Tropical Hepatogastroenterology [1st ed.] 8131231585, 9788131231586, 8131203131, 9788131203132

Citation preview

Tropical Hepatogastroenterology

“This page intentionally left blank"

xx

Tropical Hepatogastroenterology

BN Tandon

MD, FNA, FAMS

Chairman, Digestive Diseases Foundation Formerly Dean and Head, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi

ELSEVIER A division of Reed Elsevier India Private Limited

Tropical Hepatogastroenterology Tandon ELSEVIER A division of Reed Elsevier India Private Limited Mosby, Saunders, Churchill Livingstone, Butterworth Heinemann and Hanley & Belfus are the Health Science imprints of Elsevier.

© 2008 Elsevier All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher. ISBN: 978-81-312-0313-2 Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs become necessary. The authors, editors, contributors and the publisher have, as far as it is possible, taken care to ensure that the information given in this text is accurate and up-to-date. However, readers are strongly advised to confirm that the information, especially with regard to drug dose/usage, complies with current legislation and standards of practice. Published by Elsevier, a division of Reed Elsevier India Private Limited, Sri Pratap Udyog, 274, Captain Gaur Marg, Sriniwaspuri, New Delhi-110 065, India. Commissioning Editor: Sonali Dasgupta Managing Editor (Development): Shabina Nasim Manager (Editorial Projects): Radhika Menon Production Manager: Sunil Kumar Production Executive: Ambrish Choudhary Typeset by Krishtel eMaging Solutions Pvt. Ltd., Chennai-600 017. Printed and bound at Replica Press, Kundli, India. xx

Chapter

0 Preface Why did I start this book? In an era where libraries are accessible, and good textbooks published in the west are available, is there the need for another book? I believe that the answer is “Yes”. Medicine, in terms of both disease pattern and therapeutic practices, shows tremendous geographical variations. Data and recommendations from different socioeconomic settings may not correctly reflect the picture at home. Is diverticulitis the commonest cause of lower gastrointestinal bleeding? Should we always ask for ambulatory pH monitoring in patients with gastroesophageal reflux? Does the diagnosis of gastrointestinal tuberculosis always require histological confirmation before the initiation of antitubercular therapy? Does variceal bleeding in pregnancy mean mortality in a country where prehepatic portal hypertension is common? Is interferon therapy appropriate for all settings of chronic hepatitis? The answers to these and several other questions would depend largely on the country in which the questions are asked. Medicine must be socially relevant for the community which it serves, and this principle applies as much to primary health care as to the practice of secondary and tertiary-level medicine. It is important for doctors to be able to refer to sources from their own medical environment, but they are often handicapped from the lack of available literature. (To say nothing of the fact that books published in the west are often prohibitively expensive!) Yet, there is no scarcity of gastroenterologists who are very highly qualified. I was convinced that it would be a shame not to tap their skills. I was fortunate that my colleagues offered enthusiastic support, and this project was very quickly under way. I took the decision to make this a book not about gastroenterology, which is a purely medical discipline, but about gastrointestinal diseases, which is a medical-cum-surgical subject. Many chapters are written by surgeons, who were able to write well about the indications and results of surgery. I did, however, ask them to avoid intricate surgical details, since this book is not about teaching the reader how to actually operate on a patient. The result has been a book that provides a gratifying balance between a medical and a surgical perspective. The other decision that I made at the start of the project was to ensure that the chapters did, indeed, fulfill their objective of enabling the readers to treat patients according to current practices in the tropics. This meant meticulous, even ruthless editing, and, while this has contributed generously to the time taken to bring out the book (over four years), the approach has been uncompromising. I believe that the wait has been worth the effort. A word about the selection of chapters. From the start, this was not to be a textbook of gastroenterology. This is primarily a selection of subjects of importance to the tropics, subjects that receive lesser emphasis v

vi

Preface

in books published from other regions. In most cases the authors are those who have worked extensively with the conditions that they have written about. At the end, this book has been able to include almost all the chapters planned at the start of the project.

BN Tandon

xx

Chapter

0 Acknowledgments There is no way that I could have completed an undertaking of this magnitude without substantial help. I have several persons to thank for this. I have always felt that my knowledge and skills derive from my association with my patients. It is because of them that I am competent to write a book like this, and I am in their debt. I have been particularly fortunate that the contributors, all senior professionals, have so willingly given of their time and have written such excellent chapters. Dr Siddharth Dutta Gupta and Dr Anil Agarwal have kindly provided illustrations for several chapters in the book. Mr Rajeev Banerji, Mr Sumeet Rohatgi, and Ms Shabina Nasim from Elsevier were the real force behind this enterprise. I must say that they showed a rare combination of pressure and patience, and I have developed a great respect for Elsevier because of their wonderful staff. Mr Sajeev has provided extensive secretarial support. He has been the one constant throughout this enterprise, and has organized my papers, maintained the records, arranged my meetings and telephone calls, and more. Mr Shankar has also provided considerable secretarial support, in association with Mr Sajeev. All books during their preparation take on a life of their own, and this one was no exception, eating into my personal time like a newborn baby. My work would have remained incomplete without the encouragement, and sometimes tolerance, from my family and colleagues. Inevitably there were times when I wondered if I would complete this project, and at such moments they were the ones who gave me the most hope, and I am truly grateful.

BN Tandon

vii

“This page intentionally left blank"

xx

Chapter

0 Contributors AC Anand vsm, md, dm, ficp, facg Consultant and Professor (Hepatogastroenterology), Army Hospital R & R, New Delhi-110010 Adarsh Chaudhary ms Senior Consultant, Department of Gastrointestinal Surgery, Sir Ganga Ram Hospital, New Delhi Ajay Duseja md, dm Assistant Professor, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh AK Jain md, dm Professor, Department of Gastroenterology, Banaras Hindu University, Varanasi AK Kakar ms Professor and Head, Department of Surgery, Maulana Azad Medical College, New Delhi Anil Arora md, dm Consultant Gastroenterologist and Hepatologist, In-charge Liver Clinic and Chief of Hepatologist Services, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi-110060 Anil K Agarwal ms, mch Professor and Head, Department of Gastrointestinal Surgery, GB Pant Hospital and Maulana Azad Medical College, New Delhi

Anoop Saraya md, dm Professor, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Anu Behari ms Assistant Professor, Department of Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014 Anurag Krishna ms, mch, fams Senior Consultant, Department of Pediatric Surgery, Sir Ganga Ram Hospital, New Delhi Anurag Tandon md, dm Senior Consultant, Metro Center for Liver and Digestive Diseases, Noida Arun Kumar Sharma md Assistant Professor, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh Atul K Sharma ms, dnb Senior Adviser Surgery and GI Surgery, Command Hospital (CC), Lucknow-226002 BN Tandon md, fna, fams Chairman, Digestive Diseases Foundation

ix

x

Contributors

Chandrasekhar md, dm Senior Consultant, Department of Gastroenterology, Yashoda Hospitals, Hyderabad

MP Sharma md, dm, fams, ficp, facg Head, Department of Gastroenterology, Rockland Hospital, New Delhi

Deepak Govil md, phd Senior Consultant, Department of Surgical Gastroenterology, Apollo Hospital, New Delhi

N Ananthakrishnan ms, mnams, frcs (ed), frcs (glasgow), fams Director, Professor and Head, Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry-605006

Ganesh Bhat md, dm Assistant Professor, Department of Gastroenterology, Kasturba Medical College, Manipal Girish SP ms, mch Resident, GB Pant Hospital, New Delhi Gourdas Choudhuri md, dm, fams, ficp, facg Professor and Head, Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014 Govind K Makharia md, dm, dnb, mnams Assistant Professor, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi110029

Pankaj Vohra md Diplomate American Board of Pediatrics; Diplomate American Board of Pediatric Gastroenterology; Senior Consultant, Pediatric Gastroenterology, Hepatology and Nutrition, Max Super Speciality Hospital, Saket, New Delhi-110017 PK Mishra ms, phd (aiims) Associate Professor, Department of Gastrointestinal Surgery, GB Pant Hospital, New Delhi Premashis Kar md, dm Professor of Medicine, Gastroenterology Division, Department of Medicine, Maulana Azad Medical College and Dean, Faculty of Medical Sciences, University of Delhi, Delhi-110007

Kartar Singh md, dm Professor, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh

Radha K Dhiman md, dm, mnams, facg Assistant Professor, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh

Kaushal Madan md, dm Assistant Professor, Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029

Radha Krishnan md, dm Senior Resident, Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014

Manisha Dwivedi md, dm, ficp, facg Professor and Head, Department of Gastroenterology and Hepatology, MLN Medical College, University of Allahabad, Allahabad

K Rajkumar ms Senior Resident, Department of Gastrointestinal Surgery, GB Pant Hospital and Maulana Azad Medical College, New Delhi

xx

Contributors

Rajneesh Kumar ms Senior Resident, Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Rakesh Aggarwal md, dm Professor, Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Ramesh Roop Rai md, dm Professor and Head, Department of Gastroenterology, SN Medical College, Jaipur S Nijhawan md, dm Professor, Department of Gastroenterology, SMS Medical College, Jaipur SS Gandhe Research Assistant, Hepatitis Division, National Institute of Virology, Pune Saket Goel ms Associate Consultant, Department of Surgical Gastroenterology, Apollo Hospital, New Delhi Sanjay Jain md, dnb (fellow, gastroenterology) Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi Sanjoy Mandal ms, mch Senior Resident, Department of Gastrointestinal Surgery, GB Pant Hospital and Maulana Azad Medical College, New Delhi Sethu Babu md, dm Senior Consultant in Gastroenterology, Sai Vani Hospital, Hyderabad Shivendra Singh ms, mch Assistant Professor, Department of Gastrointesti-

Part / xx

xi

nal Surgery, GB Pant Hospital and Maulana Azad Medical College, New Delhi SP Misra md, dm, frcp (london), frcp (edinburg), fnasc, facg, ficp Professor of Hepatology, MLN Medical College, University of Allahabad, Allahabad SS Negi ms, mch Consultant, Department of Gastrointestinal Surgery, Sir Ganga Ram Hospital, New Delhi Subrat Kumar Acharya md, dm Professor and Head, Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Sudhir Kumar ms Senior Resident, Department of Surgical Gastroenterology, Apollo Hospital, New Delhi Sujoy Pal ms, mch Assistant Professor, Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Suneet Sood ms, mams Professor, Department of Surgery, Universiti Teknologi Mara, Shah Alam, Malaysia Surinder S Rana md Assistant Professor, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh Sushma md (pathology) Senior Consultant, Global Hospital, Hyderabad TK Chattopadhyay ms Professor and Head, Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029

xii

Contributors

Usha Dutta md, dm Associate Professor, Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh

Vishal Gupta ms Senior Resident, Department of Surgical Gastroenterology, GB Pant Hospital, New Delhi

Vidya A Arankalle phd, msc Deputy Director and Head, Hepatitis Division, National Institute of Virology, 20-A, Dr Ambedkar Road, Pune

Vivek Tandon ms, mch Senior Consultant, Metro Center for Liver and Digestive Diseases, Noida

Vikram Bhatia Senior Research Officer, Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 Vineet Ahuja, md, dm Associate Professor, Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029

VK Kapoor ms, facs, frcs, facg Professor and Head, Department of Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014 YK Chawla md, dm, mnams, facg Professor and Head, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh

xx

Chapter

0 Contents Preface Acknowledgments Part I 1 2 3 4 Part II 5 6 7 Part III 8 9 Part IV 10 11 12

v vii

Esophagus

1

Cancer of the Esophagus Corrosive Injuries of the Esophagus and Stomach Gastroesophageal Reflux Disease Achalasia Cardia

3 39 57 82

Stomach

95

Peptic Ulcer Disease and Nonulcer Dyspepsia Benign Tumors of the Stomach Carcinoma of the Stomach

97 116 126

Small Bowel

153

Tropical Malabsorption Infections of the Small Bowel

155 167

Large Bowel

195

Management of Ulcerative Colitis Benign Colorectal Tumors Malignant Colorectal Tumors

197 213 221

xiii

xiv

Part V 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Part VI 28 29 30 Part VII 31 32 33 34 Part VIII 35 36 37

Contents

Liver

241

Jaundice in the Infant Hepatitis Viruses: Virology and Epidemiology Virological Diagnosis of Hepatitis Hepatitis A Infection Hepatitis B and D Virus Hepatitis C: An Indian Perspective Hepatitis E Hepatic Drug Toxicity Toxic Liver Injury Hepatic Granulomas Autoimmune Hepatitis Cirrhosis of the Liver Noncirrhotic Portal Fibrosis Extrahepatic Portal Venous Obstruction Budd-Chiari Syndrome

243 261 269 277 286 311 321 330 344 354 363 375 388 404 413

Liver Failure

423

Acute Liver Failure Subacute Hepatic Failure Benign Liver Tumors

425 445 450

Gallbladder and Biliary Tract

467

Gallstone Disease Gallbladder Cancer and Cholangiocarcinoma Choledochal Cysts Benign Bile Duct Strictures

469 485 514 528

Pancreas

537

Acute Pancreatitis Chronic Pancreatitis Cancer of the Pancreas

539 566 597

xx

Contents

Part IX 38 39 40 Part X 41 42 43 44 45 46 47 48

xv

Parasitic Diseases

613

Intestinal and Extraintestinal Amebiasis Hydatid Cyst of the Liver Schistosomiasis

615 629 641

Special Topics

651

Abdominal Tuberculosis Diarrhea in Children Nonvariceal Upper Gastrointestinal Tract Bleeding Lower Gastrointestinal Bleeding Hepatorenal Syndrome Hepatic Encephalopathy Ascites in Cirrhosis Malignant Liver Tumors

653 678 703 722 738 746 755 761

Index

780

“This page intentionally left blank"

xx

Part I Esophagus

1 2 3 4

Cancer of the Esophagus Corrosive Injuries of the Esophagus and Stomach Gastroesophageal Reflux Disease Achalasia Cardia

3 39 57 82

“This page intentionally left blank"

xx

Chapter

1 CANCER OF THE ESOPHAGUS Rajneesh Kumar, Sujoy Pal, and TK Chattopadhyay

1.1 INTRODUCTION Esophageal cancer is an important cause of cancer related death in old age. Dysphagia, which is the predominant symptom, significantly affects the quality of life of the patients. Therefore, palliation of the disease is as important as the treatment for cure. More than two decades ago, in a classic review, Earlam and Cunha–Melo[1] noted that of every 100 patients with esophageal carcinoma, 58 will be explored, 39 will have the tumor resected, and 13 will die in hospital. Of the 26 patients leaving hospital with the tumor excised, 18 will survive for 1 year, 9 for 2 years, and 4 for 5 years. While this dismal prognosis may not be true any longer, no single modality of treatment has been proven as the gold standard even today. Hence the current focus is on early detection and multimodality treatment for achieving better results.

of adenocarcinoma has been increasing steadily in the West.[2, 3] In USA, adenocarcinoma is the most common subtype of esophageal carcinoma at present.[4] Certain geographic regions have a high incidence of esophageal carcinoma (Table 1.1). The so-called ‘Asian esophageal cancer belt’ stretches from Turkey, east of the Caspian Sea through northern Iran, northern Afghanistan, southern regions of the former USSR such as Turkmenistan, Uzbekistan, Tajikistan; to India, China, and Mongolia.[5] Other regions with high incidence are certain parts of Africa (e.g., Transkei region of South Africa) and South America. The incidence of esophageal cancer relative to other cancers in India is shown in Table 1.2. Men are more affected than women, probably due to the high prevalence of risk factors like smoking and alcohol intake in males.

1.2 EPIDEMIOLOGY

1.2.2 Dysplasia/Carcinoma Sequence

1.2.1 Incidence and Prevalence Both squamous cell and adenocarcinoma commonly affect the esophagus. Worldwide, squamous cell carcinoma (SCC) has been the most common subtype. However, cancer incidence trends show an overall decrease in SCC, whereas the incidence

Various lesions of the esophageal epithelium are precursors to cancer. They include chronic esophagitis, atrophy, dysplasia, papilloma, and carcinoma in situ.[6, 7] Esophageal carcinoma may develop at the site of these precursors. These lesions are prevalent in high risk populations, and 3

4

Chapter 1 / CANCER OF THE ESOPHAGUS

TABLE fy 1.1 IARC (International Agency for Research on Cancer) (WHO): Incidence of esophageal cancer world over (year 2000) Country

ASR (per 100,000 population)

Kenya Malawi Botswana Lesotho South Africa China Mongolia Iran Turkmenistan India World (overall)

21.8 38.6 37.2 37.2 16.3 24.5 24.4 24.0 26.4 7.5 10.7

ASR = age-standardized rate

TABLE fy 1.2 IARC (International Agency for Research on Cancer) (WHO): Incidence of esophageal and other cancers in India (year 2000) Site of cancer

ASR (per 100,000 population) Males

Females

12.8 9.5 7.5 9.0 6.2 4.5 5.6 4.7 – – –

7.4 1.8 5.1 1.9 0.7 – 2.8 3.2 19.1 30.6 4.8

1.2.3 Risk Factors and Associations 1.2.3.1 Alcohol and tobacco

Alcohol and tobacco are well established etiologic factors for esophageal carcinoma, and, in fact, are associated with most cancers of the upper aerodigestive tract.[8] Several carcinogens are present in cigarette smoke. These include nitrosamines and polynuclear aromatic hydrocarbons such as benzpyrene. Pipe and cigar smoking is found to be worse as a risk association. Black tobacco and hand rolled cigarette smoking has a higher relative risk. The risk increases with the number of cigarettes and the duration of smoking. For alcoholic drinks, the risk varies with the type of drink consumed. It is least with beer and intermediate with wine. Alcohol and tobacco exert a synergistic effect. They potentiate each other, leading to a field within the upper aerodigestive tract where the epithelium is exposed to carcinogens, and is thus prone to develop multiple tumors. This explains the high risk of synchronous and metachronous carcinoma in the upper aerodigestive tract in patients with esophageal cancer.[9]

ASR = age-standardized rate

1.2.3.2 Dietary carcinogens N-nitroso compounds like nitrosamines are known dietary carcinogens, and are found in high levels in the diet in high incidence regions like the Linxian Province of China.[10] Cured, smoked, or sun-dried salted meat, fish, or vegetables are rich in such carcinogens. In Kashmir, Khuroo and colleagues[11] found that the high risk diet contained substantial amounts of N-nitroso compounds in foods such as salt, tea, dried fish, certain vegetables, and red chilies.

may be present alongside invasive carcinoma in esophagectomy specimens.

1.2.3.3 Nutritional deficiencies Certain micronutrient and vitamin deficiencies are associated with esophageal cancer. Diets deficient

Oral Pharynx Esophagus Lung Larynx Prostate Stomach Colorectum Breast Cervix Ovary

Tropical Hepatogastroenterology

EPIDEMIOLOGY

in vitamins A, C, E, niacin, riboflavin, magnesium, selenium, and zinc, diets rich in processed and starchy foods, and diets poor in fresh fruits and vegetables are associated with increased risks of esophageal carcinoma.[12] In the Transkei region, pellagra used to be very prevalent. Patients with pellagra had intensely inflamed esophageal mucosa, which placed these patients at a very high risk for developing esophageal carcinoma.[13] 1.2.3.4 Environmental factors and pollutants

The soil theory gained credence from studies done in Transkei, South Africa.[14] There appears to be an inverse correlation between mortality from esophageal cancer and the soil content of molybdenum, manganese, zinc, magnesium, silicon, nickel, iron, bromine, iodine, chlorine, potassium, sodium, phosphorus, and bicarbonate. How these substances affect the esophageal epithelium is not known. Molybdenum is a cofactor of the enzyme nitrate reductase which affects nitrite and nitrate content in plants. Petroleum contamination of water and occupational exposure of metal dust such as chromium, chromates, beryllium may increase the risks of esophageal cancer.[15] Vulcanization workers, plumbers, and pipe fitters have been identified in some studies as high risk groups.[16] 1.2.3.5 Infections

Human papilloma virus (HPV), especially types 16 and 18, are implicated in the pathogenesis of cancers developing in several squamous epithelia including cervix, vulva, larynx, and skin. HPV DNA sequence has been found in both benign and malignant esophageal conditions.[17] Fungi have been implicated as agents especially from studies in China. Of the various fungal infections of the esophagus, candida is the most common. Common

Part I / Esophagus

5

fungi such as Fusarium, Alternaria, Aspergillus, and Cladosporium have been found contaminating the grains.[18] These can reduce nitrates to nitrites, and can also decompose proteins and promote the formation of nitrosamines. 1.2.3.6 Chronic esophageal irritation

Chronic thermal and mechanical irritation due to dietary factors is frequently associated with the risk of esophageal cancer. Hot tea is consumed in large amounts in high incidence regions of Iran.[19] Drinking of the plant extract ‘mate’ has a frequent association in high incidence regions of South America.[20] Hot rice intake has been implicated in China.[21] In Iran and the Middle East, food grains contain fibrous material from contaminating seeds of common Mediterranean grass. This fibrous material has carcinogenic properties. Spicy and improperly chewed foods have been implicated in the risk of esophageal carcinoma. 1.2.3.7 Achalasia cardia

Patients with long-standing achalasia are at high risk of esophageal carcinoma, most likely from chronic stasis and inflammation. The prevalence of esophageal carcinoma in various studies of long-standing achalasia varies from 0% to 8.6%.[22–24] Recently, histological mapping of the resected esophageal specimens has demonstrated marked hyperplastic changes of stratified squamous epithelium and multiple foci of dysplastic changes.[25] In recent studies, the changes in p53, p16, p21, epidermal growth factor immunoreactivity, marked squamous hyperplasia, and increased numbers of CD3+ cells have been found in the at risk epithelium.[26] The tumor usually occurs in the dilated middle third part of the esophagus. Most

6

Chapter 1 / CANCER OF THE ESOPHAGUS

of these are squamous cell carcinoma. However, reflux following myotomy may cause Barrett’s esophagus and adenocarcinoma. The diagnosis is usually made late, and the prognosis is poor. Patients with achalasia for over 15–20 years should undergo surveillance with 6-monthly endoscopy and biopsy.[27] Some cases of carcinoma may clinically mimic achalasia; this presentation is termed pseudoachalasia. Liu and colleagues[28] recently studied pseudoachalasia. They found that most cases were due to neoplastic infiltration of the myenteric plexus, and a few represent a paraneoplastic syndrome due to a distant neoplasm (e.g., lung carcinoma). 1.2.3.8 Corrosive strictures

Between 1% and 7% of patients with esophageal carcinoma have a history of corrosive intake. Carcinoma develops after about 40 years.[29] Men are more frequently affected than females, and the carcinoma usually develops at the region of the corrosive stricture. The mechanism is chronic inflammation associated with the stricture. Appelqvist and Salmo[30] noted a better prognosis for these ‘scar’ carcinomas and proposed that this was because of younger age, early obstructive symptoms, and scar tissue which prevents early dissemination of the tumor.[31] This risk of late malignancy has led some surgeons to perform esophagectomy in patients with severe corrosive injury of the esophagus.[32]

1.2.3.10 Others

Irradiation and chemotherapy have been implicated as causing esophageal carcinoma in anecdotal reports. Endoscopic sclerotherapy has been associated as an etiologic agent. However, it is believed that this relationship is only due to coexisting factors. A previous history of gastrectomy for benign diseases is found in 0.7%–10.4% of patients with squamous cell carcinoma of the esophagus.[34] It is difficult to separate this risk from confounding factors and formulate any definite guidelines for surveillance. Plummer–Vinson syndrome (Paterson–Kelly syndrome) is characterized by iron deficiency anemia, atrophy of oral, pharyngeal and esophageal mucosa, and esophageal webs. These patients are predisposed to developing carcinoma in the upper digestive tract.[35] The risk of developing carcinoma is about 10%. Tylosis is a rare autosomal dominant disease characterized by hyperkeratosis of the palms and soles. Up to 95% of these patients develop squamous cell carcinoma by the age of 65 years.[36] Celiac disease and scleroderma have been associated with the development of squamous cell and adenocarcinoma respectively, but the relationship is thought to be secondary. Genetic predisposition has a relatively minor role in esophageal carcinoma. In China a few families have been identified with a strong genetic susceptibility of developing esophageal carcinoma.[37]

1.2.3.9 Esophageal diverticula

Malignant transformation in chronic Zenker’s diverticulum is rare, and a very small number of cases have been reported. A large Mayo clinic series of 961 Zenker’s diverticulum had a 0.3% prevalence of carcinoma.[33]

1.2.3.11 Barrett’s metaplasia

Barrett’s intestinal metaplasia is protective response to acid reflux in the esophagus. Endoscopically it can be divided into three types: (a) long segment Barrett’s where the metaplastic

Tropical Hepatogastroenterology

PATHOLOGY

epithelium extends for more than 3 cm proximal to the gastroesophageal junction; (b) short segment Barrett’s where it is limited to within 3 cm of the cardia; and (c) gastric cardia metaplasia, which is restricted to the region of the cardia only. The prevalence of Barrett’s is 5%–15% in patients undergoing endoscopy for symptoms of reflux.[38] The risk of adenocarcinoma in long segment Barrett’s metaplasia is 0.5% annually.[39] The magnitude of risk in short segment Barrett’s is less.[40] The risk is even lower in patients with gastric cardia metaplasia. Though no high risk group can be clearly identified in the patients with Barrett’s metaplasia, some characteristics may help in selecting patients at higher risk for developing carcinoma. These include obesity, white males, young age, ulceration, and long-standing disease.[41] The presence of H. pylori has an inverse relationship with the development of esophageal adenocarcinoma. 1.2.3.12 Genetics of esophageal carcinoma

Several genetic mutations have been identified which are associated with esophageal carcinoma (Table 1.3). Epidermal growth factor receptor (EGFr) gene is overexpressed in approximately 30%–80% of cases. TGF-alpha (transforming growth factor alpha) is expressed in 40% of tumors. TABLE fy 1.3 Expression of genetic mutations in esophageal carcinoma Tumor suppressor genes

Oncogenes

Others

FHIT Rb p53 p16 P14 Telomerase

EGFr erbB2 Cyclin D1

Survivin VEGF E-cadherin Catenins Ki-67 Interleukin-1

Note: For details of abbreviations see text

Part I / Esophagus

7

It binds to EGFr to stimulate growth. The overexpression of the ErbB2 and cyclin D1 genes has been observed in 30%–50% and 40%–60% of cases of esophageal carcinoma respectively. Ras mutations are uncommonly found with esophageal carcinoma[42] Fragile histidine triad (FHIT) gene mutations have been found in 60%–100% of esophageal cancer as well as in Barrett’s metaplasia. This appears to be a relatively early event in carcinogenesis in Barrett’s epithelium.[43] Retinoblastoma (Rb) gene product is a critical mediator of cell cycle arrest after DNA damage, and its mutations have been found in 20%–40% of the tumors. The p53 gene product regulates cell cycle, DNA repair, apoptosis, and controls the cell cycle. P53 mutations are associated with poorly differentiated tumors and poor survival in patients with esophageal adenocarcinoma.[44] P16 gene mutations have been identified in about 20% of esophageal squamous cell carcinoma. Esophageal carcinoma is not a vascular tumor, but we have found VEGF (vascular endothelial growth factor) expression to correlate with lymph node metastasis and patient survival.[45] In a recent review, the principal genes implicated in the progression from Barrett’s metaplasia to dysplasia and adenocarcinoma are the loss of p16 and p53 gene expression, increase in cyclin D1 expression, induction of aneuploidy, and loss of Rb, DCC (deleted in colon cancer), and APC (adenomatous polyposis coli) gene chromosomal loci.[46]

1.3 PATHOLOGY 1.3.1 Squamous Cell Carcinoma Worldwide, this is the most common form of esophageal carcinoma. Most tumors (55%) are located in the middle third of the esophagus.[47]

8

Chapter 1 / CANCER OF THE ESOPHAGUS

Thirty percent are located in the lower third, and 15% in the upper third of the esophagus. As previously mentioned, there is some evidence for a dysplasia—carcinoma-in-situ— invasive carcinoma sequence in esophageal carcinoma. Screening methods are designed to identify these preinvasive lesions. It has been estimated that carcinoma-in-situ takes 3–4 years to develop into invasive carcinoma.[48] Grossly, the lesion may vary from a subtle mucosal abnormality to a macroscopically obvious lesion that may be exophytic or endophytic. Exophytic variants include fungating, polypoidal, or plaque-like tumors. Endophytic tumors are infiltrative. Microscopically, the tumor may vary from a well differentiated squamous type to poorly differentiated pleomorphic cells. The tumor spreads by transmural invasion through various layers of the esophageal wall. Since there is no serosa, mediastinal structures like the recurrent laryngeal nerve, aorta, trachea, and others are involved early. Invasion of the tracheobronchial tree is the most common, and may lead to the formation of a tracheoesophageal fistula. Lymphatic spread occurs to the nodes of the mediastinum, neck, and upper abdomen. Twenty percent to thirty percent of lower third tumors spread to the superior mediastinal nodes, and the same numbers of upper third tumors involve abdominal nodes.[49, 50] Transmural tumor

spread correlates with lymphatic dissemination (Table 1.4).[51–53] The esophagus is rich in submucosal lymphatics, and longitudinal spread along the esophagus may give rise to tumor deposits in the submucosa as far away as 15 cm from the main tumor.[54, 55] This fact itself is sufficient justification for a total esophagectomy as opposed to a subtotal esophagectomy. Blood borne metastasis may involve the lung, liver, bone, and kidney. Lymph node micrometastases do not significantly affect survival in patients with esophageal carcinoma,[56] but bone micrometastases do. In one study, up to 90% of resected ribs were positive for marrow micrometastases, and this factor correlated with prognosis on multivariate analysis.[57]

TABLE fy 1.4 Transmural extension of tumor: Correlation with nodal metastases[51–53]

Type I – Adenocarcinoma of the distal esophagus, located at least 1 cm above the cardia and usually arising from an area of Barrett’s metaplasia. Type II – Tumors arising from cardiac epithelium or from intestinal metaplasia at the gastric cardia. Type III – Subcardial gastric carcinoma.

Tumor extent

Nodal spread

Mucosal Submucosal Muscularis propria Transmural

3% 30% 60% Nearly 100%

1.3.2 Adenocarcinoma Most adenocarcinomas arise in the background of Barrett’s metaplasia. However, this may not be identifiable in a large tumor. Often, it is difficult to separate gastric carcinoma from an esophageal carcinoma at the gastroesophageal junction. In a bid to separate these tumors, Siewert proposed a classification that is now commonly accepted.[58, 59] Adenocarcinomas of the gastroesophageal junction are defined as tumors whose centers lie within 5 cm of the anatomic cardia. They can be subclassified as:

Tropical Hepatogastroenterology

SYMPTOMS AND SIGNS

The anatomic location of the tumor center determines the assignment of subcategory. Ichikura and colleagues[60] have defined type II tumors (cardia carcinoma) as adenocarcinomas with their epicenter between 1 cm proximal and 2 cm distal to the esophagogastric junction. Lower esophageal adenocarcinoma spreads both to mediastinal as well as abdominal nodes. Adenocarcinoma of the cardia and subcardial stomach spreads predominantly to the celiac, splenic hilar, and periaortic nodes.[61]

1.3.3 Uncommon Subtypes Verrucous carcinoma is a superficial, slow growing tumor. Spindle cell carcinoma is a polypoidal tumor which tends not to infiltrate deeply. Mucoepidermoid and adenoid cystic carcinoma are aggressive tumors, and nodal metastases are common. Small cell carcinomas are usually large exophytic masses. These are often associated with squamous differentiation. Secretion of ACTH, hypercalcemia, and SIADH may occur as associated paraneoplastic syndromes. Overall these are aggressive tumors with poor survival.

1.3.4 Prognostic Factors The most important prognostic factor is the TNM stage. The depth of tumor infiltration, and the presence or absence of nodal and distant metastasis are primary determinants of prognosis. Recently, the number of involved nodes has been identified as an important factor. Involvement of more than four nodes is associated with a poorer survival.[62, 63] A lymph node positivity ratio of more than 0.1 is a poor prognostic factor.[64] Gross morphology and tumor type are not independent prognostic factors. Some tumors such as verrucous carcinoma and spindle cell carcinoma carry a better

Part I / Esophagus

9

outcome. While length of the tumor has a lesser bearing on prognosis than the TNM stage, a recent series found that the increasing length of the tumor beyond 5 cm worsens the prognosis.[65] It was previously thought that adenocarcinoma has a worse prognosis. However, this appears to be a function of a more advanced stage at presentation. The long-term prognosis is otherwise similar to squamous cell carcinoma.[66] Osugi and colleagues[67] showed that vascular and lymphatic invasion worsen the prognosis. Advanced age is no longer considered a poor prognostic factor. Elderly patients, if properly selected, have results as good as younger patients.[68] Perioperative blood transfusion may worsen the prognosis.[69] Lately, improved molecular techniques have identified newer prognostic markers. Although DNA aneuploidy (flow cytometry), p53 mutation, elevated EGF, EGFr, and TGF-alpha have correlated with worse outcome, more evidence is needed for the clinical relevance of these factors.

1.4 SYMPTOMS AND SIGNS Although esophageal carcinoma is typically a disease of old age (sixth to seventh decade), in our country one frequently encounters much younger patients. In fact the youngest patient in our experience was a 23 year old lady. The duration of symptoms is typically short, as opposed to benign esophageal disorders. Symptom duration longer than 6 months indicates an advanced tumor.[70] Dysphagia is the cardinal symptom which, if present in an old individual, should be considered suspicious of an esophageal cancer. Dysphagia, initially to solids and later to liquids, is present in 90% of cases, and occurs once the luminal compromise is at least two-thirds. The absence of serosa in most of the esophagus enables tumors to expand into surrounding tissues before luminal stenosis becomes symptomatic. Hence it

10

Chapter 1 / CANCER OF THE ESOPHAGUS

follows that most patients with esophageal carcinoma present with an advanced malignancy. Only in regions of the world where screening has been successfully employed (e.g., China), early lesions are detected in substantial numbers. Anorexia and weight loss are frequently associated symptoms, and are present in up to 75% of the patients. Other symptoms like odynophagia, regurgitation, and cough may be present. A preceding history of heartburn may be the only indicator of reflux in Barrett’s esophagus with malignant change. Sinister symptoms are weight loss (> 10%), hoarseness (from recurrent laryngeal nerve palsy), cough on swallowing (from an esophagorespiratory fistula), and back or chest pain (indicating invasion of mediastinal structures).[71] Cough may be due to esophagorespiratory fistula or aspiration due to an obstructed esophagus. Esophagorespiratory fistulae occur in about 5% of the cases, and are essentially incurable, with a short survival of 1.5 to 4 months.[72] Significant cough in the absence of either of the above may occur in chronic smokers, and tuberculosis should be kept in mind in these poorly nourished individuals. Hematemesis is an uncommon symptom. Although it is usually due to tumor erosion and ulceration, massive exsanguinating hemorrhage can occur due to an esophagoaortic fistula from tumor infiltration of the aorta. Clinical features due to metastasis may be bone pains, lump in the upper abdomen due to a lymph nodal mass or hepatic metastasis, or a lump in the neck due to cervical nodal metastasis. Clinical examination may not reveal diseasespecific findings in most patients. However, it is important to assess the nutritional status of the patient by recording the body weight, triceps skinfold thickness, pedal edema, and pallor. Since these patients are frequently chronic smokers, clinical examination should look for features of chronic

obstructive airway disease and pulmonary infections. Breath holding time is a useful bedside test to assess the pulmonary reserve. Details of cardiopulmonary disease, diabetes, and tuberculosis should be carefully sought. Assessment for tobacco and alcohol abuse is important. In the Indian subcontinent, chewable forms of tobacco are quite commonly used. Careful oral and pharyngeal examination may occasionally reveal synchronous tumors.

1.5 DIAGNOSTIC INVESTIGATIONS Laboratory investigations usually show anemia and hypoalbuminemia. Serum alkaline phosphatase may be elevated in patients with liver or bone metastasis. Hypercalcemia may occur as a paraneoplastic syndrome in squamous cell carcinoma. It is due to a parathyroid hormone-like peptide produced by the tumor. Hypercalcemia may also be due to extensive bone metastasis. The rare small cell carcinoma is associated with other paraneoplastic syndromes.

1.5.1 Barium Swallow Contrast radiography using barium sulfate gives valuable information. It shows the level of esophageal obstruction, its nature, proximal esophageal dilatation (usually not marked due to the short duration of illness), and the distal extent of the lesion particularly with regard to the involvement of the gastroesophageal junction and the stomach (Fig. 1.1). Barium swallow is particularly useful in defining the presence of an esophagorespiratory fistula. Water soluble contrast agents like ‘gastrografin’ should not be used because of the potential of causing lung damage due to its hyperosmolarity. Esophageal axis deviation on barium swallow predicts an advanced, unresectable tumor (Table 1.5).[73, 74]

Tropical Hepatogastroenterology

SCREENING

11

deviation is an important feature which predicts unresectability.[75, 76]

1.5.2 Endoscopy

FIGURE 1.1 Barium swallow showing irregular narrowing with shouldering in the distal esophagus, typical of esophageal carcinoma.

TABLE fy 1.5 Constituents of axis deviation fy • • •

Tortuosity of the esophageal axis proximal to the tumor Angulation of the esophageal axis Deviation of the esophageal axis – Above and below the tumor – Of the tumor itself – Abnormality of the distance of the tumor from the spine

Barium swallow was the cornerstone of diagnosis before the advent of endoscopy. Today, we continue to advocate this simple and cheap investigation before endoscopy because (i) it serves as a roadmap to the endoscopist, and often for the surgeon who does not see the tumor himself before surgery; (ii) its use in defining an esophagorespiratory fistula is unquestionable; (iii) axis

Part I / Esophagus

Fiberoptic endoscopy has now become the gold standard for the diagnosis of esophageal carcinoma. At least six biopsy samples from nonnecrotic tumor areas are required to get the best possible yield nearing 100%. Occasionally, dilatation of the tumor may be required before access becomes adequate for biopsies. Nondiagnostic biopsies may sometimes be an indication to take a biopsy with a large angled cup forceps through a rigid esophagoscope. While brush cytology should complement the yield of biopsy, it has not been used extensively in the diagnosis of carcinoma esophagus. In addition to biopsy, endoscopy can be used to assess the degree of obstruction caused by the tumor, the proximal and distal extent (in passable lesions), the presence of a second synchronous tumor, and to place a nasogastric tube for feeding. The location of the tumor is measured in centimeters from the incisors. The distal extent of the tumor is particularly important in adenocarcinoma at the gastroesophageal junction, where the extent of stomach involvement will influence its use as the conduit of choice after esophagectomy. When this cannot be assessed by endoscopy, this should be seen by barium swallow.

1.6 SCREENING Most cases of esophageal carcinoma are detected in advanced stages, hence the long-term results of therapy are poor. Detecting esophageal carcinoma early is an effective way of improving survival. In these early cancers the long-term survival sometimes exceeds 90%. Screening may be useful in high risk populations with diseases

12

Chapter 1 / CANCER OF THE ESOPHAGUS

like upper aerodigestive cancers, gluten enteropathy, Plummer-Vinson disease, achalasia, and males over the age of 50 years with a history of heavy abuse of cigarettes or alcohol.

1.6.1 Screening for Squamous Cell Carcinoma Screening for squamous cell carcinoma has been effective only in high-incidence regions of the world. One such region is the Linxian province of China, where nonendoscopic screening using abrasive balloon cytology has been successfully used to detect early carcinoma.[77] Various modalities which have been used for screening are as follows: 1.6.1.1 Endoscopy

Early lesions may appear as mild irregularity, erythema, or ulceration, or they may be missed altogether on routine screening endoscopy. Chromoendoscopy increases the probability of identifying dysplasia. Chromoendoscopy refers to the vital staining of tissues with topical dyes to improve localization during endoscopy. The dyes used are Lugol’s iodine, toluidine blue, indigo carmine, and methylene blue. Lugol’s iodine stains the glycogen of the normal squamous epithelium black, and the biopsy should be taken from the unstained areas.[78] The other dyes are taken up by abnormal epithelium. Toluidine blue has an affinity for staining the cellular nuclei. Unfortunately these may be taken up in areas of inflammation, erosions, and ulcerations also. Methylene blue stains absorptive epithelium like small intestine, colonic epithelium, and Barrett’s epithelium, but does not stain nonabsorptive epithelium such as squamous or gastric epithelium. Compared to nondirected biopsy, methylene blue increases the yield for Barrett’s epithelium.

1.6.1.2 Nonendoscopic methods

Two popular methods for screening have been developed and used extensively. The mesh covered balloon has been used in China and the gelatin encapsulated sponge has been evaluated in Japan. The balloon is swallowed and inflated in the stomach with 20–30 ml of air. It is gradually withdrawn through the esophagus, and after removal is smeared on a slide. The sponge sampler is swallowed and left in the stomach for 5 minutes where the gelatin dissolves and the sponge expands. This is then withdrawn through the esophagus. After removal it is shaken in fluid and cytological examination is carried out after centrifugation of the fluid. The largest experience of the use of cytological screening has been in China.[79, 80] The accuracy in symptomatic individuals is higher than in asymptomatic individuals. Another form of blind cytology is with a standard cytology brush inserted through a nasoesophageal tube.

1.6.2 Screening in Barrett’s Esophagus 1.6.2.1 Endoscopy

The annual risk for developing adenocarcinoma in Barrett’s metaplasia is 0.5% to 1.5%.[81, 82] Endoscopy with biopsy is, therefore, required for surveillance in patients with Barrett’s metaplasia. Biopsies should be taken from each quadrant every 2 cm within the Barrett’s epithelium. Jumbo biopsy forceps and brush cytology increase the yield of positive diagnosis of dysplasia or cancer. In the absence of dysplasia, screening should be done once in 2–3 years.[81] The presence of low-grade dysplasia warrants treatment with a high dose course of antisecretory drugs and repeat biopsy. Endoscopy should be done half-yearly for one year, and then yearly.

Tropical Hepatogastroenterology

STAGING: IMAGING AND OTHER METHODS

TABLE fy 1.6 Techniques used to increase the efficacy of surveillance • • • • • • • •

Magnification endoscopy Chromoendoscopy (e.g., by methylene blue) Brush cytology Optical coherence tomography Laser induced fluorescence spectroscopy Flow cytometry (to measure the DNA content) P53 immunohistochemistry Proton magnetic resonance spectroscopy (of esophageal biopsies)

In high-grade dysplasia the risk of adenocarcinoma is 27% over 3 years.[83] Current recommended treatment for high-grade dysplasia is esophagectomy. Less often, authors recommend intensive endoscopic surveillance.[84] 1.6.2.2 Other modalities

Several techniques have been used to increase the efficacy of surveillance (Table 1.6). Methylene blue is particularly used in screening for Barrett’s epithelium.

1.7 STAGING: IMAGING AND OTHER METHODS The American Joint Committee on cancer staging system is based on the primary tumor, nodal involvement, and distant metastasis (Table 1.7).[85] The tumor size and spread cannot be evaluated clinically, and staging depends entirely upon imaging. This staging system has been most applicable to upper and middle third squamous cell carcinoma as opposed to the lower third adenocarcinoma.

1.7.1 Chest X-Ray Conventional posteroanterior chest radiographs should be done in all patients of carcinoma

Part I / Esophagus

13

esophagus. Findings may include lung metastasis, changes of chronic obstructive airway disease, pneumonitis, mediastinal widening, and esophageal air-fluid level. The presence of pulmonary metastasis precludes long-term survival, hence unnecessary expensive staging investigations are avoided. TABLE fy 1.7 AJCC (1997) TNM staging for esophageal carcinoma T (Primary tumor) • Tx : Tumor cannot be assessed • T0 : No evidence of primary tumor • Tis : High-grade dysplasia • T1 : Tumor invades lamina propria, muscularis mucosa, or submucosa. Does not breach submucosa • T2 : Tumor invades into but beyond muscularis propria • T3 : Tumor invades periesophageal adventia but does not invade the adjacent organs • T4 : Tumor invades adjacent structures N (Regional nodal metastasis) • Nx : Nodal status not assessable • N0 : No nodes involved • N1 : Regional nodes involved M (Nonregional nodes and distant metastasis) • Mx : Distant metastasis not assessable • M1a *: Upper thoracic tumors metastatic to cervical nodes. Lower thoracic tumors metastatic to celiac nodes • M1b : Upper and lower thoracic tumors metastatic to other nonregional nodes or distant sites. Middle thoracic tumors metastatic to any nonregional nodes or distant metastasis Stage grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIa T2 N0 M0 , T3 N0 M0 Stage IIb Stage III

T1 N1 M0 , T2 N1 M0 T3 N1 M0 , T4 N0 M0 , T4 N1 M0

Stage IV

Any T, any N, M1a or M1b

∗ No M 1a

category exists for middle thoracic tumors. Any nonregional nodal metastasis has the same prognosis as distant metastasis

14

Chapter 1 / CANCER OF THE ESOPHAGUS

1.7.2 Bronchoscopy Bronchoscopy is mandatory in upper and middle third tumors due to their proximity to the major airways. Displacement of the airway does not preclude resection, but is a significant finding for the surgeon.[86] Early features of involvement include mucosal edema or elevation with contact bleeding. Direct infiltration of the trachea or bronchi contraindicates resection. Widening, of the carina may be because of the tumor, or, more likely, because of subcarinal nodes. Transcarinal fine needle aspiration cytology (FNAC) can be used to confirm nodal metastasis, but is usually unnecessary.

1.7.3 Computed Tomography (CT Scan): Chest and Upper Abdomen Contrast enhanced CT scan of the chest and upper abdomen has the highest accuracy for distant metastasis (M stage), particularly lung, liver, bone, and adrenal metastasis. CT has limited value in assessing the primary tumor (T stage) and nodal involvement (N stage). Wall thickness more than 5 mm is abnormal on CT scan. Primary tumor may appear as esophageal wall thickening or as a mediastinal mass in advanced stages (Fig. 1.2). Length of the tumor may be underestimated by 2 to 3 cm by CT scan. Invasion of mediastinal structures is an important determinant of resectability and prognosis. Although loss of fat planes is considered a criterion of invasion, this may be lost not only due to invasion but also due to cachexia, prior operation or radiotherapy. The cervical esophagus and gastroesophageal junction are particularly difficult to evaluate because of lack of natural fat planes. Aortic invasion is best predicted by an angle of contact of the tumor with the aorta greater than 90◦ . The overall accuracy of prediction of invasion of mediastinal structures is 80%–85%, but the sensitivity is as low as 50%–55%.[86, 87] Lymph nodal involvement is

FIGURE 1.2 Contrast enhanced CT scan of lower chest and upper abdomen. There is a concentric wall thickening with a soft tissue mass lesion causing luminal narrowing in the esophagus (A – aorta).

diagnosed on the basis of node size larger than 1 cm. However, nodal metastasis may be present in normal size nodes, and nodal enlargement may be due to reactive hyperplasia.[88] Hence the accuracy of predicting nodal involvement is less than 60% and the sensitivity is even lower at about 30%.[89, 90]

1.7.4 Magnetic Resonance Imaging Magnetic resonance imaging (MRI) has no discernable advantage over CT scan in the evaluation of esophageal carcinoma.

1.7.5 Positron Emission Tomography Metabolically active tumor tissue takes up 18 Ffluorodeoxyglucose (FDG). The uptake can be

Tropical Hepatogastroenterology

STAGING: IMAGING AND OTHER METHODS

15

imaged by the positron emission tomography (PET). PET is most useful in picking up distant metastasis. The accuracy for M staging is 90%, including about 10%–20% of metastasis that are not detectable with conventional staging imaging.[91] PET is not of much use as far as T staging is concerned. PET cannot differentiate adjacent N1 nodes from primary tumor; hence the accuracy for N staging is low, though variable (about 30%– 40%).[92] It gives better results for distant nodes (M1a ). PET may be more useful for staging after neoadjuvant therapy.

1.7.6 Endoscopic Ultrasound Endoscopic ultrasound (EUS) has proved highly accurate in T, and, to a certain extent, in N staging.[93] Five layers are identified (Table 1.8, Fig. 1.3). Radial (360◦ view) and linear array (100◦ forward view) probes scanners are most often used. The probe frequencies most often used are 7.5 and 12 MHz. In a large review the accuracy for T staging was 84%.[94] While conventional EUS can identify T1 and T2 stage tumor, EUS probes of higher frequency (20 MHz) can give further definition of the infiltration of mucosa (T1a ) and submucosa (T1b ).[90] Such information is useful when endoscopic resection is being considered. The limitations with T staging are an obstructing tumor, microscopic tumor invasion, TABLE fy 1.8 Five layers of esophagus seen on EUS 1. 2. 3. 4. 5.

Inner hyperechoic layer – superficial mucosa (epithelium and lamina propria) Inner hypoechoic layer – deep mucosa (muscularis mucosa) Middle hyperechoic layer – submucosa Outer hypoechoic layer – muscularis mucosa Outer hypoechoic layer – periesophageal fatty tissue

Part I / Esophagus

FIGURE 1.3 Endoscopic ultrasound showing a large transmural growth (arrow) invading into the periesophageal tissues: T4 lesion.

peritumoral inflammatory changes, and fibrosis because of neoadjuvant therapy.[95] EUS is less accurate for nodal staging. The characteristics associated with nodal involvement are size greater than 1 cm, hypoechogenicity, discrete margins, and rounded shape. When all four features are present the diagnostic accuracy is 80%.[96] However, these characteristics are present in only 25% cases. EUS guided FNAC can enhance the value of EUS in nodal staging. The impact of EUS on clinical decision making will vary depending on the local treatment policy. The usefulness is minimal if the surgery is considered the preferred treatment even if the intent is palliative. Bronchoscopic ultrasound and intra-aortic ultrasound have been studied in staging local invasion in esophageal carcinoma but have not been commonly used.[97, 98]

16

Chapter 1 / CANCER OF THE ESOPHAGUS

1.7.7 Bone Scan (Tc99m -Labelled Diphosphonate) A bone scan is useful in picking up bone metastasis, but inflammatory lesions and fractures can be confounding factors. It is not in routine use for staging esophageal carcinoma.

1.7.8 Minimally Invasive Staging Thoracoscopic and laparoscopic staging have added to the diagnostic accuracy of preoperative investigations. Thoracoscopy is done from the right side, and the nodes between the subclavian vessels and the inferior pulmonary vein are sampled. Some oncologists also use mediastinoscopy to assess mediastinal lymphadenopathy in esophageal cancer. Laparoscopic staging includes celiac node sampling and laparoscopic ultrasound for detecting liver metastasis. Laparoscopy may be better than EUS in abdominal staging, given the limitations of EUS in this part. Minilaparotomy has also been used to look for small peritoneal (subdiaphragmatic) and hepatic surface metastasis. Minimally invasive techniques, however, have not been used extensively in world literature and require to be evaluated much more thoroughly before being recommended. They have the advantage of being extremely specific, but are invasive and require general anesthesia. Krasna et al.[99, 100] have reported an accuracy of 94% in laparoscopy and 91% in thoracoscopy for staging esophageal cancer.

1.7.9 Biological Staging Nonanatomic techniques for staging esophageal carcinoma assess genetic alterations, oncogenes, DNA content, and other prognostic determinants. The DNA content is inversely related to survival. Similarly, several genetic alterations are found in

relation to esophageal carcinoma. Biological staging refers to process of prognosticating the tumor behavior based on these alterations. In the future the genetic and molecular characteristics of the tumor will help in stratifying the patients in order to individualize therapy.

1.7.10 Pathologic Staging Pathologic stage is the clinical stage modified by additional information acquired by surgery and pathologic examination of the specimen. For esophageal cancer the pathologic and clinical staging is similar. Overall, staging techniques will vary according to protocols adopted by the treating physicians (Table 1.9).

1.8 TREATMENT 1.8.1 Preparation before Surgery for Operable Patients Most patients are cachectic due to dysphagia, anorexia, and recurrent chest infections. Low serum albumin and body weight correlate with a poor surgical outcome.[101] The surgeon should attempt to achieve a serum albumin more than 3.5 gm% if possible, by enteral rather than parenteral nutrition. If the patient is unable to eat sufficiently, he needs a nasogastric tube, or even TABLE fy 1.9 Our approach to staging We get a barium swallow in all patients with dysphagia. Cancer is confirmed with endoscopy and biopsy. The tumor is staged with a contrast enhanced CT scan of the chest and upper abdomen. Bronchoscopy is done if indicated. Lately we have used EUS in case of diagnostic dilemmas. Since our policy is of offering surgery as the primary modality of treatment and attempting resection in all reasonably fit patients with localized tumor; EUS, PET and invasive staging do not offer any significant advantage in clinical decision making.

Tropical Hepatogastroenterology

SURGERY

a feeding jejunostomy under local or general anesthesia. Pulmonary preparation includes steam inhalation, incentive spirometry, bronchodilators and antibiotics, and pulmonary function tests as required. An FEV-1 (forced expiratory minute volume at one second) under 65% indicates high surgical risk.[102] The hemoglobin should exceed 9 gm%. Transfusion may be required. Hydration, serum electrolytes, and urine output should be optimal before surgery. Orodental hygiene should be carefully assessed as these patients are often chronic tobacco chewers. The obstructed esophagus is often infected with fungi, especially Candida.[68] We routinely use antifungal lozenges in such patients to decrease the incidence of fungal infections postoperatively.

17

1.9.1 Surgery – Treatment of Choice Curative treatment of esophageal carcinoma may be attempted by surgery or radiotherapy. Surgery best resolves dysphagia, sialorrhea, and recurrent aspiration. However, surgery is associated with mortality up to 10%–20%, although this drops to less than 5% in specialized units. In comparison, more than 50% of patients receiving only radiotherapy develop strictures, and about half of these are due to local recurrence of tumor.[105] Complications of high dose radiotherapy can be as devastating as the morbidity following surgery. There are two randomized studies which compare surgery with radiotherapy. Both conclude that surgery is superior to radical radiotherapy.[106, 107]

1.8.2 Aims of Treatment The ideal objective is the total eradication of the disease with full functional restoration. This is not possible in most patients, therefore treatment is focused on relief of dysphagia, relief from sialorrhea, and prevention of recurrent aspiration. However, for the last two decades some surgeons have been attempting curative surgery for esophageal carcinoma and have reported good results.

1.9 SURGERY [103]

Czerny is credited with the first esophageal resection in humans. Torek [104] performed the first transthoracic esophagectomy. Surgery is still the gold standard of treatment for esophageal carcinoma. The basic surgical procedure consists of removal of a part or whole of the esophagus and its replacement with a conduit. There are several controversies in the surgical treatment of esophageal carcinoma. Of these the important areas are addressed below.

Part I / Esophagus

1.9.2 Perioperative Management Several procedural protocols are devised by teams that routinely carry out esophageal surgery. These are designed to minimize operative complications, improve the chances of successful surgery, as well as to speed recovery (Table 1.10).[108, 109]

TABLE fy 1.10 Perioperative measures for best results[108,109] • Optimization of the preoperative comorbid illnesses • Colon preparation in lower third carcinoma or previous gastrectomy (in case the stomach cannot be used as a conduit). Assess the mesenteric circulation with angiography in those susceptible to atherosclerosis. In Western populations exclude diverticular disease • Careful intraoperative monitoring and fluid management • Use of double lumen endotracheal tube; this facilitates exposure during thoracotomy • Deep vein thrombosis prophylaxis • Feeding jejunostomy during surgery, to start early postoperative enteral feeding

18

Chapter 1 / CANCER OF THE ESOPHAGUS

1.9.3 Operability and Resectability Operability is the feasibility of surgery according to both tumor factors and patient factors. Between 50% and 80% of patients are operable, that is, they are explored surgically.[110] Resectability is the feasibility of tumor resection in operable patients. Seventy percent to ninety percent of operable patients have resectable tumor.[107] If the surgeon believes in undertaking palliative resection, the resectability rate is higher.[111]

1.9.4 Subtotal versus Partial Esophagectomy Submucosal lymphatic flow in the esophagus forms an important route of malignant spread. Submucosal deposits are often found far from the main tumor, especially in squamous cell carcinomas, and form one cause of multicentric tumors. Deposits may occur as far away as 15 cm from the main tumor, and are often not obvious on naked eye examination.[112, 113] This makes a strong case for total esophagectomy (in fact, a near-total esophagectomy, because a small part of the cervical esophagus is left behind for anastomosis and a good functional result). While some workers favor esophageal resection 5–10 cm proximal to the main tumor, the incidence of local recurrence is unacceptably high.[114] A total esophagectomy also gives the opportunity to perform the anastomosis in the neck with its advantages.

1.9.5 Transhiatal versus Transthoracic Esophagectomy Esophagectomy is ordinarily performed through incisions in the abdomen and chest. The chest incision allows for dissection under vision. In addition,

there is always the potential for a radical surgery and cure. The gastroesophageal anastomosis may be carried out in the chest (infrequently), or in the neck (most cases), in which case a neck incision is added. A transhiatal esophagectomy is carried out through abdominal and neck incisions. The surgeon removes the entire esophagus by manipulating the esophagus through the esophageal hiatus at the diaphragm, and through the neck behind the manubrium sterni. This surgery is always palliative (recurrence is locoregional in 25%, systemic in 15%, and both in 15%).[115] The gastro-esophageal anastomosis is always made in the neck. Since there is no thoracic incision, transhiatal esophagectomy theoretically has lower morbidity. Most studies comparing the two approaches are retrospective and fail to show significant difference in terms of blood loss, mortality, and pulmonary or other morbidity (Table 1.11).[116–119] In literature, there is always a bias due to the poor pulmonary risk patients being favored to undergo transhiatal rather than transthoracic esophagectomy. TABLE fy 1.11 Retrospective comparison of transhiatal and Ivor Lewis transthoracic esophagectomy from a review of 33 series[119]

• • • • • •

2675 patients undergoing transhiatal esophagectomy, 2808 patients undergoing Ivor Lewis transthoracic esophagectomy Respiratory complications (24% vs. 25%) Cardiovascular complications (12.4% vs. 10.5%) Wound infection (8.8% vs. 6.2%) Chylothorax (2.1% vs. 10%) Anastomotic strictures (28% vs. 16%) Recurrent laryngeal nerve injury (11.2% vs. 4.8%) The 30-day mortality was lower for transhiatal group (6.3% vs. 9.5%) mainly due to the high mortality of the anastomotic leaks in the transthoracic group. The operating time was longer for the Ivor Lewis group.

Tropical Hepatogastroenterology

SURGERY

19

FIGURE 1.4 Esophagectomy specimen showing the entire esophagus and the tumor at the lower end.

Patients at high risk for pulmonary morbidity should be selected for transhiatal esophagectomy. Those with bulky tumors, or suspicion of involvement of the tracheobronchial tree or aorta should undergo transthoracic esophagectomy.

1.9.6 Radical versus Standard Esophagectomy Radical esophagectomy consists of en bloc transthoracic esophagectomy with lymph node dissection. The objective is to remove the thoracic duct, azygos vein, posterior pericardium,

Part I / Esophagus

bilateral adjacent parietal pleurae, and the right intercostal vessels adjacent to the tumor (Fig. 1.4).[120, 121] Akiyama et al. and others reported that 12.2% of the upper esophageal cancer involved abdominal nodes and 27.2% of lower esophageal cancers involved cervical nodes.[50, 122, 123] There are three lymphatic fields (upper abdominal, mediastinal, and cervical) in relation to the esophagus. Lymphadenectomy may be two field, removing the upper abdominal and mediastinal nodes, or three field. Patients with no nodes involved do not benefit from lymphadenectomy, nor do patients with extensive lymphatic dissemination.[62–64, 124–128]

20

Chapter 1 / CANCER OF THE ESOPHAGUS

The morbidity of radical lymphadenectomy is predominantly pulmonary (about 20%– 30%).[122, 129] Recurrent laryngeal nerve injury occurs in 40%–70% of cases, particularly in three-field lymphadenectomy.[126, 129] The result is hoarseness, recurrent aspiration, and a high incidence of permanent tracheostomy.[130] The pulmonary morbidity also occurs due to bronchorrhea following damage to the tracheobronchial vagal fibers, and ischemic ulcers occur in the tracheobronchial tree. Phrenic nerve palsy contributes to the pulmonary infections and atelectasis. Anastomotic leak is common (about 20%). The long-term sequelae are permanent tracheostomy, hoarseness, recurrent aspirations, and functional dysphagia. Studies on the quality of life after radical surgery have shown that these problems lead to a poor quality of life, lack of weight gain, and malnutrition on long-term follow-up.[124, 131] There is little literature on direct comparison between radical and standard esophagectomy. The morbidity of radical esophagectomy is high, and the benefits doubtful.[132, 133] Even transhiatal esophagectomy may show a 5-year survival over 20%.[134, 135] A radical lymphadenectomy is therefore best reserved for clinical studies.

may be suitable for small lesions at the cardia provided a proximal clear margin of at least 5 cm is obtained.[136] These tumors require resection of the proximal stomach with about half of the lesser curvature to obtain this tumor-free margin. An esophagogastric anastomosis may be done through the hiatus via a thoracotomy. For the Siewert’s type-II and type-III adenocarcinomas (cardia and subcardia carcinoma) the recommended surgery is total gastrectomy with D2 type lymphadenectomy and partial esophagectomy.[59] For middle and upper third carcinoma of the thoracic esophagus, the procedure is a subtotal esophagectomy with an esophagogastric anastomosis in the neck. A thoracotomy is usually required. Transhiatal esophagectomy may be done for palliation in small lesions. Carcinoma of the cervical esophagus can be dealt with by a combined pharyngo-laryngoesophagectomy with neck dissection of nodes and a permanent tracheostomy.[137, 138] The thoracic esophagus is removed by a transhiatal dissection. The conduit of choice is stomach. Colon may be used if stomach is not suitable. For small tumors, a local excision of the cervical esophagus and replacement with a jejunal free graft can be done by surgeons with experience in microvascular surgery.

1.9.7 Selection of Approach For a lower third esophageal squamous cell carcinoma, the options are a partial esophagogastrectomy with an esophagogastric anastomosis in the chest (through a left or right thoracotomy), or a subtotal esophagectomy (transhiatal or transthoracic) with an esophagogastric anastomosis in the neck. Where the stomach cannot be used, the colon may be used to replace the esophagus. For adenocarcinoma of the lower esophagus (Siewert’s type-I), a partial esophagectomy

1.9.8 Minimal Access Esophagectomy Minimal access esophagectomy is feasible,[139] but does not as yet have demonstrable advantage over open surgery. The benefit of small incisions is offset by the increased time of single lung anesthesia. Further, the extent of mediastinal dissection remains the same, therefore the morbidity is similar. Port site recurrence is another concern. The following are the main steps of minimal access esophagectomy:

Tropical Hepatogastroenterology

SURGERY

• Thoracoscopic esophageal mobilization. • Video assisted transhiatal mediastinal esophageal mobilization using a laparoscope inserted through the diaphragmatic hiatus. • Laparoscopic gastric mobilization. • Laparoscopic and thoracoscopic gastric and esophageal mobilization. • Mediastinoscopic dissection.

1.9.9 Choice of Conduit and Route Several organs have been used as conduits to replace the esophagus after esophagectomy (Table 1.12). The stomach is the overwhelming favorite (Table 1.13). The gastroepiploic arcade provides a good collateral blood supply, and the robust TABLE fy 1.12 Structures used as esophageal replacements • • • • • • • • •

Stomach Greater curvature gastric tube Reversed gastric tube Nonreversed gastric tube Right colon Left colon Jejunum (Roux loop) Jejunal (free graft) Myocutaneous free or pedicled grafts

submucosal plexus takes care of the blood supply at the fundus. The neoesophagus can be taken up through several routes (Table 1.14). It may be made to traverse the posterior mediastinum (usual) in place of the resected esophagus, or the presternal route, anterior to the heart. The conduit may even be taken up presternally, directly under the skin! This path requires the longest length of conduit (4 cm more than the posterior mediastinal route).

1.9.10 Esophageal versus Neck Anastomosis In patients who have distal third tumors, the surgeon has a choice: subtotal esophagectomy with esophagoconduit anastomosis in the neck, or partial esophagectomy with the anastomosis in the chest. The chest anastomosis infrequently leaks, but when it does the mortality is close to 50%.[140] The rate of leak for the anastomosis in the neck is higher, but it usually heals, and rarely if ever leads to sepsis and mortality, since the pleural cavity and mediastinum are not contaminated.[141] Gastroesophageal reflux is also commoner in chest anastomoses. Recurrent Barrett’s metaplasia has been reported due to such reflux.

TABLE fy 1.13 Comparison of conduits after esophagectomy

Vascularity Length Ease Reflux Nutritional problems Respiratory problems Preoperative preparation Anastomotic complications

Part I / Esophagus

21

Stomach

Colon (left)

Jejunum

Very good Adequate Easy ++ + + – +

Good Adequate Tedious – – – + ++

Uncertain Short Cumbersome + – – – ++

22

Chapter 1 / CANCER OF THE ESOPHAGUS

TABLE fy 1.14 Routes of pull-up of conduit after esophagectomy Route

Advantages

Disadvantages

Posterior mediastinal

• • •

Shortest Best function Least complications

•

May be affected by residual tumor, recurrence, scarring, and adjuvant radiotherapy

Substernal (retrosternal)

•

Always available

• • • •

Longer route Compression at thoracic inlet Graft angulation Cardiac access restricted

Subcutaneous (presternal)

• •

Easiest to construct Avoids mediastinum altogether

• • •

Longest route Cosmetically unacceptable Poor function and emptying problems

Transpleural

•

Useful for left thoracic approach

•

Displaces lung

Endoesophageal

• •

Short and direct Straight lie of conduit

• •

Not usually feasible Constriction of conduit

1.9.11 Need for a Pyloroplasty or Pyloromyotomy

anastomotic leak or severe pulmonary infection are at a higher risk of death.[146]

The stomach is denervated after esophagectomy. It was thought that the pylorus would form a barrier to the normal emptying of the denervated stomach after pull-up. Some surgeons therefore carry out a pyloroplasty or pyloromyotomy. However, the pulled-up stomach drains well enough, and the benefits of pyloroplasty are unproved.[142–145] We favor a selective approach in which the pylorus is manually dilated at surgery, and pyloromyotomy/pyloroplasty is reserved for a very muscular and narrow pylorus.

1.9.13 Intraoperative Complications

1.9.12 Complications of Esophagectomy The accepted in-hospital mortality of esophagectomy reported from experienced units world over is about 5% or less (Table 1.15). Large tumors (locally advanced) would require difficult surgery and hence are at higher risk of both morbidity and mortality. Patients facing major postoperative complications such as an intrathoracic

Injury to various organs in the abdomen, chest or the neck, and hemorrhage are the major intraoperative complications (Table 1.16). Mediastinal bleeding may occur from the esophageal arteries, aorta, pulmonary vessels, or from cardiac injury. Transhiatal esophagectomy is based on the fact that periesophageal arteries break up into a network of fine vessels 1 cm before entering the esophagus. If the dissection plane is kept close to the esophagus the chances of major hemorrhage are slim. Tracheobronchial injury occurs in about 1% of the cases and may be recognized during operation or after the endotracheal tube is removed. The only remedy is direct repair. Pneumothorax is so common (25%–75%) after transhiatal dissection that it should be considered a sequel rather than a complication. Recurrent laryngeal nerve injury can occur in the neck or the chest and leads to postoperative hoarseness and recurrent pulmonary

Tropical Hepatogastroenterology

SURGERY

23

TABLE fy 1.15 Results of selected series of esophagectomy for carcinoma (transhiatal and radical) Study

No.

Mortality

Five-year survival

800 250 78 367 115 80

4% 6% 6.4% 11% 3% 7.5%

23% 5% 21.3% 38% 45% (3-year survival) 37%

147 913 80 250 235 190

6.1% 5.2% 5% 3.6% 5% 4.7%

28% 42% 51% 48% (3-year survival) 49% 41%

Transhiatal • • • • • •

Orringer MB (2001) Gupta NM (1996) Authors’ series (1999)∗ Authors’ series (2002)∗∗ van Sandick JW (2002) Dudhat SB (1998)

Radical • • • • • •

Stilidi I (2003) Akiyama H (1994) Altorki N (2002) Swanson SJ (2001) Collard JM (2001) Nishimaki T (1998)

∗ Prashad

et al. 1999; ∗∗ Rao et al. 2002

aspiration. The incidence varies from 1% to 20%. It may recover if it is due to neuropraxia, but complete injury may require medialization of the cord later if adequate compensation by the opposite cord does not occur.

1.9.14 Early Postoperative Complications Pulmonary complications are the most common cause of morbidity after esophagectomy (Table 1.7). Atelectasis, pneumonitis, and pleural effusion predominate. Intensive physiotherapy and pulmonary toileting is extremely important in improving results. Cardiac complications are most commonly supraventricular arrhythmias, and the incidence is up to 30%.[147] The most common of these is atrial fibrillation and may occur during or after surgery. Studies of digoxin or betablockers have proved unsuccessful in preventing these. An anastomotic leak is the most dramatic complication of this surgery.[148] The incidence varies

Part I / Esophagus

widely in various studies (2%–41%).[149] The factors that increase risks of leak are poor vascularity of the conduit (less often esophageal blood supply), neck anastomoses (which leaks more often than intrathoracic), and poor nutritional condition of the patients. Some leaks in the cervical anastomosis can be managed by continued oral intake in a localized salivary fistula, using digital occlusion of the fistula during swallowing. The tract is cleaned later with a swallow of water. The intrathoracic leak that causes sepsis may require reoperation and dismantling of the anastomosis. Chylothorax should be suspected in case of excessive drainage from the intercostal drains. It occurs due to thoracic duct injury in the chest behind the esophagus. The incidence is usually about 1%. The classical milky discharge is seen only if the patient is on an enteral diet. Confirmation is obtained when the patient is given 100 gm of cream or butter via the feeding jejunostomy. The discharge turns milky, and on standing has an upper milky and a lower clear layer. The

24

Chapter 1 / CANCER OF THE ESOPHAGUS

TABLE fy 1.16 Complications of esophagectomy Intraoperative complications • • • • •

Injury to tracheobronchial tree, lungs, pleura, heart, major vessels, etc. Hemorrhage (aorta, pulmonary vessels, esophageal vessels, etc.) Pneumothorax Recurrent laryngeal nerve injury Hypotension and arrhythmias

Early postoperative complications • • • • • • •

Pulmonary complications (atelectasis, collapse, consolidation, pleural effusion, etc.) Cardiac complications (arrhythmias, hypotension, myocardial infarction) Leak (anastomotic leak, gastric suture line leak, etc.) Conduit necrosis Mediastinitis, wound infection Intestinal obstruction Chylothorax

Late postoperative complications • • • • • •

Anastomotic stricture Dumping syndrome Diarrhea Nutritional deficiencies (vitamin deficiencies, weight loss, osteomalacia) Gastric outlet obstruction Reflux and aspiration

milky layer dissolves and clears up on adding an organic solvent like ether or acetone. The drain fluid can be analyzed for chylomicrons and triglycerides for further evidence. Lymphangiography and lymphoscintigraphy are for the most part unnecessary in clinical practice. The management is initially conservative, and consists of a medium chain triglyceride diet orally supplemented by parenteral nutrition. Indications for surgery are high discharge despite conservative management (> 1 liter/d after 5 days), nutritional depletion or water, and electrolyte imbalance. Surgery consists

of suture ligation of the thoracic duct above and below the site of leak. Other early postoperative complications are conduit necrosis (especially in case of colon), intestinal obstruction, and hiatal herniation.

1.9.15 Late Postoperative Complications Anastomotic stricture is usually a sequel of a major leak (Table 1.7). The incidence is between 5% and 30%. Other factors which increase the chances of a stricture are a stapled anastomosis and a small esophagus.[150] We have introduced a simple method of managing the cervical strictures by teaching the patient self-dilatation using a Foley’s catheter.[151] The low cost and ease of the procedure increase the patient compliance and give good results. Intrathoracic anastomotic strictures require dilatation in hospital with various dilator systems, e.g., Savary-Gilliard dilators. Other important late complications are gastric outlet obstruction, dumping syndrome, nutritional problems due to vagotomy, and loss of gastric reservoir capacity.

1.10 RADIOTHERAPY Multimodal therapy for esophageal carcinoma is the current field of interest. Lot of hope has been raised by the results of various combinations of radiotherapy and chemotherapy, but lot of work need to be done before these can be universally recommended.

1.10.1 Primary Radiotherapy Squamous cell carcinoma of the esophagus is a radiosensitive tumor. Radical radiotherapy has traditionally been the choice of treatment in patients who were considered too weak to withstand surgery. Conventional external beam radiotherapy

Tropical Hepatogastroenterology

RADIOTHERAPY

(EBRT) is administered by high energy photon beams. Lower energy radiation is frequently used in brachytherapy. When radiotherapy is used as a single modality in definitive treatment, a dose of 60–64 Gy in conventional fractionation of 180– 200 cGy/day is used. Primary radiotherapy results in 5 year survival of 2%–20%[152] and the results are best with early lesions less than 5 cm in length, noncircumferential and nonobstructing. Radiation fields extend 5 cm above and below the tumor and 2.5–3 cm radially around the tumor. Patients should be in good general health for tolerating high dose radiotherapy. The early toxicity of radiotherapy includes a marked esophagitis, redness and irritation of skin, decreased blood counts, and hair loss in treated area. Other toxicity includes nausea, vomiting, ulceration, hemorrhage, radiation injury to spinal cord and lungs. It was initially thought that radiotherapy caused increased incidence of tracheoesophageal fistulae and hence this complication was thought to be a contraindication to radiotherapy. Recent results have shown that this is not the case, and radiotherapy may in fact facilitate closure of some tracheoesophageal fistulae.[153, 154] Late complications of radiotherapy include esophageal stricture, esophageal motility disorders, and pulmonary fibrosis. A late esophageal stricture is the most important complication of radiotherapy from the functional standpoint. The incidence is 12%–50%, and the median time to develop stricture is 6 months. About half of these are malignant due to tumor recurrence. Two randomized trials directly comparing surgery versus radiotherapy have shown that results are better with surgery.[106, 107]

1.10.2 Brachytherapy Iridium-192 is the isotope which has renewed interest in brachytherapy. First a catheter is inserted into

Part I / Esophagus

25

the esophagus after identifying the region of interest with barium swallow or endoscopy. Radioactive source is inserted into this catheter. Two techniques are used — high dose rate (HDR) and low dose rate (LDR) brachytherapy. High dose rate (HDR) brachytherapy uses short intense applications of several minutes and requires advanced automated technology. With low dose rate brachytherapy the treatment is administered over a total treatment time of 24–48 hours, and is less technology intensive but requires prolonged esophageal intubation. The low availability of brachytherapy and paucity of data showing its superiority over EBRT has resulted in low clinical usage.

1.10.3 Preoperative Radiotherapy Enthusiasm for preoperative radiotherapy dwindled after several randomized trials reported no clear benefit. Recently, we have shown a resectability rate of 81% using a novel regime of 25 Gy preoperative radiotherapy over 5 days.[155] There were no side effects, and in the unselected patient population the actuarial 5-year survival was 32%. The proposed advantages were down-staging of the tumor, sterilization of the margins reducing spill of cancer cells during surgery, and radiotherapy induced edema which makes resection easier.[156] A meta-analysis of all randomized trials on the role of preoperative radiotherapy came out with a small but statistically insignificant survival advantage of about 3%–4% in favor of preoperative radiotherapy.[157] To demonstrate that the effect is consistent, a much larger trial is necessary. In view of the high toxicity of the preoperative chemoradiotherapy schedules tested in literature, this relatively nontoxic regime makes sense till clear answers are available.

26

Chapter 1 / CANCER OF THE ESOPHAGUS

1.10.4 Postoperative Radiotherapy Postoperative radiotherapy has traditionally been out of favor after esophagectomy because the patients are unable to tolerate adjuvant therapy after such major surgery. In addition the radiotherapy would damage the neoesophagus. Most evidence indicates no survival benefit and increased problems due to the stomach being affected. Postoperative radiotherapy has thus been reserved for gross residual disease or positive resection margins though the evidence for this is weak. However a recently published large Chinese series has shown good results with postoperative radiotherapy.[158] More work is needed to validate these findings.

1.11 CHEMOTHERAPY Single agent chemotherapy using drugs such as 5fluorouracil (5-FU), mitomycin-C, cisplatin, vindesine, methotrexate, bleomycin, and etoposide yields complete tumor response of 5% to 15% and partial response in an addition 10% to 25%. Thus the overall response rate is about 40%. Combination chemotherapy results in complete tumor response of about 5% to 15% and partial tumor response of about 40% to 50%.

1.11.1 Preoperative Chemotherapy Most small trials have been unable to show a survival advantage with preoperative chemotherapy. The American Intergroup-0113 trial[159] and the recent British Medical Research Council trial[160] are the two largest trials of preoperative chemotherapy. The former showed no benefit, while the latter showed survival benefit of preoperative chemotherapy. Thus the data is conflicting, but it is clear that patients who respond to preoperative therapy are a good prognosis group and

in general do well especially in case of complete pathological response.

1.11.2 Postoperative Chemotherapy Little data exists on the adjuvant use of chemotherapy. Postoperative adjuvant chemotherapy does not appear to improve survival in these patients.

1.11.3 Chemoradiotherapy 1.11.3.1 Neoadjuvant chemoradiotherapy

A combination of preoperative chemotherapy and radiotherapy has resulted in complete pathological response rates of 25%–40%.[161–163] The available studies of neoadjuvant chemoradiotherapy are small, often flawed, and show no consistent improvement in survival. Locoregional control is improved. Patients with complete response (25%– 40%) have a survival advantage. Adenocarcinoma and squamous cell carcinoma respond equally well to the regimes tested. What often remains unsaid in the critical analysis of neoadjuvant therapy is the toxicity profile. These patients are often nutritionally depleted and in poor health. The side effects of therapy are pronounced and lead to a high dropout rate. Although data is conflicting, we believe that the regimes tested so far are too toxic, even though they do work, and add to the mortality and morbidity of surgery. We have used a low dose 5-FU and cisplatin based chemotherapy with 25 Gy short course radiotherapy and have got good results in a pilot study. This is an active area of research in esophageal carcinoma and may provide answers in the near future.[164] Selective surgery after chemoradiotherapy has been studied in a few studies. The results in these studies have been encouraging but much more

Tropical Hepatogastroenterology

PALLIATION

work needs to be done to establish clear and validated criteria for avoiding surgery.[165] 1.11.3.2 Adjuvant chemoradiotherapy

Insufficient controlled literature is available on this aspect to be able to recommend it after curative resection. 1.11.3.3 Primary chemoradiotherapy

The rationale of adding chemotherapy to radiotherapy was to take care of systemic micrometastasis and have a local synergistic effect with radiotherapy. There are six randomized trials of primary chemoradiotherapy published so far. Most studies have used suboptimal dosages of chemotherapy or radiotherapy. The landmark RTOG (Radiation Therapy Oncology Group) study[166] and the ECOG (Eastern Cooperative Oncology Group) study[167] showed a 5-year survival of 9% to 26% with chemoradiotherapy compared to the radiotherapy. However, the local failure (local persistence or recurrence) rates with primary chemoradiotherapy were high, and there was no direct comparison to surgery exist in literature. Combined chemoradiotherapy gives better results than only radiotherapy but is also associated with a definitely higher incidence of acute toxicity.[168] Thus, so far primary chemoradiotherapy is reserved for reasonably well preserved patients who have unresectable tumor or in whom the operative risk is prohibitively high.

1.12 PALLIATION Two important clinical features that need palliation in these patients are dysphagia and tracheoesophageal fistula. There are several methods and techniques of palliation of dysphagia.

Part I / Esophagus

27

1.12.1 Dilatation Tumor dilatation using bougies or balloon dilators are the oldest method of palliation. Used in isolation the relief is short lived, therefore it is used in combination with other procedures such as placement of a stent. The dilatation required for placing a plastic stent is about 15 mm, while the applicator for a self-expanding metallic stent requires only about 10 mm lumen. Without stenting, dilatation large enough to palliate dysphagia is fraught with complications such as tumor rupture and fistulization. Recently balloon dilatation has been combined with chemoradiotherapy.[169]

1.12.2 Surgical Palliation Esophagectomy provides excellent and long lasting relief from dysphagia. As discussed earlier, the philosophy of surgical treatment in some centers, including ours, is to provide relief from symptoms. We would offer esophagectomy in all reasonably fit patients. For this reason extensive staging using endoscopic ultrasound, PET, and invasive methods is not done. Comparison of surgery with nonsurgical methods of palliation revealed that surgery provided a much better palliation and quality of life after 3 months.[170] Hence features which suggest a short (< 3 months) survival, such as poor performance status, obvious local invasion, nonregional nodal metastasis, and distant metastasis, should discourage the use of palliative resection. Surgical bypass using the stomach, colon, or jejunum was used extensively earlier. The Kirschner operation using the retrosternal stomach pull-up to anastomose to the cervical esophagus was the most popular approach. There is no doubt that surgical bypass provides the best relief from dysphagia. However, it remains a formidable operation in patients with advanced disease who are

28

Chapter 1 / CANCER OF THE ESOPHAGUS

at poor surgical risks and the mortality and morbidity are high. Recently the Hong Kong group published their experience with the Kirschner operation.[171] The high mortality and morbidity lead them to conclude that it should be reserved for patients with unresectable disease encountered intraoperatively.

1.12.3 Endoprosthesis 1.12.3.1 Plastic tubes

These have historical importance and infrequently used after the advent of self-expanding metallic stents. They are of two types: the ‘pull’ type and the ‘push’ type. Recently a series from India demonstrated good results with a modified tube design and gradual tumor dilatation.[172] The overall morbidity was 16% and the mortality was 3.9%. The estimated treatment cost was very low. Selfexpanding plastic stents (SEPS) are now being developed, and feasibility studies have shown good results.[173]

tion, by endoclipping, or by external radio-opaque markers. The stent is placed under endoscopic, fluoroscopic, or combined control. Both proximal and distal release systems are available. Only the ultraflex stent, which has weak radial force, may require dilatation with a balloon for full expansion. Each of these SEMS has specific properties which continue to evolve over time. One innovation has been a distal valve to prevent reflux in stents deployed across the gastroesophageal junction. The initial technical success rates are high (90%–95%). Early complications are mild chest pain and incomplete expansion. Late complications include tumor ingrowths, stent migration, food impaction, hemorrhage, and fistulization. In a review the incidence of late complications was 36%.[174] There have been concerns about the increased incidence of fistulae in SEMS placement after chemotherapy or radiotherapy. It has thus been recommended that 4 weeks should elapse between any such treatment and placement of SEMS.

1.12.4 Photodynamic Therapy 1.12.3.2 Self-expanding metallic stents

The most commonly used stents are: (a) Gianturco Z-stent, (b) wall stent, (c) ultraflex stent, and (d) esophacoil stent. These can be uncovered or covered. The covered stents are coated with polyurethane and are specifically useful in preventing tumor in-growth and in tracheoesophageal fistulae. The advantage of self-expanding metallic stents (SEMS) is the small delivery system. SEMS need minimal lumen (up to 10 mm) for placement of the applicator. While choosing the length of the stent, 5 cm should be added to the estimated tumor length to account for shortening of the SEMS. Before deployment the proximal and distal ends of the tumor can be marked by mucosal contrast injec-

This unique form of treatment uses the photosensitizing drugs such as the FDA approved Photofrin and 5-aminolevulinic acid. Photosensitizers are drugs which emit singlet oxygen on exposure to light of a particular wavelength. This singlet oxygen is cytotoxic to the tumor cells. The usual dose of Photofrin is 2 mg/kg and the patient is exposed to laser at 690 nm wavelength after 48–72 hours. The advantage of photodynamic therapy is that it can be used in long, obstructing, tortuous, angulated, and cervical lesions as well. The disadvantage is the skin photosensitivity for 4 weeks. 5-ALA has been reported to have fewer side effects as compared to Photofrin. Complications reported are perforation, fistulae, and strictures in 10%–20%.[175]

Tropical Hepatogastroenterology

CONCLUSIONS

1.12.5 Laser Therapy The Nd:YAG (neodymium: yttrium aluminum garnet) laser has been the workhorse of laser therapy. Recently KTP:YAG (potassium titanyl phosphate:YAG) laser has been used for this indication. Laser can be used in a high power noncontact mode or low power contact mode. The tumor can be treated in an antegrade or prograde fashion. Tumor dilatation and retrograde technique is preferred. In a totally obstructing tumor antegrade technique is used, and charred debris needs to be removed to proceed further. In addition the chances of perforation are higher with the antegrade technique. The overall functional success is about 75%–80%. Major complications are infrequent and consist of perforation (3%), fistula (2.3%), and hemorrhage (1.4%).[176] The disadvantage of laser therapy is the recurrent dysphagia (in about 33% to 50%) and the need for repeated treatment every 4 to 6 weeks. To obviate this disadvantage laser therapy has been combined with brachytherapy and EBRT, and has shown good results.

1.12.6 Palliative Radiotherapy and Chemoradiotherapy Radiotherapy palliates dysphagia in about threefourths of patients. We have used a short course intensive regime of radiotherapy of 25 Gy over five fractions of 500 cGy each in 5 days, and have got good results in the palliation of dysphagia. The problems are that the relief is not immediate, and the radiotherapy side effects may reduce the quality of life. The improvement starts in 2 weeks and the median time to maximal improvement is 4 weeks (range 2 to 21 weeks). Late esophageal strictures are common and reduce the quality of palliation. Combined modality chemoradiotherapy improves dysphagia in 59%–88% of the patients.

Part I / Esophagus

29

Keeping in mind the toxicity of high dose regimes these are best applied if the performance status is at least fair, and the life expectancy is more than 3 months. For patients with poor life expectancy lower dose regimes are better applied. Chemoradiotherapy suffers the same disadvantages for palliation as with radiotherapy alone.

1.12.7 Injection Therapy for Palliation Various chemicals have been injected in the tumor in an attempt to induce necrosis and relieve dysphagia. These include alcohol, polidocanol, chemotherapeutic agents, and others. The response is variable. However this forms relatively cheap method of temporarily relieving dysphagia when compared to the expensive SEMS.

1.12.8 Palliation of Esophagorespiratory Fistula The presence of esophagorespiratory fistula in a patient of esophageal carcinoma indicates a short survival. The presence of constant contamination of the airway from esophageal contents results in a poor quality of life. The options of treatment include covered stents (SEMS) and surgical bypass (Kirschner operation). Lately, chemoradiotherapy has shown to result in closure of fistulae in some patients.[153, 154]

1.13 CONCLUSIONS The poor prognosis of esophageal carcinoma as concluded by Earlam two decades ago has shown a change for the better in the last two decades. The large experience (1970–2001) from the MD Anderson Cancer Center [177] exemplifies the improvement in resectability and (78% to 94%) mortality (12% to 6%). The current focus

30

Chapter 1 / CANCER OF THE ESOPHAGUS

is on the results of radical surgery and the advantage gained from neoadjuvant therapy. In the near

future, molecular biology may throw up answers where conventional surgery has failed.

REFERENCES [1] Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma: I. A critical review of surgery. Br J Surg 1980;67:381–90. [2] Newnham A, Quinn MJ, Babb P et al. Trends in the subsite and morphology of oesophageal and gastric cancer in England and Wales 1971-1998. Aliment Pharmacol Ther 2003;17:665–76. [3] Younes M, Henson DE, Ertan A et al. Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol 2002;37:1359–65. [4] Vizcaino AP, Moreno V, Lambert R et al. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973-1995. Int J Cancer 2002;9:860–8. [5] Ribeiro U Jr, Posner MC, Safatle-Ribeiro AV et al. Risk factors for squamous cell carcinoma of the oesophagus. Br J Surg 1996;83:1174–85. [6] Kuwano H, Nakajima M, Miyazaki T et al. Distinctive clinicopathological characteristics in esophageal squamous cell carcinoma. Ann Thorac Cardiovasc Surg 2003;9:6–13. [7] Dry SM, Lewin KJ. Esophageal squamous dysplasia. Semin Diagn Pathol 2002;19:2–11. [8] Znaor A, Brennan P, Gajalakshmi V et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 2003;105:681–6. [9] Ribeiro U Jr, Cecconello I, Safatle-Ribeiro AV et al. Squamous cell carcinoma of the esophagus and multiple primary tumors of the upper aerodigestive tract. Arq Gastroenterol 1999;36: 195–200. [10] Lu SH, Yang WX, Guo LP et al. Determination of N-nitrosamines in gastric juice and urine and a comparison of endogenous formation of Nnitrosoproline and its inhibition in subjects from

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

high- and low-risk areas for oesophageal cancer. IARC Sci Publ 1987;84:538–43. Khuroo MS, Zargar SA, Mahajan R et al. High incidence of oesophageal and gastric cancer in Kashmir in a population with special personal and dietary habits. Gut 1992;33:11–5. Li K, Yu P. Food groups and risk of esophageal cancer in Chaoshan region of China: a high-risk area of esophageal cancer. Cancer Invest 2003;21: 237–40. Jaskiewicz K, Marasas WF, Lazarus C et al. Association of esophageal cytological abnormalities with vitamin and lipotrope deficiencies in populations at risk for esophageal cancer. Anticancer Res 1988;8:711–5. Burrell RJ, Roach WA, Shadwell A. Esophageal cancer in the Bantu of the Transkei associated with mineral deficiency in garden plants. J Natl Cancer Inst 1966;36:201–9. Amer MH, El-Yazigi A, Hannan MA et al. Water contamination and esophageal cancer at Gassim Region, Saudi Arabia. Gastroenterology 1990;98:1141–7. Kaminski R, Geissert KS, Dacey E. Mortality analysis of plumbers and pipe fitters. J Occup Med 1980;22:183–9. Zhou XB, Guo M, Quan LP et al. Detection of human papillomavirus in Chinese esophageal squamous cell carcinoma and its adjacent normal epithelium. World J Gastroenterol 2003;9: 1170–3. Liu GT, Qian YZ, Zhang P et al. Etiological role of Alternaria alternata in human esophageal cancer. Chin Med J (Engl) 1992;105:394–400. Ghavamzadeh A, Moussavi A, Jahani M et al. Esophageal cancer in Iran. Semin Oncol 2001;28: 153–7. Castellsague X, Munoz N, De Stefani E et al. Influence of mate drinking, hot beverages and diet on

Tropical Hepatogastroenterology

REFERENCES

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

esophageal cancer risk in South America. Int J Cancer 2000;88:658–64. Ren A, Han X. Dietary factors and esophageal cancer: a case-control study. Zhonghua Liu Xing Bing Xue Za Zhi 1991;12:200–4. Chuong JJ, DuBovik S, McCallum RW. Achalasia as a risk factor for esophageal carcinoma. A reappraisal. Dig Dis Sci 1984;29:1105–8. Sandler RS, Nyren O, Ekbom A et al. The risk of esophageal cancer in patients with achalasia. A population-based study. JAMA 1995;274: 1359–62. Brucher BL, Stein HJ, Bartels H et al. Achalasia and esophageal cancer: incidence, prevalence, and prognosis. World J Surg 2001;25:745–9. Chino O, Kijima H, Shimada H et al. Clinicopathological studies of esophageal carcinoma in achalasia: analyses of carcinogenesis using histological and immunohistochemical procedures. Anticancer Res 2000;20:3717–22. Lehman MB, Clark SB, Ormsby AH et al. Squamous mucosal alterations in esophagectomy specimens from patients with end-stage achalasia. Am J Surg Pathol 2001;25:1413–8. Dunaway PM, Wong RK. Risk and surveillance intervals for squamous cell carcinoma in achalasia. Gastrointest Endosc Clin N Am 2001;11:425–34. Liu W, Fackler W, Rice TW et al. The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity. Am J Surg Pathol 2002;26:784–8. Isolauri J, Markkula H. Lye ingestion and carcinoma of the esophagus. Acta Chir Scand 1989;155:269–71. Appelqvist P, Salmo M. Lye corrosion carcinoma of the esophagus: a review of 63 cases. Cancer 1980;45:2655–8. Csikos M, Horvath O, Petri A et al. Late malignant transformation of chronic corrosive oesophageal strictures. Langenbecks Arch Chir 1985;365: 231–8. Kim YT, Sung SW, Kim JH. Is it necessary to resect the diseased esophagus in performing reconstruction for corrosive esophageal stricture? Eur J Cardiothorac Surg 2001;20:1–6.

Part I / Esophagus

31

[33] Wychulis AR, Gunnlaugsson GH, Clagett OT. Carcinoma occurring in pharyngoesophageal diverticulum: report of three cases. Surgery 1969;66: 976–9. [34] Tachibana M, Abe S, Yoshimura H et al. Squamous cell carcinoma of the esophagus after partial gastrectomy. Dysphagia 1995;10:49–52. [35] Hoffman RM, Jaffe PE. Plummer-Vinson syndrome. A case report and literature review. Arch Intern Med 1995;155:2008–11. [36] Risk JM, Evans KE, Jones J et al. Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer (TOC) locus. Oncogene 2002;21:6395–402. [37] Min S, Dong-Ping T, Xiao-Yun L et al. Four case reports of families with esophageal cancer in a high-risk region on the Guangdong Chaoshan coast of China. Dis Esophagus 2002;15: 257–61. [38] Finley RJ. Adenocarcinoma of the oesophagus and esophagogastric junction. In : Pearson FG, Cooper JD, Deslauriers J, Ginsberg RJ, Hiebert CA, Patterson GA, Urschel HC, eds. Oesophageal surgery. 2nd ed. New York: Churchill Livingstone, 2002, 725–734. [39] Shaheen NJ, Crosby MA, Bozymski EM et al. Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 2000;119:333–8. [40] Rudolph RE, Vaughan TL, Storer BE et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 2000;132:612–20. [41] Gadour M, Ayoola EA. Barrett’s esophagus: a review. Trop Gastroenterol 2002;23:157–61. [42] Schrump DS, Casson AG. Biology of oesophageal cancer. In: Pearson FG, Cooper JD, Deslauriers J, Ginsberg RJ, Hiebert CA, Patterson GA, Urschel HC, eds. Oesophageal surgery. 2nd ed. New York: Churchill Livingstone, 2002, 655–67. [43] Jankowski JA, Wright NA, Meltzer SJ et al. Molecular evolution of the metaplasia-dysplasiaadenocarcinoma sequence in the esophagus. Am J Pathol 1999;154:965–73.

32

Chapter 1 / CANCER OF THE ESOPHAGUS

[44] Rosa AR, Schirmer CC, Gurski RR et al. Prognostic value of p53 protein expression and vascular endothelial growth factor expression in resected squamous cell carcinoma of the esophagus. Dis Esophagus 2003;16:112–8. [45] Mukherjee T, Kumar A, Mathur M et al. Ets-1 and VEGF expression correlates with tumor angiogenesis, lymph node metastasis, and patient survival in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2003;129:430–436. [46] Jenkins GJ, Doak SH, Parry JM et al. Genetic pathways involved in the progression of Barrett’s metaplasia to adenocarcinoma. Br J Surg 2002;89:824–37. [47] Lewin KJ. Malignant and premalignant lesions of the esophagus. Keio J Med 1992;41:177–83. [48] Guanrei Y, He H, Sungliang Q et al. Endoscopic diagnosis of 115 cases of early esophageal carcinoma. Endoscopy 1982;14:157–61. [49] Liu CC, Fahn HJ, Li WY et al. Lymph node metastasis in squamous cell carcinoma of the intrathoracic esophagus. Zhonghua Yi Xue Za Zhi (Taipei) 1998;61:77–84. [50] Akiyama H, Tsurumaru M, Kawamura T et al. Principles of surgical treatment for carcinoma of the esophagus: analysis of lymph node involvement. Ann Surg 1981;194:438–46. [51] Yoshida M, Momma K. Endoscopic evaluation of the depth of invasion in cases of superficial esophageal cancer in determining indications for endoscopic mucosal resection. Nippon Geka Gakkai Zasshi 2002;103:337–42. [52] Nigro JJ, DeMeester SR, Hagen JA et al. Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 1999;117:960–8. [53] Rice TW, Zuccaro G Jr, Adelstein DJ et al. Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg 1998;65:787–92. [54] Kuwano H, Masuda N, Kato H et al. The subepithelial extension of esophageal carcinoma for determining the resection margin during esophagectomy: a serial histopathologic investigation. Surgery 2002;131:S14–21.

[55] Blewett CJ, Miller JD, Ramlawi B et al. Local recurrence after total or subtotal esophagectomy for esophageal cancer. J Exp Clin Cancer Res 2001;20:17–9. [56] Nakamura T, Ide H, Eguchi R et al. Clinical implications of lymph node micrometastasis in patients with histologically node-negative (pN0) esophageal carcinoma. J Surg Oncol 2002;79: 224–9. [57] O’Sullivan GC, Sheehan D, Clarke A et al. Micrometastases in esophagogastric cancer: high detection rate in resected rib segments. Gastroenterology 1999;116:543–8. [58] Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998;85:1457–9. [59] Siewert JR, Feith M, Werner M et al. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000;232:353–61. [60] Ichikura T, Ogawa T, Kawabata T et al. Is adenocarcinoma of the gastric cardia a distinct entity independent of subcardial carcinoma? World J Surg 2003;27:334–8. [61] Schroder W, Monig SP, Baldus SE et al. Frequency of nodal metastases to the upper mediastinum in Barrett’s cancer. Ann Surg Oncol 2002;9: 807–11. [62] Igaki H, Kato H, Tachimori Y et al. Prognostic evaluation of patients with clinical T1 and T2 squamous cell carcinomas of the thoracic esophagus after 3-field lymph node dissection. Surgery 2003;133:368–74. [63] Tabira Y, Kitamura N, Yoshioka M et al. Significance of three-field lymphadenectomy for carcinoma of the thoracic esophagus based on depth of tumor infiltration, lymph nodal involvement and survival rate. J Cardiovasc Surg (Torino) 1999;40:737–40. [64] Nigro JJ, Hagen JA, DeMeester TR et al. Prevalence and location of nodal metastases in distal esophageal adenocarcinoma confined to the wall: implications for therapy. J Thorac Cardiovasc Surg 1999;117:16–23.

Tropical Hepatogastroenterology

REFERENCES

[65] Eloubeidi MA, Desmond R, Arguedas MR et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002;95:1434–43. [66] Alexandrou A, Davis PA, Law S et al. Squamous cell carcinoma and adenocarcinoma of the lower third of the esophagus and gastric cardia: similarities and differences. Dis Esophagus 2002;15:290–5. [67] Osugi H, Takemura M, Takada N et al. Prognostic factors after oesophagectomy and extended lymphadenectomy for squamous oesophageal cancer. Br J Surg 2002;89:909–13. [68] Bonavina L, Incarbone R, Saino G et al. Clinical outcome and survival after esophagectomy for carcinoma in elderly patients. Dis Esophagus 2003;16:90–3. [69] Langley SM, Alexiou C, Bailey DH et al. The influence of perioperative blood transfusion on survival after esophageal resection for carcinoma. Ann Thorac Surg 2002;73:1704–9. [70] Rothwell JF, Feehan E, Reid I et al. Delay in treatment for oesophageal cancer. Br J Surg 1997;84:690–3. [71] Christein JD, Hollinger EF, Millikan KW. Prognostic factors associated with resectable carcinoma of the esophagus. Am Surg 2002;68:258–62. [72] Altorki NK, Migliore M, Skinner DB. Esophageal carcinoma with airway invasion. Evolution and choices of therapy. Chest 1994;106:742–5. [73] Akiyama H, Kogure T, Itai Y. The esophageal axis and its relationship to the resectability of carcinoma of the esophagus. Ann Surg 1972;176: 30–6. [74] Mariette C, Finzi L, Fabre S et al. Factors predictive of complete resection of operable esophageal cancer: a prospective study. Ann Thorac Surg 2003;75:1720–6. [75] Gupta S, Levine MS, Rubesin SE et al. Usefulness of barium studies for differentiating benign and malignant strictures of the esophagus. AJR Am J Roentgenol 2003;180:737–44. [76] Drudi FM, Trippa F, Cascone F et al. Esophagogram and CT vs endoscopic and surgical spec-

Part I / Esophagus

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

33

imens in the diagnosis of esophageal carcinoma. Radiol Med (Torino) 2002;103:344–52. Roth MJ, Guo-Qing W, Lewin KJ et al. Histopathologic changes seen in esophagectomy specimens from the high-risk region of Linxian, China: potential clues to an etiologic exposure? Hum Pathol 1998;29:1294–8. Dawsey SM, Fleischer DE, Wang GQ et al. Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China. Cancer 1998;83:220–31. Roth MJ, Liu SF, Dawsey SM et al. Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China. Cancer 1997;80:2047–59. Yang H, Berner A, Mei Q et al. Cytologic screening for esophageal cancer in a high-risk population in Anyang County, China. Acta Cytol 2002;46: 445–52. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93:1028–32. Shaheen NJ, Crosby MA, Bozymski EM et al. Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 2000;119:333–8. Weston AP, Sharma P, Topalovski M et al. Longterm follow-up of Barrett’s high-grade dysplasia. Am J Gastroenterol 2000;95:1888–93. Schnell TG, Sontag SJ, Chejfec G et al. Longterm nonsurgical management of Barrett’s esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607–19. Fleming ID, Cooper JS, Henson DE et al. Digestive system : Oesophagus. In : Flemming D, ed. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 1997, 65–69. Riedel M, Hauck RW, Stein HJ et al. Preoperative bronchoscopic assessment of airway invasion by esophageal cancer: a prospective study. Chest 1998;113:687–95.

34

Chapter 1 / CANCER OF THE ESOPHAGUS

[87] Schirmer CC, Osvaldt AB, Gurski RR et al. Efficacy of computed axial tomography in the evaluation of the involvement of the respiratory tract in patients with squamous cell carcinoma of esophagus. Dis Esophagus 1999;12:196–201. [88] Schroder W, Baldus SE, Monig SP et al. Lymph node staging of esophageal squamous cell carcinoma in patients with and without neoadjuvant radiochemotherapy: histomorphologic analysis. World J Surg 2002;26:584–7. [89] Hansen CP, Oskarsson K, Mortensen D. Computed tomography for staging of oesophageal cancer. Ann Chir Gynaecol 2000;89:14–8. [90] Wu LF, Wang BZ, Feng JL et al. Preoperative TN staging of esophageal cancer: comparison of miniprobe ultrasonography, spiral CT and MRI. World J Gastroenterol 2003;9:219–24. [91] Kato H, Kuwano H, Nakajima M et al. Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 2002;94: 921–8. [92] Yoon YC, Lee Ks, Shim Ym et al. Metastasis to regional lymph nodes in patients with esophageal squamous cell carcinoma: CT versus FDG PET for presurgical detection prospective study. Radiology 2003;227:764–70. [93] Kienle P, Buhl K, Kuntz C et al. Prospective comparison of endoscopy, endosonography and computed tomography for staging of tumors of the oesophagus and gastric cardia. Digestion 2002;66:230–6. [94] Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 1995;5:537–47. [95] Meining A, Dittler HJ, Wolf A et al. You get what you expect? A critical appraisal of imaging methodology in endosonographic cancer staging. Gut 2002;50:599–603. [96] Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion. Gastrointest Endosc 1997;45: 474–9.

[97] Osugi H, Nishimura Y, Takemura M et al. Bronchoscopic ultrasonography for staging supracarinal esophageal squamous cell carcinoma: impact on outcome. World J Surg 2003;27:590–4. [98] Koda Y, Nakamura K, Kaminou T et al. Assessment of aortic invasion by esophageal carcinoma using intraaortic endovascular sonography. AJR Am J Roentgenol 1998;170:133–5. [99] Krasna MJ, Reed CE, Nedzwiecki D et al. CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer. Ann Thorac Surg 2001;71:1073–9. [100] Krasna MJ, Jiao X, Mao YS et al. Thoracoscopy/laparoscopy in the staging of esophageal cancer: Maryland experience. Surg Laparosc Endosc Percutan Tech 2002;12:213–8. [101] Nozoe T, Kimura Y, Ishida M et al. Correlation of preoperative nutritional condition with postoperative complications in surgical treatment for oesophageal carcinoma. Eur J Surg Oncol 2002;28:396–400. [102] Avendano CE, Flume PA, Silvestri GA et al. Pulmonary complications after esophagectomy. Ann Thorac Surg 2002;73:922–6. [103] Czerny J. Neue operationen. Zentralbl Chir 1877;4:433. [104] Torek F. The first successful case of resection of the thoracic portion of the esophagus. Surg Gynaecol. Obstet 1913;16:614–617. [105] O’Rourke IC, Tiver K, Bull C et al. Swallowing performance after radiation therapy for carcinoma of the esophagus. Cancer 1988;61:2022–6. [106] Badwe RA, Sharma V, Bhansali MS et al. The quality of swallowing for patients with operable esophageal carcinoma: a randomized trial comparing surgery with radiotherapy. Cancer 1999; 85:763–8. [107] Fok M, Law SY, Wong J. Operable esophageal carcinoma: current results from Hong Kong. World J Surg 1994;18:355–60. [108] Kita T, Mammoto T, Kishi Y. Fluid management and postoperative respiratory disturbances in patients with transthoracic esophagectomy for carcinoma. J Clin Anesth 2002;14: 252–6.

Tropical Hepatogastroenterology

REFERENCES

[109] Tsutsumi K, Udagawa H, Kajiyama Y et al. Pulmonary thromboembolism after surgery for esophageal cancer: its features and prophylaxis. Surg Today 2000;30:416–20. [110] Aleksic M, Wolf B, Ulrich B. Results of surgical therapy of esophageal carcinoma in a general hospital. Chirurg 1995;66:1247–53. [111] Rao YG, Pal S, Pande GK et al. Transhiatal esophagectomy for benign and malignant conditions. Am J Surg 2002;184:136–42. [112] Kuwano H, Masuda N, Kato H et al. The subepithelial extension of esophageal carcinoma for determining the resection margin during esophagectomy: a serial histopathologic investigation. Surgery 2002 Jan;131(1 Suppl): S14–21. [113] Szanto I, Voros A, Nagy P et al. Esophageal intramural metastasis from adenocarcinoma of the gastroesophageal junction. Endoscopy 2002;34:418– 20. [114] Law S, Arcilla C, Chu KM et al. The significance of histologically infiltrated resection margin after esophagectomy for esophageal cancer. Am J Surg 1998;176:286–90. [115] Hulscher JB, van Sandick JW, Tijssen JG et al. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 2000;191: 143–8. [116] Chu KM, Law SY, Fok M et al. A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg 1997;174:320–4. [117] Goldminc M, Maddern G, Le Prise E et al. Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial. Br J Surg 1993;80:367–70. [118] Hulscher JB, Tijssen JG, Obertop H et al. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 2001;72:306–13. [119] Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor-Lewis oesophagectomy: is there a difference? Aust N Z J Surg 1999;69:187–94. [120] Altorki NK, Girardi L, Skinner DB. En bloc esophagectomy improves survival for stage III

Part I / Esophagus

[121]

[122]

[123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

35

esophageal cancer. J Thorac Cardiovasc Surg 1997;114:948–55. Hagen JA, Peters JH, DeMeester TR. Superiority of extended en bloc esophagogastrectomy for carcinoma of the lower esophagus and cardia. J Thorac Cardiovasc Surg 1993;106:850–8. Akiyama H, Tsurumaru M, Ono Y et al. Esophagectomy without thoracotomy with vagal preservation. J Am Coll Surg 1994;178:83–5. Isono K, Sato H, Nakayama K. Results of a nationwide study on the three-field lymph node dissection of esophageal cancer. Oncology 1991;48: 411–20. Nishimaki T, Suzuki T, Suzuki S et al. Outcomes of extended radical esophagectomy for thoracic esophageal cancer. J Am Coll Surg 1998;186:306– 12. Baba M, Aikou T, Yoshinaka H et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg 1994;219:310–6. Fujita H, Sueyoshi S, Tanaka T et al. Threefield dissection for squamous cell carcinoma in the thoracic esophagus. Ann Thorac Cardiovasc Surg 2002;8:328–35. Katayama A, Mafune K, Tanaka Y et al. Autopsy findings in patients after curative esophagectomy for esophageal carcinoma. J Am Coll Surg 2003;196:866–73. Akiyama H, Tsurumaru M, Udagawa H et al. Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 1994;220:364–72. Nishihira T, Hirayama K, Mori S. A prospective randomized trial of extended cervical and superior mediastinal lymphadenectomy for carcinoma of the thoracic esophagus. Am J Surg 1998;175:47–51. Dumont P, Wihlm JM, Hentz JG et al. Respiratory complications after surgical treatment of esophageal cancer. A study of 309 patients according to the type of resection. Eur J Cardiothorac Surg 1995;9:539–43. Baba M, Natsugoe S, Shimada M et al. Does hoarseness of voice from recurrent nerve

36

[132]

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

Chapter 1 / CANCER OF THE ESOPHAGUS

paralysis after esophagectomy for carcinoma influence patient quality of life? J Am Coll Surg 1999;188:231–6. Hulscher JB, van Sandick JW, de Boer AG et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662–9. Dutkowski P, Kneist W, Sultanow F et al. Adenocarcinoma of the esophagus: prognostic comparison between transthoracic esophageal resection with expanded 2-field lymph node dissection and trans-hiatal esophageal dissection with abdominal lymph node excision. Kongressbd Dtsch Ges Chir Kongr 2002;119:333–8. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy for treatment of benign and malignant esophageal disease. World J Surg 2001;25:196–203. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 1999;230:392–400. Casson AG, Darnton SJ, Subramanian S et al. What is the optimal distal resection margin for esophageal carcinoma? Ann Thorac Surg 2000;69:205–9. Draf W. The reconstruction of the hypopharynx and the cervical oesophagus. Laryngol Rhinol Otol (Stuttg) 1979;58:640–7. Ullah R, Bailie N, Kinsella J et al. Pharyngolaryngo-oesophagectomy and gastric pull-up for postcricoid and cervical oesophageal squamous cell carcinoma. J Laryngol Otol 2002;116:826–30. Fernando HC, Luketich JD, Buenaventura PO et al. Outcomes of minimally invasive esophagectomy (MIE) for high-grade dysplasia of the esophagus. Eur J Cardiothorac Surg 2002;22:1–6. Whooley BP, Law S, Alexandrou A et al. Critical appraisal of the significance of intrathoracic anastomotic leakage after esophagectomy for cancer. Am J Surg 2001;181:198–203. Chasseray VM, Kiroff GK, Buard JL et al. Cervical or thoracic anastomosis for esophagectomy for carcinoma. Surg Gynecol Obstet 1989;169:55–62. Manjari R, Padhy AK, Chattopadhyay TK. Emptying of the intrathoracic stomach using three

[143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

different pylorus drainage procedures–results of a comparative study. Surg Today 1996;26:581–5. Chattopadhyay TK, Gupta S, Padhy AK et al. Is pyloroplasty necessary following intrathoracic transposition of stomach? Results of a prospective clinical study. Aust N Z J Surg 1991;61:366–9. Urschel JD, Blewett CJ, Young JE et al. Pyloric drainage (pyloroplasty) or no drainage in gastric reconstruction after esophagectomy: a metaanalysis of randomized controlled trials. Dig Surg 2002;19:160–4. Sinha S, Padhy AK, Chattopadhyay TK. Dumping syndrome in the intra-thoracic stomach. Trop Gastroenterol 1997;18:131–3. Katariya K, Harvey JC, Pina E et al. Complications of transhiatal esophagectomy. J Surg Oncol 1994;57:157–63. Amar D, Burt ME, Bains MS et al. Symptomatic tachydysrhythmias after esophagectomy: incidence and outcome measures. Ann Thorac Surg 1996;61:1506–9. Casson AG, Porter GA, Veugelers PJ. Evolution and critical appraisal of anastomotic technique following resection of esophageal adenocarcinoma. Dis Esophagus 2002;15:296–302. Urschel JD, Urschel DM, Miller JD et al. A metaanalysis of randomized controlled trials of route of reconstruction after esophagectomy for cancer. Am J Surg 2001;182:470–5. Law S, Fok M, Chu KM et al. Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial. Ann Surg 1997;226:169–73. Shad SK, Gupta S, Chattopadhyay TK. Selfdilatation of cervical oesophagogastric anastomotic stricture: a simple and effective technique. Br J Surg 1991;78:1254–5. Sykes AJ, Burt PA, Slevin NJ et al. Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery. Radiother Oncol 1998;48:15–21. Ahmed HF, Hussain MA, Grant CE et al. Closure of tracheoesophageal fistulas with chemotherapy and radiotherapy. Am J Clin Oncol 1998;21:177–9.

Tropical Hepatogastroenterology

REFERENCES

[154] Muto M, Ohtsu A, Miyamoto S et al. Concurrent chemoradiotherapy for esophageal carcinoma patients with malignant fistulae. Cancer 1999;86:1406–13. [155] Singh RK, Parida DK, Mohanti BK et al. Preoperative radiotherapy for squamous cell carcinoma of the oesophagus – reopening the debate: Results from a north Indian center. Int J Surg Investig 2001;3:401–6. [156] Ou GF, Wang M, Wang LH et al. Relation between pathologic tumor response to preoperative radiotherapy and the prognosis in patients with esophageal carcinoma. Zhonghua Zhong Liu Za Zhi 2003;25:278–81. [157] Arnott SJ, Duncan W, Gignoux M et al. Preoperative radiotherapy in esophageal carcinoma: a metaanalysis using individual patient data (Oesophageal Cancer Collaborative Group). Int J Radiat Oncol Biol Phys 1998;41:579–83. [158] Xiao ZF, Yang ZY, Liang J et al. Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients. Ann Thorac Surg 2003;75:331–6. [159] Kelsen DP, Ginsberg R, Pajak TF et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979–84. [160] Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33. [161] Urba SG, Orringer MB, Turrisi A et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19: 305–13. [162] Bosset JF, Gignoux M, Triboulet JP et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161–7. [163] Walsh TN, Noonan N, Hollywood D et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462–7.

Part I / Esophagus

37

[164] Suntharalingam M, Moughan J, Coia LR et al. 1996-1999 Patterns of Care Study. The national practice for patients receiving radiation therapy for carcinoma of the esophagus: results of the 19961999 Patterns of Care Study. Int J Radiat Oncol Biol Phys 2003;56:981–7. [165] Wilson KS, Lim JT. Primary chemo-radiotherapy and selective oesophagectomy for oesophageal cancer: goal of cure with organ preservation. Radiother Oncol 2000;54:129–34. [166] Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623–7. [167] Smith TJ, Ryan LM, Douglass HO Jr et al. Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 1998;42:269–76. [168] Wong RK, Malthaner RA, Zuraw L et al. Cancer Care Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease Site Group. Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline. Int J Radiat Oncol Biol Phys 2003;55:930–42. [169] Ko GY, Song HY, Hong HJ et al. Malignant Esophagogastric Junction Obstruction: Efficacy of Balloon Dilation Combined with Chemotherapy and/or Radiation Therapy. Cardiovasc Intervent Radiol 2003;26:141–5. [170] O’Rourke IC, McNeil RJ, Walker PJ et al. Objective evaluation of the quality of palliation in patients with oesophageal cancer comparing surgery, radiotherapy and intubation. Aust N Z J Surg 1992;62:922–30. [171] Whooley BP, Law S, Murthy SC et al. The Kirschner operation in unresectable esophageal cancer: current application. Arch Surg 2002;137: 1228–32. [172] Maydeo AP, Bapaye A, Desai PN et al. Endoscopic placement of indigenous plastic esophageal endoprostheses–does it still have a role in the era of

38

Chapter 1 / CANCER OF THE ESOPHAGUS

expandable metallic stents? A prospective Indian study in 265 consecutive patients. Endoscopy 1998;30:532–7. [173] Dormann AJ, Eisendrath P, Wigginghaus B et al. Palliation of esophageal carcinoma with a new self-expanding plastic stent. Endoscopy 2003;35: 207–11. [174] Ell C, May A. Self-expanding metal stents for palliation of stenosing tumors of the esophagus and cardia: a critical review. Endoscopy 1997;29: 392–8.

[175] Saidi RF, Marcon NE. Nonthermal ablation of malignant esophageal strictures. Photodynamic therapy, endoscopic intratumoral injections, and novel modalities. Gastrointest Endosc Clin N Am 1998;8:465–91. [176] Reed CE. Endoscopic palliation of esophageal carcinoma. Chest Surg Clin N Am 1994;4: 155–72. [177] Hofstetter W, Swisher SG, Correa AM et al. Treatment outcomes of resected esophageal cancer. Ann Surg 2002;236:376–84.

Tropical Hepatogastroenterology

Chapter

2

CORROSIVE INJURIES OF THE ESOPHAGUS AND STOMACH N Ananthakrishnan

2.1 EPIDEMIOLOGY Corrosive strictures are by far the most common cause of benign esophageal obstruction in India. Over the last 20 years, our centre has treated over 300 patients with corrosive upper alimentary tract injuries. Eighty-five patients have been surgically treated for chronic gastric injuries, and 90 patients have had an esophagocoloplasty. During this period there have been 26 patients with acute injuries requiring emergency resection. Abroad, most corrosive injuries occur due to accidental ingestion, and children, particularly in low socioeconomic groups, account for over four-fifths of cases.[1] In the United Kingdom, of 40,000 pediatric poisoning occurring per year, one-third are due to household goods.[2–4] Most children are younger than 10 years.[5–7] In India, however, the victims are usually adults as suicidal intent is more common than accidental. In a personal series of our 300 patients seen over 20 years, only 3 were less than 5 years of age and only 10 less than 15 years of age. Most series report a varying male preponderance.[3, 5, 6, 8] However, in our experience, more than 60% were women. The chemicals that are most commonly responsible are alkalis such as potassium and sodium hydroxide.[9, 10] Acids come next, particularly

TABLE fy 2.1 Chemicals commonly responsible for corrosive injuries • • • • • • • • • • •

Alkalis (KOH, NaOH)[9, 10] Acids (HCl, H2 SO4 )[6, 8] Dettol liquid[11] Chlorine[12] Ammonia[12] Decalcifier (formic acid)[12] Washing machine detergent (metasilicates)[12] Ferrous sulphate[13] Bleaching agent with sodium hypochlorite[14] Bathroom cleaning acid (HNO3 ) Aqua regia (HCl + HNO3 )[15]

hydrochloric[8] and sulphuric acid.[6] Several other chemicals may be involved (Table 2.1).[11–15] Alkaline agents account for over 90% of corrosive injuries abroad,[7] whereas over 75% of injuries in India are due to acid.[16] The acid is usually either bathroom cleaning acid, or goldsmith acid, both of which are easily available.[16]

2.2 PATHOPHYSIOLOGY[15] The pathophysiological changes seen in corrosive alimentary tract injuries are similar to those seen after thermal burns. Burns are classified likewise into three degrees.[17] First-degree burns 39

40

Chapter 2 / CORROSIVE INJURIES OF THE ESOPHAGUS AND STOMACH

manifest as superficial mucosal hyperemia, edema, or superficial ulcers. They usually heal without scarring. Second-degree burns are transmural injuries involving all layers of the esophagus. There is exudation and extensive ulceration. Healing results in stricture. Third-degree burns involve periesophageal tissues including mediastinum, pleura and peritoneum. Early resectional surgery is necessary to salvage life. The extent of damage depends on the substance ingested, the concentration, the amount, whether ingested in solid or liquid form, and contact time with mucosa. Alkaline agents cause injury by liquefaction necrosis. They are viscous, adhere to the esophageal mucosa, and are not cleared by peristalsis to the stomach. Esophageal contact time is, therefore, long, and depth of injury greater. The stomach is often spared, since not enough agent reaches the stomach, and the little that reaches is neutralized by gastric acid. On the other hand, acidic agents cause coagulation necrosis leaving eschars. Esophageal peristalsis quickly clears them into the stomach where they induce pylorospasm, thus leading to prolonged contact with the prepyloric mucosa, and resulting in prepyloric strictures. Corrosive gastric strictures are usually 2–3 cm long with considerable thickening of the mucosa proximal to it. They are not amenable to strictureplasty.

agents may not produce symptoms. Severity of symptoms, or presence or absence of oral ulceration, does not predict severity of esophageal or gastric injury.[19–23] In case of aspiration of the agent, there may be hoarseness, stridor, or dyspnea.[18] Massive hematemesis is rare, although mild transient hematemesis may occur.[18] Transmural injury produces chest pain, signs of pleural gas, or pleural effusion in case of thoracic complications, or signs of peritonitis in case of intra-abdominal injury. Ten percent to thirty-three percent of patients with corrosive injuries progress to stricture.[24] Early strictures appearing within 8 weeks progress rapidly, while those appearing after this period progress slowly.[25]

2.4 INVESTIGATIONS Endoscopy (Fig. 2.1). Endoscopy remains the mainstay of diagnosis. Sixty percent to eighty percent of patients with caustic ingestion may not have esophageal injury,[26] or there may be esophageal injury without oral ulceration.[5] Especially with alkalis, there is no correlation between oral injury

2.3 CLINICAL FEATURES Symptoms depend on the agent ingested, its concentration, and quantity.[18] Clinical features include vomiting, odynophagia, drooling of saliva, and evidence of labial or lingual ulceration.[1] Perioral blackening due to cutaneous burns is often present. Early dysphagia is due to edema of the cricopharynx. Ingestion of mild corrosives or very small quantity of dilute

FIGURE 2.1 Endoscopic appearance of an esophageal stricture. Note the scarring and ulceration.

Tropical Hepatogastroenterology

INVESTIGATIONS

and esophageal or gastric injury.[26, 27] Although there are differences of opinion, the consensus is towards early endoscopy after injury to assess the extent of damage. A thin pediatric esophagoscope is used, and it is wise to screen the whole esophagus, although some endoscopists advocate stopping at the most proximal limit of injury.[28] Early endoscopy without undue distension is relatively safe.[18] Our policy is to do endoscopy 2–5 days after injury. Earlier than this, one may see only hyperemia, and treat the injury as a lesser grade. Ulceration, on the other hand, may develop few days later. Endoscopy is not recommended between 5–15 days after ingestion due to the risk of perforation.[18] The endoscopic procedure in all instances should be followed by skiagrams of the neck, chest and abdomen to detect signs of perforation. It should be mentioned that there are endoscopists who oppose early endoscopy due to the risk of perforation.[29, 30] Recently, endoscopic ultrasound using a 20 MHz probe has been advocated for diagnosis of depth of esophageal injury.[31] Radiological investigations in the form of a contrast study are of limited use in the early phase. In established strictures, endoscopy may not reveal the number, length or extent of the stricture, and a barium study is useful for this purpose (Fig. 2.2). If sufficient barium reaches the stomach, delayed films can be done to rule out gastric outlet obstruction. In our centre, we have found that, in patients with established impassable esophageal strictures, a gastric fluid level on a plain erect abdominal skiagram, after overnight fasting, is an absolute indicator of gastric outlet obstruction. Preoperative angiograms have been advocated for assessment of colonic vasculature prior to bypass.[32, 33] We have not found this to be necessary or of any use. Colonic vascularity is best assessed intraoperatively. Some surgeons have used intraoperative Doppler for this purpose.[32]

Part I / Esophagus

41

FIGURE 2.2 Barium swallow in a patient with a benign stricture showing smooth narrowing with proximal dilatation. (Courtesy: Diwan Chand Satya Pal Aggarwal X-ray Clinic.)

2.4.1 Endoscopic Grading of Esophageal Injuries[34] Grade I

: Inflammation of the mucosa, hyperemia and edema but not ulceration. These heal uneventfully. Grade IIA : Ulceration of the mucosa with slight hemorrhage. Grade IIB : Limited or circular necrosis. Grade III : Extensive necrosis, involving the whole organ with massive hemorrhage. The submucosa is involved and healing may take several months. Grade IV : All characteristics of Grade II plus metabolic acidosis and/or DIC. Zargar and Kochhar have modified this grading as follows:[35]

42

Chapter 2 / CORROSIVE INJURIES OF THE ESOPHAGUS AND STOMACH

Grade IIA : Friability, hemorrhages, erosions, blisters, exudates and superficial ulcers. Grade IIB : IIA plus deep discrete or circumferential ulcers. Grade IIIA : Grade II plus scattered areas of necrosis (blackened mucosa). Grade IIIB : Grade II plus extensive necrosis. Grade I and IIA recovered uneventfully while 71% of Grade IIB and 100% of survivors of Grade III developed strictures.

