Pancreas (Gastrointestinal Surgery Library) [Team-IRA] 0192858440, 9780192858443

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Pancreas

GA ST RO IN T E ST IN A L S URGERY L IBR A RY Abdominal Trauma, Peritoneum, and Retroperitoneum Aditya Nanavati and Sanjay Nagral Appendix, Colon, and Rectum Parul J. Shukla, Jeffrey Milsom, and Kota Momose Duodenum and Small Bowel John A. Windsor, Sanjay Pandanaboyana, and Anil K. Agarwal Liver, Gall Bladder, and Bile Duct Mohamed Rela and Pierre-​Alain Clavien Oesophagus and Stomach Matthias Reeh and Jakob R. Izbicki Pancreas Shailesh V. Shrikhande and Markus W. Büchler

Pancreas EDITED BY

Shailesh V. Shrikhande Deputy Director, Head, Division of Cancer Surgery, Chief, GI and HPB Surgery, Professor, Department of Surgical Oncology, Tata Memorial Centre, Mumbai, India

Markus W. Büchler Professor of Surgery and Chairman, Surgical Hospital, Heidelberg University, Heidelberg, Germany

SERIES EDITORS

Samiran Nundy Emeritus Consultant, Sir Ganga Ram Hospital, New Delhi, India

Dirk J. Gouma Emeritus Professor of Surgery, Amsterdam University Medical Centre, Amsterdam, The Netherlands

Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2023 The moral rights of the authors have been asserted First Edition published in 2023 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2022935776 ISBN 978–​0–​19–​285844–​3 DOI: 10.1093/​med/​9780192858443.001.0001 Printed and bound by CPI Group (UK) Ltd, Croydon, CR0 4YY Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Foreword to the Gastrointestinal Surgery Library We are currently led to believe that textbooks are déclassé. Information is no longer gathered other than online through PubMed or Google and their equivalents. This is not so. First, much of the world, especially in low-​ and middle-​income countries, still derives scholarly information from textbooks; and second, we ignore the obvious—​where does the online information come from? Certainly, for a narrow, topic-​specific search, we can immediately reach for PubMed, but where does generic, broad disease-​based topic information come from? Is it possible to educate our current and future surgeons on Wikipedia alone? Truth is hard to find, truth in surgery even harder. We surgeons, like the rest of the world, find it easy to fall back on the confirmation biases of our already held beliefs. We all still struggle with ‘we do this this way, because that is the way we have always done so’. Only in recent decades have surgeons moved from numerator doctors remembering the energizing success and the damaging failure to provide denominators for our actions. How to find the truth or even the facts is a great challenge in our information-​overloaded society. Clinical trials in the discipline of surgery are hard to do, and even harder where equipoise does not exist. Our best recourse is to begin with those leading their respective fields, often in academic environments where challenge and controversy are healthy endeavours. A culture where the student becomes the conscience of the professor is what academia should be about. Where can we go to look for the most current validated information? Where can our trainees go beyond their immediate environment? Nowhere is this more important as we become a global

surgical society. The low-​and middle-​income countries look to the high-​income countries for leadership and guidance, but is that correct? What we do in tertiary institutions may well not serve our colleagues in resource-​poor countries. This should be a two-​way street; what can we in tertiary centres learn from less privileged, but equally demanding, societies? We embrace technology for technology’s sake, we think little of value but only of perceived benefit. What an opportunity to embrace excellence and define the greater benefit for the greatest number. The Gastrointestinal Surgery Library series has taken on this Herculean task. The lead editors Professor Samiran Nundy from New Delhi and Professor Dirk J. Gouma from Amsterdam have the stature and fortitude to lead this challenge. A mammoth text focused on a global readership in print, e-​book, and online editions. To do this, they have assembled a cadre of volume editors from six countries. The volume editors have then recruited leaders within the gastrointestinal surgical fraternity from several more countries to address global problems in gastrointestinal surgery, from oesophagus to anus and all tissues and viscera that surround the alimentary tract. Together, they provide a comprehensive umbrella that most will find weatherproof, but not impermeable. Sir Murray F. Brennan Memorial Sloan Kettering Cancer Center New York, United States

Introduction from the Series Editors Gastrointestinal (GI) surgery is performed for a range of benign and malignant diseases, in both the elective and emergency settings. Although there are many textbooks related to GI surgery, most of them are addressed to a predominantly Western readership or deal with individual organs or organ systems. We have strived to create a comprehensive Gastrointestinal Surgery Library in which each of these six books deals with a specific organ and is edited by internationally recognized experts from both the developed as well as the developing countries. We thus have 14

editors and 350 contributors from 24 different countries from as far afield as Argentina and New Zealand. The Gastrointestinal Surgery Library will, we hope, serve as reference manuals on this important subject and cater to a global audience. The inclusion of experts across the world to edit the individual volumes and contribute to the chapters will also result in the description of effective management protocols which are relevant to both developed and developing nations. Samiran Nundy Dirk J. Gouma

Introduction from the Volume Editors The pancreas continues to fascinate clinicians and researchers perhaps far more than any other organ. The reasons are multifactorial—​ the anatomical location deep inside the abdominal cavity and the various functions of the gland, some of which are well understood, but with many remaining ill defined and ill understood. Last, but certainly not least, pancreatic surgery, along with liver surgery, remains the final frontier for the vast majority of abdominal surgeons. The information explosion that we face in this era can be a boon, but can also confuse interested readers about the various cutting-​ edge developments in acute pancreatitis, chronic pancreatitis, and pancreatic cancer. This book strives to update not only the pancreas specialist, but also the postgraduate student, the general surgeon with interest in pancreatic diseases, and the pancreas researcher. We have been fortunate to have had the opportunity to compile and edit excellent evidence-​based contributions from some of the finest

authors who are recognized leaders in pancreatology. We have aimed to cover contemporary issues in acute and chronic pancreatitis, and also pancreatic cancer, in a way that would help practising surgeons and pancreatologists with the most modern and up-​to-​date concepts in management and then hope to provide further impetus to pancreatic researchers to unravel the mysteries of this gland. It has been a delight to partner with two leaders in hepato-​ pancreato-​biliary (HPB) surgery Professors Samiran Nundy and Dirk J. Gouma, whom we have known many years, and we thank them for inviting us as volume editors for this book. We sincerely hope you enjoy reading this book as much as we have enjoyed working on it. Shailesh V. Shrikhande Markus W. Büchler

About the Series Editors Samiran Nundy was a medical undergraduate in Cambridge and Guy’s Hospital London, UK, and then trained, first in Medicine at the Hammersmith Hospital, and later in Surgery at Guy’s, Addenbrooke’s Cambridge, the Hammersmith, and the Massachusetts General Hospital in Boston, USA. He has taught at the University of Cambridge, London, and Harvard, and returned to the All India Institute of Medical Sciences (AIIMS) in 1975 where he eventually became Professor and Head of the Department of Gastrointestinal Surgery. He left AIIMS in 1996 to start the Surgical Gastroenterology and Liver Transplantation Department in the Sir Ganga Ram Hospital in New Delhi, India. His clinical and research interests are in the management of complicated diseases of the liver, bowel, and pancreas, and the quality of Indian medical research and publications and health information on the web. He has written or edited 37 books and authored or co-​authored 236 research papers. He has been Editor of the National Medical Journal of India, Tropical Gastroenterology, the Indian Journal of Medical Ethics, and the website DrRaxa.com, and has served on 24 journal editorial boards, including the BMJ. He is Emeritus Editor of Current Medicine Research and Practice; he is on the Board of Trustees of Sir Ganga Ram Hospital and is President of the AIIMS, Rishikesh. Dirk J. Gouma is Emeritus Professor of Surgery at the Academic Medical Center (AMC) in Amsterdam, The Netherlands. He served as Chairman of the Department of Surgery and Chairman of the

Division of Surgical Specialties at the AMC. During his surgical training, he worked as Fellow at Maastricht University and thereafter as Associate Professor. He conducted his PhD research programme at Maastricht; Hammersmith Hospital in London, UK; Massachusetts General Hospital in Boston, USA; and Hermann Hospital in Houston, USA. His clinical and research efforts concentrated on outcome of treatment of hepatobiliary and pancreatic diseases, as well as on evaluation of diagnostic strategies and pathophysiology of obstructive jaundice and biliary drainage. More recently, aspects of patient safety programmes and quality control, such as centralization and development and implementation of checklist, have been included. He has served as Chairman of the Scientific Committee of the European Surgical Association (ESA), Council Member of the United European Gastroenterology (UEG), President of the European–​African Hepato-​Pancreato-​Biliary Association (E-​AHPBA), Secretary General of the International Hepato-​Pancreato-​Biliary Association (IHPBA), and Chairman of the European Digestive Surgery (EDS). He was Member of the National Health Council, The Netherlands, Chairman of the Concilium Chirurgicum (the Dutch advisory board of surgical education training), and Member of the Editorial Board of several medical journals. He was supervisor of over 50 PhD fellows and is the author/​co-​author of over 660 publications in peer-​reviewed journals (H-​index 95) and of more than 150 non-​peer-​reviewed papers and/​ or book chapters.

About the Volume Editors Shailesh V. Shrikhande is Deputy Director, Head of the Division of Cancer Surgery, and Chief of Gastrointestinal and HepatoPancreato-Biliary Surgical Service at Tata Memorial Hospital, Mumbai, India. He is Chairman of the Indian Council Medical Research (ICMR) committee for developing guidelines for management of pancreatic and gastric cancer in India, and President of the Indian Chapter of IHPBA. He is also the President Elect of the Asian-​Pacific Hepato-​Pancreato-​Biliary Association (A-​PHPBA). In recognition of his work on pancreatic cancer and digestive cancer surgery in India, Professor Shrikhande was awarded an Honorary Fellowship of the Royal College of Surgeons of England in 2014 (FRCS Ad Eundem). He was awarded an Honorary Fellowship of the American Surgical Association (ASA) in Seattle in April 2021. He is the first HPB specialist and only the second Indian surgeon to receive this honour in the last 140 years. He has edited nine books and authored over 75 book chapters and 285 journal articles.

Markus W. Büchler is Executive Director and Professor of Surgery at Heidelberg University Hospital, Germany. After studying medicine in Heidelberg and Berlin, he started surgical training at the University of Ulm. In 1993, he became Professor of Surgery and Clinical Director at Bern University, Switzerland. In 2001, he returned to Germany to lead the surgical department in Heidelberg. Today he additionally heads the surgical departments of four general hospitals in the Heidelberg region. He is an internationally respected expert in the field of surgery, especially of pancreatic surgery. More than 2900 scientific manuscripts published by him focus on the molecular basis of gastrointestinal cancer and pancreatic diseases, as well as on clinical surgical problems. Professor Büchler is an honorary member of several national and international societies. He is on the Editorial Boards of many scientific journals and has received multiple awards.

Contents Contributors  xvii Abbreviations  xix

8. Tropical Chronic Pancreatitis: Aetiology, Diagnosis, and Approach to Management  64 Rupjyoti Talukdar and G. V. Rao

PART 1 Acute Pancreatitis  1. Acute Pancreatitis: Aetiopathogenesis, Diagnosis and Approach to Management  3 Savio George Barreto

2. Management of Oedematous Pancreatitis, Fluid Collections, and Walled-​Off Necrosis  11 Minas Baltatzis, Saurabh Jamdar, and Ajith K. Siriwardena

3. Management of Acute Necrotizing Pancreatitis  20 Thomas K. Maatman and Nicholas J. Zyromski

PART 3 Pancreatic Tumours  9. Molecular Biology of Pancreatic Cancer  71 Yoshiaki Sunami, Ibrahim Büdeyri, Johanna Häußler, Christoph W. Michalski, and Jörg Kleeff

10. Periampullary and Pancreatic Cancer  80 Rosa Klotz and Thilo Hackert

11. Neuroendocrine Tumours of the Pancreas  87 Manish S. Bhandare, Vikas Gupta, Vikram A. Chaudhari, and Shailesh V. Shrikhande

12. Cystic Neoplasms of the Pancreas  100

PART 2 Chronic Pancreatitis  4. Molecular Understanding and Pathophysiology of Chronic Pancreatitis  33 Jonas Rosendahl

5. Chronic Pancreatitis: Medical and Endoscopic Management  36 Anshuman Elhence, Soumya Jagannath Mahapatra, and Pramod Kumar Garg

6. Surgery for Chronic Pancreatitis  45 Norbert Hüser, Volker Aßfalg, Daniel Hartmann, Güralp Ceyhan, and Helmut Friess

7. Autoimmune Pancreatitis  55 Sushil Kumar Garg and Suresh T. Chari

Atsushi Oba, Y. H. Andrew Wu, Richard D. Schulick, and Marco Del Chiaro

PART 4 Miscellaneous  13. Pancreas and Splenic Trauma  107 Martin D. Smith, Vicky A. Jennings, and John W. Devar

14. Pancreas Transplantation: Improving Survival in Diabetes  123 Vrishali P. Patil and Hans W. Sollinger

Index  139

Contributors Volker Aßfalg

Helmut Friess

Thomas K. Maatman

Assistant Professor, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Chair, Full Professor, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Surgical Resident, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

Minas Baltatzis

Pramod Kumar Garg

Soumya Jagannath Mahapatra

Senior HPB Fellow, Regional Hepato-​Pancreato-​ Biliary Unit, Manchester Royal Infirmary, Manchester, UK

Professor, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

Assistant Professor, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

Savio George Barreto

Sushil Kumar Garg

Christoph W. Michalski

Senior Lecturer in Surgery, College of Medicine and Public Health, Flinders University, South Australia, Australia

Assistant Professor, Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, WI, USA

Professor, Department of Surgery, University of Ulm, Ulm, Germany

Manish S. Bhandare

Vikas Gupta

PDF GI and HPB Surgical Oncology, Associate Professor, GI and HPB Surgery, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai, India

Fellow GI and HPB Oncology, Assistant Professor (Surgical Oncology), Department of Surgery, MGM Medical College, Navi Mumbai, India

Ibrahim Büdeyri

Thilo Hackert

Resident, Department of Surgery, University of Münster, Münster, Germany

Vice Chairman, Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA; Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

Güralp Ceyhan

Full Professor, Department of General Surgery, HPB Unit, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey Suresh T. Chari

Daniel Hartmann

Assistant Professor, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Atsushi Oba

Vrishali P. Patil

Consultant Multi-​organ Transplant Surgeon, Department of Abdominal Transplant and Hepatobiliary Surgery, Deenanath Mangeshkar Hospital and Research Centre, Pune, India G. V. Rao

Martin-​Luther-​University Halle-​Wittenberg, Halle (Saale), Germany

Director, Chief of Surgical Gastroenterology and Minimally Invasive Surgery, Asian Institute of Gastroenterology Hospitals, Hyderabad, India

Norbert Hüser

Jonas Rosendahl

Professor, Department of Gastroenterology, Hepat and Nutr, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Johanna Häußler

Vikram A. Chaudhari

Professor, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Vice Director, Department of Medicine, Clinic for Internal Medicine I, Martin Luther University, Halle (Salle), Germany

Saurabh Jamdar

Richard D. Schulick

PDF GI and HPB Surgical Oncology, Associate Professor, GI and HPB Surgery, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai, India Marco Del Chiaro

Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Cancer Center, Aurora, CO, USA John W. Devar

Professor, Department of Surgery, School of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; Senior Hepato-​ pancreatico-​biliary Consultant, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Anshuman Elhence

Assistant Professor, Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Consultant Hepatobiliary Surgeon, Regional Hepato-​pancreato-​biliary Unit, Manchester Royal Infirmary, Manchester, UK Vicky A. Jennings

Trauma Surgeon, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, and Netcare Milpark Hospital Level 1 Trauma Centre, Johannesburg, South Africa Jörg Kleeff

Professor of Surgery, Department of Visceral, Vascular, and Endocrine Surgery, University Medical Center Halle, Martin-​Luther-​University Halle-​Wittenberg, Halle (Saale), Germany Rosa Klotz

Physician, Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Cancer Center, Aurora, CO, USA Shailesh V. Shrikhande

Deputy Director, Head, Division of Cancer Surgery, Chief, GI and HPB Surgery, Professor, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, India Ajith K. Siriwardena

Professor of Hepatobiliary Surgery, Regional Hepato-​pancreato-​biliary Unit, Manchester Royal Infirmary, Manchester, UK Martin D. Smith

