-411. doi:10.1001/ archsurg.1996.01430160065012. 106. Tranter SE, Thompson MH. Comparison of endoscopic sphincterotomy and laparoscopic exploration of the common bile duct. Br J Surg. 2002;89(12):1495-1504. doi:10.1046/j.1365-2168. 2002.02291.x. 107. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101-125. 108. Cuschieri A, Croce E, Faggioni A, et al. EAES ductal stone study. Preliminary findings of multi-center prospective randomized trial comparing two-stage vs single-stage management. Surg Endosc. 1996;10(12):1130-1135. doi:10.1007/s004649900264. 109. Ding G, Cai W, Qin M. Single-stage vs. two-stage management for concomitant gallstones and common bile duct stones: a prospective randomized trial with long-term follow-up. J Gastrointest Surg. 2014;18(5):947-951. doi:10.1007/s11605-014-2467-7. 110. Rhodes M, Sussman L, Cohen L, Lewis MP. Randomised trial of laparoscopic exploration of common bile duct versus postoperative endoscopic retrograde cholangiography for common bile duct stones. Lancet. 1998;351(9097):159-161. doi:10.1016/s0140-6736 (97)09175-7. 111. Rogers SJ, Cello JP, Horn JK, et al. Prospective randomized trial of LC1LCBDE vs ERCP/S1LC for common bile duct stone disease. Arch Surg. 2010;145(1):28-33. doi:10.1001/archsurg.2009.226. 112. Singh AN, Kilambi R. Single-stage laparoscopic common bile duct exploration and cholecystectomy versus two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with gallbladder stones with common bile duct stones: systematic review and meta-analysis of randomized trials with trial sequential analysis. Surg Endosc. 2018;32(9):3763-3776. doi:10.1007/s00464-018-6170-8. 113. Lyu Y, Cheng Y, Li T, Cheng B, Jin X. Laparoscopic common bile duct exploration plus cholecystectomy versus endoscopic retrograde cholangiopancreatography plus laparoscopic cholecystectomy for cholecystocholedocholithiasis: a meta-analysis. Surg Endosc. 2019;33(10):3275-3286. doi:10.1007/s00464-018-06613-w. 114. Dowsett JF, Vaira D, Hatfield AR, et al. Endoscopic biliary therapy using the combined percutaneous and endoscopic technique. Gastroenterology. 1989;96(4):1180-1186. doi:10.1016/0016-5085(89) 91639-9. 115. Martin DF. Combined percutaneous and endoscopic procedures for bile duct obstruction. Gut. 1994;35(8):1011-1012. doi:10. 1136/gut.35.8.1011. 116. Tomizawa Y, Di Giorgio J, Santos E, McCluskey KM, Gelrud A. Combined interventional radiology followed by endoscopic therapy as a single procedure for patients with failed initial endoscopic biliary access. Dig Dis Sci. 2014;59(2):451-458. doi:10. 1007/s10620-013-2913-5. 117. Verstandig AG, Goldin E, Sasson T, et al. Combined transhepatic and endoscopic procedures in the biliary system [published correction appears in Postgrad Med J. 1993 Aug;69(814):667]. Postgrad Med J. 1993;69(811):384-388. doi:10.1136/pgmj.69.811.384. 118. Calvo MM, Bujanda L, Heras I, et al. The rendezvous technique for the treatment of choledocholithiasis. Gastrointest Endosc. 2001;54(4):511-513. doi:10.1067/mge.2001.118441. 119. Iwashita T, Lee JG, Shinoura S, et al. Endoscopic ultrasoundguided rendezvous for biliary access after failed cannulation. Endoscopy. 2012;44(1):60-65. doi:10.1055/s-0030-1256871. 120. Yeh YH, Huang MH, Yang JC, Mo LR, Lin J, Yueh SK. Percutaneous trans-hepatic cholangioscopy and lithotripsy in the treatment of intrahepatic stones: a study with 5 year follow-up. Gastrointest Endosc. 1995;42(1):13-18. doi:10.1016/s0016-5107(95) 70236-9. 121. van der Velden JJ, Berger MY, Bonjer HJ, Brakel K, Laméris JS. Percutaneous treatment of bile duct stones in patients treated unsuccessfully with endoscopic retrograde procedures. Gastrointest Endosc. 2000;51(4 Pt 1):418-422. doi:10.1016/s0016-5107 (00)70441-x. 122. Ozcan N, Kahriman G, Mavili E. Percutaneous transhepatic removal of bile duct stones: results of 261 patients. Cardiovasc Intervent Radiol. 2012;35(4):890-897. doi:10.1007/s00270-011-0197-8.

538.e4 123. Ellington SR, Flowers L, Legardy-Williams JK, Jamieson DJ, Kourtis AP. Recent trends in hepatic diseases during pregnancy in the United States, 2002-2010. Am J Obstet Gynecol. 2015;212(4): 524.e1-e7. doi:10.1016/j.ajog.2014.10.1093. 124. Jamidar PA, Beck GJ, Hoffman BJ, et al. Endoscopic retrograde cholangiopancreatography in pregnancy. Am J Gastroenterol. 1995; 90(8):1263-1267. 125. Kahaleh M, Hartwell GD, Arseneau KO, et al. Safety and efficacy of ERCP in pregnancy. Gastrointest Endosc. 2004;60(2):287-292. doi:10.1016/s0016-5107(04)01679-7. 126. Simmons DC, Tarnasky PR, Rivera-Alsina ME, Lopez JF, Edman CD. Endoscopic retrograde cholangiopancreatography (ERCP) in pregnancy without the use of radiation. Am J Obstet Gynecol. 2004;190(5):1467-1469. doi:10.1016/j.ajog.2004.02.030. 127. Tham TC, Vandervoort J, Wong RC, et al. Safety of ERCP during pregnancy. Am J Gastroenterol. 2003;98(2):308-311. doi:10.1111/ j.1572-0241.2003.07261.x. 128. Inamdar S, Berzin TM, Sejpal DV, et al. Pregnancy is a risk factor for pancreatitis after endoscopic retrograde cholangiopancreatography in a National Cohort Study. Clin Gastroenterol Hepatol. 2016;14(1):107-114. doi:10.1016/j.cgh.2015.04.175. 129. Kaw M, Al-Antably Y, Kaw P. Management of gallstone pancreatitis: cholecystectomy or ERCP and endoscopic sphincterotomy. Gastrointest Endosc. 2002;56(1):61-65. doi:10.1067/mge.2002.125544. 130. Boerma D, Rauws EA, Keulemans YC, et al. Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial. Lancet. 2002;360(9335): 761-765. doi:10.1016/S0140-6736(02)09896-3. 131. McAlister VC, Davenport E, Renouf E. Cholecystectomy deferral in patients with endoscopic sphincterotomy. Cochrane Database Syst Rev. 2007;(4):CD006233. doi:10.1002/14651858.CD006233.pub2. 132. ASGE Standards of Practice Committee, Maple JT, Ikenberry SO, et al. The role of endoscopy in the management of choledocholithiasis [published correction appears in Gastrointest Endosc. 2012 Jan;75(1):230-230.e14]. Gastrointest Endosc. 2011;74(4):731-744. 133. Adams MA, Hosmer AE, Wamsteker EJ, et al. Predicting the likelihood of a persistent bile duct stone in patients with suspected choledocholithiasis: accuracy of existing guidelines and the impact of laboratory trends. Gastrointest Endosc. 2015;82(1):88-93. doi:10.1016/j.gie.2014.12.023. 134. Sethi S, Wang F, Korson AS, et al. Prospective assessment of consensus criteria for evaluation of patients with suspected choledocholithiasis. Dig Endosc. 2016;28(1):75-82. doi:10.1111/den.12506. 135. Boey JH, Way LW. Acute cholangitis. Ann Surg. 1980;191(3):264270. doi:10.1097/00000658-198003000-00002. 136. Thompson Jr JE, Tompkins RK, Longmire Jr WP. Factors in management of acute cholangitis. Ann Surg. 1982;195(2):137-145. doi:10.1097/00000658-198202000-00003. 137. Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326(24):1582-1586. doi:10.1056/NEJM199206113262401. 138. Hui CK, Lai KC, Yuen MF, et al. Does the addition of endoscopic sphincterotomy to stent insertion improve drainage of the bile duct in acute suppurative cholangitis? Gastrointest Endosc. 2003; 58(4):500-504. doi:10.1067/s0016-5107(03)01871-6. 139. Opie EL. The etiology of acute hemorrhagic pancreatitis. Bull Johns Hopkins Hosp. 1901;12:182-188. 140. Hirano T, Manabe T. A possible mechanism for gallstone pancreatitis: repeated short-term pancreaticobiliary duct obstruction with exocrine stimulation in rats. Proc Soc Exp Biol Med. 1993; 202(2):246-252. doi:10.3181/00379727-202-43534. 141. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute pancreatitis. N Engl J Med. 1974;290(9):484-487. doi:10.1056/ NEJM197402282900904. 142. Kelly TR, Wagner DS. Gallstone pancreatitis: a prospective randomized trial of the timing of surgery. Surgery. 1988;104(4):600-605. 143. Kelly TR. Gallstone pancreatitis: the timing of surgery. Surgery. 1980;88(3):345-350. 144. Acosta JM, Rossi R, Galli OM, Pellegrini CA, Skinner DB. Early surgery for acute gallstone pancreatitis: evaluation of a systematic approach. Surgery. 1978;83(4):367-370. 145. Ranson JH. The timing of biliary surgery in acute pancreatitis. Ann Surg. 1979;189(5):654-663. doi:10.1097/00000658-19790500000016.

146. Stone HH, Fabian TC, Dunlop WE. Gallstone pancreatitis: biliary tract pathology in relation to time of operation. Ann Surg. 1981; 194(3):305-312. doi:10.1097/00000658-198109000-00008. 147. Banks PA. Predictors of severity in acute pancreatitis. Pancreas. 1991;6(suppl 1):S7-S12. doi:10.1097/00006676-199101001-00003. 148. Kim U, Shen HY, Bodner B. Timing of surgery for acute gallstone pancreatitis. Am J Surg. 1988;156(5):393-396. doi:10.1016/s00029610(88)80195-8. 149. Osborne DH, Imrie CW, Carter DC. Biliary surgery in the same admission for gallstone-associated acute pancreatitis. Br J Surg. 1981;68(11):758-761. doi:10.1002/bjs.1800681103. 150. Kelly TR, Wagner DS. Gallstone pancreatitis: a prospective randomized trial of the timing of surgery. Surgery. 1988;104(4):600-605. 151. Nealon WH, Bawduniak J, Walser EM. Appropriate timing of cholecystectomy in patients who present with moderate to severe gallstone-associated acute pancreatitis with peripancreatic fluid collections. Ann Surg. 2004;239(6):741-751. doi:10.1097/01. sla.0000128688.97556.94. 152. da Costa DW, Bouwense SA, Schepers NJ, et al. Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial. Lancet. 2015; 386(10000):1261-1268. doi:10.1016/S0140-6736(15)00274-3. 153. Cameron DR, Goodman AJ. Delayed cholecystectomy for gallstone pancreatitis: re-admissions and outcomes. Ann R Coll Surg Engl. 2004;86(5):358-362. doi:10.1308/147870804227. 154. Mador BD, Panton ON, Hameed SM. Early versus delayed cholecystectomy following endoscopic sphincterotomy for mild biliary pancreatitis. Surg Endosc. 2014;28(12):3337-3342. doi:10. 1007/s00464-014-3621-8. 155. Murphy PB, Paskar D, Parry NG, et al. Implementation of an acute care surgery service facilitates modern clinical practice guidelines for gallstone pancreatitis. J Am Coll Surg. 2015;221(5): 975-981. doi:10.1016/j.jamcollsurg.2015.07.447. 156. Tenner S, Baillie J, DeWitt J, Vege SS, American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis [published correction appears in Am J Gastroenterol. 2014 Feb;109(2):302]. Am J Gastroenterol. 2013;108(9):1400-1416. doi:10.1038/ajg.2013.218. 157. Gurusamy KS, Nagendran M, Davidson BR. Early versus delayed laparoscopic cholecystectomy for acute gallstone pancreatitis. Cochrane Database Syst Rev. 2013;(9):CD010326. doi:10.1002/ 14651858.CD010326.pub2. 158. May GR, Shaffer EH. Should elective endoscopic sphincterotomy replace cholecystectomy for the treatment of high-risk patients with gallstone pancreatitis? J Clin Gastroenterol. 1991;13(2):125128. doi:10.1097/00004836-199104000-00002. 159. Beltsis A, Kapetanos D. Early ERCP in acute biliary pancreatitis: 20 years of dispute. Ann Gastroenterol. 2010;23(1):27-30. 160. Fogel EL, Sherman S. ERCP for gallstone pancreatitis [published correction appears in N Engl J Med. 2014 Jan 30;370(5):488]. N Engl J Med. 2014;370(2):150-157. doi:10.1056/NEJMct1208450. 161. Neoptolemos JP, London N, Slater ND, Carr-Locke DL, Fossard DP, Moosa AR. A prospective study of ERCP and endoscopic sphincterotomy in the diagnosis and treatment of gallstone acute pancreatitis. A rational and safe approach to management. Arch Surg. 1986;121(6):697-702. doi:10.1001/archsurg.1986. 01400060093013. 162. Fan ST, Lai EC, Mok FP, Lo CM, Zheng SS, Wong J. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med.1993;328(4):228-232.doi:10.1056/NEJM199301283280402. 163. Nowak A, Nowakowska-Dulawa E, Marek TA, et al. Final results of the prospective, randomized, controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis, Gastroenterology 1995;108:A380. 164. Fölsch UR, Nitsche R, Lüdtke R, Hilgers RA, Creutzfeldt W. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med. 1997;336(4):237-242. doi:10.1056/NEJM199701233360401. 165. Uy MC, Daez ML, Sy PP, Banez VP, Espinosa WZ, Talingdan-Te MC. Early ERCP in acute gallstone pancreatitis without cholangitis: a meta-analysis. JOP. 2009;10(3):299-305.

CHAPTER 38 Cholecystolithiasis and stones in the common bile duct: Which approach and when? Joshua T. Cohen, Rachel E. Beard, Lygia Stewart, and Mark P. Callery

DIAGNOSTIC CONSIDERATIONS Imaging Modalities: Why and When Determining the presence of cholecystolithiasis and choledocholithiasis can be challenging and often relies on indirect evidence of obstruction. For choledocholithiasis, clinicians use predictive models based on risk factors that include clinical features, abnormal liver function tests (LFTs), jaundice, and common bile duct (CBD) dilation. These are very sensitive (96%–98%) but not very specific (0%–70%).1 The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) provides a practical strategy for the approach to diagnosis of choledocholithiasis in patients with documented cholelithiasis based on the number of relevant risk factors that are present. These risk factors include visualization of a CBD stone on transabdominal ultrasound (US) or a dilated CBD, clinical evidence of acute cholangitis, and total bilirubin greater than 1.7 mg/dL. Patients with 0, 1, or 21 risk factors have low (,5%), intermediate (% to ,50%), or high (50%–94%) risk for CBD stones, respectively.2 Low-risk patients require no additional testing to exonerate the duct. Highrisk patients should be assumed to have choledocholithiasis and undergo either an endoscopic retrograde cholangiopancreatogram (ERCP) or CBD exploration (CBDE). Intermediate-risk patients require further interrogation of the CBD, either with magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), or intraoperative cholangiogram (IOC).2 These imaging modalities are discussed in depth later.

Transabdominal Ultrasound Transabdominal US is the diagnostic test of choice in evaluating patients with right upper quadrant (RUQ) abdominal pain thought to be related to biliary pathology (see Chapter 16). It can readily identify cholelithiasis and signs of gallbladder inflammation and is an appropriate initial modality in the evaluation of CBD stones.3–5 US can identify bile duct dilation because of stone obstruction, and it can visualize the actual stone in some cases (sensitivity 0.3, specificity 1.0). If the extrahepatic bile duct diameter is less than 5 mm, CBD stones are exceedingly rare, whereas a diameter greater than 10 mm with signs of jaundice predicts the presence of CBD stones in more than 90% of cases.6 Axial computed tomography (CT) scans have better sensitivity (84%) for choledocholithiasis than US. Helical CT scans outperform conventional nonhelical CT, with 88% sensitivity and 73% to 97% specificity.7 In terms of availability, cost, and radiation exposure, US prevails as the firstline diagnostic.

Magnetic Resonance Cholangiopancreatography MRCP is the most accurate noninvasive modality available (see Chapter 16). It is useful as an adjunct when a definitive diagnosis is not readily apparent on US.4 MRCP is the standard investigation for CBD stones for patients with intermediate probability or for those who need to be investigated to exclude other differential diagnoses. MRCP is especially helpful when anatomic considerations preclude ERCP (status post–Billroth II gastrectomy, Roux-en-Y biliary bypass, duodenal stenoses). The drawback of MRCP is its high cost, which challenges its routine use as a more front-line diagnostic modality.8

Endoscopic Retrograde Cholangiopancreatography ERCP is still considered the gold standard diagnostic modality, although it is invasive, requires radiation, and has significant complications9 (see Chapters 20 and 30). Observed complications after ERCP include pancreatitis, hemorrhage, cholangitis, perforation, and a clinically relevant mortality rate.10 Routine ERCP before all laparoscopic cholecystectomies is impractical and unnecessary and should be reserved for patients with high pretest probability of or known choledocholithiasis.2 When overused, most cholangiograms are normal, and costs and complication rates are prohibitive. Even in patients at high risk, namely those with jaundice, cholestatic LFTs, CBD dilation, and a history of pancreatitis, half will not have CBD stones at the time of ERCP. The utility of ERCP now lies more with its therapeutic capabilities rather than for diagnostic purposes.11

Endoscopic Ultrasound EUS is very sensitive for choledocholithiasis,12 and a metaanalysis reveals that EUS can reduce unnecessary diagnostic ERCP13 (see Chapter 22). A systematic review reveals that patients who undergo EUS can avoid ERCP in 67% of cases, with fewer complications and less pancreatitis compared with those undergoing ERCP initially.14 The diagnostic efficacy of EUS and MRCP compared with ERCP have revealed the tests to be quite comparable.15,16

Intraoperative Cholangiography IOC during cholecystectomy can accurately diagnose CBD stones and both minimize and maximize the need for ERCP (see Chapter 24). It is best used for intermediate-risk patients.2 The technique can be performed safely in both open and laparoscopic approaches. Surgeons can respond to such findings, flushing the duct to clear stones or debris. Open and laparoscopic IOC can successfully be completed in about 95% of patients, with sensitivity for detecting CBD stones between 539

540

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

80% and 92% and specificity of 93% to 97%.17 Regardless, an ongoing debate remains whether IOC should be performed routinely or selectively during cholecystectomy. When used routinely, it has high sensitivity and specificity both for suspected CBD stones and for the 3% to 4% of stones that are not clinically suspected but may become symptomatic postoperatively. Other suggested benefits specifically relate to the prevention of bile duct injuries.18 The randomized trials that have been performed to address this question are small, and even a systematic review of these trials was not sufficiently powered to demonstrate a significant benefit.19 Because no large prospective randomized trial has answered the question of whether routine IOC is beneficial, most practicing surgeons perform IOC selectively.

CHOLECYSTOLITHIASIS Indications for Cholecystectomy Asymptomatic Gallstones Gallstones are one of the most common pathologies affecting the general population. From 10% to 20% of the Western population has gallstones, and the majority of patients with gallstones, about 65% to 80%, are asymptomatic.20 Studies of the natural history of silent gallstones have shown that symptoms develop in 1% to 2% of patients per year (see Chapter 33). Among patients with asymptomatic gallstones, about 10% develop symptoms in 5 years, and about 20% develop symptoms by 20 years. Importantly, most patients experience symptoms before the development of a complication.21–24 Therefore the majority of patients with asymptomatic gallstones can be observed, and surgical intervention (laparoscopic cholecystectomy) should be offered only when symptoms develop. There are certain groups for which prophylactic cholecystectomy has previously been recommended for asymptomatic gallstones. This is an area of controversy, however, and the recommendations are changing. These populations include solidorgan transplant patients; patients with diabetes; patients with chronic liver disease, sickle cell anemia, or other chronic hemolytic anemias; patients undergoing bariatric or other gastrointestinal (GI) operations; and those with a potentially increased risk of gallbladder carcinoma (Table 38.1). Prophylactic cholecystectomy for asymptomatic cholelithiasis was previously recommended for patients with diabetes mellitus. Studies in the late 1960s reported a higher mortality after emergency cholecystectomy in patients with diabetes; however, subsequent meta-analysis revealed that diabetes was not an independent variable. Rather, associated risk factors such as cardiovascular, peripheral vascular, cerebrovascular, or prerenal azotemia were associated with more severe acute cholecystitis.24,25 More recent series have shown similar complication rates for acute cholecystectomy among diabetic and nondiabetic patients. Patients with diabetes with asymptomatic gallstones today are managed expectantly. The incidence of gallstones is twice as high in patients with chronic liver disease. Most of these patients remain asymptomatic. Operative morbidity and mortality rates for patients with chronic liver disease are also significantly higher (see Chapter 75). Metaanalyses report no increase in mortality in asymptomatic patients with an expectant management approach.23,24 Although laparoscopic cholecystectomy has been shown to be safe in well-selected Child-Pugh class A and B cirrhotic patients, it is contraindicated

TABLE 38.1  Management of Asymptomatic Gallstones PATIENT POPULATION

MANAGEMENT

Healthy adults

Expectant

Children (without hemoglobinopathy or hemolytic anemia) Diabetes mellitus Chronic liver disease Concomitant cholecystectomy at time of bariatric procedure Previous bariatric surgery Abdominal aortic aneurysm repair Transplant Kidney or pancreas Cardiac

Expectant Expectant Expectant Only if symptomatic Expectant Expectant Expectant Likely cholecystectomy posttransplant, but remains controversial Incidental cholecystectomy

Undergoing gastrointestinal operation Hemoglobinopathy/chronic hemolytic Elective cholecystectomy anemia (sickle cell disease, spherocytosis, elliptocytosis, b-thalassemia) High-risk group for gallbladder Consideration for prophylactic carcinoma (.3 cm gallstones, calcholecystectomy, although cified gallbladder, data from randomized Native-American race) controlled trials are lacking

in all but emergent settings in Child-Pugh class C patients because of high complication rates.26 Because of the association between morbid obesity and cholelithiasis, a high proportion of patients undergoing bariatric surgery have gallbladder pathology. Patients undergoing bariatric surgery have a higher incidence of cholelithiasis, related both to obesity and rapid weight loss. Studies report a cholelithiasis incidence of 27% to 35% before bariatric operations and a 28% to 71% increase in gallstone formation after bariatric surgery.27 Some surgeons use bile salt medications during periods of rapid weight change to help prevent cholesterol gallstone formation; however, more recent studies have shown that this approach is not cost-effective.28 The question of whether or not to perform concomitant cholecystectomy at the time of bariatric surgery is controversial, but an increasing number of studies suggest that prophylactic cholecystectomy in the absence of symptoms is not indicated.29,30 In the case of gallstone formation after bariatric surgery without concomitant cholecystectomy, management should be expectant because the majority of patients remain asymptomatic.23 For patients with symptomatic cholelithiasis and concomitant morbid obesity, elective cholecystectomy is indicated. Some favor directed referral for cholecystectomy to bariatric surgical specialists, given their technical experience and enhanced facilities and equipment for the care of such patients. Several factors must be considered for potential solidorgan transplant patients with asymptomatic cholelithiasis. In these patients, cholelithiasis is common, immunosuppression may increase infectious morbidity, and morbidity and mortality may be increased with emergency surgery. This problem was examined with decision analysis, using probabilities and outcomes derived from a pooled analysis of published studies.31 For pancreas and kidney transplant patients

A. Gallstones and Gallbladder  Chapter 38  Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?

with asymptomatic cholelithiasis, however, expectant management was recommended, an approach that is widely agreed upon in the literature.31 Kao and colleagues32 recommended prophylactic after transplantation cholecystectomy for cardiac transplant recipients with asymptomatic cholelithiasis, an approach advocated by other studies as well because of the increased morbidity and mortality that has been demonstrated with subsequent urgent or emergent cholecystectomy compared with the general populace.33 This remains an area of debate, however, because other studies have demonstrated that expectant management of asymptomatic gallstones is safe.34 Asymptomatic gallstones found at an unrelated open GI operation should prompt a cholecystectomy, if exposure is adequate and if the operation can be done safely. Studies of expectant management for patients with asymptomatic gallstones undergoing laparotomy for other conditions have shown a high (up to 70%) incidence of symptoms and/or complications from the biliary system, and a significant percentage (up to 40%) of patients require a cholecystectomy within 1 year of the initial operation. Further, no increase in morbidity is associated with concomitant cholecystectomy.24,35 The management of patients with asymptomatic gallstones undergoing abdominal aortic aneurysm (AAA) repair has evolved, especially with the advent of endovascular aortic procedures. In the past, when AAA repair and cholecystectomy were open operations, concomitant cholecystectomy was recommended to prevent the higher morbidity associated with the development of acute cholecystitis in the postoperative period. Studies reported no increase in graft infection or morbidity when cholecystectomy was performed after closure of the retroperitoneum; however, more recent data show similar mortality rates with or without concomitant cholecystectomy. Current management is typically expectant, and laparoscopic cholecystectomy can be performed after AAA repair without increased morbidity if symptoms develop. Although simultaneous laparoscopic cholecystectomy and endovascular AAA repair has been reported,36,37 it is not widely practiced and certainly not for asymptomatic gallstones. Children with asymptomatic gallstones fall into two main etiologic groups: those with hemolytic anemia (sickle cell disease,b-thalassemia, hemoglobinopathies) and those whose cholelithiasis stems from some other cause (total parenteral nutrition, short bowel syndrome, cardiac surgery, leukemia, lymphoma). Expectant management for children with hemolytic anemia is associated with a significant increase in morbidity and postoperative hospital stay, and elective cholecystectomy is therefore recommended.38 For patients with sickle cell disease and asymptomatic gallstones, elective cholecystectomy is advised because expectant management yields more than a 2-fold increase in morbidity. Further, the diagnosis of acute cholecystitis can be difficult to differentiate from acute vasoocclusive sickle cell crisis.38 There is also a high incidence of choledocholithiasis in this population, and studies have demonstrated that ERCP can be safely used in children to perform sphincterotomy and stone extraction.39 In contrast, children with asymptomatic gallstones caused by other etiologies can be safely managed expectantly, and these gallstones have been shown to regress in 17% to 34% of cases.38 Finally, gallstones have a proven association with gallbladder carcinoma40 (see Chapter 49). In a review of 200 consecutive calculous cholecystitis specimens, Albores-Saavedra and

541

colleagues41 reported that 83% exhibited epithelial hyperplasia, 13.5% atypical hyperplasia, and 3.5% carcinoma in situ. It is not known whether such data apply today, but chronic cholecystitis changes may equate to hyperplasia and dysplasia if not infrequent. Cholecystectomy alone remains sufficient. In areas endemic for gallbladder cancer, the risk of carcinoma increases with larger gallstones. The relative risk rises from 2.4 for stones 2 to 2.9 cm in diameter to 10 for gallstones larger than 3 cm. Some patients with gallbladder calcification also have a higher incidence of gallbladder cancer. Elective cholecystectomy has been recommended in patients with gallstones greater than 3 cm in diameter, but no proof is available to support that such an approach is warranted from an oncologic standpoint.40,42,43 Preemptive elective cholecystectomy for asymptomatic gallstones is considered in some parts of the world with unusually high gallbladder cancer rates, including some parts of India, Chile, and Mexico.44

Symptomatic Gallstones Approximately 20% to 30% of patients with gallstones will develop symptoms, and once this occurs, cholecystectomy is usually indicated for both symptomatic improvement and to prevent further complications (see Chapter 33). The spectrum of severity characterizing symptomatic gallstones ranges from episodic pain to life-threatening infection and shock. BILIARY COLIC. Biliary colic is the most typical clinical presentation of symptomatic gallstones. It usually occurs a few hours after a meal, especially one of high fat or spice content, as a slowly progressive and constant pain that occurs in the epigastrium and RUQ of the abdomen and often radiates posteriorly to the scapula and right shoulder. This visceral pain likely reflects the gallbladder contracting against a cystic duct blocked by an impacted gallstone. If pain persists and escalates, it can herald a worse complication of gallstones, such as cholecystitis, cholangitis, or pancreatitis. Pain often remits after several hours, which can create a false sense of security in some patients. More than 60% of patients will suffer recurrent pain within 2 years of their initial attack, and several studies have indicated that gallstone-associated complications occur more frequently in patients who experience biliary colic. Biliary colic is therefore the most common indication for cholecystectomy. CHOLECYSTITIS. Acute cholecystitis occurs in about 20% of patients with symptomatic gallstones (see Chapter 34). The pathogenesis is prolonged calculous obstruction of the cystic duct with resulting inflammation. The inflamed gallbladder becomes dilated and edematous, manifested by wall thickening, and an exudate of pericholecystic fluid can develop. If the gallstones are sterile, the inflammation is initially sterile, which can occur in patients with cholesterol gallstones. In other cases, however, gallstone formation occurs as a result of bacterial colonization of the biliary tree, rendering pigmented gallstones containing bacterial microcolonies.45 In these cases, obstruction of the cystic duct results in a contained infection of the gallbladder. Research on the pathogenesis of gallstone-associated infections has shown that patients with bacteria-laden gallstones have more severe biliary infections. In addition, acute cholecystitis can coexist with choledocholithiasis, cholangitis, or gallstone pancreatitis. In the general population, 5% of patients presenting with cholecystitis have co-existing CBD stones. In the elderly, however, this figure rises to 10% to 20%.46

542

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

The initial treatment for patients with acute cholecystitis is intravenous (IV) hydration, antibiotics, and bowel rest. Many patients should be offered early cholecystectomy, but others will benefit from delayed intervention, either after conservative therapy or percutaneous gallbladder drainage. Several factors govern the approach to patients with acute cholecystitis. One consideration is patient comorbidity; emergency cholecystectomy in patients with significant comorbidities can be associated with high morbidity (20%–30%) and mortality (6%–30%) rates. Guidelines for the management of acute cholecystitis and acute cholangitis were described at an international consensus meeting held in Tokyo in 2006. Updated guidelines were then published in 2013 and re-adopted without modification in 2018.4,47,48 The Tokyo Guidelines define three levels of severity for acute cholecystitis and serve as a useful tool in the management of acute cholecystitis (Table 38.2).4,49 GRADE I ACUTE CHOLECYSTITIS. Patients presenting with mild grade I acute cholecystitis should be offered early cholecystectomy, performed laparoscopically if possible. Several studies have documented high success rates for laparoscopic cholecystectomy when the procedure is performed within 72 hours of onset of acute cholecystitis.50,51 Further, a Cochrane Review of five randomized trials showed a shorter hospital stay for early cholecystectomy patients and no significant difference in complication rates or conversion rates between early laparoscopic cholecystectomy (within 7 days) versus delayed laparoscopic cholecystectomy (6–12 weeks).52 Conversion rates, however, were 45% among patients randomized to the delayed group, which required a cholecystectomy between 1 and 6 weeks. For patients with significant medical problems, cholecystectomy may need to be delayed to maximize medical therapy. Most of these patients with acute cholecystitis can be safely managed

TABLE 38.2  Tokyo Guidelines (TG18/TG13) Severity Grading for Acute Cholecystitis GRADE

CRITERIA

I: Mild

Acute cholecystitis that does not meet the criteria for a more severe grade. Mild gallbladder inflammation, no organ dysfunction The presence of one or more of the following: 1. Elevated white blood cell count (.18,000/mm3) 2. Palpable tender mass in the right upper abdominal quadrant 3. Duration of complaints . 72 hr 4. Marked local inflammation (biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis, emphysematous cholecystitis) Associated with dysfunction of any one of the following: 1. Cardiovascular system: hypotension requiring dopamine .5 mg/kg/min or any dose of norepinephrine 2. Nervous system: decreased level of consciousness 3. Respiratory system: Pao2/Fio2 ratio , 300 4. Renal system: oliguria, serum creatinine . 2.0 mg/dL 5. Hepatic system: PT-INR . 1.5 6. Hematologic system: platelet count , 100,000/mm3

II: Moderate

III: Severe

Fio2, Forced inspiratory oxygen concentration; Pao2, partial pressure of oxygen in arterial blood; PT-INR, prothrombin time/international normalized ratio.

with antibiotics and bowel rest, with resolution of their acute illness; they can then undergo an elective cholecystectomy once their medical problems have been addressed. GRADE II ACUTE CHOLECYSTITIS. Patients presenting with grade II acute cholecystitis are a more diverse group. Many will be well managed with early cholecystectomy; this is particularly true for cases with delayed presentation as their only grade II finding. In these cases, laparoscopic cholecystectomy should be performed, if possible, within 7 days of the acute illness. In cases with severe local inflammation, early gallbladder drainage (percutaneous or surgical) is recommended as the initial treatment of choice, followed by elective cholecystectomy once the acute inflammation resolves. The key is to identify which patients have such an inflammatory process. Several studies have correlated such findings as age older than 50 years, male sex, presence of diabetes, elevated bilirubin level (.1.5 mg/dL), and leukocytosis (white blood cell count . 15,000 mm3) with gangrenous cholecystitis.53 These findings are also frequently associated with a severe inflammatory process. Other factors suggestive of a significant inflammatory process include symptoms of gastric outlet obstruction. Patients with such symptoms should have crosssectional imaging, with either CT or magnetic resonance imaging (MRI), to determine whether a severe inflammatory process is present (Fig. 38.1), followed by percutaneous cholecystostomy if such is found.47 In the updated 2013 Tokyo Guidelines, percutaneous transhepatic gallbladder drainage remains the standard drainage method for grade II cholecystitis that does not respond to conservative therapy, although techniques such as percutaneous transhepatic gallbladder aspiration and endoscopic nasobiliary gallbladder drainage were also cited as alternatives.54 GRADE III ACUTE CHOLECYSTITIS. Patients presenting with grade III acute cholecystitis have associated organ dysfunction. Although this occurs rarely, approximately 6% of the time, it is important because these patients require intensive organ support and medical treatment.55 Because the source of their inflammatory (septic) response and organ dysfunction is the severe cholecystitis, percutaneous cholecystostomy is necessary to treat the

FIGURE 38.1  Computed tomographic scan demonstrating a severe inflammatory process in the setting of acute cholecystitis (see Chapter 16). This patient was treated with percutaneous cholecystostomy (see Chapter 35), followed by elective laparoscopic cholecystectomy once the inflammatory process had resolved.

A. Gallstones and Gallbladder  Chapter 38  Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?

severe infection as well as the associated organ dysfunction. Numerous studies have documented the success of percutaneous cholecystostomy in achieving control of the underlying infection within 24 to 48 hours.56 In rare cases, urgent cholecystectomy may be required, such as cases with biliary peritonitis as a result of perforation of the gallbladder; but in general, cholecystectomy in the acute phase of grade III acute cholecystitis should be avoided.47,57 DURABILITY OF THE TOKYO GUIDELINES. The Tokyo Guidelines derived for the diagnostic criteria and severity grading of acute cholecystitis and cholangitis originated in 2007.47 These were embraced and validated worldwide but understandably revisited and modified by consensus experts in 2013 (known as the TG13).57 The TG13 updates provided better specificity and higher diagnostic accuracy. They have indeed since stood the test of time, and are now offered as TG18/TG13 Guidelines (see Tables 38.2, 38.4, and 38.5). As part of the 2018 interval consensus update, evidence was sought and evaluated from published studies worldwide, which may have prompted additional modifications of the 2013 guideline. Their impact and validity were proven durable.4 UNCOMMON PRESENTATIONS OF ACUTE CHOLECYSTITIS. Acalculous cholecystitis arises in the absence of cholecystolithiasis, and associated risk factors include trauma, burns, and GI surgery.58 Emphysematous cholecystitis is caused by infection with gas-forming anaerobes, such as Clostridium perfringens. Patients with diabetes are at risk, and the disease can progress quickly to profound sepsis. Emergent cholecystectomy is indicated. Gallbladder torsion can also occur when the gallbladder is especially mobile because of a connection to the liver by a thin elongated mesentery. Gallbladder perforation can occur as a result of gallbladder wall ischemic and resulting necrosis. A localized perforation can result in formation of a pericholecystic abscess, whereas free perforation can lead to biliary peritonitis. A biliary fistula can also form between the gallbladder and the duodenum as a sequela of cholecystitis, and this can result in a gallstone ileus if a stone passes via this fistula and causes a mechanical obstruction at the ileocecal valve59 (see Chapter 32).

Cholecystectomy Technique (see Chapter 36) Choosing Laparoscopic Versus Open Techniques For typical uncomplicated symptomatic gallstone disease, laparoscopic cholecystectomy is the preferred method of removing the gallbladder.51,60 Since its origin, cholecystectomy rates have increased worldwide, reflecting general acceptance of the laparoscopic technique. Because the technical aspects of this operation are covered in other chapters, this section will focus on concepts of feasibility and safety that relate to disease severity and the choice between laparoscopic and open cholecystectomy.61 Laparoscopic cholecystectomy for severe acute and chronic inflammation is a technically difficult and advanced operation. Less experienced surgeons must recognize this and seek help from a more experienced surgeon, when appropriate, to avoid the potentially disastrous complication of bile duct injury. Furthermore, the surgeon must understand that conversion to open cholecystectomy may be necessary and is more likely in these cases.62 Biliary injuries are more likely to occur during

543

difficult laparoscopic operations, no different than with open operations, but at a higher incidence. When laparoscopic cholecystectomy is performed for acute cholecystitis, biliary injuries occur three times more often than during elective laparoscopic cases and twice as often compared with open cholecystectomy for acute cholecystitis. Surgeons should therefore not hesitate to convert to an open operation if they experience difficulties with the laparoscopic dissection or are unable to clearly identify the critical view of safety.63 Surgeons should also be aware of certain patient risk factors, including male gender, advanced cholecystitis, the presence of jaundice, and previous abdominal surgery, which are associated with an increased risk of conversion to open procedure.51 The decision to perform open cholecystectomy may be difficult for some. Over the past 20 years, open cholecystectomy has been far less frequently performed. Trainees during this period have less experience with open cases.64 The experience and training needed to learn the laparoscopic operation likely reduces the level of comfort with the open technique. Finally, there is the pressure related to patient expectation for rapid recovery as well as, perhaps, the hospital expectation for decreased length of stay and cost because conversion is associated with lengthier stays and increased expense.65 Certain scenarios may thus arise that might subtly account, in part, for static biliary injury rates.66 Because of inexperience, the surgeon may ignore or resist the sensible default option to convert to the open technique, persists with the laparoscopic approach, and causes injury. In other instances, the surgeon overextends laparoscopic experience when disease severity warrants conversion. To prevent this, patients need to be made fully aware that open cholecystectomy is always a possibility, and the surgeon should not hesitate to seek help if needed, rather than rely on marginal laparoscopic or open cholecystectomy experience. Conversion from laparoscopic to open cholecystectomy is not a defeat but rather is reflective of caution and good judgment.67,68 Ideally, a surgeon anticipates the likelihood of conversion on clinical grounds. The anesthesia and operative teams should be so notified and prepared. Open-case instruments need to be readily available, and trocar placement should be along a predrawn right subcostal incision line. Unless there is need to control bleeding, the surgeon enters the RUQ deliberately and is not stressed by the decision to convert. Everyone should be ready for what lies ahead, and it should be clear to all that it will be a difficult operation. The difficult open cholecystectomy demands adequate exposure, retraction, and identification of anatomy by dissection in the anterior and posterior aspects of the triangle of Calot, followed by dissection of the gallbladder off the liver bed. The surgeon achieves conclusive identification of the cystic structures as the only two structures entering the gallbladder, eliminating the possibility of misidentification.61 As with the laparoscopic technique, once the critical view is attained, the cystic structures can be ligated and divided. Failure to achieve this critical view should prompt cholangiography to define ductal anatomy. Avoidance of ductal injury in the liver bed depends on a combination of patience and staying in the correct plane of dissection, with meticulous technique and experience. In some cases of acute cholecystitis, the gallbladder “shells out” relatively easily from its edematous hepatic bed. In other cases, and especially in chronic cholecystitis, the dissection of the gallbladder out of the liver bed can be tedious, frustrating, and bloody. Hemostasis can take time and may require an argon

544

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

beam, cautery, packing, and topical hemostatics. Subtotal cholecystectomy is always a valid option, especially in patients with cirrhosis or in those with severe inflammation that obscures the anatomy within the porta hepatis. Surgeons should indicate in operative notes for open and laparoscopic cholecystectomy precisely how they identified the cystic structures for division. For conversions, they should specify the circumstances, stressing safety and surgical judgment.

Subtotal Cholecystectomy If subtotal cholecystectomy is determined to be the safest approach to completing the operation, options include whether to proceed with a minimally invasive approach versus converting to an open operation, and whether to fenestrate or reconstitute (see Chapter 36). These terms have recently been clarified and standardized. Subtotal reconstituting cholecystectomy indicates excision of the free, peritonealized portion of the gallbladder, with subsequent closure of the lowest portion with sutures or staples. The risk of a postoperative biliary fistula is reduced, but a remnant gallbladder is created, which could result in recurrence of disease. Subtotal fenestrating cholecystectomy is defined as excision of the gallbladder with the exception of a lip at the lowest portion, with the cystic duct then either being left open or closed from the inside. The risk of postoperative biliary fistula is increased, but there should be no risk of recurrent symptomatic cholecystolithiasis.69 Advantages and disadvantages of each approach continue to be debated, with some studies suggesting that laparoscopic and reconstituting techniques may reduce the risk of perioperative complications.70,71 Regardless, as application of these procedure has increased, so have their unique complications, including remnant cholecystitis, recurrent stones, and even remnant gallbladder carcinoma.

Robotic Cholecystectomy The Da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) was designed to expand on the technical capabilities of minimally invasive surgery (see Chapters 36 and 127). Advantages of robotic-assisted surgery compared with a laparoscopic approach include simulating a surgeon’s wrist motion with full articulating movement, an improved three-dimensional camera view of the surgical field, elimination of physiologic tremor, and enhanced instrument dexterity for suturing and dissection. Disadvantages include the equipment expense, a learning curve when the platform is newly adopted, and a perceived loss of tactile feedback for the surgeon, although this last point is somewhat debatable. Several early series demonstrated the safety and feasibility of robotic surgery when employed in abdominal surgery to treat a variety of diseases, including cholecystectomy.72,73 Most recent studies have redemonstrated low complication rates and equivalent clinical outcomes for roboticassisted cholecystectomy compared with laparoscopic cholecystectomy, with some studies suggesting lower conversion rates but increased cost with a robotic approach.74

Percutaneous Cholecystostomy (see Chapter 35) The indications for percutaneous cholecystostomy include grade II acute cholecystitis with a severe inflammatory process, grade III acute cholecystitis with associated organ dysfunction, or acute cholecystitis in patients with severe medical morbidity that limits surgical options.47,51,56,57,75,76 The technical success rate of percutaneous radiologically guided cholecystostomy is 98% to 100%, with few procedure-related complications (mortality and major

complications, 0%–6.5%; minor complications, 0%–20%).56,77 Potential complications include intrahepatic hematoma, pericholecystic abscess, and biliary peritonitis and pleural effusion caused by puncture of the liver and subsequent migration of the catheter.51

Timing of Subsequent Operation for Cholecystitis Once the inflammatory process has resolved, elective cholecystectomy can be performed early (within 1–7 days) or delayed (6–8 weeks) with excellent success and conversion rates as low as 3%.78 The optimal timing remains controversial because of a lack of randomized controlled trials; however, early cholecystectomy after percutaneous drainage may be preferable if the procedure is free of complications and the patient’s condition improves.51 Some have reported using percutaneous cholecystostomy as definitive treatment for acute cholecystitis in highrisk, elderly, and debilitated patients. In patients who do not have subsequent cholecystectomy, recurrent biliary symptoms occur in 9% to 33%.77,79

CHOLEDOCHOLITHIASIS (SEE CHAPTER 37) The clinical clues of CBD stones were recognized during the Roman Empire by Soranus of Ephesus, who described jaundice, itching, dark urine, and acholic stools. Not all CBD stones render such a classic clinical scenario, but they still carry risk if left unidentified and untreated. More than 85% of CBD stones originate in the gallbladder and secondarily migrate into the CBD. For patients undergoing cholecystectomy for symptomatic gallstones, the prevalence of choledocholithiasis ranges from 10% to 18%.80 Primary CBD stones are far less common and are typically associated with conditions of biliary infection and stasis, such as benign biliary strictures, sclerosing cholangitis, and choledochal cysts. Primary CBD stones are more prevalent in Asians and can sometimes be related to parasitic infections.81

Silent Common Bile Duct Stones Published reports using routine intraoperative cholangiography have found that at least 12% of CBD stones are clinically silent,82 and approximately 6% do not exhibit abnormalities in LFTs or in the diameter of the CBD.83 When prospectively followed, data suggest that more than one-third of asymptomatic stones will pass spontaneously after the first 6 weeks after cholecystectomy.84

Symptomatic Common Bile Duct Stones The symptoms of CBD stones relate to partial or complete biliary obstruction with and without inflammatory complications, such as cholangitis, hepatic abscesses, or pancreatitis. In chronic scenarios, and depending on the extent and duration of biliary obstruction, choledocholithiasis may also lead to secondary biliary cirrhosis and portal hypertension. Because of the uncertain clinical behavior and potential harmful complications, it is currently accepted that in the great majority of situations, CBD stones should be removed, even if they are asymptomatic.5

Definitive Treatment Approaches: Biliary Obstruction Catheter-Based Approaches ERCP (SEE CHAPTERS 20, 30, AND 37C). Before the laparoscopic era, ERCP was not commonly used because open surgical bile duct

A. Gallstones and Gallbladder  Chapter 38  Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?

clearance was superior to ERCP in terms of success and morbidity.85 This changed as laparoscopic cholecystectomy emerged and outpaced the abilities of most surgeons to perform laparoscopic CBD stone removal (see Chapter 37B). Indeed, ERCP captured and has held its role as the first-line approach to CBD stones, being successful in more than 90% of patients.86 Although well tolerated in most, a 10% rate of complications remains constant for ERCP,9 with a serious morbidity rate of 1.5% and an overall mortality rate of 0.2% to 0.5%.87 When surgical and endoscopic teams are inexperienced with CBD stones, the perceived need for preoperative ERCP increases. In this setting, ERCP allows laparoscopic cholecystectomy to be performed quickly and with confidence that CBD stones are already managed. If ERCP fails, the surgical plan will need to consider intraoperative management of choledocholithiasis. Conversely, in centers where successful sphincterotomy and stone extraction is almost assured, the rate of preoperative ERCP will be lower. If the surgeon finds a stone at operation, ERCP becomes a reliable postoperative option. Current consensus accepts the use of ERCP before laparoscopic cholecystectomy for patients with a high probability of choledocholithiasis. It is recommended that patients with a low or intermediate index of suspicion for choledocholithiasis undergo additional imaging techniques (MRCP, EUS, IOC) to avoid unnecessary biliary instrumentation.5,88,89 PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY (SEE CHAPTERS 20, 31, AND 37C). Compared with ERCP, percutaneous transhepatic cholangiography (PTC) is time-consuming, more involved, and likely more stressful for a patient. It is usually reserved for patients in whom anatomic considerations preclude safe ERCP, such as in the case of an impossible ampullary cannulation. Experienced PTC groups have reported successful stone removal rates in more than 90% of cases, with complication rates around 5%,90 although these are hardly the norms. PTC stone removal takes time, involving insertions of catheters that are upsized over time, before stones are actually retrieved with stone baskets. Consequently, there are many reports of attempts to make it easier. Gil and colleagues91 have reported the safety and utility of balloon dilation of the papilla in the clearing of CBD stones using occlusion balloon pushing. This has also gained some popularity for the laparoscopic surgeon during IOC.

Surgical Approaches: Open and Laparoscopic Techniques (see Chapters 37A and 37B) The same issues discussed in choosing open versus laparoscopic cholecystectomy are accentuated when CBDE is considered. Today, many trainees will graduate residency having never performed an open CBDE. Their ability to succeed with laparoscopic CBDE is quite variable because many train with a default dependence on ERCP.

Approach to Recurrent Common Bile Duct Stones In some instances, even after successful decompression and stone removal of the common duct with ERCP, patients will continue to present with recurrent choledocholithiasis. Such patients present a management challenge, with varying treatment options. One possible endoscopic approach is balloon dilation of the papilla with concurrent stone removal, which has been shown to decrease subsequent CBD stone recurrences compared with stone extraction alone.92,93 For patients who fail nonoperative treatments, surgical drainage may be necessary.

545

Described approaches include choledocholithotomy and T-tube drainage, choledochoduodenostomy, and choledochojejunostomy, and there is evidence indicating that choledochoduodenostomy is the most successful approach for preventing future recurrences.94–96 CHOLECYSTECTOMY WITH INTRAOPERATIVE CHOLANGIOGRAPHY (SEE CHAPTERS 24, 37A, AND 37B). Open and laparoscopic IOC can successfully be completed in the majority of patients by the majority of surgeons.17 IOC can be performed through the direct insertion of contrast medium into the gallbladder or more often by intubating the cystic duct. Plain radiographs have largely been replaced by digital fluoroscopic imaging. IOC is common, and most surgeons receive sufficient training. Laparoscopic ultrasound cholangiography is also efficacious but not broadly used, and its utility is limited by its longer learning curve.97 Newer techniques such as hyperspectral cholangiography and near-infrared fluorescence cholangiography hold promise and may become more widely used in the future.98 Since the introduction of laparoscopic cholecystectomy, the debate over routine versus selective IOC has been rekindled because of the increased incidence of CBD injuries and the inability to palpate the CBD during laparoscopy. IOC accurately defines the biliary anatomy and may protect against intraoperative bile duct injuries18 and may reduce their severity.99 Opponents claim that routine IOC may lead to bile duct injury and unnecessary CBDEs because of false positives and that it may add time and costs unnecessarily. Selective IOC relies on predicting the probability of choledocholithiasis. In general, patients with a low probability (normal LFTs, normal CBD diameter) may undergo cholecystectomy with no further preoperative investigation and selective IOC. Patients with intermediate risk (isolated abnormal LFTs or CBD dilation) may undergo further preoperative imaging (MRCP) and routine IOC at an absolute minimum. Patients with high risk (jaundice, cholangitis) warrant confirmatory/ therapeutic ERCP88 at most centers. In fact, today many patients are triaged for this purpose, but in years past, many would undergo open CBDE. Ultimately, the choice of modality depends on local availability and expertise in minimally invasive treatments coupled with considerations of cost and convenience. COMMON BILE DUCT EXPLORATION: TRANSCYSTIC VERSUS CHOLEDOCHOTOMY ACCESS (SEE CHAPTERS 37A AND 37B). When IOC reveals CBD stones, they can be removed during cholecystectomy. The open choledochotomy to allow cholangioscopy, flushing, forceps and balloon clearance, and T-tube placement is rarely performed or taught today. Instead, laparoscopic CBDE (LCBDE) has evolved as an efficient and more commonly used technique, as described in other chapters. Several studies have shown LCBDE to be at least as efficient as preoperative or postoperative ERCP in terms of stone clearance, morbidity, mortality, and short hospital stay, and thus LCBDE is recommended for surgeons with appropriate skills and facilities.85 A 2013 Cochrane Review of randomized trials actually demonstrated the superiority of both open and laparoscopic CBDE when compared with ERCP in clearing the CBD, without any associated increased morbidity.80 For capable surgeons, LCBDE is as safe and efficient as ERCP, thus avoiding the discomfort, costs, and potential complications of an extra procedure.85,100

546

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

Although LCBDE can be safely performed through either transcystic or choledochotomy approaches, most surgeons prefer the transcystic approach. It is feasible in most cases, saves time, does not violate the CBD, and shows no higher morbidity than standard laparoscopic cholecystectomy alone.101,102 Techniques available for transcystic CBD stone extraction mirror those used in an open approach. After a cholangiogram, 1 to 2 mg of glucagon can be administered and small stones (,4 mm) can be flushed out of the duct with 30 mL of saline through the cholangiogram catheter.103 Larger stones can be extracted with a 4 French (F) Fogarty balloon or wire basket under fluoroscopic guidance or direct visualization using a choledochoscope. To accommodate the choledochoscope and allow for extraction of larger stones, the cystic duct often will need to be dilated with a 5 to 8 mm angioplasty balloon.103,104 The most consistent risk factor for failing transcystic stone clearance is the size of the stone. Once stones exceed 5 mm, the likelihood of transcystic extraction falls considerably,105 and laparoscopic choledochotomy becomes necessary. However, many surgeons do not have the laparoscopic dissection and suturing expertise to perform this procedure; they rely instead on ERCP, or they convert to an open operation. Experienced surgeons can remove larger or multiple CBD stones with reported success rates of up to 90%.106 The question of how to close the CBD after exploration remains a topic of debate. A 2007 Cochrane Review was not able to conclude significant differences in outcomes for primary closure of the CBD versus the routine use of T-tube drainage after open CBDE.107 However, two 2013 Cochrane Reviews reported that T-tube drainage results in longer operating times and hospital stays without any apparent benefit over primary closure in both open and laparoscopic CBDE.108,109 Another 2012 meta-analysis of randomized controlled trials confirmed the superior safety and effectiveness of primary closure over T-tube drainage after laparoscopic CBDE.110

mid 1980s, urgent surgery with biliary decompression was studied as a treatment of choice for patients with acute gallstone pancreatitis, but this approach was associated with an increased mortality rate among patients with severe pancreatitis. As such, surgical treatment during the acute phase of the gallstone pancreatitis is not recommended. The role of nonsurgical intervention, before definitive surgical therapy, has been examined in several prospective randomized studies in which patients with cholangitis were excluded. Integral to any interpretation of treatment approach is the severity of the gallstone pancreatitis. These studies defined severe pancreatitis using a number of systems that included the Ranson criteria (.3), Glasgow criteria (.3), or the Acute Physiology and Chronic Health Evaluation (APACHE) II score (.8). The Ranson and Glasgow criteria have the advantage of ease of use and considerable areas of overlap (Table 38.3). A meta-analysis analyzed five prospective randomized studies that examined the use of early biliary decompression in cases of gallstone pancreatitis without cholangitis114 (see Chapters 54 and 55). This study reported a significant reduction in pancreatitis-related complications in patients with predicted severe pancreatitis (rate difference of 38.5%; 95% confidence interval, –53% to 223.9%; P , .0001), but no advantage was seen in cases with mild pancreatitis, and no difference in mortality rate was noted. A 2012 Cochrane Review did not demonstrate any differences between early ERCP and conservative management in pancreatitis of any severity without evidence of cholangitis or biliary obstruction. However, in patients with concurrent cholangitis or biliary obstruction, early ERCP significantly reduced mortality and systemic complications.115

CRITERIONa

ACTION

Gallstone Pancreatitis (see Chapters 54 and 55)

Ranson Age . 55 years WBC count . 16,000/mm3

Admission Admission

Glucose . 200 mg/dL AST . 250 IU/L LDH . 350 IU/L Increased BUN . 8 mg/dL Pao2 , 60 mm Hg Calcium , 8.0 mg/dL Base deficit , 4 mEq/L Fluid sequestration  6 L

Admission Admission Admission 48 hr 48 hr 48 hr 48 hr 48 hr

Glasgow Age . 55 years WBC count . 15,000/mm3 Glucose . 200 mg/dL AST/ALT . 96 IU/L LDH . 219 IU/L BUN . 45 mg/dL Pao2 , 76 mm Hg Calcium , 8.0 mg/dL Albumin , 3.4 g/dL

Admission Admission Admission 48 hr 48 hr Admission Admission 48 hr 48 hr

Acute gallstone pancreatitis is the most frequent form of acute pancreatitis in Western countries. The two most commonly accepted mechanisms for the pathogenesis of gallstone pancreatitis are reflux of bile into the pancreatic duct and transient ampullary obstruction caused by temporary impaction of a stone in the ampulla. The disease is mild in approximately 80% of patients, but 20% experience a more severe clinical course that includes complications such as pancreatic necrosis, multisystem organ failure, and even death.111–113 In many patients, the biliary obstruction has spontaneously resolved at the time of presentation, so biliary decompression is not needed. These patients should undergo elective cholecystectomy once the pancreatitis has resolved, with many favoring operation during the index hospitalization. At the other end of the spectrum are patients with gallstone pancreatitis and associated acute cholangitis. Clear evidence shows that endoscopic biliary drainage is beneficial in patients with acute cholangitis; thus these patients should have early biliary decompression. A secondary question is whether patients with gallstone pancreatitis, without cholangitis, benefit from biliary decompression. Clinical and experimental studies suggest that impacted ampullary stones and persistent biliopancreatic obstruction are associated with a more severe clinical course. In theory, early endoscopic removal of obstructing ampullary gallstones should improve outcomes.111,112 Between the late 1970s and

TABLE 38.3  Ranson and Glasgow Criteria for Severity of Acute Pancreatitis

a

Mortality rates: 0–2 5 2%, 3–4 5 15%, 5–6 5 40%, .7 5 100%.

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; Pao2, partial pressure of oxygen in arterial blood; WBC, white blood cell count.

A. Gallstones and Gallbladder  Chapter 38  Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?

The severity of the patient’s illness guides the timing of intervention. Patients whose biliary obstruction has spontaneously resolved at the time of presentation and those who have mild predicted pancreatitis should have early elective cholecystectomy once their pancreatitis has resolved. Patients with severe predicted pancreatitis and those with associated cholangitis should undergo early biliary decompression (ERCP or PTC). Among cases of escalating pancreatitis, biliary decompression should be performed within 24 to 72 hours of admission.114 For cases with associated cholangitis, biliary decompression should occur within 24 hours of presentation. Elective cholecystectomy can then be performed once the severe illness has resolved.

Risk of Recurrence Historically, recurrence rates of gallstone pancreatitis have been reported as high as 25% to 76% for patients who do not undergo a cholecystectomy at their index presentation.116 A more contemporary report of 1,119 patients described an overall recurrence rate of 14.6% at a median follow up of 2.3 years. The risk of recurrence was mitigated by ERCP and sphincterotomy with an estimated 5-year recurrence rate of 11.1% compared with 22.7% in patients who underwent no intervention. Median time to recurrence was under 1 year in both groups. Cholecystectomy restores the risk of recurrence of gallstone pancreatitis to that of the general population but does not prevent it entirely.117

Cholangitis (see Chapter 43) Clinical findings associated with acute cholangitis include RUQ abdominal pain, jaundice, fever and chills—also known as Charcot’s triad (1877). Charcot’s triad demonstrates high specificity but low sensitivity because not all patients with cholangitis manifest all findings: 90% develop fever, but only about 50% to 70% of patients develop all three symptoms.118 Reynold’s pentad (1959)—Charcot’s triad plus shock and altered mental status—represents a form of severe (grade III) cholangitis, which can also manifest with multiorgan dysfunction.

A

cm

547

Severe cholangitis is reported in 12% to 30% of patients with acute cholangitis.118,119 The 2013 updated Tokyo guidelines, which were subsequently re-affirmed in 2018, provide a more sensitive (91.8%) and specific (77.7%) definition for cholangitis based on signs of systemic inflammation, laboratory evidence of cholestasis, and imaging findings consistent with biliary obstruction (Table 38.4).120 Patients with systemic inflammation and evidence of either cholestasis or biliary obstruction are said to have a suspected diagnosis, whereas patients with both cholestasis and biliary obstruction are said to have a definitive diagnosis.120 Cholangitis is a localized infection of the biliary tree, and an understanding of the pathophysiology of cholangitis guides treatment decisions. Research into this disease has shown that bacteria-laden gallstones are often the source of infection. These bacteria exist in a bacterial microcolony (biofilm) within the pigmented matrix of gallstones (Fig. 38.2).45 The bacteria must detach from the biofilm to cause a localized infection,

TABLE 38.4  Tokyo Guidelines (TG18/TG13) Diagnostic Criteria for Acute Cholangitis CRITERIA

THRESHOLD

A. Systemic inflammation

Fever .38°C WBC ,4 or .10 CRP  1 T-Bili  2 ALP . 1.5 3 upper limit of normal GGT . 1.5 3 upper limit of normal AST . 1.5 3 upper limit of normal ALT . 1.5 3 upper limit of normal Biliary Dilation Evidence of the etiology on imaging (stricture, stone, stent, etc.)

B. Cholestasis

C. Imaging

ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, c-reactive protein; GGT, r-glutamyltransferase; T-Bili, total bilirubin; WBC, white blood cell count.

B

FIGURE 38.2  A, Black-pigment gallstones. B, Scanning electron micrograph of the black-pigment stones demonstrating bacterial microcolonies. Note the bacterial bridges and three-dimensional nature of the biofilm. (From Stewart L, Oesterle AL, Erdan I, Griffiss JM, Way LW. The pathogenesis of pigment gallstones in Western societies: The central role of bacteria. J Gastrointest Surg. 2002;6:891–904.)