2.5 COEXISTENT GASTRIC AND ESOPHAGEAL INJURY It is not uncommon to find both gastric and esophageal involvement, especially after ingestion of acids. In a personal series of over 170 surgically treated patients with corrosive injuries of the upper alimentary tract, concomitant gastric and esophageal involvement severe enough to warrant surgery for both organs was seen in approximately a third of patients. In a series of 80 patients with corrosive gastric stricture, Popovici found concomitant esophageal stricture in 78.8%.[36] Chaudhary et al. found combined esophageal and gastric stricture in 53% of patients.[37] The varying frequency of association is probably a reflection of the type of corrosive ingested in different regions.

2.6 SITE OF STRICTURE Fibrotic strictures occur at points of normal narrowing of the esophagus, viz. at the cricopharynx, at the crossing of the arch of the aorta and the gastroesophageal junction. Unlike peptic strictures, which are restricted to the lower esophagus, corrosive strictures are more often long and involve a considerable portion of the esophagus.

In the stomach, the stricture is most often in the prepyloric region since the corrosive agent causes pylorospasm with consequent pooling of the corrosive in the prepyloric segment. Rarely, the stricture in the stomach may be midgastric. This was seen in only 3 of 85 gastric strictures seen by us. Duodenal strictures are rare since very little of the agent escapes beyond the pylorus, unless ingested in large quantities. It is our experience that hesitant sipping of the corrosive agent with suicidal intent more often causes cricopharyngeal stricture, whereas accidental swallowing in large gulps involves the mid and lower esophagus. In a study of 75 patients, Wu and Lai found the hypopharynx to be involved in 14.7%, the cervical esophagus in 16%, and the thoracic esophagus in 56% of patients.[8]

2.7 COMPLICATIONS OF CORROSIVE INJURIES Several complications other than perforation and stricture formation may occur after corrosive ingestion. Acute complications include mediastinitis (20%), esophageal perforation (15%), gastric perforation (10%), peritonitis (15%), laryngeal edema (6%) and pneumonia (14%).[4] Perforation leading to mediastinitis is a slowly progressive condition, and presents after few days of ingestion.[18] Early perforations occur after ingestion of large quantities of corrosive, generally alkali abroad, or acid in India. Upper gastrointestinal hemorrhage may occur in a few patients. Mortality in the acute phase is due to shock and septicemia, and is seen in 5%–15% of patients.[27, 28, 38] In a series of over 2267 cases seen over 20 years, Postlethwait reported a mortality of 13.6%.[38] In our experience of over 300 patients, mortality rate was less than 10%. In another study, the overall mortality was 21%, but was 56% for those with a third degree injury.[39]

Tropical Hepatogastroenterology

COMPLICATIONS OF CORROSIVE INJURIES

Other complications include tracheoesophageal or aortoesophageal fistula,[40] and multiple intramural diverticulosis involving the whole esophagus or the upper half.[41] The latter condition makes blind dilatation hazardous. The diverticula tend to disappear after guided dilatation. Superinfection with candida may occur.[42] Chronic complications include fibrotic stricture, which may take several weeks to develop,[18] and malignant change. Corrosive gastric cicatrization occurs in about a third of patients in our experience, although others have reported a lower incidence of about 2%.[28] This difference is because most corrosive injuries abroad are due to lye which predominantly involves the esophagus, while in India acid ingestion is much more common. Corrosive induced gastric outlet obstruction usually precedes esophageal stenosis. Occasionally, they may present simultaneously. In our experience, in about 5% of patients the gastric obstruction presents several months after the esophageal obstruction. A rare event of hiatal hernia due to shortening of the injured esophagus has also been reported.[10]

2.7.1 Malignant Change Fear of malignant change is the primary indication for esophagectomy after corrosive injuries. The risk of malignancy is about 2.4%, which is one thousand-fold that seen in the general population.[43, 44] Others have mentioned a smaller risk of 22–100 times the expected risk of cancer,[22, 45] Ti, and Joske and Benedict reported an incidence of malignant change of 4%–5.2%.[45, 46] Incidence of carcinoma after a corrosive burn constitutes 0.85%[47] to 7.2% of all esophageal cancers.[48] The average time interval between ingestion and cancer is about 40 years,[18] although esophageal cancer has been reported in a 15 year old patient with the history of corrosive ingestion.[43] In

Part I / Esophagus

43

children the lag period is longer.[48] Most of the cancers are resectable, and the long-term prognosis after resection is good.[43, 49] A younger age at diagnosis, early diagnosis due to early onset of symptoms and limitation of spread by scar lesions are the reasons for the relatively good prognosis.[43] However, this applies only when the esophagus remains the food conduit. Malignant change in a bypassed esophagus is difficult to detect. Nevertheless, it has been suggested that the risk of cancer occurs only in a functional esophagus.[50] The long-term complications of acid ingestion on the stomach are not well documented, and it is not known whether there is a risk of development of gastric carcinoma.[4] Though there are a few reports of squamous metaplasia and gastric cancer in patients with a history of caustic ingestion, the etiological relationship is not well established.[51, 52] Resection of the esophagus obviates the risk of malignant change, mucocele, abscess formation, or rupture of an esophagus which is closed at both ends due to stricture.[53] However, the technical hazards of resection of a scarred esophagus (e.g., injury to adjacent structures, hemorrhage, thoracic duct injury, and consequences of vagotomy) far outweigh the benefits of resection.[54] Use of stomach for esophageal bypass mandates esophagectomy, whereas esophagocoloplasty can be done leaving an in situ esophagus.

2.7.2 Mucocele of the Esophagus Cystic dilatation of the retained esophageal segment between two strictures was reported in 8 out of 15 patients in one study.[55] Mannell and Epstein found mucoceles in 20 out of 89 patients.[56] In 19 of these, it remained asymptomatic. Occasionally, it can be large enough to cause pressure symptoms. However, cystic dilatation occurs only when there are islands of normal esophageal mucosa, and

44

Chapter 2 / CORROSIVE INJURIES OF THE ESOPHAGUS AND STOMACH

is not common when the mucosa is extensively damaged by the corrosive agent.

2.8 PREVENTION OF COMPLICATIONS Once the acute injury has occurred, strictures must be prevented, especially in deep injuries. The incidence of stricture formation is between 0.5% and 5.3% in children.[57, 59] Development of a stricture after corrosive injury takes about 4–6 weeks.[18] The ideal method of preventing synechiae, or complete obstruction of the lumen is to leave a nasogastric tube for 6–8 weeks. Even when stenosis occurs, this procedure leaves a dilatable passage. This practice is followed by us, and has been advocated by others.[60] Oral feeding as tolerated also prevents synechiae and total obstruction, besides preventing stenosis in superficial injuries. Recent studies have shown that application of topical agents such as mitomycin-C has prevented restenosis after dilatation of laryngeal and tracheal stenosis.[61] This approach has been tried in corrosive injuries in a child with encouraging results.[62] Animal studies have shown that other topical agents such as pentoxifylline and interferon-α may reduce stricture formation after corrosive injury.[63]

2.9 ACUTE INJURIES AND INITIAL TREATMENT The early management of corrosive injuries is conservative. Emergency surgery is required if the patient has transmural injury with mediastinitis, peritonitis, or massive hemorrhage. In this situation the patient needs resection of the esophagus, stomach, or both. In these critically ill patients, it is safer to close the duodenal stump, and bring out the proximal esophagus as an esophagostomy, and leave reconstruction to a second stage.

Airway obstruction due to laryngeal edema may occur, and requires intubation or tracheostomy.[25] Induction of emesis and gastric lavage are dangerous. Small sips of water may wash the residual corrosive agent away. In our experience, endoscopy is best postponed to three to four days after injury to diminish risks of perforation. At this time, the passage of a thin nasogastric tube after endoscopy prevents synechiae and ensures a dilatable tract, should stricture formation occur. Makela et al. and others, report an alternate approach of early endoscopy and immediate surgery for Grade III injuries.[64–66]

2.9.1 Corticosteroids Howell and colleagues reviewed the role of steroids and antibiotics in detail from 13 published series of 361 patients.[67] The role of steroids in preventing strictures after corrosive ingestion is controversial. Animal and human studies have shown conflicting results.[24, 28, 29, 49, 58, 68] A recent prospective study in children showed no benefits from prednisolone at doses of 2–2.5 mg/day for 3 weeks and tapering doses for 2–3 weeks.[49] Steroids are not needed in Grade I injuries and are not useful in Grade III.[18] Since efficacy in Grade II is doubtful and side effects are significant, steroids should have no role in the management of corrosive injuries.[18] The role of antibiotics is less controversial. Transmural infection is common after corrosive injuries, and a course of broad spectrum antibiotics is beneficial.

2.9.2 Stents Stents may prevent primary stenosis or restenosis after dilatation, but reports are few.[4, 18, 69, 70] Hill et al. found the procedure useful in 3 patients.[69] However, they did not recommend

Tropical Hepatogastroenterology

ACUTE INJURIES AND INITIAL TREATMENT

45

more widespread use until more experience was gained. Several other studies have also recommended stenting of the damaged esophagus with silastic or silicone tubes.[71–74] This approach is, however, not universally accepted, and has led to serious complications requiring esophagectomy. On occasions corrosive injury can lead to an esophagotracheal or esophagocarinobronchial fistula. We have managed these adequately using covered self-expanding stents.

2.9.3 Dilatation Dilatation is undoubtedly the primary modality of treatment for corrosive strictures. However, corrosive strictures are often multiple, tortuous, and involve a long segment unlike peptic strictures. Broor et al. reported on a series of 123 patients of esophageal strictures. Of these, 33 were peptic and 36 were corrosive. Initial success rates of 93.6% for corrosive strictures were comparable to 100% for peptic strictures. However, on follow up, the mean number of symptomatic recurrences per patient per month in the corrosive group was 0.27 versus 0.07 in the peptic group. At 36 months, the recurrence rate was not significantly different.[75] Dilatation is considered to be successful if a lumen of at least 15 Fr can be maintained. The two current methods of dilatation are inflatable balloons and Savary–Gilliard over-the-wire dilators (Fig. 2.3). Both are safely done using a ‘C’ arm and image intensification. The balloon exerts a radial pressure, whereas with Savary– Gilliard the pressure is initially axial. A recent study comparing the two methods concluded that both were effective, though Savary–Gilliard dilators were slightly easier to use.[76] The authors recommended use of balloon dilators initially for high cervical strictures or multiple strictures, and thereafter the Savary–Gilliard.[76] Blind-use

Part I / Esophagus

FIGURE 2.3 Savary-Gilliard bougies (above) and a balloon dilator set (below).

dilators like Eder–Puestow, Tucker’s, or Hurst bougies are obsolete. Initial response to dilatation is good. Long-term efficacy drops.[77, 78] However, recurrences can be managed successfully by re-dilatation.[78] In one study, 49.3% of patients responded to dilatation of less than 1 year duration. However, 50.7% required it for more than 1 year, 32.9% for more than 2 years, 26.7% for more than 3 years and 15.4% for more than 4 years.[3] This is the main disadvantage as compared to surgery for long, tortuous, or multiple strictures, since cure is achieved more rapidly with surgery. Dilatation is best started after about 6 weeks. Initially, the process may be repeated weekly till a lumen of at least 15 F is obtained. Thereafter, monthly dilatations may be required till about 6 months. Frequency of further dilatation depends on when the lumen stabilizes. For difficult cases, a retrograde dilatation through a gastrostomy may be safer.[79, 80] Antegrade dilatation over a string through a cervical

46

Chapter 2 / CORROSIVE INJURIES OF THE ESOPHAGUS AND STOMACH

esophagostomy or per orally is also possible.[81] These are only required in exceptional situations. For high short segment cervical strictures, selfdilatation has also been advocated[82, 83] with good results. In studies in children, dilatation followed by topical mitomycin has reduced recurrence rates.[61, 62] Although excellent results have been reported from India,[75, 84] long-term results are poorer than with surgical bypass. Objective criteria are required for assessing long-term results of surgery and dilatation. One such method devised in our center has been published elsewhere, and is shown in Table 2.2. With these criteria overall good-to-excellent results were obtained in 95.0% of surgical patients as opposed to only 52.4% of patients on dilatation.[15] In view of these findings, more patients are now offered early surgery. With current methods of dilatation, perforation is uncommon, and is less than 1% in good hands.[75] A cervical perforation presents as TABLE fy 2.2 Criteria for functional grading Ranking Criteria

Excellent

Good

Fair

Dysphagia

Nil

Nil

To solids

Weight loss

Nil

Nil

+

Other symptoms Fullness Belching Heart burn Diarrhea

Poor To liquids and solids ++

subcutaneous emphysema. Thoracic and abdominal perforations show up on plain skiagrams as mediastinal gas, pleural fluid, or pneumothorax on chest X-ray, and pneumoperitoneum on erect abdominal skiagrams. Occasionally, water soluble contrasts may be required to confirm perforations. Small perforations often heal after adequate pleural drainage when the distal lumen is open. However, a perforation proximal to a stricture seldom heals, and requires esophagectomy. Abdominal esophageal perforations always require surgery, either a closure of the perforation, or a Thal type of gastric patch.

2.10 SURGICAL TREATMENT 2.10.1 Preoperative Preparation Although gastrostomy has been advocated for preoperative nutritional correction,[1] a jejunostomy is better. A preoperative gastrostomy causes fixation of the stomach, and may preclude its use for esophageal bypass later on. Also, a proportion of patients with esophageal injury will concomitantly have or develop gastric outlet obstruction, subsequently contraindicating a gastrostomy. The creation of a lateral esophagostomy facilitates dilatation of a cricopharyngeal stricture. Once this has been corrected, the esophagostomy can be enlarged and used for the esophagocolic bypass.

2.10.2 Surgical Procedures for Esophageal Strictures Nil

+

+

Barium swallow

Free

Free

Mild stasis

Dilatations

None

None

+ Marked stasis

Infrequent Frequent (>3 monthly) ( 20 mmHg). Transient LES relaxations occur independently of swallowing, are not accompanied by peristalsis, but by diaphragmatic inhibition, and persist for longer periods than do swallowinduced LES relaxations (> 10 seconds). Prolonged manometric recordings have not demonstrated an increased frequency of transient LES relaxation in GERD patients compared to normal controls. The frequency, however, of acid reflux (as opposed to gas reflux) during transient LES relaxations is greater in GERD patients. The antireflux barriers are imperfect by design to allow swallowed material to enter the stomach, and to permit the nesting of gas (belch reflux) from a distended stomach. When the LES relaxes reflexively through a long vasovagal pathway to permit gas venting, the phenomenon is called a transient LES relaxation (TLESR).[26] Indeed TLESRs account for almost all episodes of acid reflux in healthy subjects and the large majority of reflux events in patients with nonerosive disease. Patients with reflux esophagitis, in general, have more reflux episodes than do healthy subjects,[27] indicating that impaired antireflux barrier function is an important factor in the development of disease. Moreover, the episodes accounting for pathologic reflux have been associated with 1 of 3 LES phenomena: (1) incompetence of LES, (2) increased intraabdominal pressure transients across a low pressure LES, and (3) increased frequency of TLESRs.

62

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

The major cause for the frequent TLESRs in GERD is unclear. Abnormalities of the stomach that could cause an increase in TLESRs, at least theoretically, are delayed gastric emptying, resulting in gastric distension, or gastric inflammation, causing increased sensitivity to normal degrees of gastric distension. The dominant stimulus for transient LES relaxation is distension of proximal stomach, not surprising, given that transient LES relaxation is the physiological mechanism for belching. The degree to which TLESR frequency is augmented by gastric distension is directly related to the size of hiatal hernia suggesting that the associated anatomical alteration affects the function of the afferent mechanoreceptors believed responsible for eliciting this reflex. The transient relaxation reflex is abolished by vagotomy.

3.3.2 Hiatal Hernia The maintenance of esophagogastric junction (EGJ) competence is suggested to be the function of two sphincters. Both intrinsic smooth muscle LES and extrinsic crural diaphragm serve the sphincter function, and have separate nerve supply. During belching and vomiting, selective inhibition of electrical activity of crural diaphragm can be demonstrated, though the respiration is continuing. The crural diaphragmatic contraction is augmented during abdominal compression, straining, and coughing. An anatomical disruption occurs when the esophagogastric junction is axially placed, i.e., higher than the crural hiatal canal indentation, causing herniation of a part of stomach in to the thorax. This, in turn, leads to potential loss of the functions of the EGJ. The components of EGJ, viz. extrinsic compression of

LES by crural diaphragm, acute angle of His with its flap-valve mechanism, and the intrinsic smooth muscle contraction induced LES pressure zone are compromised. This leads to disruption of antireflux barrier function of EGJ. This increases the susceptibility and magnitude of gastroesophageal reflux events, both in quantity and quality of reflux material. Also, the clearance of refluxed material from distal esophagus is hampered. Of the various physiologic and anatomical variables tested, the size of hiatal hernia has been reported to have the highest correlation with the susceptibility to strain induced reflux events. Another impact of hiatal hernia on antireflux barrier is the diminished intraluminal pressure within EGJ as compared to normal individuals. It also reduces the length of EGJ high-pressure zone to less than 2 cm. It has been observed that the proportion with which the EGJ opens is directly related to the diameter of hiatal hernia. All the anatomical and physiological alterations produced by hiatal hernia impair the resistance of the EGJ. It results in increased esophageal acid exposure, and more frequent TLESRs associated with postprandial gastric distension, during periods with low LES pressure, straining, and swallowing. This causes occurrence of more severe esophagitis in patients with hiatal hernia.

3.3.3 Gastroesophageal Flap Valve The positioning of distal esophagus in the intraabdominal cavity is responsible for another barrier function of EGJ. A flap valve is formed by musculomucosal folds created by the entry of the esophagus into the stomach along the lesser curvature, producing an acute angle of His. Increased intra-abdominal or intragastric pressure decreases the angle of His, and compresses the

Tropical Hepatogastroenterology

FUNCTIONAL CONSTITUENTS OF THE ESOPHAGOGASTRIC JUNCTION

sub-diaphragmatic portion of esophagus, thereby preventing reflux during periods of abdominal straining. Grade 1 — Normal ridge of tissue closely approximated to the shaft of the retroflexed scope Grade 2 — The ridge is slightly less well defined and opens with respiration Grade 3 — The ridge is barely present and the hiatus is patulous. Grade 4 — There is no muscular ridge and the hiatus is wide open at all times. The presence of a hiatal hernia disrupts the gastroesophageal flap valve. This results in increased reflux episodes. With increasing disruption of the flap valve associated with hiatal hernia, there is an increase in the angle of His, and subsequently no sub-diaphragmatic segment of esophagus remains. The second tier of defense is the luminal clearance mechanisms, which protect after a bout of reflux by limiting the duration of contact between refluxed gastric contents, and the esophagus. Currently four factors contribute to luminal clearance. Two factors – gravity and esophageal peristalsis – handle bolus clearance, and after bolus clearance reduces refluxate volume to about 1 ml. Two factors – salivary and esophageal gland secretions – handle clearance of luminal acidity.[28] Salivary and esophageal gland secretions are effective for luminal acid clearance because both secretions are rich in bicarbonate for HCl neutralization. There is no difference in bolus clearance between GERD patients and healthy subjects, and there is no difference in salivary secretion between the two groups.[29] Nonetheless, a variety of abnormalities that delay acid clearance have been identified in GERD, including: (1) lower amplitude peristaltic contractions, (2) greater frequency of aperistaltic

Part I / Esophagus

63

contractions, (3) greater numbers of failed contractions on swallowing as compared to healthy subjects, and (4) early retrograde reflux in patients with nonreducing hiatal hernias.[28, 30] By delaying luminal acid clearance, these abnormalities, combined with defects in the antireflux mechanisms, can account for the prolonged exposure of the esophagus to acid, as identified on pH monitoring. The third tier of defense is tissue resistance, which protects by limiting damage to the epithelium during its contact with acid/pepsin in the refluxate. Tissue resistance is not a single factor but a group of dynamic mucosal structures and functions that interact to minimize damage during contact of epithelium with noxious luminal contents. Conceptually tissue resistance can be broken down into three areas: (i) pre-epithelial, (ii) epithelial, and (iii) postepithelial defense. Pre-epithelial defense, although important in the stomach and small intestine, has a minimal role in the esophagus as there is a lack of well defined mucus layer, and capacity to secrete bicarbonate into unstirred water layer. The epithelial defense in the esophagus consists of structural and functional components. Structural components include all membranes and the intercellular junctional complex. These protect by limiting the rate of HCl diffusion between the cells. The functional components of tissue resistance include the ability of esophageal epithelial cells to buffer and transport acid, proteins, phosphates, and bicarbonate ions within the intercellular matrix, and may buffer the hydrogen ions that penetrate the surface. When the cytosolic buffering capacity is overwhelmed, the basolateral membrane transporters act to extrude hydrogen ion from epithelial cells, and preserve intracellular pH.[31, 32] The postepithelial defense in the esophagus is provided principally by the blood supply.[33] Blood flow delivers oxygen, nutrients and bicarbonate,

64

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

and removes H+ and CO2 . These functions provide protection by maintaining the normal tissue acidbase balance. Half of all patients with nonerosive esophagitis and one-third of patients with erosive esophagitis have acid contact times that are within the normal range. Defect in tissue resistance is the likely explanation for the development of GERD in patients with normal acid contact times.

3.4 CLINICAL FEATURES GERD can have both esophageal and extraesophageal manifestations. The esophageal manifestations are those caused directly by contact between refluxed gastric juice and the esophageal mucosa. The extraesophageal manifestations of GERD are caused by contact between refluxed gastric juice and extraesophageal organs or by reflexes triggered by acid in the esophagus that affect extraesophageal organs. The esophageal symptoms include heartburn, acid regurgitations and dysphagia. Heartburn is an uncomfortable retrosternal burning sensation associated with the reflux of noxious gastric juice into the esophagus.[33] The sensation may originate in the epigastrium and radiate up to the chest. Heartburn is an intermittent symptom, most commonly experienced within 60 minutes of eating, during exercise, and while lying recumbent. There is a poor correlation between heartburn and the degree of esophageal acid exposure. Most episodes of acid reflux (defined as a drop in esophageal pH below 4) do not trigger the sensation of heartburn. In patients with verified reflux esophagitis, 24-hour esophageal pH monitoring studies have shown that fewer than 20% of acid reflux events are accompanied by heartburn.[34] The mechanism whereby acid reflux causes heartburn is not clear. Although, it has long been assumed that acid in the esophagus triggers pH sensitive nociceptors in the mucosa that convey the sensation of heartburn,

it has recently been proposed that the sensation is caused by sustained contraction of the esophageal longitudinal muscle.[35, 36] In addition to causing heartburn, esophageal irritation by acid reflux can cause a variety of atypical chest pains, some of which can mimic the angina pectoris of ischemic heart disease.[37] Nonheartburn chest pains caused by GERD have been called noncardiac chest pain or atypical chest pain syndromes. Regurgitation is the effortless returns of esophageal or gastric contents into the pharynx without nausea or retching. Patients note a sour or burning fluid in the throat or mouth that may also contain undigested food particles. Banding, belching, or moving in a manner that increases intraesophageal pressure can provoke regurgitations. Some degree of dysphagia is reported by more that 30% of individuals with GERD. It can be caused by peptic stricture, a Schatzki ring (Bring), peristaltic dysfunction, or simple mucosal inflammation. Dysphagia also occurs in the absence of any identifiable abnormality, in which case it is likely the result of abnormal sensitivity to bolus movement during peristalsis.

3.4.1 Extraesophageal Presentations of GERD The majority of patients presenting with extraesophageal symptoms of GERD do not have classic symptoms of heartburn or acid regurgitation. GERD has now definitely been associated with pulmonary symptoms, ENT symptoms, or other extraesophageal findings. The silent reflux of this syndrome contributes to the difficulties in making this diagnosis. The physician must consider GERD in the differential diagnosis of these problems, either early in the course when classic reflux symptoms are present or when alternative diagnoses have been excluded.

Tropical Hepatogastroenterology

CLINICAL FEATURES

65

Symptoms may be produced by direct acid pepsin injury to susceptible supraesophageal tissue, or may be mediated through an esophageal reflex mechanism.

silent GER. Antireflux therapy results in improvement in asthma in approximately 70% of patients. To assess asthma outcome, a therapeutic trial of high dose proton pump inhibition therapy should be used for > 3 months.[44]

3.4.2 Asthma and Gastroesophageal Reflux

3.4.3 Chronic Cough and GER

The prevalence of GER is more common in asthmatics compared to control populations, with 82% of consecutive asthmatics having abnormal esophageal acid contact times.[38, 39] The largest study[40] investigating the association between GERD and asthma using data from more than 100,000 cases, showed that patients who suffered from esophagitis or peptic stricture had an odds ratio of 1.5% (95% confidence interval 1.43 to 1.59) for asthma compared with control subjects. Gastroesophageal reflux may be clinically silent from an esophageal standpoint.[41, 42] Not all asthmatics with GERD have esophageal symptoms, with up to 65% of asthmatics without heartburn or regurgitation having abnormal esophageal pH study results. The mechanism of esophageal acid induced bronchoconstriction includes a vagally mediated esophageal bronchial reflex, airway hyperresponsiveness, and microaspiration.[43] GER should be considered a potential trigger in patients with difficult-to-control asthma, nonallergic patients with asthma, patients with asthma with moderate to severe GERD, and patients with nocturnal asthma. GER induced asthma is difficult to diagnose definitively in the clinical setting as there is no standard for the diagnosis, and many patients having GER induced asthma do not have typical symptoms of GERD like heartburn or regurgitation. Esophageal pH testing is especially useful in documenting adequate acid suppression while patients are on antireflux therapy, and in identifying patients with clinically

Chronic cough has been variably defined as lasting from > 3 weeks to 8 weeks in duration.[45] GERD along with postnasal drip syndrome due to a variety of rhinosinus conditions and asthma is among the three most common causes of chronic cough in all age groups.[45] GERD can potentially stimulate the sensory limb of the cough reflex in multiple ways. Although, it can irritate the upper respiratory tract without aspiration (e.g., larynx) and the lower respiratory tract by either macro- or microaspiration, there is evidence that strongly suggests that GERD can also cause cough by stimulating an esophagobronchial cough reflex.[46] By this useful reflex mechanism, refluxate into the distal esophagus alone is a sufficient stimulus to cause cough. GERD related cough occurs predominantly during the day and in the upright position, however some patients may have nocturnal symptoms. Cough may be the sole manifestation of GERD. It is often long standing. The diagnosis of GERD as a cause of chronic cough can be made with certainty only when cough goes away with specific antireflux therapy. In patients who do not respond to proton pump inhibitors (PPIs), pH testing with a symptoms diary is appropriate. During pH testing, a drop to < 4 must be closely scrutinized. The positive and negative predictive values for 24-hour pH testing for GER induced cough are approximately 89% and 100% respectively.[47, 48] Thus, a normal pH study with a poor correlation of symptoms with acid reflux can confidently exclude acid related

Part I / Esophagus

66

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

cough, but a positive pH test does not guarantee the success of acid suppression therapy.

3.4.4 Laryngitis and GER It is estimated that 4%–10% of patients presenting to an otolaryngology practice will have symptoms and/or findings related to GERD,[49, 50] of which reflux laryngitis is perhaps the most common. Other disorders such as contact ulcers, granulomas, laryngeal and tracheal stenosis, globus sensation, paroxysmal laryngospasm, and laryngeal cancer represent other possible ENT manifestations of GERD. There are two schools of thought regarding the pathogenesis of reflux laryngitis. The first subscribes to the theory that acid and pepsin directly injure the larynx and surrounding tissues. The second proposed mechanism is that esophageal reflux stimulates vagally mediated reflex, resulting in chronic throat clearing and coughing which eventually leads to injury. In many patients the cause of laryngeal symptoms may be multifactorial, and it is difficult to identify those patients definitively in which GER may be playing a role. Documentation of GER using 24-hour pH monitoring may assist in identifying such patients. Pharyngeal pH probe monitoring, although not without limitations, may be the optimal method to evaluate such patients in terms of documenting the presence of esophagopharyngeal reflex.

is also reasonable to assume a diagnosis of GERD in patients who respond to a trial of potent antisecretory therapy. In a short trial of high dose proton pump inhibitors, Johnsson et al.[52] have shown patients to have a 75% sensitivity for a diagnosis of GERD. However, only 55% specificity for reflux was seen in heartburn patients using ambulatory pH testing, which is considered the “gold standard”. Numans et al.[53] in a meta-analysis have pointed out problems with sensitivity and specificity of using a therapeutic trial as a test for GERD, and have suggested that such an approach must be weighed against the ease of use and cost effectivity (primarily related to decreased use of diagnostic testing of this approach). It must be recognized that empirical treatment may be associated with false positive results, by masking the symptoms of peptic ulcer disease or malignancy. Such a pragmatic approach does not allow a physician to diagnose Barrett’s metaplasia, if present. Endoscopy for the diagnosis of GERD (Fig. 3.2) should be considered in patients, who do not respond to conventional therapy, or are accompanied

3.5 DIAGNOSTIC EVALUATION Patients with typical history of heartburn (pyrosis), regurgitation, or both, which often occurs after meals,[51] especially large or fatty meals are highly specific for GERD. It is neither practical nor necessary to embark on a diagnostic evaluation of such patient. An empirical therapy is appropriate in patients with symptoms consistent with GERD. It

FIGURE 3.2 Lower esophageal endoscopy. The illustration on the left shows an endoscopic view of a hiatal hernia with part of the gastric mucosa extending proximal to the diaphragmatic crus. The patient on the right has moderate esophagitis, although there is no hiatal hernia.

Tropical Hepatogastroenterology

DIAGNOSTIC EVALUATION

by the so-called warning signs of complicated diseases like dysphagia, odynophagia, gastrointestinal bleeding, weight loss, or anemia. Such patients are more likely to have peptic strictures and esophagitis than those without alarm symptoms. Patients with history of extremely chronic heartburn have high possibility of Barrett’s metaplasia. In comparison to patients with symptoms consistent with GERD for less than 1 year, the odd’s ratio for Barrett’s esophagus in patients with symptoms for 1–5 years is 3, and for greater than 10 years is 6.4. Endoscopy should be used as the first diagnostic test of suspected GERD patients with the above symptoms, because it provides the means for both detecting and managing complications of GERD, and excludes the presence of other diseases. It is diagnostic of GERD if erosive esophagitis is present, with a specificity of 90%–95%. Occasional false positive results may be due to infection or pill induced mucosal injury. The sensitivity of endoscopy is poor because only 30%–40% of patients with GERD have erosive esophagitis. The remaining 60%–70% patients with normal endoscopy are labeled as nonerosive reflux disease (NERD).[54] The Los Angeles System of scoring mucosal injury as grade A, B, C and D is a good system, but it does not consider strictures, hiatal hernia, or Barrett’s metaplasia in its classification (Table 3.2, Fig. 3.3). The endoscopist should describe these separately.[55] Documentation of the presence or absence of esophagitis does not usually direct the initial approach to patients with GERD, but confirms the diagnosis of GERD. Johnson et al.[56] have shown that higher grades of esophagitis are more difficult to heal, but once healed can be maintained in remission with medical or surgical therapy. Endoscopic biopsy should be performed to diagnose Barrett’s epithelium. Biopsy should be performed probably after a course of PPIs to allow better identification

Part I / Esophagus

67

TABLE fy 3.2 Los Angeles Endoscopic Grading Scheme for esophageal severity Grade A

Grade B

Grade C

Grade D

One (or more) mucosal breaks, no longer than 5 mm, that do not extend between the tops of two mucosal folds. One (or more) mucosal breaks more than 5 mm that do not extend between the tops of two mucosal folds. One (or more) mucosal breaks that are continuous between the tops of two mucosal folds but involve < 75% of the circumference. One (or more) mucosal breaks that involve at least 75% of the esophageal circumference.

FIGURE 3.3 Diagrammatic representation of the Los Angeles Endoscopic Grading Scheme for the severity of esophagitis.

of Barrett’s and to decrease the prevalence of inflammatory changes that are misinterpreted as dysphagia.

68

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

in patients with erosive esophagitis. However, in patients with typical symptoms with negative first pH testing, 22% of the second test was positive. Despite these limitations, ambulatory pH testing is the best method to study the actual amount of reflux occurring in a given patient. A tubeless method of acid monitoring is a new technology. A radiotelemetry capsule is endoscopically attached to the esophageal mucosa, and monitored without the discomfort of nasoesophageal tube.

3.5.1 Differential Diagnosis FIGURE 3.4 A barium swallow in a patient with a large hiatal hernia. The fundus (F) has herniated through the diaphragmatic hiatus into the thorax; the body (B) of the stomach is in the abdomen. In this patient a plain film of the chest (inset, lower left) showed an air-fluid level (arrow) in the fundus.

Barium radiography shows a reticular pattern in patients of GERD, but is neither sensitive (26%) nor specific (50%) when compared to endoscopy with biopsy.[57] It is reasonably accurate in patients of severe esophagitis (80%), but is much less accurate in mild esophagitis (less than 25%). Patients, who reflux barium at fluoroscopy or have hiatal hernia (Fig. 3.4), have more acid exposure by ambulatory pH testing, but these findings have poor specificity and sensitivity, and should not be used as a screening test for GERD. Barium studies are useful for determining the length of strictures.[58] Ambulatory pH monitoring for reflux of acid helps to confirm the gastroesophageal reflux in patients with persistent typical or atypical symptoms, without evidence of mucosal damage, especially when a trial of acid suppression has failed. Mattox et al.[59] have shown 84%–93% reproducibility, with sensitivity and specificity of 96%,

Symptoms of GERD are usually quite characteristic, but must be distinguished from the symptoms of infectious esophagitis, pill esophagitis, peptic ulcer disease, biliary colic, coronary artery disease, and esophageal motor disorder. Patients with inferior myocardial ischemia may experience only gastrointestinal symptoms without chest pain, but have dyspnea, diaphoresis, and fatigue. An electrocardiogram with stresstreadmill is essential for diagnosis. Endoscopy differentiates between infectious esophagitis, which has diffuse and punctate ulcerations compared to reflux esophagitis, which is present in distal esophagus. Pill induced ulcers are one or two, on opposite walls, and are placed in proximal esophagus.

3.6 MANAGEMENT OF GERD Only a few sufferers report for treatment by physicians. Instead of this, they use over-the-counter antacids or H2 receptor blockers. Lifestyle modifications may benefit many patients with GERD, although these changes alone are unlikely to control symptoms in the majority of patients. Avoidance of tight fitting garments, bending after food intake, head-end elevations by 9 inches by putting blocks under the bed legs at the head-end have shown to improve esophageal acid clearance. This

Tropical Hepatogastroenterology

MANAGEMENT OF GERD

is useful only in patients with night-time reflux. Decreased fat intake and fried food, cessation of smoking, and avoidance of recumbency for 3 hours postprandially decreases distal esophageal exposure.[60] Although data reflecting the true efficacy of these maneuvers in patients is almost completely lacking, certain foods (chocolate, alcohol, coffee and perhaps onions and garlic) have been noted to lower LES pressure, although randomized trials are not available to test the efficacy of these maneuvers. It is unlikely that these lifestyle modifications will suffice except in mild GERD cases, but they are useful as an adjuvant to the major pharmacological therapy.

3.6.1 Acid Suppressive Medications In GERD patients, hypersecretion of acid is rare. Even then the most common and effective treatment in GERD is suppression of acid and raising the intragastric pH above 4, during the time when reflux is occurring in a patient. The more the amount and the time of esophageal acid exposure, the greater the degree of acid suppression required. Antacid and antirefluxants such as algenic acid in combinations are superior to antacid alone in the control of symptoms, in approximately 20% of patients as observed in two long-term trials.[61] These agents raise the pH faster but the effect is short-lived as compared to H2 receptor antagonist. Hence these are not very useful for healing esophagus, but are useful for symptomatic control of esophagitis. H2 receptor antagonists (cimetidine, ranitidine, famotidine, or nizatidine) suppress gastric acid secretion most effectively during fasting and sleep. These agents block only one (histamine) of the three classes of membrane receptors (histamine, acetylcholine, gastrin). There is rapid development of tachyphylaxis; they are unable to suppress meal

Part I / Esophagus

69

related acid suppression effectively. Hence, H2 receptor antagonists have limited use. Proton pump inhibitors (PPI) are agents which inhibit the final pathway in acid secretion in the parietal cell by acting on membrane bound activated H+ , K+ - adenosine triphosphatase (H+ , K+ ATPase molecules). PPIs should be administered about 30 minutes before meals for optimal acid suppression. There are 5 PPIs in common use: omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole magnesium. An analysis of results of 33 randomized trials, including about 3000 patient with erosive esophagitis,[62] showed that symptomatic relief can be expected in 27% of placebo treated, 60% of H2 RA treated, and 83% of PPI treated patients. Esophagitis healed in 2% of placebo treated, 50% of H2 RA treated, and 78% of PPI treated patients. PPIs eliminate symptoms, and heal esophagitis more frequently and more rapidly than H2 RA. Havelund et al.[63] have shown that PPI therapy normalizes the impaired quality of life caused by GERD. All these 5 available PPIs have been demonstrated to control GERD symptoms and heal esophagitis when used at prescription doses, viz. omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, pantoprazole 40 mg, and esomeprazole 20 mg. Higher doses of PPIs are required when esophagitis is severe. In a study from Netherlands, in which patients with severe esophagitis resistant to prolonged therapy with H2 RA were treated with omeprazole at a dose of 40–60 mg per day, 100% of such refractory patients healed during 20 weeks therapy. Higher doses of PPI are needed in some situations, viz. during a diagnostic trial of noncardiac chest pain,[64] during empirical trial for supraesophageal symptoms of GERD, in patients with partial response to standard dose therapy,[65] in patients who have responded but are having breakthrough symptoms,[66] in patients with nocturnal breakthrough, and in patients with Barrett’s

70

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

esophagus. When a second dose is added, it should be given prior to the evening meal and not at bedtime. The proton pump inhibitors do not exhibit tachyphylaxis, but produce rebound hypersecretion with discontinuation as a result of secondary hypergastrinemia. All the PPIs do not maintain intragastric pH greater than 4 for all 24 hours. A study by Lind et al.[67] with cross-over of PPIs has shown that 45% of patients taking omeprazole 20 mg per day, 54% of patients taking esomeprazole 20 mg per day, and 92% of patients taking esomeprazole 40 mg per day maintained intragastric pH greater than 4 for at least 12 hours (Fig. 3.5). Proportionately, only 14% patients on omeprazole 20 mg, 24% on esomeprazole 20 mg, and 56% taking esomeprazole 40 mg per day maintained pH above 4 for at least 16 hours. These results showed that: (1) more potent or higher doses of PPI are

more likely to be effective and (2) there is a rationale for using proton pump inhibitors in twice a day regime if once a day regime proves ineffective. Several physiological studies have suggested modest benefits of one agent over another, but in clinical practice all have similar effects. However esomeprazole, a stereoisomer of omeprazole, is the first PPI to show a statistical advantage in healing, and symptom control in C and D grade of erosive esophagitis. Kahrilas et al.[68] have shown statistically significant (p < 0.05) better healing and symptom relief in patients on esomeprazole 40 mg (94.1%), as compared to 30 mg of lansoprazole (86.9%) at 8 weeks, across all grades of erosive esophagitis. There are currently two approaches to the medical management of GERD: (A) The “step-up” approach calls for initiating minimum therapy with a progressive increase to higher doses or more effective agents until an adequate patient response is achieved. (B) Alternatively, “stepdown” approach recommends starting with the most potent therapy and tapering down. Starting with the most effective therapy seems to be the most cost-effective approach, and is thus recommended by many clinicians and researchers involved in GERD management.

3.6.2 Pro-motility Therapy

FIGURE 3.5 A cross-over study showing the efficacy of PPI regimes in inhibiting gastric acid secretion after 5 days of treatment. In each case, the percentage of patients maintaining intragastric pH > 4 for at least 12 and 16 hours is shown. Group A — omeprazole 20 mg. Group B — esomeprazole 20 mg. Group C — esomeprazole 40 mg.

Defects in esophagogastric motility are central to the pathogenesis of GERD. If these defects could be corrected, GERD would be controlled, making suppression of normal amounts of gastric acidity unnecessary. Metoclopramide has an antidopaminergic activity, and acts as 5-hydroxytryptamine (5-HT3 ) antagonist, a 5-HT4 agonist, and a cholinomimetic. In a comparative trial with H2 receptor antagonist and metoclopramide either alone or in combination, marginal benefit has been demonstrated. Metoclopramide has shown CNS

Tropical Hepatogastroenterology

MANAGEMENT OF GERD

side effects in up to 25% of patients. Cisapride is also a mixed serotoninergic agent in a dose of 10 mg four times a day, and was shown to be as efficacious as standard H2 receptor antagonist therapy in grade I and grade II esophagitis. Its use has been curtailed as a result of its cardiotoxic effects, especially when used in combination with agents that are metabolized by cytochrome P-450 system, by prolonging the QT interval, leading to ventricular arrythmias and death. Domperidone is a dopamine receptor blocker, but unlike metoclopramide does not easily cross blood-brain barrier, and hence has little CNS effects. It has similar efficacy for grade I and grade II esophagitis when used alone. The transient LES relaxation is the dominant mechanism in pathogenesis of GERD. Agents targeted to decrease relaxation provide an attractive treatment option. Baclofen has been reported to reduce both the number of reflux episodes and percentile esophageal acid exposure after a single dose of 40 mg. The mechanism appears to be suppression of transient LES relaxation. All other GABAB receptor agonists, which have been tested clinically, have little benefit, when used alone.

3.6.3 Maintenance Therapy Hetzel et al.[69] have shown that almost all severe esophagitis patients could be healed with PPI therapy, but recurrence occurred in approximately 80% of the patients within 6 months of stopping the therapy. This was probably related to the initial severity of esophagitis. This necessitates maintenance medical therapy essentially to prevent relapse of esophagitis. H2 receptor antagonists or cisapride are significantly less effective than PPIs as maintenance therapies. In a randomized prospective study of 125 patients with esophagitis, Vigneri et al.[70] have reported that remission was maintained for 12 months in 49% of the ranitidine group, 54% in the cisapride group, 66%

Part I / Esophagus

71

in the ranitidine + cisapride group, 80% of the omeprazole group, and 89% in the omeprazole and cisapride group. Klinkenberg-Knol[71] have shown that the median dose required to maintain remission was near the dose required for healing esophagitis initially. Most of the patients, who healed with PPIs, would need the same dose of PPI, but some of them (although difficult to determine which patient) could be managed on H2 RAs. Inadomi et al.[72] in 71 PPI-dependant GERD patients observed that on discontinuation of PPI, 42% could not be taken off PPI, 42% could be managed with H2 RAs, prokinetics or combination, and 15% could be taken off. It is not clear as to whether these data could be applied in general. The use of such an attempt is to economize therapy. However, efficacy and safety data support that continuous PPI therapy is the most effective management for patients with GERD. Step-up therapy for maintenance of symptom relief has been evaluated with the view of cutting down the cost. Recently, a comparative study assessed and compared the effectiveness of management of heartburn symptoms in patients with GERD by sustained treatment with either an H2 RA, or a PPI, or with step-up and stepdown regimens of PPI, and H2 RA. At the end of 20 weeks, the group treated with continuous PPIs experienced less severe heartburn and more 24hour heartburn-free periods than did the other three groups.[73] Once a patient has failed less effective therapy, he or she should be maintained on PPIs because these are the only medical therapies that keep patients in symptomatic and endoscopic remission. PPIs have an excellent shortterm safety profile. The most common side effects, viz. headache, nausea, and diarrhea are seen with similar frequency as with placebo. KlinkenbergKnol et al.[74] showed that omeprazole given for 11 years has no long-term side effects. No studies

72

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

to date have reported development of dysplasia or gastric adenocarcinoma with long-term PPI usage in humans.[75] The drugs stimulate cytochrome P-450 system in the liver, sometimes necessitating the need for adjustment of doses of warfarin, phenytoin, and diazepam. The genetic polymorphism of cytochrome P450 enzyme (Cyp2C19), a major metabolic pathway of PPI, is an important factor responsible for variable response amongst different individuals. The efficacy of PPIs is reduced when over-expression of Cyp2C19 occurs, and efficacy is enhanced when a person is Cyp2C19 deficient.

3.6.4 Nonerosive Gastroesophageal Reflux Disease Achem[76] has observed that the prevalence of endoscopic esophagitis among symptomatic GERD population is lower than those without esophagitis. About 55%–81% of patients had endoscopic negative GERD. Using ambulatory esophageal pH monitoring to define GERD, it has been observed that only 48%–79% patients with pathologic acid exposure have esophagitis. All the nonerosive gastroesophageal reflux disease (NEGERD) patients have similar symptoms as those with erosive GERD, possibly because they have hypersensitive esophagus to refluxing acid. In nonerosive GERD patients, the end point of evaluation of drug therapy is symptom control rather than healing of erosions as in erosive GERD. The Genwal workshop report,[77] reported that complete relief of heartburn was obtained in only 35% to 57% patients kept on omeprazole 20 mg per day. These data do not support the viewpoint that nonerosive GERD patients could be made symptom-free with less potent or lesser doses of PPI. On the contrary, these patients may require higher doses of PPI and for more prolonged

periods, to attain symptomatic relief when compared to the doses required for even severe erosive esophagitis patients. Although for symptom relief higher PPI doses are required by the nonerosive GERD patients, they require less potent and less doses of PPI to maintain symptom relief. Bardhan et al.[78] and Lind et al.[79] have shown that patients with nonerosive GERD healed with either H2 RA or PPIs while maintained on-demand therapy with either of healing drugs. Fifty percent of patients did not require any acid suppressive drugs to maintain symptom relief, achieved for a period of six to twelve months. About 83% of patients could be maintained on 20 mg omeprazole, showing thereby that on-demand therapy is a viable option. However, contrary to the erosive GERD patients, only 50% of the nonerosive GERD patients usually require maintenance therapy.

3.6.5 Management of Refractory GERD GERD that is refractory to medical therapy is rare. In most of the patients, PPIs ameliorate their symptoms and heal erosions, as they are the most potent drugs available for treatment of GERD. PPIs are definitely the standard by which medical refractoriness should be defined. Patients may fail PPI therapy due to: (i) incorrect diagnosis of GERD, (ii) nonacid gastroesophageal reflux, (iii) failure to control gastric acid pH to > 4, and (iv) other causes of suboptimal PPI response, which include: (a) Variable bioavailability of PPI: the effect of PPI may decrease when taken along with antacids or H2 RAs. (b) Periods of parietal cells quiescence, when PPIs are least effective, and have lesser effect when they are not taken before meals. (c) Genetic variation in cytokine P-450, 2C19 enzyme, which may cause rapid

Tropical Hepatogastroenterology

ENDOSCOPIC THERAPY FOR GERD

metabolism of PPI thereby, limiting their potency. (d) Eradication of H. pylori, which (controversially) may decrease efficacy of PPIs Peghini et al.[80] demonstrated that 70% of the GERD patients with twice a day PPI therapy have periods of gastric pH less than four which lasts for 60 min or longer during the night. This is termed as nocturnal acid breakthrough (NAB). When this is associated with reflux of acid into esophagus, clinical symptoms may occur. This is seen in about 50% of patients with Barrett’s esophagus and scleroderma, and less frequently in uncomplicated GERD patients.[81] These patients may be benefited by either double dose PPI therapy or added H2 RA given at bedtime. But the results of trials by Fackler et al.[82] have shown that the beneficial effects of combined H2 RA and PPI are maximal with the first dose, but the effect is lost after first week because of tolerance to H2 RA. It is usually tempting to refer such patients to surgery, but it should be remembered that best results of surgery are obtained in patients who show complete response to PPI therapy. Therefore, the ideal candidate would be those young patients who have shown complete elimination of symptoms, but do not want to take medications for long period. Such refractory patients should be counseled that surgery does not carry a guarantee of success. GERD that is refractory to medical therapy is rare. The diagnosis should be carefully confirmed, preferably after ambulatory pH testing, prior to antireflux surgery.[83]

3.7 ENDOSCOPIC THERAPY FOR GERD Esophagogastric junction (EGJ) incompetence is the main defect in GERD patients. It is most attrac-

Part I / Esophagus

73

tive to correct this defect with some endoscopic therapy. There are three main categories of endoscopic therapies: (a) radiofrequency application to LES area, (b) endoscopic sewing devices, and (c) injection into LES region All three methods are intended to alter the mechanical properties of GERD to reduce the occurrence of reflux. In each case, the alteration imposed on EGJ has the potential to restore compliance of EGJ, and decrease the frequency of transient lower esophageal sphincter relaxation. (a) Radiofrequency application (Stretta) is designed to increase the reflux barrier by producing scarring at LES. Corley[84] have shown in a randomized sham control trial that it produced significant improvement in heartburn, quality of life, median heartburn score, and SF 36 physical quality of life scores. No difference was found as regards to acid exposure and ability to discontinue daily medication, 47% — after active treatment, 37% — after sham treatment (p = NS). (b) With endoscopic sewing technique, six months follow-up revealed that 62% of 64 patients could remain off PPI. Two year follow-up suggests that only 25% of the patients could remain off PPI. (c) Injection of nonabsorbable polymer (Enteryx) have been shown to control GERD symptoms, and allow 74% of patients to discontinue PPI at 6 months, and 70% to discontinue the PPI at 12 months of follow-up.[85] All these technique have yet not demonstrated long-term durability, safety, and their ability to discontinue PPI after a long follow-up. Therefore, endoscopic therapy controls symptoms in selected patients of well documented GERD.

74

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

3.8 SURGICAL THERAPY Incompetence of the esophagogastric junction is the main defect in GERD, which is compounded by presence of hiatal hernia. Antireflux surgery is aimed at re-establishing the competence of antireflux barrier by repair of hiatal hernia and wrapping gastric fundus around the lower the end of esophagus.[86] Proper selection and preoperative evaluation of patients is vital. Jackson et al.[87] in a study of 100 patients reported that predictors of good response were — age less than 50 yrs, and typical symptoms that had completely resolved on medical therapy. It is also clear that patients with typical symptoms are more likely to resolve after surgery rather than those with atypical and supraesophageal symptoms, and those who are refractory to or failed PPI therapy. Currently, the two most popular procedures are laparoscopic Nissen (360 degree) fundoplication (Fig. 3.6) and the Toupet (270 degree) fundoplication. The operations are associated

with morbidity of surgery and postoperative symptoms, viz. dysphagia, difficulty with belching, increased flatulence, and diarrhea. Controversy exists in regards to durability of these repairs.[88] In a study conducted in 55 patients for a mean period of 2.9 years after surgery, who had undergone laparoscopic Toupet fundoplication, 67% reported heartburn, 33% regurgitation, and 33% returned to PPI therapy. Considerable controversy too exists over the long-term efficacy of surgery and whether it is equal to or superior to chronic medical therapy. Lundell et al.,[89] in a randomized trial of 310 patients, compared between surgery and PPI, and found that surgery was superior to PPIs at the end of 5 years, but if dose titration up to 40–60 mg per day of omeprazole was used, the two treatments were equal. Choosing a patient for surgery remains something of a paradox. Patients who respond fully to PPIs appear to be the best candidates for surgery, but one wonders how advisable it is to subject a well controlled patient to the morbidity of antireflux surgery. Hence antireflux surgery performed

FIGURE 3.6 Laparoscopic fundoplication. (a) The gastric fundus (F) has been brought around from the right to the left under the esophagus (E). (b) The completed wrap.

Tropical Hepatogastroenterology

COMPLICATIONS OF GERD

by experienced surgeon is a maintenance option for the patients with well documented GERD.

3.9 COMPLICATIONS OF GERD Long-term consequences of severe regurgitation and esophagitis are peptic stricture and Barrett’s esophagus. Compared with patients with symptoms consistent with GERD for less than one year, the odds ratio for Barrett’s esophagus in patients with symptoms for 1–5 years is 3–0 and for greater than 10 years, it is 6.4. Patients with alarm symptoms are more likely to have peptic stricture and esophagitis than those without alarm symptoms.

3.9.1 Peptic Strictures The prevalence of peptic stricture in patients with erosive esophagitis ranges between 8% and 20%. With increasing and widespread use of PPIs, occurrence of strictures is decreasing. Usually, the severe strictures occur at the onset of disease only like severe esophagitis, which is also present at the onset of disease. It is not clear as to what factors predict the development of strictures in one patient and healing in another one. However, these patients, who have profound disruption of antireflux barrier, have heightened acid exposure, leading to severe ulcerations and reactive fibrosis, resulting in fixed stricture that is not altered by antisecretory therapy. The primary aims for the treatment of peptic strictures is to: (i) restore the lumen patency, (ii) heal the esophagitis, and (iii) prevent recurrence. Successful dilation of peptic stricture to lumen size 15 mm (45 French) usually relieves dysphagia. This can be achieved with Savary-Gilliard dilators using metal tip, metal guide wire, or through the scope pneumatic dilators. These two modalities appear to be equally effective and safe.

Part I / Esophagus

75

The main risks of esophageal dilatation are perforation, bleeding and bacteremia. As repeated dilatations are effective, surgery is rarely required. Most of the studies reveal that repeated dilatation is required in more than 50% patients. It has been observed that adjuvant use of PPIs decreases the need for recurrent dilatation.

3.10 BARRETT’S METAPLASIA, DYSPLASIA, AND ADENOCARCINOMA ln persons undergoing endoscopy about 1% have the endoscopic presence of islands of Salmon colored epithelium, which is called Barrett’s esophagus and is lined by specialized columnar intestinal metaplastic epithelium. It can occur in three distinct settings: (i) classic long segment Barrett’s metaplasia, in which salmon colored epithelium extends at least 3 cm proximal from esophagogastric junction; (ii) short segment Barrett’s metaplasia, which is similar endoscopically with evidence of metaplastic epithelium, but projects less than 3 cm from esophagogastric junction; and (iii) gastric cardiointestinal metaplasia, in which no metaplastic tongue projects, but the biopsy shows specialized intestinal metaplasia. There is general agreement that both long and short segment Barrett’s are associated with, and caused by GERD, adenocarcinoma development occurs in them although natural history of gastric cardiointestinal metaplasia remains controversial. Development of this is related both to H. pylori infection and GERD. Incidence of dysphagia is low and is estimated to be 1.4% per year (Fig. 3.7).

3.10.1 Pathophysiology Although the cause of Barrett’s metaplasia is uncertain, it is clearly associated with GERD and is believed to occur as a consequence of excessive

76

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

Histopathologically, specialized intestinal metaplasia exhibits a villous architecture containing goblet cells usually seen in crypt bases. This metaplastic epithelium can become dysplastic and potentially malignant. Dysplastic alteration in Barrett’s metaplasia have been classified as low or high-grade dysplasia, depending on the degree of nuclear pleomorphism, hyperchromatism, and altered nuclear polarity — high-grade dysplasia isolated with adenocarcinoma.

3.10.3 Management Management of patients with Barrett’s metaplasia has two aspects: 1. Treating the underlying GERD and FIGURE 3.7 Hiatal hernia and grades of Barrett’s esophagitis.

esophageal acid exposure.[90] These patients have increased number of reflux events and prolonged esophageal acid exposure compared with both normal and GERD patients.[91] This increased acid exposure may be related to a number of motor abnormalities associated with severe esophagitis. Most of severe esophagitis patients have a hiatal hernia. Cameron[92] have reported presence of hiatal hernia in about 96% patients with long segment Barrett’s and in 72% of patients with short segment Barrett’s metaplasia. In some patients, who present as Barrett’s, genetic predisposition is suggested.

3.10.2 Histology The gold standard of diagnosing Barrett’s is the presence of specialized intestinal metaplasia.

2. Managing the risk of development of adenocarcinoma. The principle for treating esophagitis is the same as for uncomplicated GERD, but it will likely require more intensive therapy. But, benefit of complete acid control in maintenance of Barrett’s esophagus is not proven. As there is no clinical evidence that aggressive antisecretory therapy prevents the occurrence of adenocarcinoma or causes regression of intestinal metaplasia, repeated biopsy is needed to diagnose dysplasia. Detecting highgrade dysplasia is important because in about 25% high-grade dysplasia patients, adenocarcinoma develops during 46 months of follow-up. There is controversy regarding management of patients with high-grade dysplasia. Esophagectomy, intensive endoscopic surveillance and mucosal ablation have all been advocated. Esophagectomy has operative mortality of about 3%–10%, hence in an otherwise normal person, endoscopic ablative therapy has been proposed as an alternative treatment of high-grade dysplasia.

Tropical Hepatogastroenterology

CONCLUSION

3.11 CONCLUSION Recent investigations have resulted in better understanding of GERD pathogenesis and natural course of disease with various management strategies. Current therapy is targeted at acid suppression, to deal with consequences of mucosal injury and to achieve resolution of symptoms. The H2 receptor antagonists have modest efficacy compared to PPIs, therefore there is no longer much support for initiating the treatment with H2 RAs. PPIs have been shown to provide the highest level of symptomatic relief and esophageal healing. They prevent the relapses during maintenance therapy. The complications with this class of agents are not common; hence the clinician is able to prescribe PPIs that are as effective as surgery. Clinicians do

77

not have to worry about the long-term sequelae of acid suppression. It appears that patients with extraesophageal GERD must be treated with higher doses of pharmacologic therapy, principally with PPIs, to achieve complete relief of symptoms for longer periods of time when compared to patients with heartburn and erosive esophagitis. There is still no clear consensus as to whether aggressive acid suppression alters the natural history of Barrett’s esophagus. Based on their initial success, it appears that the next generation of evolving medical therapies will continue to play an important role in the management of GERD. The outcome of medical therapy is the standard, against which the results of novel endoscopy antireflux treatment will be measured.

REFERENCES [1] DeVault KR, Castell DO. Update guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434–42. [2] Dent J, Brun J, Fendrick AM et al. An evidence – based appraisal of reflux disease management – the Genval Workshop Report. Gut 1999;44(suppl 2):S1–S16. [3] Nebel OT, Forms MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976;21:953–6. [4] Ruth M, Manssorn I, Sandberg N. The prevalence of symptoms suggestive of esophageal disorders. Scand J Gastroenterol 1991;26:73–81. [5] Ruth M, Mjornheim AC, Ludnell L. Symptoms suggestive of esophageal disorders in a normal population – a 10 year follow-up study. Gastroenterology Hepatol 2002;14:279–84. [6] Ho KY, Kang JY, Seow A. Prevalence of gastrointestinal symptoms in a multiracial Asian population,

Part I / Esophagus

[7]

[8]

[9]

[10]

[11]

with particular reference to reflux – type symptoms. Am J Gastroenterol 1998;93:1816–22. Chang CS, Poon SK, Lien HC et al. The incidence of reflux esophagitis among the Chinese. Am J Gastroenterol 1997;92:668–71. Segal l. The gastro-oesophageal reflux disease complex in sub-Saharan Africa. Eur J Cancer Prev 2001;10:209–12. Wienbeck M, Barnett J: Epidemiology of reflux disease and reflux esophagitis. Scand J Gastroenterol Suppl 156:7, 1989. Bainbridge ET, Temple JG, Nicholas SP et al. Symptomatic gastrooesophageal reflux in pregnancy: A comparative study of white Europeans and Asians in Birmingham. Br J Clin Pract 37:53, 1983. Voutilainen M, Sipponen P, Mechlin JP et al. Gastroesophageal reflux disease: Prevalence, clinical, endoscopic and histopathological findings in 1,128 consecutive patients referred for endoscopy due to dyspeptic and reflux symptoms. Digestion 2000;61:6–13.

78

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

[12] Johansson KE, Ask P, Boeryd B et al. Oesophagitis, signs of reflux, and gastric acid secretion in patients with symptoms of gastro-oesophageal reflux disease. Scand J Gastroenterol 1986;21:837–47. [13] Armstrong D. Endoscopic evaluation of gastroesophageal reflux disease. Yale J Biol Med 1999;72:93–100. [14] Lind T, Havelund T, Carlsson R et al. Heart burn without esophagitis: efficacy of omeprazole therapy ad features determining therapeutic response. Scand J Gastroenterol 1997;32:974–9. [15] Pace F, Santalucia F, Bianchi PG. Natural history of gastro-oesophageal reflux disease without oesophagitis. Gut 1991;32:845–8. [16] Trimble KC, Douglas S, Pryde A et al. Clinical characteristics and natural history of symptomatic but not excess gastroesophageal reflux. Dig Dis Sci 1995;40:1098–104. [17] Marks RD, Shukla M. Diagnosis and management of peptic esophageal strictures. Gastroenterologist 1996;4:2524–9. [18] Sonnenberg A, Massey BT, Jacobsen SJ. Hospital discharges resulting from esophagitis among Medicare beneficiaries. Dig Dis Sci 1994;39: 183–8. [19] Shaheen N, Ransohoff DF. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review. JAMA 2002;287:1972–81. [20] Spechler SJ, Zeroogian JM, Antonioli DA et al. Prevalence of metaplasia at the gastro-oesophageal junction. Lancet 1994;344:1533–6. [21] Csendes A, Smok G, Burdiles P et al. Prevalence of Barrett’s esophagus by endoscopy and histologic studies: a prospective evaluation of 306 control subjects and 376 patients with symptoms of gastroesophageal reflux. Dis Esophagus 2000;13:5–11. [22] Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett’s esophagus in asymptomatic individuals. Gastroenterology 2002;123:461–7. [23] Tobey NA, Hosseini S, Caymaz-Bor C et al. The role of pepsin in acid injury to esophageal epithelium. Am J Gastroenterol 2001;96:3062–70. [24] Lillemoe KD, Johnson LF, Harmon JW. Alkaline esophagitis: a comparison of the ability of compo-

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

nents of gastroduodenal contents to injure the rabbit esophagus. Gastroenterology 1983;85:621–8. Hirschowitz BI. A critical analysis, with appropriate controls of gastric acid and pepsin secretion in clinical esophagitis. Gastroenterology 1991;101: 1149–58. Mittal RK, Holloway RH, Penagini R et al. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109:601–10. Dodds WJ, Dent J, Hogen WJ et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547–52. Orlando RC. Reflux esophagitis. In: Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, editors. Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins;1999, p 1235–63. Sonnenberg A, Steinkamp U, Weise A et al. Salivary secretion in reflux esophagitis. Gastroenterology 1982;83:889–95. Kahrilas PJ, Shi G. Pathophysiology of gastroesophageal reflux disease: the antireflux barrier and luminal clearance mechanisms. In: Orlando RC, editor. Gastroesophageal reflux disease. New York: Marcel Dekker; 2000, p 137–64. Tobey NA, Reddy SP, Keku TO et al. Studies of pH in rabbit esophageal basal and squamous epithelial cells in culture. Gastroenterology 103:830, 1992. Tobey NA, Reddy SP, Khalbuss WE et al. Na+ dependent and independent Cl− /HCO3 – exchangers in cultured rabbit esophageal epithelial cells [published erratum appears in Gastroenterology 105(2):649, 1993]. Gastroenterology 104:185,1993. Richter JE. Dysphagia, odynophagia, heartburn, and other esophageal symptoms. In: Feldman M, Sleisenger MH, Scharschmidt BF, eds. Gastrointestinal and liver disease: pathophysiology, diagnosis, management. 6th ed. Philadelphia: Saunders, 1998:97–105. Baldi F, Ferrarini F, Longanesi A et al. Acid gastroesophageal reflux and symptom occurrence. Analysis of some factors influencing their association. Dig Dis Sci 1989;341890–3. Pehlivanov N, Liu J, Mittal RK. Sustained esophageal contraction: a motor correlate of

Tropical Hepatogastroenterology

REFERENCES

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

heartburn symptom. Am J Physiol Gastrointestinal Liver Physiol 2001;281:G743–51. Steinbach J, Fass R, Mittal RK. Assessment of relationship between acid reflux and heartburn using receiver operating characteristic curves. Gastroenterol Clin North Am 2002;31(4 Suppl): S45–58. Richter JE. Chest pain and gastroesophageal reflux disease. J Clin Gastroenterol 2000;30(3 Suppl):S39–41. Sontag SJ, O;Connell S, Khandelwal S et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990;99:613–20. Field SK, Underwood M, Brant R et al. Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996;109:316–22. el-Seraq HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997;113:755–60. Irwin RS, Curley RJ, French CL. Difficult-to-control asthma: Contributing factors and outcome of a systematic protocol. Chest 1993;103:1662–9. Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med (in press). Harding SM. Gastroesophageal reflux and asthma: Insight into the association. J Allergy Clin Immunol 1999;104:251–9. Harding SM, Richter JE, Guzzo MR et al. Asthma and gastroesophageal reflux: Acid suppressive therapy improves asthma outcome. Am J Med 1996;100:395–405. Irwin RS, Boulet L-P, Cloutier MM et al. Managing cough as a defense mechanism and as a symptom: A consensus panel report of the American College of Chest Physicians. Chest 1998;114(suppl):133–81s. Ing Aj, Ngu MC, Breslin ABX. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am J Respir Crit Care Med 1994;149:160–7. Irwin RS, Curley FJ, French CL. Chronic cough: The spectrum and frequency of causes, key components

Part I / Esophagus

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

79

of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141:640–7. Symrnios NA, Irwin RS, Curley FJ. Chronic cough with a history of excessive sputum production, the spectrum and frequency of causes, and key components of diagnostic evaluation and outcome of specific therapy. Chest 1995;108:991–7. Koufman JA, Weiner GJ, Wallace CW et al. Reflux laryngitis and its sequela: The diagnostic role of ambulatory 24-hour monitoring. J Voice 1998;2: 78–9. Toohil RJ, Mushtag E, Lehman RH. Otolaryngologic manifestations of gastroesophageal reflux. In: Sacristan T, Alvarez Vincent JJ, Bartual J et al., eds. Proceedings of XIV world Congress of Otolaryngology, Head and Neck Surgery. Amsterdam: Kugler & Ghedini Publications 1990:3005–9. Klauser AG, Shrindbeck NE Muller-Lissner SA. Symptoms in gastro esophageal reflux disease. Am J Gastroenterol 1999;94: 1434–42. Johnsson F, Weywadt L, Solhaug JH et al. One week Omeprazole treatment in the diagnosis of gastroesophageal reflux disease. Scand J Gastroenterol 1998;33:15–20. Numans ME, Lau J, de Witt NJ et al. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease. A meta-analysis of diagnostic test characteristics. Ann Intern Med 2004;140:518–27. Armstrong D. Endoscopic evaluation of gastroesophageal reflux disease. Yale J Biol Med 72:93, 1999. Lundell LR, Dent J, Bennett JR et al. Endoscopic assessment of oesophagitis: Clinical and functional correlates, and further validation of the Los Angeles classification. Gut 45:172, 1999. Johnson DA, Benjamin SB, Vakil NB et al. Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis, and for controlling gastroesophageal reflux disease symptoms: A randomized, double-blind, placebocontrolled study of efficacy and safety. Am J Gastroenterol 2001;96:27–34. Vincent ME, Robbins AH, Spechler SJ et al. The reticular pattern as a radiographic sign of

80

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

Chapter 3 / GASTROESOPHAGEAL REFLUX DISEASE

Barrett’s esophagus: An assessment. Radiology 1984;153:333–5. Johnston BT, Troshinsky MB, Castell JA et al. Comparison of barium radiology with esophageal pH monitoring in the diagnosis of gastroesophageal reflux disease. Am J Gastroenterol 1996;91:1181–5. Mattox HE, Richter JE. Prolonged ambulatory esophageal pH monitoring in the evaluation of gastroesophageal reflux disease. Am J Med 1990;89:345–56. Meyers WF, Herbst JJ. Effectiveness of positioning therapy for gastroesophageal reflux. Pediatrics 1982;69:768–72. Behar J, Sheahan DG, Biancani P et al. Medical and surgical management of reflux esophagitis. A 38month report on prospective clinical trial. N Engl J Med 1975;293:263–8. DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Arch Intern Med 1995;155:2165–73. Havelund T, Lind T, Biklund I et al. Quality of life in patients with heartburn but without esophagitis: Effects of treatment with omeprazole. Am J Gastroenterol 1999;94:1782–9. Fass R, Fennerty MB, Ofman JJ et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 1998;115:42–9. Katzka DA, Paoletti V, Leite L et al. Prolonged ambulatory pH monitoring in patients with persistent gastroesophageal reflux disease symptoms: Testing while on therapy identifies the need for more aggressive anti-reflux therapy. Am J Gastroenterol 1997;97:907–9. Klinkenberg-Knol EC, Nelis F, Dent J et al. Longterm omeprazole treatment in resistant gastroesophageal reflux disease: Efficacy, safety and influence on gastric mucosa. Gastroenterology 2000;118: 661–9. Lind T, Rydberg L, Kyleback A et al. Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro-esophageal reflux disease. Aliment Pharmacol Ther 14:861, 2000.

[68] Kahrilas PJ, Falk GW, Johnson DA et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators. Aliment Pharmacol Ther 2000;14:1249–58. [69] Hetzel DJ, Dent J, Reed WD et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95:903, 1988. [70] Vigneri S, Termini R, Leandro G et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 333:1106, 1995. [71] Klinkenberg-Knol EC, Nelis F, Dent J et al. Longterm omeprazole treatment in resistant gastroesophageal reflux disease: Efficacy, safety, and influence on gastric mucosa. Gastroenterology 118:661, 2000. [72] Inadomi JM, Jamal R, Murata GH et al. Step-down management of gastroesophageal reflux disease. Gastroenterology 2001;121:1095–100. [73] Howden CW, Henning JM, Huang B et al. Management of heartburn in a large randomized communitybased study: Comparison of four therapeutic strategies. Am J Gastroenterol 2001;96:1704–10. [74] Klinkenberg-Knol E, Nelis F, Dent J et al. Long term omeprazole treatment in resistant gastroesophageal reflux disease. Gastroenterology 2000;118:661–9. [75] Proton pump inhibitor relabelling for cancer risk is not warranted. FDA reports, November 11, 1996. [76] Achem SR. Endoscopy-negative gastroesophageal reflux disease: The hypersensitive esophagus. Gastroenterol Clin North Am 28:893, 1999. [77] An evidence-based appraisal of reflux disease management—the Genval Workshop Report. Gut 44(suppl 2):S1, 1999. [78] Bardhan KD, Muller-Lissner S, Bigard MA et al. Symptomatic gastro-esophageal reflux disease: Double blind controlled study of intermittent treatment with Omeprazole or Ranitidine: The European Study Group. BMJ 318:502, 1999. [79] Lind T, Havelund T, Lundell L et al. On demand therapy with Omeprazole for the long term management of patients with heartburn without esophagitis

Tropical Hepatogastroenterology

REFERENCES

[80]

[81]

[82]

[83]

[84]

[85]

– a placebo-controlled randomized trial. Aliment Pharmacol Ther 13:907, 1999. Peghini PL, Katz PO, Bracy NA et al. Nocturnal recovery of gastric acid secretion with twice daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763–7. Katz PO, Anderson C, Khoury RM et al. Gastroesophageal reflux associated with nocturnal acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998;12:1231–4. Fackler WK, Ours TM, Vaezi MF et al. Longterm effect of H2RA therapy on nocturnal acid breakthrough. Gastroenterology 2002;122: 625–32. Kenneth R, DeVault, and Donald O. Castell et al. Updated Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100:190–200. Corley DA, Katz P, Wo JM et al. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: A randomized, sham-controlled trial. Gastroenterology 2003;125:668–76. Johnson DA, Ganz R, Aisenberg J et al. Endoscopic, deep mural implantation of Enteryx for the treatment

test

Part I / Esophagus

[86] [87]

[88]

[89]

[90]

[91]

[92]

81

of GERD: 6-month follow-up of a multicenter trial. Am J Gastroenterol 2003;98:1921–30. Rydberg L, Ruth M, Lundell L. Mechanism of action of antireflux procedures. Br J Surg 86:405, 1999. Jackson PG, Cleiber MA, Askari R et al. Predictors of outcome in 100 consecutive laparoscopic antireflux procedures. Am J Surg 2001;181:231–5. Brand DL, Eastwood IR, Martin D et al. Esophageal symptoms, manometry and histology before and after antireflux surgery: A long-term follow-up study. Gastroenterology 1979;76:1393. Lundell LR, Meyer JC, Jamieson CG. Delayed gastric emptying and its relationship to symptoms of “gas bloat” after antireflux surgery. Eur J Surg 1994;160:161–6. Lidums I, Holloway R. Motility abnormalities in the columnar-lined esophagus. Gastroenterol Clin North Am 26:519, 1997. Singh P, Taylor RH, Colin-Jones DG. Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett’s metaplasia is present. Am J Gastroenterol 89:349, 1994. Cameron AJ. Barrett’s esophagus: Prevalence and size of hiatal hernia. Am J Gastroenterol 94:2054, 1999.

Chapter

4 ACHALASIA CARDIA Anil Arora and Sanjay Jain

Achalasia (Greek “achalasia” = lack of relaxation), cardia is an esophageal motility disorder characterized by the absence of esophageal peristalsis, a failure of the lower esophageal sphincter (LES) to relax completely in response to swallowing. It is usually associated with increased LES pressure and diminished to absent peristalsis in the distal esophagus. Sir Thomas Willis first described achalasia in 1674, when he successfully treated a patient by dilating the LES with a cork tipped whalebone.[1]

of familial clustering of achalasia in the form of monozygotic twins,[6] and in siblings.[7] In a survey of 1012 first-degree relatives of 159 patients with achalasia, no relatives were affected.[8] Occasionally, achalasia may occur as part of a congenital syndrome such as the triple ‘A’ syndrome (achalasia, alacrima, and resistance to adrenocorticotrophic hormone) and Alport’s syndrome.

4.2 ETIOPATHOGENESIS 4.1 EPIDEMIOLOGY Achalasia is a relatively uncommon disorder with an estimated incidence of one case per million population per year.[2] Because it is a chronic condition, its prevalence (7–10 cases per million persons) greatly exceeds its incidence. The disease affects both sexes equally, and usually presents in adult life, most commonly between the ages of 25 and 60 years.[3, 4] Cases from infancy to the ninth decade have been reported, and though children constitute only 2%–5% cases they constitute a majority of the familial cases.[5] There is no racial predilection. Achalasia shows no definitive evidence of genetic predisposition, though case reports exist 82

The disease starts with progressive loss of ganglion cells in the myenteric (Auerbach’s) plexus, which is embedded between the longitudinal and circular muscle layers of the esophagus. The characteristic finding is loss of ganglion cells. This loss of cells appears to be selective for inhibitory neurons producing nitric oxide (NO) and/or vasoactive intestinal peptide (VIP), and there is relative sparing of the cholinergic (stimulatory) neurons. Thus, the normal balance of excitatory and inhibitory neural input to smooth muscle is upset. The loss of inhibition, coupled with a relative preservation of the excitatory stimulus, is responsible for the failure of relaxation of the LES. A mononuclear inflammatory infiltrate is also commonly seen in the myenteric plexus.[9] The degree of ganglion

CLINICAL FEATURES

cell loss parallels the duration of disease, with almost complete loss of ganglion cells in patients with disease lasting for more than 10 years.[10] The ultimate cause of ganglion cell degeneration in achalasia is unknown. Earlier studies raised the possibility of a herpes virus infection (because of the predilection of herpes virus for squamous mucosa). An increase in the incidence of varicella – zoster virus (VZV) antibodies as well as demonstration of VZV in tissue removed at esophagectomy has been demonstrated in patients with achalasia.[11] However, subsequent investigations using the polymerase chain reaction to detect different markers found no evidence for any known viral agent. There is increasing evidence that achalasia is an immune mediated process. Immunohistochemical studies of inflammatory infiltrate in myenteric plexus showed that most cells were CD3/CD 8 positive cytotoxic T lymphocytes.[12] There is an association with the class II human leukocyte antigens DQ B1[13] and DQW1.[14] Antibodies against myenteric neurons have also been described.[15] The progressive immune mediated destruction of ganglion cells preferentially affects inhibitory (NO ± VIP) neurons with partial preservation of postganglionic cholinergic pathways. This also explains why resting LES pressure is elevated in about two-third of cases. This finding led to the discovery of therapeutic potential of botulinum toxin, which is a potent inhibitor of acetylcholine release from the presynaptic nerve terminals, in achalasia.[16]

4.3 CLINICAL FEATURES Dysphagia is the commonest presenting symptom in patients with achalasia cardia, and occurs in more than 95% of patients. In general, the dysphagia due to motor disorders of the esophagus

Part I / Esophagus

83

occurs with solids as well as liquids. However, most patients with achalasia complain predominantly, if not exclusively, of dysphagia to solid food. The converse, dysphagia for liquids only, almost never occurs. Patients often localize the dysphagia to the region of the LES. The natural history of dysphagia varies. Some patients notice that the dysphagia reaches to certain degree of severity, and then stops progressing. In others, the dysphagia continues to worsen to the extent that it results in markedly reduced oral intake, malnutrition and inanition. Emotional stress and the ingestion of cold liquids are well known exacerbating and precipitating factors. The duration of dysphagia averages two years at presentation.[3, 4] Eighty to ninety percent of patients with achalasia experience spontaneous regurgitation of food from the esophagus. The regurgitation is because of progressive stasis of food that the patient has eaten hours, or even days, previously. Some patients learn to induce regurgitation to relieve the retrosternal discomfort related to the distended esophagus. As the disease progresses, the likelihood that aspiration will occur increases. According to Vantrappen and associates, 30% of patients with achalasia report nocturnal coughing episodes.[17] Patients may present with serious pulmonary complications like pneumonia, lung abscesses, bronchiectasis, and hemoptysis. Chest pain is present in two thirds of patients.[18] Typically, patients describe chest pain as being retrosternal. This is a more common feature in patients with early or so-called vigorous achalasia, which is characterized by prominent contractions in the body of the esophagus, documented by radiography or manometry. These contractions are simultaneous and hence aperistaltic. As the disease progresses and as the esophageal musculature gets fatigued, chest pain tends to abate or disappear.

84

Chapter 4 / ACHALASIA CARDIA

The chronic obstruction at the level of the LES may occasionally result in the development of an esophageal diverticulum in the distal esophagus. Identification of this is important as its presence increases the risk of esophageal perforation during pneumatic dilatation to treat the achalasia. It is important to rule out secondary causes of achalasia (secondary achalasia, pseudoachalasia), such as gastroesophageal cancer and paraneoplastic syndromes, prior to making a diagnosis of idiopathic achalasia. Sandler et al. have shown that the accuracy of clinical features such as age over 55 years, duration of dysphagia less than 1 year, and significant weight loss in differentiating idiopathic from secondary achalasia is low.[19] It is therefore better to base the decision on endoscopy with a judicious use of CT scan and endosonography. If a patient with achalasia presents with significant loss of weight over a short period, esophageal cancer should be ruled out. When cancer develops, it is usually squamous, and arises in the dilated middle part of esophagus, rendering it relatively silent until late. Heartburn, and response to antacids, is indistinguishable from that seen in patients with gastroesophageal reflux disease (GERD). In fact, some patients with achalasia are mistakenly diagnosed with GERD for many years. Other rare symptoms of achalasia include airway compromise and stridor because of compression of the trachea by the dilated esophagus.[20]

4.4 DIAGNOSIS Achalasia cardia should be considered for differential diagnosis in all patients with a history of dysphagia for both solids and liquids. A definitive diagnosis requires two steps: (1) confirmation of the underlying abnormal pathophysiology of LES by doing esophageal manometry and (2) exclusion

of a neoplastic process at the GE junction, which mimics symptoms of achalasia (pseudoachalasia), by doing endoscopic examination.

4.4.1 Radiological Examination The following are the features of achalasia at barium swallow study under fluoroscopic guidance: 1. Failure of peristalsis to clear the esophagus of barium in the recumbent position. 2. Antegrade and retrograde motion of barium in the esophagus secondary to uncoordinated, nonpropulsive, tertiary contractions. 3. Pooling or stasis of barium in the esophagus when the esophagus has become atonic or noncontractile (usually seen late in the course of disease). 4. Nonrelaxation or uncoordinated relaxation of LES. 5. Dilatation of the esophageal body, which is typically maximum in the distal esophagus. The proximal esophagus may have a normal contour, as skeletal muscle portion of the esophagus is least involved in the disease process. An epiphrenic diverticulum is occasionally present.[21] 6. Tapering of the barium column at the unrelaxed LES, resulting in the bird beak sign (Fig. 4.1). Approximately 90% of patients with achalasia undergoing barium swallow examination have some degree of esophageal dilatation and a classic bird beak sign.[22] Several disease processes can mimic achalasia on barium studies, such cases are referred to as pseudoachalasia. These include esophageal carcinoma, gastric carcinoma, colon adenocarcinoma, nonsmall cell lung cancer, amyloidosis, lymphoma, and collagen vascular diseases. A pseudoachalasia from carcinoma of the

Tropical Hepatogastroenterology

DIAGNOSIS

85

normal in a number of patients in whom achalasia is not suspected before the procedure. Typical endoscopic findings are seen in cases that are more obvious; and include esophageal dilatation, lack of contractions, and retained food and secretions. With progressive dilatation and stasis, erythema, friability, and superficial ulcerations of esophageal mucosa may occur. Candida infection of the esophageal epithelium in the form of whitish plaques may be present. Endoscopy should be done in all cases of suspected achalasia to rule out diseases that mimic achalasia, and to evaluate the esophageal mucosa before therapeutic applications.

4.4.3 Manometric Examination

FIGURE 4.1 Barium swallow appearance of achalasia cardia. (Courtesy: Diwan Chand Satya Pal Aggarwal X-ray Clinic.)

cardia and gastroesophageal junction may be difficult to differentiate from achalasia. A careful endoscopic examination of the gastroesophageal region, including a retroflexed view of gastroesophageal junction from the stomach, is mandatory. Biopsies should be taken from any suspicious area or lesion. Even so, the sensitivity of this method in excluding underlying cancer is around 80% or less.[23] Endoscopic ultrasound (EUS) may provide additional information, but this has yet to be convincingly demonstrated.

4.4.2 Endoscopic Examination Endoscopy is relatively insensitive in establishing a diagnosis of achalasia, and may be reported as

Part I / Esophagus

Manometry is the gold standard for establishing the diagnosis of achalasia. This is particularly important when radiological examination is normal or equivocal. Typical manometric features of achalasia are:[24] 1. Lack of peristalsis in the distal 50%–60% of esophageal body, which is composed exclusively of smooth muscle cells. This is an absolute requirement for diagnosis. 2. Demonstration of nonpropagatory, lowamplitude, simultaneous wave pattern. As the esophagus distends, the amplitude further decreases. The term ‘vigorous achalasia’ has been used to describe a subgroup of patients, who show high amplitude and repetitive esophageal contractions on manometry. Clinically, these patients are usually younger and often have chest pain as a prominent symptom. It is unclear if this is an earlier stage of the disease. 3. Failure of or incomplete LES relaxation on deglutition. This is more commonly seen as

86

Chapter 4 / ACHALASIA CARDIA

well as more specific to the diagnosis than an elevated resting LES pressure. 4. High LES resting pressure (> 20 mmHg) seen in 60% of patients.

4.5 DIFFERENTIAL DIAGNOSIS Although achalasia is most often idiopathic, it may occur in various conditions, when clinical and radiological features, as well as manometric evaluation may be similar to that of primary achalasia. These disorders are collectively called secondary achalasia. The examples of secondary achalasia are: 1. 2. 3. 4. 5.

Chagas’ disease Amyloidosis Sarcoidosis Intestinal pseudo-obstruction Connective tissue disorders.

A high index of suspicion is required to diagnose these disorders. Chagas’ disease is characterized by cardiomyopathy and the presence of other tubular organ involvement, e.g., megacolon, megaureter, megaduodenum, and megarectum. Amyloidosis and sarcoidosis are infiltrative disorders with characteristic systemic involvement. Patients with intestinal pseudo-obstruction have predominant symptoms related to bowel motility. Connective tissue disorders have characteristic features like skin rash, arthropathy, vasculitis, and the presence of specific autoantibodies. Other diseases produce an achalasia-like syndrome, which is mainly due to an infiltrating lesion of the gastroesophageal (GE) junction. This is known as pseudoachalasia. Pseudoachalasia must always be suspected in patients with advanced age (> 50 years), shorter (less than one year) duration of symptoms at the time of presentation, and significant weight loss of more than 7 kg

(Kahrilas, 1987). The tumors produce achalasialike symptoms by encircling or compressing the distal esophagus and GE junction, or by infiltrating the esophageal neural network, and impairing postganglionic LES innervation.[25] The following malignancies have been associated with features resembling achalasia: 1. Gastric adenocarcinoma (about two third of cases) 2. Esophageal squamous cell carcinoma 3. Lung carcinoma 4. Lymphoma 5. Pancreatic carcinoma 6. Hepatocellular carcinoma 7. Prostatic carcinoma 8. Colon carcinoma. A clue to the presence of pseudoachalasia during endoscopic examination is the degree of resistance felt, when the endoscope crosses the GE junction. In achalasia, the endoscope renders a resistive though elastic feel as it pops through the GE junction. Greater degrees of resistance or inability to pass the scope despite moderate amounts of pressure are highly suggestive of an inflammatory or neoplastic stricture. When suspicion of pseudoachalasia persists, endoscopic biopsy, computed tomography, magnetic resonance imaging or endoscopic ultrasound should be considered for further work up of such patients to rule out malignancy.

4.6 TREATMENT Treatment of achalasia is directed at palliation of symptoms, because the underlying degenerative neural lesion cannot be corrected. The goal is to decrease the resistance to the food bolus transit caused by the dysfunctional LES. No treatment modality restores esophageal peristaltic activity,

Tropical Hepatogastroenterology

TREATMENT

but improved esophageal emptying by reducing LES pressure provides symptomatic relief in most patients. Four types of palliative treatment are available: pharmacotherapy, botulinum toxin injection, dilatation, and surgical myotomy.

4.6.1 Pharmacotherapy Pharmacological treatment for achalasia relies on agents that relax the smooth muscle of the distal esophagus and LES. Calcium channel blockers and nitrates have been most studied and applied. Nitrates are probably more effective than calcium channel blockers, but have significant adverse sideeffects such as headache that lead to discontinuation of the drug in up to 30% of patients. Isosorbide dinitrate, given in doses of 5–10 mg sublingually before meals starts acting within 15 minutes, and the effect lasts for more than 1 hour. A 19-month trial of this therapy reported marked or complete symptomatic relief by reducing the resting LES pressure by 66% for 90 minutes.[26] Calcium channel blockers (nifedipine, diltiazem, verapamil) reduce the LES pressure by 30% to 40%, and the effect lasts for more than an hour.[27] Nifedipine is probably more effective than diltiazem and verapamil. Contrary to popular belief, nifedipine is poorly absorbed sublingually. Oral doses of 10–20 mg reportedly improve symptom in 50%–70% of patients.[28] The limiting side effects of nifedipine are flushing, dizziness, headache and peripheral edema. Sildenafil, mainly used for penile erectile dysfunction, reduces LES pressure by its smooth muscle relaxant property. It acts by inhibiting phosphodiesterase type 5-enzyme, thereby increasing cyclic guanosine monophosphate within smooth muscle, and resultant relaxation. A recent double-blind placebo-controlled trial using 50 mg oral dose of sildenafil showed

Part I / Esophagus

87

significant reduction in LES pressure compared with placebo.[29] Other agents like anticholinergics (cimetropium bromide), opioids, loperamide, theophylline, and β 2 agonists have been used in treatment of achalasia with varying success. The use of pharmacotherapy is at best temporizing. Most patients require additional forms of treatment after 6 months or so because of side effects, progression of disease, or development of tolerance to drugs. Its use should be restricted for those who either cannot tolerate endoscopic therapy, or are unfit for surgical intervention, or as an adjunct to dilatation, or myotomy if the symptoms are persistent.

4.6.2 Botulinum Toxin (BoTx) Injection Botulinum toxin binds to presynaptic cholinergic neuronal receptors and irreversibly inhibits acetylcholine release. The ability of botulinum toxin to reduce LES basal tone and improve symptoms in patients with achalasia, was first reported by Pasricha and colleagues.[30] These investigations found that intrasphincteric injection of botulinum toxin decreased LES pressure by 33% and improved dysphagia in 66% of patients for a 6 months period. The technique for administration of botulinum toxin involves flexible upper endoscopy using routine sedation and injection of a total of 80 units into four quadrants of the LES via a 5 mm sclerotherapy needle, piercing the mucosa about 1 cm above the Z-line. The original dose of 80 Units was chosen empirically. Doses higher than 100 units are not more effective.[31] Pasricha et al. published the long term results of BoTx injection in their patients in 1996. Sixty-five percent of their patients had sustained remission at 6 months. In those who responded, the probability of remission at one year was 68% with the average duration of sustained response being 1.3 years. Factors that predicted a

88

Chapter 4 / ACHALASIA CARDIA (a)

(b)

FIGURE 4.2 (a) Pneumatic balloon dilatation in achalasia. (b) Lower end of esophagus after dilatation.

favorable outcome with BoTx injection included age less than 50 years, manometric criteria to suggest vigorous achalasia, a 1 week postinjection LES pressure less than 20 mmHg, and a 5 minute radionuclide retention of less 80%.[32] Therefore, patients who respond to an initial injection remain in remission for several months (range, 4 months to more than 12 months). The recurrence of symptoms is explained by the growth of new axons. When symptoms return, patients usually respond to repeat injection of botulinum toxin. Overall, this treatment is relatively safe, simple and effective. The major drawback is cost of therapy coupled with the need for multiple sessions. Studies comparing botulinum toxin with pneumatic dilatation suggest that increased expense with repeated sessions of injection therapy outweighs the potential economic benefits of the increased safety.[33] Moreover, an inflammatory reaction at the site of injection followed by local fibrosis may interfere with subsequent surgical intervention, if needed.[34]

4.6.3 Pneumatic Dilatation The limiting factor in the dilatation of the LES, to relieve symptoms in achalasia, used to be the

almost universal recurrence of symptoms, when using simple mercury filled or guide wire bouginage.[35] This however is no longer true with the development of balloons made of polyethylene. Raizman et al. reported a 65% reduction in LES pressure with the use of pneumatic dilatation as against 15% with mercury bougies.[36] Esophageal balloons of sizes varying from 12F to 120F (4 to 40 mm) are available. However, forceful dilatation of the LES can be achieved by stretching it to at least 30 mm or more to disrupt the circular muscle of the sphincter partially and to cause lasting reduction of LES pressure.[37] The most commonly available device is the Rigiflex balloon dilator (Microvasive, Millford, MA), which is passed over a guide wire and requires fluoroscopic monitoring. A less common device is the Witzel dilator (Medi-Globe, Tempe, AZ), which consists of a polyethylene balloon mounted on a forward viewing endoscope that is inflated under direct visualization (with the endoscope in a retroflexed position in the stomach). It has the advantage of not requiring fluoroscopy [Fig. 4.2(a), (b)]. An adequate stretch in pneumatic dilatation requires obliteration of balloon waist. Considerations of duration, pressure, number of inflations, and presence of blood on balloon are of little, if any,

Tropical Hepatogastroenterology

TREATMENT

importance in determining efficacy. Reported balloon inflation pressures range from 360 mmHg (7 psi) to 775 mmHg (15 psi), with periods of inflation ranging from a few seconds to 5 minutes.[38–41] The results of trials comparing different dilating systems indicate little difference in their efficacies. Also the effect of factors, such as balloon diameter, rate of inflammation, dilatation pressure, graduated versus single size dilatation, and number of dilatations per session, on the final results of dilatations remains unclear. A wise approach is to begin dilatation with a smaller diameter balloon (30 mm to 35 mm) at low inflation pressures. A larger balloon (up to 40 mm) may be used, if symptoms do not respond to the first dilatation. The clinical efficacy of pneumatic dilatation is 32% to 98%.[4, 42] Patients with a symptom duration of less than 5 years and those less than 40 years of age tend to have a poor response; while those with a postdilatation LES pressure values less than 10 mmHg have a good response with prolonged asymptomatic periods.[43] The same study also reported that while 60% of their patients had symptomatic relief at 1 year, at 5 years more than half of these had a recurrence of symptoms. Most patients who respond well to the first dilatation will respond well to the second dilatation also, while if the initial response to the dilatation has been poor then subsequent attempts at dilatation also do not have a very good result. Although, the response to surgery is unaffected by a history of previous pneumatic dilatation, dissection and myotomy may become difficult due to scarring of tissues. The major risk of dilatation is perforation. The estimated incidence in various series is between 1% and 5%.[4, 44, 45] The LES is relatively resistant to complete tears and most perforations take place in the distal left lateral aspect of the esophageal wall starting about 5 mm proximal or distal to the squamocolumnar junction.[46] It is important

Part I / Esophagus

89

to exclude stricture, to ensure a nearly empty esophagus, and to perform all manipulations of the balloon under fluoroscopic guidance to minimize the risk of perforation. Gastroesophageal reflux disease is uncommon after forceful dilatation, with an incidence of 2%. The low incidence is probably related to the residual pressure in the LES. Also if it occurs it responds well to standard medical treatment for reflux. Because of its ease, excellent efficacy and cost effectiveness, pneumatic dilatation is usually the first mode of treatment in most patients with achalasia cardia.

4.6.4 Surgical Myotomy The surgical procedure to manage achalasia cardia entails performing a myotomy with or without an antireflux procedure. Heller performed the first esophageal myotomy in 1913. In Heller’s operation, both anterior and posterior myotomies were performed via a laparotomy. However, minimally invasive techniques now allow performance of myotomy by either a thoracoscopic[47] or laparoscopic[47, 48] approach. Appropriate patient selection for surgery is imperative for good results. Probably the most common indication for surgical therapy in achalasia cardia is the group of patients, who have recurrent or persistent symptoms after pneumatic dilatation or BoTx injection. Studies suggest that about 15%–35% patients undergoing dilatation eventually require surgery.[50, 51] It however remains a matter of debate as to how many dilatations should be done prior to offering surgery to a patient. Patients with a dilated tortuous esophagus, epiphrenic diverticula, or previous surgery at the gastroesophageal junction are at a higher risk of perforation during pneumatic dilatation, and thus surgery may be preferred in these patients. Also BoTx injection, in this group of patients, is technically difficult as poor endoscopic access to

90

Chapter 4 / ACHALASIA CARDIA

the gastroesophageal junction prevents a precise injection to be made. The third group of patients where surgery should be recommended primarily is those who are less than 40 years of age and pediatric patients. These patients have a less than 50% success with pneumatic dilatation as the initial treatment.[52, 53] In contrast, cardiomyotomy is successful in 90% cases with relatively low morbidity.[54] For this reason, some patients may actually choose surgery over dilatation as primary treatment of their disease.

GERD. However, Abir et al.[55] observed their collective review of 21 series from 1976–2001, and concluded that overall incidence of GERD was about 10%, not significantly different from the transabdominal approach. A good result was achieved in 86% cases. However the mortality was much lower being just 0.01%, i.e., 100 times less than the transabdominal group.

4.6.4.1 Transabdominal (open) cardiomyotomy

The progression to this approach was only natural considering the advantages of minimally invasive surgery. While significant improvement in symptoms is reported in 76% patients, the unacceptably high rate of persistent dysphagia (up to 26%) and secondary GERD (35%) has led to some diminution of enthusiasm for this procedure.[55] This is probably due to the technical difficulties in performing the myotomy. The reasons for a shift from this to the laparoscopic approach include:[56]

This probably remains the commonest route for the performance of a cardiomyotomy. Abir et al. reviewed the published series in 2004 and reported that of the 2680 patients included in 18 series from 1975–2002, over 83% patients had a good to excellent result.[55] The cumulative incidence of gastroesophageal reflux disease (GERD) in the different series was 12%, though exact figures may be difficult to evaluate with the varied definitions of GERD. They have suggested that in view of this relatively high incidence of GERD, it is probably better to add an antireflux procedure to the cardiomyotomy. Perforation of the esophageal mucosa may occur at surgery; and if suspected, must be checked out by operative endoscopy or insufflation; and the mucosal defect, if any be repaired. The overall mortality in the series reviewed by Abir et al. was 1.2%. 4.6.4.2 Transthoracic (open) cardiomyotomy

This approach via a left thoracotomy has been suggested with the argument that it would minimize the disruption of the normal antireflux mechanism, thereby reducing the problem of postoperative

4.6.4.3 Thoracoscopic and laparoscopic approach

1. Excellent visualization of the distal esophagus, GE junction and stomach 2. The myotomy can be carried well on to the stomach (at least 3 cm) 3. An antireflux procedure (to prevent postoperative gastroesophageal reflux) can be easily performed 4. It avoids the anesthetic complexity of single lung ventilation and chest tube as required for thoracoscopy 5. Shorter hospital stay. Furthermore, numerous studies have reported that the laparoscopic approach has a cumulative good to excellent clinical response rate of 95% with a low incidence (14%) of postoperative GERD, and no reported mortality.[57] The LES pressure is

Tropical Hepatogastroenterology

REFERENCES

decreased by 59% (range 42%–72%) and appears to correlate with the postoperative symptoms.[55] 4.6.4.4 Should an antireflux procedure be done?

The possibility that myotomy may result in GERD has led to the argument that a prophylactic antireflux procedure be added. However, the additional procedure of a fundoplication has its own risk, and controversy exists as to the ideal type of fundoplication that should be added. The absence of randomized prospective data on the issue prevents any definitive opinion to be made. It is felt that while inadequate division of the muscle wall results in postoperative dysphagia, an excessively long myotomy (> 2 cm beyond the GE junction) may result in GERD.[58] The arguments against combining a fundoplication with myotomy are that it may increase the resistance to the flow of food and increase the operative time with its associated risks. It is suggested that if symptoms of GERD occur, it may be better to medically manage the condition rather than to add a fundoplication in all patients. Others argue

91

that adding an antireflux procedure eliminates the symptoms of reflux better. In a retrospective review Hunter et al. reported that in laparoscopic Heller myotomy with fundoplication (only 1 of their 40 patients did not undergo a fundoplication), they were able to eliminate dysphagia in 90% of patients, regurgitation in 95%, and heartburn in 81% of patients.[59] This study was unable to show any symptomatic reflux difference between the patients who underwent either the Dor (anterior) or Toupet (posterior) fundoplication. It has been claimed that the Dor anterior fundoplication is associated with less heartburn (24% vs. 42%, p < 0.05) and a decreased prevalence of persistent dysphagia (4% vs. 22%, p < 0.05).[60] The overall success rate of minimally invasive surgery ranges between 80% and 95%,[61] which is higher than that achieved by pneumatic dilatation. Although laparoscopic myotomy is invasive, its morbidity is low. On the other hand, pneumatic dilatation has a risk of perforation in 1% to 5% of patients. Thus, it seems that laparoscopic myotomy with an antireflux procedure may be the optimal treatment of achalasia, if proven by prospective randomized controlled trials.

REFERENCES [1] Earlam R, Cunha Melo JR. Benign esophageal strictures: Historical and technical aspects of dilatation. Br J Surg 1981;68:829–36. [2] Earlam RJ, Ellis FH Jr, Nobrega FT. Achalasia of the esophagus in a small urban community. Mayo Clin Proc 1969;44:478–83. [3] Kahrilas PJ, Kishk SM, Helm JF et al. Comparison of pseudoachalasia and achalasia. Am J Med 1987;82:439–46. [4] Tandon RK, Arora A, Mehta S. Pneumatic dilatation is a satisfactory first-line treatment for achalasia. Indian J Gastroenterol 1991;10:4–6.

Part I / Esophagus

[5] Nihoul-Fekete C, Bawab F, Lortat-Jacob S et al. Achalasia of the esophagus in childhood. Surgical treatment cases, with special reference to familial cases and glucocorticoid deficiency association. Hepatogastroenterology 1991;38:510–13. [6] Stein DT, Knauer CM. Achalasia in monozygotic twins. Dig Dis Sci 1982;27:636–40. [7] Bosher LP, Shaw A. Achalasia in siblings: clinical and genetic aspects. Am J Dis Child 1981;135: 709–10. [8] Mayberry JF, Atkinson M. A study of swallowing difficulties in first-degree relatives of patients with

92

Chapter 4 / ACHALASIA CARDIA

achalasia. Thorax 1985;40:391–3. [9] Csendes A, Smok G, Braghetto I et al. Gastroesophageal sphincter pressure and histological changes in distal esophagus in patients with achalasia of the esophagus. Dig Dis Sci 1985;30:941–5. [10] Cassella RR, Brown AL, Sayre J et al. Achalasia of the esophagus: pathologic and etiologic considerations. Ann Surg 1964;160:474–87. [11] Robertson CS, Martin BAB, Atkinson M. Possible role of herpes viruses in the etiology of achalasia of the cardia. Gut 30:A371, 1990. [12] Clark SB, Rice TW, Tubbs RR et al. The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis. AM J Surg Pathol 2000;24: 1153–8. [13] Verne GN, Hahn AB, Pinearu BC et al. Association of HLA-DR and- DQ alleles with idiopathic achalasia. Gastroenterology 1999;117: 26–31. [14] Wong RK, Maydonovitch CL, Metz SJ et al. Significant DQw1 association in achalasia. Dig Dis Sci 1989;34:349–52. [15] Verne GN, Sallustio JE, Eaker EY. Antimyenteric neuronal antibodies in patients with achalasia: A prospective study. Gastroenterology 1995;108: A705. [16] Holloway RH, Dodds WJ, Helm JF et al. Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia. Gastroenterology 1986; 90–924. [17] Vantrappen G, Hellemans J, Deloof W et al. Treatment of achalasia with pneumatic dilatations. Gut 1971;12:268–75. [18] Eckardt VF, Stauf B, Bernhard G. Chest Pain in achalasia: patient characteristics and clinical course. Gastroenterology 1999;116:1300–4. [19] Sandler RS, Bozymski EM, Orlando RC. Failure of clinical criteria to distinguish between primary achalasia and achalasia secondary to tumor. Dig Dis Sci 1982;27:209–13. [20] Panzini L, Traube M. Stridor from tracheal obstruction in a patient with achalasia. Am J Gastroenterol 1993;88:1097–100. [21] Ott DJ, Hodge RG, Chen MY et al. Achalasia associated with esophageal diverticula: prevalence

[22]

[23] [24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

and potential implications. J Clin Gastroenterol 1994;18:343–6. Schima W, Stacher G, Pokieser P et al. Esophageal motor disorders: video-fluoroscopic and manometric evaluation. A prospective study in 88 symptomatic patients. Radiology 1992;185: 487–91. Reynolds JC, Parkman HP. Achalasia. Gastroenterol Clin North Am 1989;18:223–55. Shi G, Ergun GA, Manka M et al. Lower esophageal sphincter relaxation characteristics using a sleeve sensor in clinical manometry. Am J Gastroenterol 1998;93:2373–9. Song CW, Chun HJ, Kim CD et al. Association of pseudoachalasia with advancing cancer of the gastric cardia. Gastrointest Endosc 1999;50: 486–91. Gelfond M, Rozen P, Keren S et al. Effect of nitrates on LOS pressure in achalasia: a potential therapeutic aid. Gut 1981;22:312–8. Traube M, McCallum RW. Calcium-channel blockers and the gastrointestinal tract: American College of Gastroenterology’s Committee on FDA related matters. Am J Gastroenterol 1984;79: 892–6. Bortolotti M, Labo G. Clinical and manometric effects of nifedipine in patients with esophageal achalasia. Gastroenterology 1981;80: 39–44. Bortolotti M, Mari C, Lopilato C et al. Effect of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 2000;118:253–7. Pasricha PJ, Ravich WJ, Hendrix TR et al. Treatment of achalasia with intrasphincteric injection of botulinum toxin: a pilot trial. Ann Intern Med 1994;121:590–1. Annese V, Bassotti G, Coccia G et al. A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia: GISMAD Achalasia study group. Gut 2000;46: 597–600. Pasricha PJ, Rai R, Ravich WJ et al. Botulinum toxin for achalasia: Long term outcome and predictors of response. Gastroenterology 1996;110: 1410–5.

Tropical Hepatogastroenterology

REFERENCES

[33] Panaccinone R, Gregor JC, Reynolds RP et al. Intrasphincteric botulinum toxin versus pneumatic dilatation for achalasia: a cost minimization analysis. Gastrointest Endosc 1999;50: 492–8. [34] Horgan S, Hudda K, Eubanks T et al. Does botulinum toxin injection make esophagomyotomy a more difficult operation? Surg Endosc 1999;13: 576–9. [35] Mandelstam P, Block C, Newell L et al. The role of bougienage in the management of achalasia—the need for reappraisal. Gastrointest Endosc 1982;28: 169–72. [36] Raizman RE, DeRezende JM et al. A clinical trial with pre and post treatment manometry comparing pneumatic dilatation with bougienage for treatment of achalasia. Am J Gastroenterol 1980;74:405–9. [37] Richter JE. Motility disorders of the esophagus. In Yamada T (ed): Textbook of Gastroenterology. New York, JB Lippincott, 1991, pg 1083. [38] Stark GA, Castell DO, RichterJE et al. Prospective randomized comparison of Brown – McHardy and Microvasive balloon dilators in the treatment of achalasia. Am J Gastroenterol 1990;85:1322–6. [39] Puestow KL. Conservative treatment of stenosing diseases of the esophagus. Postgrad Med 1955;18:6. [40] Okike N, Payne WS, Neufeld DM et al. Esophagomyotomy versus forceful dilation for achalasia of the esophagus: Results in 899 patients. Ann Thorac Surg 1979;28:119–25. [41] Lishman AH, Dellipiani AW. Management of achalasia of the cardia by forced pneumatic dilation. Gut 1982;23:541–4. [42] Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA 1998;280: 638–42. [43] Eckardt VF, Aignherr C, Bernhard G. Predictors of outcome in patients with achalasia treated by pneumatic dilation. Gastroenterology 1992;103: 1732–8. [44] Vantrappen G, Hellemans J. Treatment of achalasia and related motor disorders. Gastroenterology 1980;79:144–54. [45] Kurlander DJ, Raskin HF, Kirsner JB et al. Therapeutic value of the pneumatic dilator in achalasia of

Part I / Esophagus

[46]

[47]

[48]

[49]

[50]

[51]

[52] [53]

[54]

[55] [56]

[57]

93

esophagus: long term results in 62 living patients. Gastroenterology 1963;45: 604–13. Wong RKH, Johnson LF. In Castell DO, Johnson LF (eds): Esophageal Function in Health and Disease. New York, Elsevier Biomedical, 1983, p 99. Pellegrini C, Wetter LA, Patti M et al. Thoracoscopic esophagomyotomy: initial experience with a new approach for the treatment of achalasia. Ann Surg 1992;216:291–99. Cuschieri A, Shimi S, Nathanson LK. Laparoscopic cardiomyotomy for achalasia. JR Coll Surg Edinb 1991;36:152–54. Yamamura MS, Gilster JC, Myers BS et al. Laparoscopic Heller myotomy and anterior fundoplication for achalasia results in a high degree of patient satisfaction. Arch Surg 2000;135: 902–06. Parkman HP, Reynolds JC, Oyuyang A et al. Pneumatic dilatation or esophagomyotomy treatment for idiopathic achalasia: clinical outcomes and cost analysis. Dig Dis Sci 1993;38:75–85. Sauer L, Pelligrini CA, Way LW. The treatment of achalasia: A current perspective. Arch Surg 1989;124:929–32. Ferguson MK: Achalasia: Current evaluation and therapy. Ann Thorac Surg 1991;52:336–342. Nakayama DK, Shorter NA, Boyle JT et al. Pneumatic dilatation and operative treatment of achalasia in children. J Pediatr Surg 1987;22: 619–622. Paricio PP, Matinez de Haro L, Oritz A et al. Achalasia of the cardia: Long term results of oesophagomyotomy and posterior fundoplication. Br J Surg 1990;77:1371–4. Abir F, Modlin I, Kidd M et al. Digestive Surgery 2004;21:165–76. Stewart KC, Finley RJ, Clifton JC et al. Thoracoscopic versus laparoscopic modified Heller myotomy for achalasia: efficacy and safety in 87 patients. J Am Coll Surg 1999;189: 164–69. Sharp KW, Khaitan L, Scholz S et al. 100 consecutive minimally invasive Heller myotomies: Lessons learned. Ann Surg 2002;235:631–39.

94

Chapter 4 / ACHALASIA CARDIA

[58] Shiino Y, Filip CJ, Awad ZT et al. Surgery for achalasia: 1998. J Gastrointest Surg 1999;3: 447–55. [59] Hunter JG, Trus TL, Branum GD et al. Laparoscopic Heller myotomy and fundoplication for achalasia. Ann Surg 1997;225:655–65.

[60] Balaji NS, Peters JH. Minimally invasive surgery for esophageal motility disorders. Surg Clin North Am 2002;82:763–82. [61] Patti MG, Pellegrini CA, Horgan S et al. Minimally invasive surgery for achalasia: An 8-year experience with 168 patients. Ann Surg 1999;230:593–94.

test

Tropical Hepatogastroenterology

Part II Stomach

5 6 7

Peptic Ulcer Disease and Nonulcer Dyspepsia Benign Tumors of the Stomach Carcinoma of the Stomach

97 116 126

“This page intentionally left blank"

xx

Chapter

5

PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA MP Sharma and Vineet Ahuja

“Peptic ulcer is an epidemic during this century” –Sir Avery Jones

5.1 HISTORY Peptic ulcers were rare in the 19th century, and became prevalent in the 1950s and 1960s. Since then, peptic ulcer disease has declined in incidence, especially in the developed countries. Susser introduced the concept of birth cohort (i.e., those born during the same time) to explain this.[1] In the west, the annual death rate for duodenal ulcer was greatest in the final quarter of the 19th century, probably due to H. pylori infection, which later became less frequent. In south east Asian countries, the incidence of ulcer disease rose as in the west, but the decline has started in the last decade and has been slow. From 1881 onwards, Bilroth pioneered gastric surgery for peptic ulcer. Black in 1972 used H2 receptor blocking agents to swing the pendulum back to medical therapy. Marshall revolutionized management by demonstrating the etiological role of Helicobacter pylori. Peptic ulcer disease affects males and females equally in the west. In India, men are affected 1.8 times more commonly than women. Duodenal and gastric ulcers are equally common in the west, but in the tropics, duodenal ulcers are much more

common. Chuttani and co-workers conducted the first epidemiological study on peptic ulcer in north India in 1963,[2] and found an urban population prevalence of 0.6%, with a male to female ratio of 1.7:1. The ulcer was located in the duodenal bulb in over two-thirds of patients. High socioeconomic groups had a higher prevalence; 63% of patients were wheat eaters, thus challenging the ‘rice theory’ of southern India. Smoking habits were similar in ulcer and control groups, but alcohol consumption was higher in the ulcer group. South India, where rice is staple, has a higher prevalence of peptic ulcer disease than north India.[3] Patients in south India are younger, and presenting symptoms are related to gastric outlet obstruction rather than to perforation or hemorrhage. On comparison of the clinical presentation of duodenal ulcer in the 80s vs. the 90s, it is seen that day time pain continues to remain a universal phenomenon, while the prevalence of night time pain seems to be higher in the present era. In recent years, longer working hours and increased stress have resulted in a greater occurrence of night time pain, and complications such as gastrointestinal (GI) bleed.[4] The prevalence of H. pylori is declining. Persons in the east acquire this infection younger. By adulthood, most are infected. In the west, the peak incidence of infection occurs in the adult age. 97

98

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

5.2 PATHOPHYSIOLOGY The most important factors in the pathogenesis of peptic ulcer disease are gastric acid secretion and H. pylori. NSAIDs, smoking, and genetic factors may also increase the risks of ulcer formation.

5.2.1 Acid Secretion 5.2.1.1 Duodenal ulcer

Gastric acid is obligatory for a peptic ulcer formation, even though most patients secrete normal quantities of acid. Hypersecretion of gastric acid by itself rarely leads to ulceration. Duodenal ulcer patients, as a group, have increased basal acid output (BAO), expressed as a percentage of maximal acid output (MAO). Only 10% to 20% of duodenal ulcer patients hypersecrete acid. Nocturnal gastric acid secretion is also increased. MAO is also greater than normal, but there is substantial overlap. Only a third of duodenal ulcer patients have an abnormally large secretory capacity. The roles of altered gastric emptying and altered duodenal pH are unproved in the pathogenesis of duodenal ulcer. Bicarbonate production in the duodenal bulb markedly diminishes in patients with active duodenal ulcer. This affects duodenal mucosal defense. 5.2.1.2 Gastric ulcer

Most gastric ulcers are associated with nonsteroidal anti-inflammatory drug (NSAID) use and H. pylori infection. Gastric ulcers may be one of three types. Type I ulcers occur in the body of the stomach. Type II ulcers are also located in the body of the stomach, and are associated with a duodenal ulcer. Type III ulcers are prepyloric. The pathophysiology of type II and III ulcers is similar to that of duodenal ulcer, but type I ulcers tend

to be associated with normal or low acid secretion. Resting and meal stimulated pyloric sphincter pressures fall in some patients with peptic disease. This permits greater duodenogastric reflux, and bile and lecithin have the potential to damage gastric mucosa. Mucosal blood flow decreases in a small group of gastric ulcer patients. NSAIDs decrease gastric mucosal blood flow in humans. It is possible that diminished blood flow serves as a co-factor in ulceration.

5.2.2 H. pylori H. pylori infects the antral mucosa in 95%–100% of patients with duodenal ulcer disease, and in 70%–80% of patients with gastric ulcer. The mechanism by which H. pylori leads to these disease states is not established.[5–7] Bacterial virulence factors include urease, adhesins, protease, lipase, catalase, superoxide dismutase, and platelet activating factor. H. pylori strains carry in their genes a pathogenicity island which encodes for cag A (cytotoxin associated gene protein), and a gene (pig B) which encodes for a cytokine inducer. Approximately, 50% of H. pylori strains produce a vacuolating cytotoxin (vac A). Cag A expression was initially reported to represent an enhanced risk for the development of both gastric cancer and duodenal ulcer disease. Mucosal immune responses are produced by H. pylori that promote inflammation and epithelial damage without conferring immunity against infection. Responses include increased interleukin-1 (IL-1), IL-6, IL-8 and TNFalpha. Hypergastrinemia associated with H. pylori infection may result from a decrease in antral somatostatin content.[6] There is a greater acid response to gastrin in patients with duodenal ulcer disease. Mucosal bicarbonate secretion falls, and cure of H. pylori infection normalizes

Tropical Hepatogastroenterology

CLINICAL COURSE

the decreased duodenal bicarbonate secretion in patients with duodenal ulcers. Gastric metaplasia may occur from H. pylori. It has been postulated that H. pylori organisms from the stomach colonize areas of gastric metaplasia in the duodenal bulb, leading to duodenitis and ulcer formation but this has not been substantiated.

5.2.3 Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a five fold relative risk of developing a gastric ulcer. New gastric ulcers form in 10%–15% of patients taking aspirin and NSAIDs during the first 3 months of use.[8, 9] Risks are higher in elderly patients, those with a history of ulcer disease, use of high doses of or multiple NSAIDs. Duodenal ulcers also occur from NSAID use, but less frequently than gastric ulcers. NSAIDs induce ulcers by direct mucosal injury and systemic effects mediated by prostaglandin depletion. Topical damage is because of ‘ion trapping’ whereby the NSAIDs, being weak organic acids, reach high intracellular drug concentrations. Ion trapping causes direct cellular injury. NSAIDs also attenuate the hydrophobic properties of mucosa. The systemic effects of NSAIDs are due to inhibition of cyclo-oxygenase, with a resultant decrease in prostaglandins (PG), of which PGE2 and PGI2 are the most important. Mucin secretion, bicarbonate secretion, surfaceactive phospholipid secretion, and epithelial cell proliferation, all decrease consequently with the use of NSAIDs.

5.2.4 Smoking Peptic ulcer disease and smoking are strongly associated. The mechanisms whereby smoking causes these effects are unclear. Chronic smoking

Part II / Stomach

99

increases maximal gastric acid secretion. Nicotine significantly reduces duodenal mucosal blood flow. It also inhibits duodenal and pancreatic bicarbonate secretion.

5.2.5 Genetic Factors First-degree relatives of ulcer patients have a threefold increased lifetime risk of developing an ulcer. The concordance for peptic ulcer among identical twins is approximately 50%.

5.3 CLINICAL COURSE Peptic ulcer disease is a chronic disease with frequent relapses and remissions. Eradication of H. pylori or long-term acid suppression diminishes the risks of complications and lowers the relapse rate. Pain is the predominant symptom in 60%–80% of subjects. The typical pain of duodenal ulcer is epigastric, occurs 1–3 hours after meals, and frequently awakens the patient at night. This discomfort is relieved by food or antacids, and is sometimes described as a burning hunger pain or a vague discomfort. Ulcer symptoms are typically episodic with relapses lasting up to two weeks. Gastric ulcer is often asymptomatic, particularly in elderly patients taking NSAIDs. The pain of gastric ulcer is not helped by food, and symptoms are less likely to show periodicity. Vomiting in ulcer disease may signify gastric outlet obstruction following chronic ulceration or pyloric obstruction. Weight loss may occur in patients with peptic ulcer, particularly gastric ulcer. Symptoms that have discriminant value in differentiating duodenal from peptic ulcer are night pain, and relief from pain with food, milk or antacids. Complications of ulcer disease include hemorrhage, perforation, penetration, and obstruction. Hemorrhage is the most common complication,

100

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

FIGURE 5.1 Endoscopic view of a duodenal ulcer. The margins are punched out and the edges are edematous.

followed by perforation. Duodenal ulcers tend to perforate anteriorly while gastric ulcers tend to perforate along the anterior wall of the lesser curvature of the stomach.

5.4 DIAGNOSTIC STUDIES Endoscopy is the gold standard for diagnosis of a peptic ulcer (Fig. 5.1).[10] Radiography is obsolete, except for suspected outlet obstruction. Endoscopy can pick up superficial lesions, ulcer scars as well as active ulcers. It enables multiple biopsies from gastric ulcers and other lesions that may be malignant. Biopsies for the diagnosis of H. pylori can also be taken. Endoscopy in the assessment of upper gastrointestinal bleeding is accurate and may be therapeutic.

5.5 HELICOBACTER PYLORI AND PEPTIC ULCER DISEASE 5.5.1 Epidemiology Humans are the natural reservoir for H. pylori. The organism lodges most frequently in the stomach,

and is spread by oro-oral and orofecal transmission. The prevalence of H. pylori infection in healthy or asymptomatic persons in India varies from 31% to 84%. It depends on age, socioeconomic class, housing and sanitation, rural versus urban dwelling, and the method used for diagnosis.[11–21] A major proportion of the population in India is exposed by the age of 20 years.[12] Infection occurs at an earlier age than in the west, where the prevalence reaches 50% only by the age of 60 years. In India, the prevalence of IgG and IgA antibodies to H. pylori rises with age until 20 years, remains constant until the fifth decade, and then declines again. The prevalence of IgG and IgA antibodies is 22%, 56%, and 87%, and 48%, 58%, and 83% in the 0–4, 5–9, and 10–19 years age groups, respectively. Thereafter it remains constant up to the fifth decade, with a fall in later decades.[17] There is also a 46% prevalence on antral biopsy in patients without acid peptic symptoms, and a peak prevalence of 70% in the age group of 20–40 years.[14] A study in asymptomatic persons in north India showed that chronic active gastritis was present in 80% of those carrying H. pylori, but in only 33% of those who did not harbor the bacillus. In asymptomatic noncarriers, peptic ulcer prevalence is 3%.[19] Among symptomatic persons, H. pylori is present in 64%–90% of Indian patients with duodenal ulcer. The prevalence of H. pylori in other gastroduodenal diseases in Indian patients is gastric ulcer: 50%–65%, gastric cancer: 38%–62%, and nonulcer dyspepsia: 42%–74%. H. pylori infection has declined rapidly in all developing countries, which probably has contributed to declines in duodenal ulcer disease and gastric cancer. Since the organism is difficult to culture, and animal models have not helped in studying transmission, neither oral nor fecal exposure is

Tropical Hepatogastroenterology

HELICOBACTER PYLORI AND PEPTIC ULCER DISEASE

established conclusively as a route of transmission. There is no evidence that sexual transmission occurs. In developing countries with poor public sanitation, it is possible that exposure to contaminated drinking water and food causes infection. H. pylori was present in water samples obtained from various municipal wards in Mumbai,[22] and in feces and in sewage water. Some, but not all, studies have isolated H. pylori from dental plaque in patients with dyspepsia.[23–26] Spouses of H. pylori positive duodenal ulcer patients have a higher prevalence of infection (83%) than do spouses of uninfected patients (28.5%), and are likelier to reinfect after eradication.[27] Iatrogenic transmission may occur through gastrointestinal endoscopes. However, an Indian study did not show increased frequency of H. pylori infection in children with variceal bleeding, despite repeated sessions of endoscopic sclerotherapy.[28] Strain characterization: Indian strains of H. pylori differ from Western ones. 80%–90% of strains in Kolkata carried the cag pathogenicity island, and potentially toxigenic vacAs1 alleles of the vacuolating cytotoxin gene (vacA), independent of disease status.[29] This exceeds west figures, but is lower than the prevalence of virulent strains in east Asia. However, cag A status is not helpful in predicting nonulcer dyspepsia from peptic ulcer disease.[30]

5.5.2 Diagnosis of H. pylori Infection Choosing the appropriate H. pylori test depends on several factors, such as indications for endoscopy, previous H. pylori therapy, current or recent medications, and accuracy as well as cost of available testing alternatives. The diagnosis of H. pylori infection depends on endoscopy or on noninvasive tests. No single test is diagnostic. A definitive diagnosis requires a consensus of two or more tests.

Part II / Stomach

101

The rapid urease test (RUT), performed on a mucosal biopsy sample, is the cheapest and most available of all tests. The basis of this test is the principle that H. pylori produces urease, which cleaves urea into ammonia and carbon dioxide, which will turn the pH indicator solution red from yellow. The result takes from minutes to 24 hours. Commercial kits are available, though most centers prepare the solution in-house. The sensitivity and specificity of this test are 95% and 90% respectively.[31] The RUT gives best results at room temperature with prewarmed media, because of the enzyme’s higher activity at increased temperature. Unfortunately, all biopsy-based methods suffer from ‘patchiness’. One gastric mucosal biopsy specimen may throng with H. pylori colonies, whereas another sample a centimeter away may contain very few organisms. H. pylori culture is diagnostic, but suffers from poor sensitivity (60%–90%). It requires special conditions for specimen transportation and incubation, and expensive media with difficult maintenance. Histology is also diagnostic, but accuracy is determined by the site, number, and size of gastric biopsy specimens. Special stains as Warthin Starry and modified Giemsa give better results than hematoxylin-eosin. In one study, the RUT and histology performed together had sensitivity and specificity rates of 88% and 100% respectively.[31] Three to five biopsy specimens (two antral, two corpus, one incisura), as suggested by the Sydney system, correctly identify infected mucosa from uninfected mucosa. The antral biopsy specimen may be subjected to crushed smear and imprint cytology, which are as accurate and convenient as histology.[32–34] The same biopsy specimens can be used for histology. A Delhi study evaluated the sensitivity and specificity of histology, touch smear, RUT, and brush cytology of endoscopic antral biopsy. The best method for diagnosis was a combination of the

102

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

RUT or brush cytology with histology.[35] Brush cytology or touch smear are the single best tests. Polymerase chain reaction (PCR) techniques (using urea primer on antral biopsy specimens) show good sensitivity but poor specificity. PCR does not distinguish between viable and nonviable organisms. PCR is still a research technique in this field. The urea breath test is noninvasive; its basis is the organism’s urease activity, which liberates carbon dioxide from urea. Ingestion of C13 or C14 labeled urea results in production of isotopetagged carbon dioxide, which is detectable in the breath. C13 is nonradioactive but expensive. C14 is radioactive but affordable, and exposure to radioactivity is minimal at the doses used. It is sensitive and specific, with a diagnostic accuracy of 93%. There is no sampling error as seen in endoscopic tests. The urea breath test obviates the need for antral biopsies to confirm eradication of H. pylori after completion of therapy.[36–39] Serology is the commonest method of noninvasive diagnosis of H. pylori, but cannot distinguish between past and present infection. Serology detects IgG and IgA antibodies in the serum. The commercial ELISA kit has a high sensitivity of 95%–100%, and is excellent for use in primary health care settings. Serologic testing is more differentiating, if antigenic epitopes of H. pylori are distinguishable, based on the antigenic epitopes that specifically associate with gastric cancer, peptic ulcer, and nonulcer dyspepsia. The idea of differentiating antigens for H. pylori may open a new area for use of serologic testing in the diagnostic approach of H. pylori infection. The choice of a diagnostic test will depend on the clinical situation. ELISA is best for epidemiological studies. Thyagrajan at Chennai has developed a cost-effective indigenous serological kit.[40, 41] If endoscopy is planned then the RUT or histology will be sufficient. To reduce the cost, one

sample may be used for RUT and the other sample preserved. If the RUT is negative at 24 hours, the second sample may be sent for histology. If endoscopy is not planned, the urea breath test is a good alternative. Four weeks after completion of therapy, the C14 urea breath test is sufficient to demonstrate eradication of the organism. For clinical trials, one may use a combination of two of the following tests: RUT, histology or urea breath test.