Assistant Head of School of Clinical Medicine, Academic Head of Department of Surgery, WITS School of Clinical Medicine, Johannesburg, South Africa

xviii

Contributors

Hans W. Sollinger

Rupjyoti Talukdar

Nicholas J. Zyromski

F. O. Belzer Professor of Surgery (Emeritus), Founder ENDSULIN, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Director, Pancreatology, Clinical Pancreatologist and Clinician Scientist, Head, Pancreas Research Group and Division of Gut Microbial Research, Institute of Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology Hospitals, Hyderabad, India

Professor, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

Yoshiaki Sunami

Research Associate, Department of Visceral, Vascular, and Endocrine Surgery, University Medical Center Halle, Martin-​Luther-​University Halle-​Wittenberg, Halle (Saale), Germany

Y. H. Andrew Wu

Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Abbreviations AAST ADM AGA AIDS AIIMS AIP AMC ANC AO AP APA APC APFC A-​PHPBA ASA ASGE ATLS ATP ATX AV BAL BBS BCR BD-​IPMN BD-​SES BMI CADM1 CAF CASR CCK CCND2 CDH13 CDKN1B CEA CECT CEL CFA CFTR CgA CgB

American Association for the Surgery of Trauma acinar-​to-​ductal metaplasia American Gastroenterological Association acquired immune deficiency syndrome All India Institute of Medical Sciences autoimmune pancreatitis Academic Medical Center acute necrotic collection antioxidant acute pancreatitis American Pancreatic Association adenomatous polyposis coli acute peripancreatic fluid collections Asian-​Pacific Hepato-​Pancreato-​ Biliary Association American Surgical Association American Society for Gastrointestinal Endoscopy Acute Trauma Life Support adenosine triphosphate autotaxin arteriovenous bronchoalveolar lavage benign biliary stricture B-​cell receptor branch duct IPMN biodegradable self-​expanding stents body mass index cell adhesion molecule 1 cancer-​associated fibroblast calcium-​sensing receptor cholecystokinin coding cyclin D2 cadherin 13 cyclin-​dependent kinase inhibitor 1B carcinoembryonic antigen contrast-​enhanced computed tomography carboxyl ester lipase coefficient of fat absorption cystic fibrosis transmembrane regulator chromogranin A chromogranin B

CHA CHEK2 CI CMV COVID-​19 CP CPB CPN CSC CT CTRC DCC DCCT DCS DPA DP-​CAR DPDS DPL DPPHR DSE D-​SOC DUSP6 DVT E-​AHPBA EAST ECM ECOG EDS EGFR EHL ENETS ERC ERCP ERP ESA ESWL

common hepatic artery checkpoint kinase 2 confidence interval cytomegalovirus coronavirus disease 2019 chronic pancreatitis coeliac plexus block coeliac plexus neurolysis cancer stem cell computed tomography chymotrypsinogen C distal bile duct cancer Diabetes Control and Complications Trial damage control surgery diagnostic peritoneal aspiration distal pancreatectomy with coeliac axis resection disconnected pancreatic duct syndrome diagnostic peritoneal lavage duodenum-​preserving pancreatic head resection dobutamine stress echocardiography digital single-​operator cholangioscopy dual specificity phosphatase 6 deep vein thrombosis European–​African Hepato-​Pancreato-​ Biliary Association Eastern Association for the Surgery of Trauma extracellular matrix Eastern Cooperative Oncology Group European Digestive Surgery epidermal growth factor receptor electrohydraulic lithotripsy European Neuroendocrine Tumor Society endoscopic retrograde cholangiography endoscopic retrograde cholangiopancreatography endoscopic resonance pancreatography European Surgical Association extracorporeal shock wave lithotripsy

xx

Abbreviations

EUS EWS EWSR1 5-​FU FAEE FAP FAST FCPD fcSEMS FDG FNA F-​p-​NET GAD GAP Gd GDA GDP GEL GEP-​NET GI GIA GI-​NEC GTP GWAS 5-​HIAA Hb Hct HGD HHIP HIV HLA HOP HPB HPF HTK IAP IBD ICDC ICMR ICU IDCP IDF IFN IgG4 IgG4-​RD IGSF4 IHC IHPBA IKβ IKK IL-​2

endoscopic ultrasound/​ ultrasonography Early Warning Score Ewing sarcoma breakpoint region 1 5-​fluorouracil fatty acid ethyl ester familial adenomatous polyposis focused assessment with sonography fibrocalcific pancreatic diabetes fully covered self-​expanding metal stent fluorodeoxyglucose fine-​needle aspiration functioning p-​NET glutamic acid decarboxylase GTPase-​activating protein gadolinium gastroduodenal artery guanosine diphosphate granulocyte epithelial lesion gastro-​entero-​pancreatic neuroendocrine tumour gastrointestinal gastrointestinal anastomosis Gastrointestinal Necrotising Enterocolitis guanosine triphosphate genome-​wide association studies 5-​hydroxyindoleacetic acid haemoglobin haematocrit high-​grade dysplasia hedgehog interacting protein human immunodeficiency virus human leucocyte antigen head of the pancreas hepato-​pancreato-​biliary high-​power field histidine–​tryptophan–​ketoglutarate International Association of Pancreatology inflammatory bowel disease International Consensus Diagnostic Criteria Indian Council Medical Research intensive care unit idiopathic duct-​centric pancreatitis International Diabetes Federation interferon immunoglobulin G4 IgG4-​related disease immunoglobulin superfamily member 4 immunohistochemistry International Hepato-​Pancreato-​Biliary Association inhibitor of NF-​κB IκB kinase interleukin-​2

IMV INR IPMN IPTR ISGPS JAK1 LAMS LAR LDH LGD LPSP LT MAP MAPK MAP2K MAP3K MCN MCT MD-​IPMN MDT MEK MEN1 MGMT MiNEN MMP-​12 MPS MR MRCP MRI MRP MT-​IPMN mTOR mTORC1 NAT NCCN NEC NEMO NET NF-​1 NF-​p-​NET NMDA NOM NPOS NSAID NSE OPSI PAK PanIN

inferior mesenteric vein international normalized ratio intraductal papillary mucinous neoplasm International Pancreas Transplant Registry International Study Group for Pancreatic Surgery Janus kinase 1 lumen-​apposing metal stent long-​acting release lactate dehydrogenase low-​grade dysplasia lymphoplasmacytic sclerosing pancreatitis liver transplantation mitogen-​activated protein MAP kinase MAP kinase kinase MAP kinase kinase kinase mucinous cystic neoplasm medium-​chain triglyceride main duct IPMN multidisciplinary team MAPK/​extracellular signal-​ regulated kinase multiple endocrine neoplasia type 1 O-​6-​methylguanine-​DNA methyl transferase mixed neuroendocrine non-​ neuroendocrine neoplasm matrix metalloproteinase-​12 myocardial perfusion scan magnetic resonance magnetic resonance cholangiopancreatography magnetic resonance imaging magnetic resonance pancreatography mixed-​type IPMN mammalian target of rapamycin mammalian target of rapamycin complex 1 nucleic acid testing National Comprehensive Cancer Network neuroendocrine carcinoma NF-​κB essential modulator neuroendocrine tumour neurofibromatosis type 1 non-​functioning p-​NET N-​methyl-​D-​aspartate non-​operative management National Pancreas Offering Scheme non-​steroidal anti-​inflammatory drug neuron-​specific enolase overwhelming post-​splenectomy infection pancreas after kidney

Abbreviations

PC PCN PCR PD PDAC PDD PDGF PDGFR-​β PDRI PE PEI PERT PET PFS PFT PI3K PI3KCA PI4,5P2 PIMS PIP3 p-​NET POPF PP P-​PASS PPI PPPD PRA PRRT PSC PTA PTEN PV RASSF1A RB1 RCT RFLP Rheb RR RTX SA SAE SAP SAPK SARS-​CoV-​2 SCN SEMS SETD2

pancreatic cancer pancreatic cystic neoplasm polymerase chain reaction pancreatic duct; pancreatoduodenectomy pancreatic ductal adenocarcinoma portal duodeno-​duodenostomy platelet-​derived growth factor platelet-​derived growth factor receptor β Pancreas Donor Risk Index pulmonary embolism pancreatic exocrine insufficiency pancreatic enzyme replacement therapy positron emission tomography progression-​free survival pancreatic function test phosphatidylinositol-​4,5-​bisphosphate 3-​kinase PI3K catalytic subunit α phosphatidylinositol 4,5-​bisphosphate Pancreatic Injury Mortality Score phosphatidylinositol 3,4,5-​triphosphate pancreatic neuroendocrine tumour post-​operative pancreatic fistula pancreatic polypeptide pre-​procurement pancreas suitability score proton pump inhibitor pylorus-​preserving pancreatoduodenectomy Panel reactive antibody peptide receptor radionuclide therapy pancreatic stellate cell; primary sclerosing cholangitis; pancreatic stellate cell pancreas transplant alone phosphatase and tensin homolog portal vein Ras association domain family member 1A retinoblastoma 1 randomized controlled trial restriction fragment length polymorphism Ras homolog enriched in brain risk ratio rituximab splenic artery splenic artery embolization severe acute pancreatitis stress-​activated protein kinase severe acute respiratory syndrome coronavirus 2 serous cystic adenoma self-​expanding metal stent SET domain containing 2

Shh SIRS SMA SOCS1 SPECT SPINK1 SPK SPN SRS SRTR SSA SSTR SSTR2 STK11 TACE TARE TCP TCR TGF-​β TGFBR1 TGFBR2 TMD TNFR TPD TPS TRPV6 TSC TSLC1 T1WI T2WI UEG UICC UNOS USG USP UW VARD VAS VEGF VHL VIP VTE WDHA WHO WON WSES WWOX

sonic hedgehog systemic inflammatory response syndrome smooth muscle actin; superior mesenteric artery suppressor of cytokine signalling 1 single-​photon emission computed tomography serine protease inhibitor Kazal type 1 simultaneous pancreas–​kidney solid pseudopapillary neoplasm somatostatin receptor scintigraphy Scientific Registry of Transplant Recipients somatostatin analogue somatostatin receptor somatostatin receptor type 2 serine/​threonine kinase 11 transarterial chemoembolization transarterial radioembolization tropical chronic pancreatitis T-​cell receptor transforming growth factor β TGF-​β receptor 1 TGF-​β receptor 2 transmural drainage tumour necrosis factor receptor transpapillary drainage Total Points Score transient receptor potential cation channel subfamily V member 6 tuberous sclerosis complex tumour suppressor in lung cancer 1 T1-​weighted images T2-​weighted images United European Gastroenterology Union for International Cancer Control United Network for Organ Sharing ultrasonography United States Pharmacopeia University of Wisconsin videoscopic-​assisted retroperitoneal debridement visual analogue scale vascular endothelial growth factor von Hippel–​Lindau vasoactive intestinal peptide venous thromboembolism watery diarrhoea, hypokalaemia, and achlorhydria World Health Organization walled-​off necrosis World Society of Emergency Surgery WW domain containing oxidoreductase

xxi

PART 1

Acute Pancreatitis

1. Acute Pancreatitis: Aetiopathogenesis, Diagnosis and Approach to Management  3 Savio George Barreto 2. Management of Oedematous Pancreatitis, Fluid Collections, and Walled-​Off Necrosis  11 Minas Baltatzis, Saurabh Jamdar, and Ajith K. Siriwardena 3. Management of Acute Necrotizing Pancreatitis  20 Thomas K. Maatman and Nicholas J. Zyromski

1

Acute Pancreatitis Aetiopathogenesis, Diagnosis, and Approach to Management Savio George Barreto

Introduction Acute pancreatitis (AP), an acute inflammatory process of the pancreas, with variable involvement of other regional tissues or remote organ systems,1 is one of the most common causes for emergency department admissions2–​5 all over the world. The presentation and course of the disease range from a mild, self-​limiting course and complete resolution of signs and symptoms within a few days in up to 87% of patients,6,7 to severe disease with an attendant mortality rate of 12–​16%.6,8,9 This chapter will discuss the causation of the disease, along with a systematic, clinically relevant approach to its diagnosis and management.

Aetiology The major risk factors for AP are alcohol and gallstone disease.10

Alcohol Alcohol is believed to cause AP via numerous mechanisms, including increased gastric acid secretion and resultant duodenal acidification, protein plug formation in the pancreatic duct, induced state of transient hypertriglyceridaemia, reduced sphincter of Oddi tone with attendant reflux of duodenal contents into the pancreatic tree,11 and abnormal cytosolic calcium signalling.12

Gallstones The three classic theories in the causation of biliary AP include the ‘flow/​reflux theory’, which refers to direct damage to the sphincter of Oddi due to passage of a stone resulting in reflux of duodenal contents into the pancreatic ductal system, the ‘common channel reflux theory’13 that proposes the creation of a common channel between the terminal portions of the bile and pancreatic ducts due to impaction of the stone at the ampulla, and ‘the obstruction theory’ referring to obstruction of the pancreatic duct by the biliary calculus leading to intraductal hypertension owing to continued secretion

into the duct and consequent pancreatic juice extravasation into the parenchyma.

Metabolic causes Hypertriglyceridaemia Hypertriglyceridaemia, where serum triglyceride levels are in excess of 1000 mg/​dl (as seen mainly in type V hyperlipoproteinaemia, but also in types IV and I), can contribute to the causation of AP due to ischaemic injury to the pancreatic microcirculation from the formation of free fatty acids resulting from hydrolysis of excess triglycerides by pancreatic lipase.14 Hypercalcaemia Hypercalcaemia (as encountered in patients with hyperparathyroidism or disseminated cancers), on the other hand, contributes to calcium-​induced activation of trypsinogen (pancreatic exocrine hypersecretion) and consequent autodigestion of the pancreas, thereby resulting in AP.

Obstructive causes (other than gallstones) Sphincter of Oddi dysfunction A hypertensive sphincter of Oddi is defined as a transient or fixed elevation of its basal sphincter pressure to >40 mmHg, as measured endoscopically, and may result from papillary inflammation or cholesterolosis, or inflammation of the transampullary septum or fibrosis, mucosal oedema, or hypertrophy of the muscle.15 Sphincter of Oddi dysfunction leads to a hold-​up of pancreatic secretions and consequent increased ductal pressures which may, or may not, be coupled with the creation of a common channel between the bile and pancreatic ducts (alluded to above). Tumours Pancreatic ductal obstruction secondary to pancreatic carcinomas, cystic pancreatic tumours or even metastases to the pancreas may lead to AP.

4

1  Acute Pancreatitis

Pancreas divisum Congenital failure of embryological fusion of the dorsal and ventral pancreatic analogues and the resultant non-​union of the ducts of Santorini and Wirsung lead to drainage of the pancreas via the accessory papilla. This leads to increased pancreatic ductal pressures, rendering the individual susceptible to AP as a result of a lowered threshold to the other causative factors. Thus, patients with a proven attack of AP who are then noted to have pancreas divisum must be advised about their potentially increased susceptibility to AP. Iatrogenic AP has been reported following procedures such as endoscopic retrograde cholangiopancreatography (ERCP) (1–​10%), endoscopic sphincterotomy (1–​2%), and sphincter of Oddi manometry, owing to pancreatic duct over-​distension and reflux of biliary or duodenal contents into the pancreatic duct. Infestation with Ascaris lumbricoides or Clonorchis sinensis These parasites16 invade the biliary tree, leading to physical obstruction of the pancreatic and/​or bile ducts, resulting in AP.

Trauma AP may result from direct physical injury to the pancreas secondary to blunt trauma and disruption of the pancreatic ductal system or following pancreatic (endosonographic or percutaneous) biopsies.

Toxic injury Drugs and other agents The effects of drugs in the causation of AP has been well documented.17–​21 Drugs may cause direct injury by a hypersensitivity phenomenon or through the accumulation of a toxic metabolite. Indirect effects of drug-​mediated AP include hypercalcaemia and intravascular thrombosis.

Vascular causes AP has been seen in patients recovering from coronary bypass or in those with serious cardiac illnesses. The predominant underlying mechanism in these patients is ischaemia. This may be the result of pre-​existing atherosclerotic plaques, compounded by low-​flow states in severe heart failure or the administration of potent inotropes (with their attendant vasoconstrictive effect), or embolization from a fibrillating heart, and vasculitis associated with granulomatous diseases. In cardiopulmonary bypass patients,22 perioperative hypotension, renal insufficiency, and perioperative intravenous infusion of calcium chloride have been linked to the causation of AP. While the pancreas is richly perfused from several arterial sources, the arterioles supplying the pancreas are eventually end-​arterioles.23 Thus, in the absence of collaterals, an obstruction will result in infarction.