548

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

and it must reflux into the cholangiovenous circulation to cause a more severe illness, including bacteremia and organ dysfunction.121,122 Cholangiovenous reflux occurs with biliary pressures greater than 20 cm H2O, and even at this pressure, bacterial characteristics (slime production) influence cholangiovenous reflux. In addition, bacterial breakdown by complement releases endotoxin, and this influences the induction of inflammatory cytokines that drive the septic manifestations. It is important to note that although choledocholithiasis is a common cause of biliary obstruction, benign and malignant biliary stenosis and biliary anastomotic strictures are also etiologies.118 The 2018/2013 updated Tokyo Guidelines describe three grades of acute cholangitis (Table 38.5): grade III is associated with organ failure, grade II cases should undergo prompt early biliary drainage, and grade I is all others.120 All patients with suspected cholangitis should be treated with IV hydration and antibiotics that cover the most common biliary organisms: Escherichia coli, Klebsiella spp., Enterococcus, Enterobacter cloacae, Pseudomonas spp., and anaerobic pathogens. Patients with severe grade III cholangitis also require organ support and stabilization of organ dysfunction. The critical component of the treatment of cholangitis is biliary decompression. Because elevated biliary pressure drives cholangiovenous reflux, decompression of the biliary tree with ERCP is crucial; PTC may be used if ERCP is not available. Not only does biliary drainage prevent bacterial cholangiovenous reflux, it has also been shown to be associated with a marked decreased in bile and serum endotoxin levels. In the setting of acute cholangitis, biliary drainage via a noninvasive procedure is preferable. Drainage can be achieved using ERCP

TABLE 38.5  Tokyo Guidelines (TG18/TG13) Severity Assessment Criteria for Acute Cholangitis GRADE

CRITERIA

I: Mild

Does not meet the criteria of grade III (severe) or grade II (moderate) acute cholangitis at initial diagnosis Associated with any two of the following conditions: 1. Abnormal WBC count (.12,000/mm3, ,4,000/mm3) 2. High fever (39°C) 3. Age (75 years) 4. Hyperbilirubinemia (total bilirubin  5 mg/dL) 5. Hypoalbuminemia (,STD 3 0.7) Associated dysfunction in at least one of the following organ systems: 1. Cardiovascular system: hypotension requiring dopamine .5 mg/kg/min or any dose of norepinephrine 2. Nervous system: disturbance of consciousness 3. Respiratory system: Pao2/Fio2 ratio , 300 4. Renal system: oliguria, serum creatinine . 2.0 mg/dL 5. Liver: PT-INR . 1.5 6. Hematologic system: platelet count , 100,000/mm3

II: Moderate

III: Severe

Fio2, Forced inspiratory oxygen concentration; Pao2, partial pressure of oxygen in arterial blood; PT-INR, prothrombin time/international normalized ratio; STD, standard deviation; WBC, white blood cell count.

or PTC cannulation of the biliary tree. Open surgical drainage may be necessary in medical centers lacking interventional radiology or gastroenterology ERCP capability, or in rare cases where anatomic abnormalities limit noninvasive approaches.57 The Tokyo Guidelines provide a useful tool for the management of acute cholangitis (see Table 38.5). Patients with grade I cholangitis who respond to medical therapy can be treated with ERCP (within 24 hours), followed by definitive surgical treatment (laparoscopic cholecystectomy), or the surgeon can proceed to laparoscopic cholecystectomy with intraoperative LCBDE after medical stabilization.47,123 Factors guiding these choices include the patient’s clinical findings and the surgeon’s experience with LCBDE. Patients with grade II cholangitis require urgent biliary decompression, whereas patients with severe (grade III) cholangitis require urgent endoscopic or percutaneous transhepatic biliary drainage after stabilization of organ dysfunction. For patients with grade II or III cholangitis, the initial therapy should emphasize biliary decompression rather than definitive removal of all CBD stones. Prolonged procedures with excessive manipulation in an attempt to remove large stones should be avoided in patients with active infectious manifestations. Once the acute illness has resolved, early cholecystectomy can be performed within 6 weeks of biliary decompression with no increase in postoperative complications.124

Need for Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography/Sphincterotomy There has been considerable debate over whether cholecystectomy is required after ERCP/sphincterotomy for patients who initially present with choledocholithiasis. Retrospective studies have reported a low incidence of cholecystectomy among patients with a gallbladder in situ after ERCP/sphincterotomy managed by watchful waiting (10%–15% over 5–14 years).77,125 Many of these studies involved older patient populations and patients with multiple medical illnesses. A Cochrane Review of prospective randomized studies reported that elective cholecystectomy is recommended to decrease mortality, recurrent biliary symptoms, and the need for repeat interventions such as ERCP and cholangiography.126 Other contemporary studies also support this recommendation, particularly if there is a history of pancreatitis or if more than 6 months have passed since sphincterotomy was performed.127 However, when the combined surgical and anesthetic risks are prohibitive, usually because of comorbidities and age, reliance on a sufficient protective sphincterotomy is certainly reasonable.

CHALLENGES IN ADHERING TO THE STANDARD OF CARE Events have unfolded in the modern era that have forced surgeons to develop new approaches to surgical diseases and modify what is generally considered to be the standard of care. Since 2020, the COVID-19 pandemic profoundly impacted healthcare worldwide and hospitals struggled to cope as their capacities and resources were strained. In March of 2020, as COVID-19 cases in the United States surged, both the American College of Surgeons (ACS) and SAGES issued guidelines encouraging the postponement of elective surgical and endoscopic cases. The care of cholelithiasis/choledocholithiasis was particularly impacted because both endoscopy and laparoscopy

A. Gallstones and Gallbladder  Chapter 38  Cholecystolithiasis and Stones in the Common Bile Duct: Which Approach and When?

were considered aerosol-generating procedures (AGPs), which increased the risk of healthcare workers. The ACS advised that AGPs should only be performed while wearing full personal protective equipment (PPE) including an N95 mask or power, air-purifying respiratory (PAPR) designed for the operating room. Likewise, SAGES emphasized the enhanced risk of viral exposure to endoscopists and encouraged the use of N95 masks and face shields. Given the profound shortages of PPE in many regions, the challenges in adhering to these guidelines were profound. SAGES additionally advocated for the use of air filtration devices for the evacuation of pneumoperitoneum during laparoscopic or robotic cases to prevent aerosolization, which were not necessarily readily available.128 On March 25, 2020, the ACS issued the COVID-19 Guidelines for Triage of Emergency General Surgery Patients, wherein they offered more specific advice for the management of average risk, non–COVID-19 positive patients with surgical diseases during the pandemic. They specifically advised that patients with symptomatic cholelithiasis should have surgery delayed if possible, with consideration of laparoscopic cholecystectomy for those with crescendo symptoms or refractory to medical management. Laparoscopic cholecystectomy was also recommended in healthy patients with cholecystitis to minimize hospital stays, with antibiotics and possible percutaneous cholecystostomy tube advised for high-risk patients or if an operating room was not available. Expectant management was recommended in the setting of choledocholithiasis in the absence of cholangitis, but ERCP and sphincterotomy, with appropriate precautions, were advised if necessary. Another ACS communication by Hughes and Strasberg agreed with postponing surgery in the setting of biliary colic and biliary dyskinesia but proceeding with cholecystectomy in the setting of cholecystitis when resources allowed it.129 As the pandemic progressed, additional information was gained, illustrating the significantly increased risk for COVID-19 patients undergoing operations. An international multicenter cohort study analyzed 1,128 patients with SARS-CoV-2 infection who underwent surgery, including 372 who had GI or general surgery130; 51.2% of all patients and 53.6% of those undergoing GI/general surgery developed pulmonary complications and an exceedingly high 30-day mortality rate of 23.8% overall and 23.1% after GI/general surgery was demonstrated. Nonoperative management was encouraged whenever possible for COVID-19 patients, particularly male patients and those aged 70 and older who were at increased risk for perioperative mortality. In 2021, with the improvement of COVID-19 treatments, vaccination strategies and patient safety and distancing guidelines, there has been at least some return to normalcy. COVID-19 testing is providing important reassurance of the safety to proceed more and more often along elective guidelines. Questions remain, and will for some time, especially as case numbers continue to rise worldwide, new COVID variants emerge, and breakthrough infections occur.

SPECIAL POPULATIONS: MANAGEMENT OF CHOLELITHIASIS AND CHOLECYSTITIS IN PREGNANCY Out of concern for spontaneous abortion and preterm labor, traditional recommendations dictated that operations should

549

be avoided in the first and third trimesters of pregnancy.131 With the introduction of laparoscopic surgery, further concerns were raised over the risk of trocar injuries to the gravid uterus.132 Over the past 3 decades as prenatal care and laparoscopic techniques have improved, there has been a concerted effort to delineate better the optimal management of cholelithiasis and cholecystitis in pregnant patients. Sedaghat et al. performed a meta-analysis of 11 studies and 10,632 patients comparing open and laparoscopic cholecystectomy in pregnancy. They found a significant decrease in the rate of fetal and maternal complications, with a shorter length of hospital stay when laparoscopy was employed. Patients who underwent laparoscopic cholecystectomy had a gestational age 6 weeks younger compared with the open approach in this study (18 vs. 24 weeks). The conversion rate from laparoscopic to open cholecystectomy was reported to be relatively low at 3.8%.133 As patients exit the first trimester, there are important technical adaptations that are required to accommodate the gravid uterus. Patients should be placed in partial left lateral decubitus to prevent compression of the inferior vena cava (IVC). Initial access and subsequent port placement should be adjusted for fundal height but can be safely accomplished with a Veress needle or open Hassan technique. Typically, a right subcostal trocar allows for safe access to the peritoneal cavity. Standard insufflation pressures can ordinarily be used but should be adjusted based on the patient’s hemodynamics.134 Regarding the timing of surgery, there is no difference in the rates of preterm delivery and spontaneous abortion when symptomatic cholelithiasis is managed conservatively or by laparoscopic cholecystectomy regardless of trimester.135 However, when patients present with complicated biliary disease, the rates of preterm labor and spontaneous abortion increase, with studies reporting rates of fetal loss as high as 60% in severe disease. Patients are at high risk of recurrent disease, with rates as high as 92%, 64%, and 44% in the first, second, and third trimester, respectively.134 Ultimately, 50% of these patients will require hospitalization, with 23% of those patients developing complicated biliary disease.134,136 Given the high rates of recurrence and risk of preterm labor and spontaneous abortion, in 2017 SAGES published guidelines for the evaluation and management of cholecystitis in pregnancy, advocating for the use of laparoscopic cholecystectomy in all trimesters for the treatment of cholecystitis.134

CONCLUSION In 1970, who could have predicted that the common ailments of cholecystolithiasis and choledocholithiasis would soon face historical advances in technology? Patients now benefit from improved imaging and minimally invasive endoscopic and laparoscopic techniques, especially when combined. Nevertheless, although our technical strategies only occasionally resemble those of a bygone era in biliary surgery, our treatment strategies should reflect enduring principles. Disease severity grading, diagnostic criteria, drainage, timing and patient selection will always be critical. By combining technical versatility and flexibility upon these principles, we can continue to drive improved outcomes worldwide for these conditions. References are available at expertconsult.com.

549.e1

REFERENCES 1. Koo KP, Traverso LW. Do preoperative indicators predict the presence of common bile duct stones during laparoscopic cholecystectomy? Am J Surg. 1996;171(5):495–499. 2. Narula VK, Fung EC, Overby DW, Richardson W, Stefanidis D, SAGES Guidelines Committee. Clinical spotlight review for the management of choledocholithiasis. Surg Endosc. 2020;34(4):1482–1491. 3. Bennett GL. Evaluating patients with right upper quadrant pain. Radiol Clin North Am. 2015;53(6):1093–1130. 4. Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):41–54. 5. Williams EJ, Green J, Beckingham I, et al. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7):1004–1021. 6. Abboud PA, Malet PF, Berlin JA, et al. Predictors of common bile duct stones prior to cholecystectomy: a meta-analysis. Gastrointest Endosc. 1996;44(4):450–455. 7. Tseng CW, Chen CC, Chen TS, Chang FY, Lin HC, Lee SD. Can computed tomography with coronal reconstruction improve the diagnosis of choledocholithiasis? J Gastroenterol Hepatol. 2008;23(10):1586–1589. 8. Epelboym I, Winner M, Allendorf JD. MRCP is not a cost-effective strategy in the management of silent common bile duct stones. J Gastrointest Surg. 2013;17(5):863–871. 9. Andriulli A, Loperfido S, Napolitano G, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol. 2007;102(8):1781–1788. 10. Katsinelos P, Lazaraki G, Chatzimavroudis G, et al. Risk factors for therapeutic ERCP-related complications: an analysis of 2,715 cases performed by a single endoscopist. Ann Gastroenterol. 2014;27(1):65–72. 11. Daradkeh S, Shennak M, Abu-Khalaf M. Selective use of perioperative ERCP in patients undergoing laparoscopic cholecystectomy. Hepatogastroenterology. 2000;47(35):1213–1215. 12. Garrow D, Miller S, Sinha D, et al. Endoscopic ultrasound: A meta-analysis of test performance in suspected biliary obstruction. Clin Gastroenterol Hepatol. 2007;5(5):616–623. 13. Tse F, Liu L, Barkun AN, Armstrong D, Moayyedi P. EUS: A meta-analysis of test performance in suspected choledocholithiasis. Gastrointest Endosc. 2008;67(2):235–244. 14. Petrov MS, Savides TJ. Systematic review of endoscopic ultrasonography versus endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis. Br J Surg. 2009;96(9):967–974. 15. Palmucci S, Mauro LA, La Scola S, et al. Magnetic resonance cholangiopancreatography and contrast-enhanced magnetic resonance cholangiopancreatography versus endoscopic ultrasonography in the diagnosis of extrahepatic biliary pathology. Radiol Med. 2010;115(5):732–746. 16. Verma D, Kapadia A, Eisen GM, Adler DG. EUS vs MRCP for detection of choledocholithiasis. Gastrointest Endosc. 2006;64(2): 248–254. 17. Machi J, Tateishi T, Oishi AJ, et al. Laparoscopic ultrasonography versus operative cholangiography during laparoscopic cholecystectomy: review of the literature and a comparison with open intraoperative ultrasonography. J Am Coll Surg. 1999;188(4):360–367. 18. Fletcher DR, Hobbs MS, Tan P, et al. Complications of cholecystectomy: risks of the laparoscopic approach and protective effects of operative cholangiography: a population-based study. Ann Surg. 1999;229(4):449–457. 19. Ford JA, Soop M, Du J, Loveday BP, Rodgers M. Systematic review of intraoperative cholangiography in cholecystectomy. Br J Surg. 2012;99(2):160–167. 20. Sakorafas GH, Milingos D, Peros G. Asymptomatic cholelithiasis: Is cholecystectomy really needed? A critical reappraisal 15 years after the introduction of laparoscopic cholecystectomy. Dig Dis Sci. 2007;52(5):1313–1325. 21. Festi D, Reggiani ML, Attili AF, et al. Natural history of gallstone disease: expectant management or active treatment? Results from a population-based cohort study. J Gastroenterol Hepatol. 2010;25(4):719–724. 22. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg. 1985;202(1):59–63.

23. Gallstones and laparoscopic cholecystectomy. NIH Consens Statement. 1992;10(3):1–28. 24. Stewart L, et al. Asymptomatic gallstones: nonsurgical versus surgical approach. Prob General Surg. 1989;6:73–80. 25. Hickman MS, Schwesinger WH, Page CP. Acute cholecystitis in the diabetic. A case-control study of outcome. Arch Surg. 1988; 123(4):409–411. 26. Currò G, Iapichino G, Melita G, Lorenzini C, Cucinotta E. Laparoscopic cholecystectomy in Child-Pugh class C cirrhotic patients. JSLS. 2005;9(3):311–315. 27. Wudel Jr LJ, Wright JK, Debelak JP, Allos TM, Shyr Y, Chapman WC. Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study. J Surg Res. 2002;102(1):50–56. 28. Benarroch-Gampel J, Lairson DR, Boyd CA, Sheffield KM, Ho V, Riall TS. Cost-effectiveness analysis of cholecystectomy during Roux-en-Y gastric bypass for morbid obesity. Surgery. 2012; 152(3):363–375. 29. D’Hondt M, Sergeant G, Deylgat B, Devriendt D, Van Rooy F, Vansteenkiste F. Prophylactic cholecystectomy, a mandatory step in morbidly obese patients undergoing laparoscopic Roux-en-Y gastric bypass? J Gastrointest Surg. 2011;15(9):1532–1536. 30. Warschkow R, Tarantino I, Ukegjini K, et al. Concomitant cholecystectomy during laparoscopic Roux-en-Y gastric bypass in obese patients is not justified: a meta-analysis. Obes Surg. 2013;23(3):397–407. 31. Kao LS, Flowers C, Flum DR. Prophylactic cholecystectomy in transplant patients: a decision analysis. J Gastrointest Surg. 2005;9(7):965–972. 32. Melvin WS, Meier DJ, Elkhammas EA, et al. Prophylactic cholecystectomy is not indicated following renal transplantation. Am J Surg. 1998;175(4):317–319. 33. Kilic A, Sheer A, Shah AS, Russell SD, Gourin CG, Lidor AO. Outcomes of cholecystectomy in US heart transplant recipients. Ann Surg. 2013;258(2):312–317. 34. Takeyama H, Sinanan MN, Fishbein DP, Aldea GS, Verrier ED, Salerno CT. Expectant management is safe for cholelithiasis after heart transplant. J Heart Lung Transplant. 2006;25(5):539–543. 35. Klaus A, Hinder RA, Swain J, Achem SR. Incidental cholecystectomy during laparoscopic antireflux surgery. Am Surg. 2002;68(7):619–623. 36. Cadot H, Addis MD, Faries PL, et al. Abdominal aortic aneurysmorrhaphy and cholelithiasis in the era of endovascular surgery. Am Surg. 2002;68(10):839–844. 37. Pitoulias GA, Papaziogas BT, Atmatzidis SK, Papadimitriou DK. Abdominal aortic aneurysm with symptomatic cholelithiasis: report of a case treated by simultaneous endovascular aneurysm repair and laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2012;22(5):e291–e293. 38. Currò G, Meo A, Ippolito D, Pusiol A, Cucinotta E. Asymptomatic cholelithiasis in children with sickle cell disease: early or delayed cholecystectomy? Ann Surg. 2007;245(1):126–129. 39. Al-Salem AH, Issa H. Laparoscopic cholecystectomy in children with sickle cell anemia and the role of ERCP. Surg Laparosc Endosc Percutan Tech. 2012;22(2):139–142. 40. Tewari M. Contribution of silent gallstones in gallbladder cancer. J Surg Oncol. 2006;93(8):629–632. 41. Albores-Saavedra J, Alcántra-Vazquez A, Cruz-Ortiz H, HerreraGoepfert R. The precursor lesions of invasive gallbladder carcinoma. Hyperplasia, atypical hyperplasia and carcinoma in situ. Cancer. 1980;45(5):919–927. 42. Gupta SK, Shukla VK. Silent gallstones: a therapeutic dilemma. Trop Gastroenterol. 2004;25(2):65–68. 43. Mohandas KM, Patil PS. Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in northern Indian women. Indian J Gastroenterol. 2006;25(3):147–151. 44. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-E386. 45. Stewart L, Oesterle AL, Erdan I, Griffiss JM, Way LW. Pathogenesis of pigment gallstones in Western societies: the central role of bacteria. J Gastrointest Surg. 2002;6(6):891–904. 46. Siegel JH, Kasmin FE. Biliary tract diseases in the elderly: management and outcomes. Gut. 1997;41(4):433–435. 47. Takada T, Kawarada Y, Nimura Y, et al. Background: Tokyo Guidelines for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Surg. 2007;14(1):1–10.

549.e2 48. Takada T, Strasberg SM, Solomkin JS, et al. TG13: Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):1–7. 49. Yokoe M, Takada T, Strasberg SM, et al. TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2013;20(1):35–46. 50. Hadad SM, Vaidya JS, Baker L, et al. Delay from symptom onset increases the conversion rate in laparoscopic cholecystectomy for acute cholecystitis [published correction appears in World J Surg. 2008;32(12):2747. Hussain, Kashif [added]]. World J Surg. 2007;31(6):1298–1303. 51. Yamashita Y, Takada T, Strasberg SM, et al. TG13 surgical management of acute cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):89–96. 52. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database Syst Rev. 2006;(4):CD005440. 53. Nguyen L, Fagan SP, Lee TC, et al. Use of a predictive equation for diagnosis of acute gangrenous cholecystitis. Am J Surg. 2004;188(5):463–466. 54. Tsuyuguchi T, Takada T, Kawarada Y, et al. Techniques of biliary drainage for acute cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):35–45. 55. Kimura Y, Takada T, Strasberg SM, et al. TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):8–23. 56. Howard JM, Hanly AM, Keogan M, Ryan M, Reynolds JV. Percutaneous cholecystostomy—a safe option in the management of acute biliary sepsis in the elderly. Int J Surg. 2009;7(2):94–99. 57. Tsuyuguchi T, Itoi T, Takada T, et al. TG13 indications and techniques for gallbladder drainage in acute cholecystitis (with videos) [published correction appears in J Hepatobiliary Pancreat Sci. 2013;20(5):545–546]. J Hepatobiliary Pancreat Sci. 2013;20(1): 81–88. 58. Crichlow L, Walcott-Sapp S, Major J, Jaffe B, Bellows CF. Acute acalculous cholecystitis after gastrointestinal surgery. Am Surg. 2012;78(2):220–224. 59. Kimura Y, Takada T, Strasberg SM, et al. TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):8–23. 60. Keus F, de Jong JA, Gooszen HG, van Laarhoven CJ. Laparoscopic versus open cholecystectomy for patients with symptomatic cholecystolithiasis. Cochrane Database Syst Rev. 2006;(4):CD006231. 61. Callery MP. Avoiding biliary injury during laparoscopic cholecystectomy: technical considerations. Surg Endosc. 2006;20(11):1654–1658. 62. Ishizaki Y, Miwa K, Yoshimoto J, Sugo H, Kawasaki S. Conversion of elective laparoscopic to open cholecystectomy between 1993 and 2004. Br J Surg. 2006;93(8):987–991. 63. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg. 1995;180(1):101–125. 64. Schulman CI, Levi J, Sleeman D, et al. Are we training our residents to perform open gall bladder and common bile duct operations? J Surg Res. 2007;142(2):246–249. 65. Lengyel BI, Panizales MT, Steinberg J, Ashley SW, Tavakkoli A. Laparoscopic cholecystectomy: what is the price of conversion? Surgery. 2012;152(2):173–178. 66. Khan MH, Howard TJ, Fogel EL, et al. Frequency of biliary complications after laparoscopic cholecystectomy detected by ERCP: experience at a large tertiary referral center. Gastrointest Endosc. 2007;65(2):247–252. 67. Jenkins PJ, Paterson HM, Parks RW, Garden OJ. Open cholecystectomy in the laparoscopic era. Br J Surg. 2007;94(11):1382–1385. 68. Wolf AS, Nijsse BA, Sokal SM, Chang Y, Berger DL. Surgical outcomes of open cholecystectomy in the laparoscopic era. Am J Surg. 2009;197(6):781–784. 69. Strasberg SM, Pucci MJ, Brunt LM, Deziel DJ. Subtotal cholecystectomy-”fenestrating” vs “reconstituting” subtypes and the prevention of bile duct injury: definition of the optimal procedure in difficult operative conditions. J Am Coll Surg. 2016;222(1):89–96. 70. Koo JGA, Chan YH, Shelat VG. Laparoscopic subtotal cholecystectomy: comparison of reconstituting and fenestrating techniques. Surg Endosc. 2021;35(3):1014–1024. 71. Nzenwa IC, Mesri M, Lunevicius R. Risks associated with subtotal cholecystectomy and the factors influencing them: a systematic

review and meta-analysis of 85 studies published between 1985 and 2020. Surgery. 2021;170(4):1014–1023. 72. Tomulescu V, Sta˘nciulea O, Ba˘lescu I, et al. First year experience of robotic-assisted laparoscopic surgery with 153 cases in a general surgery department: indications, technique and results. Chirurgia (Bucur). 2009;104(2):141–150. 73. Giulianotti PC, Coratti A, Angelini M, et al. Robotics in general surgery: personal experience in a large community hospital. Arch Surg. 2003;138(7):777–784. 74. Shenoy R, Mederos MA, Ye L, et al. Intraoperative and postoperative outcomes of robot-assisted cholecystectomy: a systematic review. Syst Rev. 2021;10(1):124. 75. Hirota M, Takada T, Kawarada Y, et al. Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):78–82. 76. Yamashita Y, Takada T, Kawarada Y, et al. Surgical treatment of patients with acute cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):91–97. 77. Sugiyama M, Tokuhara M, Atomi Y. Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very elderly? World J Surg. 1998;22(5):459–463. 78. Akyürek N, Salman B, Yüksel O, et al. Management of acute calculous cholecystitis in high-risk patients: percutaneous cholecystotomy followed by early laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2005;15(6):315–320. 79. Griniatsos J, Petrou A, Pappas P, et al. Percutaneous cholecystostomy without interval cholecystectomy as definitive treatment of acute cholecystitis in elderly and critically ill patients. South Med J. 2008;101(6):586–590. 80. Dasari BV, Tan CJ, Gurusamy KS, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013;2013(12):CD003327. 81. Kaufman HS, Magnuson TH, Lillemoe KD, Frasca P, Pitt HA. The role of bacteria in gallbladder and common duct stone formation. Ann Surg. 1989;209(5):584–592. 82. Murison MS, Gartell PC, McGinn FP. Does selective preoperative cholangiography result in missed common bile duct stones? J R Coll Surg Edinb. 1993;38(4):220–224. 83. Majeed AW, Ross B, Johnson AG, Reed MW. Common duct diameter as an independent predictor of choledocholithiasis: is it useful? Clin Radiol. 1999;54(3):170–172. 84. Collins C, Maguire D, Ireland A, Fitzgerald E, O’Sullivan GC. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: natural history of choledocholithiasis revisited. Ann Surg. 2004;239(1):28–33. 85. Martin DJ, Vernon DR, Toouli J. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2006;(2): CD003327. 86. Rieger R, Wayand W. Yield of prospective, noninvasive evaluation of the common bile duct combined with selective ERCP/sphincterotomy in 1390 consecutive laparoscopic cholecystectomy patients. Gastrointest Endosc. 1995;42(1):6–12. 87. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335(13):909–918. 88. ASGE Standards of Practice Committee, Maple JT, BenMenachem T, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc. 2010;71(1):1–9. 89. Tse F, Barkun JS, Barkun AN. The elective evaluation of patients with suspected choledocholithiasis undergoing laparoscopic cholecystectomy. Gastrointest Endosc. 2004;60(3):437–448. 90. García-Vila JH, Redondo-Ibáñez M, Díaz-Ramón C. Balloon sphincteroplasty and transpapillary elimination of bile duct stones: 10 years’ experience. AJR Am J Roentgenol. 2004;182(6): 1451–1458. 91. Gil S, de la Iglesia P, Verdú JF, de España F, Arenas J, Irurzun J. Effectiveness and safety of balloon dilation of the papilla and the use of an occlusion balloon for clearance of bile duct calculi. AJR Am J Roentgenol. 2000;174(5):1455–1460. 92. Tsai TJ, Lai KH, Lin CK, et al. Role of endoscopic papillary balloon dilation in patients with recurrent bile duct stones after endoscopic sphincterotomy. J Chin Med Assoc. 2015;78(1):56–61. 93. Yoon HG, Moon JH, Choi HJ, et al. Endoscopic papillary large balloon dilation for the management of recurrent difficult bile duct stones after previous endoscopic sphincterotomy. Dig Endosc. 2014;26(2):259–263.

549.e3 94. Li ZF, Chen XP. Recurrent lithiasis after surgical treatment of elderly patients with choledocholithiasis. Hepatobiliary Pancreat Dis Int. 2007;6(1):67–71. 95. Matsushima K, Soybel DI. Operative management of recurrent choledocholithiasis. J Gastrointest Surg. 2012;16(12):2312–2317. 96. Uchiyama K, Onishi H, Tani M, et al. Long-term prognosis after treatment of patients with choledocholithiasis. Ann Surg. 2003;238(1):97–102. 97. Stiegmann GV, Soper NJ, Filipi CJ, McIntyre RC, Callery MP, Cordova JF. Laparoscopic ultrasonography as compared with static or dynamic cholangiography at laparoscopic cholecystectomy. A prospective multicenter trial. Surg Endosc. 1995;9(12):1269–1273. 98. Buddingh KT, Nieuwenhuijs VB, van Buuren L, Hulscher JB, de Jong JS, van Dam GM. Intraoperative assessment of biliary anatomy for prevention of bile duct injury: a review of current and future patient safety interventions. Surg Endosc. 2011;25(8):2449–2461. 99. Woods MS, Traverso LW, Kozarek RA, et al. Biliary tract complications of laparoscopic cholecystectomy are detected more frequently with routine intraoperative cholangiography. Surg Endosc. 1995;9(10):1076–1080. 100. Clayton ES, Connor S, Alexakis N, Leandros E. Meta-analysis of endoscopy and surgery versus surgery alone for common bile duct stones with the gallbladder in situ. Br J Surg. 2006;93(10):1185–1191. 101. Hanif F, Ahmed Z, Samie MA, Nassar AH. Laparoscopic transcystic bile duct exploration: the treatment of first choice for common bile duct stones. Surg Endosc. 2010;24(7):1552–1556. 102. Tinoco R, Tinoco A, El-Kadre L, Peres L, Sueth D. Laparoscopic common bile duct exploration. Ann Surg. 2008;247(4):674–679. 103. El Geidie A, Atif E, Naeem Y, El Ebidy G. Laparoscopic bile duct clearance without choledochoscopy. Surg Laparosc Endosc Percutan Tech. 2015;25(5):e152–e155. 104. Topal B, Aerts R, Penninckx F. Laparoscopic common bile duct stone clearance with flexible choledochoscopy. Surg Endosc. 2007;21(12):2317–2321. 105. Strömberg C, Nilsson M, Leijonmarck CE. Stone clearance and risk factors for failure in laparoscopic transcystic exploration of the common bile duct. Surg Endosc. 2008;22(5):1194–1199. 106. Lien HH, Huang CC, Huang CS, et al. Laparoscopic common bile duct exploration with T-tube choledochotomy for the management of choledocholithiasis. J Laparoendosc Adv Surg Tech A. 2005;15(3):298–302. 107. Gurusamy KS, Junnarkar S, Farouk M, Davidson BR. Cholecystectomy for suspected gallbladder dyskinesia. Cochrane Database Syst Rev. 2009;(1):CD007086. 108. Gurusamy KS, Koti R, Davidson BR. T-tube drainage versus primary closure after open common bile duct exploration. Cochrane Database Syst Rev. 2013;(6):CD005640. 109. Gurusamy KS, Koti R, Davidson BR. T-tube drainage versus primary closure after laparoscopic common bile duct exploration. Cochrane Database Syst Rev. 2013;(6):CD005641. 110. Wu X, Yang Y, Dong P, et al. Primary closure versus T-tube drainage in laparoscopic common bile duct exploration: a meta-analysis of randomized clinical trials. Langenbecks Arch Surg. 2012;397(6): 909–916. 111. Acosta JM, Rubio Galli OM, Rossi R, Chinellato AV, Pellegrini CA. Effect of duration of ampullary gallstone obstruction on severity of lesions of acute pancreatitis [published correction appears in J Am Coll Surg. 1997;185(4):423–424]. J Am Coll Surg. 1997;184(5):499–505. 112. Alexakis N, Lombard M, Raraty M, et al. When is pancreatitis considered to be of biliary origin and what are the implications for management? Pancreatology. 2007;7(2–3):131–141. 113. NIH state-of-the-science statement on endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and therapy. NIH Consens State Sci Statements. 2002;19(1):1–26. 114. Moretti A, Papi C, Aratari A, et al. Is early endoscopic retrograde cholangiopancreatography useful in the management of acute biliary pancreatitis? A meta-analysis of randomized controlled trials. Dig Liver Dis. 2008;40(5):379–385.

115. Tse F, Yuan Y. Early routine endoscopic retrograde cholangiopancreatography strategy versus early conservative management strategy in acute gallstone pancreatitis. Cochrane Database Syst Rev. 2012;(5):CD009779. 116. Trust MD, Sheffield KM, Boyd CA, et al. Gallstone pancreatitis in older patients: are we operating enough? Surgery. 2011;150(3):515–525. 117. Hwang SS, Li BH, Haigh PI. Gallstone pancreatitis without cholecystectomy. JAMA Surg. 2013;148(9):867–872. 118. Kiriyama S, Takada T, Strasberg SM, et al. TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci. 2013;20(1):24–34. 119. Gouma DJ. Management of acute cholangitis. Dig Dis. 2003;21(1):25–29. 120. Kiriyama S, Kozaka K, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):17–30. 121. Raper SE, Barker ME, Jones AL, Way LW. Anatomic correlates of bacterial cholangiovenous reflux. Surgery. 1989;105(3):352–359. 122. Stewart L, Oesterle AL, Grifiss JM, Jarvis GA, Way LW. Cholangitis: bacterial virulence factors that facilitate cholangiovenous reflux and tumor necrosis factor-alpha production. J Gastrointest Surg. 2003;7(2):191–199. 123. Miura F, Takada T, Kawarada Y, et al. Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):27–34. 124. Li VK, Yum JL, Yeung YP. Optimal timing of elective laparoscopic cholecystectomy after acute cholangitis and subsequent clearance of choledocholithiasis. Am J Surg. 2010;200(4):483–488. 125. Schreurs WH, Vles WJ, Stuifbergen WH, Oostvogel HJ. Endoscopic management of common bile duct stones leaving the gallbladder in situ. A cohort study with long-term follow-up. Dig Surg. 2004;21(1):60–65. 126. McAlister VC, Davenport E, Renouf E. Cholecystectomy deferral in patients with endoscopic sphincterotomy. Cochrane Database Syst Rev. 2007;(4):CD006233. 127. Archibald JD, Love JR, McAlister VC. The role of prophylactic cholecystectomy versus deferral in the care of patients after endoscopic sphincterotomy [published correction appears in Can J Surg. 2007;50(2):100]. Can J Surg. 2007;50(1):19–23. 128. Zheng MH, Boni L, Fingerhut A. Minimally invasive surgery and the novel coronavirus outbreak: lessons learned in China and Italy. Ann Surg. 2020;272(1):e5–e6. 129. Strasberg S, Hughes T. Management of Symptomatic Gall Bladder Disease in Acute Cholecystectomy during COVID-19 Pandemic ACS: COVID-19 Bulletin Vol 6 . 2020. Available at: https:// www.facs.org/-/media/files/covid19/symptomatic_gallbladder_ recommendations.ashx. 130. COVIDSurg Collaborative. Mortality and pulmonary complications in patients undergoing surgery with perioperative SARSCoV-2 infection: an international cohort study [published correction appears in Lancet. 2020]. Lancet. 2020;396(10243):27–38. 131. Balinskaite V, Bottle A, Sodhi V, et al. The risk of adverse pregnancy outcomes following nonobstetric surgery during pregnancy: estimates from a retrospective cohort study of 6.5 million pregnancies. Ann Surg. 2017;266(2):260–266. 132. Fatum M, Rojansky N. Laparoscopic surgery during pregnancy. Obstet Gynecol Surv. 2001;56(1):50–59. 133. Sedaghat N, Cao AM, Eslick GD, Cox MR. Laparoscopic versus open cholecystectomy in pregnancy: a systematic review and meta-analysis. Surg Endosc. 2017;31(2):673–679. 134. Pearl JP, Price RR, Tonkin AE, Richardson WS, Stefanidis D. SAGES guidelines for the use of laparoscopy during pregnancy. Surg Endosc. 2017;31(10):3767–3782. 135. Date RS, Kaushal M, Ramesh A. A review of the management of gallstone disease and its complications in pregnancy. Am J Surg. 2008;196(4):599–608. 136. Jorge AM, Keswani RN, Veerappan A, Soper NJ, Gawron AJ. Non-operative management of symptomatic cholelithiasis in pregnancy is associated with frequent hospitalizations. J Gastrointest Surg. 2015;19(4):598–603.

CHAPTER 39 Intrahepatic stone disease Itaru Endo, Ryusei Matsuyama, Norifumi Kumamoto, and Yuki Homma

OVERVIEW Hepatolithiasis (intrahepatic stones) is defined as the presence of gallstones in the bile ducts peripheral to the confluence of the right and left hepatic ducts. These intrahepatic stones can simultaneously be present with stones in the common bile duct (CBD) and/or gallbladder. Hepatolithiasis, which is most prevalent in East Asia, is characterized by recurrent bouts of cholangitis and can lead to sepsis, biliary cirrhosis, and even death if not properly treated (see Chapters 43 and 44). Hepatolithiasis is also associated with intrahepatic cholangiocarcinoma (ICC; see Chapter 50). Although the incidence of primary hepatolithiasis has decreased as a result of urbanization in endemic areas, the prevalence of secondary hepatolithiasis associated with past biliary surgery has increased with recent increases in hepatobiliary surgery and increased long-term survival. Hepatolithiasis can be diagnosed by ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). Direct cholangiography and three-dimensional CT are useful in deciding treatment strategies (see Chapter 16). Treatment for hepatolithiasis can be divided broadly into partial hepatectomy and endoscopic treatment. Treatment must be tailored to each patient, depending on performance status, liver function, stone location, and liver atrophy. With liver resection, bile duct strictures can also be eliminated, so stone recurrence rates are generally lower. Although satisfactory stone removal rates can be achieved with endoscopic treatment, rates of clinical failure are higher if bile duct strictures are not completely resolved, which can lead to recurrent cholangitis and subsequent ICC. Hepatectomy can be performed when the disease is limited to the right or left hemiliver with ipsilateral atrophy. In patients with multiple bile duct strictures in both hemilivers, percutaneous transhepatic cholangioscopic lithotomy (PTCSL) with balloon dilation is generally applied to remove stones and treat biliary strictures (see Chapters 20 and 31). Bilateral hepatic resections may offer better stone clearance and a reduced risk of ICC because of effective clearance of the affected liver in selected patients. Hepatolithiasis requires careful management for the possible presence of ICC, even after stone clearance. Long-term follow-up for at least 10 years is recommended.

EPIDEMIOLOGY Hepatolithiasis is commonly seen in East Asian patients, but the incidence varies, even among Asian countries (Table 39.1).1–12 In Japan, the Ministry of Health, Labour, and Welfare organized a research group to evaluate the epidemiology of hepatolithiasis and improve outcomes. This research group has conducted nationwide surveys seven times in the past 40 years. Their studies 550

revealed that the incidence of hepatolithiasis among all patients with gallstone disease has decreased from 3% to 1.8%.13 Although hepatolithiasis has largely been limited to Asia, the incidence has increased in Western countries as a result of more common worldwide travel and increasing Asian immigration.

ETIOLOGY The etiology of hepatolithiasis is unknown in about 70% to 80% of cases. Intrahepatic stones are classified by composition into calcium bilirubinate or cholesterol stones (see Chapter 8). Calcium bilirubinate stones are predominant, representing about 75% of cases, whereas stones formed within the gallbladder are composed mainly of cholesterol, suggesting differences in the lithogenic mechanism of gallbladder stones. Hepatolithiasis is thought to be generated by four factors: infection, bile metabolism changes, anatomic abnormalities, and bile stasis.14,15 The higher incidence of hepatolithiasis in rural compared with urban areas also suggests that poor nutrition and environmental factors play additional roles.16,17 In Japan, as the urbanization of society has advanced, the chance of bacterial contamination decreased, which may also explain the decreasing incidence of bile pigment stones. In fact, a decrease in the presence of bactibilia, from 92.1% in 1913 to 67.3% in 1961, has been documented.18 A survey conducted in the town of Kamigoto in Nagasaki Prefecture, an area in Japan with a high incidence of hepatolithiasis (about 30% of all gallstone diseases), reported that the expression of specific human leukocyte antigens—A26, B44, BW54, CW7, and DR6—was higher in patients with than in those without intrahepatic stones.19 However, the etiologic role of these genetic factors remains undefined. Infection of the biliary tree has long been regarded as a cause of bile pigment stones. Maki and colleagues found increased b-glucuronidase activity in bile harboring bile pigment stones.20,21 It has been suggested that the increased activity of b-glucuronidase caused by bacterial contamination may be an important factor in lithogenicity. Glucuronic acid–conjugated bilirubin, the major component of bile bilirubin, is water soluble. However, it converts to unconjugated bilirubin, which is less soluble, when hydrolyzed by b-glucuronidase, which may be derived from bacteria. It is thought that unconjugated bilirubin combines with a calcium ion in bile before being deposited as bilirubin calcium. Despite reports of an association between Escherichia coli and CBD stones in Western Europe, the incidence of intrahepatic stones remains very low, and therefore biliary infection alone is an unlikely cause of hepatolithiasis. The presence of chronic biliary inflammation has been shown to accelerate stone formation via increased secretion of mucin core proteins (MUCs). In addition, in biliary tract infection, pathogen-associated molecular patterns, such as increased

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

551

TABLE 39.1  Incidence of Intrahepatic Stones in Studies Involving Patients With Hepatolithiasis REFERENCE, YEAR

COUNTRY

TOTAL PATIENTS

HEPATOLITHIASIS

PERCENTAGE (%)

Malaysia

661

120

18.2

Asia King1 Nakayama

Singapore

647

11

1.7

Nakayama3

China

394

83

21.1

Su4

Taiwan

17,182

3,486

20.3

2

Han

Korea

1344

145

10.8

Uchiyama6

Japan

10,5062

2,353

2.2

456

35

7.6

5

North and South America Best7

United States

Glenn

United States

169

22

13.0

Bove9

Brazil

2000

20

1.0

Chile

17,200

251

1.5

8

Yarmuch

10

Europe Lindström11

Sweden

804

5

0.6

Simi

Italy

2700

36

1.3

12

bacterial lipopolysaccharide and lipoteichoic acid, bind to Tolllike receptors on bile duct epithelial cell membranes. The production of inflammatory cytokines from biliary epithelium is also increased. This activates intracellular signal molecules and increases the expression of protein kinase, nuclear factor kappa B (NF-kB), MUC2, and MUC5. Tian et al. reported that neutrophil elastase can stimulate MUC5AC expression in human biliary epithelial cells.22 The increased secretion of mucin induces gel formation of bile and may accelerate bile stasis, leading to crystallization. Therefore these factors are considered to be associated with stone formation and chronic proliferative cholangitis (CPC). This disease entity includes recurrent pyogenic cholangitis (see Chapter 44), which is endemic in Southeast Asia, as first reported by Digby and colleagues at Hong Kong University.23 Clonorchiasis (Clonorchis sinensis), ascariasis (Ascaris lumbricoides), and fascioliasis (Fasciola spp.; see Chapter 45) can lead to inflammation of the biliary epithelium. Patients with clonorchiasis (C. sinensis) are usually asymptomatic when the number of flukes is small, but bile duct obstruction, suppurative cholangitis, and intrahepatic stones usually occur when 500 to 1000 flukes (hepatic distomiasis) are present because the parasite’s fragments or eggs can act as a nidus for stone formation. Fluke eggs in the feces or bile and peripheral blood eosinophilia are important diagnostic findings for this disease. The presence of hepatolithiasis in regions without endemic parasitic infection supports the concept that biliary parasites may not be regarded as a primary cause of hepatolithiasis. In regard to bile metabolic changes, a feature of intrahepatic calcium bilirubinate stones is that, compared with calcium bilirubinate stones in the gallbladder and CBD, a relatively high cholesterol content has been reported.24,25 Cholesterol in hepatic bile may result from relative cholesterol supersaturation because of increased cholesterol secretion from hepatocytes or to relatively decreased bile phospholipids and acids.26 Specifically, decreased phospholipid secretion leads to reduced cholesterol dissolution and easier formation of lithogenic bile.27–29

Transporter proteins in the bile canalicular membrane are involved in secretion and thus may also be a factor leading to changes in bile composition30 (see Chapter 8). Multidrug resistance-associated protein 3 (MRP3), encoded by the ABCB4 gene, is involved in phospholipid secretion. MRP2, encoded by the ABCC2 gene, is involved in bilirubin excretion, and bile salt export pump protein (BSEP), encoded by the ABCB11 gene, is involved in bile acid secretion.31–33 Therefore the role these transport proteins play as membrane proteins leading to changes in bile composition and the development of hepatolithiasis has received increasing attention.33 Recent studies have revealed that a single nucleotide polymorphism of the ABCB4 and ABCB11 genes might affect the expression of pertinent transporter proteins.34,35 Gan et al. (2019) reported that rs497692 and rs118109635 mutations affected translation of the ABCB11 gene, resulting in the downregulation of BSEP expression.36 Dysregulation of these transporter proteins may change the composition of bile and lead to cholestasis and cholelithiasis. These genetic changes could explain the different racial and regional distributions of hepatolithiasis. Whether simple anatomic bile stenosis or bile stasis alone can cause stone formation remains unclear; however, biliary stenosis and bile stasis usually co-exist, and can cause a high rate of stone formation. Indeed, numerous studies have reported that biliary stricture and stasis are strong predictors of stone recurrence and cholangitis after treatment for hepatolithiasis.

SECONDARY HEPATOLITHIASIS Secondary hepatolithiasis associated with past biliary surgery or congenital biliary malformation is an example of a case in which the etiology can be presumed.37 With recent increases in hepatobiliary surgery and long-term survival, secondary hepatolithiasis because of bilioenteric stenosis or duct-to-duct biliary anastomoses has increased38,39 (see Chapters 32 and 42).

552

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

Congenital choledochal cysts (CCs), including those in Caroli syndrome, are well known for their anatomic features, which include dilation and strictures of the intrahepatic and extrahepatic biliary tract (see Chapter 46). Congenital CCs are associated with intrahepatic stones (12%–17% of adult patients),40–42 as well as a high incidence of biliary tract carcinoma (10.6%–20.3%).42,43 Hepatolithiasis occurs in 3.5% to 23.5% of patients after flow-diversion surgery for congenital CCs.44–48 Bile contamination and anastomotic strictures resulting from hepaticojejunal (Roux-en-Y) anastomosis may be contributing factors,49 but much remains unknown about the mechanisms of onset. Type IV-A cysts are most commonly associated with cholangitis and intrahepatic stone formation.45,46 Aota et al. (2018) reported a higher postoperative incidence of hepatolithiasis in Type IV-A than in Type I cysts (7/20 [35%] vs. 1/20 [5.0%], respectively).50 Because complete resection of the dilated left and right hepatic ducts is difficult in Type IV-A cysts, part of the dilated ducts often remains, possibly leading to bile stasis. In such instances, creating a wide anastomosis by extending the incision along the lateral wall of both hepatic ducts by common hepatic duct-plasty is often attempted to obtain a wide hepaticoenterostomy at the hepatic hilum. In addition to the possible carcinogenesis related to longterm stimulation of the biliary mucosa by pancreatic juices, bilioenteric anastomosis itself may accelerate carcinogenesis as a result of irritation from contaminated bile, even in benign conditions (see Chapter 51).51–53 The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital CCs has been reported to be 0.7% to 5.4%.46,54–56 Indeed, the risk of biliary malignancy remains elevated, even more than 15 years after CC excision.57 Therefore long-term surveillance is important after hepaticojejunostomy for congenital biliary cysts because the risk of cancer is suspected to be doubled.58 Bile duct stones, sludge, and casts, which represent bile duct filling defects, occur in approximately 5% of patients after living donor liver transplantation (LDLT),59 with the majority of such defects caused by stones60 (see Chapter 111). Because the anastomotic site is more peripheral to that in orthotopic liver transplantation, hepatic ducts at the anastomotic site are usually small and thin walled. Therefore anastomotic stricture is likely to occur more frequently in LDLT than in deceased donor liver transplantation. Persistent cholangitis caused by small stones is sometimes difficult to discriminate from T-cell– mediated rejection and drug-induced liver dysfunction. Because delayed diagnosis and treatments may affect both longterm graft and patient survival, early recognition and prompt treatment of intrahepatic stones after liver transplantation is essential.

CHOLANGIOCARCINOMA The development of cholangiocarcinoma (CCA) in patients with hepatolithiasis is associated with poor outcomes (see Chapters 50 and 51). The incidence of CCA in patients with hepatolithiasis reported from Asian centers ranges from 2.1% to 15.6% (Table 39.2).61–78 By contrast, hepatolithiasis is uncommon in Western countries, with a reported incidence of only 2.4%.11,12,79,80 Vetrone and colleagues (2006) found only one case with intramucosal adenocarcinoma of the extrahepatic bile duct out of 22 patients with hepatolithiasis who underwent surgical therapy.70 On the other hand, Tabrizian and colleagues

TABLE 39.2  Incidence of Intrahepatic Cholangiocarcinoma in Hepatolithiasis REFERENCE

HEPATOLITHIASIS

Koga, 1985

61

3

Chen, 1989

1105

55

5.0

Sheen-Chen, 199163

101

5

5.0

Kubo, 199564

113

10

8.8

Liu, 199865

96

15

15.6

Huang, 200366

209

5

2.4

Chen, 2004

103

10

9.7

Cheung, 200568

174

10

5.7

69

Herman, 2005

48

1

2.1

Vetrone, 200670

22

1

4.5

Lee, 2007

123

3

2.4

Al-Sukhni, 200872

42

5

12

Uenishi, 2009

87

10

11.5

Suzuki, 2012

336

23

6.8

Tabrizian, 201275

30

7

23.3

Lin CC, 201376

211

10

4.7

Guglielmi, 201477

161

23

14.3

Zhu QD, 201478

2056

107

5.2

61 62

67

71

73

74

ICC PERCENTAGE (%) 4.9

ICC, Intrahepatic cholangiocarcinoma.

(2012) reported a much higher incidence of concomitant CCA (7/30 [23.3%]) during a 14-year follow-up period.75 In addition, Al-Sukhni and colleagues (2008) reported identifying CCA in 5 (12%) of 42 patients during a 20-year study period.72 Guglielmi and colleagues (2014) prospectively collected a cohort of 161 patients with hepatolithiasis from five Italian tertiary hepatobiliary centers.77 From their database, 23 (14.3%) patients with concomitant ICC were identified. From the aforementioned reports, although the overall incidence of hepatolithiasis is low in Western countries, the incidence of CCA arising in conjunction with hepatolithiasis is similar when comparing Eastern and Western countries. Therefore hepatolithiasis needs to be carefully evaluated for the possible presence of ICC, even in Western countries. Although the association between hepatolithiasis and CCA is well recognized, the exact mechanism of carcinogenesis remains unclear. Persistent inflammation because of cholangitis can cause repeated tissue damage and regeneration; this recurrent inflammatory process may lead to carcinogenesis. Hyperplastic epithelial cells often show a papillomatous or adenomatous pattern, which is frequently associated with the presence of stones.61 Ohta and colleagues (1991) reported that various degrees of hyperplastic biliary epithelium exist around impacted stones and are associated with CPC.81 Mucosal dysplasia accompanied by MUC and cytokeratin expression may be a precursor to CCA.82 Recent studies have suggested that multiple factors, including NF-kB, epidermal growth factor receptor, prostaglandin E2, c-Met, and p16, are associated with cell proliferation, inflammation, and carcinogenesis.83 However, no clear symptoms or clinical presentations have been reported to be associated with the presence of CCA in

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

patients with hepatolithiasis. Therefore the possibility of coexisting CCA should be considered in all cases but especially in unusual presentations, such as weight loss, anemia, and intractable pain.63 Some risk factors for ICC concomitant with hepatolithiasis have been reported (Box 39.1).74,84,85 Atrophic liver segments with persistent cholangitis are well-accepted risk factors. CCA is likely to be found in atrophic liver with obliterated portal flow.64 Therefore hepatectomy of an atrophic liver with intrahepatic stones and biliary strictures may reduce the risk of CCA.73 Concomitant CCA has been reported to be a strong negative predictive factor for overall survival after hepatectomy for hepatolithiasis.67 Zhu et al. (2014) found that 107 of 2056 patients who had undergone surgical treatment for hepatolithiasis had CCA.78 Overall, the 5-year survival rate was 20.2%, and a subgroup of patients who had undergone potentially curative resection showed good 5-year survival (50.0%). However, only about 40% (38/97) of patients underwent curative resection; the other 60% underwent either palliative resection, radiofrequency ablation, or were not resected. Zhang et al. (2018) reported that patients with hepatolithiasis-associated CCA had worse long-term outcomes than those with conventional ICC.86 Five-year overall survival among patients with hepatolithiasisassociated ICC was 18.3% compared with 38.0% for those with conventional ICC. It should be noted that subsequent ICC may occur even after primary treatment for hepatolithiasis. Chijiiwa and colleagues (1995) reported that among 85 patients with hepatolithiasis, 6 (7%) died of subsequent CCA during a mean followup period of 6 years.87 Cheon et al. (2009) also reported that the rate of late development of CCA in patients with intrahepatic stones during follow-up was 4.8% (11/225).88 More recently, Kim et al. (2018) analyzed Korean National Health Insurance data.89 Among the 7419 patients who had undergone liver resection for hepatolithiasis, subsequent ICC developed in 107 (1.98%). Table 39.3 shows the incidence of subsequent ICC (approximately 0.3%–9.1%) among patients with hepatolithiasis.58,61,66,71,73,76,88–95 The mean interval from initial treatment to the development of CCA was 10.7 years (range, 6.6– 19.7 years). Half of those patients developed CCA at a site different from the initial site of hepatolithiasis. Regarding the risk factors for subsequent ICC, age older than 65 years and stone removal only as the initial treatment were significant risk factors for the subsequent development of CCA.13 Further, the study revealed that age older than 65 years and the presence of biliary strictures were significant risk factors for the development of CCA in patients with a history of bilioenteric anastomosis. On the other hand, in patients

BOX 39.1  Predictive Factors for Concomitant Cholangiocarcinoma Liver atrophy (Suzuki74) Smoking (Liu84) Family history of cancer (Liu84) Duration of symptoms . 10 years (Liu84) History of gastrectomy (Jo85) History of cholechochoenterostomy (Suzuki74; Jo85) Elevated serum CA19-9 (Jo85)

553

TABLE 39.3  Rate of Metachronous ICC After Primary Treatment for Intrahepatic Stones REFERENCE

YEAR

HL

ICC

PERCENTAGE (%)

Koga

1985

61

2

3.3

Chijiiwa

1993

109

8

7.3

Jan91

1996

427

12

2.8

Furukawa

1998

122

3

2.5

Huang66

2003

209

5

2.4

Lee

2007

123

2

1.6

61 90

92

71

Uenishi

2009

77

2

2.6

Cheon88

2009

227

11

4.8

93

Li

2012

718

2

0.3

Lin76

2013

137

12

6.1

Tsuyuguchi

2014

121

11

9.1

Kim94

2015

236

16

6.8

Meng

2017

981

55

5.6

Kim

2018

7419

107

1.98

73

58

95

89

HL, Hepatolithiasis; ICC, intrahepatic cholangiocarcinoma.

without a history of a bilioenteric anastomosis, left lobe location and stone recurrence were significant risk factors for the development of subsequent CCA. Although partial hepatectomy as the initial treatment was associated with a reduced risk of CCA, it did not reach the level of statistical significance (P 5 .066). On the other hand, Kim et al. (2015) reported that subsequent CCA occurred with similar rates in patients treated with and without hepatic resection (6.3% vs. 7.1%, respectively).83 They emphasized that the presence of residual stones was the most significant risk factor for subsequent CCA regardless of the initial treatment; therefore hepatic resection is considered to have limited value in preventing CCA. Meng et al. (2017) reported that the presence of stone-affected remaining liver segments after initial hepatic resection was also a predictive factor for subsequent CCA.95 Long-term outcomes of patients with subsequent CCA after treatment for hepatolithiasis are extremely poor. The mean interval from diagnosis of CCA to disease-related death has been reported to be 4 months, compared with 41 months for patients with concomitant CCA at the time of initial diagnosis.76 Based on a Korean national database, patients with subsequent CCA had very poor survival outcomes compared with those with concomitant CCA, with a median survival time of 0.9 years.89 Intensive follow-up is therefore mandatory, especially in patients with risk factors for subsequent CCA, such as residual stones, hepaticojejunostomy, and a remaining stone-affected liver segment.

SYMPTOMS Charcot’s triad of symptoms—abdominal pain, fever, and jaundice—occur in about 60% of patients with hepatolithiasis65 (see Chapter 43). These pyogenic cholangitis-related symptoms tend to recur over the long term. Severe cholangitis is sometimes concomitant with liver abscess and septic shock. Patients with septic shock often develop disseminated intravascular

554

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

cholangiopathy. On the other hand, some patients with hepatolithiasis present without any symptoms. According to a Japanese survey, 20% of patients with hepatolithiasis showed no symptoms.96 In another study, 14 (11.5%) of 122 patients with asymptomatic hepatolithiasis developed symptoms during long-term follow-up.97 In difficult-to-treat cases, when stones cannot be completely removed or bile duct strictures are not eliminated, hepatolithiasis is likely to recur. Symptoms occur in patients with biliary cirrhosis because of chronic recurrent cholangitis; this often progresses to liver failure. Patients in whom CCA develops during follow-up often present with an abdominal mass, bloating because of ascites, and weight loss.

DIAGNOSIS Acute cholangitis accompanied by hepatolithiasis is diagnosed by findings of systemic inflammation, cholestasis, and imaging showing intrahepatic biliary dilation, strictures, and stone formation.98 Acute cholangitis can present with a wide range of severity. The diagnosis of acute cholangitis is usually made, or at least suspected, on the basis of a physical examination and the patient’s medical history. Charcot’s triad—abdominal pain, fever, and jaundice—is the classic presentation of acute cholangitis. However, only 50% to 70% of patients show all three features at acute presentation (see Chapter 43). Blood test findings commonly show an elevated white blood cell count, elevated levels of hepatobiliary enzymes, and hyperbilirubinemia. Amylase levels are also elevated in about 20% of patients. Blood cultures are often positive, and the most commonly isolated microorganisms are E. coli, Morganella morganii, Klebsiella spp., and Enterobacter spp.69 Bacteria in bile, when tested, are isolated from cultures in about 85% of cases. Biliary cultures usually grow Gram-negative bacteria, such as E. coli, Klebsiella spp., and Enterobacter spp. Cholangitis caused by Enterococcus spp. and Pseudomonas aeruginosa has become more common.99,100 In one study, serum carbohydrate antigen 19-9 was elevated in 18 (78.3%) of 23 patients with CCA.101

IMAGING DIAGNOSIS The presence of stones in intrahepatic bile ducts represents an important imaging finding for diagnosing hepatolithiasis, but the location of the bile duct branches in which intrahepatic stones are present is also very important in planning treatment.102–104 Concerning the location of stones, the Japan Research Group for the Study of Hepatolithiasis classifies patients with stones only in the intrahepatic bile duct as type I and those with stones both in the intrahepatic and extrahepatic bile ducts as type IE. Furthermore, patients are classified by the location of stones as follows: right side: type R; left side: type L; right and left sides: type LR; and caudate lobe: type C. Several other classifications according to the location of biliary strictures have been proposed. Figure 39.1 summarizes the classification system proposed by Takada and colleagues (1978).105 Useful imaging modalities include US, CT, and MRI (see Chapter 13), but direct imaging techniques such as percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiography (ERC), and transpapillary or percutaneous cholangioscopy are available (see Chapters 20, 30, 31, 37, and 52). The radiologic diagnosis of hepatolithiasis can be difficult because of changes and technical constraints associated with

Classification of hepatolithiasis

Type I

Type II

Type III

Type IV

Type V

FIGURE 39.1  Classification of hepatolithiasis proposed by Takada and colleagues (1978). This classification is divided into five types according to the location of the stones and strictures. Type I: no strictures in the intrahepatic and extrahepatic biliary tract, with mild dilation of the biliary system. Type II: biliary stricture in the lower bile duct or ampulla of the duodenum, showing remarkable dilation of the bile ducts. Type III: stricture at the hepatic hilum. Type IV: biliary stricture in the unilateral hepatic lobe. Type V: multiple biliary strictures in the bilateral hepatic lobe or bilateral congenital biliary cysts.

cholangitis, which may also co-exist with cholelithiasis, and previous biliary surgery. Therefore highly technical procedures such as hepatectomy and/or several kinds of endoscopic lithotripsy may be required. As a result, unlike patients with cholecystitis or choledocholithiasis, patients with hepatolithiasis are often treated at high-volume tertiary centers. The number of new cases of primary hepatolithiasis has recently decreased, whereas the number of cases of secondary hepatolithiasis is increasing in patients with prior biliary reconstructive surgery. In the latter case, the diagnosis may be more difficult because of previous biliary reconstruction such as hepaticojejunostomy. The diagnosis of co-existing ICC is important (see Chapter 50). CCA may occur at biliary stricture sites; however, differential diagnosis based on imaging alone may be difficult because of the background presence of stones, inflammation, or pneumobilia. As a result, ICC is often incidentally found during surgery.64,81,106 Preoperative bile cytology and intraoperative frozen-section examination of resection margins are recommended in older patients with severe biliary strictures. Intrahepatic stones include calcium bilirubinate and cholesterol stones. Calcium bilirubinate stones are often present in the left and right bile ducts near the porta hepatis, and severe morphologic changes, such as strictures and dilation, are common. On the other hand, cholesterol stones, which are smaller and may be multiple, are found in segmental and peripheral biliary branches. Biliary dilation (cholangiectasis) is usually limited to sites where stones are present, and the dilation of upstream bile ducts is uncommon. In addition, a stricture of downstream bile ducts is not usually seen, a finding that differs from calcium bilirubinate stones. In addition, cholesterol stones cannot be visualized on CT. When a diagnosis of hepatolithiasis is suspected, noninvasive abdominal US should initially be performed. If hepatolithiasis is strongly suspected, performing CT or magnetic resonance cholangiography (MRC) is also important to avoid other unnecessary tests. If the presence of stones is confirmed, further testing to identify the site of stones, such as direct cholangiography, is useful in planning a treatment strategy.

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

ABDOMINAL ULTRASOUND Abdominal US is a convenient and noninvasive method that provides excellent depiction of stones and dilated bile ducts; therefore it is the initial imaging modality of choice when hepatolithiasis is suspected (see Chapter 15). Calcium bilirubinate stones, which are common in hepatolithiasis, show the same or slightly higher echogenicity than the liver, and a weaker acoustic shadow (Fig. 39.2A–B). Bile ducts above the stone site are often dilated. Meanwhile, cholesterol stones have higher echogenicity than surrounding liver parenchyma and a stronger acoustic shadow (see Fig. 39.2C). Areas of biliary dilation are often limited to where the stones are located.107,108 Other findings that suggest the presence of hepatolithiasis include segmental liver atrophy and decreased segmental blood flow.109 An important point is that stones may not always have acoustic shadows. Pneumobilia can also appear as a hyperechoic area with acoustic shadows within bile ducts, so careful attention should be paid to the differential diagnosis with intrahepatic

555

stones (see Fig. 39.2C). Another pitfall is that bile ducts may not be depicted if filled with biliary sludge and showing high echogenicity.65

ABDOMINAL COMPUTED TOMOGRAPHY Abdominal CT can depict not only stones but also the location they are located within the intrahepatic ducts, in addition to any bile duct dilation or strictures proximal and distal to the stone sites110 (see Chapter 13). Calcium bilirubinate stones with high calcium content appear as hyperintensities on CT (Fig. 39.3). However, intrahepatic stones often have a lower calcium content than CBD stones and may not be depicted because of CT density values similar to those of bile. Cholesterol stones show almost the same pixel value as bile, and thus may not be depicted on CT (Fig. 39.4). Segmental hepatic atrophy in hepatolithiasis is an indication for liver resection and, therefore, atrophy on CT is an important finding. Segmental atrophy on CT may appear as a crowding of

D

L–liver

L. BD Stone

A

C

B

FIGURE 39.2  A, Abdominal ultrasound of the liver shows a shadowing echogenic mass. B, A cluster of small echogenic stones without shadowing (arrows). Note the moderate dilation of subsegmental bile ducts with a thick wall. C, A strong shadowing stone with linear round-shaped echo (arrow). L. BD, left bile duct. (See Chapter 13.)

556

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

bile duct branches, diminished portal blood flow, and a loss of portal vein branches (Fig. 39.5). Patients with severe liver damage may also show splenomegaly.111 In most cases, intrahepatic calcification, a finding often observed on screening, is not because of intrahepatic stones but rather because of tuberculosis, bleeding, or parasitic infestation. Therefore other findings must also be present for a diagnosis of hepatolithiasis. When clay-like stones fill the biliary branch segments, they may not be easily identifiable in imaging studies.

MAGNETIC RESONANCE IMAGING

FIGURE 39.3  Noncontrast computed tomography shows high-density shadows in the bilateral hepatic lobe (arrows). (See Chapter 13.)

A

C

MRI carries no radiation exposure risks, can identify intrahepatic stones and bile duct strictures, and is useful in diagnosing hepatolithiasis112–114 (see Chapter 13). In MRC, stones with little water content have relatively low signal intensity compared with signal-hyperintense bile and appear as filling defects (Fig. 39.6). However, if bile stasis is present, inspissated bile demonstrates low signal intensity. Therefore stones may not be able to be diagnosed, and bile ducts may not be

B

FIGURE 39.4  A, Noncontrast computed tomography (CT) shows a low-density mass in the medial section of the liver adjacent to the umbilical portion (arrow). B, Enhanced CT shows a round-shaped lowdensity lesion, which represents a large stone (arrow), accompanying dilated bile ducts and atrophy of the left hemiliver. C, Endoscopic retrograde cholangiogram shows a large stone in the left hepatic duct.