5.5.3 Treatment of H. pylori Infection H. pylori infection responds to antimicrobial agents. The best adjuvant therapy comprises drugs that increase the pH of the stomach, such as proton pump inhibitors (PPI). Indications for treatment Eradication of H. pylori cures peptic ulcer disease, and conversely relapses of peptic ulcer disease are associated with reappearance of H. pylori. Therefore, H. pylori is best eradicated. In 1994, the National Institute of Health consensus development conference had recommended eradication of H. pylori in all cases of duodenal ulcer infected with H. pylori. Subsequently, the European Helicobacter study group, American College of Gastroenterology and 1997 Asia Pacific working party had also recommended eradication of H. pylori in peptic ulcer disease. Eradication should be primary therapy in endoscopically proven duodenal ulcer, according to the first (1997) positioned paper on H. pylori.[42] Eradication is also recommended in all patients with low-grade gastric MALT (mucosa-associated lymphoid tissue) lymphoma with co-existing H. pylori, bleeding peptic ulcer disease, or a past history of ulcer with proven H. pylori infection. Eradication is unnecessary in nonulcer dyspepsia with or without antral gastritis. The indications for treatment as outlined in the recently revised Maastricht Consensus report[43] are shown in Table 5.1.

Tropical Hepatogastroenterology

HELICOBACTER PYLORI AND PEPTIC ULCER DISEASE

TABLE fy 5.1 Strongly recommended indications for treatment of H. pylori based on Maastricht Consensus Report 2 (The level of scientific evidence is given in italics)[43] H. pylori should be treated in the following situations: 1. Duodenal or gastric ulcer (active or inactive): Well designed and appropriately controlled studies 2. MALT lymphoma: Well defined case or control studies which may have some flaws or indirect evidence 3. Atrophic gastritis: Well defined case or control studies which may have some flaws or indirect evidence 4. Postgastric cancer resection: Suggestive indirect evidence and case reports 5. Patients who are first degree relatives of gastric cancer patients: Suggestive indirect evidence and case reports 6. Patient’s wishes (after full consultation with the physician): Insufficient evidence for opinion formation

First-line therapy Drugs effective against H. pylori include bismuth salts (colloidal bismuth subcitrate, bismuth subsalicylate), metronidazole, tinidazole, secnidazole, tetracycline, amoxicillin, clarithromycin, azithromycin, omeprazole, lansoprazole, quinolones, and ranitidine bismuth citrate (RBC). Single drug therapy is ineffective, and promotes resistance. Dual therapy with a PPI and amoxicillin (which does not reach high concentrations in gastric mucosa) was popular in the early 1990s, but was abandoned because the results were inferior to PPI based triple therapies. High dose dual therapy (omeprazole 40 mg 3 times a day with amoxicillin 1 gm 3 times a day) gave 80% eradication rates in initial studies. A three or four drug regimen is now preferred. The regimen should include a PPI and two antibacterials (triple therapy), or a PPI, bismuth, and two antibiotics (quadruple therapy).[44–55] The time of therapy should be 14 days, as 7 days’ therapy does not produce optimal eradication rates. No single therapy is suitable for all India, as there are wide

Part II / Stomach

103

variations in the resistance patterns. Some of the more commonly used regimens are: PPI (Lansoprazole 30 mg BD or omeprazole 20 mg BD) + amoxicillin 1 gm twice daily + clarithromycin 500 mg twice daily for 14 days PPI + amoxicillin 1 gm BD/clarithromycin 500 mg BD + tinidazole 500 mg BD for 14 days Colloidal bismuth subcitrate 240 mg BD + PPI + amoxicillin/clarithromycin + tinidazole for 10–14 days Several factors may affect outcome. These include the following: (a) Factors linked to treatment: Dose of clarithromycin: Increasing the dose of clarithromycin to 1.5 gm/day improves cure rates. Duration of treatment: Better cure rates are achieved with longer treatment duration: 14 days, greater than 10 days, greater than 7 days. (b) Factors linked to strains: Resistance of H. pylori to antimicrobial agents Strain type. (c) Factors linked to patient: Geographical region Patient compliance. Second-line therapies The choice of second line treatment largely depends on initial therapy. If first-line treatment included clarithromycin, second-line treatment should include metronidazole, and vice-versa, as acquired bacterial resistance to metronidazole and clarithromycin primarily results from previous treatment failure.[56] Quadruple therapy includes a PPI twice daily, colloidal bismuth subcitrate 120 mg four times a day, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day.[57, 58] A seven-day treatment duration is sufficient, and increasing the duration does not increase efficacy. Recently, RBC has shown better results than PPI

104

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

and bismuth salts, and has shown a higher efficacy than quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure. In nonresponders, if initial therapy has been metronidazole based, then rescue therapy should be nonmetronidazole based. If the first line of therapy had been nonmetronidazole based, the new regimen should be either a quadruple drug regimen, or a long length (up to 14 days) therapy. Patient compliance needs rigorous monitoring. Testing for eradication is required in relapse of duodenal ulcer, complicated duodenal ulcer, and gastric ulcer when ulcer healing needs documenting. Newer compounds, currently under evaluation for eradication of Helicobacter pylori, include macrolides other than clarithromycin, fluoroquinolones, rifamycin derivatives, and nitazoxanide. The macrolide azithromycin reaches high gastric concentrations that persist for several days. Its dose is 500 mg once daily for three days during a seven-day triple therapy. The absorption of azithromycin falls markedly when administered with food. In treatment regimens in which azithromycin was given to fasting patients, cure rates ranged from 86%–93%.[58, 59] Spiramycin, another macrolide, achieves eradication rates of about 90% when administered for 10 days with metronidazole and bismuth subnitrate or ranitidine bismuth subcitrate. Levofloxacin, a fluoroquinolone, at 500 mg daily with rabeprazole and either amoxicillin or tinidazole for 1 week results in eradication of H. pylori in 90%–92% of treated patients.[60] Rifabutin, a rifamycin derivative, is useful in triple or quadruple therapy for nonresponders to standard regimens. Rifabutin 150 mg daily achieves eradication in 66.6% of cases, and at 300 mg daily it achieves eradication in 86.6% (p < 0.025).[61] Nitazoxanide, which resembles nitroimidazoles, yielded eradication rates of 83% in combination with omeprazole.[62]

Genomic sequencing may allow the development of specifically targeted drugs. Recurrence Recurrence, documented 4 weeks after eradication, may be due to recrudescence of the same strain, or reinfection by a new strain. Recrudescence is most likely to occur during the first 12 months after apparent eradication, whereas reinfection may account for recurrence after this period.[63–69] Recrudescence is seen in about 60% of patients, 3–6 months after therapy. The reinfection rate in India is 11%–40%, per patient year follow up after eradication. The ulcer relapse rates are 17% during an average follow up of one year. This is in contrast to developed countries where the reinfection rate is 0%–3% per patient year follow up. The higher reinfection and ulcer relapse rates in India may be due to genetic susceptibility or re-exposure to H. pylori. Eradication failure may occur due to drug resistance. Most isolates in India are resistant to metronidazole as well as to clarithromycin.[70, 71]

5.5.4 H. pylori and Nonulcer Dyspepsia H. pylori is present in 50%–80% of patients with nonulcer dyspepsia (NUD) in India, and in a similar proportion of healthy adults. H. pylori eradication does not appear to benefit the majority of patients with NUD and H. pylori infection.[72–74] Indian gastroenterologists do not recommend H. pylori eradication for nonulcer dyspepsia. NUD is multifactorial, and H. pylori may be causative in only a small proportion of patients.

5.6 NSAIDs NSAIDs can injure the gastroduodenal mucosa through both systemic and topical effects. Superficial gastric injury in the form of petechiae and erosions can occur within minutes of ingesting

Tropical Hepatogastroenterology

REFRACTORY ULCER

NSAIDs. In acidic gastric juice weakly acidic NSAIDs such as aspirin are unionized, and can freely penetrate gastric cells. Ulceration is probably due to the cascade effect of reduced mucosal prostaglandin synthesis that accompanies NSAID induced inhibition of cyclo-oxygenase. Inhibition of prostaglandin synthesis leads to decreased epithelial secretion of mucous and carbonate, diminished mucosal blood flow, reduced mucosal proliferation, and impaired resistance to peptic injury. Endoscopy confirms ulcers in 15%–30% of patients on chronic NSAID therapy.[75] Peptic ulcerations not associated with H. pylori infection are usually associated with NSAID ingestion. NSAIDs also increase the risk of ulcer complications such as bleeding and perforation. NSAID injury is aggravated by concomitant use of steroids, previous peptic ulceration or gastrointestinal bleeding, advanced age, associated systemic disorders, and associated H. pylori infection. NSAID users infected with H. pylori have an almost two fold increased risk for developing bleeding peptic ulcers compared with uninfected NSAID users. Low dose aspirin causes more gastric injury in H. pylori infected subjects than in uninfected individuals. However, physicians do not yet ordinarily recommend H. pylori eradication, before long-term planned NSAID therapy. Laine[76] recommends the use of nonNSAID analgesic such as acetaminophen; NSAIDs in the lowest effective dose, and safer NSAIDs such as etodolac, nonacetylated salicylates, and cyclooxygenase-2 selective agents like celecoxib and rofecoxib. He also advocates co-therapy with misoprostol or a PPI.

5.7 REFRACTORY ULCER A refractory ulcer is a duodenal ulcer that fails to heal in 8 weeks, or a gastric ulcer that fails to heal

Part II / Stomach

105

in 12 weeks of therapy.[77, 78] Five percent to ten percent of all ulcers are refractory. These ulcers relapse more frequently.[79] Common factors contributing to nonhealing are lack of compliance, inadequate suppression of gastric acid, H. pylori infection, and incorrect diagnosis. Persistence of H. pylori is common particularly in our country, where most of the triple therapies achieve an eradication rate of 75%–85%. H. pylori infection can also be easily missed as patients on PPI may give false negative results due to suppression of H. pylori. NSAID ingestion is a cause in 40% of refractory ulcers. Surreptitious NSAID ingestion may be uncovered by measuring serum salicylate levels, or evaluating platelet cyclo-oxygenase inhibition, but these tests are usually unavailable.[80, 81] Smoking is an important risk factor for refractory ulcer, and patients must discontinue smoking. Gastrinoma can be a cause of refractory ulcer, and requires exclusion with a fasting serum gastrin level or a secretin stimulation test. It is likely that acid hypersecretion contributes to refractory duodenal ulcers in a subset of patients. However, there is so much overlap of gastric acid secretion between groups with and without refractory ulcers, that measurement of gastric acid secretion is seldom useful in evaluating refractory duodenal ulcers or in guiding therapy. Tolerance to H2 -receptor antagonists develops over time, decreasing their efficacy. Tolerance may occur due to upregulation of histamine H2 receptors and secondary hypergastrinemia, with increased basal and meal stimulated acid secretion. PPIs do not result in tolerance. Big ulcers take longer to heal. There is much scarring, which impairs angiogenesis and tissue repair.

106

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

A gastric malignancy may masquerade as a chronic nonhealing ulcer. Adequate biopsies are mandatory. Unusual causes of refractory ulcer include Crohn’s disease, amyloidosis, sarcoidosis, eosinophilic gastroenteritis, lymphoma, ischemia, and infections such as tuberculosis, syphilis, and cytomegalovirus. Biopsies from duodenal and gastric nonhealing ulcers will exclude these conditions.

5.7.1 Evaluation of Refractory Ulcer Upper GI endoscopy confirms the refractory ulcer. Biopsies or breath tests will exclude H. pylori infection. Serum gastrin levels will pick up patients with the Zollinger-Ellison syndrome. Gastric acid secretory studies are occasionally required. With refractory duodenal ulcer, in the absence of H. pylori or NSAID use, endoscopic biopsy is mandatory to exclude other benign or malignant diseases. Endoscopic ultrasound or computed tomography will detect an ulcerated malignancy.

5.7.2 Therapy of Refractory Ulcer Persistent H. pylori infection requires treatment with nonmetronidazole based triple therapy for a minimum of 2 weeks. A marked reduction in gastric acid secretion usually results in healing of most refractory duodenal ulcers. Of ulcers that are unhealed after 8 weeks of standard H2 RA therapy, 50%–60% heal with an additional 8 weeks of H2 RA therapy. PPIs are the drugs of choice for refractory ulcers. Omeprazole (40 mg/day) and lansoprazole (30–60 mg/day) produce healing in more than 90% of refractory duodenal ulcers after 8 weeks of therapy. In gastric ulcers, PPIs heal more than 90% of refractory ulcers.

Frequent ulcer recurrence is a major problem. Patients who are H. pylori positive require eradication therapy. Maintenance therapy with full dose or half dose H2 RA yields a 1-year symptomatic recurrence rate of 50%–70%. Omeprazole 40 mg/day is extremely effective; a dose of 20 mg/day is less effective.

5.7.3 Surgery for Refractory Ulcer A truly refractory ulcer will require surgery. The surgical options include highly selective vagotomy or vagotomy with a drainage operation. Patients, who do poorly with medical therapy, are also more likely to respond poorly to surgery, especially to highly selective vagotomy.[82]

5.8 NONULCER DYSPEPSIA Nonulcer dyspepsia or functional dyspepsia is defined as upper abdominal or retrosternal pain, discomfort, heartburn, nausea, vomiting, or other symptom referable to the proximal alimentary tract, and lasting for more than 4 weeks. NUD indicates dyspepsia in a patient in whom no abnormality is identifiable by conventional gastroenterological examination. Table 5.2 lists the symptoms of dyspepsia.

TABLE fy 5.2 Dyspeptic symptoms • Abdominal pain • Postprandial fullness • • • • • • •

Abdominal bloating Belching Anorexia Nausea Vomiting Heartburn Regurgitation

Tropical Hepatogastroenterology

NONULCER DYSPEPSIA

Functional dyspepsia has several facets. Colin Jones et al.[83] in 1988 identified four categories: ulcer-like, reflux-like, dysmotility-like, and essential dyspepsia. Ulcer like dyspepsia includes symptoms resembling peptic ulcer disease, but with a normal endoscopy. Reflux like dyspepsia describes the occurrence of symptoms considered typical of gastroesophageal reflux disease, without endoscopic features of esophagitis. Dysmotility like dyspepsia includes patients with diffuse upper abdominal pain aggravated by food, bloating, distension, and early satiety. Essential dyspepsia includes patients who do not fit into these groups. Unequivocal allocation to any of these groups is usually not possible. The interpretation of upper GI symptoms relies heavily on clinical wisdom, often unsupported by scientific evidence. The relationship of pain to meals is of little diagnostic value in distinguishing dyspepsia from peptic ulcer disease. The occurrence of nocturnal pain has a lesser predictive value for peptic ulcer disease. Antacids are equally effective in duodenal ulcer disease, and in functional dyspepsia. Epigastric pain with the pointing sign is of the same diagnostic value as a diffusely localized upper abdominal pain.

excitability, or recruitment of dorsal horn neurons in the spinal cord that may result in amplification of visceral stimuli. Autonomic neuropathy may be a consequence of a decreased vagal tone secondary to acute and chronic life stresses. Psychological factors probably contribute to symptoms, and influence the patient’s decision to seek medical help. Anxiety and neuroticism are common in these patients. H. pylori does not play a major causal role in functional dyspepsia. The prevalence of H. pylori infection in patients with functional dyspepsia is similar to that in general population.

5.8.2 Approach to a Patient with Dyspepsia Upper GI endoscopy alone is probably sufficient to exclude most organic disease in a majority of dyspeptic patients.[84, 85] Table 5.3 lists the tests that the physician should consider in the investigation of a dyspeptic patient. Anemia, weight loss, and recent onset dyspepsia in patients over

TABLE fy 5.3 Investigations in patients with dyspepsia First line tests

5.8.1 Pathophysiology Several factors contribute to the development of symptoms of NUD. Gastroduodenal motility is impaired in NUD. Manometry and scintigraphic studies with radioisotopes show delayed postprandial gastric emptying, impaired antral motility, impaired gastric accommodation, and myoelectric abnormalities. Visceral hypersensitivity and autonomic neuropathy may contribute to NUD. These changes probably arise from the sensitization of peripheral gastric mechanoreceptors, or increased

Part II / Stomach

107

• Hematology including ESR • Stool examination for ova and parasites • Fecal occult blood tests • Upper gastrointestinal endoscopy • Mucosal biopsies • Ultrasonography Optimal tests • Measurement of gastric emptying • Tests for H. pylori • 24 hr esophageal pH metry • Esophageal manometry • Formal psychiatric evaluation • Tests for food intolerance

108

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

45 are cause for alarm, and mandate endoscopy. For patients without these features, empirical treatment may precede endoscopy, which the physician can conduct if clinical response does not occur.

Helicobacter eradication. H. pylori eradication probably confers no clinical benefits for patients with NUD.[87–91]

5.8.3 Therapy of NUD

Peptic ulcer disease may require surgery because of perforation, hemorrhage, and penetration.

The treatment of NUD is difficult and unsatisfactory. Not all patients require pharmacological therapy. A lifestyle change or following a particular dietary regimen along with a reassurance by the physician may be effective in certain patients. Tobacco, alcohol, and excessive use of coffee probably contribute to treatment failure, although objective evidence of this is lacking. There are no dietary restrictions or recommendations, but patients should avoid foods that aggravate symptoms. The role of pharmacotherapy in the management of dyspepsia is not yet fully settled. There is a high placebo response rate of 30%–60%, which hinders evaluation of drug efficacy. Antacids. In NUD, three placebo-controlled trials of antacid therapy have shown no advantage over placebo. Antisecretory therapy. Patients with epigastric pain or heartburn may benefit from anti-secretory drugs. PPIs are not definitely superior to the cheaper H2 receptor antagonists. Promotility agents. Promotility agents may benefit some patients with NUD by decreasing gastroesophageal reflux, improving gastric emptying, and facilitating gastric accommodation. Visceral analgesics. Visceral analgesics may alleviate dyspeptic symptoms by suppressing perception of afferent signals arising from the stomach and duodenum. The clinical benefits of fedotozine, an agonist of peripheral K receptor located on afferent gut wall neurons, is presently unclear.[86]

5.9 SURGERY FOR PEPTIC ULCER DISEASE

5.9.1 Time Trends There has been a dramatic reduction in the need for surgery for an intractable peptic ulcer, and today peptic ulcers very rarely require elective surgery.[92–94] In the authors’ experience, operations for intractable ulcer have dropped from one case per week in the late 1970s to less than a case a year at present. The fall is no doubt due to the efficacy of proton pump inhibitors and H2 antagonists. The frequency of emergency surgery, in contrast, has not decreased.[82, 94–96] Medical therapy has improved, but NSAID use has increased, especially among older persons, therefore complications are as frequent, and more common among the elderly.[97]

5.9.2 Operations for Peptic Ulcer and its Complications[98, 99] The following operations are available for treating peptic ulcer and its complications: 5.9.2.1 Vagotomy and drainage

A total vagotomy renders the stomach achlorhydric. A parietal cell vagotomy (also called highly selective vagotomy) decreases pH but spares the nerves to the pylorus, and also spares the other visceral branches of the vagus. This allows good gastric function and prevents postvagotomy diarrhea,

Tropical Hepatogastroenterology

SURGERY FOR PEPTIC ULCER DISEASE

but the recurrence rates are somewhat high since some vagal fibers to the stomach are spared. (MAINGOT) Parietal cell vagotomy is now of historical interest, since H2 blockers and proton pump inhibitors work as well.[94] A total vagotomy (also called truncal vagotomy) more effectively decreases gastric pH, but makes the stomach unable to empty itself. A gastric drainage procedure must, therefore, accompany the truncal vagotomy. There are two drainage procedures: gastrojejunostomy and pyloroplasty. Thus, peptic ulcer surgery may be a parietal cell vagotomy, or a truncal vagotomy + gastrojejunostomy, or a truncal vagotomy + pyloroplasty. Recurrence rates after vagotomy with drainage are about 5%. 5.9.2.2 Gastric resection

Gastric resection removes acid-producing cells, and is therefore an effective method of treating peptic ulcer. The classical gastric resection is a partial gastrectomy, with removal of two-thirds of the stomach. Partial gastrectomy does not need to be accompanied by a vagotomy. Recurrence rates after partial gastrectomy are about 1%, but the mortality is 2%–4%. An alternative to partial gastrectomy is antrectomy, in which the surgeon removes a fourth to a third of the stomach. Antrectomy is effective only if accompanied by a vagotomy. Recurrence rates for antrectomy with vagotomy are 1%–2%, and the mortality is about 1%–2%. A gastric resection includes antrectomy (25%– 30% gastric resection) plus truncal vagotomy (TV), or a partial gastrectomy (50%–60% gastric resection) without the need for a vagotomy. The recurrence rates for gastric resection are 1%– 2%, and the mortality is 1%–2% (more for partial gastrectomy). These resections have little value

Part II / Stomach

109

today, but may be indicated for a giant prepyloric ulcer, a bleeding antral ulcer, or a large gastric perforation. Small peptic perforations in the stomach respond well to simple closure. After vagotomy with antrectomy, postvagotomy diarrhea may occur in 20% of patients; this diarrhea is severe and debilitating in 1%–2%. Less often the patient experiences the dumping syndrome in the form of cardiovascular (sweating, fainting) or hypoglycemic episodes after meals.

5.9.3 Complications of Peptic Ulcer Requiring Surgery Peptic ulcer complications requiring surgery are perforation, hemorrhage, pyloric stenosis, and penetration. Perforations of the duodenum or stomach are the commonest of emergency procedures for peptic ulcer (Fig. 5.2).[100] Patients with perforation are

FIGURE 5.2 Perforation in the anterior wall of the first part of the duodenum (arrow). The white flakes are slough that forms from infected exudates and are always present in peritonitis.

110

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

usually smokers, or have been on NSAIDs. The typical history is that of sudden upper or mid-abdominal pain that gradually becomes diffuse with the onset of peritonitis. Examination shows the guarding and rigidity characteristic of peritonitis; percussion may reveal loss of liver dullness. The only diagnostic investigation required is a plain X-ray of the chest with the patient standing; the erect plain X-ray of the abdomen will do as well if the diaphragm is included. Once there is a pneumoperitoneum on plain X-ray, the localization: gastric, duodenal, ileal, appendicular, or large bowel, is of academic interest since the patient always needs surgery. Most surgeons treat perforated peptic ulcers by simple closure of the hole in the gastric or duodenal wall, and infrequently perform a definitive procedure like vagotomy with drainage.[101, 102] In low-risk patients with small perforations, a laparoscopic repair is safe. The conversion rates are about 15%.[103, 104] The treatment of gastric perforation is by simple closure of the hole in the stomach wall. The surgeon will excise a 1 cm rim of tissue at the ulcer edge before suture. This freshens the ulcer edge for better healing, and provides a sample for biopsy. If (very rarely) the perforation is very large and the tissue is very unhealthy, it is better to perform a resection that incorporates the perforation. The treatment of duodenal perforation is also a simple closure of the duodenal hole. Two to four interrupted absorbable sutures will satisfactorily close small perforations. Large perforations are a different matter. It is unwise to try to close large duodenal holes in this way since the sutures cut through the inflamed tissue. A better technique is to apply a thin flap of omentum to plug the duodenal defect.

Postoperative mortality is about 10%. Patients are more likely to die if they have comorbid conditions (especially glucocorticoid use, which nearly doubles the risk), septic shock, or delayed surgery.[101, 102, 105–107] 5.9.3.1 Bleeding

Bleeding duodenal ulcers require suture control of the arterial spurter. Therefore, a duodenotomy is mandatory. Simple ligature control is followed by high recurrent bleeding rates, therefore surgeons are more likely to add a definitive procedure for bleeding than for perforation.[108] Since the patient has already undergone duodenotomy, a TV+pyloroplasty is the usual choice of operation. Chapter 43 discusses bleeding peptic ulcer in greater detail. 5.9.3.2 Pyloric stenosis

Pyloric stenosis is a common complication, and develops when a duodenal ulcer heals with scarring. The pylorus narrows to the extent that gastric emptying is compromised. Patients complain of vomiting and loss of weight; usually the vomit contains food ingested over 12 hours earlier.[82] Examination of a fasting patient reveals a succession splash. The X-ray will show a markedly distended stomach; a CT scan confirms the large gastric capacity. An endoscopy is mandatory, which will confirm the narrowing in the pylorus or in the first part of the duodenum. Endoscopy will also exclude other causes of gastric outlet obstruction, such as cancer. The treatment of pyloric stenosis is by a drainage operation, usually a GJ. (The deformed pylorus and duodenum do not permit a satisfactory pyloroplasty.) Most surgeons add a TV to the GJ, since a gastrojejunostomy alone does not cure a duodenal ulcer.

Tropical Hepatogastroenterology

REFERENCES

5.9.3.3 Penetration

A progressively deepening ulcer may adhere to adjacent organs and penetrate, without causing a free perforation. Penetration occurs most commonly into the pancreas; less often the ulcer penetrates into the gastrohepatic omentum, biliary tract, liver, and other structures.[82] Typically the

111

pain changes from intermittent to continuous, and tends to become more refractory to treatment. Penetration may cause pancreatitis, abscesses, hemorrhage, and choledochoduodenal and other fistulas. CT scan may show a sinus tract or an ectopic pocket of gas, but in general diagnosis is difficult. Treatment depends on the symptoms and specific complications.

REFERENCES [1] Susser M. Period effects, generation effects and age effects in peptic ulcer mortality. J Chronic Dis 1982;35:29–40. [2] Chuttani HK, Wig KL, Chablani TD et al. Epidemiology of peptic ulcer: prevalence of peptic ulcer in an urban community in Delhi. Ind J Med Res 1963;55:1121–28. [3] Tovey FI, Jayaraj AP. Peptic ulcer in India. Gut 1990;31: 123–24. [4] Sharma MP, Choudhari G. Nocturnal pain and duodenal ulcer. Br J Clin Pract 1988;42:198–99. [5] Peura D. The report of the Digestive Health Initiative International Update Conference on Helicobacter pylori. Gastroenterol 1997;113:S4–S8. [6] Crespo A, Suh B. Helicobacter pylori infection: epidemiology, pathophysiology, and therapy. Arch Pharm Res 2001;24:485–98. [7] Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and the risk for duodenal and gastric ulceration. Ann Intern Med 1994;120:977–81. [8] Fendrick AM, Bandekar RR, Chernew ME et al. Role of initial NSAID choice and patient risk factors in the prevention of NSAID gastropathy: a decision analysis. Arthritis Rheum 2002;47:36–43. [9] Wolfe F, Anderson J, Burke TA et al. Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy. Rheumatol 2002;29:467–73.

Part II / Stomach

[10] Fraser GM, Earnshaw PM. The double-contrast barium meal: a correlation with endoscopy. Clin Radiol 1983;34:121–31. [11] Gill HH, Desai HG. Editorial: Helicobacter pylori and gastroduodenal disorders in India— lessons from epidemiology. J Clin Gastroenterol 1993;16:6–9. [12] Graham DY, Adam E, Reddy P et al. Seroepidemiology of Helicobacter pylori infection in India. Comparison of developing and developed countries. Dig Dis Sci 1991;36:1084–8. [13] Guha Mazumder DN, Ghoshal UC. Epidemiology of Helicobacter pylori in India. Indian J Gastroenterol 1997;16(suppl 1):S3–S5. [14] Ranganathanan S, Prabhu SR, Gill HH et al. Role of Helicobacter pylori in Gastroduodenal diseases: an histologic study in Indian population. Bombay Hospital J 1993;35:1173–7. [15] Prabhu SR, Ranganathanan S, Amarapurkar DN. Helicobacter pylori in normal gastric mucosa. J Assoc Physicians India 1994;42:863–4. [16] Gill HH, Desai HG, Mazumdar P et al. Epidemiology of Helicobacter pylori: the Indian scenario. Indian J Gastroenterol 1993;12:9–11. [17] Gill HH, Mazumdar P, Shankaran K et al. Agerelated prevalence of H. pylori antibodies in Indian subjects. Indian J Gastroenterol 1994;13:92–4. [18] Alaganantham TP, Pai M, Vaidehi T et al. Seroepidemiology of Helicobacter pylori infection in an

112

[19]

[20]

[21]

[22]

[23]

[24]

[25] [26]

[27]

[28]

[29]

[30]

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

urban, upper class population in Chennai, Indian J Gastroenterol 1999;18:66–8. Misra V, Misra SP, Dwivedi M et al. Point prevalence of peptic ulcer and gastric histology in healthy Indians with Helicobacter pylori infection. Am J Gastroenterol 1997;92:1487–91. Bhandarkar PV, Abraham P. Helicobacter pylori infection in the Indian environment. Trop Gastroenterol 2000;21:51–9. Bhatia SJ, Abraham P. Helicobacter pylori in the Indian environment. Indian J Gastroenterol 1995;14:139–44. Mulchandani R, Sandhu N, Abraham P et al. Detection of Helicobacter pylori by polymerase chain reaction in water supply samples in Mumbai. Indian J Gastroenterol 1998;17(suppl1):S2. Bhandarkar PV, Desai HG. Reservoirs and routes of transmission of Helicobacter pylori in India. Indian J Gastroenterol 1997;16(suppl 1):S9–S12. Majumdar P, Shah SM, Dhunjibhoy KR et al. Isolation of Helicobacter pylori from dental plaques in healthy volunteers. Indian J Gastroenterol 1990;21:271–2. Shankaran K, Desai HG. Helicobacter pylori in dental plaque. J Clin Gastroenterol 1991;21:82–4. Desai HG, Gill HH, Shankaran K et al. Dental plaque: a permanent reservoir of Helicobacter pylori? Scand J Gastroenterol 1991;26:1205–8. Singh V, Trikha B, Vaiphei K et al. Helicobacter pylori: evidence for spouse to spouse transmission. Indian J Gastroenterol 1998;17(suppl1): S56. Yachha SK, Ghoshal UC, Gupta R et al. Portal hypertensive gastropathy in children with extrahepatic portal venous obstruction: role of variceal obliteration by endoscopic sclerotherapy and Helicobacter pylori infection. J Pediatric Gastroenterol Nutr 1996;223:20–3. Mukhopadhyay AK, Kersulyte D, Jeong JY et al. Distinctiveness of genotypes of Helicobacter pylori in Calcutta,India. J Bacteriol 2000;182:3219–27. Kumar S, Dhar A, Srinivasan S et al. Antibodies to Cag A protein are not predictive of serious gastroduodenal disease in India patients. Indian J Gastroenterol 1998;17:126–8.

[31] Kumar A, Sreenivas DV, Laxmi V et al. Combination of rapid urease test and histology is ideal in our set up in detection of H. pylori in DU patients. Indian J Gastroenterol 1998;17:S24–5. [32] Nijhawan R, Kocchar R, Panigrahi D et al. Identification of H. pylori by endoscopic crush cytology. Indian J Gastroenterol 1993;12:45–6. [33] Ayyagari A, Ray P, Kocchar R et al. Evaluation of different methods for detection of H. pylori in patients with gastric disease. Indian J Med Res 1990;91:126–8. [34] Misra SP, Misra V, Dwivedi M et al. Diagnosing Helicobacter pylori by imprint cytology: can the same biopsy specimen be used for histology? Diagnostic Cytopathology 1998;18:330–2. [35] Saksena S, Dasarathy S, Verma K et al. Evaluation of endoscopy based diagnostic methods for the detection of Helicobacter pylori. Indian J Gastroenterol 2000:19:61–3. [36] Kaul A, Bhasin DK, Pathak CM et al. Normal limits of 14C-urea breath test. Tropical Gastroenterol 1998;19:110–3. [37] Ahuja V, Bal CS, Sharma MP. Can the C-14 urea breath test replace follow-up endoscopic biopsies in patients treated for Helicobacter pylori infection? Clinical Nuclear Medicine 1998;18:330–2. [38] Sharma BC, Bhasin DK, Pathak CM et al. (14C)-urea breath test to confirm eradication of Helicobacter pylori. J Gastroenterol Hepatol 1999;14:309–12. [39] Pathak CM, Bhasin DK, Panigraphi D et al. Evaluation of 14C-urinary excretion and its comparison with 14-CO2 in breath after 14C-urea administration in H. pylori infection. Am J Gastroenterol 1994;89:734–8. [40] Dewan R, Sachdev GK. Diagnosis of Helicobacter pylori infection in primary and tertiary care centers. Indian J Gastroenterol 2000:19(suppl1):S11–14. [41] Sharma MP. Diagnosis of Helicobacter pylori infection: who should be tested with intention to treat? Indian J Gastroenterol 2000;19(suppl1):S36. [42] Abraham P, Bhatia SJ. Position Paper on H. pylori in India. Indian J Gastroenterol 1997;16(suppl 1):S29.

Tropical Hepatogastroenterology

REFERENCES

[43] Malfertheiner P, Megraud F, O’Morain C et al. European Helicobacter Pylori Study Group (EHPSG). Current concepts in the management of Helicobacter pylori infection–the Maastricht 22000 Consensus Report. Aliment Pharmacol Ther. 2002;16:167–80. [44] Khanna MU, Abraham P, Nair NG et al. Collidal bismuth subcitrate in nonulcer dyspepsia. J Postgrad Med 1992;38:106–87. [45] Gill HH, Desai HG, Maheta PR et al. Mono and dual therapy for H. pylori associated gastritis. J Assoc Physicians India 1991;39:743–5. [46] Kumar M, Yachha SK, Aggarwal R et al. Healing of chronic antral gastritis: effect of sucralfate and colloidal bismuth subcitrate. Indian J Gastroenterol 1996;15:90–3. [47] Gupta VK, Dhar A, Srinivasan S et al. Eradication of H. pylori in a developing country: comparison of lansoprazole versus omeprazole with norfloxacin, in a dual therapy study. Am J Gastroenterol. 1997;92:1140–2. [48] Goenka MK, Das K, Vaiphei K et al. H. pylori eradication evaluation of triple therapy containing omeprazole. Indian J Gastroenterol 1996;15: 1–3. [49] Dayal VM, Kumar P, Kamal J et al. Triple drug therapy of H. pylori in duodenal ulcer disease. Indian J Gastroenterol 1997;16:46–8. [50] Ahuja V, Dhar A, Bal C et al. Lansoprazole and secnidazole with clarithromycin, amoxycillin or pefloxacin in eradication of Helicobacter pylori in a developing country. Alimentary Pharmacol Ther 1998;12:551–5. [51] Kumar D, Ahuja V, Dhar A et al. Triple versus quadruple drug regime for eradication of H. pylori in patients with duodenal ulcer-results of a prospective randomized trial. Indian J Gastroenterol 2001;20:191–4. [52] Bhasin DK, Sharma BC, Ray P et al. Comparison of seven and fourteen days of lansoprazole, clarithromycin and amoxycillin therapy for eradication of Helicobacter pylori: A report from India. Helicobacter 2000;5:84–87. [53] Bhasin DK, Sharma BC, Sinha SK et al. Helicobacter pylori eradication: comparison of three

Part II / Stomach

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

113

treatment regimens in India. J Clin Gastroenterol 1999;28:348–51. Bhasin DK, Singh V, Ayyagari A et al. Effect of various antiulcer drugs on rapid urease test for campylobacter pylori infection. Lancet 1989;ii:918–9. Mishra SC, Dasarathy S, Sharma MP. Omeprazole versus famotidine in the healing and relapse of duodenal ulcer. Aliment Pharmacol Ther 1993;7: 443–9. Gisbert JP, Pajares JM. Helicobacter pylori therapy: first line option and rescue regimen. Dig Dis 2001;2:134–143. Segura AM, Gutierrez O, Otero W et al. Furazolidine, amoxicillin, bismuth citrate based therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11:529–532. Coelho LG, Leon-Barua R, Ramirez-Ramos et al. The Latin American Consensus Conference on Helicobacter pylori infection. Am J Gastroenterol 2000;95:2688–91. Calabrese C, Di Febo G, Areni A et al. Pantoprazole, azithromycin and tinidazole: short duration triple therapy for eradication of Helicobacter pylori infection. Aliment Pharmacol Ther 2000;14: 1613–1617. Cammarota G, Cianci R, Cannizaro O et al. Efficacy of two one week omeprazole/ levofloxacin based triple therapies for Helicobacter pylori infection. Aliment Pharmacol Ther 2000;14: 1339–1343. Perri F, Festa V, Climente R et al. A randomized study of two ‘rescue’ therapies for Helicobacter pylori infected patients after failure of standard triple therapies. Am J Gastroenterol 2001;96: 58–62. M´egraus F, Occhialini A, Rossignol IF. Nitazoxamide, a potential drug for eradication of Helicobacter pylori with no cross resistance to metronidazole. Amtimicrob Agents Chemother 1998;42: 1836–2840. Nanivadekar SA, Sawant PD, Patel HD et al. Association of peptic ulcer with Helicobacter pylori and the recurrence rate. A three year follow up study. J Assoc Physicians India 1990;38(suppl 1): 703–6.

114

Chapter 5 / PEPTIC ULCER DISEASE AND NONULCER DYSPEPSIA

[64] Gupta S, Jain AK, Gupta JP. Is H. pylori eradication in duodenal ulcer subjects useful in Indian environment? Indian J Gastroenterol 1996;15(suppl1):A83. [65] Dewan R, Gautam S, Monga A. Concomitant treatment of spouses to prevent H. pylori reinfection in duodenal ulcer patients. J Assoc Physicians India 1996;44:A88. [66] Eapen CE. Recurrence of Helicobacter pylori infection after eradication. Indian J Gastroenterol 2000;19:S25–27. [67] Jain AK, Dayal VM. H. pylori recolonisation and ulcer relapse after its eradication in India. Indian J Gastroenterol 1997;16(suppl 1):S22–S24. [68] Konar A, Das As, De PK et al. Natural history of severe duodenal ulcer disease. Indian J Gastroenterol 1998;17:48–50. [69] Ahuja V, Sharma MP. Recurrence of H. pylori after successful eradication. Gastroenterology 2002; 123:653–4. [70] Abraham P, Sandhu N, Naik SR. In vitro sensitivity of Helicobacter pylori in India. Indian J Gastroenterol 1997;16(suppl 1):S20–1. [71] Bhasin DK,Sharma BC,Ray P. Drug resistance in Helicobacter pylori infection. Indian J Gastroenterol 2000;19(suppl1) :S29–32. [72] Mukhopadhaya DK, Tandon RK, Dasarathy S et al. A study of H. pylori in north Indian subjects with nonulcer dyspepsia. Indian J Gastroenterol 1992;11:176–9. [73] Dhali GK,Garg P, Sharma MP. Role of antiHelicobacter pylori treatment in H. pylori-positive and cytoprotective drugs in H. pylori-negative, nonulcer dyspepsia: results of a randomized, double-blind, controlled trial in Asian Indians. J Gastroenterol Hepatol 1999;14:523–8. [74] Dhar A, Sharma MP. Lacunae in data on Helicobacter pylori from India. Indian J Gastroenterol 1997;16(suppl 1):S13–15. [75] Larkai EN, Smith JL, Lidsky MD et al. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 1987;82:1153–58.

[76] Laine L. Approaches to nonsteroidal antiinflammatory drug use in high risk patients. Gastroenterology 2001;120:594–606. [77] Lanas AI, Ramacha B, Esteva F et al. Risk factors associated with refractory peptic ulcers. Gastroenterology 1995;109:1124–33. [78] Bardhan KD. Refractory duodenal ulcer. Gut 1984;25:711–7. [79] Bardhan KD. Is there any acid peptic disease that is refractory to proton pump inhibitors? Aliment Pharmacol Ther 1993; 7 (suppl1):13–24. [80] Lanas A. NSAID use and abuse in gastroenterology: refractory peptic ulcer. Acta Gastroenterol Belg 1999;62:418–20. [81] Lanas A, Remacha B, Sainz R et al. Study of outcome after targeted intervention for peptic ulcers resistant to acid suppression therapy. Am J Gastroenterol 2000; 95:513–9. [82] Soll AH. Peptic ulcer and its complications. In Feldman M, Scharschmidt BF, Sleisenger MH (Editors): Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. WB Saunders Co, Philadelphia, 1998;620–78. [83] Collin Jones DG, Bloom B, Bodemar G et al. Management of dyspepsia. Report of a working party. Lancet 1988;1576–9. [84] Nyren O, Adami HO, Bates S et al. Absence of therapeutic benefit from cimetidine or antacids in nonulcer dyspepsia. N Engl J Med 1986;314: 339–43. [85] Drossman DA, Thompson WG, Talley NJ et al. Identification of subgroups of functional gastrointestinal disorders: working team report. Gastroenterol Int 1990;3:159–72. [86] Delvaux M. Pharmacology and clinical experience with fedotozine. Expert Opin Investig Drugs 2001;10:97–110. [87] Talley NJ. Dyspepsia: management guidelines for the millennium. Gut 2002;50 Suppl 4: 72–8. [88] Axon A.Management of uninvestigated dyspepsia: review and commentary. Gut 2002;50 Suppl 4: 51–53. [89] Moayyedi P. Helicobacter pylori test and treat strategy for young dyspeptic patients: new data. Gut 2002;50 Suppl 4:47–50.

Tropical Hepatogastroenterology

REFERENCES

[90] Bazzoli F, De Luca L, Pozzato P et al. Helicobacter pylori and functional dyspepsia: review of previous studies and commentary on new data. Gut 2002;50 Suppl 4:33–5. [91] Talley NJ, Quan C. Helicobacter pylori and nonulcer dyspepsia.Aliment Pharmacol Ther 2002;16 Suppl 1:58–65. [92] Bardhan 2004, Bardhan KD, Williamson M et al. Admission rates for peptic ulcer in the Trent region, UK, 1972–2000. Changing pattern, a changing disease? Dig Liver Dis 2004;36:577–88. [93] Thors H, Svanes C, Thjodleifsson B. Trends in peptic ulcer morbidity and mortality in Iceland. J Clin Epidemiol 2002;55:681–6. [94] Paimela H, Oksala NK, Kivilaakso E. Surgery for peptic ulcer today. A study on the incidence, methods and mortality in surgery for peptic ulcer in Finland between 1987 and 1999. Dig Surg 2004;21(3):185–91. [95] Kurata JH. Epidemiology of peptic ulcer. Semin Gastrointest Dis 1993;4:2–12. [96] Christensen A, Bousfield R, Christiansen J. Incidence of perforated and bleeding peptic ulcers before and after the introduction of H2 -receptor antagonists. Ann Surg 1988;207:4–6. [97] Ohmann C, Imhof M, Ruppert C et al. Time-trends in the epidemiology of peptic ulcer bleeding. Scand J Gastroenterol 2005;40:914–20. [98] Soybel DI, Zinner MJ. Stomach and duodenum: operative procedures. In: Zinner MJ, Schwartz SI, Ellis H (editors): Maingot’s Abdominal Operations, 10th edition, Prentice Hall Inc, London, 1997, p1079–1127. [99] Seymour NE. Operations for peptic ulcer and their complications. In Feldman M, Scharschmidt BF, Sleisenger MH (Editors): Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. WB Saunders Co, Philadelphia, 1998; P697–710.

test

Part II / Stomach

115

[100] Towfigh S, Chandler C, Hines OJ et al. Outcomes from peptic ulcer surgery have not benefited from advances in medical therapy. Am Surg 2002;68:385–9. [101] Testini M, Portincasa P, Piccinni G et al. Significant factors associated with fatal outcome in emergency open surgery for perforated peptic ulcer. World J Gastroenterol 2003;9(10):2338–2340. [102] Gupta BS, Talukdar RN, Neupane HC. Cases of perforated duodenal ulcer treated in College of Medical Sciences, Bharatpur over a period of one year. Kathmandu Univ Med J (KUMJ). 2003;1:166–9. [103] Siu WT, Leong HT, Law BK et al. Laparoscopic Repair for Perforated Peptic Ulcer: A Randomized Control Trial. Ann Surg 2002;235: 313–319. [104] Lunevicius R; Morkevicius M. Management strategies, early results, benefits, and risk factors of laparoscopic repair of perforated peptic ulcer. World J Surg 2005; 29:1299–310. [105] Christensen S, Riis A, Norgaard M et al. Perforated peptic ulcer: use of preadmission oral glucocorticoids and 30-day mortality. Aliment Pharmacol Ther. 2006;23:45–52. [106] Ersumo TW, Meskel Y, Kotisso B. Perforated peptic ulcer in Tikur Anbessa Hospital: a review of 74 cases. Ethiop Med J. 2005;43:9–13. [107] Madiba TE, Nair R, Mulaudzi TV et al. Perforated gastric ulcer–reappraisal of surgical options. S Afr J Surg 2005;43:58–60. [108] Gilliam AD, Speake WJ, Lobo DN, Beckingham IJ. Current practice of emergency vagotomy and Helicobacter pylori eradication for complicated peptic ulcer in the United Kingdom. Br J Surg 2003;90:88–90. [109] Madrazo B, Halpert RD, Sandler MA et al. Computed tomographic findings in penetrating peptic ulcer. Radiology 1984;153:751–4.

Chapter

6 BENIGN TUMORS OF THE STOMACH AK Kakar and Vishal Gupta

6.1 INTRODUCTION Benign tumors of the stomach are rare, and account for only 2% of gastric neoplasms. They are important because they may cause marked bleeding, and because they are often amenable to endoscopic removal. This chapter describes the more frequently encountered varieties of benign gastric tumors.

6.2 CLASSIFICATION These tumors are of two types: epithelial and mesenchymal. The epithelial tumors are polyps. The non-epithelial or mesenchymal tumors include lipomas, leiomyomas, gastrointestinal stromal cell tumors (GIST), carcinoids, neuroendocrine tumors and others. Other rare lesions include inflammatory pseudotumors and cysts.

6.2.1 Gastric Polyps Although submucosal benign lesions may produce an apparently polypoid lesion, the term polyp in the gastrointestinal tract is generally confined to the lesions arising from the mucosa. Gastric polyps are uncommon and are found in approximately 0.4% of autopsies and 3%–5% of adults.[1] 116

Gastric polyps are classified as neoplastic and non-neoplastic. 6.2.1.1 Neoplastic polyps

Neoplastic polyps are the adenomas, and are true neoplasms. Adenomatous polyps account for 5%– 10% of polypoid lesions of the stomach. The polyps can be sessile, pedunculated or villous, and are usually single, and located in the antrum. They are mostly > 2 cm in size, but may grow up to 3–4 cm before detection. These polyps contain dysplastic proliferative epithelium, and thus have malignant potential. Adenomatous polyps larger than 2 cm have a 50%–66% risk of becoming malignant. A focus of in situ or invasive carcinoma is present in about one-third of such polyps at the time of presentation.[2–4] The incidence of gastric adenomatous polyps increases with age, and most patients are between 60 and 80 years old. These polyps are twice as common in males as in females. Only half of the patients are symptomatic, and present with non-specific symptoms like epigastric discomfort or pain, nausea, vomiting (30%), or GI bleeding (20%). Achlorhydria, due to associated atrophic gastritis, may be present in 80%–90% of patients with adenomatous polyps.

CLASSIFICATION

6.2.1.2 Non-neoplastic polyps

Non-neoplastic polyps are more common (90%) than neoplastic polyps. They include hyperplastic polyps, fundic gland polyps, inflammatory fibroid polyps, juvenile polyps and mixed polyps. Hyperplastic polyps Hyperplastic polyps are also known as inflammatory, regenerative, or hamartomatous polyps. They are the most common (65%–90%) epithelial gastric polyps. The polyps are predominantly located in the antrum and are multiple in 50% of cases, small, usually less than 2 cm, and sessile. Microscopically, these polyps contain a mixture of hyperplastic pyloric type glandular tissue and the intervening edematous lamina propria that contains inflammatory cells and smooth muscle. Hyperplastic polyps occur most commonly in association with chronic active superficial gastritis and H. pylori infection.[5] They also present in solid organ transplant patients, indicating that their development is perhaps related to immunosuppression.[6] Polyps tend to be multiple and are predominantly located in the antrum. A rare type of gastric hyperplastic polyp is the inverted hyperplastic polyp (IHP). These inverted polyps are characterized by the downward growth of the hyperplastic mucosal component into the submucosa.[7] Although, hyperplastic polyps are considered non-neoplastic, they are found in about 20% of gastric specimens resected for carcinoma, and the dysplasia-carcinoma transformation is probably important.[8] The rate of malignant transformation is 1%–3%, and depends on the size and number of polyps.[9] Malignant transformation may correlate to over-expression of p53, p21WAF1/CIP1, and Cyclin D1 genes, and to the mutation of p53, but not of c-Ki-ras.[10]

Part II / Stomach

117

While most patients with hyperplastic polyps are asymptomatic, dyspepsia and epigastric discomfort are the most common presenting complaints in symptomatic cases. Fundic gland polyps They are also known as fundic gland hyperplasia, hamartomatous cystic polyps, and polyps with fundic glandular cysts. Histologically, they show hyperplasia of normal fundic glands. Unlike hyperplastic polyps, fundic gland polyps do not have malignant potential. These polyps occur in multiple polyposis syndromes like familial polyposis coli, Peutz-Jeghers syndrome, familial juvenile polyposis, CronkhiteCanada syndrome, and Cowden syndrome. 6.2.1.3 Management of gastric polyps

Gastric polyps show up on gastroscopy. Endoscopy and biopsy are required to differentiate between benign and malignant polyps. Symptomatic pedunculated polyps less than 2 cm in size can be removed endoscopically. Gastric resection is usually required for pedunculated polyps larger than 2 cm, and for sessile polyps.[11] If the histology of the removed polyps shows an in situ carcinoma, a wedge resection will suffice. If it shows invasive cancer, a radical gastrectomy is required after proper evaluation. In patients with hyperplastic polyps and associated H. pylori infection, eradication of H. pylori should be attempted before endoscopic removal, as these polyps tend to disappear after antibiotic therapy. In asymptomatic patients, a polyp larger than 2 cm in size is best removed, since it has a higher malignant potential. These patients need followup by yearly gastroscopy. Multiple polyps less than 2 cm can be followed up by 6-monthly gastroscopy. To summarize, polyps less than 2 cm in size, multiple, pedunculated and randomly distributed in the stomach can be safely observed.

118

Chapter 6 / BENIGN TUMORS OF THE STOMACH

FIGURE 6.1 A gastric leiomyoma. Most leiomyomas project into the lumen. This one protruded serosally (S – stomach wall, L – left lobe of liver). Inset shows cut section of the tumor. Note the variegated appearance.

6.2.2 Leiomyomas Leiomyomas are the most common mesenchymal tumors of the stomach, constituting 55%–60% of all benign gastric tumors[12] and 1%–2% of all gastric tumors.[13] Leiomyomas and other mesenchymal tumors are largely similar in their macroscopic appearance and clinical behavior. They are usually single, well circumscribed, and roughly spheroidal (Fig. 6.1). Located submucosally, they show no predilection for any specific part of the stomach. The different forms of leiomyomas are exogastric, endogastric, intramural, endo-exogastric (hourglass), ulcerated exogastric, and ulcerated endogastric (Fig. 6.2). As they enlarge, they tend to bulge into the gastric lumen (endogastric type). Exogastric types are less common. Although, they are benign, they can extend and involve adjacent organs like the transverse colon.[14]

FIGURE 6.2 Morphological forms of leiomyomas with respect to position within the gastric wall.

Histologically, muscle fibers are arranged in whorls or in palisades. There is a thin pseudocapsule. Degenerating changes like myxoid degeneration, necrosis, calcification, or ossification can occur. Malignant transformation is rare. These tumors are slowly growing, and may remain asymptomatic even when large. There are no specific signs and symptoms referable to leiomyoma, and other mesenchymal tumors. Leiomyomas occur most commonly in the age group of 30 to 70 years, with equal sex distribution. The most common presenting feature is hemorrhage. It occurs in 5% of symptomatic cases, and presents as hematemesis or melena. It results from ulceration of the overlying mucosa. Ulceration may occur spontaneously, or following NSAIDs or steroid use.[15] Spontaneous hemoperitoneum may also occur. Other less common symptoms are epigastric pain or discomfort, palpable mass, dyspepsia, weakness and weight loss. Pain may result from contraction of the smooth muscle of the tumor. Unusual presentations include gastroduodenal

Tropical Hepatogastroenterology

CLASSIFICATION

intussusception with acute pancreatitis,[16] duodenal occlusion with cholestasis[17] and achalasia.[18] On barium upper GI series, these tumors appear as well defined, mobile filling defects with a smooth outline. The mucosal folds end sharply at the edge of the tumor. There is no alteration in peristaltic waves or in gastric distensibility. On endoscopy, leiomyomas appear as smooth, welldefined tumors with stretched and effaced mucosal folds, overlying the tumor (Schindler sign). However, no gross feature is specific for leiomyoma. Endoscopic ultrasound is the best test for the detection, staging, and follow-up of these tumors.[19] CT scan can outline these tumors and demonstrate extragastric extension. 6.2.2.1 Management

Management in symptomatic cases is by excision of the tumor with a few millimeters of surrounding gastric wall. Giant leiomyomas may require partial gastrectomy.

6.2.3 Gastrointestinal Stromal Cell Tumors Gastrointestinal stromal cell tumors (GIST) arise from the interstitial cells of Cajal (ICCs), and are specific, c-Kit expressing and Kit signaling driven mesenchymal tumors.[20] They are the commonest mesenchymal tumors of the GI tract.[21] The ICCs constitute a network of cells along the entire length of the GI tract, between the outer longitudinal and inner circular muscle layers. They act as the pacemaker cells of the GI tract, and initiate peristalsis in the stomach and small bowel. ICCs cells express the c-Kit (CD117) transmembrane protein. This protein is a type III receptor tyrosine kinase, and is encoded by the Kit protooncogene located on chromosome 4q. The gene’s expression during embryogenesis forms the ICCs. Gainof-function mutations of the Kit proto-oncogene

Part II / Stomach

119

occur in up to 90% of GISTs, allowing activation of tyrosine kinase, aberrant cell division and tumor growth.[22] Immunohistochemically, the ICCs are positive only for CD117, as well as for CD34 and vimentin. GISTs, in addition, are also positive for P glycoprotein 9.5, and α-smooth muscle actin, and negative for desmin, muscle specific actin, S-100, neurofilament, and chromogranin. GISTs constitute 1% of all gastric neoplasms. They can present anywhere in GI tract from the lower esophagus to the anus, but are found most commonly in the stomach (60%–70%) and small intestine (25%–35%).[21] They may occur in relation to neurofibromatosis (NF 1) or Carney’s triad (extra-adrenal paraganglioma, pulmonary chondroma, and leiomyomas in children). GISTs are often found incidentally. Some GISTs appear as primaries in the omentum, mesentery, or retroperitoneum, but most GISTs in these sites are metastases from gastric or intestinal primaries.[21] Histologically, GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones, and the morphology differs somewhat by site. They can present in any age group, but typically present in adults over 40 years of age, with a peak incidence in the 5th–6th decades. They have an equal sex distribution, and usually present with abdominal fullness, pain, nausea, or dysphagia. Acute presentations like perforation or bleeding occur less commonly. Large gastric GISTs may even be palpable. Endoscopy with biopsy establishes the diagnosis. A major diagnostic criterion is the demonstration of expression of the Kit protein (CD117).[20] Abdominal and pelvic CT scans help to assess the extent of the tumor. Between 10% and 30% of GISTs are malignant.[23] Malignant GISTs are typically large, wellcircumscribed, heterogeneous, centrally necrotic tumors that arise in the stomach wall. They rarely

120

Chapter 6 / BENIGN TUMORS OF THE STOMACH

obstruct viscera, despite their large size, and have a propensity to metastasize to the liver and peritoneum.[24] Prediction of malignancy is very difficult. Tumors with a mitotic activity count more than 5 per 50 high power field (HPF), or those larger than 5 cm, are at high risk of developing intra abdominal recurrences and liver metastases. Tumors less than 2 cm in size and mitotic activity counts less than 5 per 50 HPF are likely to be benign.[20] 6.2.3.1 Management

TABLE fy 6.1 Indicators of poor prognosis in GISTs Fujimoto and co-workers found the following to indicate a poorer outcome: • Male sex • Tumor size > 10 cm • Presence of ulceration • Epithelioid cell component • Severe nuclear atypia • High cellularity • Mitotic index > 10 • Exogastric or invasive growth pattern • Necrosis

The tumour requires complete surgical excision. Submucosal excision is not recommended because of transmural origin, and a complete transmural excision, with at least 1 cm margin, is needed. As lymph node involvement is rare, nodal dissection is unnecessary. Small gastric GISTs can be removed laparoscopically or at laparotomy. After surgery, recurrence rates are high. These tumors are unresponsive to standard chemotherapy and radiotherapy. There was no effective chemotherapy until the introduction of imatinib mesylate. Imatinib mesylate (Gleevec, Glivec) is a competitive inhibitor of tyrosine kinases associated with the Kit protein. Median survival is about 10–20 months in unresectable, metastatic, or recurrent disease.[22] Prognosis depends on tumor location, tumor size, presence of metastases, and other factors (Table 6.1).[25]

• Hemorrhage • Invasion of surrounding tissues

6.2.4 Gastric Endocrine Tumors

6.2.4.1 Well-differentiated gastric endocrine tumors

Tumors arising from the endocrine cells of the stomach include carcinoids and neuroendocrine tumors. Gastric endocrine tumors are rare and comprise about 0.3% of all gastric tumors[26, 27] and 11%–41% of all gastrointestinal endocrine tumors.[28] Gastric carcinoids (endocrine tumors or neuroendocrine tumors) arise

• Negative caldesmon immunoreactivity • Positive S-100 immunoreactivity • MIB-1 antigen labeling index > 10% (On multivariate analysis, male sex, size > 10 cm, presence of epithelioid component, and mitotic index of > 10 were significant indicator of poor prognosis.)[24]

most commonly from argyrophilic enterochromaffin-like (ECL) cells, but they can also arise from argentaffin cells that produce serotonin. Based on the degree of differentiation, gastric endocrine tumors are classified as well differentiated (carcinoids) and poorly differentiated (neuroendocrine carcinoma). Well-differentiated gastric carcinoids (also known as argyrophil cell tumors) are mainly composed of ECL cells, or rarely antral gastrin producing G-cells.

Well-differentiated gastric endocrine tumors (carcinoids) are further classified as types 1, 2, and 3[28] (Table 6.2). Type 1: Type 1 tumors are the most common type of well-differentiated gastric carcinoid. They are associated with chronic atrophic gastritis (CAG)

Tropical Hepatogastroenterology

CLASSIFICATION

121

TABLE fy 6.2 Gastric carcinoid tumorsy Type

I II III

Sex

F M=F M

Mean

Associated

Gastrin

age

pathology

level

63 50 55

CAG ZES/MEN 1 ↑↑ –

↑ < 1.5 cm N

and hypergastrinemia secondary to CAG. Argyrophilic ECL cell hyperplasia is present in 60%– 80% of patients with pernicious anemia/CAG, and gastric carcinoids occur in 4%–7% of these patients.[29] As they are secondary to hypergastrinemia, they tend to be multicentric (60%). Most of these tumors (91%) lie in the mucosa and submucosa.[28] They are usually small, over three-fourths being < 1 cm in size, and are predominantly found in the fundus and body. Grossly they appear flat or as sessile, reddish yellow polyps, and may be difficult to differentiate from hyperplastic polyps, which are more common in patients with CAG. They present most commonly in females (71%), the mean age of presentation being 63 years. Complications like ulceration and bleeding are uncommon. These tumors have a low malignant potential, and an excellent prognosis. Type 2: Type 2 endocrine tumors, the welldifferentiated gastric carcinoids, arise in the background of hypertrophic gastropathy with or without ZES/MEN1 (Zollinger–Ellison syndrome/ Multiple Endocrine Neoplasia). The gastric carcinoids in ZES/MEN1 are associated with diffuse ECL cells hyperplasia.[29] Small gastric carcinoids may be present in up to 30% of patents with MEN1 syndrome. Like type 1, they are also associated with hypergastrinemia and tend to be multicentric. Most (73%) of these gastric carcinoids are < 1.5 cm in size and are confined to the mucosa and submucosa.[28] Deeper invasion into the gastric wall is more common in type 2 as compared to

Part II / Stomach

Size < 1.5 cm Common > 1 cm

Multifocal/

Malignant

Multicentric

potential

Common Low (> type 1) Rare

Low Good High

Prognosis

Good Poor

type 1. The tumors occur in both sexes, at a mean age of 45 years. Malignant potential is low, and these tumors tend to have a benign course, though they are more aggressive than type 1 tumors. Type 3: These tumors are sporadic and are the least common type of well-differentiated gastric carcinoids. They are not associated with any significant gastric pathology. They tend to be solitary, occur in the nonatrophic gastric mucosa. Serum gastrin level is normal. Males are more commonly affected, and the mean age of presentation is 55 years. As liver metastases are common, a carcinoid syndrome may develop in 5%–30% of patients.[29] They are relatively larger (70% of these tumors are larger than > 1 cm), more deeply invasive, and more commonly associated with metastases. Regional nodal involvement occurs in 20%–50% of the patients, and liver involvement ultimately develops in two-thirds.[30] Type 3 gastric carcinoids may be typical or atypical. Atypical tumors tend to be larger, more invasive, and more commonly associated with local and liver metastases. Management of well-differentiated gastric endocrine tumors

Type 1 and type 2: The management of type 1 and type 2 gastric carcinoids is the same. Smaller tumors may be observed. Spontaneous resolution is known to occur.[31] Tumors 1.0 cm to 2.0 cm in size are endoscopically removable,

122

Chapter 6 / BENIGN TUMORS OF THE STOMACH

if deep gastric wall invasion can be excluded histopathologically. Recurrence is common if deep invasion has occurred, therefore surgical excision is preferred, with lymph node dissection if the nodes are involved. Tumors > 2 cm should be removed surgically, and gastrectomy should be considered in multifocal, larger or deeply invasive lesions. As these lesions are associated with hypergastrinemia, antrectomy with subsequent decrease in gastrin level has been used to reduce the risk of tumor progression. Antrectomy is effective in at least 50% of the patients with type 1 carcinoids, but is ineffective in large, locally invasive, or metastatic tumors.[29] While regression sometimes occurs,[32, 33] total gastrectomy may be required due to incomplete regression.[34, 35] Type 3: Type 3 tumors with typical histology and a size smaller than 1 cm can be safely removed endoscopically. Those larger than 1 cm require operative excision and nodal dissection. Tumors > 2 cm in size with an atypical histology or gastric wall invasion are most appropriately managed by gastrectomy.[30] 6.2.4.2 Poorly differentiated endocrine tumors (Neuroendocrine carcinomas)

Poorly differentiated endocrine tumors (neuroendocrine carcinomas) of the stomach are high-grade carcinomas.[36] These tumors are composed of cells strongly positive for neuron specific enolase (NSE) and protein gene product 9.5 (PGP 9.5), which are the cytosolic markers of neuroendocrine differentiation. These cells have a low content of endocrine granules, and stain poorly with granule markers, e.g., chromogranin. They are commoner among elderly males. They may arise in any part of the stomach, and tend to be larger, more deeply invasive, and more commonly associated with metastases to regional nodes, liver, lungs, and skin.

They are poorly differentiated and are not associated with endocrine symptoms. Prognosis is poor. Management of poorly differentiated endocrine tumors (Neuroendocrine carcinomas) As patients with neuroendocrine carcinoma usually present with metastatic disease, radical curative surgery is not possible at presentation. These patients have a mean survival of about 6 months.[28]

6.2.5 Lipomas Gastric lipomas are rare tumors with an incidence of 0.03% in autopsy series. They account for 6.3% of all benign non-epithelial tumors[12] and 5% of all gastrointestinal lipomas.[37] The tumors arise most commonly from the posterior wall of the pylorus and the antrum.[38, 39] Ninety percent are submucosal and the remaining subserosal.[38] Grossly they appear as vegetating lesions with a smooth surface and soft consistency. A gastric lipoma may present with a synchronous epithelioid stromal tumor.[40] Most gastric lipomas are asymptomatic, and present incidentally during exploration for unrelated reasons. They are usually found in adults, and show an equal sex distribution. Symptomatic lipomas present with ulcer-like pain, and upper gastrointestinal (GI) hemorrhage.[41] Upper GI bleeding results from ulcerated overlying mucosa, and may be severe. They may also present with gastrointestinal obstruction.[42] Pedunculated gastric lipomas may move through the pylorus, and cause gastroduodenal[43] or even gastrojejunal[44] intussusceptions. Such patients may present with vomiting, regurgitation, and heartburn. On esophagogastroscopy (Table 6.3), a definite differentiation between gastric lipoma and other gastric submucosal tumors is difficult, because routine endoscopic gastric biopsy does not reach the submucosal layer. Endoscopic ultrasound is a

Tropical Hepatogastroenterology

REFERENCES

TABLE fy 6.3 Endoscopic features of gastric lipomas Cushing sign :

Sponge like sinking impression as one advances the forceps into the lesion

Tenting sign

Grasping the mucosa with forceps and pulling it away from the underlying mass

:

Naked fat sign:

Protrusion of fat from the mass after multiple biopsies removing the overlying mucosa

good investigation to detect gastric lipoma and for guided biopsy. The lipoma appears as a diffuse hyperechoic mass within the submucosa. CT scan is the investigation of choice. Lipomas are diagnosed on the basis of specific density of fat, and appear as homogeneous structures with negative (−30 to −100) HU values. Lipomas differ from liposarcomas, which have a classic hetero-

123

geneous fatty density. Upper GI series show a smooth filling defect without any alteration in gastric motility or distension. 6.2.5.1 Management

Lipomas require simple submucosal excision. Gastric lipomas less three 3 cm can be removed by an endoscopic snare. Larger ones need removal by submucosal excision, performed laparoscopically or by conventional laparotomy.[45] Laparoscopic submucosal resection is technically feasible and safe.[46] Some patients may require partial gastrectomy. Management of asymptomatic lipomas is controversial. Small lipomas need observation, while many surgeons prefer removal of larger lipomas in view of risks of complications like obstruction and bleeding.

REFERENCES [1] Ming S-C, Epithelial polyps of the stomach. In: Ming S-C, and Goldman H (eds): Pathology of the Gastrointestinal Tract. Philadelphia, WB Saunders, 1992, p547. [2] Dekker W, Op den Orth JO. Polyps of stomach and duodenum: Significance and management. Dig Dis 1992;10:199–207. [3] Monaco A, Roth S, Castleman B et al. Adenomatous polyps of the stomach: A clinical and pathologic study of 153 cases. Cancer 1962;15:456–57. [4] Brunn H, Pearl F. Diffuse gastric polyposis: Adenopapillomatosis gastrica. Surg Gynecol Obstet 1926;43:559–61. [5] Ljubicic N, Kujundzic M, Roic G et al. Benign epithelial gastric polyps – frequency, location, and age and sex distribution. Coll Antropol 2002;26: 55–60. [6] Amaro R, Neff GW, Karnam US et al. Acquired hyperplastic gastric polyps in solid organ transplant

Part II / Stomach

patients. Am J Gastroenterol 2002;97:2220–4. [7] Yamashita M, Hirokawa M, Nakasono M et al. Gastric inverted hyperplastic polyp. Report of four cases and relation to gastritis cystica profunda. APMIS 2002;110:717–723. [8] Yao T, Kajiwara M, Kuroiwa S et al. Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. Hum Pathol 2002;33: 1016–22. [9] Cheung LY, Declore R. Stomach. In: Sabiston’s Textbook of Surgery. Townsend CM Jr (ed). 16th edition. New Delhi, Elsevier, 2001, p. 837–872. [10] Murakami K, Mitomi H, Yamashita K et al. P53, but not c-Ki-ras, mutation and down regulation of p21WAF1/CIP1 and cyclin D1 are associated with malignant transformation in gastric hyperplastic polyps. Am J Clin Pathol 2001;115: 224–34.

124

Chapter 6 / BENIGN TUMORS OF THE STOMACH

[11] King R, van Heerden J, Weiland L. The management of gastric polyps. Surg Gynecol Obstet 1982;155:846–8. [12] Palmer ED. Benign intramural tumors of the stomach: A review with special reference to gross pathology. Medicine 1951;30:81–181. [13] Nikolvaev NO, Chekmazov IA, Stavinskaia AA et al. Leiomiomy zheludka. Klin Med 1991;69:56 (Abs). [14] Goodman P, Raval B, Bonmati C et al. Leiomyoma involving the gastrocolic ligament: CT demonstration. Comput Med Imaging Graph 1990;14: 431–435. [15] Stalnikowicz R, Eliakim R, Ligumsky M et al. Drug induced bleeding of gastric leiomyoma. Am J Gastroenterol 1987;82:419. [16] White PG, Adams H, Sue Ling HM et al. Case report: Gastroduodenal intussusception – an unusual case of pancreatitis. Clin Radiol 1991;44: 357. [17] Grignani G, Pacchiarini L, Gamba G et al. Invagination of a gastric leiomyoma causing duodenal subocclusion and cholestasis. Minerva Med 1985;76:1623–6 (Abstract). [18] Chambon J, Gaudric M, Amouyal P et al. Achalasia associee a un leiomyome gastrique. Interet de l’echo-endoscopie. Gastroenterol Clin Biol 1990;14:605–7. [19] Tio TL, Tytgat GN, den Hartog Jager FC. Endoscopic ultrasonography for the evaluation of smooth muscle tumors in the upper gastrointestinal tract: An experience with 42 cases. Gastrointest Endosc 1990;36:342–50. [20] Meittinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal cell tumors (GISTs). Eur J Cancer 2002;38 suppl 5: S39–51. [21] Meittinen M, Lasota J. Gastrointestinal stromal cell tumors (GISTs): definition, occurrence pathology, differential diagnosis and molecular genetics. Pol J Pathol 2003;54:3–24. [22] Croom KF, Perry CM. Imatinib mesylate: in the treatment of gastrointestinal stromal tumors. Drugs 2003;63:513–22.

[23] Greenson JK. Gastrointestinal stromal tumors and other mesenchymal lesions of the gut. Mod Pathol 2003;16:366–75. [24] Burkill GJ, Badran M, Al-Muderis O et al. Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology 2003;226:527–32. [25] Fujimoto Y, Nakanishi Y, Yoshimura K et al. Clinicopathological study of primary malignant gastrointestinal stromal tumor of the stomach, with special reference to prognostic factors: analysis of results in 140 surgically resected patients. Gastric Cancer 2003;6:39–48. [26] Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560–62. [27] McDonald RA. A study of 356 carcinoids of the gastrointestinal tract. Am J Med 1956;21:867–78. [28] Rindi G, Bordi C, Rappel S et al. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology and behavior. World J Surg 1996;20:168–172. [29] Akerstrom G. Management of carcinoid tumors of the stomach, duodenum, and pancreas. World J Surg 1996;20:173–182. [30] Gough DB, Thompson GB, Crotty TB et al. Diverse clinical and pathologic features of gastric carcinoids and the relevance of hypergastrinemia. World J Surg 1994;18:473–9. [31] Harvey RF. Spontaneous resolution of multifocal gastric enterochromaffin-like cell carcinoid tumors (letter). Lancet 1988;1:821. [32] Richards AT, Hinder RA, Harrison AC. Gastric carcinoid tumors associated with hypergastrinemia and pernicious anemia-regression of tumors by antrectomy. S Afr Med J 1987;72:51–3. [33] Olbe L, Lundell L, Sundler F. Antrectomy in a patient with ECL-cell gastric carcinoids and pernicious anemia. Gastroenterol Int 1988;1:340–42. [34] Morgan JE, Kaiser CW, Johnson W et al. Gastric carcinoid (gastrinoma) associated with achlorhydria (pernicious anemia). Cancer 1983;51:2332–40. [35] Kern SE, Yardly JH, Lazenby AJ et al. Reversal by antrectomy of endocrine cell hyperplasia in the gastric body in pernicious anemia: a morphometric study. Mod Pathol 1990;3:561–6.

Tropical Hepatogastroenterology

REFERENCES

[36] Rindi G, Luinetti O, Cornaggia M et al. Three subtypes of gastric argyrophil carcinoids and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 1993;104:994–1006. [37] Alberti D, Grazioli L, Orizio P et al. Asymptomatic giant gastric lipoma. Am J Gastroenterol 1999;94:3634–7. [38] Fernandez MJ, Davis RP, Nora PF. Gastrointestinal lipomas. Arch Surg 1983;118:1081–3. [39] TaylorAJ, Stewart ET, Dodds WJ. Gastrointestinal lipomas: A radiological and pathologic review. Am J Radiology 1990;55:1205–10. [40] Al-Brahim N, Radhi J, Gately J. Synchronous epithelial stromal tumor and lipoma in the stomach. Can J Gastroenterol 2003;17:374–5. [41] Regge D, Lo Bello G, Martincich L et al. A case of bleeding gastric lipoma: US, CT and MR finding.

test

Part II / Stomach

[42]

[43]

[44]

[45]

[46]

125

Eur Radiol 1999;9:256–8. Treska V, Pesek M, Kreuzberg B et al. Gastric lipoma presenting as upper gastrointestinal obstruction. J Gastroenterol 1998;33:716–9. Sankaranunni B, Ooi DS, Sircar T et al. Gastric lipoma causing gastroduodenal intussusception. Int J Clin Pract 2001;55:731–2. Moues CM, Steenvoorde P, Viersma JH et al. Jejunal intussusception of gastric lipoma: a review of literature. Dig Surg 2002;19:418–20. Lacy AM, Tabet J, Grande L et al. Laparoscopic assisted resection of a gastric lipoma. Surg Endosc 1995;9(9):995–7. Choi YB, Oh ST. Laparoscopy in the management of gastric submucosal tumors. Surg Endosc 2000;14:741–5.

Chapter

7 CARCINOMA OF THE STOMACH AK Kakar and Vishal Gupta

7.1 EPIDEMIOLOGY Gastric cancer is among the world’s most common cancers, and a leading cause of cancer deaths. In 2000 AD it was the 5th most common cancer with nearly 14 million total cases, and about 90,000 new cases.[1] Over 75% of patients died of their disease. Though gastric cancer is prevalent world wide, it occurs most commonly in developing countries. In the developed countries of Western Europe and North America, its frequency has decreased in the last few decades. The higher gastric cancer mortality figures have been reported from Japan, South Korea, Costa Rica, Chile, and Iceland. In USA and Europe, its incidence is overshadowed by bronchogenic, colorectal and breast cancers. In India the incidence of gastric cancer varies from 1.2 to 13.6 per 100,000 population.[2, 3] Its incidence is higher in Southern India as compared to Northern India. However, Kashmir has a 3- to 6-fold higher incidence of gastric cancer as compared to the rest of the India.[4] Based on the available population data, Mohandas et al. had estimated that during the year 2001, approximately 23100 new cases of gastric cancer in men and 11890 new cases in women would have been reported.[5] Unfortunately in our country the overall scenario of gastric cancer is gloomy as late 126

presentation is the rule rather than exception. Unlike Japan and South Korea where early gastric cancer (EGC) accounts for 50%–60% of all gastric cancers, in India early cancer is rare. In India 98% of all gastric cancers are diagnosed in an advanced stage, and serosal infiltration is present in more than 70% of those subjected to surgery.[3]

7.2 ETIOLOGY Gastric cancers constitute a heterogenous group of malignancies. The human stomach is divided into three parts – the cardia, corpus (body), and the pyloric antrum. In populations at high risk for gastric cancer, antral tumors predominate, followed by cancers of the corpus. Cancer of the cardia is seen in low risk populations with a low incidence of gastric cancer. In this chapter the discussion will be mainly related to cancers of antral and corpus regions, as tumors of cardia and esophagogastric junction behave more like esophageal carcinoma. Though the exact etiology of gastric cancer is still elusive, the factors that play an important role in gastric carcinogenesis are genetic, environmental, and the presence of a precursor lesion.

ETIOLOGY

127

7.2.1 Genetic Factors

7.2.2.2 Autoimmune gastritis

Eight percent to ten percent of all gastric cancers are related to an inherited genetic factor.[6] First degree relatives of gastric cancer patients are at increased risk of developing gastric cancer, especially if the index case has diffuse type of gastric cancer. Unlike familial colon and breast cancers, the age of onset of familial gastric cancer is not different from sporadic gastric cancer.[7] An increased risk of familial gastric cancer is weakly transmitted to successive generations. Inherited risk factors play a role in association with environmental factors, in the generation of familial gastric cancer. Familial gastric cancer is associated with hereditary nonpolyposis colon cancer, familial adenomatous polyposis, LiFraumeni syndrome, Peutz-Jegher syndrome, and the familial stomach cancer syndrome. Familial clustering of gastric cancer is seen in 1%–15% of all gastric cancers.[8, 9] The association of blood group A is strong with diffuse cancers. There are several other genetic factors influencing the development of stomach cancer,[10–14] further described below in the section on molecular biology.

Autoimmune gastritis is a precursor of gastric polyps, carcinoma, and carcinoid tumor. In autoimmune gastritis there is gradual loss of parietal cells and chief cells leading to achlorhydria in late stage. In late stages, normal oxyntic mucosa is replaced by intestinal and antral type glands. The antrum is spared, and the resulting achlorhydria causes hypergastrinemia and also favors abnormal proliferation of bacterial flora due to near-normal pH of gastric juice. While prolonged hypergastrinemia has a trophic effect on gastric glands, bacterial flora convert dietary amines to carcinogenic nitroso compounds. The relative risk of developing gastric cancer with autoimmune gastritis is 2.1–5.6. Risk increases with the size of polyp.[16]

7.2.2 Precursor Lesions 7.2.2.1 Gastric polyps

Two common forms of gastric polyps are found in the stomach – hyperplastic and adenomatous. Both hyperplastic and adenomatous polyps are associated with an increased risk of gastric cancer in mucosa outside the polyp, the risk being higher with adenomatous polyp. The risk of carcinoma in a hyperplastic polyp is 0.4%–4%, and co-existing carcinoma outside the polyp is reported in 8%–28% of cases. The malignant potential of an adenomatous polyp is as high as 58%.[15]

Part II / Stomach

7.2.2.3 Intestinal metaplasia

This is characterized by replacement of gastric epithelium by small intestinal type epithelium. It can be of complete or incomplete types. The less common incomplete type differs from more common complete type by the absence of Paneth cells, mucous substance commonly present in large bowel, and deletion of one or more of the glycosylated enzymes normally present in small intestine.[17] Incomplete intestinal metaplasia is best seen along the distal greater curvature in the antrum and carries a higher risk of gastric cancer. The risk of gastric cancer increases with the extent of intestinal metaplasia. With advancing age, intestinal metaplasia gradually extends towards the gastroesophageal junction, thus replacing oxyntic mucosa, leading to decreased acid and Pepsinogen 1 secretion. Several theories have been proposed to explain the conversion of intestinal metaplasia to carcinoma. In experimental animals radiation and nitroso compounds induce gastric carcinoma, preceded by intestinal metaplasia.[18, 19]

128

Chapter 7 / CARCINOMA OF THE STOMACH

Incomplete intestinal metaplasia occurs more often when irradiation is combined with nitroso compounds.[20] Achlorhydria occurring in late stages may favor proliferation of abnormal bacterial flora that produces carcinogenic nitroso compounds. 7.2.2.4 Multifocal atrophic gastritis

Atrophic gastritis is the most common precursor for gastric cancer in a high risk population. Intestinal metaplasia is the key histological feature. It is associated with H. pylori infection, high salt intake, high nitrate intake, smoking, and lack of fresh vegetables in diet. Cancer developing in multifocal gastritis occurs in men older than 60 years, and is associated with the formation of intestinal type glands. It usually spares the proximal fundic part of the greater curvature, unlike autoimmune gastritis which may involve the proximal greater curvature. Chronic atrophic gastritis has a 10% risk of developing gastric cancer over 15 years. 7.2.2.5 Prior gastrectomy

Prior gastrectomy is associated with an increased risk of cancer in the gastric remnant.[21, 22] This increased risk is observed only after a latency period of at least 15 yrs. In fact the risk is reduced in the initial 15 yrs after gastrectomy because of removal of the metaplastic antrum. The risk increases thereafter, with an overall incidence of 1%–5%.[23] Gastric stump cancer is more common after surgery for gastric ulcer than for duodenal ulcer; after gastrojejunostomy (Billroth II) than after gastroduodenostomy (Billroth I); in males and in smokers. According to Lygidakis, such cancer should occur at least 5 years after gastrectomy to differentiate it from locally recurrent cancer.[24] Reflux of alkaline duodenal contents causes increased cell turnover in the gastric stump

mucosa, and may be responsible for stump cancer. Buffering effect of duodenal contents also favor appearance and proliferation of mixed colonic type bacteria with risk of cancer (Domeloff et al. 1980).[25] Deficiency of fat soluble vitamins due to altered fat absorption, because of rapid intestinal transit, may be the cause of stump cancer after a Billroth II operation.[26] The Epstein Barr virus may also be associated with gastric stump cancer.[27] 7.2.2.6 Gastric ulcer

It is well-known that gastric cancer commonly ulcerates, but gastric ulcer rarely become cancer. The usual incidence is 3% after a latent period of 15–20 years.

7.2.3 Environmental Factors 7.2.3.1 Helicobacter pylori

H. pylori is a gram negative spiral bacterium, usually present between gastric mucus layer and gastric epithelium. Although H. pylori infection is present in up to 75% of high risk populations, cancer develops in less than 5% of infected persons. In spite of the low incidence of gastric cancer in persons infected with H. pylori, a significant association exists between the two directly.[28] H. pylori infection is more common in persons of lower socioeconomic status, those who have large families, and live in crowded conditions.[29] This infection is usually acquired in childhood, and is more common in the youngest children of a large family.[30] This infection is associated with increased risk of both intestinal and diffuse type of gastric cancer. H. pylori causes superficial gastritis that affects the whole stomach except the cardia. Chronic superficial gastritis causes mucosal atrophy with

Tropical Hepatogastroenterology

ETIOLOGY

the appearance of foci of intestinal metaplasia. Intestinal metaplasia first appears at the antrocorpus junction (junction of antral and oxyntic mucosa).[31] This metaplastic epithelium gradually replaces the whole antral mucosa, and also extends proximally in the corpus to replace the oxyntic mucosa. Cancer develops in 5% of H. pylori infected persons because of other risk factors and infection with the most carcinogenic strain of H. pylori, i.e., cag-A (cytotoxic associated gene A) strain.[32] Diffuse type gastric cancer, associated with H. pylori infection, is not preceded by intestinal metaplasia or mucosal atrophy, is more common in persons below 50 yrs of age, and predominantly arises in the corpus. H. pylori is present in noncancerous tissue in 90% of patients with intestinal type, and a third of patients with diffuse type of gastric cancer.[33] 7.2.3.2 Dietary factors

Diet plays a major role in the gastric carcinogenesis. Migration from high to low risk areas reduces the risk in second or third generations, if the dietary habits of the host country are adopted.[34] A high risk of gastric cancer is associated with high intake of salts and low consumption of vegetables.[35] Dietary nitrates and nitrites are directly associated with gastric cancer in experimental animals.[36] An abnormal bacterial flora converts these compounds to N-nitroso compounds, toxic to proliferating mucosa. These bacteria may reach the stomach through contaminated food or may proliferate in a favorable environment provided by achlorhydria, prior gastrectomy, atrophic gastritis, and pernicious anemia. While green tea is protective,[37] the protective role of black tea is still unclear.[35] Several other dietary factors like vitamin C, fruits, and α-tocopherol have been proposed as protective factors.[38] Intragastric formation of

Part II / Stomach

129

nitrosamines is blocked up to 80% by ascorbic acid, and up to 50% by tocopherols.[39] Polyunsaturated fats may be initiators or modulators.[40] Lipid peroxides, formed from unsaturated fats, can damage the gastric mucosa. Low incidence of gastric cancer in India may be related to the fact that traditional Indian diet is predominantly vegetarian; and is rich in tubers, cereals, fruits, onions, turmeric and other natural foods. Onions[41] and turmeric[42] are protective against gastric cancer. 7.2.3.3 Smoking

A positive dose-dependent association between smoking and gastric cancer is present in only one third of patients. One third show positive but doseindependent association, and a third of patients show no association.[43] 7.2.3.4 Ionizing radiation

Ionizing radiation is related to cancer of the cardia and proximal corpus. Gastric cancer, following radiation, is seen to develop in younger patients. Patients receiving radiotherapy for Hodgkin’s lymphoma and ankylosing spondylitis may be at an increased risk of developing gastric cancer. Such cancers develop within 12–14 yrs of receiving radiotherapy.[44] Also an increased frequency of gastric cancer has been observed in Japanese atomic bomb survivors.[45] 7.2.3.5 Epstein Barr virus infection

EB virus infection is found in 7%–18% of all gastric cancers.[46, 47] An apparently healthy person positive for EBV capsid antibody has a 4-fold increased risk of developing EBV infected gastric cancer.[48] EB virus related gastric cancers tend to occur in younger patients (< 35 yrs), in the

130

Chapter 7 / CARCINOMA OF THE STOMACH

TABLE fy 7.1 Summary of risk factors associated with gastric cancer Anatomic subtype

Tumor type

Antrum

Intestinal

Multifocal atrophic gastritis Intestinal metaplasia Gastric ulcer

Body

Diffuse

Superficial gastritis

Intestinal

Autoimmune atrophic gastritis G-cell hyperplasia Enterochromaffin cell hyperplasia Polyps, Reflux gastritis Barrett’s esophagus

Cardia

Intestinal

Anatomic marker

proximal stomach, and in the gastric stump after a previous gastrectomy.[27, 49] Such EB virus infected gastric cancers may be confused with lymphomas as they are heavily infiltrated with lymphocytes, specially T-lymphocytes.[50] 7.2.3.6 Occupation

Occupation is an important risk factor. It is the largest known exogenous source of nitroso compounds.[51] Professions with high levels of N– nitrosamines in the work environment include rubber industry, metal industry, and leather industry. Low level exposure may also result from direct contact with certain cosmetics, drugs, agricultural chemicals, rubber products, and packaging materials.[52] A high risk of gastric cancer is seen in carpenters, steel foundry workers, and tin workers. Increased risk occurs in chemical industry workers, oil refinery workers (due to contact with known carcinogens like polyaromatic hydrocarbons), coal miners (contact with polyaromatic hydrocarbons, cadmium, chromium, etc.), coke plant workers, and rubber and leather industry workers. A possible risk of gastric cancer is also present in agricultural

Risk factors High salt, nitrite, & nitrate intake Low intake of vegetable and fruits Chronic H. pylori infection Smoking Age < 50, Blood group A Rest as above Autoimmune disease Previous gastrectomy

Obesity, male, white race

workers, gold miners, lorry and coach drivers, and jewellery workers. Gastric cancer subtype by anatomic location and histological types, and associated risk factors are summarized in Table 7.1.

7.3 PATHOGENESIS Gastric cancer is multifactorial in causation. Gastric carcinogenesis is a multistep process, in which inherited or acquired genetic factors are acted upon by different environmental factors, and the resulting mutations in the genes present as precancerous lesions and gastric cancer. Correa[53] has suggested a model for human gastric carcinogenesis based on the effect of environmental factors on progression from gastritis to neoplasia (Fig. 7.1).

7.4 MOLECULAR BIOLOGY OF GASTRIC CANCER The process of carcinogenesis in the stomach occurs as a stepwise accumulation of genetic

Tropical Hepatogastroenterology

MOLECULAR BIOLOGY OF GASTRIC CANCER

131

loss or loss of only one allele.[57] Chromosomal aneuploidy is present in up to 72% of differentiated and up to 43% of undifferentiated stomach cancer.[58] Microsatellite instability occurs in 13%–44% of sporadic gastric tumors.[59–61] Significant instability, i.e., microsatellite instability – high type (MSI-H) is associated with intestinal type, antral type, and a favorable prognosis.[62–67]

7.4.1 Tumor Suppressor Genes

FIGURE 7.1 Correa’s model for human gastric carcinogenesis. p53 and microsatellite instability may play a role in metaplastic changes in atrophic gastritis. The APC or β-catenin gene may play a role during conversion from dysplasia to carcinoma.

abnormalities. However, the mechanisms of multistage carcinogenesis are still not clear. Abnormalities in chromosomes 3, 6, 8, 11, and 13 appear in sporadic gastric cancer, but no abnormality is consistent. Loss of heterozygosity (LOH) analysis has been identified on chromosomes 17p, 18q, and 5q; these regions on chromosomes may contain tumor suppressor genes important in gastric carcinogenesis.[54–56] Allelic loss of both 17p and 18q in proximal gastric tumor are associated with a poorer prognosis as compared to no

Part II / Stomach

Mutation in the p53 gene is present in 30%– 50% cases of gastric cancer.[68] p53 mutation occurs most commonly in advanced tumor. Mutation in APC, β-catenin, LKB1 (STK11) and Smadgenes also have been identified in sporadic gastric cancer. Mutation in APC gene occurs in up to 20% of sporadic gastric cancer and adenoma,[69] and up to 60% in well differentiated intestinal cancers.[70] APC gene products inactivate cytoplasmic β-catenin, and thus inhibit its growth promoting action. Mutation in APC gene results in decreased inhibition of β-catenin. Similarly mutation of β-catenin prevents its inactivation by APC gene product. Mutation of β-catenin is found in 16%–27% of sporadic intestinal type of gastric cancer.[71, 72] As LOH of APC gene is seen in gastric cancer but not in gastric dysplasia, mutation of the APC gene may be involved in the final step of development of gastric cancer from gastric dysplasia.[73]

7.4.2 Proto-oncogenes and Other Molecular Changes Over expression of erbB-2(HER-2/neu) gene has been observed in 14% of advanced gastric cancer, and is associated with a poor prognosis.[74, 75] Over expression of the c-met gene occurs in 46% of gastric cancer. Its over expression

132

Chapter 7 / CARCINOMA OF THE STOMACH

TABLE fy 7.2 Genetic abnormalities in gastric cancer Gene

Location

Frequency

p53 APC

17p 5q21

30%–50% 20%–60%

FHIT DCC E-cadherin

3p14 18q21 16q

60% 50% < 5%

c-met

7q31

45%

β-Catenin k-sam k-ras Her2 neu/c-erbB2

3p21 10q25 12p 17q11

16%–27% 20% 10%–15% 14%

Clinical significance

Tumor suppressor genes Mutated in both well & poorly differentiated tumors. Preferentially associated with well differentiated tumor, plays a role during early steps of carcinogenesis. Mutation occurs early during gastric carcinogenesis. Necessary for the development and progression of poorly differentiated or scirrhous cancer.[80] Mutated in at least 50% of diffuse type, no mutation in intestinal type.[81] Associated with inherited gastric cancer syndrome.

Oncogenes Necessary for the development and progression of poorly differentiated or scirrhous cancer.[81] ↑ Lymph node involvement, ↑ invasion, poor prognosis. Exclusively mutated in intestinal type. Prognostic factor for diffuse type gastric cancer. Associated with well differentiated gastric cancer. Associated with well differentiated gastric cancer, prognostic factor for diffuse type gastric cancer.

Mismatch repair genes (Microsatellite instability) MSH3, MSH6 & others

-

13%–44%

Associated with intestinal type, antral tumor with favorable prognosis.

70%

Aspirin may play a protective role (as in colorectal cancers).

Risk modifier COX-2

1q25

is associated with an increased depth of invasion, lymph node metastases and decreased survival.[76] Cyclo-oxygenase-2 (COX-2) enzymes may play a role in gastric carcinogenesis. COX-2 is not normally present in gastric epithelium, but its level is increased by inflammation. Increased levels are also present in gastric cancer mucosa, and there is evidence that COX-2 participates in the proliferation of gastric cancer cells.[77] The role of COX-2 in gastric cancer was first suggested by Thun et al., who showed a 50%–60% reduction in the incidence of gastric cancer with long term

ingestion of aspirin.[78] Aspirin is an inhibitor of COX-2 enzyme. The protective role of aspirin is supported by other studies.[79] Besides other molecular changes, loss of TFF1 gene, loss of FHIT (Fragile Histidine Triad) gene, increased expression of EGFR/k-sam protein, increase in vascular endothelial growth factor (VEGF), increase in matrix metalloproteinases, and increased expression of Bcl-2, nm-23 may also play role in the development and progression of carcinoma of stomach. Genetic factors associated with gastric cancer are summarized in Table 7.2.

Tropical Hepatogastroenterology

PATHOLOGY

133

TABLE fy 7.3 Pathological classification of gastric cancer Based on the depth of invasion

Early gastric cancer (EGC)

Advanced gastric cancer

Morphological

Histopathological Lauren classification

WHO classification

Borrmann’s classification

1. Diffuse

1. Papillary

Type 1: Polypoid

2. Intestinal 3. Unclassified

2. Tubular 3. Mucinous

Type 2: Fungating Type 3: Ulcerated Type 4: Infiltrative

4. Signet ring cell Ming classification[83]

Mulligan classification

1. Expanding 2. Infiltrative

1. Intestinal 2. Mucinous cell 3. Pylorocardiac

Goseki classification

Nagayo-Komagome classification

7.5 PATHOLOGY Gastric cancer has a predilection for origin at mucosal junction areas such as antrum, prepyloric area, and lesser curvature. Greater curvature and cardia are less common sites. However, an increasing incidence of cancer at cardia (along with gastroesophageal junction) has been observed during the last decade. The exact cell of origin of gastric cancer is not clear. It may originate from undifferentiated cells, within the replication zone, in the neck of mucosal glands.[82] The commonly used term, gastric cancer, refers to adenocarcinoma of the stomach, which constitutes more than 95% of primary gastric malignancies. The remaining malignant tumors include gastric parietal cell tumor, adenosquamous carcinoma, squamous cell carcinoma, medullary carcinoma, choriocarcinoma, carcinosarcoma, hepatoid adenocarcinoma, and spindle

Part II / Stomach

cell carcinoma. Many pathological classifications have been proposed for gastric cancer. These depend upon the biological behavior, morphological features, degree of differentiation, etc. These classifications include WHO, Lauren, Borrmann, Mulligan, Goseki, and others (Table 7.3). Depending upon the biological behavior, the gastric cancers may be early or advanced.

7.5.1 Early Gastric Cancer Early gastric center (EGC) is defined as “gastric cancer that is confined to mucosa or mucosa and submucosa irrespective of lymph node metastases”. EGC in not synonymous with “intramucosal carcinoma”, “carcinoma in situ”, or “superficial spreading carcinoma”. ‘Intramucosal carcinoma’ involves only the mucosa and does not invade the submucosa. ‘Carcinoma in situ’ is a term now

134

Chapter 7 / CARCINOMA OF THE STOMACH

Recurrence is commoner in elevated types than in depressed types. Blood borne metastases to liver usually occur within 3 years from diagnosis in EGC.

7.5.2 Advanced Gastric Cancer It is characterized by invasion into the muscularis propria or beyond. 7.5.2.1 Borrmann’s classification (Fig. 7.3) FIGURE 7.2 Early gastric cancer, Japanese classification. EGC is confined to the mucosa, or mucosa and submucosa irrespective of lymph node metastases. EGC may also show combination of different morphological forms.

replaced by “high-grade dysplasia”. ‘Superficial spreading carcinoma’ refers to the mode of spread of a peculiar entity characterized by serpiginous and irregular ulcerations, usually without deep invasion. It is important to diagnose and differentiate EGC from gastric dysplasia, as consensus exists that gastric surgery is justified in EGC. The proportion of EGC in resected cases of gastric cancer ranges from 30% to 50% in Japan,[84] while in western countries it rarely exceeds 16%.[85] No such figures are available from India. Based on the gross morphology, the Japanese Gastroenterological Endoscopic Society has classified EGC into three main types: Type I – protruded, type IIa – elevated, type IIb-flat, IIc – depressed, and type III – excavated (Fig. 7.2). Elevated (type IIa) are often well differentiated, tubular or papillary type, while flat (type IIb) tend to be poorly differentiated adenocarcinoma or signet cell carcinoma of the diffuse type.

Borrmann first classified these tumors into four groups based on the gross morphology. Type 1 – polypoid, type 2 – fungating, type 3 – ulcerated, and type 4 – infiltrative. Any of the four types can coexist with one another. Polypoid type protrudes in to the gastric lumen without major visible ulceration. Fungating tumors are irregular in shape, variable in size and appear as exophytic growths with ulcerated areas. Ulcerated type lacks an endoluminal component, and appears as irregular ulcer with raised edges. Overhanging margin may appear hard. Infiltrative type spread superficially in the mucosa and submucosa, producing flat, plaque like lesion. The tumor tends to flatten the mucosal folds, and as they extend into the gastric wall, they produce dense fibrous tissue that fixes the mucosa to the muscularis propria. When infiltration is extensive, it may produce “linitis plastica” or “leather bottle stomach”. According to Borrmann classification most common subtypes are fungating36%, infiltrative-26%, ulcerated-25%, and polypoid-7%. 7.5.2.2 Lauren classification (DIO classification)

Based on histology, Lauren classified gastric cancers into two major types, intestinal and diffuses.

Tropical Hepatogastroenterology

PATHOLOGY

135

FIGURE 7.3 Borrmann classification. The fungating type is the most common type. Extensive infiltration produces linitis plastica, which is also present in breast cancer metastasizing to stomach.

A third type of cancer with mixed features is called unclassified. Also known as DIO classification, i.e., Diffuse, Intestinal, and Other type. The intestinal type is usually sufficiently differentiated to have recognizable glandular structure lined by goblet cells. The cells of the diffuse type cancer usually appear round and small. Connective tissue reaction is more intense, and inflammatory cells infiltrate is less common in the diffuse type. This classification is well accepted by the American Joint Committee on Cancer. The different features of the two types are compared in Table 7.4. 7.5.2.3 WHO classification

The WHO International Reference Center for the Histologic Classification of Gastric Tumors has

Part II / Stomach

classified gastric cancers into well differentiated, moderately differentiated and poorly differentiated. Gastric adenocarcinoma is also classified according to histology into four types: papillary, mucinous, tubular and signet ring cell. Papillary tumors usually present as a well differentiated exophytic growth. The tubular subtype shows wide variation in degree of differentiation and desmoplasia. The mucinous type is also known as colloid or gelatinous carcinoma. Signet ring-cell types have gross features of Borrmann type 4, and contain intracytoplasmic mucin. The WHO classification is reasonably simple and uses traditional terms, and hence is quite reproducible.

136

Chapter 7 / CARCINOMA OF THE STOMACH

TABLE fy 7.4 Comparative features of Lauren’s types of gastric cancer Features Gross morphology Differentiation Mucin production Growth pattern Associated intestinal metaplasia Epidemiology Age Sex ratio Site Precancerous states Prognosis

Intestinal

Diffuse

Polypoid, fungating Well differentiated Limited Expansile Almost universal Epidemic type, environmental factors important Older, mean 55 yrs 2:1 Antrum, cardia Pernicious anemia, atrophic gastritis, intestinal metaplasia Better

TABLE fy 7.5 Goseki classificationy Group

Tubular differentiation

Cytoplasmic mucin content

I II III IV

Well Well Poor Poor

Poor Rich Poor Rich

Ulcerative, infiltrative Poorly differentiated Extensive-colloid carcinoma Noncohesive Less common Endemic type, genetic factors more important Young, middle, mean 48 yrs 1:1 Body None Poor

that of Lauren. This system also accommodates tumors that cannot be classified by Lauren system. Because of this it has gained wide acceptance after its introduction. 7.5.2.6 Goseki classification (Table 7.5)

Goseki divided gastric cancers into four groups based on their histologic architecture, differentiation, and mucin staining pattern.[87]

7.5.2.4 Mulligan classification

Mulligan classified gastric cancer into three major forms: intestinal cell type (46.7%), mucous cell type (29.7%), and the pylorocardiac gland cell type (23.6%).[86] This classification system is not widely used.

7.5.3 Patterns of Gastric Cancer Spread Carcinoma stomach is a good example of the various modes by which carcinoma can spread. Distant spread is unusual before local involvement, and distant metastases are uncommon in the absence of lymph node metastases.

7.5.2.5 Ming classification

Ming classified gastric cancers into expanding (67%) and infiltrative (33%) types, based on the biological behavior, as reflected by their growth patterns. Expanding types often present as bulky tumors located in the antrum. The prognostic significance of Ming classification is comparable to

7.5.3.1 Direct spread

The initial growth of the tumor is by radial intramural spread as well as deep invasion. After penetrating the gastric serosa, it directly invades the adjacent viscera, e.g., colon, pancreas, adrenal, omentum, and diaphragm. At surgery

Tropical Hepatogastroenterology

CLINICAL FEATURES

137

gross assessment of the submucosal extension is usually inaccurate. Invasion of the surgical margin may be present in up to 15% of cases, therefore the resected margin should be evaluated by frozen section.[88, 89]

7.5.3.3 Hematogenous spread

7.5.3.2 Lymphatic spread

7.5.3.4 Transcoelomic spread

The stomach has abundant submucosal and subserosal lymphatic channels. Lymphatic spread occurs through embolization and permeation. The submucosal plexus is also prominent in the esophagus, and the subserosal plexus is prominent in the duodenum. This allows proximal extension into the esophagus, and distal, but limited, spread into the duodenum. Initial lymphatic drainage is usually to nodes along the lesser and greater curvature, i.e., perigastric nodes (N1 level). Thereafter lymphatic spread goes to nodes along all three branches of the celiac trunk- common hepatic artery, splenic artery, and left gastric artery (N2 level). More distal nodes include hepatoduodenal, peripancreatic, and mesenteric root nodes (N3), and periaortic and middle colic (N4 level) nodes. The incidence of infiltration of the proximal margin of resection is significantly higher when the tumor penetrates the serosa. Proximal or distal infiltration for a distance greater than 3 cm does not occur, if the growth is confined to the mucosa, submucosa and muscularis propria. Lymph node micrometastases may be present even when lymph nodes are normal on gross examination and on routine histopathological examination. These micrometastases are detected by immunohistochemistry using anticytokeratin antibody or RT-PCR (reverse transcriptasepolymerase chain reaction).[90] The incidence of micrometastases in EGC with pathologically negative nodes (pN0) is 10%–25%[91–93] and is 33%–75% in advanced gastric cancer.[94, 95] The prognostic significance of these micrometastases is presently unclear.

Transperitoneal drop metastases may occur in the gastric cancer. They gravitate to the pelvis, where secondary tumors get palpable on the rectal examination (Blumer’s shelf). In females, they involve the ovaries giving rise to Krukenberg’s tumors, which are liable to cause diagnostic confusion. Route of spread may vary in different type of gastric cancers. Intestinal type preferentially spreads to liver, while diffuse type tends to involve lymph nodes.[96]

Part II / Stomach

Common sites of metastases are liver, lungs, and bone. Hematogenous spread may occur even in the absence of lymphatic spread.

7.6 CLINICAL FEATURES Patients with gastric cancer usually present with epigastric pain, anorexia, nausea, vomiting, melena, hematemesis, abdominal mass, diarrhea, and weight loss. Classical clinical presentations are usually of an advanced tumor. Clinical features may be divided in to following types:

7.6.1 Persistent Indigestion Persistent vague indigestion, occurring for the first time in person over 40 years of age, should be investigated to rule our gastric cancer.

7.6.2 Insidious Onset Patients usually present with nonspecific symptoms. They feel tired and weak. Epigastric pain, weight loss, nausea may be other symptoms. “Anemia, Asthenia and Anorexia” is the

138

Chapter 7 / CARCINOMA OF THE STOMACH

classical triad of gastric cancer. This type may resemble pernicious anemia, and oncoming uremia.

about 40% of gastric cancer patients and indicates advanced disease.

7.6.7 Paraneoplastic Syndromes 7.6.3 Obstructive Symptoms Patients with gastric cancer of the cardia may present with gradually progressing dysphagia. Weight loss may be excessive. If the growth involves the pyloric end, patients present with gastric outlet obstruction. This mimics pyloric stenosis due to peptic ulcer. A short history, old age, and no preceding peptic ulcer symptoms may help in reaching the diagnosis.

7.6.4 Latent Presentation Patients may present with extragastric symptoms and signs. These include jaundice due to extensive liver metastases or hilar lymphadenopathy, ascites, umbilical nodule (Sister Mary Joseph nodule), Krukenberg’s tumor, left axillary lymph nodes (Irish’s nodes), left supraclavicular nodes (Troisier’s sign), pelvic secondaries palpable as a ridge on digital rectal examination (Blumer’s shelf) due to drop metastases in the cul de sac, sclerotic bone secondaries, and carcinomatous meningitis.

A number of patients with gastric cancer present with clinical features unrelated to the gastrointestinal tract. These are grouped as paraneoplastic syndromes and include: 1. 2. 3. 4.

Acanthosis nigricans Polymyositis, dermatomyositis Dementia, cerebellar ataxia Superficial venous thrombosis (Trousseau’s sign) 5. Circinate erythema, pemphigoid 6. Ectopic Cushing’s syndrome 7. Sudden appearance of seborrheic keratosis (Leser-Trelat sign).

7.7 STAGING OF GASTRIC CANCER Presently two staging systems are widely used for carcinoma stomach, TNM system of UICC and AJCC, and the Japanese Research Society for Gastric Cancer (JRSGC).

7.7.1 TNM System 7.6.5 Peptic Ulcer Symptoms Carcinomatous change in a chronic gastric ulcer may be indicated by change in the periodicity of symptoms, when the pain becomes constant and less severe, and is not relieved by vomiting or medications.

7.6.6 Lump The patient may present with an abdominal lump with no other symptoms. A lump is palpable in

The TNM system is widely used in western countries. It is based on the primary tumor (T), lymph nodes (N), and metastases (M). There are five anatomical subsites: cardia, fundus, corpus, antrum and pylorus. Regional lymph nodes include nodes along the lesser and greater curvature, common hepatic artery, splenic artery, left gastric artery and celiac arteries and the hepatoduodenal nodes. Retropancreatic, mesenteric, and para-aortic nodes are classified as distant metastases. A minimum of 15 nodes should be resected and analyzed

Tropical Hepatogastroenterology

WORK UP OF A CASE OF GASTRIC CANCER

for proper N staging. Current AJCC/UICC TNM staging (6th edition, 2000) has further divided T2 tumors into T2a and T2b depending on the involvement of muscularis propria or subserosal involvement. (Table 7.6)

7.7.2 Japanese Staging System According to the system developed by the Japanese Research Society for Gastric Cancer, the stomach is divided in to three anatomic regions to determine the location of tumor. These are the upper third (fundus and cardia, C), the middle third (corpus, M), and the lower third (antrum, A). Regional lymph nodes are classified into 16 distinct locations, and grouped into 4 levels, N1 to N4. The primary location of the tumor is important as it determines which of the 16 lymph nodes groups will be included in each of the N1, N2, N3, and N4 levels. N1 level is removed in R1 dissection, N2 in R2 dissection, N3 in R3 dissection, and N4 in R4 dissection. There is no similarity in nodal staging between TNM staging and Japanese staging. (See TNM staging above). Involvement of N3 nodes of the Japanese system is considered as distant metastases in the TNM staging.

7.8 WORK UP OF A CASE OF GASTRIC CANCER Once a patient is suspected of harboring gastric cancer, investigations are required to confirm the diagnosis, and thereafter to assess the extent of disease, to stage the disease and to assess the fitness of patient for surgery.

7.8.1 Gastroduodenoscopy and Barium Meal Examination Both gastroduodenoscopy and barium meal examination are useful in the diagnosis and assessment

Part II / Stomach

139

of gastric cancer. However, accurate staging is not possible with either. The double contrast barium meal examination has been used extensively in Japan for the screening of their high risk population. Disadvantages of this examination are radiation exposure, patient’s discomfort with barium meal, inability to take tissue biopsy, and inability to examine the growth under direct vision. Gastroduodenoscopy is more accurate. Tissue diagnosis is possible with over 95% accuracy. At least 6–8 biopsies should be taken from the edge and base of the nonhealing ulcer to rule out malignancy. It gives a better assessment of site, size, extension, number of lesions, and morphology of the lesion. Also there is no radiation exposure. Gastroduodenoscopy is therefore the initial investigation of choice. However, these modalities are unable to define the depth of invasion and extragastric extent.

7.8.2 Transcutaneous Ultrasonography Ultrasonography is an inexpensive and rapid method for evaluation of the liver, ascites, and intra-abdominal lymphadenopathy, in a known case of gastric cancer.

7.8.3 Contrast Enhanced Computed Tomography (CECT) CECT is usually the next staging investigation. It is able to detect liver metastases, intra- and retroperitoneal lymphadenopathy, ascites, peritoneal metastases, omental metastases, and other areas of spread (Fig. 7.4). Liver metastases usually appear as hypodense round lesions with enhancement after intravenous contrast. Peritoneal metastases may appear as omental thickening or irregularity of contour of the bowel surface. Though CT scan has been used extensively for the preoperative staging of gastric cancer, it is only 25%–43% accurate for T staging and 33%–51% for N staging.[97, 98] For peritoneal metastases it is

140

Chapter 7 / CARCINOMA OF THE STOMACH

TABLE fy 7.6 TNM staging of gastric cancer T- Primary tumor TX T0

Primary tumor can not be assessed No evidence of primary tumor

Tis

Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria

T1 T2

Tumor invades lamina propria Tumor invades muscularis propria or subserosa

T2a T2b

Invades muscularis propria Invades subserosa[1]

T3 T4

Tumor penetrates serosa (viscera; peritoneum) without invasion of adjacent structures[1,2,3] Tumor invades adjacent structures[1,2,3] 1. A tumor penetrating muscularis propria, and extending into the greater and lesser omentum without perforation of the visceral peritoneum covering these structures is classified as T2. Penetration of peritoneal layers of these structures is classified as T3. 2. The adjacent structures include spleen, transverse colon, liver, pancreas, abdominal wall, adrenal gland, kidney, small intestine, retroperitoneum, and diaphragm. 3. Intramural extension of the duodenum or esophagus is classified by the depth of greatest invasion in any of these sites including stomach.

N- Regional lymph nodes NX Regional lymph nodes can not be assessed N0 No regional lymph node metastases N1 N2 N3

Metastases in 1–6 regional lymph nodes Metastases in 7–15 regional lymph nodes Metastases in more than 15 regional lymph nodes

M- Distant metastasis MX Distant metastases can not be assessed M0 M1 Stage grouping Stage 0 Tis Stage IA T1 Stage IB T1 T2a/b Stage II T1 T2a/b T3 Stage IIIA T2a/b T3 T4 Stage IIIB T3 Stage IV T4 T1-3 Any T

No distant metastasis Distant metastasis N0 N0 N1 N0 N2 N1 N0 N2 N1 N0 N2 N1-3 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

From: AJCC Cancer Staging Manual, 6th ed. Springer-Verlag, 2002

Tropical Hepatogastroenterology

WORK UP OF A CASE OF GASTRIC CANCER

FIGURE 7.4 CT scan of the abdomen showing antral wall thickening with a mass lesion (white arrow) projecting into the gastric lumen, suggestive of carcinoma.

141

involvement can be better assessed with the low frequency probe. Lymph node metastases are suspected by their round, rather than oval shape, and low echogenicity. EUS enables assessment of a maximum radius of 7 cm immediately surrounding the bowel. Although EUS is significantly better than CT scan for T and N staging, it has several limitations. Besides a limited ability to accurately identify distant metastases, assessment of ulcerating lesions has remained a problem. Intense inflammatory reaction surrounding the tumor may result in overestimation of the depth of tumor invasion.[101] Enlarged reactive perigastric nodes may also be over staged as malignant nodes. Despite its many advantages, EUS has not yet become part of routine preoperative staging in gastric cancer.

7.8.5 Other Investigations 81% accurate with only a 8% sensitivity, while for hepatic metastases it is 79% accurate with a 52% sensitivity.[99] A Spiral CT scan is more accurate for preoperative staging. It is 7% sensitive for peritoneal and 57% sensitive for hepatic metastases.[100] Though CT scans can miss a large number of peritoneal metastases, it is still used for the initial evaluation of the patients.

7.8.4 Endoscopic Ultrasound (EUS) With endoscopic ultrasound the transducer lies in close contact with the stomach and the growth. Thus artifacts due to bowel gases can be eliminated. High frequency probes are generally used: 7.5 MHz (resolution = 1 mm, depth of field = 5– 7 cm) and 12 MHz (resolution = 0.5 mm, depth of field = 3 cm). The layers of the bowel wall can be assessed easily. EUS shows the five layer architecture of the stomach wall. The tumor penetration in each layer is visible as focal disruption of that layer. Extramural spread, local and regional lymphadenopathy, and adjacent organ

Part II / Stomach

A chest x-ray should be done, to rule out metastases to the lung.

7.8.6 Diagnostic Staging Laparoscopy and Laparoscopic USG (LUS) Diagnostic laparoscopy is particularly helpful in identification of those intraperitoneal metastases that are not detected by conventional imaging methods. Conlon et al. have reported prevalence rates of 30%–40% for metastases in gastric, pancreatic, and hepatic malignancies, and in cases in which other imaging modalities have failed to reveal metastatic disease.[102] Diagnostic laparoscopy allows detailed assessment of the stomach from outside, including its serosal surface, posterior wall through lesser sac, perigastric lymph nodes, liver, omentum, ascites, peritoneal surface, and pelvic deposits under direct vision. The sensitivity of diagnostic laparoscopy is further improved by using a sonography transducer attached to the laparoscope. Laparoscopic USG

142

Chapter 7 / CARCINOMA OF THE STOMACH

allows assessment of depth of invasion, lymphadenopathy that was not visible directly, and of liver for deeply located secondaries. Mortensen et al. compared EUS, diagnostic laparoscopy, LUS, CT, and transcutaneous USG for evaluating patients with upper GI malignancies.[103] The accuracy for predicting resectability and curability were 95% for LUS, 95% for combined LUS and EUS, 91% for EUS, 68% for diagnostic laparoscopy, and 64% for CT scan and USG combined together. This study suggests that LUS can replace EUS in the work up of a patient with gastric cancer. Positron emission tomography (PET scanning) for gastric cancer is 93% sensitive, 100% specific and 95% accurate for detecting the primary lesion.[104] It may be limited in distinguishing lymph nodes involved close to the primary tumor from peritoneal spread early in the course of disease, when tumor deposits are small. Presently, it is still an investigational tool in the management of gastric cancer.

7.8.7 Other Laboratory Investigations Anemia (42%), hypoproteinemia (26%), abnormal liver function tests (26%), and fecal occult blood (40%) may be present in the gastric cancer patient. There are no reliable serum markers for gastric cancer. CEA and CA19-9 may be useful tumor markers in gastric cancer, and are prognostically important. The gastric carcinoma-associated antigen MG7-Ag has been found in the serum of 82% of gastric cancer patients.[105] A change in the autofluorescence spectrum of gastric juice in gastric cancer has been found useful in the diagnosis and screening of gastric cancer.[106]

7.9 MANAGEMENT Surgical resection is the only curative treatment for gastric cancer. About 85% of patients are operable,

and the lesion is resectable in 50%. However, curative resection is possible in only 50% of resectable cases.

7.9.1 Early Gastric Cancer The treatment of EGC is excision of the neoplastic lesion along with healthy margins. This can be achieved either endoscopically, or by laparoscopic, or open surgery. The method and extent of resection depends upon characteristics of the primary lesion and general condition of the patient. Endoscopically, these lesions can be removed by either laser ablation or mucosal resection. However, endoscopic surgery is inappropriate in the presence of lymph node metastases. A cure rate of more than 90% and an overall mortality of less than 2% have been reported by Hiki et al.[107] The ideal indications for endoscopic surgery are:[108] 1. Protuberant cancer (type I, IIa), less than 2 cm. 2. Depressed cancers (type IIC) less than 1 cm in diameter without ulcer or ulcer scars. 3. Histologically well differentiated lesions, as the incidence of lymph node metastases is very low. 4. Symptomatic treatment for poor risk patients. Endoscopic mucosal resection is considered better than laser therapy, as tumor tissue is not available for histological examination after laser surgery. Though endoscopic therapy is a good option, most patients are not suitable for endoscopic surgery, either because of the characteristics of primary tumor or the presence of nodal metastases. In such cases, laparoscopic or open surgery is mandatory if cure is to be attempted. The extent of surgical resection remains controversial. Most European and American surgeons favor total or subtotal gastrectomy with N1 or N2 lymph node

Tropical Hepatogastroenterology

MANAGEMENT

dissection. The role of limited surgery with associated diminished operative mortality and morbidity has been assessed.[109, 110] Limited surgery for the EGC includes wedge resection, pylorus preserving gastrectomy, vagus preserving gastrectomy, proximal gastrectomy, and modified radical gastrectomy. Wedge excision is recommended for mucosal lesions, which are too large for endoscopic surgery, but too small to merit modified radical gastrectomy. Wedge resection can be performed laparoscopically.[111] Pylorus preserving gastrectomy has been found to be suitable for the EGC less than 4 cm size located in the corpus.[112] Outside Japan, surgeons favor radical gastrectomy for EGC. The extent of clearance both proximally and distally is, however, debatable. Different authors have recommended a clear margin of 5 to 7 cm.[113, 114] The extent of lymph node dissection is equally controversial. Since over 95% of patients with mucosal lesions and nearly 70%–75% of those with submucosal infiltration have node-negative disease; gastrectomy with N1 dissection is adequate for cure. However, in young patients with type IIc or type III lesions, and those with poorly differentiated and diffuse pathology, a more radical lymph node resection, N2, is advocated because of a 20%–35% risk of metastases in N1 group of nodes. Significant improvement in 5 year survival is observed with R2/R3 gastrectomy over R1 gastrectomy.[115, 116] Presently, R2 resection is the standard operation for EGC, and R1 resection is considered adequate only for a lesion confined to the mucosa that is smaller than 1 cm in size.[117] The ideal extent of surgery , total or subtotal gastrectomy, is also controversial. Most surgeons in Europe, USA, and Japan recommend subtotal gastrectomy. They believe that as the recurrence rates following a procedure smaller than a total gastrectomy are less than 3%, and the mortality and morbidity of total gastrectomy

Part II / Stomach

143

are significantly high, a subtotal gastric resection with clearance of N1 or N2 nodes is adequate for cure. Total gastrectomy is recommended in patients with multicentric disease, gastric stump cancer, and recurrent cancer after previous subtotal gastrectomy.

7.9.2 Advanced Gastric Cancer As surgery is the only curative treatment, the goal of curative surgery should be complete resection of the tumor with no residual neoplasm left behind at the completion of operation. The type of surgical resection depends on the location of the tumor within the stomach. As with EGC, these tumors should be excised with a minimum safe margin of 5 cm for diffuse type and 3 cm for intestinal type. Resected margins must be checked by frozen section. Lesions of the proximal third of the stomach require total gastrectomy and distal esophagectomy (extended gastrectomy). Intestinal continuity is re-established by Roux-en-Y esophagojejunostomy. Splenectomy and distal pancreatectomy is usually performed to ensure complete lymph node dissection. A total gastrectomy is preferred over subtotal gastrectomy, as total gastrectomy provides better functional results. Lesions of the middle third of the stomach require total gastrectomy, while lesions of the distal third require a total (for diffuse type cancer) or subtotal (for intestinal type cancer) gastrectomy. In Japan, surgeons favor an extensive prophylactic lymphadenectomy. Resection of the stomach and lymph nodes is described as R0 to R4. R0 resection indicates gastrectomy with incomplete resection of N1 level of nodes. R1, R2, R3, and R4 indicate complete removal of N1, N2, N3, and N4 levels of lymph nodes respectively. As described earlier, lymph node groups included in R1 to R4 resection vary according to the location of the primary tumor within the stomach. During

144

Chapter 7 / CARCINOMA OF THE STOMACH

FIGURE 7.5 Extent of gastric resection and lymph node dissection according to the location of gastric cancer. (a) Upper third lesions: left, nodes removed in R1 dissection; right, nodes removed in R2 dissection. Optionally, a total gastrectomy may be done. (b) Middle third lesions: left, nodes removed in R1 dissection; right, nodes removed in R2 dissection. Optionally, a total gastrectomy or distal (85%) gastrectomy may be done. (c) Lower third lesions: left, nodes removed in R1 dissection; right, nodes removed in R2 dissection. Optionally, a distal (85%) gastrectomy may be done.

prophylactic lymphadenectomy, the level of lymph nodes resected is one level higher than level of documented nodal involvement. Outside Japan, prophylactic lymph node dissection is not routinely performed. R0 resection is incomplete removal of perigastric nodes, R1 is complete removal of perigastric nodes, R2 is complete removal of nodes along the three named branches of celiac trunk in addition to perigastric nodes, R3 resection is removal of nodes along celiac trunk in addition to R2 resection, and R4 resection is R3 resection plus removal of the paraaortic nodes. Prophylactic splenectomy and distal pancreatectomy is not performed routinely, as it increases the morbidity of operation without any proven survival advantage. Extensive resectional procedures like Appleby procedure and left upper abdomen evisceration have been used in an attempt to achieve R3/R4 resection in advanced gastric cancer. In Appleby’s operation gastric cancer is removed en bloc with surrounding structures such as spleen and the distal pancreas along with celiac axis.[119] By this method, lymph nodes around the celiac axis are almost completely removed. Hep-

atic perfusion is maintained by the gastroduodenal artery from the superior mesenteric artery arcade. This retrograde blood flow may not be sufficient in some patients leading to complications like liver dysfunction or gallbladder necrosis. The Appleby operation has been modified to reduce such complications. In the modified Appleby operation,[120] the common hepatic artery is directly anastomosed with celiac trunk stump. Left upper abdominal evisceration (LUAE) includes total gastrectomy, pancreatosplenectomy, and transverse colectomy. Sometimes, it includes left hepatectomy, left nephrectomy, left adrenalectomy, or resection of diaphragm. The purpose of this operation is to resect the greater omentum completely in an attempt to eradicate all microdeposits scattered in it. Even after such an extensive procedure, no survival advantage is seen with LUAE over total gastrectomy and pancreatosplenectomy.[121] R2 resection is not found to be superior to R1 resection in prospective controlled trials. The Medical Research Council (MRC) Trial showed that classic Japanese R2 resection offers no surviva advantage over R1 resection.[122] Similarly,

Tropical Hepatogastroenterology

MANAGEMENT

145

significantly higher morbidity (43% vs. 25%), and mortality (10% vs. 4%) rates were observed with R2 resection in a Dutch trial.[123] A generally increased body mass index (BMI) of the European patients has been assumed to be a major cause for increased postoperative morbidity. A recent study, however, has not found increased morbidity after D2 resection in patients with higher BMI.[124] Although the role of minimally invasive surgery in GI cancers is still controversial, gastric resections including D1 and D2 gastrectomy[125] have been successfully performed laparoscopically for early[126–128] and advanced gastric cancers.[129] After gastric resection, reconstruction is performed by Billroth II, Roux-en-Y, Braun or Lawrence procedures. Noh’s operation has been proposed as an alternative procedure, in an attempt to decrease the incidence of postgastrectomy syndromes.[130]

7.9.3.2 Radiotherapy

7.9.3 Adjuvant Treatment

As the aim of treatment at this stage is symptomatic relief, surgery should be offered only when it can provide sustained symptomatic relief with minimal operative morbidity and need for prolonged hospitalization. Palliative surgery can be offered for bleeding, obstruction, or unremitting pain. For bleeding, endoscopic fulguration is attempted first, failing which surgery can be tried. Palliative resection is preferred over bypass alone, as resection provides better palliation.