Cystic fibrosis Bicarbonate secretion by the pancreatic ductal cells serves two important roles, namely, elevation in intraductal pH to prevent premature activation of trypsinogen in the duct, and rapid flushing of trypsinogen through the duct. In cystic fibrosis, due to a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene, there is reduced pancreatic ductal secretion, leading to the risk of prematurely activated trypsinogen within the duct itself, coupled with a

slow transit. While this is insufficient to lead to an attack of AP on its own, cystic fibrosis lowers the threshold for AP caused by other causative factors.

Mixed mechanisms Infections Infections (viruses, including the human immunodeficiency virus (HIV)) can cause AP by multiple mechanisms, including a direct effect on the gland, medications used to treat HIV or acquired immune deficiency syndrome (AIDS), the result of opportunistic infections (cytomegalovirus, Cryptosporidium, Cryptococcus, Toxoplasma gondii, Mycobacterium tuberculosis, and Mycobacterium avium complex), HIV-​associated neoplasm such as Kaposi’s sarcoma, lymphoma, or, simply, the coexistence of other aetiological factors such as alcohol and gallstones. Inflammatory bowel disease The relationship between the development of AP and inflammatory bowel disease (IBD) is likely to be an indirect one, either due to ampullary stenosis secondary to the inflammatory process (including fistula formation) affecting the duodenum or a result of drugs used to treat the disease such as azathioprine, 6-​mercaptopurine, sulfasalazine, and 5-​aminosalicylic acid. Scorpion venom Scorpion24 venom is an uncommon cause of AP. It affects the autonomic nervous system, more specifically, cholinergic discharge, and stimulates pancreatic exocrine secretion and premature enzyme activation. It also has the ability to obstruct the common bile duct and stimulate the release of serotonin, with its attendant downstream effects such as increase in capillary permeability and free trypsin releasing kallikrein, a precursor of bradykinin.

Idiopathic Idiopathic AP is ranked amongst the more common causes of AP in some series around the world. It is a diagnosis of exclusion after the more common causes, such as alcohol, gallstones, metabolic causes, drugs, and morphological abnormalities of the pancreas, have been ruled out. Common underlying factors that have led to patients being labelled as having idiopathic AP include microlithiasis in the bile, sphincter of Oddi dysfunction, autoimmune pancreatitis, and hereditary pancreatitis resulting from mutations in four main genetic variants, namely, cationic trypsinogen (PRSS1), CFTR, serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes.25 It is thus clear that thorough efforts must be made to determine the underlying cause of an attack of AP because those patients being labelled as having idiopathic AP are likely to have an increased risk of recurrence. While the role of factors such as diet26,27 and smoking28 have been linked to the causation of AP, their clinical relevance needs further clarification.

Pathogenesis of acute pancreatitis We have recently proposed that an attack of clinically evident AP is caused by a critical level of acinar cell injury. This first critical threshold is reached when local protective responses are exceeded, a

Approach to management

nidus of inflammation propagates, and multiple inflammatory mediators are released. Feed-​forward necroinflammatory amplification loops increase local pancreatic damage and spill into a systemic inflammatory response, which, above a second critical threshold, induces distant organ injury that can be profound.29 It has been well established, based on experimental evidence, that the initiating events in AP occur in the acinar cell.30 Figure 1.1 provides an elaborate depiction of the sequence of events that occur from initiation to the development of interstitial oedematous and necrotizing pancreatitis. From a clinically relevant point of view, the pathogenesis of AP commences in the acinar cell where premature activation of trypsinogen leads to the discharge of enzymes via the basolateral surface of the cell into the interstitial space rich in blood vessels. This leads to two major effects, namely, activation of local pro-​inflammatory processes and discharge of toxic enzymes into the bloodstream. Phospholipase A2 leaks into the circulation and affects the surfactant of the lung, whereas elastases digest its elastic tissue, contributing to the effects of AP on the lung. Lipases digest fat in the retroperitoneal, as well as intraperitoneal, spaces, leading to saponification and the utilization of calcium (the consequence of which is hypocalcaemia). Trypsin and elastase can act on blood vessels in the retroperitoneum to eventually lead to blood vessel injury, ranging from minor oozing to pseudoaneurysm formation in medium-​sized arteries. The inflammatory response in the retroperitoneum affects the coeliac plexus, causing pain, one of the hallmarks of AP. It is also accompanied by third space losses and hypovolaemia—​the hallmark of clinical AP. Hypovolaemia contributes to acute kidney injury and a rise in the haematocrit. If hypotension ensues, blood gets diverted from the splanchnic circulation in order to preserve the function of the vital organs. This results in reduced pancreatic microcirculation, ischaemia, and eventually necrosis of the pancreas. The resultant bowel wall oedema is accompanied by decreased appetite, disuse of the intestine, and bacterial translocation31—​one of the important sources of bacterial seeding of necrotic pancreatic tissue. Other pathways for the spread of bacteria to the pancreas include the haematogenous route, ascites, the biliary tree, lymphatics, and via the duodenum. The revised Atlanta classification32 acknowledges that the two main forms of AP are: • Interstitial oedematous AP—​characterized by acute peripancreatic fluid collections in the short term and organized pseudocysts (Figure 1.2) containing enzyme-​rich fluid after 4 weeks of the disease. • Necrotizing AP—​characterized by pancreatic and peripancreatic necrosis (sterile or infected) (Figure 1.3) and walled-​off necrosis (WON) (sterile or infected) after 4 weeks.

Diagnosis of acute pancreatitis The diagnosis of AP is based on three parameters:1 • Abdominal pain—​the classical pain of AP is gradual in onset, located in the epigastrium, radiating to the back and relieved by sitting or bending forward. It may be accompanied by nausea, anorexia and vomiting.

• Raised levels of serum amylase and/​or lipase—​these are usually elevated to >3 times the upper limit of normal values for the laboratory. A study by Ventrucci and colleagues33 provided objective evidence to guide the choice of these markers. Serum amylase levels rise early in the course of AP, but they also decline within 24 hours of onset of the pain. Thus, they are useful in patients who present within 36 hours of onset of the pain but may be falsely negative if the test is performed later. Serum lipase levels, on the other hand, have a slower rise but last for 3 days before they decline, making them a more reliable test in patients who present after 12–​24 hours of onset of the disease. • Radiological investigations—​computed tomography (CT) evidence of AP provides the most objective evidence of the disease. CT scans at admission were performed more frequently in the past and even led Emil Balthazar to propose a severity score based on CT findings.34 CT scanning is seldom performed for diagnosis in modern medicine. It is reserved for diagnostic dilemmas where other possible causes for abdominal pain, including duodenitis, ischaemia of the bowel, peritonitis, etc., are being considered, based on the clinical history and examination. Every clinician should take a thorough history and perform a detailed clinical examination, as this not only helps them arrive at the diagnosis, but also provides clues to the severity of the disease, as well as the underlying aetiology (new drugs introduced or onset of pain after taking pain relief medications containing codeine and morphine are invaluable in teasing out the aetiology such as AP secondary to drugs or abnormalities of the sphincter of Oddi, especially when all other common risk factors have been ruled out).

Ruling out differential diagnoses In patients presenting with symptoms suggestive of AP, it is important to rule out other pathology, the most important being perforative peritonitis. Thus, every patient should have an erect chest X-​ray at admission to rule out free air under the diaphragm. Cholecystitis may mimic AP and can be ruled out by performing ultrasound. Gastro-​duodenitis may mimic AP, with attendant elevation in serum amylase and lipase concentrations. The initial management of the two conditions, namely AP and gastro-​duodenitis, is not dissimilar—​clear fluids, fluid resuscitation, and analgesia. The only difference between the two conditions is the administration of a proton pump inhibitor in the latter. If the symptoms are suspicious for gastro-​duodenitis, then consideration must be given to the performance of a gastroscopy 4–​6 weeks after the presentation. The only conditions which can mimic AP and go undiagnosed if not suspected are intestinal ischaemia and aortic aneurysm. These are possibly the only two differential diagnoses in which performance of a CT scan of the abdomen should be considered if there is clinical suspicion.

Approach to management The key steps in the management of AP are listed in Box 1.1.

Determine the severity Once the diagnosis of AP has been made, the next step involves determining the severity of the disease. Over the last three decades,

5

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1  Acute Pancreatitis

Predisposing factors to AP Alcohol, gallstones, metabolic factors, etc.

Acinar cell hyperstimulation/blockade of secretion at the apex Premature intra-acinar activation of trypsin

Abnormal acinar cell response

Intra-acinar cytoskeletal changes

Co-localization hypothesis

Defect in intracellular transport and enzyme sorting

Basolateral exocytosis

Co-localization of lysosomal hydrolases and zymogen granules in same organelles

Release of enzymes (activated) into interstitium

Trypsinogen activation by cathepsin B Neutrophils Increased organelle fragility and rupture Increased oxidative stress

Intracytoplasmic release of activated enzymes

Acinar cell damage

Inflammatory reaction

? now behaving as a pro-inflammatory cell

Protective mechanisms–anti-inflammatory cytokines/ genetic mechanisms Damaged acinar cells attain ‘critical threshold’ Inflammatory cascade

Sensory afferent nerve stimulation

Release of substance P

Neurogenic inflammation Increased vascular permeability, capillary leakage, neutrophil chemotaxis and diapedesis

Leucocyte adhesion to capillary endothelium, leucocyte rolling and occlusion

Sluggish intravascular circulation

Microvascular instability/ischaemia Interstitial oedematous pancreatitis

Figure 1.1  Flow chart demonstrating the pathogenesis of acute pancreatitis.

Necrotizing pancreatitis

Approach to management

• C =​calcium 16 mmol/​L (sign of dehydration from third space losses—​as a risk factor for acute kidney injury) • E(nzymes) =​lactate dehydrogenase (LDH) >600 U/​L (associated with a risk of persistent organ failure)42 • A =​albumin 10 mmol/​L (hyperglycaemia is associated with poor clinical outcomes of AP).44

Figure 1.2  Axial post-​contrast computed tomography image showing pseudocyst formation.

there have been numerous scoring systems1,32,34–​37 proposed to help classify the severity of AP. These have been compared in studies.38–​40 The determinant-​based classification37 has helped to clarify the subgroup of moderately severe AP patients with transient organ failure (15 × 109/​L (sign of dehydration or infection/​cholangitis)

The patient is assigned a score of 1 for every positive variable. Patients with a score >3 should be managed in a high dependency unit or an intensive care unit (ICU). Caution is advised in dismissing a patient scoring 48 hours that the patient suffers from the effects of prolonged biliary obstruction. All patients with mild biliary AP should have their gall bladder removed during the index admission to prevent recurrence

Acknowledgements

of AP that is reported to be between 32% and 61% in the first 6 weeks following discharge.59 In the case of patients with severe AP, cholecystectomy should be deferred till after the inflammatory process (including pseudocysts) resolves, which is generally not before 6 weeks from the onset of the attack.60,61 The actual timing is dependent on the general condition of the patient and the status of the pseudocysts—​which can be surgically treated simultaneously.62 Patients with AP secondary to malignancy of the pancreas should be appropriately staged after resolution of the episode and managed accordingly. An uncommon indication for ERCP/​side-​viewing endoscopy in non-​biliary AP is in the setting of AP secondary to A. lumbricoides where the worm is trapped in the pancreatobiliary tree. Endoscopy offers the best chance to remove the dead/​trapped worm.63 In patients with hypercalcaemia-​induced AP, the most common underlying cause is hyperparathyroidism and its treatment in the acute setting, along with involvement of the endocrinologist, is warranted. In patients with hypertriglyceridaemia-​induced AP, it is important to be aware of the high (approximately 50%) mortality associated with this entity within the first 14 days, which occurs as a result of systemic inflammatory response and multi-​organ dysfunction syndrome.64 In addition to routine management of AP, other treatment options that need to be considered include plasmapheresis, intravenous insulin, and/​or intravenous heparin. The ICU team should be involved in the management of these patients. Once the acute episode has been treated, the patient needs to be advised about lifestyle modifications, including dietary adjustments. Patients should also be commenced on appropriate drug therapy (fibrates, nicotinic acid, and fish oil).64

Conclusion While the trigger for a clinical attack of AP, as well as a specific treatment, remains to be determined, there has been a tremendous body of research that has gone into understanding the underlying aetiopathogenesis of this common medical condition. Evolution in our collective understanding of the course of the disease has helped shape guidelines that are readily available to appropriately manage these patients. Every attempt must therefore be made to manage patients well at the outset, using fluid resuscitation, adequate pain relief, and nutritional supplementation. Determining the cause of the episode is also important as it empowers the clinician to help the patient by preventing another attack of AP in the future.

Acknowledgements I would like to thank Mr Eric Lum, Flinders Medical Centre, Adelaide, Australia for help with the illustration shown in Figure 1.1.

REFERENCES 1. Bradley EL, 3rd. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:586–​90.

2. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012;143:1179–​87.e3. 3. McNabb-​Baltar J, Ravi P, Isabwe GA, et al. A population-​based assessment of the burden of acute pancreatitis in the United States. Pancreas 2014;43:687–​91. 4. O’Farrell A, Allwright S, Toomey D, Bedford D, Conlon K. Hospital admission for acute pancreatitis in the Irish population, 1997 2004: could the increase be due to an increase in alcohol-​ related pancreatitis? J Public Health (Oxf) 2007;29:398–​404. 5. Shaddique S, Cahill RA, Watson RG, O’Connor J. Trends in the incidence and significance of presentations to the emergency department due to acute pancreatitis. Eur J Emerg Med 2006;13:209–​13. 6. Barreto SG, Rodrigues J. Acute pancreatitis in Goa—​a hospital-​ based study. J Indian Med Assoc 2008;106:575–​6, 578. 7. Gao YJ, Li YQ, Wang Q, et al. Analysis of clinical features of acute pancreatitis in Shandong Province, China. J Gastroenterol Hepatol 2007;22:340–​4. 8. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 2015;386:85–​96. 9. Gullo L, Migliori M, Olah A, et al. Acute pancreatitis in five European countries: etiology and mortality. Pancreas 2002;24:223–​7. 10. Barreto SG, Saccone GT. Alcohol-​induced acute pancreatitis: the ‘critical mass’ concept. Med Hypotheses 2010;75:73–​6. 11. McCutcheon A. Reflux of duodenal contents in the pathogenesis of acute pancreatitis. Gut 1964;9:296–​310. 12. Petersen OH, Sutton R. Ca2+​signalling and pancreatitis: effects of alcohol, bile and coffee. Trends Pharmacol Sci 2006;27:113–​20. 13. Opie E. The relation of cholelithiasis to disease of the pancreas and to fat necrosis. Am J Med Sci 1901;121:27–​43. 14. Cameron J, Capuzzi D, Zuidema G, Margolis S. Acute pancreatitis with hyperlipidemia: evidence for a persistent defect in lipid metabolism. Am J Med 1974;56:482–​7. 15. Barreto S, Toouli J. Physiology and pathophysiology of function of Sphincter of Oddi. In: Beger H, Warshaw A, Hruban R, Buechler M, Lerch M, editors. The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, 3rd ed. Wiley, Hoboken –​New Jersey; 2018. pp. 75–​83. 16. Sardesai S, Sharma M, Barreto G. A case of isolated pancreatic duct ascariasis in a child—​a case report. Indian J Radiol Imaging 2006;16:571–​2. 17. Barreto SG, Tiong L, Williams R. Drug-​induced acute pancreatitis in a cohort of 328 patients. A single-​centre experience from Australia. JOP 2011;12:581–​5. 18. Lankisch PG, Droge M, Gottesleben F. Drug induced acute pancreatitis: incidence and severity. Gut 1995;37:565–​7. 19. Spanier BW, Tuynman HA, van der Hulst RW, Dijkgraaf MG, Bruno MJ. Acute pancreatitis and concomitant use of pancreatitis-​ associated drugs. Am J Gastroenterol 2011;106:2183–​8. 20. Barreto S. Drugs and the risk of acute pancreatitis. Astrocyte 2014;1:242–​3. 21. Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, Tenner S. Drug-​induced acute pancreatitis: an evidence-​based review. Clin Gastroenterol Hepatol 2007;5:648–​61; quiz 4. 22. Fernandez-​del Castillo C, Harringer W, Warshaw A. Risk factors for pancreatic cellular injury after cardiopulmonary bypass. N Engl J Med 1991;325:382–​7. 23. Brooke-​Smith ME, Carati CJ, Bhandari M, Toouli J, Saccone GT. Galanin in the regulation of pancreatic vascular perfusion. Pancreas 2008;36:267–​73. 24. Bartholomew C. Acute scorpion pancreatitis in Trinidad. Br Med J 1970;1:666–​8.