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

A

557

B

FIGURE 39.5  A, Noncontrast computed tomography (CT) reveals a stone (arrow) with ring-like calcification in the left hemiliver, showing marked atrophy. B, Enhanced CT shows severe atrophy of the left hemiliver. Arrow indicates an intrahepatic stone. (See Chapter 13.)

A

B

FIGURE 39.6  A, Magnetic resonance cholangiography shows multiple low-intensity nodules (arrows) in the anterior sectoral bile duct. (See Chapter 13.) B, Endoscopic retrograde cholangiography shows multiple filling defects (arrows) in the dilated anterior sectorial branch. (See Chapters 20 and 30.)

depicted. Pneumobilia also shows low signal intensity, and misdiagnosis as a “stone” frequently occurs, so careful attention must be paid to the differential diagnosis. In addition, tumors must be considered in the differential diagnosis when diagnosing intrahepatic duct filling defects and bile duct strictures in MRC.

PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY AND ENDOSCOPIC RETROGRADE CHOLANGIOGRAPHY PTC and ERC are invasive and, as such, are now performed less frequently for diagnostic purposes (see Chapters 20, 30, 31, and 52). However, no superior diagnostic modalities for direct cholangiography are available (Fig. 39.7). Bile duct findings may include straightening, rigidity, decreased arborization, and increased branching angles111 (Fig. 39.8). When intrahepatic stones are present, identifying the bile duct branches in which the stones are located is important for choosing a treatment strategy, which often makes direct cholangiography essential.

FIGURE 39.7  Cholangiogram through percutaneous transhepatic biliary drainage catheter shows markedly dilated left hepatic duct with proximal stricture (arrows).

558

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

Cholangioscopy can also be a helpful examination; it can be performed after access routes to bile ducts used for imaging are sequentially dilated and a fistula is created (Fig. 39.9). Stones and strictures can be directly visualized by cholangioscopy, and biopsy and treatment such as stone removal (lithotomy) can be performed. In hepatolithiasis that occurs after Roux-en-Y hepaticojejunostomy for congenital CCs, ERC can be technically challenging. Recently, double-balloon enteroscopy has been used for examinations and stone removal in this situation115 (Fig. 39.10A–B).

TREATMENT FOR HEPATOLITHIASIS

FIGURE 39.8  Endoscopic retrograde cholangiogram shows multiple filling defects in both intra and extrahepatic bile ducts. Intrahepatic ducts show straightening, rigidity, decreased arborization, increased branching angles, and abrupt tapering.

A

For more information, see Chapter 44. The initial management of all patients with acute cholangitis should include intravenous fluid resuscitation and antibiotics. Supportive measures may also include invasive monitoring, intensive care, and inotropic and ventilation support in patients with severe cholangitis. Given the wide range of possible infecting organisms and the likelihood of mixed infection, broad-spectrum

B

FIGURE 39.9  A, A case of secondary hepatolithiasis after excision of congenital choledochal cysts. Cholangiogram through percutaneous cholangioscopy shows a stone in the right hepatic duct (arrow). B, The stone was pulled down into the jejunum (arrow) using basket forceps.

A

B

C

FIGURE 39.10  A, A case of secondary hepatolithiasis after left hemihepatectomy and caudate lobectomy for hilar cholangiocarcinoma. Cholangiogram through double-balloon enteroscopy shows multiple stones in the posterior branch. B, The stones were removed using basket forceps. C, Brownish stones were observed in the posterior duct.

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

antibiotics are required.116 The severity of cholangitis must be assessed, and treatment with biliary drainage is necessary.98 With advances in drainage procedures and appropriate antibiotic therapy, death from acute cholangitis is now less frequent. However, mortality rates of 2.1% to 14.3% are still reported in cases of severe cholangitis117; therefore careful management is required in such patients. On the other hand, some patients show no symptoms. Kusano et al. (2001) reported that 122 (39.2%) of 311 patients with hepatolithiasis were asymptomatic.97 Approximately 5.3% to 11.5% of these patients may develop some symptoms attributed to hepatolithiasis.118 In particular, patients with peripheral-type hepatolithiasis have been reported to be less symptomatic than those with main duct-type hepatolithiasis (8/31 [25.8%] vs. 1/39 [2.6%], respectively).118 Therefore patients with asymptomatic, peripheral-type hepatolithiasis can be observed without the need for invasive treatment; however, longterm observation is required. Definitive treatment of intrahepatic stones generally includes complete clearance of stones and elimination of bile stasis. Biliary strictures, which are found in 35% to 96% of patients with hepatolithiasis, are a major factor in the recurrence of stones and cholangitis. If strictures are not treated, a high rate of stone recurrence is observed. When complete stone removal and elimination of biliary strictures cannot be achieved, progression to biliary cirrhosis and the subsequent development of CCA is inevitable.73 When stone removal (lithotomy) is considered, stricture sites, severity, variations in stone sites, prior biliary surgery, and the possibility of concomitant CCA must be evaluated. Specifically, when one side of the liver is atrophied with severe bile duct strictures and dilation, liver resection should be considered. However, when stones are present in multiple liver segments or in both the left and right lobes, complete stone removal, even with hepatectomy, is sometimes difficult. In such cases, serial cholangioscopic lithotomy in addition to hepatectomy may be effective. In patients with a poor general condition, history of multiple surgeries, or biliary cirrhosis, cholangioscopic lithotomy, in addition to or without hepatectomy, should be the treatment of choice. A treatment algorithm based on symptoms, liver atrophy, and past history of biliary surgery was proposed by the Guideline Committee for the Japanese Society of Gastroenterology.119 This algorithm is highly dependent on individual conditions such as the severity of comorbidities, accessibility to the biliary system, and liver functional reserve. Generally, treatment modalities are classified into pharmacologic, percutaneous transhepatic, peroral cholangioscopic, and surgical approaches often combined with an endoscopic approach.120

PHARMACOLOGIC THERAPY Because the etiology of intrahepatic stone formation has not been elucidated, drug therapy for hepatolithiasis has yet to be established, and no pharmacologic agents have been proven to be effective for stone dissolution in large-scale clinical trials. Therefore medical therapy plays only a supplementary role. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, offers liver cytoprotection and promotes accelerated bile acid/bilirubin metabolizing enzyme activity, ABC transporter protein activity, an increased bile flow rate, and reduced bile mucin viscosity.121,122 In an observational study conducted between

559

1981 and 1991, 17 of 20 patients with a diagnosis of Caroli syndrome were found to have intrahepatic stones.123 Complete dissolution of intrahepatic stones was observed in three patients after treatment with UDCA (pretreatment stone diameters, 6–9 mm) after 12, 18, and 48 months. Nine patients showed partial dissolution, three had no further decrease in stone size or number after treatment for 18 to 36 months, and six had stones that were still dissolving. Simvastatin reduces plasma and biliary cholesterol levels primarily by inhibiting cholesterol synthesis.124 The reduction in CBD bile lithogenicity and bile acid hydrophobicity caused by simvastatin suggests that this agent might be useful for patients in the early stages of cholesterol gallstone development, especially when stones have higher levels of cholesterol content. The long-term use of statins in Europe has been reported to be associated with a decreased risk of gallstones requiring cholecystectomy.125 On the other hand, a study in East Asia did not provide support for a beneficial association between the use of statins and gallstone disease.126 Because prostaglandin E receptor (PGE) is thought to be associated with CPC, selective COX-2 inhibitors and PGE antagonists may play a role in improving inflammatory changes in hepatolithiasis.127 Japanese/Chinese herbal medicine, inchin-ko-to, has long been considered to have choleretic effects in Asia. Inchin-ko-to increases bile flow through the upregulation of MRP2, which results in the expectation of reduced stone formation.128 Inchinko-to also has a potent cytoprotective effect against ischemia– reperfusion stress to the liver, 129 and thereby a preventive effect against postoperative liver dysfunction.130 Furthermore, Uji et al. (2018) revealed that the administration of inchin-ko-to was associated with a reduction of so-called harmful bacteria in feces.131 However, these potential beneficial effects in regard to hepatolithiasis should be confirmed in large-scale clinical trials.

PERCUTANEOUS TRANSHEPATIC CHOLANGIOSCOPIC LITHOTOMY With the technical development of percutaneous transhepatic biliary drainage and dilation procedures, it is now possible to place catheters into the intrahepatic duct without laparotomy132,133 (Fig. 39.11; see Chapters 31 and 52). Before 2006, PTCSL was the most frequently performed treatment for nonsurgical lithotripsy in Japan, but recently, ERC with stone extraction has been performed more frequently than PTCSL (22.7% vs. 11.7%, respectively).13 However, PTCSL may be a suitable alternative when endoscopic retrograde cholangioscopic lithotomy cannot be performed. Thus PTCSL may still play a role in stone clearance among patients in whom hepatectomy is not suitable or serial lithotripsy after liver resection with bilioenterostomy is required. Stones are removed according to size using basket forceps, an electric hydraulic lithotripter, or a laser lithotripter.132,134,135 When bile duct strictures exist, narrow segments should be dilated using a balloon or dilators.136–138 In selected cases, the rate of complete stone removal with PTCSL has been reported to range from 63.9% to 96.4% (Table 39.4). Biliary strictures are a factor that can impede the complete removal of stones. Takada and colleagues (1996) reviewed 86 patients who underwent PTCSL and analyzed data from 27 patients in whom complete stone removal was unsuccessful: 15 patients (56%) had severe strictures, 7 (26%) had

560

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

drainage variation in the posterior sectoral duct, and 4 (15%) had drainage variations with severe strictures.139 According to Otani and colleagues (1999), 18.2% of patients (4/22) who underwent partial hepatectomy had residual strictures, whereas 58.3% of patients (14/24) who underwent PTCSL (despite dilation in all cases) still had residual strictures.138 The time required for complete stone removal is also an issue. The mean reported number of treatments ranges from 3.9 to 6. Stone recurrence despite complete removal ranges from 14.5% to 50.8% (see Table 39.4) and tends to be higher than after hepatectomy. Biliary strictures are a common cause of stone recurrence. Although Huang and colleagues (2003) reported no significant difference in stone recurrence rates based on the presence or absence of strictures, they identified a significantly shorter mean time (11 vs. 18 years, respectively) until stone recurrence in patients with bile duct strictures.66 Lee and colleagues (2001) reported strictures and co-existing biliary cirrhosis as risk factors (Child’s type B and C 5 89%, Child’s type A 5 29%).137 Tsuyuguchi and colleagues (2014) reported that patients with liver atrophy treated with nonsurgical modalities showed a poor long-term prognosis.58 An important point to keep in mind is that stone recurrence is associated with the late development of cholangiocarcinoma (see Chapters 50 and 51). Among 209 patients with complete stone removal, 4 (6.6%) of 61 with recurrent intrahepatic stones during follow-up had ICC66; on the other hand, only 1 of 148 patients without stone recurrence had ICC. In patients with recurrent hepatolithiasis because of biliary strictures, Jeng and colleagues (1999) compared repeated placement of external–internal stents and expandable metallic stents (EMS) and found significantly lower rates of stone recurrence in the EMS group.140 Meanwhile, with placement of self-EMS in stricture areas, 2-year patency rates were estimated to be approximately 40%.141 However, these results are somewhat controversial and include some recommendations that these stents should not be used for dilation.

A

B FIGURE 39.11  A, Percutaneous transhepatic cholangioscopic lithotomy from the left hepatic duct. Arrow indicates stones in the right anterior branch. B, Stones in the right anterior section were removed using an electrohydraulic lithotripter and basket forceps. Arrow indicates no filling defects after lithotripsy.

PERORAL CHOLANGIOSCOPIC LITHOTRIPSY Since the description of endoscopic sphincterotomy and stone extraction in the early 1970s, endoscopic management has

TABLE 39.4  Treatment Outcomes REFERENCE

COMPLETE STONE REMOVAL (%)

RECURRENT STONES (%)

PROCEDURE-RELATED MORBIDITY (%)

IN-HOSPITAL MORTALITY (%)

Peroral Cholangioscopic Lithotripsy Tanaka, 1996142

36.8

0

—

—

Okugawa, 2002148

63.9

21.7

2.8

0

Cheon, 2009

57.1

17.9

—

—

Tsuyuguchi, 201458

57.8

—

—

—

88

Percutaneous Transhepatic Cholangioscopic Lithotomy Yeh, 1995149

80.0

32.6

28.5

—

Jan, 1995150

83.3

40.0

14.5

—

Otani, 1999

96.4

31.5

21.4

3.6

Lee, 2001137

80.4

29.4

10.9

—

Huang, 200366

85.3

49.8

1.6

—

136

Chen, 2005

82.4

50.8

17.6

0

Cheon, 200988

63.9

14.5

3

—

138

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

561

TABLE 39.4  Treatment Outcomes—cont’d REFERENCE

COMPLETE STONE REMOVAL (%)

RECURRENT STONES (%)

PROCEDURE-RELATED MORBIDITY (%)

IN-HOSPITAL MORTALITY (%)

Common Bile Duct Exploration 1 T-Tube Drainage 1 Postoperative Cholangioscopy Hwang, 1980

151)

Yamakawa, 1980147 Choi, 1982145

83

—

—

0

92.1

0

—

—

—

23.6

—

5.4

Takada, 1995

68.6

3.4

—

—

Jan, 199691

84.9

28.2

—

—

Li, 2006152

66.0

35.7

16.0

133

Hepaticojejunostomy (With/Without Subcutaneous Jejunostomy) Fan, 1993153

92.7

15.8

—

—

Akiyama, 1994154

81.3

30.8

—

0

—

13.8

—

0

Kusano, 2001156

Ker, 1994

68.6

30.6

—

—

Li, 2006152

74.1

27

—

25.7

—

—

155

Hepatectomy Tsunoda, 1985157 Jeng, 1996 (bilat.)

158

Fan, 1993153 Chen, 1997 (bilat.)159

92.5

11.9

—

5.5

—

15.9

32

1.6

40-84

12

—

1.7

Kim, 1998

64

11

—

3.9

Liu, 199865

77.0

3.0

29.0

1.0

Otani, 1999138

96.2

5.6

38.5

3.8 2

160

Chen, 2004

98

7.9

28

Cheung, 200568

98

13

44.2

0

Lee, 200771

96

5.7

33.3

1.6

Uchiyama, 2007161

100

13.9

23.7

0

Cheon, 200988

83

18

—

0

Uenishi, 200973

95

10

—

3.5

162)

83.1

29.3

46.3

2.2

Shah, 2012 (unilat.)163

97.8

5.2

—

0 0.4

67

Yang, 2010 (bilat.) Li, 201293 (unilat.)

99.3

6.2

20.4

(bilat.)

90.2

16.7

38.5

0.4

Li, 2019 (bilat.)164

92.9

13.5

26.8

2.9

bilat., Bilateral stones; unilat., unilateral stones.

become the optimal mode of treatment for many patients with various conditions, including acute cholangitis with hepatolithiasis.13 The aim of ERC with endoscopic sphincterotomy is to decompress the biliary tract quickly to resolve biliary sepsis (see Chapter 30); this choice allows the extraction of stones via the duodenal papilla. However, the incidence of residual and recurrent stones after ERC with stone removal is higher than after PTCSL and hepatectomy. Suzuki and colleagues (2014) reported that biliary strictures and dilation were predictive factors for stone recurrence after ERC with stone removal.13 In addition, peripheral stone impaction and ductal angulation can lead to difficulties. Because endoscopic sphincterotomy induces bile reflux and contamination, the divergent effects of endoscopic sphincterotomy

on long-term hepatolithiasis outcomes, especially in patients with remaining stones, have been noted.142 Therefore the complete clearance of intrahepatic calculi is mandatory if adverse effects are to be avoided. Endoscopic therapeutic interventions are sometimes difficult in patients with Roux-en-Y anastomosis and hepaticojejunostomy. However, recent advances in double-balloon enteroscopy and cholangioscopy have allowed direct lithotripsy and biliary stricture treatments in some cases115 (see Fig. 39.10). Endoscopic US-guided hepaticogastrostomy is another option to access intrahepatic stones.143,144 This method is useful for patients with a surgically altered anatomy, such as Roux-enY hepaticojejunostomy, when it is difficult to approach by double-balloon enteroscopy (Fig. 39.12).

562

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

SURGICAL TREATMENT (SEE CHAPTER 44)

A 300

B2

B

C FIGURE 39.12  A, A case of Bismuth type IV benign biliary stricture caused by laparoscopic cholecystectomy, which was reconstructed by multiple hepaticojejunostomy in the hospital. The left hepatic duct, anterior sections, and posterior sections were reconstructed separately. B, Endoscopic ultrasonography (EUS) from the stomach showed a dilated bile duct of segment 2. C, Left hepatic duct was opacified through an EUS-guided hepaticogastrostomy showing complete obstruction of hepaticojejunostomy.

In the 1970s, the primary surgical treatment was cholecystectomy with stone removal and insertion of a T-tube to allow removal of remnant stones by postoperative cholangioscopy.145–147 Using this treatment, stones were successfully removed in repeated postoperative examinations in 66% to 83% of cases (see Table 39.4).58,65–68,71,73,88,91,93,133,136–138,142,145,147–149,150–164 However, high stone recurrence rates of 23.6% to 35.7% after Ttube removal have been reported.145,152 Recently, the use of cholecystectomy with stone removal and insertion of a T-tube has decreased remarkably (50.2% in 1985–1988 vs. 1.0% in 2011).13 Choledochojejunostomy and transduodenal pupilloplasty were also performed in the 1970s but are now seldom performed. Generally, stones localized in a unilateral hemiliver, severe biliary strictures, atrophy, and the presence of ICC are indications for partial hepatectomy (Fig. 39.13; see Chapter 101). Intrahepatic stones limited to the left lobe, accounting for about half of cases, are a good indication for liver resection alone from the perspectives of cure and treatment time.163 The incidence of residual stones after hepatectomy is usually lower than that after endoscopic lithotripsy (see Table 39.4). Stones recur at rates of 0% to 18% in cases without bilateral disease. Moreover, the resection of atrophic liver and stricture areas is expected to reduce the future incidence of ICC.73,91 Jan and colleagues (1996) reported significantly superior results with hepatectomy versus nonsurgical treatment (stone recurrence: 9.5% vs. 29.6%, secondary biliary cirrhosis: 2.1% vs. 6.8%, and late development of ICC: 0% vs. 2.8%, respectively).91 The management of bilateral hepatolithiasis is more complicated than that of unilateral hepatolithiasis. Even in patients with affected liver segments on both hemilivers, resection of the atrophied segments is often applied (Fig. 39.14). In such instances, hepatectomy combined with postoperative stone removal from a T-tube fistula, or with stone removal by PTCSL, is recommended to obtain high complete stone removal rates. Indeed, Chen and colleagues (1997) reported that the rate of complete stone clearance was 84% 1 year after operation, despite 60% of the patients having remnant stones immediately after the operation.159 In addition, combining hepatectomy and hepaticojejunostomy with anchoring of the jejunal limb to the abdominal wall within subcutaneous tissue for the purpose of postoperative stone removal and treatment of bile duct strictures has long been performed (Fig. 39.15; see Chapter 101B). If stones recur several years after complete stone clearance, this jejunal limb can be used as an access route to the biliary system under local anesthesia. Some consider this to be a useful procedure for the prevention of bacterial reflux into the liver.165 However, complementary hepaticojejunostomy itself may cause cholangitis.97 Herman and colleagues (2010) confirmed that all patients undergoing liver resection showed good results, whereas 7 (41.2%) of 17 patients who underwent liver resection associated with hepaticojejunostomy had late complications during the follow-up period.165 In an attempt to clarify the drawbacks of bilioenteric anastomosis, they compared only patients with unilateral disease with and without hepaticojejunostomy; a significant difference was found between groups, indicating the negative effects of bilioenteric anastomosis on patient outcomes. Likewise, Li et al. (2006) noted that if intrahepatic stone clearance could not be achieved during surgery,

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

A

C

563

B

D

FIGURE 39.13  A, A case of secondary hepatolithiasis after excision of congenital choledochal cysts. Some filling defects (arrows) in the left hepatic duct are seen on magnetic resonance cholangiopancreatography. B, Three-dimensional computed tomography shows marked atrophy of the left hemiliver with diminished portal flow. C, Left hemihepatectomy with caudate lobectomy was carried out. The anastomotic site of the right hepatic duct and the jejunal limb were intact. The jejunal orifice for the left hepatic duct anastomosis was closed. D, Resected specimen shows marked atrophy and impacted stones in the left hemiliver.

T-tube placement within the CBD rather than hepaticojejunostomy would facilitate postoperative choledochoscopic lithotripsy.152 Bilateral partial resection of the liver may provide good longterm results, even in patients with bilateral intrahepatic stones and stenosis.162 In that study, the incidences of stone recurrence after bilateral and unilateral hepatectomy for bilateral intrahepatic stones were 11.8% and 34.1%, respectively. It should be noted, however, that three hospital deaths related to postoperative liver failure occurred in 54 patients in the bilateral resection group. Extended parenchymal resections to eliminate the persistence of CPC may reduce stone recurrence. Even in patients with bilateral stones, stone recurrence rates are low and comparable with that of unilateral stones if the extent of liver resection is equal to the stone-affected segments.93 Recently, a combination of intraoperative lithotomy with hepatectomy achieved satisfactory stone clearance of 92.9% (52/56) in patients with complicated bilateral hepatolithiasis.164 In addition, resection of liver parenchyma with CPC may also reduce the late development of ICC because CPC is thought to be a possible precursor lesion of ICC.81

The safety of hepatectomy has improved, but postoperative complication rates, including those for wound infection, hemobilia, and biliary fistula, still range from 15.7% to 38.5%.159 Li and colleagues (2012) reported that left lobectomy or hepatectomy within 1 month of the last episode of cholangitis is a risk factor for postoperative bile leakage.93 With recent advances in laparoscopic techniques, laparoscopic liver resection is increasingly being performed for hepatolithiasis.166 Although the number of patients is still limited, operative mortality and residual stone rates are comparable to those of open hepatectomy.167,168 On the other hand, increased postoperative complications have been reported169 and thus no consensus has been reached regarding its clinical utility. Further investigation in a larger number of patients is therefore necessary. Because of its complicated clinical features, such as repeated cholangitis and multiple operations, diffusely distributed hepatolithiasis is untreatable by hepatectomy, cholangiojejunostomy, or choledochoscopy, and thus often leads to portal hypertension and liver failure. Liver transplantation has been performed in patients who have progressed to liver failure170–173 (see Chapter 105).

564

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

A

B

C

D

E

F

FIGURE 39.14  A, A case of primary hepatolithiasis. Magnetic resonance image demonstrating dilated right posterior intrahepatic duct containing multiple stones. Arrow indicates filling defects in the dilated right to posterior segment branch. B, Three-dimensional computed tomography shows multiple biliary stenosis and dilation in the left lateral section. In addition, remarkable cystic dilation is observed from the right to the posterior hepatic duct. Portal flow is decreased to both the left lateral and right posterior sections. Note the absence of right posterior ductal strictures. C, Bilateral hepatectomy, left lateral sectionectomy, and posterior sectionectomy with T-tube insertion were carried out. Stones were extracted from the cut end of the posterior sectional branch. The orifice was then additionally resected and sutured to reduce the size of the remnant dilated posterior duct to be as small as possible. At that time, attention was paid not to tuck the caudate lobe branches. D, After closure of the posterior sectional branch stump. E, Cholangiography through the cholangioscopy. F, Postoperative cholangioscopy reveals a remnant stone that was subsequently removed using basket forceps.

A. Gallstones and Gallbladder  Chapter 39  Intrahepatic Stone Disease

565

PROGNOSIS Even when intrahepatic stones are completely removed, stone recurrence rates are high. The major factors that predict the long-term outcome of intrahepatic stones are concomitant CCA, cholangitis, liver abscess, and biliary cirrhosis because of repeated cholangitis. Recurrence rates, depending on the type of treatment and the presence or absence of bile duct strictures, range from 0% to 50.8% (see Table 39.4). Patients with recurrence may have repeated/chronic cholangitis and develop biliary cirrhosis over a period of 10 to 20 years. In addition, the rate of late development of CCA is about 0.3% to 9.1% (see Table 39.3). Long-term outcomes of patients with subsequent CCA are extremely poor. Based on Korean national data, patients with subsequent CCA had very poor survival outcomes compared with concomitant CCA.89 Therefore patients with risk factors should be observed carefully over the long term because cancer is known to emerge even after 10 to 20 years. The overall 10-year survival rate for patients with hepatolithiasis is about 80% to 90%.73,91 Nevertheless, a 5-year survival rate of only 9% has been reported in patients with concomitant ICC.67 References are available at expertconsult.com.

FIGURE 39.15  A drawing of combining hepaticojejunostomy with anchoring of a Roux-en-Y jejunal limb to the abdominal wall for the purpose of postoperative stone extraction (upper). A cholangiogram after lithotomy shows no remnant stones in the dilated left hepatic duct (arrowheads) (lower).

565.e1

REFERENCES 1. King MS. Biliary-tract disease in Malaya. Br J Surg. 1971;58: 829–832. 2. Nakayama F, Koga A. Hepatolithiasis: present status. World J Surg. 1984;8(1):9–14. 3. Nakayama F, Koga A, Ichimiya H, et al. Hepatolithiasis is East Asia: comparison between Japan and China. J Gastroenterol Hepatol. 1991;6:155–158. 4. Su CH, Lui WY, P’eng FK. Relative prevalence of gallstone diseases in Taiwan. A nationwide cooperative study. Dig Dis Sci. 1992;37:764–768. 5. Han JK, Choi BI, Park JH, Han MC. Percutaneous removal of retained intrahepatic stones with a preshaped angulated catheter: review of 96 patients. Br J Radiol. 1992;65:9–13. 6. Uchiyama K, Tanimura H, Ishimoto K. Hepatolithiasis in Japan. Arch Jpn Chir. 1996;65:145–157. 7. Best R. The incidence of liver stones associated with cholelithiasis and its clinical significance. Surg Gynecol Obstet. 1944;78: 425–428. 8. Glenn F, Moody FG. Intrahepatic calculi. Ann Surg. 1961;153: 711–724. 9. Bove P, De Oliverira MR, Speranzini M. Intrahepatic lithiasis. Gastroenterology. 1963;44:251–257. 10. Yarmuch J, Csendes A, Díaz JC, et al. Result of surgical treatment in patients with Western intrahepatic lithiasis. Hepatogastroenterology. 1989;36:128–131. 11 . Lindström CG. Frequency of gallstone disease in a well-defined Swedish population. A prospective necropsy study in Malmö. Scand J Gastroenterol. 1977;12:341–346. 12. Simi M, Loriga P, Basoli A, Leardi S, Speranza V. Intrahepatic lithiasis. Study of thirty-six cases and review of the literature. Am J Surg. 1979;137(3):317–322. 13 . Suzuki Y, Mori T, Yokoyama M, et al. Hepatolithiasis: analysis of Japanese nationwide surveys over a period of 40 years. J Hepatobiliary Pancreat Sci. 2014;21(9):617–622. 14 . Balasegaram M. Hepatic calculi. Ann Surg. 1972;175:149–154. 15. Ran X, Yin B, Ma B. Four major factors contributing to intrahepatic stones. Gastroenterol Res Pract. 2017;2017:1–5. 16 . Hamaloglu E. Biliary ascariasis in fifteen patients. Int Surg. 1992; 77(2):77–79. 17. Matsushiro T, Suzuki N, Sato T, Maki T. Effects of diet on glucaric acid concentration in bile and the formation of calcium bilirubinate gallstones. Gastroenterology. 1977;72:630–633. 18 . Nakayama F, Miyake H. Changing state of gallstone disease in Japan. Composition of the stones and treatment of the condition. Am J Surg. 1970;120(6):794–799. 19. Furukawa M, Furui J, Yasaka T, et al. Hepatolithiasis in the Kamigoto District, Nagasaki Prefecture [in Japanese]. Tan to Sui. 1994;15:409–413. 20. Maki T, Sato T, Sato T. A study on the activity of beta-glucuronidase in bile in connection with precipitation of calcium bilirubinate. Tohoku J Exp Med. 1962;77:179–186. 21. Maki T. Pathogenesis of calcium bilirubinate gallstone: role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg. 1966;164:90–100. 22. Tian Y, Li M, Wu S, et al. Neutrophil elastase stimulates MUC5AC expression in human biliary epithelial cells: a possible pathway of PKC/Nox/ROS. Arch Med Sci. 2017;13(3):677–685. 23. Digby KH. Common duct stones of liver origin. Br J Surg. 1930;17:578–591. 24 . Shoda J, Tanaka N, Matsuzaki Y, et al. Microanalysis of bile acid composition in intrahepatic calculi and its etiological significance. Gastroenterology. 1991;101:821–830. 25 . Yamashita N, Yanagisawa J, Nakayama F. Composition of intrahepatic calculi. Etiological significance. Dig Dis Sci. 1988;33: 449–453. 26. Shoda J, He BF, Tanaka N, Matsuzaki Y, Yamamori S, Osuga T. Primary dual defect of cholesterol and bile acid metabolism in liver of patients with intrahepatic calculi. Gastroenterology. 1995;108(5): 1534–1546. 27 . Komichi D, Tazuma S, Nishioka T, Hyogo H, Une M, Chayama K. Unique inhibition of bile salt-induced apoptosis by lecithins and cytoprotective bile salts in immortalized mouse cholangiocytes. Dig Dis Sci. 2003;48(12):2315–2322.

28. Nishioka T, Having R, Tazuma S, Stellaard F, Kuipers F, Verkade HJ. Administration of phosphatidylcholine-cholesterol liposomes partially reconstitutes fat absorption in chronically bile-diverted rats. Biochim Biophys Acta. 2004;1636:90–98. 29. Sakamoto M, Tazuma S, Chayama K. Less hydrophobic phosphatidylcholine species simplify biliary vesicle morphology, but induce bile metastability with a broad spectrum of crystal forms. Biochem J. 2002;362:105–112. 30 . Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339:1217–1227. 31. Gerloff T, Stieger B, Hagenbuch B, et al. The sister of P-glycoprotein represents the canalicular bile salts export pump of mammalian liver. J Biol Chem. 1998;273:10046–10050. 32. Gros P, Neriah YBB, Croop JM, Housman DE. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature. 1986;323(6090):728–731. 33. Marschall HU, Einarsson C. Gallstone disease. Intern Med. 2007; 261:529–542. 34 . Meier Y, Pauli-Magnus C, Zanger UM, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-Transporter expression in human liver. Hepatology. 2006;44:62–74. 35. Pan S, Li X, Jiang P, et al. Variations of ABCB4 and ABCB11 genes are associated with primary intrahepatic stones. Mol Med Rep. 2015;11(1):434–446. 36 . Gan L, Pan S, Cui J, Bai J, Jiang P, He Y. Functional analysis of the correlation between abcb11 gene mutation and primary intrahepatic stone. Mol Med Rep. 2019;19(1):195–204. 37 . Kim MH, Sekijima J, Lee SP. Primary intrahepatic stones, Am J Gastroenterol. 1995;90(4):540–548. 38. Pitt HA, Venbrux AC, Coleman JA, et al. Intrahepatic stones. The transhepatic team approach. Ann Surg. 1994;219:527–537. 39. Schmidt SC, Langrehr JM, Raakow R, Klupp J, Steinmüller T, Neuhaus P. Right hepatic lobectomy for recurrent cholangitis after combined bile duct and right hepatic artery injury during laparoscopic cholecystectomy: a report of two cases. Langenbecks Arch Surg. 2002;387(3–4):183–187. 40. Fujii H, Yang Y, Matsumoto Y, Suda K. Current problems with intrahepatic bile duct stones in Japan–congenital biliary malformations as a cause. Hepatogastroenterology. 1997;44(14):328–341. 41 . Matsumoto Y, Fujii H, Itakura J, et al. Pancreaticobiliary maljunction: pathophysiological and clinical aspects and the impact on biliary carcinogenesis. Langenbecks Arch Surg. 2003;388:122–131. 42. Morine Y, Shimada M, Takamatsu H, et al. Clinical features of pancreaticobiliary maljunction: update analysis of 2nd Japan-nationwide survey. J Hepatobiliary Pancreat Sci. 2013;20:472–480. 43. Tashiro S, Imaizumi T, Ohkawa H, et al. Committee for Registration of the Japanese Study Group on Pancreaticobiliary Malfunction: pancreaticobiliary malfunction: retrospective and nationwide survey in Japan. J Hepatobiliary Pancreat Surg. 2003;10: 345–351. 44 . Chijiiwa K, Komura M, Kameoka N. Postoperative follow-up of patients with type IVA choledochal cysts after excision of extrahepatic cyst. J Am Coll Surg. 1994;179(6):641–645. 45. Kim JH, Choi TY, Han JH, et al. Risk factors of postoperative anastomotic stricture after excision of choledochal cysts with hepaticojejunostomy. J Gastrointest Surg. 2008;12:822–828. 46 . Takeshita N, Ota T, Yamamoto M. Forty-year experience with flowdiversion surgery for patients with congenital choledochal cysts with pancreaticobiliary maljunction at a single institution. Ann Surg. 2011;254:1050–1053. 47. Tsuchida Y, Takahashi A, Suzuki N, et al. Development of intrahepatic biliary stones after excision of choledochal cysts. J Pediatr Surg. 2002;37:165–167. 48. Uno K, Tsuchida Y, Kawarasaki H, Ohmiya H, Honna T. Development of intrahepatic cholelithiasis long after primary excision of choledochal cysts. J Am Coll Surg. 1996;183:583–588. 49. Kaneko K, Ando H, Seo T, Ono Y, Ochiai K, Ogura Y. Bile infection contributes to intrahepatic calculi formation after excision of choledochal cysts. Pediatr Surg Int. 2005;21:8–11. 50 . Aota T, Kubo S, Takemura S, et al. Long-term outcomes after biliary diversion operation for pancreaticobiliary maljunction in adult patients. Ann Gastroenterol Surg. 2019;3:217–223. 51. Bettschart V, Clayton RA, Parks RW, Garden OJ, Bellamy CO. Cholangiocarcinoma arising after biliary-enteric drainage procedures for benign disease. Gut. 2002;51:128–129.

565.e2 52. Hakamada K, Sasaki M, Endoh M, et al. Late development of bile duct cancer after sphincteroplasty: a ten- to twenty-two-year follow-up study. Surgery. 1997;121:488–492. 53 . Tocchi A, Mazzoni G, Liotta G, Lepre L, Cassini D, Miccini M. Late development of bile duct cancer in patients who had biliaryenteric drainage for benign disease: a follow-up study of more than 1,000 patients. Ann Surg. 2001;234:210–214. 54. Kobayashi S, Asano T, Yamasaki M, Kenmochi T, Nakagohri T, Ochiai T. Risk of bile duct carcinogenesis after excision of extrahepatic bile ducts in pancreaticobiliary maljunction. Surgery. 1999; 126:939–944. 55 . Ohashi T, Wakai T, Kubota M, et al. Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. J Gastroenterol Hepatol. 2013;28:243–247. 56 . Watanabe Y, Toki A, Todani T. Bile duct cancer developed after cyst excision for choledochal cyst. J Hepatobiliary Pancreat Surg. 1999;6:207–212. 57 . Soares KC, Arnaoutakis DJ, Kamel I, et al. Choledochal cysts: presentation, clinical differentiation, and management. J Am Coll Surg. 2014;219(6):1167–1180. 58 . Tsuyuguchi T, Miyakawa K, Sugiyama H, et al. Ten-year long-term results after non-surgical management of hepatolithiasis, including cases with choledochoenterostomy. J Hepatobiliary Pancreat Sci. 2014;21:795–800. 59. Moy BT, Birk JW. A review on the management of biliary complications after orthotopic liver transplantation. J Clin Transl Hepatol. 2019;7(1):61–71. 60. Shin M, Joh JW. Advances in endoscopic management of biliary complications after living donor liver transplantation: comprehensive review of the literature. World J Gastroenterol. 2016;22(27): 6173–6191. 61 . Koga A, Ichimiya H, Yamaguchi K, Miyazaki K, Nakayama F. Hepatolithiasis associated with cholangiocarcinoma. Possible etiologic significance. Cancer. 1985;55:2826–2829. 62 . Chen MF, Jan YY, Wang CS, et al. Intrahepatic stones associated with cholangiocarcinoma. Am J Gastroenterol. 1989;84:391–395. 63. Sheen-Chen SM, Chou FF, Eng HL. Intrahepatic cholangiocarcinoma in hepatolithiasis: a frequently overlooked disease. J Surg Oncol. 1991;47(2):131–135. 64 . Kubo S, Kinoshita H, Hirohashi K, et al. Hepatolithiasis associated with cholangiocarcinoma. World J Surg. 1995;19:637–641. 65. Liu CL, Fan ST, Wong J. Primary biliary stones: diagnosis and management. World J Surg. 1998;22:1162–1166. 66. Huang MH, Chen CH, Yang JC, et al. Long-term outcome of percutaneous transhepatic cholangioscopic lithotomy for hepatolithiasis. Am J Gastroenterol. 2003;98(12):2655–2662. 67 . Chen DW, Poon RTP, Liu CL, et al. Immediate and long-term outcomes of hepatectomy for hepatolithiasis. Surgery. 2004;135(4): 386–393. 68. Cheung MT, Kwok PCH. Liver resection for intrahepatic stones. Arch Surg. 2005;140:993–997. 69. Herman P, Bacchella T, Pugliese V, et al. Non-Oriental primary intrahepatic lithiasis: experience with 48 cases. World J Surg. 2005;29:858–862, discussion 863–864. 70. Vetrone G, Ercolani G, Grazi GL, et al. Surgical therapy for hepatolithiasis: a Western experience. J Am Coll Surg. 2006;202: 306–312. 71. Lee TY, Chen YL, Chang HC, et al. Outcomes of hepatectomy for hepatolithiasis. World J Surg. 2007;31:479–482. 72 . Al-Sukhni W, Gallinger S, Pratzer A, et al. Recurrent pyogenic cholangitis with hepatolithiasis–the role of surgical therapy in North America. J Gastrointest Surg. 2008;12:496–503. 73 . Uenishi T, Hamba H, Takemura S, et al. Outcomes of hepatic resection for hepatolithiasis. Am J Surg. 2009;198(2):199–202. 74. Suzuki Y, Mori T, Abe N, Sugiyama M, Atomi Y. Predictive factors for cholangiocarcinoma associated with hepatolithiasis determined on the basis of Japanese multicenter study. Hepatol Res. 2012;42:166–170. 75 . Tabrizian P, Jibara G, Shrager B. Hepatic resection for primary hepatolithiasis: a single-center Western experience. J Am Coll Surg. 2012;215(5):622–626. 76 . Lin CC Lin PY, Chen YL. Comparison of concomitant and subsequent cholangiocarcinomas associated with hepatolithiasis: clinical implications. World J Gastroenterol. 2013;19(3):375–380. 77 . Guglielmi A, Ruzzenente A, Valdegamberi A, et al. Hepatolithiasisassociated cholangiocarcinoma: results from a multi-institutional

national database on a case series of 23 patients. Eur J Surg Oncol. 2014;40:567–575. 78. Zhu QD, Zhou MT, Zhou QQ, Shi HQ, Zhang QY, Yu ZP. Diagnosis and surgical treatment of intrahepatic hepatolithiasis combined with cholangiocarcinoma. World J Surg. 2014;38: 2097–2104. 79 . Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96. 80. Shore JM, Berci G. Operative management of calculi in the hepatic ducts. Am J Surg. 1970;119(6):625–631. 81 . Ohta T, Nagakawa T, Ueda N, et al. Mucosal dysplasia of the liver and intraductal variant of peripheral cholangiocarcinoma in hepatolithiasis. Cancer. 1991;68(10):2217–2223. 82. Zen Y, Sasaki M, Fujii T, et al. Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct: an immunohistochemical study of 110 cases of hepatolithiasis. J Hepatol. 2006;44: 350–358. 83. Kim HJ, Kim JS, Joo MK, et al. Hepatolithiasis and intrahepatic cholangiocarcinoma: a review. World J Gastroenterol. 2015;21(48): 13418–13431. 84. Liu ZY, Zhou YM, Shi LH, Yin ZF. Risk factors of intrahepatic cholangiocarcinoma in patients with hepatolithiasis: a case-control study. Hepatobiliary Pancreat Dis Int. 2011;10:626–631. 85. Jo JH, Chung MJ, Park JY, et al. High serum CA 19-9 levels are associated with an increased risk of cholangiocarcinoma in patients with intrahepatic duct stones: a case-control study. Surg Endosc. 2013;27:4210–4216. 86 . Zhang XF, Chakedis J, Bagante F et al. Implications of intrahepatic cholangiocarcinoma etiology on recurrence and prognosis after curative-intent resection: a multi-institutional study. World J Surg. 2018;42:849–857. 87 . Chijiiwa K, Yamashita H, Yoshida J, Kuroki S, Tanaka M. Current management and long-term prognosis of hepatolithiasis. Arch Surg. 1995;130:194–197. 88 . Cheon YK, Cho YD, Moon JH, et al. Evaluation of long-term results and recurrent factors after operative and nonoperative treatment for hepatolithiasis. Surgery. 2009;146(5):843–853. 89 . Kim HJ, Kang TU, Swan H, et al. Incidence and prognosis of subsequent cholangiocarcinoma in patients with hepatic resection for bile duct stones. Dig Dis Sci. 2018;63:3465–3473. 90 . Chijiiwa K, Ichimiya H, Kuroki S, Koga A, Nakayama F. Late development of cholangiocarcinoma after the treatment of hepatolithiasis. Surg Gynecol Obstet. 1993;177:279–282. 91 . Jan YY, Chen MF, Wang CS, et al. Surgical treatment of hepatolithiasis: long-term results. Surgery. 1996;120:509–514. 92 . Furukawa M, Sasaki M, Otsubo M, et al. Natural history of primary hepatolithiasis. Tan to Sui. 1998;19:1021–1027. 93. Li SQ, Liang LJ, Peng BG, et al. Outcomes of liver resection for intrahepatic stones: a comparative study of unilateral versus bilateral disease. Ann Surg. 2012;255(5):946–953. 94 . Kim HJ, Kim JS, Suh SJ, et al. Cholangiocarcinoma risk as longterm outcome after hepatic resection in the hepatolithiasis patients. World J Surg. 2015;39:1537–1542. 95. Meng ZW, Han SH, Zhu JH, Zhou LY, Chen YL. Risk factors for cholangiocarcinoma after initial hepatectomy for intrahepatic stones. World J Surg. 2017;41:835–843. 96. Nimura Y, Momiyama M, Yamada T, Kamiya J, Oda T. Current status of intrahepatic stones in Japan according to the grade classification of hepatolithiasis. In: Annual Reports of the Japanese Ministry of Health and Welfare [in Japanese]. Tokyo, Japan: Japanese Government; 2001:33–38. 97. Kusano T, Isa T, Ohtsubo M, et al. Natural progression of untreated hepatolithiasis that shows no clinical signs at its initial presentation. J Clin Gastroenterol. 2001;33:114–117. 98 . Kiriyama S, Takada T, Strasberg SM, et al. Tokyo Guidelines Revision Committee: TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci. 2013;20(1):24–34. 99. Csendes A, Burdiles P, Maluenda F, Diaz JC, Csendes P, Mitru N. Simultaneous bacteriologic assessment of bile from gallbladder and common bile duct in control subjects and patients with gallstones and common duct stones. Arch Surg. 1996;131:389–394.

565.e3 100. Kwon W, Jang JY, Kim EC, et al. Changing trend in bile microbiology and antibiotic susceptibilities: over 12 years of experience. Infection. 2013;41:93–102. 101. Han SL, Zhou HZ, Cheng J, et al. Diagnosis and surgical treatment of intrahepatic hepatolithiasis associated cholangiocarcinoma. Asian J Surg. 2009;32(1):1–6. 102 Federle MP, Cello JP, Laing FC, Jeffrey RB Jr. Recurrent pyogenic cholangitis in Asian immigrants. Use of ultrasonography, computed tomography, and cholangiography. Radiology. 1982;143(1): 151–156. 103. Ohto M, Kimura K, Tsuchiya Y, et al. Diagnosis of hepatolithiasis. Prog Clin Biol Res. 1984;152:129–148. 104. van Sonnenberg E, Casola G, Cubberley DA, et al. Oriental cholangiohepatitis: diagnostic imaging and interventional management. AJR Am J Roentgenol. 1986;146(2):327–331. 105. Takada T, Uchida Y, Fukushima Y, et al. Classification and treatment of intrahepatic calculi. Jap J Gastroenterol Surg. 1978;11(9):769–774. 106. Chijiiwa K, Ohtani K, Noshiro H, et al. Cholangiocellular carcinoma depends on the kind of intrahepatic calculi in patients with hepatolithiasis. Hepatogastroenterology. 2002;49(43):96–99. 107. Cohen SM, Kurtz AB. Biliary sonography. Radiol Clin North Am. 1991;29:1171–1198. 108. Lim JH, Ko YT, Lee DH, Hong KS. Oriental cholangiohepatitis: sonographic findings in 48 cases. AJR Am J Roentgenol. 1990;155(3):511–514. 109. Tanaka K, Komokata T, Ikoma A, Yamaoka A, Fukumoto Y, Taira A. Portal vein obstruction accompanied by intrahepatic stones. Angiology. 1996;47(12):1151–1156. 110. Itai Y, Araki T, Furui S, Tasaka A, Atomi Y, Kuroda A. Computed tomography and ultrasound in the diagnosis of intrahepatic calculi. Radiology. 1980;136:399–405. 111. Lim JH. Oriental cholangiohepatitis: pathologic, clinical, and radiologic features. AJR Am J Roentgenol. 1991;157(1):1–8. 112. Kubo S, Hamba H, Hirohashi K, et al. Magnetic resonance cholangiography in hepatolithiasis. Am J Gastroenterol. 1997;92(4): 629–632. 113. Park MS, Yu JS, Kim KW, et al. Recurrent pyogenic cholangitis: comparison between MR cholangiography and direct cholangiography. Radiology. 2001;220(3):677–682. 114. Park DH, Kim MH, Lee SS, et al. Accuracy of magnetic resonance cholangiopancreatography for locating hepatolithiasis and detecting accompanying biliary strictures. Endoscopy. 2004;36: 987–992. 115 Ono S, Maeda K, Baba K, et al. The efficacy of double-balloon enteroscopy for intrahepatic bile duct stones after Roux-en-Y hepaticojejunostomy for choledochal cysts. Pediatr Surg Int. 2013;29(11):1103–1107. 116. Gomi H, Solomkin JS, Takada T, et al. Tokyo Guideline Revision Committee: TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20:60–70. 117. Murata A, Matsuda S, Kuwabara K, et al. Evaluation of compliance with the Tokyo Guidelines for the management of acute cholangitis based on the Japanese administrative database associated with the Diagnosis Procedure Combination system. J Hepatobiliary Pancreat Sci. 2011;18(1):53–59. 118. Tsuchiya S, Tsuyuguchi T, Sakai Y, Sugiyama H, Miyakawa K, Yokosuka O. Long-term follow-up of silent stones in the peripheral bile duct. Tan to Sui. 2007;28(7):505–508. 119. Tazuma S, Unno M, Igarashi Y, et al. Evidence-based clinical practice guidelines for cholelithiasis 2016. J Gastroenterol. 2017;52(3):276–300. 120. Lorio E, Patel P, Rosenkranz L, Patel S, Sayana H. Management of hepatolithiasis: review of the literature. Curr Gastroenterol Rep. 2020;22:30. 121. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005;129(2):476–485. 122. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531. 123. Ros E, Navarro S, Bru C, Gilabert R, Bianchi L, Bruguera M. Ursodeoxycholic acid treatment of primary hepatolithiasis in Caroli’s syndrome. Lancet. 1993;342(8868):404–406.

124. Smith JL, Roach PD, Wittenberg LN, et al. Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones. J Gastroenterol Hepatol. 2000;15(8):871–879. 125. Bodmer M, Brauchli YB, Krähenbühl S, Jick SS, Meier CR. Statin use and risk of gallstone disease followed by cholecystectomy. JAMA. 2009;302(21):2001–2007. 126. Chiu HF, Chen CC, Kuo HW, Lee IM, Wu TN, Yang CY. Statin use and the risk of gallstone disease: a population-based casecontrol study. Expert Opin Drug Saf. 2012;11:369–374. 127. Shoda J, Ueda T, Kawamoto T, et al. Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the pathobiological significance for cholangitis. Clin Gastroenterol Hepatol. 2003;1(4): 285–296. 128. Shoda J, Miura T, Utsunomiya H, et al. Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology. 2004;39:167–178. 129. Kawai K, Yokoyama Y, Kokuryo T, Watanabe K, Kitagawa T, Nagino M. Inchinkoto, an herbal medicine, exerts beneficial effects in the rat liver under stress with hepatic ischemia-reperfusion and subsequent hepatectomy. Ann Surg. 2010;251:692–700. 130. Ogasawara T, Morine Y, Ikemoto T, Imura S, Shimada M. Beneficial effects of Kampo medicine Inchin-ko-to on liver function and regeneration after hepatectomy in rats. Hepatol Res. 2008;38: 818–824. 131. Uji M, Yokoyama Y, Asahara T, et al. Does the intestinal microenvironment have an impact on the choleretic effect of inchinkoto, a hepatoprotective herbal medicine? Hepatol Res. 2018;48(3): E303–E310. 132. Nimura Y, Shionoya S, Hayakawa N, et al. Value of percutaneous transhepatic cholangioscopy (PTCS). Surg Endosc. 1988;2(4): 213–219. 133. Takada T, Yasuda H, Hanyu F. Technique and management of percutaneous transhepatic cholangiole drainage for treating an obstructive jaundice. Hepatogastroenterology. 1995;42:317–322. 134. Jeng KS, Sheen IS, Yang FS. Are modified procedures significantly better than conventional procedures in percutaneous transhepatic treatment for complicated right hepatolithiasis with intrahepatic biliary strictures? Scand J Gastroenterol. 2002;37(5): 597–601. 135. Uchiyama K, Onishi H, Tani M, Kinoshita H, Ueno M, Yamaue H. Indication and procedure for treatment of hepatolithiasis. Arch Surg. 2002;137:149–153. 136. Chen CH, Huang MH, Yang JC, et al. Reappraisal of percutaneous transhepatic cholangioscopic lithotomy for primary hepatolithiasis. Surg Endosc. 2005;19(4):505–509. 137. Lee SK, Seo DW, Myung SJ, et al. Percutaneous transhepatic cholangioscopic treatment for hepatolithiasis: an evaluation of long-term results and risk factors for recurrence. Gastrointest Endosc. 2001;53:318–323. 138. Otani K, Shimizu S, Chijiiwa K, et al. Comparison of treatment for hepatolithiasis: hepatic resection versus cholangioscopic lithotomy. J Am Coll Surg. 1999;189:177–182. 139. Takada T, Uchiyama K, Yasuda H, Hasegawa H. Indications for the choledochoscopic removal of intrahepatic stones based on the biliary anatomy. Am J Surg. 1996;171:558–561. 140. Jeng KS, Sheen IS, Yang FS. Are expandable metallic stents better than conventional methods for treating difficult intrahepatic biliary strictures with recurrent hepatolithiasis? Arch Surg. 1999;134: 267–273. 141. Siriwardana HPP, Siriwardena AK. Systematic appraisal of the role of metallic endobiliary stents in the treatment of benign bile duct stricture. Ann Surg. 2005;242(1):10–19. 142. Tanaka M, Ikeda S, Ogawa Y, Yokohata K, Matsumoto S, Chijiiwa K. Divergent effects of endoscopic sphincterotomy on the longterm outcome of hepatolithiasis. Gastrointest Endosc. 1996;43: 33–37. 143. Sato T, Nakai Y, Kogure H, Isayama H, Koike K. Electrohydraulic lithotripsy through a fistula of EUS-guided hepaticogastrostomy: a new approach for right intrahepatic stones. VideoGIE. 2019;4(9): 420–422. 144. Ogura T, Masuda D, Takeuchi T, Fukunishi S, Higuchi K. VideoGIE. 2016;84(3):531–532. 145. Choi TK, Wong J, Ong GB. The surgical management of primary intrahepatic stones. Br J Surg. 1982;69:86–90.

565.e4 146. Sato T, Suzuki N, Takahashi W, Uematsu I. Surgical management of intrahepatic gallstones. Ann Surg. 1980;192:28–32. 147. Yamakawa T, Komaki F, Kitano Y, Iizumi S, Shikata J. Intrahepatic stones and postoperative choledochoscopy. Gastroenterol Jpn. 1980;15(6):577–583. 148. Okugawa T, Tsuyuguchi T, SK C, et al. Peroral cholangioscopic treatment of hepatolithiasis: long-term results. Gastrointest Endosc. 2002;56(3):366–371. 149. Yeh YH, Huang MH, Yang JC, Mo LR, Lin J, Yueh SK. Percutaneous trans-hepatic cholangioscopy and lithotripsy in the treatment of intrahepatic stones: a study with 5 year follow-up. Gastrointest Endosc. 1995;42:13–18. 150. Jan YY, Chen MF. Percutaneous trans-hepatic cholangioscopic lithotomy for hepatolithiasis: long-term results. Gastrointest Endosc. 1995;42:1–5. 151. Hwang MH, Yang JC, Lee SA. Choledochofiberoscopy in the postoperative management of intrahepatic stones. Am J Surg. 1980;139:860–864. 152 Li SQ, Liang LJ, Peng BG, et al. Hepaticojejunostomy for hepatolithiasis: a critical appraisal. World J Gastroenterol. 2006;12(26): 4170–4174. 153. Fan ST, Lai ECS, Wong J. Hepatic resection for hepatolithiasis. Arch Surg. 1993;128:1070–1074. 154. Akiyama T, Nagakawa T, Kayahara M, et al. Recurrence of intrahepatic stones after an end-to-side choledochojejunostomy. Surg Today. 1994;24:599–605. 155. Ker CG, Kuo KK, Tsai CC, Chen JS, Lee KT, Sheen PC. Evaluation of choledochojejunostomy with subcutaneous jejunostomy for treatment of intrahepatic stones. Int Surg. 1994;79:110–113. 156. Kusano T, Isa T, Muto Y, et al. Long-term results of hepaticojejunostomy for hepatolithiasis. Am Surg. 2001;67:442–446. 157. Tsunoda T, Tsuchiya R, Harada N, et al. Long-term results of surgical treatment for intrahepatic stones. Jpn J Surg. 1985;15: 455–462. 158. Jeng KS, Ohta I, Yang FS. Reappraisal of the systematic management of complicated hepatolithiasis with bilateral intrahepatic biliary strictures. Arch Surg. 1996;131:141–147. 159. Chen MF, Jan YY, Wang CS, et al. Role of hepatic resection in surgery for bilateral intrahepatic stones. Br J Surg. 1997;84: 1229–1232. 160. Kim KH, Sung CK, Park BG, et al. Clinical significance of intrahepatic biliary stricture in efficacy of hepatic resection for intrahepatic stones. J Hepatobiliary Pancreat Surg. 1998;5:303–308.

161. Uchiyama K, Kawai M, Ueno M, Ozawa S, Tani M, Yamaue H. Reducing residual and recurrent stones by hepatectomy for hepatolithiasis. J Gastrointest Surg. 2007;11:626–630. 162. Yang T, Lau WY, Lai ECH, et al. Hepatectomy for bilateral primary hepatolithiasis: a cohort study. Ann Surg. 2010;251(1): 84–90. 163. Shah OJ, Robbani I, Shah P, et al. Left-sided hepatic resection for hepatolithiasis: a longitudinal study of 110 patients. HPB (Oxford). 2012;14:764–771. 164. Li EL, Yuan RF, Liao WJ, et al. Intrahepatic duct exploration lithotomy is a useful adjunctive hepatectomy method for bilateral primary hepatolithiasis: an eight-year experience at a single centre. BMC Surg. 2019;19:16. 165. Herman P, Perini MV, Pugliese V, et al. Does bilioenteric anastomosis impair results of liver resection in primary intrahepatic lithiasis? World J Gastroenterol. 2010;16:3423–3426. 166. Cai X, Wang Y, Yu H, Liang X, Peng S. Laparoscopic hepatectomy for hepatolithiasis: a feasibility and safety study in 29 patients. Surg Endosc. 2007;21:1074–1078. 167. Lai EC, Ngai TC, Yang GP, Li MK. Laparoscopic approach of surgical treatment for primary hepatolithiasis: a cohort study. Am J Surg. 2010;199(5):716–721. 168. Li H, Zheng J, Cai JY, et al. Laparoscopic VS open hepatectomy for hepatolithiasis: an updated systematic review and meta-analysis. World J Gastroenterol. 2017;23(43):7791–7806. 169. Zhou F, Shao JH, Zou SB, Huang MW, Yin XB, Yu X. Laparoscopic hepatectomy is associated with a higher incident frequency in hepatolithiasis patients. Surg Today. 2013;43:1371–1381. 170. Chen ZY, Yan L, Zeng Y, et al. Preliminary experience with indications for liver transplantation for hepatolithiasis. Transplant Proc. 2008;40(10):3517–3522. 171. Hirohashi K, Uenishi T, Kubo S, et al. Living-related liver transplantation in a patient with end-stage hepatolithiasis and a biliarybronchial fistula. Hepatogastroenterology. 2004;51:822–824. 172. Pan GD, Yan LN, Li B, et al. Liver transplantation for patients with hepatolithiasis. Hepatobiliary Pancreat Dis Int. 2005;4: 345–349. 173. Strong RW, Chew SP, Wall DR, et al. Liver transplantation for hepatolithiasis. Asian J Surg. 2002;25(2):180–183.

PART 5  Biliary Tract Disease

SECTION I.  Inflammatory, Infective, and Congenital B. Biliary Stricture and Fistula

CHAPTER 40 Extrahepatic biliary atresia Alex G. Cuenca and Heung Bae Kim INTRODUCTION Extrahepatic biliary atresia or biliary atresia (BA) is an obstructive fibroinflammatory disease that presents in infancy. First described in a case series of 49 patients by John Thompson in 1892, this disease is characterized by a destructive inflammatory cholangiopathy that can affect both the intrahepatic and extrahepatic biliary tree. If left untreated, the disease is progressive and leads to death from complications of biliary cirrhosis by age 2 years in most cases (see Chapters 74 and 76). There are two therapies that are currently used and widely accepted for this condition: the Kasai hepatoportoenterostomy (HPE) and liver transplantation (see Chapters 105 and 110). Although there is still some controversy as to whether patients should proceed to transplant as the primary therapy, most centers, including ours, agree with performing the HPE first and as early as possible to allow for the possibility of biliary drainage and delay the need for transplant. BA affects approximately 1 in every 10,000 live births with higher incidences in Asian/Polynesian and black South African ethnicities. For example, the populations of Taiwan, Japan, and Hawaii have been shown to have 1.5 to 2 times the rate of BA compared with European countries.1 The reasons for this are unclear, but a study of Asians born in the United States (US) shows a higher prevalence of BA than the general US population, suggesting a strong genetic component to the disease.2 Several classification schemes have been proposed to describe the anatomic variants of BA, but the most widely used is the Japanese Association of Pediatric Surgeons classification, which groups BA into three main variants (Fig. 40.1).3 Type I, or the distal BA present in approximately 5% of cases, affects only the common bile duct (CBD) distal to the cystic duct, with the cystic duct and hepatic ducts remaining patent. In type II BA (approximately 5% of cases), the hepatic duct is obliterated but the proximal intrahepatic ducts are patent and frequently terminate in an extrahepatic cystic structure. Type II is further subdivided into IIa, in which the gallbladder and CBD are patent, and IIb, in which the gallbladder, CBD, and hepatic ducts are scarred and atretic. The most common variant of BA is type III or complete BA, present in greater than 90% of cases, in which the intrahepatic as well as extrahepatic ducts are completely obliterated. Although most patients have isolated BA, a minority (10%–20%) of patients with BA have a congenital or syndromic association with additional anatomic anomalies affecting the spleen, heart, hepatic anatomy and orientation, and intestinal rotation; this is known as BA 566

splenic malformation syndrome (BASM).1 In contrast to isolated BA, patients with BASM are more likely to be found in European populations.1 This is further supported by Japanese BA registry data, which found associated anomalies in only 2% of their patients.4

ETIOLOGY Despite advances in medical and surgical care in the management of BA, its etiology remains a mystery. The association of multiple anatomic anomalies in addition to a significant poorly understood inflammatory component suggest a multifactorial origin to BA. This is further supported by the fact that animal models have failed to isolate a specific gene that leads to the BA phenotype. This section will outline our current progress and understanding of the etiology of the disease.

A Genetic Component BASM describes a distinct association of anatomic anomalies found in a minority of BA patients, including cardiovascular defects, situs inversus or heterotaxy, intestinal malrotation, polysplenia, preduodenal portal vein, and interrupted inferior vena cava with azygous continuation.1 Mutations in the developmental genes CFC1 and inversin, which have been associated with heterotaxy/ malrotation, have been speculated to be associated with BASM.5,6 However, CFC1, despite a higher association, was not found in all patients with BASM and although inversin mutations cause situs inversus as well as hyperbilirubinemia in mice, inversin was not found to be associated with these findings in BASM patients.7,8 Using a powerful tool that can determine the association of individual common genetic variants to a given disease, known as single nucleotide repeats (SNPs), genome-wide association studies (GWAS) have identified several genes associated with BA. For example, a Chinese study identified an SNP variant in the ADD3 gene, which led to lower expression levels of ADD3 and was associated with BA in the Han population of China.9 Another candidate identified through GWAS in China is glypican 1 or GPC1.9 This gene, when knocked out in a zebrafish animal model, leads to disorganized biliary tract/ductule formation.10 ADD3 SNPs have been examined in Caucasians, and although a different SNP of ADD3 was found to be correlative of BA in Caucasians, the data suggest that defects in ADD3 expression may have implications in the development of BA.11 Other SNPs that have been examined and are thought to be associated are ARF6 and EFEMP1.12 More definitive analyses

B. Biliary Stricture and Fistula  Chapter 40  Extrahepatic Biliary Atresia

567

genes that are important for bile duct/system development, bile acid transport, vasculogenesis, left-right axis/development, and organogenesis. Although still unclear, efforts to elucidate the role of these genes in the biology of BA continues with the goal of targeted therapy for BA patients.

Infection and Inflammation in Biliary Atresia

I

IIa

IIb

III

FIGURE 40.1  Classification and anatomy of biliary atresia. Type 1: Obliteration of common bile duct. Type IIa: Atresia of common hepatic duct with cystic dilations of the proximal intrahepatic ducts. Type IIb: Atresia of the gallbladder, cystic duct, and common hepatic ducts. Type III: Obliteration of the entire intrahepatic and extrahepatic biliary trees.

TABLE 40.1  Genes Associated With the Development of Biliary Atresia and Their Cellular Function GENE

FUNCTION

ADD3 (Aducin) GPC1 (Glypican-1) ARF6 (adenosine diphosphateribosylation-6) EFEMP1 (extracellular matrix protein 1) JAG1 (Jagged 1)

Regulation of cell-cell contact Signaling/developmental pathways Bile duct development (?)