7.9.3.1 Chemotherapy

Prognosis of gastric cancer depends on various factors, including the stage of disease. While EGC has a good prognosis, patients with locally advanced cancer without nodal involvement have a 5 year survival of only 50% even after curative surgery. In advanced stages there are more chances of systemic failure. Adjuvant therapy has been used in an attempt to improve survival in patients after curative surgery. A number of chemotherapeutic agents have been studied in combinations, including nitrosurea, mitomycin, anthracyclin, and cisplatin based regimens. However, currently adjuvant chemotherapy is not recommended after curative resection as only a modest benefit is observed with it.[131–133] With the development of new chemotherapeutic agents and regimens, the role of adjuvant chemotherapy after curative resection of gastric cancer needs to be re-evaluated.

Part II / Stomach

Radiotherapy is usually combined with 5-fluorouracil (5FU). Radiotherapy may decrease local recurrence in cases with positive nodes, positive margins, and serosal involvement. A combination of 5FU and radiotherapy improves survival.[134] The British Stomach Cancer Group Study[135] randomized patients to postoperative radiotherapy, postoperative chemotherapy combined with FAM (5FU, Mitomycin, Adriamycin), and surgery alone. After 5 years of follow up, no significant difference was seen among these three groups, but the local recurrence was decreased by radiotherapy.

7.9.4 Management of Advanced and Metastatic Gastric Cancer: Palliative Treatment 7.9.4.1 Surgery

7.9.4.2 Radiotherapy

Palliative radiotherapy is effective in controlling bleeding and pain. Control of bleeding requires low dose radiotherapy, while pain control requires high dose radiotherapy. 7.9.4.3 Chemotherapy

Several chemotherapeutic agents have been tried in isolation and in combination for metastatic

146

Chapter 7 / CARCINOMA OF THE STOMACH

TABLE fy 7.7 Summary of the management of gastric cancer[136] • Stage IA: Local excision, best performed by combined endoscopic and laparoscopic approach. • Stage IB, II, possibly IIIA: Radical surgery. • Stage IIIB, possibly IIIA: R0 resection is usually not possible. These cases should be included in ongoing trials to assess the role of neoadjuvant chemotherapy. • Stage IV: Palliative surgery for obstruction, bleeding. Palliative chemotherapy.

gastric cancer in an attempt to improve survival, and to provide symptomatic palliation. 5-FU is the most extensively studied single agent with an overall response rate of 21%. Mitomycin C and Adriamycin have response rates of 30% and 17% respectively. Combination chemotherapy has higher response rates in the range of 30%–50%. The management of gastric cancer is summarized in Table 7.7.

7.10 PROGNOSIS AND PROGNOSTIC FACTORS Gastric cancer survival rates in Japan and USA have been compared in Table 7.8. The survival rates are clearly better in Japan than in America.

TABLE fy 7.8 Comparison of survival in gastric cancer over two different periods Survival (%) Wanebo et al., 1993[137]

Hundahl et al., 2000[138]

Stage

Japan

USA

I II

95.6 70.1

50 29

IA-95, IB-86 71

III IV

36.3 23.1

13 3

IIIA-59, IIIB-35 IIIA-20, IIIB-18 17 7

∗ Survival

Japan

USA IA-95, IB-58 34

in resected patients.

Overall 5-year survival in Japan is 56.3%, and in USA is 19%.[137] Untreated, median survival is 4–6 months in patients with liver metastases, and 4–6 weeks in patients with peritoneal metastases. Established prognostic factors include TNM stage, R category, number of involved nodes, lymph node quotient (the ratio between positive and negative nodes, with a ratio below 0.2 having a good prognosis), and preoperative raised tumor markers (CEA, CA19-9). Other prognostic factors include histological type, grading, DNA content (ploidy status), S-phase fraction, Ki-67, PCNA antigens, and certain genetic alteration as described earlier.

REFERENCES [1] Parkin DM, Bray F, Ferlay J. Estimating the world cancer burden: Globocan. Int J cancer 2001; 94:153–156. [2] Consolidated report of PBCRs: 1990-1996. National Cancer Registry Programme 2001, ICMR New Delhi. [3] Mohandas KM, Nagral A. Epidemiology of digestive tract cancers in India. II. Stomach and gas-

trointestinal lymphomas. Indian J Gastroenterol 1998;17:24–7. [4] Khuroo MS, Zargar SA, Mahajan R et al. Higher incidence of esophageal and gastric cancer in Kashmir in a population with special personal and dietary habits. Gut 1992;33:11–15. [5] Mohandas KM, Jagannath P. Epidemiology of digestive tract cancers in India. VI. Projected

Tropical Hepatogastroenterology

REFERENCES

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

burden in new millennium and the need for primary prevention. Indian J Gastroenterol 2000;19:74–8. La Vecchia C, Negri E, Franceschi S et al. Family history and the risk of stomach and colorectal cancers. Cancer 1992;70:50–55. Ogawa H, Kato I, Tominaga S. Family history of cancer among cancer patients. Jpn J Cancer Res 1985; 76:113–118. Shinmura K, Kohno T, Takahashi M et al. Familial gastric cancer: Clinicopathological characteristics, RER phenotype and germline p53 and E-Cadherin mutations. Carcinogenesis 1999;20:1127–31. Zanghieri G, Di Gregorio C, Sacchetti C et al. Familial occurrence of gastric cancer in the 2 yr experience of a population based registry. Cancer 1990;66:2047–51. Guilford P, Hopkins J, Harraway J et al. Ecadherin germline mutation in familial gastric cancer. Nature 1998;392:402–405. Westervelt BD, Pals G, Defize J et al. Pepsinogen A polymorphism in gastric mucosa and urine: with special reference to gastric cancer. Clin Genet 1986; 30:202–212. Ketoh T, Nagata N, Kuroda Y et al. GlutathioneS- transferase M1(GSTM1) and T1(GSTT1) genetic polymorphism and susceptibility to gastric and colorectal cancer. Carcinogenesis 1996;17: 1855–1859. Bell DA, Castriano T, Watson M et al. A new genetic risk factor: NAT 1 gene defect increases the risk for advanced stage gastric cancer. Proc Am Assoc Cancer Res 1995;36 (abstract 1688). Shepherd T, Tolbert D, Noffsinger A et al. Alteration in exon 4 of the p53 gene in gastric cancer. Gastroenterology 2000;118:1039–1044. Cristiallinni EG, Ascani S, Bolis GB. Association between histologic types of polyp and carcinoma of the stomach. Gastrointest Endosc 1992;38: 481–484. Stemmermann GN, Feniglio-Preiser C. Gastric carcinoma distal to the cardia: A review of the epidemiological pathology of the precursors to a preventable cancer. Pathology 2002;34:494–503. Matsukura N, Suzuki K, Kawachi T et al. distribution of marker enzymes and mucin in the intestinal

Part II / Stomach

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

147

metaplasia of stomach, and relations of complete and incomplete types of metaplasia to minute gastric cancer. J Natl Cancer Inst 1980;65:231–236. Watanabe H. Experimentally induced intestinal metaplasia in wistar rats by X-ray irradiation. Gastroenterology 1978;75:796–799. Samaria K, Kawachi T, Matsukura N. Intestinal metaplasia and adenocarcinoma induced in the stomach of rats by N-propyl-N-nitroguanidine. Jpn Cancer Res Clin Oncol 1979;94:201–207. Watanabe H, Ito A. Relationship between gastric tumorigenesis and intestinal metaplasia in rats given γ -radiation and /or N-methyl–N’nitro-N-nitrosoguanidine. J Natl Cancer Inst 1986;76’:865–870. Stalnikowicz R, Benbasoat J. Risk of gastric cancer after gastric surgery for benign disorders. Arch Intern Med 1990;150:2022–6. Tersmette AC, Otteshaus GJ, Tersmette KW et al. Meta-analysis of the risk of gastric stump cancer: detection of high risk patient subset for stomach cancer after remote partial gastrectomy for benign conditions. Cancer Res 1990;50:6486–9. Soybel DI, Modlin IM. Implications of sustained suppression of gastric acid secretion. Am J Surg 1992;163:613–22. Lygidakis NJ. Gastric stump Carcinoma after surgery for gastroduodenal ulcer. Ann R Coll Surg Engl 1981; 63:203–5. Domeloff L, Reddy BS, Weisberger JH. Microflora and deconjugation of bile acids in alkaline reflux after partial gastrectomy. Am J Surg 1980;140:291–295. Stemmermann GN, Nomura A, Chyou P-H. Cancer incidence following subtotal gastrectomy. Gastroenterology 1991;101:711–715. Bass IO, van Rees BP, Muster A et al. Helicobacter pylori and Epstein Barr virus infection and the p53 tumor suppressor pathway in gastric stump cancer compared with carcinoma in nonoperated stomach. J Clin Pathol 1998;51:662–64. Huang JQ, Sridhar S, Chen Y et al. Metaanalysis of the relation between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998; 114:1169–1174.

148

Chapter 7 / CARCINOMA OF THE STOMACH

[29] Mendall MA, Goggin PM, Molineaux N et al. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet 1992;339:896–897. [30] Blaser M, Perez-Perez GI, Kleanhous H et al. infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of stomach. Cancer Res 1995;55:2111–2115. [31] Stemmermann GN, Hayashi T. Intestinal metaplasia of the gastric mucosa: a gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst 1968;41:627–634. [32] Blaser MJ, Chyou PH, Namura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer and duodenal ulcer risk. Cancer Res 1995; 55:562–565. [33] Parsonnet J, Vandersteen D, Goates J et al. Helicobacter pylori infection in intestinal and diffuse type gastric adenocarcinoma. J Natl Cancer Inst 1991;83:640–3. [34] Hansel W, Urinary M, Sega M et al. Stomach cancer among Japanese in Hawaii. J Natl Cancer Inst 1972; 49:969–988. [35] Kono S, Hirohata T. Nutrition and stomach cancer. Cancer Causes Control 1996;7:41–55. [36] Shimsato Y, Tanaka N, Kogure K et al. Histopathology of tumors of the canine alimentary tract produced by N-methyl–N’-nitroso-N-guanidine, with particular reference to gastric carcinoma. J Natl Cancer Inst 1971;47:1053–1070. [37] Yu GP, Hseh CG, Wang LY et al. Green tea consumption and stomach cancer: a population based case control study in Shanghai, China. Cancer Causes Control 1995;6:532–538. [38] Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995;333:32–41. [39] Irish SS. Formation of N-nitrosocompounds: chemistry, kinetics and in vivo occurrence. Toxicol Appl Pharmacol 1975; 31:325–351. [40] Risch HA, Jain M, Choi NW et al. Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985; 122:947–959. [41] Dorant E, Van den Brandt PA, Goldbohm A et al. Consumption of onions and a reduced risk of

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52] [53]

[54]

stomach carcinoma. Gastroenterology 1996;110: 12–20. Azuine MA, Bhide SV. Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 1992; 17:77–83. Nomura A. Stomach cancer. In: Schottenfield D, Fraumeni JF (eds). Cancer epidemiology and prevention. New York: Oxford University Press, 1996:707–724. Tarbell NJ, Gelber RD, Weinstein HJ. Sex difference in second cancer after Hodgkin disease in childhood. Lancet 1993;341:1428–1430. Kato H, Schull WJ. Studies on the mortality of Abomb survivors. 7. Mortality, 1950-1978: Part 1 Cancer Mortality. Radiat Res 1982;90:395–432. Tokunaga M, Land CE, Uemura Y et al. Epstein Barr virus in gastric carcinoma. Am J Pathol 1993;143: 1250–52. Ott G, Kirchner TH, Muller-Hermelink HK. Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric cancer. Histopathology 1994; 25:323–329. Levine PH, Stemmermann GN, Lennette ET et al. Elevated antibody titres to Epstein- Barr virus prior to the diagnosis of Epstein Barr associated gastric adenocarcinoma. Int J Cancer 1995;66:642–644. Tokunaga M, Uemura Y, Tokudome T et al. Epstein Barr virus related gastric cancer in Japan: A molecular pathoepidemiological study. Acta Pathol Jpn 1993;43:574–581. Nakamura S, Ueki T, Yao T et al. Epstein Barr virus in gastric carcinoma with lymphoid stroma. Cancer 1994;73:2239–2249. Tricker AR, Spiegelhalder B, Preussman R. Environmental exposure to preformed nitroso compounds. Cancer Surveys 1989;8:251–272. Raj A, Mayberry JF, Podas T. Occupation and gastric cancer. Postgrad Med J 2003; 79:252–258. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process –First Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735–40. Sano T, Tsujino T, Yoshida K et al. Frequent loss of heterozygosity on chromosome 1q, 5q, and 17p

Tropical Hepatogastroenterology

REFERENCES

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

in human gastric carcinoma. Cancer Res 1991; 51:2926–2931. Uchino S, Tsuda H, Noguchi M et al. Frequent loss of heterozygosity at the DCC locus in gastric cancer. Cancer Res 1992;52:3099–3102. Rhyu MG, Park WS, Jung YJ et al. Allelic detection of MCC/APC and p53 are frequent late events in human gastric carcinogenesis. Gastroenterology 1994;106:1584–1588. Wu MS, Lee CW, Shun CT et al. Clinicopathological significance of altered foci of replication error, and microsatellite instability associated mutation in gastric cancer. Cancer Res 1998;58:1494–1497. Sasaki O, Soejima K, Korenage D et al. Comparison of the intratumor DNA ploidy distribution pattern between differentiated and undifferentiated gastric carcinoma. Anal Quant Cytol Histol 1999;21:161–165. Seruca R, Santos NR, David L et al. Sporadic gastric carcinoma with microsatellite instability displays a particular clinicopathologic profile. Int J Cancer 1995;64:32–36. Lacopetta BJ, Soong R, House AK et al. Gastric carcinomas with microsatellite instability: clinical features and mutation of the TGF beta type II receptor, IGF II receptor, and BAX genes. J Pathol 1999; 187:428–432. Honchel R, Halling KC, Thibodeau SN. Genomic instability in neoplasia. Semin Cell Biol 1995;6:45–52. Strickler JG, Zheng J, Sku Q et al. p53 mutation and microsatellite instability in sporadic gastric, when guardian fail. Cancer Res 1994;54(17): 4750–4755. dos Santos NR, Seruca R, Constancia M et al. Microsatellite instability at multiple loci in gastric carcinoma: clinocopathologic implications and prognosis. Gastroenterology 1996;110: 38–44. Ottini L, Palli D, Fatchetti M et al. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high risk population from Tuscany. Cancer Res 1997;57:4523–4529. Olivera C, Seruca R, Seixas M et al. The clinicopathological features of gastric carcinoma with

Part II / Stomach

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

149

microsatellite instability may be mediated by mutation of different target genes: a study of the TGF-beta R II, IGRF II, and BAX genes. Am J Pathol 1998;153:1211–1219. Wu T-T, Watanabe T, Heitmiller R et al. Genetic alterations in Barrett’s esophagus and adenocarcinoma of the esophagus esophagogastric junction region. Am J Pathol 1998; 153:287–294. Yamamota H, Perez-Piteira J, Yoshida T et al. Gastric cancers of the microsatellite mutator phenotype display characteristics genetic and clinical features. Gastroenterology 1999;116:1348–1357. Hollstein M, Shomer B, Green Blatt M et al. Somatic point mutation in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acid Res 1996;24:141–146. Tamira G, Maesawa C, Suzuki y et al. Mutations of the APC gene occur during early stages of gastric adenomas development. Cancer Res 1994;54:1149. Nakatsura S, Yanagisawa A, Ichii S et al. Somatic mutations of the APC gene in gastric cancer: Frequent mutations in very well differentiated adenocarcinoma and signet ring carcinoma. Hum Mol Genetics 1992;52:3099. Caca K, Kulligs Ji X et al. beta- and gamma-catenin mutations, but not º-cadherin activation, underlie T cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differ 1999;10:369. Park W, Oh R, Park J et al. Frequent somatic mutations of the β-catenin in intestinal type gastric cancer. Cancer Res 1999; 59:4257. Koh TJ, Wana TC. Tumors of the stomach. In: Sleisenger and Fordtran’s Gastrointestinal and Liver disease. Feldman M, Friedman LS, Sleisenger MH (eds). 7th edition. Saunders, Elsevier Science 2002, p 829–855. Uchino S, Tsuda H, Maruyama K et al. Overexpression of c-erb-B2 protein in gastric cancer. Cancer 1993;72:3179–3184. Yonemura Y, Ninomiya I, Yamaguchi A et al. Evaluation of immunoreactivity for erbB2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 1991; 51:1034–1038.

150

Chapter 7 / CARCINOMA OF THE STOMACH

[76] Nakajima T, Nishi M. Surgery and adjuvant chemotherapy for gastric cancer. Hepatogastroenterol 1989;36:70–85. [77] Tsuji S, Kawano S, Sawaoka H et al. Evidence for involvement of cyclo-oxygenase-2 in proliferation of the two gastrointestinal cancer lines. Prostaglandins Leukot Essent Fatty Acids 1996;55:179–183. [78] Thun MJ, Namboodri MM, Calle EE et al. Aspirin use and risk of fatal cancers. Cancer Res 1993;53:1322–1327. [79] Zaridze D, Borisova E, Maximovitch D et al. Aspirin protects against gastric cancer: results of case and control study from Moscow, Russia. Int J Cancer 1999; 82:473–476. [80] Yokozaki H, Yasui W, Tahara E. Genetic and epigenetic changes in stomach cancer. Int Rev Cytol 2001;204:49–95. [81] Becker KF, Atkinson MJ, Reich U et al. E-Cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 1994;54:3845–52. [82] Yamashina M. A variant of early gastric carcinomaHistologic and histochemical studies of early signet ring carcinomas discovered beneath preserved surface epithelium. Cancer 1986;58:1333–1339. [83] Ming S-C. Gastric carcinoma. A pathobiological classification. Cancer 1977;39:247–54. [84] Ohta H, Noguchi Y, Takagi K et al. Early gastric carcinoma with special reference to macroscopic classification. Cancer 1987;60:1099–1106. [85] Green PH, O’Toole KM, Weinberg LM et al. Early gastric cancer. Gastroenterology 1981;81:247–56. [86] Mulligan RM: Histogenesis and biological behavior of gastric carcinoma. In: Pathology Annual, vol 7. New York: Appleton Century Crofts, 1972, p349. [87] Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of the gastric cancer classified by the histological type: new histological classification of the gastric carcinoma. Gut 1992;33:606–612. [88] Bozzeti F, Bonfanti G, Bufalino R et al. Adequacy of resection in gastrectomy for cancers. Ann Surg 1982;196:685–87.

[89] Papachristou DN, Agnanti N, D’Agostino H et al. Histologically positive margins in the surgical treatment of gastric cancer. Am J Surg 1980;139:711–3. [90] Mori M, Mimori K, Inouse H et al. Detection of cancer micrometastases in lymph nodes by reverse transcriptase-polymerase chain reaction. Cancer Res 1995;55:3417–20. [91] Morgagni P, Saragoni L, Scarpi E et al. Lymph node micrometastases in early gastric cancer and their impact on prognosis. World J Surg 2003;27: 558–561. [92] Cai J, Ikeguchi M, Maeta M et al. Micrometastases in lymph nodes and microinvasion of the muscularis propria in primary lesions of submucosal gastric cancer. Surgery 2000;127:32–39. [93] Cai J, Ikeguchi M, Tsujitani S et al. Micrometastases in lymph nodes mucosal gastric cancer. Gastric cancer 2000;3:91–96. [94] Fukagawa T, Sasako M, Mann BG et al. Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma. Cancer 2001;92:753–760. [95] Kikuchi Y, Tsuchiya A, Ando Y et al. Immunohistochemical detection of lymph node microinvolvement in node negative gastric cancer. Gastric Cancer 1999;2:173–178. [96] Esaki Y, Hirayama R, Hirokawa K. A comparison of patterns of metastases in gastric cancer by histologic type and age. Cancer 1990;65: 2086–88. [97] Ziegler K, Sarift C, Zimmer T et al. Comparison of computed tomography, endosonography, and intraoperative assessment in TN staging of gas tric carcinoma. Gut 1993;34:604–610. [98] Botet JF, Lightdale CJ, Zauber AG et al. Preoperative staging of gastric cancer: comparison of endoscopic US and dynamic CT. Radiology 1991;181:426–432. [99] Stell DA, Carter CR, Stewart I et al. Prospective comparison of laparoscopy, ultrasonography and computed tomography in the staging of gastric cancer. Br J Surg 1996;83:1260–1262. [100] Davies J, Chalmers AG, Sue-Ling HM et al. Spiral computed tomography and operative staging

Tropical Hepatogastroenterology

REFERENCES

[101]

[102]

[103]

[104]

[105]

[106]

[107] [108]

[109]

[110]

[111]

[112]

of gastric adenocarcinoma: a comparison with histopathological staging. Gut 1997;41:314–319. Fein J, Gardes H, Karpeh M et al. Overstaging of ulcerated gastric cancer by endoscopic ultrasonography. Gastrointest Endosc 1993;39:274. Conlon KC, Karpeh MS. Laparoscopy and laparoscopic ultrasound in the staging of gastric cancer. Semin Oncol 1996;23:347–351. Mortensen MB, Scheel-Hincke JD, Madsen MR et al. Combined endoscopic ultrasonography and laparoscopic ultrasonography in the pretherapeutic assessment of resectability in patients with upper gastrointestinal malignancies. Scand J Gastroenterol 1996; 31:1115–1119. Yeung HWD, Macapinlac H, Karpeh M et al. Accuracy of FDG-PET in gastric cancer: preliminary experience. Clin Positron Imaging 1998;1:21–221. Ren J, Chen Z, Juan S et al. Detection of circulating gastric carcinoma associated antigen MG7Ag in human sera using an established single determinant immuno-polymerase chain reaction technique. Cancer 2000;88:280–5. Li Y, Lin SR, Zhou LY et al. The value of autofluorescence spectrum analysis of gastric juice in diagnosing gastric carcinoma: a preliminary result. Zhonghua Nei Ke Za Zhi 2003;42:31–33. Hiki Y, Shimao H et al. Endoscopic treatment of gastric cancer. Surg Endosc 1991;5:11–13. Kakar AK. Early gastric cancer. In: GI Surgery Annual, Vol 3. Chattopadhyay TK (ed). New Delhi, Indian Association of Surgical Gastroenterology, 1996, p 1–9. Heesakkers JP, Gouma DJ, Thunnissen FB et al. Nonradical therapy for early gastric cancer. Br J Surg 1994;81:551–553. Sawai K, Takahashi T, Suzuki H. New trends in surgery for gastric cancer in Japan. Jpn J Surg Oncol 1994;56:221–226. Kitajima M, Kumari K, Ohgami M. Laparoscopic wedge resection of the stomach for early gastric cancer. Abstracts of UICC Kyoto International Symposium on Recent Advances in the Management of Digestive Cancer 1993;91–94. Kodama M, Koyama K. Indications for pylorus preserving gastrectomy for early gatric cancer located

Part II / Stomach

[113] [114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

151

in the middle third of the stomach. World J Surg 1991;15:628–634. Carmalt HL, Gillet DJ, Lin BPC. Early gastric cancer. Aust NZ J Surg 1990;60:865–869. Macdonald I, Kotin P. Biological predeterminism in gastric carcinoma as the limiting factor of curability. Surg Gynecol Obstet 1954;98:148–152. Nakajima T, Ota K, Ishihara S et al. Extended radical gastrectomy for advanced gastric cancer. Surgical Oncology Clinics of North America 1993;2:467–481. Kodama Y, Sugimachi K, Seijima K et al. Evaluation of extensive lymph node dissection for carcinoma of the stomach. World J Surg 1981;5: 241–248. Cheung LY, Declore R. Stomach. In: Sabiston’s Textbook of Surgery. Townsend CM Jr (ed). 16th edition. New Delhi, Elsevier 2001. p 837–872. Smith JW, Shiu MH, Kelsey L et al. Morbidity of radical lymphadenectomy in curative resection of gastric carcinoma. Arch Surg 1991;126:1469–73. Appleby LH. The celiac axis in the expansion of the operation for gastric carcinoma. Cancer 1953;6:704–7. Takenaka H, Iwase K, Ohshima S et al. A new technique for the resection of gastric cancer: modified Appleby procedure with reconstruction of hepatic artery. World J Surg 1992;16:947–951. Nakajima M, Sawada H, Yamada Y et al. The prognostic significance of amplification and overexpression of c-met and c-erbB2 in human gastric carcinomas. Cancer 1999;85:1894–902. Cuschieri A, Weeden S, Fielding J et al. Patient survival after D1 resections for gastric cancer: long term results of the MRC randomized trial. Surgical Cooperative Group. Br J Cancer 1999;79:1522–30. Bonenkamp JJ, Songun I, Hermans J et al. Randomized comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 1995;345:745–48. Gretschel S, Christoph F, Bembenek A et al. Body mass index does not affect systematic D2 node dissection and postoperative morbidity in gastric cancer patients. Ann Surg Oncol 2003;10: 363–368.

152

Chapter 7 / CARCINOMA OF THE STOMACH

[125] Azagra J, Goergen M, Simone PD et al. Minimally invasive surgery for gastric cancer. Surg Endosc 1999;13:351–7. [126] Shimizu S, Uchiyama A, Mizumoto K et al. Laparoscopically distal gastrectomy for early gastric cancer: is it superior to open surgery? Surg Endosc 2000;14:27–31. [127] Yano H, Monden T, Kinuta M et al. The usefulness of laparoscopy associated distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer. Gastric Cancer 2001;4: 93–97. [128] Mochiki E, Kamimura H, Haga N et al. The technique of laparoscopically assisted total gastrectomy with jejunal interposition for early gatric cancer. Surg Endosc 2002;16:540–544. [129] Goh PM, So JB. Role of laparoscopy in the management of stomach cancer. Semin Surg Oncol 1999; 16(4):321–326. [130] Noh SM, Jeong HY, Cho JS et al. New type of reconstruction method after subtotal gastrectomy (Noh’s operation). World J Surg 2003;27: 562–566. [131] Hermans J, Banenkamp JJ, Boon MC et al. Adjuvant chemotherapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 1993;11:1441–1447. [132] Earle CC, Maroun JA. Adjuvant therapy after curative resection for gastric cancer in non-Asian

[133]

[134]

[135]

[136]

[137]

[138]

patients: revisiting meta-analysis of randomized trials. Eur J Cancer 1999;35:1059–64. Mari E, Floriani I, Tinazzi A et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published trials. A study of the GISCAD (Gruppo Italiano per lo Studio Dei Carcinomi dell’Apparato Digerente). Ann Oncol 2000; 11:837–843. Childs D, Moertel C, Holbrook M et al. Treatment of unresectable adenocarcinomas of the stomach with a combination of 5-fluorouracil and radiation. Am J Roentgenol Radium Ther Nucl Med 1968;102:541. Hallissey MT, Dunn JA, Ward LC et al. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five year follow-up. Lancet 1994;343:1309. Stein HJ, Sendler A, Fink U et al. Multidisciplinary approach to esophageal and gastric growth. Surgical Clinics of North America 2000;80: 659–681. Wanebo HJ, Kennedy BJ, Chmiel J et al. Cancer of the stomach: A patient care study by the American College of Surgeons. Ann Surg 1993;218:583–592. J, Menck H. The National Cancer Data Base Report on poor survival of US gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer Staging, proximal disease, and the “different disease” hypothesis. Cancer 2000;88:921–32.

test

Tropical Hepatogastroenterology

x

Part III Small Bowel

8 9

Tropical Malabsorption Infections of the Small Bowel

155 167

“This page intentionally left blank"

xx

Chapter

8 TROPICAL MALABSORPTION Usha Dutta and Kartar Singh

8.1 INTRODUCTION Tropical malabsorption is defined as a malabsorptive condition affecting people living in or visiting tropical regions due to causes that are present commonly in these areas (Table 8.1).[1] The common causes of malabsorption in the tropics are giardiasis, tropical sprue, tropical enteropathy, and enteropathy associated with human immunodeficiency virus (HIV) infection. The focus of this chapter is on tropical sprue and tropical enteropathy. Though tropical sprue was described in 600 BC by Charaka from India, it was only in the 17th century that interest in this disease resurfaced when travelers from Europe were affected. It took three centuries to understand the clinical presentation of the disease. The important milestones in the understanding of this disease are mentioned in Table 8.2.[2] In 1957 Baker described 60 cases of tropical sprue from south India, which was later followed by descriptions from other parts of India.[3] Earlier, it was thought that tropical sprue only affected travelers to the tropics. However, a similar kind of illness was described among the indigenous population from Calcutta and Gujarat, which was labeled as para-sprue.[4]

TABLE fy 8.1 Causes of tropical malabsorption Caused by a single pathogen Protozoal: Giardia lamblia Isospora belli Cryptosporidium parvum Enterocytozoon bieneusi Encephalitozoon intestinalis Cyclospora cayetanensis Helminths: Strongyloides stercoralis Capillaria philippinensis Bacterial: Enteropathogenic Escherichia coli Mycobacterium tuberculosis Viral: Rota virus Enteric adenovirus types 40, 41 Norwalk virus Measles Human immunodeficiency virus Caused by possibly more than one pathogen Tropical enteropathy Tropical sprue Immunoproliferative small intestinal disease Malnutrition related malabsorption Primary hypolactasia

8.2 DEFINITION Tropical sprue is a syndrome among inhabitants or visitors of the tropics, who have morphological small bowel abnormalities associated with

155

156

Chapter 8 / TROPICAL MALABSORPTION

TABLE fy 8.2 Historical perspective of tropical sprue 600 BC : Charaka was to first describe it as “Grahani Vyadhi” in Charaka Samhita 1672 : Ketelaer described the disease in the Dutch East Indies 1759 : William Hillary described the disease in Barbados 1880 : Manson coined the word “sprue” by anglicizing the word “indische sprouv” 1912 : Manson-Bahr described the small bowel changes 1924 : Small bowel was identified as the primary site of the disease 1950 : Peroral jejunal biopsy was used for diagnosis 1957 : Baker described 60 cases from south India

malabsorption of two or more unrelated substances, without ascertainable etiology.[5] However, this definition has certain pitfalls: it does not specify whether patients have to be symptomatic or not, whether folate deficiency is present or not, and whether response to therapy is necessary or not. Clarification of the symptom status is necessary to differentiate it from the condition known as “tropical enteropathy”, in which there are no overt clinical symptoms. Also a predictable response to standard therapy is characteristic, which helps in the confirmation of diagnosis. Nutritional deficiency of folate is again a characteristic aspect of the disease. The lack of a specific consensus definition is reflective of our inadequate understanding of the disease and has also hampered the systematic study of this disease. We propose the following modified definition: Tropical sprue is a syndrome occurring among residents/travelers to certain regions in the tropics who develop diarrhea and nutritional deficiencies, with evidence of malabsorption of at least two unrelated substances, morphological abnormalities of the small bowel, absence of any identifiable etiology, and response to folic acid supplementation and antibiotic therapy.

Tropical sprue and tropical enteropathy possibly represent two ends of the spectrum of the same phenomenon.[6] Tropical enteropathy has previously been called “subclinical malabsorption”. At birth, neonates born in developing countries have a bowel villus height similar to those of neonates in the developed countries. After six months of exposure to an “infected” environment, the villus height decreases and inflammatory cells appear in the lamina propria. The differences between the healthy individuals in developed parts of the world and developing regions are contrasted with tropical enteropathy and sprue in Table 8.3.

8.3 EPIDEMIOLOGY 8.3.1 Endemic Areas Two main determinants of endemicity seem to be location and socioeconomic status. Predominantly tropical areas between latitude 30◦ north and south of equator, and those with poorer socioeconomic status are affected.[7] These include certain regions in South and South-east Asia, Caribbean islands, and central and South America.[8–11] There are rare reports from Egypt, Zimbabwe, Nigeria, and other parts of sub-Saharan Africa.[12] This disease does not affect natives of affluent European countries. The prevalence in endemic areas in south India is reported to be 1.4%.[9] In a study from north India, the prevalence among outpatients was 0.2%.[13]

8.3.2 Age and Gender Predisposition Tropical sprue predominantly affects adults, and is relatively rare among children. However, 10% of the patients affected in Puerto Rico were aged less than 10 years.[14, 15] The attack rate in an epidemic in south India (1960–62) was 2% among those < 20 years in contrast to 8%–10% among older individuals.[9] The attack rate among children

Tropical Hepatogastroenterology

PATHOGENESIS

157

TABLE fy 8.3 Clinical differences between tropical sprue and enteropathy Changes

Healthy individuals in Developed Developing countries countries

Tropical enteropathy

Tropical sprue

Symptoms Villus height Inflammation D-Xylose B12 Absorption Malnutrition Response to Rx

Absent Taller Absent Normal Normal No –

Absent Short Mild Abnormal Abnormal No Variable

Present Shortest Moderate Abnormal Abnormal Yes Predictable

Absent Tall Mild Normal Normal No –

increased during the next wave of the epidemic in the same regions, as the previous epidemic had conferred protective immunity on the previously affected individuals.[7] Males and females seem to be equally affected among natives.[2] However, among the travelers, this disease is commoner among men, as expatriates are usually men.

adults in the first wave and children in the second wave of the epidemic. The spread within a village followed a characteristic pattern of interfamilial spread and clustering of affected households, suggesting the role of a transmittable agent.[9] The incubation period ranged from 3–5 days. Certain epidemics have occurred after rainy seasons, suggesting the possibility of water borne transmission.

8.3.3 Predisposing Factors Those who are malnourished prior to the onset of illness tend to develop more protracted and severe disease. In an experimental primate model, those who were fed on 2% protein diet had more severe and protracted illness than those fed on 5% protein diet.[16]

8.3.4 Epidemics of Tropical Sprue The epidemic form of tropical sprue occurs in natives of, as well as travelers to, endemic regions. The epidemic in south India near Vellore in 1960–62 affected 100,000 people with a mortality of 30%.[7] The cause for early mortality was dehydration-related deaths, and the cause for late mortality was protracted diarrhea and resultant malnutrition. The population most affected was

Part III / Small Bowel

8.3.5 Changing Trends There has been a steady decline in the incidence of tropical sprue over the last 4 decades with improvement in sanitation and water supply, nutrition and increased availability of refrigerators. From 1927 to 1953, a decline from 2% to 0.4% was documented in Cuba and from 1953 to 1961, a decline of 7.4 to 0.3 per 100,000 population was noted in Puerto Rico.[17, 18] In India also a similar trend has been observed, however, it has not been methodically documented.

8.4 PATHOGENESIS The literature is replete with various conflicting theories for the pathogenesis of tropical sprue and enteropathy, but the last word is yet to be

158

Chapter 8 / TROPICAL MALABSORPTION

said. The dominant hypothesis are infective, nutritional, reduced small bowel transit, and genetic. We will first discuss these four hypotheses, and then propose a unifying hypothesis.

8.4.1 Infective Hypothesis Tropical sprue is due to persistent intestinal contamination by more than one organism resulting in mucosal abnormality, which reverses with antibiotics. The following points strongly favor this hypothesis. The disease is prevalent in the less developed regions, where bacterial contamination is very likely in view of inadequate sanitation facility, nonavailability of safe drinking water, and inadequate refrigeration facility. Within these tropical regions also, the places worst affected are those with poorer living conditions. With an improvement in the socioeconomic conditions, there has been a steady decline in the incidence of tropical sprue in these areas.[17, 18] Various enteropathogens like Klebsiella, Enterobacter cloacae, Escherichia coli, Alcaligenes faecalis and Enterobacter aerogenes have been isolated from the proximal bowel.[1, 19, 20] These are quantitatively and qualitatively different from those isolated from healthy controls living in the same region, or from people living in developed countries.[21] However, studies from India on patients with tropical sprue have not demonstrated coliforms in excess of that seen in normal control population, except for a few sparse reports. There are also instances of isolation of Rotavirus like particles in the intestinal mucosa, and Corona virus like particles in the stool of these patients.[22] However, the overwhelming evidence favors a bacterial rather than a viral pathogen. The height of the small bowel villi at birth in neonates of developing countries is similar to that of their counterparts in the developed countries. However, after weaning is commenced, their villus height reduces and inflammation in the lamina propria

starts appearing. Both these features represent the mildest end of the spectrum of intestinal insult by pathogens. Several other features indicate that a transmissible agent causes tropical sprue.[1, 7] The spread of illness is interfamilial and intrafamilial. The disease occurs in epidemics. Travelers become afflicted within a short period of arrival to endemic areas. The illness has an onset often like an infective diarrhea. Occurrence is more after rainy season. A protective immunity develops. In a locality where groups of people have already been affected during the first wave of the epidemic, the second wave does not affect the previously affected.[9] Unfortunately, no single pathogen has been identified. The relationship between colonization and mucosal damage is still unclear, and not all workers have been able to isolate organisms from the small bowel.

8.4.2 Nutritional Theory There are many advocates for this theory, as nutritional deficiencies are the hallmark of the disease. Moreover, almost miraculous clinical and histological improvement occurs on substitution of folic acid and vitamin B12 . The dietary folate, which is in the form of polyglutamates, needs to be deconjugated by the enzyme “folate conjugase” present on the intestinal brush border. The hydrolysis of oral polyglutamates is impaired in tropical sprue leading to a functional deficiency of folate.[23] The DNA synthesis for regeneration of the intestinal epithelium is dependent on the folate dependant enzyme “thymidylate synthetase”. This results in villous atrophy and crypt hyperplasia. However, oral folic acid, which is in the form of monoglutamate, is easily absorbed, and reverses the underlying folate deficiency. In experimental models, protein deficient primates develop more severe disease than do those on normal protein diet.[17] Intrauterine riboflavin

Tropical Hepatogastroenterology

PATHOLOGY

159

deficiency results in irreversible riboflavin resistant reduction in villus height. In Hong Kong, the consumption of rancid unsaturated long chain fatty acids (produced due to reheating and lack of refrigeration) results in toxic small bowel injury. It was noticed that Gurkas who consumed only Ghee, a saturated fat prepared from milk, did not develop tropical sprue. The incidence was high in countries where lard (unsaturated fat) was used, and very low in regions like Jamaica where saturated vegetable oils (resistant to oxidative changes induced by reheating) were used.

with resultant bacterial overgrowth in the proximal gut. The treatment with antibiotics possibly eliminates the harmful bacteria, which either initiated the process or have subsequently proliferated secondary to bacterial overgrowth, thus restoring the “normal” milieu. Folic acid therapy restores the process of normal mucosal regeneration, thus restoring the normal absorptive function of the intestine.

8.4.3 Genetic Hypothesis

Though the dominant structural and functional changes occur in the proximal small bowel, the rest of the luminal tract is also affected, albeit in a milder fashion, with consequent pathophysiological disturbances (Table 8.4). The degree of change depends upon the duration and severity of the illness. The structural changes in the stomach, in 30% to 70% of patients with tropical sprue,[24] are of chronic atrophic gastritis. However, these studies have been done in the pre-H. pylori era, and thus the relationship to tropical sprue needs to be confirmed. The two key structures affected in the small bowel are the villus-crypt unit and the lamina propria. The villus becomes broader, and its height steadily decreases with increasing severity of the disease. Coalition of adjacent villi results in formation of leaf like villi and ridges, when viewed under a dissection microscope. Reduced villous height and crypt hyperplasia together increase the cryptvillus ratio (normal 1:4). However, despite the increased cell turnover, the newly formed epithelial cells are abnormal and are shed more quickly, resulting in a net decrease in active cells on the villus. The surface lining cells also become cuboidal with time. There is also an increase in nonspecific inflammatory cells in the lamina propria, and an increase in intraepithelial lymphocytes in

The villus height of a British native is more than that of a Caribbean settler in Britain, even if he has not visited the Caribbean islands for long. Persons with HLA AW-31 are at 10.6 times higher risk of developing tropical sprue. There is also an association with the AW-19 series.

8.4.4 Unifying Hypothesis (Fig. 8.1) The initiating event is usually a gastrointestinal infection, which tends to persist and cause either direct or toxin mediated mucosal injury. Among nutritionally deprived individuals, any gastrointestinal infection is more likely to result in greater damage to the intestinal mucosal brush border enzymes, which subsequently results in functional folate deficiency. Folate deficiency impairs the process of mucosal repair and regeneration, which in turn impairs the absorptive process, with resultant nutritional deficiency. The initial pathogen may or may not continue to reside in the gut, thus explaining the inability to isolate a pathogen in all patients with tropical sprue. The presence of excess undigested fat in the ileum results in production of enteroglucagon, motilin and peptide YY, that slows down small bowel intestinal transit

Part III / Small Bowel

8.5 PATHOLOGY

160

Chapter 8 / TROPICAL MALABSORPTION

FIGURE 8.1 Pathogenesis of tropical sprue: Unifying hypothesis. Malabs = Malabsorption; FFA = Free fatty acid

Tropical Hepatogastroenterology

CLINICAL FEATURES

TABLE fy 8.4 Pathophysiological alterations in tropical sprue Stomach:

↓ Gastric acid production ↓ Intrinsic factor (IF)

Small bowel: ↓ D-Xylose absorption ↓ Fat absorption ↓ Lactose absorption ↓ Disaccharidase activity ↓ Folic acid absorption as polyglutamates ↓ Vitamin B12 absorption (↓ IF and ileal involvement) ↓ Aminoacid and dipeptide absorption ↓ Vitamin D absorption ↓ Intestinal transit ↑ Surface pH (6.0) : impairs ion transport. Pancreas:

Impaired secretin test

Colon:

↑ Water secretion (inhibition of Na+ K+ ATPase and Mg+ K+ ATPase by FA)

Stools:

↑ Free fatty acids ↑ Water content ↑ Bile acid

Blood:

↓ Folate and B12 levels ↑ Monoenoic fatty acid ↓ Linolenic acid

the crypts but not in the villous. The cells are predominantly plasma cells and lymphocytes. There is accumulation of lipid droplets beneath the intestinal epithelium and thickening of basement membrane, which stains for collagen. Electron microscopy shows that the brush border is damaged, the microvilli are short, thick and reduced in number, and there is increase in lysosomes and intracellular fat. The basement membrane shows amorphous deposit with increased collagen fibers. The key lesion in tropical sprue is a stem cell defect in the crypts resulting in production of defective intestinal epithelial cells. The damage to the enterocyte does not seem to be immunologically mediated.[25]

Part III / Small Bowel

161

8.6 CLINICAL FEATURES[1, 5] Classical tropical sprue evolves in 3 phases over a period of 2–4 years. Fatigue, asthenia, weight loss and diarrhea characterize the first phase. The second phase is characterized by the appearance of nutritional deficiencies, and third phase by the development of severe anemia. The onset is usually with an episode of acute diarrhea; rarely the onset is insidious. Occasionally, the onset may be sub-clinical, termed latent sprue. The episode of diarrhea does not subside, and instead evolves into a chronic illness with persistent diarrhea, bloating, borborygmi, and lactose intolerance followed by frank steatorrhea. As the disease progresses, features of protein calorie malnutrition supervene with frank signs of vitamin deficiency such as glossitis, angular cheilitis, stomatitis, cutaneous pigmentation, pellagroid rashes, features of subacute combined degeneration of the spinal cord (namely paresthesias, numbness, decreased vibration sense and proximal muscle weakness), Bitot spots and keratomalacia. These features are followed by development of frank megaloblastic anemia followed by pancytopenia. Low-grade pyrexia is noticed in 30% to 60% of the cases. Electrolyte abnormalities such as hypokalemia and hypomagnesemia are common, however tetany is rare. Rarely, hypokalemic periodic paralysis has been reported.

8.7 INVESTIGATIONS AND DIAGNOSIS (Fig. 8.2) The laboratory evaluation of these patients is done with 3 main objectives: to establish the diagnosis, assess severity of the disease, and to exclude other known etiologies. Hematological work up usually reveals megaloblastic or dimorphic anemia with evidence of megaloblastosis in the marrow.

162

Chapter 8 / TROPICAL MALABSORPTION

FIGURE 8.2 Stepwise approach to diagnosis of tropical sprue. Org = Organism; TB = Tuberculosis; IPSID = Immunoproliferative small intestinal disease

Tropical Hepatogastroenterology

DIFFERENTIAL DIAGNOSIS

There is evidence of hypoalbuminemia, hypocalcemia, low B12 and folate levels. The D-Xylose test with 25G of D-Xylose is abnormal in most (94%–100%) patients. Also, studies using 5 GMS of D-Xylose, which has higher patient acceptability, has been shown to be abnormal in 94%.[26] However, occasionally mild malabsorption may be missed by the lower dose of D-Xylose. Most patients have mild steatorrhea ranging from 6– 12 gm in 24 hours. Endoscopic examination of the upper small bowel in severe cases may reveal flattened folds and scalloping. Magnification and chromoendoscopy improve yield by allowing targeted biopsy.[27] Biopsy of the duodenum and jejunum is characterized by presence of partial or subtotal villous atrophy with evidence of increased nonspecific inflammation in the lamina propria. Barium evaluation of the small bowel shows features of malabsorption in the form of flocculation and segmentation of the barium column, diffuse thickening of folds, and slow small bowel transit. The yield of these investigations is given in Table 8.5. Tests done to exclude other causes are stool examination, duodenal fluid examination and mucosal biopsy to rule out giardiasis; serological studies to exclude celiac sprue; and barium studies to look for strictures, fistulas (which suggest bacterial overgrowth), or nodularity (which suggests immunoproliferative small intestinal disease [IPSID]). TABLE fy 8.5 Yield of commonly used investigations in tropical sprue Investigation

Simplicity of use

Yield

D-Xylose Fecal fat Barium study Small bowel biopsy B12 Malabsorption

Easy Difficult Easy Easy Difficult

94% 69% 29% 73% (66%–100%) 96%

Part III / Small Bowel

163

8.8 DIFFERENTIAL DIAGNOSIS The diagnosis of tropical sprue is based on 4 caveats: diarrhea in the patient living in or returning from a tropical region, presence of small bowel mucosal structural and functional abnormality, exclusion of certain specific causes, and response to therapy. The common causes which need exclusion depending on the clinical setting are celiac sprue, giardiasis, tuberculosis, HIV enteropathy, and IPSID (Table 8.6). Celiac sprue may mimic tropical sprue, and should be suspected especially if the patient belongs to a susceptible ethnic group (north Indians in contrast to south Indians), if a family history of celiac disease is present, or if there is iron deficiency anemia and tetany. Testing for specific antibodies and gluten withdrawal will help in substantiating the diagnosis. Giardiasis usually presents with small bowel diarrhea. Features of frank nutritional deficiencies are lacking, and evaluation of the stool or duodenal fluid/mucosa can confirm/exclude the diagnosis. The diagnosis of IPSID should be suspected if abdominal pain is the dominant complaint with fever, clubbing, jejunal nodularity on the barium

TABLE fy 8.6 IPSID vs tropical sprue IPSID

Tropical sprue

Pain Fever

+++ +++

+ ±

Clubbing Pathogenesis Infiltrate Atypical cells Alpha chain Mesenteric LN Prognosis Chemotherapy

++ Immunoproliferation Monomorphic + + ++ Poor +

– Epithelial destruction Polymorphic – – – Good –

164

Chapter 8 / TROPICAL MALABSORPTION

studies with evidence of monoclonal lymphocytic proliferation in the jejunal mucosa. With increasing HIV disease in the very regions where tropical sprue was so common, a new dimension gets added. Infection due to unusual organisms like microsporidia. Cryptosporidium, Mycobacterium avium intracellulare, and others need to be specifically looked for. Tuberculosis would remain a differential diagnosis though it predominantly involves the ileum, features of frank malabsorption are less common, and features of systemic inflammatory responses would be present. Strongyloides stercoralis is rare mimicker of tropical sprue, which needs exclusion by fecal culture and Baermann test for the larva.

8.9 TREATMENT The therapy for tropical sprue has largely been empirical starting from the use of liver extracts in 1950s. As the disease has been on the decline, no recent research inputs have been in this area. Spontaneous improvement without therapy has been seen in 50% of those affected during an epidemic. This is possibly because these patients are less likely to have underlying nutritional deficiencies, and are more likely to return to a normal dietary pattern that may prevent the folate deficiency, which is the main perpetuator of the disease.

8.9.1 Supportive Therapy These patients often require correction of dehydration and electrolyte abnormalities such as hypokalemia, hypomagnesemia, hypophosphatemia. If anemia results in circulatory failure, it would need blood transfusion for immediate correction. Nutritional therapy with easily digestible solids should be instituted as early as is tolerated.

Preferably lactose-containing products should be avoided in the initial phase of nutritional rehabilitation. Re-feeding hypophosphatemia and edema are common, and should be appropriately managed. Oral iron supplementation is useful to correct depleted iron stores, which is usually due to inadequate dietary intake.

8.9.2 Specific Therapy The three key drugs which have a specific role in the management of tropical sprue are folic acid, vitamin B12 , and antibiotics. Folic acid is given orally in doses of 5 or 10 mg daily for one year. There is no need for parenteral therapy as oral therapy is very effective. However, there are no randomized controlled trials which have compared various modalities of therapy, and thus the recommendations remain empirical. Vitamin B12 is administered as intramuscular injections 1000 micrograms daily for one week followed by once a month for one year.[28] Antibiotics hasten the recovery, and result in lasting remissions. The antibiotics commonly used are tetracycline 250 mg four times a day or doxycycline 100 mg twice a day for 6 months. Though a study from Vellore suggested that antibiotics were not particularly necessary,[23] most authors would advocate antibiotic therapy. Oral sulfonamides with minimal systemic absorption like Sulfasuxidine have been tried with success. The feeling of well being and improvement in appetite are first to return with 48– 72 hours of therapy. Histological improvement is also noticeable within 3–6 days. Improvement in other parameters occurs within the first month of therapy.

8.10 PROGNOSIS The best prognosis is among travelers, and those with shorter duration of illness (< 6 months).

Tropical Hepatogastroenterology

FUTURE DIRECTIONS

Usually, complete long lasting recovery ensues if the appropriate therapy for adequate duration is given. However, relapses are known if the person revisits the same or other endemic zones. Also, those travelers who return to the temperate regions experience faster recovery than those who continue to live in the endemic regions. Among natives, even after apparent clinical recovery some subclinical malabsorption may persist. Overall, the disease has a good prognosis, and is thus an eminently treatable cause of malabsorption.

8.11 FUTURE DIRECTIONS With improved socioeconomic status, sanitation, water supply, and health care in endemic regions,

165

and with better awareness of the disease among doctors, the disease expectedly will show a further decline in incidence. However, with the emergence of increasing HIV disease in Africa and South-east Asia, the definitive diagnosis of tropical sprue will be more difficult. However, if the changing trends are systematically studied, some more light will be shed on the pathogenesis of this entity. With the advent of antibiotics with lesser side effects like the quinolone group of drugs, randomized controlled trials are necessary to establish their efficacy in this condition in comparison to the time-honored tetracycline. Probiotics are emerging as effective therapy in various luminal conditions; their role needs to be evaluated as a therapeutic agent in the prevention and treatment of tropical sprue.

REFERENCES [1] Farthing MJG. Tropical malabsorption and diarrhea. In Sleisenger and Fordtran’s Gastroenterology and liver disease. Eds Felman M, Friedman LS, Sleisenger MH. Edition 7th 2002. Saunders Philadelphia, pp 1842–53. [2] Klipstein FA, Baker SJ. Regarding the definition of tropical sprue. Gastroenterology 1970;58:717–21. [3] Baker SJ. Idiopathic tropical steatorrhea. A report of sixty cases. Ind J Med Res. 1957;11:687–703. [4] Jain SR, Sepaha GC. Para-sprue — a malabsorption syndrome. A hematological, biochemical and therapeutic study. Ind J Med Sci 1961;15:1–19. [5] Lindenbaum J. Tropical enteropathy. Gastroenterology 1973;64:637–52. [6] Klipstein FA. Recent advances in tropical malabsorption. Scan J Gastroenterol (Suppl 6) 1970;64: 93–114. [7] Mathan VI, Baker SJ. The epidemiology of tropical sprue. In the Wellcome trust collaborative study. 1961–69. London, Churchill Livingstone 1971, pp 159–88.

Part III / Small Bowel

[8] Moshal MG. Tropical sprue in Africa. Lancet 1970;2:827. [9] Baker SJ. Tropical sprue. Br Med Bull 1972;87–91. [10] Klipstein FA, Samloff Im, Smarth G et al. Malabsorption in rural Haiti. Am J Clin Nutr 1968;21: 1042. [11] Ramakrishna BS. Malabsorption syndrome in India. Ind J Gastroenterol 1996;15:135–41. [12] Failaye JM. Tropical sprue in Nigeria. J Trop Med Hyg 1970;73:119. [13] Misra RC, Chuttani HK. Prevalence of tropical sprue in a hospital population in north India. Ann Trop Med Parasitol 1969;63:117–22. [14] Mehta S, Wadhwa UN, Prakash A et al. Small bowel function in severe chronic diarrhea in children. J Assoc Physic India 1968;16:343–9. [15] Santiago-Borrero PJ, Maldonado N, Horta E. Tropical sprue in children. J Pediatr 1970;76:470–9. [16] Mehta SK, Chakratravarti RN, Nain CK et al. Primate model of sprue like syndrome. Isr J Med Sci 1979;15:348–55.

166

Chapter 8 / TROPICAL MALABSORPTION

[17] Milanes F. Changes in the epidemiology and clinical behaviour of sprue occurring in Cuba during the 3 decades 1927-57. Arch Hosp Univ 1960;12: 125–44. [18] Tropical Sprue: studies in US Army sprue team in Puerto Rico. US Army Medical Science Publication 1958:5:55–6. [19] Gorbach SL, Mitra R, Jacob B et al. Bacterial contamination of the upper small bowel in tropical sprue. Lancet 1969;1:74. [20] Klipstein FA, Haldeman LV, Corcino JJ et al. Enterotoxigenic intestinal bacteria in tropical sprue. Ann Intern Med 1973;79:632. [21] Baker SJ, Mathan M, Mathan VI et al. Chronic enterocyte infection with coronavirus. One possible cause of the syndrome of tropical sprue? Dig Dis Sci 1982;27:1039–43. [22] Corcino Jj, Reisenauer AM, Halsted CH. Jejunal perfusion of simple and conjugated folates in tropical sprue. J Ciln Invest 1976;58:298–305. [23] Baker SJ, Mathan VI. Tropical sprue in Southern India. In Tropical sprue and megaloblastic

[24]

[25]

[26]

[27]

[28]

anemia London, Churchill Livingstone 1971, pp 189–260. Mathan MM, Ponniah J, Mathan VI. Epithelial cell renewal and turnover and relationship to morphologic abnormalities in jejunal mucosa in tropical sprue. Dig Dis Sci 1986;31:586–92. Baker SJ, Jacob R, Mathan VI. An evaluation of the 5 gm D-xylose absorption test with fractional urine collections in subjects living in southern India. Ind J Med Res 1971;59:1869–77. Siegel LM, Stevens PD, Lightdale CJ et al. Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption. Gastrointest Endosc 1997;46:226–30. Rickles FR, Klipstein FA, Tomasini J et al. Long term follow up of antibiotic treated tropical sprue. Ann Intern Med 1972;76:203–10. Tandon BN, Bose SL, Saikia B. The evaluation of prednisolone, tetracycline and high protein diet for the therapy of idiopathic tropical malabsorption. Indian J Med Res 1964;62:704–11.

test

Tropical Hepatogastroenterology

Chapter

9 INFECTIONS OF THE SMALL BOWEL Arun Kumar Sharma and Kartar Singh

Diarrheal illnesses are among the most common infectious diseases in the developing and developed world, and cause significant morbidity and mortality. Many bacteria, viruses, and parasites infect the small intestine, leading to diarrhea. Whether by toxin-mediated effects or by direct destruction of intestinal epithelial cells, these pathogens disrupt the normal fluid-handling capabilities of the intestinal tract and cause diarrhea. In tropical countries, the common pathogens infecting the small intestine are bacterial, viral, protozoal, helminthic, mycotic, and mycobacterial. Tropical sprue is another disease of infective etiology (Table 9.1).

TABLE 9.1 Common pathogens infecting the small intestine •

• • • • • •

Bacterial (including bacterial food poisoning): Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, enterotoxigenic and enteropathogenic E. coli, Vibrio species, Salmonella species Viral: Rotavirus, enteric adenovirus 40 and 41, caliciviruses, astrovirus, HIV Protozoa: Giardia duodenalis, Isospora belli, Cryptosporidia, Cyclospora, Microsporidia Helminths: Nematode, Cestodes, Trematodes Mycotic: Histoplasma, Aspergillus, Candida Mycobacteria Tropical sprue

This chapter describes bacterial, viral, protozoal, helminthic and fungal infections of the small bowel. Gastrointestinal tuberculosis and tropical sprue are dealt with in other chapters in this book.

9.1 BACTERIAL INFECTIONS (INCLUDING BACTERIAL FOOD POISONING) 9.1.1 Staphylococcus aureus Infections Staphylococcal food poisoning outbreaks occur in the summer months, particularly when many persons eat together. S. aureus colonizes the mucosa and skin in 20% to 50% of healthy persons including cooks, who are sources of food contamination. S. aureus produces enterotoxins A, B, C, D, and E, which are polypeptides causing fluid secretion in the intestine. These toxins are resistant to heat, extremes of pH, and proteolysis. Foods high in salt, protein, and sugar content, kept at an ambient temperature, allow the multiplication of organisms and release of toxin. 9.1.1.1 Clinical features

The incubation period is approximately 3 hours. Profuse vomiting, nausea, and abdominal cramps occur. Fever is common, and recovery occurs in 24–48 hrs. Antibiotics are not indicated. No 167

168

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

specific therapy is available. Supportive fluid therapy is helpful. Proper hygiene of cooks and safe food handling prevents disease. Refrigerated food after reheating should be consumed immediately, as microbes proliferate fast on reheating.

9.1.2 Bacillus cereus Bacillus cereus is a ubiquitous, anaerobic, motile, spore-forming, gram positive bacillus, and colonizes 10% to 40% of humans. Two types of clinical syndromes occur after ingestion of this organism: diarrheal and emetic. An emetic syndrome occurs within 1 to 6 hours with vomiting and abdominal pain. It develops after eating fried rice prepared by flash frying. The rice contains a preformed toxin which is resistant to heat. In contrast, the diarrheal syndrome occurs by ingestion of a 36–48 kd, heat-labile toxin present in sauce, pudding and vegetables. The diarrheal syndrome has a longer incubation period of 6 to 14 hours, with watery diarrhea, abdominal cramps, and occasional vomiting. These illness are mild and self-limiting. Antibiotics are not indicated. Boiled rice should be properly refrigerated and properly heated before consumption.

9.1.3 Clostridium perfringens Clostridium perfringens (C. perfringens) is a foodborne pathogen producing vomiting and diarrhea. The enterotoxin is released by type A strains of C. perfringens. 9.1.3.1 Epidemiology

The incubation period in outbreaks is between 8 to 14 hours after consumption of precooked meat, which has been reheated to be served. An outbreak with consumption of poorly cooked pork in New Guinea was labeled as pigbel.[1]

9.1.3.2 Etiopathogenesis

Clostridia are gram-positive, spore-forming, obligate anaerobes. They are found in raw meat, feces, and soil. C. perfringens is aerotolerant and produces 12 toxins including several enterotoxins. Food poisoning is caused by a heat labile enterotoxin that is a structural component of the spore coat, formed during sporulation. In an outbreak, meat cooked in bulk leads to insufficient killing of spores. Inadequate cooking of food allows clostridium spores to germinate at 50◦ C to produce bacteria, with accumulation of enterotoxins. 9.1.3.3 Clinical features

C. perfringens poisoning is characterized by watery diarrhea and severe abdominal pain without vomiting, 8 to 24 hours after eating contaminated meat. Fever, chills, and headache may occur, but the illness resolves in 14 hours. No specific treatment is required. Risks can be reduced by serving food immediately after proper cooking. Cooked meat should be kept either below 4◦ C or hot above 60◦ C.

9.1.4 Enterotoxigenic Escherichia coli Enterotoxigenic Escherichia coli (ETEC) produces disease by elaborating enterotoxin without invading intestinal epithelial cells. Enterotoxins produced are LT (heat labile toxin), STa and STb (heat-stable toxins). LT is remarkably similar to cholera toxin, with 5 identical B subunits and one enzymatically active A subunit, which activates adenylate cyclase in an NAD-dependent reaction. STa toxin activates the transmembrane guanylate cyclase system leading to intestinal secretion. 9.1.4.1 Epidemiology

ETEC has a worldwide distribution, and is the cause of approximately 40% of cases of traveler’s

Tropical Hepatogastroenterology

BACTERIAL INFECTIONS (INCLUDING BACTERIAL FOOD POISONING)

diarrhea. It is an important etiologic agent of diarrhea in children from developing countries (10% to 40%). It is still a major cause (93%) of childhood diarrhea in children up to 3 years of age in Bangladesh.[2] Acquisition of ETEC is primarily through ingestion of contaminated food. 9.1.4.2 Clinical features

The incubation period is 24 to 48 hours, and often begins with upper intestinal distress followed by watery diarrhea, which may be mild, or severe enough to mimic cholera. Headache, arthralgia, and vomiting last for 3 to 5 days. Stools are watery, yellow, and devoid of mucus, pus or fecal leukocyte. 9.1.4.3 Treatment

Fluid replacement is helpful. Treatment with antimicrobials (ampicillin/tetracycline) shortens the duration of disease. Avoidance of uncooked food and untreated water are important preventive measures.

169

9.1.5.1 Epidemiology

EPEC is an endemic diarrheal pathogen in infants of developing countries, and outbreaks are common. Infected children less than 2 years old have watery diarrhea which may become protracted. Older children and adults may serve as reservoirs, as it has been found in the feces of asymptomatic contacts of ill infants during outbreaks. Well known serotypes O55, O111, and O114 are associated with outbreaks of neonatal diarrhea. 9.1.5.2 Clinical features

Infants may have profuse watery diarrhea with vomiting and fever. Severe dehydration may lead to metabolic acidosis. 9.1.5.3 Diagnosis

Diagnosis is based on slide agglutination of suspected E. coli colonies on stool culture using polyvalent antisera recognizing the O antigen. DNA probes for detecting E. coli adherence factor (EAF) are used to detect EPEC.

9.1.5 Enteropathogenic Escherichia coli Enteropathogenic Escherichia coli (EPEC) organisms are those which lack shiga-like invasive properties, and fail to produce ETEC type enterotoxin. The bacteria attach intimately to, and efface, the microvilli of enterocytes, destroying them, and disrupting the underlying cytoskeleton. The attachment of bacterium to host cell membrane is mediated by intimin, an outer membrane protein. This is encoded by eae A gene cluster of the EPEC chromosome. This acts as a virulence factor in human EPEC infection.[3] E. coli adherence factor (EAF) is a plasmid which increases intimin production. EAF-positive classic EPEC is frequently identified in infants with acute diarrhea in developing countries.[4]

Part III / Small Bowel

9.1.5.4 Treatment

Fluid and electrolyte replacement is helpful as the disease is self limiting. Severe illness and prolonged diarrhea cases may need antimicrobial therapy.

9.1.6 Vibrio Species An estimated 5.5 million cases of cholera occur worldwide in epidemics caused by Vibrio cholerae O group 1 (Vibrio cholerae O1).[5] Cholera is endemic in Southern Asia, Africa and Latin America with a high toll in mortality. Gastroenteritis is caused by 7 to 10 known pathogenic Vibrio species, e.g., V. cholerae, V. parahemolyticus, V. mimicus,

170

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

and V. vulnificus. Strains associated with epidemic or endemic cholera are designated as O1 and non-O1. 9.1.6.1 V. cholerae

V. cholerae O1 has two biotypes: El Tor and Classical, each with 3 separate serotypes: Ogawa, Inaba and Hikojima. V. cholerae is a motile, monoflagellated, short gram negative curved rod. Toxigenic V. cholerae O1 El Tor causes milder clinical disease compared to the classical type. A toxigenic nonO1 strain called V. cholerae O139 Bengal caused an epidemic in Southern India in 1992; this epidemic rapidly spread to many countries of South East Asia.[6] In an epidemic in 1991 at Delhi, 49% of isolates were V. cholerae O1 El Tor, and 4 were V. cholerae O139.[7] In endemic areas cholera typically affects children between 2 to 9 years old, and women in child bearing ages. Patients who recover from V. cholerae O1 infection have long lasting immunity. Pathogenesis After ingestion, V. cholerae O1 bacilli must pass through stomach acidity to colonize the small intestine. They adhere with intestinal epithelia, and produce intracellular cholera toxin, neuraminidase, and hemolysin. Cholera toxin is a protein with a molecular weight of 84000 daltons. It has five binding B subunits, and one active A subunit with A-1 and A-2 peptides. The B subunit binds holotoxin to enterocyte receptor ganglioside GM-1. Then A-1 peptide catalyzes ADP ribosylation of GTP binding protein, which activates adenylate cyclase persistently. The resultant increase of cAMP in cells stimulates chloride secretion, and decreased Na+ reabsorption with loss of fluid and electrolytes. This results in massive watery diarrhea. The duodenum and the upper jejunum are more affected than the ileum.

Clinical features Symptoms range from subclinical gastroenteritis to severe cholera with the frequent passage of “rice water” stools. For most patients the illness is of sudden onset with profound dehydration and hypovolemic shock leading to renal failure. Diagnosis The diagnosis is based on clinical features, stool examination, and stool culture. Phase contrast microscopy may show darting motility. Stool is transported in alkaline peptone water (pH. 8.2), and vibrios are grown in thiosulfate citrate bile salt-sucrose (TCBS) agar media, and may be serotyped for identification. Treatment Patients with severe dehydration (> 10% body weight) need rapid intravenous rehydration therapy using Ringer’s lactate solution. In mild to moderate cases oral rehydration solutions are adequate. The drug of choice is Tetracycline 500 mg 6 hourly for 3 days. Alternative drugs include co-trimoxazole, norfloxacin, and furazolidone. The currently available vaccine, a parenteral killed whole cell vaccine, provides less than 50% protection from disease for 3 to 6 months only. The vaccine does not reduce the rate of asymptomatic infection, and hence cannot prevent transmission of disease.[8] 9.1.6.2 V. parahemolyticus

V. parahemolyticus is a halophilic (salt loving) vibrio present commonly in marine water. It causes acute diarrheal disease. Patients are infected by eating raw fish or shellfish. Most outbreaks have been reported in Japan and United States. The incubation period is less than 24 hours. Abdominal pain, nausea, vomiting, and watery explosive diarrhea are common. The duration of illness is short. Diagnosis is confirmed by culture for organism in TCBS media.

Tropical Hepatogastroenterology

BACTERIAL INFECTIONS (INCLUDING BACTERIAL FOOD POISONING)

Treatment Treatment is by prompt replacement of lost fluid and electrolytes. Use of antibiotics does not shorten the natural course of illness or the duration of pathogen excretion. Prevention includes avoidance of poorly cooked seafood, including oysters. 9.1.6.3 Vibrio cholerae Non-O1

These are a diverse group of organisms which are morphologically and biochemically identical to V. cholerae, but do not agglutinate with ‘O’ group antisera. They cause a wider range of infection including watery diarrhea, dysentery, wound infection, and septicemia. V. vulnificus infection is acquired by wound infection among people swimming in salt water, with the subsequent development of septicemia. V. fluvialis is mostly found in Asia; patients complain of watery diarrhea.[9]

9.1.7 Aeromonas Aeromonas are gram negative, oxidase positive bacteria from the family Vibrionaceae. A. hydrophila, A. caviae, and A. sobria are human pathogens. They produce an array of toxins including a cytotoxin, a hemolysin, and a heat labile enterotoxin. 9.1.7.1 Epidemiology

Aeromonas infections are associated with drinking well water and spring water. Children suffer from diarrhea, and the organism has been isolated from stool. A. caviae and A. sobria have been isolated from children with gastroenteritis in Chennai.[10] 9.1.7.2 Clinical features

Common presentations are mild diarrhea to a severe form requiring hospitalization. It may cause

Part III / Small Bowel

171

wound infection and bacteremia in immunocompromised hosts, who swim in fresh or brackish water. 9.1.7.3 Treatment

Organisms are consistently resistant to β-lactam antibiotics.[11] Trimethoprim-sulfamethoxazole may be useful.

9.1.8 Salmonella Species Salmonellosis is due to infection by one of many members of the genus Salmonella. The organism causes disease by complete invasion of the mucosa of the small intestine and colon. Salmonella are gram-negative, nonspore forming, motile, facultative anaerobic bacilli of the family Enterobacteriaceae. After biochemical identification they are further serotyped by identifying the ’O’ (somatic) antigen, the H (flagellar) antigen, and the Vi (virulence) antigen (for example, S. typhi is O9,12M, Dl). Ninety percent of Salmonella pathogenic to humans are from the A to E group containing 40 serotypes. These pathogens cause a spectrum of disease ranging from gastroenteritis to septicemia. The genus is also divided into typhoidal species (agents of enteric fever), e.g., S. typhi, S. paratyphi A (S. paratyphi), S. paratyphi B (S. schottmilleri), S. paratyphi C (S. hirschfeldii) and nontyphoidal species, e.g., S. typhimurium, S. dublin, S. newport, and others. 9.1.8.1 Typhoid (enteric) fever

Typhoid fever is a febrile illness of prolonged duration with abdominal symptoms and splenic enlargement. It can occur with any Salmonella serotype but is most commonly caused by S. typhi and S. paratyphi A, B, and C. Man is the only natural reservoir for S. typhi, whereas

172

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

other Salmonellae are associated mostly with animals. S. typhi is normally transmitted by ingestion of material contaminated by human feces, either from ill persons or asymptomatic carriers. Epidemiology Improved sanitation has reduced the incidence of typhoid fever in industrialized nations. Epidemic typhoid fever occurs in developing countries like Thailand, Malaysia, Mexico, Brazil, and Africa. Since S. typhi cohabits exclusively with humans, the appearance of a fresh case indicates the presence of a carrier in the community. Exclusive identification of S. typhi from chronic carriers is done by phage-typing to know the source of infection in the event of an outbreak. Immigrants from developing countries are responsible for two-thirds of acute infections in the United States.[12] Etiopathogenesis The usual pathogen is S. typhi. Biochemically, it is similar to S. paratyphi A, S. paratyphi B (S. schottmilleri), and S. paratyphi C (S. hirschfeldii), but it can be distinguished by serotyping. Increased susceptibility to infection occurs due to many predisposing factors, e.g., impaired cell-mediated immunity, poor phagocytic function, extremes of age, gastric acidity, and altered normal bowel flora. After oral ingestion, typhoid bacilli penetrate the small bowel mucosa, sparing the stomach, and pass through lymphatics, mesenteric nodes, and ultimately to the blood stream. There is very little local inflammation, hence no intestinal symptoms occur at this stage. After bacteremia, organisms multiply in macrophages and monocytes to re-emerge with newer waves of bacteremia. The organisms are seeded in Peyer’s patches in the terminal ileum, and often colonize the gallbladder. Hyperplasia in reticuloendothelial system leads to enlargement of lymph nodes, spleen and liver.

Clinical features The incubation period of S. typhi is generally 7 to 14 days, with wide variations. Following ingestion of organism, persons may have diarrhea for several days. The diarrhea usually resolves before the onset of fever. Without treatment typhoid fever lasts about 4 weeks, traditionally as a series of one week stages which may be altered by antibiotic therapy.[13] High fever and diffuse or right upper abdominal pain occur during the first week. Relative bradycardia (pulse relatively slow for degree of fever) is seen in less than 50% of patients. Constipation is more common than diarrhea in children. Blood culture is positive in 90% of patients, and 30% of patients have a faint salmon-colored maculopapular rash (rose spots) on the trunk, liver and spleen are enlarged with abdominal tenderness over lower quadrants (at times mimicking appendicitis). During the second week patients have continuous fever and look sick. In the third week of illness, extreme toxemia occurs with disordered mentation, intestinal hemorrhage and perforation, and there is focal infection in the form of cholecystitis, pneumonia, pyelonephritis, and liver or spleen abscess. Metastatic infection to bone and large joints may occur. About 3% patients with typhoid fever experience perforations in the ileum.[14] Symptoms abate after the third week of untreated illness in 90% of patients who survive. Relapses occur 8 to 10 days after cessation of drug therapy in 20% of patients, but with a milder and shorter illness. Carriers Fifty percent of typhoid victims shed organisms in their feces after 6 weeks, but after a year only 1% to 3% are excreters. The organisms usually harbor in gallbladder. Diagnosis Blood culture is positive in 90% of patients at the first week, and remains so for several weeks in untreated patients. Bone marrow culture has a high yield. Stool cultures become positive by

Tropical Hepatogastroenterology

VIRAL INFECTIONS

the second and third weeks. The titer of agglutinin (Widal test) against somatic (O) antigen rises during the second and third weeks of illness. An O titer of 1:80 or more in nonimmunized patients is suggestive of typhoid fever. A four-fold rise provides stronger evidence. Antibody rise to ‘H’ antigen is less specific. PCR assay for diagnosis has been developed. Treatment Chloramphenicol is highly active against most clinical isolates. Third generation cephalosporins namely cefotaxime and ceftriaxone are used successfully to treat typhoid fever. Ciprofloxacins are highly effective in multidrug resistant S. typhi.[15] Intestinal perforation requires surgery. Mild hemorrhage is common and selflimiting, but profuse gastrointestinal bleeding may require emergency surgery.[16] Vaccine therapy Three types of vaccine are available, namely (a) phenol-inactivated formulation (b) live attenuated S. typhi strain Ty 21a and (c) purified Vi capsular polysaccharide vaccine.[17] Each of these offers 55% to 85% protection for 3 to 5 years. 9.1.8.2 Nontyphoid salmonellosis

This refers to disease caused by any serotype of genus Salmonella with the exception of S. typhi and S. paratyphi. Approximately 2000 serotypes of salmonellae are potentially pathogenic for humans. Epidemiology The major route of passage is by food, fingers, feces, flies, and fomites. Large outbreaks have occurred associated with a common source due to S. enteritidis, S. typhimurium, S. heidelberg, S. newport, and S. haden.[18] The major reservoir for salmonella organism is poultry and domestic livestock. Poultry and poultry products account for 50% of salmonella outbreaks, beef and

Part III / Small Bowel

173

pork for 13%, and dairy products for 4%.[19] Egg and egg products are also a source of infection. Clinical features Symptoms of gastroenteritis develop within 48 hours of ingestion of contaminated food. Symptoms range from a mild illness to profuse diarrhea. Fecal leukocytes are present. Fever, abdominal pain, and nausea may occur. Diarrhea lasts 3 to 7 days, and fever may resolve earlier. Bacteremia and focal abscess are complications seen in AIDS patients.[20] Therapy Antibiotics should not be used in mild to moderately ill patients with gastroenteritis, as they prolong the intestinal carriage of nontyphoidal salmonella.[21] Antimicrobials are advised to neonates and persons older than 50 years in immunodeficiency states or in the presence of sepsis. In seriously ill patients with nontyphoidal salmonella infection, two antimicrobial agents from different classes may be used pending sensitivity reports. These agents could be ampicillin, amoxicillin, trimethoprimsulfamethoxazole, cefotaxime, or ceftriaxone. Trials using amoxicillin and trimethoprimsulfamethoxazole for 6 weeks show 80% success rates in chronic carriers of salmonella.[22]

9.2 VIRAL INFECTIONS Different viruses cause infections of the intestinal tract and cause diarrheal diseases, that are virtually indistinguishable from each other. These viruses are Rotavirus, Enteric Adenovirus 40 and 41, Calicivirus, Astrovirus, and HIV virus causing HIV enteropathy.

9.2.1 Rotavirus Rotavirus is a double stranded RNA virus having a triple layered icosahedral structure with 70 to

174

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

75 nm diameter. The icosahedral structure resembles the spokes of wheel – hence the name “rota”. The rotavirus genome is fragmented and has 11 segments of double stranded RNA. Three groups of rotavirus A, B, and C cause diarrhea in humans. Worldwide, most endemic causes of severe diarrhea in infants fall under Group A rotavirus.[23] Group B strains have been identified primarily in China and also in India,[24] whereas group C strains occur sporadically around the world.[25] 9.2.1.1 Epidemiology

Worldwide, rotavirus infection accounts for 125 million cases of diarrheal disease, with more than 800,000 deaths.[25] The virus spreads by the fecal-oral route. In temperate zones it is common in winter, but in the tropics it occurs round the year. It primarily causes illness in children between the ages of 3 months and 3 years.[26] Immunity is partial and not long-lived. 9.2.1.2 Clinical features

Clinical illness ranges from an asymptomatic carrier state to severe dehydration. Symptomatic infection follows an incubation period of 1 to 3 days. It is characterized by the rapid onset of fever, malaise, vomiting, and watery diarrhea. The average duration of illness is 5 to 7 days. In immunocompromised children, disease may be prolonged. Stools are watery but do not contain red or white blood cells. 9.2.1.3 Diagnosis

Rapid diagnosis is by detection of rotavirus antigen in stool using enzyme immunoassays. Rotavirus can be detected by electropherotyping of RNA isolated from stool samples.[27] RT-PCR assay and nucleic acid hybridization can detect the virus, and identify its serogroup.[28]

9.2.1.4 Treatment

Rehydration is the mainstay of therapy using oral rehydration fluid. Natural rotavirus infections have a protective efficacy of 93% against recurrent rotavirus disease. However, rotavirus vaccine is a subject of intense research activity. A tetravalent rhesus-human reassortment rotavirus vaccine has demonstrated moderate protection against rotavirus gastroenteritis.[29]

9.2.2 Enteric Adenovirus 40 and 41 Enteric adenovirus (DNA virus) serotype 40 and 41 causes gastroenteritis in children below 2 years of age. Five percent to ten percent of childhood diarrheas are caused by enteric adenovirus 40 and 41; there is no seasonal variation.[30] Illness due to enteric adenovirus 40 and 41 may last up to two weeks. Clinical features in children include diarrhea (96.9%), fever (54.7%), vomiting (45.3%), mild dehydration (43.8%), upper respiratory tract infection (21.9%), and abdominal pain (12.5%).[31] The virus can be serotyped, visualized in stool by immune electron microscopy,[32] and detected by immunoassay. Molecular methods by PCR to detect enteric adenovirus DNA have been developed.[33]

9.2.3 Caliciviruses Caliciviruses are single stranded RNA viruses in the family Caliciviridae. They include four genera: Norwalk-like viruses, Sapporo-like viruses, Vesiviruses, and Lagoviruses.[34] Caliciviruses are also called small round structured viruses (SUVs). A person acquires infection and gastroenteritis by eating contaminated raw food products. Being antigenically diverse, members of this group are named after the location of first discovery,

Tropical Hepatogastroenterology

VIRAL INFECTIONS

175

e.g., Norwalk virus (Norwalk, Ohio),[35] Hawaii virus,[36] and Snow Mountain virus.[37] Sapporolike viruses include the Manchester virus[38] and London/92.[39] These viruses cannot be cultivated in the laboratory. Immunity following Norwalklike virus infection is short lived.

rural community.[45] Antibodies develop to many of the seven serotypes by 4 years of age. Severe dehydration (17%) may occur in association with serotype HAst V-1 and HAst V-8 (Human astrovirus serotype 8).[46] The prevalence of Astrovirus causing gastroenteritis is 1.5% in Korea.[47]

9.2.3.1 Epidemiology

9.2.4.1 Clinical features

Caliciviruses infect all age groups and are transmitted by fecal-oral contamination. Norwalk-like viruses cause epidemic diarrhea due to consumption of contaminated salad, sandwich, and oysters.[40] Gastroenteritis due to Norwalk-like virus was found in 21% of symptomatic cases in Indonesia.[41] Infected food handlers shed viruses in their stool causing outbreaks of gastroenteritis in settings like restaurants, hospitals, and ships (Oyoto B A 1999).[42] In Japan, children acquire antibody against Sapporo-like viruses by the time they are five years old.[43]

Mild diarrhea accompanied with abdominal pain, vomiting, and fever lasts for 2 to 3 days. In children symptoms are indistinguishable from those of rotavirus infection. In immunocompromised patients prolonged illness may be seen.

Shedding of up to 10[14] astrovirus particles per gram of stool may be found.[48] Virus can be detected by electron microscopy. ELISA based detection of all seven serotypes is available.[49]

9.2.3.2 Clinical features

9.2.4.3 Treatment

Vomiting and diarrhea are the common symptoms. Illness lasts 1 to 2 days with an incubation period of 1 to 3 days with or without dehydration.

No specific treatment is available. Oral rehydration solutions are helpful for symptomatic relief.

9.2.3.3 Diagnosis and treatment

Electron microscopy for detection of the viral particle in stool is useful. ELISA has been developed to detect human calicivirus from stool but has limited availability.[44] Treatment is with oral rehydration solution.

9.2.4 Astrovirus Astrovirus is small star shaped, nonenveloped ssRNA virus with a structure similar to calicivirus. In adults it has low infectivity but it is a major cause of diarrheal illness in children, specially in the

Part III / Small Bowel

9.2.4.2 Diagnosis

9.2.5 HIV In a patient with acquired immunodeficiency syndrome (AIDS), the term HIV enteropathy has been applied to diarrhea for which no cause is known despite evaluation. Chronic inflammation of small and large bowel is commonly seen in HIV infected patients. Small bowel atrophy, reduced lactase activity, malabsorption of vitamin B12, and increased small bowel permeability are striking features. The cause of these abnormalities is not clearly defined. There may be loss of CD4 lymphocytes in the lamina propria.[50]

176

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

9.3 SMALL INTESTINAL PROTOZOA 9.3.1 Giardia duodenalis Giardia duodenalis (formerly Giardia lambia) is the only human parasite of the genus. It was described in 1681 by Van Leeuwenhoek. The trophozoite inhabits the duodenum and jejunum, where encystations also occur. The motile trophozoites are bilaterally symmetric, pear shaped (10–20 × 5–15 microns) organisms with two nuclei, one on either side of a central axostyle, and 4 pairs of flagella. G. duodenalis cysts are distinctly oval (8–20 microns in diameter). They have a thin, smooth membrane with four nuclei clustered at one end, a longitudinal parabasal body near the center of the cell, and fibrils. 9.3.1.1 Epidemiology

Protozoal infections of the small bowel are prevalent worldwide. Giardia duodenalis is most commonly identified parasite in the United States. Endemic areas include Mexico, India, Russia, and wilderness areas of the United States. Infection is feco-oral. The prevalence among children varies worldwide from 4% to 42%, depending on the source and quality of water consumed.[51] It is responsible for traveler’s diarrhea in virtually every part of the world.[52] Giardia spreads frequently by sexual or other close person-to-person contact in which fecal contamination may occur. Infective cysts of giardia are resistant to standard chlorination practices, hence it can be acquired despite chlorination of water supplies or swimming pools. 9.3.1.2 Etiopathogenesis

Ingested giardia cyst (infective form) undergoes excystation in the duodenum releasing two pear shaped trophozoites. These trophozoites establish themselves extracellularly among the intesti-

nal villi to colonize the proximal small intestine. Possible factors of diarrhea and steatorrhea include mechanical occlusion of the mucosa by a massive number of organisms, normal to severe villous atrophy with crypt hyperplasia, competition of the parasite and host for nutrients, and excess mucus secretion.[53] Other features observed include reversible vitamin B12 and folate malabsorption, bile salt deconjugation in the proximal small intestine, and reversible disaccharidase deficiency.[54] 9.3.1.3 Clinical features

Most patients harboring this parasite remain asymptomatic. It may cause watery, nonbloody diarrhea, which may be continuous or intermittent in acute or chronic form, and may alternate with constipation. There may be diffuse, crampy abdominal pain, nausea, vomiting, and flatulence along with nonspecific nervous symptoms. Children may have malabsorption, steatorrhea, and developmental delay due to persistent infection. 9.3.1.4 Diagnosis

Examination of three or more stool specimens, collected several days or weeks apart, increase the diagnostic yield for detection of Giardia duodenalis, since intermittent shedding of parasite is common. Several concentration methods including zinc sulfate floatation method may be helpful in detecting the cyst. Enzyme linked immunoassay (ELISA) can detect giardia antigens in stool with a sensitivity of 95.9% and specificity of 97.4%.[55] Endoscopy may reveal patchy intestinal lesions of variable severity, ranging from normal villi to abnormal flat mucosa in HIV infected patients with giardiasis,[56] but immunocompetent patients may have normal bowel mucosa.[57] Duodenal aspirates may reveal trophozoites on microscopy.

Tropical Hepatogastroenterology

SMALL INTESTINAL PROTOZOA

9.3.1.5 Treatment

Treatment with oral or parenteral rehydration solution for fluid and electrolyte depletion may be needed. Metronidazole 250 mg three times daily for 5 days in adults and 15 mg/kg/day for children is effective.[58] Tinidazole is at least as effective in a single dose (2 gm in adults; 50 mg/kg in children). However, giardia cysts are unaffected by these drugs. Furazolidone for 7 days, 100 mg four times a day in adults or 1.25 mg/kg four times a day in children, may be useful.[52] Paromomycin (25 mg/kg/ thrice daily for 7 days), which is not absorbed from the intestines, may be useful in pregnant women. Albendazole (400 mg/day for 5 days) seems to be an effective alternative. Reinfections and treatment failure should be treated with alternative drugs, combinations of drugs or the same drug for a longer period. Octreotide may help in controlling severe persistent diarrhea.[59]

9.3.2 Spore-forming Protozoas Acute intestinal infections caused by sporeforming protozoa are self-limited in immunocompetent persons. The pathogenic protozoa are Coccidia (Isospora, Cyclospora, and Cryptosporidia) and the obligate intracellular agents, i.e., Microsporidia (Enterocytozoon bieneusi and Septata intestinalis). These are opportunistic parasitic protozoa causing severe diarrhea in immunocompromised AIDS patients.[60] Infection is feco-oral, usually by ingestion of water or food contaminated with spores. These organisms alternate between a gut phase (trophozoite stage) and soil–water phase (spores) without an intermediate host. Except Isosporiasis, the other ones are not associated with eosinophilia. 9.3.2.1 Isospora belli

Isospora belli parasitizes the epithelial cells of the duodenum and jejunum. Infection with this

Part III / Small Bowel

177

opportunistic pathogen is considered an AIDS defining illness, if present for over 4 weeks, in the form of diarrhea, weight loss, and pain abdomen.[61] Epidemiology Geographical distribution is worldwide. The microorganism is endemic in Africa, Asia, and South America. The frequency of infection in Haitian AIDS patients is 15% whereas data from Los Angles during 1985–92 suggests isosporiasis in 127 (< 1%) of 16,351 AIDS patients.[62] Etiopathogenesis Human infection follows ingestion of infective mature sporulated oocysts (20–33 pmX1 0–19 pm) containing 2 sporocysts each. Sporulated oocysts excyst in the proximal small intestine releasing sporozoites, which invade the enterocytes. They become round trophozoites, and multiply asexually (schizogony) forming mature schizonts. The merozoites, released from mature schizonts, invade the adjacent epithelial cells. On invasion, they either undergo further schizogony or become sexual gametocytes. After fertilization (sporogony), the macrogametocyte (female) becomes a nonsporulated oocyst, which is extruded into the intestinal lumen. This oocyst matures into sporoblasts and then into the sporocyst, each of which has 4 sporozoites. Sporocysts are eliminated in the feces.[66] Diagnosis Immunocompromised persons frequently develop voluminous diarrhea with severe malabsorption, dehydration, weight loss and colicky abdominal pain. Diagnosis is made from the finding of thick walled ovoid mature oocysts elongated at one end and constricted at the other, each containing four sporozoites. The fecal sample should be incubated for 2 days at room temperature to allow maturation of oocyst. Oocysts fluoresce bright yellow with auramine-rhodamine stain, and appear pink with red-purple sporocyst with a

178

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

modified Ziehl–Neelsen stain.[64] Small bowel biopsy may show various stages of schizogony. Immature schizonts and unsporulated/sporulated oocyst may be seen in duodenal aspirates. Treatment Trimethoprim – sulfamethoxazole (TMP/SMX) – 160 mg + 800 mg) four times daily for 10 days followed by twice daily for 3 weeks is the treatment of choice.[58] In AIDS patients, this regimen given three times each week is necessary for long term maintenance therapy.[65] For patients allergic to sulfonamides, an alternative to prevent relapse is pyrimethamine (75 mg/day) until clearance of infection, followed by pyrimethamine 25 mg/day. 9.3.2.2 Cryptosporidia

This is a small coccidian parasite and was considered veterinary pathogen until the early 1980s, when it was recognized in patients with AIDS.[66] This causes mild self-limiting diarrhea among travelers drinking water contaminated with feces or after contact with farm animals. It causes life-threatening diarrhea in immunodeficient persons. Sclerosing cholangitis may occur in AIDS patients. Epidemiology This coccidian has worldwide geographical distribution, with increased incidence in developing countries. Prevalence rates of over 12% are seen in asymptomatic persons, including those infected with HIV.[67] Etiopathogenesis The coccidian species considered to be pathogenic in humans is Cryptosporidium parvum (4–6 microns). It infects enterocytes of the intestinal microvilli. After ingestion, infective mature oocysts release sporozoites, which enter the enterocytes of the small intestine. These then develop into trophozoites, which appear as multiple round basophilic bodies in the brush border

of enterocytes, i.e., in the extracytoplasmic vacuole. They develop into meronts, which undergo division to form merozoites. These merozoites are released from enterocytes to reinfect other cells, and give rise to the second generation of meronts.[68] These develop further into microgamonts and macrogamonts, which fuse to give rise to oocysts. Diagnosis The incubation period ranges from 1 to 14 days. The features include a self-limiting (3–14 days) watery diarrhea with abdominal pain, nausea, and vomiting. Fever is rare. HIV infected patients with CD 4+ counts less than 100/mm[3] develop severe, prolonged, cholera-like diarrhea, weight loss, dehydration, and malabsorption.[69] Extraintestinal sites such as biliary and pancreatic ducts, and parts of respiratory tract may become infected.[70] Four to six micron mature oocysts with 4 fully developed sporozoites (80% are thickwalled and 20% thin walled) are found in feces using a modified Ziehl-Neelsen stain, auramine, or specific FITC labeled monoclonal antibody staining. Sigmoidoscopy demonstrates reddened, nonfriable mucosa without ulcers. The diagnosis is best done by mucosal biopsy showing basophilic bodies in the microvillous border. Treatment Treatment consists of correction of fluid and electrolyte abnormalities. Paromomycin (500 mg three times daily for 2 weeks) reduces diarrhea. Maintenance treatment with paromomycin 500 mg twice daily is needed in immunocompromised patients to prevent relapse. Azithromycin produces a favorable clinical response in some patients.[71] 9.3.2.3 Cyclospora cayetanensis

Cyclospora cayetanensis, acid fast organisms often called cyanobacterium like bodies (CLBs), have been associated with diarrhea. Transmission

Tropical Hepatogastroenterology

SMALL INTESTINAL PROTOZOA

is by feco-oral route or by contaminated water supply.[72] Epidemiology Cyclospora are worldwide source of water-borne diarrheal disease. They have been reported from USA, Caribbean islands, Central South America, and Southern and South Asia. They were detected in 11% of travelers and foreign residents in Nepal with diarrhea but only in 1% of symptom free controls.[73] Etiopathogenesis The genus Cyclospora belongs to phylum Apicomplexa, class Coccidia, order Eimeriidae. Infective forms are oocysts with a central refractile morula-like structure, composed of a cluster of globules, enclosed within a cell membrane. This matures into a sporulated oocyst with 2 ovoid sporocysts containing sporozoites which, after excystation, enter the enterocyte. In enterocytes, these organisms are present singly or in groups within vacuoles, indicating intracytoplasmic proliferation.[74] Diagnosis Ingestion of mature oocysts results in watery diarrhea with weight loss, abdominal pain, fatigue, bloating and flatulence. The illness may be prolonged, lasting 2–3 weeks. In patients of AIDS with CD4+ count less than 100/mm,[3] diarrhea is severe with prolonged illness.[75] It may also be associated with biliary tract disease.[76] Endoscopy reveals jejunitis with mild villous blunting, and increased intraepithelial leukocytes.[77] In wet mounts of stool, Cyclospora appear as nonrefractile spherical bodies (8–10 microns) containing a variable number of granular inclusions. Modified Ziehl-Neelsen staining shows dark red organisms with dark inclusion bodies. Under autofluorescence, the organisms appear as intense green structures.[74] Treatment Trimethoprim 160 mg plus sulfamethoxazole 800 mg (TMP/SMX) twice a day

Part III / Small Bowel

179

for 7 days clears infection in immunocompetent patients.[58] In patients with AIDS, one double strength TMP/SMX taken four times daily for 10 days, followed by maintenance treatment three times weekly, is effective in controlling the infection. 9.3.2.4 Microsporidia

Microsporidia is a term used for a group of obligate intracellular spore-forming protozoa belonging to the phylum Microspora.[78] They are ubiquitous among insects, fish, and carnivorous animals. They have true nuclei without mitochondria, and ribosomal RNA is of prokaryotic size. Five genera: Enterocytozoon, Encephalitozoon, Microsporidium, Nosema, and Pleistophora species have been seen in immunocompromised hosts in various organs. Some microsporidia cause self-limiting diarrhea in travelers.[79] Enterocytozoon localizes in the small intestine enterocytes, and occasionally in epithelial cells of the biliary tree, liver, pancreas, and respiratory tract. Encephalitozoon localizes in macrophages, and in the epithelial cells of the conjunctiva, respiratory, and urinary systems. Septata (Encephalitozoon) intestinalis is found in enterocytes and in macrophages of the lamina propria, besides the epithelia of biliary tree and bronchus. Pleistophora is found in muscles, causing myositis. Microsporum africanum and Nosema comeum cause keratitis. Microsporidia were detected as the most common pathogen (39%) in a study on 250 AIDS patients.[81] Etiopathogenesis Enterocytozoon bieneusi and Septata (Encephalitozoon) intestinalis infect gut enterocytes. The infective form is the highly resistant microsporidian spore. They are of uniform size (2 microns), and have a 3-layered spore wall (exospore, endospore, and cytoplasmic membrane). Sporoplasm is uninucleate or binucleate with a unique extrusion apparatus (polar tubule)

180

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

for injecting the sporoplasm into new host. The possible modes of acquiring microsporidiosis are probably infection by aerosols or ingestion from animals and sexual partners. In infected HIV positive patients CD4+ lymphocyte counts are less than 50/mm.[3, 81] The ingested spore penetrates the host cell through polar tube. The sporoplasm passes through the polar filament into the host cell. Merogony, the proliferative vegetative stage (binary fission) follows with development of sporoblasts. Sporogony follows with sporoblasts finally developing into sporonts, with the formation of a dense amorphous surface coat around the cell. Diagnosis Infection with microsporidia may be latent asymptomatic or chronic mild symptomatic in adults with normal immunity. Microsporidiosis was detected in 7.2% of children (16/344) suffering from diarrhea.[82] In patients of AIDS with severe watery nonbloody diarrhea, malabsorption, epigastric pain, and weight loss, microsporidiosis should be considered when no other pathogens are identified. Endoscopic biopsy of the duodenum may show partial villous atrophy with mild inflammatory infiltrates. Microsporidia are difficult to discern in paraffin-embedded intestinal mucosa section by a light microscopic stain.[81] Light microscopy of stool and duodenal aspirate using modified trichome stain shows refractile ovoid spores with the wall stained bright pinkish red. ELISA has been shown to be useful in animals for antibody detection.[83] Treatment Controlled trials for treating Enterocytozoon bieneusi or Septata intestinalis are not known. However, Albendazole, 400 mg twice a day for 2 to 4 weeks, has been found effective for Septata intestinalis.[84] Long term suppressive treatment may be needed to prevent relapse.

9.4 HELMINTHS 9.4.1 Ascaris lumbricoides (Roundworm) Ascaris lumbricoides has worldwide distribution. About 1.2 billion people, mostly living in hot and humid countries, are infected. It is endemic in China, South and Southeast Asia, Africa, and Latin America. The infective form is the embryonated egg or ovum ingested by contaminated food or drink. Adult forms are found in the small intestine, and may migrate to the large bowel, bile duct, or pancreatic duct causing symptoms. There may be allergic symptoms due to absorption of product of living or dead worm. In children it may lead to malnutrition. 9.4.1.1 Life-cycle

After it is ingested, the embryonated egg releases larvae which penetrate the intestinal wall and migrate through the portal venous system to the liver and lung. In the lung a larva breaks out into the alveolus, molts twice, and ascends to the respiratory tract. The patient may have cough and pneumonia at this stage. The larva migrates to pharynx, is swallowed, and reaches the intestine. Here it matures to an adult worm in 2 months. The adult female (200–350 × 4–6 mm) has a nonsegmented unstriated smooth cuticle with a pointed tail. It lays 2,00,000 ova daily. The male worm (1150–200 × 2–4 mm) has a curved tail. 9.4.1.2 Diagnosis

Intestinal ascariasis may be asymptomatic or be associated with vague abdominal pain. In children a heavy worm load may cause obstruction or perforation. Worm migration may cause biliary colic, jaundice, acute cholecystitis, and pancreatitis. Larva migration may cause allergic pneumonitis.

Tropical Hepatogastroenterology

HELMINTHS

Malnutrition in children is common. Diagnosis of ascariasis is by stool examination showing brown color and a thick mamillated (60 × 45 microns) ovoid egg with an albuminous coat. Unfertilized eggs are longer and narrower (90 × 40 microns) with a thin inner shell, and absent albuminous coat. The adult worm may be seen in stools. Worms may be noticed incidentally on barium study or during endoscopic retrograde cholangiopancreatography (ERCP).

181

americanus has characteristic sharp cutting plates, while the scolex of Ancylostoma duodenale is fitted with chitinous teeth. The infective forms are filiform larvas (8–10 × 0.6 mm), which penetrate the skin to reach the lungs. After maturation, larvae are swallowed, and mature into adult worms in 35 days. Eggs are released containing the embryo, which matures in 7–8 days in soil to release filiform larvas. 9.4.2.2 Diagnosis

9.4.1.3 Treatment

Effective medication includes mebendazole 100 mg twice daily for 3 days, or pyrantel pamoate 11 mg/kg to a maximum of 1 gm in single dose,[58] or albendazole 400 mg once. If ova still remain in the stool 3 weeks after the initial therapy, the patient should be retreated. In highly endemic areas, periodic mass treatment of school children with antihelminthic drugs improves their growth. Intestinal obstruction may require surgery. Preventive measures include good personal hygiene and sanitary disposal of human excreta.

Eosinophilia frequently accompanies hookworm infection. Stool examination shows hookworm ova (60×40 microns) with characteristic thin colorless oval shells containing the 4–8 cell embryo. 9.4.2.3 Treatment

Mebendazole 100 mg twice daily for 3 days, pyrantel pamoate 11 mg/kg/day for 3 days or Albendazole 400 mg once are curative. Preventive measures include use of footwear and sanitary disposal of feces.

9.4.3 Strongyloides stercoralis 9.4.2 Hookworm About 900 million people are infected worldwide with the hookworm, Ancylostoma duodenale and Necator americanus. They are endemic in tropical and subtropical regions of Asia and Africa. They cause iron deficiency anemia and malnutrition. 9.4.2.1 Life-cycle

The adult worm attaches to the small intestinal mucosa, and with help of its buccal mucosa, it consumes blood. The average blood loss is 0.01 to 0.3 ml per worm per day, and over time results in iron deficiency anemia. Adult males are about 2 mm in length, with the posterior caudal bursa containing rib-like ray. The scolex of Necator

Part III / Small Bowel

Strongyloides stercoralis resides in the proximal intestine for long periods causing the classic triad of diarrhea, abdominal pain, and urticaria. Adult worms also exist in free-living forms in warm moist climates, where there is frequent fecal contamination of soil. Due to increasing HIV infection and due to the widespread use of immunosuppressive drugs, S. stercoralis infection is emerging as an opportunistic pathogen. Isospora belli and S. stercoralis as dual infection were isolated in an HIV patient with weight loss.[85] 9.4.3.1 Life-cycle

The infective form is the filariform larva (600 × 20 microns) which penetrates the skin, enters the

182

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

circulation, and reaches the lung. The larvas rupture into the alveoli to mature into adults either in the bronchus or after being swallowed into the duodenum. The fertilized female enters the duodenal mucosa and hatches the rhabditiform larvas (250 × 20 microns), which re-enter the bowel lumen to escape into the gut, and are passed out in the stool. Autoinfection occurs if rhabditiform larvas mature to filariform larvae in the gut or on the perianal skin. These worms may be present for 40 years or more in the gut.[86] 9.4.3.2 Diagnosis

Mild infections may cause no symptoms. Severe involvement causes diarrhea alternating with constipation, abdominal pain, malaise, fever, vomiting, and steatorrhea. The pulmonary phase is characterized by cough, dyspnea, transient pulmonary infiltrates, and eosinophilia. Cutaneous migration of larvas causes a serpiginous urticarial rash called larva currens. Stool examination shows rhabditiform larvas with a short (1 mm) cavity, which is distinguished from rhabditiform larvas of hookworm, which have a long buccal cavity. Duodenal aspirate or bronchial washings may show S. stercoralis larvas. Duodenal biopsy may show an adult worm embedded in the mucosa. Serologic tests such as enzyme immunoassays are useful in diagnosis. 9.4.3.3 Treatment

Thiabendazole 50 mg/kg/day in two doses for 2 days or Ivermectin 200 micrograms/kg/day for 2 days are effective therapy. For disseminated infection Thiabendazole should be continued for five days.

9.4.4 Trichuris trichiura (Whipworm) Trichuris trichiura is distributed world wide. About 1.3 billion people carry this parasite. It is

commonly found in the tropics and in areas with poor sanitation. Prevalence is high in rural Southeast Asia.[87] The infective form is an unsegmental, embryonated, barrel-shaped egg (50 × 22 microns) with a plug at both ends. Infection occurs after ingestion of food contaminated with soil containing eggs. The egg shell is dissolved by digestive juices, and the larva is released in the small intestine. After 3 to 10 days, larvae migrate to localize in the caecum and appendix. Adult worms (male and female) range from 30 to 50 mm in size with a whip-like appearance of thin and long anterior segment containing the esophagus. They attach to the mucosa with the anterior end to mature in 30– 90 days. Adults female lays 2000 to 6000 eggs per day in the feces. Maturation of these eggs in soil takes 3–5 weeks to become infective. 9.4.4.1 Diagnosis

Mild infections are asymptomatic with eosinophilia, abdominal pain, distension, and diarrhea, sometimes with rectal prolapse in children. Stool examination by the concentration method shows barrel-shaped brown ova with characteristic colorless hyaline plugs at each pole. Colonoscopy may reveal adult worms embedded in the mucosa. 9.4.4.2 Treatment

Mebendazole in a dosage of 100 mg twice a day for 3 days, or albendazole 400 mg once daily is highly effective.[88] Prevention by means of sanitary disposal of human feces, hand washing before meal, and properly cooked food may be helpful.

9.4.5 Capillaria philippinensis Prevalence of Capillaria philippinensis is restricted to rural areas of Philippines and Thailand. A patient may be an asymptomatic cyst

Tropical Hepatogastroenterology

HELMINTHS

passer, or have features of chronic diarrhea. It is acquired by eating raw fish infected with Capillaria larvae. Humans and birds are definitive hosts. The adult worm invades the small intestinal mucosa. Ova are released in the lumen, passed with the stool, and eaten by fish. Some ova excyst during passage through gut to release larvas which mature into adults (autoinfection). 9.4.5.1 Diagnosis

Patients are asymptomatic or suffer from chronic diarrhea if the worm load is high, as may occur from autoinfection or malabsorption. Body wasting occurs, leading to death if untreated. Examination of stool may reveal eggs, larvae, or adult worms. 9.4.5.2 Treatment

Mebendazole 200 mg twice daily for 20 days is the drug of choice. Albendazole (200 mg twice daily for 10 days) or Thiabendazole (25 mg/kg/day for 30 days) may be alternatives. Water, electrolyte, and nutritional replacement are important. Prevention is by eating cooked fish.

183

shows the presence of typical eggs, which may be mistaken for eggs of hookworm. Treatment includes Bephenium hydroxynaphthoate or Pyrantel derivatives.

9.4.7 Trichinella spiralis Trichinosis occurs through ingestion of undercooked pork, wild boar, and walrus containing infective encysted larvae of T. sprialis. After eating contaminated raw meat, the cyst is digested in stomach, and released larvae (90–100 × 6 microns) invade the intestinal mucosa. Larvae mature into adult male (1.5 × 0.45 mm) and adult female (3–4 × 0.6 mm) worms. After mating, the viviparous female worms deposit numerous larvae, which invade the mucosa leading to enteritis and diarrhea. They enter the blood stream and disseminate through any tissue in the body, but ultimately localize by encystment in striated muscles, specially the muscles of respiration and the tongue. Cysts remain viable for several years. Two hosts (black rat, dogs, cats) both carnivores, are needed to complete the life-cycle. 9.4.7.1 Diagnosis

9.4.6 Trichostrongylus Trichostrongylus are intestinal parasites of cattle, sheep, and goats. T. orientalis infects persons in close contact with herbivore. Infective larvae are present on plants and vegetables due to exposure to contaminated feces. On eating raw vegetables these larvae attach to intestinal mucosa. They develop into adult worm, and lay eggs which are excreted with stool. 9.4.6.1 Diagnosis and treatment

Patients remain asymptomatic but may have pain abdomen and eosinophilia. Stool examination

Part III / Small Bowel

Acute secretory gastroenteritis may persist for a week during maturation of larvae into adult after ingestion of raw flesh. After 5 to 7 days of incubation, larvae liberated by the adult female worm undergo tissue invasion. The patient may develop orbital edema, muscle pain, headache, remittent fever of 40–41◦ C, salivary gland enlargement, and eosinophilia. Cardiac and central nervous system infection may cause myocarditis, encephalitis or meningitis. During muscle encystation there may be edema, cachexia, and extreme dehydration. Diagnosis is based on marked eosinophilia (between 20% and 75% on a differential WBC count), and raised creatine kinase and aspartate

184

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

aminotransferase due to muscle damage. Muscle biopsy and muscle crush preparation of the deltoid, gastrocnemius, biceps, and pectoralis may show encysted larvae. Serological ELISA tests are available.

attach to the small intestinal mucosa. Adult worms develop in 12 weeks, and may remain in the gut for 25 years. Each adult worm is 2–8 meters long, and contains segments called proglottids. The gravid proglottids release eggs in the feces.

9.4.7.2 Treatment

9.4.8.2 Clinical features

Mebendazole 600 mg daily, increased by 300 mg/day to a total daily dose of 1500 mg for 10 days is effective against the established tissue phase. Corticosteroids should be used for severe symptoms during tissue invasion and encystations.

Adult tapeworms rarely cause symptoms. The dangerous complication of tapeworm infestation is cysticercosis of the brain. Neurocysticercosis can cause debilitating disease with seizures and neurologic deficits. Ocular cysticercosis results in uveitis, retinitis, and cyst formation.

9.4.8 Taenia solium (Pork Tapeworm) Taenia solium is prevalent in South East Asia, India, China, Africa, and Latin America. Five million people are infected world wide. Ingestion of T. solium eggs cause cysticercosis in multiple organs of the body. 9.4.8.1 Life-cycle

Cysticercosis, or infiltration of tissue by cysticerci (larvas), occurs after ingestion of the egg of T. solium by human or other mammals. The eggs on digestion by gastric juice releases ‘oncosphere’, which penetrate the intestinal wall to enter mesenteric vasculature. They are distributed throughout the body and trapped in muscles to become cysticerci in 70 days. The larval stage produces symptoms as per location, namely subcutaneous tissue, eye, brain, heart, liver, lung and abdominal cavity. Neutrophil, eosinophil, and plasma cell infiltration occur. Fibrosis follows necrosis of the capsule, with ultimate calcification of larvae. Tape warm infestation occurs by ingestion of raw or uncooked infected pork (“measly pork”). The larvas (cysticerci) are released from pork flesh in the jejunum. Their its heads evaginate from the cysticerci, and

9.4.8.3 Diagnosis

Stool examination shows characteristic spherical eggs with a thick, radially striated outer wall. The mature egg contains a hexacanth embryo with six hooklets or proglottids, with 8 to 13 lateral stems. The diagnosis of cysticercosis is made by excision and biopsy of a palpable lesion, for example a subcutaneous nodule. Microscopy shows the invaginated scolex of the larva with four suckers and anterior hooklets. 9.4.8.4 Treatment

Praziquantel, 5 to 10 mg/kg, should be administered in three divided doses for 14 days. Alternatively, Albendazole 15 mg/kg in divided doses for 30 days may be advised. Ocular cysticercosis is treated by excision of cyst.

9.4.9 Taenia saginata (Beef Tapeworm) Taenia saginata is acquired by the ingestion of raw beef containing viable cysticercus larvae. The adult worm diverts digested material from the host. It may cause diarrhea, hunger pain, and weight loss.

Tropical Hepatogastroenterology

HELMINTHS

185

9.4.9.1 Life-cycle

9.4.10.2 Diagnosis

On consumption of cysticercus-infected uncooked or raw beef, cysticercus is released in the intestine. The scolex evaginates and attaches to intestinal wall mucosa. Adult worms are 4 to 5 meters in length with 1000–2000 proglottids at a given time. Cysticercosis caused by larvae of T. saginata is not as common as that of T. solium.

The patient develops pallor, weakness, anemia, and, in severe cases, congestive heart failure. Stool examination shows operculated ova (50 pm× 76 microns); each ovum has a tiny knob at the other end. It is characteristically brown with a thick smooth shell. Proglottids are broader than longer, with a nondescript coiled uterus appearing as a compact rosette. Blood examination shows macrocytic anemia with mild eosinophilia. Barium studies may show the worm as long thin translucent filling defect.

9.4.9.2 Diagnosis

Eosinophilia and the presence of ova in the stool establish the infection. Proglottids are longer than wide with 15–20 lateral branches. A scolex may be present, with four suckers, devoid of a hooked rostellum.

9.4.10.3 Treatment

Praziquantel 5 to 10 mg/kg in single dose is curative. Alternatively, Niclosamide 500 mg in a single dose will eradicate the disease.

9.4.9.3 Treatment

Praziquantel 5 to 10 mg/kg for 14 days is effective treatment.

9.4.10 Diphyllobothrium latum (Fish Tapeworm) D. latum is a hermaphrodite worm, usually 3 to 10 meters long. It contains 3000 or more proglottids. It is common in northern Europe and Alaska. The worm causes vitamin B12 deficiency leading to megaloblastic anemia in the affected person. 9.4.10.1 Life-cycle

Infection occurs by ingestion of infected raw fish. Larvae mature to adult worms in the small intestine, which release ova in the stool. Ova hatch and release free coracidia in fresh water; the coracidia infects the water flea, Cyclops. Fish ingest the infected Cyclops, which releases the larvae that penetrate the fish muscle.

Part III / Small Bowel

9.4.11 Hymenolepsis nana (Dwarf Tapeworm) H. nana is the most prevalent human cestode. It has no intermediate host, and is transmitted from patient to patient on ingestion of the embryonated egg. The worm causes abdominal discomfort and diarrhea in heavy infestation. It is common in Southeast Asia and in California. 9.4.11.1 Life-cycle

Infection is acquired by the feco-oral route. After ingestion of ova, the oncosphere is liberated, and penetrates the intestinal villi. Here it metamorphoses into the cercocyst, which migrates to the intestinal lumen to form adult worms in 2 weeks. The worm gets attached with the scolex. Autoinfection is common. 9.4.11.2 Diagnosis

Mild infections cause no symptoms. Heavy infestations may cause abdominal discomfort and

186

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

diarrhea. Eosinophilia may occur. Stool examination shows characteristics eggs (40 microns) with an outer smooth, thickened shell, and an inner membrane enclosing the oncosphere with faintly visible three pairs of hooklets and small polar filaments.

and severe weakness. Leukocytosis with absolute eosinophilia and neutrophilic leucopenia is present. Stool examination may show large, operculated eggs (140 microns × 85 microns).

9.4.11.3 Treatment

Praziquantel 75 mg/kg/day eradicates the infection.

A single dose of praziquantel, 25 mg/kg, is the treatment of choice. Alternatively, therapies are Niclosamide 2 gm, single dose, followed by 1 gm daily for 6 days, or Paromomycin 45 mg/kg daily for 7 days.

9.4.13 Heterophyes heterophyes and Metagonimus yokogawai

9.4.12 Fasciolopsis buski (Giant Intestinal Fluke) Fasciolopsis is endemic in the far east, where people consume fresh water plants and rear pigs. Heavy infection in the small intestine causes diarrhea, mucosal ulceration, and protein losing enteropathy. 9.4.12.1 Life-cycle

The infective form is the metacercarium present in water plants after expulsion from the snail. The freshwater plant is ingested by the pig or human. In the duodenum, the metacercaria excyst and develop into adult flukes. Adult flukes release ova in feces. On reaching water, the ova release miracidia, which enter snails, and develop into cercariae. The snail sheds cercaria, which encyst on water plants, and develop into infective metacercariae. 9.4.12.2 Diagnosis

Abdominal pain and ascites occur in heavy infestations. Edema of the face and legs is common. There may be anorexia, nausea, vomiting,

9.4.12.3 Treatment

Heterophyes heterophyes and Metagonimus yokogawai are endemic in the far East. They are intestinal trematodes with a similar life-cycle. Abdominal pain and diarrhea are the presenting features. 9.4.13.1 Life-cycle

Adult worms live in the small intestine, and pass eggs in the stool. The eggs hatch to release miracidia which enter the first intermediate host, usually a freshwater snail. The snail releases cercariae, which infect freshwater fish (second intermediate host). The cyst lodges into the fish muscle. Human infection occurs by eating raw fish containing infective cysts. 9.4.13.2 Diagnosis and treatment

Diagnosis is based on identification of eggs in the stool. Praziquantel 75 mg/kg/day in three divided dose is the treatment of choice.

9.4.14 Schistosoma mansoni and Schistosoma japonicum Schistosomiasis is endemic in the Middle east, Asia, Africa, and Latin America. It may occur in association with roundworm and Trichuris trichiura among children with poor hygiene and

Tropical Hepatogastroenterology

MYCOTIC INFECTIONS

low sanitation.[89] More than 200 million people in tropical and subtropical regions harbor the schistosome fluke. A patient may be asymptomatic, but heavy infection may cause ulceration, intestinal stricture, fever, and hepatosplenomegaly. 9.4.14.1 Life-cycle

Infection occurs after release of cercariae from the freshwater snail. The cercariae, penetrate the skin of the host. Cercariae of S. mansoni and S. japonicum migrate to the lung, settle in mesenteric venules to mature into adult worm, and produce ova. The ova migrate through the intestinal wall, and leave the host with feces. Eggs hatch in water releasing miracidia to infect another freshwater snail (intermediate host). Cercariae released from the snails enter man through the skin (definitive host) for continuing the cycle. 9.4.14.2 Diagnosis

Pruritus may occur at the site of entry of cercariae. Katayama fever occurs in the early stages of infection by S. japonicum. There may be systemic manifestations of fever and arthralgia due to immune complex formation in response to oviposition. Patients with heavy infection may have inflammatory polyps (pseudopolyps) and strictures. Eggs may be carried by portal blood flow to the liver, causing hepatic fibrosis, presinusoidal portal hypertension, and variceal bleed. Diagnosis is by rectal biopsy, and the finding of characteristic eggs with a lateral spine (S. mansoni) in the stool. Antischistosomal antibody may be helpful. 9.4.14.3 Treatment

Praziquantel 60 mg/kg/day in three divided doses is the treatment of choice for schistosomiasis. Prevention can be done by avoiding swimming in contaminated water and removal of snails.

Part III / Small Bowel

187

9.5 MYCOTIC INFECTIONS Mycotic infections of the intestine typically result from dissemination from a pulmonary source in immunocompromised persons. They may occur in immunocompetent hosts also. Fungi causing disease include histoplasmosis, aspergillosis, mucormycosis, and candidiasis.

9.5.1 Histoplasmosis Histoplasmosis commonly invades the lungs, causing respiratory symptoms in patients. However, gastrointestinal features develop due to widespread dissemination in the body, among immunocompromised hosts. 9.5.1.1 Etiopathogenesis

Histoplasma capsulatum is a dimorphic fungus that exists in mycelial form at ambient temperature, and yeast form at body temperature (37◦ C).It produces macroconidia and microconidia in clinical samples.[90] Endoscopy findings may be normal, or reveal single or multiple ulcers with tissue necrosis or polypoid protrusions.[91] Silver methenamine, Wrights-Giemsa or Periodic Acid Schiff stain of biopsied tissue, on microscopic examination, may reveal 2–3 micron oval yeast cells inside macrophages. Cultures require up to 6 weeks for a positive result.[90] 9.5.1.2 Diagnosis

Symptoms of small intestinal histoplasmosis include diarrhea, diffuse or localized abdominal pain, nausea, vomiting, weight loss, fever, and lethargy.[92] However, gastrointestinal symptoms are often overshadowed by systemic or pulmonary complaints.[93] Stools are liquid or semi-liquid, and on occasion bloody if the colon is involved. Other complaints include edema of the legs and eyelids

188

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

following steatorrhea or protein-losing enteropathy.[94] The frequent complication is perforation of the small bowel, specially in AIDS patients.[95] The diagnosis is confirmed by finding a positive H. capsulatum growth in blood culture, a positive H. capsulatum antigen test in blood, or a four fold rise in titer, or a titer equal to or greater than 1:32 of serum complement fixation test for H. capsulatum. An upper gastrointestinal endoscopy with jejunal biopsy, or terminal ileal biopsy by colonoscopy is necessary for determining involvement of the gastrointestinal tract. Upper gastrointestinal contrast studies may show constricting lesions or abnormally thickened bowel loops, that can mimic mycobacterium enteritis, Crohn’s disease, and carcinoma.[93]

Aspergillus flavus. It grows by branching Y-shaped 2–5 μm wide septate hyphae. Lesions are in form of vascular invasion and necrosis leading to hemorrhagic infarcts.[98]

9.5.1.3 Treatment

The prognosis of disseminated aspergillosis is poor unless the underlying immunosuppression state is reversed if possible.[102] Amphotericin B 1 mg/kg/day is recommended till clinical response occurs. Itraconazole can be given in those who fail to amphotericin B therapy. Besides, antibiotics should be instituted early in the course of the disease.

In immunocompetent hosts itraconazole 200– 400 mg per day for 9 months is the drug of choice. It should be taken with food as it depends on gastric acidity for absorption. Fluconazole is an alternative but is not as effective as the former. Amphotericin B 0.6 to 0.8 mg/kg/day intravenously for a total dose of 1.5 to 2.0 gm should be given in AIDS patients or those with life threatening infection. A maintenance therapy either with itraconazole 200 mg per day or Amphotericin B biweekly should be given lifelong in AIDS patients.[96]

9.5.2 Aspergillosis Aspergillosis is only seen in severely immunocompromised patients.[97] Involvement of the small intestine is seen among 5% of patients of disseminated aspergillosis.[98] 9.5.2.1 Etiopathogenesis

Aspergillosis is an infection usually caused by moulds namely Aspergillus fumigatus and

9.5.2.2 Diagnosis

The common symptom is gastrointestinal bleeding or small intestinal perforation.[99] Endoscopic findings include linear ulcers or necrotic mucous plaques.[97] Biopsy and histological finding of angioinvasion is important for diagnosis of Aspergillosis.[100] Isolation of Aspergillus on culture may signify contamination or colonization.[101] 9.5.2.3 Treatment

9.5.3 Candidiasis Candidiasis is involved with esophageal lesions in persons with HIV infection or malignancies, or on immunosuppressive agents. Candida species are normal colonizers of gastrointestinal tract, and rarely cause disease of small intestine.[103] 9.5.3.1 Etiopathogenesis

Candida species are budding small ovoid yeast like cells of 4–6 Am in diameter. In biopsy, yeast form or pseudohyphae can be seen, which grows on culture. Candida albicans is the commonest organism associated with single or multiple ulcers in the small intestine.[104]

Tropical Hepatogastroenterology

OTHER DISEASES

9.5.3.2 Diagnosis

The commonest symptoms associated with intestinal involvement by Candida species is diarrhea.[100] Patient may have complaints of nausea, vomiting, abdominal pain, melena or hematochezia. Endoscopic findings may be white plaques, thickened mucosal folds, superficial erosions, pseudomembranes, and blood mass.[100] Diagnosis is made by the histological finding of yeast like cells or pseudohyphae in the biopsy. Aspergillus may be found associated on histology. 9.5.3.3 Treatment

Amphotericin B 1 mg/kg/day till clinical remission is recommended in biopsy proven candida infection. Fluconazole may be alternative treatment. Resection of the affected bowel may be required among immunosuppressed patient.

9.5.4 Mucormycosis Mucormycosis of the small intestine occurs through dissemination from the lungs in immunosuppressed patients.[105, 106] Premature infants may present with gastrointestinal mucormycosis, which may prove fatal within weeks after birth.[107] 9.5.4.1 Etiopathogenesis

The infectious particles are sporangiospores of either Rhizopus, Absidia, or Mucor, which are ubiquitous in nature. After inhalation they invade the pulmonary vessels resulting in infarction and necrosis.[106] The paranasal sinuses, orbit, and brain are important sites of infection. Gastrointestinal lesions occur as a part of dissemination. test

Part III / Small Bowel

189

Lesions may resemble carcinoma, or involve the ileocecal region in a pattern resembling a perforated appendix. It may cause superinfection of preexisting lesions, e.g., peptic ulcer or penetrating wound.[108] Large, nonseptate, thick-walled hyphae with right angle branching are confirmatory features on histologic examination of biopsied tissue.[106] 9.5.4.2 Diagnosis

Fever, abdominal pain, and abdominal distension are the usual symptoms. Nausea, vomiting, hematemesis, hematochezia, and diarrhea are less commonly seen. The physical findings of abdominal mass or intestinal perforation as a complication may be present. Endoscopy may reveal ulceration of ileum. The diagnosis is confirmed by histologic evidence of tissue invasion.[109] Culture showing growth of fluffy molds may only signify colonization. 9.5.4.3 Treatment

There is a high mortality rate despite therapy. Amphotericin B 1.0 to 1.5 mg/kg/day and surgical resection are the treatments of choice.[110] No case control study is available for duration of therapy.

9.6 OTHER DISEASES Two important infections of the small bowel are tuberculosis and tropical sprue. These are covered in detail in Chapters 8 and 41, and will not, therefore, be discussed here.