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25. Del Vecchio Blanco G, Gesuale C, Varanese M, Monteleone G, Paoluzi OA. Idiopathic acute pancreatitis: a review on etiology and diagnostic work-​up. Clin J Gastroenterol 2019;12:511–​24. 26. Barreto SG. Acute pancreatitis: watch what you eat! Am J Clin Nutr 2015;101:1097. 27. Thomas T, Mah L, Barreto SG. Systematic review of diet in the pathogenesis of acute pancreatitis: a tale of too much or too little? Saudi J Gastroenterol 2012;18:310–​15. 28. Barreto SG. How does cigarette smoking cause acute pancreatitis? Pancreatology 2016;16:157–​63. 29. Barreto SG, Habtezion A, Gukovskaya A, et al. Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis. Gut 2021;70:194–​203. 30. Saluja A, Dudeja V, Dawra R, Sah RP. Early intra-​acinar events in pathogenesis of pancreatitis. Gastroenterology 2019;156:1979–​93. 31. Schmid SW, Uhl W, Friess H, Malfertheiner P, Buchler MW. The role of infection in acute pancreatitis. Gut 1999;45:311–​16. 32. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—​2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102–​11. 33. Ventrucci M, Pezzilli R, Gullo L, Plate L, Sprovieri G, Barbara L. Role of serum pancreatic enzyme assays in diagnosis of pancreatic disease. Dig Dis Sci 1989;34:39–​45. 34. Balthazar EJ. CT diagnosis and staging of acute pancreatitis. Radiol Clin North Am 1989;27:19–​37. 35. Ranson JH. Diagnostic standards for acute pancreatitis. World J Surg 1997;21:136–​42. 36. Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984;25:1340–​6. 37. Dellinger EP, Forsmark CE, Layer P, et al. Determinant-​based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012;256:875–​80. 38. Mounzer R, Langmead CJ, Wu BU, et al. Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. Gastroenterology 2012;142:1476–​ 82; quiz e15–​16. 39. Barreto SG, Rodrigues J. Comparison of APACHE II and Imrie Scoring Systems in predicting the severity of acute pancreatitis. World J Emerg Surg 2007;2:33. 40. Lee KJ, Kim HM, Choi JS, Kim YJ, Kim YS, Cho JH. Comparison of predictive systems in severe acute pancreatitis according to the Revised Atlanta Classification. Pancreas 2016;45:46–​50. 41. Zubia-​Olaskoaga F, Maravi-​Poma E, Urreta-​Barallobre I, Ramirez-​Puerta MR, Mourelo-​Farina M, Marcos-​Neira MP. Comparison between Revised Atlanta Classification and determinant-​based classification for acute pancreatitis in intensive care medicine. Why do not use a modified determinant-​ based classification? Crit Care Med 2016;44:910–​17. 42. Cui J, Xiong J, Zhang Y, et al. Serum lactate dehydrogenase is predictive of persistent organ failure in acute pancreatitis. J Crit Care 2017;41:161–​5. 43. Hong W, Lin S, Zippi M, et al. Serum albumin is independently associated with persistent organ failure in acute pancreatitis. Can J Gastroenterol Hepatol 2017;2017:5297143. 44. Mentula P, Kylanpaa ML, Kemppainen E, et al. Early prediction of organ failure by combined markers in patients with acute pancreatitis. Br J Surg 2005;92:68–​75. 45. Barreto SG, Bazargan M, Zotti M, et al. Galanin receptor 3—​a potential target for acute pancreatitis therapy. Neurogastroenterol Motil 2011;23:e141–​51.

46. Solanki NS, Barreto SG. Fluid therapy in acute pancreatitis. A systematic review of literature. JOP 2011;12:205–​8. 47. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–​17.e1. 48. Tenner S, Baillie J, DeWitt J, Vege SS. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013;108:1400–​15; 1416. 49. Crockett SD, Wani S, Gardner TB, Falck-​Ytter Y, Barkun AN. American Gastroenterological Association Institute guideline on initial management of acute pancreatitis. Gastroenterology 2018;154:1096–​101. 50. Forsmark CE, Baillie J. AGA Institute technical review on acute pancreatitis. Gastroenterology 2007;132:2022–​44. 51. Faghih M, Fan C, Singh VK. New advances in the treatment of acute pancreatitis. Curr Treat Options Gastroenterol 2019;17:146–​60. 52. Capurso G, Traini M, Piciucchi M, Signoretti M, Arcidiacono PG. Exocrine pancreatic insufficiency: prevalence, diagnosis, and management. Clin Exp Gastroenterol 2019;12:129–​39. 53. Poropat G, Giljaca V, Hauser G, Stimac D. Enteral nutrition formulations for acute pancreatitis. Cochrane Database Syst Rev 2015:CD010605. 54. Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial medical treatment of acute pancreatitis: American Gastroenterological Association Institute Technical Review. Gastroenterology 2018;154:1103–​39. 55. Barreto G, Rodrigues J, Pinto R, et al. Pancreatic abscess due to Aspergillus fumigatus. J Cytol 2005;22:191–​3. 56. Lee HS, Lee SK, Park DH, et al. Emergence of multidrug resistant infection in patients with severe acute pancreatitis. Pancreatology 2014;14:450–​3. 57. Barreto S, Saccone G. Pancreatic nociception: revisiting the physiology and pathophysiology. Pancreatology 2012;12:104–​12. 58. Bulyez S, Pereira B, Caumon E, et al. Epidural analgesia in critically ill patients with acute pancreatitis: the multicentre randomised controlled EPIPAN study protocol. BMJ Open 2017;7:e015280. 59. Yokoe M, Takada T, Mayumi T, et al. Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015. J Hepatobiliary Pancreat Sci 2015;22:405–​32. 60. Dedemadi G, Nikolopoulos M, Kalaitzopoulos I, Sgourakis G. Management of patients after recovering from acute severe biliary pancreatitis. World J Gastroenterol 2016;22:7708–​17. 61. 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–​15. 62. 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;239:741–​9; discussion 9–​51. 63. Alam S, Mustafa G, Ahmad N, Khan M. Presentation and endoscopic management of biliary ascariasis. Southeast Asian J Trop Med Public Health 2007;38:631–​5. 64. Rawla P, Sunkara T, Thandra KC, Gaduputi V. Hypertriglyceridemia-​induced pancreatitis: updated review of current treatment and preventive strategies. Clin J Gastroenterol 2018;11:441–​8.

2

Management of Oedematous Pancreatitis, Fluid Collections, and Walled-​Off Necrosis Minas Baltatzis, Saurabh Jamdar, and Ajith K. Siriwardena

Introduction This chapter deals with the diagnosis and management of interstitial oedematous pancreatitis, together with the management of post-​inflammatory fluid collections. The 2012 update of the Atlanta classification of acute pancreatitis subdivides this disease into two categories: interstitial oedematous pancreatitis and necrotizing pancreatitis.1 Interstitial oedematous pancreatitis typically manifests clinically as mild acute pancreatitis. The 2012 update of the Atlanta consensus conference also categorizes post-​pancreatitis fluid collections as early or late and additionally differentiates between fluid collections without necrosis and those containing semi-​solid necrosis.1 This terminology, together with the diagnosis and management of post-​inflammatory fluid collections, is overviewed.

Oedematous acute pancreatitis Definition of oedematous acute pancreatitis Oedematous interstitial acute pancreatitis is defined as pancreatic inflammation without parenchymal necrosis and is generally a self-​limiting disease resolving within 1 week of onset. Using the terminology of the revised Atlanta classification of acute pancreatitis, interstitial oedematous acute pancreatitis is mild pancreatitis, characterized by the absence of organ failure and of local or systemic complications.1 The diagnosis is made on clinical grounds, supported by biochemical and haematological tests, together with assessment of organ function.2 The diagnosis can be confirmed by contrast-​enhanced computed tomography (CT) with the typical features being relatively homogeneous enhancement without necrosis (Figure 2.1). The peripancreatic fat usually shows some mild inflammatory changes of haziness and there may also be some peripancreatic fat stranding. The clinical symptoms of interstitial oedematous pancreatitis usually resolve within the first week. Patients with mild acute pancreatitis will usually be well enough to be discharged during the early phase and rarely require pancreatic imaging, and episode-​related mortality is low.2

Diagnosis of oedematous acute pancreatitis The diagnosis of acute pancreatitis is established when two out of the three following criteria are fulfilled:1 • Acute abdominal pain consistent with acute pancreatitis. This typically refers to the acute onset of persistent, severe epigastric pain, often radiating through to the back and also often associated with vomiting. • Serum lipase (or serum amylase) at least three times greater than the upper limit of the normal laboratory reference range. • Characteristic findings of acute pancreatitis on imaging: either contrast-​enhanced CT or magnetic resonance (MR) scanning, or transabdominal ultrasonography.

Biochemical diagnostic tests in oedematous acute pancreatitis Typically, the diagnosis is based on a 3-​fold elevation above laboratory normal of either serum lipase or amylase. Serum amylase remains the most commonly used biochemical marker for the diagnosis of acute pancreatitis, but its sensitivity can be reduced by late presentation, hypertriglyceridaemia, and chronic alcoholism.3 A Cochrane systematic review examined ten studies including 5056 participants and compared serum amylase, serum lipase, and urinary trypsinogen-​2 at the standard threshold levels of >3 times normal for serum amylase and serum lipase, and a threshold of 50 ng/​mL for urinary trypsinogen-​2, and concluded that all appear to have similar sensitivities and specificities for the diagnosis of acute pancreatitis.4 Amylase is also produced by salivary glands, whereas there are no extra-​pancreatic sources of lipase. False positive elevations in serum amylase can be seen in patients with acute cholecystitis, acute cholangitis, and retroperitoneal sepsis. False negative amylase values can be seen in patients with a late presentation where the time course of elevated amylase has been missed. Compared with serum amylase, serum lipase activity remains increased for longer (up to 8–​14 days), thereby giving greater sensitivity in patients with a delayed presentation. Pancreatic lipase activities are also >4 times that of amylase and, as such, are less likely to be affected by chronic pancreatic insufficiency.3 The 2005 UK guidelines on acute pancreatitis recommend

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2  Management of Oedematous Pancreatitis, Fluid Collections, and Walled-Off Necrosis

• CT should be considered when there is failure to respond to conservative treatment or in the setting of clinical deterioration. Imaging findings on CT consistent with oedematous acute pancreatitis are: (1) oedema of the pancreas with homogeneous enhancement; and (2) inflammatory infiltration of the peripancreatic fat, often described as haziness or mild fat stranding (Figure 2.1). Inflammation may involve the entire gland (diffuse type) or part of the pancreas (focal type). MR scan is not typically utilized early in the disease course of oedematous acute pancreatitis. MR features of oedematous pancreatitis include hypointensity of the parenchyma on T1-​weighted images (T1WI) and hyperintensity on T2-​weighted images (T2W1).8 Typically, the pancreas shows homogeneous enhancement after intravenous administration of a contrast agent such as gadolinium (Gd)-​DTPA).8 MR can be utilized later in the disease course to assess the nature of fluid collections. Figure 2.1  Acute oedematous pancreatitis with acute post-​ inflammatory fluid collection. Contrast-​enhanced CT showing acute oedematous pancreatitis. Note that the pancreas is swollen and there is an acute post-​inflammatory fluid collection at the tail of the gland running down the left paracolic gutter. There is patchy enhancement throughout the gland.

that where lipase is available, it should be used for the diagnosis of acute pancreatitis.5 The level of elevation of either serum lipase or amylase does not correlate with either the severity of the episode of acute pancreatitis or the aetiology.5

Radiological diagnostic tests in oedematous acute pancreatitis Transabdominal ultrasonography is typically the first test undertaken in patients with mild acute pancreatitis.6 Although ultrasonography is of limited value for either the diagnosis or assessment of the severity of acute pancreatitis, it is useful in ruling out other diagnoses and is the test of choice for demonstrating gallstones and/​or biliary dilatation.6 Contrast-​enhanced CT is the optimal diagnostic test for acute pancreatitis.2 Administration of intravenous contrast can be a source of concern in acutely ill patients, as contrast agents can be nephrotoxic.7 Modern non-​ionic contrast agents minimize this risk.7 In patients with oedematous acute pancreatitis, CT is not necessary in order to establish the diagnosis. A practical management algorithm is to use transabdominal ultrasonography as the first diagnostic test, reserving early CT for those patients in whom there is diagnostic uncertainty. If CT is not undertaken early in the course of oedematous acute pancreatitis, it may be possible to discharge the patient without scanning. However, in those patients in whom the clinical course is less favourable, CT is invaluable in confirming or excluding the presence of pancreatic necrosis. The role of CT in acute pancreatitis is succinctly summarized in the International Association of Pancreatology (IAP)/​American Pancreatic Association (APA) guidelines (2013) as follows:2 • Consider early CT when there is diagnostic uncertainty. • CT can be used to confirm the clinical severity in patients with a likely severe disease course.

Assessment of disease severity in oedematous acute pancreatitis The severity of an episode of acute pancreatitis cannot be judged by bedside assessment of the severity of abdominal pain or the degree of elevation of pancreatic enzymes. Although there is no specific medical treatment for acute pancreatitis, and although early surgery is not beneficial, early categorization of severity is of value in helping to provide the optimal level of care for the patient with acute pancreatitis in the appropriate setting. Because of this difficulty in assessing the severity and clinical course at the bedside, multiple factor scoring systems were developed in the 1970s and 1980s as prognostic aids.9,10 It is worth bearing in mind that these systems pre-​date current definitions of mild, moderate, and severe acute pancreatitis and, in particular, the contemporary knowledge that patients with transient organ failure responsive to resuscitation often have a relatively mild clinical course.1 Thus, tests based on a one-​off assessment may incorrectly categorize patients. The time required to calculate a prognostic score is also critical. If a test requires 24 or 48 hours for complete collection, then it is less valuable in clinical practice, as an immediate decision about location of care is required at the time of admission or shortly thereafter. In this category, the Ranson criteria are no longer recommended.9,11 They cannot be completed until 48 hours after admission to hospital and the variable of fluid sequestration, in particular, is a notoriously difficult parameter to assess. Assessment of blood urea nitrogen or serum creatinine provides equivalent discrimination to the use of multiple factor prognostic scores for the assessment of severity of an episode of acute pancreatitis.11 The criteria proposed by Imrie avoid the difficulties inherent in needing to assess fluid sequestration.10 Collection of the tests required to complete an Imrie score requires a comprehensive physiological assessment, but in contemporary critical care medicine, an Imrie score of >5 will not mandate intensive care admission unless the various parameters themselves indicate the need for critical care. Thus, it is logical to use severity assessments that are used in assessing critically ill patients in other disease scenarios, rather than the Imrie score which is specific to acute pancreatitis. In this regard, the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score has validity, but in many healthcare systems,

Oedematous acute pancreatitis

variants of the Early Warning Score (EWS) are used and this is likely to be the most practical early admission test of severity.12 The EWS has been validated for assessing the severity of acute pancreatitis.13 Many acute hospitals record the EWS as acute phase observations and have protocol-​based escalation pathways when patients deteriorate. Thus, this score is recommended as being the most likely to engage with critical care.

Overview of management of oedematous acute pancreatitis The management of oedematous pancreatitis involves fluid resuscitation, adequate analgesia, close monitoring of organ function, adequate nutrition, and identification and treatment of the aetiology of the episode.2

Fluid resuscitation in oedematous acute pancreatitis Early fluid resuscitation is the cornerstone of the management of oedematous acute pancreatitis. Volume depletion due to vomiting, fever, diaphoresis, and fluid shift towards the interstitial space as a result of the systemic inflammatory response syndrome (SIRS) requires aggressive fluid resuscitation. Furthermore, adequate perfusion of the pancreatic parenchyma aims to prevent pancreatic ischaemia and limit progression to pancreatic necrosis and multi-​organ failure. Preservation of the pancreatic and intestinal microcirculation reduces the risk of intestinal ischaemia, therefore preserving the intestinal barrier and avoiding translocation of enteric bacteria.14,15 A retrospective analysis of 436 patients with acute pancreatitis examining early versus late fluid resuscitation found that early resuscitation was associated with a decreased systemic inflammatory response, lower rates of organ failure at 72 hours, and a lower rate of admission to critical care, all of which translated into a reduced length of hospital stay.16 An elevated haematocrit on admission or failure of this to decrease within 24 hours of admission has been identified as a risk factor for the development of pancreatic necrosis.17,18 Moreover, the development of pancreatic necrosis seems to be strongly associated with an increase in serum creatinine within 48 hours of admission.19 According to a meta-​analysis of 1043 patients with acute pancreatitis, a urea level of 20 mg/​dL or greater on admission and urea elevation within 24 hours were associated with a significantly increased risk of mortality.20 Ringer’s Lactate (a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water) was evaluated in a small randomized trial of 40 patients with acute pancreatitis.21 Although this was an underpowered study, the results showed that patients with acute pancreatitis who were resuscitated with Lactated Ringer’s solution had reduced systemic inflammation, compared to those who received saline. Further evaluation of the type of resuscitation fluid is required to assess whether the type, rather than the volume, of resuscitation fluid has any genuine beneficial effect on morbidity and mortality of acute pancreatitis.