CFTR (Cystic fibrosis transmembrane conductance receptor) ZIC3 (Zic family member 3) INVS (Inversin) VEGF (Vascular endothelial growth factor) FXR (Farnesoid X receptor) CFC1 (Cryptic)

Bile duct development (?) Cell-cell signaling, associated with Allagile’s syndrome Ion transport Zinc finger protein Left-right axis development Growth factor Bile acid receptor Growth factor, associated with heterotaxy

SOX17

of these SNP variants in other populations have not been done but are underway. Other developmental genes that have been investigated and implicated in clinical investigations or preclinical models in the development of BA are listed in Table 40.1. Although the exact mechanism in which they may contribute to the development of BA in patients is unknown, it has been inferred from their function and/or association with BA tissue samples. These are

Because no clear single genetic factor has been found in all BA patients, some investigators have suggested that infection may play a critical role in the etiology of BA, particularly given the well-known seasonal variation in the incidence of BA.13 It has been proposed that a virally induced bile duct injury could lead to a progressive fibroinflammatory and obliterative process that ultimately leads to the destruction of the biliary tree. Several viruses have been implicated in BA, such as cytomegalovirus (CMV), reovirus, and rotavirus. With a worldwide seroprevalence that ranges from 70% to 100% depending on the country, infection with CMV in most patients is typically benign, with most infections described as asymptomatic. The association of CMV with the development of BA varies widely depending on the study referenced.14–17 CMV infection has also been suggested to delay the resolution of jaundice in BA patients.18 However, results are inconclusive because these studies suffer from low numbers and associative nonmechanistic findings that make interpretation of the data difficult. Reovirus has also been implicated in BA development. This association is based on murine studies and the identification of reoviral particles in neonates with BA.17 Unlike CMV or other viruses, however, reoviral infections produce no identifiable symptomology in patients and no study has demonstrated a definite link between the two processes. Another virus that has been associated with the development of BA is rotavirus. Animal models using specific rotaviral strains appear to cause similar cholangiopathy to what is seen in humans and studies examining for the presence of rotavirus suggest an increase in viral titers or rotavirus antibody compared with controls.19 As with all of the viral studies previously described, however, the numbers of patients included within these studies is small and it is still unclear as to whether or not any of these viral infections lead to or exacerbate BA. Because inflammatory infiltrates are typically found throughout the liver of explants of patients with BA at the time of transplant, many have speculated that inappropriate innate/ adaptive immune responses or even an autoimmune component may be driving the progressive fibro-obliterative process in BA.20,21 In this setting, the innate immune response is responsible for the production of many inflammatory cytokines and chemokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6. This can be through the stimulation of pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs), which are present not only on innate immune effector cells but also on cholangiocytes. These PRRs are designed to respond to pathogens but can also be stimulated by damage-associated molecular patterns (DAMPs), which are intracellular “self” proteins that are released during cell death. Therefore it is possible that cholangiocyte cell death, through either infection or other processes, could set off an unchecked cyclical inflammatory response that could lead to the pathology we associate with BA. Pang et al. examined the serum of 124 BA patients pre-Kasai and found that 56.5% of these patients were positive for one or multiple autoantibodies compared with less than 5% in healthy controls.22 In addition, a study of T-cell receptors (TCR) in BA patients demonstrated that the TCR

568

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

repertoire was more limited and oligoclonal in nature, suggesting that these patients might be mounting an immunologic response to an autoantigen.23 Also, cholangiocytes from BA patients have also been found to express not only major histocompatibility complex (MHC) Class I but also MHC Class II, which is likely caused by the inflammatory milieu.24 This is important because this aberrant expression of MHC Class II on cholangiocytes could also be propagating an adaptive immune response in situ as well as systemically. Although the antigen that may be responsible for or contributing to this inflammatory response is unknown, another possibility is that BA may result from the activation of maternal resident T cells against a variety of paternal antigens resulting from maternofetal microchimerism. This suggestion comes from data in which infants with BA have been shown to have high numbers of maternally derived CD81 T cells within their livers.25 In support of this, longitudinal studies of living related liver transplant recipients with maternal grafts have demonstrated increased graft survival, decreased rejection, and more successful undergoing of intentional withdrawal of immunosuppression.26

hepatobiliary iminodiacetic acid (HIDA) scan is typically performed during the patient evaluation (see Chapter 18). Although the HIDA scan is highly sensitive for detecting excretion of bile from the liver, it is not very specific to the diagnosis of BA. However, a HIDA scan demonstrating excretion rules out BA. Magnetic resonance cholangiopancreatography (MRCP) has also been suggested as a possible tool in the diagnosis of BA because of the increased fidelity and visualization of the intra- and extrahepatic biliary tree. Studies from the late 1990s and early 2000s suggested a reported sensitivity and specificity of greater than 90%.28,29 Regardless of the imaging study, the vast majority of infants in whom the suspicion for BA is high will progress to the gold standard for diagnosis of intraoperative cholangiography with biopsy. Although some centers perform a liver biopsy before operative cholangiography, we generally do not because the pathologic findings in the liver of BA patients early in the disease are not pathognomonic and therefore cannot entirely rule out BA.

CLINICAL FEATURES DIAGNOSIS AND WORKUP

The preoperative management of a child with BA includes the correction of coagulopathy if present and the administration of broad-spectrum antibiotics with biliary coverage. Developed by Morio Kasai in 1959, the Roux-en-Y hepatoportoenterostomy (HPE) is the gold standard approach in the surgical management of BA. Although there has been some recent controversy over whether or not liver transplant should be offered as the primary operative treatment, most centers agree that HPE should be performed first to give each child the chance to have improved biliary drainage and to delay the progression to endstage liver failure requiring liver transplant. The entire operation may be performed through a small right upper quadrant incision approximately one fingerbreadth below the costal margin. Keeping the incision well below the costal margin will ensure that the same incision can be used in the future should liver transplantation be required. Incisions made too close to the costal margin may ultimately migrate to the lower ribs as the child grows. The gallbladder of BA patients is typically shrunken, contracted, or absent and is often partially intrahepatic below a cleft in the liver edge. Upon entry into the gallbladder for the introduction of a cholangiogram catheter, “white bile” is often encountered, which confirms the lack of continuity between the intrahepatic bile ducts and the gall bladder. Unless this is proven to result from isolated cystic duct obstruction, the presence of “white bile” is confirmatory for BA and some surgeons would not proceed with the cholangiogram. If normal golden bile is encountered, a cholangiogram should be performed via the gall bladder to further delineate the biliary anatomy. To perform the cholangiogram, a purse string suture is placed in the fundus of the gallbladder and a small catheter (3.5 French [F] feeding tube or angiocatheter) is placed within the lumen for the instillation of contrast. If it appears that contrast flows into the intrahepatic ducts and duodenum, BA is excluded. If the intrahepatic ducts, extrahepatic ducts, and/or the duodenum do not fill with contrast, surgical correction is typically required. The cholangiogram can be performed laparoscopically, but most centers perform an open procedure because of the high likelihood of proceeding to HPE.30 Once the decision has been made to proceed with HPE, the biliary tract is carefully dissected to the portal plate, which is typically at the bifurcation of both the portal vein and hepatic

The clinical presentation of infants with BA can be variable but usually includes jaundice lasting longer than the first 2 weeks of life, acholic stools, choluria, and hepatomegaly. If left untreated, all patients will progress to cirrhosis with the development of ascites, splenomegaly, and the stigmata of portal hypertension. Coagulopathy may also develop early in the course of disease, not from liver failure, but rather from poor fat-soluble bile acid absorption, malnutrition, and Vitamin K deficiency. This coagulopathy can be severe and lead to mortality from intracranial or gastrointestinal (GI) hemorrhage. Evaluation of an infant with suspected BA begins with standard laboratory testing including a liver function test (including g-glutamyl transpeptidase [GGT]), standard chemistries, prothrombin time (PT)/ international normalized ratio (INR), and complete blood counts (CBCs). Infants with BA typically have direct hyperbilirubinemia greater than 2 mg/dL and elevated alkaline phosphatase and GGT. Transaminases are typically mildly elevated, whereas chemistries and CBC are usually within normal limits. PT/INR elevation that cannot be corrected with Vitamin K administration is a late finding of decompensated cirrhosis. Numerous other conditions can cause conjugated hyperbilirubinemia in newborns, including neonatal infection with the TORCH pathogens (toxoplasma, other viruses, rubella, cytomegalovirus, and hepatitis), as well as metabolic disorders, cystic fibrosis, and alpha 1-antitrypsin deficiency, and should be considered during the evaluation as well. An abdominal ultrasound is typically performed to evaluate the liver parenchyma and vascular flow and the presence of a gallbladder or intra/extrahepatic bile ducts. In infants with BA, the gallbladder is typically shrunken or absent and intrahepatic ducts are typically not visualized. The presence of the “triangular cord sign” on ultrasound is highly suggestive of BA and when combined with some novel ultrasound modalities to identify liver fibrosis has been suggested to increase the diagnostic sensitivity of ultrasound to greater than 90%.27 However, although these new data are promising, these are small preliminary studies and more rigorous evaluations are required (see Chapter 13). Additional studies have also been suggested to be important in the evaluation of an infant with hyperbilirubinemia. The

SURGICAL MANAGEMENT Preoperative Care and Surgical Technique

B. Biliary Stricture and Fistula  Chapter 40  Extrahepatic Biliary Atresia

artery. The extrahepatic biliary tree is then excised, leaving a thin layer of fibrotic portal plate in place. It is at this interface that any remaining biliary ductules will be found. Care is taken to limit the use of cautery in this area because this may cause destruction of the remaining ductules. We often place dilute epinephrine–soaked gelfoam directly on the portal plate for hemostasis while a retrocolic Roux-en-Y limb of approximately 45 cm is created from the proximal jejunum. We typically anastomose the open end of the Roux-en-Y limb around the remnant portal plate with 6-0 PDS sutures placed into any appropriate surrounding tissue including portal vein adventitia posteriorly and liver capsule anteriorly. It is critical to avoid suturing any areas of the portal plate where bile flow is observed. Postoperative abdominal drainage is not necessary. Although the open approach is most commonly used to perform HPE, some groups have attempted a minimally invasive approach. Several studies, including larger meta-analyses, have found no difference in the clearance of jaundice between the laparoscopic and open approaches with short-term follow-up. However, longer-term outcomes of laparoscopic HPE have been shown to be inferior to the open procedure with respect to native liver survival in several studies and therefore the majority of centers have abandoned the laparoscopic approach to HPE.31,32 We and others have adapted a minimally invasive open approach to HPE to facilitate the future liver transplant that is required in the majority of these patients.33 This includes a smaller abdominal incision (approximately 3–4 cm), minimal dissection of the porta hepatis structures, and minimal to no dissection of the peritoneal/ diaphragmatic attachments to the liver. These modifications serve to minimize adhesions and preservation of dissection planes, resulting in fewer intraabdominal varices and a less hostile abdomen at the time of future liver transplantation. In addition, because the Roux-en-Y will also be used for biliary drainage at the time of transplant, it is our practice to perform a retrocolic Roux-en-Y and leave a significant amount of Roux limb above the colonic mesentery so that the Roux-en-Y does not have to be mobilized during the liver transplant. In our experience, these small modifications do not compromise the safety of the operation but do significantly reduce some of the technical challenges that may be encountered during a future liver transplant.

569

Although liver transplant is typically considered the definitive treatment in the algorithm for those with an unsuccessful HPE, some centers have advocated for a redo HPE in certain circumstances. In 2012 the Cincinnati group published their experience with redo HPE in a select group of patients that either had recurrent cholangitis or had sudden cessation of bile drainage.34 Although the differences were not statistically significant, they found that 39% that underwent HPE revision versus 22% of those that did not were alive with their native livers after 15 years.34 These findings have also been supported by additional studies suggesting an increase in survival of the native liver with redo HPE versus those with no revision.35,36 Despite this, the decision to perform a redo HPE is controversial. Given that additional surgery in these patients can increase adhesions, which become vascularized in the setting of portal hypertension and can increase operative times, blood loss, and mortality during liver transplant, most centers do not perform redo HPE.

POSTOPERATIVE OUTCOMES Although previously uniformly fatal within the first 2 years of life, outcomes in BA have improved substantially since the development of the HPE. After HPE, patients are followed for the production of pigmented stool, which is usually associated with successful biliary drainage and an associated decrease in serum bilirubin. This process can take up to 2 to 3 months after HPE, although improvements are usually noted within the first few weeks. Most centers cite initial success in approximately 60% of patients and a 5-year native liver survival ranging from 20% to 80% depending on the study4,37,38 (Table 40.2). Recently, several longitudinal studies of 20-year native liver survival have been published and range from approximately 20% to 50% depending on the country (see Table 40.2). Unfortunately, approximately half of patients in whom the HPE is initially successful will have continued inflammation, cholangitis, fibrosis, and eventual liver failure that may occur over months to years. In those patients in whom HPE was unsuccessful, end-stage liver disease will develop more rapidly and liver transplantation will be required within the first 2 years of life. In either case, liver transplantation is the only option and

TABLE 40.2  National Patient Outcomes and Native Liver Survival CLEARANCE OF NATIVE LIVER JAUNDICE (%) SURVIVAL (%) STUDY

YEAR COUNTRY

Nio et al. Schneider et al. Schreiber Wildhaber et al. Davenport et al. Leonhardt et al. Nio Chan et al. Parolini et al. Fanna et al.

2003 2006 2007 2008 2011 2011 2017 2019 2019 2019

ERA

Japan 1989 US 1997–2000 Canada 1985–1995 Switzerland 1994–2004 England and Wales 1999–2009 Germany 2001–2005 Japan 1989–2015 China 1993–2007 Italy 1975–1996 France 1986–2015

HPE, Hepatoportoenterostomy; NR, not reported. Table adapted from prior Blumgart chapter.

N

TIME TO CLEARANCE HPE (DAYS) OF JAUNDICE

108 104 349 48 443 137 3160 20 174 1428

.65 61 65 68 54 57 68 53 60 NR

NR 40 NR 40 55 NR 60 45 52 40

4 TO 5 YEARS 10 YEARS 20 YR. 30/40 YR. 62 56 36 37 46 20 NR 85 41 41

53 NR 26 33 40 NR NR 85 32 35

NR NR NR NR NR NR 49 NR 18 26

NR NR NR NR NR NR

15 22

570

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

referral to a pediatric transplant center for evaluation should be initiated. We and others have examined outcomes related to success or failure after HPE. In a study of 185 BA patients, Chung et al. found that repeated cholangitis was a significant risk factor for early and late (.3 years) failure after HPE.39 In our study of 81 BA patients that had undergone HPE, we identified two factors that seemed to be important predictors of failure and need for transplantation. These included total bilirubin greater than 2 mg/dL and albumin less than 3.5 g/dL at 3 months after HPE.40 This was further supported by a recent study published by Wang et al. in which they found that the high rates of jaundice clearance over the course of 4 weeks was protective and was directly proportional to native liver survival.37

POSTOPERATIVE COMPLICATIONS Although the development of HPE is an important bridge and temporizing measure to transplant, complications associated with the pathophysiology of BA and end-stage liver disease occur. These include cholangitis, portal hypertension, hepatopulmonary syndrome, and malignancy. A brief overview of these complications will be described next.

Cholangitis Continued inflammation, intermittent obstruction of bile flow, and reflux of intestinal contents likely contribute to cholangitis after HPE. This is the most common complication of HPE and affects approximately 50% of patients, usually within the first 2 years postoperatively.41 Patients will present with fevers, increasing liver function tests, elevated white blood cell count, and acholic stools. Not surprisingly, gram-negative bacteremia with Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa is also frequent.42 Most centers recommend postoperative oral or intravenous (IV) antibiotic prophylaxis, but evidence to support this is not strong. The only randomized control trial (RCT) to date found that postoperative antibiotics were protective (risk ratio [RR] 0.42–0.52), but the study population was very small (n 5 34).43 Some authors have advocated for redo HPE in this setting to ensure proper drainage through the Roux and prolong native liver survival; however, this remains controversial.34,44

Portal Hypertension Because of the persistence of liver injury and the progression of liver fibrosis in most patients after HPE, approximately 70% of BA infants will develop portal hypertension with esophageal varices (see Chapter 76). Although most are asymptomatic, up to 25% of these patients present with a variceal bleed within a year of HPE and half will have at least one variceal bleed over time.45 Many studies have developed predictive models in an attempt to identify patients that would be most at risk for variceal bleeding. These studies suggested that patients with thrombocytopenia (platelet count , 100 X 109/L), transient elastography, or Fibroscan value greater than 31.5 kPa and/or failure clear jaundice early after HPE were at higher risk.46–49 Although there is no consensus on the appropriate surveillance or variceal bleeding prophylaxis of children with portal hypertension, a recent survey of centers in France found that 75% of centers used endoscopy as primary prophylaxis and only 20% of centers use nonselective beta-blockers.50

The most serious sequela of portal hypertension is variceal bleeding, which can present as melena/hematemesis with or without hemodynamic instability. Treatment for variceal bleeding is fairly standard across centers and involves endoscopy with banding and/or sclerotherapy after resuscitation (see Chapters 80 and 81). Medical adjuncts such as octreotide, vasopressin, antibiotic prophylaxis, and/or proton pump inhibitors are often employed as well. In addition to these therapies, surgical shunts and transjugular intrahepatic portosystemic shunt (TIPS) procedures have been considered and will be discussed in more detail (see Chapter 85).

Pulmonary Vascular Complications In addition to the abdominal manifestations of portal hypertension previously described, patients with portal hypertension are prone to develop pulmonary complications such as hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPHTN; see Chapter 76). Although the pathophysiology of HPS is not completely understood, it is thought that intrapulmonary vessel dilation and increased pressure leads to the stimulation of angiogenesis and the development of intrapulmonary shunting and hypoxemia. This is typically diagnosed using contrast-bubble echocardiography, lung perfusion scans, and/or pulmonary arteriography. It has been estimated that the incidence of HPS in children with BA occurs in 3% to 20% of children with end-stage liver disease.51 Although cardiac catherization or pulmonary angiography may identify a treatable lesion or shunt, there is no definitive medical or surgical therapy for HPS except for liver transplantation. Portopulmonary hypertension (PoPHTN) related to cirrhosis occurs in a minority of patients and develops in response to pulmonary arterial vasoconstriction secondary to soluble mediators (e.g., endothelin-1), which are increased in the setting of end-stage liver disease. Although more common in adult patients, PoPHTN does occur in the pediatric population but usually in adolescents secondary to long-standing cirrhosis.51 Pulmonary vasodilators such as sildenafil and a fairly novel class of drugs designed to target the endothelin receptor antagonists are currently being used in these patients.51,52

Malignancy With significant liver inflammation and the development of fibrosis and cirrhosis in the native liver, there is thought to be a significant risk for malignant transformation. Hadzic et al. reported that 5 of 387 BA patients developed hepatocellular carcinoma (HCC) at a median age of 2.1 years.53 An earlier study by Esquivel et al., which examined the histology of 72 livers from pediatric patients that underwent liver transplantation, found that 9 had HCC or severe dysplasia.54 Two of these livers were from patients with BA and were found to have liver cell dysplasia in one and HCC in the other. Case reports of cholangiocarcinoma and hepatoblastoma have also been reported but are more rare than HCC.55,56

CONTROVERSIES IN THE MANAGEMENT OF BILIARY ATRESIA Postoperative Steroids Because of the persistent inflammatory response that exists after HPE in BA patients, steroids have been used postoperatively after HPE for over 3 decades. In addition to their antiinflammatory

B. Biliary Stricture and Fistula  Chapter 40  Extrahepatic Biliary Atresia

571

Review: Glucocorticosteroids for infants with biliary atresia following Kasai portoenterostomy Comparison: 2 Secondary outcomes Outcome: 2 All-cause mortality or liver transplantation at two years Study or subgroup

Glucocorticosteroid n/N

Placebo n/N

Bezerra 2014

29/70

Davenport 2007

13/34

Total (95% CI)

104

Risk ratio M-H, fixed, 95% CI

Weight

Risk ratio M-H, fixed, 95% CI

29/70

68.4%

1.00 [0.67, 1.48]

14/37

31.6%

1.01 [0.56, 1.83]

107

100.0%

1.00 [0.72, 1.39]

Total events: 42 (glucocorticosteroid), 43 (placebo) Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.98); I2 = 0.0% Test for overall effect: Z = 0.02 (P = 0.98) Test for subgroup differences: Not applicable 0.5 0.7 Favours gluco

1

1.5 2 Favours placebo

FIGURE 40.2  Forrest plot depicting efficacy of glucocorticoid on overall native liver survival. (Tyraskis A, Parsons C, Davenport M. Glucocorticosteroids for infants with biliary atresia following Kasai portoenterostomy. Cochrane Database Syst Rev. 2018;2018[5]).

response, steroids are thought to have choleretic properties. However, data supporting the use of steroids in the early or late postoperative setting are equivocal. Multiple studies have either demonstrated a trend towards significance or significant increases in the rate of jaundice clearance in those patients treated with steroids. However, the majority of studies fail to show any differences in long-term native liver or patient survival. A recent Cochrane review of glucocorticoids in BA identified two RCTs in which glucocorticoids were administered to BA patients after HPE.57 When the glucocorticoid-treated groups were compared with placebo/no intervention, there was no significant difference in all-cause mortality (Fig. 40.2), serious adverse events (defined as events leading to disability or death), clearance of jaundice, or liver transplantation at 2 years.57 Despite these findings, the majority of centers around the world except the US use high-dose steroids postoperatively.15

TIPS or Surgical Shunts BA patients with severe portal hypertension (portosystemic gradient [PSG] . 12 mm Hg) are at high risk for variceal hemorrhage. Although GI bleeding in children is typically managed through endoscopy, some centers have advocated for the use of TIPS in cases where further endoscopy has been deemed inadequate/futile or in diuretic refractory ascites (see Chapter 85). In one study of 34 pediatric patients with a median age of 12, TIPS was used in patients that had either a GI bleed, ascites, or splenomegaly with sequestration.58 Of these, BA was the etiology of liver disease in 5 patients. Technical success was defined as the decrease in PSG to less than 12 mm Hg or a decrease of the PSG by half in those with PSG less than 12 mm Hg. Of the BA patients, all had early technical success with good outcomes except one that had ongoing bleeding and was transplanted 3 days later. No details of the transplant were offered in the report. In another retrospective series of 59 patients, of whom 12 (20%) were BA patients, TIPS was successful in 94% of patients that presented with bleeding in preventing subsequent variceal bleeding.59 Interestingly, three of the four technical failures were in BA patients secondary to their hepatic venous anatomy, which included an interrupted inferior vena cava with azygous extension. In addition, one of the five deaths was as a

result of sepsis from puncture of the portal plate during TIPS placement that resulted in bowel perforation. These anatomic differences in the BA population versus other pediatric endstage liver failure patients must be considered when a TIPS procedure is being considered. Other groups have challenged the utility of TIPS and have advocated for the creation of surgical shunts to control bleeding or ascites or delay time to transplant (see Chapters 83 and 84). For example, Guerin et al. recently published a series of 38 patients with BA and significant variceal hemorrhage (Grade 2/3 varices with stigmata of bleeding) after HPE who underwent surgical shunt (SS) creation.60 Also included in the analysis were 7 BA patients that underwent a TIPS procedure for similar reasons. This study demonstrates that a SS may be used in place of TIPS or repeated endoscopy to delay time to transplant and stabilize a bleeding patient. Because of the sample size and short follow-up, it is difficult to draw other conclusions. The TIPS cohort in their study population had poor outcomes with four patients experiencing immediate technical failure, one mortality, and one with hepatic encephalopathy, suggesting that the SS may be better. However, because GI bleeding is a common complication of portal hypertension in BA patients, these interventions should be discussed in the event that endoscopy fails to control ongoing hemorrhage.

Liver Transplantation Despite our best efforts, most studies demonstrate that only 30% of native livers of BA patients that have undergone an HPE survive after 15 years and BA remains the most common reason for liver transplantation in the pediatric population4,38 (see Chapter 110). Although the factors that are associated with failure of the native liver and progression to transplant are still somewhat unclear, many studies have found that early clearance of bilirubin after HPE as well as age at HPE are critical for HPE success40,61 (Fig. 40.3). In support of this, our group has found that total bilirubin greater than 2 and albumin less than 3.5 at 3 months post-HPE were the most significant factors associated with progression to transplant or mortality.40 Given this poor long-term native liver survival, some centers have questioned the role of HPE in BA. A recent study by LeeVan et al. examining a California administrative database

572

PART 5  BILIARY TRACT DISEASE  Section I  Inflammatory, Infective, and Congenital

% A B 50

C D E F 10

20

Years

Age at surgery (days): A; –30, B; 31–60, C; 61–90, D; 91–120, E; 121–150, F; 151– FIGURE 40.3  Long-term native liver survival by age at hepatoportoenterostomy. (Nio M. Japanese biliary atresia registry. Pediatr Surg Int. 2017;33[12]:1319–1325.)

has suggested that BA patients should undergo liver transplant as a primary therapy, completely eliminating HPE as an option.62 This conclusion was based on their findings that BA patients undergoing primary liver transplant had significantly better outcomes compared with those patients who underwent HPE (after 2002) or those who underwent salvage liver transplant after HPE (hazard ratio [HR] 0.16–0.43). Although these data are thought provoking, there are several major limitations to the study. The majority of centers still recommend HPE as

the initial surgical therapy for most patients suspected to have BA because of the high potential benefit and low morbidity of the procedure as it is currently performed.63

CONCLUSIONS Infants diagnosed today with BA can expect to have an excellent long-term survival rate because of the surgical advances made over the past 50 years (Fig. 40.4). The HPE developed by Morio Kasai remains the gold standard for the initial treatment of these infants when diagnosed before the development of decompensated cirrhosis. Liver transplantation outcomes in children have improved dramatically and with the additional surgical options including living donation and split liver transplantation that have become commonplace, waitlist mortality among infants and children awaiting liver transplantation has become rare. Future advancements in the management of BA patients are likely to result from research to identify and/or modulate the genetic components and/or the inflammatory response, which continues to destroy the biliary system in these patients. Our hope is that these advances will ultimately convert BA from a surgical to a medical disease. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

Patient survival first liver transplant 100

Graft survival first liver transplant 100

Log-rank test; P-value = ↓EH (1971–2001)

Denmark 1.27 ↓EH>↓IH (1978–2002)

Finland 1.05

Germany Saarland 2 Hamburg 3 ↑EH=↑IH (1970–2006) Poland 0.7

France 1.3 ↑EH>↑IH ↓ ↓ (1976–2005) Puerto Rico 0.35

Hong Kong 2.25 Guangzhou 0.97 IH>EH

Spain 0.5

Italy 3.36 ↑EH>↑IH (1988–2005)

Incidence (per 100,000 people) Rare cancer: 6 cases

Israel 0.3

Singapore 1.45 IH>EH

Thailand North East 85 North 14.6 Central 14.4 ↑IH>↑EH ↓ (1998–2002) South 5.7 ↑IH>↑EH ↓ (1998–2002)

South Korea Gwangju 8.75 Daegu 7.25 Busan 7.1 ↑IH>↑EH (1999–2005)

Japan Osaka 3.5 Hiroshima 3.05 ↓EH>↑IH (1985–2005)

Austria 2.67 ↑EH>↑IH (1990–2009)

Switzerland 0.45 Costa Rica 0.3

China Shanghai 7.55 Qidong 7.45 IH>EH

Taiwan 4.7 IH>EH Vietnam 0.1 IH>EH

Philippines 1.2 IH>EH Australia 0.43

New Zealand 0.4

FIGURE 50.1  Graphic summarizing the worldwide incidence (cases per 100,000 population) of cholangiocarcinoma for the period 1971–2009. The green color identifies countries with lower incidence (,6 cases per 100,000 population, rare cancer) and the pink color identifies countries with higher incidence (.6 cases per 100,000 population). When available, incidence data from intrahepatic cholangiocarcinoma (IH) and extrahepatic cholangiocarcinoma (EH) and the temporal trend of incidence (h increasing trend; hg stable trend; g decreasing trend) is presented. (With permission under the Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/.)

are sudden development of jaundice, weight loss, marked biliary dilation proximal to a dominant stricture, a sudden rise in carbohydrate antigen 19-9 (CA 19-9), the presence of a hypovascular mass with late contrast enhancement on radiologic imaging, and cytologic evidence of dysplasia or malignancy obtained on brushings.23

Parasitic Infections Chronic infection with the liver flukes (Opisthorchis viverrini and Clinorchis sinensis) is the most common risk factor for developing cholangiocarcinoma in Southeast Asia24–26 (see Chapter 45). The mechanism of carcinogenesis is unclear. However, mechanical irritation, excreted metabolic products, and the actions of proinflammatory cytokines, particularly those that stimulate the release of nitric oxide from activated white cells, are all important.16,17,27 A further parasitic hepatic infestation is caused by the Trematodes Fasciola hepatica or Fasciola gigantica (see Chapters 45 and 71). These parasites are widely spread throughout Asia, Africa, the Americas, and Oceania. Fasciola species migrate into the liver from the duodenum and cause hepatic fibrosis.28 There is no evidence that fascioliasis increases the risk of cholangiocarcinoma per se, although the radiologic and fibrotic pathologic changes accompanying an infection can be difficult to distinguish from carcinoma.29,30

Hepatolithiasis Recurrent pyogenic cholangiohepatitis (previously known as oriental cholangiohepatitis) is characterized by recurrent episodes of ascending cholangitis, hepatolithiasis, biliary strictures,

and biliary dilation (see Chapters 39 and 44). The syndrome is present in one fifth of the population of Southeast Asia and up to 10% of these patients develop IHCC,31–34 possibly because of chronic bile stasis leading to chronic infection and inflammation with malignant transformation.16 Patients present with recurrent episodes of cholangitis and, on investigation, have significant hepatolithiasis and associated inflammatory biliary strictures.35 The mean interval between the treatment of hepatolithiasis and the development of cholangiocarcinoma is between 3 and 8 years,36 and patients remain at risk of developing IHCC following hepatectomy if affected parts of the liver remain.37 Infection with liver flukes may also occur concurrently in many patients, but recurrent pyogenic cholangitis is a separate condition and can develop in the absence of parasitic infection.38

Congenital Biliary Cystic Disease Untreated choledochal cysts and Caroli disease carry an increased risk of developing cholangiocarcinoma (see Chapter 46). The incidence of cholangiocarcinoma is estimated at between 10% and 20% if the cyst is not resected by a patient age of 20 years.39,40 Correspondingly, patients who have had their cysts resected have a very low incidence of cholangiocarcinoma,41 although subsequent development of cholangiocarcinoma has been recorded following cyst excision.42 The mechanism of malignant transformation is not understood but many patients with choledochal cysts have an abnormally high union of the pancreatic and bile ducts, suggesting that biliary stasis and chronic reflux of pancreatic secretions may contribute to the development of chronic inflammation of biliary epithelium. In

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

patients with pancreaticobiliary maljunction alone there is a 7% risk of cholangiocarcinoma.43

Hepatic Cirrhosis and Viral Infections The risk of developing IHCC is increased in patients with cirrhosis (10.7% versus 0.7% in the general population),44,45 and 1% of explanted cirrhotic livers will harbor a previously unsuspected IHCC46 (see Chapters 9B, 9C, 68, 74, and 89). An association between hepatitis C infection and IHCC was postulated in 1991.47 A case control study from Japan demonstrated that the risk of developing IHCC is 3.5% at 10 years in patients with hepatitis C–related cirrhosis.48 A separate large cohort study found a significant association between IHCC and hepatitis C after adjusting for potential confounders, including the presence of cirrhosis with a relative risk of 2.55 (95% confidence intervals 1.3–4.95).49 In these patients carcinogenesis may be due to a direct viral effect since biliary dysplasia is more commonly observed in explanted livers of patients transplanted for hepatitis C–related cirrhosis than in other conditions.50 IHCC is also more frequent in patients with chronic hepatitis B viral infection (11.5% versus 5.5% in the general population),51 although the relative risk (RR) is less than for hepatitis C infection (RR 1.8, 95% confidence interval 1.4–2.4).52 IHCC developing in the setting of hepatitis B infection is more likely to present with a mass-forming growth pattern, which carries a more favorable prognosis following resection.53 It has been suggested the increasing incidence of IHCC in the West is related to the increasing prevalence of chronic liver disease and chronic viral infection.8,54 Co-infection with both hepatitis B and Opisthorchis viverrini or Clinorchis sinensis is an important factor in the high incidence of IHCC observed in Asia.54 In addition there is evidence that nonalcoholic steatohepatitis is present in up to 20% of patients with IHCC, although this may reflect lifestyle rather than representing an etiologic factor.55 Diabetes and obesity have been associated with an increased risk of cholangiocarcinoma,56–58 although this association may be stronger for carcinoma of the gallbladder.17 Human immunodeficiency virus (HIV) does not cause cirrhosis, but cholangiocarcinomas have been found in up to 0.5% of patients infected with the virus compared with 0.1% in controls, suggesting that it too is associated with an increased risk of biliary carcinogenesis.59

Benign Biliary Tumors The development of biliary cystadenocarcinomas from biliary cystadenomas is rare and, in general, occurs if a cystadenocarcinoma is untreated for many years. Biliary cystadenomas without ovarian stromal tissue appear to be at higher risk of malignant change and patients present with cystadenocarcinomas in the 6th or 7th decades of life, whereas cystadenomas present at an earlier age.60 IHCCs have also been reported developing in patients with biliary papillomata,61,62 and three related pathologic precursor lesions are now recognized for IHCC—flat intraepithelial neoplasia (BillN), intraductal papillary mucinous neoplasm of the bile duct (IPNB; previously recognized as biliary papillomatosis), and intraductal tubulopapillary neoplasm (ITNB).63 All three lesions are often seen in the context chronic biliary inflammation.63 Progression of bile duct adenoma to IHCC has been reported, and Von Meyenberg complex has also been suggested as a possible premalignant lesion for IHCC due to the occasional association of Von Meyenberg complexes and IHCC.64

713

Chemical Agents Thorotrast (thorium dioxide) was used as a radiologic contrast agent between 1928 and 1950. It is an alpha emitter with a biologic half-life of 400 years. Thorotrast accumulates in reticuloendothelial cells in the liver and spleen, and increases the risk of cholangiocarcinoma by 300 times in comparison to the general population.65 It is now no longer in use, although the latency period of 16 to 45 years means that patients will occasionally still present having received this agent during childhood radiologic examinations.66 A number of other agents have been implicated in the development of cholangiocarcinoma. Associations have been shown for asbestos,67 vinyl chloride,68 nitrosamines,69 the antituberculosis agent isoniazid,70 and first-generation oral contraceptives.71

General Risk Factors Surgical biliary-enteric bypass and surgical sphincteroplasty increase the risk of developing cholangiocarcinoma.72 Tobacco smoking is a significant risk factor for the development of cholangiocarcinoma in patients with PSC,73 although the relationship is less marked in the general population.59 Finally, congenital hepatic fibrosis has also been associated with an increased risk of developing cholangiocarcinoma in later life.8

PATHOGENESIS IHCC develops within the hepatic biliary system in second-order and more proximal bile ducts (septal, interlobular bile ducts, and ductules).63 Hepatic bile ducts are lined with specialized cholangiocytes whose function centers around the modification of bile at the canalicular surface and detoxification of xenobiotics.74

Cell of Origin Within the liver the segmental and septal bile ducts are lined with cylindrical mucin-producing cholangiocytes. IHCC that develop from these cells form adenocarcinomas with significant mucus secretion.75 These tumors may invade along the biliary tree and morphologically form periductal infiltrating or large nodular mass-forming tumors. However, the interlobular bile ducts and ductules are lined with cuboidal cholangiocytes that do not secrete mucus. IHCCs developing from these cells are non–mucin-secreting adenocarcinomas and usually form mass lesions at the periphery of the liver.75 The ductules also contain hepatic progenitor stem cells, which can display varying degrees of hepatocyte or cholangiocytic differentiation. Cholangiolocellular carcinoma is considered to develop from these progenitor cells and also forms mass lesions at the periphery of the liver.75,76

Chromosomal Aberrations Recent investigations have defined chromosomal aberrations in patients with IHCC (see Chapter 9E). Deleted genomic areas were defined in 1p, 3p, and 4q, and the main areas of amplification were present in 1q, 7p, 7q, and 8q.77,78 Interestingly, these investigations suggest that hepatocellular carcinoma and IHCC may be closely related at a molecular level as they share chromosomal gains at 1q, 8q, and 17q, as well as chromosomal losses at 4q, 8p, and 17p (Fig. 50.2).79

Genomic and Epigenetic Alterations Two distinct genomic classes have been characterized in IHCC (see Chapter 9E): an inflammatory class with predominant

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

LX EG Rβ FR

100

125 150

75

0

10

5

12

3

0

50

50

4 3 R β 1 D BR 7A A YP C

8

0

75

NA T2

0

25 50 75

10

25

0

0

CAS

5

10

25

BTC

0

12

7

CCA

5

15

12 5 15 0

75

4

25

MS CC T1 OG R5 G1

M

17

50

GBC

0 50

CA

0

0

10

R

AL

75

0

175

75

150 125 100

25

50

5 17 0 15

6

5

25

KA CC

1 B1 GA F EG L8 I

ES

R1

714

25 50 75

25 0

P8

100 125

9

225 200

175 150

25 50

2

100

0

125

10

75

75

100

50

125

25

25

0

50

11

225

CR1 PTGS2 IL-6R

75

200

100 125

1

12

125 100

75 50

25 50 75

100 125

25 0

13

25 50 75

y

14

x

0

0

25

0

0

25

ERCC 2 APOE XRCC

50

25

0

9 MMP

TP53

DCC

0

A2 P1 1 CYYP1A 5 C TR SS P2 MM

50 75

50

75

25

25

50

25

25

0

NR

R2 ES AT A1

50

0

0

75 50

10

ML

0

50 75

25

0

17

18

50 75

19

10

20

16

0

50

10

15

21

25

22

10 25

75

12

1

50

0 50

0

5

25

0

50

VDR

0

H

FEN1 PGR

0

175 150

MY

CYP17

0

IL-1RN IL-1B MSH2 ABCG8 APOB

FIGURE 50.2  Circa plot of the gene variants and chromosomal locations associated with cholangiocarcinoma (CCA), as well as gallbladder cancer (GBC) and biliary tract cancer (BTC). (Reproduced from Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR. Biliary tract cancers: Epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol. 2016;5[5]:11. With permission.)

activation of inflammatory pathways (38% of IHCCs) and a proliferation class (62% IHCCs) with predominant activation of oncogenic signaling pathways, the latter correlating with a worse prognosis (Fig. 50.3).80 Within the inflammatory group of tumors STAT3 activation and overexpression of interleukin-6 (IL-6) is common. IL-6 stimulates cholangiocyte growth via activation of the MAPK pathway and epigenetic control of gene expression and apopotosis.81 In addition, inflammatory cytokines induce the expression of nitric oxide synthetase, which in turn enhances the expression of COX-2, a proliferative stimulus for cholangiocytes. Nitric oxide synthetase also increases tissue levels of nitric oxide, which promotes DNA damage and inhibits DNA repair mechanisms.82,83 Within the proliferative class of tumors there are widespread alterations in pathways related to DNA repair (TP53),84 the WNT-CTNNB1 pathway,85 tyrosine kinase signaling (KRAS, BRAF, SMAD4, and FGFR2),86,87 protein tyrosine phosphatase (PTPN3),88 epigenetic remodeling factors (IDH1, IDH2),86,87 chromatin-remodeling factors (histonelysine N-methyltransferase 2C),89 the SW1/SNF complex, and deregulated Notch signaling.90,91 Variations have also been

found in the genetic signaling for human telomerase reverse transcriptidase (TERT) in IHCC associated with chronic hepatitis.81

Growth and Tissue Factors The presence of numerous hormones (estrogens, secretin, gastric, cholecystokinin), bile acids, and growth factors (serotonin, dopamine, leptin, histamine, endothelin-1, opioids, and endocannabinoids)8 promote or retard proliferation and apoptosis in cholangiocytes, indicating that the development of a malignant phenotype is a complex, multistep process and confirming the clinical observation of significant biologic heterogeneity with IHCC. In addition, it has been suggested that specific cancerassociated fibroblasts, derived from activated hepatic stellate cells that form the characteristic desmoplastic stroma of IHCC, contribute to cholangiocyte proliferation, migration, and invasion.92,93 The extent of neovascularization has also emerged as an important determinant of IHCC prognosis, with patients having a high tumor microvessel density having a poorer outcome following resection than those with low microvessel density.94

Risk factors MMP-6

MMP-7

Inflammation

Cholestasis Wnt 7b

↑ cell migration

Wnt 10a

Liver flukes

IL-6

TNF-α

Fibroblasts

↑ growth Angiogenesis Metastasis

↑ proliferation ↑ differentiation Apoptosis

TGF-β

SOCS3 ↓ Negative feedback Prevents apoptosis

COX-2

β-catenin

GLUT1

N-cadherins

INOS PDGF-D Progranulin

miR-152 miR-370

↑ proliferation ↓ apoptosis ↑ migration

Granulins

MAP3K3

Twist

NO

miR-let-7a

COX-2

p44/42MAPK

Akt pathway

miR-214

p21 IncRNA uc.158

↑ survival ↑ proliferation ↑ migration

COX-2

Oxidative DNA damage

↑ growth Resists apoptosis miR-200b

p16

β-catenin TCF/LEF

AID

FXR

NFxB

Telomerase

Rassf1a

NF2

SUZ12 Bcl-2

↑ genetic mutations

↑ proliferation ↓ apoptosis

↑ cell survival

↓ tumour suppression

Cancer stem cell formation

Resists apoptosis

PTEN

miR-21

Tumorigenesis

CLOCK

miR-141

FIGURE 50.3  The molecular pathogenesis of cholangiocarcinoma. The majority of the risk factors cause chronic inflammation or cholestasis. Inflammatory mediators (IL-6 and TNF-a) activate a number of pathways, such as JK-STAT, p38 MAPK, and Akt, resulting in increased cell growth, survival, and proliferation. Macrophages secrete ligands that activate the Wnt/b-catenin pathway, leading to TCF/LEF-mediated gene transcription. Prolonged exposure to bile acids leads to up-regulation of COX-2 and Mcl-1 resulting in resistance to apotosis. Liver flukes can also cause activation of the Akt pathway and upregulation of iNOS, increasing cell survival and proliferation. A number of microRNAs are up- or down-regulated in cholangiocarcinoma. (Reproduced from Labib PL, Goodchild G, Pereira S. Molecular pathogenesis of cholangiocarcinoma. BMC Cancer. 2019;19:7. With permission under the Creative Commons Attribution 4.0 International License, http://creativecommons.org/ licenses/by/4.0/.)

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

↑ cell viability ↓ apoptosis

E-cadherins

p38 MAPK

miR-148a DNMT1

↑ growth ↓ apoptosis

Sodium iodide symporter

JAK STAT3

Mid-1

Akt pathway ERK1/2 pathway

miR-193b

Notch1

C-Met

IL6R

HGF

VEGFR

ErbB2

EGFR

S1PR2

GPBAR1

TNFR1/2

FZD

LRP5/6

Ov-GRN-1 VEGF

715

716

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

PATHOLOGIC SUBTYPES AND MODE OF SPREAD Macroscopic Appearance IHCCs are firm, white sclerotic tumors often with associated satellite lesions nearby (see Chapter 47). The Liver Study Group of Japan has subdivided IHCC into four categories95,96: 1. Mass-forming (MF) type consisting of a well-delineated, firm, nonencapsulated mass with no discernable connection to a bile duct. This is the most common subtype and accounts for 65% of all IHCCs. 2. Periductal infiltrating (PI; 6% of IHCC) type characterized by growth spreading along portal tracts with biliary stenoses and proximal biliary dilation. 3. Intraductal growth (IG; 4% of IHCC) type, usually a polypoid or papillary lesion growing within the lumen of large bile duct. 4. Mixed growth pattern which demonstrates features of several of the other growth patterns and accounts for 25% of IHCC. This morphologic classification does have prognostic implications with the MF type having a better 5-year survival than the PI type53 and lymph node metastases being rare in the IG type compared with the other histotypes.63 Intrahepatic metastases occur commonly with IHCC, usually on the basis of vascular invasion. Metastases to intraabdominal lymph nodes are present in up to 75% of cases at presentation,97 and up to two thirds of patients may have evidence of remote organ metastases, most commonly lung and bone, at presentation.9,97 Nozaki et al.98 showed that there were significant differences in lymphatic spread between left lobar and right lobar tumors. Patients with right lobar tumors always had lymph node metastases in the hepaticoduodenal ligament; in patients with left lobar tumors, 50% of the nodal metastases were found distant from the hepaticoduodenal ligament in the cardia and around the lesser curvature of the stomach. Furthermore, in these patients, no lymph node metastases were present in the hepatoduodenal ligament.

Microscopic Appearance Histologically, IHCCs are usually well-to-moderately differentiated adenocarcinomas with varying degrees of desmoplasia.63 Sempoux et al.100 proposed a detailed subclassification of IHCC (Box 50.1). Of these, the pathologic classification of unconventional IHCC is the subject of significant investigation. These tumors most commonly develop on a background of chronic

liver disease and cirrhosis and may mimic hepatocellular carcinoma in appearance63 (see Chapter 47). Immunohistochemistry examination demonstrates CK 7 and CK 19 (biliary subtype cytokeratin) expression. N-cadherin expression is increased in IHCC compared with extrahepatic cholangiocarcinomas. Hepatocyte markers (HepPar1 and arginase 1) are occasionally seen in IHCCs, and albumin mRNA in-situ hydridization is also useful in distinguishing IHCC from perihilar cholangiocarcinoma and metastatic adenocarcinoma from other primary malignancies.63

CLINICAL PRESENTATION IHCCs often present as asymptomatic hepatic masses incidentally detected on cross-sectional imaging examinations. In patients with symptoms, abdominal pain is the most common presentation.101,102 A significant proportion of patients may also report nonspecific constitutional symptoms such as weight loss, decreased energy, and diminished appetite.103 Jaundice may be present in centrally placed tumors that compress or invade the biliary confluence. Extensive replacement of hepatic parenchyma by tumor, portal vein compromise, intrabiliary tumor invasion, or mucobilia can also present with jaundice due to hepatic failure. An increase in serum liver enzymes, most commonly alkaline phosphatase (ALP) or gamma glutamyl transferase (GGT), without symptoms may also be the only presenting feature and prompt further investigations, including physical examination and cross-sectional imaging.

DIAGNOSIS AND EVALUATION Currently, resection is the only potentially curative therapy for IHCC, and evaluation of patients is focused on establishing the diagnosis of IHCC and ruling out metastatic adenocarcinoma from another primary tumor. Thorough evaluation should include a detailed history, physical examination, assessment of comorbid conditions, assessment of hepatic function, measurement of tumor markers, and radiologic imaging to assess the extent of disease. History and examination may reveal presenting symptoms and a liver mass, signs of jaundice, and occasionally metastatic disease. Liver function should be assessed with measurement of platelet count, serum levels of bilirubin, GGT, aspartate transaminase (AST), ALP, albumin, total protein, and prothrombin

BOX 50.1  Pathologic Classifications of IHCC World Health Organization Classification4 Adenocarcinoma Well differentiated Moderately differentiated Poorly differentiated

New Classification by Komuta et al.99 Mucin-IHCC (large bile duct type) Mixed-IHCC (small bile duct type) Cholangiocellular carcinoma

Rare Variants Adenosquamous Squamous Mucinous Signet-ring cell Clear cell Lymphoepithelial Sarcomatoid Others

Conventional IHCC Unconventional IHCC Trabecular subtype Hilar subtype Intraductal neoplasia of intrahepatic bile ducts Intraductal papillary neoplasm of the bile duct Intraductal tubulopapillary neoplasm of the bile duct IHCC with ductal plate malformation Cholangiocellular carcinoma

New Classification by Sempoux et al.100

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

time or international normalized ratio (INR). Any abnormality in hepatic function, particularly signs of underlying chronic liver disease, should be investigated in more detail. The diagnosis of IHCC is established with the typical finding of a hypovascular mass present on cross-sectional imaging104 (see Chapter 16). Gastrointestinal metastases are excluded by performing upper and lower gastrointestinal endoscopies without the finding of a primary tumor. The absence of other primary malignancies (e.g., pancreas, kidney, lung, breast) on cross-sectional imaging of the chest, abdomen, and pelvis is mandated. Routine tumor biopsy is not recommended in patients with resectable tumors because of the small risk of tumor dissemination associated with biopsy.105 Biopsy is indicated only to establish the diagnosis in the presence of irresectable disease, which is present in over half of patients at their initial presentation.9 Irresectability is determined by local tumor factors such as involvement of the vascular supply or biliary drainage of the future liver remnant or the presence of metastatic disease. Staging laparoscopy is also useful in the evaluation of IHCC to exclude peritoneal disease, nodal disease, or abdominal wall invasion, particularly when these are suspected on preoperative imaging.106

SCREENING The Cholangiocarcinoma Screening and Care Program (CASCAP) was developed in Thailand and is functioning in Northern Thailand where there is a high incidence of cholangiocarcinoma. Patients 40 years of age or older with a history of liver fluke infection or having eaten uncooked freshwater fish are screened with hepatic ultrasound every 12 months, increasing to every 6 months for patients with periductal fibrosis, steatosis, or cirrhosis. Referral for computed tomography (CT) or magnetic resonance imaging (MRI) is made if a liver mass or biliary dilation is detected107 (see Chapter 16). This screened cohort includes 150,000 individuals living in high-risk areas. In addition, a further 25,000 surveillance patients will be added following treatment for cholangiocarcinoma.107

BIOMARKERS FOR CHOLANGIOCARCINOMA Serum Tumor Markers CA 19-9 and carcinoembryonic antigen (CEA) are the most widely used serum markers used in the diagnosis and monitoring of IHCC. For CA 19-9, a recent meta-analysis confirmed a sensitivity of 72% and specificity of 84% in distinguishing patients with cholangiocarcinoma and benign biliary disease.108 Similarly, the sensitivity and specificity of CEA for cholangiocarcinoma ranges between 42% to 85% and 70% to 89%, respectively.109,110 Consequently both these markers are a useful part of the workup and monitoring of patients with cholangiocarcinoma, but normal results are not necessarily diagnostic. Elevations in both serum CEA and CA 19-9 have been shown to be independent prognostic markers, but the cutoff values vary significantly between investigations.111 Other biomarkers investigated, but not yet in clinical practice, have included osteopontin,111 IL-6,111 matrix metalloproteinase 7,111–113 S110A6,101 DKK1,101,112 SSP411,107 KL-6 mucin,111,112 MUC5AC,112,113 hTERTmRNA,112,113 RCAS1,112 cytokeratin fragment 19,113 and C-reactive protein.113 Using multiple tumor markers, Lumachi et al.114 have used CEA, CA

717

19-9, cytokeratin-19 fragment, and matrix metalloproteinase-7, which collectively achieved a sensitivity of 92% and a specificity of 96% in diagnosing cholangiocarcinoma.Yoh et al.115 have also shown that elevations in CA 19-9, C-reactive protein, and the neutrophil-to-lymphocyte ratio are predictive of poor survival following treatment. Collectively this indicates that multiple diagnostic markers may be required to diagnose and monitor treatment outcomes in cholangiocarcinoma.

Bile Markers for Cholangiocarcinoma Bile markers of cholangiocarcinoma have been investigated for their use in the diagnosis of biliary obstruction and may have a significant role in the evaluation of extrahepatic biliary obstruction because they can be easily measured if bile is collected during endoscopic retrograde cholangiopancreatography (ERCP). These have included a variety of specific proteins, including WFAL1Cam, SSP411, and Mac-2BP,112 as well as micro-RNAs.116 It is uncommon for IHCC to present with biliary obstruction and their use in this tumor is, therefore, limited.

IMAGING IHCCs often present with vague and nonspecific symptoms.117 Accurate cross-sectional imaging is required to diagnose and stage the tumors as well as plan resection or other possible treatments. Most patients will be imaged with a number of modalities.

Transabdominal Ultrasound Ultrasound is often used as a screening examination by primary healthcare practitioners investigating patients with right upper quadrant pain, a palpable mass, or unexplained jaundice. IHCC has a nonspecific appearance with the mass-forming subtype appearing as a hypoechoic hepatic mass, whereas the periductal infiltrating type presents as a small mass-like lesion with diffuse periductal thickening and distal dilation118,119 (see Chapter 16). The intraductal subtype usually presents as diffuse segmental or lobar biliary dilation, and an intrabiliary polypoid mass may be visible.118 Satellite lesions may be seen as well as capsular retraction. The tumors are hypovascular and usually have minimal Doppler evidence of internal blood flow. Ultrasound is useful for defining associated biliary dilatation, portal venous invasion, hepatic venous invasion, and, rarely, portal lymphadenopathy.120 Contrast-enhanced ultrasound is useful in distinguishing between IHCC and hepatocellular carcinoma based on the presence of peripheral arterial enhancement commonly observed in IHCC.121

Computed Tomography Triple-phase CT scan is widely available and is the single most effective investigation in diagnosing and staging IHCC. Mass-forming tumors present as hypodense lesions with irregular, infiltrative margins and a variable degree of delayed enhancement in the portal venous phase (see Chapter 16). Progressive enhancement may be observed on delayed images (3–6 minutes following contrast injection) and is related to the amount of fibrous stroma present.122 In periductal infiltrating and intraductal IHCC, CT will detect biliary dilation and in the intraductal type may demonstrate an expanded bile duct containing a mass lesion.119 In all tumor subtypes CT scan will also demonstrate portal or hepatic venous involvement,123 and lobar atrophy due to longstanding biliary obstruction or

718

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

portal venous involvement.124 CT scan is also useful in detecting metastatic disease affecting regional lymph nodes, peritoneum, or lung fields.122 Data from newer multiphase, fast acquisition scanners can also be used to construct three-dimensional models of hepatic and tumor anatomy to facilitate resection,125 as well as accurate assessment of hepatic volumetry, particularly in relation to remnant volume and the risk of postoperative liver failure.126

Magnetic Resonance Imaging Mass-forming IHCCs appear as hypointense lesions on T1weighted images and mild to moderately hyperintensity on T2weighted images, depending on the content of desmoplastic stroma and mucin. There is also typically pooling of contrast within the lesions on delayed images (6–8 minutes after contrast injection).122 Periductal infiltrating tumors demonstrate diffuse periductal thickening with enhancement with biliary stricturing and proximal biliary dilation.119,122 However, differentiation of benign intrahepatic fibrous strictures from periductal tumors is challenging and relies on the presence of contrast enhancement within the stricture, and an irregular stricture margin, asymmetry, or the presence of an associated soft tissue mass.118,122 Most commonly the intraductal subtype is seen as dilated bile duct with a polypoid mass.118 MRI is also useful in defining venous and arterial involvement by tumor, and magnetic resonance cholangiography is useful in defining biliary anatomy to facilitate resection and reconstruction, if required (see Chapter 16).

Positron Emission Tomography Positron emission tomography (PET) scanning is now a commonly used modality for staging gastrointestinal malignancy, and the integration of PET and CT scans now provides the

opportunity to obtain anatomic and functional information in a single scan122 (see Chapter 18). IHCCs are present as glucose avid lesions within the liver; however, PET is most effective in detecting mass-forming tumors $1 cm in diameter but is less effective in assessing infiltrating periductal tumors.122,127 PET/ CT is also useful in tumor staging detecting intraabdominal lymph node metastases (sensitivity 42%, specificity 80%) and distant metastases (sensitivity 56%, specificity 88%).128 However, PET is limited by the finding of false-positive results in patients with biliary inflammation,129 and patients with mucinous tumors can present with false-negative scans.130

STAGING IHCCs are classified as primary cancers of the liver by the American Joint Committee on Cancer (AJCC), and Western hepatobiliary centers commonly use the AJCC systems to stage tumors. Before the 7th edition of the AJCC staging manual, a single staging system was applied to both hepatocellular carcinomas and IHCCs. The 8th edition of the AJCC staging manual131 presents a revised version (Table 50.1) of the dedicated IHCC staging system first presented in the 7th edition.132 This new staging incorporates tumor size of 5 cm to separate the T1 category into T1A and T1B because tumor size has been shown to be an independent prognostic factor and increasing size is associated with increasing tumor grade and the presence of microscopic vascular invasion.133,134 For T4 tumors the presence of periductal invasion has been removed because of a paucity of data on its prognostic significance.130 Three investigations135–137 have confirmed that the 8th edition staging system is effective in stratifying patients’ overall survival. Two other staging systems have been described (see Table 50.1) from the Liver Cancer Study Group of Japan138 and the National

TABLE 50.1  Staging Systems for IHCC AMERICAN JOINT COMMISSION ON CANCER, 8TH EDITION131

LIVER CANCER STUDY GROUP OF JAPAN138

NATIONAL CANCER CENTRE HOSPITAL OF JAPAN139

T1

Criteria • Tumor size #2 cm • Tumor number 5 1 • No portal vein, hepatic vein, or serosal invasion T1 All three criteria present

T1 Solitary tumor without vascular invasion

T2 two of three criteria present

T2 Solitary tumor with vascular invasion

T3 One of three criteria present

T3 Multiple tumors with or without vascular invasion

T1A: Solitary tumor #5 cm without vascular invasion T1B: Solitary tumor .5 cm without vascular invasion T2 Solitary tumor with vascular invasion or multiple tumors with or without vascular invasion T3 Tumor perforating the visceral peritoneum T4 Tumor involving extrahepatic structures by direct invasion N0 No regional lymph node metastases N1 Regional lymph node metastases M1 Distant metastases

T4 None of three criteria present N0 No regional lymph node metastases N1 Regional lymph node metastases M1 Distant metastases

N0 No regional lymph node metastases N1 Regional lymph node metastases M1 Distant metastases

STAGE GROUPING

STAGE GROUPING

STAGE GROUPING

IA IB II IIIA IIIB IV

I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 IVA T4 N0 M0, Any T N1, M0 IVB Any T, Any N, M1

I II IIIA IIIB IV

T1A N0 M0 T1B N0 M0 T2 N0 M0 T3 N0 M0 T4 and/or N1 M0 Any T, any N, M1

T1 N0 M0 T2 N0 M0 T3 N0 M0 Any T, N1, M0 Any T, Any N, M1

719

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

Cancer Centre of Japan.139 Although these systems are not in common usage in Western hepatobiliary centers, the AJCC staging manual does recommend collection of tumor growth patterns (mass-forming, periductal infiltrating, or mixed) based on the Liver Cancer Study Group of Japan classification.138

TREATMENT Patients with untreated IHCC have a median survival of less than 12 months.140,141 Resection of IHCC has been the only treatment associated with a significant disease-free survival and it remains the only potentially curative treatment modality. Orthotopic liver transplantation has now been studied in some detail, and the roles of neoadjuvant and adjuvant systemic and regional chemotherapy, immunotherapy, conformal radiation, intraarterial radiation therapy, and ablative therapies are under intense investigation and have led to the early development of multimodality treatment pathways for IHCC.142

Surgical Hepatic Resection Complete resection of IHCC is based on the surgical principles applied to resections for hepatocellular carcinoma and metastatic tumors (see Chapter 101). Staging laparoscopy can be used before resection to investigate areas of potential extrahepatic disease106 (see Chapter 24). Criteria for irresectability of IHCC are locally advanced solitary tumors involving either inflow or outflow bilaterally, multiple intrahepatic tumors, and distant metastatic disease.9 An R0 resection is the goal of surgical

therapy.133 Ideally, hepatic resection is undertaken with the aim of obtaining a clear margin of 1 cm or greater, while leaving a well-vascularized remnant with adequate venous and biliary drainage. However, tumor size and proximity to vascular structures often mandate a close margin. Resection of up to 80% of hepatic volume can be contemplated in patients with good liver function and 60% in patients with compromised liver function.143 However, often resections of this magnitude will need to be proceeded by portal vein embolization,126 or other interventions to optimize remnant volume.144 The results of contemporary series of IHCC treated with hepatic resection are summarized in Table 50.2.145–165 Although there is a role for minimally invasive surgical approaches (see Chapters 127D and 127E),166 all reported series emphasize the use of aggressive, open hepatic resection to achieve R0 margins including associating liver partition and portal vein ligation for staged hepatectomy (ALPP)144 and the use of re-resections in patients with localized recurrences.159 Recent experience confirms single-figure perioperative mortality, except when ALPP is employed (see Chapter 102D),164 and 5-year survival of approximately 40% (see Table 50.2). There is also a steady increase in utilization of adjuvant therapy following resection, particularly in patients with nodal metastases, multiple tumors, and vascular invasion.147,148,153,157,158 For patients undergoing resection survival is reduced in those with multiple tumor foci (median survival 15 months versus 38 months with solitary lesions).164 Raoof et al.161 have shown that multifocality, extrahepatic tumor extension, high tumor grade, lymph node positivity, and age greater than 60 years were independently associated with worse survival following resection. Using these factors,

TABLE 50.2  Summary of Contemporary Results for Surgical Resection of Intrahepatic Cholangiocarcinoma AUTHOR

YEAR

COUNTRY

Lanthaler et al.145 Saxena et al.146 Cho et al.147 De Jong et al.148 Ellis et al.149 Farges et al.150 Saiura et al.151 Sulpice et al.152 Dhanasekaran et al.153 Sriputtha et al.154 Luo et al.155 Murakami et al.156 Schiffman et al.157 Ali et al.158 Bergeat et al.159 Tabrizian et al.160 Raoof et al.161 Reames et al.162 Le Roy et al.163 Buettner et al.164 Schnitzbauer et al.165 Li et al.144

2010 2010 2010 2011 2011 2011 2011 2012 2013 2013 2014 2014 2014 2015 2015 2015 2017 2017 2018 2019 2020 2020

Austria Australia Korea USA/Europe USA France Japan France USA Thailand China Japan USA USA France USA USA USA/Europe France Multinational Germany Multinational

NR, Not reported; USA, United States of America.

NUMBER OF PATIENTS

PERIOPERATIVE MORTALITY

ADJUVANT THERAPY

25 40 63 449 31 212 44 87 53 73 1333 45 34 150 107 82 275 1087 82 1013 511 102

4% 2% 2% NR 6% NR 0 5% NR NR 0.6% 2% 6% NR 9.2% 1% 4.4% 4.8% 10% 4.4% 3% 21.2%

No No Yes Yes NR NR No NR Yes NR NR Yes Yes NR Yes NR NR NR Yes NR NR NR

SURVIVAL (%)

1 YR

3 YR

5 YR

84 79 68 78

57 48 50 44 40 44 56 47 33 23 25

45 29 32 31

77 87 79 82 52 58 68 84 80 60 80 80 80 70-95 64

40 49 24 46 51 45 55 40-70 52

28* 39 31 19 11 17 42 30 43 35 16 36 40 24 40 28-70 39

720

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

and assigning each a score of 1, these investigators developed the MEGNA prognostic score (minimum score: zero, no factors present; maximum score 5, five factors present), which Schnitzbauer et al.165 have confirmed correctly stratifies patient survival at 1, 3, and 5 years (see Table 50.2). A more recent study showed that genomic alterations in TP53, KRAS and/or CDKN2 predicted much worse outcome after resection or treatment with systemic chemotherapy.