190

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

REFERENCES [1] Murell TG. The ecology & epidemiology of pigbel syndrome In New Guinea. J Hyg Comb 1966– 64:375. [2] Qadri F, Das SK, Faruque ASG et al. Prevalence of toxin types and colonization factors in ETEC isolated during 2 years period from diarrheal patients in Bangladesh. J Clin Microbiol 2000;38:27–31. [3] Levine MM, Nataro JP, Karch H et al. The diarrheal response of human to classic EPEC is dependent on a plasmid encoding enteroadhesive factor. J Infect Dis 1985;152:550–9. [4] Levine MM, Ferreccio C, Prado V et al. Epidemiologic study of E. coli diarrhea infection in low socio-economic periurban community in Santiago, Chile. Am J Epidem 1993;138:849–69. [5] Development of vaccine against cholera & diarrhea due to ETEC E. Coli. Bull WHO 1990;68:303. [6] Cholera working group. Large epidemic in Bangladesh caused by Vibrio cholerae 0139 synonym Bengal. Lancet 1993;342:387. [7] Singh J, Sachdeva V, Bhatia R et al. Endemic Cholera in Delhi 1995: analysis of data from a sentinel center. J Diarr Dis Res 1998;16:66–73. [8] Centre for Disease Control. Cholera vaccine. Morb Mortal Wkly Rep 1988;137:617,618,623. [9] Blake PA. Disease of human (other than cholera) caused by vibrios. Ann Rev Microbiol 1980;34:341. [10] Anathan S, Alavardi SV. Biochemical characteristics & secretory activity of Aeromonas species mutated from children with gastroenteritis in Chennai. IJMR 1999;109:136–140. [11] Jones BL, Wilcox MH. Aeromonas infection and their treatment. J Antimicrob Chemotherapy 1995;35:453–6. [12] Ryan CA, Hargreft-Bean NT, Blake PA. Salmonella typhi infections in the United States. 1975–1984; Increasing role of foreign travel. Rev Infect Dis 1989;11:1–8. [13] Stuart BM, Pullen RL. Typhoid: clinical analysis of 360 cases. Arch Intern Med 1964;78:629.

[14] Butler T, Knight J, Nath SK et al. Typhoid fever complicated by intestinal perforation. A persisting fatal disease requiring surgical management. Rev Infect Dis 1985;7:244. [15] Alam MN, Haq SA, Das KK et al. Efficacy of ciprofloxacin in enteric fever. Comparison of treatment in sensitive and multidrug resistant salmonella. Am J Trop Med Hyg 1995;55: 306–11. [16] Sood S, Dargan P. Surgical complications of typhoid fever. In: Sood S, Krishna A (Eds). Surgical Diseases in Tropical Countries, Jaypee Brothers, New Delhi 1996. [17] Bennish MF. Immunization against Salmonella typhi. Infect Dis Clin Pract 1995;4:114. [18] Centre for Disease Control and Prevention. Salmonella surveillance summary, 1993–1194. [19] AsKerkoff B. Salmonella in the United States a five year review. Am J Epidem 1970;92:13. [20] Glaser JB. Mortonkule L, Berger SR. Recurrent salmonella typhimurium bacteremia associated in AIDS. Ann Intern Med 1985;102:189. [21] Neill MA, Opal SM, Heelan J et al. Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis. Ann Intern Med 1991;114:195. [22] Freerksen E, Rosenfield M, Freerksen R et al. Treatment of chronic salmonella carrier. Study with 40 cases of S. typhi, 19 of S. paratyphi B and 28 cases of S. entefidis. Chemotherapy 1997;23: 192. [23] Kapikian AZ, Chanock RM. Rota virus in Fields BN, Knipe DM, Chanock RM (eds). Virology, Raven Press, 1990;p. 1353. [24] Sen A, Kobayashi N, Das S et al. Amplification of various genes of human gp 8 rotavirus from stool specimens by RT-PCR. J Clin Virol 2000;17:177–181. [25] Kapikian AZ, Chano RM. Rotavirus in Fields BN, Knipe DM, Chanock RM (eds). Virology, Raven Press, 1996;p. 1657.

Tropical Hepatogastroenterology

REFERENCES

[26] Huilan S, Zhen LG, Mathan MM. Etiology of acute diarrhea in children in developing country. A multicentre study in five countries. Bull World Health Organ, 1991;69:549. [27] Herring AJ, Inglis NF, Ojeh CK et al. Rapid diagnosis of rotavirus infection by direct detection of viral nucleic acid in silver stained polyacrylamide gels. J Clin Microbiol 1982;16:473. [28] Gouvea V, Allen JR, Glass RI et al. Detection of gp B & C rotavirus by polymerase chain reaction. J Clin Microbiol 1991;29:519. [29] Rennel MB, Glass RI, Dennehy PH et al. Safety and efficacy of high dose rhesus human reassortment rotavirus vaccine - Report of national multicentre trial. Pediatrics 1996;97:7. [30] Cruz JR. Adenovirus types 40 and 41 and rotavirus; associated with diarrhea in children from Guatemala. J Clin Microbiol 1990;28: 1780. [31] Hsiochuan L, Chuanliang K, Chunyi L et al. Enteric adenovirus infection in children in Taipe. J Microb Imm Inf 2000;33:176–180. [32] Wood DJ, Bailay AS. Detection of adenovirus 40 & 41 in stool by IEM. J Med Virol 1987;21: 191. [33] Herman JE. Enteric adenoviruses. In Blaster MJ, SmM PD (eds). Infection of gastrointestinal tract. Raven Press 1995;1047. [34] Berke T, Golding B, Jiang X et al. Phylogenetic analysis of the Caliciviruses. J Med Virol 1997;52:419–424. [35] Adler 1, Zickl R.Winter vomiting disease. J Infect Dis 1969;119:668–673. [36] Wyatt RG, Dolin R, Blacklow NR et al. Comparison of three agents of acute infectious nonbacterial gastroenteritis by cmss challenge in volunteers. J Infect Dis 1974;129:709–714. [37] Dolin R, Reichman RC, Roessner KD et al. Detection by immune electron microscopy of Snow Mountain agent of acute viral gastroenteritis. J Infect Dis 1982;146:184–189. [38] Liu BL, Clarke IN, Caul EO et al. Human enteric Caliciviruses have unique genome structure and are distinct from Norwalk-like viruses. Arch Virol 1995;140:1345–1356.

Part III / Small Bowel

191

[39] Jian XCubitt WD, Berke T et al. Sapporo like human caliciviruses are genetically and antigenically diverse. Arch Virol 1997;142:1813–1827. [40] Morse DL, Guzewich JJ, Hannahan JP et al. Widespread outbreak of clam & oyster associated gastroenteritis. Role of Norwalk virus. N Engl J Med 1986 Mar; 13:314,678–81. [41] Subektj D, Lesman H, Tjaneidi P et al. Incidence of Norwalk like virus, Rota virus and Adeno virus infection in patients with acute gastroenteritis in Jakarta. FEMS Immunol Med Microbiol, 2002;33:27–33. [42] Oyoto BA, Suderquist R, Lesmana V et al. Norwalk like virus &bacterial pathogen associated gastroenteritis on board a US Navy ship. Am J Trop Med Hyg 1999 Dec;61:904–8. [43] Nakata S, Kogawa K, Numata K et al. The epidemiology of human Calicivirus/Sapporo 182/ Japan. Arch Virol 1996;12:5263–5270. [44] Estes MK, Atmar RL. Norwalk and Mated diarrhea. In Richman DD, Whitley RJ (eds.). Clinical Virology. Churchill Livingstone, 1997;1073–9. [45] Cruz JR, Bartlett A, Herman JE et al. Astrovirus associated diarrhea in Guatemalan rural children. J Clin Microbiol 1992;30:1140. [46] Naficy AB, Rao MR, Holmes JL et al. Astrovirus diarrhea in Egyptian children. J Infection Dis 2000;182:685–690. [47] Kang YH, Yark YK, Ahu JB et al. Identification of human Astrovirus from stool samples with diarrhea in Korea. Arch Virol 2002 Sep;147:1821–2. [48] Kurtz JB, Lee TW. Astrovirus human and animal. Novel diarrhea viruses. John Wiley & Sons 1987;92. [49] Herman JE. Diagnosis of astrovirus gastroenteritis antigen by monoclonal antibody. J Infect Dis 1990;161:226. [50] Keating J, Bjarnason L, Soma Sundram S et al. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV & their relation to diarrhea. Gut. 1995;37:623–629. [51] Strickland GT. Hunter’s Tropical Medicine. 7th ed. Philadelphia: W.B. Saunders, 1991. [52] Thompson RCA, Reynolbon. JA. Giardia and Giardiasi. Adv Parasitol 1993;32:71.

192

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

[53] Waterspiel A, Pickering LK. Giardia and Giardiasis. Prog Clin Parasitol 1994;4:1. [54] Wolfe MS. Giardiasis Clin Microbiol Rev 1992;5:93. [55] Garcia LS, Shimija RY, Bernard CN. Detection of Giardia lamblia, Entamoeba histolytica/ Entamoeba dispar and Cryptosporidium parvurn antigens in human fecal specimens using the Triage parasite panel enzyme immunoassay. J Clin Microbiol 2000;38:3337–3340. [56] Ament ME, Rubin CE. Relation of giardiasis to abnormal intestinal structure and function in Gastrointestinal immunodeficiency syndrome. Gastro enterology 1972;62:216. [57] Bandborg LL, Tankersley CB, Gottlejab S. et al. Histological demonstration of mucosal invasion by Giardia lamblia in man. Gastroenterology 1967;52:143. [58] Drugs for parasitic disease. Lancet 1982;1: 1284–5. [59] Gottumukkala SR, Brandt U (ed). Clinical Practice of Gastroenterology 1999;61:535–552. [60] Kang G. Opportunistic protozoan parasitic infections of the Gastrointestinal tract. Indian J Med Mircobiol 2000;18:50–54. [61] Dettovilz JA, Pape JW, Boncy M et al. Clinical manifestation and therapy of Isospora belli infections in patients with the acquired immunodeficiency syndrome. N Engl J Med; 1986;315: 87–90. [62] Sorvillo FJ, Lieb LE, Seidel J. Epidemiology of isosporiasis among patients with acquired immuno deficiency syndrome in Los Angeles county. Am J Trop Med Hyg 1995;53:656–9. [63] Soave R, Johnson WD Jr. Cryptosporidium and Isospora belli infections. J Infect Dis 1988;157:225–229. [64] Weber R, Bryan RT, Schwartz DA et al. Human Microsporidial infection. Clin Microbiol Rev 1994;7:426. [65] Liw LX, Weller PF. Antiparasite drug. New Eng J Med 1996;334:1178. [66] Soave R, Armstrong D. Cryptosporidium and Cryptosporidiosis in homosexual men. Rev Infect Dis 1986;8:1012–1023.

[67] Janoff EN, Limace, Gebhard RL et al. Cryptosporidial carriage without symptoms in the AIDS. Ann Intern Med 1990;112:75–76. [68] Current WL, Garcia LS. Cryptosporidiosis. Clin Microbiol Rev 1991;4:325:358. [69] Blanchard C, Jackson AM, Shanson DC et al. Cryptosporidiosis in HIV-positive patients. QJ Med 1992;85:813–823. [70] McGowan 1, Hawkins AS, Weller IVD. The natural history of Cryptosporidial diarrhea in HIV – infected patients. AIDS 1993;7:349–54. [71] Russell TS, Lynch J, Ottalini MG. Eradication of cryptosporidium in a child undergoing maintenance chemotherapy for leukaemia using high dose azithromycin therapy. J Pediatric Hematol Uncoil 1998;83–85. [72] Casemore DP. Cyclospora:another ‘new’ pathogen. J Med Microblol 1994;41:217–219. [73] Hoge CW, Shlim DR, Rajesh R et al. Epidemiology of diarrheal illness associated with coccidian like organism among travellers and foreign nationals in Nepal. Lancet 1993;341:1175–9. [74] Ortega YR, Sterling CR, Gilman RH et al. Cyclospora species- a new protozoan pathogen of humans. N Engl J Med 1993;328:1308–1312. [75] Hart AS, Ridinger MT, Soundarajan R et al. Novel organisms associated with chronic diarrhoea in AlDS. Lancet 1990;335:169–179. [76] Sifurntes Osornio J. Cyclospora cayetanensis infection in patients with and without AIDS. Biliary disease as another clinical manifestation. Clin Infect Dis 1995;21:1092. [77] Bendall RP, Lucas S, Moody A et al. Diarrhoea associated with cyanobacterium like bodies. A new coccidian enteritis of man. Lancet 1993;341:590. [78] Weber R, Bryan RT, Schwartz DA et al. Human microsporidial infection. Clin Microbiol Rev 1994;7:426–61. [79] Curry A, Canning EV. Human microsporidiosis. J Infect 1994;27:229–236. [80] Weber R, Bryan RT. Microsporidial infections in immunodeficient and immunocompetent patients. Clin Infect Dis 1994;19:517–521. [81] Weber R, Bryan RT, Owen RL et al. Improved light microscopical detection of microsporidial spore

Tropical Hepatogastroenterology

REFERENCES

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

in stool and duodenal aspirate. N Engl J Med 1992;326:161. Valperga SM, Jogna Prat SA De, Valverga GJO De et al. Microsporidian spores in the faeces of young children with and without diarrhoea from Tucuman, Argentina. Revista Argentina de Microbiologia 1999;31:157–164. Coreoran GD, Tovey DG, Mooday AH. Detection and identification of gastrointestinal microsporidia using non invasive technique. J Clin Pathol 1995;48:725–727. Aarous EJ, Woodron D, Hollister WS et al. Reversible renal failure cased by a microspoddian infection. AIDS 1994;8:1119. Ayyagari A, Sharma AK, Prasad KN et al. Spectrum of opportunistic infections in human HIV infected cases in a tertiary care hospital. Indian J Med 1999;17(2):78–80. Gill GV, Bell DR. Strongyloides stercoralis infection in Former Far East prisoners of war BMJ 1979; 2:572. Warren KS, Mahmood AA. Algorithms in the diagnosis and management of exotic disease. IX Trichuriasis. J Infect Dis 1976;133:596–60. Goldsmith RS. Clinical Pharmacology of the antihelminthic drugs. In Katzing (ed). Basic and clinical pharmacology 6th Edition. Norwalk, Appleton & Large 1995 p. 8704. Brooker S, Miguel EA, Molin S et al. Epidemiology of single and multiple species of helminth infection among school children in Kenya East African Med J 2000;77:157–161. Bullock WE. Histoplasma Capsulaturn In Mandell GL, Bennett JE, Dolin R eds. Principles and practice of infectious disease. 4th ed. New York, Churchill Livingstone 1995;2340. Goodwin RA. Disseminated histoplasmosis: Clinical and pathological correlation. Medicine 1980;59:1. Reddy P, Gorclick DF, Lash H. Progressive disseminated histoplasmosis as seen in adults. Am J Med 1970;48:629. Bank S, Trey C, Gans I et al. Histoplasmosis of the small bowel with giant intestinal villi and sec-

Part III / Small Bowel

[94] [95]

[96]

[97]

[98]

[99]

[100]

[101]

[102] [103]

[104]

[105]

[106]

193

ondary protein – losing enteropathy, Am J Med 1965;39–492. Orchard JL. Malabsorption due to gastrointestinal histoplasmosis Am J Med 1992;93:237. Heneghan SJ, Ci J, Petrossioan E, Bizer LS. Intestinal perforation from gastrointestinal histoplasmosis in acquired immunodeficiency syndrome Arch Surg 1993;128:464. Wheat LJ, Hafner R, Wulfsohn M et al. Prevention of relapse of histoplasmosis with itraconazole in pts with the acquired immunodeficiency syndrome. The National Institute of Allergy and Infectious Disease Clinical Trails and Mycoses Study Group Collaborators. Ann Intern Med 1993;118:610. Meyer RD, Young LS, Armstrong D et al. Aspergillosis complicating neoplastic disease. Am J Med 1973;54:6. Young RC, Bennelt JE, Vogel CL et al. Aspergillosis. The spectrum of disease in 98 patients Medicine 1970;49:147. Cohen R, Heffner JE. Bowel infarction as the initial manifestation of disseminated aspergillosis Chest 1992;101:877. Prescott RJ, Harris M, Banerjee SS. Fungal infection of the small and large intestine J. Clin Path 1992;45:806. Bennett JA. Aspergillus species, In: Mandell GL, Bennett JE, Dolin R. eds Principles and practice of infectious disease, 4 th ed, New York, Churchill Livingstone 1995;2306. Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis 1996;23:608. Edwards JE. Candida species. In: Mandell GL, Bennett JE, Dolin R eds. Principles and practice of infectious disease. 4 th edition. New York Churchill Livingstone 1995;2289. Joshi SN, Garvin PJ, Sunwoo YC. Candidiasis of the duodenum and jejunum. Gastroenterology 1981;80:829. Lyon DT, Schubert TT, Manita AG et al. Phycomycosis of the Gastrointestinal tract. Am J gastroenterol 1979;72:379. Nolan RL, Carter RR, Griffith JE et al. Case report Subacute disseminated mucormycosis in a diabetic male. Am J Med Sci 1989;298:252.

194

Chapter 9 / INFECTIONS OF THE SMALL BOWEL

[107] Graig NM, Lucder FL, Pensler JM et al. Disseminated rhizopus infections in a premature infant. Ped Dermatol 1994;11:346–50. [108] Thomson SR, Bade PG, Tuams M et al. Gastrointestinal Mucormycosis Br. J Surg 1991;78:952. [109] Parfey NA. Improved diagnostic prognosis of

mucormycosis. A clinicopathologic study of 33 cases. Medicine 1986;65:113. [110] Sugar AM. Agents of mucormycosis & related specials. Mandell th G.L. Beneft J E eds. Principles and practice of infections disease. 4 ed. New York, Livingstone 1995;2311.

Tropical Hepatogastroenterology

x

Part IV Large Bowel

10 11 12

Management of Ulcerative Colitis Benign Colorectal Tumors Malignant Colorectal Tumors

197 213 221

“This page intentionally left blank"

xx

Chapter

10

MANAGEMENT OF ULCERATIVE COLITIS Anoop Saraya and Govind K Makharia

10.1 INTRODUCTION Inflammatory bowel disease (IBD) is a chronic ulcerative and inflammatory disease of the large and small intestine, and consists of three diseases: ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis. Ulcerative colitis is more common in India.[1–3] Before 1960, most patients presenting with chronic bloody diarrhea were diagnosed to have amebic colitis or infective colitis. In the early sixties, Tandon et al.[4, 5] and Chuttani et al. described the occurrence of UC in India.[6] During the last four decades this disease has been recognized and reported from almost every part of India.[7–10] The incidence of UC varies from 10–20 per 100,000 per year and the prevalence from 100– 200 per 100,000 in various parts of the western world.[11, 12] Sood et al. recently reported a prevalence of 44.3 per 100,000 inhabitants, and an incidence of 6.02 cases per 100,000 inhabitants in Northern state of India.[2] UC begins in the rectal mucosa and extends proximally to involve varying portions of the colon. The inflammation in the colon is superficial and limited to the mucosa and submucosa, unlike Crohn’s disease where the inflammation is usually transmural. The involvement of the mucosa is continuous and circumferential, meaning thereby that

there are no skip areas. The extent of the disease is limited to only the rectum (proctitis) in 20%, rectum and sigmoid (proctosigmoiditis) in 30%– 40%, and to the splenic flexure (left sided colitis) in 30%–40%. The remaining 20% can have whole colon involvement (pancolitis).[1, 13, 14] Histologically, the inflammatory process is limited to the mucosa and spares the deeper layers of the bowel wall. It shows features of both acute colitis such as infiltration of acute inflammatory cells in the lamina propria, crypts (cryptitis), and epithelial cells (crypt abscesses); and chronic colitis such as infiltration by chronic inflammatory cells, cryptal architectural abnormalities, goblet cell depletion, and presence of lymphoid aggregates.[15]

10.2 DIAGNOSIS The diagnosis of inflammatory bowel disease depends on the aggregate constellation of the clinical history, physical findings, endoscopic (Fig. 10.1), radiologic (Fig. 10.2), and histologic features (Fig. 10.3), as well as on the results of routine laboratory tests. The course of UC is marked by periods of relapses and remissions. Symptoms of UC depend upon the extent of colonic involvement and severity of the disease. 197

198

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

Though major symptoms of UC include bloody diarrhea, tenesmus, and abdominal discomfort; in severe disease fever, tachycardia, anemia and hypoalbuminemia occur. UC may present at any age. Men and women are equally affected.[1] Virtually all patients with UC have rectal bleeding or bloody diarrhea. Many such patients with bleeding per rectum are diagnosed to have hemorrhoids, and diagnosis is delayed for a considerable period of time. Bleeding per rectum which is mixed with

FIGURE 10.1 Endoscopic picture of a patient with severe ulcerative colitis showing marked pseudopolyposis.

stool suggests involvement of colonic or rectal mucosa, and sigmoidoscopic examination should be done in all such patients. Treatment must begin with an accurate diagnosis. Clinical manifestations, endoscopic features,

FIGURE 10.2 Barium enema showing the colon in ulcerative colitis. Note the complete loss of haustrations. (Courtesy: Dr Manisha Dwivedi.)

FIGURE 10.3 Photomicrograph from a patient with ulcerative colitis showing epithelial destruction, crypt abscesses, and infiltration with acute and chronic inflammatory cells. (Courtesy: Dr Siddharth Dutta Gupta.)

Tropical Hepatogastroenterology

TREATMENT OF ULCERATIVE COLITIS

and histological features help in making a firm diagnosis of IBD, and the distinction between UC and CD. However, in as many as 10 percent of patients with IBD that is limited to the colon, it may not be possible to distinguish UC from CD, at least initially; thus, these patients are considered to have indeterminate colitis. The clinical presentation of UC is generally characteristic; however, other infectious causes of colitis such as shigellosis, salmonellosis, amebiasis, and tuberculosis should also be considered and excluded. The initial test for the diagnosis of UC is sigmoidoscopic examination, as rectum is involved almost universally. A full length colonoscopic examination is required to assess the extent of the disease. The characteristic endoscopic features of UC include loss of vascular pattern, friability, granularity, and punctate or superficial ulcerations. The mucosa is involved in a confluent manner.[1, 16] Serologic markers, including perinuclearstaining antineutrophil cytoplasmic antibodies, are present in up to 70 percent of patients with ulcerative colitis, and anti–Saccharomyces cerevisiae antibodies in 60%–80% of those with CD.[17] Although, these markers may help in the differential diagnosis of the few patients, in whom the nature of colitis cannot be determined according to the usual criteria, they are not recommended for routine diagnosis.

10.3 TREATMENT OF ULCERATIVE COLITIS The long-term management of IBD disease must be multidimensional, and governed by the type of disease and sites involved.[18, 19]

10.3.1 Aminosalicylates Sulfasalazine and the newer aminosalicylates are first line therapy for the treatment of UC.

Part IV / Large Bowel

199

Sulfasalazine contains a 5-aminosalicylic acid (5ASA) moiety that is linked to sulfapyridine by an azo bond, and is delivered intact to the colon. On entering the colon, the azo bond is cleaved by the bacterial enzyme azo-reductase, and sulfasalazine releases sulfapyridine and 5-ASA (Fig. 10.4). The sulfapyridine is absorbed systemically, and accounts for most of the drug’s toxicity and intolerance.[20]

FIGURE 10.4 Metabolism of sulfasalazine.

The 5-ASA is the active anti-inflammatory compound, and ultimately is excreted in the feces. When 5-ASA is administered by mouth, it is rapidly absorbed into the jejunum and consequently does not reach the colon. Therefore, various delivery systems have been used to obtain high concentrations of the drug in the colonic lumen. The first method is to coat 5-ASA with a resin or a semipermeable membrane that is pH-sensitive. The second is to link 5-ASA with another molecule by an azo-bond. Mesalamines (Mesacol, Tidocol) are coated with Eudragit S, which dissolve at pH 7.0 or higher, whereas salofalk or claversal are coated with Eudragit L.[20] Pentasa is mesalamine within a semipermeable membrane that releases the drug at luminal pH values of more than 6.0 in a time-release manner. Among the topical preparations of mesalamines, the suppository preparations

200

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

reach up to upper rectum, whereas the enema formulations reach up to splenic flexure.[21] Sulfasalazine and 5-ASA are anti-inflammatory agents that interfere with the production of arachidonic acid by affecting the thromboxane and lipoxygenase synthesis pathways. Although, the precise mechanism of action of the medications in the treatment of UC is not known, sulfasalazine and the aminosalicylates may also have an immunomodulatory effect.[20, 21] Sulfasalazine and the newer 5-ASA preparations are effective treatment for mild-to-moderate UC. Sulfasalazine controls disease activity and induces remission in approximately 70% of patients. There is a dose response for sulfasalazine, and although the maximal recommended dose is 4 g/day, there are data showing increased efficacy at 6 g/day. The newer 5-ASA agents have similar efficacy to sulfasalazine, and cause clinical improvement in 50% to 75% of treated patients. Sulfasalazine and the 5-ASA formulations are effective for maintenance of remission of UC.[18, 22, 23] When the active disease is controlled, the dose required to maintain remission is the same as that used to induce remission. Generally, 2 to 4 g/day of sulfasalazine and 0.75 to 4.8 g/day of the newer 5-ASA agents are necessary to maintain remission.

10.3.2 Corticosteroids Corticosteroids were the first medications to be evaluated systemically in patients with inflammatory bowel disease. In addition to their nonspecific effects on cellular and humoral immune functions, corticosteroids inhibit the production of cytokines and inflammatory mediators, enhance sodium and water re-absorption, and improve the sense of well-being. Systemic corticosteroids are effective treatment for moderate to severe UC, and for controlling acute exacerbations.[24, 25] Topical

corticosteroids are delivered rectally and are effective treatment for distal colitis. Several modifications of the glucocorticoid backbone have been developed to maximise the mucosal delivery and enteric anti-inflammatory effects, while minimizing systemic side effects. Budesonide and Tixocortol pivalate are new steroid molecules which have enhanced receptor binding properties and more rapid presystemic metabolism.[1, 18, 24, 26] Various forms of steroid enemas such as prednisolone enema, 20– 40 mg; hydrocortisone enema 100 mg; and retention enema of betamethasone – 17 valerate, are also available for topical use.

10.3.3 Immunosuppressants 10.3.3.1 Azathioprine and 6-mercaptopurine

Azathioprine (AZA) and 6-mercaptopurine (6MP) are immunomodulators that are effective for the treatment of steroid dependent UC.[25] After absorption, AZA is nonenzymatically converted to 6-MP, which then is metabolized to the active end product, 6-thioguanine nucleotide. The 6thioguanine nucleotide inhibits ribonucleotide synthesis and exhibits antiproliferative effects on activated lymphocytes. These agents have a direct anti-inflammatory effect due to suppression of T-cell function and natural killer cell activity. The usual doses are 2.0 to 2.5 mg/ug/day for azathioprine and 1.0–1.5 mg/ug/day for 6-MP.[25] AZA and 6-MP are effective steroid sparing agents for active colitis. In an early trial, the 1-year relapse rate was reduced by 50% in steroiddependent patient treated with AZA. AZA and 6-MP are useful agents for maintenance of remission in UC. Idiosyncratic or allergic type reactions to AZA include pancreatitis, fever, rash, arthralgia, diarrhea, and nausea. Nonallergic type reactions

Tropical Hepatogastroenterology

TREATMENT OF ULCERATIVE COLITIS

201

include bone marrow suppression, infection and hepatitis.[25–30] AZA or 6-MP induced pancreatitis usually occurs within the first few weeks of treatment, and resolves on discontinuation of the drug.

hypertrichosis, tremor, hypertension, nausea, gingival hyperplasia, vomiting, headaches, nephrotoxicity, and seizures.[25]

10.3.3.2 Cyclosporine

Intestinal flora and microbial superinfection have been implicated as possible triggering factors in the cascade of immunoinflammatory events leading to inflammatory bowel disease. Antibiotics may inhibit chemotactic peptides released by luminal bacteria, and have been shown to prevent inflammation in animal models of colitis. Despite a trend toward improvement, there was no statistical difference compared with placebo for the treatment of active disease or maintenance of remission with ciprofloxacin, vancomycin or metronidazole.[34–36]

Cyclosporine is a lipophilic peptide that inhibits the proliferation and activation of T-helper cells by interfering with interleukin (IL)-2 production. It also decreases the recruitment of cytotoxic T cells, and inhibits the production of IL-3, IL-4, tumor necrosis factor (TNF)-α, and interferonγ .[25] In contrast to 6-MP and AZA, intravenous cyclosporine has an onset of action within days. Compiled results from 20 uncontrolled trials showed a benefit of cyclosporine for patients with severe UC not responding to steroids. Of the 185 patients treated with cyclosporine, 68% initially avoided colectomy, but only 42% had a sustained response after discontinuing therapy.[31] In a randomized, placebo-controlled trial, 20 patients with severe UC unresponsive to intravenous steroids were randomized to either intravenous cyclosporine (4 mg/kg/day) or placebo.[32] Nine of the 11 (82%) patients treated with cyclosporine achieved a response by day 7 compared with none of the patients in the placebo group. At 6 monthly follow up, only 59% maintained a response on oral cyclosporine, and approximately 30% required colectomy. The oral microemulsion form of cyclosporine (Neoral) has similar bioavailability compared with intravenous cyclosporine, and is more effective than the standard low-dose oral formulations.[33] Monitoring of cyclosporine blood levels is required to reduce the chance of toxicity. Potential toxicity limits the use of cyclosporine, and common side effects include paresthesias,

Part IV / Large Bowel

10.3.4 Antibiotics

10.3.5 Heparin Patients with UC may develop thrombotic complications as a result of an inherent hypercoagulable state. The unexpected improvement of UC in patients treated with heparin for deep venous thrombosis has led to further study. Heparin has anti-inflammatory properties, including blocking adhesion molecules involved in leukocyte recruitment, binding antiulcerogenic growth factors, and reducing tumor necrosis factor and C-reactive protein levels.[37, 38] In several uncontrolled trials, patients with steroid-resistant UC treated with intravenous heparin had a clinical response; however, another controlled trial did not support the use of heparin for treatment of moderate to severe UC, and compare with corticosteroids. Reported bleeding complications have been rare, and there should not be any hesitation in a physician’s mind to use heparin in patients with UC who develop thrombotic complications.[16, 18, 19]

202

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

10.3.6 Probiotics Intestinal microflora may play an important role in the pathogenesis of UC. Several studies have reported an unusually high number of pathogenic Escherichia coli strains in patients with UC. Probiotics have been used in induction of remission of active disease and maintenance of remission. However, the evidence is not sufficient to recommend probiotics for routine use.[16, 39] Probiotics, especially VSL#3, have been found to be very effective in both inducing remission in active pouchitis and maintenance of remission in pouchitis.[40, 41]

10.3.7 Other Drugs Various other drugs including chloroquine, nicotine, clonidine, short chain fatty acid have been tried, but none of them has a established role in management of UC.

10.3.8 Biological Agents As understanding of the initiating and amplifying components of the immunoinflammatory response contributing to the syndromes of UC or CD is developing further, novel therapeutic approaches are also evolving. We now have the ability to interrupt both proximal (e.g., lymphocyte or cytokine) and distal (e.g., arachidonic acid derivatives – leukotrienes, platelet activating factor, oxygen free radicals, nitric oxide) mediators. As is anticipated from the experience with steroids and cyclosporine, the more proximal the inhibition, the more the potential for systemic immune compromise.[18, 42] Thus, the future of therapy, however, will likely evolve to a more targeted therapy such as neutralization of inflammatory cytokines (anti-TNF-gα), and inhibition of specific lymphocytic population. TNF-α is a key pro-inflammatory

cytokine in patients with CD, but is also found in increased concentrations in the blood, colonic tissue, and stools of patients with UC.[43] Infliximab, a chimeric IgG1 monoclonal antibody, binds with high affinity to TNF-gα, neutralizing its biologic activity. Infliximab therapy is effective for the induction and maintenance of clinical remission; closure of enterocutaneous, perianal, and rectovaginal fistulas; maintenance of fistula closure; and corticosteroid sparing in patients with CD.[18, 42] However, the few small studies of infliximab in patients with active ulcerative colitis have yielded conflicting results.[44, 45] Two recent randomized,[46] double-blind, placebocontrolled studies–the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) evaluated the efficacy of infliximab for induction and maintenance therapy in adults with UC. In each study, 364 patients with moderate-to-severe active UC, despite treatment with concurrent medications, were given either placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6, and then every eight weeks till 46 weeks (in ACT 1) or 22 weeks (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P < 0.001 for both comparisons with placebo). In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P < 0.001 for both comparisons with placebo).[46] RDP58, a novel anti-inflammatory decapeptide, blocks TNF production at a posttranscriptional level, and inhibits the production of INF-γ , IL2, and IL-12. RDP 58 has been effective in murine

Tropical Hepatogastroenterology

MANAGEMENT GUIDELINES FOR ULCERATIVE COLITIS

and primate models of colitis. In a phase II study, 127 patients with mild to moderate ulcerative colitis were randomized to receive placebo or an oral solution of RDP 58 at 100 mg, 200 mg, 300 mg daily for 4 weeks. Clinical remission was reported in 72%, 70%, 29%, and 40% in the 300 mg, 200 mg, 100 mg, groups and placebo, respectively (p < 0.0006).[47] Antileucocyte adhesion therapies are a novel approach to prevent egress of inflammatory cells into the tissues of patients with IBD. Preliminary studies have been conducted in patients with ulcerative colitis.[18, 42] Visilizumab, a humanized antibody with a mutated immunoglobulin G2 Fc region directed at CD3e chain of the T-cell receptor complex, has been shown to selectively induce apoptosis in activated T cells. Preliminary results of an ongoing phase I dose escalation study described 7 patients with severe steroid –refractory ulcerative colitis, who received 2 daily doses of visilizumab 15 μg/kg. Data presented for 5 patients described clinical and endoscopic remission for all 5 patients that persisted for several months as steroids were tapered.[48] Anti-interleukin-2, daclizumab, a recombinant humanized immunoglobulin G1 monoclonal antibody to IL-2 R alpha (CD25), binds with high

affinity. In a open label, single-center pilot study, 2 infusions of daclizumab 1 mg/kg 4 weeks apart in 10 patients with refractory ulcerative colitis resulted in significant decrease in clinical activity scores after 2 weeks.[49]

10.4 MANAGEMENT GUIDELINES FOR ULCERATIVE COLITIS Therapeutic decisions regarding treatment of ulcerative colitis depend on activity and the extent of the disease.

10.4.1 Assessment of Disease Activity Disease activity is best evaluated objectively using a clinical activity indices such as Truelove and Witts[50] or the Simple Clinical Colitis index[51] (Table 10.1). Patients with severe disease require hospital admission, whereas those with mild/moderate disease can generally be managed as outpatients.[16]

10.4.2 Assessment of Extent of the Disease Disease extent can broadly be divided into distal and more extensive disease. Topical management is appropriate for some patients with active disease.

TABLE fy 10.1 Criteria for evaluation of severity of ulcerative colitis Variables

Mild

Severe

Fulminant

Stools (number/day) Blood in the stool Temperature (◦ C) Pulse (per minute) Hemoglobin ESR (mm/hour) S. albumin (g/dL)

6 Frequent > 37.5◦ C 90–100 < 75% of normal > 30 < 3.0

> 10 Continuous > 37.5◦ C > 100 Transfusion requirement > 30 < 3.0

Based on the criteria of Truelove and Witts[50] Moderate disease includes features of both mild and severe disease

Part IV / Large Bowel

203

204

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

This is usually the case for those with proctitis, and is often the case if the disease extends into the sigmoid. For those with more extensive disease, oral or parenteral therapy are the mainstays of treatment, although some of these patients may get additional benefit from topical therapy. For the purposes of these guidelines, “left sided” disease is defined as disease extending proximal to the sigmoid-descending junction up to the splenic flexure, and “extensive” UC as that extending proximal to the splenic flexure. Extent of the disease is assessed preferably by a colonoscopic examination or a barium enema.[1, 16]

10.4.3 Active Distal Ulcerative Colitis Patients with mild to moderate distal colitis should be treated either with oral aminosalicylates or topical mesalamines or topical steroids. The choice of topical formulation should be determined by the proximal extent of the inflammation.[16, 18, 22] Given through the rectal route, suppositories reach up to 10 cm from the anal verge, foam reaches up to 25–20 cm, and drugs given in enema form reach up to the splenic flexure. In mild to moderate disease, topical mesalamine 1 g daily (in appropriate form for extent of disease) combined with oral mesalamines 2–4 g daily, balsalazide daily, are effective first line therapy.[16, 18, 22] Topical corticosteroids are less effective than topical mesalamines, and should be reserved as second line therapy for patients who are intolerant of topical mesalamines.[16, 18, 19] Patients who have failed to improve on a combination of oral mesalamines with either topical mesalamines or topical corticosteroids should be treated with oral prednisolone 40 mg daily. Topical agents may be used as adjunctive therapy in this situation. Prednisolone should be reduced gradually according to severity and response, generally over 8 weeks. Sulfasalazine 2–4 g daily has a higher incidence of side effects

compared with newer 5-ASA drugs. Sulfasalazine may be a better drug for those patients with UC, who have arthropathy as an extraintestinal manifestation. These drugs are efficacious within 2–4 weeks, and are effective in up to 80% of patients.[16, 18, 19]

10.4.4 Active Mild to Moderate Left Sided or Extensive UC When inflammation extends proximal to the reach of topical therapy (splenic flexure), the drugs should be given orally so as to provide the drug all along the diseased area, either solely or in combinations with topical therapy. For mild to moderate, but anatomically extensive disease, mesalamine 2–4 g daily or balsalazide 6.75 g daily are effective first line therapy.[16, 18, 19, 22] The efficacy of newer aminosalicylates such as mesalamines (Mesacol, Tidocol), olsalazine, ethylcellulosecoated mesalamine (Pentasa) is equivalent to sulfasalazine. Oral steroids are generally reserved for patients who are refractory to oral aminosalicylates or for those patients whose symptoms are so troubling as to demand a “quick fix” therapy. Oral prednisolone is used in the doses of 40– 60 mg/day until significant clinical improvement occurs. Prednisolone should be reduced gradually according to severity and patient response, generally over 8 weeks. More rapid reduction is associated with early relapse. Long term treatment with steroids is undesirable. Patients with chronic active steroid dependent disease should be treated with azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day. Topical agents (either steroids or mesalazine) may be added to the above agents. Although, they are unlikely to be effective alone, they may benefit some patients with troublesome rectal symptoms.[16, 18, 19]

Tropical Hepatogastroenterology

MANAGEMENT GUIDELINES FOR ULCERATIVE COLITIS

TABLE fy 10.2 Treatment of severe ulcerative colitisy General • Hospitalization • Hemodynamic monitoring • Observation for rebound tenderness, bowel activity • Assessment of biochemical and hematological parameters • Avoidance of narcotics, antidiarrheals and anti-cholinergics • Exclusion of superinfection including CMV • Bowel rest • Intravenous fluid supplementation Specific • • • • •

Intravenous hydrocortisone Broad spectrum antibiotics Surgical consultation Intravenous cyclosporine Surgery

10.4.5 Severe Ulcerative Colitis (Table 10.2) Patients who have failed to respond to maximal oral treatment with a combination of mesalamines and/or steroids, with or without topical therapy, or those who present with severe disease should be admitted for intensive intravenous therapy. Ideally, all such patients should be treated jointly by both the medical and surgical team. Acute onset UC is sometimes difficult to distinguish from infective colitis, but treatment with corticosteroids should not be delayed until stool microbiology results are available. Cytomegalovirus (CMV) infection of the colon may precipitate the acute exacerbation of UC, and if not recognized may prove to be fatal. Corticosteroids used for control of acute exacerbation of UC may further complicate the course of superimposed CMV colitis.[52] The patient should be monitored for number and consistency of stool, amount of blood in the stool, vital signs and abdominal signs (fullness, abdominal

Part IV / Large Bowel

205

tenderness, rebound tenderness, and bowel sound). One should not be reassured that the patient is recovering if the frequency of stool comes down. In fact a decrease in number of stool may also mean worsening and toxic megacolon. Therefore a constant vigil on the overall condition of the patient is mandatory. Hemogram, ESR, C-reactive protein, serum electrolytes, and serum proteins should be examined every 2–3 days. If on an initial abdominal radiography, the transverse colon is found to be dilated (diameter > 5.5 cm), the abdominal skiagram should be repeated every day. Hemoglobin should be kept above 10 gm/dL, and if the hemoglobin is less or there is ongoing bleeding, blood should be transfused. Intravenous corticosteroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day) should be started. Higher doses of steroids offer no greater benefit, but lower doses are less effective. Anticholinergic, antidiarrheal agents, NSAID and opioid drugs are best avoided as they can precipitate colonic dilatation. Most patients are generally on mesalamines, which may be continued once oral intake resumes. Topical therapy (corticosteroids or mesalamine) if tolerated and retained, may also be continued. Although, intravenous antibiotic has become a standard care in patients with acute severe colitis, the evidence of benefit is lacking. Therefore, it is recommended that intravenous antibiotics should be used if infection is considered, or immediately before surgery (Table 10.2). Patients who do not improve significantly after 7–10 days of maximal medical management are unlikely to benefit from prolongation of this form of management, and should either be referred for surgery or offered treatment with an intravenous cyclosporine. In one placebo controlled double blind trial, 80% of patients treated with intravenous cyclosporine (4 mg/kg/day) improved, and were able to avoid colectomy in the acute stage.[16, 18, 19]

206

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

Immediate surgical referral is necessary if there is evidence of toxic megacolon (transverse colon diameter > 5.5 cm, or cecum > 9 cm). The urgency with which surgery is undertaken after recognition of colonic dilatation depends on the condition of the patient: the greater the dilatation, and the greater the degree of systemic toxicity, the sooner surgery should be undertaken, but signs may be masked by steroid therapy. In selective patients with mild colonic dilatation, an expectant conservative management can be continued, and clinical, laboratory, or radiological deterioration mandates immediate colectomy. Those with toxic megacolon, colonic decompression can be augmented by frequent change in posture to knee elbow position. Broad spectrum antibiotics should be used empirically in these patients. If no obvious clinical improvement is noted within 72 hours, surgical intervention is recommended.[16, 18, 19]

10.5 MAINTENANCE OF REMISSION 10.5.1 Maintenance Therapy—How Long? As most of the patients with ulcerative colitis have a relapsing and remitting course, they require a long term therapy in order to achieve a long term remission and to prevent frequent relapses. Based on studies, lifelong maintenance therapy is generally recommended for all patients, especially those with left sided or extensive disease, and those with distal disease, who relapse more than once a year. Discontinuation of medication may be reasonable for those with distal disease who have been in remission for 2 years and are averse to such medication.[16, 18, 19, 23] Furthermore, patients with a mild first episode may opt for being followed up without long-term medical maintenance therapy. There are some evidences that maintenance therapy reduces the risk of colorectal cancer.

For the maintenance of remission of UC, oral mesalamine 1–2 g daily or balsalazide 2.5 g daily should be considered as first line therapy. Sulfasalazine 2–4 g daily has a higher incidence of side effects compared with newer 5-ASA drugs.[16, 23] Selected patients, such as those with a reactive arthropathy, may benefit with sulfasalazine. Topical mesalamine 1 g daily may be used in patients with distal disease with or without oral mesalamine, but patients are less likely to be compliant. All aminosalicylates have been associated with nephrotoxicity, which appears both to be idiosyncratic and in part dose related. Reactions are rare, but patients with preexisting renal disease are at higher risk. Occasional (perhaps annual) measurement of creatinine is sensible, although there is no evidence that monitoring is necessary or effective. Aminosalicylates should be stopped if renal function deteriorates. The advantages and disadvantages of continued treatment with aminosalicylates are best discussed with the patient, especially if a patient has been in remission for a substantial length of time (> 2 years). Steroids are ineffective at maintaining remission. Azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day are effective at maintaining remission in UC.[16, 18, 28] However, in view of toxicity, they should be reserved for patients who frequently relapse despite adequate doses of aminosalicylates, or are intolerant of 5ASA therapy. It is common practice to continue aminosalicylates with azathioprine, but there is limited evidence that this is necessary. Patients with gastrointestinal intolerance of azathioprine may be cautiously tried on mercaptopurine before being considered for other therapy or surgery.

10.5.2 Surgery for Ulcerative Colitis Approximately 25% to 50% of patients with UC require surgical intervention at sometime during

Tropical Hepatogastroenterology

MAINTENANCE OF REMISSION

207

FIGURE 10.5 The steps in proctocolectomy with ileal pouch anal anastomosis (IPAA). Illustration 1 shows the normal anatomy. In the first stage the colon is removed (illustration 2) and the terminal ileum comes out as an end-ileostomy (I) (illustration 3). In the second stage, the terminal ileum is fashioned into an ileal pouch. The rectum is removed, leaving only the anal canal. The ileal pouch is anastomosed to the anal canal. To prevent leakage, a proximal limb of ileum is brought out, this time as a loop ileostomy (LI) (illustration 4). In the third stage, this loop ileostomy is closed (illustration 5).

their lifetime. The indications may be classified as emergency (exsanguinating hemorrhage, intestinal perforation and severe colitis unresponsive to intensive medical treatment) and elective (documented or strongly suspected carcinoma, medically intractable symptoms or intolerable side effects of drugs and unaffordability of medical treatment). Patients requiring surgery for IBD are best managed under the joint care of a surgeon and a gastroenterologist.[16, 53, 54]

Part IV / Large Bowel

The procedure of choice in acute fulminant UC is a subtotal colectomy leaving a long rectal stump, either incorporated into the lower end of the abdominal wound or exteriorized as a mucus fistula, to facilitate rectal excision later, and minimize the risk of intraperitoneal dehiscence (Figs. 10.5 to 10.7). Patients requiring elective surgery for UC should be counseled regarding all surgical options, including ileo-anal pouch where appropriate.[53, 54]

208

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

10.5.3 Pouchitis

FIGURE 10.6 Operative picture showing the construction of the anal pouch.

Up to 45% of patients who undergo ileal pouch surgery for UC suffer from pouchitis.[41] The differential diagnosis of pouchitis includes pelvic sepsis, and prepouch ileitis. The pouchitis can be acute or chronic. The treatment of choice for acute pouchitis includes metronidazole 400 mg thrice daily or ciprofloxacin 250 mg twice/day for 2 weeks.[16, 18, 55, 56] Mesalamines or corticosteroids may also be used in acute pouchitis if antibiotics are ineffective.[16, 18, 41] Chronic pouchitis requires prolonged low dose metronidazole or ciprofloxacin. Multiple randomized controlled trials have shown that a probiotic VSL#3 is effective in not only achieving remission but maintaining remission of pouchitis.[39–41, 57]

FIGURE 10.7 The resected specimen after total colectomy. Note the severe pseudopolyposis. The colon was resected leaving only the smallest possible stump of terminal ileum (arrow).

Tropical Hepatogastroenterology

MANAGEMENT DURING PREGNANCY

10.6 MANAGEMENT DURING PREGNANCY As both UC and CD often occur in young adults, one often gets a chance to treat a patient with IBD during her pregnancy. It has been estimated that approximately 25% of female patients conceive after the diagnosis of IBD has been made. Maintaining adequate disease control during pregnancy is essential for both maternal and fetal health. If pregnancy is planned, patients should be counseled to conceive during remission, and advised to continue their maintenance medication. Before conception, patients should be well nourished and should be advised folate supplements. If the disease flares up during pregnancy, the patient should be managed as per the guidelines similar to that laid down for nonpregnant patients. Sulfasalazine should be stopped if there is suspected neonatal hemolysis. Azathioprine should in general be continued during pregnancy, as the risks to the fetus from disease activity appear to be greater than continued therapy.[58, 59] Babies born to mothers on azathioprine may be lighter than normal, and the risk-benefit ratio should be discussed with patients. Corticosteroids can be used for active disease, as the risks to the pregnancy from disease activity are greater than from continued therapy. Methotrexate is absolutely contraindicated in pregnancy.[58, 59]

10.6.1 Nutrition There is little evidence to implicate dietary components in the etiology or pathogenesis of test test

Part IV / Large Bowel

209

UC. However, patients are prone to malnutrition and its detrimental effects. A proper nutritional assessment should be done, and nutritional status should be improved. There is no evidence that artificial nutritional support alters the inflammatory response in UC, in contrast to CD.[16]

10.7 MANAGEMENT OF EXTRAINTESTINAL MANIFESTATIONS Extraintestinal manifestations are found in both CD and UC. Those associated with active intestinal disease largely respond to therapy aimed at controlling disease activity, whereas those that occur even when the disease is inactive or quiescent, run a course independent of therapy for intestinal disease. Osteoporosis is common in patients with IBD, and steroids may further enhance the risk. Calcium and vitamin supplementations must be given especially during the periods of steroid administration.

10.8 CONCLUSIONS The progressive, chronic course and sequelae of IBD calls for a long term perspective on treatment, and an approach that maximizes the mucosal antiinflammatory effects while minimizing the systemic impact. The current therapies for UC act at multiple sites along the immune and inflammatory cascades. As basic and clinical scientists unravel the inflammatory sequences, there is the promise of more specific inhibitors with enhanced potency and limited toxicity.

210

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

REFERENCES [1] Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417–429. [2] Sood A, Midha V, Sood N et al. Incidence and prevalence of ulcerative colitis in Punjab, north India. Gut 2003;52:1587–90. [3] Makharia GK. Rising incidence and prevalence of Crohn’s disease in Asia: Is it apparent or real? J Gastroenterol Hepatol 2006;21:929–31. [4] Tandon BN, Upadhyaya AK, Tandon HD et al. Ulcerative colitis in north Indian subjects: a Preliminary report. J Assoc Physicians India 1964;12: 43–52. [5] Tandon BN, Mathur AK, Mohapatra LN et al. A study of the prevalence and clinical pattern of nonspecific ulcerative colitis in northern India. Gut 1965 Oct;6:448–53. [6] Chuttani HK, Nigam SP, Sama SK et al. Ulcerative colitis in the tropics. Br Med J 1967;4:204–7. [7] Sharma MP, Sarin SK. Ulcerative colitis in a north Indian hospital: current trends. J R Coll Physicians Lond 1985;19:99–102. [8] Duphare H, Misra SC, Patnaik PK et al. Spectrum of ulcerative colitis in north India. J Clin Gastroenterol 1994;18:23–6. [9] Venkataraman S, Mohan V, Ramakrishna BS et al. Risk of colorectal cancer in ulcerative colitis in India. J Gastroenterol Hepatol 2005;20:705–9. [10] Kochhar R, Mehta SK, Nagi B et al. Extraintestinal manifestations of idiopathic ulcerative colitis. Indian J Gastroenterol 1991;10:88–9. [11] Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004;126:1504–17. [12] Ouyang Q, Tandon R, Goh KL et al. The emergence of inflammatory bowel disease in the Asian Pacific region. Curr Opin Gastroenterol. 2005;21: 408–13. [13] Herfarth H, Rogler G. Inflammatory bowel disease. Endoscopy 2005;37:42–7. [14] Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology 2004;126:1518–32.

[15] Jenkins D, Balsitis M, Gallivan S et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Path 1997;50:93–105. [16] Carter MJ, Lobo AJ, Travis SPL, on behalf of the IBD Section of the British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53:v1–v16. [17] Sandborn WJ. Serological markers in inflammatory bowel disease: State of the art. Rev Gastrointest Disord 2004;4:167–174 [18] Hanauer SB. Medical therapy of ulcerative colitis 2004. Gastroenterology 2004;126:1582–1592. [19] Van Assche G, Vermeire S, Rutgeerts P. Medical treatment of inflammatory bowel diseases. Curr Opin Gastroenterol 2005;21:443–7. [20] Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine prodrugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 2003;17:29–42. [21] Sutherland L. Topical treatment of ulcerative colitis. Med Clin North Am 1990;74:119–31. [22] Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2003;CD000543. [23] Sutherland LR, Roth D, Beck P et al. Oral 5aminosalicylic acid for maintaining remission in ulcerative colitis. Cochrane Database Syst Rev 2002;CD000544. [24] Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and SASP therapy in ulcerative colitis. BMJ 1962;2:1708–11. [25] Lichtenstein GR, Abreu MT, Cohen R et al. American Gastroenterological Association. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–87. [26] Kane SV, Schoenfeld P, Sandborn W et al. Systematic review: the effectiveness of budesonide

Tropical Hepatogastroenterology

REFERENCES

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

for Crohn’s disease. Aliment Pharmacol Ther 2002;16:1509–17. Hawthorne AB, Logan RFA, Hawkey CJ et al. Randomised controlled trial of azathioprine-withdrawal in ulcerative colitis. BMJ 1992;305:20–22. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50:485–9. Sharma MP, Makharia G. In search of a better treatment for ulcerative colitis. Indian J Gastroenterol 2003;22:77–8. Connell WR, Kamm MA, Ritchie JK et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34:1081–5. Sandborn W. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995;1:48–63. Lichtiger S, Present DH, Kornbluth A et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–5. Actis GC, Aimo G, Priolo G et al. Efficacy and efficiency of oral microemulsion ciclosporin versus intravenous and soft gelatin capsule ciclosporin in the treatment of severe steroid-refractory ulcerative colitis: an open-label retrospective trial. Inflamm Bowel Dis 1998;4:276–9. Dickinson R, O’Connor H, Pinder I et al. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985;26:1380–4. Turunen U, Farkkila M, Hakala K et al. Long term treatment of ulcerative colitis with ciprofloxacin. A prospective, double blind, placebo controlled study. Gastroenterology 1998;115:1072–8. Chapman R, Selby W, Jewell D. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210–2. Gaffney P, Doyle C, Gaffney A et al. Paradoxical response to heparin in 10 patients with ulcerative colitis. Am J Gastroenterol 1995;90:220–3. Irving PM, Pasi KJ, Rampton DS. Thrombosis and inflammatory bowel disease. Clin Gastroenterol Hepatol 2005;3:617–28.

Part IV / Large Bowel

211

[39] Bibiloni R, Fedorak RN, Tannock GW et al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol 2005;100:1539–46. [40] Gionchetti P, Rizzello F, Helwig U et al. Prophylaxis of pouchitis onset with probiotic therapy: a doubleblind, placebo-controlled trial. Gastroenterology 2003;124:1202–9. [41] Akerlund JE, Lofberg R. Pouchitis.Curr Opin Gastroenterol 2004;20:341–4. [42] Ardizzone S, Bianchi Porro G. Biologic therapy for inflammatory bowel disease. Drugs. 2005;65: 2253–86. [43] Braegger CP, Nicholls S, Murch SH et al. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992;339: 89–91. [44] Sands BE, Tremaine WJ, Sandborn WJ et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001;7:83–88. [45] Probert CS, Hearing SD, Schreiber S et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 2003;52:998–1002. [46] Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353: 2462–76. [47] Travis S, Yap L, Hawkey CJ. Novel and effective therapy for ulcerative colitis: results of parallel prospective placebo-controlled trials (abstr). Am J Gastroenterol 2003;98:S239. [48] Plevy SE, Salzberg BA, Regueiro M. A humanized anti-CD3 monoclonal antibody, visilizumab, treatment of severe steroid refractory ulcerative colitis: preliminary results of a phase I study (abstr). Gastroenterology 2003;124:A7. [49] Van Assche G, Dalle I, Noman M et al. A pilot study on the use of the humanized anti-interleukin2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol 2003;98:369–76. [50] Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. BMJ 1955;ii:1041–8.

212

Chapter 10 / MANAGEMENT OF ULCERATIVE COLITIS

[51] Walmsley RS, Ayres RCS, Pounder RE et al. A simple clinical colitis index. Gut 1998;43:29–32. [52] Kishore J, Ghoshal U, Ghoshal UC et al. Infection with cytomegalovirus in patients with inflammatory bowel disease: prevalence, clinical significance and outcome. J Med Microbiol 2004;53:1155–60. [53] Karch LA, Bauer JJ, Gorfine SR et al. Subtotal colectomy with Hartmann’s pouch for inflammatory bowel disease. Dis Colon Rectum 1995;38: 635–9. [54] Pal S, Sahni P, Pande GK et al. Outcome following emergency surgery for refractory severe ulcerative colitis in a tertiary care centre in India. BMC Gastroenterol 2005;5:39. [55] Mimura T, Rizzello F, Helwig U et al. Four week open-label trial of metronidazole and ciprofloxacin

[56]

[57]

[58]

[59]

for the treatment of recurrent or refractory pouchitis. Aliment Pharmacol Ther 2002;16:909–17. Shen B, Achkar JP, Lashner BA et al. A randomized trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7: 301–5. Gionchetti P, Rizello F, Venturi A et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebocontrolled trial. Gastroenterology 2000;119: 305–9. Katz JA, Pore G. Inflammatory bowel disease and pregnancy. Inflamm Bowel Dis 2001;7: 146–57. Sathyanarayana G, Saraya A. Ulcerative colitis and pregnancy. Trop Gastroenterol 2004;25:4–8.

test

Tropical Hepatogastroenterology

Chapter

11 BENIGN COLORECTAL TUMORS Atul K Sharma

11.1 INTRODUCTION Colonic polyps are benign neoplasms that arise from the epithelial cells lining the colon. They are slow-growing overgrowths of the colonic mucosa that carry a small risk (< 1%) of becoming malignant. They are commonly found in the elderly, predominantly affect the left colon (80%– 90%), and confer a certain predisposition to colon cancer, hence are mostly removed when detected. Benign tumors of the colon are almost invariably sessile or pedunculated polyps. This is true whether they are hyperplastic or adenomatous polyps, gastrointestinal stromal tumors, benign nodular lymphoid hyperplasia, carcinoids, or intestinal neurofibromatosis. Polyps can also occur as part of inherited polyposis syndromes in which not only is their number greater but the risk for malignant progression is also much higher as compared to the risk with isolated polyps.

11.2 EPIDEMIOLOGY Population and autopsy studies from the US suggest that 30% of middle-aged or elderly individuals have colonic polyps. Alaskan natives have the highest incidence (75 cases per 100,000), while

the incidence is low among American Indians in New Mexico (18.6 cases per 100,000 men and 15.3 cases per 100,000 women).[1] Environmental causes contribute to differences in polyp incidence in geographically distinct populations, but the responsible factors have remained elusive. Furthermore, in Asian populations race does not appear to be a risk factor for the development of colonic adenoma.[2] The risk is higher for men than for women. The male-female difference is most marked among Filipinos and Japanese (60% difference). In other groups, the difference of incidence by sex ranges is 13%–22%. The incidence of polyps increases with age. In the general population, the incidence rises from 10 cases per 100,000 people aged 40– 45 years to 300 cases per 100,000 in those aged 75–80 years. Differences in consumption of dietary fiber and antioxidants may play a role in the development of polyps. Individuals who smoke more than 20 cigarettes per day have 250% more polyps, and individuals who smoke and drink have 400% more polyps than those who do not smoke. Three-fourths of polyps in whites, and half of all polyps in black populations occur in the distal colon and rectum, whereas in blacks this occurs in only half. Synchronous polyps are commoner among black populations. Therefore, 213

214

Chapter 11 / BENIGN COLORECTAL TUMORS

total colonic surveillance is essential in black patients to adequately screen for large-bowel neoplasia.[3]

11.3 CLASSIFICATION Benign colonic polyps may be hyperplastic, hamartomatous (containing a mixture of normal tissues), inflammatory (containing an epithelial reaction), or adenomatous. Adenomatous polyps are either sporadic or secondary to familial polyposis syndromes, and are the only type of polyp considered premalignant.

11.3.1 Hyperplastic Polyps Hyperplastic polyps comprising 90% of all polyps, are usually less than 0.5 cm in diameter, and are totally benign. Hyperplastic polyps most commonly occur in the rectosigmoid region during adulthood. Most guidelines for colorectal cancer screening do not consider distal hyperplastic polyps (HPs) to be markers for proximal colon neoplasia. The discovery of HPs on screening flexible sigmoidoscopy need not automatically prompt follow-up colonoscopy.[4]

11.3.2 Adenomas Adenomas (Fig. 11.1) comprise approximately 10% of polyps. Most (∼90%) are small, usually less than 1.5 cm in diameter, and have a very low potential for malignancy. The remaining 10% of adenomas are larger, and have a significant chance of containing invasive cancer. Adenomas have been divided into 3 types depending on their histological appearance as tubular, tubulovillous and villous. Tubular adenomas (with branched tubular glands) are the most common and can be found

FIGURE 11.1 A large polyp in the colon.

anywhere in the colon. Most are pedunculated. The risk of progression to carcinoma is related to the size of the adenoma. Tubulovillous adenomas (with both tubular and villous elements) are most commonly found in the rectal area. The degree of villous component of these adenomas correlates with the degree of cellular atypia or dysplasia and risk of progression to carcinoma. Villous adenomas (with long finger-like projections of the surface epithelium) most commonly occur in the rectal area. They tend to be larger than the other two types; and nonpedunculated, velvety, or cauliflower like in appearance. Among all polyps, villous adenomas are associated with the highest morbidity and mortality rates. They can cause hypersecretory syndromes characterized by profuse mucous discharge, or hypokalemia, and may harbor in situ

Tropical Hepatogastroenterology

CLASSIFICATION

or invasive carcinoma more frequently than other adenomas. The risk of cancer depends upon the size and histologic type of the polyp. A tubular adenoma smaller than 1 cm in diameter has < 5% risk, where as the risk of cancer in a tubular adenoma larger than 2 cm is 35%. A villous adenoma larger than 2 cm carries 50% chance of containing a cancer.[5]

11.3.3 Polyposis Syndromes Familial adenomatous polyposis (FAP), formerly known as familial polyposis coli (FPC) or hereditary adenomatosis of the colon and rectum, is an autosomal dominant disorder, responsible for the widespread development of adenomas which carpet the colon and rectum.[6] FAP was first linked to extracolonic manifestations in 1923 by Nichols, when he commented on the association of FAP and desmoid tumors. In 1951, Gardner described the occurrence of FAP with the extracolonic manifestations of intestinal polyposis, desmoids, osteomas, and epidermoid cysts (Gardner syndrome). Since then, a number of other hereditary polyposis syndromes have been described such as Turcot syndrome, PeutzJeghers syndrome, Cowden disease, and familial juvenile polyposis. Some of the syndromes have extraintestinal features that help differentiate one from the other. FAP is best understood in terms of the genetic basis, and subsequent pathological and genetic events leading to carcinoma. It is an autosomal dominant inherited disorder characterized by the presence of hundreds to thousands of adenomatous polyps throughout the colon. All patients with this syndrome develop colon cancer if not treated.[6] The possible genetic defects which lead to FAP are: 1. Mutation of the APC gene, located on chromosome 5

Part IV / Large Bowel

215

2. Loss of DNA methylation 3. Mutation of the RAS gene, located on chromosome 12 4. Deletion of the deleted colon cancer gene (DCC), located on chromosome 18 5. Mutation of the TP53 gene, located on chromosome 17. Because the genetic defect in the germline of patients with FAP has been well characterized, syndromes once thought to be distinct from FAP are now recognized to be, in reality, part of the phenotypic spectrum of FAP. Syndromes with a germline mutation in the adenomatous polyposis coli gene (APC) include FAP, Gardner syndrome, some Turcot syndrome families, and attenuated adenomatous polyposis coli (AAPC). 11.3.3.1 Pathophysiology of FAP

The APC gene, considered the gatekeeper of colonic neoplasia, is a tumor suppressor gene that is inactivated as initial step in the formation of an adenomatous polyp. When inherited, every cell in the affected person contains a mutated and a normal copy of APC. Mutation of APC almost always results in a truncated protein. Every colonic epithelial cell in patients with FAP has one APC allele mutated because they already are affected by the germline mutation. Inactivation of the remaining normal copy of APC, by deletion or mutation, completely removes the tumor suppressive function of APC, thus initiating growth of adenomatous polyps. Numerous adenomas develop throughout the colon because inactivation of the second APC allele occurs frequently in the colon.[7] Normal APC protein promotes apoptosis in colonic cells. Its most important function may be to sequester the growth stimulatory effects of β-catenin, a protein that transcriptionally

216

Chapter 11 / BENIGN COLORECTAL TUMORS

activates growth-associated genes in conjunction with tissue-coding factors. Therefore, the loss of APC function would prevent apoptosis, and allow β-catenin to accumulate intracellularly and stimulate cell growth. As the clonal expansion of cells that lack APC function occurs, their rapid growth increases the possibility for other growthadvantageous genetic events to occur. Ultimately, enough genetic events happen that allow the adenomatous polyp to become malignant in patients with FAP. This process is similar to that which occurs in sporadic adenoma. Cowden disease is associated with mutations in the pentaerythritol tetranitrate (PTEN) protein phophatase. 11.3.3.2 Epidemiology of FAP

As much as 20% of the world population is genetically predisposed to FAP. Jewish people of Eastern European descent also may have a genetic predisposition, which doubles their risk. Estimates of the incidence of FAP in the US vary from one in 6,850 to one in 31,250 persons. The frequency is constant worldwide. FAP has been described in all races. It is due to congenital inheritance in a Mendelian dominant fashion in 80% of patients. The remaining 20% represent spontaneous mutations, with no family history reported. The male:female ratio is 1:1. The average age of onset of polyposis in FAP is 16 years, and average age of onset for colorectal cancer is 39 years. The average age of onset for polyps in AAPC is 36 years, and the average age of onset for cancer in AAPC is 54 years.[8] 11.3.3.3 Natural history of FAP

The principal cause of mortality is colorectal cancer, which develops in all patients unless they are treated. As many as 20% of patients may develop desmoids after colectomy, which can compromise

intra-abdominal organs and vessels. Additionally, adenocarcinoma of the duodenum and the papilla of Vater occurs in as many as 12% of patients. Rarer cancers associated with FAP include medulloblastomas (Turcot syndrome), hepatoblastomas, thyroid cancer, and adrenal hyperplasia and cancer.

11.3.4 Juvenile Polyps Poddar et al. described their experience of 236 children with colonic polyps.[9] The mean age of these children was 6 years, with a male preponderance (3.5:1). Rectal bleeding was the presenting symptom in 98.7%. Solitary polyps were seen in 76% and 85% were rectosigmoid in location. Seven percent of children with five or more juvenile polyps were labeled as having juvenile polyposis. Adenomatous changes, seen in 11%, were more common in juvenile polyposis (59%) than in juvenile polyps (5%). Among those with juvenile polyposis, colon clearance was achieved in eight, six required colectomy for intractable symptoms, and three were still on the polypectomy program. Polyps recurred in 5% of children with juvenile polyps and 37.5% of those with juvenile polyposis. The need for total colonoscopy is emphasized in all, since in a significant number of children the polyps are multiple and proximally located. The authors recommend that juvenile polyps should be removed even if asymptomatic because of their neoplastic potential. They conclude that colonoscopic polypectomy is effective even in juvenile polyposis, and surveillance colonoscopy is required in juvenile polyposis only. Oncel et al.[10] evaluating the outcome of surgery for juvenile polyposis concluded that onehalf of the patients, who initially underwent rectal preservation, required subsequent proctectomy. The number of colonic or rectal polyps does not influence the choice of the surgical procedure. Both

Tropical Hepatogastroenterology

CLINICAL PRESENTATION

restorative proctocolectomy and subtotal colectomy with ileorectal anastomosis need endoscopic follow-up because of the high recurrence rates of juvenile polyps in the remnant rectum or pouch.

11.4 CLINICAL PRESENTATION Patients with polyps of the colon are often asymptomatic. The common symptoms are bleeding per rectum, diarrhea, intestinal obstruction and progression to cancer. Bleeding can be frank hematochezia but is often chronic, and goes unnoticed by the patient. In a study from the All India Institute of Medical Sciences, New Delhi, polyps were found to be the cause in 19% of patients with lower GI bleeding.[11] If uncompensated, intestinal blood loss can cause anemia, typically due to iron deficiency. Although colonic polyps occur typically in older individuals, a positive family history of polyposis should prompt referral for screening in younger individuals. A common practice is to begin screening in a patient 5 years earlier than the age at which polyps were diagnosed in a first-degree relative.

11.5 DIAGNOSIS Distal rectal polyps can be detected by digital rectal examination. Occult blood in stools, although nonspecific, should prompt an evaluation of colon in most patients. No laboratory test helps determine whether a given patient has a colonic polyp. A patient with a family history of FAP may inherit a mutation in the APC gene. Because most APC mutations involve truncations of the protein, an in vitro protein truncation assay has been developed by Powell et al. in 1993.[13] This assay amplifies segments of APC messenger RNA (mRNA), and expresses the protein parts in vitro to readily detect the truncated products. A positive

Part IV / Large Bowel

217

test finding indicates only susceptibility, not the actual presence of polyp.

11.5.1 Imaging Air contrast barium enema can detect larger polyps but can miss smaller ones. In a recent study, air contrast barium enema detected only about 50% of polyps greater than 1 cm in diameter.[14] It has a low false-positive rate. Virtual colonoscopy is performed by CT scanning or MRI, and has shown promise in research studies, detecting more than 80% of large polyps.[15] A thorough colon preparation is required, and colonoscopy must be subsequently performed to remove the lesions. Recently however, low-dose multidetector computed tomographic colonography, without cathartic preparation, has compared favorably with colonoscopy for the detection of colorectal polyps.[16] MR colonography was evaluated by Ajay et al. in 2005,[17] who found it to be reliable in evaluating the majority of colonic segments inaccessible with conventional colonoscopy. The identification of additional disease at MR colonography underscores the need for a second diagnostic step in the setting of incomplete conventional colonoscopy.

11.5.2 Endoscopy Flexible sigmoidoscopy has been used as a screening test, but it does not examine the entire colon. Screening usually begins at the age of 50 years in patients who are at average risk. Randomized controlled trials have documented a reduction in mortality from colon cancer in populations screened by flexible sigmoidoscopy. However, recent studies suggest that about 40% of highrisk proximal adenomas remain undetected when this procedure is used as the primary screening modality.[5] Colonoscopy is the preferred modality

218

Chapter 11 / BENIGN COLORECTAL TUMORS

used to detect colonic polyps, obtain biopsies, and perform endoscopic resection.[14]

11.6 MEDICAL MANAGEMENT No drug therapy is proven or recommended for colonic polyps. Some studies in the past had demonstrated that medical treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the number and size of polyps. However, a recent meta analysis from China has concluded that aspirin might prevent the development of colorectal adenomas, but there is no evidence to support that sulindac and celecoxib might cure or prevent colorectal adenomas or familial adenomatous polyposis, or that regular aspirin use might reduce the risk of colorectal cancer.[18]

11.7 SURGICAL OPTIONS 11.7.1 Polypectomy In the case of a solitary pedunculated polyp, colonoscopic removal can be performed concurrently with the search for other lesions. Removal of a solitary polyp is probably curative. However, a complete colonoscopic examination should be performed because the finding of a single adenomatous polyp confers an increased risk for the development of others. The rate of polyp recurrence (discovered at follow-up colonoscopy) at 1-year postpolypectomy is small, and recurrence may in fact represent missed synchronous lesions. Endoscopic procedures of the large bowel reduce the risk for developing colon and rectal cancer by 50%, their protective influence lasting 6 years.[19] The efficacy of removal of pedunculated polyps by polypectomy can usually be accurately assessed by histology. In contrast, sessile lesions are often

removed in pieces or have cautery artifacts precluding correct determination of the resection margin. If the endoscopist is uncertain whether a lesion has been eliminated, follow-up colonoscopy at about 6 months to one year may be advisable (a shorter period if malignancy is suspected). Otherwise, most gastroenterologists advocate repeat colonoscopy 3 years following complete removal of an adenomatous polyp. If no polyps are found at the initial examination, follow-up colonoscopy at 5 year intervals is recommended.

11.7.2 Colonic Resection (Fig. 11.2) In patients with multiple intestinal polyps associated with FAP, resection remains the only feasible option. Surgical options include total colectomy versus rectum sparing subtotal colectomy. Colectomy with mucosal proctectomy and ileoanal pouch pull-through is the procedure of choice at many centers. This procedure allows retention of rectal function. Sigmoidoscopic surveillance and ablation of any polyps in the retained rectum or ileal pouch

FIGURE 11.2 Right hemicolectomy specimen showing a cecal lipoma in a patient who presented with bleeding. Right: The tumor cut open.

Tropical Hepatogastroenterology

PROGNOSIS

should be performed every 3–6 months in patients with FAP, who have undergone an operation. Because of the inability to control polyps medically, eventual rectal resection is usually necessary. The other option of total proctocolectomy with ileostomy is usually not acceptable to most patients.

11.8 PROGNOSIS Colonic polyps are curable if removed. If not treated, the patient may develop complications such as bleeding, and the condition may even be fatal if malignant transformation occurs. Fortunately, polyps grow slowly; cancer development

219

is estimated to occur usually about 10 years after the formation of a small polyp. Patients with FAP must be aware of the potential benefits of screening family members, beginning at puberty, for the mutant APC gene. Screening is particularly important because of the inevitable development of colon cancer in affected individuals and the benefits associated with colonic resection. The ability to prevent colon cancer by polypectomy implies a responsibility to do so when possible. No screening tool is 100% effective; inevitably, polyps will be missed. However, once detected, ensuring that the lesion does not develop into a cancer is generally within the physician’s ability.

REFERENCES [1] Miller BA, Kolonel LN, Bernstein L et al. eds. Racial/Ethnic Patterns of Cancer in the United States 1988–1992, National Cancer Institute. National Institutes of Health Publication No. 96-4104. Bethesda, MD: National Cancer Institute, National Institutes of Health; 1996. [2] Rajendra S, Ho JJ, Arokiasamy J. Risk of colorectal adenomas in a multiethnic Asian patient population: race does not matter. J Gastroenterol Hepatol. 2005; 20:51–5. [3] Johnson H Jr, Margolis I, Wise L. Site-specific distribution of large-bowel adenomatous polyps. Emphasis on ethnic differences. Dis Colon Rectum. 1988;31:258–60. [4] Lin OS, Gerson LB, Soon MS et al. Risk of proximal colon neoplasia with distal hyperplastic polyps: a meta-analysis. Arch Intern Med 2005;165: 382–90. [5] Cappell MS. The pathophysiology, clinical presentation and diagnosis of colon cancer and adenomatous polyps. Med Clin North Am 2005;89:1–42. [6] Bussey HJR. Genetic and epidemiological features

Part IV / Large Bowel

[7] [8]

[9]

[10]

[11]

[12]

of familial polyposis coli. In: Bussey HJR, ed. Familial Polyposis Coli. Baltimore, Md: Johns Hopkins University Press; 1975;9–17. Jo WS, Chung DC. Genetics of hereditary colorectal cancer. Semin Oncol. 2005;32:11–23. Nandakumar G, Morgan JA, Silverberg D et al. Familial polyposis coli: clinical manifestations, evaluation, management and treatment. Mt Sinai J Med 2004;71:384–91. Poddar U, Thapa BR, Vaiphei K et al. Colonic polyps: experience of 236 Indian children. Am J Gastroenterol 1998;93:619–22. Oncel M, Church JM, Remzi FH et al. Colonic surgery in patients with juvenile polyposis syndrome: a case series. Dis Colon Rectum 2005;48: 49–55. Bhargava DK, Rai RR, Dasarathy S et al. Colonoscopy for unexplained lower gastrointestinal bleeding in a tropical country. Trop Gastroenterol 1995;16:59–63. Burke CA, Beck GJ, Church JM. The natural history of untreated duodenal and ampullary adenomas

220

Chapter 11 / BENIGN COLORECTAL TUMORS

in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc 1999;49:358–64. [13] Powell SM, Petersen GM, Krush AJ. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982–7. [14] Rockey DC, Paulson E, Niedzwiecki D et al. Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison. Lancet 2005;365(9456): 305–11. [15] Kawamura YJ, Sasaki J, Okamaoto H et al. Clinical significance of virtual colonoscopy (CT colonography) with special reference to polyp morphology. Hepatogastroenterology 2004;51:1686–8.

[16] Iannaccone R, Laghi A, Catalano C et al. Computed tomographic colonography without cathartic preparation for the detection of colorectal polyps. Gastroenterology 2004;127:1300–11. [17] Ajaj W, Lauenstein TC, Pelster G et al. MR colonography in patients with incomplete conventional colonoscopy. Radiology 2005;234:452–9. [18] Wang YP, Wang Q, Gan T et al. Nonsteroidal anti-inflammatory agents for chemoprevention of colorectal polyps: a meta-analysis. Zhonghua Nei Ke Za Zhi 2004;43:10–2 (Abstract). [19] Muller AD, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 1995;123:904–10.

Tropical Hepatogastroenterology

Chapter

12 MALIGNANT COLORECTAL TUMORS Atul K Sharma

12.1 INTRODUCTION The large bowel is a leading site for cancers in developed countries. The incidence varies in the tropics. The epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. If detected early, colorectal cancer is curable by surgery, however, most patients in the tropics report late, with locally advanced lesions. Adjuvant chemotherapy can prolong survival in disease that has reached the lymph nodes. Perioperative radiotherapy is used in rectal cancer to reduce the risk of local recurrence. Long-term survival correlates with stage of disease.

12.2 EPIDEMIOLOGY Colorectal cancer (CRC) is a leading cause of cancer mortality in the Western world, with more than 1,000,000 new cases per year, an estimated lifetime risk of 5%–6%, and nearly 50% mortality.[1, 2] Adenocarcinomas (98%) comprising the large majority. Rare colorectal cancers include carcinoid (0.1%) (Fig. 12.1), lymphoma (1.3%), sarcoma (0.3%), and melanoma. The incidence of large bowel cancer is low in India, and rectal cancer is more common than colon cancer. The frequency of colon cancer varies from

FIGURE 12.1 Right hemicolectomy specimen showing a carcinoid of the cecum (arrow).

0.7 to 3.7/100,000 among men and 0.4 to 3/100,000 among women. For rectal cancer, the incidence rates range from 1.6 to 5.5/100,000 among men and 0 to 2.8/100,000 among women.[3] The high rates of rectal cancers in young Indians could suggest 221

222

Chapter 12 / MALIGNANT COLORECTAL TUMORS

a different etiopathogenesis, neither inherited nor traditional diet-related. Rural incidence rates for large bowel cancers in India are approximately half of urban rates. The increase in the incidence of large bowel cancers in immigrants and urban Indians compared to rural populations supports a role for environmental risk factors including diet. In a 10-year study on the examination of surgical specimens of colorectal malignancy, in Nigerians, colorectal carcinoma was found to constitute 80% of large bowel malignancies. The male: female ratio was 2.28:2. Most patients (65.9%) were 50 years or younger, and the peak incidence was in the 41–50 year age group.[4] In the west, the incidence peaks in the seventh decade. The above observations also suggest a difference in the biology of colorectal carcinomas in the tropics. The association with chronic granulomatous diseases may be indicative of an entirely different oncogenic mechanism. The demography of colorectal cancer from Malaysia was also found to be different from western patients. Tumors were mainly left sided in these patients. However, no differences in anatomic location were found between races, men and women, and younger and older age groups. Colorectal cancer presented in an advanced stage in the majority of patients.[5]

12.3 ETIOPATHOGENESIS Colorectal cancer typically results from a complex interaction between genetic and environmental influences.

12.3.1 Genetic Changes Most colorectal cancers are adenocarcinomas, and arise from preexisting adenomatous polyps that develop in the normal colonic mucosa.

This adenoma-carcinoma sequence is a wellcharacterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated.[6] Pioneering work by Bert Vogelstein and colleagues over the last 15 years has identified a number of critically important genetic alterations that contribute, through their multiplicity over many years, to the eventual development of colorectal cancer. The earliest event appears to involve the adenomatous polyposis coli (APC) gene, which is mutated in individuals affected by familial adenomatous polyposis (FAP). The protein encoded by the APC gene targets the degradation of beta-catenin, a protein component of a transcriptional complex that activates growthpromoting oncogenes, such as cyclin D1 or c-myc. In sporadic colorectal cancer, APC mutations are very common and beta-catenin mutations have also been identified. DNA methylation changes are a relatively early event, and have been detected at the polyp stage. Colorectal cancers and polyps have an imbalance in genomic DNA methylation, with global hypomethylation and regional hypermethylation. Hypomethylation can lead to oncogene activation, whereas hypermethylation can lead to silencing of tumor suppressor genes. Ras gene mutations are observed commonly in larger polyps but not in smaller polyps, suggesting a role for this oncogene in polyp growth. Chromosome arm 18q deletions are a later event associated with cancer development. These deletions are likely to involve the targets DPC4 (a gene deleted in pancreatic cancer and involved in the transforming growth factor [TGF]-beta growth-inhibitory signaling pathway) and DCC (a gene frequently deleted in colon cancer). Chromosome arm 17p losses and tumor suppressor p53 mutations are common late events in colon cancer. Bcl2 overexpression leading to inhibition of cell death

Tropical Hepatogastroenterology

ETIOPATHOGENESIS

signaling has been observed as a relatively early event in colorectal cancer development. 18q deletions detected in Dukes stage B colon cancers have been associated with an increased risk of recurrence following surgery, and studies are in progress to determine whether patients with 18q deletions might benefit from more aggressive adjuvant chemotherapy. Another predisposing condition is hereditary nonpolyposis colon cancer, in which affected individuals inherit a mutation in one of the several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. Ras gene mutations have been detected in the stool of patients with colorectal cancer, and may in the future be useful in early diagnosis.

12.3.2 Hereditary Syndromes and Predisposing Conditions As many as 25% of patients with colorectal cancer have a family history of the disease, which suggests the involvement of a genetic factor. Such inherited colon cancers can be divided into two main types: the well-studied but rare familial adenomatous polyposis (FAP) syndrome, which accounts for approximately 1% of cases of colon cancer annually, and the increasingly well-characterized, more common hereditary nonpolyposis colorectal cancer (HNPCC), which accounts for 5% to 10% of cases.[7] 12.3.2.1 Familial adenomatous polyposis

FAP formerly known as familial polyposis coli (FPC) or hereditary adenomatosis of the colon and rectum, is an autosomal dominant disorder, responsible for the widespread development of adenomas which carpet the colon and rectum.[8] FAP was first linked to extracolonic manifestations in 1923 by Nichols, when he commented

Part IV / Large Bowel

223

on the association of FAP and desmoid tumors. In 1951, Gardner described the occurrence of FAP with the extracolonic manifestations of intestinal polyposis, desmoids, osteomas, epidermoid cysts, pigmented retinal lesions, upper gastrointestinal tract polyps, and periampullary cancers (Gardner syndrome) or brain tumors (Turcot syndrome).[7] Because the genetic defect in the germline of patients with FAP has been well characterized, syndromes once thought to be distinct from FAP are now recognized to be, in reality, part of the phenotypic spectrum of FAP. Syndromes with a germline mutation in the adenomatous polyposis coli gene (APC) include FAP, Gardner syndrome, some Turcot syndrome families, and attenuated adenomatous polyposis coli (AAPC). Estimates of the incidence of FAP in the US vary from one in 6,850 to one in 31,250 persons. The frequency is constant worldwide, and FAP has been described in all races. It is due to congenital inheritance in a Mendelian dominant fashion in 80% of patients. The remaining 20% represent spontaneous mutations, with no family history reported. The male: female ratio is 1:1. Persons with FAP are born with normal-appearing colonic mucosa, and the average age of onset of polyposis in FAP is 16 years; the average age of onset for colorectal cancer is 39 years. The average age of onset for polyps in AAPC is 36 years, and the average age of onset for cancer in AAPC is 54 years.[9] FAP is associated with a deletion of chromosome 5q21 also known as the APC gene in neoplastic cells (somatic mutation) and normal cells (germline mutation); this deletion apparently leads to abnormal proliferative patterns in the colonic mucosa.[10, 11] Mutations at the far 5’ end and the far 3’ end, and occasional specific mutations in other areas of the APC gene result in an attenuated form of FAP characterized by fewer adenomas, a proximal colonic distribution of polyps, a somewhat delayed development of

224

Chapter 12 / MALIGNANT COLORECTAL TUMORS

adenomas and cancer, and a decreased colon cancer risk.[12] Genetic testing is now the standard of care for FAP. Despite the detailed genetic knowledge of FAP that is now available, genetic testing is often poorly interpreted. Consequently, genetic counseling is an integral part of management and should precede genetic testing.[13] Testing for FAP in a family is most informative when it begins with the affected family member, to identify the mutation responsible for FAP within that family. Once a causal mutation has been identified in an affected person, predictive testing can be done to identify other family members at risk. DNA testing for APC gene mutations has a sensitivity of 70% to 90% and a specificity of 100%. If the test result is positive or the test is not available, flexible sigmoidoscopy is performed at 10 to 12 years of age. During the procedure, mucosal biopsy specimens are taken to identify subtle adenomatous changes. Colonoscopy with mucosal biopsies is advisable at 18 to 20 years of age. If adenomas are detected, surgical prophylaxis should be considered. Routine gastroduodenoscopic surveillance is also recommended for patients with FAP, because these patients are at high risk for potentially precancerous gastric and duodenal adenomas. 12.3.2.2 Hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is also an autosomal dominant disorder however, the median age at which adenocarcinomas appear in HNPCC is below 50 years, which is 10 to 15 years lower than the age at which they appear in the general population.[14, 15] HNPCC is associated with a high frequency of cancers in the proximal large bowel. Also, families with HNPCC often include patients with multiple

primary cancers in which endometrial or ovarian carcinoma is especially prominent. Several criteria have been developed for identifying patients with this syndrome. The Amsterdam-2 criteria comprise the following: histologically documented colorectal cancer (or other HNPCC-related tumor) in at least three relatives, one of whom is a first-degree relative of the other two; a family history of one or more cases of colorectal cancer diagnosed before 50 years of age; and cases of colorectal cancer in at least two successive generations of the family. Affected relatives should be on the same side of the family (maternal or paternal), FAP must be excluded in colorectal cancer cases, and tumors must be pathologically verified. The Bethesda criteria are more sensitive than the Amsterdam criteria but are less specific. These selection criteria were developed to identify patients whose tumors should be tested for features consistent with HNPCC, such as microsatellite instability (MSI).[16, 17] In a recent study of the mutation profile, in hMSH2 and hMLH1 genes in HNPCC patients in India, MSS or MSI-L were found to be low incidence regions for most of the early-onset colon (4/7) and early-onset rectal (15/21) cancers.[18] In addition to testing for MSI, genetic testing is available for two mismatch repair genes, hMSH2 and hMLH1, which account for about 60% of all HNPCC cases. Unfortunately, tests for mutations of hMSH2 and hMLH1 are not perfectly sensitive, and genetic sequencing is expensive. The discovery of a mutation in a family provides a rationale for predictive testing for at-risk family members, although such testing may cause the unaffected individuals unnecessary concern and lead to unnecessary screening procedures.[19] If HNPCC is confirmed, affected family members should undergo colonoscopy between the ages of 20 and 25 or at the age, 10 years younger than the

Tropical Hepatogastroenterology

ETIOPATHOGENESIS

youngest age at diagnosis in the family, whichever is earlier. This procedure should be repeated every 1 to 2 years.[20] If an adenoma or adenocarcinoma of the colon is identified, total abdominal colectomy with an ileorectal anastomosis is recommended. 12.3.2.3 Adenomatous polyps (Adenomas)

Epidemiological evidence suggests that colorectal cancer develops from premalignant adenomatous polyps. Recent evidence suggests that serrated adenomas, hyperplastic polyps, and admixed polyps may arise through a pathway different from that of conventional adenomatous polyps, i.e., through abnormalities in mismatch repair.[6] Adenomatous polyps are grossly visible, glandforming mucosal protrusions that may be pedunculated. Histologically, adenomatous polyps may be tubular, villous or tubulovillous. The larger the adenoma, the greater the likelihood that a villous component will be present. Villous polyps are more likely to contain invasive carcinoma than are tubular polyps of the same size. The risk of cancer depends upon the size and histologic type of the polyp. A tubular adenoma smaller than 1 cm in diameter has < 5% risk, whereas the risk of cancer in a tubular adenoma larger than 2 cm is 35%. A villous adenoma larger than 2 cm carries 50% chance of containing a cancer.[21] Autopsy studies have demonstrated that adenomatous polyps are present in more than 30% of persons older than 50 years, and that their prevalence increases with age. However, less than one percent become malignant. Synchronous lesions occur in approximately 33% of cases. Patients in whom one adenomatous polyp is detected have a 30% to 50% risk of developing another adenoma and are at higher than average risk for colorectal cancer. The risk of subsequent colon cancer appears to depend on the histologic type,

Part IV / Large Bowel

225

size, and number of adenomas found at the time of initial examination. It is thought that adenomatous polyps require more than 5 years of growth before they become clinically significant. 12.3.2.4 Inflammatory bowel disease

Long-standing, extensive inflammatory bowel disease, including both ulcerative colitis (UC) and Crohn colitis, increases the risk of colon cancer. A recent retrospective cohort study from, Vellore, India, revealed that risk of developing CRC in Indian patients with UC is lower than that reported from the West. The incidence density and risk of developing either CRC or high-grade dysplasia is reportedly zero in the first 10 years of disease. In those with disease duration of 10–20 years, the incidence was 2.34 per 1000 person years’ duration (PYD) for all patients with colitis and 4.5 per 1000 PYD for patients with pancolitis alone. This corresponded to risks of 2.3% and 4.4%, respectively. For those with disease duration longer than 20 years, incidence density was 2.73 per 1000 PYD for all patients and 4.9 per 1000 PYD for patients with pancolitis. This corresponded to risks of 5.8% and 10.2%, respectively. Strategies for cancer surveillance in Indian patients with UC need to be tailored accordingly.[22] In the west, surveillance colonoscopy with multiple biopsies of the entire colon should be considered every 1 to 2 years after 8 years of disease in patients with pancolitis or after 15 years in those with left-sided colitis. Colectomy must be carefully considered in each case, depending on the biopsy results.[20]

12.3.3 Environmental Factors 12.3.3.1 Role of diet

Both the total energy intake and individual components of diet have a role in the etiology

226

Chapter 12 / MALIGNANT COLORECTAL TUMORS

of colorectal cancer. The relationship between total energy intake and colorectal cancer risk is possibly related to increased levels of endogenous hormones such as sex steroids, insulin, and insulin-like growth factor. A prospective study of a large United States cohort suggested that a high body mass index is a significant risk factor for the development of colorectal cancer.[23] (a) Fat: Epidemiologic and experimental evidence suggests that diets high in total fat may increase the risk of colorectal cancer. Dietary fat is thought to increase the concentration of bile acid in the bowel or to promote the formation of excess intraluminal diacylglycerol as a result of the interaction of fat, bile acids, and bacteria.[24] The effect of diacylglycerol may be to amplify cell-replication signals.[25] (b) Red meat: Data concerning the association of red meat intake with increased risk of colorectal cancer is not entirely consistent. The Nurses’ Health Study reported that frequent consumption of red meat increased the risk of colon cancer.[26] However, two other large prospective studies: the American Cancer Society’s Cancer Prevention Study II and the Iowa Women’s Health Study, revealed increase in risk with meat or fat consumption.[27, 28] It is thought that the heterocyclic amines formed when fish or meat is cooked at high temperature may contribute to increased risk, but the mechanisms are not well understood. (c) Dietary fiber, vegetables and fruit: The role of dietary fiber in carcinogenesis of the large bowel also remains controversial. A metaanalysis of 13 case-control studies from nine countries concluded that intake of fiber-rich foods is inversely related to cancers of both the colon and the rectum.[29] However, results

from the Nurses’ Health Study found no difference in risk of colorectal cancer with respect to dietary fiber.[30] In a multicenter, randomized, controlled trial, a diet low in fat and high in fiber, fruits and vegetables did not reduce the risk of recurrence of colorectal adenomas.[31] High-fiber cereal supplements also did not influence the rate of recurrence of colorectal adenomas.[32] Another prospective study utilized food-frequency questionnaires to study dietary intake in 88,764 women and 47,325 men; no association was found in men or women between overall fruit and vegetable consumption and risk of colon or rectal cancer.[33] (d) Folate and methionine: Leafy vegetables and fruits are rich in folate, and meat, chicken, and fish have high concentrations of methionine, both of which supply the methyl groups necessary for nucleotide synthesis and gene regulation. Both the level and duration of intake are important. A number of studies support an inverse association between dietary folate or methionine intake and the risk of colorectal adenomas and carcinomas.[34] (e) Antioxidants: The postulation that antioxidants such as retinoids, carotenoids, ascorbic acid, α-tocopherol, and selenium prevent carcinogen formation by neutralizing free radicals is difficult to confirm because antioxidants are present in common foods such as fruits and vegetables. ß-Carotene may reduce the risk of adenoma recurrence in nonsmokers but increases the risk in those who both smoke and drink. (f) Calcium: Epidemiologic and experimental studies have shown an inverse relationship between calcium intake and cancer risk.[35] Calcium may indirectly inhibit colorectal cancer by binding bile acids into insoluble soaps,

Tropical Hepatogastroenterology

SCREENING FOR COLORECTAL NEOPLASIA

thereby blocking contact with the luminal epithelium. A randomized, placebo-controlled trial tested the effect of supplementing 3 g of calcium carbonate daily, on the risk of recurrent adenoma.[36] The effect was modest and supplemental calcium reduced the risk of recurrence by 19%. 12.3.3.2 Role of drugs

The ability of certain drugs or chemicals to reduce the incidence of colorectal cancer has been demonstrated in epidemiologic studies. Some of the commonly used drugs are: (a) Hormone replacement therapy: In a metaanalysis of 18 epidemiologic studies, postmenopausal hormone replacement therapy (HRT) was associated with 33% reduction in the risk of colon cancer in recent users. The relative risk was 0.67, compared with a relative risk of 0.92 in women who had used HRT more than 1 year ago.[37] (b) NSAIDs: A 30% to 40% reduction in colorectal cancer has been reported in regular users of aspirin.[38, 39] Patients with prior colorectal cancer, who had undergone curative resection and were given 325 mg of aspirin a day over 13 months, had a 35% reduction in risk of recurrent adenoma, compared with those given a placebo.[40] In a study of patients with advanced colonic neoplasms, ingestion of 81 mg of aspirin a day for an average of 3 years reduced the risk of recurrence by 41%.[41] 12.3.3.3 Lifestyle factors

(a) Physical activity: An inverse relationship has been found between physical activity and the incidence colon cancer. The relative risk reduction on regular physical activity of

Part IV / Large Bowel

227

2 hours or more a week is 40%.[42] The mechanism of protection may be linked to effects on colonic mucosal prostaglandins. (b) Smoking: The Cancer Prevention Study II has observed an increased risk of colon cancer after 20 years or more of smoking. The mortality was highest in current smokers, intermediate in former smokers, and lowest in those who never smoked. In the Nurses’ Health Study, the minimum induction period for cancer appears to be at least 35 years.[43, 44]

12.4 SCREENING FOR COLORECTAL NEOPLASIA The rationale for screening for colorectal neoplasia is two-fold. First, screening detects adenomas and permits their removal, which prevents subsequent development of colorectal cancer. Second, screening detects localized, superficial tumors in asymptomatic individuals which should increase the surgical cure rate.[45] Despite the acknowledged benefits of screening, the majority of population in tropics does not undergo screening for colorectal cancer. Of the four screening tests currently in use, fecal occult blood testing (FOBT) is supported by the strongest evidence. Intermediate-level evidence is available for flexible sigmoidoscopy, and only indirect evidence supports the use of colonoscopy and double-contrast barium enema.

12.4.1 Fecal Occult Blood Testing Meta-analyses of mortality results, from randomized controlled trials, show that patients screened with FOBTs had a decrease in colorectal cancer mortality of 16%. When adjusted for screening attendance in the individual studies, this reduced the mortality by 23%.[46]

228

Chapter 12 / MALIGNANT COLORECTAL TUMORS

Estimates of the sensitivity of FOBT have ranged from 25% to over 90%. Newer tests include the use of enhanced guaiac reagents, which improve sensitivity with minimal loss of specificity, if recommended dietary measures are followed. The sensitivity of immunochemical FOBTs is better than that of guaiac-based tests, without an unacceptable decline in specificity. Newer immunochemical FOBTs are also more user friendly, can be read by automated techniques, and do not require any alteration in diet or medication.[47]

12.4.2 Endoscopic Screening Tests 12.4.2.1 Flexible sigmoidoscopy

A number of studies have demonstrated a risk reduction ranging from 60% to 70% for death from cancers within reach of the sigmoidoscope, and the data suggests that the benefit may last as long as 10 years. Sigmoidoscopy detects 70% to 85% of advanced lesions in the entire colon, and patients with an apparently normal sigmoidoscopy have 1% to 2% risk of an advanced proximal lesion.[48] Proximal adenomas were detected in 19% of those undergoing colonoscopy, and proximal cancer was detected in 0.4%; 62% of cancers were Dukes stage A. There was one perforation after flexible sigmoidoscopy, and four after colonoscopy.[49] Combining FOBT with flexible sigmoidoscopy is a recognized approach to screening, but the data regarding the impact on mortality are limited. 12.4.2.2 Colonoscopy

Several studies have demonstrated that colonoscopic polypectomy lowers the incidence of colorectal cancers by 50% to 90%.[50, 51] The American Cancer Society currently recommends colonoscopy every 10 years, starting at the age

of 50, for asymptomatic adults at average risk for colorectal cancer.[52] Repeat examinations at more frequent intervals are indicated for patients at increased or high risk.

12.4.3 Emerging Technologies for Screening (a) Molecular detection methods: It has been technically feasible to detect APC and p53 mutations, long DNA, and K-ras mutations in the stool for over a decade.[53, 54] Rightsided lesions can in addition be detected by the identification of BAT-26 mutations. The cost of such techniques is high, and it remains to be proved whether their use will be cost-effective relative to other techniques, including newer immunochemical tests. (b) Virtual colonoscopy (Computed tomography colonography): Sophisticated graphic software is able to assemble, from a fast CT scan, an endoluminal image that includes surface and volume characteristics. Recent data from patients at increased risk suggest a sensitivity of 90% for lesions larger than 1 cm however, it remains to be seen whether similar results can be attained in general screening use. Advances in this technique include the possibility that patients may not need extensive bowel preparation. Cost analysis suggests that CT colonography is unlikely to be cheaper than colonoscopy or other screening modalities.[55]

12.5 DIAGNOSIS 12.5.1 Clinical Features Fifty percent of patients present with abdominal pain, 35% with altered bowel habits, 30% with occult bleeding, and 15% with intestinal obstruction. The symptomatology of patients with

Tropical Hepatogastroenterology

DIAGNOSIS

FIGURE 12.2 Carcinoma, ascending colon in a 55-year-old female. The tumor had caused intestinal obstruction. Proximal to the obstruction there was necrosis of the wall with perforation (H - hepatic flexure, G - gangrenous patch, C - cecum, I - terminal ileum). On the right is the tumor seen after opening the specimen.

colorectal cancer varies with the location of the tumor. Right-sided colon cancers (Fig. 12.2) tend to be larger and more likely to bleed, whereas leftsided tumors tend to be smaller and more likely to obstruct. Lesions in the cecum and ascending colon can become large and palpable, and may markedly narrow the bowel lumen without causing any obstructive symptoms or altering bowel habits. Lesions in the ascending colon frequently ulcerate, leading to chronic blood loss in the stool and subsequent anemia. Cancers arising in the transverse colon may cause abdominal cramping, occasional obstruction, and even proximal perforation. Cancers developing in the rectosigmoid are commonly associated with narrowing of the stool, chronic intestinal obstruction and hematochezia. Although, many early rectal cancers produce no symptoms, and are discovered during dig-

Part IV / Large Bowel

229

ital or proctoscopic screening examinations in the west, such programs are virtually nonexistent in the tropics. Bleeding per rectum is the most common symptom of rectal cancer and occurs in 60% of patients. Profuse bleeding is rare, and may be accompanied by the passage of mucus. It is often attributed to other causes such as hemorrhoids, and warrants further investigation. A change in bowel habits is found in about 40% of patients with rectal cancer, and has several different presentations. Often, it presents as diarrhea, especially if the tumor has a large villous component. These patients may even develop hypokalemia. Tumors located low in the rectum may cause a feeling of incomplete evacuation and tenesmus. Altered bowel habits, rectal bleeding or both mandate a digital rectal examination and colonoscopy. The colonoscopy will document the cancer and allow a biopsy. The colonoscopy should be followed by a CT scan (Fig. 12.3).

12.5.2 Tumor Spread, Staging, and Prognosis The prognosis of patients with colorectal cancer depends on the depth of tumor penetration into the bowel wall, and the presence or absence of regional lymph node involvement and distant metastases. The staging system introduced by Dukes, and later modified by Kirklin, Astler and Coller, incorporates these prognostic variables. More recently, the Dukes system has been applied to the TNM classification method, and these staging systems subdivide colorectal cancer into the following categories.[56] 12.5.2.1 Stage A (T1N0M0)

These are superficial lesions that do not penetrate the muscularis and do not involve regional lymph nodes.

230

Chapter 12 / MALIGNANT COLORECTAL TUMORS

FIGURE 12.3 CECT abdomen showing a concentric irregular thickening (arrow) of the wall of the ascending colon with luminal narrowing. There is stranding of the pericolic fat planes indicating inflammation.

12.5.2.2 Stage B

These are tumors that penetrate more deeply into the bowel wall without lymph node involvement. Stage B is subdivided into stage B1 (T2N0M0), in which the tumor is restricted to the muscularis, and stage B2 (T3-4N0M0), in which the tumor penetrates into or through the serosa. 12.5.2.3 Stage C

These are tumors that involve regional nodes; they are sub divided, in a manner analogous to stage B lesions, into stage C1 (T2N1M0) and stage C2 (T3-4N1M0). 12.5.2.4 Stage D

These are tumors that have metastasized to liver, lung, bone, or other anatomically distant sites (TXNXM1). In the absence of obvious evidence of metastatic disease, the stage of the disease can be accurately determined only after resection and histopathologic analysis of the specimen.

TABLE fy 12.1 Stage and prognosis of colorectal cancer Dukes stage

TNM stage

Five-year survival (%)

A B1 B2 C1 C2 D

T1 N0 M0 T2 N0 M0 T3–4 N0 M0 T2 N1 M0 T3 N1 M0 TX NX M1

> 95 85 70–75 35–65 As above 4 weeks to 24 weeks Subclassification I. Etiological to indicate specific cause of AHF. II. Temporal to indicate the rapidity of encephalopathy. Hyperacute – Encephalopathy within 10 days of icterus. Fulminant – Encephalopathy between 10 days and 30 days of the onset of jaundice. III. Not otherwise specified. Example (AHF, hyperacute –A)

hepatitis A or B are hyperacute. Most cases due to nonacetaminophen drug reactions and non-A non-B hepatitis are acute or subacute in onset. In contrast to these observations, all patients seen in India present with encephalopathy within 3 weeks of the onset of jaundice and 4 weeks of the onset of prodromal symptoms. The International Association for the Study of the Liver (IASL) has defined ALF as “a potentially reversible, often sudden, persistent, and progressive liver dysfunction (in the absence of pre-existing liver disease) characterized by the occurrence of encephalopathy within 4 weeks from the onset of symptoms.”[5] The rapidity of onset of encephalopathy does not influence survival.[6, 7] Liver failure occurring more than

4 weeks after the onset of an acute hepatic illness manifests with progressive ascites and preterminal encephalopathy, and is labeled as subacute hepatic failure (SHF). The mortality rate of this group of patients is 70%; among the survivors, 60% develop chronic liver disease.[8] Similar patients have been described from the West as having late onset hepatic failure (LOHF).[9] The nomenclature and definitions provided by the IASL subcommittee has been depicted in Table 28.1.

28.2 COMPLICATIONS AND SEQUELAE OF ALF The survival frequency of the patients at our center is approximately 33%. Two-thirds of all deaths occur within the first 72 hours of hospitalization, and the median survival time is 4 days.[6, 7]

28.2.1 Cerebral Edema The cranium is a rigid container containing three relatively noncompressible compartments: brain substance, cerebrospinal fluid (CSF), and the intravascular blood. As the volume of any one compartment increases, there must be a compensatory decrease in the volume of the others, if the intracranial pressure (ICP) is to remain stable. The major cause of increased ICP in ALF is an increase in the brain water content. With increasing swelling of the brain parenchyma, the intracranial CSF shifts into the spinal subarachnoid space and the venous blood volume in the dural sinuses diminishes. Cerebral arterial blood flow may also diminish. These compensatory changes reflect the intracranial compliance. With further brain swelling, the intracranial compliance diminishes and even small volume changes of any compartment can lead to a precipitous rise in the ICP.

Tropical Hepatogastroenterology

COMPLICATIONS AND SEQUELAE OF ALF

Brain is protected by blood brain barrier (BBB) from changes in the blood concentration of various substances that may interfere with neurotransmission. Many lipid soluble and small polar molecules (< 0.8 nm) cross the BBB easily, while larger molecules are excluded. The exceptions are metabolically important substances like glucose, lactate, and amino acids which cross the BBB by facilitated or active transport. Hence, unlike peripheral tissues the water flux across the BBB is determined not only by the protein concentration (i.e., oncotic pressure), but also the concentration of the solutes (i.e., osmotic pressure).[10] Glutamine which accumulates in the astrocytes and extracellular space as a result of ammonia detoxification in the brain, acts as an organic osmolyte and draws water into the brain. In experimental models of ALF, ammonia induced cerebral edema can be prevented by an inhibitor of glutamine synthetase – methionine sulfoximine.[11] Replacement of fluid losses with hypertonic or isotonic glucose infusion, or sodium free albumin may aggravate brain edema as the plasma sodium decreases. Hyponatremia is a predictor of poor outcome for patients with ALF,[12, 13] and a recent study has shown that hypernatremia ameliorates cerebral edema.[14] The second important determinant of brain water is the capillary hydrostatic pressure as reflected by the cerebral blood flow (CBF). CBF correlates very closely with the brain water and ICP in experimental ammonia-induced brain edema.[15] Normally, in brain, autoregulation can maintain a normal CBF at arterial pressures from 65 to 140 mmHg. This autoregulation of cerebral blood flow (CBF) is lost in ALF, and signifies that even mildly elevated cerebral perfusion pressure (CPP) will increase CBF and hydrostatic pressure across the BBB; while episodes of arterial hypotension may stop capillary blood flow leading

Part VI / Liver Failure

427

to cerebral hypoxia. This phenomenon has been called ‘dissociated cerebral vasoparalysis’.[16] CBF is variable in ALF, and may be excessive at some point of time, and inadequate at others. CBF is reduced in most patients with grade 3 or 4 encephalopathy, even with maintained mean arterial pressure.[17] However, increased CBF precedes high ICP and cerebral herniation.[18, 19] This loss of CBF autoregulation is rare in patients with cirrhosis or sepsis. In addition, there may be a gradual decrease in the cerebral arteriolar tone leading to gradual cerebral hyperemia and increase in the hydrostatic pressure gradient in the cerebral capillaries. Cerebral autoregulatory capacity is restored after liver transplantation. Raised ICP can lead to two deleterious consequences: (1) compromise of cerebral blood flow with resultant brain ischemia; (2) compression and displacement of brain stem or cerebellum leading to cingulate, uncal or cerebellar herniation. Clinical manifestations of raised ICP commonly occur with levels of more than 30 mmHg (Table 28.2), but there is a poor correlation between the level of ICP and specific clinical signs. The presence of cerebral edema can be defined clinically by spontaneous or inducible decerebrate posturing, or by the presence of any two of the following: hypertension (BP≥ 150/90 mmHg), bradycardia, pupillary changes, or neurogenic hyperventilation.[6, 7]

TABLE fy 28.2 Clinical features of raised ICPy • • • • • •

Hyperventilation Bradycardia Arterial hypertension (Cushing reflex) Terminal hypotension Terminal respiratory arrest

• • • • • •

Agitation Increased muscle tone Decerebrate rigidity Myoclonus Seizures Abnormal pupillary reflexes

428

Chapter 28 / ACUTE LIVER FAILURE

Cerebral edema is the most common cause of mortality. In India 58% of ALF patients have cerebral edema at the time of hospitalization. The mortality rate of patients with cerebral edema is 82% as compared to 44% among patients without cerebral edema.[6, 7]

28.2.2 Encephalopathy Accumulation of ammonia, disturbance of central glutamatergic, serotoninergic, and noradrenergic pathways, production of false neurotransmitters, activation of central gamma-amino butyric acid (GABA) and benzodiazepines (BZD) receptors and altered cerebral energy metabolism may be important in the genesis of hepatic encephalopathy in ALF.[20] There is evidence of increased blood-brain ammonia transfer and brain ammonia utilization rates in patients with ALF. Brain-blood ammonia concentration ratios (normally of the order of 2) are increased up to fourfold in liver failure, and arterial blood ammonia concentrations are good predictors of cerebral herniation in patients with acute liver failure.[20, 21] The brain does not have a urea cycle and relies on glutamine synthesis in astrocytes for the removal of excess ammonia. Increased intracellular glutamine in the astrocytes may be a contributory cause of brain edema in hyperammonemia. Damage to astrocytes characterized by cell swelling (acute liver failure) or Alzheimer Type II astrocytosis (chronic liver failure) can be readily reproduced by acute or chronic exposure of these cells in vitro to ammonia. In addition to changes in astrocyte morphology, increased brain ammonia concentrations also result in altered expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters, and “peripheral-type” (mitochondrial) BZD receptors. Accumulation of ammonia in brain

results in a redistribution of cerebral blood flow from cortical to subcortical structures, and has direct effects on neurotransmission.[22] Increased ammonia concentration (following upregulation of the peripheral-type benzodiazepine receptors (PTBR) in the outer membrane of astroglial mitochondria) enhances the synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA (A) receptor complex, with specific binding sites.[23] The clinical grading of encephalopathy is as follows:[24] Grade 1: Loss of sleep rhythm, drowsiness, confusion and flapping tremor. Grade 2: Features of grade 1 encephalopathy with loss of sphincter control in addition. Grade 3: Unconsciousness with no response to oral commands, but responding to painful stimuli. Grade 4: Deep unconscious state, with no response to pain.

28.2.3 Immunologic Break Down and Infectious Complications Several immune abnormalities occur in ALF including a decrease in complement levels, decrease in neutrophil chemotaxis, opsonization, superoxide production, and a decreased reticuloendothelial capacity to clear bacteria.[25–27] Plasma fibronectin levels are significantly reduced in patients with ALF as compared to patients with acute viral hepatitis and healthy persons.[28] In addition, there are frequent breaches in the host barrier by the use of intravenous lines, urinary catheters, intracranial monitors, and endotracheal tubes. Nearly one third of patients with sepsis remain afebrile with a normal white blood cell count and hence, daily microbiological surveillance is important.

Tropical Hepatogastroenterology

COMPLICATIONS AND SEQUELAE OF ALF

429

In a prospective study by Rolando et al., bacteriologically proven infections were found in 80% of ALF patients usually within the first few days. The most common source was pneumonia followed by bacteremia of unknown origin and urinary tract infections. In this western study, gram positive organisms were predominant and Staphylococcus aureus was the most common isolate.[29] The same group reported fungal infections in 32% of cases.[30] Sepsis as a cause of death has been identified in 24% to 49% of Indian patients with ALF.[6, 7] In an Indian study including 125 ALF patients, 52% of patients had positive cultures. 69% of these culture positive patients did not have any clearly identified site of infection. Gram negative infections were more common (57% isolates) in contrast to the western studies. 23% of patients with a positive blood culture had Aspergillus infection. The mortality of ALF patients with sepsis was significantly higher than patients without sepsis.[7] There is now growing evidence that infections can worsen cerebral edema and encephalopathy by the effect of cytokines. Cytokines can affect the brain either by signaling via peripheral or autonomic nerves, or through the brain vasculature by production of endothelial factors such as nitric oxide and prostanoids, or by a direct action after crossing the BBB.[31] In a retrospective review of 887 ALF patients admitted to a single center during a period of 11 years, it was found that systemic inflammatory response syndrome (SIRS), whether or not precipitated by infection, was related to progression of encephalopathy and confers a poorer prognosis.[32] Patients with more SIRS components were also more likely to develop intracranial hypertension.

content aspiration, and increased respiratory drive. In late stages and in severe cases of ALF, acidosis develops due to renal failure, sepsis, and lactic acid accumulation. Spontaneous hypoglycemia is often seen due to decreased hepatic glycogen stores and decreased gluconeogenesis. The level of free fatty acids is elevated and there is a change in arterial ketone body levels with decrease in acetoacetate to β-hydroxybutyrate ratio (arterial ketone body ratio, AKBR).[33]

28.2.4 Metabolic Dysfunction

Blood urea nitrogen levels may be decreased due to reduced hepatic urea synthesis. Normal serum creatinine also does not exclude renal failure. Hyperbilirubinemia can cause falsely low

A mixed metabolic and respiratory alkalosis occurs frequently and is caused by vomiting, gastric

Part VI / Liver Failure

28.2.5 Coagulopathy Coagulopathy is universal in patients with ALF due to reduced factors II, V, VIII, IX, and X. Reduced factor V and VII activities are of prognostic importance. There may be a contribution of increased consumption of coagulation factors due to disseminated intravascular coagulation. INR may be misleading in ALF and prothrombin time prolongation reported in seconds should be used.[34]

28.2.6 Cardiovascular Effects A hyperdynamic circulatory state exists in ALF. Increased nitric oxide levels seem to play an important role. Tachycardia and increased stroke volume lead to an increased cardiac output. In patients with raised intracranial pressure (ICP), bradycardia can be present. The ability to extract oxygen at the cellular level is impaired. Hence, tissue hypoxia can develop despite adequate cardiac output and arterial oxygenation with resultant lactic acidosis.

28.2.7 Renal Failure

430

Chapter 28 / ACUTE LIVER FAILURE

creatinine value when it is measured by methods based on the Jaffe reaction. Renal failure has been described in 40% to 80% of patients from Western series.[35] Renal failure occurs in approximately 70% of patients with acetaminophen induced ALF, and 30% of patients with other causes in western series.[36] Renal failure is rare among patients reported from India.[6, 7] The four major causes of renal failure occurring in the context of ALF are volume depletion, acute tubular necrosis, sepsis, and type I hepatorenal syndrome.[37]

28.2.8 Hematologic Disturbances Mild anemia and thrombocytopenia can occur. Aplastic anemia can complicate ALF due to infection with parvovirus B19, HAV, HBV, and HCV. Hemolysis may occur either because of hemolytic diathesis or Wilson’s disease related liver failure.

28.3 ETIOLOGY Hepatitis viruses are the major cause of ALF in the east while acetaminophen over dosage is the most common etiology in the west (Table 28.3). All the published reports from the Indian subcontinent have identified hepatitis viruses as the etiological agent in 95% to 100% of patients (Table 28.4).[6, 7] In 15% to 44% of the total cases of ALF, no etiology can be identified.[7]

28.3.1 Hepatitis A (HAV) HAV accounts for less than 10% of cases of ALF in most of the reported series. The risk of liver failure after HAV infection ranges between 0.01% and 0.1%. The risk markedly increases among persons older than 40 years and in the context of preexisting chronic liver disease. HAV infection has the best survival rate among the viral causes

TABLE fy 28.3 Etiology of ALF in various geographical areas[7] India

USA

UK

France

Viral (%) Major cause Drugs (%) Major cause

95 HEV/ HBV 4.5 INH/ Rifampicin

60 Cryptogenic 30–35 Paracetamol

30 Non-A, Non-B 60 Paracetamol

Other

0.5

5

10

60–60 HBV/ HAV 15–20 NSAID/ Paracetamol 15–Oct

AHF, acute hepatic failure; HEV, hepatitis E virus; HBV, hepatitis B virus; HAV, hepatitis A virus; INH, isoniazid; NSAID, nonsteroidal anti-inflammatory drugs.

TABLE fy[7] 28.4 Etiology of ALF in India[7] Percentage etiologies Acharya 1999 458 4 10.5 4.4 0 et al.

23

6

47

5

Khuroo et al.

1997 119 3 15

3

3

38

NR

39

1

Jaiswal et al.

1996

2

5

41

4

15

0

95 4 27

of ALF, and spontaneous survival is seen in up to 40% to 60%.[38] HAV infection in patients with underlying chronic hepatitis C may be more severe. In a study from Italy, 7 of 10 patients with underlying HCV infection developed ALF after superinfection with hepatitis A, with 85% mortality.[39] IgM antibodies can be detected in up to 95% of patients. However, 98% to 100% of patients with chronic liver disease in India are protected against HAV, due to subclinical HAV infection in the childhood associated with acquirement of protective antibody.

28.3.2 Hepatitis B (HBV) The risk of ALF after acute HBV infection is less than 1%.[40] The overall mortality of HBV related

Tropical Hepatogastroenterology

ETIOLOGY

ALF is approximately 60%. Vigorous immune clearance of the virus often leads to absence of detectable HBsAg, HBeAg, and HBV–DNA in the acute phase sera. HBsAg may be absent in up to 30% to 50% of patients within the first few days.[41] Those with rapid viral clearance have a more favorable outcome (mortality 53%) compared to those who remain HBsAg positive (mortality 83%).[42] The diagnosis of HBV induced ALF is thus based on detecting IgM anti-HBC. However, in a Japanese study, IgM anti-HBC was also not detectable in nearly 50% of patients in whom HBV–DNA could be detected by a sensitive polymerase chain reaction (PCR).[43] HBV is the etiological agent of 15% to 42% of ALF cases in India.[6, 7, 44] Preexisting HBsAg carriage also greatly increases the risk of ALF after superinfection with other hepatotropic viruses.[45]

28.3.3 Hepatitis B Mutants HBV precore mutants have been reported to cause more severe acute hepatitis than the wild type virus. Mutations in the HBV core region that cause changes in the amino acid profile of the core protein could result in a production of anti-HBC that may not be detected by commercial ELISA kits. More commonly, mutants implicated in ALF have a point mutation of nucleotide 1896 (G to A) resulting in a stop codon (TGG to TAG) at the end of the precore region, and in these case IgM anti-HBC is invariably detected. Sera from 59 of the 216 apparent non A-E ALF patients at our center were evaluated for the presence of HBV–DNA by using PCR techniques. Detectable HBV–DNA was found in the sera of 39% (23/59) of these patients.[7]

431

immunosuppression, massive hepatocyte necrosis may lead to liver failure. In contrast to ALF resulting from acute HBV infection, ALF after HBV reactivation usually follows a subacute clinical course. ALF due to spontaneous reactivation in chronic HBV carriers, unrelated to immunosuppression withdrawal, is more common than de novo HBV infection in Taiwan and other far eastern countries.[46]

28.3.5 Hepatitis D (HDV): Superinfection/Coinfection Both superinfection and coinfection with HDV increases the risk of liver failure in HBV infected patients by 2 to 5 times. The risk is higher in superinfected patients in whom the replicative machinery of HBV is well established (mortality 1% to 10% in coinfected vs. 5% to 20% in superinfected patients).[47, 48] Epidemics of severe HDV hepatitis and liver failure in parenteral drug abusers and their sexual contacts have been described in the United States, Brazil, and Columbia (‘Santa Marta hepatitis’).[49] Studies from Italy, France, and the United Kingdom have found HDV markers in 39% of those with fulminant HBV infection.[50] In contrast, HDV seems to be uncommon among ALF patients in India. HDV superinfection and coinfection were found in 4.5% and 3.6% respectively, among ALF patients in India.[51] Acute HDV infection is confirmed by presence of IgM-HDV and the coinfection is distinguished from the superinfection by the presence of IgManti-HBC.

28.3.6 Hepatitis C 28.3.4 Reactivation of Hepatitis B Immunosuppression increases HBV replication and hepatocyte infection. On withdrawal of the

Part VI / Liver Failure

It is controversial whether HCV independently causes ALF. Studies from Japan and Taiwan have detected HCV antibodies and RNA in up to 59%

432

Chapter 28 / ACUTE LIVER FAILURE

of non-A non-B cases of ALF.[52] The clinical course of HCV induced ALF progresses slowly from jaundice to encephalopathy (subacute liver failure), and the transaminases may rise multiple times. Western studies have not found evidence of isolated HCV infection as a cause of ALF.[53] In one report as many as 43% of patients with ALF in India were found to have dual infection with HEV and HCV.[54] However, a large series of reports from India have not reported association of HCV infection with ALF.

28.3.7 Hepatitis E This enteric virus is prevalent in developing countries and has been reported to account for 42% of cases in India.[6, 7] During epidemics of hepatitis in developing countries, it has been seen that pregnant women develop hepatitis more often (12%–20%) than non-pregnant women and men (2%–4%). The frequency of ALF is significantly higher (10%–22%) among pregnant women with hepatitis than among nonpregnant women and men with hepatitis (1%–2%). As a result, the mortality among pregnant women who contract hepatitis during epidemics is significantly higher (10%–39%) than that of the general population (4%–13%).[6, 7]

28.3.8 Mushrooms ALF can result from ingestion of three medium sized mushrooms (50 g) of genus Amanita (A. phalloides, A. verna, and A. virosa). The toxins α-amanita and phalloidin are heat stable and are not degraded by cooking. Abdominal pain, vomiting and diarrhea precede liver dysfunction. Renal failure and pancreatitis are common. Early identification is important, as antidotes such as penicillin and silymarin are of benefit. The overall mortality rate is between 10% and 40%.[53]

28.3.9 Wilson’s Disease Wilson’s disease can present as ALF in a young patient, accompanied by Coomb’s negative hemolytic anemia, hypouricemia, and low alkaline phosphatase levels.

28.3.10 Other Viruses Hepatitis G virus and TT virus infection is relatively common in individuals with indeterminate ALF. There is however no evidence for an etiological relationship. With Epstein-Barr virus, cytomegalovirus (CMV), varicella zoster virus, enterovirus, parvovirus B19, adenovirus, and herpes simplex virus (HSV), liver involvement occurs as a part of the disseminated infection.

28.3.11 Drugs Drugs form the etiology of only 1% to 5% cases of ALF in India, in contrast to the west where drug toxicity (predominantly acetaminophen) is the most important cause. Antitubercular drugs are the most common cause of drug induced ALF in India. Isoniazid (INH) toxicity resembles acute viral hepatitis. Half of the cases present within two months but the onset may be delayed from 3–12 months in the remainder. Jaundice may be the only initial manifestation in 10% to 30% of cases. The mortality of INH hepatitis is around 10%. Rifampicin given alone is seldom hepatotoxic and mainly produces cholestatic liver injury. However, the incidence of acute hepatitis is higher when rifampicin is combined with INH (5%–8%) and occurs sooner, usually within the first month. Fulminant INH-rifampicin hepatitis develops even earlier, after about one week of treatment. Pyrazinamide hepatotoxicity is not associated with hypersensitivity manifestations and is probably due to direct toxicity. While

Tropical Hepatogastroenterology

PROGNOSTIC CRITERIA

INH- rifampicin hepatitis occurs mainly during the first month of treatment, pyrazinamide hepatitis is usually associated with longer treatments.