Antibiotics in oedematous acute pancreatitis The IAP/​APA state that intravenous antibiotic prophylaxis is not recommended for prevention of infective complications in acute pancreatitis.2 The reason for this is that the inflammatory response of early acute pancreatitis is a form of SIRS, rather than bacterial

infection. The guidelines support antibiotic use for suspected infection of necrotizing pancreatitis, together with consideration for further intervention. There is no role for antibiotics for either prophylaxis or treatment in acute pancreatitis. Thus, most patients with oedematous acute pancreatitis should not receive antibiotics. Antibiotic overuse is, however, widespread and contributes to the emergence of resistant flora.22 In an effort to reduce overuse of antibiotics in acute pancreatitis, the role of procalcitonin-​based algorithms to guide prescribing is currently being evaluated.23 Procalcitonin (the precursor of calcitonin) is a hormokine, which is involved in the maintenance of vascular tone. In health, there are negligible levels in the circulation, but procalcitonin is produced in response to bacterial infection and levels fall rapidly after successful treatment.24,25 Procalcitonin has been evaluated earlier as a marker to predict the severity of acute pancreatitis and also the presence of infected necrosis, so it is a logical test to ‘rule out’ antibiotic overuse in oedematous acute pancreatitis.26 Antibiotic treatment is appropriate to cover patients undergoing laparoscopic cholecystectomy for mild gallstone pancreatitis. Antibiotic treatment is also appropriate for the treatment of secondary bacterial infections such as urinary tract infection or pneumonia.

Nutrition in oedematous acute pancreatitis Historically, the management of acute pancreatitis involved placing the patient ‘nil by mouth’. The reasoning was to ‘rest’ the inflamed pancreas. It has been known for over 25 years that following pancreatic acinar injury, escalation of the systemic inflammatory response is a cytokine-​mediated process and is not thought to be influenced by gastric content. In contrast, the turn of the century witnessed an increase in interest in enteral nutrition early in the disease course of acute pancreatitis, as it was thought that provision of nutrients helped to preserve gut barrier function and thus may prevent subsequent bacterial colonization of necrosis.27 A meta-​analysis of ten randomized trials of early enteral nutrition, compared to delayed nutrition, totalling 1051 patients showed that early enteral nutrition is technically feasible and safe but had little influence on the systemic inflammatory response, morbidity, or mortality.28 In practice, oral intake is often compromised in the initial period of acute pancreatitis when there is abdominal pain and vomiting. Thus, a modern, pragmatic approach would be to allow all patients oral fluids. There is no need for patients with acute pancreatitis to be placed ‘nil by mouth’. However, pain and vomiting can appreciably compromise the ability to take adequate calories and thus supplemental feeding is often required. Where possible, this should be delivered via the enteral route.

Analgesia in oedematous acute pancreatitis Acute pancreatitis is characterized by severe abdominal pain and early provision of adequate analgesia is important. Opioids and non-​steroidal anti-​inflammatory drugs (NSAIDs) are commonly used for pain relief. Opioids carry a theoretical risk of sphincter of Oddi constriction. Although diclofenac prevents post-​endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, there are also reports of diclofenac-​induced acute pancreatitis. In a small randomized trial, tramadol and diclofenac both provided adequate relief of pain without adversely modifying the disease course.29 In alert patients, analgesia can be provided with an intravenous opiate

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using a patient-​controlled analgesia delivery device. The small theoretical risk of opiate-​induced sphincter of Oddi spasm worsening the clinical course of acute pancreatitis does not justify withholding of opiate analgesia.

Identification and treatment of the cause of oedematous acute pancreatitis Pancreatitis due to gallstones should be identified and treated.30 Optimal treatment for mild gallstone-​induced acute pancreatitis is laparoscopic cholecystectomy. The timing of cholecystectomy is important and there is strong evidence to support early cholecystectomy after gallstone pancreatitis.31 A meta-​analysis of five randomized trials including a total of 629 patients (318 in the early cholecystectomy group and 311 in the delayed cholecystectomy group) showed that recurrent biliary events requiring re-​admission were reduced in patients undergoing early cholecystectomy, with no difference in the rate of intraoperative or post-​operative complications.32 Endoscopic retrograde cholangiography (ERC) was evaluated as a treatment to remove impacted stones causing gallstone pancreatitis.33 A meta-​analysis of four randomized trials published in 1999 suggested that early ERC reduced morbidity.34 The role of early endoscopic sphincterotomy was evaluated in the Dutch national APEC trial.35 APEC, a randomized controlled trial, compared early endoscopic sphincterotomy within 24 hours of presentation to the emergency department in patients with biliary pancreatitis without cholangitis and at high risk of complications to conservative management. The results, presented in abstract form at the 2019 World Congress of the American Gastroenterology Association, showed that in the early group, ERCP was performed a median of 29 hours after symptom onset, whereas in the conservative group, 31% of patients underwent on-​demand ERCP a median of 8 days after onset of symptoms (Besselink MG, personal communication). Cholangitis was significantly less common in the early treatment group (2% versus 10%; P =​0.01), but admission to the intensive care unit (ICU) was more common (21% versus 12%). However, the number of days spent in the ICU was similar for the two groups. Currently, ERC is recommended only in the setting of mild acute pancreatitis with biliary obstruction (typically a bilirubin level in excess of 90 µmol/​ L or 5 mg/​L).2 Endoscopic sphincterotomy as a definitive treatment for mild acute pancreatitis secondary to gallstones can be considered in patients who are too frail or unfit for cholecystectomy. There is a moderate risk of subsequent gall bladder-​related biliary sepsis in such patients. Lee and colleagues followed a cohort of 171 patients with gallstone-​induced acute pancreatitis treated either by cholecystectomy or by endoscopic sphincterotomy.36 Their mean follow-​up period was 58 months (range 6–​125 months). There was no difference in the incidence of recurrent pancreatitis, although the cholecystectomy group had a lower risk of biliary events.36 The American Society for Gastrointestinal Endoscopy (ASGE) Clinical practice guidelines recommend endoscopic ultrasonography (EUS), together with side-​viewing duodenoscopy, to assess the ampulla and head of the pancreas in older patients with acute pancreatitis in whom a cause is not identified.37 EUS is an accurate test for detection of biliary sludge or small stones and, in combination with side-​viewing duodenoscopy, will detect the rare patient with ampullary cancer causing acute pancreatitis.37

Management of peripancreatic fluid collections in acute pancreatitis Introduction Fluid collections are part of the pathophysiology of acute pancreatitis.38 Their aetiology is complex and multifactorial. Intra-​ abdominal fluid collections can occur because of capillary leak during the acute phase of illness39 and fluid sequestration, and are also related to enzyme-​rich leakage of fluid from the inflamed pancreas. Later, persistent pancreatic enzyme-​rich peripancreatic collections may be associated with disruption of the main pancreatic duct and a continued leak, although this is more typically seen in acute necrotizing pancreatitis.40 Enzyme-​rich fluid typically collects around the pancreas, in the retroperitoneum and paracolic gutters. Involvement of peripancreatic tissues and fat results in collections which contain semi-​solid material. Bacterial infection arising in any of these collections, especially in the presence of necrosis, gives rise to infected necrosis. The original 1992 Atlanta consensus conference was a pathfinding effort to standardize the terminology of the complications of acute pancreatitis.41 The 1992 Atlanta consensus disposed of terms such as phlegmon which were difficult to standardize and concentrated on acute fluid collections, and later fluid-​dominant collections were called pseudocysts and infection in a fluid collection was called a pancreatic abscess.41 In the 2012 update, two important categorizations were made in order to differentiate the behaviour and guide better management of post-​inflammatory fluid collections.1 The first categorization was by time into early and late collections, with the cut-​off point being 4 weeks after the index episode. The second categorization was by the presence or absence of necrosis. The second feature applied to both early and late collections. This categorization thus led logically to four different types of fluid collection—​early collections without necrosis were termed acute peripancreatic fluid collections (APFCs), whereas early collections with necrosis were termed acute necrotic collections. Late collections, arising after 4 weeks of an episode and containing minimal or no solid material, were termed pseudocysts, a continuation of a long-​established term, whereas late collections containing necrosis were termed walled-​off necrosis (WON). The diagnosis and management of these four types of post-​inflammatory fluid collections will now be discussed.

Acute peripancreatic fluid collections APFCs can occur in interstitial oedematous pancreatitis. They occur early in the disease course (within the first 2 weeks) and can be seen on cross-​sectional imaging around the pancreas, liver, and spleen and in the retroperitoneum (Figure 2.1). The key practical point to appreciate about APFCs is that they rarely require any intervention. They are simply a radiological marker of acute pancreatitis and will typically resolve by themselves. Xu and colleagues reported a small series of patients with a spectrum of post-​inflammatory collections.42 Their paper is useful in that it serves as a reminder that patients with extensive fluid collections may have an ongoing capillary leak and thus may benefit from supplemental nutrition. Intra-​abdominal hypertension from large post-​inflammatory fluid collections is a rare early complication but is typically seen in patients with necrotizing pancreatitis.43 Indications for intervention

Management of peripancreatic fluid collections in acute pancreatitis

include respiratory compromise due to diaphragmatic dysfunction ‘splinting’.44 Percutaneous drainage can be considered in this scenario of intra-​ abdominal hypertension, but any potential benefits to be obtained from drainage of fluid must be balanced against the risks of introducing infection. In clinical practice, it should be remembered that there can be an overlap in these entities and that they represent a continuous spectrum of disease severity.

Acute necrotic collection The term ‘acute necrotic collection’ was introduced in the 2012 update of the Atlanta consensus criteria and is the result of a drive to differentiate fluid-​only, late collections (pseudocysts) from collections which contain solid or semi-​solid material.1 Thus, an acute necrotic collection contains variable amounts of both fluid and necrosis and is typically associated with necrotizing or severe acute pancreatitis (Figure 2.2). In terms of time course, these occur in the first 4 weeks of an episode of severe acute pancreatitis (necrotizing pancreatitis). Acute necrotic collections may be multiple or single. The important distinction between an acute necrotic collection and an APFC is that acute necrotic collections arise in the presence of pancreatic necrosis. Although the description of an early fluid collection complicating severe acute pancreatitis and containing a mixture of liquid and semi-​solid material is logical, it is a term from the 2012 update of the Atlanta consensus that is not widely used. This may be because the principles of management of an acute necrotic collection are not dissimilar to the management of an acute

post-​inflammatory fluid collection. The goals are to categorize the extent of the acute necrotic collection and to assess the degree of corresponding necrosis of the pancreas. MR is invaluable for the assessment of the extent of semi-​solid material in the collection and may also help to define the association between the pancreas and acute necrosis.45 Recent evidence indicates that the site of extra-​pancreatic necrosis may have an influence on outcome.46 Gupta and colleagues demonstrated in a small retrospective analysis of 119 patients that larger size and remote location from the pancreas were predictors of adverse outcome.46 The recent American Gastroenterological Association (AGA) Institute Clinical Practice Update provides expert recommendations regarding the clinical care of patients with pancreatic necrosis.46 In relation to acute necrotic collections, the AGA update recommends that pancreatic debridement should be avoided in the early acute period (first 2 weeks) as it has been associated with increased morbidity and mortality. Debridement should be optimally delayed for 4 weeks and performed earlier only when there is an organized collection and a strong indication such as extensive necrotic collection that is not amenable to percutaneous or endoscopic drainage and confirmed infection in a deteriorating patient.46

Pancreatic pseudocyst Definition of pancreatic pseudocyst The term pancreatic pseudocyst is well established. It is succinctly defined in the 1992 Atlanta terminology as a collection of pancreatic enzyme-​rich fluid lined by granulation tissue and typically seen >6 weeks after an episode of acute pancreatitis.41 The 2012 update provides greater precision to the diagnosis and stipulated the following for the diagnosis of a pancreatic pseudocyst:1 • An encapsulated collection of fluid with a well-​defined inflammatory wall, usually outside the pancreas, with minimal or no necrosis. • This entity usually occurs >4 weeks after onset of interstitial oedematous pancreatitis to mature. This terminology emphasized the link between oedematous acute pancreatitis and the subsequent formation of a pseudocyst. The 2012 Atlanta update stipulates the following contrast-​ enhanced CT criteria and timeline-​related criteria for the diagnosis of a pancreatic pseudocyst: • Well circumscribed, usually round or oval • Homogeneous fluid density • No non-​liquid component • Well-​defined, completely encapsulated wall • Maturation usually requiring >4 weeks after onset of acute pancreatitis • Occurs after interstitial oedematous pancreatitis.

Figure 2.2  Acute necrotic collection. Contrast-​enhanced CT showing acute necrotic collection. Note that the tail of the pancreas enhances but that there is an area of necrosis in the head and neck. The fluid collections complicating this necrotizing pancreatitis are correctly labelled as an acute necrotic collection. This patient is at high risk of subsequent development of walled-​off necrosis.

The rationale behind this restrictive definition is to guide management. According to the 2012 terminology, pseudocysts occur in the absence of necrosis and thus management is guided accordingly. A note of caution is that this strict definition of the term pseudocyst has probably not been universally adopted, with the most common confounder being fluid-​dominant post-​inflammatory collections which contain some necrosis.

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Differential diagnosis of pancreatic pseudocysts There are two important differential diagnoses. The first is a pancreatic pseudocyst arising against a background of chronic pancreatitis.48,49 The second important differential diagnosis is a cystic tumour.50 Clinical history of an antecedent episode of acute pancreatitis, cross-​sectional radiological imaging, and EUS-​guided fine-​ needle aspiration (FNA) can all help in establishing the diagnosis. Management of pancreatic pseudocysts The mainstays of management are assessment of symptoms and establishment of the diagnosis. In the setting of a post-​inflammatory pseudocyst following a clear-​cut episode of acute pancreatitis, this diagnosis can be readily established. The principles of treatment are to drain the pseudocyst into the gastrointestinal tract, usually the stomach. External drainage should be avoided, as patients can be left with a troublesome pancreatic fistula. Although the principles of treatment have remained the same, the methods of treatment have undergone a transformation in approach. As recently as the 1980s, in a series of 42 patients with pancreatic pseudocysts treated by the expert centre at the Massachusetts General Hospital, 39 underwent surgical drainage.51 Pseudocysts which were not in a retrogastric location could be drained into a Roux loop.52 The advent of minimally invasive interventions constituted a change in the paradigm of management.53 Indications for intervention are symptoms (abdominal pain, gastric outlet obstruction), persistent pseudocysts >6 cm in size, and complications such as bleeding or infection.54–​56 A systematic review comparing surgical drainage (either open surgery or laparoscopic) to endoscopic drainage showed no difference in outcome.53 Length of hospital stay was shorter in patients treated endoscopically. Complications of pancreatic pseudocysts

Figure 2.3  Walled-​off necrosis. Contrast-​enhanced CT demonstrating walled-​off necrosis. This CT shows a mature retrogastric intra-​pancreatic parenchymal collection which contains air. There is enhancement of the wall highlighted by the white arrow.

WON usually occurs >4 weeks after the onset of necrotizing pancreatitis.1 As with pancreatic pseudocysts, the CT criteria for diagnosis are defined as: • Heterogeneous with liquid and non-​liquid density with varying degrees of loculations (some may appear homogeneous). • Well-​defined, completely encapsulated wall. • Either intra-​pancreatic and/​or extra-​pancreatic in location. • Maturation usually requiring 4 weeks after onset of acute necrotizing pancreatitis.