The Status of Lymphadenectomy Lymph node metastases are present in between 30% and 40% of patients presenting with IHCC and are an important prognostic factor,132 although the role of routine lymph node dissection in the surgical treatment of patients with IHCC continues to be debated. Amini et al.167 have reported that over 75% of patients now undergo lymph node dissection in addition to resection. However, the current 8th edition of the AJCC staging system131 recommends resecting at least six lymph nodes for adequate staging, and a recent review demonstrates that only 25% of patients undergoing lymphadenectomy for IHCC have at least six lymph nodes present in the operative specimen.168 On the other hand, two recent publications showed that patients with N0 disease based on lymph node sampling/lymphadenectomy had a median survival that was no different than patients deemed N0 based on imaging and intraoperative assessment. The composition of lymph node dissection is also debated. There is agreement that portal nodes should be included, and Nozaki et al.98 have recommended routine dissection of cardia and lesser curvature nodes for left-sided tumors and dissection of the hepatoduodenal ligament for right-sided tumors. Because preoperative imaging is insensitive at detecting nodal metastases, routine lymphadenectomy has been advocated for all IHCCs168,169 to provide accurate staging information, to assist in selecting patients for adjuvant therapies, and to potentially decrease locoregional recurrence. Currently the European Society for Medical Oncology (ESMO) recommends routine lymphadenectomy within the hepatoduodenal ligament,170 the National Comprehensive Cancer Network (NCCN) considers lymphadenectomy reasonable,171 and the European Association for the Study of the Liver (EASL) states that lymphadenectomy should be strongly considered at the time of resection.172 This uncertainty has encouraged the development of preoperative tools to predict the presence of nodal metastases assisting in the application of therapeutic nodal dissection. Yoh et al.173 have shown that elevated CA 19-9 levels, IHCC with hilar invasion, and the presence of lymph nodes larger than 10 mm in short-axis diameter accurately predicted the presence of nodal metastases with a falsenegative rate of 2.3%.

Liver Transplantation Currently IHCC is a contraindication for liver transplant in most centers worldwide172,173 (see Chapter 105). Historically, outcomes for transplantation for IHCC were poor with the first report174 noting a median survival of 5 months and a 1-year survival of 14% in 18 patients treated with liver transplantation. Several studies confirmed these findings,175,176 although Cherqui et al.177 reported two long-term survivors and concluded that an intrahepatic tumor with no extrahepatic spread that cannot be resected for anatomic reasons may be a candidate for liver transplantation. Subsequently, Robles et al.178 reported a

5-year survival of 42% in 23 patients undergoing liver transplant, although in 10 patients the IHCC was discovered incidentally after transplant. Similarly, Sapisochin et al.179 reported a 47% 5-year survival in patients who underwent transplant for presumed hepatocellular carcinoma (HCC) but were found to have IHCC on explant pathology. Facciuto et al.180 compared patients with IHCC with matched patients with HCC. When patients were stratified by the Milan criteria,180 overall survival was equivalent for tumors within the criteria (78% IHCC versus 79% for HCC) and also for patients outside the criteria (48% IHCC versus 53% HCC). A multicenter study reviewed 48 patients with IHCC on explant pathology and found that 15 patients with tumors #2 cm in diameter (“very early” IHCC) had a 5-year actuarial survival of 65% compared with 45% in patients with “advanced” disease (single tumor .2 cm in diameter or multifocal disease).181 These findings indicate that patients with “very early” IHCC could be considered for transplantation.182 However, transplantation was undertaken either for a presumed diagnosis of HCC or hepatic decompensation in all of the reported patients found to have an IHCC in the explant. The outcomes of patients with known IHCC before transplant are yet to be fully investigated, and the role, if any, of pretransplant neoadjuvant chemotherapy or radiotherapy in IHCC is unknown.183

Tumor Ablation Tumor ablation refers to the destruction of tumors using thermal energy. Historically cryotherapy has been employed, but radiofrequency and microwave ablation are currently most commonly used. Ablation is performed under ultrasound guidance with the aim to ablate the index lesion and a 5- to 10-mm margin of uninvolved tissue. Usually, a single electrode is placed for small tumors (#3 cm in diameter) and larger lesions require the use of multiple or clustered applicators with multiple overlapping ablation zones. Multivariate analysis confirms that tumor diameter is a significant factor in determining the effectiveness of ablation and patient survival.184 In a metaanalysis of radiofrequency ablation for IHCC the rate of incomplete ablation following one treatment was 21% and the rate of major complication was 8%.185 The 1-, 3-, and 5-year survival rates were 82%, 47%, and 24%, respectively,185 although only 5% of patients with IHCC are treated with ablation therapy alone,186 due to the size and multiplicity of tumors at presentation. Consequently, in patients who cannot be considered for resection due to significant comorbidity but who have small, solitary IHCC, ablation therapy is a useful primary treatment. Similarly, Zhang et al.187 have shown that, in patients with solitary liver only recurrence, percutaneous ablation has an efficacy similar to repeat resection but is associated with a complication rate of 4% compared with a complication rate of 47% in patients undergoing repeat resection.

Chemotherapy IHCC has proven to be difficult to treat with chemotherapy. Much of the information on the effectiveness of chemotherapy for this tumor has been derived from phase 2 trials rather than phase 3 trials, and many of these trials have been carried out in groups of patients with all tumors arising from biliary epithelia and include patients with intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and even pancreatic cancer. However, the publication of Valle et al.188 established systemic gemcitabine and cisplatin as the standard

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

of care for treatment of biliary cancers. In addition, regional delivery of chemotherapy has been explored and recent investigations evaluating biologic agents have been driven by better understanding of the potential genetic and regulatory targets in IHCC.189

Regional Chemotherapy TRANSARTERIAL CHEMOEMBOLIZATION OR TRANSARTERIAL DRUGELUTING BEADS. Patients with unresectable liver disease without extrahepatic disease have been considered for treatment with transarterial chemoembolization (TACE; commonly with cisplatin, doxorubicin, and mitomycin C) or transarterial treatment with drug-eluting beads (DEB-TACE; doxorubicin, oxaliplatin, or irinotecan).190 A large multi-institutional study191 evaluated both treatments and found similar overall survivals in patients treated with TACE (13.4 months) and DEB-TACE (10.5 months). In a prospective study, Kiefer et al.192 have reported 62 patients treated with intraarterial doxorubicin, cisplatin, and mitomycin C with a median overall survival of 20 months. Survival was improved in those patients receiving concomitant systemic chemotherapy (overall survival 28 months). Combination therapy appears to be more effective than singleagent therapy,193 with large tumor size, tumor hypovascularity, and Child-Pugh class B being adverse prognostic factors.194 A survival benefit of up to 7 months over best supportive care can be expected.190 TACE (5-fluorouracil, epirubicin, and hydroxycamptothecin) has also been used as an adjuvant therapy following resection of IHCC. One investigation gave mixed results where adjuvant TACE was associated with an improved survival but a greater risk of intrahepatic recurrence.195 In a second study, 5-year recurrence rates were reduced in patients treated with TACE following an R0 resection and an improved overall 5-year survival noted (38% versus 30% in patients treated without TACE).196

Hepatic Artery Infusion Using an implanted, subcutaneous pump, patients with IHCC have been treated with continuous hepatic artery infusions of floxuridine (FUDR),197 5-fluorouracil and oxaliplatin,198 gemcitabine,199 epirubicin, and cisplatin.200 A number of investigations have also administered concurrent systemic chemotherapy.193,200,201 In an early report, Jarnagin et al.197 demonstrated an objective response rate of 47% and converted one initially unresectable patient to resection with intraarterial FUDR treatment. A recent investigation using FUDR combined with systemic gemcitabine and oxaliplatin confirmed a response rate of 46% with a 2-year overall survival of 53%,201 although 10% of patients developed significant complications (portal hypertension, gastroduodenal artery aneurysm, catheter displacement, and jaundice). Consequently, hepatic artery infusion chemotherapy remains an attractive concept to potentially downstage large, localized IHCC for subsequent resection, or to prevent intrahepatic tumor progression, and appears to be more effective than TACE or intraarterial radioembolization.202 Importantly, thorough pre-treatment staging must be undertaken to exclude extrahepatic disease, and patients with underlying cirrhosis cannot be treated because of the risk of liver-related complications.197

Systemic Chemotherapy NEOADJUVANT CHEMOTHERAPY. There are several case reports of the use of neoadjuvant systemic therapy, most commonly

721

with gemcitabine and platinum-based chemotherapy, in the literature.203 However, Le Roy et al.163 have published a comprehensive series using neoadjuvant systemic therapy in a group of patients with initially unresectable IHCC. Seventyfour patients were treated with neoadjuvant therapy, most commonly with gemcitabine and oxaliplatin, of whom 24% responded, 45% stabilized tumor growth, and 31% progressed. Overall, 53% (39 patients) of this cohort underwent resection (R0 resection in 31%) with 3- and 5-year overall survival rates of 45% and 24%, respectively. Only the presence of lymph node metastases was a significant adverse prognostic factor on multivariate analysis. Importantly, this investigation confirmed that neoadjuvant therapy is feasible for IHCC and outcomes can be achieved that are comparable to patients who are treated with upfront resection. However, the rate of major hepatectomy is higher and the R1 resection rates are twice those observed in patients able to undergo resection without neoadjuvant treatment. ADJUVANT CHEMOTHERAPY. Two retrospective investigations have evaluated adjuvant therapy (most commonly with gemcitabine and platinum) following resection of IHCC. Sur et al.204 reported that patients receiving adjuvant therapy were more likely to have lymph node metastases and positive resection margins, and in these patient groups administration of adjuvant therapy, both alone and in combination with radiation therapy, was associated with a significant improvement in survival. Miura et al.205 also demonstrated in a matched cohort study that administration of adjuvant chemotherapy was associated with improved survival in patients resected with positive margins and those with lymph node metastases. The phase III BILCAP trial, published in 2019,206 compared capecitabine with observation in patients with resected biliary tract cancer (of whom one fifth had a diagnosis of IHCC) and demonstrated a significant trend toward improved survival in a per-protocol analysis (median survival 51 months versus 36 months in the observation group). In contrast, the PRODIGE-12 study207 demonstrated no significant survival benefit for adjuvant gemcitabine and oxaliplatin. The results of the ACTICCA-1 trial comparing gemcitabine and cisplatin with capecitabine in patients with resected biliary cancers are awaited.208 Of the current guidelines the NCCN suggests that adjuvant chemotherapy may be an option for patients with either negative or positive surgical margins and lymph node metastases,171 whereas ESMO guidelines suggest that adjuvant therapy should be considered in all patients because of the high rate of recurrence following resection.170 In 2019 the American Society for Clinical Oncology suggested, in a clinical practice guideline, that patients with resected biliary tract cancer should be offered adjuvant capecitabine for 6 months on the basis of the BILCAP study,209 and this is supported by a recent meta-analyisis.210

Chemotherapy for Advanced Disease In 1996 Glimelius et al.211 reported that patients with advanced biliopancreatic tumors treated with chemotherapy had an improved quality of life and survival over those treated with best supportive care. Subsequently, eight further randomized trials of systemic therapy in advanced cholangiocarcinoma have been published (Table 50.3).212–219 The publications of Valle et al.188,214 established gemcitabine and cisplatin as the standard of care first-line treatment for advanced cholangiocarcinoma, and a further trial carried out in Japan confirmed this

722

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

TABLE 50.3  Summary of Randomized Clinical Trials of Chemotherapy in Advanced Cholangiocarcinoma AUTHOR Morizone Kang213 Valle214 Okusaka215 Valle188 Ducreux216 Rao217 Kornek218 Glimelius211

212

YEAR

INTERVENTION

2018 2012 2010 2010 2009 2005 2005 2004 1996

Gem vs Cis/Gem Gem vs Cis/Gem Cis/Gem vs Gem Cis/Gem vs Gem Cis/Gem vs Gem 5FU/FA/Cis vs HD5FU ECF vs FELV MMC/CAPE vs MM/Gem 5FU ± etoposide vs BSC

PATIENT NUMBER 354   96   86   84   86   58   54   51   90

ORR/DCR (%)

MEDIAN OS (MONTHS)

29.8 vs 32.4 / NA 23.8 vs 19.6 / 85.7 vs 71.7 27.8 vs 22.7 vs 58 19.5 vs 11.9 / 68.3 vs 50 27.8 vs 22.7 vs 58 18.5 vs 7.1 / 62.5 vs 53.1 19.2 vs 15 / 65.4 vs 60 65 vs 56 / 31 vs 20 8/46

15.1 vs 13.4 10.1 vs 9.9 11.7 vs 8.1 11.2 vs 7.7 NA 8 vs 5 9 vs 12 9.2 vs 6.7 6 vs 2.5

C, CAPE, Capecitabine; Cis, cisplatin; ECF, epirubicin/cisplatin/5-fluorouracil; FA, folinic acid; FELV, 5-fluorouracil, etoposide, folinic acid; Gem, gemcitabine; HD5FU, high-dose 5-fluorouracil; MMC, mitomycin; NA, not available; ORR/DCR, overall response rate/disease control rate; OS, overall survival. Redrawn from Adeva et al.219

finding.215 Treatment with both agents is associated with neutropenia in up to 25% of patients as well as fatigue in up to 20% of patients; however, up one quarter of patients demonstrate a response, and median survival in treated patients now approaches 12 months.188,215,216 Other agents have been assessed in nonrandomized trials. Three investigations have evaluated the use of oxaliplatin in addition to gemcitabine (GEMOX) and have confirmed response rates of between 22% and 50% and median overall survivals between 11 and 15 months, which are comparable to gemcitabine and cisplatin.220–223 Similarly, combination oxaliplatin with capecitabine has shown similar response rates to cisplatin and gemcitabine but a median survival of less than 12 months.224 FOLFOX (5-fluorouracil, folinic acid, and oxaliplatin) has also shown similar results to gemcitabine and cisplatin,225,226 and combination gemcitabine/capecitabine has shown a similar response rate of 25% to gemcitabine/cisplatin and has become established as a reasonable alternative first-line therapy in patients in whom cisplatin or oxaliplatin are not recommended.227,228 There are currently no randomized phase III trials of second-line chemotherapy in advanced biliary cancer and therefore no established second-line therapy.228 A retrospective analysis of patients receiving second-line therapy, most commonly fluoropyrimidine doublet therapy, following first-line gemcitabine and cisplatin demonstrated a 3.4% response rate and an overall survival of 7 months.229,230 Consistent predictors of a response to second-line therapy are good performance status, low CA 19-9 levels, and absence of distant metastatic disease.229,231

Targeted Biologic Treatments Contemporary genomic analysis of IHCC has highlighted the presence of common genetic mutations, specifically isocitrate dehydrogenase (IDH), KRAS, and TP53,189 demonstrating that increasing understanding of the genetic and metabolic aberrations observed in IHCC will facilitate targeted biologic therapy.232 In vitro, RNA synthesis inhibitors, microtubuletargeting agents, topoisomerase and pololike kinase 1 inhibitors, and mTOR pathway modulators exhibited the greatest efficacy.189 Early clinical use of the IDH inhibitor ivosidenib in IDH-mutated patients resulted in a 12-month progression-free

survival of 21%.233 A recent phase 2 study of pemigatinib showed promising results in patients with FGFR2 fusions or rearrangements, with objective response rate of 35.5%. Treatment with the BRAF inhibitors dabrafenib and trametinib was associated with a 42% response rate and median overall survival of 12 months in a cohort of cholangiocarcinoma patients pre-treated with at least two lines of chemotherapy.234 Other agents now under active investigation are MET inhibitors (tivantinib), AKT selective inhibitors (everolimus), TRK inhibitors (iarotrectinib), PD-1 inhibitors (pembrolizumab and nivolumab),219,232 and the fibroblast growth factor inhibitor (pemigatinib).235

Radiation Therapy Cholangiocarcinomas are radiosensitive tumors, although careful targeting and dosimetry are required to minimize radiationrelated damage to non–tumor-bearing liver and adjacent visceral structures. HEPATIC ARTERY RADIOEMBOLIZATION. Radioembolization using Yttrium-90 (90Y)–loaded microspheres administered via the hepatic artery has been used to treat unresectable IHCC,146,236,237 with acceptable adverse effects and median survival following the procedure of 15 to 22 months.237 In early series of patients treated with advanced unresectable disease up to 5% of patients also downstaged sufficiently to be considered for resection.236-238 Rayer et al.239 have reported on the neoadjuvant use of 90Y infusion when used in association with gemcitabine/ cisplatin chemotherapy. Of 45 patients in their series with unresectable IHCC, 8 patients with single IHCC in noncirrhotic livers were resected following downsizing in tumor volume of between one third and one half. The median disease-free survival was 19 months following resection, although there was a 25% perioperative mortality rate. EXTERNAL BEAM RADIATION THERAPY. Three investigations have assessed the efficacy of external beam radiation therapy in achieving local control of large, irresectable IHCC. Tao et al.240 achieved a local control rate of 78% with a treatment dose of 85 Gy, and Hong et al.241 demonstrated a local control rate of 94% for patients treated with a median dose of 58Gy. Smart et al.242 reported a 2-year local control rate of 84% for all

C. Malignant Tumors  Chapter 50  Intrahepatic Cholangiocarcinoma

patients (93% for patients with liver only disease). Overall, 11% of patients reported grade 3 or 4 toxicity—significantly less than reported for gemcitabine-cisplatin chemotherapy.188,214 In addition, radiation treatment was well tolerated in patients with reduced performance status who are not always able to manage systemic chemotherapy.229 External beam radiation therapy can be considered as a viable treatment modality in patients with large, unresectable IHCC with the aim of achieving local disease control.243

BEST SUPPORTIVE CARE Over half of patients presenting with IHCC may not be candidates for resection because of patient comorbidity or extent of disease and will be managed with best supportive care alone or in conjunction with other treatments.244 Important priorities for these patients are management of capsular-related pain, ascites, maintenance of adequate nutritional intake, and psychological support for patients and their family members.

723

SUMMARY IHCCs develop in intrahepatic biliary epithelium and constitute 10% of primary hepatic tumors. Although many are sporadic, conditions leading to chronic inflammation of biliary epithelium constitute significant risk factors for their development. For patients with liver only disease, R0 resection offers the chance of cure, which occurs in 30% to 40% of patients. The last 5 years has seen significant advances in the effectiveness of systemic and regional chemotherapy, as well as radiation and liver-directed therapies such as TACE and radioembolization. Combination gemcitabine/cisplatin is now standard of care for the neoadjuvant treatment and the treatment of advanced disease, and capecitabine is the preferred adjuvant agent. Trials of targeted biologic agents, driven by improved understanding of the molecular pathogenesis of IHCC, are ongoing. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

723.e1

REFERENCES 1. Steiner PE, Higginson J. Cholangiocellular carcinoma of the liver. Cancer. 1959;12:753-759. 2. Ariizumi SI, Yamamoto M. Intrahepatic cholangiocarcinoma and cholangiolocellular carcinoma in cirrhosis and chronic viral hepatitis. Surg Today. 2015;45:682-687. 3. Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment. Ann Surg. 1990;211:277-287. 4. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. 4th ed. WHO Classification of Tumours, IARC WHO Classification of Tumours, No 3; 2010. 5. Foster JH, Berman MM. Solid liver tumors. Major Probl Clin Surg. 1977;22:1-342. 6. Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA Oncol. 2015;1:505-527. 7. Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR. Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol. 2016;5(5):61. doi:10.21037/cco. 2016.10.09. 8. Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261-280. doi:10.1038/nrgastro.2016.51. 9. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma. Rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84-96. 10. American Cancer Society. What is Bile Duct Cancer? Availbale at: http://www.cancer.org/cancer/bileductcancer/detailedguide/bileduct-cancer-what-is-bile-duct-cancer. Accessed June 1, 2020. 11. Lowe RC, Afdhal NH, Anderson CD. Epidemiology, Pathogenesis and Classification of Cholangiocarcinoma. Available at: http:// www.uptodate.com/contents/epidemiology-pathogenesis-andclassification-of -cholangiocarcinoma. Accessed June 1, 2020. 12. Yanala U, Malhotra G, Chandrakanth A, Padussis J. Intrahepatic cholangiocarcinoma: rising burden and glaring disparities. Ann Surg Oncol. 2019;26:1979-1980. 13. Antwi SO, Mousa OY, Patel T. Racial, ethnic, and age disparities in incidence and survival of intrahepatic cholangiocarcinoma in the United States; 1995-2014. Ann Hepatol. 2018;17(4):604-614. 14. Uhlig J, Sellers CM, Cha C, et al. Intrahepatic cholangiocarcinoma: socioeconomic discrepancies, contemporary treatment approaches and survival trends from the National Cancer Database. Ann Surg Oncol. 2019;26:1993-2000. 15. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology. 2005;128:1655-1667. 16. Labib PL, Goodchild G, Pereira S. Molecular pathogenesis of cholangiocarcinoma. BMC Cancer. 2019;19:185. doi:10.1186/s12885019-5391-0. 17. Rustagi T, Dasanu CA. Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates. J Gastrointestinal Cancer. 2012;43:137-147. 18. Farrant JM, Hayllar KN, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710-1717. 19. Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol. 2009;50:158-164. 20. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332(14):924-933. 21. Rosen CB, Nagorney DM, Wiesner RH, Coffey Jr RJ, LaRusso NF. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg. 1991;213:21-25. 22. Ruzumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383(9935):1215-1229. 23. Harewood G. Endoscopic tissue diagnosis of cholangiocarcinoma. Curr Opin Gastroenterol. 2008;24:627-630. 24. Hasweel-Elkins MR, Mairiang E, Mairiang P, et al. Cross-sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high risk area in northeast Thailand. Int J Cancer. 2008;59:505-509. 25. Jang KT, Hong SM, Lee KT, et al. Intraductal papillary neoplasm of the bile duct associated with Clinorchis senesis infection. Virchows Arch. 2008;453:589-598.

26. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol. 2008;24:349-356. 27. Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med. 2007;4:1148-1155. 28. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg. 2002;89:962-970. 29. Marcos L, Terashima A, Gotuzzo E. Update on hepatobiliary flukes: fascioliasis, opisthorchiasis and clinorchiasis. Curr Opin Infect Dis. 2008;21:523-530. 30. Kim YH, Kang KJ, Kwon JH. Four cases of hepatic fascioliasis mimicking cholangiocarcinoma. Korean J Hepatol. 2005;11:169-175. 31. Lesurtel M, Regimbeau JM, Farges O, Colombat M, Sauvanet A, Belghiti J. Intrahepatic cholangiocarcinoma and hepatolithiasis: an unusual association in Western countries. Eur J Gastroenterol Hepatol. 2002;14:1025-1027. 32. Su CH, Shyr YM, Lui WY, P’Eng FK. Hepatolithiasis associated with cholangiocarcinoma. Br J Surg. 1997;84:969-973. 33. Kubo S, Kinoshita H, Hirohashi K, Hamba H. Hepatolithiasis associated with cholangiocarcinoma. World J Surg. 1995;19:637-641. 34. Chen MF, Jan YY, Wang CS, Jeng LB, Chen SC, Chen TJ. A reappraisal of cholangiocarcinoma in patients with hepatolithiasis. Cancer. 1993;71:2461-2465. 35. Chu K, Lo C, Liu C, Fan ST. Malignancy associated with hepatolithiasis. Hepatogastroenterology. 1997;44:352-357. 36. Liu ZY, Zhou YM, Shi LH, Yin ZF. Risk factors for intrahepatic cholangiocarcinoma in patients with hepatolithiasis: a case control study. Hepatobiliary Pancreat Dis Int. 2011;10(6):626-631. 37. Meng ZW, Han SH, Zhu JH, Zhou LY, Chen YL. Risk factors for cholangiocarcinoma after initial hepatectomy for intrahepatic stones. World J Surg. 2017;41:835-843. 38. Kim YT, Byun JS, Kim J, et al. Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis. Hepatogastroenterology. 2003;50:8-12. 39. Ohtsuka T, Inoue K, Ohuchida J, Nabae T. Carcinoma arising in a choledochocele. Endoscopy. 2001;33:614-619. 40. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg. 1994;220:644-652. 41. Hewitt PM, Krige JE, Bornman PC, Terblanche J. Choledochal cysts in adults. Br J Surg. 1995;82:382-385. 42. Goto N, Yasuda I, Uematsu T, et al. Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilatation. J Gastroenterol. 2001;36:856-862. 43. Funabiki T, Matsubara T, Miyakawa S, Ishihara S. Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy. Langenbecks Arch Surg. 2009;394:159-169. 44. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115-125. 45. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology. 1998;28:921-925. 46. Vallin M, Sturm N, Lamblin G, et al. Unrecognised intrahepatic cholangiocarcinoma: an analysis of 993 adult cirrhotic liver explants. Clin Transplant. 2013;27:403-409. 47. Nagaoka T, Ohkawa S, Ito Y, et al. A case of a minute cholangiocellular carcinoma which was found in the follow-up periods of liver cirrhosis and was indistinguishable from hepatocellular carcinoma on hepatic angiography. Nihon Shokakibyo Gakkai Zasshi. 1991; 88(6):1369–1374. 48. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer. 2000;88(11):2471-2477. 49. El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a populationbased study of U.S. veterans. Hepatology. 2009;49(1):116-123. 50. Torbenson M, Yeh MM, Abraham SC. Bile duct dysplasia in the setting of chronic hepatitis C and alcohol cirrhosis. Am J Surg Pathol. 2007;31(9):1410-1413. 51. Ariizumi S, Yamamoto M. Intrahepatic cholangiocarcinoma and cholangiocellular carcinoma in cirrhosis and chronic viral hepatitis. Surg Today. 2015;45:682-687. 52. Shin HR, Oh JK, Masuyer E, et al. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci. 2010; 101(3):579-585. 53. Wu ZF, Yang N, Li DY, Zhang HB, Yang GS. Characteristics of intrahepatic cholangiocarcinoma in patients with hepatitis B virus

723.e2 infection: clinicopathologic study of resected tumours. J Viral Hepat. 2013;20(5):306-310. 54. Doherty B, Nambudiri VE, Pamer WC. Update on the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep. 2017;19:2. doi:10.1007/s11894-017-0542-4. 55. Reddy SK, Hyder O, Marsh JW, et al. Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma. J Gastrointestinal Surg. 2013;17:748-755. 56. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol. 2007;5(10):1221-1228. 57. Malhi H, Gores GJ. Review article: the modern diagnosis and therapy of cholangiocarcinoma. Aliment Pharmacol Ther. 2006;23:1287-1296. 58. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol. 2005;23:4742-4754. 59. Shaib Y, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors for intrahepatic cholangiocarcinoma in the United States: a case control study. Gastroenterology. 2005;128:620-626. 60. Buetow PC, Buck JL, Pantongrag-Brown L, et al. Biliary cystadenoma and cystadenocarcinoma: clinical-imaging-pathologic correlation with emphasis on the importance of ovarian stroma. Radiology. 1995;196:805-810. 61. Cox H, Ma M, Bridges R, et al. Well differentiated intrahepatic cholangiocarcinoma in the setting of biliary papillomatosis: a case report and review of the literature. Can J Gastroenterol. 2005;19: 731-733. 62. Galluoglu MG, Ozden I, Poyanli A, Cevikbas U, Ariogul O. Intraductal growth-type mucin-producing peripheral cholangiocarcinoma associated with biliary papillomatosis. Ann Diagn Pathol. 2007;11:34-38. 63. Vijgen S, Terris B, Rubbia-Brandt L. Pathology of intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017;6(1):22-34. 64. Gibiino G, Fabbri C, Fagiuoli S, Ianiro G, Fornelli A, Cennamo V. Defining the biology of intrahepatic cholangiocarcinoma: molecular pathways and early detection of precursor lesions. Eur Rev Med Pharmacol Sci. 2017;21:730-741. 65. Lipshutz GS, Brennan TV, Warren RS. Thorotrast-induced liver neoplasia: a collective review. J Am Coll Surg. 2002;195:713-718. 66. Case records of the Massachusetts General Hospital. N Eng J Med. 1981;304:893-899. 67. Szendroi M, Nemeth L, Vajta G. Asbestos bodies in a bile duct cancer after occupational exposure. Environ Res. 1983;30:270-280. 68. Wong O, Whorton MD, Foliart DE, Ragland D. An industry-wide epidemiologic study of vinyl chloride workers. Am J Ind Med. 1991;20:317-334. 69. Mitacek EJ, Brunnemann KD, Hoffmann D, et al. Volatile nitrosamines and tobacco specific nitrosamines in the smoke of Thai cigarettes: a risk factor for lung cancer and a suspected risk factor for liver cancer. Carcinogenesis. 1999;20:133-137. 70. Lowenfels AB, Norman J. Isoniazid and bile duct cancer. JAMA. 1978;240:434-435. 71. Yen S, Hsieh CC, MacMahon B. Extrahepatic bile duct cancer and smoking, beverage consumption, past medical history and oral contraceptive use. Cancer. 1987;59:2112-2116. 72. Hakamada K, Sasaki M, Endoh M, Itoh T, Morita T, Konn M. Late development of bile duct cancer after sphincteroplasty: a ten- to twenty-two-year follow-up study. Surgery. 1997;121:488-492. 73. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis. Hepatology. 1998;27:311-316. 74. Alpini G, Prall RT, LaRusso NF. The pathobiology of biliary epithelia. In: Arias IM, Boyer JL, Chisari FV, et al, eds. The Liver: Biology and Pathobiology. 4th ed. Philadelphia: Williams & Wilkins; 2001:421-425. 75. Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol. 2010;2:419-427. 76. Komuta M, Govaere O, Vandecaveye V, et al. Histological diversity in cholangiocellular carcinoma reflects different chiolangiocyte phenotypes. Hepatology. 2012;55:1876-1888. 77. Dalmasso C, Carpentier W, Guettier C, et al. Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma. BMC Cancer. 2015;15:126.

78. Arnold A, Bahra M, Lenze D, et al. Genome wide DNA copy number analysis in cholangiocarcinoma using high resolution molecular inversion probe single nucleotide polymorphism assay. Exp Mol Pathol. 2015;99:344-353. 79. Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013;32:4861-4870. 80. Sia D, Hoshida Y, Villaneuva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013;144:829-840. 81. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promotor methylation and gene expression. Cancer Res. 2006;66: 1128-1133. 82. Jaiswal M, LaRusso NF, Shapiro RA, Billiar TR, Gores GJ. Nitric oxide–mediated inhibition of DNA repair potentiates oxidative DNA damage by cholangiocytes. Gastroenterology. 2001;120:190-199. 83. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and DNA repair in cholangiocarcinoma by a nitric oxide dependent mechanism. Cancer Res. 2000;60:184-190. 84. Jiao Y, Pawlik TM, Anders RA, et al. Exome-sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinoma. Nat Genet. 2013;45:1470-1473. 85. Boulter L, Guest RV, Kendall TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015;125:1269-1285. 86. Sia D, Losic B, Moeini A, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun. 2015;6:6087. 87. Zou S, Li J, Zhou H, et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun. 2014;4:5596. 88. Gao Q, Zhao YJ, Wang XY, et al. Inactivating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence. Gastroenterology. 2014;146: 1397-1407. 89. Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke associated cholangiocarcinoma. Nat Genet. 2012;44:690-693. 90. Chan-On W, Nairismagi ML, Ong CK, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45: 1474-1478. 91. Fujimoto A, Furuta M, Totoki Y, et al. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat Commun. 2015;6:6120. 92. Kim Y, Kim MO, Shin JS, et al. Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. Ann Surg Oncol. 2014;21:2684-2698. 93. Okabe H, Beppu T, Hayashi H, et al. Hepatic stellate cells may relate to the progression of intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2009;16:2555-2564. 94. Thelen A, Scholz A, Weichart W, et al. Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma. Am J Gastroenterol. 2010;105:1123-1132. 95. Sanada Y, Kawashita Y, Okada S, Azuma T, Matsuo S. Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma. World J Gastrointest Pathophysiol. 2014;5:188-199. 96. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg. 2003;10: 288-291. 97. Shirabe K, Shimada M, Harimoto N, et al. Intrahepatic cholangiocarcinoma: its mode of spreading and therapeutic modalities. Surgery. 2002;131(1 Pt 2):S159-S164. 98. Nozaki Y, Yamamoto M, Itai I, et al. Reconsideration of the lymph node metastases pattern (N factor) from intrahepatic cholangiocarcinoma using the International Union Against Cancer TNM staging system for primary liver cancer. Cancer. 1998;83:1923-1929. 99. Komuta M, Govaere O, Vandecaveye V, et al. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology. 2012;55:1876-1888. 100. Sempoux C, Jibara G, Ward SC, et al. Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis. 2011;31:49-60. 101. De Oliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 cases at a single institution. Ann Surg. 2007;245:755-762.

723.e3 102. Martin RC, Jarnagin WR. Peripheral intrahepatic cholangiocarcinoma: current management. Minerva Chir. 2003;58:469-478. 103. Weber SM, Jarnagin WR, Klimstra DS, DeMatteo RP, Fong Y, Blumgart LH. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg. 2001;193:384-391. 104. Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvise M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver Int. 2019;39(suppl 1):98-107. 105. Metcalfe MS, Bridgewater FHG, Mullin EF, Maddern GJ. Useless and dangerous—fine needle aspiration of hepatic colorectal metastases. BMJ. 2004;328:507-508. 106. D’Angelica M, Fong Y, Weber S, et al. The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg Oncol. 2003;10:183-189. 107. Khuntikeo N, Chamadol N, Yongvanit P, et al. Cohort profile: Cholangiocarcinoma screening and care program (CASCAP). BMC Cancer. 2015;15:459. 108. Liang B, Zhiong L, He Q, et al. Diagnostic accuracy of serum CA 19-9 in patients with cholangiocarcinoma: a systematic review. Med Sci Monit. 2015;21:3555-3563. 109. Li Y, Li DJ, Chen J, et al. Application of joint detection of AFP, CA 19-9, CA125 and CEA in identification and diagnosis of cholangiocarcinoma. Asian Pac J Cancer Prev. 2015;16(8):3451-3455. 110. Loosen SH, Roderburg C, Kauertz KL, et al. CEA but not CA 19-9 is an independent prognostic factor in patients undergoing resection of cholangiocarcinoma. Sci Rep. 2017;7(1):16975. 111. Macias RI, Kornek M, Rodrigues PM, et al. Diagnostic and prognostic biomarkers in cholangiocarcinoma. Liver Int. 2019;39 (suppl 1):108-122. 112. Haga H, Patel T. Molecular diagnosis of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2015;22;114-123. 113. Malaguarnera G, Paladina I, Giordano M, Malaguarnera M, Bertino G, Berretta M. Serum markers of intrahepatic cholangiocarcinoma. Dis Markers. 2013;34:219-228. 114. Lumachi F, Lo Re G, Tozzoli R, et al. Measurement of serum carcinoembryonic antigen, carbohydrate antigen 19-9, cytokeratin-19 fragment and matrix metalloproteinase-7 for detecting cholangiocarcinoma: a preliminary case-control study. Anticancer Res. 2014;34:6663-6667. 115. Yoh T, Seo S, Hatano E, et al. A novel biomarker-based preoperative prognostic grading system for predicting survival after surgery for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2017;24: 1351-1357. 116. Li L, Masica D, Ishida M, et al. Human bile contains microRNAladen extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology. 2014;60:896-907. 117. Bartella I, Dufour JF. Clinical diagnosis and staging of intrahepatic cholangiocarcinoma. J Gastrointestin Liver Dis. 2015;24(4): 481-489. 118. Weber S, Robero D, Reilly EM, Kokudo N, Miyasaki M, Pawlik TM. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB 2015;17:669-680. 119. Chung YE, Kim MJ, Park YN, et al. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics. 2009;29:683-700. 120. Hann LE, Greatrex KV, Bach AM, Fong Y, Blumgart LH. Cholangiocarcinoma at the hepatic hilus: sonographic findings. AJR. 1997;168:985-989. 121. Chen CD, Xu HX, Xie XY, et al. Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: differential diagnosis with contrast enhanced ultrasound. Eur J Radiol. 2010;20(3);743-753. 122. Ringe KI, Wacker F. Radiological diagnosis in cholangiocarcinoma: application of computed tomography, magnetic resonance imaging and positron emission tomography. Best Pract Res Clin Gastroenterol. 2015;29:253-265. 123. Asayama Y, Yoshimitsu K, Irie H, et al. Delayed-phase dynamic CT enhancement as a prognostic factor for mass-forming intrahepatic cholangiocarcinoma. Radiology. 2006;238:150-155. 124. Kim TK, Choi BI, Han JK, Jang HJ, Ch SG, Han MC. Peripheral cholangiocarcinoma of the liver: two-phase CT findings. Radiology. 1997;204:539-543. 125. Yeo CT, MacDonald A, Ungi T, et al. Utility of 3D reconstruction of 2D liver computed tomography/magnetic resonance images as a surgical planning tool for residents in liver resection surgery. J Surg Educ. 2018;75(3):792-797.

126. Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts posthepatectomy outcomes: toward zero liver-related mortality in patients with colorectal liver metastases and small future liver remnant. J Am Coll Surg. 2013;216(2):201-209. 127. Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg. 2004;8:90-97. 128. Srinivasa S, McEntee B, Koea JB. The role of PET scans in the management of cholangiocarcinoma and gallbladder cancer: a systematic review for surgeons. Int J Diagn Imaging. 2015;2:1–10. 129. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol. 2006;45:43-50. 130. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, et al. FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun. 2001;22:1277-1285. 131. Amin MB, American Joint Commission on Cancer, American Cancer Society. AJCC Cancer Staging Manual. 8th ed. American Joint Commission on Cancer, Springer; 2017:xvii,1024. 132. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. American Joint Commission on Cancer; 2009:201-209. 133. Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma. JAMA Surg. 2014;149(6):565-574. 134. Lee AJ, Chun YS. Intrahepatic cholangiocarcinoma: the AJCC/ UICC 8th edition updates. Chin Clin Oncol. 2018;7(5):52. doi:10.21037/cco.2018.07.03. 135. Kang SH, Hwang S, Lee YJ, et al. Prognostic comparison of the 7th and 8th editions of the American Joint Committee on Cancer staging system for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2018;25:240-248. 136. Kim Y, Moris DP, Zhang XF, et al. Evaluation of the 8th edition of the American Joint Commission on Cancer (AJCC) staging system for patients with intrahepatic cholangiocarcinoma: a surveillance, epidemiology and end results (SEER) analysis. J Surg Oncol. 2017;116:643-650. 137. Spolverato G, Bagante F, Weiss M, et al. Comparative performances of the 7th and 8th editions of the American Joint Committee on Cancer staging systems for intrahepatic cholangiocarcinoma. J Surg Oncol. 2017;115:696-703. 138. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg. 2003;10:288-291. 139. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer. 2001;92:2374-2383. 140. Chu KM, Fan ST. Intrahepatic cholangiocarcinoma in Hong Kong. J Hepatobiliary Pancreat Surg. 1999;6:149-153. 141. Kim HJ, Yun SS, Jung KH, Kwun WH, Choi JH. Intrahepatic cholangiocarcinoma in Korea. J Hepatobiliary Pancreat Surg. 1999;6:142-148. 142. Simo KA, Halpin LE, McBrier NM, et al. Multimodality treatment of intrahepatic cholangiocarcinoma: a review. J Surg Oncol. 2016;113:62-83. 143. Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nagino M. Portal vein embolization before extended hepatectomy for biliary cancer: current technique and review of 494 consecutive embolizations. Dig Surg. 2012;29:23-29. 144. Li J, Moustafa M, Limecker M, et al. ALPPS for locally advanced intrahepatic cholangiocarcinoma: did aggressive surgery lead to oncological benefit? An international multi-center study. Ann Surg Oncol. 2020;27(5):1372-1384. 145. Lanthaler M, Biebl M, Strasser S, et al. Surgical treatment of intrahepatic cholangiocarcinoma—a single center experience. Am Surg. 2010;76;411-417. 146. Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol. 2010;17:484-491. 147. Cho SY, Park SJ, Kim SH, et al. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol. 2010;17: 1823-1830.

723.e4 148. De Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29:3140-3145. 149. Ellis MC, Cassera MA, Veto JT, Orloff SL, Handen PD, Billingsley KG. Surgical treatment of intrahepatric cholangiocarcinoma: outcomes and predictive factors. HPB (Oxford). 2011;13:59-63. 150. Farges O, Fuks D, Bolesawski E, et al. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma by the AFC-IHCC-2009 study group. Cancer. 2011;117(10):2170-2177. 151. Saiura A, Yamamoto J, Kokudo N, et al. Intrahepatic cholangiocarcinoma: analysis of 44 consecutive cases including 5 cases with repeat resections. Am J Surg. 2011;201;203-208. 152. Sulpice L, Rayar M, Boucher E, Pracht M, Meunier B, Boudjema K. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg. 2012;99:1711-1717. 153. Dhanasekaran R, Hemming AW, Zendejas I, et al. Treatment outcomes and prognostic factors for intrahepatic cholangiocarcinoma. Oncol Rep. 2013;29:1259-1267. 154. Sriputtha S, Khuntikeo N, Promthet S, Kamsa-Ard S. Survival rate of intrahepatic cholangiocarcinoma patients after surgical treatment in Thailand. Asian Pac J Cancer Prev. 2013;14:1107-1110. 155. Luo X, Yuan L, Wang Y, Ge R, Sun Y, Wei G. Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study. J Gastrointest Surg. 2014;18:562-572. 156. Murakami S, Ajiki T, Okazaki T, et al. Factors affecting survival after resection of intrahepatic cholangiocarcinoma. Surg Today. 2014;44:1847-1854. 157. Schiffman SC, Nowaki MR, Spencer L, McMasters K, Scoggins CR, Martin RC. Molecular factors associated with recurrence and survival following hepatectomy in patients with intrahepatic cholangiocarcinoma: a guide to adjuvant clinical trials. J Surg Oncol. 2014;109:98-103. 158. Ali SM, Clark CJ, Mounajjed T, et al. Model to predict survival after surgical resection of intrahepatic cholangiocarcinoma: the Mayo Clinic experience. HPB. 2015;17(3):244-250. 159. Bergeat D, Sulpice L, Rayar M, et al. Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe. Surgery. 2015; 157:656-665. 160. Tabrizian P, Jibara G, Hechtman JF, et al. Outcomes following resection of intrahepatic cholangiocarcinoma. HPB. 2015;17: 344-351. 161. Raoof M, Dumitra S, Ituarte PG, et al. Development and validation of a prognostic score for intrahepatic cholangiocarcinoma. JAMA Surg. 2017;152(5):e170117. 162. Reames BN, Ejaz A, Koerkamp BG, et al. Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis. J Surg Oncol. 2017;116:133-139. 163. Le Roy B, Gelli M, Pittau G, Allerd MA, Pereira B, Serji B. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018;105:839-847. 164. Bartsch F, Paschold M, Baumgart J, Hoppe-Lotichius M, Heinrich H, Lang H. Surgical resection for recurrent intrahepatic cholangiocarcinoma. World J Surg. 2019;43:1105-1116. 165. Schnitzbauer AA, Eberhard J, Bartsch F, et al. The MEGNA Score and preoperative anemia are major prognostic factors after resection in the German Intrahepatic cholangiocarcinoma cohort. Ann Surg Oncol. 2020;27:1147-1155. 166. Shiraiwa DK, Carvalho PF, Maeda CT, Silva LC, Forones NM, Lopes-Filho GJ. The role of minimally invasive hepatectomy for hilar and intrahepatic cholangiocarcinoma: a systematic review of the literature. J Surg Oncol. 202;121(5):863-872. 167. Amini N, Ejaz A, Spolverato G, Maithel SK, Kim Y, Pawlik TM. Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Surg. 2014;18:2136-2148. 168. Pawlik TM. Routine lymphadenectomy should be recommended regardless of morphologic type of intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2019;26:2251-2252. 169. Zhang XF, Chakedis J, Bagante F, et al. Trends in the use of lymphadenectomy in surgery with curative intent for intrahepatic cholangiocarcinoma. Br J Surg. 2018;105:857-866.

170. Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T, Arnold D, ESMO Guidelines Committee. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and followup. Ann Oncol. 2016;27:v28-v37. 171. Benson AB III, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw. 2017;15:563-573. 172. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268-1289. 173. Yoh T, Hatano E, Seo S, et al. Preoperative criterion identifying a low-risk group for lymph node metastases in intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2018;25:299-307. 174. Pichlmayr R, Lamesch P, Weimann A, Tusch G, Ringe B. Surgical treatment of cholangiocellular carcinoma. World J Surg. 1995;19: 83-88. 175. Ismail T, Angrisani L, Gunson BK, et al. Primary hepatic malignancy: the role of liver transplantation. Br J Surg. 1990;77: 983-988. 176. O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Ann Surg. 1988;207: 373-376. 177. Cherqui D, Tantawi B, Alon R, et al. Intrahepatic cholangiocarcinoma. Results of aggressive surgical treatment. Arch Surg. 1995; 130:1073-1078. 178. Robles R, Figueras J, Turrion V, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg. 2004;239:265-271. 179. Sapisochin G, Fidelman N, Roberts JP, Yao FY. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl. 2011;17:934-942. 180. Facciuto ME, Singh MK, Lubezky N, et al. Tumors with intrahepatic bile duct differentiation in cirrhosis: implications on outcomes after liver transplantation. Transplantation. 2015;99: 151-157. 181. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-699. 182. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al, for the iCCA International Consortium. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting prospective assessment. Hepatology. 2016;64: 1178-1188. 183. Goldaracena N, Gorgen A, Sapisochin G. Current status of liver transplantation for cholangiocarcinoma. Liver Transpl. 2018;24: 294-303. 184. Kim JH, Won HJ, Shin YM, Kim KH, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. Am J Roentgenol. 2011;196:W205-W209. 185. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Vasc Interv Radiol. 2015;26:943-948. 186. Amini N, Ejaz A, Spolverato G, Kim Y, Herman JM, Pawlik TM. Temporal trends in liver-directed therapy of patients with intrahepatic cholangiocarcinoma in the United States: a populationbased analysis. J Surg Oncol. 2014;110:163-170. 187. Zhang SJ, Hu P, Wang N, et al. Thermal ablation versus hepatic resection for recurrent intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2013;20:3596-3602. 188. Valle JW, Wasan H, Johnson P, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicenter randomized phase II study—the UK ABC-01 study. Br J Cancer. 2009;101:621-627. 189. Nepal C, O’Rourke CJ, Oliveira DV, et al. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology. 2018;68(3):949-963. 190. Mondaca S, Yarmohammadi H, Kemeny N. Regional chemotherapy for biliary tract tumors and hepatocellular carcinoma. Surg Oncol Clin N Am. 2019;28:717-729. 191. Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol. 2013;20(12):3779-3786.

723.e5 192. Kiefer MV, Albert M, McNally M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, Ethiodol, and polyvinyl alcohol: a 2-center study. Cancer. 2011;117(7):1498-1505. 193. Gusani NJ, Balaa FK, Steel JL, et al. Treatment of unresectable cholangiocarcinoma with gemcitabine-based transcatheter arterial chemoembolization (TACE): a single institution experience. J Gastrointest Surg. 2008;12:129-137. 194. Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer. 2008;113:1614-1622. 195. Li T, Qin LX, Zhou J, et al. Staging, prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma after curative resection. Liver Int. 2014;34(6):953-960. 196. Li J, Wang Q, Lei Z, et al. Adjuvant transarterial chemoembolization following liver resection for intrahepatic cholangiocarcinoma based on survival risk stratification. Oncologist. 2015;20(6): 640-647. 197. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DEC-MRI as a biomarker of survival. Ann Oncol. 2009;20(9):1589-1595. 198. Massani M, Nistri C, Ruffolo C, et al. Intrahepatic chemotherapy for unresectable cholangiocarcinoma: review of the literature and personal experience. Updates Surg. 2015;67(4):389-400. 199. Inaba Y, Arai Y, Yamaura H, et al. Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol. 2011;34(1):58-62. 200. Mambrini A, Guglielmi A, Pacetti P, et al. Capecitabine plus hepatic intra-arterial epirubicin and cisplatin in unresectable biliary cancer: a phase II study. Anticancer Res. 2007;27(4C):3009-3013. 201. Cercek A, Boerner T, Tan BR, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2019;6(1):60-67. 202. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213-220. 203. Grendar J, Grendarova P, Sinha R, Dixon E. Neoadjuvant therapy for downstaging of locally advanced hilar cholangiocarcinoma: a systematic review. HPB (Oxford). 2014;16:297-303. 204. Sur M, In H, Sharpe SM, et al. Defining the benefit of adjuvant therapy following resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22:2209-2217. 205. Miura JT, Johnston FM, Tsai S, et al. Chemotherapy for surgically resected intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22(11):3716-3723. 206. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary cancer (BILCAP): a randomized, controlled, multicenter, phase 3 study. Lancet. 2019;20(5): 663-673. 207. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and oxaliplatin or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019;37(8):658-667. 208. https://gicancer.org.au/clinical-trial/acticca-1/. Accessed June 1, 2020. 209. Shroff R, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019;37:1015-1027. 210. Ma WJ, Jin YW, Wu ZR, Shi YJ, Li QS, Cheng NS. Meta-analysis of randomized clinical trials of adjuvant chemotherapy for resected bile duct cancers. HPB (Oxford). 2020;22(7):939-949. https://doi.org/10.1016/j.hpb.2020.02.001. 211. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7(6):593-600. 212. Morizane C, Okusaka T, Mizusawa J, et al. Randomized phase III study of gemcitabine plus S-1 combination therapy vs gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer: a Japan Clinical Oncology Group study (JCOG1113, FUGA-BT). J Clin Oncol. 2018. doi:10.1200/JCO.2018.36.4_ suppl.205.

213. Kang MJ, Lee JL, Kim TW, et al. Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract cancer. Acta Oncol (Madr). 2012;51(7): 860-866. 214. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362:1273-1281. 215. Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicenter study in Japan. Br J Cancer. 2010; 103(4):469-474. 216. Ducreux M, Van Cutsem EV, Van Laethen JL, et al. A randomized phase II trial of weekly high-dose-5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract cancer: results from the 40955 EORTC trial. Eur J Cancer. 2005; 92(9):398-403. 217. Rao S, Cunningham D, Hawkins RE, et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005;92(9):1650-1654. 218. Kornek GV, Schuell B, Laengle F, et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary cancer: a randomized phase II trial. Ann Oncol. 2004;15:478-483. 219. Adeva J, Sangro B, Salati M, et al. Medical treatment for cholangiocarcinoma. Liver Int. 2019;39(suppl 1):123-142. 220. Andre T, Reyes-Vidal JF. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br J Cancer. 2008;99(6):862-867. 221. Andre T, Tornigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004;15:1339-1343. 222. Harder J, Riecken B, Kummer O, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006;95:848-852. 223. Halim A, Ebrahim MA, Saleh Y. A phase II study of outpatient biweekly gemcitabine-oxaliplatin in advanced biliary tract cancer. Jpn J Clin Oncol. 2011;41:217-224. 224. Graham JS, Boyd K, Coxon FY, et al. A phase II study of capecitabine and oxaliplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gallbladder or biliary tract. BMC Res Notes. 2016;9:161. 225. Novarino AM, Satolli MA, Chiappino I, et al. FOLFOX-4 regimen or single agent gemcitabine as first-line chemotherapy in advanced biliary tract cancer. Am J Clin Oncol. 2013;36:466-471. 226. Lee S, Kim KH, Kim HJ, et al. Oxaliplatin, 5-FU and leucovorin (FOLFOX) in advanced biliary tract cancer. J Clin Oncol. 2011;29:4106. doi:10.1200/jco.2011.29.15_suppl.4106. 227. Iqbal S, Rankin C, Lenz HJ, et al. A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202. Cancer Chemother Pharmacol. 2011;68:1595-1602. 228. Jordan E, Abou-Alfa GK, Lowery MA. Systemic therapy for biliary cancers. Chin Clin Oncol. 2016;5(5):65-79. 229. Fornaro L, Vivaldi C, Cereda S, et al. Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data. J Exp Clin Cancer Res. 2015;34:156. doi:10.1186/s13046-015-0267-x. 230. Suzuki E, Ikeda M, Okusaka T, et al. A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol. 2013;171:1141-1146. 231. Brieau B, Dahan L, De Rycke Y, et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabineplatinum combination: a large multicenter study by the Association des Gastro-Enterologues Oncologues. Cancer. 2015;121: 3290-3297. 232. Dabney RS, Khalife M, Shahid K, Phan AT. Molecular pathways and targeted therapy in cholangiocarcinoma. Clin Adv Hematol Oncol. 2019;17(11):630-637. 233. Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: results from the cholangiocarcinoma dose escalation and expansion cohorts. J Clin Oncol. 2017;35(suppl 15):4015. doi:10.1200/JCO.2017.35.15_ suppl.4015.

723.e6 234. Wainberg ZA, Lassen UN, Elez E, et al. Efficacy and safety of dabrafenib and trametinib in patients with BRAF V600E-mutated biliary tract cancer: a cohort of the ROAR basket trial. ASCO GI. J Clin Oncol. 2019;37(suppl 4):187. doi:10.1200/JCO.2019.37.4_suppl.187. 235. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicenter, open label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. 236. Rafi S, Piduru SM, El-Rayes B, et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol. 2013;36:440-448. 237. Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using Yttrium-90 microspheres: results from a pilot study. Cancer. 2008;113:2119-2128. 238. Mouli S, Memon K, Baker T, et al. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol. 2013;24:1227-1234. 239. Rayer M, Sulpice L, Edeline J, et al. Intra-arterial Ytterium-90 radioembolization combined with systemic chemotherapy is a

promising method for downstaging unresectable huge intrahepatic cholangiocarcinoma to surgical treatment. Ann Surg Oncol. 2015;22:3102-3108. 240. Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34:219-226. 241. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34:460-468. 242. Smart AC, Goyal L, Petkovska N, et al. Hypofractionated radiation therapy for unresectable/locally recurrent intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2020;27:1122-1129. 243. Smart AC, Wo JY. ASO author reflections: high-dose radiation offers local control for inoperable intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2020;27:1130-1131. 244. McKinley SK, Chawla A, Ferrone CR. Inoperable biliary tract and primary liver tumors. Palliative treatment options. Surg Oncol Clin N Am. 2019;28:745-762.

CHAPTER 51A Extrahepatic biliary tumors Kevin C. Soares, Michael I. D’Angelica, and William R. Jarnagin

OVERVIEW Extrahepatic biliary tumors are rare. Patients classically present with painless jaundice secondary to biliary obstruction. Management of bile duct tumors is challenging and best approached with input from an experienced multidisciplinary team. This chapter focuses on the cause of most common of these tumors, cholangiocarcinoma. We describe its epidemiology, preoperative evaluation, management, surgical technique, and longterm outcomes.

EPIDEMIOLOGY AND RISK FACTORS Cholangiocarcinoma accounts for 3% of all digestive cancers and is classically divided into three subtypes: intrahepatic cholangiocarcinoma (ICC) (20% of all cholangiocarcinoma in the United States) (see Chapter 50) and extrahepatic cholangiocarcinoma (EHC), which includes both perihilar cholangiocarcinoma (HC) (50%–60%) and distal cholangiocarcinoma (DC) (20%–30%).1 Although derived from biliary epithelial cells, the subtypes of cholangiocarcinoma differ in epidemiology, prognosis, and treatment paradigms.2 The incidence of both ICC and EHC are increasing over time. The incidence of EHC increased 20% from 1973 to 2012, from 1.6 per 100,000 individuals in 1973 to 1975 to 2.3 per 100,000 in 2011 to 2012 (Fig. 51A.1).3 In the United States, there are approximately 2500 new cases of EHC annually. The incidence of EHC is evenly distributed between sexes.4 Rates among blacks and whites appear to be increasing in contrast to those of Hispanics and people of non-Hispanic ethnicity.3,4 Although most cases of EHC occur in older patients, approximately 20% of EHCs are diagnosed before the age of 60, with the largest rise in incidence seen in 18- to 44-year-olds.4 Several risk factors are associated with an increased incidence of cholangiocarcinoma; however, it must be noted that most cholangiocarcinoma cases in Western countries are sporadic, with no obvious risk factors. Conditions associated with cholangiocarcinoma include primary sclerosing cholangitis (PSC) (see Chapter 41), choledochal cysts (see Chapter 46), recurrent pyogenic cholangiohepatitis (see Chapter 44), hepatolithiasis (see Chapter 39), and biliary parasites (see Chapters 45 and 71). Commonalities across these risk factors include the likelihood of these conditions to cause cholestasis and chronic inflammation. Cholestatic liver diseases such as PSC, congenital hepatic fibrosis, Caroli disease, and choledochal cysts are well-recognized risk factors. Genetic disorders with an increased risk of EHC are rare and include Lynch syndrome and bile salt transporter protein gene defects5 (see Chapter 9E). More recently, metabolic conditions such as type 2 diabetes have been found to be associated with an increased risk of EHC. For example, in a meta-analysis, individuals with type 2 724

diabetes had an increased risk of cholangiocarcinoma (relative risk [RR], 1.60; 95% CI 1.38–1.87), EHC (RR, 1.63; 95% CI, 1.29–2.05) and ICC (RR, 1.97; 95% CI, 2.57–2.46).5 Nonalcoholic fatty liver disease, obesity, dyslipidemia, and hypertension are also associated with an increased risk of EHC.7,8 These conditions are increasing worldwide and, in part, may explain the rising incidence of EHC.

TUMOR LOCATION AND HISTOPATHOLOGY Extrahepatic cholangiocarcinoma can arise anywhere from firstorder bile ducts within the liver down to the ampulla of Vater. Perihilar cholangiocarcinoma (HC or Klatskin tumors) was first described in 1965 by Klatskin and comprises 50% of all cholangiocarcinomas.9 HC arises in the right or left hepatic duct or at the confluence of the right and left ducts, whereas DC arises in the common bile duct distal to the takeoff of the cystic duct (Fig. 51A.2). Any extrahepatic biliary strictures are highly suggestive of malignancy; however, histopathologic assessment with brushing or biopsy has limited sensitivity although are highly specific.1 Thus, in the absence of histologic findings indicating malignancy, preoperative differentiation between cholangiocarcinoma and benign strictures (also known as malignant masquerade) is difficult.10,11 Benign strictures may arise from autoimmune cholangiopathy, autoimmune pancreatitis, stone-related disease, or primary sclerosing cholangiopathy and should be treated accordingly when recognized (see Chapter 42). Adenocarcinoma is the dominant histologic group, comprising more than 75% of extrahepatic biliary tumors. Precancerous lesions include biliary intraepithelial neoplasia, intraductal papillary neoplasm of the biliary tract, intraductal tubular papillary neoplasm, and mucinous cystic neoplasm. Common immunohistochemical markers of EHC include mucin, MUC5AC, MUC6, S100P, SMAD4 loss, and BAP1.9 Adenocarcinomas are subdivided into three subtypes: sclerosing, nodular, and papillary (Figs. 51A.3 and 51A.4). Papillary tumors are seen in up to 25% of EHCs and are associated with improved survival compared with nodular sclerosing lesions (see Fig. 51A.4).12,13 Molecular profiling of cholangiocarcinoma is distinct, depending on the subtype. KRAS (55%) and TP53 (40%) mutations in HC are common.14,15 IDH, EPHA2, and BAP1 mutations and FGFR2 fusions are more common in ICC, whereas EHCs contain PRKACA and PRKACB fusions and mutations in ELF3, ERBB2, and ARID1B.9,16,17 In contrast to ICC, targetable mutations in extrahepatic cholangiocarcinoma are rare.

CLINICAL PRESENTATION Clinical presentation depends on tumor size and location. HC presents with jaundice in 90% of patients.18 Nonspecific symptoms such as abdominal pain, weight loss, nausea, and pruritus

725

2.0 1.8

ICC

ECC

1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 19 73 –1 97 19 5 76 –1 98 19 0 81 –1 98 19 5 86 –1 99 19 1 92 –1 99 19 5 96 –1 99 20 9 00 –2 00 20 5 06 –2 01 20 0 11 –2 01 2

Age-adjusted incidence rates/100,000

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

FIGURE 51A.1  Temporal trends in age-adjusted incidence rates of cholangiocarcinoma by anatomic location. ECC, Extrahepatic cholangiocarcinoma; ICC, intrahepatic cholangiocarcinoma (From Mukkamalla SKR, Naseri HM, Kim BY, et al. Trends in incidence and factors affecting survival of patients with cholangiocarcinoma in the United States. J Natl Compr Canc Netw. 2018;16[4]:370–376.)

FIGURE 51A.3  Gross appearance of sclerosing cholangiocarcinoma with thickening of the bile duct walls (arrows) and dilation of intrahepatic bile ducts (arrowheads). (From Lee WJ, Lim HK, Jang KM, et al. Radiologic spectrum of cholangiocarcinoma: emphasis on unusual manifestations and differential diagnoses. Radiographics. 2001;21[Spec No]:S97– S116, 2001.)

A FIGURE 51A.4  Gross appearance of a papillary-type cholangiocarcinoma within the right hepatic duct. Note the expansion of the duct lumen.

B FIGURE 51A.2  A, Contrast-enhanced computed tomography scan showing hilar bile duct tumor involving the right and left hepatic ducts (see Chapter 16). B, Gross appearance of a nodular-sclerosing tumor invading the hepatic parenchyma (arrowhead).

are also common.19 In general, tumors become clinically apparent as a result of jaundice and jaundice-related symptoms such as pruritus, acholic stools, choluria, or abnormal liver function tests. Cholangitis is rare at the time of initial presentation because of a lack of bactibilia in an uninstrumented biliary tree. Laboratory evaluations are consistent with biliary obstruction and includes elevated total bilirubin, direct bilirubin, alkaline phosphatase and gamma-glutamyl transferase. Tumor markers such as carbonic anhydrase 19-9 (CA19-9) and carcinoembryonic antigen (CEA) are elevated; however, the former is often markedly elevated in the setting of jaundice. The presentation of DC is similar to those of other periampullary tumors in which painless jaundice is classically described. HC presenting with jaundice can be indicative of a late finding in the disease course because early on, incomplete obstruction of the biliary tree or unilateral obstruction does not cause jaundice and may manifest with nearly normal liver function

726

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

tests. A common finding in these scenarios is an isolated elevation in alkaline phosphatase (even minimal changes) which ultimately leads to the diagnosis. Additionally, papillary hilar tumors may manifest with intermittent jaundice as a result of small fragments of tumor detaching from a friable papillary tumor of the right or left hepatic duct or a mobile main tumor causing a ball valve effect at the hepatic duct confluence. The level of bilirubin elevation may help determine the cause of obstruction. Significantly elevated bilirubin levels (.10 mg/dL) suggests malignant obstruction, whereas obstruction from choledocholithiasis is often associated with lower bilirubin levels typically ranging from 2 to 4 mg/dL, although there is significant overlap.20 Cholangitis at presentation in patients without a history of biliary manipulation is rare; however, the incidence of bactibilia is 100% after biliary instrumentation that compromises the sphincter of Oddi. Although common bile duct stones or gallstones may coexist with bile duct cancer, it is rare for choledocholithiasis to cause obstruction at the hepatic confluence in the absence of predisposing conditions such as PSC, choledochal cyst, or hepatolithiasis. A thorough and complete evaluation outlining the level of obstruction and nature of obstructing lesion is critical to avoid missing a diagnosis of carcinoma. The physical examination, other than the presence of jaundice, is generally unremarkable. Evidence of liver dysfunction, enlarged liver, and portal hypertension may be noted in cases of long-standing biliary obstruction and portal vein involvement. An enlarged gallbladder on examination prompts consideration of biliary obstruction distal to or involving the cystic duct. With proximal biliary obstruction the gallbladder is typically collapsed.