28.4 PROGNOSTIC CRITERIA It is important to be able to predict which patients with ALF will recover with medical management alone and which will succumb without liver transplantation. Variables that correlate with survival are age and etiology. Survival of patients aged between 10 to 40 years is 30% to 35%, whereas survival of patients older and younger than this is less than 10%. Patients with HAV and acetaminophen toxicity have the highest survival rate; those with HBV and HDV have intermediate survival rates; and patients with drug-induced and cryptogenic ALF have the poorest survival rates. Patients with Wilson’s disease or malignancy-induced ALF rarely survive.[55] Among the dynamic variables, the degree of encephalopathy is a strong predictor of outcome. Spontaneous recovery of patients only reaching grade 2 encephalopathy is 65% to 70%, with grade 3 between 40% and 50%, and with grade 4, 20% or lower.[55] A number of liver transplantation centers have evaluated various predictive criteria to identify high-risk patients. The most widely used criteria were proposed by investigators at King’s College, London based on a retrospective, multivariate analysis of 588 ALF patients (Table 28.5). These criteria were validated prospectively in 175 patients. Among the patients with a non-acetaminophen cause of ALF, the presence of any single adverse characteristic was associated with 80% mortality rate, and the presence of three adverse characteristics was associated with more than 95% mortality. For patients with acetaminophen-induced ALF, the presence of any one adverse characteristic was associated with

Part VI / Liver Failure

433

TABLE fy 28.5 King’s college criteria for liver transplantation[7] Acetaminophen induced pH < 7.3 Or all 3 of: INR > 7 Creatinine > 300 micromoles/L Encephalopathy grade 3 or more Nonacetaminophen induced INR > 7 Or any 3 of: Age < 10 or > 40 years Etiology: non-A-E hepatitis; halothane hepatitis; drug reaction, jaundice to encephalopathy > 7 days INR > 3.5 Bilirubin > 300 micromoles/L

a 55% mortality rate, and severe acidosis was associated with a mortality rate of 95%. Thus, the presence of any single indicator of a poor prognosis should place the patient on a waiting list for liver transplantation. Bernuau et al. reported that the factor V level may be an accurate prognostic indicator in postviral ALF (Clichy criteria). Factor V levels of less than 20% in patients younger than 30 years, and less than 30% in patients older than 30 years, predicted around 90% mortality.[56] However, factor V levels do not have prognostic value in acetaminophen induced ALF. Low levels of Gc globulin – an actin scavenger protein synthesized by the liver have also been shown to correlate with the prognosis.[57] In a large Indian study[6] the following variables present at admission have been identified as independent risk factors for patient outcomes: (i) age ≥ 40 years (ii) bilirubin ≥ 15 mg/dL; (iii) prothrombin time prolongation ≥ 25 seconds (iv) clinical features of cerebral edema. The presence of 3 or more factors was associated with

434

Chapter 28 / ACUTE LIVER FAILURE

93% mortality, whereas the presence of one factor was associated with a mortality rate of 26%.

28.5 MANAGEMENT The management of ALF patients can be divided into 3 stages: 1. Medical and supportive management 2. Artificial liver support devices 3. Liver transplantation All patients are candidates for medical and supportive care in an intensive care unit (ICU). Early referral to a specialist center is important for improving the outcome. A subgroup of patients will be candidates for artificial liver support and liver transplantation.

TABLE fy 28.6 Factors that increase intracranial pressure Valsalva maneuver Positive end-expiratory pressure (PEEP) Head and body turning or moving Neck veins compression Respiratory suctioning Fever Horizontal decubitus Severe hypoxemia Any degree of hypercapnia

Arterial hypertension Vomiting, shivering Psychomotor agitation Noxious stimuli Seizures Vasodilatory agents Isometric muscle contractions Trendelenburg position Coughing, sneezing

short acting benzodiazepines and small doses of morphine should be reserved as a last resort for serious psychomotor agitation.

28.5.1 Neurologic Support Factors known to worsen hepatic encephalopathy such as hypoxemia, hypoglycemia, sepsis, hypokalemia, and gastrointestinal bleeding, should be diligently sought and treated. All patients should be nursed in a 20 to 30 degree head-up tilt to improve venous drainage. As in the case of neurosurgical head trauma patients, the elevation should be confined to the head, neck, and chest of the patient. Patient turning and other tactile stimulation should be minimized. Respiratory suctioning should be limited to less than 15 seconds duration at a time. One to two milliliters of lidocaine instilled in the endotracheal tube and ventilation with 100% oxygen prior to suctioning may be helpful in preventing surges of raised ICP. Control of agitation is important, as a Valsalva maneuver from psychomotor agitation may lead to elevation of the ICP. The physician should make a diligent search for treatable causes of agitation like distended bladder and bedsores (Table 28.6). Small intravenous doses of

28.5.2 Intracranial Pressure Monitoring Traditional signs of elevated ICP are unreliable in ALF. Computed scanning (CT scanning) of the head is not a reliable way to estimate ICP in ALF. Currently, most centers install an extradural ICP monitor device once the patient has developed grade 3 or 4 encephalopathy. Prior endotracheal intubation is necessary under propofol anesthesia. Aggressive correction of coagulopathy and thrombocytopenia must be undertaken with a goal of achieving a platelet count of > 500, 000/ml and an international normalized ratio (INR) of < 1.7 or PT within 2 to 3 seconds of normal. Correction of the PT usually requires bolus administration of 2 units of FFP followed by a continuous FFP infusion at a rate of 75 to 150 ml/ hour. Early institution of continuous veno-venous hemodiafiltration (CVVHD) is usually required even in patients with a good urine output to prevent volume overload. Many patients require repeated exchange plasmapheresis to correct their PT. The

Tropical Hepatogastroenterology

MANAGEMENT

transducer to measure the ICP is placed by a neurosurgeon in the ICU under local anesthesia, via a 71 mm burr hole placed with a hand drill. The standard site is the right frontal area chosen to avoid the (right handed) dominant lobe, sagittal sinus, and motor cortex. Epidural transducers are used most commonly and carry the lowest complication rate (3.8%). Subdural bolts and parenchymal monitors carry complication rates (mainly bleeding) of 20% and 22% respectively.[58] Colonization of ICP devices increases significantly after about 5 days of insertion, and the risk of superficial wound infection and meningitis rises. In adults, the average ICP ranges from 0 to 10 mmHg. The maximal permissible upper limit is 20 mmHg. The overall goal is to maintain an ICP of less than 20 mmHg and CPP (MAP – ICP) above 50mmHg at all times. A slow progressive increase in ICP to > 25 mmHg, or pressure waves rising to 30 to 50 mmHg lasting for 5 to 20 minutes, reflect falling cerebral compliance. Prolonged (> 2 hours) elevation of ICP to > 40 mmHg or a reduction in CPP < 50 mmHg are considered a contraindication for liver transplantation.

28.5.3 Reverse Jugular Venous Monitoring Jugular bulb venous saturation is frequently used in neurosurgical intensive care and involves insertion of a fine catheter in a retrograde fashion until its tip lies in the jugular bulb. Blood returning from the cerebral circulation can then be sampled. A jugular venous saturation of < 55% represents an ischemic brain, while a saturation of > 85% represent a hyperemic brain.[59] Measures to improve oxygen supply are indicated in the former situation, and measures to reduce cerebral blood flow in the latter one.

Part VI / Liver Failure

435

28.5.4 Osmotherapy Mannitol lowers the ICP by reducing the brain water and changing the rheological characteristics of blood. When the ICP rises to over 20 to 25 mm Hg for more than 5 minutes, an intravenous bolus of mannitol should be given (0.5 to 1 g/kg, 20% solution, over 5 minutes). Repeated mannitol boluses may be administered as long as the serum osmolality is < 320 mOsm/liter. The response to a mannitol bolus may be expected 15 to 60 minutes postinjection. In about 20% of patients a paradoxical increase in ICP occurs after mannitol infusion.[60] High doses can result in acute renal failure and damage to the BBB. Mannitol works best in mild to moderate intracranial hypertension and is less effective when the ICP is greater than 60 mmHg.[61] In anuric patients, mannitol should only be given in combination with continuous venovenous or arteriovenous hemodiafiltration. In oliguric patients, bedside ultrafiltration should be instituted with an aim of removing two to three times the volume of infused mannitol.

28.5.5 Thiopentone Based on data suggesting that barbiturates may be of value in controlling the intracranial hypertension of head injury, intravenous thiopental was assessed in 13 patients with fulminant hepatic failure complicated by unresponsive intracranial hypertension. The ICP was reduced in all cases, and in eight cases thiopentone infusion achieved stable normal intracranial and cerebral perfusion pressure. Five patients made a complete recovery.[62] The recommended dose of pentobarbital is a loading dose of 3 to 5 mg/kg (maximum 500 mg) over 15 minutes, followed by a continuous infusion at 0.5 to 2.0 mg/h. Barbiturate therapy must be used with

436

Chapter 28 / ACUTE LIVER FAILURE

simultaneous continuous ICP and arterial blood pressure monitoring.

28.5.6 Hypothermia Moderate hypothermia (32◦ C to 35◦ C) leads to a reduction in CBF, cerebral metabolism, ammonia uptake by the brain, and glutamine synthesis, and reduces intracranial pressure in patients with ALF.[63, 64] Moderate hypothermia may also serve as a bridge to OLT. Data from studies in patients undergoing liver transplantation for ALF suggest that increases in intracranial pressure can be prevented during the dissection and reperfusion phases of the operation if the patients are maintained hypothermic during surgery.[65, 66]

28.5.7 Prophylactic Phenytoin It has been suggested that subclinical seizure activity in patients with deep encephalopathy on ventilation may remain unrecognized and lead to exacerbation of cerebral hypoxia and edema. Hence, it was recommended that all patients with grade III or IV encephalopathy should be monitored for subclinical seizure activity and treated with prophylactic phenytoin.[67] However in a randomized, controlled clinical trial of 42 patients, it was found that prophylactic use of phenytoin did not prevent cerebral edema or seizures, or improve survival.[68]

28.5.8 Hyperventilation Patients with ALF often hyperventilate spontaneously, and attempts to control this are of no use. Hyperventilation reduces CBF, and may be useful in the subgroup of patients with cerebral hyperemia as reflected by a jugular bulb venous saturation of more than 75%. Prophylactic hyperventilation does not reduce the frequency of intracranial hypertension in ALF but a moderate reduction in

pCO2 to 25 to 30 mmHg is helpful in decreasing the ICP once cerebral edema has begun to develop.[69] Excessive hyperventilation may lead to cerebral vasoconstriction.

28.5.9 Ammonia Lowering Measures Lactulose has not been found useful in ALF possibly because of its slow onset of action. Ornithine aspartate is a compound salt that has been found useful in lowering ammonia levels and improving encephalopathy in patients with cirrhosis.[70]

28.5.10 Other Therapies N-acetylcysteine, CSF drainage, high volume plasmapheresis, indomethacin, and total hepatectomy have been used in uncontrolled trials. N-acetyl cysteine may restore normal BBB water flux and prevent edema by its antioxidant effect on endothelial cells and astrocytes. In a controlled trial of 44 patients it was found that the use of dexamethasone could not prevent the development of cerebral edema or improve survival.[71] In a recent prospective randomized trial involving 30 patients with ALF, it was found that the use of hypertonic (30%) sodium chloride infusion to maintain serum sodium levels between 145 to 155 mmol/L led to a significant decrease in ICP.

28.5.11 Prevention and Treatment of Infection Aseptic nursing techniques should be followed. Intravenous catheters should be changed every 72 hours, and removed catheter tips cultured. Urinary catheters should be removed from anuric patients and as soon as possible from the recovering patients. The vast majority of the bacterial infections occur within 72 hours of

Tropical Hepatogastroenterology

MANAGEMENT

admission. Hence, prophylactic broad spectrum parenteral antibiotics should be started at admission. Rolando et al. stratified patients at the time of admission based on the presence or absence of clinically evident infection. Those who were infected received either cefuroxime or selective parenteral and enteral antibiotics (SPEAR regimen). The SPEAR regime consisted of oral colistin, tobramycin, and amphotericin B with a 5-day course of an intravenous cephalosporin. Those who were not infected were randomized to SPEAR or no antibiotics. The outcome was similar among those randomized to cefuroxime and SPEAR in the infected group. In contrast SPEAR significantly decreased the infection rate compared to no treatment in the initially ’non infected’ group.[72] Addition of oral and absorbable antibiotics does not confer any advantage over parenterally administered antibiotics.[73] In the above studies, many patients continued to have positive cultures 1 and 2 days after antibiotic were started. Hence, surveillance cultures should be continued even after starting the antibiotics. Any unexplained decrease in blood pressure, drop in urinary output, worsening encephalopathy, and development of severe acidosis or disseminated intravascular coagulation (DIC) should be considered as signs of sepsis. Fungal infection should be strongly considered in the setting of unresponsive fever, leukocytosis, deterioration of neurologic status after initial improvement, and presence of renal failure. GM-CSF has been reported to improve neutrophil function both in vitro and in vivo among ALF patients.[74, 75]

437

hypotension. An adequate cardiovascular filling pressure (PCWP: 8–14 mmHg) must be assured. The goal is to maintain the mean arterial pressure (MAP) above 60 mmHg. Vasopressor agents are indicated if the MAP is < 60 mmHg despite adequate intravascular volume. Oxygen consumption may decrease with the use of vasopressor agents despite the increased arterial pressure as a result of reduction in oxygen delivery and extraction rates. Reduced oxygen extraction may be prevented with concurrent use of prostacyclin. Arterial hypotension in spite of an adequate intravascular volume should be considered a sign of bacterial or fungal sepsis and treated accordingly. Arterial hypotension in ALF may lead to a critical reduction in CPP even with a mildly increased ICP. The coexistence of arterial hypotension and intracranial hypertension requires extremely careful management.

28.5.13 Coagulopathy The coagulopathy of ALF may be clinically silent or manifested by bleeding from mucosal membranes. One of the earliest favorable signs in ALF is the stabilization or improvement of the prothrombin time in the absence of transfusion of FFP. Infusion of fresh frozen plasma is indicated only for active bleeding or before invasive procedures. The risk of bleeding from stress ulceration of gastric mucosa is reduced by the prophylactic use of sucralfate. This agent may be preferable to antisecretory drugs, which predispose to gastric bacterial overgrowth and nosocomial pneumonia.

28.5.12 Hemodynamic Support

28.5.14 Mechanical Ventilation of Patients with Liver Failure

ALF patients have a high cardiac output, low systemic vascular resistance, and relative arterial

The lungs are relatively spared in ALF and standard modes of mechanical ventilation can

Part VI / Liver Failure

438

Chapter 28 / ACUTE LIVER FAILURE

be used. Most patients will tolerate ventilation with minimal sedation. The risks of paralysis may outweigh the benefits in the majority of patients but may have a role in selected patients with refractory intracranial hypertension. Barbiturates and midazolam produce a dose-dependent reduction in metabolic rate, CBF, and cerebral blood volume. A traumatic intubation may induce a sudden rise in the ICP and provoke herniation. Hence tracheal intubation must be gentle. Standard ventilation modes, most commonly synchronized intermittent mandatory ventilation (SIMV), are used. The usual initial ventilatory settings are: respiratory rate of 14 to 18 breaths/minute; tidal volume of 10 to 12 times the body weight in kilograms; inspiratory period of 25% to 33%; pause time of 10% of total cycle; and PEEP of 2 to 4 mmHg. High levels of PEEP (more than 10 to 15 mmHg) worsened or facilitated the development of cerebral edema, and a decrease in hepatic arterial blood flow. Propofol inhibits sympathetic vasoconstrictor activity and has a negative inotropic effect. Among the muscle relaxants, pancuronium, vecuronium, and rocuronium exhibit a prolonged elimination in the presence of liver failure. Atracurium is degraded by the nonenzymatic Hoffman elimination and hydrolysis by nonspecific plasma esterases. Neither hepatic nor renal disease leads to accumulation of atracurium.

maintain adequate activity of endothelium-derived relaxing factor. N-acetylcysteine infusion was shown to facilitate hemodynamic stability in association with a mean 46% and 29% increase in global tissue oxygen consumption after 30 min in patients with acetaminophen and other causes of ALF respectively. Prostacyclin infusion also improved oxygen delivery and consumption.[76] More recently, another group found a more variable systemic hemodynamic response to N-acetylcysteine with clear responders and nonresponders. Overall a small (6%) and unsustained improvement in tissue oxygen consumption was found.[77]

28.5.16 Renal Support Hemodialysis in ALF patients requires standard heparinization in spite of the coagulopathy due to coexisting antithrombin III deficiency. Only a lactate free bicarbonate buffer as the dialysis fluid, and biocompatible dialysis membranes like polysulfone or polyacrylnitrate should be used. Continuous forms of renal support therapy like CVVHD are preferable to conventional hemodialysis or intermittent hemofiltration, which may reduce CPP by increasing cerebral edema through rapid osmolar shifts or reducing the MAP.

28.5.17 Nutritional and Metabolic Support 28.5.15 Microcirculation Inappropriate vasodilatation and vasoconstriction of microcirculatory units may result in inadequate distribution of blood flow. N-acetylcysteine improves tissue oxygen extraction. This effect is potentiated when epoprostenol and N-acetylcysteine are infused together. N-acetylcysteine may promote dilatation of vasoconstricted microcirculatory units by replenishing tissue sulfhydryl groups, which are necessary to

Almost half of ALF patients develop hypoglycemia. Development of hypoglycemia can be sudden and may confound the interpretation of mental changes. Glucose requirements in these patients are highly variable and require close monitoring. Blood sugar should be monitored at 2–3 hourly intervals. Whenever the blood glucose level is lower than 60 mg/dl, an intravenous bolus of 50 to 100 ml of 50% dextrose should be administered. The amount of water administered

Tropical Hepatogastroenterology

MANAGEMENT

as a solvent for dextrose should be minimized by providing solutions concentrated to 25% to 50%. Recent evidence suggests that the glucose transport across the blood brain barrier is increased because of upregulation of glucose carriers in ALF patients. Hyperglycemia may contribute to raised ICP because increased glucose influx leads to cerebral lactic acid accumulation.[78] Hence, it may be prudent to keep blood glucose within the normal limits. ALF is a hypercatabolic state. Energy requirements in ALF are increased by as much as 60% and are further elevated by the presence of complicating infection. The predominant reason for the accelerated degradation of whole body protein is reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1). Whole body protein catabolism may be increased up to four times the normal rate. Massive amino acid losses occur in the urine. A combination of parenteral dextrose and lipid emulsions, and at least 40 gm protein/day should be administered initially. It has been shown that lipid emulsions may be used safely in patients with ALF.[79] There is no reason to restrict proteins in ALF. Branched chain amino acids (BCAA) offer no additional advantage, with the exception of the patients requiring frequent dialysis, in whom large BCAA losses may occur. Hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia are common and must be corrected. Either the enteral or parenteral route may be used for feeding, but the former route has obvious advantages.

28.5.18 Liver Transplantation Overall, the 1-year survival after cadaveric orthotopic liver transplantation (OLT) ranges from 50% to 75%. In experienced centers, the outcome with split liver grafts is comparable with that after

Part VI / Liver Failure

439

the use of full size organs. Survival is substantially reduced among patients with sepsis and multiorgan failure before OLT. Use of auxiliary partial OLT may be considered as a form of temporary liver support in most recipients and has a comparable survival rate. Withdrawal of immunosuppression leading to graft atrophy may be possible in up to 65% of patients surviving 1 year. Living related liver transplantation has been more often used in children. The 1-year survival rate after living related OLT in a total of 35 pediatric cases in 3 series was 59% to 90%.[80–82] The 1-year survival in the largest series of living related OLT in adults, a study that included 53 patients, has reported a 75% survival at 1 year.[83]

28.5.19 Nontransplant Therapies for Liver Support Therapeutic interventions that have been used to treat ALF in lieu of OLT are listed in Table 28.7. Extracorporeal liver support may be artificial, which contains no biologic component

TABLE fy 28.7 Attempted non-OLT therapies for ALF–ALF toxin removal Plasma exchange Hemodialysis Hemofiltration Charcoal hemoperfusion Hemodiabsorption Toxin removal with hepatic cell assistance Extracorporeal perfusion with animal or human liver Artificial liver support systems using hepatocytes Hepat Assist ELAD system Gerlach system BAL system Hepatocyte transplantation Molecular adsorption recirculating system (MARS)

440

Chapter 28 / ACUTE LIVER FAILURE

(e.g., MARS), or bioartificial, which includes viable liver cells in culture within bioreactors or involves perfusion of the patients blood through an isolated human, or porcine whole liver. Extracorporeal liver assist device (ELAD) uses human hepatoblastoma cell line, and the Bioartificial liver (BAL) uses porcine hepatocytes. However, none of these bioartificial support systems till date have been shown to improve survival among patients with ALF 28.5.19.1 Molecular adsorbent recirculating system (MARS)

MARS (Teraklin AG, Rostock, Germany) is a dialysis treatment. It uses a recirculating dialysate containing 20% albumin that is regenerated on line by dialysis against a bicarbonate buffered dialysate, followed by passage through a column with uncoated charcoal and a second column with an anion exchange resin. This allows the removal of both water-soluble substances such as urea, creatinine, and ammonia, and of albumin-bound substances such as phenol, bile acids, bilirubin, branched chain amino acids, and short chain fatty acids. MARS treatment can also remove cytokines like TNF-α and IL-6. MARS therapy has been commercially available since 1999, and 38 patients with ALF have been reported to the International MARS registry till 2002.[84] The majority of these cases were drug-induced. Overall 19 patients survived, of whom 6 were transplanted. The average number of treatment sessions was 3.97 ±

2.68 (range: 1–12), with a mean duration of 10.8± 7.3 (range: 3–48) hours. Preliminary data shows that MARS treatment improves encephalopathy, and leads to a reduction in bilirubin and ammonia levels.[85] However no randomized trials of MARS therapy in ALF are available.

28.6 CONCLUSIONS ALF is a fatal complication of acute hepatitis, but can also be induced by other causes. It carries a high mortality. In India 95% of cases of ALF are due to hepatitis viruses, and HEV remains the most important viral etiology of ALF in the Indian subcontinent. In the west, drugs like paracetamol/NSAIDS and metabolic causes like Wilson’s/autoimmune diseases are more frequent causes of ALF. In the Indian subcontinent the pregnant female constitutes the high risk group for the development of ALF. Cerebral edema and sepsis are the major cause of death in this condition. Prognostic criteria for ALF vary from center to center, because etiology, a major factor influencing outcome, varies geographically. Therapy in such patients includes aggressive organ support in an ICU setting, amelioration of cerebral edema using mannitol, ammonia-lowering measures, and prophylactic antibiotics. Artificial liver assist devices have shown promising results but are yet to provide evidence in support of improving survival. Liver transplant continues to be the main salvage in those who have poor prognostic criteria.

REFERENCES [1] Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F (eds). Progress in liver failure. New York: Grune & Stratton 1970;282–98.

[2] Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: Definitions and causes. Semin Liver Dis 1986;6:97–106. [3] O’Grady JG, Schalm SW, William R. Acute

Tropical Hepatogastroenterology

REFERENCES

[4]

[5]

[6]

[7]

[8] [9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

liver failure: Redefining the syndromes. Lancet 1993;342:373–5. O’Grady JG, Alexander GJ, Hayllar KM et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–45. Tandon BN, Bernauau J, O Grady J et al. Recommendations of the International Association for the Study of the Liver Subcommittee on nomenclature of acute and sub acute liver failure. J Gastroenterol Hepatol 1999;14:403–4. Acharya SK, Dasarathy S, Kumer TL et al. Fulminant hepatitis in a tropical population: clinical course, cause and early predictors of outcome. Hepatology 1996;23:1448–55. Acharya SK, Panda SK, Saxena A et al. Acute liver failure in India: a perspective from the East. J. Gastroenterol. Hepatol 2000;15:473–9. Tandon BN, Joshi YK, Acharya SK. Subacute hepatic failure. Natl Med J Ind 1988;1:124–6. Nernuau J, Rueff B, Benhmaou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97–106. Larson FS, Wendon J. Brain edema in liver failure: Basic physiologic principles and management. Liver Transpl 2002;8:983–9. Takahashi H, Koehler RC, Brusilow SW et al. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 1991;261:R1491–R1496. Tandon BN, Joshi YK,Tandon M. Acute liver failure. Experience with 145 patients. J Clin Gastroenterol 1986;8:664–8. Srivastava KL, Mittal A, Kumar A et al. Predictors of outcome in fulminant hepatic failure in children. Indian J Gastroenterol 1998;17:43–5. Murphy N, Auzinger G, Bernal, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004;39:464–70. Larson FS, Gottstein J, Blei AT. Cerebral hyperemia and nitric oxide synthetase in ammonia-induced brain edema in rats with portacaval shunt. J Hepatol 2001;34:548–54. Larson FS, Hansen BA, Pott F et al. Dissociated cerebral vasoparalysis in fulminant hepatic failure:

Part VI / Liver Failure

[17]

[18] [19]

[20]

[21]

[22] [23]

[24] [25]

[26]

[27]

[28]

[29]

[30]

441

A hypothesis of gradual cerebral hyperemia. J Hepatol 1996;24:145–54. Wendon JA, Harrison PM, Keays R et al. Cerebral blood flow and metabolism in fulminant hepatic failure. Hepatology 1994;19:1407–13. Larson FS. Cerebral circulation in liver failure. Semin Liver Dis. 1996;16:281–92. Blei AT, Larson FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999;31:771–6. Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis. 2002;7:221–7. Clemmesen JO, Larsen FS, Kondrup J et al. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999;29:648–53. Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol. 2002;67:259–79. Jones EA. Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab Brain Dis. 2002;17:275–81. Riegler JL, Lake JR. Fulminant hepatic failure. Med Clin North Am 1993;77:1057–83. Wyke RJ. Bacterial infection complicating liver disease. Baillieres Clin Gastroenterol 1989;3: 187. Altin M, Rajkovic IA, Hughes RD et al. Neutrophil adherence in chronic liver disease and fulminant hepatic failure. Gut 1983;24:746. Bailey RJ, Woolf IL, Cullens H et al. Metabolic inhibition of polymorphonuclear leucocytes in fulminant hepatic failure. Lancet 1976;1: 1162. Irshad M, Acharya SK, Joshi YK et al. Role of fibronectin and complement in immunopathogenesis of acute and subacute hepatic failure. J Gastroenterol Hepatol. 1994;9:355–60. Rolando N, Harvey F, Brahm J et al. Prospective study of bacterial infection in acute liver failure; an analysis of fifty patients. Hepatology 1990;11:50–53. Rolando N, Harvey F, Brahm J et al. Fungal infection: a common, unrecognized complication of acute liver failure. J Hepatol 1991;12:1–9.

442

Chapter 28 / ACUTE LIVER FAILURE

[31] Licinio J, Wong ML. Pathways and mechanisms for cytokine signalling of the central nervous system. J Clin Invest 1997;100:2941–7. [32] Rolando N, Wade J, Davalos M et al. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000;32:734–9. [33] Saibara T, Onishi, Maeda T et al. Arterial blood ketone body ratio as a possible indicator for predicting fulminant hepatitis in patients with acute hepatitis. Liver 1992;12:392. [34] Robert A, Chazouilleres O. Prothrombin time in liver failure time, ratio, activity percentage, or international normalized ratio? Hepatology 1996;24: 1392. [35] Bihari DJ, Gimson AE, Williams R. Cardiovascular pulmonary and renal complications of fulminant hepatic failure. Semin Liver Dis 1986;6:119. [36] O’Grady JG, Gimson AE, O’Brien CJ et al. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988;94:1186–92. [37] Moore K. Renal failure in acute liver failure. Eur J Gastroenterol Hepatol 1999;11:967. [38] Gimson AE, White YS, Eddleston AL et al. Clinical and prognostic differences in fulminant hepatitis type A,B and non-A non-B. Gut 1983;24:1194. [39] Vento S, Garofano T, Renzini C et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998;338:286–90. [40] Sanyal AJ, Stravitz RT. Acute liver failure. In: Zakim D and Boyer TD, eds. Hepatology: A textbook of liver disease. 4th ed. Philadelphia: Saunders. Elsevier Science,2003:445–96. [41] Saracco G, Macagno S, Rosina F et al. Serologic markers with fulminant hepatitis in persons positive for hepatitis B surface antigen. A worldwide epidemiologic and clinical survey. Ann Intern Med 1988;108:380. [42] Bernuau J, Rueff B, Benhamou JP. Fulminant and sub-fulminant liver failure: clinical, serological and histological features. Hepatology 1986;6: 288–94. [43] Inokuchi K, Nakata K, Hamasaki K et al. Prevalence of hepatitis B or C virus infection in patients

[44]

[45]

[46]

[47]

[48] [49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

with fulminant viral hepatitis. J Hepatol 1996;24: 258–64. Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut. 1996;38(Suppl2):S56–S9. Papaevangelou G, Tassapoulos N, RoumeliotouKarayannis A et al. Etiology of fulminant viral hepatitis in Greece. Hepatology 1984;4:369. Williams R, Riordan. Fulminant Hepatic Failure. In: Schiff ER, Sorrel MF, Maddrey WC, editors. Diseases of the Liver. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2003:941–70. Govindarajan S, Chin KP, Redeker AG et al. Fulminant B viral hepatitis: role of delta agent. Gastroenterology 1984;86:1417. Hoofnagle JH. Type D (delta) hepatitis. JAMA1989; 261:1321. Buitrago B, Hadler SC, Popper H et al. Specific Epidemiologic aspects of Santa Marta hepatitis over a 40-year period. Hepatology 1986;6:1292. Smedile A, Farci P, Verme G et al. Influence of delta infection on severity of hepatitis B. Lancet 1982;2:945–7. Irshad M, Acharya SK. Hepatitis D virus (HDV) infection in severe forms of liver diseases in north India. Eur J Gastroenterol Hepatol 1996;8: 995–8. Yanagi M, Kaneko S, Unoura M et al. Hepatitis C virus in fulminant hepatic failure. N Eng J Med 1991;324:1895. Ostapowicz G, Lee WM. Acute hepatic failure: A western perspective. J Gastroenterol Hepatol 2000;15:480–8. Madan K, Gopalkrishna V, Kar P et al. Detection of hepatitis C and E virus genomes in sera of patients with acute viral hepatitis and fulminant hepatitis by their simultaneous amplification in PCR. J Gastroenterol Hepatol 1998;13: 125–30. Hoofnagle JH, Carithers RL, Shapiro C et al. Fulminant hepatic failure: summary of a workshop. Hepatology 1995;21:240–52. Bernuau J, Goudeau A, Poynard T et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986;6:648–51.

Tropical Hepatogastroenterology

REFERENCES

[57] Lee WM, Gailbraith RM, Watt GH et al. Predicting survival in fulminant hepatic failure using serum Gc protein concentrations. Hepatology 1995;21: 101. [58] Blei AT, Olafsson S, Webster S et al. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993;34:157–8. [59] Bernal W, Wendon J. Acute liver failure; clinical features and management. Eur J Gastro Hepatol 1999;1:977–84. [60] Hamid MA, Davies M, Mellon PJ et al. Clinical monitoring of intracranial pressure in fulminant hepatic failure. Gut 1980;21:866–9. [61] Munoz SJ. Difficult management problems in fulminant hepatic failure. Semin Liver Dis 1993;4:395–413. [62] Forbes A, Alexander GJ, O’Grady JG et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989;10:306–10. [63] Chatauret N, Rose C, Butterworth RF. Mild hypothermia in the prevention of brain edema in acute liver failure: mechanisms and clinical prospects. Metab Brain Dis 2002;17:445–51. [64] Chatauret N, Rose C, Therrien G et al. Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure. Metab Brain Dis 2001;16:95–102. [65] Jalan R, Olde Damink SW, Deutz NE et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 2003;75:2034–9. [66] Jalan R, Damink SW, Deutz NE et al. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999;354: 1164–8. [67] Ellis AJ, Wendon JA, Williams R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology 2000;32:536–41. [68] Bhatia V, Batra Y, Acharya SK. Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure–a controlled clinical trial. J Hepatol 2004;41:89–96.

Part VI / Liver Failure

443

[69] Ede RJ, Gimson AES, Bihari DJ et al. Controlled hyperventilation in the prevention of cerebral edema in fulminant hepatic failure. J Hepatol 1986;2:43–51. [70] Rose C, Michalak A, Rao KV et al. L-ornithineL-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 1999;30:636–40. [71] Canalese J, Gimson AE, Davis C et al. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982;23:625–9. [72] Rolando N, Gimson A, Wade J et al. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 1993;17:196. [73] Rolando N, Gimson A, Wade JJ et al. Prospective study comparing the efficacy of prophylactic parenteral antimicrobials, with or without enteral decontamination, in patients with acute liver failure. Liver Transpl Surg 1996;2:8. [74] Rolando N, Clapperton M, Wade J et al. Granulocyte colony-stimulating factor improves function of neutrophils from patients with acute liver failure. Eur J Gastoenterol Hepatol 2000;12: 1135–40. [75] Rolando N, Clapperton M, Wade J et al. Administering granulocyte colony-stimulating factor to acute liver failures patients corrects neutrophil defects. Eur J Gastroenterol Hepatol 2000;12:1323–8. [76] Harrison PM, Wendon JA, Gimson AES et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852–7. [77] Walsh TS, Hopton P, Philips BJ et al. The effect of N-acetyl cysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology 1998;27:1332–40. [78] Kodakat SK, Gopal PB, Wendon JA. Hyperglycemia is associated with intracranial hypertension in patients with acute liver failure (Abs). Liver Transpl 2001;7:C21. [79] Nagayama M, Okuno M, Takai T et al. Effect of fat emulsion in patients with liver disorders. Nutrition 1991;7:267.

444

Chapter 28 / ACUTE LIVER FAILURE

[80] Emre S, Schwartz ME, Shneider B et al. Living related liver transplantation for acute liver failure in children. Liver Transpl Surg 1999;5: 161–5. [81] Miwa S, Hasikura Y, Mita A et al. Living related liver transplantation for patients with fulminant and subfulminant hepatic failure. Hepatology 1999;30:1521–6. [82] Uemoto S, Inomata Y, Sakurai T et al. Living related donor liver transplantation for fulminant hepatic failure. Transplantation 2000;70:152–7.

[83] Ichida T, Todo S, Fujiwara K et al. Living related donor liver transplantation for adult fulminant hepatic failure. Hepatology 2000;32:340A. [84] Steiner C, Mitzner S. Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry. Liver 2002;22:20–5. [85] Novelli G, Rossi M, Pretagostini R et al. MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure. Liver 2002;22:43–7.

Tropical Hepatogastroenterology

Chapter

29 SUBACUTE HEPATIC FAILURE BN Tandon

29.1 DEFINITION Subacute hepatic failure (SHF) is a clinical syndrome of progressive liver dysfunction occurring in the absence of preexisting liver disease. It is characterized by features of persistent acute hepatitis followed by the development of ascites and/or encephalopathy from five to 24 weeks after the onset of symptoms of acute illness. An etiological label is mandatory to the diagnosis.[1]

29.1.1 Synonyms Subacute hepatic failure has several, often confusing, synonyms. In 1963 William Tisdate[2] labeled it as ‘subacute hepatitis’, a grave variant of acute viral hepatitis. Boyer and Klastski,[3] and Radekar et al.,[4] gave this condition the name of ‘subacute hepatic necrosis’. Later from the same country, other hepatologists labeled this disease as “Protracted viral hepatitis with impaired regeneration[5] ”. Tandon et al. from India reported it as a distinct clinical entity with the title of subacute hepatic failure.[6] British hepatologists published it as a clinical entity with late onset hepatic failure.[7] French and Japanese hepatologists have also described similar patients overlapping with acute liver failure.[8, 9]

TABLE fy 29.1 Terminology of subacute hepatic failure Subacute hepatitis Subacute hepatic necrosis Subacute hepatitis Protracted viral hepatitis with impaired regeneration Subacute hepatic failure Late onset hepatic failure Subacute hepatic failure

William Tisdale, 1963[2] Boyer and Klatskin, 1970[3] Radekar et al., 1973[4] Peters et al., 1978[5] Joshi et al., 1978,[1] Tandon et al., 1988[6] Gimson et al., 1986[7] IASL 1999

The maximum contribution to the literature have come from India under the label of subacute hepatic failure.[10, 11] Table 29.1 summarizes the terminology suggested by different hepatologists.

29.2 ETIOLOGY Viral hepatitis is the commonest cause of subacute hepatic failure.[12] Other hepatotoxic agents such as alcohol, drug, plant toxins, and metabolic diseases may also lead to SHF in a small number of patients.[13] Hepatitis E is most important etiology in India (34%) and neighboring countries, followed by Hepatitis B (32%), with a few patients of HAV infection (3%) and HCV infection (10%). A history of alcohol consumption is present in 445

446

Chapter 29 / SUBACUTE HEPATIC FAILURE

8%, hepatotoxic drugs in 21%, indigenous drugs in 30%, and diabetes mellitus in 16% of patients.

29.3 PATHOLOGY Liver biopsy is the gold standard for diagnosis. The major abnormalities are (i) necrosis (ii) hepatocytolysis (iii) ductular and cellar cholestasis and (iv) mesenchymal reaction.[14] Necrosis in SHF is characteristically described as bridging necrosis, which represents necrosis of columns of hepatic lobular parenchyma consisting of one are more liver cell plates and connecting vascular territories (Fig. 29.1). Bridges are broad in fatal cases and narrow in survivors. Orcein staining of elastic tissue demonstrates the bridging necrosis with very little or no elastic tissue. Hematoxylin-eosin stain alone may be misleading. It gives the wrong diagnosis of cirrhosis. Besides classical bridging necrosis, spotty and segmental panlobular necrosis may occur. Hepatocyte injury shows variety of alterations which include hydropic changes, ballooning

degeneration, and apoptosis. A ‘nonreactive’ response is universally observed in fatal patients. Absence of mitosis is also an observation. Regeneration activity is very poor in fatal patients (Fig. 29.2). Marked ductular cholestasis is another unique feature of this condition. It is quite pronounced at the interface of hepatic lobules and portal tracts. Sometime it may appear as rounded, tubular irregular-shaped flakes with mild to moderate inspissation of bile (Fig. 29.3). Ductular cholestasis is associated with cellular cholestasis in most of the biopsies. Mesenchymal reactions include inflammatory cell infiltration with lymphocytes, histocyte,

FIGURE 29.2 Photomicrograph of a liver biopsy specimen showing hepatocyte ballooning.

TABLE fy 29.2 Histopathological features of subacute hepatic failure FIGURE 29.1 Photomicrograph of a liver biopsy specimen showing bridging necrosis.

1. 2. 3. 4.

Bridging necrosis Hepatocyte necroinflammatory apoptosis Ductular cholestasis Mesenchymal inflammation

Tropical Hepatogastroenterology

INVESTIGATIONS

447

TABLE fy 29.3 Liver function profile

FIGURE 29.3 Photomicrograph of a liver biopsy specimen showing ductular cholestasis.

neutrophils, and a few plasma cells. Mild to moderate Kupffer cell hyperplasia is noted. Neovascularization and early fibroblast reaction is observed in necrosed areas.

29.4 INVESTIGATIONS Liver function tests record the abnormalities corresponding to histological injury.[13] Serum bilirubin is elevated, reflecting cholestasis. Serum enzymes are elevated moderately in the range of 4 to 5 times of the upper limit of normal. Serum alkaline phosphatase is usually normal or slightly elevated. Two important synthetic functions show significant abnormalities, characterized by low serum albumin and prolonged prothrombin time. US upper abdomen classically, ultrasound upper abdomen shows mild to moderate ascites, a normal size liver with altered echogenicity, and occasional slight splenomegaly. There are no visible portosystemic collaterals. These observations have also been confirmed by CT scan. Imaging findings exclude cirrhosis of the liver.

Part VI / Liver Failure

LFT

Mean + SD

S. Bilirubin (mg%) ALT (KU/I) AST (KU/I) S Alk PO4 (KAU/I) T. Protein (gm%) S. Albumin (gm%) Prothrombin time (sec prolonged)

20.1 ± 6.84 127.1 ± 88.2 127.3 ± 91.5 13 ± 5.7 6.35 ± 0.57 2.7 ± 0.49 18.4 ± 10.7

Upper gastrointestinal endoscopy does not reveal esophageal varices or congestive gastropathy. Some patients may show doubtful grade-I varices during the peak period of illness with moderate or severe ascites. Viral marker studies on standard protocol for etiological diagnosis are done to establish the etiology. If a viral etiology is not confirmed, special tests may be required to find out uncommon causes of SHF.

29.5 CLINICAL FEATURES SHF is disease of adult males in the Indian subcontinent as against older females in the western hemisphere. In the largest series of 148 patients published from Delhi, India, the peak distribution was recorded in the age group of 40–49 years with a male female ratio of 1.5:1. The distribution of symptoms and signs is given in Tables 29.4 and 29.5. Moderate or deep icterus and ascites are two cardinal features of SHF. It is also important to note that the liver in this condition is not contracted. It is of normal size or mildly enlarged.

29.5.1 Clinical Course and Prognosis SHF is a serious disease with progressive deterioration and death within 1 year.[13] Renal

448

Chapter 29 / SUBACUTE HEPATIC FAILURE

TABLE fy 29.4 Symptoms of subacute hepatic failure (148 patients) Symptom

No. of patients

%

145 132 122 110 83 81 76 44 40 19

98 89 82 74 56 55 51 30 27 13

Jaundice Abdominal distension Anorexia Pedal oedema Fever Nausea Abdominal pain Itching Vomiting Gastrointestinal bleeding

TABLE fy 29.5 Signs of subacute hepatic failure (148 patients) Sign Jaundice Ascites Pedal oedema Hepatomegaly (Palpable liver) Splenomegaly (Palpable spleen) Encephalopathy (Grades I & II) Spiders

No. of patients

%

148 143 123 63 25 24 25

100 97 83 43 17 16 17

failure is the commonest cause of death (44% of patients in India and 62% in UK). Gastrointestinal bleeding is noted as the second and infection as the third most frequent fatal complication. Cerebral edema and hepatic encephalopathy are uncommon complications of SHF. The prognosis of SHF has improved recently with better treatment modalities for infection, renal failure, and gastrointestinal bleeding. Patients who recover

have high probability of developing chronic hepatitis.

29.6 TREATMENT The notable therapeutic advances in the last fifteen years have been improved supportive care, better treatment of complications in liver intensive care units, and special therapeutic measures with intravenous glycyrrhizin and/or liver transplant. during last fifteen years.[14] Supportive treatment includes the following measures: (i) low salt (3 to 5 gm sodium) and less fluid (1.2 L in 24 hours), vegetarian diet, (ii) slow diuretic therapy with frusemide and aldactone to ensure a negative fluid balance of 250 ml to 300 ml daily (3) fresh frozen plasma infusion of 2–3 units daily to keep INR below 1.5 (iv) vitamins, H2 receptor antagonists and third or fourth generation cephalosporins. The following two specific measures are recommended: (i) intravenous glycyrrhizin is a successful medical treatment, given as a 40–60 ml intravenous bolus or dispensed in dextrose daily for 4–6 weeks, followed thrice a week for a few weeks and once a week till the patient recovers. It has decreased the mortality rate from more than 70% to 40%.[14] SHF is an indication for liver transplant, with expected good results, but no data is available on this mode of therapy. It has been reported that after recovery nearly 37% of the patients may develop the complication of chronic hepatitis. There is no long term follow up data to know whether this group ultimately develops cirrhosis of the liver and hepatocellular cancer.

Tropical Hepatogastroenterology

REFERENCES

449

REFERENCES [1] Joshi YK, Tandon HD, Tandon BN. Study of Subacute hepatitis. J Assoc Phys 1978;26:13–17. [2] Tisdale WA. Subacute hepatitis. N Engl J Med 1963;268:2:88–89 and 268:3,138–142. [3] Boyer JL, Klatskin GK. Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis). N Engl J Med 1970; 283:1063–1071. [4] Redeker AG. Fulminant hepatitis. In: Schaffner F, Sherlock S, Carull L (eds). Liver and its Diseases. International Medical Book Corporation, New York, 1974;149–55. [5] Peters RL, Omata M, Aschavai M et al. Protracted Viral Hepatitis with Impaired Regeneration in Viral Hepatitis Ed. Vyas GN, Cohen SN and Schmid R. Pub. Franklin Institute Press 1978; 79–84. [6] Tandon BN, Joshi YK, Acharya SK. Subacute hepatic failure. Nat Med J Ind 1988;124–127. [7] Gimson AE, O’Grady J, Ede RJ et al. Late onset hepatic failure: Clinical, serological and histological features. Hepatology 1986;6:288–94. [8] Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: Definitions and causes; Semin Liver Dis 1986;6:97–106.

test

Part VI / Liver Failure

[9] Yoshiyata Takahashi, Kunio Okuda. Fulminant and subfulminant hepatitis in Japan-etiological considerations. Ind J Gastroenterol 1993;12 (Supp 3):19–21. [10] Tandon BN. Subacute hepatic failure: Definition, nomenclature and criteria for diagnosis. Ind J Gastroenterol 1993;12(Suppl 3):5–6. [11] Dhawan PS, Desai HG. Subacute hepatic failure diagnosis of exclusion?. J Clin Gastroenterol 1998; 26:98–100. [12] Tandon BN ed. Subacute Hepatic Failure: Proceedings of the International Conference on Subacute Hepatic Failure, New Delhi, 1983. [13] Nisman et al. Acute viral hepatitis with bridging hepatic necrosis: An overview. Arch Intern Med Nov 1979;139:1289–1291. [14] Nayak NC, Gupta SD, Tandon A et al. Pathology of subacute hepatic failure. Ind J Gastroenterol 1993;12 (Suppl 3):11–14. [15] Acharya SK, Dasarathy S, Tandon A et al. A preliminary open trial on Interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Ind J Med Res (B) 1993;98:69–74.

Chapter

30 BENIGN LIVER TUMORS Subrat Kumar Acharya and Vikram Bhatia

Benign tumors of the liver are less commonly encountered than liver metastasis or malignant liver tumors. They may be discovered incidentally during radiographic evaluation or surgical exploration for other clinical indications, or may present clinically with symptoms due to a mass effect. Many benign liver masses are true neoplasms, while others result from reactive proliferation of hepatocytes, biliary cells, mesenchymal, or inflammatory cells. The potential for malignant transformation is sometimes of concern. Benign liver tumors are classified in Table 30.1. In this chapter the clinically relevant tumors are discussed in detail.

30.1 HEPATIC ADENOMA Hepatic adenoma is an uncommon benign neoplasm that was rarely reported before 1960. Since the introduction of oral contraceptive (OC) pills, the incidence of adenomas has increased, although they still remain rare.[1] Two case control studies established the association between OC use and adenoma risk. Edmonson reported that adenomas were more frequent in patients using high doses of estrogens for a longer time.[2] Rooks found that the risk was 450

TABLE fy 30.1 Benign liver tumors in adults Hepatocellular origin • Hepatocellular adenoma • Hepatocellular hyperplasia Focal nodular hyperplasia (FNH) Nodular regenerative hyperplasia (NRH) Monoacinar and multiacinar nodules Cirrhotic regenerative nodules Cholangiocellular origin • Hepatic cysts Simple cyst Polycystic disease • von Meyenburg complex • Bile duct adenoma • Biliary cystadenoma Mucinous Serous • Biliary papillomatosis Mesenchymal origin • Hemangioma • Lymphangioma • Lipomatous tumors Lipoma, angiomyolipoma, myelolipoma

the highest in above-30 women who had used OCs for more than 5 years.[3] After 5 years of OC use, the risk increased by 20–100 times. After OCs are discontinued, the adenomas often decrease in size or even disappear, or may continue to grow.

HEPATIC ADENOMA

Adenomas have also been reported only after 6–13 months of OC use (Schiff) and even after their discontinuation.[4] The tumors in OC users are larger and more prone to complications like bleeding than adenomas arising in patients without a history of OC use.[1] The incidence of adenomas has decreased with the decrease in estrogen content in OC pills. In women who have never used OCs, the annual incidence of hepatic adenoma is about 1 per million. This increases to 30–40 per million in long- term users of OC.[5] Other associations of liver adenoma are diabetes mellitus, glycogen storage disease (GSD), long term use of androgenic anabolic steroids, and pregnancy. In the former two conditions, the pathogenesis involves an imbalance of insulin and glucagon, hepatocyte glycogen overload and proto-oncogene activation.[4] Multiple hepatic adenomas are associated with glycogen storage disease (GSD) type I and III, occurring in about half and one quarter of the cases respectively.[4] Adenomas in GSD develop at an earlier age, usually before 20 years, and show a male predominance. Malignant transformation of adenomas in GSD occurs at a mean age of 23 years with a mean adenoma to carcinoma interval of 2 to 7 years.[4]

451

accumulation in the adenoma cells is responsible for the characteristic yellow appearance of the cut surface of the adenomas, and evidence of lipid at CT or MRI can be helpful in diagnosing hepatocellular adenoma.[5] The cells are arranged in plates separated by dilated sinusoids. No bile ducts or portal tracts are seen. Absence of bile ductules is a key histologic feature that helps distinguish an adenoma from FNH. Contrary to the prior belief, Kupffer cells are present in adenomas, usually in reduced numbers, and have little or no functional activity (Fig. 30.1).[5] Adenomas are hypervascular tumors, perfused solely by the hepatic arteries. The extensive sinusoids, feeding arteries and poor connective tissue support predisposes to hemorrhage. As a tumor capsule is usually absent or incomplete, hemorrhage may spread into the liver or abdominal cavity. Percutaneous biopsy of an adenoma carries an increased risk of bleeding and is usually nondiagnostic. Liver adenomatosis is defined as the presence of more than 10 adenomas in the liver. This condition occurs in the absence of OC use or underlying GSD.[7] Patients are usually symptomatic with pain and hepatomegaly, and develop complications of bleeding, rupture and malignant transformation.

30.1.1 Pathology Grossly, adenomas are large, well-circumscribed, and fleshy tumors. Areas of central necrosis and hemorrhage are often present. Adenomas are usually solitary. Multiple tumors are seen in 10%–20% cases (Oxford). The tumors vary in size from less than 1 cm to more than 15 cm.[5] A complete or partial capsule is present in one-third of tumors.[6] Microscopically, the adenoma cells closely resemble normal hepatocytes, though they are larger and often contain glycogen and fat. Lipid

Part VI / Liver Failure

30.1.2 Clinical Features Adenomas usually occur in young or middle aged women. They are usually symptomatic, and present with upper abdominal pain. The pain may be severe and sudden in onset in one-third of cases.[1] Acute symptoms are more common during or just after the menstrual period, or during pregnancy.[3] The cause of the pain is usually intratumoral hemorrhage or necrosis. The complication of bleeding results in a high mortality. Bleeding can be intraperitoneal or

452

Chapter 30 / BENIGN LIVER TUMORS

FIGURE 30.1 Photomicrograph of a patient with a hepatic adenoma. Note the relative absence of biliary channels and portal tracts in the low-power (4x) view (a), and the fat-laden cells in the high-power (20x) view (b).

30.1.3 Imaging of Adenomas

fat in 7%, calcification in 5%, and a tumor capsule in 25% of the adenomas.[10] On arterial phase CT, adenomas are hyperdense due to their hypervascularity. On unenhanced CT as well as on portal venous and delayed images, these tumors are nearly isodense to the liver.

30.1.3.1 Ultrasonography (USG)

30.1.3.3 Magnetic resonance imaging (MRI)

Adenomas often appear hyperechoic on sonography due to their high lipid content. However, the echogenicity of adenomas may be variable, and a specific diagnosis cannot be made by sonographic examination.[5, 9]

On T1-weighted MRI images, adenomas have a variable appearance but most of them appear bright. On T2-weighted images most lesions are heterogeneous with a combination of hyperand hypointensity due to hemorrhage and necrosis.[5, 11]

subcapsular and has been described in 25%–41% patients.[8] Other symptoms include the presence of an abdominal mass and chronic or intermittent pain.

30.1.3.2 Computed tomographic (CT) scan

CT demonstrates most adenomas as sharply defined masses with smooth borders. Adenomas are usually heterogeneous due to the presence of hemorrhage, necrosis and/or fat. CT is less definitive in detection of these specific features than MRI, but demonstrates hemorrhage in 25%,

30.1.3.4 Radionuclide imaging

Even though adenomas contain well-differentiated hepatocytes and may form bile, they lack the bile ductules to excrete it. Radionuclide scans show traces of uptake in some adenomas but, unlike FNH, no delayed excretion. Compared with

Tropical Hepatogastroenterology

FOCAL NODULAR HYPERPLASIA

normal liver, adenomas usually show absent or decreased uptake of Tc-99m sulfur colloid. 30.1.3.5 Angiography

Adenomas have a wide spectrum of angiographic appearances. Portal vein invasion, arterio-venous shunting and other angiographic signs of malignancy are absent.[5] The differentiation of an adenoma from hypervascular metastasis may be difficult or impossible based on imaging alone. Among the available imaging modalities, MRI characteristics are likely to be distinctive. Hypervascular metastasis are usually hypointense on T1- and markedly hyperintense on T2-weighted images. Areas of fat and hemorrhage are commonly detected in adenomas with MRI, but are rare in hypervascular metastasis.[5]

30.1.4 Treatment If adenomas are not resected, pregnancy should be avoided. Women should avoid OC use whether or not the adenoma has been resected. Surgical removal is indicated in all cases of adenoma, usually by enucleation or resection. The rare patients with multiple adenomas, GSD, or suspicion of malignancy may require orthotropic liver transplantation. Arterial embolization is useful to control bleeding acutely, reduce tumor size preoperatively, or relieve symptoms when surgery is refused or is not feasible.

30.2 FOCAL NODULAR HYPERPLASIA Focal nodular hyperplasia (FNH) is the second most common benign solid liver tumor. Autopsy series have reported a prevalence between 0.31%

Part VI / Liver Failure

453

and 0.6%.[12] FNH is most prevalent in women between 20 and 50 years of age. FNH must be differentiated from a fibrolamellar variant of hepatocellular carcinoma, with which it shares imaging and gross features.

30.2.1 Pathogenesis The incidence of FNH has not increased since the introduction of OCs. Use of OC pills does not increase the risk of developing new lesions, but lesions among women who use OC are larger and more symptomatic.[4, 6] Some reports state that the size of FNH increases during pregnancy.[12] Hence it is likely that estrogens could have a trophic effect on FNH.[1] FNH develops as a hyperplastic, nonneoplastic, proliferative response of hyperperfused hepatocytes. The lesion is supplied by a single large artery, unaccompanied by a portal vein. The artery divides in the shape of a star and separates the parenchyma into nodules.[4] Wanless proposes that FNH is a hyperplastic response of the hepatocytes to a preexisting arterial spider like malformation, which ensures localized overperfusion.[13] All the normal constituents of the liver are present in FNH, but only in an abnormally organized pattern.

30.2.2 Pathology FNH is lobulated and sharply demarcated but does not have a true capsule. The lesion is solitary in about two-third of cases and is usually subcapsular.[6] The tumor is usually less than 5 cm in diameter and rarely exceeds 10 cm in size.[4] A macroscopic central scar is seen in about half the cases on a cut specimen, with radiating fibrous septa dividing the tumor into lobules.[14] The central scar contains an arterial malformation with spider-like branches supplying the component

454

Chapter 30 / BENIGN LIVER TUMORS

and 3% patients had 15–30 nodules. The lesions ranged in size from 1 mm to 19 cm in diameter. A central scar was visible grossly in 45% of the 305 tumors.[14] Needle biopsy of the liver is often inconclusive because of sampling error. Furthermore, the presence of fibrous septa may give a false appearance of cirrhosis. Hence accurate tissue diagnosis may be possible only by surgical resection or surgical biopsy.

30.2.4 Clinical Features FIGURE 30.2 Photomicrograph of a patient with a focal nodular hyperplasia. Note the radiating fibrous septa that divide the tumor into lobules.

nodules. The parenchyma between the septa contains normal cords of hepatocytes, sinusoids and Kupffer cells.[8] Intratumoral calcification, fat, hemorrhage, and necrosis are extremely rare (Fig. 30.2).[10]

30.2.3 Multiple FNH Syndrome An International Working Party in 1995 defined multiple FNH syndrome as the association of two or more FNH lesions with liver hemangioma and vascular malformations of the central nervous system, or tumors of meningeal or astrocytic origin.[15] The telangiectatic form of FNH is a variant that lacks a central scar and architectural nodular distortion. Instead, a central telangiectatic lesion with radiating septa is present. In a large study of 168 patients with FNH, Nguyen et al found that 76% of patients had a solitary mass, 21% of patients had 2–5 nodules

FNH is found most often in women (50%–90% cases). Most of the lesions are incidental discoveries on imaging, surgery or autopsy. Abdominal pain is uncommon with an FNH, unlike an adenoma with which it is often confused. Symptoms are more common among women using OC. Rupture and hemorrhage are very rare. Malignant transformation does not occur. Liver function tests are normal. Coexistence of FNH and hemangiomas has been described in OC users.[16] Other described associations are with Budd-Chiari syndrome, pulmonary hypertension, primary sclerosing cholangitis, hemochromatosis, agenesis of portal vein (Schiff), and Klippel-Trenaunay-Weber Syndrome.[4, 17]

30.2.5 Imaging of FNH 30.2.5.1 USG

USG is highly sensitive but not specific. The USG findings in FNH are variable and overlap with those of hepatic adenomas and hepatocellular carcinomas. The lesion appears as a homogeneous mass that may be isoechoic or hypoechoic, or sometimes hyperechoic.[17, 18] FNH may be missed sonographically if the signal is isoechoic, and

Tropical Hepatogastroenterology

FOCAL NODULAR HYPERPLASIA

455

30.2.5.3 MRI

MRI is more sensitive than CT in demonstrating the characteristic central scar. FNH appears isointense or slightly hypointense on T1- and slightly hyperintense on T2-weighted images. The central scar is hypointense in relation to the lesion on T1 and hyperintense on T2-weighted images.[17, 19] MRI can demonstrate the central scar of FNH in 78% of cases.[17] 30.2.5.4 Radionuclide imaging FIGURE 30.3 CT scan of a patient with focal nodular hyperplasia of the liver showing an enhancing lesion (L) in the right lobe. (Courtesy: Dr Anil Agarwal.)

may only be suggested by a mass effect and displacement of intrahepatic blood vessels. The central scar is seen on USG in only 20% of patients. Doppler studies demonstrate an enlarged afferent blood vessel with central arterial hypervascularity.[18] Large draining veins may be seen at the periphery of the mass. Power Doppler increases the sensitivity further, and may help distinguish FNH from hepatocellular carcinoma.[18] 30.2.5.2 CT scan

Helical CT demonstrates characteristic and definitive findings in most patients. FNH is hypervascular and hyperdense to liver on arterial phase images, and enhances homogeneously (Fig. 30.3).[10, 17, 18] The lesion is nearly isodense with liver on unenhanced, portal venous, and delayed-phase enhanced CT scans. The margins of FNH are usually ill-defined. For lesions more than 3 cm in diameter, CT demonstrates a central scar in 65% of cases.[10]

Part VI / Liver Failure

FNH has Kupffer cells as well as bile ductules. Uptake of 99mTc-sulfur colloid (present in 50%–60%) or Tc-hepatic imino-diacetic acid derivatives (present in 80%–90%) may be seen. FNH can show a normal (30% tumors), increased (30% tumors) or decreased (30% tumors) sulfur colloid uptake compared with normal liver. In 10% of cases the uptake is intense, and is considered as a very specific finding.[17, 19] 30.2.5.5 Angiography

FNH is a hypervascular tumor. Blood supply begins from the center of the lesion with peripheral ramifications in a spoke-wheel fashion.[17] However the angiographic findings in FNH are not specific. There are several limitations of the available techniques. The diagnosis of FNH is based on the demonstration of a central scar. However, a typical central scar is not demonstrated by imaging in as many as 20% of patients. Moreover, a central scar may be found in some patients with fibrolamellar carcinoma, adenoma, and intrahepatic cholangiocarcinoma. Thus, in patients in whom the diagnosis is not clearly determined by imaging alone, open biopsy or surgical resection may be needed, because needle-biopsy findings can overlap substantially with those of a well-differentiated hepatocellular carcinoma.

456

Chapter 30 / BENIGN LIVER TUMORS

30.2.6 Natural History Most patients remain asymptomatic and their lesions do not change in size. Weimann et al report that significant tumor enlargement occurs in only 10% of patients on follow up, and only 8% of patients require surgical resection because of severe symptoms or an increase in tumor size.[20] In Di Stasi’s series no lesion increased, whereas a size reduction or complete disappearance occurred in 50% of cases.[21] No case of malignant transformation of an FNH has been reported in literature.[17]

30.2.7 Treatment No treatment is required for the vast majority of patients. Serial imaging studies are not indicated once a confident diagnosis has been made.[4] Some lesions decrease in size after discontinuation of OC pills. When required, enucleation is the surgery of choice. Angiographic embolization and hepatic artery ligation are the alternative therapies for unresectable lesions.[4]

30.3 NODULAR REGENERATIVE HYPERPLASIA Nodular regenerative hyperplasia (NRH) is defined by the presence of hepatocellular nodules throughout the liver in the absence of fibrous septa between the nodules. NRH has been described in association with a wide variety of hepatic and systemic diseases. The common conditions associated with NRH are vascular diseases (Budd-Chiari syndrome, portal vein thrombosis), drugs like azathioprine, collagen vascular diseases (systemic lupus, scleroderma, rheumatoid arthritis, Felty syndrome), primary biliary cirrhosis, myeloproliferative disorders, after

bone marrow transplantation, non-Hodgkin’s lymphoma, immunodeficiency states (HIV and common variable immunodeficiency), and diabetes mellitus.

30.3.1 Pathogenesis Many of the associated conditions have in common a disturbance of liver perfusion either at a gross or at a microscopic level. Wanless considers NRH to be of vascular origin since obliteration of small portal veins is seen in all cases.[22] It is a response to disturbed hepatic circulation, usually obstruction of portal and/or hepatic veins, or the sinusoidal circulation.

30.3.2 Pathology Grossly there is diffuse and fine nodularity of the liver with individual nodes measuring 1–2 mm in diameter. Microscopically, the normal liver architecture is replaced by mono-acinar regenerative nodules often containing portal tracts. The nodules are surrounded by compressed liver cell plates. The nodularity may be best demonstrated by using a reticulin stain. Reticulin staining clearly demonstrates the micronodularity with a maintained acinar structure. There is overlap histologically, with idiopathic portal hypertension, partial nodular transformation and incomplete septal cirrhosis. When looked for, cholestasis is a frequent feature.[23]

30.3.3 Clinical Features NRH manifests clinically as splenomegaly and gastroesophageal varices. The variceal bleeds are well tolerated. Ascites does not occur. In general, the prognosis is good. Serum alkaline phosphatase levels may be elevated.

Tropical Hepatogastroenterology

POLYCYSTIC LIVER DISEASE

30.3.4 Imaging of NRH 30.3.4.1 USG

Sonographically, cirrhosis is often diagnosed due to the nodularity of the liver. 30.3.4.2 CT scan

CT does not directly demonstrate NRH, and the liver morphology may appear normal. Multiacinar or large regenerative nodules may distort the liver surface or may be present in more central parts of the liver.[10] When nodules are detected in the Budd-Chiari syndrome, they are usually multiple (> 10), small (1–4 cm) and homogeneous.[10] Some nodules may have a hypodense ring demonstrated on CT (or MRI). Arterial phase CT demonstrates uniform enhancement. 30.3.4.3 MRI

The large regenerative nodules are hyperintense on T1 and hypointense on T2-weighted images, and show a hypervascular pattern of enhancement helping to distinguish them from cirrhotic regenerative nodules and HCC.

30.3.5 Treatment Treatment is mainly directed towards the complications of portal hypertension.

30.4 POLYCYSTIC LIVER DISEASE Polycystic liver disease (PCLD) is defined as the presence of 4 or more thin walled cysts within the hepatic parenchyma.[24] PCLD can occur both as an isolated finding and in association with autosomal-dominant polycystic kidney disease (ADPKD). Autopsy series suggest a prevalence ranging from 0.15% to 0.13%.[25, 26] PCLD is associated

Part VI / Liver Failure

457

with ADPKD in 16% of patients. The presence of liver cysts in ADPKD depends on the age, gender and degree of renal dysfunction in the patients. The cysts generally begin to form after the onset of puberty and the cyst prevalence increases progressively with age. Women tend to have more and larger cysts. Women with more pregnancies and those using OCs have more cysts.

30.4.1 Pathology The cysts are usually scattered throughout the liver. The liver is grossly enlarged. Their (cysts) sizes vary from less than 1 cm to more than 10 cm. The cysts are lined by flat or cuboidal biliary-type epithelium. These cysts form by progressive dilatation of von-Meyenburg complexes which become disconnected from the biliary tract as they enlarge.[27]

30.4.2 Clinical Features Symptoms in PCLD are caused by the mechanical effect of the enlarging cysts and include a dull upper abdominal ache, fullness and palpable abdominal mass. The liver function is well preserved and the patients rarely succumb to loss of hepatic function. Development of portal hypertension in PCLD is rare. Obstructive jaundice and hepatic outflow obstruction are rare complications. Infection of the cysts occurring de-novo is also rare and is seen only in 1%–3% of patients. Infection is more common in the presence of renal failure.[4] Both isolated and ADPKD associated PCLD is associated with intracranial aneurysms. Screening of all patients for aneurysms is not recommended but patients with a family history of subarachnoid hemorrhage should be studied noninvasively with MR-angiography. Colonic diverticula, mitral valve

458

Chapter 30 / BENIGN LIVER TUMORS

prolapse and cysts in spleen, pancreas, and ovaries have also been observed in these patients.

30.4.3 Treatment Percutaneous drainage is followed by rapid refilling. Sclerosis of the larger liver cysts with various sclerosants has been tried. When the cyst number is small, laparoscopic fenestration may be useful in symptomatic patients. Open surgery with cyst de-roofing is appropriate for larger number of cysts and those situated deeper.

30.5 SIMPLE HEPATIC CYSTS The prevalence of simple cysts in the general population is around 2.5% with an increasing frequency with advancing age.[24] They are lined with a biliary type epithelium and contain serous fluid. Simple hepatic cysts can be differentiated from PCLD by the lack of an autosomal dominant inheritance, lack of associated renal cysts and smaller number of cysts (less than four). Simple hepatic cysts are more often discovered in women and are almost always asymptomatic.

30.5.1 Imaging of Liver Cysts 30.5.1.1 USG

A simple liver cyst has three acoustic properties which are pathognomonic: It is anechoic, has a well defined capsule, and exhibits posterior enhancement (increased through transmission of sound). Some cysts may contain a thin septum. Occasionally hemorrhage or infection in a cyst gives rise to low-level, fine echoes within it. Sonography is usually definitive but simple cysts must be distinguished from cystadenomas, pancreatic pseudocyst within an interlobular

fissure, abscess, and a large arteriovenous malformation. Cystic metastases are seen with neuroendocrine tumors, sarcoma, melanoma, certain subtypes of lung and breast carcinoma, and mucinous adenocarcinomas such as colorectal or ovarian carcinoma. Presence of debris, mural nodularity, thick septa, and thick walls argue against a diagnosis of simple cyst.[10] 30.5.1.2 CT scan

On a CT, cysts appear as water density (−10 to +10 Hounsfield units), sharply defined lesions with no visible wall and no more than two internal septa. No enhancement of the cyst contents or wall is found. Cysts in PCLD are often altered due to hemorrhage. Calcification in some cyst walls is frequently seen in polycystic disease.[10] 30.5.1.3 MRI

Unenhanced MRI may not be definitive, as cysts, hemangiomas, and necrotic and hypervascular neoplasms may all appear hypointense on T1-weighted and markedly hyperintense on T2 weighted images.[10] No enhancement is seen after administration of gadolinium chelates.[28] On the basis of the above features, either CT alone or MR imaging alone is sufficient to establish an accurate diagnosis of a simple hepatic cyst in most of the cases. For detection of complications in PCLD, MR imaging is more sensitive than CT scan.[28]

30.6 BILIARY MICROHAMARTOMAS (VON MEYENBURG COMPLEX) 30.6.1 Prevalence Biliary microhamartomas are a common incidental findings in either sex.[29] In a series of 2,834

Tropical Hepatogastroenterology

BILE DUCT ADENOMA

autopsies in adults, biliary microhamartomas were found in 5.6% of cases. Of the patients with biliary microhamartomas, 11% had adult polycystic kidney disease, whereas 97% of patients with adult polycystic kidney disease had biliary microhamartomas.[30]

30.6.2 Pathology Biliary microhamartomas are small – usually less than 0.5 cm in diameter. They appear grossly as tiny gray-white or green nodules and are usually found throughout the liver. Bile duct hamartomas originate from embryonic bile ducts that fail to involute.[31] Microscopically, they appear as irregular, ecstatic, branched ductal structures lined by flattened or cuboidal epithelium.[31] They are in direct communication with the normal biliary radicals of neighboring portal tracts and their lumen contains proteinaceous or bile stained secretions. Obliteration of the biliary communication can lead to progressive dilation and cyst formation.[31]

459

characterize by morphology or hemodynamics on a CT scan.[10] 30.6.3.3 MRI

All lesions are hypointense relative to liver parenchyma on T1-weighted images and strongly hyperintense on T2-weighted images. At MR cholangiography, bile duct hamartomas appear as multiple tiny cystic lesions that do not communicate with the biliary tree. Gadolinium enhanced T1-weighted MR images shows that some of the lesions have a rim like peripheral enhancement.[28] At both CT and MR imaging, multiple small cystic lesions in the liver without renal involvement should favor the diagnosis of Biliary hamartomas. However MR imaging may be superior to CT scan.[28] In contrast, CT and MR imaging in Caroli disease show hypoattenuating dilated cystic structures of varying sizes that communicate with the biliary tree. Presence of strong central contrast enhancement (the ‘central dot’ sign) is very suggestive of Caroli disease.

30.6.3 Imaging of Biliary Microhamartomas 30.6.3.1 USG

30.7 BILE DUCT ADENOMA

Sonography is useful to confirm that the tiny lesions are not cysts.

Also referred to as ‘benign cholangioma’ and ‘cholangioadenoma’, the main significance of a bile duct adenoma (BDA) lies in its potential for confusion with adenocarcinoma at laparoscopy or laparotomy.[31]

30.6.3.2 CT scan

Nonenhanced CT shows multiple, hypoattenuating, cyst-like hepatic nodules occurring throughout both lobes of the liver and measuring less than 1.5 cm in diameter.[28] Bile duct hamartomas have a more irregular outline whereas simple cysts are typically regularly outlined. No enhancement is seen on contrast-enhanced CT images. Often the lesions are too small to

Part VI / Liver Failure

30.7.1 Clinical Features No symptoms or signs have been attributed to this tumor and BDA is invariably an incidental finding at surgery or autopsy. Most reported patients are men over 40 years of age.[4]

460

Chapter 30 / BENIGN LIVER TUMORS

30.7.2 Pathology In 90% of cases, BDA is a solitary, subcapsular nodule, 0.5–1 cm in size. Over 90% of BDAs are 1 cm or less in diameter, but tumors up to 4 cm in diameter have been reported. Grossly, they are firm, grey-white, well-demarcated but unencapsulated tumors. BDAs are composed of small, round, normal appearing bile ducts in a fibrous stroma. The lining epithelium is biliary type cuboidal cells.[31] The supporting stroma is scanty and typically contains numerous lymphocytes.

30.7.3 Pathogenesis The origin of BDA is obscure. The most favored hypothesis is a reactive process to a focal biliary injury, possibly postinflammatory.[32] BDAs undergo progressive hyalinization with attenuation of ductules, resulting in a scar. Malignant change has not been documented.

30.8 BILIARY CYSTADENOMA A biliary cystadenoma (BCA) is a rare, slow growing, multilocular cystic tumor. There are two histological variants: mucinous and serous. The former variety is much more common. BCAs resemble their histological counterparts in the pancreas.

30.8.1 Mucinous BCA 30.8.1.1 Pathology

Grossly, the tumor appears as a multilocular (rarely unilocular) cyst. The size ranges from 2.5 to 28 cm (mean 15 cm), and the cyst contains clear to cloudy, mucinous or gelatinous fluid, of white, yellow or brown color. BCAs are lined by mucin-secreting columnar or cuboidal, biliary type epithelium. The epithelium

FIGURE 30.4 Photomicrograph of a patient with a biliary cystadenoma (10x), demonstrating a cyst lined by mucin-secreting biliary type epithelium and a cellular stroma.

is single layered but may form small papillary foldings and cystic invaginations.[28] The immunohistochemical profile (positive for cytokeratin, epithelial membrane antigen and carcinoembryonic antigen) is similar to that of normal bile ducts (Fig. 30.4). The tumor is supported by a compact and cellular stroma. The stroma cells are spindle shaped and are immunoreactive with Vimentin, Actin, and Desmin. Interestingly, this ‘mesenchymal stroma’ is found exclusively in female patients.[33, 34] A pseudocapsule of collagenous tissue often separates the cyst from adjacent liver parenchyma. BCA must be differentiated from solitary cysts and polycystic disease. 30.8.1.2 Clinical features

BCA is predominantly a tumor of middle aged women. Over 90% of cases are females and 80% of them are over 30 years in age.

Tropical Hepatogastroenterology

BILIARY PAPILLOMATOSIS

BCA are nearly always symptomatic.[31] The most frequent presentation is abdominal swelling and/or pain. Biliary obstruction with jaundice and cholangitis, hemorrhage, rupture or inferior vena-cava obstruction, and symptoms of gastric compression can occur.[35] BCA is a slow growing tumor and frequently reaches a large size. It is considered a premalignant lesion. In the largest reported series, 6 of 18 cystadenocarcinomas had areas of benign cystadenoma, and 7 of 51 cystadenomas harbored foci of dysplasia.[36] 30.8.1.3 Imaging of BCA

CT scan: On CT, BCA appears as a solitary, cystic mass with a well defined thick fibrous capsule, mural nodules, internal septa, and, rarely, capsular calcification.[28] Papillary areas and polypoid projections from the wall may be seen. MRI offers no advantage over a CT scan. It shows homogenous low signal intensity on T1- and high signal intensity on T2- weighted images. No current imaging technique is capable of distinguishing between cystadenoma and cystadenocarcinoma. 30.8.1.4 Treatment

Complete surgical removal is mandatory and usually curative. Recurrence is inevitable following incomplete excision.[35]

30.8.2 Serous BCA Serous type of BCA is rare. It consists of numerous small cystic spaces lined by a single layer of cuboidal cells. There is no mesenchymal stroma, unlike the mucinous variety. The serous variety does not seem to have malignant potential.

Part VI / Liver Failure

461

30.9 BILIARY PAPILLOMATOSIS Biliary papillomatosis is very rare. Only 50 cases have been reported in the literature.[31]

30.9.1 Pathology Grossly, soft and friable papillary masses fill the dilated intra- and extrahepatic bile ducts. The gallbladder and main pancreatic duct may also be involved.[37] Microscopically, the papillary adenomas are composed of branching papillary fronds covered by mucus secreting columnar epithelium and supported by delicate fibrovascular stalks. The epithelium is adenomatous with variable degrees of atypia. The bile duct walls are fibrotic and show features of chronic inflammation.

30.9.2 Clinical Features Biliary papillomatosis is seen in middle-aged and older age groups with a higher reported incidence in males. The disease manifests with recurrent episodes of obstructive jaundice and cholangitis. Hemobilia and secondary choledocholithiasis may occur.[10] The natural history of the disease is characterized by relentless progression. Patients die within a span of few years as a result of recurrent biliary infections, liver failure or malignant transformation.

30.9.3 Treatment Treatment is difficult because of the multicentricity of the tumor, and the propensity to grow and spread along the biliary tree.

30.10 HEMANGIOMA Hemangioma is the most common benign hepatic tumor. The prevalence of liver hemangioma in autopsy studies varies from 0.4% to 20%.[8, 10, 38, 39]

462

Chapter 30 / BENIGN LIVER TUMORS

fibrotic and shrink in patients with progressive cirrhosis.[41]

30.10.2 Clinical Features

FIGURE 30.5 Photomicrograph of a patient with a hemangioma of the liver, showing thin walled vascular spaces lined by a single layer of endothelial cells and separated by fibrous septa.

Hemangiomas are congenital hamartomas with growth in size occurring because of progressive ectasia.

30.10.1 Pathology The size of liver hemangiomas varies from less than 1 cm to more than 20 cm. Tumors larger than 4 cm are called ‘giant hemangiomas’. Hemangiomas are commonly located in a subcapsular location in the right lobe of liver.[10] Hemangiomas consist of an aggregation of thin walled vascular spaces, lined by a single layer of endothelial cells and separated by fibrous septa (Fig. 30.5). The vascular spaces may thrombose and develop fibrosis or calcification. Hemangiomas are uncommon in cirrhotic livers; the fibrotic process in cirrhotic liver may prohibit their development.[40] According to the findings of a recent study, hemangiomas become

Hemangiomas are most prevalent in women (5:1) in the third to fifth decades of life. They are often symptomatic and discovered incidentally during imaging for unrelated disorders. Lesions larger than 4 cm cause symptoms in 40% of cases and those lager than 10 cm are symptomatic in 90% of cases.[4] Symptoms attributable to larger hemangiomas include a dull upper abdominal discomfort and compressive symptoms, including early satiety and nausea. Some hemangiomas become symptomatic initially during pregnancy or show an increase in size.[38, 39] Thrombosis in a hemangioma may lead to the triad of right upper quadrant pain and fever with a normal leucocyte count.[6] Consumptive coagulopathy may develop in a large hemangioma and the patient may develop disseminated intravascular coagulopathy – called the ‘KasabachMerritt syndrome’. Rare associations of hepatic hemangiomas have been described with focal nodular hyperplasia (FNH), extra hepatic hemangiomas and Osler-Rendu-Weber syndrome. 30.10.2.1 Hepatic hemangiomatosis

A hemangioma involving a large part of the liver in a diffuse manner is very rare. It can be isolated or associated with extrahepatic hemangioma or Osler-Rendu-Weber disease.

30.10.3 Imaging of Hemangiomas 30.10.3.1 USG

In most patients, the sonographic signs of a hemangioma can be considered definitive. Small

Tropical Hepatogastroenterology

HEMANGIOMA

463

lesions considered too small to characterize on CT can often be well evaluated by USG. At USG, hemangiomas appear as well-circumscribed, uniformly hyperechoic lesions. Hemangiomas are usually very echogenic on sonography due to fibrous septa between the vascular spaces.[10] The increased echogenicity is caused by multiple interfaces between the walls of the cavernous spaces and the blood within them. Hemangiomas may appear hypoechoic in fatty livers. Although USG alone can establish the diagnosis for small lesions, larger hemangiomas are more heteroechoic and require further imaging studies.[9] Because of the slow rate of blood flow within hemangiomas, Doppler and Power Doppler lack sensitivity.

uncommon, and may be marginal or central, spotty or chunky.

30.10.3.2 CT scan

MRI is more sensitive and specific than other imaging modalities for the diagnosis of hemangiomas. Hemangiomas appear as smooth, lobulated, homogeneous, sometimes septate, hypointense lesions on T1-weighted images. On T2-weighted images, they appear hyperintense relative to the liver. When USG or CT is not definitive, MRI can be helpful. Bolus intravenous administration of gadolinium demonstrates the same nodular peripheral enhancement and centripetal fill in T1-weighted images.[43, 44]

Using proper CT techniques, a confident diagnosis should be achieved in at least 90% of cases. Hemangiomas are nearly isodense to large blood vessels on an unenhanced CT. After contrast injection, hemangiomas show nodular or cloudlike peripheral enhancement with progressive centripetal fill-in with time. This pattern of a progressive centripetal fill-in is considered pathognomonic for hemangiomas. Small hemangiomas may demonstrate rapid uniform enhancement. Hemangiomas remain isodense to blood vessels on portal venous and delayed phases of enhancement whereas other benign and malignant masses usually become hypodense to blood vessels and liver.[10, 42] Classically, the lesion completely opacifies with a delay of more than 3 minutes and remains hyperdense on delayed images for up to 60 minutes.[4] Larger hemangiomas more than 5 cm in diameter may have a central area of necrosis that may rarely calcify. Overall, calcification in a hemangioma is

Part VI / Liver Failure

30.10.3.3 Radionuclide studies

Red blood cells labeled with Tc-pertechnetate show an initial hypoperfusion (cold spot) followed by a gradual accumulation of the tracer that peaks at 30–60 minutes and is then retained on delayed images. The specificity of the radionuclide study approaches 100% with a variable sensitivity.[43] Combining the use of single photon emission CT (SPECT) increases the sensitivity and spatial resolution. 30.10.3.4 MRI

30.10.3.5 Angiography

At angiography, the feeding vessels are of normal caliber, except those in large tumors. During the late arterial/hepatic parenchymal phases, a dense, nodular pattern of opacification persists into the venous phase. Although hemangiomas have characteristic angiographic features, the use of angiography is not warranted for diagnosis, given the diagnostic capabilities of less invasive techniques, such as CT and MRI.

464

Chapter 30 / BENIGN LIVER TUMORS

Hemangiomas that show early, homogeneous contrast enhancement at dynamic CT and/or MRI may be mistaken for other hypervascular liver tumors such as hepatoma, focal nodular hyperplasia, adenoma, and hypervascular metastases. The absence of a history of cirrhosis and/or primary malignancy is an important factor in diagnosing hemangioma. The characteristic features of a hemangioma on dynamic CT, radionuclide scintigraphy, and/or MRI should permit a confident diagnosis in more than 95% of cases.

30.10.4 Natural History During follow up periods of up to 15–20 years most patients remain symptom and complication free.[39, 45] Spontaneous rupture is very rare

and malignant transformation does not occur. Gandolfi et al followed 158 hemangiomas with ultrasonography for 12–60 months. Only one initially asymptomatic patient became symptomatic during the follow up. None developed any complication.[46] Liver hemangiomas may grow during pregnancy or with oral contraceptive use.[38]

30.10.5 Treatment Biopsy carries a risk of bleeding and is not indicated. No treatment is indicated in the majority of cases. Surgical enucleation, arterial embolization, steroids and radiation have been used to treat symptomatic hemangiomas.

REFERENCES [1] Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386–394. [2] Edmonson H, Henderson B, Benton B. Liver cell adenomas associated with use of oral contraceptives. N Engl J Med 1976;294:470–472. [3] Rooks J, Ory H, Ishak K et al. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979;242:644–648. [4] Molina EG. Benign solid lesions of the liver. In: Schiff ER, Sorrel MF, Maddrey WC, eds. Diseases of the Liver. Volume 2. 9th edition. Lippincott Williams & Wilkins, 2003:1353–1376. [5] Grazioli L, Federle MP, Brancatelli G et al. Hepatic adenomas: imaging and pathologic findings. RadioGraphics 2001;21:877,894. [6] Benhamou JP, Bruguera M, Flejou JF et al. Benign hepatic and biliary tumors. In: Bircher J, Benhamou JP, McIntyre N, Rizzeto M, Rodes, eds. Oxford Textbook of Clinical Hepatology. Volume

[7]

[8] [9]

[10]

[11]

[12]

2. 2nd edition. Oxford University Publications 1999:1483–1490. Arsenault T, Johnson D, Gorman B et al. Hepatic adenomatosis. Mayo Clin Proc 1996;71: 478–480. Rubin R, Mitchell D. Evaluation of the solid hepatic mass. Med Clin North Am 1996;86:907–928. Nisembaum H, Rowling S. Ultrasound of focal hepatic lesions. Semin Roentgenol 1995;30: 324–346. Federle MP, Brancatelli G. Imaging of benign hepatic masses. Semin Liver Dis 2001;21: 237–249. Chung K, Mayo-Smith W, Saini S et al. Hepatocellular adenoma: MR imaging features with pathologic correlation. Am J Roentgenol 1995;165:303–308. Scott L, Katz A, Duke J et al. Oral contraceptives, pregnancy and focal nodular hyperplasia of the liver. JAMA 1984;251:1461–1463.

Tropical Hepatogastroenterology

REFERENCES

[13] Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985;5:1194–1200. [14] Nguyen B, Flejou J, Terris B et al. Focal nodular hyperplasia of the liver. Am J Surg Pathol 1999;23:1441–1454. [15] International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995; 22:983–993. [16] Mathieu D, Zafrani E, Anglade M et al. Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology 1989;97: 154–157. [17] Kehagias D, Moulopoulos L, Antoniou A et al. Focal nodular hyperplasia: imaging findings. Eur Radiol 2001;11:202–212. [18] Mathieu D, Bruneeton J, Drouillard J et al. Hepatic adenomas and focal nodular hyperplasia: dynamic CT study. Radiology 1986;160:53–58. [19] Mortele K, Praet M, Van Vlierberghe et al. CT and MRI imaging findings in focal nodular hyperplasia of the liver. Am J Roentgenol 2000;175: 687–692. [20] Weimann A, Ringe B, Klempnauer J et al. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 1997;21:983–991. [21] Stasi M di, Caturelli E, Sio I da et al. Natural history of focal nodular hyperplasia of the liver: an ultrasound study. J Clin Ultrasound 1996;24:345–350. [22] Wanless I. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11:787–797. [23] Butron Vila MM, Haot J, Desmet VJ. Cholestatic features in focal nodular hyperplasia of the liver. Liver 1984;4:387–395. [24] Gaines PA, Sampson MA. The prevalence and characterization of simple hepatic cysts by ultrasound examination. Br J Radiol 1989;62: 335–337. [25] Karhunen PJ, Tenhu M. Adult polycystic liver and kidney disease are separate entities. Clin Genet 1986;30:29–37.

Part VI / Liver Failure

465

[26] Kwok MK, Lewin KT. Massive hepatomegaly in adult polycystic liver disease. Am J Surg Pathol 1988;12:321–324. [27] Ramos A, Torres VA, Holley KE et al. The liver in autosomal dominant polycystic kidney disease. Implications for pathogenesis. Arch Pathol Lab Med 1990;114:180–184. [28] Mortele KT, Ros PR. Cystic focal liver lesions in the adult: differential CT and MR imaging features. RadioGraphics 2001;21:895–910. [29] Chung EB. Multiple bile-duct hamartomas. Cancer 1970;26:287–296. [30] Redston M, Wanless I. The hepatic von Meyenburg complex with hepatic and renal cysts. Med Pathol 1996;9:233–237. [31] Colombari R, Tsui WMS. Biliary tumors of the liver. Semin Liver Dis 1995;15:402–413. [32] Allaire GS, Rabin L, Ishak KG et al. Bile duct adenoma: a study of 152 cases. Am J Surg Pathol 1988;12:708–715. [33] Wheeler DA, Edmondson HA. Cystadenoma with mesenchymal stroma (CMS) in the liver and bile ducts: A clinicopathologic study of 17 cases, 4 with malignant change. Cancer 1985;56: 1434–1445. [34] Akwari OE, Tucker A, Seigler HP et al. Hepatobiliary cystadenoma with mesenchymal stroma. Ann Surg 1990;211:18–27. [35] Lewis WD, Jenkins RL, Rossi RL et al. Surgical treatment of biliary cystadenoma: A report of 15 cases. Arch Surg 1988;123:563–568. [36] Devaney K, Goodman ZD, Ishak KG. Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. Am J Surg Path 1994:18:1078–1091. [37] Hubens G, Delvaux G, William G et al. Papillomatosis of the intra- and extra-hepatic bile ducts with involvement of the pancreatic duct. Hepatogastroenterology 1991;32:413–418. [38] Hobbs K. Hepatic hemangiomas. World J Surg 1990;14:466–471. [39] Nicholas F, Van Heerden J, Weiland L. Benign liver tumors. Surg Clin North Am 1989;69:297–315. [40] Dodd GD III, Baron RL, Oliver JH 3rd et al. Spectrum of imaging findings of the liver in

466

Chapter 30 / BENIGN LIVER TUMORS

end-stage cirrhosis: Part II, focal abnormalities. Am J Roentgenol 1999;173:1185–92. [41] Brancatelli G, Federle MP, Blachar A et al. Hemangioma in the cirrhotic liver: diagnosis and natural history. Radiology 2001;219:69–74. [42] Van Leeuwen, Noordzij J, Feldberg M et al. Focal liver lesions: characterization with triphasic spiral CT. Radiology 1996;201:327–336. [43] Kinnard M, Alavi A, Rubin R et al. Nuclear imaging of solid hepatic masses. Semin Roentgenol 1995;30:375–395.

[44] Stark D, Felder R, Wittemberg et al. Magnetic resonance imaging of cavernous hemangioma of the liver: tissue specific characterization. Am J Roentgenol 1985;145: 213–222. [45] Trastek V, Van Heerden, Sheedy P II et al. Cavernous hemangiomas of the liver: resect or observe? Am J Surg 1993;145:49–53. [46] Gandolfi L, Leo T, Solmi L et al. Natural history of hepatic hemangiomas: clinical and ultrasound study. Gut 1991;32:677–680.

test

Tropical Hepatogastroenterology

x

Part VII Gallbladder and Biliary Tract

31 32 33 34

Gallstone Disease Gallbladder Cancer and Cholangiocarcinoma Choledochal Cysts Benign Bile Duct Strictures

469 485 514 528

“This page intentionally left blank"

xx

Chapter

31 GALLSTONE DISEASE Gourdas Choudhuri and Radha Krishnan

Gallstone disease is an important cause of morbidity in the Indian population. Clinical descriptions of biliary tract disease appeared vividly in the writing of the ancient Indian physicians, Charaka (2nd Century BC) and Shushruta (6 century BC). Operations on the biliary tract are more frequent than any other major surgical intervention in the abdomen. Significant advances have occurred in our understanding of the physiochemical relationship of the biliary lipids providing insight into, if not complete, elucidation of the mechanisms of gallstone formation.

31.1 COMPOSITION OF GALLSTONES Gallstones are classified on the basis of composition into cholesterol and pigment (brown or black) types. Each type of stone has unique epidemiologic features and characteristic risk factors. This classification is based not only on the physical properties of stone but also on studies of their composition using: (a) chemical analysis (b) scanning electron microscopy of the outer or split surface of the stone (c) X-ray powder diffraction (to study the crystalline content of the stone) (d) electron microprobe analysis

(e) radiology of ultrathin sections (f) staining techniques analogous to those used in biochemistry–for example, to show qualitatively, the process of mucus glycoprotein. Cholesterol stones are the most common type of gallstones in the Western population, and are composed purely of cholesterol or have cholesterol as the major chemical constituent. The pure cholesterol stones are generally large and yellow-white in appearance. They are microscopically composed of many long, thin cholesterol monohydrate crystals bound together by a matrix of mucin glycol protein with a black core composed of a calcium salt of unconjugated bilirubin. Mixed cholesterol gallstones consist of more than 50% cholesterol and are slightly more common than pure cholesterol stones. Mixed stones tend to be smaller than pure cholesterol stones which are often multiple. Cholesterol gallstones obtained from different geographical regions have been reported to show significant variations in their physiochemical characteristics that may explain the differences in their brittleness to lithotripsy.[1] Black pigment stones are composed of either pure calcium bilirubinate or polymer-like complexes with calcium, copper and large amounts of mucin glycoproteins. Black gallstones are more 469

470

Chapter 31 / GALLSTONE DISEASE

common in patients with cirrhosis and chronic hemolysis. Brown pigment stones are composed of calcium salts of unconjugated bilirubin with varying amounts of cholesterol and protein. These stones are usually associated with infection. Microscopically, brown stones contain cytoskeletons of bacteria, which is consistent with the notion that bacterial infection is a prerequisite for brown stone formation.

TABLE fy 31.1 Gallstone prevalence in four different communities of rail road workers in Delhi[3] Community no. (%)

(N)

Punjabis Gujaratis Bengalis South Indians N = number of subjects studied

(203) 15(7.4%) (142) 6(7.4%) (545) 24(4.4%) (214) 4(1.8%) (GUT 1968;9:290–295)

GS Prevalence

31.1.1 Composition of Gallstones in India The predominant morphological type of gallstones in India is the mixed stone or the pigment stone as opposed to the West where cholesterol stones predominate. Even within India, there is a striking difference both in the incidence of gallstone disease and the type of stones seen in different parts of the country. Mixed stones and cholesterol stones are commonly seen in north India. Pigment stones are more frequent in south India.[2]

31.2 INCIDENCE AND PREVALENCE With the advent of portable ultrasound machines, several authors have estimated the prevalence of gallstones in the community. Most studies have shown 5%–20% of women under the age of 55, and 25%–30% of them above that age, to harbor stone in their gallbladder; the prevalence for men was approximately half of that of women. The true prevalence of gallstones in India is not known. It can only be estimated by doing an extensive ultrasonographic survey of random populations in different parts of the country. At Delhi, two epidemiological study showed prevalence of 1.8%–7.4% (Mixed population composed of South Indians, North Indians and Bengalis) (Table 31.1).[3, 4]

FIGURE 31.1 Changing trends in etiopathogenesis and types of gallstones.

In a study from Kashmir the prevalence of gallstones was found to be 6.12% (Men 3.1% and women 9.6%) (Fig. 31.1).[5]

31.3 RISK FACTORS (Table 31.2) 31.3.1 Genetic and Racial Factors Gallstones and supersaturated bile are more common in first degree relatives of known gallstone carriers than the general population.[6] The prevalence of gallstones varies widely throughout the world. In many cases genetic factors play a significant role.

Tropical Hepatogastroenterology

RISK FACTORS

TABLE fy 31.2 Risk factors for gallstone formation Increasing age∗ Obesity, rapid weight loss Pregnancy Fibric acid derivatives (or fibrates), contraceptive steroids, postmenopausal estrogens, progesterone, octreotide (Sandostatin), ceftriaxone (Rocephin) Ethnicity Pima Indians, Scandinavians Family Maternal family history of gallstones Gender Females Hyperalimentation Total parenteral nutrition,† fasting Ileal and other Ileal disease (Crohn’s disease), metabolic diseases resection or bypass,∗ high triglycerides, diabetes mellitus, chronic hemolysis,∗ alcoholic cirrhosis,∗ biliary infection,∗ primary biliary cirrhosis, duodenal diverticula,∗ truncal vagotomy, hyperparathyroidism, low level of high-density lipoprotein cholesterol

Age Body habitus Childbearing Drugs

∗ Risk † Risk

factors for pigment gallstone formation factor for cholesterol and pigment gallstone formation

The well studied populations include Pima Indians in Southern Arizona with an extremely high prevalence of gallstones of 70% among women elder than 25 years. Other high-risk populations are the Scandinavians, in 50% of whom gallstone disease develops by the age of 50 years, as well as other American Indian groups in Alaska, Canada, the continental United States and Bolivia. Populations at the lowest risk reside in sub-Saharan Africa and Asia. In India an epidemiological study in 1966 demonstrated in rail road workers that the gallstones occurred seven times more frequently in north Indians than in south Indians.[3] Besides ethnic influence, dietary differences in the two regions of the country were suspected to be responsible for the difference in the prevalence rate.

Part VII / Gallbladder and Biliary Tract

471

31.3.2 Age and Sex The prevalence of gallstones increases with age, without other risk factors, they are rare before puberty. The average age of female population with gallstone disease in India is 43 years which is a decade younger than that in the west.[4] The peak incidence for male and female patients in north India has been reported to be 47.8 and 43.7 years compared to 50.6 and 45.8 years respectively from south India. In India 3/4th of the patients with gallstones are women. The male: female ratio in north India is 1:2.7–3.3 as compared to 1:1.2 in south Indian studies. The higher frequency of gallstones in women suggests that female sex hormones increase the risk of gallstone formation. Many studies suggest that both endogenous and exogenous estrogens (OC Pills or hormone replacement therapy) reduce bile flow and adversely affect bile lipid composition.

31.3.3 Pregnancy and Parity Pregnancy is a clear risk factor for the development of biliary sludge and gallstones, and frequency of new sludge and gallstone formation during pregnancy is approximately 30% and 2% respectively. Sludge disappears in 60%–70% and stones in 20%–30% of woman after delivery. Parity is a frequently found risk factor for development of gallstones. In several studies fecundity was associated with increased prevalence of gallstones. However the absolute risk seems to be small.

31.3.4 Obesity, Weight Loss, and Total Parental Nutrition Gallstones are more common in obese people than in the nonobese. This is due partly to abnormalities

472

Chapter 31 / GALLSTONE DISEASE

in bile lipid secretion and composition. There is 3 fold increase in gallstones prevalence in obese females. In males no association with BMI is present but there is significant relationship with waist/hip ratio. In Indian patient with gallstone disease obesity was not found to be a common feature, the mean BMI being 23.5.[4] Rapid weight loss is a recognized risk factor for cholesterol gallstone formation. Gallstones developed in 25% of obese patients who are on strict dietary restriction, and in up to 50% of patients who have gastric bypass, gallbladder sludge or gallstone developed within 6 months of surgery. TPN is associated with development of gallbladder sludge and gallstone formation, presumably because of gallbladder hypomotility with bile stasis.

31.3.5 Dietary Factors and Hyperlipidemia There has been much debate over the role of diet in cholesterol gallstone disease and increase intake of cholesterol, fat, calories and refined, carbohydrate or a lack of dietary fiber have all been blamed.[7–9] In a study among north Indian population, higher intake of calories and carbohydrates was found in gallstone patients.[5] Among south Indian population, significant association between gallstone formation and use of tamarind was found. (Common ingredient of diet in south India)[8] A high serum cholesterol level does not seem to be a risk factor for the development of gallstones. In fact, some studies have shown an inverse relationship between serum cholesterol level and the risk of gallstones. On the other hand, hypertriglyceridemia is positively associated with an increased incidence of gallstones.

31.3.6 Drugs Drugs which increase the risk of developing gallstones include: (a) Clofibrate (b) Estrogen rich OC pills, also estrogen containing hormone replacement therapy. (c) Octreotide (d) Ceftriaxone.[10]

31.3.7 Systemic Diseases Studies from the west show gallstones occur two to three times more often in patients with cirrhosis than controls. Factors such as hypersplenism with a shortened red cell survival time, and a reduced activity of hepatic glucuronyl transferase might account for a greater than normal ‘spill’ of unconjugated bilirubin into bile, and the formation of calcium bilirubinate stones. In a study of 615 patients of portal hypertension by Sarin et al,[11] gallstones were observed in 7.2% of PHTN patients compared with 3.1% of controls. The prevalence of gallstones was 6.8% in cirrhosis, 10.2% in NCPF and 4.3% in EHPVO patients. The overall prevalence was similar in cirrhotics and noncirrhotics (6.8% vs. 6.6%). Since gallstones are equally common in cirrhotic and noncirrhotic PHTN patients, a role of portal hypertension (PHTN) per se in the genesis of gallstones needs to be considered. Gallstones are more common in patients with chronic hemolytic disorders such as sickle cell disease, thalassemia and spherocytosis than in individuals with normal hematology. Tripathy et al detected a 10% incidence of gallstones in patients with sickle cell disease from Orissa.[12] In a study, increased prevalence of gallstone in patients who had evidence of insulin resistance associated with hypertriglyceridemia, obesity, and

Tropical Hepatogastroenterology

PATHOGENESIS

473

gallbladder hypomotility was observed, but it is difficult to prove that diabetes is an independent risk factor for gallstone formation.

31.4 PATHOGENESIS 31.4.1 Pathogenesis of Cholesterol Gallstones Three defects are intimately involved in gallstone formation–cholesterol supersaturation, accelerated nucleation, and gallbladder hypomotility. 31.4.1.1 Cholesterol supersaturation

Cholesterol, phospholipids, and bile acids are the major lipid components in the bile. The degree of cholesterol saturation in gallbladder bile is the single determinant of crystal formation in human beings. Cholesterol is virtually insoluble in aqueous solution but in bile, it is made soluble by association with bile salts and phospholipids in the form of mixed micelles and vesicles.[13–16] The cholesterol saturation index (CSI) (ratio of cholesterol content to phospholipids) more than 1 indicates saturated bile and increased risk of cholesterol precipitation and crystal formation. In unsaturated bile, cholesterol is predominantly in simple and mixed micelles forms. Micelles are aggregates of lipids with nonpolar hydrocarbon chains directed inward and polar phosphate or hydroxyl groups directed outward towards the aqueous solvent. Vesicles are spherical bilayers of phospholipids with nonpolar hydrocarbon chains hidden inside the bi-layer and polar directed outward towards the aqueous solvent. At higher cholesterol concentrations increasing amounts of cholesterol are carried in vesicles. Single layered (unilamellar) vesicles fuse into multilayered (multilamellar) vesicles

Part VII / Gallbladder and Biliary Tract

FIGURE 31.2 Triangular coordinates showing the solubility of cholesterol in a mixture containing phospholipids and bile salts.

and cholesterol crystals can grow from their surfaces.[17] These crystals presumably grow and agglomerate with mucin proteins in bile to form stones. The molar proportions of cholesterol, phospholipids, and bile acids in bile are often represented on triangular coordinates (Fig. 31.2).[18–20] Each side of the triangle shows the molar fraction of total lipids represented by its constituent as an example, the three dotted lines define a mixture containing a molar ratio of 15% cholesterol, 30% lecithin and 55% bile salts at higher saturations. Cholesterol exists in multiple phases–as crystals, micelles, or vesicles. The phase diagram indicates that this cholesterol content is greater than that which can exist in stable micellar liquid, or in a metastable saturated liquid. Eventually therefore, cholesterol crystals will precipitate from this bile.

474

Chapter 31 / GALLSTONE DISEASE

In vitro studies of model bile mixtures show that cholesterol is the most soluble in a mixture of lipids containing at least 50% bile acids with smaller amounts of phospholipids. Bile acids that flow into small bowel are recirculated by reabsorption in the terminal ileum and secretion into bile by the liver. Bile acids in liver cause a decrease in rate limiting step in bile acid synthesis. In general, greater the degree of cholesterol supersaturation greater is the risk of cholesterol gallstones. Lithogenic bile is most often the result of increased biliary cholesterol output, but in some ethnic groups there is decreased bile acid synthesis or a combined defect. 31.4.1.2 Nucleating and antinucleating factors

Cholesterol stones do not develop uniformly in persons with cholesterol supersaturated bile. When human bile supersaturated with cholesterol is filtered to remove crystals and allowed to incubate at 37◦ C, the first crystals appear after intervals of hours to more than a week. This represents the time required for the nucleation of cholesterol crystals, i.e., the formation of first microscopic collections that serve as framework for further crystal growth. A large number of potential pronucleators as well as nucleation inhibitors have been identified and studied. The physiologic relevance of these proposed factors (with the exception of mucin) continues to be debated. Mucin glycoproteins are the most important pronucleators to be identified.[17] Because mucin and bilirubin are frequently found in the core of cholesterol gallstones, this complex may serve as a nidus for stone formation. Mucin glycoproteins are normally secreted continuously from the gallbladder. However, mucin secretion is excessive in lithogenic bile. Secre-

tion of mucin is mediated, at least in part, by prostaglandins which are synthesized from arachidonic acid. Administration of aspirin prevents gallstone formation in prairie dogs and reduces mucin secretion in human beings. However, patients who chronically ingest NSAIDs have similar prevalence of gallstone diseases as those who do not do this. Other pronucleators isolated are immunoglobulin G (IgG), IgM, aminopeptidase-N, heptoglobulin, and alpha-1 acid glycoprotein. Antinucleating proteins that have been identified include apolipoprotein A1 and A2, and a biliary glycoprotein. 31.4.1.3 Role of calcium in gallstone formation

Biliary calcium concentration plays a role in bilirubin precipitation and gallstone formation because calcium salts are present in most of the cholesterol gallstones. Calcium carbonate as well as calcium bilirubinate and calcium phosphate can serve as potential nidus for cholesterol crystallization. 31.4.1.4 Gallbladder hypomotility

Gallbladder motor function and mucosal function play critical roles in the formation of gallstones. Impaired gallbladder motility and contractility in patients with cholesterol gallstones prevents complete clearance of nascent crystals presumably facilitating growth to mature gallstones. The increased cholesterol content of bile alters the cholesterol content of the sarcolemmal membrane and impairs contractility. Patients with gallstones have a diminished gallbladder contractile response to intravenously administered cholecystokinin. A potential complication of gallbladder stasis is the formation of sludge which can occur

Tropical Hepatogastroenterology

PATHOGENESIS

475

are a contributory factor in a subgroup of patients. 31.4.1.6 Genetic factors

FIGURE 31.3 Cholesterol hypersecretion: Factors influencing supersaturation (CEH – cholesterol ester hydrolase, C7αH – cholesterol 7-α hydrolase, HCA – HMG CoA reductase).

in patients who have high spinal cord injuries, prolonged use of TPN, prolonged treatment with octreotide, who are pregnant, or who experience rapid weight loss. 31.4.1.5 Role of intestinal transit

Elevated levels of the hydrophobic bile acid deoxycholate are associated with gallstone formation. The observation that cholesterol gallstones are prevalent in acromegalic patients treated with octreotide led to studies demonstrating that these patients have prolonged intestinal transit times, increased levels of deoxycholate in bile, and cholesterol hypersaturation (Fig. 31.3). Although not all patients with cholesterol gallstones have elevation in biliary deoxycholate levels, it is likely that prolonged intestinal transit time and increased deoxycholate levels together

Part VII / Gallbladder and Biliary Tract

Several genetically derived phenotypes in a population are responsible for variations in lipoprotein types, which in turn, affect the amount of cholesterol available in the gallbladder. The genetic polymorphisms in various genes for apo E, apoB, apoA1, LDL receptor, cholesterol ester transfer and LDL receptor associated protein have been implicated in gallstone formation. However, presently available information on genetic differences is not able to account for a large number of gallstones patients. The molecular studies in animal models have not only confirmed the present paradigm of gallstone formation, but also helped in identification of novel genes in human beings, which might play an important role in pathogenesis of the disease. Precise understanding of such genes and their molecular mechanisms may provide the basis of new targets for rationale drug designs and dietary interventions.[21] 31.4.1.7 Recent advances in pathogenesis of gallstones

In biliary cholesterol secretion, transport and saturation, recent developments include evidence in human beings and animals that bile lipid secretion is under genetic control. Thus in mice the md-2 gene and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a ‘flippase’ transporting phospholipids from the inner to the outer hemileaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that has ‘lith genes’ are fed a lithogenic diet, they become susceptible to high rates of gallbladder

476

Chapter 31 / GALLSTONE DISEASE

stone formation. The precipitation/nucleation of cholesterol microcrystals from supersaturated bile remains a critical step in gallstone formation. Methods of studying this phenomenon have now been refined from the original nucleation time to measurement of cholesterol appearance/detection time, and crystal growth assay. Furthermore, the results of recent studies indicate that in addition to classical rhomboid-shaped monohydrate crystals cholesterol can also crystallize transiently as needle-, spiral-, and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined. There are many situations where gallbladder stasis in humans is associated with an increased risk of gallstone formation including iatrogenic stone formation in acromegaly patients treated chronically with octreotide (OT). However, octreotide treated patients have‘bad’ bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal nucleation times and a two-fold increase in the percentage of deoxycholic acid (DCA) in bile. This increase in the proportion of deoxycholic acid seems to be due to octreotide induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to–(i) percentage of DCA in serum, (ii) the DCA pool size, and (iii) the DCA input or synthesis rate. Furthermore, the intestinal prokinetic cisapride counters the adverse effects of OT on intestinal transit and normalizes the percentage of DCA in serum/bile. Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic gram-positive anaerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values than stone free controls together. These changes lead to increased DCA formation, solubilization and absorption. Thus, in addition to the ‘lithogenic liver’ and ‘guilty gallbladder’, one must now add the ‘indolent intestine’ to the list of culprits in cholesterol gallstone formation.

FIGURE 31.4 Pathogenesis of pigment gallstones.

31.4.2 Pathogenesis of Pigment Stones Black pigment stones are composed primarily of calcium bilirubinate, but also contain calcium carbonate and calcium phosphate. As much as 20% by weight, black stones are mucin glycoprotein. The unifying characteristic of the conditions that predispose to black stone formation is the hypersecretion of bilirubin conjugates (especially monoglucuronides) into the bile. In the presence of hemolysis, the output of these bilirubin conjugates increases 10-fold (Fig. 31.4). Unconjugated monohydrogenated bilirubin is formed by the action of endogenous beta-glucuronidase, which can then co-precipitate with calcium as a result of supersaturation. An acidification defect has also been documented possibly as a result of inflammation or the buffering capacity of sialic acid and sulfate moieties of the mucus gel. This buffering effect facilitates the supersaturation of calcium carbonate and phosphate, which would not occur at a more acidic pH, and allows precipitation. No gallbladder motility defects were found in patients who had black stones, but mucin hypersecretion may result from increased levels of unconjugated bilirubin.

Tropical Hepatogastroenterology

NATURAL HISTORY OF GALLSTONE DISEASE

Brown pigment stone formation is a result of anaerobic infection of the bile as demonstrated by the finding of bacterial cytoskeletons in the stones. Stasis facilitates bacterial infection as well as accumulation of mucus and bacterial cytoskeletons in the bile ducts. The enteric bacteria produce beta-glucuronidase, phospholipase A, and conjugated bile acid hydrolase. Beta-glucuronidase activity results in the production of unconjugated bilirubin; phospholipase A produces palmitic and stearic acids from phospholipids; and bile acid hydrolases produce unconjugated bile acids. The anionic products of these enzymatic processes can complex with calcium to produce insoluble calcium salts and thereby, resulting in stone formation. Gallstones from south India are probably due to infection rather than supersaturation as evidenced by predominance of pigment calcium stones and various types of bilirubin and calcium carbonate compounds. Vaterite is important for nucleation. Further growth of stones is influenced by epitaxial relationship. These findings are dissimilar to that reported from north India indicating a different stimulus for stone precipitation in these two areas.

31.5 NATURAL HISTORY OF GALLSTONE DISEASE (Fig. 31.5) Most gallstones are asymptomatic and remain so through the lifetime of the patient. Only between 15% and 20% of stones become symptomatic, between 1% and 3% per year, with the most common initial symptom being biliary colic.[22–25] In the 2 years after initial episode, the likelihood of recurrent attacks of biliary pain is high, but the risk of developing biliary complication is only 1%

Part VII / Gallbladder and Biliary Tract

477

FIGURE 31.5 Natural history of gallstones.

to 2% per year. Gallstone disease quite rarely presents as a complication, although symptomatic disease tends to continue to remain so, or to develop complications. Thus, the natural history of asymptomatic gallstones is quite benign, whereas that of symptomatic gallstones follows a more aggressive course. These aspects are crucial in many clinical decisions regarding treatment of patients with gallstones. Diabetic patients with incidental cholelithiasis were long considered to have an increased risk of serious complications even though the gallstones were asymptomatic. More recent studies have shown that the natural history of gallstones in diabetics follows the same pattern as observed in nondiabetics. Therefore, prophylactic cholecystectomy is generally not recommended in diabetics.[25]

31.6 CLINICAL MANIFESTATIONS OF GALLSTONE DISEASE It should be emphasized once again that most gallstones never cause symptoms, and the purely incidental discovery of cholelithiasis rarely warrants specific intervention. The symptomatic stage of gallstone disease manifests itself primarily as attacks of biliary

478

Chapter 31 / GALLSTONE DISEASE

TABLE fy 31.3 Differentiating features of gallstone-induced complications∗ Feature

Biliary colic

Acute cholecystitis

Chronic cholecystitis

Cholangitis

Pancreatitis

Pain site Pain duration Mass Fever Increased WBC Increased amylase level

Epigastrium < 3 hours No masses – – Normal

RUQ > 3 hours RUQ mass ± ± ±

RUQ Variable No masses ± ± –

RUQ Variable ± ± ± ±

Epigastric Variable ± ± ± +

RUQ = right upper quadrant; WBC = white blood cell count; + = present; = absent; ± = present or absent ∗These characteristics may not always be present

colics. Biliary colic is believed to be caused by stone impaction in the cystic duct or gallbladder neck, and the term “biliary colic” is a misnomer. The complicated stage of gallstone disease includes acute and chronic cholecystitis, acute pancreatitis, choledocholithiasis, ascending cholangitis, cholecystoenteric fistula, and gallbladder cancer (Table 31.3).

31.6.1 Gallstones and Gallbladder Cancer Gallbladder cancer is one of the most common gastrointestinal malignancies seen in India. Several possible etiologic factors have been implicated. Gallstones predispose to gallbladder cancer. In a recent review by Batra et al,[26] gallstones were present in 54% of patients with gallbladder cancer. The presence of gallstones is associated with a younger age at diagnosis.[27]

31.6.2 Gallstones and Xanthogranulomatous Cholecystitis Xanthogranulomatous cholecystitis (XGC) is a focal or diffuse destructive inflammatory process

of the gallbladder characterized macroscopically by yellowish tumor–like masses in the wall of the gallbladder. Microscopically, it is characterized in the early stages by large number of foamy histiocytes and acute inflammatory cells. Later stages demonstrate increasing fibrosis. Gallstones are found in almost all patients with xanthogranulomatous cholecystitis (Fig. 31.6). The correct diagnosis of XGC is important for several reasons–first and foremost due to high frequency of complications, and last but not the least because the condition may give rise preoperatively to the suspicion of malignancy.[28]

31.7 DIAGNOSIS A wide array of imaging technologies are available to evaluate cholelithiasis.[29–31] Each test has strengths and limitations, and the tests available vary widely in relative cost and risk to the patient. With the exception of ultrasonography, none of the tests should be ordered routinely in the evaluation and should proceed in a rational, stepwise fashion based on the individual patient’s symptoms, signs and laboratory results. A plain abdominal radiograph can rarely detect gallstones because most stones are radiolucent.

Tropical Hepatogastroenterology

DIAGNOSIS

FIGURE 31.6 Xanthogranulomatous cholecystitis.

and absolutely noninvasive. Abdominal gas and obesity are limiting factors in the use of ultrasonography. Though operator dependent, the accuracy for detection of gallbladder stones, which appear as mobile echogenic foci casting an acoustic shadow, is more than 90% in general. Ultrasonography can also detect biliary sludge. A sonographic Murphy sign (gallbladder tenderness under transducer pressure) is of value in diagnosing acute cholecystitis.[31] Pericholecystic fluid is an additional quite specific indicator of this diagnosis. Despite its significant use in detecting gallbladder stones, ultrasonography even in the best hands has limited value in choledocholithiasis. Only about 25% to 45% of CBD stones are detected by transabdominal ultrasonography. This draw back is some what balanced by the ability of ultrasonography to detect CBD dilatation beyond 7 mm, which generally is regarded as the upper limit of the normal choledochus. Computed tomography (CT) (Figs. 31.8 and 31.9) has limited value in the diagnosis of gallstones for the same reasons as plain radiographs. However, CT adds to the patient evaluation by its capability of detecting or excluding complications such as pancreatitis, pericholecystic fluid, perforation, or abscess formation.

FIGURE 31.7 Typical ultrasound appearance of gallstones. Oblique ultrasound scan shows highly reflective echoes within the gallbladder (arrows), which indicate gallstones. Note the marked posterior shadowing. An oblique ultrasound scan obtained after repositioning the patient will show the mobility of the gallstones.

Fewer than 25% contain enough calcium to be detected by radiographs. Ultrasonography, on the other hand, has become the primary imaging modality in gallstone disease (Fig. 31.7). It is widely available, inexpensive

Part VII / Gallbladder and Biliary Tract

479

FIGURE 31.8 CT scan showing gallstones (arrowhead) in the gallbladder.

480

Chapter 31 / GALLSTONE DISEASE

FIGURE 31.9 CT scans showing dilated intrahepatic biliary radicals (left) caused by a stone in the bile duct (right, arrow).

FIGURE 31.10 MR cholangiogram showing a stone in the terminal bile duct (white arrow) within a markedly dilated CBD.

Oral cholecystography (OCG) was formerly in wide use for diagnosing gallstones but has largely been superseded by ultrasonography. Current use is for patients considered for oral dissolution therapy of gallstones, because OCG can asses cystic duct patency and the cholesterol content of the stones. These characteristics are prerequisites for this form of treatment.

Radionuclide scanning or cholescintigraphy after intravenous administration of a technetium −99 m-labeled iminodiacetic acid derivative is valuable in assessing cystic duct obstruction in the diagnosis of acute cholecystitis and postoperative bile leaks. Nonvisualization of gallbladder in the appropriate clinical setting is considered 95% sensitive and 90% specific for acute cholecystitis. Magnetic resonance imaging (MRI) in its conventional form has little use in gallstone disease. However, magnetic resonance cholangiopancreatography (MRCP), a three-dimensional computer–generated reconstruction of the biliary system, is noninvasive. MRCP at present is an important tool in the diagnosis of choledocholithiasis (Fig. 31.10). Endoscopic ultrasonography (EUS) is becoming increasingly helpful in the assessment of choledocholithiasis. It is superior to transabdominal ultrasonography in diagnosing small gallbladder stones, particularly in obese patients. It is also sensitive in detecting sludge and microcrystals in the gallbladder. EUS is, however significantly operator dependent and not routinely available in many practices.

Tropical Hepatogastroenterology

MANAGEMENT OF GALLSTONES

Endoscopic retrograde cholangiopancreatography (ERCP) has been a gold standard for diagnosing choledocholithiasis for the last two decades. It is an invasive procedure associated with an inherent risk of pancreatitis. Current practice is shifting to MRCP and EUS as diagnostic tools. It still remains the primary modality in managing choledocholithiasis. When gallstone disease is suspected but cannot be identified by other means, microscopic examination of duodenum contents after administration of CCK or bile obtained via an ERCP catheter may be employed to detect microcrystals. The presence of crystals is indicative of gallstone disease with sludge or small stones that may be below the limits of resolution of the imaging modalities (about 1 to 2 mm). The combination of EUS and bile analysis has been shown to be particularly sensitive.

31.8 MANAGEMENT OF GALLSTONES Cholelithiasis can be diagnosed in a variety of clinical circumstances. A patient can be asymptomatic, have a history of one or more uncomplicated biliary pain episodes or have complications of acute cholecystitis, gangrene, jaundice or even gallbladder cancer (Table 31.4).

481

TABLE fy 31.4 Management of gallstones

∗ Consider emergent therapeutic ERCP in patients with acute gallstone/biliary pancreatitis or acute suppurative cholangitis † Patients with suspected choledocholithiasis should undergo ERCP (preoperative or postoperative) or intraoperative cholangiography ‡ Consider percutaneous cholecystostomy or transpapillary endoscopic cholecystostomy in patients with acute cholecystitis

at high risk of gallbladder carcinoma. The specific groups at high risk of gallbladder cancer include patients with asymptomatic gallstones who are Pima Indians or who have a calcified gallbladder, gallbladder polyps greater than 10 mm, gallstones greater than 2.5 cm or anomalous pancreaticobiliary ductal junction, and carriers of Salmonella typhosa.

31.8.1 Asymptomatic Gallstones An estimated 60% to 80% of all gallstones are asymptomatic at some point. Adult patients with silent or incidental gallstones should be observed and managed expectantly, including patients with diabetes. In diabetic patients, the natural history of gallstones is generally benign and there is low risk of a major complication. There is no evidence to suggest that prophylactic cholecystectomy prolongs life expectancy.[32–34] However, prophylactic cholecystectomy should be performed in patients

Part VII / Gallbladder and Biliary Tract

31.8.2 Symptomatic Gallstones Once an episode of biliary colic has occurred, there is a high risk of repeated pain attacks. Cohort studies with follow-up of patients with symptomatic gallstones indicate a 38% to 50% incidence rate of recurrent biliary pain per year. Patients with symptomatic gallstones are more likely to develop biliary complications. The risk of developing biliary complications is estimated to be 1% to 2% per year.

482

Chapter 31 / GALLSTONE DISEASE

TABLE fy 31.5 Nonoperative therapies for symptomatic gallstones Agent

Advantages

Disadvantages

Oral bile acid dissolution: ursodeoxycholic acid (Actigall), at 8 to 10 mg per kg per day

Stone clearance: 30% to 90% with 0% mortality

Contact solvents: methyl tert-butyl ether/n-propyl acetate

Stone clearance: 50% to 90%

Extracorporeal shock-wave lithotripsy: electrohydraulic/ electromagnetic

Stone clearance: 70% to 90% with < 0.1% mortality

50% recurrence of stones; dissolves noncalcified cholesterol stones; optimal for stones < 5 mm; symptom relief does not start for 3 to 6 weeks; may take 6 to 24 months for results 70% recurrence of stones; experimental, with insufficient data; duodenitis; hemolysis; nephrotoxicity; mild sedation 70% recurrence; not approved by FDA; performed only at centers with expertise; selection criteria require no more than one radiolucent stone (< 20 mm in diameter), patent cystic duct, functioning gallbladder in a patient with symptomatic gallstones without complications

As many as 30% of patients who are observed for several years do not have further problems. Therefore, a management plan is dependent on the patient’s decision and surgical candidacy. For patients who do not want to risk the possibility of a future attack, a laparoscopic cholecystectomy is recommended. In the 1980s, considerable interest was generated in the evaluation of nonsurgical treatment strategies for gallstone disease. Nonsurgical therapy is costly, time-consuming and should be reserved for use in the symptomatic patient who declines surgery or has a high operative risk (Table 31.5).

31.8.3 Acute Cholecystitis Most physicians agree that early laparoscopic cholecystectomy (within 24 to 48 hours) is indicated once the diagnosis of acute cholecystitis is secure and the patient is hemodynamically stable. Use of this surgical technique is supported by large randomized trials conclusively demon-

strating its clinical superiority over open cholecystectomy. The potential advantages of laparoscopic cholecystectomy include a marked reduction in postoperative pain, a shorter hospital stay and a more rapid return to work and usual activities. A percutaneous cholecystostomy or transpapillary endoscopic cholecystostomy should be considered in patients with acute cholecystitis who are at excessive risk for surgery.

31.8.4 Choledocholithiasis When a patient with known gallbladder stones has concomitant choledocholithiasis, the management varies with the severity of clinical features. In general, the presence of obstructive cholangitis or jaundice with a dilated common bile duct detected by ultrasonography should lead promptly to a preoperative ERCP with possible sphincterotomy and stone extraction. Once the bile duct has been cleared by ERCP, the patient can undergo a routine laparoscopic cholecystectomy within one or two days. However, if liver enzyme levels are only

Tropical Hepatogastroenterology

REFERENCES

mildly elevated and there is a low suspicion for common bile duct stones, many physicians proceed directly with laparoscopic surgery. In this case, intraoperative cholangiography should be

483

performed to rule out choledocholithiasis. If common bile duct stones are present, they can be removed intraoperatively or by a postoperative ERCP.

REFERENCES [1] Choudhuri G, Agarwal DK, Phadke RV et al. Geographical variations in structure and composition of gallstones and their correlation with brittleness. J Gastroenterol Hepatol 1994;9:452–456. [2] Amin AM, Ananthakrishnan N, Nambina rayanan TK. Composition of gall stones and sequential events in biliary lithogenesis–is it different in south India compared to North? JAPI 2000;48:885–890. [3] Malhotra SL. Epidemiological study of cholelithiasis among rail road workers in India with special reference to causation. Gut 1968;9:290–5. [4] Tandon RK. Studies on pathogenesis of gallstones in India. Ann Natl Acad Med Sci (India)1989;25: 213–22. [5] Khuroo MS, Mahajan R, Zargar SA, Javid G, Sapru S. Prevalence of biliary tract disease in India: A sonographic study in adult population in Kashmir. Gut 1989;30:201–5. [6] Sarin SK, Negi VS, Dewan R et al. High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology 1995;22: 138–41. [7] Tandon RK, Saraya A, Sushma P et al. Dietary habits of gallstone patients in northern India: A case control study. J Clin Gastroenterol 1996;22: 23–27. [8] Jayanthi V, Anand L, Ashok L et al. Dietary factors in pathogenesis of gallstone disease in southern India–a hospital based case-control study. Indian J Gastroenterol 2005 May–Jun;24(3):97–9. [9] Pandey M,Shukla VK. Lifestyle, parity, menstrual and reproductive factors and risk of gallbladder cancer. Eur J Cancer Prevention August 2003;12(4):269–272.