Important complications include bleeding into a pseudocyst.57 This is rare and seen most typically in patients with pseudocysts complicating chronic pancreatitis and often related to a false aneurysm of the gastroduodenal artery. Treatment is by angiographic embolization, followed by definitive treatment of the pseudocyst. The true incidence of infection in pancreatic pseudocysts is difficult to gauge, as the 2012 terminology update limits the term ‘pseudocyst’ to collections arising in patients without necrosis. The presence of necrosis is the main driver for infection. Rupture of the pseudocyst into the peritoneal cavity can produce pancreatic ascites.40,58 Rupture into the pleural cavity can produce a pancreato–​pleural fistula.59

Diagnosis of walled-​off necrosis

Follow-​up after treatment of a pancreatic pseudocyst

Late mortality in severe acute pancreatitis is driven by infected necrosis, and even in the twenty-​first century, this is an important determinant of lethality.62,63 The pathophysiology of infection of pancreatic necrosis is thought to be related to gut-​derived bacterial colonization, possibly by translocation.64,65 The initial IAP guidelines on the surgical management of acute pancreatitis published in 2002 recommended the use of FNA of pancreatic necrosis to detect infection.66 Anecdotally, FNA of pancreatic necrosis seems to be less widely used or reported in current practice, with reliance now being placed on serial cross-​sectional imaging and close monitoring of the clinical status. The IAP guidelines recommended that the entity of sterile necrosis could be managed conservatively, although surgery may be indicated in patients with apparently sterile necrosis and features of pancreatic infection, together with failure to recover.66

Initial follow-​up requires surveillance imaging to exclude recurrence. Pancreatic exocrine insufficiency is common, especially in patients with pseudocysts complicating chronic pancreatitis, and thus exocrine replacement therapy should be provided. Long-​term follow-​up is typically not required and patients should be able to regain their pre-​illness quality of life.

Walled-​off necrosis Definition WON is defined in the 2012 Atlanta update as a mature, encapsulated collection of pancreatic and/​or peripancreatic necrosis that has developed a well-​defined inflammatory wall or lining (Figure 2.3).

The presence of post-​inflammatory necrosis is a continuance from acute necrotic collections, with a well-​defined cavity being present after 4 weeks. Contrast-​enhanced CT can be used for diagnosis and remains the mainstay diagnostic test.60 The radiological scoring system developed and validated by Balthazar and colleagues is useful for the diagnosis of pancreatic necrosis.60 MR can also be of value in differentiating semi-​solid, non-​viable tissue from enhancing parenchyma.61 Infection in walled-​off necrosis

Management of peripancreatic fluid collections in acute pancreatitis

Management of walled-​off necrosis Timing of intervention is critical. There is evidence that colonization of necrosis occurs early in the disease process, with infection seen as early as the eighth day of the episode in a Dutch cohort study.67 However, demarcation of necrotic tissue and development of a peri-​ collection capsule ‘WON’ takes at least 4 weeks. Thus, early intervention is not beneficial. Traditionally, the approach for the patient with symptomatic infected necrosis was to undertake open surgical necrosectomy.68 The current model for management of patients with WON was defined by a landmark Dutch study comparing the step-​ up approach to open necrosectomy.69 In this multicentre study, 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue were randomized to undergo primary open necrosectomy or a step-​up approach to treatment. The step-​up approach consisted of percutaneous drainage, followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary endpoint was a composite of major complications (new-​onset multi-​ organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death. The results showed that the primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-​up approach (risk ratio (RR) with the step-​up approach, 0.57; 95% confidence interval (CI) 0.38–​0.87; P =​ 0.006). Of the patients assigned to the step-​up approach, 35% were treated with percutaneous drainage only. New-​onset multi-​ organ failure occurred less often in patients assigned to the step-​up approach than in those assigned to open necrosectomy (12% versus 40%; P =​ 0.002). The rate of death did not differ significantly between groups (19% versus 16%; P =​ 0.70). Patients assigned to the step-​up approach had a lower rate of incisional hernias (7% versus 24%; P =​0.03) and new-​onset diabetes (16% versus 38%; P =​0.02).69 This study established the minimally invasive approach as the preferred treatment. The benefits of the minimally invasive approach were sustained on long-​term follow-​up.70 The demonstration that necrosis could be better debrided by minimally invasive approaches had two consequences: first, primary open necrosectomy is no longer the treatment of choice; and second, endoscopic transgastric approaches could adopt a better minimally invasive approach than surgery.71 EUS-​guided endoscopic drainage was compared to the surgical step-​up approach of percutaneous catheter drainage, followed, if necessary, by retroperitoneal necrosectomy, by the Dutch Pancreatitis Study Group.72 In this multicentre randomized trial, adult patients with infected necrotizing pancreatitis and an indication for invasive intervention were randomly assigned to either the endoscopic or the surgical step-​up approach. The endoscopic approach consisted of EUS-​guided transluminal drainage, followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage, followed, if necessary, by video-​assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-​month follow-​up. Ninety-​eight patients were enrolled and randomly assigned to the endoscopic step-​up approach (n =​51) or the surgical step-​up approach (n =​ 47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group, and in 21 (45%) of 47 patients in the surgery group (RR 0.97, 95% CI 0.62–​1.51; P =​0.88). Mortality did not differ between groups (nine (18%) patients in the endoscopy group versus six (13%) patients in the surgery group; RR

1.38, 95% CI 0.53–​3.59; P =​ 0·50), nor did any of the major complications included in the primary endpoint.72 Technical evolution in endoscopic necrosectomy has followed the introduction of lumen-​apposing metal stents (LAMS) in 2013 (Axios stent, Niti-​S Spaxus stent, Nagi stent, Aixstent), designed to reduce the risk of stent migration during debridement.73 The stents are fully covered with a silicone membrane to minimize tissue ingrowth and difficulty with removal. The technique of Direct Endoscopic Necrosectomy (DEN) with LAMS involves dilatation of the cysto-​gastric tract with a balloon, followed by placement of the LAMS and advancement of the endoscope into the cavity of WON. Subsequently, the cavity is lavaged with normal saline and necrotic debris are removed under direct vision using snares or baskets. High rates of technical and clinical success have been reported for LAMS placement for drainage of post-​inflammatory collections (pseudocysts and WON). A large retrospective review from 15 centres of all patients who underwent placement of LAMS for the management of pancreatic fluid collections reported 333 procedures in 328 patients. Technical success was achieved in 321 (97.9%). The rate of clinical success was 89.5%. Data from this large international retrospective study confirm that the use of LAMS for management of pancreatic fluid collections has excellent technical and good clinical success rates.73 The rate of complications, which include bleeding (1–​7%), perforation (1–​2%), stent migration (1–​6%), and infection (1–​11%), is not negligible and should be carefully considered before using these stents for drainage of pancreatic fluid collections and, in particular, for WON.73

REFERENCES 1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—​2012: revision of the Atlanta classification and definitions. Gut 2013;62:102–​11. 2. Working Group IAP/​APA Acute Pancreatitis Guidelines. IAP/​ APA evidence-​based guidelines for the management of acute pancreatitis. Pancreatology 2013;13:e1–​15. 3. Matull WR, Pereira SP, O’Donohue JW. Biochemical markers of acute pancreatitis. J Clin Pathol 2006;59:340–​4. 4. Rompianesi G, Hann A, Komolafe O, Pereira SP, Davidson BR, Gurusamy KS. Serum amylase and lipase and urinary trypsinogen and amylase for diagnosis of acute pancreatitis. Cochrane Database Syst Rev 2017;4:CD012010. 5. Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the diagnosis of acute pancreatitis. Gut 2005;54 Suppl iii:1–​9. 6. Johnson CD, Besselink MG, Carter CR. Acute pancreatitis. BMJ 2014;12:349. 7. Mehran R, Nikolsky E. Contrast-​induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl 2006;100:S11–​15. 8. Sun H, Zuo HD, Lin Q, et al. MR imaging for acute pancreatitis: the current status of clinical applications. Ann Transl Med 2019;7:269. 9. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Localio SA. Objective early identification of severe acute pancreatitis. Am J Gastroenterol 1974;61:443–​51. 10. Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984; 25:1340–​6.

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2  Management of Oedematous Pancreatitis, Fluid Collections, and Walled-Off Necrosis

11. Mounzer R, Langmead CJ, Wu BU, et al. Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. Gastroenterology 2012;142:1476–​82. 12. Larvin M, McMahon MJ. APACHE-​II score for assessment and monitoring of acute pancreatitis. Lancet 1989;22:201–​5. 13. Garcea G, Jackson B, Pattenden CJ, et al. Early warning scores predict outcome in acute pancreatitis. J Gastrointest Surg 2006;10:1008–​15. 14. Fisher JM, Gardner TB. The “golden hours” of management in acute pancreatitis. Am J Gastroenterol 2012;107:1146–​50. 15. Hotz HG, Foitzik T, Rohweder J, et al. Intestinal microcirculation and gut permeability in acute pancreatitis: early changes and therapeutic implications. J Gast Surg 1998;2:518–​25. 16. Warndorf MG, Kurtzman JT, Bartel MJ, et al. Early fluid resuscitation reduces morbidity among patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:705–​9. 17. Baillargeon JD, Orav J, Ramagopal V, Tenner SM, Banks PA. Hemoconcentration as an early risk factor for necrotizing pancreatitis. Am J Gastroenterol 1998;93:2130–​4. 18. Brown A, Orav J, Banks PA. Hemoconcentration is an early marker for organ failure and necrotizing pancreatitis. Pancreas 2000;20:367–​72. 19. Muddana V, Whitcomb DC, Khalid A, Slivka A, Papachristou GI. Elevated serum creatinine as a marker of pancreatic necrosis in acute pancreatitis. Am J Gastroenterol 2009;104:164–​70. 20. Wu BU, Bakker OJ, Papachristou GI, et al. Blood urea nitrogen in the early assessment of acute pancreatitis. Arch Intern Med 2011;171:669–​76. 21. Wu BU, Hwang JQ, Gardner TH, et al. Lactated ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–​17. 22. Baltatzis M, Mason JM, Chandrabalan V, et al. Antibiotic use in acute pancreatitis: an audit of current practice in a tertiary centre. Pancreatology 2016;16:946–​51. 23. Siriwardena AK, Jegatheeswaran S, Mason JM, et al. PROCalcitonin-​based algorithm for antibiotic use in Acute Pancreatitis (PROCAP): study protocol for a randomised controlled trial. Trials 2019;20:463. 24. Schuetz P, Mueller B. Procalcitonin-​guided antibiotic stewardship from newborns to centennials. Lancet 2017;390:826–​9. 25. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171:1322–​31. 26. Mofidi R, Suttie SA, Patil PV, et al. The value of procalcitonin at predicting the severity of acute pancreatitis and development of infected pancreatic necrosis: systematic review. Surgery 2009;146:72–​81. 27. Powell JJ, Murchison JT, Fearon KC, Ross JA, Siriwardena AK. Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000;87:1375–​81. 28. Song J, Zhong Y, Lu X, et al. Enteral nutrition provided within 48 hours after admission in severe acute pancreatitis: a systematic review and meta-​analysis. Medicine (Baltimore) 2018;97:e11871. 29. Kumar NS, Muktesh G, Samra T, et al. Comparison of efficacy of diclofenac and tramadol in relieving pain in patients of acute pancreatitis: a randomized parallel group double blind active controlled pilot study. Eur J Pain 2020;24:639–48.

30. O’Reilly DA, McPherson SJ, Sinclair MT, Smith N. ‘Treat the Cause’: the NCEPOD report on acute pancreatitis. Br J Hosp Med 2017;78:6–​7. 31. Siriwardena AK, O’Reilly DA. Improving care for patients with acute pancreatitis. Br J Surg 2017;104:1591–​3. 32. Moody N, Adiamah A, Yanni F, Gomez D. Meta-​analysis of randomized clinical trials of early versus delayed cholecystectomy for mild gallstone pancreatitis. Br J Surg 2019;106:1442–​51. 33. 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;8618:979–​83. 34. Sharma VK, Howden CW. Meta-​analysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary pancreatitis. Am J Gastroenterol 1999;94:3211–​14. 35. Schepers NJ, Bakker OJ, Besselink MG, et al. Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial): study protocol for a randomized controlled trial. Trials 2016;17:5. 36. Lee JM, Chung WC, Sung HJ, et al. Factor analysis of recurrent biliary events in long-​term follow up of gallstone pancreatitis. J Dig Dis 2017;18:40–​6. 37. Vinay Chandrasekhara V, Chathadi KV, Acosta RD, et al. The role of endoscopy in benign pancreatic disease. ASGE Clinical Practice Guideline. Gast Endosc 2015;82:203–​14. 38. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 2015;9988:85–​96. 39. Eibl G, Hotz HG, Faulhaber J, Kirchengast M, Buhr HJ, Foitzik T. Effect of endothelin and endothelin receptor blockade on capillary permeability in experimental pancreatitis. Gut 2000;46:390–​4. 40. Jang JW, Kim MH, Oh D, et al. Factors and outcomes associated with pancreatic duct disruption in patients with acute necrotizing pancreatitis. Pancreatology 2016;16:958–​65. 41. Bradley EL. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:586–​90. 42. Xu MM, Andalib I, Novikov A, et al. Endoscopic therapy for pancreatic fluid collections: a definitive management using a dedicated algorithm. Clin Endosc 2020; 53(3): 355–60. 43. Marcos-​Neira P, Zubia-​Olaskoaga F, López-​Cuenca S, et al. Relationship between intra-​abdominal hypertension, outcome and the revised Atlanta and determinant-​based classifications in acute pancreatitis. Br J Surg (Open) 2018;1:175–​81. 44. Liao WC, Chen YH, Li HY, et al. Diaphragmatic dysfunction in sepsis due to severe acute pancreatitis complicated by intra-​ abdominal hypertension. J Int Med Res 2018;46:1349–​57. 45. Xiao B, Xu HB, Jiang ZQ, Zhang J, Zhang XM. Current concepts for the diagnosis of acute pancreatitis by multiparametric magnetic resonance imaging. Quant Imaging Med Surg 2019;9:1973–​85. 46. Gupta P, Rana P, Bellam BL, et al. Site and size of extrapancreatic necrosis are associated with clinical outcomes in patients with acute necrotizing pancreatitis. Pancreatology 2020;20:9–​15. 47. Baron TH, DiMaio CJ, Wang AY, Morgan KA. American Gastroenterological Association Clinical Practice Update: management of pancreatic necrosis. Gastroenterology 2020;158:67–​75.

Management of peripancreatic fluid collections in acute pancreatitis

48. Dominguez-​Munoz JE, Drewes AM, Lindkvist B, et al. Recommendations from the United European Gastroenterology evidence-​based guidelines for the diagnosis and therapy of chronic pancreatitis. Pancreatology 2018;18:847–​54. 49. Löhr JM, Dominguez-​Munoz E, Rosendahl J, et al. United European Gastroenterology evidence-​based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J 2017;5:153–​99. 50. European Study Group on Cystic Tumours of the Pancreas. European evidence-​based guidelines on pancreatic cystic neoplasms. Gut 2018;67:789–​804. 51. Warshaw AL, Rattner DW. Timing of surgical drainage for pancreatic pseudocyst. Ann Surg 1985;202:720–​4. 52. Parks RW, Tzovaras G, Diamond T, Rowlands BJ. Management of pancreatic pseudocysts. Ann R Coll Surg Engl 2000;82:383–​7. 53. Farias GFA, Bernardo WM, De Moura DTH, et al. Endoscopic versus surgical treatment for pancreatic pseudocysts: systematic review and meta-​analysis. Medicine (Baltimore) 2019;98:e14255. 54. Brugge WR, Lewandrowski K, Lee-​Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–​6. 55. Yeo CJ, Bastidas JA, Lynch-​Nyhan A, et al. The natural history of pancreatic pseudocysts documented by computed tomography. Surg Gynecol Obstet 1990;170:411–​17. 56. Bradley EL, Clements JL, Gonzalez AC. The natural history of pancreatic pseudocysts: a unified concept of management. Am J Surg 1979;137:135–​41. 57. Balachandra S, Siriwardena AK. Systematic appraisal of the management of the major vascular complications of pancreatitis. Am J Surg 2005;190:489–​95. 58. Samanta J, Rana A, Dhaka N, et al. Ascites in acute pancreatitis: not a silent bystander. Pancreatology 2019;19:646–​52. 59. Kord Valeshabad A, Acostamadiedo J, Xiao L, Mar W, Xie KL. Pancreaticopleural fistula: a review of imaging diagnosis and early endoscopic intervention. Case Rep Gastrointest Med 2018;8:7589451. 60. Ranson JH, Balthazar E, Caccavale R, Cooper M. Computed tomography and the prediction of pancreatic abscess in acute pancreatitis. Ann Surg 1985;201:656–​65. 61. Porter KK, Cason DE, Morgan DE. Acute pancreatitis: how can MR imaging help. Magn Reson Imaging Clin N Am 2018;26:439–​50.