DIAGNOSTIC STUDIES (SEE CHAPTER 16) Patients are usually referred after undergoing initial evaluation Imaging for staging and assessing resectability should be performed before biliary decompression. Abdominal ultrasound is commonly performed as a first method of evaluation. Although noninvasive and cost effective, ultrasound findings are typically nonspecific and consist of biliary dilatation. The level of biliary obstruction is sometimes noted; however, ultrasound has low sensitivity in this regard.21 Duplex ultrasonography in experienced hands can accurately predict vascular involvement (Fig. 51A.5). Duplex ultrasound can be particularly useful for assessing portal venous invasion. In a series of 63 consecutive patients from Memorial Sloan Kettering Cancer Center (MSKCC), duplex US predicted portal vein involvement in 93% of cases, with a specificity of 99% and a positive predictive value of 97%.22 With the now more widespread availability of liver-specific multiphasic contrast enhanced imaging with CT and MRI/MRCP, ultrasound is less used in preoperative assessment; however, it can be a valuable adjunct when there is questionable vascular involvement. Preoperative imaging should be performed with multidetector multiphasic CT or MRI of the abdomen and pelvis. Contrast-enhanced cross-sectional imaging such as liver angiogram CT with chest and pelvis is a highly sensitive diagnostic modality to delineate the level of biliary obstruction, vascular involvement, relevant anatomy, hepatic lobar atrophy as well as assess for evidence of metastatic disease. Appropriate CT protocols consist of thin (1 mm) cuts in the arterial and portal venous phases of intravenous contrast. These can then be used to create

a

l m

p

v

FIGURE 51A.5  Transverse color Doppler ultrasound of the biliary confluence shows a papillary cholangiocarcinoma (m) extending into the right anterior (a) and posterior (p) sectoral ducts and the origin of the left duct (l). The adjacent portal vein (v) is not involved and has normal flow. (See Chapter 16.) (From Hann LE, Fong Y, Shriver CD, et al. Malignant hepatic hilar tumors: can ultrasonography be used as an alternative to angiography with CT arterial portography for determination of resectability? J Ultrasound Med. 15:37–45, 1996.)

high-quality three-dimensional images such as CT arteriography in a single session. The anatomy of the biliary tree, portal vein, and hepatic arteries, along with their relationship to the tumor, are specifically assessed (Fig. 51A.6). MRI with MRCP, including biliary tree reconstruction, has been increasingly utilized to evaluate biliary tree abnormalities. MRCP accurately depicts the level of biliary obstruction, biliary anatomy as well as obstructed or isolated ducts not always appreciated on percutaneous or endoscopic evaluations23 (Fig. 51A.7) Vascular involvement, lobar atrophy, and regional nodal and distant metastases are also assessed (Fig. 51A.8). MRCP has now replaced direct cholangiography in the initial assessment of biliary malignancy. Direct cholangiography with ERCP (see Chapters 20 and 30) and/or PTC (see Chapters 20, 31, 51B, and 52) should be used for therapeutic intervention. Specifically protocoled MRI with MRCP and contrast-enhanced CT have comparable outcomes in assessing tumor resectability.24 The role of PET/CT in EHC is limited (see Chapter 18). In a systematic review and meta-analysis of 2125 patients from 47 eligible studies exploring the diagnostic test accuracy of [18F] fluoro-2-deoxy-D-glucose (18FDG-PET) as a diagnostic tool for diagnosis of primary tumor, lymph node invasion, distant metastases, and relapsed disease, the sensitivity and specificity of 18FDG-PET for the diagnosis of primary tumor were 91.7% (95% CI, 89.8–93.2) and 51.3% (95% CI, 46.4-56.2), respectively. For lymph node involvement, sensitivity was 88.4% (95% CI, 82.6–92.8) and specificity was 69.1% (95% CI, 63.8–74.1). For distant metastases, sensitivity was 85.4% (95% CI, 79.5–90.2) and specificity was 89.7% (95% CI, 86.0–92.7). In identifying relapse after resection, sensitivity was 90.1% (95% CI, 84.4–94.3) and specificity was 83.5% (95% CI, 74.4–90.4).25 Routine use of PET/CT in the preoperative setting remains unproven although unstudied in prospective trials.

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

A

727

B

FIGURE 51A.6  A, Computed tomography images from a patient with hilar cholangiocarcinoma and jaundice. The right portal vein is invaded by tumor, and there is right-sided lobar atrophy with compensatory left hemiliver hypertrophy. B, Left portal vein is occluded, causing left lobar atrophy with crowding of dilated ducts (arrow). Note that there is no defined mass in either image. (See Chapter 16.)

A

B

FIGURE 51A.7  Coronal (A) and axial (B) magnetic resonance cholangiopancreatographic images of a patient with hilar cholangiocarcinoma. The tumor involves the right and the left hepatic ducts. The bile ducts in this study appear white. (See Chapter 16.)

PET/CT is best used as a problem-solving tool when there is an equivocal finding on cross-sectional imaging. Direct cholangiography via ERCP or PTC encompasses highly sensitive, invasive techniques which delineate the biliary tree, tumor or stricture location and extent of biliary disease. Moreover, these studies allow for biopsy to establish a diagnosis and biliary drainage can be performed when necessary (Fig. 51A.9). Both ERCP and PTC have a sensitivity and specificity of approximately 70% to 75% for obtaining a tissue diagnosis.26,27 However, a tissue diagnosis is not mandatory before proceeding with attempted resection for cholangiocarcinoma, and a negative biopsy sample in the setting of a high clinical suspicion for malignancy does not provide helpful data. Noninvasive imaging has replaced direct cholangiography for the staging of EHC, and direct cholangiography is limited to biliary decompression and tissue sampling.

Although most patients with hilar strictures and jaundice have cholangiocarcinoma, alternative diagnoses are possible in 10% to 15% of patients. The most common of these are gallbladder carcinoma, Mirizzi syndrome, and benign focal strictures, such as autoimmune cholangitis, lymphoplasmacytic sclerosing pancreatitis/cholangitis, granulomatous disease, and PSC. A thickened, irregular gallbladder wall with infiltration into segments IV and V of the liver, selective involvement of the right portal pedicle, and obstruction of the mid–bile duct with occlusion of the cystic duct on endoscopic cholangiography all suggest gallbladder carcinoma (Figs. 51A.10 and 51A.11). Distal bile duct tumors frequently are mistaken for adenocarcinoma of the pancreatic head, the most common periampullary malignancy (see Chapter 17). Cross-sectional imaging and direct cholangiography can provide valuable information regarding the level of obstruction and may show clearly that

728

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

T

T

PV

PV

A

B

FIGURE 51A.8  A, T1-weighted, gadolinium-enhanced magnetic resonance image of a patient with hilar cholangiocarcinoma. The bile ducts appear black. A hilar tumor is seen (T), apparently adherent to or encasing the right portal vein branch (PV; arrowhead). The tumor has occluded the right anterior sectoral branch of the portal vein, and the anterior sector appears atrophic (black lines) with crowded, dilated ducts. The arrow points to intrahepatic metastases. B, Magnetic resonance cholangiopancreatography cut through the same area of the liver. Similar findings are indicated in this image, in which the bile ducts appear white. (See Chapter 16.)

FIGURE 51A.10  Endoscopic retrograde cholangiopancreatography findings of a mid–common bile duct stricture are typically associated with carcinoma of the gallbladder or cystic duct. (See Chapters 20 and 30.)

FIGURE 51A.9  Endoscopic retrograde cholangiopancreatography– guided grasp biopsy of a distal bile duct tumor in a patient presenting with obstructive jaundice and requiring biliary drainage. Cross-sectional imaging had previously staged the patient with metastatic disease, and a tissue diagnosis was sought. (See Chapters 20 and 30.)

the obstruction is arising from the bile duct and does not involve the pancreatic duct. MRCP is noninvasive and evaluates for choledocholithiasis as well as visualizes the distal bile duct. ERCP is therapeutic for patients with choledocholithiasis and can clearly show the level of obstruction of the distal bile duct. A dilated extrahepatic bile duct terminating abruptly at its

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

FIGURE 51A.11  Endoscopic retrograde cholangiopancreatography from a patient with a benign stricture of the proximal bile duct. The smooth, tapered appearance (black arrow) is in contrast to the irregular stricture typical of a sclerosing tumor. Nonfilling of the cystic duct (white arrow) is an important finding, and in the appropriate setting, it should raise the suspicion of gallbladder carcinoma. In this patient, the chronic inflammatory process had involved the hepatic duct and cystic ducts. Most cases of benign strictures of the proximal bile duct spare the cystic duct. (See Chapters 20 and 30.)

distal aspect without a concomitantly dilated pancreatic duct suggests a distal bile duct carcinoma. Benign strictures such as inflammatory strictures, sclerosing cholangitis or immunoglobulin G4 (IgG4)-related cholangiopathy account for 10% to 15% of resected strictures10,28 (see Chapter 42). These can be difficult to differentiate from malignant strictures without resection. Biopsy approaches such as endoscopic brushings of the bile duct, endoscopic ultrasound–fine needle aspiration (EUS-FNA) and PTC endobiliary forceps biopsy have a high false-negative rate, and repeat attempts at biopsy can delay resection and increase procedure-related complications.29,30 In patients with a stricture of the bile duct and a clinical presentation consistent with cholangiocarcinoma, histologic confirmation of malignancy is generally unnecessary, unless nonoperative therapy is planned.31,32 Serum IgG4 levels can be helpful in diagnosing benign autoimmune strictures treatable with steroids.

PREOPERATIVE EVALUATION AND MANAGEMENT When extrahepatic cholangiocarcinoma is suspected, evaluation should focus on determining resectability, hepatic reserve

729

and overall performance status (see Chapters 51B and 52). Significant baseline comorbidities such as portal hypertension, cirrhosis, and poor performance status can preclude surgical resection. Patients with metastatic disease do not benefit from resection and should be offered palliative systemic chemotherapy. In unresectable or metastatic cases, biliary decompression in jaundiced patients and confirmation of the diagnosis with tissue sampling are warranted to move forward with palliative systemic chemotherapy. Resectability is determined by assessing four criteria: (1) extent of biliary tree involvement, (2) lobar atrophy, (3) vascular involvement, and (4) the presence of metastatic disease12,33 (Table 51A.1). High-quality cross-sectional imaging, ideally performed before biliary decompression, provides an assessment of potential portal vein and hepatic artery involvement and the extent of biliary involvement. Obstructed bile ducts appear dilated up to the level of the tumor. A dilated gallbladder on examination or cross-sectional imaging should alert the physician to the possibility of distal cholangiocarcinoma, pancreatic cancer, or gallbladder cancer rather than hilar cholangiocarcinoma. Portal vein involvement is suggested by a change in contour of the vein or occlusion. Assessment of hepatic atrophy is a critical component of assessing resectability because this may indicate extent of tumor involvement, which has implications in treatment decisions. Long-standing biliary obstruction may cause moderate atrophy, whereas concomitant ipsilateral portal venous compromise induces rapid and severe atrophy of the involved segments. Atrophy is noted on cross sectional imaging by a shrunken, hypoperfused liver with crowding of dilated bile ducts along with concomitant hypertrophy of the contralateral lobe (Fig. 51A.12). The right hepatic artery generally courses posterior to the common hepatic duct. Involvement of the right hepatic artery in left-sided biliary tumors requiring a left-sided liver resection precludes resection or requires arterial reconstruction in highly selected cases. Lymph node–positive disease has an adverse effect on long-term survival and significantly decreases the likelihood of cure; however, lymphadenopathy on cross-sectional imaging is neither sensitive nor specific for metastatic disease. Enlarged regional nodes on preoperative imaging are often reactive and nonneoplastic, particularly after biliary instrumentation; therefore surgical exploration can still be considered in these instances.

Pretreatment Biliary Drainage Identification of the level of biliary obstruction followed by selective and appropriately planned biliary drainage is a critical decision. Biliary decompression is necessary to start systemic therapies and address symptoms such as anorexia, weight loss, and pruritus. Patients with resectable tumors often require major

TABLE 51A.1  Criteria for Nonresectability in Hilar Cholangiocarcinoma PATIENT FACTORS

LOCAL TUMOR EXTENT

DISTANT TUMOR SPREAD

Patient medically unfit for major operation Cirrhosis with portal hypertension

Bilateral hepatic duct involvement up to secondary biliary radicals Encasement/occlusion of the main portal vein Encasement of portal vein branch with atrophy of contralateral hepatic lobe Hepatic duct involvement up to secondary biliary radicles with atrophy of contralateral hepatic lobe

Positive lymph nodes outside the hepatoduodenal ligament Metastases to liver, lung, peritoneum, or other distant organs

730

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

FIGURE 51A.12  Axial computed tomography demonstrates severe atrophy of the right anterior sector in a patient with a hilar cholangiocarcinoma that had invaded the respective sectoral portal vein selectively. (See Chapter 16.)

hepatectomy; therefore adequate drainage of a jaundiced future liver remnant (FLR) is often necessary to optimize postoperative liver regeneration and decrease postoperative morbidity and mortality. Cholangitis and infectious complications in resectable patients are common after biliary instrumentation and are an important source of perioperative morbidity (see Chapter 43) Appropriate resuscitation and treatment of these infections is imperative before resection. Inappropriate or misplaced biliary drains can lead to significant infectious complications which can

preclude resection. Early input from a hepatopancreatobiliary surgeon is highly recommended. Obstructive jaundice associated with HC differs from that associated with middle or distal bile duct cancer. In distal bile duct cancer, a single catheter or stent is sufficient for complete biliary drainage, whereas in HC, multiple biliary drainage catheters of the FLR may be necessary. Percutaneous and endoscopic approaches to biliary drainage are both acceptable. Internal drainage is preferred to limit bile loss, malabsorption, and dehydration. Cholangitic patients, jaundiced patients requiring systemic chemotherapy, patients with hyperbilirubinemiainduced malnutrition, those with hepatic insufficiency, and jaundiced patients undergoing portal vein embolization (PVE) require immediate biliary decompression.33 The indications for biliary drainage in resectable HC are highly debated. Routine biliary drainage before resection to reach a baseline bilirubin below 3 mg/dL has been proposed with the rationale that routine drainage improves the regenerative capacity of the FLR and thus reduces morbidity and mortality.35 Contrarily, multiple series have demonstrated an association with improved outcomes with selective biliary drainage.36–38 Kennedy et al.38 analyzed the impact of FLR volume and preoperative biliary drainage on postoperative hepatic insufficiency and mortality rates. They identified 60 patients who underwent hepatic resection for HC. Preoperative biliary drainage of the FLR appears to improve outcome if the predicted volume is less than 30% in contrast to patients with FLR greater than 30% where no patients experienced hepatic insufficiency and preoperative biliary drainage did not appear to improve outcomes (Fig. 51A.13). A subsequent multiinstitutional study combined the experiences of MSKCC and the Academic Medical Center in Amsterdam. In this study, biliary drainage appeared to reduce risk of postoperative liver failure in patients with a small FLR (defined as #50%) compared with undrained patients.39 Conversely, patients with a large FLR

60 patients Mortality = 10% Hepatic insufficiency = 8%

FLR40%

Resect

FLR 40%

Locally advanced (Blumgart T3)

Biliary decompression

Neoadjuvant therapy (Systemic therapy  XRT)

Biliary stent

Definitive systemic therapy (Gemcitabine/cisplatin)

731

Resectable (Blumgart T1–2)

Hilar biliary obstruction

Quadruple-phase liver CT + chest and pelvis (MRCP, duplex US) Selective biliary decompression*

Unresectable Metastatic

Resect

Resectable Restage perform volumetrics, selective PVE Unresectable

FIGURE 51A.14  Algorithm illustrating general approach to patients with hilar cholangiocarcinoma. *Patients presenting with obstructive cholangitis must undergo biliary decompression. CT, Computed tomography; FLR, future liver remnant; MRCP, magnetic resonance cholangiopancreatography; PVE, portal vein embolization; US, ultrasound. (From Lidsky ME, Jarnagin WR. Surgical management of hilar cholangiocarcinoma at Memorial Sloan Kettering Cancer Center. Ann Gastroenterol Surg. 2018;2[4]:304–312.)

(.50%) had increased mortality after biliary drainage compared with patients without percutaneous biliary drainage (PBD) (12% vs. 0% mortality). Taken together, these studies indicate that patients with a large FLR are able to undergo major resection without preoperative biliary drainage and that biliary drainage in these patients likely introduces morbidity and mortality without any added benefit. Small FLR, on the other hand, requires preoperative biliary drainage to improve postoperative liver regeneration and likely reduces morbidity and mortality34 (Fig. 51A.14). When indicated in resectable HC, biliary drainage should be limited to the FLR. If segmental cholangitis develops after biliary drainage, urgent decompression of the affected ducts should be performed. It should be stressed that predrainage imaging to determine resectability and a multidisciplinary decision regarding the method and target of the drainage procedures are critically important. Biliary drainage can be accomplished via endoscopic biliary drainage (EBD) (see Chapters 30 and 51B), percutaneous transhepatic biliary drainage (PTBD) (see Chapters 31 and 51B), or endoscopic nasobiliary drainage (END) (see Chapters 51B and 119B). In most centers, either EBD or PTBD is performed, with END occurring mainly in Asian centers (see Chapter 119B). The advantage of EBD versus PTBD is the ability to avoid external drains; however, stent misplacement is not uncommon, with up to half of patients requiring PTBD after inadequate or inappropriate drainage via EBD (Fig. 51A.15).40 Moreover, there is a high incidence of cholangitis, particularly when multiple obstructed ducts are instrumented but not drained.40 PTBD allows for precise placement of drainage catheters in the FLR, as well as delineation of the extent of tumor involvement in the biliary tree, which are both critical for operative planning. Additionally, PTBD allows for internal drainage of proximal bile duct strictures with termination of the stent or catheter above the ampulla. This improves catheter patency and decreases the risk of contamination of the biliary tree and infectious related complications.42 In a Surveillance, Epidemiology, and End Results (SEER)-Medicare analysis of patients with supra-ampullary cholangiocarcinoma who did not undergo resection, biliary drainage procedures that violated the sphincter of Oddi were associated with increased rates of cholangitis.43 Drawbacks to PTBD include catheter-associated discomfort and concerns with tract seeding. Tract seeding, however, is associated with distant metastatic disease and is rare.44 A multicenter, randomized controlled trial (RCT) in the Netherlands evaluated PTBD versus EBD in patients with

FIGURE 51A.15  Percutaneous transhepatic cholangiogram (PTC) shows a left hepatic duct stricture with no apparent isolation of the segment IV and left lateral ducts. PTC guides safe placement of a percutaneous biliary drain, which can permit internalization of bile flow. (See Chapter 31.)

potentially resectable HC requiring major liver resection and PBD.40 The primary end point was the rate of severe complications with a planned accrual of 106 patients; however, the study was stopped after accruing 54 patients due to increased mortality in the PTBD group versus EBD (41% vs. 11%; RR, 3.67; 95% CI, 1.15–11.7; P 5 .03). Of the 11 deaths in the PTBD cohort, 3 patients died preoperatively, and there was no difference in the preoperative mortality rate in patients who had PTBD alone (n 5 3/26), EBD alone (n 5 0/11), or crossed over to PTBD from EBD (n 5 0/16) (P 5 0.2). Patients died from

732

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

liver failure, bile leak complications, cholangitis, and disease progression, and there was no direct link to the biliary drainage procedure as the cause of death. The overall complication rate was the same with both approaches (63% vs. 67%). Of note, over half of the patients in the EBD group crossed over to PTBD compared with just 4% of the PTBD group. Early termination of the study at 50% of its intended accrual may have led to significant type I error thus implementation of its findings in clinical practice is limited. PTBD is an acceptable modality in patients with resectable HC and is the authors’ preferred approach. Advocates for ENBD over EBD cite decreased complication rates and more durable biliary drainage. Kawakubo et al.45 evaluated the complications associated with temporary ENBD in patients with HC being assessed for resection compared with EBD and PTBD. ENBD was associated with a lower risk of biliary reintervention (odds ratio [OR], 0.26; 95% CI, 0.08– 0.76, P 5 .012). The E-POD hilar study was a multicenter retrospective review of 374 malignant hilar biliary obstruction cases undergoing either ENBD or EBD for HC and showed no advantage of ENBD over EBD as the initial approach in resectable HC.46 Moreover, there is significant patient discomfort because of the nasal drainage, which cannot be ignored. Internal biliary drainage is preferred to external drainage, when possible, because of impaired intestinal barrier function from decreased intestinal cell regeneration and disruption of tight junctions between the cells in patients with prolonged external biliary drainage.47 Animal models showed that bile replacement after bile duct ligation is essential to maintain intestinal barrier function.48 Bile replacement can restore the intestinal barrier function primarily because of repair of physical damage to the intestinal mucosa. Bile replacement during external biliary drainage has been recommended for planned hepatectomy for hilar cholangiocarcinoma because of the substantial infectious morbidity associated with these resections.

Portal Vein Embolization PVE was first described by Makuuchi et al.49 in cases in which volumetric analysis predicts an inadequate FLR portending a high risk of postoperative liver dysfunction (see Chapter 102C). Originally this procedure required a transileocolic approach; however, a percutaneous transhepatic approach is more commonly performed, which obviates the need for general anesthesia and laparotomy (Fig. 51A.16). General indications for PVE consist of a FLR less than 25% in normal healthy liver, less than 30% in a setting of chemotherapy-induced liver toxicity, or less than 40% in patients with cirrhosis and underlying liver dysfunction. PVE allows for assessment in gross change in liver volume as well as a dynamic assessment of liver hypertrophy by measuring the kinetic growth rate (KGR). KGR is calculated by the degree of hypertrophy over the number of weeks since PVE and is highly predictive of postoperative liver failure. In a series of 153 patients undergoing major hepatectomy after PVE, no patients with a KGR greater than 2.66% per week experienced postoperative liver insufficiency.50 PVE is safe with a low morbidity (2%–2.5%) and mortality (0.1%) rate and increases FLR by an absolute value of 8% to 37.9%.51,52 Given that most patients present with cholestatic liver failure and commonly have advanced tumors requiring neoadjuvant chemotherapy, we typically prefer PVE in cases in which FLR is expected to be less than 40%.

FIGURE 51A.16  Portal vein embolization can be used to induce hypertrophy of the planned functional liver remnant (FLR) after major hepatectomy for hilar bile duct cancer. Percutaneous transhepatic embolization is the most widely used technique. In this patient, right portal vein branches were coil embolized 4 weeks before a planned right hepatectomy. Three-dimensional volumetric calculations of the planned FLR were analyzed before and after embolization. (See Chapter 102C.)

Preoperative Staging Various staging systems exist for HC that can help determine prognosis and resectability. The modified Bismuth-Corlette classification stratifies patients based on extent of biliary involvement (Fig. 51A.17).53 Type I tumors are distal to the biliary confluence, type II tumors involve the confluence, type IIIA tumors extend past the confluence to the right hepatic duct, and type IIIB tumors involve the confluence and left hepatic duct. Type IV tumors involve the confluence and bilateral hepatic ducts. A limitation of the Bismuth classification is that it does not describe involvement of vascular structures, resectability, or prognosis. The American Joint Commission for Cancer (AJCC) tumor-node-metastasis staging system (Table 51A.2) predicts survival after resection; however, it is based on pathologic findings and therefore has no utility in preoperative management. The eighth edition of the Cancer Staging Manual has a separate staging system for HC. Its utility is limited to the postoperative setting in patients with resectable disease and assessing prognosis in the metastatic setting. Given the limitations of both the Bismuth classification and AJCC staging, Jarnagin et al.54 proposed a staging system that aimed to address prognosis, resectability, and the need for hepatic resection. The MSKCC staging system describes the T stage of the tumor by describing the extent of tumor within the biliary tree, vascular involvement, and lobar atrophy (Table 51A.3) and predicts resectability as well as the likelihood of achieving an R0 resection.54 Despite the fact that this system does not account for N stage or M stage, it is significantly associated with overall survival.55

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

733

TABLE 51A.2  American Joint Committee on Cancer Staging System for Perihilar Bile Duct Tumors (Eighth Edition) CLASSIFICATION

Type I

Type II

Type III FIGURE 51A.17  Bismuth-Corlette classification scheme of biliary strictures. (See Chapter 42.)

Diagnostic Laparoscopy Despite significant improvement in imaging sensitivity and techniques, up to 50% of patients will have unresectable disease at exploration.12 Diagnostic laparoscopy can avoid a nontherapeutic laparotomy in approximately 25% of patients undergoing resection for HC.56,57 In a retrospective review of patients diagnosed with potentially resectable HC between January 2010 and April 2015 in the United Kingdom, 27.2% of patients were spared a nontherapeutic laparotomy.56 Another retrospective review out of MSKCC analyzed 56 patients with radiographically resectable HC, in which 14 (25%) of patients were found to have metastatic disease.57 The yield of diagnostic laparoscopy increased to 36% in patients with T2/T3 tumors. Overall, the data suggest a significant yield in staging laparoscopy for HC, particularly in patients with locally advanced, potentially resectable HC (see Chapter 24).

TREATMENT Most patients with unresectable bile duct cancer die within 1 year of diagnosis. The most common causes of death are liver failure and infectious complications related to biliary obstruction and biliary instrumentation. Although some have suggested a worse prognosis for unresectable tumors involving the hilum compared with distal bile duct tumors, the associated worse outcome is likely secondary to a higher incidence of infectious complications and later presentation in hilar tumors. Patients with resected proximal and distal cholangiocarcinoma experience similar disease-specific survival.58,59

Resection of Hilar Cholangiocarcinoma The main objective in HC resection is complete tumor extirpation and reconstitution of biliary enteric continuity (see

CRITERIA

Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue T2a Tumor invades beyond the wall of the bile duct to surrounding adipose tissue T2b Tumor invades adjacent hepatic parenchyma T3 Tumor invades unilateral branches of the portal vein or hepatic artery T4 Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery, or unilateral second-order biliary radicles with contralateral portal vein or hepatic artery involvement Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal and portal vein lymph nodes N2 Four or more positive lymph nodes from the sites described for N1 Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis (includes lymph node metastasis distant to hepatoduodenal ligament) Anatomic Stage/Prognostic Groups Stage 0 Tis N0 Stage I T1 N0 Stage II T2a, T2b N0 Stage IIIA T3 N0 Stage IIIB T4 N0 Stage IIIC Any T N1 Stage IVA Any T N2 Stage IVB Any T Any N

M0 M0 M0 M0 M0 M0 M0 M1

From Amin MB, Edge SB, Green FL et al., eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017.

TABLE 51A.3  Memorial Sloan Kettering Preoperative T-Stage Criteria for Hilar Cholangiocarcinoma STAGE

CRITERIA

T1

Tumor involving biliary confluence ± unilateral extension to second-order biliary radicles Tumor involving biliary confluence ± unilateral extension to second-order biliary radicles and ipsilateral portal vein involvement ± ipsilateral hepatic lobar atrophy Tumor involving biliary confluence ± unilateral extension to second-order biliary radicles; or Unilateral extension to second-order biliary radicles with contralateral portal vein involvement; or Unilateral extension to second-order biliary radicles with contralateral hepatic lobar atrophy; or Main or bilateral portal venous involvement

T2

T3

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

Chapters 101B and 119B). Preoperative assessment of resectability with contrast-enhanced cross-sectional imaging should be performed before biliary interventions because biliary stents and catheters can induce inflammation, thus making assessment and exploration more difficult. Criteria for irresectability include patient factors such as performance status and baseline liver disease, local factors such as involvement of secondary biliary radicles bilaterally, and distant disease (see Table 50A.1). If deemed unresectable, biliary stents combined with nonoperative therapies can achieve reasonable palliation and control local tumor growth. In patients with potentially resectable tumors, the primary goal should be complete resection with negative margins and intent to cure. The operative approach depends on biliary tumor location. Tumors involving the distal bile duct are typically removed with pancreaticoduodenectomy. To achieve an R0 resection, hilar tumors generally require a major hepatectomy with en bloc bile duct excision and often with en bloc caudate lobectomy, particularly with centrally located tumors.54 The importance of achieving negative margins has important implications for long-term survival. We routinely use hepatic resection but perform caudate resection selectively in cases with suggested tumor extension into the ducts of the caudate lobe. The main caudate lobe ducts drain into the left hepatic duct; therefore tumors extending into the left hepatic duct often involve the caudate duct requiring caudate resection.60 A dilated caudate duct suggestive of tumor involvement can usually be seen on imaging performed before biliary drainage. The improvement in long survival after complete resection of HC over time likely reflects increased implementation of en bloc partial hepatectomy and improved R0 resection rates.61 The association between disease-specific survival (DSS) and pathologic margin status after resection of HC was evaluated in retrospective series of 101 patients. The median DSS for patients with wide margins was 56 months compared with 38 months for patients with narrow margins and 32 months for margin-positive patients (P 5 .01).62 Survival after an R1 resection (histologically involved resection margins) appears to be similar to survival in patients with unresectable, locally advanced tumors identified at exploration (Fig. 51A.18). Moreover, nearly 10% of patients had a misleading interpretation of proximal bile duct margin on frozen section. Whether the ability to obtain adequate margins truly improves survival or if this is simply a surrogate for underlying tumor biological processes remains undetermined. Transection of the proximal bile duct should be performed as high as technically feasible with appropriate consideration of additional operative morbidity. Determining resectability requires a thorough evaluation of preoperative and intraoperative findings. Bilateral second-order biliary radicle involvement precludes resection. Although portal vein resection can be performed in well-selected patients, unreconstructible main portal vein encasement or occlusion is a contraindication to resection. Ipsilateral lobar atrophy and ipsilateral involvement of the bile duct and portal vein are amenable to resection, whereas contralateral involvement typically precludes this (see Chapter 122). Invasion of the main portal vein or its branches by tumor is a major determinant of resectability. The preoperative assessment of vascular involvement and ductal extension of tumor is an essential part of operative planning and gives valuable information to the surgeon with respect to the extent of operation and operative strategy. Limited tumor involvement of the portal

1.0 R0, 43 months (n = 82) R1, 24 months (n = 24) Loc Adv, 16 months (n = 29)

.75

%

734

.5

.25

P < .001 P < .19

0.0 0

20

40 60 Time (months)

80

100

FIGURE 51A.18  Actuarial survival curves after resection of hilar cholangiocarcinoma. R0 indicates complete resection with histologically negative resection margins (median survival, 43 months). R1 indicates histologically involved resection margins (median survival, 24 months; P , .001 R0 vs. R1). Loc Adv indicates a patient explored but found to have unresectable tumors because of local invasion (no metastatic disease; median survival, 16 months; P , .19 R1 vs. Loc Adv).

venous confluence or the main portal vein may be amenable to resection and portal vein reconstruction. Several technical steps during the exploration and resection of hilar cholangiocarcinoma are crucial to the success of the operation. After assessing for the presence of metastatic disease, one of the next steps in assessing resectability is assessing vascular involvement. This is particularly pertinent for planned left-sided resections in which involvement of the right hepatic artery coursing along the tumor is commonly seen. Bile duct resection alone without concomitant partial hepatectomy is sometimes possible. In this situation, resection must include removal of the entire supraduodenal bile duct, gallbladder, cystic duct, and extrahepatic hepatic ducts with clearance of the supraduodenal tissues and portal lymphadenectomy. However, local resections are associated with worse overall survival even after resection with clear margins. In 106 resections at MSKCC, 19 were local resections, and 9 of these were R0; however, no patient submitted to an R0 bile duct resection was among the 5-year survivors.12 In most patients, the option of a local resection does not exist because of intrahepatic extension of the tumor, right or left portal vein involvement, or both. In these cases, en bloc liver resection, often with caudate lobectomy, is necessary to achieve tumor clearance. Portal vein involvement by the tumor can be managed by segmental portal vein resection and reconstruction.63–65 This procedure can be done only if intraoperative assessment shows that a tumor-free remnant with intact biliary drainage and blood supply can be left in situ. Some centrally located tumors may be amenable to a more limited hepatic resection. Such resections, which include segments IV and V or IV and I, are limited in their application and are inappropriate in the face of lobar atrophy and involvement of a main portal vein branch, both of which are common findings. Operative exploration is carried out through a right subcostal incision with proximal extension to the xiphoid, a so-called “hockey stick” incision or midline incision. The exploration should begin with a thorough inspection of the peritoneal cavity

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

and distant nodal sites because metastatic disease is common in patients with hilar cholangiocarcinoma. In our experience, 73 (50%) of 145 unresectable patients had metastases to regional lymph nodes or distant sites.54 Careful bimanual palpation of the liver and intraoperative ultrasound is performed to rule out unsuspected masses in the liver. Palpation of the caudate lobe is performed after incision of the lesser omentum, allowing access to the lesser sac. A Kocher maneuver is performed to allow access to the retroduodenal lymph nodes, and the ligamentum teres is elevated, exposing the undersurface of the liver and allowing thorough examination of the subhilar and retroduodenal area. Precise assessment of tumor extension and biopsy of any suspicious lesions or distant lymph nodes with frozen section analysis should be performed. Evidence of intrahepatic metastases or spread to distant sites precludes resection. With any of these findings, the patient should be considered for palliative biliary drainage. In all cases, the surgeon must be prepared to perform a liver resection. The general principles of intraoperative management are discussed in detail in other chapters (see Chapters 101B and 119B). Preparation for surgery includes suitable intraoperative monitoring and the possibility for rapid transfusion. The patient’s central venous pressure is kept at less than 5 mm Hg during the operation to keep blood loss from hepatic veins at a minimum during retrohepatic dissection, dissection of the hepatic veins, and parenchymal transection. The following description summarizes the initial steps of dissection, exposure of the hilar structures, dissection and resection of the hilar structures, and subsequent biliary-enteric reconstruction as performed for a segmental bile duct resection. The specifics of en bloc liver resection, including caudate lobectomy, are discussed in other chapters (see Chapters 101B and 118B). To reach the confluence of the bile ducts and assess its relationship to the portal vein, the common bile duct first must be transected above the duodenum and turned upward. The liver hilus is fully exposed anteriorly by taking down the gallbladder and lowering the hilar plate by incising the Glisson capsule along the base of segment IV. Exposure of the left hepatic duct is improved by dividing the bridge of liver tissue that often connects the base of segment IV and the left lateral segment; this may be quite substantial in some patients. The entire extrahepatic biliary apparatus and adjacent lymphatic tissues are turned upward to expose the portal vein. A plane can be developed between the posterior aspect of the bile duct tumor and the portal vein, provided no tumor has invaded into the vessels (Fig. 51A.19). The dissection is continued upward toward the hilus, skeletonizing the portal vein and hepatic artery. At this point, the surgeon should assess the proximal extent of tumor by palpation and, if necessary, by biopsy. Segmental bile duct resection is possible only if an adequate length of the hepatic ducts can be achieved beyond the tumor, and if no vascular involvement is evident. This is rarely possible. If the tumor extends to the second-order biliary radicles unilaterally such that clearance cannot be achieved, or if the ipsilateral portal vein branch is involved, partial hepatectomy must be performed. Tumors extending well into the left hepatic duct may involve the caudate ducts as well and require en bloc caudate lobectomy. If partial hepatectomy is required, inflow control is obtained by ligation and transection of the ipsilateral branch of the portal vein and hepatic artery. Extrahepatic control and division of the ipsilateral hepatic vein are performed before parenchymal transection.

735

FIGURE 51A.19  Entire extrahepatic biliary apparatus is elevated together with associated portal connective tissue and nodes to allow dissection anterior to the bifurcation of the portal vein and elevation of the tumor, which is now completely mobilized. The hepatic artery and portal vein are skeletonized. (See Chapter 119B.)

When it has been established that segmental bile duct excision is feasible and will result in an R0 resection, the left and right hepatic ducts are divided above the tumor. Occasionally, irresectability as a result of main portal vein invasion or extensive bilateral intrahepatic duct involvement will not be determined until the extrahepatic biliary tree has been divided and mobilized. In both situations, biliary enteric continuity is restored by hepaticojejunostomy to a Roux-en-Y loop of jejunum. (see Chapter 32) When residual disease remains at the final level of the transected duct, appropriate consideration should be made for placement of retrograde transhepatic biliary stents (Fig. 51A.20). After removal of the tumor, the surgeon may be faced with multiple exposed duct orifices, all of which require suitable drainage. Frequently, removal of the tumor results in discontinuity of the right anterior and posterior sectoral ducts, separation of one or more caudate ducts from the left hepatic duct, or both. The sidewalls of adjacent ducts can be brought into apposition with sutures and regarded as a single duct for purposes of anastomosis. In cases of multiple exposed ducts, it is often possible to make it so that no more than two or three separate ducts need to be anastomosed. A Roux-en-Y loop of jejunum is prepared and brought up, usually in a retrocolic fashion, and anastomosis is carried out in an end-to-side fashion between the exposed ducts and the side of the jejunal loop using a single layer of interrupted absorbable sutures. High biliary anastomoses to multiple ducts can be difficult and require careful planning. Multiple disconnected ducts that

736

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

A

B

FIGURE 51A.20  A, In rare circumstances, the extrahepatic biliary tree can be excised alone with curative intent without the need for partial hepatectomy. In other situations, tumor unresectability may not be determined until the extrahepatic bile ducts are divided. The exposed right and left hepatic ducts are anastomosed individually to a retrocolic Roux-en-Y loop of jejunum. B, Retrograde transhepatic biliary stents can be passed at surgery to provide long-term palliation of obstructive jaundice and facilitate photodynamic therapy. (See Chapter 119B.)

cannot be approximated should be similarly viewed as a single duct for purposes of the anastomosis. It is usually impossible to perform sequential anastomoses in this location. The safest and most reliable method is to place the entire anterior row of sutures to all exposed ducts and separately place the entire posterior row of sutures to the duct and jejunum. The jejunum is railroaded up on the posterior sutures so that the back wall of the duct is flush with the back wall of the jejunum. The posterior layer of sutures to all exposed ducts is tied first, and the previously placed anterior sutures are passed sequentially through the anterior jejunal wall to complete the anastomosis. We routinely employ dependent drainage near the anastomosis.

FLR

HC

Associating Liver Partition and Portal Vein Embolization for Staged Hepatectomy (see Chapter 108D) Associating liver partition and portal vein embolization for staged hepatectomy (ALPPS) is a two-stage hepatectomy combined with in situ splitting of the liver and concomitant portal ligation during the first stage. This approach leads to rapid hypertrophy of the FLR with the cost of high perioperative morbidity and mortality rates (80% and 12%, respectively) (Fig. 51A.21).66–68 Although the first ALPPS procedure was performed for HC, ALPPS for this disease is now rare largely because of the high complication rates associated with perihilar resections, which can be compounded in the setting of an ALPPS resection.68 For example, most HC patients have bactibilia, which increases the likelihood to infectious complications. Additionally, intraabdominal collections and abscesses

LHA MPV DBD

RHA

FIGURE 51A.21  Intraoperative photograph demonstrating the first stage of an associating liver partition and portal vein embolization for staged hepatectomy (ALPPS) procedure. The right portal vein has been ligated (arrow), and the liver has undergone in situ splitting (arrowhead). A probe has been inserted into the left hepatic duct. DBD, Cut distal common bile duct; FLR, future liver remnant; HC, hilar cholangiocarcinoma with en bloc dissection of the extrahepatic bile duct and lymph nodes; LHA, left hepatic artery; MPV, main portal vein; RHA, right hepatic artery. (From de Santibañes E, Alvarez FA, Ardiles V. How to avoid postoperative liver failure: a novel method. World J Surg. 2012;36[1]:125–128, 2012. (See Chapter 102D.)

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

are common, resulting in significant morbidity and mortality with the ALPPS procedure. The international ALPPS registry reported a 90 day-mortality rate of 27% in patients with HC who underwent ALPPS.66 A multicenter study comprising six Italian centers (ALPPS Italian registry group) reported a 40% 90-day mortality rate for ALPPS performed for biliary tumors prompting the authors to recommend against ALPPS in patients with biliary tumors.69 Finally, a matched case– control study compared outcomes of 29 ALPPS patients from the international ALPPS registry with 29 standard resection patients based on similar future liver remnant volume. The mortality rate in the ALPPS group was twice as high as that among patients who did not undergo ALPPS (48% vs. 24%).70 The median survival was 6 months in the ALPPS group versus 29 months in the matched control group.70 Modified ALPPS approaches, including partial parenchymal transection with PVE in the first stage (rather than portal vein ligation/transection), have been suggested.67 The hilum is not dissected in the first stage; thus this approach could potentially decrease the morbidity, this has not been convincingly demonstrated in HC.

Liver Transplantation in Hilar Cholangiocarcinoma (see Chapter 108B) Initial reports of orthotopic liver transplantation for unresectable HC demonstrated dismal results.71–74 Meyer et al. reviewed 207 patients who underwent orthotopic liver transplantation OLT for unresectable cholangiocarcinoma. Half of the patients recurred in their series and 84% of these recurrences occurred within 2 years of transplantation. The 2-year overall survival was 48%.73 Additional studies reported similar findings, and liver transplantation for HC was initially thought not appropriate.71,72 More recently, however, the implementation of intense pretransplant protocols for unresectable hilar cholangiocarcinoma, which includes neoadjuvant chemotherapy, radiation, and strict diagnostic protocols, including diagnostic laparoscopies and biopsy techniques, has resulted in improved patient selection and more encouraging long-term data.75,76 Transplant is now a well-recognized and accepted treatment modality in highly selected HC patients. The Mayo HC transplant protocol consists of neoadjuvant chemotherapy, radiation, and operative assessment of regional lymph nodes and distant metastases before transplant.77 Patients are deemed eligible for transplant by meeting one of the following criteria: a mass lesion at the biliary stricture, tissue diagnosis obtained via endoluminal biopsy, or CA19-9 greater than 100. Contraindication to transplant include tumors larger than 3 cm, positive nodal or metastatic disease, previous resection attempt or transperitoneal biopsy, history of prior malignancy, and previous therapy that precludes completing neoadjuvant therapy.34,78 Approximately one third of patients will drop out pretransplant because of disease progression or death.79–81. Long-term results for this treatment approach are encouraging. Rosen et al.81 from the Mayo clinic reported on 148 patients enrolled in their HC liver transplant protocol since 1993. Of these, 90 patients went on to receive a liver transplant with a 75% 5-year overall survival. The encouraging long-term outcomes with HC transplant protocols spurred interest in broader applicability of this liver transplant for HC patients. The US Extrahepatic Biliary Malignancy Consortium performed a retrospective review of 304 patients with suspected HC who underwent resections

737

(n 5 234) or transplant n 5 70).80 Transplant was associated with a significant improvement in 5-year overall survival compared with resection (64% vs. 18%, P ,.001). Transplant remained associated with improved survival on intention-totreat analysis, even after accounting for tumor size, lymph node status, and PSC (P 5 .049) By contrast, the Mayo group evaluated patients with de novo HC treated by their liver transplant protocol (n 5 90) versus standard resection (n 5 124) and saw no difference in overall survival after adjusting for age, lymph node status, and tumor size.79 The TRANSPHIL study (NCT02232932) is a prospective, randomized multicenter study comparing liver transplantation with liver and bile duct resection in potentially resectable HC without evidence of PSC. This study is ongoing, with a primary outcome of overall survival and a planned enrollment of 60 patients. Although the data are compelling, liver transplant is applicable to only a small fraction of patients because of the highly specific selection criteria and the high incidence of lymph node metastases and distant occult metastases in this disease. There are no level 1 data to evaluate resection versus transplant in resectable HC, and organ availability for transplant remains limited. Given this, resectable tumors should continue to be treated with resection when an R0 resection is feasible. Unresectable locally advanced HC or HC in the setting of PSC should be referred for liver transplantation.32,33

Resection of Distal Cholangiocarcinoma Resection of most distal bile duct cancers requires pancreatoduodenectomy (see Chapters 62 and 117A). Compared with patients with pancreatic cancer, those with distal bile duct cancer are more often amenable to resection, less often have microscopic disease at the resection margin, and less frequently have spread of tumor to adjacent lymph nodes.82 In addition to completeness of resection, lymph node status is an important prognostic factor. Ethun et al.82 found that lymph node involvement was the only independent predictor of long-term survival in resected patients, with positive nodes conferring a 1.63 times greater likelihood of death.

OUTCOMES AFTER RESECTION After resection of hilar cholangiocarcinoma, 5-year survival rates range from 11% to 44%.12,34,64,83 Postoperative mortality ranges from 4% to 17%.39,84,85 One of the strongest associations with survival is margin status, and patients with positive bile duct margins have significantly decreased survival compared with patients with negative margins.62 Recurrences are seen in up to 75% of patients.86–88 Along with the status of the resection margin, other factors that are associated with outcome are involvement of resected regional lymph nodes, grade of the tumor, and tumor histology (nodular sclerosing vs. papillary).19,89 Table 51A.4 reviews outcomes of selected series of hilar cholangiocarcinoma resection.90–95

ADJUVANT THERAPY Resection remains the only modality to achieve long-term survival; however, recurrence is common even after R0 resection. Common sites of recurrence after resection of HC are locoregional recurrences and in the peritoneum and liver.88 In a single institution retrospective review of 404 patients who

738

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

TABLE 51A.4 

Selected Reports of Outcomes After Hilar Cholangiocarcinoma Resection

STUDY Nakeeb et al. (1996) Klempnauer et al. (1997)72 Neuhaus et al. (1999)64 Launois et al. (2000)85 Lee et al. (2000)90 Gerhards. et al (2000)91 Nishio et al. (2005)92 Jarnagin et al. (2005)12 Igami et al. (2010)93 Unno et al. (2010)94 Matsuo et al. (2012)95 Nagino et al. (2013)61 Wiggers et al. (2016)39 Komaya et al. (2018)83 84

RESECTIONS

MORBIDITY (%)

MORTALITY (%)

SURVIVAL (5-YR)

109 151 80 131 128 112 301 106 298 125 157 574 287 402

47 NR 55 NR 64 65 NR 50 43 49 59 57 NR NR

4 10 8 17 10 17 7.6 7.5 2 8 7 4.7 14 NR

11 28 22 NR 35 NR 22 40 42 35 32 33 NR 43.7

NR, Not reported. From Soares KC, Jarnagin WR. The Landmark Series: hilar cholangiocarcinoma. Ann Surg Oncol. 2021;28(8):4158–4170.

underwent R0 resection of HC with long-term follow-up, 60% of patients developed a recurrence and recurrence reached nearly 50% at 10 years after resection.88 Similarly, in a multi-institutional analysis of 306 consecutive patients with resected HC, 76% of patients recurred after resection.86 Over 25% of patients recurred after 5 years of recurrence-free survival. Moreover, node-positive disease precluded recurrencefree survival beyond 7 years. Distant metastases are more common than locoregional recurrence after R0 resection of HC.88,96 Therefore a role for systemic adjuvant therapies has been considered as a means of decreasing recurrence. Until recently, analysis of adjuvant strategies in HC and DC consisted of single-arm retrospective reviews with mixed findings. However, multiple randomized prospective studies evaluating adjuvant therapies after resection of HC and DC have now been reported, albeit also with mixed results. Takada et al. reported a phase III trial in 2002 where 508 patients with resected bile duct cancer, pancreatic, gallbladder and ampullary cancer were randomized to surgery alone versus adjuvant mitomycin C and 5-fluorouracil.97 The primary end point was overall survival, and the study showed no significant differences in overall or disease-free survival in resected bile duct tumors. The BILCAP trial was a phase III multi-institutional clinical trial in the United Kingdom investigating adjuvant capecitabine versus observation after R0/R1 resection of HC (29%), gallbladder cancer (18%), distal cholangiocarcinoma (35%), and ICC (19%).98 The primary end point of the study was overall survival designed to detect an effect size of HR 0.71. Of the 447 randomized patients between 2006 and 2014, 430 were evaluable for the primary end point by intention-to-treat analysis. Approximately 50% of patients had node-positive disease, and 38% of patients had an R1 resection. By intentionto-treat analysis, there was no significant difference in overall survival (hazard ratio [HR], 0.81; 95% CI, 0.63–1.04; P 5 .097). However, a per-protocol analysis was performed after excluding 17 patients who could not receive at least one cycle of chemotherapy or could not be randomized. This analysis showed a statistically significant improvement in both overall (HR, 0.75;

95% CI, 0.58–0.97; P 5 .03) and recurrence free survival (HR 0.70; 95% CI, 0.54–0.92; P 5 .009) in the capecitabine arm and prompted the routine use of 6 months of adjuvant capecitabine after bile duct cancer resection.34,99 The Advanced Biliary Tract Cancer (ABC)-02 trial established gemcitabine and cisplatin as the standard of care for unresectable locally advanced and metastatic biliary tract cancers.100 Subsequently, a multicenter study in France, the PRODIGE 12-Accord 18 trial, randomized 196 patients with R0/R1 resected biliary tract cancers to gemcitabine plus oxaliplatin (GEMOX) versus surveillance.101 This study included gallbladder cancer (n 5 38), ICC (n 5 86), HC (n 5 15), and DC (n 5 55) patients. Ultimately, 155 patients were evaluable for the primary end point of relapse-free survival, which showed no difference between the groups (HR, 0.88; 95% CI, 0.62–1.25; P 5 .48). The planned subgroup analyses failed to suggest any subgroup with a benefit with adjuvant GEMOX. However, it should be noted that only 37% of patients in this study had lymph node–positive disease, which could theoretically derive more benefit from adjuvant strategies. Thus further studies are necessary to determine adjuvant therapy utility in high-risk tumors. The Bile Duct Cancer Adjuvant Trial (BCAT) was a phase III RCT in Japan evaluating adjuvant gemcitabine versus observation in 225 resected patients with DC or HC.102 The primary end point was overall survival, and secondary end points included relapse-free survival and toxicity. Similarly to the PRODIGE study, there was no significant difference in overall survival (HR, 1.01; 95% CI, 0.7–1.45) or relapse-free survival. Although distant recurrence in HC is most common, isolated locoregional recurrence can be seen in up to 27% of patients.86,88 Thus adjuvant strategies targeting locoregional disease in HC patients have been suggested. Analyses of such adjuvant strategies in HC have consisted of small, single-center reports. Two separate reports from Johns Hopkins suggest no benefit for adjuvant external beam or intraluminal radiation therapy.103,104 In contrast, other series have suggested that radiation may improve overall survival,

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

particularly in patients with histologically positive hepatic duct margins.105–108 More recently, the single arm phase II SWOG S0809 trial reported on adjuvant gemcitabine and capecitabine followed by concurrent capecitabine and radiotherapy in resected R0/R1 stage pT2-4 or node-positive extrahepatic cholangiocarcinoma and gallbladder cancer.109 The radiation protocol called for 45 Gy to regional lymphatics and 54 to 59.4 Gy to the tumor bed.109 The 2-year overall survival for the entire 79 patient cohort was 65% (95% CI, 53%–74%; 67% and 60% in R0 and R1 patients, respectively). This met the primary end point of a 95% CI for the 2-year overall survival estimate greater than 45%, and R0 and R1 2-year overall survival estimates 65% or greater and 45%, respectively. Although this trial met its prespecified end point, the lack of a comparison arm limits its interpretation and widespread applicability. We do not routinely use adjuvant radiation therapy after R0 resection of HC or DC; however, this approach may benefit patients with positive resection margins.34 Further studies are needed to address the question of optimal adjuvant strategies in EHC. The ACTICCA-1 trial is a multicenter, prospective, randomized, controlled phase III trial comparing adjuvant gemcitabine and cisplatin to standard of care after curative resection of biliary tract cancer (NCT02548195).110 Of note, this trial was ongoing when BILCAP results were reported therefore the standard of care arm was switched to capecitabine rather than observation alone. Similarly, a phase II study in Asia (NCT03079427) randomizes resected EHC patients with positive lymph node to either adjuvant capecitabine or adjuvant doublet gemcitabine plus cisplatin. The primary end point is 2-year disease-free survival. The Adjuvant S-1 for Cholangiocarcinoma Trial (ASCOT) is a multicenter trial in Japan randomizing patients with resected biliary tract cancer to adjuvant S-1 versus observation (UMIN000011688) with a planned sample size of 440 patients.111 The widespread implementation of genetic analyses has led to novel approaches using immunotherapy and targeted. Emerging evidence indicates the utility of these approaches in extrahepatic cholangiocarcinoma.1 KRAS, TP53, and SMAD4 mutations in HC are common.14 HER2 gene amplification can be seen in nearly 20% of extrahepatic cholangiocarcinoma.112 Additionally, ALK and TP53 mutations are associated with a worse prognosis in extrahepatic cholangiocarcinoma.113 Mismatch repair deficiency is seen in up to 5% of HC suggesting a potential role for immunotherapy approaches in this subset of patients.9,114,115 Molecular testing of extrahepatic cholangiocarcinoma is recommended. A better understanding of the genomic drivers and epigenetic, immunologic, and molecular heterogeneity of this disease holds promise for successful combinations of targeted therapy and immunotherapy (see Chapter 9E).

PALLIATIVE THERAPY Most patients with HC are not suitable for resection. In this setting, management options include some form of biliary decompression or supportive care. Jaundice alone, without pruritus or cholangitis, is not necessarily an indication for biliary decompression, especially in a patient whose only goal is palliation. For biliary decompression in inoperable patients, our current indications are to relieve intractable pruritus, treat cholangitis, lower bilirubin, and allow recovery of hepatic parenchymal function in patients who are potential candidates for chemotherapy. Supportive care is strongly considered for

739

elderly patients with significant comorbid conditions, provided that pruritus is not a major feature. Patients who are found to be unresectable at operation represent a different group, and operative biliary decompression is usually performed successfully. In patients with unresectable HC, segment III bypass provides excellent palliation with relatively few late complications and can be performed with minimal morbidity and mortality116 (see Chapters 29, 30, 31, and 52). Assessment of palliative biliary drainage procedures is difficult, because the spectrum of patients ranges from those critically ill and unresectable to those in relatively good health with potentially resectable tumors. All patients should be assessed properly by experienced personnel with a view toward possible resection. If the patient is deemed unresectable, the diagnosis should be confirmed with a biopsy. Biliary decompression can be achieved by percutaneous transhepatic puncture or by endoscopic stent placement. Hilar tumors are more difficult to traverse with the endoscopic technique, which should be approached only by skilled endoscopists with extensive ERCP experience. The failure rates and incidence of subsequent cholangitis after endoscopic drainage can be high (see earlier discussion of pretreatment biliary drainage). Initial endobiliary drainage, even in the palliative setting, should use plastic stents.117 Exchange for metallic stents can be considered after close monitoring for adequate palliative biliary drainage with plastic stents in the short and intermediate term. Percutaneous transhepatic biliary drainage and subsequent placement of a self-expandable metallic endoprosthesis (SEM) can be performed successfully in most patients with hilar obstruction (see Chapters 31 and 52). Satisfactory drainage of only 25% to 30% of functional hepatic parenchyma is required for resolution of jaundice.118 Still, hilar tumors frequently isolate all three major hilar ducts—left hepatic, right anterior sectoral hepatic, and right posterior sectoral hepatic—and two or more uncovered stents must be placed for adequate drainage (Fig. 51A.22). In the setting of cholangitis, all infected ductal systems need to be drained. Bile duct(s) unintentionally opacified upstream from a malignant hilar stricture should be drained during the same procedure.117 Otherwise, bilateral drainage is not better or more effective than unilateral drainage, provided that an adequate volume of liver parenchyma can be decompressed. It also must be considered that jaundice may result from hepatic dysfunction secondary to portal vein occlusion. Jaundice in this setting, without intrahepatic biliary dilation, is not correctable with biliary stents. In addition, lobar atrophy is an important factor when considering palliative biliary procedures. Percutaneous drainage through an atrophic lobe does not relieve jaundice and should be avoided. The presence of multiple intrahepatic metastases or ascites also may add to the technical difficulty of the procedure. The median patency of plastic stents is only 1.4 to 3 months. SEMs are wider diameter, resulting in a median patency of approximately 6 months. Raju et al.119 reviewed 100 patients with inoperable HC at a tertiary cancer hospital. Of these, 48 patients had SEMs placed and 52 patients had plastic stents placed. The median patency times were 1.86 months in the plastic stent group and 5.56 months in the SEM group (P , .0001). A mean of 1.53 and 4.60 reinterventions were performed in the SEM and plastic groups, respectively and the complication rates between both groups were similar (8.3% SEMS and 7.7% plastic stent). Similarly, Liberato and

740

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

FIGURE 51A.22  Unresectable hilar cholangiocarcinoma tends to isolate all major hilar bile ducts from one another. In this patient, two expandable metallic stents were required for adequate biliary drainage. Self-expanding metal stents are shown here on plain radiography and coronal computed tomographic imaging. (See Chapter 16.)

Canena120 evaluated 480 patients undergoing endoscopic biliary drainage for HC. Technical success was more common with SEM versus plastic stents (98.8% vs. 88.3%, P , .001). Additionally, in an intention-to-treat analysis, functional success in patients treated with SEMs was significantly higher than in patients treated with PS (97.9% vs. 84.8%, respectively, P , .001). Finally, in a prospective trial, patients presenting for percutaneous biliary drainage for malignant biliary obstruction had a dismal survival and experienced no improvement in quality of life with drainage. The exception in this trial was an improvement in pruritus-related quality of life, which was significantly better.121 Palliating distal biliary obstruction in unresectable patients can be achieved with an operative bypass (hepaticojejunostomy or choledochojejunostomy) (see Chapter 32) or with placement of a biliary stent (see Chapters 30, 31, and 52). Endoprostheses for distal biliary obstruction are typically easy to place and have a greater long-term patency than endoprostheses placed for hilar obstruction. Operative biliary-enteric bypass, either open or laparoscopic, will provide excellent relief of jaundice and can be done with an acceptably low morbidity and mortality. Patients who are found to have unresectable disease at the time of operative exploration should be considered for biliary-enteric bypass, particularly in instances in which endoscopic or percutaneous techniques have failed. Planned palliative operative bypass should be reserved for patients expected to survive longer than 6 months,122 and SEMs should be used in patients with clear-cut metastatic disease on cross-sectional imaging or discovered with staging laparoscopy. Multiple studies evaluating surgical and nonsurgical palliative biliary drainage have failed to show a significant difference between surgical and nonsurgical approaches.122–125 Patients with hilar tumors found to be unresectable at operation may be candidates for hepaticojejunostomy or intrahepatic biliary-enteric bypass. (see Chapter 32) The segment III duct usually is the most accessible and is our preferred

approach, but the right anterior or posterior sectoral hepatic ducts also can be used.116 Typically, a segment III bypass is used to restore biliary-enteric continuity after the bile duct has been divided and a locally invasive, unresectable tumor has been discovered. Segment III bypass provides excellent biliary drainage, resolves jaundice in approximately two thirds of HC patients and is less prone to occlusion by tumor than a SEMs126,127 because the anastomosis can be placed some distance from the tumor (Fig. 51A.23). Relief of jaundice is achieved in 70% of patients if the functioning hepatic parenchyma is adequately drained.122 Communication between the right and left hepatic ducts is unnecessary, provided the undrained lobe has not been percutaneously drained or otherwise contaminated. In this circumstance, there is a high risk of persistent biliary fistula and cholangitis. Bypass to an atrophic lobe or a lobe heavily involved with tumor is ineffective. In a report of 55 consecutive bypasses in patients with malignant hilar obstruction, segment III bypass in patients with hilar cholangiocarcinoma (n 5 20) yielded the best results. The 1-year bypass patency in this group was 80%, with no perioperative deaths.116 Patients with unresectable, locally advanced tumors but without evidence of widespread disease may be candidates for palliative radiation therapy. External beam radiation and stereotactic body radiation therapy (SBRT) can be delivered percutaneously. Although there is little evidence to support this, this approach appears safe in well-selected patients.128,129 Moureau-Zabotto et al.127 performed a retrospective review of 30 patients with locally advanced extrahepatic cholangiocarcinoma treated with external beam radiotherapy: 24 with a primary tumor and 6 with a local relapse. Toxicity was acceptable, and median overall survival the cohort was 12 months. The 1-year and 3-year progression-free survivals were respectively 38% and 16%. Radiation therapy is inappropriate in patients with widespread disease. Systemic chemotherapy is the only option for these patients, but response rates are low.

C. Malignant Tumors  Chapter 51A  Extrahepatic Biliary Tumors

741

A systematic review of 761 patients with advanced biliary tract cancer evaluated the efficacy of second-line chemotherapy.130 Eligible studies reported survival and/or response data for patients with advanced biliary cancer. The authors concluded that there is insufficient evidence to recommend a second-line chemotherapy schedule in advanced biliary cancer. Further prospective randomized trials are needed. Photodynamic therapy is an ablative therapy used in unresectable hilar cholangiocarcinoma. This method has been used in the treatment of tumors of the esophagus, colon, stomach, bronchus, bladder, and brain. It is a two-step procedure. First, a photosensitizing drug is injected, followed by direct illumination with a light of a specific wavelength via cholangioscopy, which activates the compound, causing tumor cell death. Two randomized studies in patients with unresectable cholangiocarcinoma suggested improved survival with biliary stenting combined with photodynamic therapy compared with biliary stenting alone.131,132 The improved survival observed with photodynamic therapy is likely related to better biliary decompression and avoidance of early segmental duct isolation and subsequent cholangitis, rather than any significant reduction in tumor burden.133

SUMMARY FIGURE 51A.23  Transhepatic cholangiography obtained through a temporary percutaneous drainage tube shows a widely patent anastomosis from the segment III duct to a Roux-en-Y loop of jejunum (arrows). (See Chapter 31.)

Palliative systemic chemotherapy has been investigated. The Advanced Biliary Cancer (ABC) 02 trial randomized 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin followed by gemcitabine or gemcitabine alone for up to 6 months.100 This study showed an improvement in median survival from 8.2 to 11.7 months for patients receiving cisplatin plus gemcitabine without the addition of substantial toxicity. This regimen remains the first-line recommendation for patients with unresectable or metastatic biliary tract cancers.

Improvements in high-resolution cross-sectional imaging have permitted better patient selection and enhanced preoperative planning and preparation before the safe performance of operations for hilar cholangiocarcinoma. Long-term disease-free survival is the primary goal of operative resection. Judicious use of adjunctive preoperative interventions that include biliary drainage and PVE may help improve outcomes, especially when major perioperative and postoperative complications are anticipated. Selection of appropriate nonoperative therapies for palliation of unresectable tumors arising from the proximal and distal bile ducts should be tailored, according to the patient’s expected longevity and technical expertise of the multidisciplinary team charged with treating bile duct cancer. Future studies in extrahepatic cholangiocarcinoma should focus on adjuvant strategies along with implementation of genomics, epigenetics, targeted therapies, and immunotherapy. References are available at expertconsult.com.