Part VII / Gallbladder and Biliary Tract

[10] Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge: in vitro studies of calcium-ceftriaxone binding and solubility. Gastroenterology 1990;99:1772–1778. [11] Sarin SK, Guptan RC, Malhotra S. Increased frequency of gallstones in cirrhotic and noncirrhotic portal hypertension. J Assoc Phys Ind 2002;Apr;50:518–22. [12] Tripathy D, Dash BP, Mohapatra BN et al. Cholelithiasis in sickle cell disease in India. J Assoc Phys Ind 1997 Apr;45:287–9. [13] Tandon RK. Pathogenesis of gallstones in India. Trop Gastroenterol 1988;9(2). [14] Tandon RK. Studies on pathogenesis of gallstones in India. Ann Natl Acad Med Sci (India) 1989;25: 213–222. [15] Juvonen T. Pathogenesis of gallstones. Scand J Gastroenterol 1994;29:577–82. [16] Paumgartner G, Sauerbruch T. Gallstones: pathogenesis. Lancet 1991;338:1117–1121. [17] LaMont JT, Smith BF, Moore JRL. Role of gallbladder mucin in the pathophysiology of gallstones. Hepatology 1984;4:Suppl:51S–56S. [18] Einarsson K, Nilsell K, Leijd B, Angelin B. Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med 1985;313:277–282. [19] Thijs C, Knipschild P, Brombacher P. Serum lipids and gallstones: a case-control study. Gastroenterology. 1990;99:843–849. [20] Everson GT. Gallbladder function in gallstone disease. Gastroenterol Clin North Am 1991;20:85–110. [21] Singh M, Pandey UB, Sikora SS et al. Association of Xba1 polymorphism of apo B100 gene in gallbladder diseases. Proc 27th annual meeting

484

[22]

[23]

[24]

[25]

[26]

[27]

Chapter 31 / GALLSTONE DISEASE

Ind Soc Hum Genet (ISHG), Thiruvanthapuram, 2002. Gracie WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Engl J Med 1982;307:798–800. Del Favero G, Caroli A, Meggiato T et al. Natural history of gallstones in noninsulin-dependent diabetes mellitus: a prospective 5-year follow-up. Dig Dis Sci 1994;39:1704–7. Thistle JL, Cleary PA, Lachin JM et al. The natural history of cholelithiasis: the National Cooperative Gallstone Study. Ann Intern Med 1984;101: 171–5. Gupta SK, Shukla VK. Silent Gallstones: a therapeutic dilemma. Trop Gastroenterol 2004; Apr– jun;25(2):65–8. Batra Y, Pal S, Dutta U et al. Gallbladder cancer in India: a dismal picture. J Gastroenterol Hepatol 2005;20:309–14. Dutta U, Nagi B, Garg PK et al. Patients with gallstones develop gallbladder cancer at an earlier age. European Journal of Cancer prevention 2005;14:381–385.

[28] Ladefoged C, Lorentzen M. Xanthogranulomatous cholecystitis. A clinicopathological study of 20 cases and review of the literature. APMIS 1993;101:869–75. [29] Way LW, Sleisenger MH. Cholelithiasis: chronic and acute cholecystitis. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease: pathophysiology, diagnosis, management. 4th ed. Vol. 2. Philadelphia: W.B. Saunders, 1989:1691–714. [30] Zeman RK, Garra BS. Gallbladder imaging: the state of the art. Gastroenterol Clin North Am 1991;20:127–156. [31] Marton KI, Doubilet P. How to image the gallbladder in suspected cholecystitis. Ann Intern Med 1988;109:722–729. [32] McSherry CK. Cholecystectomy: the gold standard. Am J Surg 1989;158:174–178. [33] Wetter LA, Way LW. Surgical therapy for gallstone disease. Gastroenterol Clin North Am 1991;20: 157–169. [34] Salen G, Tint GS, Shefer S. Treatment of cholesterol gallstones with litholytic bile acids. Gastroenterol Clin North Am 1991;20:171–182.

Tropical Hepatogastroenterology

Chapter

32

GALLBLADDER CANCER AND CHOLANGIOCARCINOMA Anu Behari and VK Kapoor

32.1 GALLBLADDER CANCER Gallbladder cancer (GBC), the most common malignancy of the biliary tract worldwide, is an aggressive cancer which has a dismal prognosis, due mainly to the late stage at presentation and absence of an effective management algorithm. An understanding of tumor biology, natural history and routes of spread allows rational decision making about diagnostic algorithms and treatment options. Despite improvements in results following curative radical surgery, management of gallbladder cancer remains largely palliative in majority of patients.

32.1.1 Epidemiology Incidence of GBC shows wide geographical and racial-ethnic variations with some geographical areas and ethnic populations having as much as a 25 times higher incidence than others. The highest incidences are reported from South America and in the native American Indians and Americans of Mexican origin. Intermediate rates are observed in many eastern European countries and in Japan (6/100,000). Low rates are observed in the UK (1/100,000) and the US (1/100,000).[1] Unlike previous reports, recently established cancer registries in north India have reported very high incidence rates akin to the Latin American countries. GBC is,

in fact, the fourth commonest cancer (after cervix, breast and uterus) and the most common digestive tract malignancy in females in north India and, in several series, the most common cause of malignant obstructive jaundice.[2] Paralleling the low prevalence of gallstones the incidence of GBC in south India is contrastingly low in comparison to north India. The age adjusted rate for GBC in women in Chennai is 0.88/100,000 whereas that in Delhi and Bhopal is 9.8 and 3.8/100,000 respectively.[3] Women stand a two to four fold higher risk of developing GBC than men. In women, a positive relationship has been reported between GBC and parity, with early menarche, early first pregnancy, number of live births and late menopause being associated with a higher incidence.[4, 5] In both sexes, incidence increases steadily with age. Although familial clustering of cases has been occasionally reported, no definite genetic predisposition has been proved. Gallstones are the most important risk factors for GBC; gallstones being reported in 60%–98% of patients with GBC. Gallstones and GBC share several epidemiologic features including identical geographical and racial-ethnic variations in incidence, female preponderance as well as increasing incidence with age. A causal relationship between gallstones and GBC is, however, far from established. The risk of GBC in patients with 485

486

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

gallstones is variable and is dependent on race and sex as well as duration of exposure to stones.[6] In studies from the West, risk of GBC in patients with asymptomatic stones has been reported to be only marginally higher than in those without stones. The risk increases with increase in size of stones and with increasing volume of stones.[7] Patients with large stones (> 3 cm) have about a ten times higher risk of developing GBC than those with small (< 1 cm) stones.[8, 9] Large stones or multiple stones probably represent long-standing gallstone disease with a higher risk of complications like Mirizzi’s syndrome and Xanthogranulomatous cholecystitis – conditions associated with a higher incidence of GBC.[10, 11] The role of bacterial infection in causation of GBC remains unproven. Patients with positive bile cultures have been reported to have higher levels of secondary bile acids in bile.[12] Significantly higher levels of secondary bile acids (lithocholic and deoxycholic) in bile and a higher incidence of positive bile cultures has been reported in patients with GBC as compared to patients with only gallstones and normal controls.[13] Long-term typhoid carrier state has been reported to be a risk factor with carriers having a six times higher risk of developing hepatobiliary cancers including GBC.[14] Chemical carcinogens have been the target of investigation in many malignancies. Significantly higher mean biliary concentration of heavy metals, such as cadmium, chromium, and lead have been reported in patients with GBC as compared to those with gallstones alone.[15] Bile in patients with GBC has been shown to have high levels of 4-hydroxynonenal (HNE).[16] This product of liver microsomal lipid peroxidation is secreted in bile and if retained in the gallbladder for prolonged periods may induce neoplasmogenesis. Patients with porcelain gallbladder are reported to have a markedly increased risk of develop-

ing GBC. Whether the increased risk results from gallbladder calcification per se or the preceding long-standing inflammation, is unclear. An anomalous pancreatobiliary duct junction (APBDJ) leads to increased reflux of pancreatic juice into the bile duct which in turn is thought to cause chronic inflammation and metaplasia of bile duct epithelium. Patients with APBDJ without a choledochal cyst are thought to have a higher risk of developing GBC as compared with patients with APBDJ with choledochal cyst.[17] Most gallbladder polyps are benign cholesterol polyps. The likelihood of a polypoid lesion of the gallbladder being malignant increases with increasing age of the patient, increasing size of the lesion, when the lesion is sessile rather than pedunculated, and single rather than multiple.[18, 19] Cholecystectomy is advisable when the patient is more than 50 years old, when a polyp is more than 1 cm in size, when it is sessile even if it is less than 1 cm, or when clinical symptoms are present or rapid growth is evident on follow-up ultrasound.[19, 20] In a recent report, aggressive surgical approach was recommended even for small gallbladder polyps when there are fewer than 3 polyps regardless of their sizes.[21] Adenomyomatosis of gallbladder has been shown to be associated with a higher incidence of GBC especially when it is segmental (6.4%) rather than diffuse (3.1%).[22] A high body mass index, especially in females, has been reported to be associated with a higher incidence of GBC and a positive association has been reported between incidence of GBC and high total caloric intake and high carbohydrate intake. High dietary fiber and micronutrients as well as vitamin C and vitamin E, on the other hand, have been reported to be inversely related to GBC.[23] A 15% incidence of GBC has been reported in patients with cholecystoenteric fistula.

Tropical Hepatogastroenterology

GALLBLADDER CANCER

32.1.2 Pathology and Modes of Spread Macroscopically, GBC may take various forms. As described by Sumiyoshi et al., tumors may be papillary-pedunculated, nodular nonpedunculated, papillary infiltrative, nodular infiltrative, infiltrative (no elevation), filling up form, massive types, or special types.[24] Microscopically, the majority (80%–90%) are adenocarcinomas. The remaining 10% is constituted by squamous cell carcinoma, adenoacanthoma, and undifferentiated carcinoma. Carcinoids, sarcomas, malignant melanoma, and lymphoma have been reported rarely. GBC spreads directly, via venous, lymphatic, and perineural pathways as well as intraductally, and by peritoneal seeding into the locoregional neighborhood as well as to distant sites in the later stages.[25] Liver involvement is common in patients with GBC. The mechanisms of hepatic spread include direct extension, hematogenous spread, and lymphatic spread. Microscopic angiolymphatic invasion of portal tracts has been described as a major mode of hepatic involvement. Japanese surgeons have described various types of hepatic involvement in GBC which has a bearing on surgical resection. The ‘gallbladder bed type’ tumors tend to invade the liver bed contiguously and have an expansive tumor margin, as against the ‘hepatic hilar type’ tumors which invade the loose connective tissue in the hepatic hilum with lymphatic and perineural invasion and thus, have an infiltrative tumor margin.[26] Involvement of the hepatoduodenal ligament is common and occurs due to tumor spread into the interstitial tissue, lymphatic permeation, venous invasion, and perineural invasion and often makes the lesion unresectable. Also, increasing severity of hepatoduodenal ligament involvement is associated with a high incidence of para-aortic lymph node involvement.[27] Unsus-

Part VII / Gallbladder and Biliary Tract

487

pected microscopic invasion of hepatoduodenal ligament is present in a large number of tumors.[28] Lymph node metastases are generally related to the T stage of the tumor.[27, 29] The incidence of lymph node metastases increases with increasing depth of tumor invasion. Shimada et al. reported the incidence of lymph node metastasis in T1, T2, and T3–T4 lesions as 0%, 62%, and 81% respectively.[27] Though T1 tumors are reported as not having nodal spread, the pattern of recurrence in patients with T1b lesions indicates that these tumors are not free of the risk of lymph node metastases.[30] With increasing depth of penetration, not only does the incidence of lymph node metastases increase but also it becomes more widespread. Kondo et al. reported a disconcertingly high incidence (33%) of para-aortic nodal involvement in patients in whom extended nodal dissection had been carried out.[31] Studies of lymphatic spread of GBC indicate that, in general, the lymphatic drainage descends around the bile duct and involves cystic and pericholedochal lymph nodes first.[27, 32] The lymph flow to the right of the hepatoduodenal ligament (the pericholedochal, posterior pancreatoduodenal and interaortic nodes) is the main route of spread and the left route (pericholedochal, lymph nodes along the hepatic artery to the common hepatic artery, retroportal or celiac and inter-or left lateral para-aortic lymph nodes) comprises an alternate route. The right and left routes communicate at the lymph nodes around the pancreatic head. Direct channels between retropancreatic and para-aortic nodes have been described. Four percent of all, but as many as 19% of papillary carcinomas, may spread intraductally into the distal biliary tracts. Perineural spread occurs in about 20% of patients and prognosticates a poor survival. Peritoneal dissemination is common

488

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

in advanced stages and is usually missed on the preoperative imaging investigations. The mode of spread, therefore, is predominantly locoregional and theoretically amenable to surgical extirpation. The close proximity to and frequent invasion of vascular and ductal structures in the hepatoduodenal ligament not only makes resection technically demanding but also decreases the likelihood of achieving a histologically complete resection. At surgery, the surgical margins should stay away from the tumor edge on the hepatic, hepatoduodenal as well as lymph nodal fronts to ensure complete removal and hence, the extent of surgery needs to be tailored to the stage of the disease.

T4 – Tumor invades main portal vein or hepatic artery, or invades two or more extrahepatic organs or structures N – Regional lymph nodes Regional lymph nodes are the cystic duct node and the pericholedochal, hilar, periduodenal, periportal, celiac, peripancreatic (head only), and superior mesenteric nodes. The hilar nodes include those along the inferior vena cava, hepatic artery, portal vein, and hepatic pedicle. Peripancreatic nodes located along the body and tail of pancreas are sites of distant metastases. Nx - Regional lymph nodes can not be assessed N0 - No regional lymph node metastasis N1 - Regional lymph node metastasis

32.1.2.1 Staging

Stage Tumor Nodal Metastasis grouping staging staging staging Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1, 2, 3 N1 M0 Stage III T4 Any M0 Stage IV Any Any M1 We had earlier proposed a modification of the AJCC staging system [34] and we feel that the latest revision makes changes which are not supported by evidence from literature, especially clubbing all nodal groups into one and undermining the importance of nodal spread by giving node-positive disease a lower stage (IIB) than in the earlier system.

The American Joint Committee for Cancer (AJCC) Tumor Node Metastasis staging system given below is the most commonly followed staging system.[33] TNM classification

T Tx T0 Tis T1

– Primary tumor – Primary tumor can not be assessed – No evidence of primary tumor – Carcinoma in situ – Tumor invades lamina propria or muscle layer T1a – Tumor invades lamina propria T1b – Tumor invades muscle layer T2 – Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 – Tumor perforates serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, e.g., stomach, duodenum, colon, pancreas, omentum, extrahepatic bile ducts.

32.1.3 Clinical Presentation The clinical presentation of early GBC is similar to and indistinguishable from that of gallstone disease with repeated episodes of pain abdomen suggestive of biliary colic.[35] Some patients with

Tropical Hepatogastroenterology

GALLBLADDER CANCER

TABLE fy 32.1 Symptoms of gallbladder cancer (n = 613) Pain abdomen Anorexia and weight loss Jaundice Lump abdomen Fever Vomiting Previous biliary colics

424 (69%) 376 (61%) 321 (49%) 304 (49%) 164 (27%) 113 (18%) 225 (37%)

long-standing gallstone disease may notice a change in the nature of pain from intermittent episodes of colicky pain to a more or less continuous dull ache. Most patients, however, present late with symptoms and signs suggestive of adjacent organ involvement. The common presenting features in 631 patients seen by us at a tertiary level referral center are shown in Table 32.1. Jaundice at presentation may be due to obstruction of the bile duct by a neck mass, compression by enlarged lymph nodes in the hepatoduodenal ligament and less commonly due to associated CBD stones. Though some authors have suggested that small neck tumors obstructing the common bile duct may present early because of early appearance of jaundice,[36] generally, presence of jaundice in a patient with GBC is ominous.[37] Pruritus is often a distressing accompanying feature of biliary obstruction as is fever due to cholangitis. Vomiting may be due to mechanical gastric outlet obstruction by tumor invasion or extrinsic compression, or may represent underlying malignant gastroparesis. Delayed gastric emptying on gastric scintigraphy has been reported in as many as 40% of these patients.[38] By the time the clinical picture is dominated by anorexia, weight loss, palpable abdominal lump and ascites, diagnosis of advanced malignancy is rarely in doubt.

Part VII / Gallbladder and Biliary Tract

489

In addition to the above presentations, GBC may be encountered unexpectedly during surgery for presumed acute cholecystitis or empyema, acute intestinal obstruction, upper and lower gastrointestinal bleeding and liver abscess,[39] as well as, in a patient with postcholecystectomy jaundice presumed to be due to biliary injury. Suspicion of GBC may arise at cholecystectomy for presumed benign stone disease (unsuspected GBC) because of presence of a mass, wall thickening (especially if localized), dense adhesions of the omentum and adjacent organs to the GB; the neck of gallbladder adhering to the bile duct and difficult dissection of gallbladder from its bed. At times, GBC may come to light only after the histopathological examination of the removed gallbladder (incidental GBC). In a patient who presents with jaundice some months after cholecystectomy, especially after an uneventful postoperative course (unlike the usual patient with a postcholecystectomy bile duct injury and stricture) and in whom histopathology of the gallbladder is not available, GBC should be kept as one of the differential diagnoses especially in geographical areas where prevalence of GBC is high. This may be due to “missed GBC” at the time of index cholecystectomy especially when the gallbladder is not cut opened and examined after removal, and is not sent for histopathological examination.

32.1.4 Diagnosis With improvements in diagnostic imaging the preoperative diagnosis of GBC is being made more often than earlier. Routine laboratory investigations usually do not identify any findings that may be specific to and diagnostic of GBC. In addition to those patients who have jaundice and therefore have altered liver function tests, a high incidence of isolated abnormal values of serum alkaline phosphatase in absence of hyperbilirubinemia has

490

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

been found in patients with gallstones who are later discovered to have incidental carcinoma on histopathological examination. 32.1.4.1 Imaging

Ultrasound (US), contrast enhanced computerized tomography (CECT), and magnetic resonance imaging (MRI) are the primary means of imaging GBC. The three major patterns of presentation on cross sectional imaging include – (a) focal or diffuse mural thickening, (b) intraluminal polypoidal mass originating from the GB wall, and (c) most commonly (45%–65%), a subhepatic mass replacing or obscuring the gallbladder often infiltrating the adjacent liver.[40] Ultrasound (US) Being an easily available, relatively inexpensive and noninvasive imaging modality often used to evaluate most of the abdominal symptoms, US is usually the first investigation to raise a suspicion of GBC, and may not only diagnose GBC but also help in staging the disease. As stated above, US findings of GBC may include focal or generalized gallbladder wall thickening, a polypoid lesion protruding into the gallbladder lumen or a heterogenous mass replacing part or whole of the gallbladder.[41, 42] A solid homogeneous or inhomogeneous mass with variable echogenicity that is difficult to separate from the liver is the most common form of GBC. Loss of interface between GB and liver may indicate liver infiltration. Carcinomas that are confined to the mucosa or slightly raised lesions may be missed sonographically.[43] The mass may be hyperechoic, isoechoic or hypoechoic relative to the liver.[42] Sonographically, polypoid carcinomas typically have a homogenous tissue texture, are fixed to the gallbladder wall at their base and do not cast an acoustic shadow.[44–46] US can also detect liver metastases, ascites and enlarged retroperitoneal lymph nodes. Intra-

hepatic biliary radical dilatation suggestive of extrahepatic obstruction due to tumor infiltration of common hepatic/bile duct, is also well demonstrated. US-guided aspiration of ascitic fluid or guided fine needle aspiration cytology (FNAC) of suspicious liver metastases and distant retroperitoneal lymph nodes can be done, and if positive, obviate the need for further diagnostic work up. US has been reported to be good for detection of liver infiltration and metastases, but not very helpful in the evaluation of local spread into adjacent gastrointestinal tract (duodenum or colon), omentum, lymph nodes, and peritoneal deposits.[47] More useful information regarding resectability may be obtained by a doppler US, study to evaluate involvement of the portal vein and hepatic artery, and angiography may be avoided. While advanced lesions may be diagnosed readily on US, early lesions may be missed especially in the presence of gallstones. Findings of discontinuous mucosa, echogenic mucosa, and submucosal lucency have been found to be significantly more common in GBC than in patients with benign gallbladder diseases.[48] Endoscopic ultrasound (EUS) has been found to be a good modality for detection of periportal and peripancreatic lymphadenopathy. EUS guided FNAC from the enlarged nodes may provide differentiation between inflammatory and malignant involvement. Contrast enhanced computerized tomography (CECT) Almost the same findings as seen on the ultrasound examination may be more objectively seen on CT scan. Although CT is inferior to ultrasound in depicting mucosal irregularity, mural thickening and cholelithiasis, it is superior for evaluating the thickness of portions of gallbladder wall that are obscured by gallstones or mural calcification on ultrasound.[43] Polypoid carcinomas enhance homogenously after contrast

Tropical Hepatogastroenterology

GALLBLADDER CANCER

FIGURE 32.1 Carcinoma of the gallbladder. The picture shows an irregular hypodense lesion (arrow) in the gallbladder fossa infiltrating into the adjacent liver parenchyma.

administration and the adjacent gallbladder wall may be thickened. Polypoid carcinomas usually do not show necrosis or calcification on CT. Infiltrating carcinomas that replace the gallbladder often show irregular contrast enhancement with scattered regions of internal necrosis on CT (Fig. 32.1). Involvement of regional nodes may be suggested by the findings of enlarged (at least 10 mm anteroposterior dimensions) soft tissue mass with a ring like or heterogenous enhancement. The overall sensitivity of CT in detecting lymph node involvement is low (< 40%),[49] while it is highly sensitive and specific for detection of significant liver infiltration and metastases. Like in US, omental infiltration, peritoneal deposits and small, superficial hepatic metastases are usually missed. Magnetic resonance imaging The role of MR imaging in the diagnosis of GBC remains to be established. Theoretically, as in cholangio-

Part VII / Gallbladder and Biliary Tract

491

carcinoma, the ability to provide simultaneous information about vascular and ductal anatomy and involvement in addition to demonstration of locoregional extent of lesion, makes MRI an attractive alternative modality for diagnosis and treatment planning in GBC, the role of which may be clarified after more frequent application. Focal thickening and a definite mass lesion rather than generalized wall thickness is more likely with GBC and a diffusely thick walled gallbladder alone is an unreliable predictor of malignancy.[50] Also, cross-sectional imaging may fail to differentiate between xanthogranulomatous cholecystitis and GBC. Cholangiography Oral and IV cholangiography are currently not used for diagnosis of GBC. Cholangiography, however, may be helpful in certain situations where there is a diagnostic dilemma, for example in patients with suspected Mirizzi’s syndrome, postcholecystectomy jaundice or patients with hilar block in whom US and CT have not shown a definite mass lesion. Pattern of ductal involvement may point towards GBC as the cause of obstruction. A mid common bile duct obstruction should be assumed to be due to a GBC unless proved otherwise. Isolated changes of segment IV and V ducts in the form of stricturing, distortion or nonfilling may result from liver infiltration by a tumor in the body or fundus of GB.[51] 32.1.4.2 Tumor markers

The role of tumor markers in the diagnosis of GBC remains to be elucidated. GBC is known to produce tumor markers like AFP, CEA and CA19-9. Evaluating patients undergoing cholecystectomy or other upper abdominal surgery for benign diseases as controls, Strom et al. found CEA value greater than 4 ng/ml to be 93% specific

492

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

for diagnosis of GBC.[52] CA19-9 at a cut off value of 20 units/ml has been reported to have a sensitivity of 79% and a specificity of 79%. Other tumor markers like CA-242 too have been studied in a small number of patients. Further studies in larger number of patients and controls (preferably patients with benign gallstone disease) would clarify the role of tumor markers in screening, early diagnosis and prognosis of GBC. 32.1.4.3 Cytology

In most instances if a gallbladder mass is apparently resectable on preoperative imaging, a potentially curative resection may be planned even without a histological diagnosis. If, however, surgical resection is considered improbable and only palliative therapy is anticipated, percutaneous US guided FNAC should be done to obtain tissue diagnosis. Zargar et al. reported a 90% sensitivity and 100% specificity of FNA in 98 patients with a gallbladder mass.[53] Akosa et al. reported an accuracy of 88% with negligible false positive rates.[54] As already mentioned, FNAC may also be done from suspicious liver metastatic lesions and enlarged retroperitoneal lymph nodes to confirm evidence of disease that precludes a curative resection. It has also been reported to diagnose lesions like xanthogranulomatous cholecystitis,[55] which may mimic GBC clinically as well as radiologically. It would be prudent to mention that a negative report on cytology does not rule out presence of malignancy. Though not studied extensively, bile cytology has been reported to have a sensitivity of 50%– 73% in diagnosing GBC.[54, 56] The false positive rate is less than 1%. Diagnosis by bile cytology also avoids violating the tumor and seeding cells in the peritoneal cavity and abdominal wound.

32.1.4.4 Upper gastrointestinal endoscopy

Upper gastrointestinal endoscopy (UGIE) before laparotomy may reveal duodenal infiltration which precludes resection unless pancreatoduodenectomy is planned. 32.1.4.5 Laparoscopy

A number of clinical studies have clarified the role of laparoscopy in pancreatic and gastric cancer, however, information regarding role of laparoscopy in GBC is scarce. In a few early studies from centers in north India it was found to be very useful with sensitivity rates of 95% in detection of liver and peritoneal metastases.[57] In one series of 23 patients, 39% of patients were found to have disseminated disease at laparoscopy.[58] In both of these studies only US was used as the preoperative imaging modality. In a more recent study from MSKCC, Vollmer et al. found evidence of metastatic disease in 55% of the 11 patients with GBC and thus could avoid needless laparotomy in more than half of the patients with apparently resectable lesions on preoperative imaging.[59] In perhaps the largest experience (n = 91) from a single center, laparoscopy avoided unnecessary surgery in 35 (38%) of the patients, was safe and did not result in any port site metastases in patients subjected to resection after staging laparoscopy.[60] It was, however not found to be useful in assessing the local extent of lesion in majority of the patients. Staging laparoscopy therefore should be an integral part of the diagnostic workup of patients with GBC.

32.1.5 Management 32.1.5.1 Surgery

Whether the diagnosis of GBC is made preoperatively, at operation, or postoperatively after

Tropical Hepatogastroenterology

GALLBLADDER CANCER

TABLE fy 32.2 Extent of surgery depending upon the stage Stage Stages 0 and IA T1sN0M0 and T1aN0M0 T1bN0M0 Stage IB T2N0M0(body,fundus) T2N0M0 (neck)

Procedure Simple cholecystectomy Extended cholecystectomy∗ Extended cholecystectomy ERH + LN dissection

493

TABLE fy 32.3 Extent of surgery in incidental GBC T1s and T1a Simple cholecystectomy if cystic duct margin is free. Re-operation with CBD excision if cystic duct margin is involved. T1b and T2 Re-operation∗ with wedge of liver and HDL clearance and full thickness excision of all port sites with or without CBD excision. T3 Re-assess as in Fig. 32.3 and re-operate with hepatectomy and lymph node clearance with or without CBD excision.

Stages IIA and IIB T1N1M0, T2N1M0 T3N0M0, T3N1M0 Stage III T4N0M0, T4N1M0

Extended cholecystectomy Seg IVb + V/ERH + LN Extended right hepatectomy/ HPD∗∗ /Palliative bypass/ ?simple cholecystectomy

TABLE fy 32.4 Indications for CBD resectiony • Tumor at the neck (or cystic duct) of gallbladder • Bulky HDL with large lymph nodes • Re-surgery following cholecystectomy especially if the cystic duct margin is positive. • As a routine to facilitate complete lymphadenectomy

Stage IV No surgery Any TN2, Any TM1 ?cholecystectomy if technically feasible ∗ as

defined in text

∗∗ Hepatopancreatico-suosenectomy

histopathologic examination reveals an unexpected carcinoma, management decisions would be dictated by 1. Performance status of the patient 2. Patient’s symptoms (especially presence of vomiting, jaundice, pruritus, cholangitis and pain) 3. Assessment of disease stage (limited to gallbladder, locally advanced or metastatic). 4. Availability of surgical/endoscopic/interventional radiological expertise. Cure for gallbladder cancer remains elusive. The vast majority of patients present at a stage that is too advanced for possible curative treatment and

Part VII / Gallbladder and Biliary Tract

palliation alone can be offered. Surgery, however, provides the only chance of cure. Depending upon the stage of the disease the extent of surgery may vary (Tables 32.2 to 32.4) from simple cholecystectomy to extended resections including hepato-pancreato-duodenectomy and extended retroperitoneal lymphadenectomy, so that the primary tumor may be removed en bloc with its area of lymphatic drainage and local spread to adjacent viscera. The aim is to stay ahead of the spreading tumor front on hepatic, nodal, hepatoduodenal and adjacent organ fronts. It is becoming increasingly clear that although simple cholecystectomy suffices for T1a tumors, tumors beyond this depth require a more extended procedure. Tumors limited to the mucosa do not have lymph nodal metastases and simple cholecystectomy would achieve complete removal of tumor with no residual disease. Tumors extending to the muscle and perimuscular connective tissue have

494

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

a significant risk of lymph nodal metastasis and there is a high likelihood of leaving behind residual disease if only the gallbladder is removed (necessarily violating the subserosal plane in dissection of the gallbladder from its bed).[61, 62] If the tumor is confined to the gallbladder or if the liver infiltration is less than 2 cm in the area of fundus or body of the gallbladder, extended cholecystectomy (en-bloc cholecystectomy with a nonanatomic 2 cm wedge of liver and lymph node clearance of hepatoduodenal ligament, with or without bile duct resection) results in a negative liver margin while taking care of the potential area of lymphatic spread.[63] If the tumor is in the neck of the gallbladder, or if the liver infiltration is more than 2 cm, more extensive hepatic resections (seg IVb+V or extended right hepatectomy) are required. Because of the close proximity of the right portal triad to the neck of gallbladder, extended cholecystectomy fails to provide an adequate tumor free surgical margin in tumors of the gallbladder neck and hence, an extended hepatectomy is required.[64] Central hepatectomy (the ‘Taj Mahal resection’) too has been advocated to achieve free surgical margins while preserving liver volume (Table 32.2). The extent of lymph node clearance in GBC has not been standardized. Most of the ‘standard’ lymph node dissections include a clearance of the hepatoduodenal ligament, removing the cystic, pericholedochal, and retroportal nodes along the hepatic artery and retropancreatic nodes behind the head of pancreas, with complete skeletonization of hepatic artery, portal vein and common duct and ensure negative surgical margins in patients with un-involved nodes or nodal involvement limited to cystic or pericholedochal nodes. If the retropancreatic nodes are involved, extended lymph node dissection (with or without pancreatoduodenectomy) may be indicated. With para-aortic, celiac or superior mesenteric lymph node involvement even extensive lymph node clearance does not

TABLE fy 32.5 Contraindications for extended resections in GBC • Presence of distant omental, peritoneal or hepatic metastases • Positive para-aortic, celiac or superior mesenteric nodes • Extensive duodenal infiltration • Portal vein or hepatic artery infiltration • Extensive hepatoduodenal ligament infiltration • Poor performance status, deep jaundice

increase survival and radical resections are contraindicated (Table 32.5).[27, 31] Combined vascular resections, involving the portal vein and hepatic artery, have been performed by Japanese surgeons who have considerable experience in extensive hepatic resections for GBC. Results of these studies indicate that vascular resections, though technically feasible, do not confer any long-term survival advantage.[65] Contraindications for extended resection in GBC are summarized in Table 32.5. Considering the risk of dissemination and port site metastases with laparoscopic cholecystectomy, patients suspected to have GBC should not be offered laparoscopic cholecystectomy. If the diagnosis is made unexpectedly during a laparoscopic cholecystectomy, the procedure should be converted to an open one. In all patients undergoing cholecystectomy for gallstone disease, the gallbladder should be opened and examined carefully and any suspicious areas should be subjected to frozen section examination. In patients with GBC discovered incidentally, on histopathology, the maximum time interval beyond which a required completion liver resection and lymph node clearance will not be of use is not clear. It has been suggested that a prior noncurative resection does not preclude the chance of long-term cure after a curative resection.[66] Although this may partly be due to the inherent selection bias involved with

Tropical Hepatogastroenterology

GALLBLADDER CANCER

495

TABLE fy 32.6 Results of extended resections in GBCy Author Nimura (1991) Nakamura (1994) Miyazaki (1996) Kondo (2002)

Number

Morbidity

Mortality

Survival (5-Year)

Long term (Actual)

Recurrence

24 7 44 (all Stage III/IV) 80 (68 Stage III/IV)

92% 71% 45% 51%

25% 0 20% 18%

– 2-Yr-28% R0-20% R1-0% III-33% IVM0-17% IVM1-3%

– 1 R0-2 R1-1 9

– 100% – –

referral of less advanced cases considered likely to benefit from resection, it does underscore the benefit of curative resections whenever they are indicated and feasible. Considering the difficulty in definitely excluding the presence of a mass lesion preoperatively, especially in a thick walled gallbladder, if the suspicion is high, an extended cholecystectomy (as defined above) may be undertaken with the risk that some of these gallbladders may have xanthogranulomatous inflammation alone and no malignancy on histopathology. Results (Table 32.6) In earlier series, cures were reported only for early GBC diagnosed incidentally (after cholecystectomy for presumed benign gallstone disease), there have been recent reports of long-term survival following extended resections for more advanced lesions also.[67–71] Results of simple cholecystectomy for Stage I disease have been generally reported as good with most series reporting more than 90% 5-year survival.[72–74] In our experience, patients with T1b lesions treated with simple cholecystectomy experienced locoregional recurrence in close to 50% (5 of 12 patients) of cases and hence, we believe that the recurrence patterns of patients with T1b lesions necessitates their treatment as that of T2 lesions and recommend extended cholecystectomy for tumors involving the muscle coat.[75]

Part VII / Gallbladder and Biliary Tract

In patients with tumors reaching the subserosa, the survival advantage provided by extended cholecystectomy is clearly evident in a number of reports.[61, 62, 66, 76, 77] For patients with more advanced lesions, recent reports of extended resections involving major hepatic resections with or without combined vascular resections and pancreatoduodenectomy indicate that a definite survival advantage is obtained (especially when resections achieve negative histological margins) when compared to the universally dismal results of untreated advanced gallbladder cancer (Table 32.6). The advantage, however, is restricted to a highly select subgroup of patients who do not have unfavorable prognostic factors (see later). The morbidity and mortality of these extensive resections remains dauntingly high. Extended hepatic resections in jaundiced patients (even after reduction of serum bilirubin levels by preoperative biliary drainage) are associated with a high incidence of liver failure in the postoperative period. Infectious complications add to the prolonged hospital stay of these patients.[65, 68] Prognosis (Table 32.7) Prognosis in GBC remains poor with overall 5-year survival being less than 10%.[78, 79] This is largely due to the late stage of the disease at presentation. Both T and N stage have important bearing on the prognosis. In patients with early lesions (T1N0M0), resection in the form of simple

496

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

TABLE fy 32.7 Predictors of outcome in GBCy Favorable

Unfavorable

R0 resection Node-ve status

Nodal involvement beyond HDL∗ Bile duct involvement Portal vein involvement Severe HDL∗ involvement Positive para-aortic nodes Poor histology Metastatic disease

∗ Hepatoduodenal

ligament

cholecystectomy for T1a lesions provides excellent long-term (80%–90%) 5-year survival. For lesions extending to the muscle or beyond, presence of nodal disease and the completeness of resection are important determinants of prognosis. The importance of achieving a complete (R0) resection in improving survival has been widely reported.[27, 63, 71, 80, 81] Statistically significant improvement in median and 5-year survival has been reported following R0 resections as compared to resections with residual microscopic or gross disease. Todoroki and associates reported a 73% 5-year survival for patients undergoing R0 resection as compared to 15% in those with microscopic residual disease.[71] Behari et al. reported a notably better median survival (26 months versus 17 months p = 0.03) in patients undergoing R0 resections when compared with those having incomplete resection.[63] The likelihood of achieving complete resection is a function of the stage of the disease. Spread of the disease beyond the gallbladder and increasing involvement of adjacent structures, as well as the presence of nodal metastases decreases the likelihood of an R0 resection. Ouchi et al. observed that no patient with serosal disease survived more than 5 years even after major resections.[82] In the experience of Yamaguchi and associates, none of the patients with T3 or T4 tumors survived for

5 years.[83] Some T3 and T4 lesions without nodal spread may constitute a biologically different subgroup of tumors, which can be resected completely with a better prognosis.[76] Presence or absence of biliary infiltration is an important predictor of poor prognosis–majority of patients with jaundice being unresectable. Miyazaki et al. reported that curative resection was possible in as many as 14 out of 15 patients with hepatic invasion alone but only in 7 out of 26 patients with hepatic and bile duct involvement.[68] In a study specifically addressing the issue of hepatoduodenal involvement, Kaneoka et al. reported that R0 resection could be achieved only in 30% of patients with bile duct involvement as compared to 75% of those without bile duct involvement. No patient with bile duct involvement survived 5 years, and 3-year survival in patients who had both bile duct and lymph nodal involvement was a dismal 5%.[80] In patients with advanced (Stage IV) disease, surgical treatment has been reported to predict prognosis. Patients in whom resection could be performed (even if it was noncurative) did better than those in whom only a bypass could be performed.[84] Papillary and nodular lesions have a better prognosis than flat, infiltrative tumors. Prognosis is better also in papillary and well-differentiated adenocarcinomas compared to moderately or poorly differentiated cancers. The presence of venous, lymphatic and perineural invasion is a predictor of poor prognosis. Lymph node involvement has been widely reported to be an indicator of poor prognosis. It also reduces the likelihood of achieving a complete resection. Bartlett and associates reported no long-term survival in patients with lymph node metastases (no patient with nodal disease lived beyond 18 months).[76] Benoist and colleagues also reported no 5-year survivors among patients with

Tropical Hepatogastroenterology

GALLBLADDER CANCER

nodal metastases compared with a 43% 5-year survival in patients with node negative disease.[85] In patients with nodal metastases limited to the hepatoduodenal ligament, notable increase in survival has been reported after complete resection.[27, 86] Chijiwa and coworkers too reported a 50% 5-year survival in patients with hepatoduodenal lymph node involvement.[87] Involvement of para-aortic nodes is akin to presence of metastatic disease in prognosticating a poor outcome.[27, 31] We have proposed that distant nodes should be classified as N3 disease and these patients should be staged as Stage IVB.[34] Predictors of outcome in GBC are summarized in Table 32.7. 32.1.5.2 Radiotherapy and chemotherapy

The role of adjuvant radiotherapy and/or chemotherapy remains unclear largely because of small number of cases reported from single centers. Theoretically, radiotherapy would eradicate the residual microscopic extensions of GBC and thereby complement surgery. However, no consensus exists regarding the optimal dose, timing, and approach to radiation therapy. The theoretical benefits of IORT (increased effective dose to target tissue with protection of normal surrounding tissues), combination of IORT and EBRT (addition of radiobiological advantages of fractionated irradiation) and EBRT have not been convincingly demonstrated in the clinical setting. Most studies are small and retrospective and the results show only marginal improvement in survival. A possible inverse relation between survival and residual volume of tumor after surgery, before adjuvant therapy, has been proposed with increasing benefits in terms of survival with decreasing residual tumor volume.[71] Further studies preferably prospective randomized controlled trials, are required to establish the role of adjuvant radiotherapy in GBC.

Part VII / Gallbladder and Biliary Tract

497

The role of chemotherapy in GBC remains to be established. The most extensively studied single agents are mitomycin C and 5-FU. Earlier reports of encouraging response rates have not been confirmed. Combination chemotherapy has not been found to be more effective than single agents. Trials with newer, potentially effective drugs are thus warranted. Gemcitabine has been widely studied in small cell lung cancer as well as pancreatic cancer; experience with gemcitabine in patients with GBC is, however, limited. Dramatic response in a patient with GBC metastasizing to liver and peritoneum with reversal of small intestinal obstruction and disappearance of hepatic metastases has been reported.[88] In a phase II study involving 26 chemo-na¨ıve patients with measurable locally advanced or metastatic histologically proven GBC, there was no complete response but 9 partial responses resulting in an overall response rate of 36% was there. Median survival time was 30 weeks (range 7–80).[89] In most studies, gemcitabine has been well tolerated as a single agent and in combination with other drugs; the number of patients with GBC treated is too small for meaningful conclusions regarding efficacy and confirmation in future randomized studies is warranted.[90] 32.1.5.3 Palliation in GBC

Considering that large majority of patients with GBC present in a stage far beyond hopes of cure, palliation constitutes an important part of management of these patients. The important factors affecting choice of therapy include performance status of the patient, symptoms and their severity, expected survival and efficacy, availability of the proposed therapy and its financial burden on the family. The main aims of palliation are relief of pain, jaundice with associated pruritus and cholangitis, and gastric outlet obstruction.

498

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA (b)

(a)

FIGURE 32.2 (a) A segment III hepatodochojejunostomy (a) anastomosing the jejunum (J) to the left hepatic duct (L) exposed very laterally at the umbilical fissure (U) (Li - ligamentum teres, S - stomach, P - proximal jejunum, C - colon). If there is a T-tube in place, the anastomosis may be evaluated by a postoperative tube cholangiogram. (b) In this X-ray the cholangiogram shows a patent segment III cholangiojejunostomy. The arrow marks the site of anastomosis.

Jaundice can be relieved by surgical or nonsurgical means. In otherwise fit patients, intrahepatic segment III cholangiojejunostomy provides significant relief of jaundice and pruritus with acceptable morbidity and mortality (Fig. 32.2).[91] Even in patients with a blocked confluence and separation of the right and left systems, segment III cholangiojejunostomy has been reported to be of similar benefit.[92] In patients with tumor at the neck of gallbladder causing empyema or mucocele, a cholecystojejunostomy to the Rouxen-Y limb used for segment III anastomosis provides a safer alternative to cholecystectomy or cholecystostomy.[93] Surgery in these patients also provides the chance to deal with the problem of intractable pain by doing celiac ganglion block and a gastrojejunostomy in patients with associated gastric outlet obstruction.

Gastrojejunostomy should be done in patients with overt gastric outlet obstruction as indicated by symptoms and endoscopy or imaging. Selective gastrojejunostomy may also be done in patients with evidence of duodenal infiltration on imaging or at surgery without symptoms of gastric stasis. Prophylactic gastrojejunostomy is, however, not indicated.[94] Endoscopic or percutaneous (at times combined endoscopic and percutaneous) stenting provides an alternative for surgical relief of biliary obstruction. Vij et al. reported endoscopic stenting in 32 patients with advanced gallbladder cancer.[95] The procedure was technically successful in 27 patients with relief of pruritus and reduction of jaundice in 25. Endoscopic stenting is more likely to be successful in patients with low blocks. Combination with a percutaneous technique can deal

Tropical Hepatogastroenterology

GALLBLADDER CANCER

499

FIGURE 32.3 Algorithm for the management of gallbladder cancer.

with even higher blocks. The procedure may be associated with complications like bleeding, pancreatitis, cholangitis, and septicemia. Repeated stent block with cholangitis requiring change of stent and frequent hospitalization may seriously impair the quality of life in these patients with a very short life expectancy. Further experience with special reference to improvements in quality of life and cost effectiveness is needed to answer these questions. Attempts have been made to combine stenting with brachytherapy with iridium implants

Part VII / Gallbladder and Biliary Tract

but the experience is limited and the exact role as yet is undefined.

32.1.6 Prevention Considering that clinically obvious GBC is lethal in a large majority of patients and that cholecystectomy done before the onset of disease would completely prevent the development of GBC, a case may be made for prophylactic cholecystectomy in patients with gallstones in areas

500

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

with a high prevalence of GBC. However the economic burden of doing cholecystectomy in a large number of people and a finite risk of complications of cholecystectomy mandates identification of high- risk subgroups among patients with gallstones. It has been proposed that taking into account the variable risk of GBC in patients with gallstones prophylactic cholecystectomy may be justified in “young parous women with a large gallstone in populations in which gallbladder cancer is common”.[96]

32.2 CHOLANGIOCARCINOMA 32.2.1 Incidence Cancer of the bile ducts may occur anywhere in the biliary tree with the biliary confluence being most commonly involved (40%–60%). The intrahepatic biliary tree is involved in about 10% of cases and in another 10% the involvement is diffuse or multifocal. Based on anatomical location (which in turn determines the type of resection required for complete removal), three subtypes are defined – hilar tumors involving the confluence and common hepatic duct (CHD); mid-duct cholangiocarcinomas involving the supraduodenal common bile duct (CBD) and; distal cholangiocarcinomas involving the intraduodenal CBD.[97] Intrahepatic cholangiocarcinomas are managed as other hepatic malignancies like hepatocellular carcinoma while the distal bile duct cancers are managed like other periampullary malignancies. The following discussion focuses on hilar cholangiocarcinoma. Cholangiocarcinomas are uncommon cancers with incidence rates of 0.01%–0.2% in autopsy series and reported incidence of < 1–2/100,000— the peak incidence being in the 8th decade. They constitute about 2% of all reported cancers. Most patients with unresectable lesions die within

6 months to 1 year of liver failure or infective complications of biliary obstruction.[98]

32.2.2 Etiology The etiology of these cancers remains unknown although several groups of patients have been identified as having an increased risk of developing cholangiocarcinomas. These include patients with Primary sclerosing cholangitis – true incidence of cholangiocarcinomas in these patients is not known. In autopsy series occult cancers have been reported in almost 40% of the patients and in 6% of liver explants in patients undergoing liver transplantation. A follow up series of 305 patients reported an 8% incidence of cholangiocarcinoma in patients with PSC.[99] Most often the lesions are multifocal and often irresectable. Medical or surgical treatment of associated ulcerative colitis does not alter the risk of development of cholangiocarcinoma. Congenital biliary cystic disease (choledochal cyst, Caroli’s disease) – malignancy is uncommon if the cyst is diagnosed and excised early in life but the risk increases (15%–20%) in patients who are not treated or previously treated by cyst drainage alone. Anomalous pancreatobiliary duct junction is said to predispose to development of bile duct cancer by permitting abnormal pancreatic juice reflux into the bile duct with injury to the bile epithelium that ultimately progresses to carcinoma. In addition, bile stasis, stone formation, and chronic inflammation within the cyst has also been implicated. Hepatolithiasis and biliary parasitic infestation is said to be associated with a 10% incidence of cholangiocarcinoma. Chemical carcinogens like thorotrast, radon, nitrosamines, and asbestos too have been implicated in the etiopathogenesis.

Tropical Hepatogastroenterology

CHOLANGIOCARCINOMA

Macroscopically, the three commonly recognized types of tumors are sclerosing, nodular and papillary. Sclerosing tumors are the most common and produce an annular thickening with diffuse infiltration and fibrosis of the periductal tissues. These tumors are more common at the hilum than in the distal bile duct. Nodular lesions project as a nodule into the duct lumen. Combination of sclerosing and nodular lesions may be seen. Papillary lesions occur as soft friable masses with little transmural invasion, the polypoid mass expanding the bile duct. Though the tumor may be large, the stalk is usually narrow and these tumors are more often resectable and have a better prognosis.[100] Microscopically > 90% of cholangiocarcinomas are adenocarcinomas–usually well differentiated and mucin producing types.[79] Other histological subtypes include squamous, mucoepidermoid, leiomyosarcoma, cystadenocarcinoma, and granular cell carcinoma. Cholangiocarcinomas spread directly to the liver and perihepatic structures via neural, perineural and lymphatic invasion.[101] Subepithelial extension is a characteristic feature with longitudinal spread along the duct wall and periductal tissue being responsible for extension of tumor beneath the epithelium for as much as 2 cm proximal and 1 cm distal to the tumor. Hematogenous spread is uncommon. Lymph nodal involvement is present in about a third of the cases.[102] About 15– 30% of patients have metastatic disease at initial presentation.

32.2.3 Clinical Presentation Majority of patients with cholangiocarcinoma are older than 65 years and the peak incidence is in the eighth decade of life, and males are more commonly affected than females. The clinical picture in early cholangiocarcinoma may be quite nonspecific with abdominal pain or discomfort, anorexia,

Part VII / Gallbladder and Biliary Tract

501

and weight loss being the most common symptoms seen in about one-third of the patients. Pruritus may predate jaundice by some weeks and presence of this symptom in an elderly patient, especially when associated with alteration in liver function tests should prompt thorough investigation. Jaundice is ultimately present in more than 90% of cases and is usually progressive and unremitting. Papillary tumors at the hilus producing a ball-valve type of obstruction or sloughing off of a friable papillary tumor may produce an intermittent type of jaundice. Jaundice may be absent initially in patients with incomplete obstruction (right or left duct), or segmental obstruction. In the latter case, the obstructed segment may undergo unrecognized atrophy. In the absence of prior biliary intervention cholangitis is uncommon at presentation. On examination, the patient is usually icteric with evidence of skin excoriations from the associated pruritus. The liver is usually enlarged and firm. Gallbladder is collapsed and non-palpable in proximal lesions. Because of its uncommon occurrence, by the time the patient with cholangiocarcinoma reaches the surgeon, a number of radiological examinations and even invasive procedures like ERCP may have been performed to rule out diagnosis of more common causes of jaundice like CBD stones.[103]

32.2.4 Differential Diagnoses Benign biliary stricture, gallbladder cancer, Mirizzi’s syndrome, porta block due to metastases and localized sclerosing cholangitis need to be differentiated from hilar cholangiocarcinoma. In a recent series of 49 consecutive patients with obstructive jaundice due to a stenosing lesion at the hepatic hilum, the final tissue diagnosis was benign in 12 (24%) patients; 4 (33%) of these had elevated tumor markers and the cholangiogram in all patients was suspicious of malignancy.[104]

502

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

Resection, therefore, remains the most reliable way to rule out malignancy at this site. Histological confirmation of diagnosis is not mandatory prior to exploration. In the absence of previous biliary tract surgery, the finding of a focal stenotic lesion combined with the appropriate clinical presentation is sufficient for a presumptive diagnosis of hilar cholangiocarcinoma.[98]

32.2.5 Preoperative Work Up and Imaging Preoperative identification of patients who are candidates for surgical resection with a high degree of certainty is the main aim of preoperative imaging. The goal is to accurately identify – extent of hepatic duct involvement – extent of soft tissue involvement (hepatic parenchyma at the hilum) – extent of vascular involvement – presence of distant metastases – systemic (peritoneum, lung, etc.) – distant nodal disease (celiac, superior mesenteric, pancreatoduodenal) Information regarding all these not only allows determination of resectability but also facilitates planning of extent of resection required for complete tumor removal.

32.2.6 Cholangiography The initial screening for obstructive jaundice is carried out by US. This will show the level of the lesion, and may occasionally demonstrate the mass as well (Fig. 32.4). Traditionally ERCP and PTC have been the two invasive radiological investigations used in defining the biliary extent of tumor. Because of the technical problem of inability to inject contrast through the obstruction and adequately delineate the proximal ductal system

FIGURE 32.4 Cholangiocarcinoma: The ultrasound shows a mass in the common bile duct.

by ERCP, PTC has been the favored investigation. In recent years, however, MR imaging has gained increasing popularity. In addition to being noninvasive, MR can provide more accurate imaging of the hepatic hilum. MRC can reveal obstructed or isolated ducts that were not appreciated at endoscopic or percutaneous study, due to the ability of this modality to visualize the biliary tree independent of contrast injection through an area of biliary obstruction. Also, computer software can manipulate the acquired data into additional images (3D reconstructions) that can be useful for preoperative surgical planning. CT scan has been considered to be the optimal cross-sectional imaging to evaluate the extent of tumor at the hilum and especially, its relationship to the hilar vasculature. With MRC, MRI is becoming the preferred modality of preoperative

Tropical Hepatogastroenterology

CHOLANGIOCARCINOMA

imaging to assess this aspect of tumor extension in hilar cholangiocarcinomas. It may be prudent to mention the importance of lobar atrophy demonstrated on cross-sectional imaging as the presence of a small, often hypoperfused lobe with crowding of the dilated intrahepatic ducts. Segmental or lobar atrophy may result from a portal venous occlusion or biliary obstruction. Long-standing biliary obstruction may cause moderate atrophy while concomitant portal venous compromise results in rapid and severe atrophy of the involved segment. Appreciation of atrophy is important because of the therapeutic implications– while ipsilateral involvement of portal vein and bile ducts may be amenable to resection, contralateral involvement is usually not. Similarly ipsilateral lobar atrophy does not preclude resection but atrophy of the contralateral lobe does.[98] Duplex ultrasound has been reported to be a sensitive investigation for identifying hilar vascular involvement.[105] Despite the use of preoperative MRI/CT scans, a large proportion of patients (about 25%) are found to have advanced nodal, peritoneal or hepatic metastatic disease that precludes curative resection. Positron emission tomography (PET) uses 2-[18F] fluoro-2-deoxyglucose (FDG) to assess metabolism in human tissue, thus highlighting areas of malignant disease. Preliminary reports of PET in investigating metastatic cholangiocarcinoma appear promising.[106, 107] Given the utility of PET scan in other malignancies, it may develop into a useful modality for cholangiocarcinoma also. Cost and availability will remain limiting features.

32.2.7 Laparoscopy Considering the high percentage of patients found to have unresectable disease at laparotomy despite extensive preoperative imaging, laparoscopy has

Part VII / Gallbladder and Biliary Tract

503

been advocated in staging of cholangiocarcinoma.[59, 108, 109] Vollmer et al. found 17% of their 23 patients with cholangiocarcinoma unresectable at laparoscopy (with the use of laparoscopic ultrasound).[59] In a series of 100 patients with potentially resectable gallbladder cancer (n = 44) and hilar cholangiocarcinoma (n = 56), staging laparoscopy was reported to have a yield of 25% (14/56) in patients with hilar cholangiocarcinoma. Its accuracy in detecting unresectable disease was 42% (14/33). Laparoscopy detected majority of liver metastases but failed to detect all locally advanced tumors and most of the nodal metastasis.[108] Connors et al. reported a yield of 24.3% (20/82) using laparoscopy alone in patients with hilar cholangiocarcinoma; this increased to 41.5% when intraoperative ultrasound was added.[109] Staging laparoscopy may, thus, be a useful adjunct in identifying metastatic disease missed on pre operative imaging. This becomes even more important in patients in whom preoperative attempts at diagnosis with FNAC may increase the risk of needle track seeding.

32.2.8 Tumor Staging Two primary staging systems currently in use for hilar cholangiocarcinoma are the Modified Bismuth-Corlette[110] and American Joint Committee on Cancer (AJCC)[111] (Tables 32.8 and 32.9). The modified Bismuth-Corlette system is an anatomical description of the location of tumor and its extension into the hepatic ductal system. It, however, takes no account of two factors which are critical in determining resectability and prognosis, namely the pattern or extent of vascular and hepatic parenchymal involvement. The AJCC system is helpful in identifying prognostic subsets, but since the T staging requires histopathologic evaluation of the resected tumor, it is not helpful in preoperative planning.

504

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

TABLE fy 32.8 Modified Bismuth-Corlette classification for hilar cholangiocarcinoma Type

Anatomic location

Type I

Below the confluence of the right and left hepatic ducts Confined to the confluence of the right and left hepatic ducts Extension into the right hepatic duct Extension into the left hepatic duct Extension into the right and left hepatic ducts

Type II Type IIIa Type IIIb Type IV

TABLE fy 32.10 Staging system proposed by MSKCC T-stage Biliary involvement

T1

T2

T3

TABLE fy 32.9 AJCC staging system for cholangiocarcinoma Group staging Stage 0 Stage I Stage II Stage III Stage IVA Stage IVB

Tumor staging

Nodal staging

Metastasis staging

Tis T1 T2 T1,2 T3 Any

N0 N0 N0 N1,2 Any Any

M0 M0 M0 M0 M0 M1

T Stage Tis-carcinoma in situ T1-tumor invades to fibromuscular layer T2-tumor invades perifibromuscular layer T3-tumor invades adjacent structures N Stage N1-metastasis in lymph nodes of the hepatoduodenal ligament (i.e., cystic duct, pericholedochal, or hilar) N2-metastasis in distant regional lymph nodes (i.e., paraduodenal, periportal, celiac, superior mesenteric, peripancreatic, or posterior pancreatoduodenal) M Stage M0-no distant metastases M1-distant metastases

The MSKCC group has proposed a staging system that incorporates factors determining resectability and thus can be of help in surgical planning in addition to prognostication

T4

Hilus and/ Or right/left Hepatic duct Hilus and/ Or right/ left Hepatic duct Hilus and/ Or right/left Hepatic duct Secondary Biliary radicals Bilaterally

Ipsilateral Ipsilateral lobar portal atrophy vein involvement

Main portal vein involvement

No

No

No

Yes

No

No

Yes/No

Yes

No

Yes/No

Yes/No

Yes

(Table 32.10).[102] It is dependent on accurate preoperative identification of the extent of tumor and on the correct interpretation of preoperative radiologic imaging. This system has been validated in a series of 225 consecutive patients with hilar cholangiocarcinomas.[112]

32.2.9 Management Surgery remains the primary curative modality in the treatment of cholangiocarcinoma though most patients are unsuitable for curative resection. Despite the recent trend towards extensive surgical resections with curative intent (especially in large-volume centers with expertise), the treatment of hilar cholangiocarcinomas more frequently involves palliative measures. The improved survival rates following curative resections being reported more frequently may be due to a combination of better patient selection, improved perioperative care and most importantly more effective resectional technique.

Tropical Hepatogastroenterology

CHOLANGIOCARCINOMA

32.2.9.1 Extent of surgery

Surgery for hilar cholangiocarcinoma involves varying combinations of bile duct excision, hepatic resection, and lymph node dissection. Complete excision of the extrahepatic bile duct is required, with division of the distal bile duct within the head of pancreas. All neural, lymphatic, and connective tissue above the superior border of head and neck of pancreas surrounding the hepatic artery and portal vein is stripped off these vessels and is removed en bloc with the hepatic duct. The proximal resection margin is determined by the extent of tumor in the hepatic duct and the planned hepatic resection. Frozen section examination of proximal duct margin should be obtained prior to restoration of bilioenteric continuity with a Rouxen-Y hepaticojejunostomy, usually to the sectoral or segmental ducts. It is becoming increasingly clear that long-term survival is achieved only in patients who undergo curative resections with histologically negative margins. This requires a hepatic resection in a large number of patients with hilar cholangiocarcinoma. In most cases, this involves a right trisegmentectomy (segment IV, V, VI, VII and VIII) and caudate lobectomy. The longer length of the left hepatic duct and its relative position with respect to the hepatic arteries allows wider clearance with right-sided resections. Multivariate analyses in studies of extended resections, which include hepatic parenchymal resection for hilar cholangiocarcinoma, indicate that the impact of hepatectomy on survival is by provision of negative margins. Hilar cholangiocarcinoma frequently extends into the bile duct radicals of caudate lobe which in turn are a frequent source of positive surgical margins following resections. Following the first report by Nimura et al.[113] who reported obtaining a histologically negative margin in 86% of 91 patients when a caudate lobectomy was performed,

Part VII / Gallbladder and Biliary Tract

505

several series advocating caudate lobectomy as a standard practice for most hilar cancers have been published.[98, 114, 115] The lymph nodal groups that have been found to be most commonly involved are pericholedochal (43%), periportal (31%) and common hepatic nodes (27%). Celiac and superior mesenteric lymph nodes are rarely involved.[116] Thus the dissection of primary tumor along with the node bearing tissue from porta to the common hepatic artery is sufficient for staging as well as disease control. Some surgeons also perform routine para-aortic node clearance from the aortocaval groove. In patients undergoing radical lymphadenectomy regional lymph node involvement has not been found to significantly reduce 5-year survival.[116, 117] Current guidelines support major vascular resections if the expertise is available. Reports from Japanese centers with large experience in complex hepatobiliary operations indicate that morbidity and mortality are not increased when portal venous resection and reconstruction is performed as part of the resection of hilar cholangiocarcinoma. Some studies have reported portal vein resection as an independent predictor of 5year survival after curative hepatic resection.[117] Hepatic artery resection and reconstruction is technically feasible but has not been found to confer any survival benefit. In patients with distal bile duct, duodenal or pancreatic invasion, pancreatoduodenectomy may help in achieving an R0 resection. Results of some of the large series of resections for hilar cholangiocarcinoma[97, 112, 114, 118–126] are summarized in Table 32.12. 32.2.9.2 Preoperative biliary drainage (PBD)

Because liver resections in jaundiced patients are considered to carry a special risk, PBD has been

506

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

TABLE fy 32.11 Contraindications to resection of cholangiocarcinoma • Distant metastases (lung, peritoneum, distant nodal metastasis) • Complete encasement or thrombosis of main portal vein • Bilateral involvement of second order portal vein branches • Lobar atrophy with contralateral portal vein invasion • Involvement of secondary biliary radicals within the hepatic lobe contralateral to the major tumor site • Bilateral involvement of hepatic duct up to secondary biliary radicals • Involvement of main trunk of hepatic artery or bilateral involvement of its branches

TABLE fy 32.12 Results of resectiony Authors Pichlmayr et al.[118] (1996) Nakeeb et al.[97] (1996) Miyazaki et al.[119] (1998) Kosuge et al.[120] (1999) Lee et al.[121] (1999) Lillemoe et al.[122] (2000) Nimura et al.[123] (2000) Launois et al.[124] (2000) Gazzaniga et al.[114] (2000) Jarnagin et al.[112] (2001) Kondo et al.[125] (2004) Silva et al.[126] (2005)

Patients

Curative resections

Survival

125

91 (73%)

3-yr-40%, 5-yr-32%

196

109 (56%)

76

54 (71%)

5-yr-40%

89

54 (61%)

5-yr-33%

151

90 (60%)

3-yr-55%, 5-yr-24%

109

56%

177

108 (61%)

307

98 (32%)

3-yr-43%, 5-yr-26% 1-yr-68%

159

75 (47%)

5-yr-17.5%

160

80 (50%)

5-yr-37%

40

40 (100%)

3-yr-40%,

172

45 (26%)

75-yr-41%

recommended prior to hepatic resection in patients with hilar cholangiocarcinoma. PBD has been suggested to improve the liver regeneration capacity that is presumed to be impaired in presence of jaundice. Recent reports indicate that despite theoretical apprehensions, major liver resections can be performed safely without PBD.[127, 128] Cherqui et al. reported that the rate of liver failure in jaundiced patients was low (5%), and recovery of liver synthetic activity was identical to controls. There was no significant difference in mortality between patients who did not have PBD and those who underwent PBD. The authors suggested that hepatic resection could be safely undertaken in the jaundiced patient in the absence of malnutrition, coagulation abnormalities, or sepsis.[127] In a retrospective study comparing two well-matched groups of patients with hilar cholangiocarcinoma, Hochwald et al. found a significant increase rate of infectious complications in patients with internal and/or external PBD. They did not observe any increase in operative time or blood loss in the nondrained group.[128] Most Japanese surgeons, however, routinely do PBD and operate on the patient once the serum bilirubin levels fall to below 3 mg%. They recommend multiple selective PTBD catheter insertions not only to decompress the obstructed segmental ducts to improve the functional capacity of the cholestatic liver but also to display the entire biliary tree for accurate preoperative diagnosis of the cancer extension along the separated biliary branches.[129] PBD may be indicated in jaundiced patients before hepatic resection in order to allow time for correction of complications like severe malnutrition, acute cholangitis and coagulation abnormalities but in absence of clear advantages, routine placement of biliary stents in patients with potentially resectable cholangiocarcinoma is not recommended.[128]

Tropical Hepatogastroenterology

CHOLANGIOCARCINOMA

32.2.9.3 Portal vein embolization (PVE)

The observation that right portal vein obstruction by tumor with resultant right lobe atrophy produced left lobe hypertrophy led to the development of selective portal vein embolization with a view to increase the volume of remnant liver after extensive hepatic resection to reduce the risk of hepatic failure. To increase the safety of major hepatic resections and to extend the indications for hepatectomy, hemihepatic PVE was developed by Makuuchi et al. in 1982 for the treatment of hilar cholangiocarcinoma.[130] In patients with obstructive jaundice, biliary decompression in the future remnant lobe should be performed first. PVE is performed when the serum total bilirubin is below 3–5 mg/dl. A recent series reported no mortality in 68 consecutive extended hepatectomies for hilar cholangiocarcinoma with this strategy. 32.2.9.4 Orthotopic liver transplantation

Orthotopic liver transplantation for otherwise unresectable lesions remains controversial as tumor recurrence has been reported in more than 90% of patients. 32.2.9.5 Adjuvant therapy

Currently there is no evidence to support the routine use of adjuvant or neoadjuvant radiotherapy or adjuvant chemotherapy in the management of hilar cholangiocarcinoma. 32.2.9.6 Palliation

As majority of patients with hilar cholangiocarcinoma are not suitable for resection, durable palliation of symptoms with minimal risk becomes an important aim of treatment. Common indications for palliative biliary decompression include

Part VII / Gallbladder and Biliary Tract

507

intractable pruritus, cholangitis, need for access for intraluminal radiotherapy and to allow recovery of hepatic function in preparation for chemotherapy. The decision regarding optimal method of palliation may have to be taken intraoperatively in patients who are found to have unresectable disease at exploration. In patients who do not undergo exploration, percutaneously placed self-expandable metal stents offer superior palliation to either endoscopically placed stents or plastic stents. Hilar tumors are more difficult to traverse with the endoscopic route. Endoscopically placed stents have been reported to have fewer acute complications than percutaneously placed stents (11% versus 33%), but one-fourth of patients initially treated endoscopically required conversion to percutaneously placed stents for adequate palliation of jaundice.[132] Hilar tumors frequently isolate the left hepatic and the right anterior and right posterior sectoral ducts and two or more stents may be required for adequate drainage. Percutaneous drainage of an atrophic lobe usually does not relieve jaundice and should be avoided. The mean patency rate of approximately 9 months in metal stents is about twice as long as that of plastic stents. Stent occlusion requiring intervention is experienced in less than 20% for metal stents compared to rates of 40%–70% with plastic stents.[133, 134] Patients found to have unresectable disease at exploration should be considered for a palliative bilioenteric bypass. Segment III duct is the most accessible and is usually preferred though right anterior and posterior sectoral ducts can also be used. The anastomosis can be placed some distance away from the tumor and provides excellent biliary drainage.[135] Communication between right and left hepatic ducts is not essential provided the undrained lobe has not been percutaneously drained or otherwise

508

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

contaminated.[92] Bypass to an atrophic lobe or a lobe heavily involved with tumor is not effective. Though the feasibility of a combination of external beam radiotherapy and intraluminal

Iridium-192 has been demonstrated, increased survival has not been documented in a controlled study. Systemic chemotherapy too has not been shown to confer any survival over biliary drainage alone.

REFERENCES [1] Parkin DM, Muir CS, Whelan SL et al. Cancer incidence in five continents, vol.vi.Lyon: International agency for research on cancer 1992. [2] Sikora SS, Kapoor R, Pradeep R et al. Palliative surgical treatment of malignant obstructive jaundice. Eur J Surg Oncol 1994;20:580–84. [3] National Cancer Registry Project New Delhi: ICMR A report of two years 1997–1998. [4] Moerman CJ, Berns Mary PH, Bueno de Mesquita HB et al. Reproductive history and cancer of the biliary tract in women. Int J Cancer 1994;57: 146–153. [5] Lambe M, Trichipoulos D, Hsieh CC et al. Parity and cancer of the gallbladder and the extrahepatic bile ducts. Int J Cancer 1993;54:941–944. [6] Lowenfels AB, Lindstrom CG, Conway MJ et al. Gallstones and risk of gallbladder cancer. JNCL1985;175:77–80. [7] Vitetta L, Sali A, Little P et al. Gallstones and gallbladder carcinoma. Aust N Z J Surg 2000;70: 667–73. [8] Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983;250:2623–2626. [9] Lowenfels AB, Walker AM, Althaus DP et al. Gallstone growth, size and risk of gallbladder cancer: an inter-racial study. Int J Epidemiol 1989;18: 50–54. [10] Redaelli CA, Buchler MW, Schilling MK et al. High coincidence of Mirizzi syndrome and gallbladder carcinoma. Surgery 1997;121: 58–63. [11] Kumar A, Krishnani N, Saxena R et al. Xanthogranulomatous cholecystitis. Ind J Gastroenterol 1996;15:122–25.

[12] Shukla VK, Tiwari SC, Roy SK. Biliary bile acids in cholelithiasis and carcinoma of the gallbladder. Eur J Cancer Prevention 1993;2:155–160. [13] Pandey M, Vishwakarma RA, Gautam A et al. Bile, bacteria and gallbladder carcinogenesis. J Surg Oncol 1995;58:282–283. [14] Caygill CPJ, Hill MJ, Braddick M et al. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet 1994;343:83–84. [15] Shukla VK, Prakash A, Tripathi BD et al. Biliary heavy metal concentration in carcinoma of the gallbladder: case control study. Br Med J 1998;387:1288–89. [16] Shukla VK, Shukla PK, Pandey M et al. Lipid peroxidation product in bile from patients with carcinoma of the gallbladder: a preliminary study. J Surg Oncol 1994;56:258–62. [17] Chijiwa K, Tanaka M, Nakayama F. Adenocarcinoma of the gallbladder associated with anomalous pancreatobiliary ductal junction. Am Surg 1993;59:430–34. [18] Farinon AM, Pacella A, Cetta F et al. “Adenomatous polyps of the gallbladder” adenomas of the gallbladder. HPB Surgery 1991;3:251–58. [19] Ishikawa O, Ohigashi H, Imaoka S et al. The difference in malignancy between pedunculated and sessile polypoid lesions of the gallbladder. Am J Gastroenterology 1989;84:1386–90. [20] Aldridge MC, Bismuth H. Gallbladder cancer: the polyp-cancer sequence. Br J Surg 1990;70: 363–64. [21] Shinkai H, Kimura W, Muto T. Surgical indications for small polypoidal lesions of the gallbladder. Am J Surg 1998;175:114–17.

Tropical Hepatogastroenterology

REFERENCES

[22] Ootani T, Shirai Y, Tsukada K et al. Relationship between gallbladder carcinoma and the segmental type of adenomyomatosis of the gallbladder. Cancer 1992;69:2647–52. [23] Zatonski WA, Vecchia CL, Przewozniak et al. Risk factors for gallbladder cancer: A Polish case-control study. Int J Cancer 1992;51: 707–711. [24] Sumiyoshi K, Nagai E, Chijiwa K et al. Pathology of carcinoma of the gallbladder. World J Surg 1991;15:315–21. [25] Fahim RB, McDonald JR, Richards JC et al. Carcinoma of the gallbladder–a study of its modes of spread. Ann Surg 1962;156:114–24. [26] Ogura Y, Tabata M, Kawarada Y et al. Effect of hepatic involvement on the choice of hepatic resection for advanced carcinoma of the gallbladder: histological analysis of 32 surgical cases. World J Surg 1998;22:262–67. [27] Shimada H, Endo I, Togo S et al. The role of lymph node dissection in the treatment of gallbladder cancer. Cancer 1997;79:892–99. [28] Shimizu I, Ohtsuka M, Hiroshi I et al. Surgery 2004;136:1012–17. [29] Tsukada K, Kurosaki I, Uchida K et al. Lymph node spread from carcinoma of the gallbladder. Cancer 1997;80:661–67. [30] Ouchi K, Suzuki M, Tominaga T et al. Survival after surgery for cancer of the gallbladder. Br J Surg 1994;81:1655–57. [31] Kondo S, Nimura Y, Hayakawa N et al. Regional and para-aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. Br J Surg 2000;87:418–22. [32] Shirai Y, Yoshida K, Tsukada K et al. Identification of the regional lymphatic system of the gallbladder by vital staining. Br J Surg 1992;79: 659–62. [33] American Joint Committee on Cancer 2002, AJCC Cancer Staging Manual;6, Springer-Verlag, New York, pp 145–149. [34] Kapoor VK, Sonawane RN, Haribhakti SP et al. Gallbladder Cancer: proposal for modification of the TNM classification. Eur J Surg Oncol 1998;24:487–91.

Part VII / Gallbladder and Biliary Tract

509

[35] Kapoor VK, Pradeep R, Haribhakti SP et al. Early carcinoma of the gallbladder: an elusive disease. J Surg Oncol 1996;62:284–287. [36] Chan KM, Yeh TS, Yu MC et al. Gallbladder carcinoma with biliary invasion: clinical analysis of the differences from nonbiliary invasion. World J Surg 2005;29:72–75. [37] Hawkins WG, DeMetteo RP, Jarnagin WR et al. Jaundice predicts advanced disease and predicts early mortality in patients with gallbladder cancer. Ann Surg Oncol 2004;11:310–15. [38] Singh B, Kapoor VK, Sikora SS et al. Malignant gastroparesis and outlet obstruction in carcinoma gallbladder. Trop Gastroenterol 1998;19: 37–39. [39] Haribhakti SP, Awasthi S, Pradeep R et al. Carcinoma gallbladder-Atypical presentations and unusual associations. Trop Gastroenterol 1997;18:32–34. [40] Gore RM, Yaghmai V, Newmark GM et al. Imaging benign and malignant disease of the gallbladder. Radiol Clin N Amer 2002;40:1307–23. [41] Franquet T, Montes M, Ruiz DA et al. Primary gallbladder carcinoma: imaging findings in 50 patients with pathologic correlation. Gastrointestinal Radiology 1991;86:143–48. [42] Bach AM, Loring LA, Hann LE et al. Gallbladder cancer: can ultrasonography evaluate extent of disease? J Ultrasound Med 1998;17:303–309. [43] Onoyama H, Yamamoto M, Takada M et al. Diagnostic imaging of early gallbladder cancers: retrospective study of 53 cases. World J Surg 1999;23:708–12. [44] Soyer P, Gouhiri M, Boudiaf M et al. Carcinoma of the gallbladder: imaging features with surgical correlation. Am J Roentgen 1997;169: 781–85. [45] Wilbur AC, Sagireddy PB, Aizenstein RI. Carcinoma of the gallbladder: color Doppler ultrasound and CT findings. Abdominal Imaging 1997;22: 187–89. [46] Veno N, Tomiyama T, Tano S et al. Diagnosis of gallbladder carcinoma with color Doppler ultrasonography. Am J Gastroenterol 1996;91: 1647–49.

510

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

[47] Haribhakti SP, Kapoor VK, Gujral RB et al. Staging of carcinoma of the gallbladder-an ultrasonographic evaluation. Hepatogastroenterology 1997;44:1210–15. [48] Wibbenmeyer LA, Sharafuddin MJ, Wolverson MK et al. Sonographic diagnosis of unsuspected gallbladder cancer: imaging findings in comparison with benign gallbladder conditions. Am J Roentgen 1995;165:1169–74. [49] Ohtani T, Shirai Y, Tsukada K et al. Spread of gallbladder cancer: CT evaluation with pathologic correlation. Abdominal Imaging 1996;21:195–201. [50] Srikanth G, Khare R, Kumar A et al. Should laparoscopic cholecystectomy be performed in patients with a thick walled gallbladder? J Hepatobiliary Pancreat Surg 2004;11(1):40–44. [51] Collier NA, Carr D, Hemingway A et al. Preoperative diagnosis and its effect on the treatment of carcinoma of the gallbladder. Surg Gynae Obstet 1984;159:465–70. [52] Strom BL, Maislin G, West SL et al. Serum CEA and CA 19-9: Potential future diagnostic or screening tests for gallbladder cancer? Int J Cancer 1990;45:821–824. [53] Zargar SA, Khuroo MS, Mahajan R et al. Ultrasound-guided fine needle aspiration biopsy of gallbladder masses. Radiology 1991;179:275–278. [54] Akosa AB, Barker F, Desa L et al. Cytologic diagnosis in the management of gallbladder carcinoma. Acta Cytol 1995;39:494–98. [55] Krishnani N, Shukla S, Jain M et al. Fine needle aspiration cytology in Xanthogranulomatous Cholecystitis, gallbladder adenocarcinoma and coexisting lesions. Acta Cytol 2000;44:508–14. [56] Mohandas KM, Swaroop VS, Gullar SV et al. Gastrointest Endosc 1994;40:50–54. [57] Kriplani AK, Jayant S, Kapur BM. Laparoscopy in primary carcinoma of the gallbladder. Gastrointest Endosc 1992;38(3):326–29 [58] Bhargava DK, Sarin S, Verma K et al. Laparoscopy in carcinoma of the gall bladder. Gastrointest Endosc 1983;29:21–22. [59] Vollmer CM, Derbin JA, Middleton WD et al. Utility of staging laparoscopy in subsets of peri-

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

pancreatic and biliary malignancies. Ann Surg 2002;235:1–7. Agarwal S, Sonawane RN, Behari A et al. Laparoscopic staging in gallbladder cancer. (in press, accepted for publication in Digestive Surgery). Shirai Y, Yoshida K, Tsukada K et al. Inapparent carcinoma of the gallbladder: an appraisal of a radical second operation after simple cholecystectomy. Ann Surg 1992;215:326–31. Chijiwa K, Nakano K, Ueda J et al. Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. J Am Coll Surg 2001;192:600–607. Behari A, Sikora SS, Kapoor VK et al. Long term follow up following extended resections in gallbladder cancer. J Am Coll Surg 2003;196: 82–88. Yamaguchi K, Chijiwa K, Shimizu S et al. Anatomical limit of extended cholecystectomy for gallbladder carcinoma involving the neck of the gallbladder. Int Surg 1998;83:21–23. Kondo S, Nimura Y, Kamiya J et al. Factors influencing postoperative hospital mortality and long-term survival after radical resection for stage IV gallbladder carcinoma. World J Surg 2003;27: 272–77. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior non-curative intervention. Ann Surg 2000;232:557–69. Kondo S, Nimura Y, Hayakawa N et al. Extensive surgery for carcinoma of the gallbladder. Br J Surg 2002;89:179–84. Miyazaki M, Itoh H, Ambiru S et al. Radical surgery for advanced gallbladder carcinoma. Br J Surg 1996;83:478–81. Nimura Y, Hayakawa N, Kamiya J et al. Hepatopancreatoduodenectomy for advanced carcinoma of the biliary tract. Hepatogastroenterology 1991;38:170–175. Nakamura S, Sakaguchi S, Suzuki S et al. Aggressive surgery for carcinoma of the gallbladder. Surgery 1989;106:467–73.

Tropical Hepatogastroenterology

REFERENCES

[71] Todoroki T, Kawamoto T, Takahashi H et al. Treatment of gallbladder cancer by radical resection. Br J Surg 1999;86:622–27. [72] Shirai Y, Yoshida K, Tsukada K et al. Early carcinoma of the gallbladder. Eur J Surg 1992;158: 545–48. [73] Wakai T, Shirai Y, Yokoyama N et al. Early gallbladder carcinoma does not warrant radical resection. Br J Surg 2001;88:675–78. [74] Aretxabala X de, Rosa I, Burgos L et al. Gallbladder cancer in Chile: a report on 54 potentially resectable tumors. Cancer 1992;69:60–65. [75] Wagholikar GD, Behari A, Krishnani N et al. Early gallbladder cancer. J Am Coll Surg 2002;194: 137–41. [76] Bartlett DL, Fong Y, Fortner JG et al. Long-term results after resection for gallbladder cancer. Ann Surg 1996;224(5):639–46. [77] Suzuki S, Yokoi Y, Kurachi K et al. Appraisal of surgical treatment for pT2 gallbladder carcinomas. World J Surg 2004;28:160–65. [78] Arnaud JP, Casa C, Georgeac C et al. Primary carcinoma of the gallbladder- a review of 143 cases. Hepatogastroenterology 1995;42:811–15. [79] Carriaga MT, Henson DE. Liver gallbladder, extrahepatic bile ducts and pancreas. Cancer 1995;75 (supplement 1) S171–S190. [80] Kaneoka Y, Yamaguchi A, Isogai M et al. Hepatoduodenal ligament invasion by gallbladder carcinoma, Histologic patterns and surgical recommendations. World J Surg 2003;27:260–65. [81] Ogura Y, Mizumoto R, Isaji S et al. Radical operations for carcinoma of the gallbladder: present status in Japan. World J Surg 1991;15: 337–43. [82] Ouchi K, Owada Y, Matsumo S et al. Prognostic factors in the surgical treatment of gallbladder cancer. Surgery 1987;101:731–37. [83] Yamaguchi K, Chijiwa K, Saiki S et al. Retrospective analysis of 70 operations for gallbladder carcinoma. Br J Surg 1997;84:200–204. [84] Agarwal S, Behari A, Kumar A et al. Simple cholecystectomy in advanced gallbladder cancer. (in press, accepted for publication in Digestive Surgery)

Part VII / Gallbladder and Biliary Tract

511

[85] Benoist S, Panis Y, Fagniez and the French University Association for Surgical Research. Long-term results after curative resection for carcinoma of the gallbladder. Am J Surg 1998;175:118–22. [86] Shirai Y, Yoshida K, Tsukada K et al. Radical surgery for gallbladder carcinoma. Ann Surg 1992;216:565–68. [87] Chijiwa K, Tanaka M. Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery 1994;115:751–756. [88] Castro MP. Efficacy of Gemcitabine in the treatment of patients with gallbladder cancer: a case report. Cancer 1998;82:639–41. [89] Gallardo J, Rubio B, Fodor M et al. A Phase II study of gemcitabine in advanced gallbladder cancer. Ann Oncol 2001;12:1403–6. [90] Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Seminars Oncol 2002;29(6 suppl 20):40–45. [91] Kapoor VK, Pradeep R, Haribhakti P et al. Intrahepatic seg III cholangiojejunostomy in advanced carcinoma of the gallbladder. Br J Surg 1996;83:1709–11. [92] Baer HU, Rhyner M, Stain SC et al. The effect of communication between the right and left liver on the outcome of surgical drainage for jaundice due to malignant obstruction at the hilus of the liver. HPB Surg 1994;8:73–77. [93] Saxena R, Sikora SS, Kaushik SP. A triple bypass procedure for advanced carcinoma of the neck of gallbladder. Br J Surg 1995;82:394–95. [94] Sikora SS, Kapoor VK. Bypass for malignant duodenal obstruction-Politics of change-therapeutic, selective, prophylactic? Ind J Gastroenterol 1999;18:99–100. [95] Vij JC, Govil A, Chaudhary A et al. Endoscopic biliary endoprosthesis for palliation of gallbladder carcinoma. Gastrointest Endosc 1996;43:121–123. [96] Kapoor VK, McMichael AJ. Gallbladder Cancer – leave no stones unturned. I JS 2002;64:29–30. [97] Nakeeb A, Pitt H, Sohn T et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996;224:463–75. [98] Jarnigan W. Cholangiocarcinoma of the extrahepatic bile ducts. Semin Surg Oncol 2000;19:156–76.

512

Chapter 32 / GALLBLADDER CANCER AND CHOLANGIOCARCINOMA

[99] Broom V, Olsson R, Loof L et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38: 610–615. [100] Pitt HA, Dooley WC, Yeo CJ et al. Malignancies of the biliary tree. (Review) Curr Probl Surg 1995;32:1–90. [101] Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinoma. J Pathol 1983;139:217–238. [102] Burke EC, Jarnagin WR, Hochwald SN et al. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a pre-surgical clinical staging system. Ann Surg 1998;228:385–94. [103] Bold RJ, Goodnight JE (Jr). Hilar Cholangiocarcinoma: Surgical and Endoscopic Approaches. Surg Clin North Am 2004;84:525–42. [104] Koea J, Holden A, ChauK et al. Differential diagnosis of stenosing lesions at the hepatic hilus. World J Surg 2004;28:466–70. [105] Hann LE, Greatrex KV, Bach AM et al. Cholangiocarcinoma at the hepatic hilus: sonographic findings. Am J Roentgenology 1997;168:985–89. [106] Kluge R, Schimdt F, CaCa K et al. Positron emission tomography with [(18)F] fluoro-2-deoxyD-glucose for diagnosis and staging of bile duct cancer. Hepatology 2001;33:1029–35. [107] Kato T, Tsukamoto E, Kuge Y et al. Clinical role of 18F-FDG PET for initial staging of patients with extrahepatic bile duct cancer. Eur J Nucl Med 2002;29:1047–54. [108] Weber SM, DeMetto RP, Fong Y et al. Staging laparoscopy in patients with extrahepatic biliary carcinoma: analysis of 100 patients. Ann Surg 2002;235:392–99. [109] Connor S, Barron E, Wigmore SJ et al. The utility of laparoscopic assessment in the pre-operative staging of suspected hilar cholangiocarcinoma. J Gastrointest Surg 2005;9:476–80. [110] Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215:31–38. [111] American Joint Committee on Cancer 2002, AJCC Cancer Staging Manual;6, Springer-Verlag, New York, pp 14.

[112] Jarnagin W, Fong Y, DeMatteo R et al. Staging, respectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507–19. [113] Nimura Y, Haykawa N, Kamiya J et al. Hilar cholangiocarcinoma-surgical anatomy and curative resection. J Hepatobiliary Pancreat Surg 1995;2:239–48. [114] Gazzaniga G, Filauro M, Bagarolo C et al. Surgery for hilar cholangiocarcinoma: an Italian experience. J Hepatobiliary Pancreat Surg 2000;7: 122–7. [115] Sugiura Y, Nakamura S, Iida S et al. Extensive resection of the bile ducts combined with liver resection for cancer of the main hepatic duct junction: a cooperative study of the Keio bile duct cancer study group. Surgery 1994;115:445–451. [116] Kitagawa Y, Nagino M, Kamiya J et al. Lymph node metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent regional and para-aortic node dissection. Ann Surg 2001;233(3):385–92. [117] Neuhaus P, Jonas S, Bechstein WO et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:808–18. [118] Pichlmayr R, Weimann A, Klempnauer J et al. Surgical treatment in proximal bile duct cancer. A single center experience. Ann Surg 1996;224: 628–38. [119] Miyazaki M, Ito H, Nakagawa K et al. Aggressive surgical approaches to hilar cholangiocarcinoma:hepatic or local resection? Surgery 1998;123:131–6. [120] Kosuge T, Yamamato J, Shimada K et al. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 1999;230:663–71. [121] Lee S, Lee Y, Park K et al. One hundred and eleven liver resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg 2000;7:135–41. [122] Lillemoe K, Cameron J. Surgery for hilar cholangiocarcinoma: the Johns Hopkins approach. J Hepatobiliary Pancreat Surg 2000;7:115–21. [123] Nimura Y, Kamiya J, Kondo S et al. Aggressive preoperative management and extended surgery

Tropical Hepatogastroenterology

REFERENCES

[124]

[125]

[126]

[127]

[128]

[129]

for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000;7: 155–62. Launois B, Reding R, Lebeau G et al. Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers. J Hepatobiliary Pancreat Surg 2000;7: 128–34. Kondo S, Hirano S, Ambo Y et al. Forty consecutive resections of hilar cholangiocarcinoma with no post operative mortality and no positive ductal margins:results of a prospective study. Ann Surg 2004;240:95–101. Silva MA, Tekin K, Ayetekin F et al. Surgery for hilar cholangiocarcinoma; a 10 year experience of a tertiary referral center in the UK. Eur J Surg Oncol 2005;31:533–39. Cherqui D, Benoist S, Malassagne B et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000;135:302–308. Hochwald SN, Burke EC, Jarnagin WR et al. Association of pre-operative biliary stenting with increased postoperative infectious complications. Arch Surg 1999;134:261–66. Tsao J, Nimura Y, Kamiya J et al. Management of hilar cholangiocarcinoma: comparison of an

test

Part VII / Gallbladder and Biliary Tract

[130]

[131]

[132]

[133]

[134]

[135]

513

American and a Japanese experience. Ann Surg 2000;232:166–74. Makuuchi M, Thai BL, Takayasu K et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107: 521–27. Seyama Y, Kubota K, Sano K et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003;238:73–83. Born P, Rosch T, Bruhl K et al. Long-term outcome in patients with advanced hilar bile duct tumors undergoing palliative endoscopic or percutaneous drainage. Z Gastroenterol 2000;38:483–89. Madoff D, Wallace M. Palliative treatment of unresectable bile duct cancer. Which stent? Which approach? Surg Oncol Clin N Am 2002;11: 923–39. Cowling M, Adam A. Internal Stenting in malignant biliary obstruction. World J Surg 2001;25:355–61. Jarnagin WR, Burke EC, Powers C et al. Intrahepatic biliary enteric bypass provides effective palliation in selected patients with malignant obstruction at the hepatic duct confluence. Am J Surg 1998;175:453–60.

Chapter

33 CHOLEDOCHAL CYSTS Anurag Krishna

33.1 INTRODUCTION Bile duct cyst is an uncommon congenital abnormality of unknown etiology. The term is derived from the Greek words chole (bile), dechomai (to receive), and kystis (a sac). Typically, this is a surgical problem of infancy and childhood with more than 60% of all cases presenting in the first decade.[1] However, in nearly 20%, the diagnosis is made in adulthood[2] and is often associated with complications of the cyst. In the past, choledochal cysts were commonly treated using drainage procedures (cystoduodenostomy or cystojejunostomy). It has now become clear that these procedures are associated with an unacceptably high rate of long term complications; in particular, malignant change, anastomotic stricture, cholangitis, pancreatitis, and biliary calculi.[3] The current recommendation is that all cysts should be excised, including those that have been previously drained.[4–6]

33.2 HISTORY The earliest description of abnormal common bile duct dilatation is credited to Abraham Vater, but the first detailed clinical account was made by Halliday Douglas[7] in a 17 year old girl. William Swain[8] performed the first successful operation 514

by anastomosing a loop of jejunum to the cyst. Morio Kasai[9] recommended cyst excision as the primary treatment even in children. Dewbury[10] first reported a case of choledochal cyst that was diagnosed on prenatal ultrasound scan.

33.3 CLASSIFICATION The term ‘choledochal cyst’ is commonly, albeit incorrectly used to describe all bile duct cysts. The latter term is semantically more appropriate as cysts may be present anywhere in the bile duct system and not only in the common bile duct or choledochus. The commonly used classification was initially proposed by Alonso-Lej[11] wherein cysts were classified into three types:- Type I – a fusiform or saccular dilatation of the common hepatic and common bile duct; Type II – a supraduodenal diverticulum; and, Type III – an intraduodenal diverticulum or choledochocele. Caroli[12] described an entity where multiple intrahepatic bile duct cysts were present in the absence of any extrahepatic cysts. Later, Caroli disease has included cases where intrahepatic cysts occur in the presence or absence of extrahepatic cysts. Todani[13] later combined the Alonso-Lej classification and the Caroli variants to describe 5 types of cysts (Table 33.1, Fig. 33.1).

EPIDEMIOLOGY

515

FIGURE 33.1 Todani’s classification. TABLE fy 33.1 Classification of choledochal cysts (Todani[13] ) Type I Type II Type III Type IV

Type V

Cystic (Ia), focal (Ib) or fusiform (Ic) (commonest) Diverticulum Choledochocele Multiple intra- and extrahepatic cysts (IVa) - (second most common) Multiple extrahepatic cysts (IVb) Multiple intrahepatic cysts

Types I and IVa, respectively, are the most common variants, and together, account for over 90% of cases.[3, 8, 14] There is some speculation whether Type II and III cysts are truly bile duct cysts or not. Type II closely resembles gallbladder duplications. Similarly, Type III cysts or choledochoceles are intraduodenal lesions lined by duodenal mucosa and have no clinical or pathologic relationship to choledochal cysts.[3, 15] Caroli’s disease may resemble true choledochal cysts radiologically, but other features suggest that it is a distinct, unrelated entity. It is an autosomal recessive condition with defined chromosomal abnormalities.[16, 17] Some patients may have associated congenital hepatic fibrosis (Grumbach’s disease), while in others there may

Part VII / Gallbladder and Biliary Tract

be intrahepatic gallstones and a high incidence of renal disease.[3] Intrahepatic dilatation may often resolve after cyst excision and this should be differentiated from true cystic dilatation of the intrahepatic ducts.[18] Visser and coworkers[3] suggest that intrahepatic dilatation is almost invariable in choledochal cysts, just the magnitude varies, and separating Types I and IV as distinct entities is an exaggeration. They recommend that the term choledochal cyst should be reserved for the single condition made up of Todani Types Ia through Ic and IVa. All others must be considered separate clinical and pathological entities.

33.4 EPIDEMIOLOGY The incidence of choledochal cyst in the west is estimated to be about 1 in 100,000 live births.[18] It is more common in the Far-East, with Japan having a hospital admission rate of 1 per 1000 admissions. Among adults referred for endoscopic retrograde cholangiopancreatography, 0.1% had choledochal cyst.[19] The disease is more common in females in a ratio of nearly 4:1.[18, 20, 21] Over 60% of cases present in the first decade of life.[1, 18, 21]

516

Chapter 33 / CHOLEDOCHAL CYSTS

33.5 CLINICAL FEATURES The clinical presentation of choledochal cysts varies with age. The classical triad of jaundice, right upper quadrant mass and abdominal pain is present only in a minority of patients, and 85% of children have at least two features of the triad, compared to only 25% of adults.[18, 22, 23]

33.5.1 Infants Neonates typically present with obstructive jaundice mimicking biliary atresia. In infants, abdominal mass, pain, vomiting, fever, and failure to thrive may be the presenting symptoms.[18] Hyperamylasemia does not occur in infants due to pancreatic immaturity. Similarly, biliary amylase levels do not reach significant proportions till 1–2 years of age.[24, 25]

33.5.2 Older Children Abdominal pain is the prominent symptom in this age group. 70% may have jaundice, which unlike in infants, is intermittent. Plasma and/or biliary amylase levels are elevated in almost all patients with abdominal pain, some of whom show evidence of pancreatitis.[18]

these patients suffered pancreatitis, compared with only a third of patients with normal ducts.[27]

33.6 INVESTIGATIONS Biochemical tests such as liver function tests may be normal. In the jaundiced patient, conjugated bilirubin and alkaline phosphatase levels may be raised. Plasma amylase is often elevated during episodes of acute pain. Ultrasonography is the initial investigation of choice, with a specificity of 97% in children.[28] The CBD diameter is less than 2 mm in normal infants and less than 3.5 mm in older children (Fig. 33.2). Radionuclide scintigraphy is a safe and sensitive imaging modality that has long been used in the diagnosis of choledochal cysts. While the sensitivity for Type I cysts is nearly 100%, only two-thirds of Type IV cysts are detected, and the extent of intrahepatic disease is often underestimated.[29] Computer tomography (CT) has been used in the diagnosis of choledochal cysts, but its utility

33.5.3 Adults Choledochal cysts may often be incidentally detected in adults.[22] Recurrent abdominal pain and mild jaundice are the commonest presenting symptom. These are typically intermittent. An abdominal mass is very uncommon.[2, 4] Symptoms often mimic biliary calculous disease. Cholangitis, uncommon in children, is a common presentation in adults.[4, 23, 26] Acute pancreatitis is also common in adults.[2, 22] and is related to the anomalous pancreatic-biliary ductal union. In one study, 57% of patients had an anomalous ductal union. All

FIGURE 33.2 Ultrasound showing the massive CBD of a choledochal cyst.

Tropical Hepatogastroenterology

PATHOLOGY

FIGURE 33.3 MRCP in an adult patient with a choledochal cyst (C) (G - gallbladder).

is nowadays considered limited when other imaging modalities are available. It may, however, give invaluable information when an associated malignancy is suspected. Magnetic resonance cholangiopancreatography (MRCP) is currently the “gold standard” in the imaging of choledochal cysts (Fig. 33.3).[5] It is noninvasive, safe and more sensitive than most other modalities. Delineation of the anomalous ductal union may not be as good as with conventional endoscopic retrograde cholangiopancreatography (ERCP), but this factor does not influence management decisions. Also, the sensitivity in children may not be as high as it is in adults.[30–32] ERCP defines the anomalous ductal anatomy much better than MRCP. However, it is invasive and often requires general anesthesia in children. ERCP in small children is technically more demanding.

33.7 PATHOLOGY The wall of the choledochal cyst is composed of fibrous tissue with elastic and smooth muscle

Part VII / Gallbladder and Biliary Tract

517

fibers. The cuboidal biliary epithelium may be ulcerated, and often only small patches of viable epithelium may be identified. Histological damage of the cyst wall directly correlates with age, with young children showing epithelial desquamation but little inflammation. In contrast, in older children and adults, the epithelial lining is barely identifiable and there is marked acute and/or chronic inflammation.[33] The gallbladder is usually normal or slightly dilated, though the cystic duct may open into the cyst. The liver may show mild inflammatory infiltration of the portal tracts with some periportal fibrosis through to cirrhosis.[18] Even livers that may appear grossly normal may show varying degrees of bile duct proliferation, cholestasis, inflammatory infiltration and fibrosis.[34, 35]

33.8 ETIOLOGY 33.8.1 Abnormal Pancreaticobiliary Duct Junction The most widely accepted theory for the etiology of choledochal cysts is related to an anomalous pancreaticobiliary junction.[36] Normally, the distal common bile duct joins the distal pancreatic duct within the wall of the duodenum to open at the ampulla of Vater. If there is an arrest of the migration of the common duct of the biliary and pancreatic ducts inwards in the duodenal wall, it results in a long common channel. This union of the bile duct and pancreatic duct occurs outside the duodenal wall and, therefore, is not surrounded by the normal arrangement of the sphincter of Oddi. This encourages reflux of pancreatic juice into the biliary tree that may result into dilatation. This argument is supported by manometric studies[37] and also by the presence of high concentrations of pancreatic enzymes in the cyst fluid.[25]

518

Chapter 33 / CHOLEDOCHAL CYSTS

The normal pancreaticobiliary junction lies outside the duodenal wall and sphincter of Oddi before 8 weeks’ gestation and gradually migrates towards the duodenal lumen.[38] Early arrest of this migration may result in pancreaticobiliary duct malunion (PBM). A common channel up to 3 mm in neonates and infants, 4 mm till 9 years of age, and 5 mm from 10–15 years of age is normal. In adults, a common channel greater than 15 mm is abnormal.[5, 39, 40] PBM occurs in 65%–95% of cases of choledochal cysts,[18, 41–43] with a higher incidence in Japanese children. Type I and IVa cysts are more commonly associated with PBM. It may also be noted that this malunion may have implications not only as a possible etiologic factor but also has a prognostic value. Patients of choledochal cyst with an anomalous pancreaticobiliary junction are significantly more likely to have complications like pancreatitis, pancreatic calculi and biliary cancer.[40, 43–46] Not all patients of choledochal cysts have PBM. Similarly, 9% of ERCP done in patients without choledochal cysts will show PBM.[47] This suggests that an abnormal common channel may not be the only factor responsible for the development of choledochal cysts.

33.8.2 Oligoganglionosis Kusunoki[48] demonstrated that the narrow portion of the CBD distal to the choledochal cyst had fewer ganglion cells than controls. He, therefore, suggested a mechanism similar to achalasia cardia or Hirschsprung’s disease in the causation of choledochal cysts. There is a high level of reoviral RNA in biliary tissue of patients with choledochal cysts.[49] This leads to the speculation that a viral infection of the ganglionic neurons may cause oligoganglionosis as described above.[5]

33.8.3 Heredity Hereditary factors may contribute to the etiology.[50–53] There are some reports of choledochal cysts in family members.

33.9 FORME FRUSTE CHOLEDOCHAL CYST Lilly.[54] described four patients with characteristic features of choledochal cyst except for the cystic component. They all had pancreaticobiliary duct malunion. Similar cases were reported by other authors also[55–57] where bile duct dilatation was virtually nonexistent. Most of these patients presented with jaundice, fever, abdominal pain and pancreatitis.[54, 57] It is recommended that these patients require excision of the common bile duct with biliary reconstruction by choledochojejunostomy (Roux-en-Y) much like the procedure for choledochal cysts. The excised CBD shows the classical pathological microscopic features of choledochal cyst. Although open sphincteroplasty[58] and endoscopic sphincterotomy[59] have also been tried, results with excision and biliary reconstruction are consistently better.

33.10 PRENATALLY DIAGNOSED CHOLEDOCHAL CYST Choledochal cysts can be diagnosed prenatally on routine maternal ultrasonography.[60] The optimum strategy of management in this group of patients has not yet been clearly determined, particularly the optimum timing of surgery. Choledochal cysts have been diagnosed as early as 15–16 weeks’ gestation,[60] at a time when the fetal pancreatic enzyme production has not started. This puts a question mark on the theory of pancreatic

Tropical Hepatogastroenterology

COMPLICATIONS

reflux in the causation of choledochal cysts; at least those diagnosed prenatally.[62] Among cystic lesions diagnosed on prenatal ultrasound scans, the differential diagnosis lies between a choledochal cyst and the cystic variant of extrahepatic biliary atresia (EHBA).[63] In one series of 13 patients with biliary disease and abnormal prenatal US scans, the correct diagnosis was made prenatally in only 15% of cases.[60] Since it is difficult to differentiate between choledochal cysts and cystic EHBA by prenatal ultrasound scan or even MRI, and since we know that the outcome of surgery for EHBA is improved if the operation is performed early, all babies with an antenatal US scan showing biliary cyst should undergo early exploration.[64, 65] This is particularly so if the baby has obstructive jaundice or the cyst is increasing in size.[60, 64] However, in babies who are not jaundiced at birth or where the cyst is not enlarging the question of the appropriate timing of surgery is unresolved. While surgery in early neonatal period may be associated with a higher rate of complications such as anastomotic leaks and strictures,[66] some workers[67] have shown this to be a safe and effective approach that prevents serious complications such as cholangitis and portal fibrosis. Most authors now suggest a middle path and recommend that surgery in this group of asymptomatic children may be delayed till 3–6 months of age.[65, 68]

33.11 COMPLICATIONS Choledochal cysts have a potential for causing a variety of complications such as cystolithiasis, biliary and pancreatic calculi, pancreatitis, cholangitis and intrahepatic abscesses, cirrhosis and portal hypertension, and biliary malignancies. While the incidence of associated complications

Part VII / Gallbladder and Biliary Tract

519

is as low 15% in children,[18] nearly 80% of adults present with complications.[2, 69] Complications are more likely with Type IVa cysts.[69]

33.11.1 Rupture of Cyst Rupture of choledochal cysts has been reported in infants and children[18, 70–72] but not in adults.[72] The incidence varies from 2% to 18%, and commonly occurs under 4 years of age.[18, 72, 73] There is usually no correlation between the size of the cyst and its rupture. Some patients may present acutely with abdominal pain and distension, vomiting, fever and mild jaundice. Alternatively, an indolent form presents with progressive biliary ascites that is less dramatic than biliary peritonitis. The acute presentation has been misdiagnosed as appendicitis for which prior laparotomy is not uncommon.[22, 72, 73] Definitive surgery in the form of cyst excision with biliary reconstruction would be the best option and has been safely done.[73, 74] However, most such patients are often in a poor general condition and inadequately worked up. A safer alternative is to institute an effective T-tube drainage and delay definitive surgery till the inflammation has subsided.[18, 72]

33.11.2 Pancreatic Complications Pancreatitis: this is a fairly common presentation of choledochal cysts in adults.[2, 23, 27] This may be due to activation of pancreatic enzymes by bile reflux as a result of the anomalous pancreaticobiliary ductal union. The diagnosis is based on the clinical findings of epigastric pain, nausea and vomiting, and hyperamylasemia. Typically, the episodes of pancreatitis associated with choledochal cysts are mild and often relapsing. Chronic pancreatitis is rare.[75] Acute pancreatitis and protein-plug formation are

520

Chapter 33 / CHOLEDOCHAL CYSTS

commonly observed in with patients treated for choledochal cysts. These complications are more common in children and in those who have undergone cystenterostomy.[76]

33.11.3 Carcinoma Biliary malignancy is very commonly associated with choledochal cysts. Cancer developing in the remaining intrapancreatic biliary tract or the pancreas in patients who have previously undergone cyst excision is extremely rare.[77–79] Biliary tract malignancy has been reported in 2.5% to 30% of patients with choledochal cyst. This is at least 20 times higher than the risk in general population.[4, 79–82] This risk is age-related, being 0.7% in the first decade, 7% in the second decade and about 15% after 20 years of age.[82] The clinical presentation in these cases may be in the form of cholangitis, gastric outlet obstruction, right upper quadrant pain, and weight loss. Intracystic lithiasis is frequently associated with tumor. The risk is the greatest in Type I, IV and V cysts.[83] Also, the risk is much higher in patients with anomalous pancreaticobiliary union (32% against 0% in those with a normal ductal union).[43] In fact, this association of malignancy with PBM was observed to be more significant than the association with choledochal cyst.[84] Cholangiocarcinoma is the most common malignancy, though adenocarcinoma, squamous cell carcinoma and other rare tumors also occur. The possible factors for carcinogenesis include chronic inflammation, reflux of pancreatic juices and bile stagnation. Most studies suggest that malignancy almost always involves the cyst wall and the gallbladder.[83, 85, 86] There is evidence to show that internal drainage procedures (cystenterostomy) may actually increase the risk of malignant change when compared with untreated patients. The

mean age of affected patients is 35 years which is a decade less than unoperated patients who develop malignancy[86] despite the fact that cholestasis has been relieved. Reflux of intestinal bacteria and enzymes into the bile ducts from the enteric anastomosis may be aggravating factors.[41] The prognosis of malignant choledochal cyst tumors is poor. They are often first diagnosed at laparotomy and may already be unresectable. The mean survival after resection is 6.2 months.[80] Cholangiocarcinoma developing metachronously after cyst excision is rare (less than 1%).[87–91] In most such cases, the previous excision is found to be incomplete. In a collective review, the mean age at cyst excision was 23 years, and cancers were detected at a mean age of 32 years, that is 9 years later. The site of the cancerous lesion is intrahepatic, anastomotic, and the intrapancreatic duct.[87] This latter observation makes it mandatory to excise the intrapancreatic portion of the cyst till just above the pancreaticobiliary duct union. The extent of resection in Type IVa cysts, whether to excise only the extrahepatic portion or perform more extensive liver resection, remains controversial. This stems from the observation that malignant change has been observed in the remaining intrahepatic dilated ducts in 8 cases in world literature.[41] On the other hand, Kagawa et al.[92] reported that nearly half of Type IVa patients with cancer already had the carcinoma at the time of initial treatment. Logically, for Type IVa cysts, radical excision with hepatic resection may be the ideal treatment option. However, given the very low risk of intrahepatic malignancy and the significant morbidity of extensive resection, it may be reasonable to excise the bulk of the cyst and perform a hepaticojejunostomy with interruption of the abnormal pancreaticobiliary duct junction.[3, 41]

Tropical Hepatogastroenterology

TREATMENT

521

33.12.1 Type I Cyst

FIGURE 33.4 Operative picture showing a choledochal cyst (C). On the right is the removed specimen that includes the cyst and the gallbladder (G).

33.12 TREATMENT The optimum recommended treatment for most choledochal cysts is complete excision of the cyst (Fig. 33.4) with mucosa-to-mucosa bilioenteric anastomosis. Cystenterostomy should almost never be done since it is associated with an unacceptably high rate of long term problems such as anastomotic stricture, cholangitis, biliary calculi, pancreatic calculi, and malignancy. In the rare instance, a drainage procedure may be required if excision is considered too risky for technical reasons or if the patient is too sick.[3] All patients who have undergone cystenterostomy earlier should be re-operated to excise the cyst whether or not symptoms are present.[3, 91] Secondary excision of choledochal cysts is technically more demanding with a significantly higher rate of early and late postoperative complications.[91] Preoperatively, all patients must receive prophylactic intravenous broad spectrum antibiotics that have a good biliary concentration. Vitamin K is given, especially if the patient is jaundiced. Bowel preparation with lactulose and oral metronidazole may be done to decontaminate the gut.

Part VII / Gallbladder and Biliary Tract

Total cyst excision is the procedure of choice in this group. Proximally, the level of excision should be at the bifurcation of the lobar ducts. Dilated intrahepatic ducts, if present, should be carefully irrigated to clean the debris. Distally, the dissection is carried well into the pancreas to a point just short of where the duct abruptly narrows. Care must be taken to avoid injury to the pancreatic duct. Protein plugs or calculi within the common channel must be meticulously removed using irrigation or intraoperative choledochoscopy.[93] Cyst excision in adults is technically different from the procedure in children for several reasons. Adults may have had earlier cyst drainage procedures or episodes of cholangitis resulting in dense adhesions. Portal hypertension associated with choledochal cysts may be present in adults, making surgery more hazardous because of the increased vascularity. Biliary reconstruction is best achieved by a retrocolic Roux loop of jejunum.[18, 94, 95] that is anastomosed to the hepatic duct bifurcation. This anastomosis may be done end-to-end[81, 96] or end-to-side (close to the end of the jejunal limb to avoid a blind pouch of bile stasis).[96] A liver biopsy must always be done. In most cases, abdominal drainage is unnecessary.[97] Many alternative biliary reconstruction techniques have been described, Todani[98] preferred the hepaticoduodenostomy which he argued was more physiological, with fewer adhesions and strictures. It may also allow endoscopic evaluation of the anastomosis and biliary epithelium in cases where complications develop.[99] However, mobility of the duodenum may limit its use, particularly in adults or in re-do surgeries. Jejunal interposition grafts between the hepatic duct and duodenum have also been described with

522

Chapter 33 / CHOLEDOCHAL CYSTS

excellent results.[100, 101] Fu et al. have used a nonrefluxing valve in the jejunal conduit to reduce the incidence of cholangitis. The use of the vascularized appendix interposition graft has been proposed by several surgeons.[102–104] However, the appendix graft is prone to stenosis, requiring revision surgery.[105]

33.12.2 Type II Cysts (Diverticulum) The treatment of these cysts is by excision.[21, 106, 107] If the neck of the cyst at its junction with the CBD is narrow, the CBD may be closed primarily or otherwise it may be closed over a T-tube.

33.12.3 Type III Cysts (Choledochocele) A majority of choledochoceles are small (≤ 2 cm). The recommended treatment for small choledochoceles is endoscopic sphincterotomy and cyst unroofing.[108, 109] While performing the endoscopic procedure it is important to identify and prevent damage to the major pancreatic duct. Large choledochoceles may need to be excised transduodenally.[21] Malignancy in a choledochocele is very uncommon, thereby justifying an endoscopic procedure rather than excision. However, one report describes malignancy in 3 of 11 patients.[110]

33.12.4 Type IV Cysts A majority of Type IV cysts will do very well long term following excision of the extrahepatic cystic component and a wide anastomosis at the hepatic duct bifurcation.[3, 75] However, patients in whom the intrahepatic ducts have stones or strictures, or are complicated by recurrent cholangitis or intrahepatic abscesses fare poorly if only the extrahepatic cyst is excised. In these cases, if the disease affects one lobe that lobe should be excised.[111, 112] In case the disease is extensive, bilobar or complicated by cirrhosis or portal hypertension, liver transplantation may provide a more durable solution.[75, 113]

33.12.5 Laparoscopic Excision of Choledochal Cysts Farello and coworkers[114] first described laparoscopic excision of choledochal cysts. Since then, many reports have appeared that claim safe excision of choledochal cysts laparoscopically in adults as well as in children.[115–120] Although technically possible and shown to be safe, the long term results, particularly anastomotic strictures and malignancy arising in the residual cyst remain to be evaluated. In one large series, the mean operation time was 4.3 hrs (range 3.5–7.6 hrs), blood loss was 5–10 ml and hospital stay was 4.5 days.[115] These parameters are no different from those seen with the conventional open surgical technique.

REFERENCES [1] Sela-Herman S, Scharschmidt BF. Choldeochal cyst, a disease for all ages. Lancet 1996;347:779. [2] Nagorney DM, McIlrath DC, Adson MA. Choledochal cysts in adults: Clinical management.

Surgery 1984;96:656–63. [3] Visser BC, Suh I, Way LW et al. Congenital choledochal cysts in adults. Arch Surg 2004;139: 855–62.

Tropical Hepatogastroenterology

REFERENCES

[4] Liu CL, Fan ST, Lo CM et al. Congenital choledochal cysts in adults. Arch Surg 2002;137: 465–8. [5] Metcalfe MS, Wemyss-Holden SA, Maddern GJ. Management dilemmas with choledochal cysts. Arch Surg 2003;138:333–339. [6] deVries JS, deVries S, Aronson DC et al. Choledochal cysts: age of presentation, symptoms, and late complications related to Todani’s classification. J Pediatr Surg 2002;37:1568–73. [7] Douglas A. Case of dilatation of the common bile duct. Mon J Med 1852;14:97–100. [8] Stain SC, Guthrie CR, Yellin AE et al. Choledochal cyst in the adult. Ann Surg 1995;222:129–33. [9] Kasai M, Asakura Y, Taira Y. Surgical treatment of choledochal cyst. Ann Surg 1970;172:844–51. [10] Dewbury KC, Aluwihare AP, Birch SJ et al. Case reports: Prenatal ultrasound demonstration of a choledochal cyst. Br J Radiol 1980;53:906–907. [11] Alonso-Lej F, Rever WB, Pessagno DJ. Collective review: congenital choledochal cyst, with report of two and analysis of 94 cases. Intl Abstracts Surg 1959;108:1–30. [12] Caroli J, Soupalt J, Kossakowski L et al. La digitations polykstique congenitale des voico biliares intrahepatiques; essai de classification. Semin Hop Paris 1958;34:488–95. [13] Todani T, Watanabe Y, Narusue M et al. Congenital bile duct cysts. Classification, operative procedures, and review of thirty seven cases including cancer arising from choledochal cyst. Am J Surg 1977;134:263–9. [14] Hara H, Morita S, Ishibashi T et al. Surgical treatment for congenital biliary dilatation, with or without intrahepatic bile duct dilatation. Hepatogastroenterology 2001;48:638–41. [15] Gorenstein L, Strasberg SM. Etiology of choledochal cysts: two instructive cases. Can J Surg 1985;28:363–67. [16] Parada LA, Hallen M, Hagerstand I et al. Clonal chromosomal abnormalities in congenital bile duct dilatation (Caroli’s disease). Gut 1999;45:780–82. [17] Wu KL, Changchien CS, Kuo CM et al. Caroli’s disease: a report of two siblings. Eur J Gastroenterol Hepatol 2002;14:1397–99.

Part VII / Gallbladder and Biliary Tract

523

[18] Stringer MD, Dhawan A, Davenport M et al. Choledochal cysts: lessons from a 20-year experience. Arch Dis Child 1995;73:528–31. [19] Schmidt HG, Bauer J, Wiessner V. Endoscopic aspects of choledochoceles. Hepatogastroenterology 1996;43:143–46. [20] Flanigan DP. Biliary cysts. Ann Surg 1975;182: 635–643. [21] Powell CS, Sawyers JL, Reynolds VH. Management of adult choledochal cysts. Ann Surg 1981; 193:666–676. [22] Samuel M, Spitz L. Choledochal cyst: varied clinical presentations and long-term results of surgery. Eur J Pediatr Surg 1996;6: 78–81. [23] Lipsett PA, Pitt HA, Colombani PM et al. Choledochal cyst disease: a changing pattern of presentation. Ann Surg 1994;220:644–52. [24] Davenport M, Stringer MD, Howard ER. Biliary amylase and congenital choledochal dilatation. J Pediatr Surg 1995;30:474–477. [25] Todani T, Urushihara N, Watanabe Y et al. Pseudopancreatitis in choledochal cyst in children: Intraoperative study of amylase levels in the serum. J Pediatr Surg 1990;25:303–306. [26] Chaudhary A, Dhar P, Sachdev A et al. Choledochal cysts – differences in children and adults. Br J Surg 1996;83:186–88. [27] Swisher SG, Cates JA, Hunt KK et al. Pancreatitis associated with adult choledochal cysts. Pancreas 1994;9:633–37. [28] Lee HC, Yeung CY, Chang PY et al. Dilatation of the biliary tree in children: sonographic diagnosis and its clinical significance. J Ultrasound Med 2000;19:177–84. [29] Rajnish A, Gambhir S, Das BK et al. Classifying choledochal cysts using hepatobiliary scintigraphy. Clin Nucl Med 2000;25:996–999. [30] Irie H, Honda H, Jimi M et al. Value of MR cholangiopancreatography in evaluating choledochal cysts. AJR 1998;171:1381–85. [31] Govil S, Justus A, Korah I et al. Choledochal cysts: evaluation with MR cholangiography. Abdom Imaging 1998;23:616–619.

524

Chapter 33 / CHOLEDOCHAL CYSTS

[32] Miyazaki T, Yamashita Y, Tang Y et al. Single-shot MR cholangiopancreatography of neonates, infants and young children. AJR 1998;170:33–37. [33] Komi N, Tamura T, Tsuge S et al. Relation of patient age to premalignant alterations in choledochal cyst epithelium: histochemical and immunohistochemical studies. J Pediatr Surg 1986; 21:430–433. [34] Nambirajan L, Taneja P, Singh MK et al. The liver in choledochal cyst. Trop Gastroenterol 2000;21:135–139. [35] Cheng MT, Chang MH, Hsu HY et al. Choledochal cyst in infancy: a follow up study. Acta Paediatr Taiwan 2000;41:13–17. [36] Babbitt DP. Congenital choledochal cysts: new etiological concepts on anomalous relationships of the common bile duct and pancreatic bulb. Ann Radiol (Paris) 1969;12:231–240. [37] Iwai N, Tokiwa K, Tsuto T et al. Biliary manometry in choledochal cyst with abnormal choledochopancreatico ductal junction. J Pediatr Surg 1986;21:873–876. [38] Wong KC, Lister J. Human fetal development of the hepato-pancreatic duct junction – a possible explanation of congenital dilation of the biliary tract. J Pediatr Surg 1981;16:139–145. [39] Guelrud M, Morera C, Rodriguez M et al. Normal and anomalous pancreaticobiliary union in children and adolescents. Gastrointestinal Endoscopy 1999;50:189–93. [40] Matsumoto Y, Fujii H, Itakura J et al. Recent advances in pancreaticobiliary maljunction. J Hepatobiliary Pancreat Surg 2002;9:45–54. [41] Ishibashi T, Kasahara K, Yasuda Y et al. Malignant change in the biliary tract after excision of choledochal cyst. Br J Surg 1997;84: 1687–91. [42] Komi N, Takehara H, Kunitomo K et al. Does the type of anomalous arrangement of pancreaticobiliary ducts influence the surgery and prognosis of choledochal cysts? J Pediatr Surg 1992;27:728–31. [43] Song HK, Kim MH, Myung SJ et al. Choledochal cyst associated with anomalous union of pancreaticobiliary duct (AUPBD) has a more

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

grave clinical course than choledochal cyst alone. Korean J Intern Med 1999;14:1–8. Todani T, Watanabe Y, Fuji M et al. Carcinoma arising from the bile duct in choledochal cyst and anomalous arrangement of the pancreatobiliary ductal union. Tan to Sui 1985;6:525–35. Kimura K, OhtoM, Saisho H et al. Association of gallbladder carcinoma and anomalous pancreaticobiliary ductal union. Gastroenterology 1985;89:1258–65. Yamauchi S, Koga A, Matsumoto S et al. Anomalous junction of pancreaticobiliary duct without congenital choledochal cyst: a possible risk factor for gallbladder cancer. Am J Gastroenterol 1987;82:20–24. Matsumoto Y, Fujii H, Itakura J et al. Pancreaticobiliary maljunction:pathophysiological and clinical aspects and the impact on biliary carcinogenesis. Langenbecks Arch Surg 2003;388:122– 131. Kusunoki M, Saitoh N, Yamamura T et al. Choledochal cysts: oligoganglionosis in the narrow portion of the choledochus. Arch Surg 1988;123: 984–986. Tyler KL, Sokol RJ, Oberhaus et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998;27:1475–82. Iwafuchi M, Ohsawa Y, Naito M et al. Familial occurrence of congenital bile duct dilatation. J Pediatr Surg 1990;25:353–55. Uchida M, Tsukhara M, Fuji T et al. Discordance for anomalous pancreaticobiliary ductal junction and congenital biliary dilatation in a set of monozygotic twins. J Pediatr Surg 1992;27: 1563–64. Iwata F, Uchida A, Miyaki T et al. Familial occurrence of congenital bile duct cysts. J Gastroenterol Hepatol 1998;13:316–19. Lane GJ, Yamataka A, Kobayashi H et al. Different types of congenital bile duct dilatations in dizygotic twins. Pediatr Surg Intl 1999;15:403–404. Lilly JR, Stellin GP, Karrer FM. Forme fruste choledochal cyst. J Pediatr Surg 1985;20: 449–451.

Tropical Hepatogastroenterology

REFERENCES

[55] Okada A. Forme fruste choledochal cyst. J Pediatr Surg 1986;21:383. [56] Miyano T, Ando K, Yamataka A et al. Pancreatobiliary maljunction associated with nondilatation or minimal dilatation of the common bile duct in children: diagnosis and treatment. Eur J Pediatr Surg 1996;6:334–337. [57] Thomas S, Sen S, Zachariah N et al. Choledochal cyst sans cyst-experience with six “forme fruste” cases. Pediatr Surg Intl 2002;18:247–251. [58] Barker AP, Ford WD, Le Quesne GW et al. The common bilio-pancreatic channel syndrome in childhood. Aust N Z J Surg 1992;62:70–73. [59] Ng WD, Liu K, Wong MK et al. Endoscopic sphincterotomy in young patients with choledochal dilatation and a long common channel: a preliminary report. Br J Surg 1992;79:550–552. [60] Redkar R, Davenport M, Howard ER. Antenatal diagnosis of congenital anomalies of the biliary tract. J Pediatr Surg 1998;33:700–704. [61] Schroeder D, Smith L, Prain HC. Antenatal diagnosis of choledochal cysts at 15 weeks gestation: etiologic implications and management. J Pediatr Surg 1989;24:936–39. [62] Benhidjeb T, Chaoui R, Kalache K et al. Prenatal diagnosis of a choledochal cyst: a case report and review of the literature. Am J Perinatol 1996;13:207–210. [63] Tsuchida Y, Kawarasaki H, Iwanaka T et al. Antenatal diagnosis of biliary atresia (type I cyst) at 19 weeks’ gestation: Differential diagnosis and etiologic implications. J Pediatr Surg 1995;30: 697–99. [64] MacKenzie TC, Howell LJ, Flake AW et al. The management of prenatally diagnosed choledochal cysts. J Pediatr Surg 2001;36:1241–43. [65] Lugo-Vicente HL. Prenatally diagnosed choledochal cysts: Observation or early surgery? J Pediatr Surg 1995;30:1288–90. [66] Ohtsuka Y, Yoshida H, Matsunaga T et al. Strategy of management for congenital biliary dilatation in early infancy. J Pediatr Surg 2002;37:1173–76. [67] Burnweit CA, Birken GA, Heiss K. The management of choledochal cysts in the newborn. Pediatr Surg Intl 1996;11:130–33.

Part VII / Gallbladder and Biliary Tract

525

[68] Okada T, Sasaki F, Ueki S et al. Postnatal management for prenatally diagnosed choledochal cysts. J Pediatr Surg 2004;39:1055–58. [69] Chaudhary A, Dhar P, Sachdev AK. Complicated choledochal cysts. Int Surg 2001;86:97–102. [70] Seema, Sharma A, Seth A et al. Spontaneous rupture of choledochal cyst. Indian J Pediatr 2000;67:155–56. [71] Maheshwari M, Parekh BR, Lahoti BK. Biliary peritonitis: a rare presentation of perforated choledochal cyst. Indian Pediatr 2002;39: 588–92. [72] Ando K, Miyano T, Kohno S et al. Spontaneous perforation of choledochal cyst: a study in 13 cases. Eur J Pediatr Surg 1998;8:23–25. [73] Karnak I, Tanyel FC, Buyukpamukcu N et al. Spontaneous rupture of choledochal cyst: an unusual cause of acute abdomen in children. J Pediatr Surg 1997;32:736–38. [74] Moss RL, Musemeche CA. Successful management of ruptured choledochal cyst by primary cyst excision and biliary reconstruction. J Pediatr Surg 1997;32:1490–91. [75] Nagorney DM. Bile duct cysts in adults. In Blumgart LH, Fong Y (Eds.) Surgery of the liver and biliary tract, Vol. 2, 3rd Edn., WB Saunders, London, 2000;pp 1229–1244. [76] Komuro H, Makino S, Yasuda Y et al. Pancreatic complications in choledochal cyst and their surgical outcome. World J Surg 2001;25:1519–23. [77] Eriguchi N, Aoyagi S, Okuda K et al. Carcinoma arising in the pancreas 17 years after primary excision of a choledochal cyst: report of a case. Surg Today 2001;31:534–37. [78] Kurokawa Y. Carcinoma of the head of the pancreas after excision of a choledochal cyst. Hepatogastroenterology 2001;48:578–80. [79] Fieber SS, Nance FC. Choledochal cyst and neoplasm: a comprehensive review of 106 cases and presentation of two original cases. Am Surg 1997;63:982–987. [80] Jan YY, Chen HM, Chen MF. Malignancy in choledochal cyst. Hepatogastroenterology 2002; 49:100–103.