62. Dellinger EP, Forsmark CE, Layer P, et al. Determinant-​based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012;256:875–​80. 63. Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology 2010;139:813–​20. 64. Fritz S, Hackert T, Hartwig W, et al. Bacterial translocation and infected pancreatic necrosis in acute necrotizing pancreatitis derives from small bowel rather than from colon. Am J Surg 2010;200:111–​17. 65. Isenmann R, Beger HG. Bacterial infection of pancreatic necrosis: role of bacterial translocation, impact of antibiotic treatment. Pancreatology 2001;1:79–​89. 66. Uhl W, Warshaw A, Imrie C, et al. IAP Guidelines for the surgical management of acute pancreatitis. Pancreatology 2002;2:565–​73. 67. Besselink MG, van Santvoort HC, Boermeester MA, et al. Timing and impact of infections in acute pancreatitis. Br J Surg 2009;96:267–​73. 68. Babu BI, Sheen AJ, Lee SH, O’Shea S, Eddleston JM, Siriwardena AK. Open pancreatic necrosectomy in the multidisciplinary management of postinflammatory necrosis. Ann Surg 2010;251:783–​6. 69. van Santvoort HC, Besselink MG, Bakker OJ, et al A step-​up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 2010;362:1491–​502. 70. Hollemans RA, Bakker OJ, Boermeester MA, et al. Superiority of step-​up approach vs open necrosectomy in long-​term follow-​ up of patients with necrotizing pancreatitis. Gastroenterology 2019;156:1016–​26. 71. Babu BI, Siriwardena AK. Practical strategies for case selection in minimally invasive necrosectomy. Pancreatology 2009;9(1–​2):9–​12. 72. van Brunschot S, van Grinsven J, van Santvoort HC, et al. Endoscopic or surgical step-​up approach for infected necrotising pancreatitis: a multicentre randomised trial. Lancet 2018;391:51–​8. 73. Fugazza A, Sethi A, Trindade AJ, et al. International multicenter comprehensive analysis of adverse events associated with lumen-​ apposing metal stent placement for pancreatic fluid collection drainage. Gastrointest Endosc 2020 Mar 1;91(3):574–83. pii: S0016-​5107(19)32471-​X. doi: 10.1016/​j.gie.2019.11.021.

19

3

Management of Acute Necrotizing Pancreatitis Thomas K. Maatman and Nicholas J. Zyromski

Introduction Necrotizing pancreatitis affects 15–​20% of all patients suffering from acute pancreatitis. Despite an improved understanding of the disease process and advances in therapeutic strategy, this complex disease is still attended by up to 15% mortality. Necrotizing pancreatitis provides the clinical challenges of working in a multidisciplinary group, determining proper timing, and identifying appropriate approaches for intervention based on individual patient anatomy, physiology, and local expertise. This chapter provides an overview of necrotizing pancreatitis, focusing on clinical care, intervention indications, and long-​term sequelae of the disease.

Incidence, aetiology, and pathophysiology Necrotizing pancreatitis, with variable degrees of pancreatic and/​ or peripancreatic necrosis, develops in 15–​20% of all patients with acute pancreatitis.1–​4 Worldwide, the incidence of acute pancreatitis is 34 per 100,000 people and, in the United States, results in about 300,000 admissions for acute pancreatitis annually.5,6 Thus, an estimated 30,000–​60,000 cases of necrotizing pancreatitis occur every year in the United States. The aetiologies inciting necrotizing pancreatitis mirror those that cause acute pancreatitis, as described in previous chapters, most commonly biliary (20–​50%) and alcohol (20–​40%).7–​9 The pathophysiology of acute pancreatitis development and associated risk factors have been discussed in previous chapters. In summary, regardless of the aetiology or inciting event, abnormal activation of proteolytic enzymes within the pancreatic acinar cells results in pancreatic acinar cell injury and death.10 The activation of trypsinogen to trypsin is believed to play a predominant role in this process, a model first proposed by the Austrian pathologist Dr Hans Chiari in 1896 and supported in subsequent studies since that time.10,11 Once released from damaged pancreatic acinar cells, trypsin activates more trypsin and additional digestive enzymes, resulting in pancreatic parenchymal autodigestion, further acinar cell injury, and injury to the vascular endothelium and surrounding

interstitium.10 Activation of the systemic inflammatory response and the coagulation cascade play a key role in acute pancreatitis and are thought to be responsible for the progression from acute pancreatitis to necrotizing pancreatitis.12,13 The human immune system, and its response to antigens, requires a delicate balance of pro-​ and anti-​inflammatory mediators acting in concert.14 In mild acute pancreatitis, the local inflammatory response is self-​limited and balanced with an appropriate anti-​inflammatory response, resulting in only mild systemic inflammation and resolution of disease with supportive care alone and minimal long-​term sequelae.15–​20 In contrast, severe acute pancreatitis (SAP) develops when an imbalance in the inflammatory response develops and pro-​inflammatory mediators are allowed to propagate unchecked.13,15–​17,21 A summary of the key pro-​and anti-​inflammatory mediators are shown in Figure 3.1. Necrotizing pancreatitis occurs when enzymatic autodigestion of the pancreatic parenchyma, vascular endothelium, and surrounding interstitium results in focal or diffuse non-​viable pancreatic or peripancreatic tissue.1 The systemic inflammatory response is intimately associated with the coagulation cascade, and compromise of the pancreatic microcirculation (arterioles, capillaries, and venules) results in ischaemic changes that lead to necrosis of the pancreas.22–​24 The development of pancreatic and peripancreatic necrosis further stimulates the systemic inflammatory response.12,13,15–​17,21 The impact of systemic inflammation on respiratory, renal, and cardiovascular failure in necrotizing pancreatitis deserves mention. The progression from acute pancreatitis to severe/​necrotizing pancreatitis and the associated inflammatory response play a direct role in end-​organ injury and multi-​organ dysfunction syndrome seen in patients with necrotizing pancreatitis. Inflammatory cytokines and chemokines released from the pancreatic parenchyma are disseminated to the respiratory, renal, and cardiovascular organ systems and result in secondary localized inflammation and injury to these tissues.25–​28 Further damage to individual organ systems can occur from necrotizing pancreatitis complications and its treatment. Understanding the pathophysiology of necrotizing pancreatitis and the role of loco-​regional and systemic inflammation is critical in its treatment, both in the early and late phases of the disease.

Definitions and diagnosis

• • • • • • • • •

Pro-inflammatory mediators: Reactive oxygen species Tumor necrosis factor (TNF) Nitric oxide Interleukin-1 Interleukin-2 Interleukin-6 Interleukin-8 Arachidonic acid metabolites Platelet-activating factor (PAF)

• • • •

Anti-inflammatory mediators: Interleukin-1 receptor antagonist Interleukin-4 Interleukin-10 Interleukin-11

Figure 3.1  Summary of key inflammatory mediators in acute pancreatitis.

Definitions and diagnosis The 2012 revision of the Atlanta classification provides the expert international consensus definition of acute pancreatitis and all associated complications, including necrotizing pancreatitis. Organ failure in necrotizing pancreatitis is defined as a modified Marshall scoring system for organ dysfunction score of 2 or greater (Table 3.1).1,29 Necrotizing pancreatitis is diagnosed on contrast-​enhanced cross-​sectional imaging as absence of pancreatic or peripancreatic enhancement, as shown in Figure 3.2.1 Comparatively, normal pancreatic parenchyma demonstrates homogeneous enhancement with contrast administration (Figure 3.2). Disease onset is defined by the timing of the onset of symptoms, and not by the presentation to hospital or the diagnosis of necrotizing pancreatitis.1 This is a critical distinction as the onset of necrotizing pancreatitis is an important reference point for the disease course, the development of complications, and the timing of intervention. It is important to realize that the degree of pancreatic necrosis will not be appreciated on imaging the first few days after the onset of symptoms; parenchymal and peripancreatic necrosis begins to become apparent after 1 week.30,31 Necrotizing pancreatitis may involve a combination of the pancreatic and peripancreatic parenchyma, isolated peripancreatic necrosis, or (uncommonly) isolated pancreatic necrosis.32–​35 Local complications in necrotizing pancreatitis include acute necrotic collections (ANCs) and walled-​off necrosis (WON). An ANC is a pancreatic or peripancreatic collection with liquid and/​or solid

necrosis within the first 4 weeks from symptom onset (Figure 3.3A).1 After 4 weeks, the pancreatic and peripancreatic necrosis matures to WON, as time has allowed for the development of a well-​defined inflammatory wall of reactive tissue (Figure 3.3B).1 In the setting of non-​necrotizing pancreatitis (interstitial oedematous pancreatitis), these terms must be differentiated from an acute peripancreatic fluid collection (4 weeks), respectively. It is of the utmost importance to understand the maturation phase of pancreatic and peripancreatic necrosis, as well as the volume of solid relative to liquid necrosis. The degree of solid necrosis is not determined reliably on computed tomography (CT) scan and can be better assessed with magnetic resonance imaging (MRI); however, the percentage of solid necrosis is best estimated with endoscopic or intraoperative ultrasound.36 It is also important to understand that fluid collections in necrotizing pancreatitis are dynamic, with a tendency towards liquefaction over time.36,37 Infected necrosis can be presumed in the setting of extraluminal gas in pancreatic and/​or peripancreatic necrosis on cross-​sectional imaging (Figure 3.4).1 The diagnosis of infected necrosis is confirmed with positive bacteria and/​or fungi on Gram staining and culture of aseptically obtained pancreatic necrosis specimens.1 Routine percutaneous fine-​ needle aspiration (FNA) of pancreatic or peripancreatic fluid collections is only occasionally used in current practice.38,39 The false negative rate of FNA ranges from 12% to 25% and FNA has the potential to introduce bacteria/​fungus to an otherwise sterile ANC/​WON.40,41 An increasingly recognized complication of necrotizing pancreatitis is the disconnected pancreatic duct syndrome (DPDS). In

Table 3.1  Modified Marshall scoring system for organ dysfunction in acute pancreatitis (organ failure is defined as a score of 2 or greater) Organ system

Score 0

1

2

3

4

Respiratory (PaO2/​FiO2)

>400

301–​400

201–​300

101–​200

≤100

Renal* (creatinine)

4.9 mg/​dL

Cardiovascular** (systolic blood pressure)

>90 mmHg

10 cells/​HPF) IgG4-​poitive cells b. Physical or radiological evidence At least one of the following: (1) Symmetrically enlarged salivary/​ lachrymal glands (2) Radiological evidence of renal involvement described in association with AIP

Histology of the pancreas

LPSP (core biopsy/​resection) At least three of the following: (1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration (2) Obliterative phlebitis (3) Storiform fibrosis (4) Abundant (>10 cells/​HPF) IgG4-​positive cells

LPSP (core biopsy) Any two of the following: (1) Periductal lymphoplasmacytic infiltrate without granulocytic infiltration (2) Obliterative phlebitis (3) Storiform fibrosis (4) Abundant (>10 cells/​HPF) IgG4-​positive cells

H

Level 2

Diagnostic steroid trial Response to steroid (Rt)*

Rapid (≤2 weeks) radiologically demonstrable resolution or marked improvement in pancreatic/​extra-​pancreatic manifestations

*

Diagnostic steroid trial should be conducted carefully by pancreatologists with caveats (see text) only after negative work-​up for cancer, including endoscopic ultrasound-​guided fine-​needle aspiration. † Atypical: some AIP cases may show low-​density mass, pancreatic ductal dilatation, or distal atrophy. Such atypical imaging findings in patients with obstructive jaundice and/​or pancreatic mass are highly suggestive of pancreatic cancer. Such patients should be managed as pancreatic cancer, unless there is strong collateral evidence of AIP and a thorough work-​up for cancer is negative (see algorithm). ‡ Endoscopic biopsy of duodenal papilla is a useful adjunctive method because ampulla often is involved pathologically in AIP. Reproduced with permission from Shimosegawa, Tooru MD; Chari, Suresh T. MD; Frulloni, Luca MD et al. International Consensus Diagnostic Criteria for Autoimmune Pancreatitis, Pancreas: 40(3):352–​358, April 2011.

unifies the diagnostic criteria,3 and this has been validated in various settings.20 The ICDC3 incorporates all the features of the Mayo Clinic’s modified HISORt criteria, including histology, imaging of the parenchymal ducts, elevated serum IgG4 levels, other organ involvement, and response to glucocorticoid therapy, with inclusion of ductal imaging and ampullary biopsies with IgG4 staining from the Japanese society (Table 7.1). Details regarding these cardinal features are discussed below.

Imaging for autoimmune pancreatitis Imaging has an essential role in the evaluation of AIP to assess the pancreatic parenchyma, pancreatic duct, biliary tree, peripancreatic tissue, and extra-​pancreatic findings21 (Figure 7.1). Computed tomography (CT) scanning of the abdomen with a pancreatic protocol is adequate for evaluation of AIP.21 At the Mayo Clinic, we obtain a pancreatic parenchymal phase typically at 40-​to 45-​second delay and a portal phase at 60-​to 70-​second delay.21 A delayed phase of 3 minutes can be added if we suspect AIP clinically or on previous imaging. For magnetic resonance imaging (MRI), T1-​weighted, T2-​weighted, diffuse-​weighted, and post-​contrast

imaging with arterial, venous, and 5-​minute delayed phases are obtained. To assess the biliary tree, we typically use magnetic resonance cholangiopancreatography (MRCP).21

Pancreatic parenchyma The typical presentation of AIP (50–​70%)22,23 includes diffuse enlargement of the pancreas, with effacement of its lobular contour, showing a featureless pancreatic border with absence of pancreatic clefts, resulting in the typically described sausage-​shaped appearance. Focal enlargement of the pancreas can be seen in 18–​40%24 of patients with AIP. This typically involves the head but can also involve the body or tail. The involved portion of the pancreas is mostly iso-​attenuating, compared to the non-​enlarged segment of the pancreatic parenchyma, but in some cases, it can appear as a low-​attenuating mass and be exceedingly difficult to differentiate from PC.22 The focal disease tends to be relatively well demarcated. Atrophy of the pancreas upstream to the mass is uncommon in patients with AIP, compared to PC. The pancreas can appear normal, or even atrophic, in some cases of AIP.25 Pancreatic atrophy usually represents a burnt-​out phase or post-​treatment state of AIP.23

Pancreatic ductal imaging

Figure 7.1  CT scans demonstrating (A) diffuse pancreatic enlargement with enhancing ‘rim’ characteristic of AIP; (B) AIP presenting as a pancreatic mass without pancreatic duct dilatation; (C) type 2 AIP presenting with focal pancreatic mass; and (D) diffuse pancreatic enlargement in type 2 AIP. Reproduced with permission from Majumder, S., Takahashi, N. & Chari, S.T. Autoimmune Pancreatitis. Dig Dis Sci 62, 1762–​1769 (2017).

A capsule-​like rim can be seen in up to 14–​48% of patients of AIP.26 This capsule is thought to be secondary to infiltration of inflammatory cells and fibrosis. The capsule rim is of low attenuation on contrast-​enhanced CT and hypointense on both T1-​ and T2-​ weighted MRI images. It shows delayed enhancement on MRI and may usually surround the entire pancreas or a focal area. This is different from the high-​attenuation rim caused by compression from PC.26 The enhancement pattern of the pancreatic parenchyma often gives a helpful clue in the diagnosis of diffuse and focal AIP. CT attenuation of the pancreas is similar or higher than that of the liver and lower than that of the spleen in the pancreatic phase, and it is similar to, or higher than, that of the liver and higher than that of the spleen in the portal phase. On the other hand, patients with PC show decreased enhancement in the pancreatic phase, with minimal change in enhancement in the portal phase.