741.e1

REFERENCES 1. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95-111. 2. Al Mahjoub A, Bouvier V, Menahem B, et al. Epidemiology of intrahepatic, perihilar, and distal cholangiocarcinoma in the French population. Eur J Gastroenterol Hepatol. 2019;31(6):678-684. 3. Mukkamalla SKR, Naseri HM, Kim BM, Katz SC, Armenio VA. Trends in incidence and factors affecting survival of patients with cholangiocarcinoma in the United States. J Natl Compr Canc Netw. 2018;16(4):370-376. 4. Van Dyke AL, Shiels MS, Jones GS, et al. Biliary tract cancer incidence and trends in the United States by demographic group, 1999-2013. Cancer. 2019;125(9):1489-1498. 5. Labib PL, Goodchild G, Pereira SP. Molecular pathogenesis of cholangiocarcinoma. BMC Cancer. 2019;19(1):185. 6. Jing W, Jin G, Zhou X, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev. 2012;21(1): 24-31. 7. Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PLoS One. 2017;12(10): e0186643. 8. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol. 2007;5(10):1221-1228. 9. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. 10. Corvera CU, Blumgart LH, Darvishian F, et al. Clinical and pathologic features of proximal biliary strictures masquerading as hilar cholangiocarcinoma. J Am Coll Surg. 2005;201(6):862-869. 11. Otsuka S, Ebata T, Yokoyama Y, et al. Clinical value of additional resection of a margin-positive distal bile duct in perihilar cholangiocarcinoma. Br J Surg. 2019;106(6):774-782. 12. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg. 2005;241(5):703-712; discussion 712-714. 13. Castellano-Megías VM, Ibarrola-de Andrés C, Colina-Ruizdelgado F. Pathological aspects of so called “hilar cholangiocarcinoma”. World J Gastrointest Oncol. 2013;5(7):159-170. 14. Lowery MA, Ptashkin R, Jordan E, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018;24(17): 4154-4161. 15. Lamarca A, Kapacee Z, Breeze M, et al. Molecular profiling in daily clinical practice: practicalities in advanced cholangiocarcinoma and other biliary tract cancers. J Clin Med. 2020;9(9):2854. doi:10.3390/jcm9092854. 16. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003-1010. 17. Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9(12):e115383. 18. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755-762. 19. Cho MS, Kim SH, Park SW, et al. Surgical outcomes and predicting factors of curative resection in patients with hilar cholangiocarcinoma: 10-year single-institution experience. J Gastrointest Surg. 2012;16(9):1672-1679. 20. Way LW. Biliary tract. In: Way LW, ed. Current Surgical Diagnosis and Treatment. 10th ed. Norwalk, CT: Appleton & Lange; 1994:537-566. 21. Bloom CM, Langer B, Wilson SR. Role of US in the detection, characterization, and staging of cholangiocarcinoma. Radiographics. 1999;19(5):1199-1218. 22. Bach AM, Hann LE, Brown KT, et al. Portal vein evaluation with US: comparison to angiography combined with CT arterial portography. Radiology. 1996;201(1):149-154. 23. Masselli G, Manfredi R, Vecchioli A, Gualdi G. MR imaging and MR cholangiopancreatography in the preoperative evaluation of hilar cholangiocarcinoma: correlation with surgical and pathologic findings. Eur Radiol. 2008;18(10):2213-2221.

24. D’Antuono F, De Luca S, Mainenti PP, et al. Comparison between multidetector CT and High-field 3T MR imaging in diagnostic and tumour extension evaluation of patients with cholangiocarcinoma. J Gastrointest Cancer. 2020;51(2):534-544. 25. Lamarca A, Barriuso J, Chander A, et al. 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) for patients with biliary tract cancer: systematic review and meta-analysis. J Hepatol. 2019;71(1):115-129. 26. Tamada K, Ushio J, Sugano K. Endoscopic diagnosis of extrahepatic bile duct carcinoma: advances and current limitations. World J Clin Oncol. 2011;2(5):203-216. 27. Silva MA, Tekin K, Aytekin F, Bramhall SR, Buckels JA, Mirza DF. Surgery for hilar cholangiocarcinoma; a 10 year experience of a tertiary referral centre in the UK. Eur J Surg Oncol. 2005;31(5): 533-539. 28. Tirotta F, Giovinazzo F, Hodson J, et al. Risk factors to differentiate between benign proximal biliary strictures and perihilar cholangiocarcinoma. HPB (Oxford). 2020;22(12):1753-1758. 29. Mohkam K, Malik Y, Derosas C, et al. Percutaneous transhepatic cholangiographic endobiliary forceps biopsy versus endoscopic ultrasound fine needle aspiration for proximal biliary strictures: a single-centre experience. HPB (Oxford). 2017;19(6):530-537. 30. Lee YN, Moon JH, Choi HJ, et al. Tissue acquisition for diagnosis of biliary strictures using peroral cholangioscopy or endoscopic ultrasound-guided fine-needle aspiration. Endoscopy. 2019;51(1):50-59. 31. Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012; 61(12):1657-1669. 32. Mansour JC, Aloia TA, Crane CH, Heimbach JK, Nagino M, Vauthey JN. Hilar cholangiocarcinoma: expert consensus statement. HPB (Oxford). 2015;17(8):691-699. 33. Lidsky ME, Jarnagin WR. Surgical management of hilar cholangiocarcinoma at Memorial Sloan Kettering Cancer Center. Ann Gastroenterol Surg. 2018;2(4):304-312. doi:10.1002/ags3.12181. 34. Soares KC, Jarnagin WR. The landmark series: hilar cholangiocarcinoma. Ann Surg Oncol. 2021;28(8):4158-4170. doi:10.1245/ s10434-021-09871-6. 35. Kawasaki S, Imamura H, Kobayashi A, Noike T, Miwa S, Miyagawa S. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg. 2003;238(1):84-92. 36. Iacono C, Ruzzenente A, Campagnaro T, et al. Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks. Ann Surg. 2013;257(2):191-204. 37. Cherqui D, Benoist S, Malassagne B, Humeres R, Rodriguez V, Fagniez PL. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg. 2000; 135(3):302-308. 38. Kennedy TJ, Yopp A, Qin Y, et al. Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma. HPB (Oxford). 2009;11(5):445-451. 39. Wiggers JK, Groot Koerkamp B, Cieslak KP, et al. Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant. J Am Coll Surg. 2016;223(2):321-331.e1. 40. Coelen RJS, Roos E, Wiggers JK, et al. Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018;3(10):681-690. 41. Xia MX, Wang SP, Wu J, et al. The risk of acute cholangitis after endoscopic stenting for malignant hilar strictures: a large comprehensive study. J Gastroenterol Hepatol. 2020;35(7):1150-1157. 42. Kubota K, Hasegawa S, Iwasaki A, et al. Stent placement above the sphincter of Oddi permits implementation of neoadjuvant chemotherapy in patients with initially unresectable Klatskin tumor. Endosc Int Open. 2016;4(4):E427-E433. 43. Kariya CM, Wach MM, Ruff SM, et al. Postbiliary drainage rates of cholangitis are impacted by procedural technique for patients with supra-ampullary cholangiocarcinoma: A SEER-Medicare analysis. J Surg Oncol. 2019;120(2):249-255. 44. Kang MJ, Choi YS, Jang JY, Han IW, Kim SW. Catheter tract recurrence after percutaneous biliary drainage for hilar cholangiocarcinoma. World J Surg. 2013;37(2):437-442.

741.e2 45. Kawakubo K, Kawakami H, Kuwatani M, et al. Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma. World J Gastrointest Endosc. 2016;8(9):385-390. doi:10.4253/wjge.v8.i9.385. 46. Nakai Y, Yamamoto R, Matsuyama M, et al. Multicenter study of endoscopic preoperative biliary drainage for malignant hilar biliary obstruction: E-POD hilar study. J Gastroenterol Hepatol. 2018; 33(5):1146-1153. 47. Assimakopoulos SF, Tsamandas AC, Louvros E, et al. Intestinal epithelial cell proliferation, apoptosis and expression of tight junction proteins in patients with obstructive jaundice. Eur J Clin Invest. 2011;41(2):117-125. 48. Ogata Y, Nishi M, Nakayama H, Kuwahara T, Ohnishi Y, Tashiro S. Role of bile in intestinal barrier function and its inhibitory effect on bacterial translocation in obstructive jaundice in rats. J Surg Res. 2003;115(1):18-23. 49. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527. 50. Leung U, Simpson AL, Araujo RL, et al. Remnant growth rate after portal vein embolization is a good early predictor of post-hepatectomy liver failure. J Am Coll Surg. 2014;219(4):620-630. 51. van Lienden KP, van den Esschert JW, de Graaf W, et al. Portal vein embolization before liver resection: a systematic review. Cardiovasc Intervent Radiol. 2013;36(1):25-34. 52. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247(1):49-57. 53. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 1992;215(1):31-38. 54. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507-519. doi:10.1097/00000658-200110000-00010. 55. Zaydfudim VM, Clark CJ, Kendrick ML, et al. Correlation of staging systems to survival in patients with resected hilar cholangiocarcinoma. Am J Surg. 2013;206(2):159-165. 56. Bird N, Elmasry M, Jones R, et al. Role of staging laparoscopy in the stratification of patients with perihilar cholangiocarcinoma. Br J Surg. 2017;104(4):418-425. 57. Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg. 2002;235(3):392-399. 58. Allen PJ, Reiner AS, Gonen M, et al. Extrahepatic cholangiocarcinoma: a comparison of patients with resected proximal and distal lesions. HPB (Oxford). 2008;10(5):341-346. 59. Nakanishi Y, Okamura K, Tsuchikawa T, et al. Time to recurrence after surgical resection and survival after recurrence among patients with perihilar and distal cholangiocarcinomas. Ann Surg Oncol. 2020;27(11):4171-4180. 60. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with special reference to the caudate lobe. World J Surg. 1988;12(1):2-10. 61. Nagino M, Ebata T,Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013;258(1):129-140. 62. Endo I, House MG, Klimstra DS, et al. Clinical significance of intraoperative bile duct margin assessment for hilar cholangiocarcinoma. Ann Surg Oncol. 2008;15(8):2104-2112. 63. Blumgart LH, Hadjis NS, Benjamin IS, Beazley R. Surgical approaches to cholangiocarcinoma at confluence of hepatic ducts. Lancet. 1984;1(8368):66-70. 64. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg. 1999;230(6):808-819. 65. Mizuno T, Ebata T, Yokoyama Y, et al. Combined vascular resection for locally advanced perihilar cholangiocarcinoma. Ann Surg. 2022; 275(2):382-390. doi:10.1097/SLA.0000000000004322. 66. Lang H, de Santibañes E, Schlitt HJ, et al. 10th Anniversary of ALPPS-lessons learned and quo vadis. Ann Surg. 2019;269(1): 114-119. 67. Sakamoto Y, Matsumura M, Yamashita S, Ohkura N, Hasegawa K, Kokudo N. Partial TIPE ALPPS for perihilar cancer. Ann Surg. 2018;267(2):e18-e20. 68. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255(3):405-414.

69. Serenari M, Zanello M, Schadde E, et al. Importance of primary indication and liver function between stages: results of a multicenter Italian audit of ALPPS 2012-2014. HPB (Oxford). 2016;18(5):419427. 70. Olthof PB, Miyasaka M, Koerkamp BG, et al. A comparison of treatment and outcomes of perihilar cholangiocarcinoma between Eastern and Western centers. HPB (Oxford). 2019;21(3):345-351. doi:10.1016/j.hpb.2018.07.014. 71. Iwatsuki S, Todo S, Marsh JW, et al. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg. 1998;187(4):358-364. 72. Klempnauer J, Ridder GJ, Werner M, Weimann A, Pichlmayr R. What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer. 1997;79(1):26-34. 73. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69(8):1633-1637. 74. Robles R, Figueras J, Turrión VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg. 2004;239(2):265-271. 75. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004;24(2):201-207. 76. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242(3):451-461. 77. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000;6(3):309-316. 78. Anderson B, Doyle MBM. Surgical considerations of hilar cholangiocarcinoma. Surg Oncol Clin N Am. 2019;28(4):601-617. 79. Croome KP, Rosen CB, Heimbach JK, Nagorney DM. Is liver transplantation appropriate for patients with potentially resectable de novo hilar cholangiocarcinoma? J Am Coll Surg. 2015;221(1):130-139. 80. Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018; 267(5):797-805. 81. Rosen CB, Heimbach JK, Gores GJ. Surgery for cholangiocarcinoma: the role of liver transplantation. HPB (Oxford). 2008;10(3): 186-189. 82. Ethun CG, Lopez-Aguiar AG, Pawlik TM, et al. Distal cholangiocarcinoma and pancreas adenocarcinoma: are they really the same disease? A 13-Institution Study from the US Extrahepatic Biliary Malignancy Consortium and the central pancreas consortium. J Am Coll Surg. 2017;224(4):406-413. 83. Komaya K, Ebata T, Yokoyama Y, et al. Recurrence after curativeintent resection of perihilar cholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach. Surgery. 2018;163(4):732-738. 84. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996; 224(4):463-475. 85. Launois B, Reding R, Lebeau G, Buard JL. Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers. J Hepatobiliary Pancreat Surg. 2000; 7(2):128-134. 86. Groot Koerkamp B, Wiggers JK, Allen PJ, et al. Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg. 2015;221(6):1041-1049. 87. Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105(3):192-202. 88. Nakahashi K, Ebata T,Yokoyama Y, et al. How long should follow-up be continued after R0 resection of perihilar cholangiocarcinoma? Surgery. 2020;168(4):617-624. 89. Cannon RM, Brock G, Buell JF. Surgical resection for hilar cholangiocarcinoma: experience improves resectability. HPB (Oxford). 2012;14(2):142-149. 90. Lee SG, Lee YJ, Park KM, Hwang S, Min PC. One hundred and eleven liver resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg. 2000;7(2):135-141. 91. Gerhards MF, van Gulik TM, de Wit LT, Obertop H, Gouma DJ. Evaluation of morbidity and mortality after resection for hilar cholangiocarcinoma—a single center experience. Surgery. 2000; 127(4):395-404.

741.e3 92. Nishio H, Nagino M, Nimura Y. Surgical management of hilar cholangiocarcinoma: the Nagoya experience. HPB (Oxford). 2005; 7(4):259-262. doi:10.1080/13651820500373010. 93. Igami T, Nishio H, Ebata T, et al. Surgical treatment of hilar cholangiocarcinoma in the “new era”: the Nagoya University experience. J Hepatobiliary Pancreat Sci. 2010;17(4):449-454. 94. Unno M, Katayose Y, Rikiyama T, et al. Major hepatectomy for perihilar cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2010; 17(4):463-469. 95. Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg. 2012;215(3): 343-355. 96. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98(8):1689-1700. 97. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95(8): 1685-1695. 98. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study [published correction appears in Lancet Oncol. 2019;20(5):663-673. 99. Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019;37(12):1015-1027. 100. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362(14):1273-1281. 101. Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019;37(8):658-667. 102. Ebata T, Mizuno T, Yokoyama Y, Igami T, Sugawara G, Nagino M. Surgical resection for Bismuth type IV perihilar cholangiocarcinoma. Br J Surg. 2018;105(7):829-838. 103. Cameron JL, Pitt HA, Zinner MJ, Kaufman SL, Coleman J. Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg. 1990;159(1):91-98. 104. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg. 1995;221(6):788-798. 105. Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol. 2008;15(11):3147-3156. 106. Kamada T, Saitou H, Takamura A, Nojima T, Okushiba SI. The role of radiotherapy in the management of extrahepatic bile duct cancer: an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy. Int J Radiat Oncol Biol Phys. 1996;34(4):767-774. 107. Kim TH, Han SS, Park SJ, et al. Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys. 2011;81(5):e853-e859. 108. Nakeeb A, Comuzzie AG, Martin L, et al. Gallstones: genetics versus environment. Ann Surg. 2002;235(6):842-849. 109. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A Phase II Intergroup Trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617-2622. 110. Stein A, Arnold D, Bridgewater J, et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015;15:564. 111. Nakachi K, Konishi M, Ikeda M, et al. A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT). Jpn J Clin Oncol. 2018;48(4):392-395.

112. Kim HJ, Yoo TW, Park DI, et al. Gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in nodepositive patients. Ann Oncol. 2007;18(5):892-897. 113. Ruzzenente A, Fassan M, Conci S, et al. Cholangiocarcinoma heterogeneity revealed by multigene mutational profiling: clinical and prognostic relevance in surgically resected patients. Ann Surg Oncol. 2016;23(5):1699-1707. 114. Silva VW, Askan G, Daniel TD, et al. Biliary carcinomas: pathology and the role of DNA mismatch repair deficiency. Chin Clin Oncol. 2016;5(5):62. 115. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. 116. Jarnagin WR, Burke E, Powers C, Fong Y, Blumgart LH. Intrahepatic biliary enteric bypass provides effective palliation in selected patients with malignant obstruction at the hepatic duct confluence. Am J Surg. 1998;175(6):453-460. 117. Dumonceau JM, Tringali A, Blero D, et al. Biliary stenting: indications, choice of stents and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 2012; 44(3):277-298. 118. Dowsett JF, Vaira D, Hatfield AR, et al. Endoscopic biliary therapy using the combined percutaneous and endoscopic technique. Gastroenterology. 1989;96(4):1180-1186. 119. Raju RP, Jaganmohan SR, Ross WA, et al. Optimum palliation of inoperable hilar cholangiocarcinoma: comparative assessment of the efficacy of plastic and self-expanding metal stents. Dig Dis Sci. 2011;56(5):1557-1564. 120. Liberato MJ, Canena JM. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients. BMC Gastroenterol. 2012;12:103. 121. Robson PC, Heffernan N, Gonen M, et al. Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction. Ann Surg Oncol. 2010;17(9):2303-2311. 122. Witzigmann H, Lang H, Lauer H. Guidelines for palliative surgery of cholangiocarcinoma. HPB (Oxford). 2008;10(3):154-160. 123. Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg. 1999;230(5): 663-671. 124. Li HM, Dou KF, Sun K, Gao ZQ, Li KZ, Fu YC. Palliative surgery for hilar cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2003;2(1):110-113. 125. Zhang BH, Cheng QB, Luo XJ, et al. Surgical therapy for hiliar cholangiocarcinoma: analysis of 198 cases. Hepatobiliary Pancreat Dis Int. 2006;5(2):278-282. 126. Guthrie CM, Banting SW, Garden OJ, Carter DC. Segment III cholangiojejunostomy for palliation of malignant hilar obstruction. Br J Surg. 1994;81(11):1639-1641. 127. Stoker J, Laméris JS. Complications of percutaneously inserted biliary Wallstents. J Vasc Interv Radiol. 1993;4(6):767-772. 128. Moureau-Zabotto L, Turrini O, Resbeut M, et al. Impact of radiotherapy in the management of locally advanced extrahepatic cholangiocarcinoma. BMC Cancer. 2013;13:568. doi:10.1186/ 1471-2407-13-568. 129. Bowling TE, Galbraith SM, Hatfield AR, Solano J, Spittle MF. A retrospective comparison of endoscopic stenting alone with stenting and radiotherapy in non-resectable cholangiocarcinoma. Gut. 1996;39(6):852-855. 130. Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25(12):2328-2333. 131. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003;125(5):1355-1363. 132. Zoepf T, Jakobs R, Arnold JC, Apel D, Riemann JF. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol. 2005;100(11):2426-2430. 133. Quyn AJ, Ziyaie D, Polignano FM, Tait IS. Photodynamic therapy is associated with an improvement in survival in patients with irresectable hilar cholangiocarcinoma. HPB (Oxford). 2009; 11(7):570-577.

CHAPTER 51B Perihilar cholangiocarcinoma: Presurgical management Roeland F. de Wilde and Bas Groot Koerkamp

The perihilar region is among the most common site of origin of cholangiocarcinoma (perihilar cholangiocarcinoma [pCCA]).1–3 However, considering the incidence of 1 to 2 per 100,000 in Western countries, which is significantly lower than in Asia, the disease remains rare.2,4 By the American Joint Cancer Committee (AJCC) definition, pCCA originates distal to the second-order intrahepatic bile ducts and proximal to the insertion of the cystic duct into the extrahepatic bile duct.5 It may be difficult to discriminate pCCA from intrahepatic cholangiocarcinoma extending into the hepatic hilum.6 Complete resection is associated with 5-year overall survival (OS) rates of up to 35%.7 However, only approximately onethird of patients are considered resectable. A resection generally requires a hemihepatectomy or greater, en bloc caudate resection with extrahepatic bile duct resection and lymphadenectomy. Reconstruction often entails complex biliary and sometimes vascular reconstruction to obtain negative surgical margins and an adequate future liver remnant (FLR).8–10 Nonetheless, positive surgical margins are observed in about one-third of patients, adversely affecting outcome11,12 (see Chapter 119B). Surgery for pCCA is associated with considerable 90-day postoperative mortality rates of 5% to 18% in Western centers. However, much lower mortality rates of 1% to 3% have been reported in recent Eastern series.12–16 Multidisciplinary treatment of pCCA is complex and should take place in tertiary referral centers. Upon suspicion of pCCA, before any intervention, referral or consultation of an expert center should take place. Failure to do so may result in a lost opportunity to obtain adequate imaging before biliary drainage, unnecessary or inadequate drainage increasing surgical risk, and lost opportunity for resection or liver transplantation. In this chapter, we will cover management of patients with pCCA before surgery.

DIAGNOSING pCCA Patients with pCCA typically present with painless jaundice (90%). Concomitant cholangitis is uncommon and occurs in 10% of patients.17,18 pCCA rarely arises in the left or right hepatic duct without jaundice. Anorexia, fatigue, weight loss, and sarcopenia are each observed in about 50% of patients.18,19 Physical examination of the abdomen may reveal a palpable mass in the upper abdomen indicative of unilateral hepatic lobe hypertrophy because of the concomitant contralateral lobar atrophy (Fig. 51B.1).20,21 Blood analysis generally reflects cholestasis and sometimes cholangitis. Serum carbohydrate antigen (CA) 19-9 level is high in most patients, but elevated CA 19-9 may be partially attributable to biliary obstruction. Moreover, about 10% of patients do not produce CA 19-9 because of the lack of the Lewis antigen.22,23 Determination of immunoglobulin G4 (IgG4) serum level can help in diagnosing eosinophilic cholangiopathy (i.e., 742

lymphoplasmatic cholangiopathy, more commonly referred to as auto-immune cholangitis), which is one of the benign diagnoses that may present as a hilar biliary obstruction24 (see Chapters 47 and 48). However, IgG4 can be normal in patients with autoimmune cholangitis and IgG4 can be elevated in patients with pCCA. A 4-fold increase in IgG4 nearly excludes pCCA. The HISORt criteria predict the presence of IgG4-associated disease based on histology, imaging (typically smooth concentric biliary wall thickening with a visible lumen, absence of a mass, skip lesions, and involvement of the extrahepatic bile duct), serology, other organ manifestation, and response to steroid treatment.25,26 Finally, liver fluke infestation (Clonorchis sinensis and Opisthorchis viverrini) can be ruled out with serology if in an endemic area27 (see Chapter 45). High-quality prestenting imaging is a crucial step in the preoperative work-up of pCCA, enabling diagnosis, staging, liver volumetry, and determination of the extent of resection22 (see Chapters 16 and 102). High-resolution thin-slice computed tomography (CT) with multiphase scanning using intravenous (IV) contrast (i.e., arterial and portovenous phases) enables a diagnostic accuracy to detect arterial involvement up to 93% and portal vein involvement as high as 87%. However, sensitivity of detecting lymph node metastases is poor (54%) and the proximal biliary extent of the tumor is often underestimated.28 Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is superior to CT in assessing the intrahepatic biliary extent of pCCA and to help discriminate benign etiologies from pCCA (e.g., Mirizzi syndrome, intrahepatic lithiasis, and primary sclerosing cholangitis [PSC]; Fig. 51B.2).29 The role of positron emission tomography (PET) scanning is limited because of false-positive results related to inflammation and is reflected by a specificity of 67%30,31 (see Chapter 18). It is of utmost importance to realize that the diagnosis and staging after biliary stenting are considerably impaired because of decompression of the biliary system and imaging artefacts induced by stenting-related inflammation. Patients with a perihilar obstruction should be referred to an expert center before biliary drainage because high-quality imaging is essential before biliary drainage, not all patients with pCCA require biliary drainage, and drainage of the FLR is only possible after an expert team has determined the resection plan (see later). Tissue diagnosis is challenging because of the low sensitivity (typically less than 40%) of an endoscopic or percutaneous brush.20,32 A tissue diagnosis is not mandatory for surgical exploration. The application of fluorescent in situ hybridization (FISH) to determine polysomy in addition to conventional cytology typically doubles the sensitivity to detect a malignancy.33 In a study on PSC patients with a dominant stricture without visible mass and equivocal cytology undergoing routine endoscopic brushing, multivariable analysis revealed FISH to be the only significant predictor of malignancy (see Chapter 43). Once

C. Malignant Tumors  Chapter 51B  Perihilar Cholangiocarcinoma: Presurgical Management

FIGURE 51B.1  Diagnostic computed tomography (CT) scan of a patient with Bismuth type 3B perihilar cholangiocarcinoma (pCCA). This image features lobar atrophy of the left liver lobe. The demarcation line is indicated with an arrow (see Chapter 16).

CA 19-9 was at least 129, a hazard ratio (HR) of 11 was found when combined with polysomy on FISH.34 Percutaneous biopsy of pCCA should be avoided in patients that may be eligible for a liver transplant (LT; see later).35 Biopsy may cause needle track metastases and LT is therefore contraindicated in many centers after any transperitoneal biopsy. Suspicious lymphadenopathy may be subjected to fine needle aspiration (FNA) through endoscopic ultrasound (EUS) or resection at staging laparoscopy.22 The current expert consensus statements of the American Hepato-Pancreato-Biliary Association (AHPBA), the National Comprehensive Cancer Network (NCCN), and the European Network for the Study of Cholangiocarcinoma (ENS-CCA) on the initial evaluation of pCCA dictate22,36–38: • The minimum diagnostic and staging work-up in suspected pCCA includes liver function, CA 19-9 level, and highquality cross-sectional imaging (preferably before biliary stenting) of the chest, abdomen and pelvis, besides cholangiography. • Early consultation of a multidisciplinary team includes a surgeon with expertise in pCCA. • Pathologic confirmation is not required before surgical exploration for resection or initiation of an LT protocol, provided that benign etiologies have been excluded and a complete staging evaluation has been completed. • Percutaneous or laparoscopic biopsy of the primary tumor is not recommended in patients who may be candidates for transplantation because of the risk of biopsy tract metastases. • Imaging by fluorodeoxyglucose-PET lacks the sensitivity and specificity required to be a routine staging tool for patients with pCCA. The diagnostic work-up for pCCA is imperfect because, after surgery for anticipated pCCA, approximately 10% of patients are diagnosed with benign disease at pathologic examination of the resected specimen.10,12,39,40

CLASSIFICATION AND STAGING Clinical staging of pCCA should first rule out metastatic disease by means of chest and abdominal/pelvic CT. Patients with

743

A

B FIGURE 51B.2  Diagnostic magnetic resonance imaging (MRI) of two patients with perihilar cholangiocarcinoma (pCCA). The left panel depicts an axial view of a Bismuth type 3A pCCA. The tumor is often iso-intense with the surrounding liver parenchyma but can be located at the abrupt cut-off (arrows) of the intrahepatic bile ducts. The right panel depicts a coronal view of a magnetic resonance cholangiopancreatography (MRCP) of a Bismuth type 2 pCCA with secondary biliary dilatation of the right (short arrow) and left (long arrow) intrahepatic bile ducts (see Chapter 16).

distant metastases (e.g., in lung and peritoneum) and lymph node involvement beyond the hepatoduodenal ligament (e.g., aortocaval) have Stage IV disease and should rarely be considered for upfront resection.9,41 Several tumor-staging systems aim to determine local disease extent, guide treatment decisions (i.e., determine resectability), and inform prognosis.42 Unfortunately, current staging of pCCA remains challenging and imperfect and most systems are based on surgical pathology and therefore not applicable to the majority of patients that do not undergo resection.43–46 The Bismuth-Corlette system was the first tumor-staging system to classify pCCA based solely on the extent of involvement of the biliary tree (Fig. 51B.3).47 However, this classification does not take into account the radial extent of pCCA into surrounding structures such as the liver, hilar soft tissue, and vasculature. Bismuth stage is insufficient to determine resectability; for example, a large study found excellent outcomes of

744

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

A

B

C

D

FIGURE 51B.3  Summary of different classification systems of perihilar cholangiocarcinoma (pCCA). A, Key anatomic structures (portal vein, hepatic artery, and bile ducts) considered in staging pCCA. B, Bismuth-Corlette staging system. Blumgart/ Memorial Sloan-Kettering Cancer Center (MSKCC) stage T1: tumor involving the bile duct bifurcation and/or unilateral extension into second-order bile ducts. C, Blumgart/MSKCC stage T2: unilateral vascular involvement and/or unilateral lobar atrophy. D, Blumgart/MSKCC stage T3: bilateral/contralateral involvement of second-order bile ducts, vascular involvement, and/or lobar atrophy. (Adapted from Hartog H, Ijzermans JN, van Gulik TM, et al. Resection of perihilar cholangiocarcinoma. Surg Clin North Am. 2016;96[2]:247–267.Original artwork by Mrs. Elsbeth Leeffers.)

resection for Bismuth IV pCCA.41 In addition to the biliary extent of the tumor, the Memorial Sloan-Kettering Cancer Center (MSKCC) staging system involves portal venous involvement and lobar atrophy (Fig. 51B.3).10 However, both classification systems perform poorly in predicting resectability because in most series about 50% of patients undergoing surgical exploration with curative intent undergo a resection.48,49 The third staging-system is the AJCC/International Union Against Cancer (UICC) tumor-node-metastasis (TNM) system, which is currently in its eighth edition.5 The T-stage of pCCA relies heavily on vascular invasion (unilateral or bilateral of portal vein or hepatic artery) but does not describe how pathologic vascular invasion can be determined on imaging or what extent of vascular invasion is still potentially resectable. Evaluation of the current eighth edition compared with the seventh edition showed slightly improved prognostic accuracy for patients after resection but remained poor in patients with unresectable disease.50,51 To inform prognosis after resection of pCCA, staging systems have been developed that perform better than the TNM staging.7

PREOPERATIVE CONSIDERATIONS TO SURGERY FOR pCCA The median OS of patients with pCCA without surgery is around 8 months compared with up to 40 months after resection with curative intent.7 Actual cure (i.e., 10-year OS) is rarely seen outside of patients with papillary or well-differentiated pCCA.52 The expected benefit of surgery should outweigh the substantial postoperative morbidity and mortality.

Resectability The aim of resection for pCCA is a margin negative resection and an adequate FLR11 (see Chapters 101B, 118A, and 119B). Because of the anatomic location and propensity for infiltration into the central liver, a hemihepatectomy or greater with enbloc caudate resection is typically required for complete resection of pCCA.53 Whether a right-sided or left-sided resection is necessary is determined by unilateral lobar atrophy, unilateral second-order bile duct involvement, unilateral portal vein, or unilateral hepatic artery involvement.9 In patients with a

C. Malignant Tumors  Chapter 51B  Perihilar Cholangiocarcinoma: Presurgical Management

Bismuth I or II tumor without unilateral atrophy or vascular involvement, both right- and left sided resections could result in an R0 resection. The disadvantage of a right-sided resection is that the right liver is larger than the left liver, resulting in a higher risk of postoperative morbidity and liver failure. In 80% of patients, the volume of the left lateral sector is below 20% and in 10% of patients the volume of the left hemiliver is below 20%.54 In general, when possible, a left-sided resection leaves a much larger FLR, minimizes the risk of postoperative liver failure, and is the preferred approach. An adequate FLR must include at least two contiguous liver segments with sufficient functional capacity and intact arterial venous inflow, portal venous inflow, and portal venous outflow.9 The FLR volume is measured by image-guided volumetry where the FLR should constitute at least 25% of the total liver volume before resection in the absence of underlying liver disease, hepatotoxic preoperative chemotherapy, or biliary obstruction. Most patients with pCCA require a larger FLR volume (.30%–40%) because of biliary obstruction to avoid postoperative liver failure.55 Obtaining an R0 resection may require portal vein reconstruction and a complex biliary reconstruction with often more than one hepaticojejunostomy. In Western countries, arterial reconstructions are rarely performed to obtain an R0 resection of pCCA: postoperative mortality rate is increased, and survival is generally poor in patients, which makes it difficult to justify.56

Patient-Related Variables Several patient-related variables should be taken into consideration to compare the benefit and risk of resection for patients with pCCA. A risk score model was developed to predict postoperative mortality after resection of pCCA.16 Independent prognostic factors for postoperative mortality included age, preoperative cholangitis, FLR volume of less than 30%, incomplete biliary drainage of the FLR in patients with an FLR volume of less than 50%, and portal vein reconstruction (Table 51B.1). Age was the most important poor prognostic factor with the risk of both postoperative liver failure and death increasing rapidly with advanced age. The predicted 90-day postoperative mortality risks were 2% (low risk: 0–2 points), 11% (intermediate risk: 3 or 4 points), or 37% (high risk: 5–9 points). Another study identified similar factors to

745

predict postoperative liver failure, including albumin level below 3.5 mg/dL, preoperative cholangitis, preoperative total bilirubin level above 3 mg/dL (51 mmol/L), and FLR volume of less than 30% (see Table 51B.1).57 In summary, several patient-related factors contribute significantly to the risk of postoperative liver failure, such as age, low serum albumin level, cholangitis, hyperbilirubinemia/jaundice and incomplete drainage of the FLR, low FLR volume, and portal vein reconstruction. These factors should be taken into account and optimized when considering a resection in patients with pCCA.

OPTIMIZING THE FUTURE LIVER REMNANT Biliary Drainage (see Chapters 30, 31, 52) Biliary drainage aims to restore the regenerative capacity of the FLR. Preoperative biliary drainage is necessary in patients with: • cholangitis, • jaundice and the need to undergo neoadjuvant therapy, • liver or renal insufficiency possibly related to hyperbilirubinemia, and • small FLR volume (,50%), especially before PVE.22 There are several approaches to biliary drainage. The two most commonly used techniques worldwide are endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD; Fig. 51B.4).58,59 There is currently no universal consensus on the preferred method of preoperative biliary drainage in patients with pCCA. Several small retrospective studies have reported higher technical success and fewer

TABLE 51B.1  Risk Factors (Multivariate Analysis) for Postoperative Mortality After Resection of pCCA from Two Studies RISK FACTOR

OR

95% CI

P VALUE

Age (per 10 years)a Preoperative cholangitis

2.1 4.1* 7.5† 2.8

1.4–3.3 1.8–9.4 1.5–29.0 1.1–7.5

.001 .001 .016 .04

2.9a 7.2b 2.3

1.2–6.9 1.4–37.0 0.9–5.8

.02 .019 .09

Incomplete biliary drainage 1 FLR ,50%a FLR ,30% Portal vein reconstructiona

CI, Confidence interval; FLR, future liver remnant; OR, odds ratio; pCCA, perihilar cholangiocarcinoma. a Data from Wiggers JK, Groot Koerkamp B, Cieslak KP, et al. Postoperative mortality after liver resection for perihilar cholangiocarcinoma: Development of a risk score and importance of biliary drainage of the future liver remnant. J Am Coll Surg. 2016;223(2):321–331.e1. b Data from Ribero D, Zimmitti G, Aloia TA, et al. Preoperative cholangitis and future liver remnant volume determine the risk of liver failure in patients undergoing resection for hilar cholangiocarcinoma. J Am Coll Surg. 2016;223(1):87–97.

FIGURE 51B.4  Diagnostic fluoroscopic image of a patient with Bismuth type 3A/B perihilar cholangiocarcinoma (pCCA) in whom a right extended hemihepatectomy was intended. Upon the initial attempt to biliary drainage through endoscopic retrograde cholangiopancreatography (ERCP), the left biliary system could not be reached to drain the future liver remnant (FLR). Thus a plastic endoprosthesis (short arrow) was placed in the right biliary system. Drainage of the FLR (i.e., the left biliary system) was accomplished through additional percutaneous transhepatic biliary drainage (PTBD) in this case (long arrow; see Chapters 31 and 52)

746

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

complications after PTBD.58,60 A multicenter randomized controlled trial (RCT) in four expert centers investigated the incidence of severe drainage-related complications of EBD or PTBD in patients with potentially resectable pCCA.61 Interim analysis after randomization of 54 patients (50% accrual) revealed a statistically significant difference in mortality at 90-day follow-up after surgery between the PTBD group (41%) and the EBD group (11%, relative risk [RR] 3.67, 1.15–11.69, P 5 .03), which led to the decision to stop the trial. This RCT included all patients who had resectable pCCA on imaging, compared with retrospective studies that only included the subgroup (typically 50%–65%) who underwent a resection.61 Mortality was higher than in retrospective studies because it also included substantial mortality in the preoperative period, as well as mortality from patients who were explored but did not undergo a resection. Technical success of biliary drainage was higher in the PTBD group than the EBD group (93% vs. 74%; P 5 .07), whereas therapeutic success one week after drainage was equal in both groups (78% vs. 63%; P 5 .21, respectively for PTBD and EBD). Crossover treatment was significantly higher in the EBD group (56%) versus the PTBD group (n 5 1, 4%, P , .0001), and 76% of patients underwent more than one drainage procedure before surgery. One or more severe drainage-related complications were observed in 67% of EBD patients and 63% of PTBN patients (RR 0.94, 0.64–1.40, absolute risk difference [ARD] 3.7%), of which cholangitis was most frequently observed (59% vs. 37%, P 5 .1, respectively amongst PTBD and EBD). Severe complications within 90days after surgery were observed in 65% of PTBD patients and 55% (RR 1.19, 0.73–1.96, ARD 10.4%) of EBD patients. The percentage of cholangitis that occurred in the PTBD group was relatively high compared with the historical series where the prevalence of cholangitis was reported below 20%.62–64 The INTERCPT trial also compared PTBD and EBD as the initial approach when managing a patient with suspected hilar malignant obstruction.65 Unfortunately, the trial was terminated in the beginning of 2020 because of slow accrual.66 A third technique to biliary drainage, as recommended by The Japanese Clinical Practice Guidelines for Biliary Tract Cancer, is the use of endoscopic nasobiliary drainage (ENBD) because of less frequently observed cholangitis in ENBD versus EBD.67 Subgroup analysis of two studies (comprising a total of 198 patients) in a meta-analysis confirmed a higher incidence of preoperative cholangitis in pCCA patients drained with EBD (47.1%, 25/53) compared with ENBD (25.5%, 37/145, odds ratio [OR] 0.40, 0.21–0.75, P 5 .005). In addition, the stent dysfunction rate was higher in EBD (62.3%, 33/53) compared with ENBD (29.7%, 43/145, OR 0.26, 0.13–0.50, P , .0001).58,68,69 A recent study by Nagino and colleagues reported a cholangitis rate of 37% in a cohort of 191 patients who underwent ENBD, and 27% of patients required a reintervention.59 We conclude that ENBD appears superior in the Japanese centers and that EBD is at least noninferior compared with PTBD for patients with resectable pCCA who require preoperative biliary drainage. Incomplete or no biliary drainage in patients with an FLR volume above 50% has not been identified as a risk factor for mortality.16 In fact, postoperative mortality at 90 days was higher with biliary drainage in patients with an FLR volume above 50%, implying that biliary drainage should be avoided in these patients.16 Farges et al. also found that mortality after left hemihepatectomy (typically with an FLR above 50%) for

pCCA was lower without preoperative biliary drainage.70 In jaundiced patients with an FLR volume below 50%, the risk of an undrained small FLR appears more important than the risk of post-drainage cholangitis and other subsequent infectious complications.16,57,71 Experts advocate to postpone surgery until the serum bilirubin level is below 2 mg/dL (i.e., 34 mmol/L).14 A bilirubin above 3 mg/dL has been associated with a 4-fold increased risk of postoperative liver failure.57 Preoperative biliary drainage should decompress the FLR. Therefore it is important that patients be referred to an expert center before biliary drainage to determine the FLR and therefore the drainage strategy. However, the contralateral liver must also be drained if it is the focus of cholangitis (e.g., after previous endoscopic contamination without drainage).9

Portal Vein Embolization (see Chapter 102C) The substantial morbidity and mortality associated with (extended) liver resection for pCCA is primarily mediated by postoperative liver failure.72 An FLR volume below 40% to 50% is the most important modifiable risk factor for postoperative mortality.57,73 PVE has been demonstrated to induce an increase in FLR volume in both healthy and compromised liver parenchyma by means of hypertrophy of the FLR.74,75 In 1990 Makuuchi presented the initial result of PVE in 14 pCCA patients without major side effects, and only temporary moderate increases of serum transaminase or bilirubin were observed after preoperative PVE.76 Postoperatively, the authors observed mortality in a patient with jaundice and suppurative cholangitis after 30 days and after 3 months in a patient with untreated hepatitis. In a meta-analysis, Jiao and colleagues examined the impact of PVE on liver resection (regardless of diagnosis) in 1,088 patients.77 The authors demonstrated that PVE is a safe and effective procedure with a morbidity rate of 2.2% and no mortality. It was demonstrated that the increase in remnant liver volume was slightly larger after percutaneous transhepatic portal embolization versus transileocolic portal embolization (11.9% vs. 9.7%, P 5 .00001). In an international study including 1,484 patients who underwent liver resection for pCCA, PVE was less frequently performed in Western centers (7%) compared with Eastern centers (55%, P , .001).12,78 Overall liver failure rate was 17% and the 90-day mortality rate was 13%. Most PVE procedures (93%) were right-sided. PVE was more frequently performed before right-sided resections (38% vs. 3%, P , .001) and most frequently in extended right hemihepatectomy (45%). Propensity score matching was possible in a cohort of 98 patients, which revealed a relative increase of liver volume after PVE of 42% (18–59) in a median of 22 (19–29 days). The use of PVE was associated with a 4.4-fold reduction in liver failure (from 36% to 8%), a reduction in postoperative bile leakage by 3.5-fold (from 35% to 10%) and a decrease in 90-day postoperative mortality from 18% to 7% (2.6-fold reduction). A drawback of PVE is that the multidisciplinary team has to decide preoperatively whether a left- or right-sided resection is best. In some patients, imaging may allow for both a left- or right-sided resection. In this regard, a left hemihepatectomy is preferable; however, involvement of the right hepatic artery may be found at surgical exploration because of the proximity of this artery to the central biliary tree. Additional ipsilateral hepatic vein embolization may be performed to induce liver regeneration even further if the desired

C. Malignant Tumors  Chapter 51B  Perihilar Cholangiocarcinoma: Presurgical Management

gain of volume by PVE is not accomplished.79 The international prospective multicenter DRAGON trial 1 (NCT04272931) is aimed to assess enrolment capacity and safety of PVE combined with hepatic vein embolization in patients with colorectal liver metastases planned for liver resection.80 The results of this trial will form the basis for the anticipated RCT DRAGON 2 to compare outcomes of PVE with PVE and hepatic vein embolization. In conclusion, PVE can be performed safely and is recommended in patients with pCCA and an FLR below 40%.81 Future studies should investigate whether patient selection for PVE can be improved by functional FLR tests such as indocyanine green-clearance testing or 99mTc-mebrofenin hepatobiliary scintigraphy.82–84

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for pCCA (see Chapters 102D and 123) Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been performed in a patient with pCCA and found to rapidly induce hypertrophy of the FLR.85 The procedure is based on the concept of a complete or partial portal venous devascularization of the tumor-carrying liver with preservation of arterial blood flow and division of the liver substance, triggering tremendous hypertrophy of the contralateral liver lobe.86 After 2007, ALPPS gained some popularity over PVE in select cases with insufficient FLR volumes. Currently, the technique is selectively used for extended liver resections, mainly to resect colorectal liver metastases otherwise deemed unresectable.86 The application of ALPPS for pCCA has been criticized because of a reported high postoperative mortality of 27% in the initial 11 patients.87–90 More recently, van Gulik and colleagues analyzed data on 37 patients who underwent ALPPS for pCCA in 23 centers. Only 29 patients had available data for analysis, with a 90-day mortality of 48% (14/29).91 Matching the 29 ALPPS patients to patients with the same FLR without ALPPS from an international cohort revealed postoperative mortality to be twice as high in the ALPSS cohort (14/29 patients vs. 7/29 patients, P 5 .100). Median OS was 6 months in the ALPPS group and 29 months for the matched controls (P 5 .048). Survival was comparable between the two groups once perioperative mortality was excluded. Based on these studies, ALPPS is not recommended for pCCA.

Liver Transplantation for pCCA (see Chapter 108B) For patients with pCCA confined to the liver that is considered unresectable, LT is a treatment option.22,92 Technically, LT avoids the risk of positive surgical margins observed in around one-third of patients undergoing resection, solves the risk of an inadequate FLR, and treats the underlying liver disease in patients with PSC.12,93 In order for patients to qualify for LT, strict criteria apply (e.g., the Mayo Clinic transplantation protocol): pCCA must be unresectable and confined to the liver and the tumor should be located proximally to the cystic duct with a maximum radial tumor diameter of 3 cm without evidence of metastases. Patients must be pretreated with induction chemoradiation therapy to qualify for LT. Once patients are eligible, staging surgery with lymph node biopsy is performed to rule out metastatic disease. Recommendations from the Working Group from the International Liver Transplantation

747

Society (ILTS) Transplant Oncology Consensus Conference further include:92 • Diagnostic criteria for pCCA in the setting of LT include a dominant stricture of the perihilar bile duct and one or more of the following: positive cytology by endoscopic brushing or biopsy demonstrating pCCA, fluorescence in situ hybridization polysomy, or elevated CA 19-9 greater than 100 U/mL in the absence of cholangitis (moderate level of evidence, conditional recommendation). • LT for pCCA can be considered in patients with unresectable disease after neoadjuvant chemoradiation therapy in centers with a specific protocol (moderate level of evidence, conditional recommendation). • Transplant teams should prepare for arterial and venous jump grafts in the setting of LT for pCCA (moderate level of evidence, strong recommendation). Initial results of LT for pCCA were unacceptable considering 3-year survival rates of 30% to 38% and a 5-year survival rate of 23% with high recurrence rates.94–96 Since these results fell short compared with outcomes after resection for pCCA, induction therapy was introduced before LT. Several studies have reported 5-year survival rates after LT of 64% (up to 80% in patients with underlying PSC) and intention-to-treat survival rates (i.e., including all patients who started the preoperative neoadjuvant regimen) of 53% to 56% at 5 years.97,98 These results compare favorably with resection of pCCA. However, in LT series, typically about two-thirds of patients have underlying PSC (see Chapter 41) compared with about 5% in resection series. Many of these series also include substantial proportions of patients who have never had a histologically proven cholangiocarcinoma on preoperative biopsies or on final pathology. A retrospective study comparing patients after resection for pCCA with those after LT and neoadjuvant therapy revealed overall 5-year survival rates of 18% and 64%, respectively.99 Subset analysis of patients with R0 resection without PSC who fulfilled the Mayo Clinic transplant criteria still showed lower 5-year survival (29%) versus transplanted patients (54%, P 5 .049). The randomized multicenter TRANSPHIL study compares overall survival at 5 years and 3-year recurrence free survival of neoadjuvant chemoradiation with LT versus liver resection.100 The rationale for the latter trial was a retrospective study that assessed the role of neoadjuvant therapy before LT for pCCA.101 Five-year OS was 59% in 28 patients with pCCA who met LT criteria but did not undergo neoadjuvant treatment before LT. The authors concluded that selection, rather than induction therapy, is key.

Neoadjuvant Therapy for Liver Resection in pCCA Induction chemoradiation therapy in the setting of LT found excellent results in patients judged unresectable by conventional hepatectomy.97 Naturally, this raises the question of whether neoadjuvant therapy would be beneficial in patients deemed upfront resectable. In a systematic review assessing neoadjuvant chemo(radio)therapy before resection of pCCA, only 7 studies were included.102 These studies included a total number of 87 pCCA patients treated in a median period of 14 years (range 4–31). In only two studies, patients (n 5 28 and n 5 9) were upfront resectable.103,104 Chemoradiation protocols differed and the reported survival in one of the studies with the most pCCA patients also included patients with other diagnoses. In summary, to date there are insufficient data available on

748

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

the effect of neoadjuvant (chemo)radiation therapy for patients with resectable pCCA.

Prehabilitation to Surgery for pCCA Enhanced Recovery After Surgery (ERAS; see Chapter 27) is aimed to improve recovery after major surgery by means of a multimodal perioperative pathway that has been validated for many surgical procedures.105 ERAS guidelines that have yet to be validated specific to liver surgery were published in 2016.106 The preoperative part of ERAS (i.e., prehabilitation) aims to improve the physical, nutritional, and psychological aspects of a patient’s health to reduce the risk of postoperative complications and facilitate a swift recovery of physical performance status.107 Patient-related factors that are significantly associated with postoperative mortality in pCCA include age, albumin level of less than 3.5 mg/dL, and sarcopenia.16,19 The albumin level and sarcopenia reflect nutritional and physical health and can be modified in a prehabilitation program.

Exercise prehabilitation had a positive effect on physical fitness after hepatopancreatobiliary (HPB) surgery, although the effect on postoperative outcomes remains inconclusive.108,109 A prospective cohort study in patients with HPB malignancies evaluated protein supplementation combined with unsupervised home-based aerobic and resistance exercises on postoperative outcome.110 Results from this study showed a significantly shorter hospital stay for patients after prehabilitation versus those who enrolled the standard preoperative course (23 vs. 30 days, P 5 .045), without a significant difference in postoperative complications. The latter studies seem to justify prehabilitation of patients before resection of pCCA, especially in patients with modifiable risk factors such as low albumin level and sarcopenia. The references for this chapter can be found online by accessing the accompanying Expert Consult website.

748.e1

REFERENCES 1. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755-762. 2. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(suppl 6):7-9. 3. Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61(12):1657-1669. 4. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98(12):873-875. 5. AJCC Cancer Staging Manual. 8th ed. 2017. 6. Lee AJ, Chun YS. Intrahepatic cholangiocarcinoma: The AJCC/ UICC 8th edition updates. Chin Clin Oncol. 2018;7(5):52. 7. Groot Koerkamp B, Wiggers JK, Gonen M, et al. Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram. Ann Oncol. 2016;27(4):753. 8. Gazzaniga GM, Filauro M, Bagarolo C, et al. Surgery for hilar cholangiocarcinoma: an Italian experience. J Hepatobiliary Pancreat Surg. 2000;7(2):122-127. 9. Hartog H, Ijzermans JN, van Gulik TM, et al. Resection of perihilar cholangiocarcinoma. Surg Clin North Am. 2016;96(2):247-267. 10. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507-517; discussion 517-519. 11. de Wilde RF, Groot Koerkamp B. Radial margin status should be determined in resected perihilar cholangiocarcinoma. Hepatobiliary Surg Nutr. 2019;8(5):557-559. 12. Olthof PB, Aldrighetti L, Alikhanov R, et al. Portal vein embolization is associated with reduced liver failure and mortality in highrisk resections for perihilar cholangiocarcinoma. Ann Surg Oncol. 2020;27(7):2311-2318. 13. Kaiser GM, Paul A, Sgourakis G, et al. Novel prognostic scoring system after surgery for Klatskin tumor. Am Surg. 2013;79(1):90-95. 14. Nagino M, Ebata T, Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Ann Surg. 2013;258(1): 129-140. 15. Nuzzo G, Giuliante F, Ardito F, et al. Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients. Arch Surg. 2012;147(1):26-34. 16. Wiggers JK, Groot Koerkamp B, Cieslak KP, et al. Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant. J Am Coll Surg. 2016;223(2):321-331.e1. 17. Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008;48(1):308-321. 18. Nagorney DM, Donohue JH, Farnell MB, et al. Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993;128(8): 871-877; discussion 877-879. 19. van Vugt JLA, Gaspersz MP, Vugts J, et al. Low skeletal muscle density is associated with early death in patients with perihilar cholangiocarcinoma regardless of subsequent treatment. Dig Surg. 2019;36(2):144-152. 20. Blechacz B, Komuta M, Roskams T, et al. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(9):512-522. 21. Hann LE, Getrajdman GI, Brown KT, et al. Hepatic lobar atrophy: association with ipsilateral portal vein obstruction. AJR Am J Roentgenol. 1996;167(4):1017-1021. 22. Mansour JC, Aloia TA, Crane CH, et al. Hilar cholangiocarcinoma: expert consensus statement. HPB (Oxford). 2015;17(8):691-699. 23. Vestergaard EM, Hein HO, Meyer H, et al. Reference values and biological variation for tumor marker CA 19-9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999; 45(1):54-61. 24. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134(3):706-715.

25. Chari ST, Takahashi N, Levy MJ, et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin Gastroenterol Hepatol. 2009;7(10):1097-1103. 26. Groot Koerkamp B, Jarnagin WR. Surgery for perihilar cholangiocarcinoma. Br J Surg. 2018;105(7):771-772. 27. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis. 1994;14(2):109-114. 28. Lee HY, Kim SH, Lee JM, et al. Preoperative assessment of resectability of hepatic hilar cholangiocarcinoma: combined CT and cholangiography with revised criteria. Radiology. 2006;239(1):113-121. 29. Vogl TJ, Schwarz WO, Heller M, et al. Staging of Klatskin tumours (hilar cholangiocarcinomas): comparison of MR cholangiography, MR imaging, and endoscopic retrograde cholangiography. Eur Radiol. 2006;16(10):2317-2325. 30. Blechacz B, Gores GJ. Positron emission tomography scan for a hepatic mass. Hepatology. 2010;52(6):2186-2191. 31. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206(1):57-65. 32. Hattori M, Nagino M, Ebata T, et al. Prospective study of biliary cytology in suspected perihilar cholangiocarcinoma. Br J Surg. 2011; 98(5):704-709. 33. Barr Fritcher EG, Kipp BR, Halling KC, et al. FISHing for pancreatobiliary tract malignancy in endoscopic brushings enhances the sensitivity of routine cytology. Cytopathology. 2014;25(5):288-301. 34. Barr Fritcher EG, Voss JS, Jenkins SM, et al. Primary sclerosing cholangitis with equivocal cytology: fluorescence in situ hybridization and serum CA 19-9 predict risk of malignancy. Cancer Cytopathol. 2013;121(12):708-717. 35. Heimbach JK, Sanchez W, Rosen CB, et al. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford). 2011;13(5):356-360. 36. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. 37. Benson AB III, Abrams TA, Ben-Josef E, et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009;7(4):350-391. 38. Forsmark CE, Diniz AL, Zhu AX. Consensus conference on hilar cholangiocarcinoma. HPB (Oxford). 2015;17(8):666-668. 39. Juntermanns B, Kaiser GM, Reis H, et al. Klatskin-mimicking lesions: still a diagnostical and therapeutical dilemma? Hepatogastroenterology. 2011;58(106):265-269. 40. Wetter LA, Ring EJ, Pellegrini CA, et al. Differential diagnosis of sclerosing cholangiocarcinomas of the common hepatic duct (Klatskin tumors). Am J Surg. 1991;161(1):57-62; discussion 62-63. 41. Ebata T, Kosuge T, Hirano S, et al. Proposal to modify the International Union Against Cancer staging system for perihilar cholangiocarcinomas. Br J Surg. 2014;101(2):79-88. 42. Sobin LH. TNM: principles, history, and relation to other prognostic factors. Cancer. 2001;91(suppl 8):1589-1592. 43. Chaiteerakij R, Harmsen WS, Marrero CR, et al. A new clinically based staging system for perihilar cholangiocarcinoma. Am J Gastroenterol. 2014;109(12):1881-1890. 44. Deoliveira ML, Schulick RD, Nimura Y, et al. New staging system and a registry for perihilar cholangiocarcinoma. Hepatology. 2011;53(4): 1363-1371. 45. Laoveeravat P, Jaruvongvanich V, Wongjarupong N, et al. Outcome and validation of a new clinically based staging system for predicting survival of perihilar cholangiocarcinoma patients. JGH Open. 2017;1(2):56-61. 46. Nagino M. Perihilar cholangiocarcinoma: a much needed but imperfect new staging system. Nat Rev Gastroenterol Hepatol. 2011;8(5): 252-253. 47. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet. 1975;140(2):170-178. 48. Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. J Am Coll Surg. 2012;215(3):343-355. 49. Zervos EE, Osborne D, Goldin SB, et al. Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach. Am J Surg. 2005;190(5):810-815. 50. Gaspersz MP, Buettner S, van Vugt JLA, et al. Evaluation of the New American Joint Committee on Cancer staging manual 8th edition

748.e2 for perihilar cholangiocarcinoma. J Gastrointest Surg. 2020;24(7): 1612-1618. 51. Lee JW, Lee JH, Park Y, et al. Prognostic predictability of American Joint Committee on Cancer 8th staging system for perihilar cholangiocarcinoma: limited improvement compared with the 7th staging system. Cancer Res Treat. 2020;52(3):886-895. 52. Groot Koerkamp B, Wiggers JK, Allen PJ, et al. Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg. 2015;221(6):1041-1049. 53. Tran Cao HS, Vauthey JN. Portal vein embolization for perihilar cholangiocarcinoma: a story worth repeating. Ann Surg Oncol. 2020;27(7):2120-2121. 54. Abdalla EK, Denys A, Chevalier P, et al. Total and segmental liver volume variations: implications for liver surgery. Surgery. 2004; 135(4):404-410. 55. Nagino M, Kamiya J, Uesaka K, et al. Complications of hepatectomy for hilar cholangiocarcinoma. World J Surg. 2001;25(10):1277-1283. 56. Abbas S, Sandroussi C. Systematic review and meta-analysis of the role of vascular resection in the treatment of hilar cholangiocarcinoma. HPB (Oxford). 2013;15(7):492-503. 57. Ribero D, Zimmitti G, Aloia TA, et al. Preoperative cholangitis and future liver remnant volume determine the risk of liver failure in patients undergoing resection for hilar cholangiocarcinoma. J Am Coll Surg. 2016;223(1):87-97. 58. Kawakami H, Kuwatani M, Onodera M, et al. Endoscopic nasobiliary drainage is the most suitable preoperative biliary drainage method in the management of patients with hilar cholangiocarcinoma. J Gastroenterol. 2011;46(2):242-248. 59. Maeda T, Ebata T, Yokoyama Y, et al. Preoperative course of patients undergoing endoscopic nasobiliary drainage during the management of resectable perihilar cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2019;26(8):341-347. 60. Kloek JJ, van der Gaag NA, Aziz Y, et al. Endoscopic and percutaneous preoperative biliary drainage in patients with suspected hilar cholangiocarcinoma. J Gastrointest Surg. 2010;14(1):119-125. 61. Coelen RJS, Roos E, Wiggers JK, et al. Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018;3(10):681-690. 62. Al Mahjoub A, Menahem B, Fohlen A, et al. Preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma: is percutaneous transhepatic biliary drainage safer and more effective than endoscopic biliary drainage? A meta-analysis. J Vasc Interv Radiol. 2017;28(4):576-582. 63. Saluja SS, Gulati M, Garg PK, et al. Endoscopic or percutaneous biliary drainage for gallbladder cancer: a randomized trial and quality of life assessment. Clin Gastroenterol Hepatol. 2008;6(8):944-950.e3. 64. Singh A, Rathi S, Kalra N, et al. Preoperative drainage for perihilar cholangiocarcinoma. Lancet Gastroenterol Hepatol. 2019;4(1):10. 65. Al-Kawas F, Aslanian H, Baillie J, et al. Percutaneous transhepatic vs. endoscopic retrograde biliary drainage for suspected malignant hilar obstruction: study protocol for a randomized controlled trial. Trials. 2018;19(1):108. 66. A trial of percutaneous vs. endoscopic drainage of suspected Klatskin tumors (INTERCPT). 2017. Available at: https://clinicaltrials.gov/ ct2/show/NCT03172832. Accessed September 9, 2020. 67. Miyazaki M, Yoshitomi H, Miyakawa S, et al. Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition. J Hepatobiliary Pancreat Sci. 2015;22(4): 249-273. 68. Kawakubo K, Kawakami H, Kuwatani M, et al. Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma. World J Gastrointest Endosc. 2016;8(9):385-390. 69. Lin H, Li S, Liu X. The safety and efficacy of nasobiliary drainage versus biliary stenting in malignant biliary obstruction: a systematic review and meta-analysis. Medicine (Baltimore). 2016;95(46):e5253. 70. Farges O, Regimbeau JM, Fuks D, et al. Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg. 2013;100(2):274-283. 71. Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford.) 2008;10(2):130-133. 72. Franken LC, Schreuder AM, Roos E, et al. Morbidity and mortality after major liver resection in patients with perihilar cholangiocarcinoma: a systematic review and meta-analysis. Surgery. 2019;165(5): 918-928.

73. Olthof PB, Wiggers JK, Groot Koerkamp B, et al. Postoperative liver failure risk score: Identifying patients with resectable perihilar cholangiocarcinoma who can benefit from portal vein embolization. J Am Coll Surg. 2017;225(3):387-394. 74. Shindoh J, Tzeng CW, Aloia TA, et al. Safety and efficacy of portal vein embolization before planned major or extended hepatectomy: an institutional experience of 358 patients. J Gastrointest Surg. 2014;18(1):45-51. 75. van Lienden KP, van den Esschert JW, de Graaf W, et al. Portal vein embolization before liver resection: a systematic review. Cardiovasc Intervent Radiol. 2013;36(1):25-34. 76. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery. 1990;107(5):521-527. 77. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247(1):49-57. 78. Olthof PB, Miyasaka M, Koerkamp BG, et al. A comparison of treatment and outcomes of perihilar cholangiocarcinoma between Eastern and Western centers. HPB (Oxford). 2019;21(3):345-351. 79. Hwang S, Lee SG, Ko GY, et al. Sequential preoperative ipsilateral hepatic vein embolization after portal vein embolization to induce further liver regeneration in patients with hepatobiliary malignancy. Ann Surg 2009;249(4):608-616. 80. Dragon 1: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) (DRAGON). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04272931. Accessed September 9, 2020. 81. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology. 1997;26(5): 1176-1181. 82. Haegele S, Reiter S, Wanek D, et al. Perioperative non-invasive indocyanine green-clearance testing to predict postoperative outcome after liver resection. PLoS One 2016;11(11):e0165481. 83. Olthof PB, Coelen RJS, Bennink RJ, et al. (99m)Tc-mebrofenin hepatobiliary scintigraphy predicts liver failure following major liver resection for perihilar cholangiocarcinoma. HPB (Oxford). 2017;19(10):850-858. 84. Yokoyama Y, Nishio H, Ebata T, et al. Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer. Br J Surg. 2010;97(8):1260-1268. 85. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012;255(3):405-414. 86. Lang H, de Santibanes E, Schlitt HJ, et al. 10th Anniversary of ALPPS-Lessons learned and quo vadis. Ann Surg. 2019;269(1): 114-119. 87. Belghiti J, Dokmak S, Schadde E. ALPPS: Innovation for innovation’s sake. Surgery. 2016;159(5):1287-1288. 88. Donati M, Basile F, Oldhafer KJ. Present status and future perspectives of ALPPS (associating liver partition and portal vein ligation for staged hepatectomy). Future Oncol. 2015;11(16):2255-2258. 89. Nagino M. Value of ALPPS in surgery for Klatskin tumours. Br J Surg. 2019;106(12):1574-1575. 90. Oldhafer KJ, Stavrou GA, van Gulik TM, et al. ALPPS—Where do we stand, where do we go?: Eight recommendations from the first international expert meeting. Ann Surg. 2016;263(5):839-841. 91. Olthof PB, Coelen RJS, Wiggers JK, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB (Oxford). 2017;19(5):381-387. 92. Sapisochin G, Javle M, Lerut J, et al. Liver transplantation for cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma: Working Group Report from the ILTS Transplant Oncology Consensus Conference. Transplantation. 2020;104(6):1125-1130. 93. Gringeri E, Gambato M, Sapisochin G, et al. Cholangiocarcinoma as an indication for liver transplantation in the era of transplant oncology. J Clin Med. 2020;9(5):1353. 94. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69(8):1633-1637. 95. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 2004;239(2):265-271.