Delayed enhancement of the pancreatic parenchyma, defined by 15 or greater increase in Hounsfield units, was found in 54% of patients with focal AIP, compared to only 15% of patients with PC.27

Pancreatic ductal imaging Patients with AIP have either small and non-​dilated main pancreatic ducts or compressed main pancreatic ducts from swelling of the pancreatic parenchyma, giving the appearance of long pancreatic duct strictures, best seen on MRCP or endoscopic retrograde cholangiopancreatography (ERCP). Sometimes one can see mild dilatation (duct calibre 2-​fold the upper limit Table 7.2  Imaging features that can help differentiate pancreatic cancer from autoimmune pancreatitis Autoimmune pancreatitis

Pancreatic cancer

Diffuse pancreatic enlargement

Atrophy of body and/​or tail

Ill-​defined mass

Well-​defined mass with reduced enhancement

Long segment (>1/​3 length) MPD stricture

Short-​segment stricture

MPD dilatation 5 mm

Multiple sites of MPD stricture

A single site of MPD stricture—​abrupt cut-​off

‘Capsule’ sign

No capsule sign

Duct-​penetrating sign

No duct-​penetrating sign

Side branch dilatation at the site of MPD stricture

No side branches seen at MPD stricture

ADC value 1.0 × 10−3 mm2/​s

Renal cortical hypoenhancing lesions

Liver metastases, but no renal masses

CBD stricture with thick (>1 cm) enhancing wall

CBD stricture, but no wall thickening

MPD, main pancreatic duct, ADC, apparent diffusion coefficient; CBD, common bile duct. Reproduced with permission from Kumaresan Sandrasegaran, Christine O. Menias, Imaging in Autoimmune Pancreatitis and Immunoglobulin G4–​Related Disease of the Abdomen, Gastroenterology Clinics of North America, Volume 47, Issue 3, 2018, Pages 603–​619.

of normal of IgG4 is a level 1 criterion in the diagnosis of type 1 AIP. Using the higher cut-​off (more than 2-​fold elevation) leads to better specificity in differentiation from PC, but it should be noted that mild elevations in serum IgG4 levels (1–​2 fold the upper limit of normal) can be present in 10% of patients with PC and 1% of patients can even have >2-​fold elevation in IgG4 levels.31 Thus, although elevated serum IgG4 levels are characteristic of AIP, IgG4 levels should in conjunction with other findings. Since AIP is uncommon, if the pretest probability of AIP is low, then an elevated IgG4 level is likely to be a false positive result.31

Histology Gross appearance The pancreas appears firm on gross inspection because of dense fibrosis. Although a mass-​like lesion is often observed on imaging, a well-​defined tumour is rarely seen. The lobular architecture of the pancreas is often destroyed by fibrosis. The main pancreatic duct appears compressed either diffusely or segmentally from periductal fibrosis. Calcification can be present, but it is rare. The intra-​ pancreatic portion of the bile duct can also be thickened and narrow with upstream dilatation.

Microscopic appearance Type 1 AIP is characterized histologically by dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterated phlebitis (Figure 7.2). Storiform fibrosis is a fibrosing lesion that is seen in almost all cases of type 1 AIP and resembles the spokes of a cartwheel with spindle cells radiating from the centre. In early storiform fibrosis, typically more lymphocytes with plasma cells are seen with little collagen. On the other hand, in late stages, very few cells are seen and it is mostly fibrosis. The spindle cells, which are either fibroblasts or myofibroblasts, are typically buried within the lymphoplasmacytic infiltrate. The storiform pattern of fibrosis may not be detected in limited samples such as from needle biopsy. The pancreatic lobules are almost always inflamed, at least focally, in type 1 AIP. With inflammation, the lobules are infiltrated by lymphocytes and plasma cells, with accompanying acinar cell loss. The interlobular spaces are fibrotic. Inflamed lobules maintain their original size and shape in type 1 AIP, in contrast to lobular atrophy seen in pancreatitis due to other causes. The lobules also occasionally become oedematous. Their architecture is relatively well preserved, but focal destruction of the pancreatic lobules with replacement by fibrosis is not uncommon. In the latter, areas of storiform fibrosis can be seen. Obliterative phlebitis is one of the unique and common findings on histology in patients with AIP. It is characterized by lymphoplasmacytic cell infiltrates in the venule wall and eventually, it leads to obstruction of the lumen. This can be seen in relatively large venules with a size of 100 μm, making it visible on haematoxylin and eosin staining. Lymphocytes and plasma cells can also infiltrate the walls of large veins such as the splenic and portal veins, but this does not lead to luminal obstruction. The adventitia and outer layer of the tunica media of arterioles can also be involved in some cases of AIP. In type 1 AIP, two types of periductal inflammation can be

Treatment

Figure 7.2  Characteristic features of lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-​centric pancreatitis (IDCP). Histological features of LPSP (A–​E) and IDCP (F). (A) Low-​power and (B) high-​power view of lymphoplasmacytic infiltration surrounding the duct. (C) Storiform fibrosis. (D) Obliterative phlebitis. (E) IgG4 infiltration (>10/​HPF). (F) Granulocyte epithelial lesion (GEL) showing neutrophilic infiltration with duct epithelial destruction. Reproduced with permission from Nagpal, Sajan Jiv Singh; Sharma, Ayush; Chari, Suresh T.; Autoimmune Pancreatitis, American Journal of Gastroenterology: September 2018 –​ Volume 113 –​Issue 9 –​p 1301.

observed. A thin layer of lymphocytes and plasma cells can be seen just beneath the ductal epithelium with an outer layer of fibrosis. These cells do not infiltrate the ductal epithelium. Other types include dense lymphoplasmacytic infiltrates with storiform fibrosis, giving the appearance of a thickened pancreatic duct with a stellate lumen. Inflammation from lymphoplasmacytic infiltrates at the pancreatic border involving both the parenchyma and peripancreatic adipose tissue leads to the formation of the rim, which appears like a capsule on imaging. Inflammation can involve each adipose cell in the peripancreatic fat until it is replaced by fibrosis.

Treatment Treatment of AIP is primarily medical, but sometimes patients with AIP undergo surgery due to diagnostic uncertainty. The key to management is to use specific terms that help to identify treatment goals and responses.32

Indications for treatment According to guidelines published by the ICDC,33 all symptomatic patients should be treated. Symptoms can be due to pancreatic inflammation (abdominal pain, back pain, and jaundice) or involvement of other organs such as jaundice from a biliary stricture. The ICDC recommends treatment of asymptomatic patients in certain conditions, including a persistent mass on pancreatic imaging or abnormal liver function tests in patients with IgG4 sclerosing

cholangitis.33 Up to 10–​25% of patients can have resolution of pancreatic changes without any treatment.34

Definition of remission Disease remission can be considered from several perspectives, including symptomatic, radiological, serological, histological, and functional remission.32 Symptomatic remission is defined as resolution of symptoms, including jaundice and abdominal pain. Radiological remission is defined as resolution of pancreatic changes of AIP on imaging such as enlargement of the pancreas and long main pancreatic duct strictures. This can take up to 2–​4 weeks. These changes may not be reversible, especially in late stages of the disease. Serological remission is defined as normalization of IgG4 levels, and lags behind symptomatic and radiological remission. Histological remission is defined as resolution of lymphoplasmacytic infiltrates from pancreatic tissue and other histological changes of AIP. This is rarely checked, given the invasive nature of a pancreatic biopsy. Functional remission is defined as restoration of pancreatic exocrine and endocrine function. Complete remission is defined as remission where the patient achieves clinical, radiological, and serological remission.35

Induction of remission According to the ICDC recommendations published in 2017,33 the first line of treatment for active untreated AIP is corticosteroids unless there is any contraindication or a high risk of steroid use. In an international multicentre study, 99.6% of type 1 AIP patients and 92.3% of type 2 AIP patients36 showed remission. High-​dose

59

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7  Autoimmune Pancreatitis

(prednisone dosing of approximately 30–​40 mg/​day) corticosteroids are used for induction of remission.37 A minimum dose of 20 mg is necessary and doses lower than 20 mg of prednisone are not as effective in inducing remission.38,39 Pulsed therapy of corticosteroids (two courses of methyl­ prednisolone 500 mg × 3 days with a 4-​day interval) can be an alternative used in refractory cases for induction of remission.40 If patients have a contraindication to steroid use or a patient fails to respond to glucocorticoid monotherapy, then rituximab (RTX) as a single agent can be used for induction of remission in AIP. RTX is a chimeric monoclonal antibody against the CD20 antigen on B cells. The induction regimen for RTX is either 375 mg/​m2 once weekly for 4 weeks or 1000 mg in two doses 2 weeks apart.1 Patients with biliary obstruction without infection can be treated with steroids without biliary stenting in cases of established AIP.41 Patients who have ascending cholangitis should have biliary stent placement, with cytology and brushing from the biliary duct, before initiation of treatment with steroids.38

Assessment of response In patients with established AIP, the typical response to treatment can be assessed at 4 weeks with serology, laboratory tests, imaging, and assessing for symptom resolution. In patients who have an excellent response to steroids after 4 weeks, prednisone is typically tapered down by 5 mg each week over 8 weeks. An alternative slow tapering proposed by Japanese experts is 5–​10 mg/​day every 1–​2 weeks until a daily dosage of 20 mg is achieved, followed by tapering by 5 mg every 2 weeks.38 In patients who do not have a confirmed diagnosis, the response should be assessed in 1–​2 weeks with serology and imaging.38

Relapse and maintenance of remission Relapse, just like remission, can be biochemical (elevation in levels of liver enzymes), serological (elevation in IgG4 levels), symptomatic (abdominal pain, back pain, jaundice), radiological (appearance of AIP imaging features), histological, and functional. Symptomatic relapse is usually accompanied by serological and radiological relapse. Serological relapse can occur in the absence of other features. Type 1 AIP is a chronic relapsing disease, with a relapse rate of 26–​ 70%.24,36,42 Risk factors for relapse include high serum IgG4 levels (e.g. more than four times the upper limit of normal) before treatment, persistently high serum IgG4 levels after steroid treatment, diffuse enlargement of the pancreas, proximal type of IgG4-​SC, and extensive multi-​organ involvement.33 A recent small study published by Fukiage et al. showed that serum autotaxin (ATX) level is predictive of AIP relapse. The authors proposed a model of prediction of relapse and out of 11 patients who were predicted to relapse using this model, ten patients experienced relapse (91%), whereas none of the patients who were predicted not to relapse did so (0%).43 The treatment approach to relapse can be different, based on patient risk factors and local availability of resources. Relapse can be treated with high-​dose steroids with taper without maintenance steroids, high-​dose steroids with taper with maintenance steroids, use of RTX for induction without maintenance, and RTX induction and maintenance. Corticosteroids are highly effective in induction of remission in the majority of patients (>95%) after relapse. It is reasonable to consider the use of high-​dose steroids after previous steroid treatment if the patient can tolerate it. In our practice at the

Mayo Clinic, after a first relapse, we use high-​dose steroids for induction with taper, but not maintenance steroids. After two relapses, we consider high-​dose steroids with taper and then maintenance steroids. The dose of maintenance prednisone is typically 2.5–​7.5 mg daily for 3 years. The single randomized controlled trial conducted in this field showed the efficacy of low-​dose prednisone (5–​7.5 mg/​ day) in preventing relapse, with a 23.3% relapse rate in the maintenance therapy group, compared to a 57.9% relapse rate in the control group.44 In our experience, we have not found additional benefits with the use of immunomodulators with steroids in the prevention of relapse. A study conducted by Hart et al. showed that relapse-​free survivals were similar when relapses were treated with corticosteroids and immunomodulators, compared to using corticosteroids alone without maintenance treatment.24 In addition, 25% of patients in the immunomodulators group required discontinuation because of poor tolerance and side effects.24 Another risk factor in long-​term use of thiopurines is the risk of lymphoproliferative disorders in inflammatory bowel disease patients treated, with odds ratio (OR) of 5.28 (2.01–​13.9), compared to controls. RTX is an anti-​CD20 monoclonal antibody which has been shown to be effective in treating IgG4-​RD, including AIP. Apart from steroids, RTX is the only medication that can induce remission for the first time and in relapsed patients. A study conducted by Hart et al. showed that RTX was effective in induction of remission in 83% (10/​12) of AIP/​IgG4-​RD patients and these patients had no relapse over 2 years with maintenance infusions of RTX every month.45 Another recent study conducted by Soliman et al.46 found 94% (16/​17) efficacy in induction and maintenance of remission over a median follow-​up of 20 months. In this study, 17 patients were treated with RTX with two perfusions at 15 days apart and only two patients needed two supplementary perfusions. This study reported no serious adverse events. A nationwide study of French patients treated with RTX for IgG4-​RD showed an efficacy of 93.5% over a follow-​up period of 24.9 ± 21 months and a relapse rate of 41.9% after a mean delay of 19 months after RTX. This study had no maintenance infusion of RTX and in cases of relapse after RTX; retreatment was efficient with longer relapse-​free survival.47 Another study conducted by our group on pancreaticobiliary IgG4-​ RD showed an efficacy of 86% (37/​46) in achieving complete or partial remission at 6 months; 89% of patients were in remission at the end of 3 years if they received induction and maintenance with RTX.48 However, RTX maintenance therapy was associated with an increased risk of infection (6/​29). Patients with RTX induction only did not develop any infection.48 Based on these data, corticosteroids are highly effective in the induction of remission of relapsed patients. If patients have a contraindication to steroid use or are at high risk of developing complications and/​or have had >2 relapses, then RTX can be used for induction and maintenance of remission. We recommend the approach of induction of remission with RTX without maintenance infusion, given an increased risk of infection. We recommend following patients clinically by measuring liver enzymes and serology periodically. RTX has the advantage of a glucocorticoid-​sparing effect, but its cost can be prohibitive. Selection of medication should be based on the patient’s previous disease history, availability of RTX, and the clinician’s familiarity with monitoring for treatment-​related complications.2

Conclusion

Complications Patients with type 1 AIP can have complications related to inflammation of the pancreas and other organs, exocrine and endocrine insufficiency, and treatment-​related side effects.

Biliary obstruction The most common complication is jaundice due to biliary obstruction from IgG4 cholangitis or pancreatic inflammation. Patients with biliary obstruction in the absence of cholangitis can be treated with steroids. A study conducted by Bi et al.49 showed that under the supervision of an experienced pancreatologist and with close monitoring, 15 patients with obstructive jaundice due to AIP were treated with corticosteroids alone and their jaundice resolved in 1 cm but no more than 2 cm in greatest dimension

T2

Tumour >2 cm but no more than 4 cm in greatest dimension

T3

Tumour >4 cm in greatest dimension

T4

Tumour involves coeliac axis, superior mesenteric artery, and/​or common hepatic artery

Most p-​NETs (about 70%) express high levels of SSTRs, mainly SSTR type 2 (SSTR2),24 and therefore can be imaged with a radiolabelled form of octreotide such as 111-​In-​DTPA-​octreotide and 99mTc-​ EDDA/​hydrazinonicotinyl-​Tyr3-​octreotide (also known as somatostatin receptor scintigraphy (SRS)). SRS provides for scanning of the whole body and allows detection of metastases outside the abdominal region. Furthermore, it can offer functional information and contribute to selection of appropriate candidates for somatostatin-​ based therapies.25 The sensitivity of SRS has been improved by the addition of single-​photon emission computed tomography (SPECT). However, SRS is limited by the expression of SSTRs and has a lower sensitivity in sub-​centimetre lesions. Poorly differentiated p-​NETs and insulinomas have lower SSTR expression and are less likely to be detected with this technique. Also, SRS does not provide any information on anatomy and surgical resectability.26 Nowadays, hybrid imaging modalities, such as PET-​CT, with somatostatin analogues (SSAs), such as 68Ga-​SSA and 18F-​DOPA, are used more frequently due to lower radiation dose, greater diagnostic accuracy, and patient convenience. With increasing proliferation (higher Ki-​67 index), SSTR expression decreases and the tumours may not show uptake on SRS. In such situations, an 18F-​fluorodeoxyglucose (FDG) positron emission tomography (PET)/​CT scan may prove more valuable in diagnosis.27 It has been observed that both these methods are complementary for the diagnosis of higher-​grade NETs and NEC, and also aid in treatment planning.28 An increased 18F-​FDG uptake correlates well with loss of differentiation, higher grade, and

N—​regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastases in 1–​3 regional lymph nodes

N2

Metastases in four or more regional lymph nodes

M—​stage

M0

No distant metastasis

M1

Distant metastasis

*

Tis also includes the ‘PanIN-​III’ classification. Reproduced under the STM agreement from JD Brierly, MK Gospodarowicz, C Wittekind. TNM Classification of Malignant Tumours, 8th ed. 2016; Wiley-​Blackwell.

Table 11.4  Functional syndromes associated with p-​NETs Tumour/​syndrome

Symptoms

Associated peptide

Incidence (per million per year)

Insulinoma/​hypoglycaemia syndrome

Confusion, sweating, dizziness, weakness, unconsciousness, relief with eating

Insulin

1–​2

Gastrinoma/​Zollinger–​Ellison syndrome

Diarrhoea with or without severe peptic ulceration

Gastrin

1–​2

Glucagonoma

Necrolytic migratory erythema, weight loss, diabetes mellitus, stomatitis, diarrhoea

Glucagon

0.1

VIPoma/​Verner–​Morrison syndrome

Profuse watery diarrhoea and marked hypokalaemia, hypochlorhydria

Vasoactive intestinal polypeptide

0.1

Somatostatinoma

Cholelithiasis, weight loss, diarrhoea, steatorrhoea, diabetes mellitus, achlorhydria

Somatostatin