748.e3 96. Seehofer D, Thelen A, Neumann UP, et al. Extended bile duct resection and [corrected] liver and transplantation in patients with hilar cholangiocarcinoma: long-term results. Liver Transpl. 2009; 15(11):1499-1507. 97. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143(1): 88-98.e3; quiz e14. 98. Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int. 2010;23(7):692-697. 99. Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018;267(5):797-805. 100. Liver Resection versus Radio-Chemotherapy-Transplantation for Hilar Cholangiocarcinoma (TRANSPHIL). 2014. Available at: https:// clinicaltrials.gov/ct2/show/NCT02232932. Accessed September 9, 2020. 101. Mantel HT, Westerkamp AC, Adam R, et al. Strict selection alone of patients undergoing liver transplantation for hilar cholangiocarcinoma is associated with improved survival. PLoS One. 2016;11(6): e0156127. 102. Baltatzis M, Jegatheeswaran S, Siriwardena AK. Neoadjuvant chemoradiotherapy before resection of perihilar cholangiocarcinoma: a systematic review. Hepatobiliary Pancreat Dis Int. 2020;19(2): 103-108. 103. Glazer ES, Liu P, Abdalla EK, et al. Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg. 2012;16(9):1666-1671.

104. Kobayashi S, Tomokuni A, Gotoh K, et al. A retrospective analysis of the clinical effects of neoadjuvant combination therapy with full-dose gemcitabine and radiation therapy in patients with biliary tract cancer. Eur J Surg Oncol. 2017;43(4):763-771. 105. Melloul E, Lassen K, Roulin D, et al. Guidelines for perioperative care for pancreatoduodenectomy: Enhanced recovery after surgery (ERAS) recommendations 2019. World J Surg. 2020;44(7): 2056-2084. 106. Melloul E, Hubner M, Scott M, et al. Guidelines for perioperative care for liver surgery: Enhanced recovery after surgery (ERAS) society recommendations. World J Surg. 2016;40(10):2425-2440. 107. Bongers BC, Dejong CHC, den Dulk M. Enhanced recovery after surgery programmes in older patients undergoing hepatopancreatobiliary surgery: what benefits might prehabilitation have? Eur J Surg Oncol. 2020;47:551-559. 108. Dunne DF, Jack S, Jones RP, et al. Randomized clinical trial of prehabilitation before planned liver resection. Br J Surg. 2016;103(5): 504-512. 109. Kaibori M, Ishizaki M, Matsui K, et al. Perioperative exercise for chronic liver injury patients with hepatocellular carcinoma undergoing hepatectomy. Am J Surg. 2013;206(2):202-209. 110. Nakajima H, Yokoyama Y, Inoue T, et al. Clinical benefit of preoperative exercise and nutritional therapy for patients undergoing hepato-pancreato-biliary surgeries for malignancy. Ann Surg Oncol. 2019;26(1):264-272.

CHAPTER 52 Interventional techniques in hilar and intrahepatic biliary strictures Karen T. Brown Malignant disease resulting in proximal or high bile duct obstruction (Fig. 52.1)—that is, in close proximity to or involving the biliary confluence—may arise from a variety of cancer types and is a common clinical problem. Historically, the proximal biliary tree was defined as above the level of the cystic duct insertion into the common hepatic duct (CHD). Given the wide anatomic variability of the cystic duct/CHD confluence (see Chapter 2), this definition is not accurate, and high bile duct obstruction is best thought of as obstruction involving the hepatic confluence and the 2 to 4 cm of CHD distal to the confluence. Although frequently seen with hilar cholangiocarcinoma and intraductal tumor (see Chapters 50 and 51), hilar obstruction can result from other common malignancies, such as colorectal, breast, and pancreatic cancers (see Chapters 62 and 90–92). Significant technical progress has occurred in both endoscopic (see Chapter 30) and percutaneous approaches to biliary drainage (see Chapter 31), allowing for safer palliative treatment of patients with such obstructions. Because these patients may be asymptomatic at presentation, the goals of treatment should be clearly defined before the physician commits the patient to any biliary drainage procedure. The most important question concerns resectability. With the exception of clearly palliative situations, these patients are ideally discussed in a multidisciplinary group with hepatobiliary surgeons, interventional radiologists, oncologists, and gastroenterologists to outline a plan of treatment. A thorough understanding of this plan (specifically involving details of the potential surgical approaches), and of the patient’s prognosis, facilitates concomitant development of a strategy for drainage, when indicated. Accepted indications for palliative biliary drainage include intractable pruritus, cholangitis, the need to restore liver function to allow for administration of chemotherapeutic agents with biliary metabolism/excretion, access for intraluminal brachytherapy, and diversion for bile leak. Given the availability of high-quality magnetic resonance cholangiopancreatography (MRCP; see Chapter 16), direct cholangiography as a diagnostic tool is rarely warranted (see Chapter 20).1,2

cancer, such as brachytherapy or photodynamic therapy. Many physicians have the impression that patients feel better and have improved performance status after relief of jaundice, but this has never been definitively demonstrated in clinical studies. Indeed, in a prospective trial, Robson and colleagues3 showed that percutaneous drainage of high biliary obstruction does not significantly improve the quality of life (QOL) of patients with malignant biliary obstruction, except for the minority with associated pruritus. Controversy remains with regard to the role of biliary drainage before surgery.4–6 Preoperative drainage of the future remnant liver is often performed for jaundiced patients that require major hepatectomy7,8 or before preoperative portal vein embolization (see Chapters 51B, 102C, and 119B). When preoperative drainage is necessary for relief of symptoms (pruritus, cholangitis), if neoadjuvant therapy is planned, or when surgery will be delayed, endoscopic methods are preferred for low bile duct obstruction because of the lower complication rate, whereas high obstruction is treated with carefully targeted percutaneous methods to reduce the risk of cholangitis in

INDICATIONS FOR BILIARY DRAINAGE Neither isolated hyperbilirubinemia nor imaging findings of bile duct dilation are an indication for biliary drainage. Pruritus, cholangitis, and the need to lower the bilirubin to administer certain chemotherapeutic agents, on the other hand, are all accepted indications for biliary drainage. Postoperative bile leaks that require drainage for diversion may develop in patients who have undergone biliary-enteric bypass as part of curative resection for a benign or malignant lesion (see Chapter 28). In some cases, access to the biliary tree may be undertaken as a method of delivering local treatment for primary bile duct

FIGURE 52.1  High bile duct obstruction refers to obstruction at or above confluence; low bile duct obstruction occurs below the common hepatic duct. Seg, Segment. (Courtesy Memorial Sloan Kettering Cancer Center Medical Graphics.)

749

750

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

undrained segments.9 Patients with Bismuth type II and higher levels of obstruction are at high risk for requiring multiple drainage procedures10 (see Chapter 42).

ENDOSCOPIC VERSUS PERCUTANEOUS DRAINAGE (SEE CHAPTERS 20, 30, AND 31) Patients with low bile duct obstruction are typically treated endoscopically. Patients with high bile duct obstruction, particularly when the obstruction extends above the hilus, have traditionally been treated percutaneously. The success rate of percutaneous drainage is higher, and the complication rate lower, when compared with endoscopic methods.11,12 This perspective is evolving while technologic advances in endoscope design occur and endoscopists become better trained and more experienced in wire-guided procedures, with access to better drainage devices and accessories. Currently, however, high bile duct obstruction, with rare exception, should be approached percutaneously. This has been called into question with a randomized trial

A

FIGURE 52.2  A, “Scout” image from abdominal computed tomography after endoscopic stent placement. The plastic stents were thought to be draining the right and left liver. The patient remained jaundiced with a bilirubin level of 10 mg/dL and white blood cell count of 18.4 K/mL. B, Plastic stent in anterior division of right hepatic duct (arrow); the anterior sector is almost completely replaced by tumor. Posterior bile ducts are undrained. C, The second plastic stent is in the caudate duct (arrow); the entire left liver is undrained.

B

C

of percutaneous versus endoscopic preoperative drainage in patients with hilar cholangiocarcinoma that was stopped prematurely because of high overall mortality in the percutaneous group. The reported 11% mortality in the percutaneous group is vastly higher than any recent report on percutaneous biliary drainage. It is also well outside the 1.7% mortality threshold established by the Society of Interventional Radiology in 2010,13 calling into question the experience and expertise of those involved in performing the trial. Two major drawbacks to endoscopic drainage for high bile duct obstruction are the lack of ability to reliably target a specific area of the liver for drainage and the risk of enteric contamination, by retrograde injection of contrast, of parts of the biliary tree that will not be drained. In a patient thought to have undergone successful endoscopic stenting of the right and left liver, repeat imaging may reveal that this is not the case at all (Fig. 52.2). Despite improvements in endoscopic techniques, a paper from Wiggers et al.14 in 2015 reported a high risk of inadequate preoperative endoscopic drainage, with 108 of 288

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

anatomy is favorable, and the percutaneous approach is technically difficult, or when the risk of contaminating the right-sided bile ducts is thought to be prohibitive. This is particularly the case when draining the right liver would be of no clinical benefit, either because of replacement of the liver by tumor or occlusion of the right portal vein (Fig. 52.3). High technical success rates with few complications are reported by some authors,15,16 whereas others report high technical success with less favorable

(38%) patients with perihilar cholangiocarcinoma requiring additional percutaneous procedures subsequent to endoscopic retrograde cholangiopancreatography (ERCP).14 Development of the linear-array echoendoscope has allowed for the expansion of endoscopic ultrasound–guided biliary drainage procedures, including choledochoduodenostomy and hepaticogastrostomy.15 Hepaticogastrostomy may be considered when a patient is best treated by draining the left lateral segment,

A

C

E

751

B

D

FIGURE 52.3  A, Central mass in right liver (circled) encasing the right portal vein and isolating right anterior and posterior bile ducts. B, Segment III duct (arrow) in close proximity to the stomach. C, Endoscopic image after puncture into segment III duct and injection of contrast. D, Image after placement of transgastric segment III stent. E, Image of the abdomen the next day demonstrates a well-expanded stent between the lesser curvature of the stomach and the segment III bile duct.

752

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

complication and stent patency rates.17 Most operators are early on the learning curve at present. When technically feasible, and in the hands of highly trained endoscopists, this procedure can be gratifying for the patient, with relief of pruritus and lowering of bilirubin without the added burden of a percutaneous catheter. Endoscopic drainage is rarely indicated in patients with papillary intraductal tumor because of inevitable tumor ingrowth into the metallic stent with early stent occlusion. Intraductal tumor can arise from cancers other than papillary cholangiocarcinoma, including colorectal metastases, gallbladder cancer, and hepatocellular carcinoma. When intraductal tumor occurs in the setting of metastatic colorectal

cancer or hepatocellular cancer, it is usually the direct extension of a parenchymal metastasis into the duct (Fig. 52.4A). Patients with intraductal tumor often require permanent indwelling catheter drainage, with an indwelling, multi-sidehole catheter allowing bile to drain around the intraductal tumor, but they may be stented when the intraductal tumor can be effectively excluded (see Fig. 52.4B–D). A realistic idea of what is feasible endoscopically and percutaneously is important when the initial decision is made regarding who will treat the patient. This depends on a thorough understanding of the goal of treatment as well as knowledge of the skill level of the interventional radiologists and endoscopists available to care for the patient.

A

C

B

D

FIGURE 52.4  A, Patient with hilar cholangiocarcinoma arising in segment IV (circle) with tumor extension into left hepatic duct (arrows). B, Cholangiogram at time of drainage demonstrates tumor in left hepatic duct (LHD) compressing hilus and extending into the common hepatic duct (CHD) (arrows). C, Image at time of stent placement. Stent extends from right side to CHD, essentially excluding tumor in LHD. D, Cholangiogram after stent placement.

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

PREPROCEDURE PREPARATION Imaging The importance of excellent preprocedure imaging in patients with bile duct obstruction cannot be overemphasized. This imaging should include, at a minimum, a contrast-enhanced computed tomography (CT) scan of the abdomen (see Chapter 16). Ultrasound is often used to establish the presence of dilated bile ducts, identify the level of obstruction, evaluate portal vein patency, and demonstrate intraductal tumor, but ultrasound is not adequate for drainage planning. Although MRCP provides a detailed three-dimensional (3D) rendering of the obstructed

A

C

753

bile ducts and is effective at delineating intraductal abnormalities and depicting isolated bile ducts (Fig. 52.5), it excludes certain details that can serve as targeting aides for percutaneous drainage. These shortcomings of MRCP include poor visualization of surgical clips, dystrophic calcifications, and bony landmarks (see Chapter 16). In addition, if the patient is unable to breath-hold during image acquisition, MRCP will be suboptimal. CT scans performed on multi-slice scanners in a picture-archiving and communication system (PACS) environment allow a 3D rendering of the anatomy, while identifying relevant landmarks that can be used for targeting and demonstration of other structures that should be avoided, such as liver tumors and bowel. Also, as with magnetic resonance imaging (MRI), one may identify ancillary

B

FIGURE 52.5  A, Magnetic resonance cholangiopancreatography (MRCP) in a patient with gallbladder cancer. The tumor extends into the low-inserting posterior right hepatic duct (arrows) and causes obstruction of the common hepatic duct. B, Series of contiguous axial computed tomographic images correlate well with MRCP, demonstrating right anterior and left hepatic ducts joining (top images) above the insertion of the posterior right duct, which contains material of soft tissue density (tumor) that extends into common hepatic duct (bottom images). C, Image taken at biliary drainage demonstrates the left hepatic duct joining the anterior division; a low-inserting posterior duct is isolated and thus is not opacified. The filling defect in left hepatic duct is a blood clot related to the placement of percutaneous catheter, not a tumor.

754

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

important findings, such as ascites, hepatic lobar atrophy, and portal vein occlusion or encasement. All this information is critical to make prognostic assessments and determine the best approach for drainage. The amount of functional parenchyma that can be drained should be estimated. Functional parenchyma is that part of the liver that is not replaced by tumor and that has an intact portal venous supply and hepatic venous drainage. If 75% of the hepatic parenchyma is replaced by tumor, even if it were possible to drain the entire biliary tree, it is unlikely that normal hepatic function or normalization of serum bilirubin level would result. The portal vein provides the trophic blood supply to the liver, and occlusion results in atrophy of the affected segment(s), particularly when the ipsilateral bile duct is also occluded (see Chapter 5).18 Atrophy may be recognized by the diminutive size of the involved part of the liver, accompanied by crowding of the bile ducts (Fig. 52.6; see Chapters 16 and 51A). When portal vein occlusion causes atrophy, drainage of the atrophied liver does not improve liver function. In addition, it is frequently difficult to manipulate catheters through the obstructed/atrophied portion of the liver into the central biliary tree. The end result is an external drainage catheter that provides no clinical benefit to the patient and only serves to risk complications and degrade QOL. Central tumors frequently obstruct the right and the left biliary tree, isolating them from one another. Obstruction may extend even higher, isolating the ductal system at the sectoral, segmental, or subsegmental level. When drainage is undertaken for relief of pruritus, draining even a segment of the liver may result in relief of symptoms.19,20 When isolation is present, and drainage is undertaken to lower the serum bilirubin, as mentioned previously, it is important to estimate how much functional parenchyma can be drained with one catheter. Drainage of at least 75% of the liver is associated with a significantly increased probability of returning the serum bilirubin to normal or near-normal levels.21 In some cases, this goal may be impossible to achieve, unless more than one drainage catheter or stent

is placed. Recognition of this allows for informing both the patient and the referring physician about the potential need for more than one catheter or stent. Cholangitis is rarely the primary indication for drainage in patients with malignant bile duct obstruction, except in patients who have undergone prior biliary instrumentation and in those who have a contaminated biliary tree related to previous biliary-enteric bypass, cross-ampullary stenting, or sphincterotomy.22 Drainage of an isolated region of the liver, either percutaneously or endoscopically, may contaminate other functionally “isolated” parts of the biliary tree. In this case, subsequent cholangitis may drive the placement of additional catheters to relieve infection. Widespread contamination of a severely isolated biliary tree with drainage of only part of the obstructed system can result in chronic recurrent cholangitis. Whether induced by endoscopic or percutaneous means, this situation can be difficult to manage and should be anticipated and avoided if possible.

Laboratory Studies Preoperative labs for biliary drainage include a complete blood count, hepatic function panel, and coagulation studies. The serum bilirubin can change rapidly when patients become obstructed. Because decisions regarding the need for further drainage in high obstruction with isolated bile ducts depend, in part, on the serum bilirubin, it is important to draw this reference laboratory value within 24 hours of drainage. The bilirubin is typically rising at the time of drainage and the serum bilirubin may be higher the morning after the drainage procedure than the morning of the procedure. Serum bilirubin values drawn 48 hours after drainage more accurately predict effectiveness of drainage. The lack of bile salts in the intestine impairs vitamin K absorption and may result in elevation of the prothrombin time (PT), international normalized ratio (INR), and the partial thromboplastin time (PTT); therefore these values should also be checked within a few days of the procedure. Coagulation abnormalities may be exacerbated if there is

*

A

B

FIGURE 52.6  A, Right hepatic atrophy. Volume of the right hemiliver is greatly diminished, with severe attenuation of the right portal vein (arrows). B, Left hepatic atrophy. Note the small size of the left hemiliver and crowding of dilated bile ducts secondary to portal vein occlusion. Endoscopic stent (asterisk) had been placed at another hospital, and subsequently the patient returned with jaundice and cholangitis.

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

also poor hepatic synthetic function. This can be corrected by the administration of vitamin K or fresh frozen plasma, depending on the urgency of drainage.

Antibiotics Preprocedure antibiotic prophylaxis is given to all patients undergoing biliary drainage. Both a history of previous instrumentation and fever have been shown to be highly predictive of bactibilia, but up to 5% of patients without these signs may have positive bile cultures23 (see Chapter 11). Many patients become bacteremic during or after the procedure, even in the absence of preexisting signs or symptoms of infection, particularly when they are known to have a colonized biliary tree. Generally, patients receive broad coverage with an agent such as ticarcillin-clavulanate or ceftriaxone, but the prophylactic antibiotic chosen should reflect common biliary organisms at the individual institution and is best chosen in consultation with institutional infectious disease stewards. When cholangitis is not present, administration of intravenous (IV) antibiotics beyond the prophylactic dose is not warranted. Patients with a history of cholangitis or sepsis or those presumed to have a contaminated biliary tree associated with transampullary stenting, biliary-enteric bypass, sphincterotomy, or recent instrumentation may be best covered with an agent such as piperacillin-tazobactam (Zosyn), which is excreted into the bile. Appropriate postprocedure coverage is determined based on bile cultures obtained at drainage.

Psychological Preparation Managing patient expectations is a major part of the process. A thorough discussion of possible outcomes is particularly

755

important before biliary drainage in patients with high bile duct obstruction. Patients should understand that, although every effort will be made to establish internal drainage with stents, this may not be achieved. Although it is usually possible to cross an obstructing lesion into the common bile duct, internalization might be precluded by extensive isolation of the biliary tree, intraductal tumor, concomitant duodenal obstruction, or other factors. Two or more catheters or self-expanding stents may be required when the tumor extends beyond the secondary confluence on one side or the other, depending on the clinical objective. Such a discussion is not intended to distress the patient but rather to promote an understanding of the complexity of the situation to mitigate sentiments of surprise or anger if stent placement is not possible at the initial encounter and subsequent procedures are necessary. Even in the presence of segmental isolation, pruritus often resolves after biliary drainage. Unfortunately, it is not always possible to lower the serum bilirubin, particularly to levels that would allow for the administration of certain chemotherapeutic agents. In certain situations, two or more biliary drainage catheters may be placed without a significant decrease in bilirubin; sometimes, the bilirubin may even increase. It is possible that a single biliary drainage catheter may drain one portion of the liver well while converting near-complete obstructions in other areas to complete obstructions (Fig. 52.7). It also is conceivable that intervening cholangitis or progression of disease may play a role. Patients who have realistic expectations and some understanding of these issues before the initial biliary drainage procedure are less likely to become distressed if multiple procedures are required or if the ultimate outcome is less than satisfactory (see Chapter 29).

FIGURE 52.7  A, Obstruction caused by tumor severely narrows the biliary tree up to the secondary confluence on right. B, After placement of a multiple sidehole catheter, the right posterior sector is well drained by the catheter, which compromises near-complete obstruction of the right anterior division duct and left hepatic duct. (Courtesy Memorial Sloan Kettering Cancer Center Medical Graphics.)

756

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

INTRAPROCEDURAL ISSUES

placed stents, surgical clips, or other radiopaque landmarks can frequently be used to facilitate targeting.

Approach

Sedation

Many interventional radiologists prefer a right-sided approach to the biliary tree. The right side of the liver is larger and more accessible than the left. Approach from the right side more easily avoids direct x-ray exposure to the hands of the operator and allows a direct approach to the hepatic hilus and common bile duct, making catheter and guidewire manipulations easier and often more successful. In addition, approach from the right side is thought to be safer because there are fewer structures between the skin and right liver that may be injured and, some believe, a lower risk of bleeding. To date, a higher risk of bleeding with a left-sided approach has not been conclusively demonstrated.24,25 Patients with low bile duct obstruction that cannot be drained endoscopically may be approached from either side. The direct approach from the right is sometimes complicated when the site of puncture is the right posterior duct and this duct enters the left hepatic duct. This anatomic variant is often evident on preprocedure imaging studies (see Chapter 2) and should be specifically evaluated; it occurs in 20% of patients and may add a 180-degree turn to the approach to the hepatic hilum, making it more difficult to traverse the obstruction. On the other hand, when the obstruction extends to involve the leftright confluence but no higher, approach from the posterior right duct will drain the right posterior sector and the entire left liver when the posterior duct joins the left. The main disadvantages to a right-sided approach are the discomfort associated with intercostal catheters and leaking of ascites around a more gravity-dependent right-sided catheter. Both of these issues can be mitigated with primary stent placement at the time of initial biliary drainage. A left-sided approach to the biliary tree is preferred in several situations. When an obstructing tumor extends above the biliary confluence, it may isolate the right and left bile ducts and may involve a secondary confluence or higher. The right hepatic duct is typically shorter than the left (see Chapter 2); as a result, tumor is more likely to extend to and isolate the right anterior and posterior sectoral ducts, while the left medial and lateral sectors continue to communicate. In such cases, it may be possible to drain more functional hepatic parenchyma by placing a single catheter or stent on the left depending on the size of the left liver. Patients with ascites are less likely to have leakage around a left anterior catheter, so a left approach is preferred when possible. When atrophy or compromise of the portal vein is present, the patient will always derive more benefit from drainage of the contralateral functional liver, as previously discussed.

Although general anesthesia is not necessary, and biliary drainage can be performed with conscious sedation, general anesthesia can be quite helpful when available. This is particularly true when the bile ducts are not dilated, or only minimally dilated, and in patients with sleep apnea in whom variable respirations can make targeting and entering a bile duct difficult. To allow for either general anesthesia or conscious sedation, patients take nothing by mouth for 8 hours before the procedure. They are well hydrated and have functional venous access, particularly if cholangitis has been present. These patients can become septic and hypotensive, requiring rapid volume expansion.

Image Guidance In most cases, biliary drainage is performed with fluoroscopic guidance (see Chapter 31). Ultrasound is often used for duct puncture from a left-sided approach; but less often from the right because bile duct orientation and the need to image through an intercostal space make the use of ultrasound more challenging. Careful review of a high-quality CT scan is helpful for identifying radiopaque landmarks that may be used to target a specific region of the biliary tree or even a specific bile duct. This review is particularly important when isolation is suspected, and the objective is to target a specific duct. If the right anterior duct is the target, it would be unfortunate to enter a segment IV duct by being too anterior or medial. Previously

Technical Aids The most significant technical development to facilitate biliary drainage and other fluoroscopically guided procedures in recent years has been the advent of multidetector CT (MDCT), particularly when used within a PACS environment. The ability to scan the liver in a single breath hold and then cine through the images facilitates identification of the level of obstruction and the likelihood of isolation (see Chapter 16). It also enables the formulation of a 3D mental image of the biliary tree. Understanding the biliary anatomy in this way facilitates a successful, uncomplicated procedure. It is frequently possible to anticipate normal variants of bile duct anatomy, which can have a significant impact on preprocedure planning (see Chapter 2). In addition, most PACS workstations allow cross-reference of the axial images (Fig. 52.8A) with the “scout” image (see Fig. 52.8B), which is a simulated frontal radiograph used for programming the extent of the scan. In this way, targeting of a specific region, or even a specific duct, is made much easier—and the final catheter resides within the planned segment of the liver (see Fig. 52.8C). Although this degree of sophistication may be unnecessary for obstruction below the hepatic hilum, MDCT facilitates drainage in patients with complex high bile duct obstruction such that it is always worth performing MDCT if a recent scan does not exist.

Drainage Catheter Versus Primary Stent Placement The suitability of a patient for primary stent placement is determined at the time of biliary drainage based on the indication for the drainage, evidence of infected bile, presence of blood or tumor within the biliary tree, and cholangiographic findings. The goal of biliary drainage is to solve the patient’s clinical problem by placing as few catheters or stents as possible, intending that the bile should drain internally when the intervention is complete. In patients with a presumed sterile biliary tree, ideally an attempt should be made to accomplish this without ever placing a drainage catheter into the duodenum. There is evidence that when stent occlusion occurs, the patient is less likely to present with cholangitis if the sphincter of Oddi has not been compromised.26 Patients with high bile duct obstruction without cholangitis may be stented primarily at the initial drainage procedure, provided significant blood is not present within the biliary tree. Blood clot within the intrahepatic bile ducts impairs drainage and may compromise flow of bile through the stent, which may result in bile leaking into the peritoneal cavity from the site of duct puncture. When clots are visible within the biliary tree, the best course might be to place a drainage catheter

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

A

C

until the bile clears, at which time the patient is stented. Patients undergoing drainage for cholangitis should not be stented primarily in most cases. Catheter manipulation in this group of patients is kept to a minimum to diminish the risk of procedurerelated sepsis. Once the biliary tree is drained and cholangitis resolves, a stent can be placed. Having addressed the decisions regarding patients who clearly can or cannot be stented, the more difficult situations that occur in patients with high bile duct obstruction must be addressed. In 1975 Bismuth and Corlette27 classified obstruction of the hepatic confluence as types I through IV (Fig. 52.9; see Chapter 42). Predictions about the level of obstruction and degree of isolation of the biliary tree can be made based on the

757

B

FIGURE 52.8  A, Cross-sectional image at level of segment III duct (arrow) in a patient after a right hepatic resection. B, The corresponding level identified by the white horizontal line on the scout image. C, Final biliary drainage catheter that clearly enters segment III duct at planned peripheral puncture site (arrow).

preprocedure imaging studies. These predictions are not always accurate, however, and it is sometimes necessary to modify the stenting approach based on cholangiographic findings; in rare cases, it may be necessary to abandon the procedure altogether. Patients with Bismuth type I obstruction can have the entire liver drained with one catheter or stent because right and left ducts communicate freely. Barring one of the previously mentioned contraindications, these patients have a primary stent placed. Patients with Bismuth type II obstruction cannot be completely drained with one catheter, although it is sometimes possible to opacify ducts in both sides of the liver. Some suggest that survival is better when both sides of the liver are drained.28

758

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

FIGURE 52.9  Bismuth-Corlette classification for malignant high bile duct obstruction. Type IV involves both right and left ducts to secondary confluence. Seg, Segment. (Courtesy Memorial Sloan Kettering Cancer Center Medical Graphics.)

A

Even in Bismuth type II and III hilar obstructions, however, Inal and colleagues29 saw no significant difference in clinical response to treatment or stent patency rate with unilobar versus bilobar drainage. When contrast material enters the obstructed side opposite the puncture, it usually does not drain effectively, and in the presence of risk factors for infection, that side may be contaminated. These patients can be stented from the ipsilateral approach by inserting one stent from the ipsilateral side to the contralateral side and a second stent from the ipsilateral side into the common bile duct or duodenum (Fig. 52.10) in a T-shaped configuration. The other option is to puncture the contralateral side and place side-by-side stents (Fig. 52.11) in a Y-shaped configuration. In either case, stenting into the common bile duct is preferred rather than into the duodenum if possible so as to preserve function of the sphincter of Oddi. Barring any contraindication, this could be done primarily at initial drainage, as advocated by Inal and colleagues,30 who found that whether stents were placed primarily or at a second sitting, cholangitis did not subsequently develop in patients without cholangitis at the time of stenting. In the Inal et al.29 study, all patients with a Bismuth type I or II obstruction achieved a serum bilirubin of 2 mg/dL or less. One advantage of the more anatomic Y-shaped configuration stent placement is

B

FIGURE 52.10  A, Patient with cholangiocarcinoma that resulted in Bismuth-Corlette type II obstruction, with near-complete isolation of right and left hepatic ducts. B, Same patient treated with side-by-side T-shaped configuration. Wall stents were placed simultaneously, with one stent placed from the left hepatic duct (LHD) to the right hepatic duct and the other from the LHD into the common bile duct (CBD). The stent from the LHD to CBD ends well short of the duodenum but extends several centimeters on either side of the obstructed segment.

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

A

759

B

FIGURE 52.11  A, Patient with history of pancreatic cancer after a Whipple procedure with recurrence at the biliary-enteric anastomosis and type II obstruction. B, Same patient after simultaneous placement of side-by-side Y-shaped configuration stents.

that if stent occlusion occurs, both stents are approachable either percutaneously or endoscopically and the patient can be restented. In addition, the patency rate of the Y-shaped configuration may be better in patients with type IV obstruction.29 Specially constructed stents have been developed that allow placement of one stent through an opening in the midbody of the other,31 but these are not in widespread use. In the absence of risk factors for bactibilia, a single ipsilateral stent can be placed. If the goal of drainage is not achieved, the patient can return after a period of observation for contralateral stenting. When the contralateral biliary tree is not opacified, precluding knowledge of the type of obstruction, or the ipsilateral obstruction is a Bismuth type III obstruction, or worse, in the absence of some other contraindication, patients being drained for pruritus alone should have a primary stent placed. If the patient is being drained in an attempt to lower the bilirubin level for chemotherapy, a stent should be considered when it is thought that 30% or more of the liver will be drained. We use this as a rule of thumb despite the fact that, in a series of 149 patients drained at Memorial Sloan Kettering Cancer Center, there was only a marginally significant difference in the number of patients attaining a bilirubin less than 2 mg/dL, based on the estimated volume of liver drained. In this analysis, 6 (29%) of 21 patients with less than one third of the liver drained attained a bilirubin level below 2 mg/dL, whereas this was achieved in 65 (51%) of 128 patients with more than one third of the liver drained (P 5 .06).32 After stent placement, if the bilirubin fails to fall to the desired level, a second drainage procedure can be performed. Given the QOL issues for the patient, as well as the risk of contaminating an undrained part of the liver by having an externalized catheter in place, the slight inconvenience of working alongside a previously placed stent is warranted.

Alternatively, a drainage catheter can be placed and when the serum bilirubin normalizes, the patient can return for secondary stent placement. If an internal/external catheter has been placed, and the bilirubin does not fall to a level that allows treatment, or cholangitis develops, it may be necessary to drain more of the isolated undrained liver. If the initial drainage is on the right side, and the tumor has extended up the right hepatic duct so as to isolate the anterior and posterior divisions from each other and from the left hepatic duct, stenting either the anterior or posterior division is often adequate. Alternatively, side-by-side self-expanding metallic stents can be placed on the right to drain both the anterior and posterior ducts. In challenging cases, one has to devise creative drainage solutions with placement of multiple stents into isolated parts of the liver when clinically indicated. Although a significant difference in patency is reported when more than one stent is placed in a noncoaxial manner,33 the mean patency of multiple stents is almost 6 months, justifying stent placement. Even when one part of the liver is not functional, drainage may be necessary to eliminate a source of ongoing cholangitis (Fig. 52.12). The concepts of biliary drainage are simple, but when high bile duct obstruction is present, the planning is complex, and execution can be difficult. The patient must have enough of the liver drained to be free of cholangitis and pruritus to reduce the serum bilirubin sufficiently to receive chemotherapy, if indicated. Given that no difference in stent patency is reported if the stent is inserted for proximal or distal obstruction, that a significant difference in patency is seen when more than one stent is placed, and that lower complication rates are reported when stents are placed primarily, primary stent placement should be considered whenever possible.29,33,34 Additional

760

PART 5  BILIARY TRACT DISEASE  Section II  Neoplastic

A

B

FIGURE 52.12  Stents placed from right anterior hepatic duct to the common bile duct, from the left hepatic duct to the common bile duct, and from the left hepatic duct to the residual undrained posterior right duct. A, Without contrast. B, After injection of contrast.

stents can be placed later if necessary. Patients with Bismuth type I or II obstructions may be treated with a single stent, whereas patients with type III or IV obstructions may require placement of additional stents.29

POSTPROCEDURE CARE Patients are monitored carefully for the first 24 hours after drainage for signs of bleeding or sepsis. With proper technique, including peripheral bile duct puncture, serious bleeding complications are uncommon. Because the hepatic artery, portal vein, and bile duct travel side by side within portal triads, at the time of drainage blood may enter the bile duct during catheter exchanges, resulting in hemobilia in the immediate postprocedure period (see Chapter 116). Hemobilia usually clears within 24 hours, and new or recurrent hemobilia within the first few days of drainage typically is related to catheter malposition. If the catheter has pulled out from its original position, a catheter sidehole may become positioned outside the biliary tree adjacent to a portal vein branch; this problem can be corrected by simply repositioning the catheter, and we often upsize the catheter as well. Significant arterial bleeding during this period is rare. No matter where the initial puncture is performed to opacify the biliary tree, attempts are always made to puncture a peripheral bile duct for catheter placement, preferably a fourthorder or fifth-order branch. The more peripheral the bile duct punctured, the smaller the accompanying hepatic artery branch, mitigating the risk of arterial injury and postprocedure bleeding.24 When bleeding occurs 1 week or more after biliary drainage— especially when the event is sudden in onset, and there is not only hemobilia but also bleeding around the catheter entry site— arterial injury should be suspected, and the patient should be studied angiographically. Although a pseudoaneurysm or extravasation of contrast is sometimes seen, as in other cases of vascular trauma, any abnormality of a hepatic arterial branch adjacent to the biliary drainage catheter should be taken as

presumptive evidence of injury to the branch, and the vessel should be selectively coil embolized (Fig. 52.13; see Chapter 116). If the operator is determined to demonstrate extravasation of contrast material angiographically, it is sometimes necessary to remove the biliary drainage catheter over a guidewire during the angiogram. In the correct clinical setting, empiric superselective embolization of the arterial branch corresponding to the bile duct punctured is acceptable. There is little downside to this approach, and the patient’s bleeding is stopped; the biliary catheter is exchanged at this point because it is usually at least partially occluded by thrombus. Despite prophylactic antibiotic coverage, sepsis may occur immediately after or within several hours of drainage and should be treated appropriately.35 This is most frequently manifested by the development of rigors with normal or low body temperature, but hypotension and fever may also occur. Sepsis is managed with typical measures: continued administration of appropriate antibiotics, expansion of intravascular volume, and pressor support if necessary. Blood cultures should be drawn to identify organisms responsible for the bacteremia. Cultures of bile obtained at drainage are routinely sent for all patients. This is particularly important for those with preprocedure fever, biliary-enteric anastomosis or sphincterotomy, previous ERCP, or an indwelling stent or catheter. Although positive bile cultures are more common in patients with benign bile duct obstruction, cultures are positive in many patients with malignant obstruction, particularly in the setting of fever and known contamination of the biliary tree. As mentioned earlier, 5% of patients without fever, previous biliary surgery, or endoscopic or percutaneous intervention can have positive bile cultures.23 Bile may leak around a biliary drainage catheter. Leaking is most often related to the catheter becoming malpositioned so that one or more sideholes are no longer within the biliary tree but are in the catheter tract or even outside the patient. This problem is managed by repositioning the catheter. Leakage may also be seen with lack of adequate sideholes above the

C. Malignant Tumors  Chapter 52  Interventional Techniques in Hilar and Intrahepatic Biliary Strictures

A

761

B

FIGURE 52.13  A, Proper hepatic angiogram in patient with hemobilia and bleeding around biliary drainage catheter 1 week after drainage. Note spasm of right hepatic artery branch (arrows) adjacent to catheter at site of duct puncture. B, Right hepatic angiogram after coil embolization (arrows) of right hepatic artery branch.

level of obstruction. Anything that impedes the flow of bile from above the obstruction, either through the catheter to below the obstruction or into a drainage bag, will result in bile leaking back along an established tract. For a properly positioned catheter with an appropriate number of sideholes, the problem is typically related to catheter occlusion and is remedied by catheter exchange. Patients with capped internalexternal catheters may have bile leak back along the catheter tract when egress of bile is obstructed internally. Distal sidehole occlusion is the most common cause, and this problem is easily remedied initially by opening the catheter to gravity drainage and then definitively by catheter exchange. Patients with duodenal obstruction or impaired small bowel motility may be relegated to obligate external drainage. Ascites may leak around the catheter and may be mistaken for bile. This happens in patients with jaundice, when the ascitic fluid is bile colored. Leaking of ascites can be difficult to manage. The best treatment is to establish internal biliary drainage with stent placement as expeditiously as possible. If the patient cannot be stented, the catheter may be upsized to tamponade the site more effectively, but eventually the leak will recur. Ascites can be tapped frequently or drained by a Tenckhoff catheter in an attempt to allow time for tract maturation. These

strategies often fail eventually, and as a last resort, a stoma device is placed around the entry site to contain the ascites.

SUMMARY Treatment of malignant high bile duct obstruction presents unique challenges to the interventional radiologist. The outcome depends on the condition of the underlying hepatic parenchyma, the degree of isolation of the biliary tree, and the technical skills of the operator. A thorough understanding of functional biliary anatomy and the availability of high-quality imaging are necessary to optimize outcome. Although pruritus may be palliated by draining even one segment of the liver, lowering the serum bilirubin to normal or near normal is best achieved by draining at least 30% of the liver, assuming the underlying parenchyma is relatively normal. Contamination of undrained parts of the biliary tree may result from drainage catheter placement, with ongoing or recurrent cholangitis becoming a problem. For this reason, primary stent placement should be considered when 30% or more of the liver can be drained at the initial procedure. References are available at expertconsult.com.

761.e1

REFERENCES 1. Choi JY, Lee JM, Lee JY, et al. Navigator-triggered isotropic threedimensional magnetic resonance cholangiopancreatography in the diagnosis of malignant biliary obstructions: comparison with direct cholangiography. J Magn Reson Imaging. 2008;27(1):94-101. 2. Park HS, Lee JM, Choi JY, et al. Preoperative evaluation of bile duct cancer: MRI combined with MR cholangiopancreatography versus MDCT with direct cholangiography. AJR Am J Roentgenol. 2008;190(2):396-405. 3. Robson PC, Heffernan N, Gonen M, et al. Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction. Ann Surg Oncol. 2010;17(9):2303-2311. 4. Johnson RC, Ahrendt SA. The case against preoperative biliary drainage with pancreatic resection. HPB (Oxford). 2006;8(6):426-431. 5. Mezhir JJ, Brennan MF, Baser RE, et al. A matched case-control study of preoperative biliary drainage in patients with pancreatic adenocarcinoma: routine drainage is not justified. J Gastrointest Surg. 2009;13(12):2163-2169. 6. Wang Q, Gurusamy KS, Lin H, Xie X, Wang C. Preoperative biliary drainage for obstructive jaundice. Cochrane Database Syst Rev. 2008;(3):CD005444. 7. Fang Y, Gurusamy KS, Wang Q, et al. Pre-operative biliary drainage for obstructive jaundice. Cochrane Database Syst Rev. 2012;9(9): CD005444. 8. Yan K, Tian J, Jingyon X, et al. The value of preoperative biliary drainage in hilar cholangiocarcinoma: a systematic review and meta-analysis of 10 years’ literature. Int J Clin Exp Med. 2018;11(4):3462-3472 9. Saxena P, Kumbhari V, Zein ME, Khashab MA. Preoperative biliary drainage. Dig Endosc. 2015;27(2):265-277. 10. Miura S, Kanno A, Masamune A, et al. Bismuth classification is associated with the requirement for multiple biliary drainage in preoperative patients with malignant perihilar biliary stricture. Surg Endosc. 2015;29(7):1862-1870. 11. Leng JJ, Zhang N, Dong JH. Percutaneous transhepatic and endoscopic biliary drainage for malignant biliary tract obstruction: a meta-analysis. World J Surg Oncol. 2014;12(1):272. 12. Rerknimitr R, Kladcharoen N, Mahachai V, Kullavanijaya P. Result of endoscopic biliary drainage in hilar cholangiocarcinoma. J Clin Gastroenterol. 2004;38(6):518-523. 13. Saad WE, Wallace MJ, Wojak JC, Kundu S, Cardella JF. Quality improvement guidelines for percutaneous transhepatic cholangiography, biliary drainage, and percutaneous cholecystostomy. J Vasc Interv Radiol. 2010;21(6):789-795. 14. Wiggers JK, Groot Koerkamp B, Coelen RJ, et al. Preoperative biliary drainage in perihilar cholangiocarcinoma: identifying patients who require percutaneous drainage after failed endoscopic drainage. Endoscopy. 2015;47(12):1124-1131. 15. Giovannini M. EUS-guided hepaticogastrostomy. Endosc Ultrasound. 2019;8(suppl 1):S35-S39. 16. Ogura T, Kurisu Y, Masuda D, et al. Novel method of endoscopic ultrasound-guided hepaticogastrostomy to prevent stent dysfunction. J Gastroenterol Hepatol. 2014;29(10):1815-1821. 17. Kawakubo K, Isayama H, Kato H, et al. Multicenter retrospective study of endoscopic ultrasound-guided biliary drainage for malignant biliary obstruction in Japan. J Hepatobiliary Pancreat Sci. 2014;21(5):328-334. 18. Hann LE, Getrajdman GI, Brown KT, et al. Hepatic lobar atrophy: association with ipsilateral portal vein obstruction. AJR Am J Roentgenol. 1996;167(4):1017-1021.

19. Abraham NS, Barkun JS, Barkun AN. Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life. Gastrointest Endosc. 2002;56(6):835-841. 20. Van Laethem JL, De Broux S, Eisendrath P, Cremer M, Le Moine O, Devière J. Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum. Am J Gastroenterol. 2003;98(6):1271-1277. 21. Thornton RH, Ulrich R, Hsu M, et al. Outcomes of patients undergoing percutaneous biliary drainage to reduce bilirubin for administration of chemotherapy. J Vasc Interv Radiol. 2012;23(1): 89-95. 22. Ozden I, Tekant Y, Bilge O, et al. Endoscopic and radiologic interventions as the leading causes of severe cholangitis in a tertiary referral center. Am J Surg. 2005;189(6):702-706. 23. Brody LA, Brown KT, Getrajdman GI, et al. Clinical factors associated with positive bile cultures during primary percutaneous biliary drainage. J Vasc Interv Radiol. 1998;9(4):572-578. 24. Quencer KB, Tadros AS, Marashi KB, et al. Bleeding after percutaneous transhepatic biliary drainage: incidence, causes and treatments. J Clin Med. 2018;7(5):94. 25. Liu YS, Lin CY, Chuang MT, Tsai YS, Wang CK, Ou MC. Success and complications of percutaneous transhepatic biliary drainage are influenced by liver entry segment and level of catheter placement. Abdom Radiol (NY). 2018;43(3):713-722. 26. Green C, Brown, KT, Erinjeri JP, et al. Does stent placement across the ampulla of Vater increase the risk of subsequent cholangitis? J Vasc Interv Radiol. 2014;25(3):S49. 27. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet. 1975;140(2):170-178. 28. Chang WH, Kortan P, Haber GB. Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage. Gastrointest Endosc. 1998;47(5):354-362. 29. Inal M, Akgül E, Aksungur E, Seydaog˘lu G. Percutaneous placement of biliary metallic stents in patients with malignant hilar obstruction: unilobar versus bilobar drainage. J Vasc Interv Radiol. 2003;14(11):1409-1416. 30. Inal M, Aksungur E, Akgül E, Oguz M, Seydaoglu G. Percutaneous placement of metallic stents in malignant biliary obstruction: onestage or two-stage procedure? Pre-dilate or not? Cardiovasc Intervent Radiol. 2003;26(1):40-45. 31. Kim CW, Park AW, Won JW, Kim S, Lee JW, Lee SH. T-configured dual stent placement in malignant biliary hilar duct obstructions with a newly designed stent. J Vasc Interv Radiol. 2004;15(7): 713-717. 32. Thornton RH, Ulrich R, Hsu M, et al. Outcomes of patients undergoing percutaneous biliary drainage to reduce bilirubin for administration of chemotherapy. J Vasc Interv Radiol. 2012;23(1):89-95. 33. Maybody M, Brown KT, Brody LA, et al. Primary patency of Wallstents in malignant bile duct obstruction: single vs. two or more noncoaxial stents. Cardiovasc Intervent Radiol. 2009;32(4): 707-713. 34. Inal M, Akgül E, Aksungur E, Demiryürek H, Yaƒümur O. Percutaneous self-expandable uncovered metallic stents in malignant biliary obstruction. Complications, follow-up and reintervention in 154 patients. Acta Radiol. 2003;44(2):139-146. 35. Smith TP, Ryan JM, Niklason LE. Sepsis in the interventional radiology patient. J Vasc Interv Radiol. 2004;15(4):317-325.

PART 6

Pancreatic Disease I. Inflammatory, Infective, and Congenital



A. Congenital Disorders 53 Congenital Disorders of the Pancreas: Surgical Considerations

B. Pancreatitis



54 Definition and Classification of Pancreatitis



55 Etiology, Pathogenesis, and Diagnostic Assessment of Acute Pancreatitis



56 Management of Acute Pancreatitis and Pancreatitis-Related Complications



57 Etiology, Pathogenesis, and Diagnosis of Chronic Pancreatitis



58 Management of Chronic Pancreatitis: Conservative, Endoscopic, Surgical

II. Neoplastic

A. General



59 Tumors of the Pancreas and Ampulla



B. Benign and Premalignant Tumors





60 Cystic Neoplasms of the Pancreas: Epidemiology, Clinical Features, Assessment, and Management

C. Malignant Tumors



61 Pancreatic Cancer: Epidemiology



62 Pancreatic Cancer: Clinical Aspects, Assessment, and Management



63 Duodenal Adenocarcinoma



64 Pancreas as a Site of Metastatic Cancer



D. Endocrine Tumors



65 Pancreatic Neuroendocrine Tumors: Classification, Clinical Picture, Diagnosis, and Therapy



66 Chemotherapy and Radiotherapy for Pancreatic Cancer: Adjuvant, Neoadjuvant, and Palliative



67 Palliative Treatment of Pancreatic and Periampullary Tumors

762

PART 6  Pancreatic Disease

SECTION I. Inflammatory, Infective, and Congenital A. Congenital Disorders

CHAPTER 53 Congenital disorders of the pancreas: Surgical considerations Ewen M. Harrison and Rowan W. Parks The pancreas is a glandular organ that lies on the posterior abdominal wall in the retroperitoneum (see Chapter 2) It is an exocrine gland that secretes enzymes of digestion into the duodenum; it also performs endocrine functions, producing insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin (see Chapter 3) Congenital abnormalities of the pancreas may be so severe that they are diagnosed in utero or in the neonatal period, such as pancreatic agenesis. However, many congenital conditions go undetected until adulthood, when the patient comes to medical attention with nonspecific symptoms or an abnormality is discovered incidentally. This chapter describes the diagnosis, investigation, and treatment of the various congenital pancreatic abnormalities.

EMBRYOLOGIC DEVELOPMENT OF THE PANCREAS The basis for the understanding of congenital abnormalities of the pancreas is the embryologic development of the organ (see Chapter 1). The pancreas develops from two buds originating from the endodermal lining of the duodenum. The dorsal bud forms posteriorly within the mesentery, whereas the ventral bud is associated with the hepaticopancreatic duct (Fig. 53.1). During the second month of development, the stomach rotates and the duodenum becomes C-shaped. As part of this process, the ventral pancreatic bud migrates dorsally, coming to lie posteroinferiorly to the dorsal bud, forming what will become the inferior head/uncinate process of the pancreas. In the majority of individuals, the main pancreatic duct (of Wirsung) is formed by the entire ventral duct and the distal dorsal duct and enters the duodenum at the major papilla. Persistence of the proximal part of the dorsal duct occurs in approximately 25% and results in an accessory duct (of Santorini), which enters the duodenum by the minor papilla (see Fig. 53.1).1 There is no known pathologic consequence of this normal variation. Failure of fusion of the ductal system occurs in roughly 10% of the normal population,2,3 resulting in the entire dorsal pancreas—superior head, body, and tail—draining through the minor papilla, and ventral pancreas—the inferior head and uncinate process—draining through the major papilla (Fig. 53.2). This abnormality is termed pancreas divisum (PD) and is described in more detail later (see Chapter 1).

Annular pancreas is a rare congenital abnormality, the embryologic basis of which is poorly understood. A complete or incomplete ring of pancreatic tissue is found around the second part of the duodenum, and it may cause symptoms (also discussed later). A number of published studies have identified mechanisms by which the pancreas is specified from the early endoderm.4 Retinoic acid and bone morphogenic peptide both appear to have important roles in defining early endodermal compartments in the embryo.5,6 The origins of the signaling mechanisms involved in the specification of the dorsal and ventral pancreas are different.7 In the dorsal pancreas, signals arising from the notochord8 and dorsal aorta9 are required; in the ventral pancreas, the lateral plate mesoderm is important.10 The specific identity of these signals has not yet been established, although the Hedgehog family of signaling molecules appears to be significant.11

PANCREAS DIVISUM PD results from incomplete fusion of the dorsal and ventral pancreatic ducts toward the end of the second month of embryogenesis. The distal dorsal pancreatic duct typically fuses with the ventral pancreatic duct to drain the entire pancreas into the duodenum by the major papilla (see Chapter 1). The proximal dorsal duct can persist as an accessory pancreatic duct and may drain by the minor papilla. Complete PD exists when there is no communication between the dorsal and ventral systems and the majority of the pancreas drains by the dorsal duct through the minor papilla (see Fig. 53.2). Variations exist in which a small branch may connect the two ducts, termed incomplete pancreas divisum. The prevalence of this variant is about 15%.12–14 Investigations have suggested that PD may be explained by distinct patterns of incomplete fusion of branches of the dorsal and ventral pancreatic ducts,12 confirming theories first proposed in early anatomic studies.2 The first description of PD is from 1865, attributed to Josef Hyrtl15 (1810–1894), Professor of Anatomy at the Universities of Prague and Vienna. However, as discussed by Stern (1986),16 a number of anatomists were aware of it much earlier than this, including Regnier de Graaf, who described the finding in 1664. In postmortem studies performed throughout the 20th century, the prevalence of PD is reported to be approximately 8% 763

764

PART 6  PANCREATIC DISEASE  Section I  Inflammatory, Infective, and Congenital

Foregut Stomach

Dorsal pancreas

Hepatic diverticulm

Liver

Portal vein

Common hepatic duct

Hepatic duct Common Bile duct Gallbladder Hepaticopancreatic duct Ventral pancreas

Gallbladder

Superior mesenteric vein

Common bile duct Ventral pancreas

Yolk Sac (cut away)

Dorsal pancreas

Hindgut 2. Beginning rotation of common duct and of ventral pancreas

1. Bud formation

Dorsal pancreas Ventral pancreas 3. Rotation completed but fusion has not yet taken place A A A

Accessory pancreatic duct (Santorini's) Pancreatic duct (Wirsung's) 4. Fusion of ventral and dorsal pancreas and union of ducts

A I I

A

A

I

I

I I

I

A

I

A

Formation of acini and islets from ducts. A–acini; I–islets in various stages of development

Relationship of intercalated duct and centroacinar cells to acini

FIGURE 53.1  Embryologic development of the pancreas. (See Chapter 1.)  (Netter illustration from http://www.netterimages.com. Copyright Elsevier, Inc. All rights reserved.)

(range, 4%–14.5%).17–37 With the development of endoscopic retrograde cholangiopancreatography (ERCP, see Chapters 20 and 30) in the late 1960s, however, the considerable congenital variation in the ductal system of the pancreas became more widely appreciated.38–41 The prevalence of PD is lower in published ERCP series than in anatomic series for reasons that are not clear, although it may be due to referral bias, difficulty in the interpretation of pancreatograms, or inability to cannulate the minor papilla. The reported prevalence is particularly low in Asian series (0.3%–0.6%) compared with Western populations (,5%).41–43 PD is clinically relevant for three reasons.22 First, the small ventral duct seen in PD must be differentiated from a similar

appearance seen in some cases of pancreatic cancer. It is important for those performing ERCP to be aware of the anomaly to become proficient in interpreting pancreatograms (Fig. 53.3). Other forms of imaging, such as computed tomography (CT) or magnetic resonance imaging, must be used if there is uncertainty whether a mass lesion is present and causing a ductal abnormality (see Chapter 17). Second, on cannulating the major papilla at ERCP, only the ventral portion of the pancreas may be visualized in PD, which risks missing important pathologic conditions if a pancreatogram is not performed via the minor papilla (see Chapters 20 and 30). It is important to become proficient at cannulation of the minor papilla, which is considerably more challenging than cannulating the major

A. Congenital Disorders  Chapter 53  Congenital Disorders of the Pancreas: Surgical Considerations

papilla. The minor papilla commonly sits in a superior, more ventral position. Cannulation may be facilitated by having the duodenoscope in the “long position” and by administration of intravenous secretin.44 Third, PD may be associated with pancreatitis or other pathologic condition (see Chapters 54 and 55), and this will be discussed in detail in this chapter.

Possible Association Between Pancreas Divisum and Pancreatitis The question of whether PD causes recurrent acute pancreatitis, chronic pancreatitis, or pancreas-related pain has been debated for many years (Table 53.1). An up-to-date systematic review concluded that “current research fails to define a clear association between PD and pancreatic disease.”45 Those proposing the theory suggest that obstruction occurs at the level of the minor papilla, the caliber of which is too narrow to provide adequate drainage of the pancreatic secretions. This is supported by an early study reporting an elevated pressure in the dorsal duct (23.7 6 1.3 mm Hg) compared with the ventral duct (10.8 6 1.9 mm Hg) in six patients with PD, whereas pressures were similar when two ducts existed in patients without PD.46 This

Common bile duct

Accessory papilla Papilla of Vater

Dorsal pancreatic duct (Santorini)

Superior mesenteric artery and vein

Ventral pancreatic duct (Wirsung) FIGURE 53.2  Pancreas divisum describes the incomplete fusion of the dorsal and ventral pancreatic ducts.

765

was contradicted in a subsequent study in which no difference in duct pressures was observed between the major and minor papillae in four patients with recurrent acute pancreatitis and PD.47 Another early report demonstrated chronic pancreatitis confined to the dorsal pancreas in two pancreatoduodenectomy specimens from patients with PD who had resections for symptom control48 (see Chapters 54 and 55). Difficulty exists in demonstrating an epidemiologic relationship between PD and pancreatitis because early anatomic studies were small and confounded by differing definitions, and ERCP series have been skewed by selection bias.48 In the largest early series of 1850 successful major ampulla cannulations, Rösch et al.1 identified PD in 63 cases (3.4%). The indications for pancreatography were not given, but pathologic findings were seen in 13 of 63 patients with PD; changes were consistent with pancreatitis in 12 patients and tumor in 1 patient. In another large series by Gregg,50 33 patients with PD were identified among 1100 patients (3%) referred primarily for investigation of pancreatic-type pain or pancreatitis. Documented pancreatitis was present in 15 patients, and another 11 had recurrent episodes of pain typical of pancreatitis. These and similar studies have been used as evidence of a link between PD and pancreatitis, but the absence of a suitable control group makes the assertion weak. Mitchell et al.52 identified this problem and performed a retrospective analysis of patients who had undergone ERCP and observed that 21 (4.7%) of 449 patients had PD, whereas 4 (3.3%) of 120 patients with pancreatitis defined by clinical and/or ERCP criteria had PD. Thus, in this series, the prevalence of PD in patients with pancreatitis was the same as the prevalence of PD in the series as a whole. This has been supported by the largest published ERCP series of 304 patients, in which the dorsal duct was visualized in 97 patients.58 The frequency of PD was similar in patients with acute or chronic pancreatitis (6.9%) as in all patients in the series undergoing ERCP (5.7%). Contrary to these findings, Cotton42 reported that in patients with primary biliary disease who had an incidental pancreatogram at the time of endoscopic retrograde cholangiogram, the prevalence of PD was 3.6%. This was compared with a prevalence of 16.4% in those with chronic or recurrent acute

FIGURE 53.3  Imaging in pancreas divisum (PD). A magnetic resonance cholangiopancreatography image shows PD with the dorsal pancreatic duct draining through the minor papilla (left). Endoscopic retrograde cholangiopancreatography in PD performed through the minor papilla (right). Contrast can still be seen in the common bile duct after cannulation of the major papilla. (See Chapters 17 and 20.) (Courtesy Dr. K. Palmer, Edinburgh.)

766

PART 6  PANCREATIC DISEASE  Section I  Inflammatory, Infective, and Congenital

TABLE 53.1  Early Series Reporting Pancreas Divisum PANCREATITIS RELATIONSHIP SUPPORTED

STUDY TYPE

N (%)

INTERVENTION

Phillip J et al., 1974 Rösch et al., 19761 Gregg, 197750 Heiss & Shea, 197851 Mitchell et al., 197952 Cotton, 198042 Tulassay & Papp, 198053 Richter et al., 198154

— — — Yes No Yes Yes Yes

ERCP ERCP ERCP ERCP ERCP ERCP ERCP ERCP

18/911 (2.0) 63/1850 (3.4) 33/1100 (3.0) 4 21/449 (4.7) 47/810 (5.8) 33/2410 (1.4) 519

Thompson et al., 198155 Cooperman et al., 198256

Yes

ERCP series Case series

11/850 (1.3) 21/314 (6.7)

Sahel et al., 198257 Blair et al., 198448

Yes Yes

ERCP series Case series

41/812 (5.0) 14

Delhaye et al., 198558

No

ERCP series

Sugawa et al., 198759

No

ERCP series

304 total; 6.9% AP/CP, 5.7% no pancreatitis 55/1529 (3.6)

— — — — — — Unspecified surgery in 11; no outcomes described Open sphincteroplasty to minor ampulla in 9; decreased pain: 5/6 with acute pancreatitis, 0/3 with chronic — Open sphincteroplasty to minor ampulla in 5; 4 of 6 “have done well” at 28 months — 15 operative resections in 14 patients with RAP; 7/14 had no pain after surgery —

Bernard et al., 199040

Yes

ERCP series

137/1825 (7.5)

STUDY 49

series series series series series series series series

Open sphincteroplasty to minor ampulla in 3; no improvement in symptoms —

AP, Acute pancreatitis; CP, chronic pancreatitis; ERCP, endoscopic retrograde cholangiopancreatography; RAP, recurrent acute pancreatitis.

pancreatitis. In 83 patients with idiopathic pancreatitis, recurrent pancreatitis with no clear cause, such as gallstones, alcohol, or trauma, the prevalence of PD was 25.6%. This controversy is a good example of the difficulty in determining a causal relationship between two factors that appear to have a clinical association. The traditional criteria used in evaluating such a relationship can be applied: (1) strength of association, (2) consistency across studies, (3) dose-response relationship, and (4) biologic plausibility. The relationship is not a strong one, and many of those in the general population who have PD (,10%) never have any related symptoms, and many with pancreatitis do not have PD; less than 5% of individuals with PD are estimated to ever develop pancreatic symptoms. Furthermore, those with a more pronounced form of the anomaly (i.e., complete PD) do not seem to be more likely to develop pancreatitis than those with incomplete PD.

Imaging in Pancreas Divisum One of the difficulties in relating PD to pancreatitis is the inconsistency in making the diagnosis. ERCP studies of patients without pancreatitis consistently report a lower prevalence of PD when compared with magnetic resonance cholangiopancreatography (MRCP) or postmortem studies (Table 53.2) (see Chapters 17, 20, and 30). The use of secretin during MRCP (S-MRCP) improves the detection rate of PD,60 yet it is still reported to be missed on S-MRCP, possibly because of suboptimal magnetic resonance techniques or inexperience of those reporting the MRCP (see Chapter 19).61 A more recent study reported the use of portal venous phase 64–multidetector-row CT (MDCT). Of 93 patients, 5 had PD diagnosed on MRCP or ERCP. Of these, one observer detected three cases, and a second observer found four cases by reviewing the MDCT images.62 ERCP features of the minor papilla that suggest the

TABLE 53.2  Prevalence of Pancreas Divisum in Patients Without Pancreatitis by Method of Investigation or Imaging Modality INVESTIGATION TYPE Postmortem MRCP S-MRCP ERCP

N 2895 505 156 16,078

% PREVALENCE OF PD (95% CI) 7.8 (6.8-8.8) 9.3 (6.8-11.8) 17.9 (11.9-24.0) 4.1 (3.8-4.4)

CI, Confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; PD, pancreas divisum; S-MRCP, secretinenhanced MRCP; cholangiopancreatography. From Fogel EL, et al: Does endoscopic therapy favorably affect the outcome of patients who have recurrent acute pancreatitis and pancreas divisum? Pancreas. 2007;34:21–45.

presence of PD include an enlarged papilla or open orifice and are thought to moderately predict the presence of PD; however, a significant number of patients with PD do not have these features.63,64 Endoscopic ultrasound (EUS) as an alternative imaging modality has gained in popularity and is reported to be useful in the investigation of patients with acute recurrent pancreatitis of unknown cause (see Chapter 22).65 The sensitivity of EUS for PD has been shown to be 85% to 95%,65–67 which was superior to the sensitivity of CT (50%–60%)69,70 or MRCP (50%–70%),61,71–73 but similar to that with secretin-enhanced MRCP (83%–86%).74,75

Therapy to the Minor Papilla in Those With Pancreas Divisum and Pancreatitis If PD is associated with obstruction at the minor papilla, which in turn contributes to the occurrence of pancreatitis and pancreatic pain, it follows that surgical intervention to relieve this

767

A. Congenital Disorders  Chapter 53  Congenital Disorders of the Pancreas: Surgical Considerations

obstruction would be beneficial. As has been discussed, significant controversy exists as to whether this assumption is correct. A number of studies have been performed examining whether therapy to the minor papilla is beneficial in patients with acute recurrent pancreatitis, chronic pancreatitis, or pancreas-related pain; however, little in the way of randomized controlled data has been generated (Table 53.3) (see Chapters 54 to 58). Interventions examined include endoscopic dilation; papillotomy; sphincterotomy of the minor papilla, with or without stent placement; and surgical sphincteroplasty. The first minor papilla endoscopic sphincterotomy was described by Cotton in 1978,91 and the majority of publications since have been small case series with short follow-up times. Lehman et al.80 described the effects of minor papilla sphincterotomy in 52 PD patients with chronic pancreatic pain (n 5 24), recurrent acute panc