526

Chapter 33 / CHOLEDOCHAL CYSTS

[81] Todani T, Watanabe Y, Urushihara N et al. Biliary complications after excisional procedure for choledochal cyst. J Pediatr Surg 1995;30:478–81. [82] Voyles CR, Smadja C, Smands WC et al. Carcinoma in choledochal cysts: age related incidence. Arch Surg 1983;118:986–988. [83] Bismuth H, Krissat J. Choledochal cyst malignancies. Ann Oncol 1999;10 suppl 4:94–98. [84] Chijiiwa K, Kimura H, Tanaka M. Malignant potential of the gallbladder in patients with anomalous pancreaticobiliary ductal junction: the difference in risk between patients with and without choledochal cyst. Intl Surg 1995;80:61–64. [85] Komi N, Tamura T, Miyoshi Y et al. Nationwide survey of cases of choledochal cyst. Analysis of coexistent anomalies, complications and surgical treatment in 645 cases. Surg Gastroenterol 1984;3: 69–73. [86] Todani T, Watanabe Y, Toki A et al. Carcinoma related to choledochal cysts with internal drainage operations. Surg Gynecol Obstet 1987;164:61–64. [87] Watanabe Y, Toki A, Todani T. Bile duct cancer developed after cyst excision for choledochal cyst. J Hepatobiliary Pancreat Surg 1999;6:207–212. [88] Koike M, Yasui K, Shimizu Y et al. Carcinoma of the hepatic hilus developing 21 years after biliary diversion for choledochal cyst: a case report. Hepatogastroenterology 2002;49:1216–20. [89] Fujisaki S, Akiyama T, Miyake H et al. A case of carcinoma associated with the remained intrapancreatic biliary tract 17 years after the primary excision of a choledochal cyst. Hepatogastroenterology 1999;46:1655–59. [90] Goto N, Yasuda I, Uematsu T et al. Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation. J Gastroenterol 2001;36:856–62. [91] Kaneko K, Ando H, Watanabe Y et al. Secondary excision of choledochal cysts after previous cyst-enterostomies. Hepatogastroenterology 1999; 46:2772–2775. [92] Kagawa Y, Kashihara S, Kuramoto S et al. Carcinoma arising in a congenitally dilated biliary tract. Report of a case and review of the literature. Gastroenterology 1978;74:1286–94.

[93] Yamataka A, Segawa O, Kobayashi H et al. Intraoperative pancreatoscopy for pancreatic duct stone debris distal to the common channel in choledochal cyst. J Pediatr Surg 2000;35: 1–4. [94] Miyano T, Yamataka A, Kato Y et al. Hepaticoenterostomy after excision of choledochal cyst in children: a 30 year experience with 180 cases. J Pediatr Surg 1996;31:1417–21. [95] Rattan KN, Khurana P, Budhiraja S et al. Choledochal cyst: a 10 year experience. Ind J Pediatr 2000;67:657–659. [96] Yamataka A, Kobayashi H, Shimotakahara A et al. Recommendations for preventing complications related to Roux-en-Y hepatico-jejunostomy performed during excision of choledochal cyst in children. J Pediatr Surg 2003;38:1830–32. [97] Stringer MD. Choledochal cysts. In Howard ER, Stringer MD, Colombani PM (Eds.) Surgery of the liver, bile ducts and pancreas in children, 2nd Edn., Arnold, London, 2002;pp 149–168. [98] Todani T, Watanabe Y, Mizuguchi T et al. Hepaticoduodenostomy at the hepatic hilum after excision of choledochal cyst. Am J Surg 1981;142:584–587. [99] Henne-Bruns D, Kremer B, Thonke F et al. “Endoscopy friendly” resection technique of choledochal cysts. Endoscopy 1993;25:176–178. [100] Oweida SW, Ricketts RR. Hepatico-jejunoduodenostomy reconstruction following excision of choledochal cysts in children. Am Surg 1989;55:2–6. [101] Fu M, Wang Y, Zhang J. Evolution in the treatment of choledochal cyst. J Pediatr Surg 2000;35: 1344–47. [102] Gopal SC, Gupta S, Gupta DK. Nonrefluxing biliary appendico-duodenostomy for choledochal cyst. Pediatr Surg Int 1995;10:207–208. [103] Wei MF, Qi BQ, Xia GL et al. Use of the appendix to replace the choledochus. Pediatr Surg Int 1998;13:494–496. [104] Crombleholme TM, Harrison MR, Langer JC et al. Biliary appendico-duodenostomy: a nonrefluxing conduit for biliary reconstruction. J Pediatr Surg 1989;24:665–667.

Tropical Hepatogastroenterology

REFERENCES

[105] Delarue A, Chappuis JP, Esposito C et al. Is the appendix graft suitable for routine biliary surgery in children? J Pediatr Surg 2000;35:1312–1316. [106] Lopez RR, Pinson CW, Campbell JR et al. Variation in management based on type of choledochal cyst. Am J Surg 1991;161:612–615. [107] Kouraklis G, Misiakos E, Glinavou A et al. Cystic dilatations of the common bile duct in adults. HPB Surg 1996;10:91–95. [108] Masetti R, Antinori A, Coppola R et al. Choledochocele: changing trends in diagnosis and management. Surg Today 1996;26: 281–285. [109] Ladas SD, Katsogridakis I, Tassios P et al. Choledochocele, an overlooked diagnosis: Report of 15 cases and review of 56 published reports from 1984 to 1992. Endoscopy 1995;27:233–239. [110] Ohtsuka T, Inoue K, Ohuchida J et al. Carcinoma arising in choledochocele. Endoscopy 2001;33:614–619. [111] Nakayama H, Masudda H, Ugajin W et al. Left hepatic lobectomy for type IV-A choledochal cyst. Am Surg 2000;66:1020–1022. [112] Kanoh K, Shimura T, Tsutsumi S et al. Left hepatectomy for the choledochal cyst (type IVa) with intrahepatic stenosis: report of a case. Hepatogastroenterology 2002;49:144–147. [113] Magid MS, Emre S, Norton KI et al. A 7-month old male infant with extra- and intrahepatic biliary cysts. Semin Liver Dis 2000;20:385–390.

test

Part VII / Gallbladder and Biliary Tract

527

[114] Farello GA, Cerofolini A, Rebonato M et al. Congenital choledochal cyst: Video-guided laparoscopic treatment. Surg Laparosc Endosc 1995;5:354–358. [115] Li L, Feng W, Fu J et al. Laparoscopic-assisted total cyst excision of choledochal cyst and Roux-en-Y hepatoenterostomy. J Pediatr Surg 2004;39:1663–1666. [116] Tanaka M, Shimizu S, Mizumoto K et al. Laparoscopically assisted resection of choledochal cyst and Roux-en-Y reconstruction. Surg Endosc 2001;15:545–551. [117] Liu DC, Rodriguez JA, Meric F et al. Laparoscopic excision of a rare type II choledochal cyst: case report and review of the literature. J Pediatr Surg 2000;35:1117–1119. [118] Shimura H, Tanak M, Shimizu S et al. Laparoscopic treatment of congenital choledochal cyst. Surg Endosc 1998;12:1268–1271. [119] Chowbey PK, Katrak MP, Sharma A et al. Complete laparoscopic management of choledochal cyst: a report of two cases. J Laparoendosc Adv Surg Tech A 2002;12: 217–221. [120] Watanabe Y, Sato M, Tokui K et al. Laparoscopeassisted minimally invasive treatment for choledochal cyst. J Laparoendosc Adv Surg Tech A 1999;9:415–418.

Chapter

34 BENIGN BILE DUCT STRICTURES SS Negi and Adarsh Chaudhary

Benign bile duct strictures usually follow surgical trauma to the bile duct. Patience and judgment in management significantly influence the final results. This chapter describes the risks of biliary injury during surgery, and the classification, presentation, and management of bile duct strictures.

34.1 OPERATIVE BILE DUCT INJURY Benign strictures of the extrahepatic bile duct most commonly occur as a result of iatrogenic injury during cholecystectomy. The popularity of laparoscopic cholecystectomy has renewed interest in biliary strictures because of concern that the procedure may lead to a higher incidence of bile duct injury.[1–4] ‘Dangerous anatomy’ and ‘dangerous pathology’ predispose to biliary injury. However, the injury in most cases is caused by ‘dangerous surgery’, the final common pathway usually being a technical error or misinterpretation of anatomy.[5, 6] Features associated with difficult laparoscopic cholecystectomy include advanced age, male sex, a long symptomatic period prior to surgery, and a higher number of episodes of clinical cholecystitis. The risk of bile duct injury is higher in patients presenting with acute cholecystitis, choledocholithiasis, gallstone pancreatitis, cholangitis, 528

or jaundice.[3, 4] If unrecognized or improperly managed, bile duct injury is potentially life threatening, and results in major morbidity, increased hospital costs, and litigation. Compared to malignant biliary obstruction, benign stricture management is tougher, as the patients are often young, productive, and are expected to survive for long. Inadequate management results in ongoing hepatic damage, recurrent cholangitis, secondary biliary cirrhosis, and portal hypertension.

34.1.1 Incidence The incidence of bile duct injury following cholecystectomy is difficult to estimate, chiefly because of under-reporting of cases and variations in definition of bile duct injury. On an average, one bile duct injury occurs in every 100–200 cases of laparoscopic cholecystectomy, and in 200–300 cases of open cholecystectomy.[7] With increasing operator experience the risk of bile duct injuries declines, according to most[2, 8–11] but not all authors.[3, 4, 12]

34.1.2 Classification of Injuries Bile duct strictures classification depends on the location of stricture with regards to the confluence of hepatic ducts (Table 34.1).[13] This classification only categorizes established strictures, and does not include lateral bile duct injury, segmental bile

CONSEQUENCES OF PROLONGED BILIARY OBSTRUCTION

TABLE fy 34.1 Bismuth classification of bile duct strictures Type 1: Low common hepatic duct strictures (> 2 cm of hepatic duct stump). Type 2: Mid common hepatic duct strictures (< 2 cm of hepatic duct stump). Type 3: Hilar stricture with no residual common hepatic duct, but hilar confluence intact. Type 4: Destruction of hilar confluence (right and left hepatic ducts separated). Type 5: Combined common hepatic duct and aberrant right hepatic duct injury.

TABLE fy 34.2 Strasberg classification of laparoscopic bile duct injuries Type A: Bile leak from a minor duct still in continuity with CBD, these leaks occur from the cystic duct or duct of Luschka. Type B: Occlusion of part of biliary tree not in continuity with CBD, this unilateral bile duct injury is almost always the result of an aberrant right hepatic duct. Type C: Bile leak from duct not in communication with CBD, this type of injury is also due to an aberrant right hepatic duct and result from transection not occlusion. Type D: Lateral injury to extrahepatic bile duct. Type E: Circumferential injury of major bile ducts corresponding to the Bismuth classification of bile duct strictures (Bismuth types E 1–5).

duct occlusion, and minor bile leaks. Strasberg and Soper [1] published a comprehensive classification of postlaparoscopic bile duct injuries and proposed specific management of individual types of injury (Table 34.2).

34.1.3 Presentation The presentation depends on the type of injury and time elapsed. Postlaparoscopic cholecystectomy bile duct injuries present more frequently with bile leaks[7, 14] and are recognized earlier than those

Part VII / Gallbladder and Biliary Tract

529

following open cholecystectomy.[15, 16] The patient might demonstrate signs of bile leak (types A, C and D), intra-abdominal collection of bile (biloma, bile ascites or bile peritonitis), recurrent cholangitis, jaundice or portal hypertension. Most patients have abdominal pain, with signs of sepsis and bile leak. Occasional patients remain asymptomatic, or present with pruritis, deranged liver function tests, anorexia, weakness or fatigue.

34.2 CONSEQUENCES OF PROLONGED BILIARY OBSTRUCTION The pathological consequences of prolonged biliary obstruction include progressive hepatic fibrosis, secondary biliary cirrhosis, atrophyhypertrophy complex, and portal hypertension. Prolonged biliary obstruction may lead to formation of intracanalicular bile thrombi, initiating hepatic fibrogenesis with resultant intrahepatic cholestasis.[17] Many of these changes are potentially reversible, especially in early stages. Advanced fibrotic changes in the liver biopsy herald a poor prognosis. Hepatic lobar atrophy and compensatory hypertrophy of contralateral lobe might occur as result of lobar or sectoral duct occlusion, associated portal vein injury or decreased hepatic perfusion consequent to secondary hepatic fibrosis. The presence of concomitant atrophy-hypertrophy complex leads to anatomical distortion and rotational deformity making surgery difficult. Portal hypertension can develop as a result of secondary hepatic fibrosis or concomitant portal vein injury; however, the possibility of an underlying chronic liver disease needs to be ruled out. Portal hemodynamic changes may occur in these patients in the absence of apparent vascular injury (latent portal hypertension) and are potentially reversible if treated early.[18] The prognosis of patients with these changes is worse.

530

Chapter 34 / BENIGN BILE DUCT STRICTURES

34.3 INVESTIGATIONS The main aim of investigation in a patient with bile duct injury is to establish the diagnosis with the least risk of morbidity and at the lowest possible cost. Because the injuries and presentations are so different, one algorithm will not work in all situations and so, several have been described.[1]

34.3.1 Cholangiography A complete visualization of the biliary tree is essential to ensure that the biliary–enteric anastomosis will adequately drain all hepatic segments.[19] The key is ‘complete cholangiography’ before surgery. Stewart and Way[20] showed that 96% of the procedures failed when cholangiogram was not done, and 69% of repairs were

unsuccessful when cholangiographic data was incomplete. Endoscopic retrograde cholangiography (ERC) and/or percutaneous transhepatic cholangiography (PTC) are usually adequate. Preoperative cholangiographic evaluation of classical postcholecystectomy bile duct injury by ERC demonstrates only the ‘cut-off’ sign and does not delineate the biliary tract proximal to the site of injury.[21, 22] Yet the surgical reconstruction depends upon the biliary anatomy proximal to the site of injury. Hence, PTC, which delineates proximal biliary anatomy, is the investigation preferred by surgeons. Recently, magnetic resonance cholangiography (MRC) has been proved to be an accurate and noninvasive imaging procedure, and may provide information which may not be available with PTC (Fig. 34.1).[23]

FIGURE 34.1 This 42-year-old lady developed a bile duct stricture following an open cholecystectomy. Some years later a small city surgeon fashioned an anastomosis between the duodenum and the left hepatic duct. This anastomosis stenosed, resulting in recurrent cholangitis. At re-laparotomy both ducts were dilated. The left duct contained bile, small stones, and plenty of sludge. The right duct contained white bile. The left hepaticoduodenostomy was dismantled, and a hepaticojejunostomy was done, anastomosing a Roux loop of the jejunum to the right and left hepatic ducts. The figure on the right explains the MRI: RHD = right hepatic duct, LHD = left hepatic duct, st = stricture of the common bile duct, a = anastomosis between the duodenum and the left hepatic duct. The intrahepatic bile ducts are dilated.

Tropical Hepatogastroenterology

MANAGEMENT AND OUTCOME

If a fistula is present, fistulography provides a cholangiogram. It also may show whether biliary drainage is adequate and whether the fistulous cavity has contracted to a tract.[19]

34.3.2 Other Imaging Ultrasonography or CT scan can identify intraabdominal fluid collections, dilatation of bile duct, and atrophy-hypertrophy complex. They may aid in placement of a percutaneous catheter for drainage of collections. Hepatobiliary scintigraphy evaluates liver function and bile flow. In evaluation of postcholecystectomy bile duct injury, HIDA scan may be used as the first test to document an intact biliary tract.[1, 19] HIDA scan is a noninvasive, dynamic, and quantitative study which is particularly useful in determination of bilioenteric continuity. It correlates the relative component of biliary obstruction and underlying chronic liver disease to the overall clinical picture. The HIDA scan provides a functional assessment of incomplete strictures, sectoral bile duct injury, and biliary-enteric anastomoses. Patients with biliary strictures sometimes also need evaluation for concomitant hepatic arterial injury, which, if present, increases the postoperative risk of complications such as hepatic necrosis, abscess formation, and development of anastomotic stricture.[24]

34.4 MANAGEMENT AND OUTCOME Management of bile duct injuries involves a multidisciplinary approach with the surgeon, endoscopist, and radiologist working as a team.

34.4.1 Endoscopic Treatment Recent studies have demonstrated 90%–100% success rate in endoscopic treatment of biliary

Part VII / Gallbladder and Biliary Tract

531

leaks[25–28] but endoscopic management of established strictures is less easy. Series of highly selected patients have reported 40%–70% success rates with dilatation and stenting, but the follow-up is limited.[29–32] Besides, these series include the more favorable cases, and do not provide information regarding cumulative morbidity, costs, and quality of life associated with repeated procedures. Certain lesions like stenosed hepaticojejunostomies with long Roux limbs, near complete transections, and major clip injuries do not appear to be amenable to endotherapy.[27] The percutaneous transhepatic route has also been utilized for balloon dilatation of such strictures with limited success on short follow-up.[33–35] Such an approach should therefore be reserved for high-risk patients or for recurrent strictures after hepaticojejunostomy.[6]

34.4.2 Surgery The aim of surgical repair of biliary strictures includes relief of biliary obstruction, prevention of secondary hepatic damage and prevention of anastomotic stricture formation. The type of surgical intervention depends upon the time of recognition of injury, the mode of presentation, and the level of injury. Every failed repair is associated with loss of ductal length, with subsequent repair becoming harder with less predictable results (Table 34.3).[36] If the surgeon recognizes bile duct injury at surgery, he should convert a laparoscopy to open surgery and should seek more experienced and expert advice if possible. Surgery at the time of cholecystectomy aims to maintain ductal length without sacrificing of tissue, and to avoid uncontrolled postoperative bile leak. The ideal procedure in this situation is a Roux-en-Y hepaticojejunostomy. A bilioenteric repair in undilated ducts is difficult and best conducted by an experienced surgeon.[20, 37] If an expert help is unavailable, and

532

Chapter 34 / BENIGN BILE DUCT STRICTURES

TABLE fy 34.3 Factors affecting outcome after surgical repair Technical factors: • Type of surgical repair • Incomplete cholangiography • Number of failed attempts at repair • Experience of surgeon Disease factors: • Level of injury • Degree of ductal dilatation • Coexisting hepatic parenchymal disease, portal hypertension or atrophy-hypertrophy complex • Concurrent cholangitis or liver abscess • Intrahepatic strictures or calculi • Presence of intra-abdominal collection Host factors: • Advanced age • Associated medical risk factors • Poor nutritional status

if the operating surgeon is inexperienced in complex biliary surgery, he should provide adequate drainage of subhepatic area for controlling bile leak, and should refer the patient to a specialized centre. If the transected duct measures 4 mm or more, it probably drains multiple hepatic segments, and needs repair. In contrast, a duct smaller than 3 mm may be safely ligated if cholangiography confirms that it drains only a single segment.[38] Lateral injuries of bile duct without loss of tissue may be amenable to direct suture repair. Complete transection injury of the bile duct is invariably associated with ischemic injury to the proximal end of bile duct or loss of ductal length due to clip application, ligation or excision of a segment of bile duct. Since repair of such injuries requires debridement of transected ends leading to further loss of ductal length, end to end repairs are almost always under tension. Hence, repairs performed for complete ductal transaction even in most favorable cases, are

associated with a high incidence of late stricture formation.[20, 39, 40] The first step in the treatment of biliary leak or fistula is to create a “controlled” fistula. This is usually done by establishing a tube drainage placed radiologically or surgically. The patient improves clinically; radiologically the intra-abdominal collection clears up. The next step is to check for biliary–enteric continuity, using hepatobiliary scintigraphy. If continuity is maintained (partial or side fistula), the fistula is likely to close spontaneously with time if there is no obstruction distal to the fistula. Following closure of fistula, the patients must remain on regular follow-up to detect the formation of a biliary stricture. Closure is facilitated by endoscopic stenting or nasobiliary drain placement across the fistulous opening. Obstruction distal to the site of fistula may occur from a calculus or stricture and is usually amenable to endoscopic management. Conservative management consists of maintenance of nutrition, correction of fluid-electrolyte and vitamin deficits, and control of sepsis. In absence of biliary-enteric continuity (total or end fistula), the fistula is unlikely to respond to conservative management, and would eventually require surgical intervention. Definitive surgical repair is usually undertaken after a reasonable period (between 3 weeks to 3 months) of conservative management (delayed approach). This gives the fistula a chance to close, lets inflammation subside, and allows ischemia of proximal bile duct stump and level of bile duct injury to stabilize. A major benefit from waiting is the development of proximal ductal dilatation, which facilitates successful surgical reconstruction. The role of laparoscopy is limited, since imaging and endoscopic techniques provide the diagnosis and even therapy in most of the patients. Repeat laparoscopy requires general anesthesia,

Tropical Hepatogastroenterology

MANAGEMENT AND OUTCOME

and is technically demanding due to inflammation adhesions. Experience is limited concerning laparoscopic repair of bile duct injuries.[41] The surgeon will expose healthy bile duct proximal to the site of injury and make an adequate sized opening in it, draining all segments of liver. He will then fashion a tensionless mucosa-to-mucosa anastomosis of bile ducts with an enteric conduit which is almost always a Roux-en-Y loop of jejunum. This loop is closed at the end and its antimesenteric border is anastomosed to the bile duct. Since 60% of the blood supply to the supraduodenal CBD comes from below, the proximal stump may be relatively ischemic. If so, the bilioenteric anastomosis will later stenose. A ‘high’ hepaticojejunostomy (within 2 cm of the hepatic duct confluence) is therefore better. To achieve this the opening in the CBD needs to be extended into the left hepatic duct.[42] A side-to-side hepaticojejunostomy has many advantages over an end-to-side anastomosis. It avoids difficult circumferential dissection of the bile duct, minimizes injury, and ischemia to the vascular plexus of the duct, and allows a wider stoma by extension of incision into extrahepatic potion of the left hepatic duct. Hepaticoduodenostomy is not feasible because inflammation and previous operations make mobilization of duodenum difficult. Anastomotic leaks result in a dangerous duodenal fistula, and subsequent surgery becomes relatively difficult in the event of anastomotic stricture.[38, 39] Some surgeons place a transanastomotic stent to decrease the risks of anastomotic stenosis and to obtain access for postoperative cholangiography.[43] However, stents are associated with problems of dislodgement, migration, occlusion, bleeding, and infection, and most surgeons avoid them. Transanastomotic stenting may be selectively recommended in the undilated ductal system, high and complex bile duct strictures, multiple previous failed attempts at repair, ques-

Part VII / Gallbladder and Biliary Tract

533

tionable mucosal apposition, and when anastomotic stenosis and stone formation appears to be a risk.[1, 42, 44, 45] The end of the Roux-en-Y loop may be brought out to the skin rather than closed. This is a “jejunal access loop”, and provides a portal of entry to an endoscope, should later dilatation of the anastomosis be required. It can be useful for difficult anastomoses, segmental or diffuse strictures, multiple failed attempts at repair, intrahepatic stricture, hepatolithiasis, hepatic fibrosis or cirrhosis, portal hypertension, atrophy-hypertrophy complex, and internal/external biliary fistula.[35, 42]

FIGURE 34.2 Isotope study to evaluate a choledochoduodenostomy. The contrast finds its way from the liver to the duodenum. The arrow marks the site of anastomosis (L - liver, S - stomach, D - duodenum).

534

Chapter 34 / BENIGN BILE DUCT STRICTURES

Long term results of treatment: Most patients with anastomotic stenosis develop jaundice and cholangitis. However, up to 20% may present with atypical symptoms.[39] Hence, even minor symptoms in these patients mandate further investigation. The length of the follow-up is important, and evaluation of any treatment requires a follow-up of at least 5 years. Several specialized centers have reported success rates of 80– 90% with surgical repairs, and many of them have identified factors associated with poor outcome (Table 34.3).[6, 16, 20, 46] There may be significant psychological stress despite excellent repairs,[47, 48] especially in patients with pending lawsuits. Several factors may contribute to recurrent symptoms following biliary-enteric anastomosis. These include anastomotic stenosis (anasto-

motic diameter less than 5 mm), excluded sectoral bile duct, intrahepatic bile duct stricture, biliary calculi, improperly constructed or oriented enteric conduit, and factors favoring bacterial overgrowth or development of abnormal intestinal flora (indwelling stent, exposed silk suture in bile duct lumen, prior gastrectomy, and duodenal diverticula).[49] An anastomotic stricture develops in 10%– 30% of patients following repair of biliary stricture.[6, 39, 43] Although majority of these patients may be salvaged with the help of surgery or interventional radiology, every failed attempt at repair is associated with loss of ductal length. This makes further repair more difficult and delays adequate biliary drainage risking the development of secondary biliary cirrhosis and portal hypertension.[6, 39, 46]

REFERENCES [1] Strasberg SM, Soper NJ. Analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg 1995;180:101–125. [2] Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct injuries following laparoscopic cholecystectomy: an audit of 5913 cases. Br J Surg 1996;83:1356–1360. [3] Adamsen S, Hansen OH, Funch-Jensen P et al. Bile duct injury during laparoscopic cholecystectomy: a prospective nationwide series. J Am Coll Surg 1997;184:571–578. [4] Fletcher DR, Hobbs MST, Tan P et al. Complications of cholecystectomy: risks of laparoscopic approach and protective effects of operative cholangiography. Ann Surg 1999;229:449–457. [5] Johnson GW. Iatrogenic bile duct strictures: an avoidable surgical hazard? Br J Surg 1986;73: 245–246. [6] Chapman WC, Holevy A, Blumgart LH et al. Postcholecystectomy bile duct strictures. Manage-

[7]

[8]

[9]

[10]

[11]

ment and outcome in 130 patients. Arch Surg 1995;130:597–604. McMohan AJ, Fullarton G, Baxter JN et al. Bile duct injury and biliary leakage in laparoscopic cholecystectomy. Br J Surg 1995;82: 307–313. Deziel DJ, Millikan KW, Economou SG et al. Complications of laparoscopic cholecystectomy: a national survey of 4292 hospitals and an analysis of 77604 cases. Am J Surg 1993;165:9–14. Woods MS, Traverso LW, Korzareck RA et al. Characteristics of biliary tract complications during laparoscopic cholecystectomy: a multi-institutional study. Am J Surg 1994;167:27–34. Russell JC, Walsh SJ, Mattie AS et al. Bile duct injuries, 1989-1993: a statewide experienceConnecticut laparoscopic cholecystectomy registry. Arch Surg 1996;131:382–388. Gigot J, Etienne J, Aerts R et al. The dramatic reality of biliary tract injury during laparoscopic

Tropical Hepatogastroenterology

REFERENCES

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21] [22]

cholecystectomy. An anonymous multicenter Belgian survey of 65 patients. Surg Endosc 1997;11:1171–1178. Wherry DC, Marohn MR, Malanosky MP et al. An external audit of laparoscopic cholecystectomy in the steady state performed in medical treatment facilities of the department of defence. Ann Surg 1996;224:145–154. Bismuth H. Postoperative strictures of bile duct. In: Blumgart LH, ed. The Biliary Tract. Clinical Surgery International. Vol. 5, Edinburgh: Churchill Livingstone 1982:209–218. Chaudhary A, Manisegran M, Chandra A et al. How do injuries following laparoscopic cholecystectomy differ from those following open cholecystectomy? J Laparoendosc Adv Surg Tech 2001;11: 187–191. Davidoff AM, Pappas TN, Murray EA et al. Mechanisms of major biliary injury during laparoscopic cholecystectomy. Ann Surg 1992;215:196–208. Lillemoe KD, Martin SA, Cameron JL et al. Major bile duct injuries during laparoscopic cholecystectomy: follow-up after combined surgical and radiological management. Ann Surg 1997;225: 459–471. Friedman SL. Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol 1997;32:424–430. Ibrarullah M, Sikora SS, Agarwal DK et al. ‘Latent’ portal hypertension in benign biliary obstruction. HPB Surg 1996;9:149–152. Steven CS, Robert CS. Repair of bile duct injuries. In: Bile duct and bile duct stones. Berci G, Cuschieri A, ed. WB Saunders Company 1997;143–153. Stewart L, Way LW. Bile duct injuries during laparoscopic cholecystectomy: Factors that influence the results of treatment. Arch Surg 1995;130: 1123–1129. Reinhold C, Bret PM. Current status of MR cholangiopancreatography. Gut 1996;166:1285–1295. Yeh TS, Jan YY, Tseng JH et al. Value of MR cholangiopancreatography in demonstrating major bile duct injuries following laparoscopic cholecystectomy. Br J Surg 1999;86: 181–184.

Part VII / Gallbladder and Biliary Tract

535

[23] Chaudhary A, Negi SS, Puri SK et al. Comparison of magnetic resonance cholangiography and percutaneous transhepatic cholangiography in the evaluation of bile duct strictures after cholecystectomy. Br J Surg 2002;89:433–6. [24] Gupta N, Solomon H, Fairchild R et al. Management and outcome of patients with combined bile duct and hepatic artery injuries. Arch Surg 1998;133: 176–81. [25] Davids PHP, Rauws EAJ, Tytgat GNJ et al. Postoperative bile leakage: endoscopic management. Gut 1992;33:1118–1122. [26] Foutch PG, Harlan JR, Hoefer M. Endoscopic therapy for patients with postoperative biliary leak. Gastrointest Endosc 1993;39:416. [27] Kozarek RA, Ball TJ, Patterson DJ et al. Endoscopic treatment of biliary injury in the era of laparoscopic cholecystectomy. Gastrointest Endosc 1994;40:10–16. [28] Fuiji T, Maguchi H, Obara T et al. Efficacy of endoscopic diagnosis and treatment for postoperative bile leak. Gastroenterology 1998;45:656–661. [29] Mueller PR, Van Sonnenberg E, Ferrucci JT et al. Biliary stricture dilatation: Multicenter review of clinical management in 73 patients. Radiology 1986;160:17–22. [30] Berkelhammer C, Kortan P, Haber GB. Endoscopic biliary prosthesis as treatment for benign postoperative bile duct strictures. Gastrointest Endosc 1989;35:95–101. [31] Davids PHP, Tanaka AKF, Rauws EAJ et al. Benign bile duct strictures: Surgery or endoscopy? Ann Surg 1993;217:237–243. [32] Dumonceau JM, Deviere J, Delhaye M et al. Plastic and metal stents for postoperative benign bile duct strictures: The best and the worst. Gastrointest Endosc 1998;47:8–17. [33] Zuidema GD, Cameron JL, Sitzmann JV et al. Percutaneous transhepatic management of complex biliary problems. Ann Surg 1982;197: 584–593. [34] Vogel SB, Howard RJ, Caridi J et al. Evaluation of percutaneous transhepatic balloon dilatation of benign biliary strictures in high-risk patients. Am J Surg 1985;149:73–79.

536

Chapter 34 / BENIGN BILE DUCT STRICTURES

[35] Schweizer WP, Matthews KB, Baeur RU et al. Combined surgical and interventional radiological approach for complex benign biliary tract obstruction. Br J Surg 1991;78:559–563. [36] Chaudhary A, Chandra A, Negi SS et al. Reoperative surgery for postcholecystectomy bile duct injuries. Dig Surg 2002;19:22–27. [37] Savader SJ, Lillemoe KD, Prescott CA et al. Laparoscopic cholecystectomy-related bile duct injuries: a health and financial disaster. Ann Surg 1997;225:268–273. [38] Lillemoe KD. Benign postoperative bile duct strictures. Baillieres Clin Gastroenterol 1997;11: 749–79. [39] Pellegrini CA, Thomas MJ, Way LW. Recurrent biliary stricture: patterns of recurrence and outcome of surgical therapy. Am J Surg 1984;147:175–180. [40] Csendes A, Diaz JC, Burdiles P et al. Late results of immediate primary end to end repair in accidental section of common bile duct. Surg Gynaecol Obstet 1989;168:125–130. [41] Azagra JS, Simone PD, Goergen M. Is there a place for laparoscopy in management of postcholecystectomy biliary injuries? World J Surg 2001;25: 1331–1334. [42] Terblanche J, Worthley CS, Spence RAJ et al. High or low hepaticojejunostomy for bile duct strictures?

Surgery 1990;108:828–834. [43] Pitt HA, Miyamoto T, Parapatis SK et al. Factors influencing outcome in patients with postoperative biliary strictures. Am J Surg 1982;144: 14–21. [44] Jarnagin WR, Blumgart LH. Operative repair of bile duct injuries involving the hepatic duct confluence. Arch Surg 1999;134:769. [45] Gazzaniga GM, Filauro M, Mori L. Surgical treatment of iatrogenic lesions of the proximal common bile duct. World J Surg 2001;25:1254–1259. [46] Tocchi A, Costa G, Lepre L et al. The long-term outcome of hepaticojejunostomy in the treatment of benign bile duct strictures. Ann Surg 1996;224: 162–167. [47] Boerma D, Rauws EAJ, Keulemans YCA et al. Impaired quality of life 5 years after bile duct injury during laparoscopic injury. Ann Surg 2001;234:750–757. [48] Melton GB, Lillemoe KD, Cameron JL et al. Major bile duct injuries associated with laparoscopic cholecystectomy: effect of surgical repair on quality of life. Ann Surg 2002;235:888–95. [49] Matthews JB, Baer HU, Schweizer WP et al. Recurrent cholangitis with and without anastomotic stricture after biliary-enteric bypass. Arch Surg 1993;128:269–272.

test

Tropical Hepatogastroenterology

xx

Part VIII Pancreas

35 36 37

Acute Pancreatitis Chronic Pancreatitis Cancer of the Pancreas

539 566 597

“This page intentionally left blank"

xx

Chapter

35 ACUTE PANCREATITIS Suneet Sood and Vivek Tandon

Acute pancreatitis, an acute inflammation of the pancreas, is usually caused by gallstones or alcohol abuse. Pain is the predominant symptom, and an elevated amylase is the classical diagnostic test. Although pancreatitis is potentially serious most patients will recover with medical management.

35.1 CLASSIFICATION OF ACUTE PANCREATITIS Pancreatologists initially classified clinical pancreatitis into acute and chronic, subclassifying a relapsing variety in each. There is, however, no benefit in this classification in terms of management and prognosis, and later modifications abandoned it. Today most pancreatologists favor the Atlanta classification for acute pancreatitis[1] which describes the following terms: • Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues of remote organ systems. (Cases of apparent acute pancreatitis might sometimes have underlying chronic pancreatitis.) • Acute pancreatitis may be mild or severe. Mild acute pancreatitis is associated with minimal organ dysfunction and no local complications. Severe acute pancreatitis is associated with

organ dysfunction and/or local complications (for example necrosis, pseudocyst). The presence of three or more of Ranson’s prognostic criteria[2] or eight or more APACHE II points[3] also indicates severe pancreatitis. • CT imaging in acute pancreatitis differentiates between interstitial pancreatitis and pancreatitis with necrosis. On contrast-enhanced CT scan, viable pancreatic tissue enhances while the areas with necrosis do not. • Findings on imaging have clear definitions. An “acute fluid collection” is a pocket of enzymerich pancreatic juice that has leaked from an injured duct or ductule. With time, the body will localize the collection and wall it off; once it has a wall it becomes a “pseudocyst”. “Necrosis” is dead pancreatic tissue. It is initially sterile; if infection is present (documented in a sample obtained by aspiration under ultrasound or CT guidance), this becomes an “infected necrosis”. A “pancreatic abscess” is a peripancreatic collection of pus; this typically follows infection in an acute collection or in a pseudocyst.

35.2 DEVELOPMENT OF ACUTE PANCREATITIS[4–6] Pancreatic enzymes meant to digest food may digest the body’s own tissues if released wrongly. 539

540

Chapter 35 / ACUTE PANCREATITIS

Inbuilt mechanisms decrease the risks of this happening. Enzymes are stored as inactive zymogen granules, and are ordinarily activated in duodenum by duodenal enterokinase and by activated trypsinogen. Within the acinar cell, enzymes can be activated by lysosomal hydrolases, which therefore mature along pathways separate from the digestive enzymes. Within the pancreas, a trypsin inhibitor prevents premature activation of trypsinogen. In the ducts, the pH and calcium ion concentration is unfavorable for the activation of the enzymes. Following an insult, the first step is probably an oxidative stress in the acinar cell. With changes in the membrane potentials, zymogen granules and lysosomal sacs come together. There is a widespread pancreatic inflammation which may be accompanied by intracellular and intrapancreatic activation of enzymes. With more severe inflammation pancreatic ductules rupture, releasing pancreatic juice into various spaces in the peritoneal cavity. Most experts believe that acute pancreatitis begins with a calcium-mediated intracellular activation of zymogens. The possible mechanisms responsible for this activation are: (a) trypsinogen may undergo increased autoactivation; its susceptibility perhaps increased by oxidants or by decreased activity of inhibitors. (b) trypsinogen may come in contact with lysosomal hydrolases, either by its own migration or by the migration of the lysozymes. Trypsinogen activation is mediated by calcium ions. There is early mobilization of calcium ions and the intracellular levels become high, and are accompanied by a fall in intracellular pH. One hypothesis is that calcium signaling is defective. Once trypsinogen activation occurs various

steps of inflammation are initiated. There is activation of transcription factors, and release of cytokines including interleukin 6. There is consequent inflammation and tissue injury, which may remain localized or may develop into a systemic inflammatory response, with multiorgan failure. Several of these steps in the pathogenesis of acute pancreatitis derive from experimental observations using inhibitory agents in experimental pancreatitis. Agents commonly used in studies of the pathogenesis of pancreatitis include those blocking transcription factors, those inhibiting calcium mobilization, and those interfering with prostaglandin and leukotriene metabolism. Scientists have also studied genetically modified animals to develop a model for experimental pancreatitis. What causes this insult? The disturbance that results in the oxidative stress is likely to be a degree of ductular obstruction and increased intrapancreatic pressure. The role of pancreatic duct occlusion was first explored by Eugene Opie in 1901, when he described a patient with pancreatitis in whom a stone was impacted at the papilla. This later became popularly known as the “common channel theory”. Whipple and Arhibald in 1999 showed that pancreatitis sometimes resulted from experimentally-induced spasm in the sphincter of Oddi.[7] In 1987 Jones et al. showed, during operative cholangiography, that a common channel was much more likely to be present in patients who had a previous history of pancreatitis than in patients who did not.[8] The mechanism of this AP consequent to PD obstruction is unclear. Hiatt and Warner reported that simple occlusion of the PD in animals produces edema of the gland followed by atrophy and not AP.[9] McCutcheon[10] has suggested that PD obstruction in the presence of other factors such as vascular damage or stimulation of pancreatic secretion may cause acute pancreatitis.

Tropical Hepatogastroenterology

PATHOLOGY

Experiments show that occlusion of the pancreatic duct causes pancreatitis (but occlusion of the biliary duct does not)[11] and pancreatic duct perfusion with bile mixed with pancreatic enzymes causes pancreatitis.[12] While there are, almost certainly, other mechanisms that may initiate pancreatitis, there is strong evidence that increased intrapancreatic pressure is an important initiator of disease.

35.3 PATHOLOGY Once pancreatic inflammation is initiated, it may progress. Progressive inflammation causes tissue damage due to the effects of the activated enzymes. There is swelling and edema of the entire gland, and leakage of pancreatic juice. Inflammation spreads to the surrounding mesentery, causing marked mesenteric inflammation seen well on a CT scan. The leaked pancreatic juice saponifies omental fat causing profuse fat deposits especially if necrosis also occurs. This process uses up calcium; these patients therefore often have hypocalcemia. Intraperitoneal hemorrhage may be present. Microscopically, there is edema with inflammatory infiltrates; if necrosis occurs, it involves the acinar cells, the islet cells, as well as the ducts. There is thrombosis of the veins and venules; arterial thrombosis is less common.[6] The necrotic tissue tends to separate from the healthy tissue over two to three weeks. The effects of inflammation may spread to the lungs and other parts of the body. A pleural effusion is very common, especially on the left side. Severe acute pancreatitis may be accompanied by multiple organ failure. At surgery or postmortem the abdominal findings are typical. Rarely, laparotomy will be carried out on a patient with mild pancreatitis following a mistaken diagnosis. The surgeon will encounter fat necrosis, which manifests as 1–2 mm whitish

Part VIII / Pancreas

541

seed-like lesions scattered all over the peritoneum, omentum, and serosal surfaces. Opening the lesser sac is difficult because of highly vascular adhesions between the gastrocolic omentum and the pancreas. The pancreatic surface is red, edematous, and bleeds easily.[13] More often, surgery is carried out on patients with severe acute pancreatitis after the third week of disease. Fat necrosis is often still present. Access to the pancreatic surface is difficult through the gastrocolic omentum, but is relatively easy through a pseudocyst. The cyst offers a narrow window to the surface of the gland. After sucking out the dark green or black cyst fluid, the necrosis, if present, appears as a mass of thick, spongy, black tissue. This tissue can be extricated as one mass, or may require piecemeal removal. At the end of necrosectomy, the walls of the cavity are well defined; the pancreatic surface may appear as a granulating layer. Cysts often track down into the lower abdomen, typically lateral to the colon. The cyst walls are irregular, and may be fibrous or granulating.

35.4 ETIOLOGY AND RISK FACTORS The two major risk factors for acute pancreatitis (AP) are gallstone disease and alcohol. Together they account for over two thirds of cases of AP. There are other causes which account for 10% of cases (Table 35.1). The treating physician will be unable to find an etiology in 10%–30%.[14] Geographical factors influence the data. In countries where alcohol consumption is rising, so is the proportion of alcohol-related AP.[15, 16]

35.4.1 Biliary Tract Disease Thirty to seventy-five percent of AP is gallstonerelated, and it is thus commoner in women.[17–19]

542

Chapter 35 / ACUTE PANCREATITIS

TABLE fy 35.1 Acute pancreatitis: Etiological factors (and incidence in India)[14] • Diseases of the biliary tract (50%) Gallstones Choledochal cysts Juxtapapillary diverticula • Alcohol abuse (25%) • Pancreatic duct obstruction Helminthic obstruction Tumors Pancreas divisum Duodenal disorders Foreign body obstruction • Infections • Drugs and toxins (1%) • Endocrine and metabolic disorders Primary hyperthyroidism and hypercalcemia Hyperlipidemia Hypothermia Pregnancy • Vascular diseases • Post-traumatic • Postprocedure ERCP (6%) Biopsy (pancreatic) Manometry of sphincter of Oddi Surgical procedures • Hereditary acute pancreatitis • Cystic fibrosis • Reye’s syndrome • Kawasaki disease • Unknown (idiopathic acute pancreatitis) (15%)

Gallstone pancreatitis occurs when a stone temporarily lodges in the sphincter of Oddi, although rarely does one find a stone actually impacted.[20] Houssin and coworkers[21] reported that the frequency of AP is inversely proportional to the size of the stone. In one study, 20% of patients had microlithiasis (< 3 mm), 5% had 3–9 mm stones, 3% had 10–20 mm stones, and 1% had large

(> 20 mm) stones. Patients with stones smaller than 5 mm should undergo early surgery.[22] Choledochal cysts[23, 24] and juxtapapillary duodenal diverticula[25] also predispose to AP.

35.4.2 Alcohol Abuse Chronic alcohol abuse is the commonest cause of AP in men.[26] Pancreatitis typically occurs after 5–10 years of use, although it may occur sooner.[27] Most patients already have chronic pancreatitis, and a persistently obstructed duct. Alcohol contributes to AP in different ways. Alcohol is directly toxic to the acinar cells. It also causes the formation of protein plugs that obstruct the pancreatic duct.[13] Alcohol also causes spasm of the sphincter of Oddi.[28] In time, the patient develops chronic pancreatitis, with ductal irregularity and presumed changes in ductal pressure. In most patients, alcohol-associated AP occurs in a gland already damaged by chronic pancreatitis, where the duct is persistently obstructed; in this case the pancreatitis would technically be an acute-on-chronic episode. In the absence of evidence of chronic pancreatitis, the episode may be considered acute. Previous alcohol-associated pancreatitis is associated with an almost 50% probability of recurrence, most of which will be within four years.[29]

35.4.3 Tumors and Other Obstructive Lesions Nearly 15% of patients with pancreatic cancer will develop acute pancreatitis; another tenth will develop hyperamylasemia.[30] Pancreatitis can also occur in pancreas with metastatic cancers.[31, 32] In pancreas divisum the dorsal duct (Santorini) constitutes the predominant drainage of the pancreas. The accessory papilla of Santorini may not allow as

Tropical Hepatogastroenterology

ETIOLOGY AND RISK FACTORS

good a flow of pancreatic secretions. The resultant obstruction increases the risk of AP.[13] Pancreatitis may also occur due to polyps or diverticula that obstruct the papilla,[33] duodenal obstruction due to annular pancreas[34] or an obstructed afferent loop following gastrectomy,[35] or obstruction of the PD by foreign bodies.[36, 37]

35.4.4 Infections and Infestations Infections that may be complicated by AP include mumps,[38] infectious mononucleosis,[39] Coxsackie B virus, varicella and measles,[40] Mycoplasma pneumoniae,[41] hepatitis B,[42] and human immunodeficiency virus infection.[43, 44] Ascariasis of the bile duct causes nearly 25% of cases of pancreatitis in Kashmir. Treatment requires endoscopic worm extraction.[45, 46]

35.4.5 Drugs and Toxins One to two percent of cases of AP are drugrelated.[47] The ones most frequently implicated includes valproic acid, azathioprine, pentamidine and 5 ASA compounds. (Table 35.2) With transplants being increasingly performed, pancreatitis associated with immunosuppressives is becoming more common.[48] Smoking is a risk factor for pancreatitis in men but not in women.[49] Other factors include organophosphate poisoning[50] and scorpion bite.[51]

35.4.6 Metabolic and Other Disorders Hypercalcemia associated with primary hyperparathyroidism can stimulate pancreatic exocrine secretion causing acinar injury. Seven percent of patients with hyperparathyroidism develop AP.[52, 53] Between 2% and 4% of cases of AP are related to hyperlipidemia or hyperlipoproteinemia.[54]

Part VIII / Pancreas

543

TABLE fy 35.2 Drugs associated with acute pancreatitis (modified from Lankisch and Banksc)[13] 1. Definitely associated drugs Immunosuppressives (e.g., azathioprine, cyclosporine) Sulfonamides Sulindac Tetracycline Valproic acid Didanosine (ddI) Methyldopa

Estrogens Furosemide 6-Mercaptopurine Pentamidine 5-ASA compounds Corticosteroids Octreotide

2. Drugs probably associated with AP Chlorothiazide and Colaspase hydrochlorothiazide Hypercalcemia (iatrogenic) Chlorthalidone Methandienone Combination cancer chemotherapy Metronidazole Cimetidine Nitrofurantoin Cisplatin Phenformin Cytosine arabinoside Piroxicam Diphenoxylate Procainamide Ethacrynic acid Propofol 3. Drugs with a proposed association with pancreatitis, but evidence is contradictory or inadequate Amoxapine Ibuprofen Amphetamines Lipid infusions β-adrenergic blocking Mefenamic acid drugs BHI Regeneration tables Opiates Carbamazepine Paracetamol Cholestyramine Phenolphthalein Colchicine Rifampicin Cyproheptadine Salicylates Diazoxide Ticarcillin/ Clavulanic acid Histamine Warfarin Indomethacin

Patients with chronic renal failure on peritoneal dialysis are susceptible to acute pancreatitis.[55, 56]

544

Chapter 35 / ACUTE PANCREATITIS

The incidence among persons undergoing hemodialysis is the same as that in the general population.[57] The risk is slightly increased in patients who have hypothermia,[58, 59] obesity,[60] diseases such as ulcerative colitis and Crohn’s disease,[61] and vascular diseases such as malignant hypertension[62] and systemic lupus erythematosus.[63] Hereditary pancreatitis is rare. It has an autosomal dominant mode of transmission and usually presents at a young age. Pancreatic ductal stones are common in this type of pancreatitis.[6] Between 1% and 2% of cases of AP follow trauma, probably as a result of direct injury to the pancreas, or as a consequence of duodenal ileus.[64, 65]

35.4.7 Postprocedure Mueller and co-authors[66] reported a 3% incidence of acute pancreatitis following fine needle aspiration cytology of the pancreas. A tenth of patients undergoing Sphincter of Oddi manometry will develop acute pancreatitis.[67, 68]

After ERCP, hyperamylasemia occurs in 15%– 20% of patients. Pancreatitis, as defined by clinical and laboratory data, occurs in 1%–7%.[69–72] (Table 35.3) Freeman et al.[70] in a review of 1963 consecutive patients estimated that the incidence of pancreatitis was 6.7% (131 patients). Of these 131 patients, 4.5% had severe pancreatitis; the remainder had mild or moderate pancreatitis. Prior ERCP-induced pancreatitis represented the highest risk (Fig. 35.1). The factors that contribute to a higher incidence of AP after ERCP include operator inexperience, sphincter disease or variant, PD stricture, preexisting pancreatitis, recent pancreatitis, and pseudocysts. TABLE fy 35.3 Incidence of acute pancreatitis after ERCP and EPT[72] Number of patients Acute pancreatitis AP: Required surgery AP: Died

Post-ERCP

Post-EPT

25,299 229(0.9%) 6(0.03%) 4(0.02%)

17,168 289(1.7%) 23(0.13%) 35(0.2%)

FIGURE 35.1 Risks from endoscopic procedures.[70]

Tropical Hepatogastroenterology

CLINICAL FEATURES

Postoperative pancreatitis may follow about 1% of abdominal[73, 74] and even extra-abdominal operations.[75–77]

35.4.8 Idiopathic Acute Pancreatitis The group referred to as idiopathic or indeterminate acute pancreatitis forms, after alcohol and gallstones, the third largest group of acute pancreatitis in most series. Rose et al.[78] have shown that most such cases have gallstone disease with microlithiasis and do well after a cholecystectomy. ERCP or endoscopic ultrasonography can markedly reduce the number of cases that appear to be idiopathic in origin.[79]

35.5 CLINICAL FEATURES The commonest symptom of acute pancreatitis is abdominal pain. Typical sites of pain are epigastrium, left upper abdomen, and the entire upper abdomen. The pain worsens gradually and reaches a maximum usually one to several hours after onset. It lasts from one to several days and can be difficult to control when severe.[13] The pain radiates to the back in about half of the patients. Other sites of radiation of pain are left anterior chest, left shoulder, and lower abdomen. In about a fourth of patients, the pain begins after a large meal or after excessive alcohol ingestion. Pain may be difficult to differentiate from gastritis, cholecystitis, acute appendicitis, mesenteric ischemia, and intestinal obstruction. The pain may closely resemble the pain of intestinal obstruction, perforation, bowel ischemia, acute cholecystitis, appendicitis, pneumonia, or myocardial infarction. Rarely, pain is absent in acute pancreatitis, and the presenting complaints are shock, anuria, or fever. Nausea and vomiting are often present; hiccoughs are less common.

Part VIII / Pancreas

545

General physical examination may be normal in patients with mild pancreatitis. If pancreatitis is severe the patient looks ill and may have tachycardia and tachypnea. Hypotension may occur in very severe pancreatitis with significant necrosis. Icterus may be present and results from bile duct compression by the inflamed pancreatic head, or may be caused by a stone at the lower end of the bile duct. Cyanosis may occur in severe pancreatitis associated with organ failure. Low-grade fever is not uncommon in the first week. High fever indicates an infected necrosis or an infected abscess. On abdominal examination the signs may be few in patients with mild pancreatitis. Epigastric tenderness is common but is mild even in severe pancreatitis. Rigidity is usually absent in mild pancreatitis but is sometimes present if the disease is severe. Occasionally, the pancreatic injury may be complicated by retroperitoneal hemorrhage. This results in a discoloration in the flanks (GreyTurner’s sign), or near the umbilicus (Cullen’s sign), and is associated with a poor outcome. Distension may be present, caused by ileus or by fluid in the peritoneal cavity. In general, however, the symptoms are more marked than the signs in acute pancreatitis, regardless of severity. Pleural effusion, especially on the left, is common and may be picked up on percussion or auscultation. In very severe pancreatitis, organ failure may manifest as hypoxia and cyanosis. In all patients, the physician must ask for a past history of gallstones, alcohol abuse, medications, or other known contributing factors.

35.6 DIAGNOSIS 35.6.1 Serum Amylase and Lipase[13, 80–83] A quantitative estimation of serum amylase levels is the most commonly performed investigation for

546

Chapter 35 / ACUTE PANCREATITIS

the diagnosis of acute pancreatitis. Amylase is a 50 kDa enzyme that hydrolyzes starch to produce maltose, maltotriose, and dextrins. Amylase levels rise in acute pancreatitis within 2 to 12 hours and remain elevated for over 5 days in most patients. Levels greater than thrice the upper limit of normal are usually enough to make a reasonably certain diagnosis of pancreatitis. The sensitivity of serum amylase estimation is 80%–90%; the half life of amylase is only about 10 hours. By day 4, only two thirds of patients have hyperamylasemia. Patients who have pancreatitis caused by hypertriglyceridemia may not develop hyperamylasemia. Lipase levels rise slightly more slowly, and stay elevated longer. Hyperlipasemia over thrice normal is specific for acute pancreatitis. The sensitivity and specificity approach 100%. Note that serum lipase levels may rise in patients with renal failure. While lipase levels tend to be higher than amylase levels, the overall kinetics of the two enzymes are not markedly different. The sensitivity values for serum amylase and lipase range from 70% to 100% and from 74% to 100% respectively, and their specificity values vary from 33% to 89% and from 34% to 100% respectively.

35.6.2 Other Laboratory Tests Serum trypsin, elastase-1, and phospholipase A2 are elevated in acute pancreatitis and are more specific but less easy to evaluate, and therefore rarely tested in the clinical setting. Serum C-reactive protein may have a prognostic value.[13] All patients should have their hematological and biochemical parameters tested. These include a complete blood count, renal function tests, liver function tests, tests of coagulation, blood sugar levels, and serum electrolytes including calcium levels.

35.6.3 Plain X-rays Most physicians will start with an X-ray of the chest and erect and supine plain films of the abdomen, followed by an abdominal ultrasound. The chest X-ray may pick up a pleural effusion, more often on the left side. Abdominal films in acute pancreatitis show a colon cut off sign, which is an abrupt end in the air column of the colon. The cut-off is caused by the inflamed pancreas, and there may be a mild proximal dilatation. The site of cut-off is the proximal transverse colon, from an inflamed head, or distal transverse colon, from an inflamed tail. A dilated loop of duodenum or small bowel may be seen: this is called the ‘sentinel loop’, and is caused by localized ileus at the site of inflammation. Plain abdominal films will also show if the patient’s pain has another cause, for example intestinal obstruction or perforation.[13]

35.6.4 Ultrasonography Ultrasonography will better document a pleural effusion. Ultrasonography may show a bulky pancreas with areas of acute fluid collection, and will confirm whether or not gallstones are present. Endoscopic ultrasonography can diagnose missed biliary tract disease, pancreas divisum, and chronic pancreatitis and tumors, and correlates well with ERCP.[84] EUS demonstrates a pathology in over four-fifths of cases of “idiopathic” pancreatitis, and Frossard and coworkers,[79] and others[85] recommend that no case should be labeled as idiopathic or indeterminate till EUS had been carried out. Tandon and Topazian[86] showed that in patients with indeterminate pancreatitis, EUS identified sludge in 16%, chronic pancreatitis in 42%, and pancreas divisum in 10% among other lesions. EUS is twice as sensitive as conventional ultrasonography or CT scanning.[87]

Tropical Hepatogastroenterology

DIAGNOSIS

35.6.5 CT and MRI CT scanning is the investigation of choice, but does not need to be done immediately unless the diagnosis itself is in doubt. CT identifies necrosis, its degree and extent, detects fluid, pseudocysts, bowel involvement, and pseudoaneurysms. It informs about associated infection and guides aspiration from which a sample can be sent for culture. Necrosis can only be identified on a contrast-enhanced CT for which the patient must have adequate renal function. The CECT will fail to enhance those parts of the pancreas which are necrotic. (Fig. 35.2) The CT picture can even be used as a prognostic index (described further in the section on prognosis)[6] and correlates well with mortality in acute pancreatitis. Thus, clinically severe disease (APACHE II > 8) nearly always indicates that necrosis is present.[88]

547

An alternative to CECT is MRI. MRI is almost similar to helical CT in detecting pancreatic necrosis.[6] However, patients with pancreatic necrosis are very sick, with multiple tubes in their bodies, and MRI needs breath-holding. It is difficult to push such unmonitored patients into a closed tunnel for 45 minutes. The advantages of MRI include excellent resolution and the avoidance of radiation. There may be a role for MRI in females in the reproductive age group.

35.6.6 ERCP The main indication for endoscopic cholangiography in acute pancreatitis is for the diagnosis of biliary pathology in severe acute pancreatitis where the etiology is uncertain. A diagnostic ERCP can be done in the first 24 to 48 hours of acute pancreatitis.[89] Endoscopic pancreatography is carried out for the assessment of pseudocysts, ascites and

FIGURE 35.2 CECT in a patient with acute pancreatitis. Note the enlarged pancreas and the mesenteric stranding (white arrow). In the figure on the left, there are areas of necrosis (such as the one marked by the black arrow), and areas of viable pancreatic tissue that enhances (as marked by the arrowhead). Compare with the picture on the right, in which the entire body and tail are necrosed.

Part VIII / Pancreas

548

Chapter 35 / ACUTE PANCREATITIS

fistulae prior to surgery.[90] It is not indicated in mild acute pancreatitis. ERCP can demonstrate the bile duct in 90% of patients despite the presence of pancreatitis and the pancreatic duct in over 70%.[91] ERCP is better than CT scan in diagnosing CBD stones, for which its sensitivity approaches 100%. However, ultrasonography is better for picking up stones in the gallbladder, and CT is superior for assessing the severity of pancreatitis. In “idiopathic” pancreatitis ERCP can demonstrate the cause of pancreatitis in nearly half of the cases.[92]

35.7 TREATMENT Acute pancreatitis is a disorder that requires medical treatment; its complications may need surgery.

35.7.1 Immediate Treatment The patient first requires painkillers and fluid resuscitation.[6] Some patients may respond to intramuscular NSAIDs, but most will need varying doses of narcotic analgesics. Patients with mild pancreatitis need maintenance fluid requirements to allow for a nil-bymouth period. Patients with severe pancreatitis need high volumes of intravenous fluid. (In cases of doubt, it is better to presume severe rather than mild pancreatitis.) The deficit can easily be in excess of five liters. It is best to be guided by central venous pressure/pulmonary artery wedge pressure and by urine output monitoring. The initial replacement is by normal saline. This will need quick adjustment once the reports of serum electrolytes are available. Patients who have mild pancreatitis may not require antibiotics or a nasogastric tube, those with severe pancreatitis always do. Antibiotic therapy is discussed in greater detail later.

Organ system failure requires treatment on merit, with attention to renal derangement, acidbase disturbances, electrolyte changes, and respiratory complications.

35.7.2 Feeding and Nutrition It is conventional to withhold oral feeds until the pancreatic inflammation has subsided significantly.[6] This decision is clinical, based on the cessation of pain, rather than radiological, since CT evidence of inflammation takes very long to resolve.[93] The period of oral restriction may vary from less than a week to three weeks or more. The patient may resume oral feeds once the pain has subsided.[6] If feeding causes a return of the pain, it should be stopped. Conventionally the initial feeds are liquid and semisolid; if the patient tolerates the initial feeds in the first few days they may be followed by the introduction of a solid diet. The composition should include only carbohydrates in the first two to three days. Proteins may be added subsequently. Most physicians restrict fat in the diet for a few weeks. Several elemental formulae are available, containing proteins and calories, but very little fat.[6] Early enteral feeding, typically in the form of elemental diets, is usually well tolerated. However, if it has not been possible to feed the patient in the first week, parenteral nutrition must be instituted. Patients with severe pancreatitis require, like most sick patients, 2 to 2.5 G protein/kg/day, and adequate calories to maintain a calorie:nitrogen ratio at about 100:1.[94] It is not necessary to restrict lipid-containing feeds, provided that the serum triglyceride levels do not rise beyond 500 mg/dl.[6] An alternative to parenteral nutrition is jejunal feeding. The feed is instilled directly into the jejunum, and pancreatic stimulation is minimal.

Tropical Hepatogastroenterology

TREATMENT

It is possible to insert a long nasojejunal tube to reach the jejunum, under radiologic control or with the help of an endoscope. If this placement is successful, enteral feeding is safer and cheaper than parenteral.[95] When patients require surgery, for example for an infected necrosis, the surgeon always places a jejunostomy tube for feeding.

35.7.3 Endoscopic Papillotomy in Severe Biliary Pancreatitis More than half of patients who die of gallstone pancreatitis still have stones in the bile duct.[96] Some gastroenterologists believe that the presence of activated enzymes can cause continuing pancreatic destruction, and that early papillotomy should clear biliopancreatic ductal obstruction and mitigate this damage.[97] There is experimental evidence to support this belief. Steer and colleagues showed that pancreatitis developed in animals with experimental pancreatic duct obstruction, and was less severe if the pancreatic ductal obstruction was relieved early.[11] Mild pancreatitis does not benefit from sphincterotomy, nor does pancreatitis from nonbiliary causes.[98, 99] In severe biliary pancreatitis (Table 35.4) Neoptolemos and co-authors[98] reported a mortality of 1.7% if papillotomy was done, compared with 18% in the control group (p < 0.001). While not all endoscopists reported statistically significant outcomes, there is invariably a clear trend towards a lower mortality. Cholangitis occurs in about 10% of patients with acute pancreatitis. Some of the benefits of papillotomy can be attributed to relief of coexisting cholangitis which is relieved after sphincterotomy.[100] Nevertheless, the improved outcomes are seen even in patients who do not have acute cholangitis.[101] Endoscopic sphincterotomy also decreases the morbidity and rate of complications, from

Part VIII / Pancreas

549

TABLE fy 35.4 Comparison of outcomes of endoscopic papillotomy (EPT) in patients with severe biliary pancreatitis Mortality (%) Morbidity (%) Control EPT Control EPT Neoptolemos et al.[98] Sulkowski et al.[102] Nowak et al.[103] Fan et al.[104] Jover et al.[105] Cuilleret et al.[106]

18 36.5 11 15 29 7.6

1.7 133 1 2 0 3

61

24

34 86 43 32

14 20 0 25

over 40%–60% down to fewer than 0%– 25%.[98, 105] Finally, Sharma and Howden[107] performed a meta-analysis on randomized controlled trials and showed that sphincterotomy reduces the incidence of complications from 38% to 25%, and nearly halves the mortality from 9% to 5%. Treating 26 patients of acute biliary pancreatitis with sphincterotomy will save one life. 35.7.3.1 Recurrence

Cholecystectomy reduces the risk of recurrent gallstone pancreatitis to about the same as that in the general population.[108] In the absence of a cholecystectomy the recurrence risks of acute biliary pancreatitis are 50%–90%.[109] Patients who come for follow-up do not necessarily require sphincterotomy if it was not done during the acute attack, but should undergo cholangiography during laparoscopic cholecystectomy.[101] Some patients who have had pancreatitis are unfit for cholecystectomy. In these patients an option is endoscopic sphincterotomy alone, without cholecystectomy. In patients who underwent sphincterotomy without cholecystectomy, Uomo and coworkers[109] observed a recurrence

550

Chapter 35 / ACUTE PANCREATITIS

in only 1 of 19 patients after 4–40 (mean 30) months of follow-up. In comparison, pancreatitis recurred in 4 of 7 patients in whom sphincterotomy was unsuccessful. Wilson et al.[101] reviewed studies adding to 176 patients to show that after about 30 months of follow-up recurrent pancreatitis developed in only 1.1%. During this period gallbladder complications occurred in 7% of patients. A study from Norway confirmed that patients who undergo sphincterotomy for gallstone pancreatitis rarely develop recurrent pancreatitis, though several patients will develop symptoms if the gallbladder is not removed.[110] 35.7.3.2 Timing

Sphincterotomy drastically lowers morbidity, and also lowers mortality, when performed in the first three days of the disease rather than later.[105] However, even if the patient arrives after day three, sphincterotomy may be of use.[103] 35.7.3.3 Risks

Endoscopic intervention is not without risk. ERCP produces hyperamylasemia in about 50% of patients, and clinicoradiological pancreatitis in 1%–5%.[97] ERCP-induced pancreatitis has a definite mortality of about 25%. Pancreatitis is more likely with high pressure injections, multiple injections into the pancreatic duct, therapeutic procedures, and operator inexperience that requires multiple attempts and consequent sphincteric edema.[97, 111, 112] In a patient with preexisting pancreatitis endoscopists are therefore understandably reluctant to intervene unless a significant benefit can be expected. The incidence and severity of pancreatitis can be decreased by somatostatin started before the procedure.[113, 114] A recent study indicated that heparin may also

be effective in protecting against ERCP-induced pancreatitis.[115]

35.8 COMPLICATIONS OF ACUTE PANCREATITIS 35.8.1 Acute Fluid Collection Rupture of the pancreatic duct or a tributary results in leakage of pancreatic juice. This leak gets quickly confined by adhesions. The resultant collection of fluid is called an acute fluid collection and occurs in 30%–50% of patients with acute pancreatitis.[13] Acute collections which typically develop in the first week are more likely to develop in patients with necrosis than in those without. They occur most often anterior to the kidneys or in the lesser sac. Fluid also commonly collects behind a kidney, lateral to the spleen or lateral to the colon (especially the left colon). Intrapancreatic collections are not uncommon. Rarely the acute collection may occur in a place other than these sites. The fluid contains pancreatic juice. Aspiration and analysis reveals very high amylase levels. Small acute collections are by themselves relatively asymptomatic, but large collections (greater than 10 cm) are often associated with abdominal discomfort that is evident even after the severe pain of the acute pancreatitis has decreased. It is usually not important to establish the presence of an acute collection unless there is a plan to intervene. An abdominal ultrasound will often show the collection, although a CT scan is much more accurate in this respect. Acute collections may resolve on their own, and usually require no intervention. One should avoid surgery in an acute collection. Therefore, if the size is causing excessive symptoms one may aspirate it (realizing that repeated aspirations may be needed).

Tropical Hepatogastroenterology

COMPLICATIONS OF ACUTE PANCREATITIS

551

With time, unresolved acute collections acquire a thick wall and are called ‘pseudocysts’.

35.8.2 Pseudocyst A pseudocyst is an acute fluid collection that did not resolve, but acquired a thick surrounding wall over time. An acute collection will take at least three weeks to develop a wall that is visible on a CT scan, and over four weeks to develop a wall that is useful for the surgeon. Pseudocysts are asymptomatic when small, but when large cause abdominal discomfort especially after meals, vomiting, and anorexia. Fever should not occur unless the pseudocyst is infected. Complications of pseudocysts include bleeding and infection.[116, 117] An ultrasound will usually pick up a pseudocyst but a CT scan is essential for an accurate imaging prior to surgery. Only the CT scan can reliably tell the correct size, the extent, and whether or not additional cysts are present. Asymptomatic pseudocysts can usually be left alone, and should resolve with time. Large pseudocysts require internal drainage into a loop of jejunum (a Roux-en-Y cystojejunostomy), or into the stomach (a cystogastrostomy); the decision mainly depends upon the location of the cyst. Presently, cystogastrostomy can often be achieved by an endoscopic technique[118] or by a laparoscopic technique.[119] Infected pseudocysts containing pus are best drained externally, operatively or percutaneously under CT guidance. Some patients will harbor massive quantities of pus (Fig. 35.3). External drainage of a pseudocyst is likely to result in a pancreatic fistula.[120] The fistula usually closes over time, during which the drainage tube must remain in place. Somatostatin and endoscopic stenting[121] may help close some nonhealing fistulae, but a few will require surgery and internal drainage.[122]

Part VIII / Pancreas

FIGURE 35.3 A CT done in a patient 3–4 weeks after the onset of acute pancreatitis. There is a large collection of fluid. A smaller loculus is present below: this may communicate with the main collection. Large collections may contain over 5 L of fluid. Typically this fluid is amylase rich and bloodstained, and may become infected and turn into pus.

35.8.3 Pancreatic Necrosis About 20% of patients with pancreatitis will develop significant necrosis of part of the organ.[6] Necrosis rarely affects the entire gland. Clinically, one may suspect necrosis in patients with severe disease, or a poor APACHE II score.[88] About half of all patients with necrosis have some degree of organ failure. Radiologically, necrosis appears as nonenhancing pancreatic tissue on a CECT. Necrosis is initially sterile. The mortality of pancreatic necrosis is about 10%; it rises to over 30% if the necrosis infects, which occurs in 20%– 60% of patients. There is a crude correlation between the extent of necrosis, occurrence of infection, and mortality.[13] Over two to three weeks, half of the patients with a sterile necrosis will develop an infected necrosis.[13] Pancreatic infection is best diagnosed

552

Chapter 35 / ACUTE PANCREATITIS

by the culture of a CT guided sample from the area of the necrosis. If cultures are negative, the necrosis is presumed sterile. A high white cell count is not by itself an indicator of infection. The treatment of a sterile necrosis is to leave it alone. Most clinicians administer prophylactic antibiotics in the hope of preventing infection; early antibiotics lower the risk of infection.[123] If the necrosis gets infected the patient will have a rising leukocytosis and persistent fever. CT guided aspiration and culture from the necrosis confirms the presence of infection, and the patient should undergo surgery. Peripancreatic gas seen on CT implies infection, and is an indication for surgery. The surgeon will drain the pus and remove as much necrotic tissue as possible. Tissue that is of doubtful viability should be preserved, and the aim should be to perform an organ-preserving necrosectomy. Re-exploration is frequently required, so much so that a “zipper” has been devised to permit quick opening and closure.[124] Another technique that permits re-access for draining the abdominal cavity is a laparostomy, following which wound irrigation and limited debridement can be performed without anesthesia. Unfortunately hernias and bowel fistulaes are common after laparostomy. A laparostomy “sponge” technique has been described in a Polish article to decrease the complications.[125] An alternative to reoperations is the technique of high-volume peritoneal lavage, through large-bore catheters placed during the surgery. Percutaneous drainage is usually insufficient.[13] Nutrition is a problem in most patients. Therefore most surgeons will place a feeding jejunostomy during surgery for pancreatitis. The mortality of an infected necrosis will range from 10% to 50%, often depending upon the extent of necrosis.

Although most patients with sterile necrosis will improve clinically, some will develop progressive organ failure. Should a sterile necrosis be treated by surgery? Probably not, as there is insufficient evidence to advise necrosectomy if infection cannot be demonstrated. Most surgeons would prefer to delay surgery till four weeks have elapsed from the time of onset of infection.[126]

35.8.4 Hemorrhage The necrosis may erode into a major vessel causing hemorrhage. The incidence of intraperitoneal hemorrhage in pancreatitis is 1%–3%, but when it occurs, it is life threatening. In some patients, an artery may develop a pseudoaneurysm as a result of destruction of its wall from a septic focus. This may rupture intraperitoneally or into the gastrointestinal tract. Treatment is by surgery; embolization may be possible sometimes.[127]

35.9 INFECTIOUS COMPLICATIONS In severe acute pancreatitis, local infection is a contributing cause of death in 80%.[23] Infective complications matter only in pancreatitis with necrosis, since they rarely complicate mild acute pancreatitis.[128] The mortality of an infected necrosis is about twice that of an abscess.[1] Confirmed infection will develop in a third or more of patients with severe acute pancreatitis,[129] and will increase the mortality three to four times,[130, 131] the risk depending on the quantity of necrosis. (Fig. 35.4). The risk of secondary infection rises from about 5% in the absence of Ranson’s prognostic signs to nearly 60% when 5 or more are present.[132] The bacteria probably reach primarily from colon.[133, 134] Infection is rare in the first week. In the majority of patients the features of infection become evident in the third week after the onset of

Tropical Hepatogastroenterology

INFECTIOUS COMPLICATIONS

553

FIGURE 35.4 Relationship between degree of necrosis and infection.

pancreatitis.[124, 135, 136] Infection should be suspected in the patient who worsens in the second week of pancreatitis or later. Patients with secondary infection will have features of sepsis, with fever, leukocytosis, increasing abdominal pain, and impending or established organ system failure. Blood or urine cultures may become positive. Infection in the pancreatic tissue can be confirmed by a contrast-enhanced CT (CECT) or by radiologically guided percutaneous sampling of the infected tissue. In a CECT, viable pancreatic parenchyma enhances with contrast, while necrotic tissue does not. The development of air in a collection is virtually diagnostic of infection.[23] Percutaneous aspiration with a 20 or 22 gauge needle, under ultrasound or CT guidance, can contaminate a sterile collection if it traverses the colon. Therefore, aspiration is better done by filling the colon with contrast so that it can be avoided.[137] It is better to aspirate the necrosis itself rather than a peripheral collection. The overall sensitivity and specificity of ultrasound or CT guided aspiration for infection are both about 90%.[138] CT or ultrasound guided pancreatic aspiration is unnecessary if the patient is stable and

Part VIII / Pancreas

improving, or if the patient is so clearly infected that surgery is anyway planned. A documented bacterial growth usually means infection, and is usually an indication for surgery.[137]

35.9.1 Bacteriology The most common organisms that infect pancreatic necrosis are Escherichia coli, Klebsiella pneumoniae, Enterococcus, Staphylococcus, and Pseudomonas. Bacteroides and fungal organisms are rare.[14, 130, 139] Between 30% and 50% of infections are polymicrobial.[129] The bacterial spectrum varies in different reports, and the distribution is roughly as follows: E. coli 30%– 50%, other coliforms 35%–50%, Staphylococcus 15%–30%, Pseudomonas 10%–15%, Enterococcus 15%–35%, fungi 5%–10% and anaerobes 5%–10%.[129] Pseudomonas was present in greater numbers in a recent study from India (Fig. 35.5).[14]

35.9.2 Prophylactic Antibiotics Nearly all recent studies have shown reduced rates of infectious complications in patients who receive prophylactic antibiotics.[140] Patients with

554

Chapter 35 / ACUTE PANCREATITIS

of the drug, tissue concentrations and MIC levels has been devised. According to this, carbapenems and fluoroquinolones are among the most effective antibiotics for use in patients with severe pancreatitis; this conclusion is supported by our own observations as well.

35.9.4 Gut Decontamination

FIGURE 35.5 Bacteria isolated from infection in patients with severe acute pancreatitis.[14]

severe acute pancreatitis should therefore receive prophylactic antibiotics for about two weeks. Some antibiotics penetrate pancreatic fluid better than others.

35.9.3 Choice of Antibiotics The choice of antibiotics will depend upon the spectrum as well as the penetration of the antibiotic into pancreatic secretions and tissue. Thirdgeneration cephalosporins, quinolones, penicillins, imipenem, metronidazole, and rifampin achieve concentrations higher than the minimum inhibitory concentration (MIC) for pathogens commonly associated with infected acute pancreatitis.[140, 141] Amikacin and other aminoglycosides, however, penetrate poorly into pancreatic tissue. Imipenem can reach over 20% of serum concentrations in pancreatic necrosis, this being enough to ensure a high efficacy. Pefloxacin and other fluoroquinolones achieve nearly 90% of serum levels in pancreatic tissue.[128, 142] An efficacy factor that takes into account the spectrum

Selective digestive tract decontamination for pancreatitis is based on the premise that most of the infection arises from the gut, particularly the colon. The administration of oral, nonabsorbable antibiotics should theoretically clear colonic bacteria, decrease continuing contamination of the necrosis, and lower sepsis. Animal models of gut decontamination have shown promise, decreasing infections and mortality. In a review, Gianotti et al.[143] showed that while all methods of decontamination decreased gut flora, not all showed systemic benefits. In human subjects, gut decontamination has not consistently shown a decrease in mortality in critically ill humans despite a reduction in infections.[144] There are few studies evaluating the technique in humans. Luiten and coworkers[145] showed a slight reduction in mortality from gut decontamination with colistin, amphotericin, and norfloxacin. However, the benefits did not reach statistical significance, and the value of gut decontamination remains unresolved. Reber and Widdison[134] showed that bacteria could reach the pancreas from parts of the body other than the colon and believed that because of this gut sterilization was unlikely to help.

35.10 PROGNOSIS It is important for the treating physician to correctly identify patients with severe pancreatitis so

Tropical Hepatogastroenterology

PROGNOSIS

TABLE fy 35.5 Ranson’s early prognostic signs of acute pancreatitis[2] Alcohol and other

Gallstone

> 55 years > 16, 000 > 200 > 350

> 70 > 18, 000 > 220 mg > 250

> 250

> 250

> 10 >5

> 10 >2

6, 000

– >5 4,000

At admission or diagnosis Age, years White blood cell count/mm3 Blood sugar level, mm/100 ml Serum lactic dehydrogenase, U/I Serum aspartate U/I aminotransferase During initial 48 h Hematocrit fall, % Blood urea nitrogen rise, mg/100 ml Serum calcium level, mg/100 ml Arterial pO2 , mmHg Base deficit, mEq/L Estimated fluid sequestration, ml

Interpretation: 6 mortality 100%

signs = signs =

as to institute aggressive supportive therapy. Clinical judgement alone has low sensitivity in the identification of patients with more severe pancreatitis.[146]

35.10.1 Ranson’s Criteria These are probably the oldest and the most widely used criteria for the grading of severity in AP. Ranson and coworkers in 1982 proposed 11 factors with prognostic significance.[2] (Table 35.5). When there are ≤ 2 positive signs the mortality is between 0% and 5%; when 3–5 positive signs are present the mortality is about 10% and with ≥ 6 positive Ranson’s signs the mortality is greater than 60%.[147–149] While these criteria have been very useful, there are limitations.[13] Ranson’s criteria

Part VIII / Pancreas

555

are not very accurate in patients with only 3–5 signs positive; they are more accurate in patients with mild (≤ 2 positive signs) and very severe disease (≥ 6 positive signs). Two days of observation are required before the signs can be measured. The overall sensitivity and specificity are about 75% each, with a positive predictive value of less than 50% and a negative predictive value of about 90%.

35.10.2 Apache II Score The other popular prognostic index is the APACHE II (Acute Physiology And Chronic Health Evaluation) system. It uses the measurement of 12 physiological variables in combination with age and preexisting health status. Each variable is given a score ranging from 0– 4 depending on degree of derangement. Sick patients have a higher score, and several studies have shown a good correlation between mortality and the APACHE II scores at admission and at 48 hours (Table 35.6). The APACHE II system is comparable to, though not better than, the Ranson system of grading of severity.[147] The advantage of the APACHE II score is that it can be calculated immediately on admission and can be repeated. It is, however, difficult to calculate, and requires the aid of a computer. The sensitivity at admission varies from 34% to 70% with the specificity being 76%–98%. At 48 hours, while the specificity approaches 100%, the sensitivity falls to below 50%.[20] However the APACHE II score is a better predictor of mortality and need for ICU admission than any radiological criterion.[150] Organ dysfunction may be a transient phenomenon, and may improve during resuscitation. Persistence or progression of organ dysfunction will predict severity.[151]

556

Chapter 35 / ACUTE PANCREATITIS

TABLE fy 35.6 APACHE II severity of disease classification system Physiological variables (◦ C)

Temperature rectal Mean arterial pressure (mmHg) Heart rate-ventricular response Respiratory rate (nonventilated or ventilated) Oxygen: A-aDO2 or PaO2 (mmHg) (a) FIO2 ≥ 0.5 record A-aDO2 (b) FIO2 < 0.5 record only PO2 Arterial pH Serum sodium (mmol/1) Serum potassium (mmol/l) Serum creatinine (mg/100 ml) (double point score for acute renal failure) Hematocrit (%) White blood cell count (total/mm3 ) (in 1000 s) Glasgow coma score (GCS) Score 15 minus actual GCS A total acute physiology score (APS): Sum of the 12 individual variable points Serum HCO2 (venous-mmol/1) (not preferred, use if no ABGs) B Age points Assign points to age as follows: Age (yrs) Points ≤ 44 0 45–54 2 55–64 3 64–74 5 ≥ 75 6 C. Chronic health points If the patient has a history of severe organ system insufficiency or is immunocompromised, assign points as follows: A-aDO2 = alveolar-arterial difference for oxygen FIO2 = fraction of inspired oxygen

+4

+3

+2

≥ 41◦

39◦ –40.9◦

≥ 160 ≥ 180 ≥ 50 – ≥ 500 – ≥ 7.7 ≥ 180 ≥ 07 – ≥ 3.5 ≥ 60 ≥ 40

130–159 140–179 35–49 – 350–499 – 7.6–7.69 41–5.9 160–179 – 2–3.4 – –

– 110–129 110–139 – – – – – – 155–159 1.5–1.9 50–50.9 – 20–39.9

–

–

–

–

–

–

> 52 41–51.9 (a) For nonoperative or emergency (b) For elective postoperative patients-2 points. Definitions organ insufficiency or immunocompromised state must have been evident prior to this hospital admission and conforms to the following criteria: Liver Biopsy proven cirrhosis and documented portal hypertension, episodes of past upper gastrointestinal bleeding attributed to portal hypertension; or prior episodes of hepatic failure/encephalopathy/coma.

–

Tropical Hepatogastroenterology

PROGNOSIS

557

yf +1

0

+1

+2

+3

+4

38.5◦ –38.9◦

36◦ –38.4◦

34◦ –35.9◦

32◦ –33.9◦

30◦ .31.9◦

– – 25–34 – 200–349 – 7.5–7.59 150–154 5.5–5.9 – 46–49.9 – 15–19.9

70–109 70–109 12–24 – < 200 PO2 > 70 7.33–7.49 130–149 3.5–5.4 0.6–1.4 30–45.9 – 3–14.9

– – 10–11 – – PO2 61–70 – – 3–3.4 – – – –

50–69 55–69 6–9 – – – 7.25–7.32 120–129 2.5–2.9 < 60 20–29.9 – 1–29

– 40–54 – – – PO2 55–60 7.15–7.24 111–119 – – – – –

≤ 29.9◦ ≤ 49 ≤ 39 ≤5 – – PO2 < 55 < 7.15 < 110 ≤ 2.5 – < 20 – 1/2 necrosis Maximum score

2 points 4 points 6 points 10 points

Tropical Hepatogastroenterology

REFERENCES

559

REFERENCES [1] Bradley III EL. The necessity for a clinical classification of acute pancreatitis: the Atlanta system. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 27–32. [2] Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982;77:633–638. [3] Knaus WA, Draper EA, Wagner DP et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29. [4] Bhatia M, Wong FL, Cao Y et al. Pathophysiology of acute pancreatitis. Pancreatology 2005;5: 132–144. [5] Nagar AB, Gorelick F. Acute pancreatitis. Curr Opin Gastroenterol 2004;20:439–443. [6] Banks P. Acute and chronic pancreatitis. In: Feldman M, Scharwschmidt BF, Sleisenger MH. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 6th Edition, WB Saunders Co, Philadelphia, 1998, p 808–62. [7] Busnardo AC, DiDio LJA, Tidrick RT et al. History of the pancreas. In: Chen TS, Chen PS (Editors) The History of Gastroenterology, Parthenon Publishing Group, New York, 1995, pp 250–1. [8] Jones BA, Salsberg BB, Mehta MH et al. Common pancreaticobiliary channels and their relationship to gallstone size in gallstone pancreatitis. Ann Surg 1987;205:123–5. [9] Hiatt N, Warner NE. Serum amylase and changes in pancreatic function and structure after ligation of pancreatic ducts. Am Surg 1969;35: 30–35. [10] McCutcheon AD. A fresh approach to the pathogenesis of pancreatitis. Gut 1968;9:296–310. [11] Steer ML. Pathophysiology and pathogenesis of acute pancreatitis. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 3–11. [12] Luthen RE, Niederau C, Grendell JH. Effects of bile and pancreatic digestive enzymes on perme-

Part VIII / Pancreas

[13] [14]

[15]

[16]

[17] [18]

[19]

[20] [21]

[22]

[23]

[24]

ability of the pancreatic duct system in rabbits. Pancreas 1993;8:671–81. Lankisch PG, Banks PA. Pancreatitis. SpringerVerlag, Berlin, 1998. Garg PK, Khanna S, Bohidar NP et al. Incidence, spectrum and antibiotic sensitivity pattern of bacterial infections among patients with acute pancreatitis. J Gastroenterol Hepatol 2001;16:1055–9. Swensen T, Osnes M, Serck-Hanssen A. Endoscopic retrograde cholangio-pancreatography in primary and secondary tumours of the pancreas. Br J Radiol 1980;53:760–764. Corfield AP, Cooper MJ, Williamson RCN. Acute pancreatitis: a lethal disease of increasing incidence. Gut 1985; 26:724–729. Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994;330:1198–1210. Banks PA. Acute Pancreatitis. In: Haubrich WS, Schafner F, Berk JE (eds) Bockus Gastroenteroloy, vol. 4, 5th edn, W.B. Saunders Comp., Philadelphia-London-Toronto etc. 1995, pp 2888–2917. Lankisch PG, Burchard-Reckert S, Petersen M et al. Morbidity and mortality in 602 patients with acute pancreatitis seen between the years 1980–1994. Z Gastroenterol 1996;34:371–377 (Abstract). Wilson C, Imrie CW, Carter DC. Fatal acute pancreatitis. Gut 1988;29:782–788. Houssin D, Castaing D, Lemoine J et al. Microlithiasis of gallbladder. Surg Gynecol Obstet 1983;157:20–24. Diehl AK, Holleman DR Jr, Chapman JB et al. Gallstone size and risk of pancreatitis. Arch Intern Med 1997 11–25;157:1674–8. Jones B. Choledochocele demonstrated on percutaneous cholangiography: a patient with acute fulminant pancreatitis. Gastrointest Radiol 1983;2:145–147. Evans WK, Ho C-S, McLoughlin MJ et al. Fatal necrotizing pancreatitis following fine-needle

560

[25]

[26]

[27] [28]

[29]

[30]

[31]

[32]

[33]

[34] [35]

[36]

[37]

Chapter 35 / ACUTE PANCREATITIS

aspiration biopsy of the pancreas. Radiology 1981;141:61–62. Leinkram C, Roberts-Thomson IC, Kune GA. Juxtapapillary duodenal diverticula. Association with gallstones and pancreatitis. Med J Aust 1980;1:209–210. Kager L, Lindberg S, Agren G. Alcohol consumption and acute pancreatitis in men. Scand J Gastroenterol 1972;15(Suppl 7):1–38. Geokas MC. Ethanol and the pancreas. Med Clin North Am 1984;68:57–75. Pirola RC, Davis AE. Effects of ethyl alcohol on sphincter resistance at the choledochoduodenal junction in man. Gut 1968;9:557–560. Pelli H, Sand J, Laippala P et al. Long-term follow-up after the first episode of acute alcoholic pancreatitis: time course and risk factors for recurrence. Scand J Gastroenterol 2000;35: 552–5. Kohler H, Lankisch PG. Acute pancreatitis and hyperamylasaemia in pancreatic carcinoma. Pancreas 1987;2:117–119. Cameron-Strange A. Acute pancreatitis associated with lymphosarcoma. Br J Surg 1983;70: 444. Balch CM. Diagnostic und Prognose des malignen Melanoms. Dtsch Med Wochenschr 1985;110:1783–1786 (Abstract). Griffen WO Jr, Schaefer JW, Schindler S et al. Ampullary obstruction by benign duodenal polyps. Arch Surg 1968;97:444–449. Alexander HC. Annular pancreas in the adult. Am J Surg 1970;119:702–704. Dreiling DA, Kirschner PA, Nemser H. Chronic duodenal obstruction : a mechano-vascular etiology of pancreatitis. I. Report of 6 cases illustrating this clinical variety. Am J Dig Dis 1960;5: 991–1005. Bedran K, Lucidarme D, Pollet E et al. Pancreatite aigue recurrente secondaire a un corps etranger vegetal dans le canal de Wirsung. Gastroenterol Clin Biol 1994;18:1154–1156 (Abstract). Melitzser SJ, Goldberg MD. Recurrent pancreatitis caused by vegetable matter obstruction. Am J Gastroenterol 1986;81:1091–1092.

[38] Feldstein JD, Johnson FR, Kallick CA et al. Acute hemorrhagic pancreatitis and pseudocyst due to mumps. Ann Surg 1974;180:85–88. [39] Hedstrom SA, Belfrage I. Acute pancreatitis in two cases of infectious mononucleosis. Scand J Infect Dis 1976;8:124–126. [40] Imrie CW, Ferguson JC, Sommerville RG. Coxsackie and mumps virus infection in a prospective study of acute pancreatitis. Gut 1977;18: 53–56. [41] Mardh P-A, Ursing B. Acute pancreatitis in mycoplasma pneumoniae infections. Br Med J 1973;2:240–241. [42] Hohenberger P. Das Pankreas als Zielorgan des Hepatitis B-Virus-Immunhistologischer Nachweis von HBsAg bei Pankreaskarzinom und chronischer Pankreatitis. Laber Magen Darm 1985;15:58–63 (Abstract). [43] Brivet F, Ofin B, Bedossa P et al. Pancreatic lesions in AIDS. Lancet 1987;2:570–571. [44] Brivet FG, Naveau SH, Lamaigre GF et al. Pancreatic lesions in HIV-infected patients. Bailliers Clin Endocrinol Metabol 1994;8:859–877 (Abstract). [45] Khuroo MS, Zargar SA, Mahajan R. Hepatobiliary and pancreatic ascariasis in India. Lancet 1990;335 (8704):1503–6. [46] Khuroo MS, Zargar SA, Yattoo GN et al. Worm extraction and biliary drainage in hepatobiliary and pancreatic ascariasis. Gastrointest Endosc 1993;39:680–685. [47] Lankisch PG, Droge M, Gottesleben F. Druginduced acute pancreatitis : incidence and severity. Gut 1995;37:565–567. [48] Ko CW, Gooley T, Schoch HG et al. Acute pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis. Bone Marrow Transplant 1997;20:1081–6. [49] Yen S, Hsieh CC, MacMahon B. Consumption of alcohol and tobacco and other risk factors for pancreatitis. Am J Epidemiol 1982;116:407–14. [50] Moore PG, James OF. Acute pancreatitis induced by acute organophosphate poisoning Postgrad Med J 1981;57:660–662. [51] Bartholomew C. Acute scorpion pancreatitis in Trinidad. Br Med J 1970;666–668.

Tropical Hepatogastroenterology

REFERENCES

[52] Cope O, Culver PJ, Mixter CG et al. Pancreatitis, a diagnostic clue to hyperparathyroidism. Ann Surg 1957;145:857–863. [53] Frick TW, Mithofer K, Fernandez-del Castillo C et al. Hypercalcemia causes acute pancreatitis by pancreatic secretory block, intracellular zymogen accumulation, and acinar cell injury. Am J Surg 1995;169:167–172. [54] Fortson MR, Freedman SN, Webster PD. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 1995;90:2134–2139. [55] Avram MM. High prevalence of pancreatic disease in chronic renal failure. Nephron 1977;18:68–71. [56] Rutsky EA, Robards M, Van Dyke JA et al. Acute pancreatitis in patients with end stage renal disease without transplantation. Arch Intern Med 1986;146:1741–1745. [57] Bruno MJ, van Westerloo DJ, van Dorp WT et al. Acute pancreatitis in peritoneal dialysis and haemodialysis: risk, clinical course, outcome, and possible aetiology. Gut 2000;46:385–9. [58] Duguid H, Simpson RG, Simpson RG et al. Accidental hypothermia. Lancet 1961;2:1213–1221. [59] Foulis AK. Morphological study of the relation between accidental hypothermia and acute pancreatitis. J Clin Pathol 1982;35:1244–1248. [60] Blomgren KB, Sundstrom A, Steineck G et al. Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis. Diabetes Care 2002;25:298–302. [61] Rasmussen HH, Fonager K, Sorensen HT et al. Risk of acute pancreatitis in patients with chronic inflammatory bowel disease. A Danish 16-year nationwide follow-up study. Scand J Gastroenterol 1999;34:199–201. [62] Pellegrini CA, Paloyan D, Acosta JM et al. Acute pancreatitis of rare causation. Surg Gynecol Obstet 1977;144:899–902. [63] Marino C, Lipstein-Kresch E. Pancreatitis in systemic lupus erythematosus. Arthritis Rheumatism 1984;27:118–119. [64] Durr H-K. Acute pancreatitis. In: Howat HT, Sarles H (eds) The Exocrine Pancreas. W.B. Saunders Comp., London-Philadelphia-Toronto, 1979, pp 352–401.

Part VIII / Pancreas

561

[65] Ryan S, Sandler A, Trenhaile S et al. Pancreatic enzyme elevations after blunt trauma. Surgery 1994;116:622–627. [66] Mueller PR, Miketic LM, Simeone JF et al. Severe acute Pancreatitis after percutaneous biopsy of the pancreas. Amer J Roentgenol 1988;151:493–494. [67] Rolny P, Anderberg B, Ihse I et al. Pancreatitis after sphincter of Oddi manometry. Gut 1990;31: 821–824. [68] Sherman S, Troiano FP, Hawes RH et al. Sphincter of Oddi manometry : decreased risk of clinical pancreatitis with use of a modified aspirating catheter. Gastrointest Endosc 1990;36:462–466. [69] Christoforidis E, Goulimaris I, Kanellos I et al. Post-ERCP pancreatitis and hyperamylasemia: patient-related and operative risk factors. Endoscopy 2002;34:286–92. [70] Freeman ML, DiSario JA, Nelson DB et al. Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc 2001;54:425–34. [71] Rabenstein T, Schneider HT, Bulling D et al. Analysis of the risk factors associated with endoscopic sphincterotomy techniques: preliminary results of a prospective study, with emphasis on the reduced risk of acute pancreatitis with low-dose anticoagulation treatment. Endoscopy 2000;32:10–9. [72] Sherman S, Lehman GA. ERCP- and endoscopic sphincterotomy-induced pancreatitis. Pancreas 1991;6:350–367. [73] Bardenchier JA, Kaminski DL, Willman VL. Pancreatitis after biliary tract surgery. Am J Surg 1968;116:773–776. [74] Burton CC, Eckman WG Jr, Haxo J. Acute postgastrectomy pancreatitis. Am J Surg 1957;94:70–79. [75] London NJM, Lloyd DM, Pearson H et al. Pancreatitis after parathyroidectomy. Br J Surg 1986;73:766–767. [76] Schwokowski CF, Albert H, Hartig W. Erfahrungen bei der postoperativen Pankreatitis nach magnresektionen. Zentralbl Chir 1974;99:1233–1238 (Abstract). [77] Wagner E, Irfanoglu ME. Die postoperative Pankreatitis. Ihre Erkennung und Behandlung. Chirurg 1971;42:162–167 (Abstract).

562

Chapter 35 / ACUTE PANCREATITIS

[78] Rose E, Navarro S, Bru C et al. Occult microlithiasis in “idiopathic” acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 1991;101: 1701–1709. [79] Frossard JL, Sosa-Valencia L, Amouyal G et al. Usefulness of endoscopic ultrasonography in patients with “idiopathic” acute pancreatitis. Am J Med 2000 15;109:196–200. [80] Draganov P, Forsmark CE. Diseases of the Pancreas. ACP Medicine, 2006, Medscape: http://www.medscape.com/viewarticle/532779− 2, accessed 21 September 2006. [81] Courtois P, Art G, Vertongen F et al. Evolution of serum amylase, lipase and immunoreactive trypsin during pancreatitis attacks. Ann Biol Clin (Paris) 1985;43:127–31. [82] Okerberg K, Lee M. Spuriously Normal Amylase Levels in a Patient With Acute Pancreatitis Secondary to Hypertriglyceridemia. J Am Board Fam Pract 1999;12:68–70. [83] Wong EC, Butch AW, Rosenblum JL. The clinical chemistry laboratory and acute pancreatitis. Clin Chem 1993;39:234–43. [84] Pezzilli R, Billi P, Barakat B et al. Ultrasonographic evaluation of the common bile duct in biliary acute pancreatitis patients: comparison with endoscopic retrograde cholangiopancreatography. J Ultrasound Med 1999;18:391–4. [85] Norton SA, Alderson D. Endoscopic ultrasonography in the evaluation of idiopathic acute pancreatitis. Br J Surg 2000;87:1650–5. [86] Tandon M, Topazian M. Endoscopic ultrasound in idiopathic acute pancreatitis. Am J Gastroenterol 2001;96:705–9. [87] Sugiyama M, Wada N, Atomi Y et al. Diagnosis of acute pancreatitis: value of endoscopic sonography. AJR Am J Roentgenol 1995;165:867–72. [88] Garg PK, Madan K, Pande GK, et al. Association of extent and infection of pancreatic necrosis with organ failure and death in acute necrotizing pancreatitis. Clin Gastroenterol Hepatol 2005;3: 159–66. [89] Scholmerich J, Lausen M, Lay L et al. Value of endoscopic retrograde cholangiopancreatography

[90]

[91]

[92]

[93]

[94]

[95]

[96] [97]

[98]

[99]

[100]

in determining the cause but not course of acute pancreatitis. Endoscopy 1992;24:244–7. Neoptolemos JP. Endoscopic retrograde cholangiopancreatography in necrotizing pancreatitis. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 69–76. Lee MJ, Choi TK, Lai EC et al. Endoscopic retrograde cholangiopancreatography after acute pancreatitis. Surg Gynecol Obstet 1986;163: 354–8. Cooperman M, Ferrara JJ, Carey LC et al. Idiopathic acute pancreatitis: the value of endoscopic retrograde cholangiopancreatography. Surgery 1981;90:666–70. Lankisch PG, Haseloff M, Becher R. No parallel between the biochemical course of acute pancreatitis and morphologic findings. Pancreas 1994;9:240–3. Kale-Pradhan PB, Elnabtity MH, Park NJ et al. Enteral Nutrition in Patients with Pancreatitis. Pharmacotherapy 1999;19:1036–1041. McClave SA, Dryden GW. Issues of nutritional support for the patient with acute pancreatitis. Semin Gastrointest Dis 2002;13:154–60. Wilson C, Imrie CW, Carter DC. Fatal acute pancreatitis. Gut 1988;29:782–8. De Beaux AC, Carter DC, Palmer KR. Endoscopic retrograde cholangiopancreatography and acute pancreatitis. Gut 1996;38:799–800. Neoptolemos JP, London NJ, James D et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gall-stones. Lancet 1988;ii: 979–83. Fan S-T, Lai ECS, Mok FPT et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 1993;328: 228–232. Neoptolemos JP, Carr-Locke DL, Leese T et al. Acute cholangitis in association with acute pancreatitis: incidence, clinical features and outcome in relation to ERCP and endoscopic sphincterotomy. Br J Surg 1987;74:1103–6.

Tropical Hepatogastroenterology

REFERENCES

[101] Wilson PG, Ogunbiyi O, Neoptolemos JP. The timing of endoscopic sphincterotomy in gallstone acute pancreatitis. Eur J Gastroenterol Hepatol 1997;9:137–44. [102] Sulkowski U, Meyer J, Kautz G et al. Arguments for a revised concept in the therapy of acute pancreatitis. On the indications for conservative, endoscopic and surgical procedures. Chirurg 1989;60:246–50 (Abstract). [103] Nowack A, Nowakowska-Duzawa E, Rybicka J. Urgent endoscopic sphincterotomy vs conservative treatment in acute biliary pancreatitis – a prospective, controlled trial. Hepatogastroenterology 1990; 37 (suppl II): A5 (abstract). [104] Fan ST, Lai CS, Mok FR et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 1993;328:228–32. [105] Jover R, Llach J, Bordas JM et al. The usefulness of the timeliness of endoscopic sphincterotomy in severe acute pancreatitis of biliary origin. Gastroenterol Hepatol 1997;20:344–6. [106] Cuilleret J, Balique JG, Barthelemy C et al. What place for endoscopic sphincterotomy in treatment of acute pancreatitis? Chirurgie 1998;123:131–7 (Abstract). [107] 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;94:3211–4. [108] Moreau JA, Zinsmeister AR, Melton LJ et al. Gallstone pancreatitis and the effect of cholecystectomy: a population-based cohort study. Mayo Clin Proc 1988;63:466–73. [109] Uomo G, Manes G, Laccetti M et al. Endoscopic sphincterotomy and recurrence of acute pancreatitis in gallstone patients considered unfit for surgery. Pancreas 1997;14:28–31. [110] Gislason H, Vetrhus M, Horn A et al. Endoscopic sphincterotomy in acute gallstone pancreatitis: a prospective study of the late outcome. Eur J Surg 2001;167:204–8. [111] Hamilton I, Lintott DJ, Rothwell J et al. Acute pancreatitis following endoscopic retrograde cholangiopancreatography. Clin Radiol 1983;34:543–6.

Part VIII / Pancreas

563

[112] LaFerla G, Gordon S, Archibald M et al. Hyperamylasemia following endoscopic retrograde cholangiopancreatography. Pancreas 1986;1: 160–3. [113] Bordas JM, Toledo V, Mondelo F et al. Prevention of pancreatic reactions by bolus somatostatin administration in patients undergoing endoscopic retrograde cholangio-pancreatography and endoscopic sphincterotomy. Horm Res 1988;29: 106–8. [114] Poon RT, Yeung C, Lo CM et al. Prophylactic effect of somatostatin on post-ERCP pancreatitis: a randomized controlled trial. Gastrointest Endosc. 1999;49:593–8. [115] Rabenstein T, Roggenbuck S, Framke B et al. Complications of endoscopic sphincterotomy: can heparin prevent acute pancreatitis after ERCP? Gastrointest Endosc 2002;55:476–83. [116] Vitsas GJ, Sarr MG. Selected management of pancreatic pseudocysts: operative versus expectant management. Surgery 1992;111:123–30. [117] Yeo CJ, Bastidas JA, Lynch-Nyhan A et al. The natural history of pancreatic pseudocysts documented by computed tomography. Surg Gynecol Obstet 1990;170:411–7. [118] Lawson JM, Baillie J. Endoscopic therapy for pancreatic pseudocysts. Gastrointest Endosc Clin North Am 1995;5:181–93. [119] Chowbey PK, Soni V, Sharma A et al. Laparoscopic intragastric stapled cystogastrostomy for pancreatic pseudocyst. J Laparoendosc Adv Surg Tech A 2001;11:201–5. [120] Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in acute pancreatitis. Radiology. 1994;193:297–306. [121] McLatchie GR, Meek D, Imrie CW. The use of endoscopic retrograde choledocho pancreatography (ERCP) in the diagnosis of internal fistulae complicating severe acute pancreatitis. Br J Radiol 1985;58:395–7. [122] Bradley EL, Allen KA. Complications of acute pancreatitis and their management. In: Trede M, Carter DC, Longmire WP (Editors) Surgery of the pancreas, Churchill Livingstone, Edinburgh, 1993, pp 245–59.

564

Chapter 35 / ACUTE PANCREATITIS

[123] Pederzoli P, Bassi C, Vesentini S et al. A randomized multicenter clinical trial of antibiotics prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993;174:480–3. [124] Laws HL, Kent RB 3rd. Acute pancreatitis: management of complicating infection. Am Surg 2000;66:145–52. [125] Lampe P, Olakowski M, Wojtyczka A et al. The modified laparostomy with the use of ultrasound dissector and garamycin sponge in the treatment of complicated acute pancreatitis. Wiad Lek 2000;53:53–9(abstract). [126] Ho HS, Frey CF. Gastrointestinal and pancreatic complications associated with severe pancreatitis. Arch Surg 1995;130:817–23. [127] Waltman AC, Luers PR, Athanasoulis CA et al. Massive arterial hemorrhage in patients with pancreatitis. Complementary roles of surgery and transcatheter occlusive techniques. Arch Surg 1986;121:439–43. [128] Bassi C, Pederzoli P. Antibiotics in necrotizing pancreatitis. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 93–8. [129] Powell JJ, Miles R, Siriwardena AK. Antibiotic prophylaxis in the initial management of severe acute pancreatitis. Br J Surg 1998;85: 582–7. [130] Gerzof SG, Banks PA, Robbins AH et al. Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 1987;93:1315–20. [131] United Kingdom guidelines for the management of acute pancreatitis. British Society of Gastroenterol Gut 1998;42 Suppl 2:S1–13. [132] Ranson JC. Stratification of severity for acute pancreatitis. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 13–22. [133] Schmid SW, Uhl W, Friess H et al. The role of infection in acute pancreatitis. Gut 1999;45: 311–6. [134] Reber HA, Widdison, AL. Pathogenesis of infected pancreatic necrosis. In: In: Bradley III EL (ed)

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144]

[145]

Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 85–92. Bassi C, Falconi M, Sartori N et al. The role of surgery in the major early complications of severe acute pancreatitis. Eur J Gastroenterol Hepatol 1997;9:131–6. Lumsden A, Bradley EL III. Secondary pancreatic infections. Surg Gynecol Obstet 1990;170: 459–67. Banks PA. The role of needle-aspiration bacteriology in the management of necrotizing pancreatitis. In: Bradley III EL (ed) Acute Pancreatitis: Diagnosis and Therapy. Raven Press Ltd, New York, 1994, p 99–103. Schoenberg MH, Rau B, Beger HG. New approaches in surgical management of severe acute pancreatitis. Digestion 1999;60 Suppl 1: 22–6. Grewe M, Tsiotos GG, de-Leon EL et al. Fungal infection in acute necrotizing pancreatitis. J Am Coll Surg 1999;188:408–14. Kramer KM, Levy H. Prophylactic antibiotics for severe acute pancreatitis: the beginning of an era. Pharmacotherapy 1999;19:592–602. Brattstrom C, Malmborg A, Tyden G. Penetration of imipenem into human pancreatic juice following single intravenous dose administration. Chemotherapy 1989;35:83–7. Buchler M, Malfertheiner P, Friess H et al. Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 1992;103: 1902–8. Gianotti L, Braga M, Alexander JW. The intestine: a central organ in the pathogenesis of septic complications in acute pancreatitis. Chir Ital 1995;47(2):14–24(Abstract). Stoutenbeek CP, van Saene HK, Miranda DR et al. The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med 1984;10:185–92. Luiten EJ, Hop WCJ, Lange JF et al. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 1995;222:57–65.

Tropical Hepatogastroenterology

REFERENCES

[146] Imrie CW. Observations on acute pancreatitis. Br J Surg 1974;61:539–544. [147] Fan ST, Choi TK, Lai CS et al. Sensitivity of the amylase-creatinine clearance ratio in acute pancreatitis. Arch Intern Med 1988;138:958–962. [148] Balthazar EJ, Ranson JHC, Naidich DP et al. Acute pancreatitis: prognostic value of CT. Radiology 1985;156:767–772. [149] Larvin M. Assessment of severity and prognosis in acute pancreatitis. Eur J Gastroenterol Hepatol 1997;9:122–30. [150] De Sanctis JT, Lee MJ, Gazelle GS et al. Prognostic indicators in acute pancreatitis: CT vs APACHE II. Clin Radiol 1997;52:842–8.

test

Part VIII / Pancreas

565

[151] Toouli J, Brooke-Smith M, Bassi C et al. Guidelines for the management of acute pancreatitis. J Gastroenterol Hepatol 2002;75:S15–S39. [152] Pironen A. Severe acute pancreatitis: contrastenhanced CT and MRI features. Abdom Imaging 2001;26:225–33. [153] Balthazar EJ. Pancreatitis. In: Gore RM, Levine MS (eds) Textbook of Gastrointestinal Radiology. 2nd edition, WB Saunders Co, Philadelphia, 2000, p 1767–95. [154] Vitellas KM, Paulson EK, Enns RA et al. Pappas TN. Pancreatitis complicated by gland necrosis: evolution of findings on contrastenhanced CT. J Comput Assist Tomogr 1999;23: 898–905.

Chapter

36 CHRONIC PANCREATITIS Vivek Tandon and Suneet Sood

36.1 INTRODUCTION Chronic pancreatitis is an inflammatory disease of the pancreas characterized by an irreversible destruction of pancreatic exocrine and endocrine tissue. While the primary symptom is pain, destruction of exocrine tissue results in steatorrhea and the loss of endocrine tissue results in the development of diabetes. Optimal management of CP is possible only at centers which follow a team approach with inputs from the gastroenterologist, surgeon, radiologist, diabetologist, psychiatrist as well as the counselors and social workers. Such an integrated approach to the disease permits timely and correct decisions to be made. It is important to emphasize that not all patients with chronic pancreatitis require surgery; in fact it is primarily a medical disease. In many large series as many as 50% of patients have been managed without surgery.[1, 2] The loss of exocrine and endocrine tissue, the hallmark of CP, is permanent and cannot be reversed by any surgical procedure. The pancreatic changes are progressive and though some reports suggest the contrary it is unlikely that any surgical procedure even slows the progression of disease.[3–5] However, half the patients with CP require some form of surgical intervention. 566

36.2 EPIDEMIOLOGY OF CHRONIC PANCREATITIS Reliable figures for the prevalence of chronic pancreatitis are difficult to ascertain, because a correct diagnosis is difficult and usually requires expensive imaging. Criteria used for diagnosis are not uniform, and acute pancreatitis may often be misdiagnosed as chronic, and vice versa.[6] The hospital incidence in most parts of the world is remarkably similar, at about 4.5/1000 admissions (Table 36.1). The frequency appears to be increasing, probably due to an improved ability to diagnose the disease. Data on community incidence is sparse. Riela and coworkers from Minnesota reported a prevalence of 4.7 per 100000 population: 6.7 for men, and 3.2 for women.[6, 7] A series of studies carried out across the country in Japan over a period of almost 25 years have shown that while the incidence has remained static at about 5.5 per 100,000, the prevalence has steadily been going up in Japan, and this again is possibly a reflection of the aging population in that country. The breakup of chronic pancreatitis in Japan shows that about half are related to alcohol and about 30% idiopathic. Other hereditary and metabolic causes are uncommon.[8] CP may be calcific or noncalcific.[9] About half of the cases have associated calcification,[6] the

ETIOPATHOGENESIS AND PATHOLOGY

TABLE fy 36.1 Incidence of chronic pancreatitis per 1000 hospital admissions Incidence in the West 6 Marseille 3.1 Cape Town 4.4 Sao Paulo 4.9 Mexico City 4.4 Incidence in India Delhi

0.7 (Estimated)

figure varying widely in different reports. CP is twice as common in males as in females,[10] most of this uneven distribution being related to a different propensity for alcohol abuse.

36.2.1 Epidemiology of Chronic Pancreatitis in India With alcohol abuse widespread in India, chronic alcoholic pancreatitis is not uncommon. The hospital incidence is unknown because of poorly maintained hospital records. Cases listed as chronic pancreatitis in the case-record’s diagnosis column may well be chronic pain of unknown etiology. Our personal communications with the records departments of some large hospitals in Delhi indicate that incidence of acute pancreatitis is 1.6/1000 admissions; chronic pancreatitis is 2.5 times less common,[11] leading to an estimated 0.7 admissions per 1000 for an average Indian hospital. There is obviously much conjecture in this figure. The community incidence of chronic pancreatitis in India was calculated in a careful study in Kerala. Balaji and coworkers[9] found that the prevalence was 1 in 793 (126/100000) inhabitants. Kerala however probably has the highest incidence in India, and the patients here have tropical calcific pancreatitis, a condition unrelated to alcohol abuse. This frequency is therefore not representative for the rest of the country. The term tropical

Part VIII / Pancreas

567

probably is not exactly accurate because the disease is not confined only to the tropics but is also seen in the subtropical zone extending between 30 degrees north and 30 degrees south latitude. It is mainly seen in South Asia, South East Asia, western, and central Africa, and isolated reports from the Western Hemisphere. Tropical calcific pancreatitis is usually identified by early onset disease involving large ducts with prominent calcification progressing to exocrine and endocrine failure that we are all familiar with. Also, fibrocalcific pancreatic diabetes has especially been described from the southern parts of our country, Chennai and other areas. It is called fibrocalcific pancreatic disease (FCPD), and the predominant presentation is with diabetes, but exocrine and endocrine insufficiency and calcification also appear in due course. How common is this condition? Hospital based data are notoriously misleading in this regard, but whatever information is available suggests that about 1 in 4 to 1 in 3 diabetics, especially young diabetics below the age of 30, suffer from chronic pancreatitis in various parts of our country. The only reliable data is from the study by Balaji et al.,[9] which had identified the prevalence of 1 in 793 in a large field study. The median age of patients was around 24 years and surprisingly revealed a female preponderance as opposed to almost all the other hospital-based reports where a male preponderance has been reported.[6, 12]

36.3 ETIOPATHOGENESIS AND PATHOLOGY Autopsy data suggests that 0.04% to 5% of all autopsies done will show changes of CP. However this may not mean that they had CP as the changes may not have developed the changes during their lifetime, but pathological change is an important component for diagnosis. Only the Japanese authors feel that pancreatic function is

568

Chapter 36 / CHRONIC PANCREATITIS

more important. Long-standing alcohol use results in histological changes of CP, but there may be no symptoms of CP. A study from Delhi reported that ageing is associated with changes seen in CP and at least four studies have shown that gallstones can produce changes of CP as defined by the Cambridge or the Atkins classification. All etiologies of CP finally lead to fibrosis, whether it is alcoholic, tropical, idiopathic, or hereditary. The final effect of the injury remains the same. In Western countries alcohol accounts for 70% to 90% of cases of CP, and the risk increases logarithmically with the increase in alcohol intake. But there is no assured value below which CP does not occur, and at what level the injury begins is not established. A study published from the Mayo Clinic showed that even as low as 50 gm a day can lead to CP. But in most patients you require at least 5 years of intake exceeding 150 gm a day and the duration is usually 15 years for males while females take 20 years to develop the disease. However it remains unclear why only 5%–15% of all healthy alcoholics develop CP? If alcohol was the sole reason everybody consuming more than 150 gm would have developed it, therefore cofactors are probably important and CP is probably a multifactorial disease. A diet rich in fat and protein and relative deficiency of antioxidants and trace elements have been reported to play an important role. Also some genetic factors may lead to precipitation and progression of the disease. Smoking appears to predispose to the rapid development of pancreatic calcification in patients with alcoholic pancreatitis. It remains to be proven till date whether and how important a role genes play. While there are some studies that show they are important, it still remains to be proven whether these genetic mutations are important in alcoholic pancreatitis as opposed to patients with idiopathic or hereditary pancreatitis, where they have been found to have a definite role.

36.3.1 Pathophysiology The pathophysiology of alcoholic CP is important but incompletely understood. The first hypothesis is the ductal obstruction hypothesis. It is postulated that chronic alcohol ingestion leads to secretion of pancreatic juice which is rich in protein and low in volume and bicarbonates. This leads to the formation of protein precipitates. Even in early alcoholic CP these protein plugs, without calcification, are seen to be present in small and large ducts. As the precipitate obstructs the smaller ductules there is damage to the ducts and the parenchyma upstream of the obstruction. These plugs may later calcify forming stones, which further cause obstruction and damage to the pancreas. The ductal stones are rich in calcium carbonate and are found in alcoholic CP, tropical CP, hereditary and idiopathic pancreatitis. Lithostathine is a protein secreted in the pancreatic juice and is a potent inhibitor of precipitation of calcium carbonate, but this protein has been found to be lower as well as higher in patients with CP. That is the paradox. The groups who have found a lower value of this protein feel that this protein stops precipitation of calcium carbonate. Since the levels are low in patients with CP, calcium carbonate precipitates and leads to calcification of the protein plug resulting in stone formation. On the other hand those who have found a higher value of this protein postulate that this is converted by the enzymes into lithostathine S1 which itself acts as a protein plug precipitating in the ductules. Later when the values go down it gets calcified. So, it is a controversial issue, whether you have higher or lower levels of lithostathine there is always an explanation. That cannot be true. Another protein known as the GP2 protein. This protein is secreted with the enzymes once a meal is ingested and is analogous to the Tamm-Horsfall protein which gives rise to the hyaline casts in the urinary system.

Tropical Hepatogastroenterology

ETIOPATHOGENESIS AND PATHOLOGY

Hypersecretion of this protein results in its deposition which gets calcified. It is well known that pancreatic stones have a major component because of GP2 proteins. In summary of the ductal obstruction theory, the effect of alcohol on the acinar and pancreatic ductal cells appears to favor the formation of protein precipitates and subsequently they get calcified and form stones. These changes, however, also seen in tropical calcific pancreatitis and idiopathic and hereditary pancreatitis also have calcification. Therefore it is not an exclusive theory for CP because of alcohol. It is not clear whether these ductal stones and the protein precipitates cause pancreatic injury or they are merely a marker of underlying pathophysiological phenomena. The second hypothesis is the toxic metabolic injury hypothesis. It is felt that alcohol or one of its metabolites, most likely acetaldehyde, is injurious to the pancreas. There is increased membrane lipid peroxidation and this is a marker of oxidative stress and free radical production. This is well seen in animal models of CP as well as in patients with alcoholic CP. Alcohol may also lead to abnormalities in the acinar cell secretion and function with increased secretion of trypsinogen and decreased secretion of trypsin inhibitors, resulting in the zymogens getting converted into active enzymes within the acini leading to damage. Alcohol and its metabolites, especially acetaldehyde are also known to stimulate the pancreatic stellate cells resulting in increased secretion of extracellular matrix and fibrosis. Repeated attacks of acute pancreatitis probably result in CP because of fibrosis and residual injury.[13] Another theory is the necrosis fibrosis hypothesis. A point that favors this hypothesis is that there are some studies that have found that there is more frequent development of CP in patients with severe and frequent attacks of acute pancreatitis.

Part VIII / Pancreas

569

Some say that about 70% to 90% of these patients have this sequence of events. But there are some studies that have found that there is evidence of CP in patients who have had the first attack of acute alcoholic pancreatitis.[14] Gene mutation is also implicated in the etiology of alcoholic CP, but gene mutations are well known to occur in hereditary and idiopathic pancreatitis. These are the cystic fibrosis transmembrane conductor regulator genes (CFTR). These genes lead to a mutant trypsin that is not suppressed by the trypsin inhibitors. Again this leads to acute pancreatitis, necrosis, fibrosis, and finally CP. Spink 1 mutation has been found in 5.8% these patients as compared to 1% in alcoholics without CP.[15] In the future we will probably identify genes which are involved in stellate cell activation and cause fibrosis. The stellate cells once activated secrete extracellular matrix which is associated with fibrosis in response to alcohol and its metabolites like acetaldehyde. The gene gets activated with some mechanism by several significant pathways of mitogen activated protein kinase that play the role in upregulating the alpha 1 procollagen gene in the stellate cell. Inhibiting stellate cells activation in vivo may inhibit or reverse the fibrosis and decrease the complications of CP like diabetes mellitus, malabsorption, calcification and pain. It has been found in rats that lovastatin, which is a HMG CoA enzyme reductase, causes a decreased stellate cells activation. So, experimental studies have already shown that this works, and probably this may become a novel therapy in treatment of CP, where one can not only stop the damage but probably can also reverse it.[16]

36.3.2 Pathophysiology of Tropical Chronic Pancreatitis (TCP) There is a lot of confusion regarding TCP. The patients with CP commonly seen in Northern India

570

Chapter 36 / CHRONIC PANCREATITIS

are usually older, have calcification in smaller ducts also, have late complications infrequently and hardly develop cancer of the pancreas. It is probably wrong to label them as TCP. TCP is a disease of young persons. Ninety percent of the patients develop the disease by the age of 40 years. They have abdominal pain, severe malnutrition, and exocrine and endocrine insufficiency, while steatorrhea is rare. Endocrine insufficiency is always a consequence of TCP and large calculi are found in more than 90% of the patients. The pathogenesis of tropical CP is unclear. Malnutrition is implicated because TCP is found amongst the poor and in developing countries. There is evidence of protein calorie malnutrition in many of the patients, but it can be the effect rather than the cause of the disease, because in Kwashiorkor, which has severe protein calorie malnutrition, TCP is rarely seen. Also, while malnutrition occurs in many parts of the world like in Ethiopia, one does not find TCP and rarely very affluent families develop this disease. The second hypothesis is the cassava cyanogen toxicity theory. This was proposed because TCP is confined to geographical locations in Kerala where cassava consumption is high. Cyanogen toxicity was thought to play a role because cassava intake, malnutrition and antioxidant toxicity aggravate the problem and leads to the disease. Cassava contains the cyanogenic glycosides linamarin and lotaustralin, and these are detoxified in the body by conversion to thiocyanates. Cyanide is poisonous but thiocyanate is not. And this conversion requires sulfur, which is given by the amino acids methionine and cysteine. Because of malnutrition, there is deficiency of the amino acids, and the resultant lack of detoxification leads to cyanogen toxicity. However, in South Africa and many parts of India where cassava intake is zero, the disease is still found.

It is known that low and high fat intake predispose to the development of alcoholic CP. So, probably a low intake in these regions may be favoring development of CP. It has been observed that monkeys fed a high carbohydrate low protein diets have a similar effect. Micronutrient deficiency and oxidative stress are also implicated in the development of TCP. Familial and genetic factors may also play a role as a familial aggregation has been observed.[6, 17]

36.3.3 Pathology of Chronic Pancreatitis Since the earliest descriptions of CP various histological studies have revealed that one of the important features in CP, in addition to inflammation, is the presence of fibrosis. Most of the definitions of CP till date, in addition to the other clinical factors have indicated that the inflammation and other changes are irreversible. But recent studies show that in the early stages of CP the pancreas may be actually normal. There have been various classifications of CP. One simple way is to classify it histologically, as to whether it is calcifying or noncalcifying. By calcifying we mean calculi within the duct and this would include 3 conditions–hereditary, alcoholic, and tropical. The rest are predominantly noncalcifying, i.e., the ducts do not have calculi. Histological features The histological features are similar in both except that in the noncalcifying, the calcification is very minimal and there are no calculi within the duct. Therefore the ductal damage is less severe in the noncalcifying forms of CP. In CP, the characteristic feature is loss of acini and the ducts, and the replacement by fibrosis and inflammation. Initially, there is loss of acini while some ducts remain, some proliferate, perhaps because of the stellate cells that are present in the ducts. The islets remain intact initially and are

Tropical Hepatogastroenterology

CLINICAL MANIFESTATIONS

perhaps the last to be destroyed. Finally, there is a mass of fibrous tissue, which actually infiltrates into fat, and gives the appearance of a malignancy. The ductal epithelium gets damaged in most of the calcific forms of CP. It is ulcerated, the epithelium may be thinned out and there may be squamous metaplasia. The end result in some cases may only be lymphocytes surrounding a few surviving ducts, and the remaining tissue is just fibrotic. Recent studies have shown that in CP, there is hypertrophy of the nerves with lymphocytic infiltration around them. Also, there is an increased secretion of neurogenic peptides including substance P which may be responsible for the severe pain that is seen in CP.[18–20]

36.3.4 Molecular Events The pathogenesis of pancreatitis rests on two theories–one is the activation of trypsinogen to trypsin within the acinus or in the duct and second is the blockage of the duct. The inflammation that is seen in the pancreas induces the production of cytokines of which the most important are NF-kappa B. This controls the transcription of inflammatory genes. It inhibits apoptosis, stimulates nitric oxide and cyclo-oxygenase or Cox 2. Cyclo-oxygenase 2 is important in the metabolism of the arachidonic acid pathway.[21] Spink 1 The pancreas normally secretes trypsinogen and this, by the action of enterokinase, is converted to trypsin. In addition, the pancreas secretes other substances that prevent the activation of trypsinogen. The most important is the pancreatic secretory trypsin inhibitor or PST 1. This is also known as ‘serine proteinase inhibitor – Kazal type 1’, that is, SPINK 1. This prevents the activation of trypsin further or it deactivates trypsin if, by chance, the trypsinogen is activated to trypsin in the acini or the ducts. There is also

Part VIII / Pancreas

571

an important receptor called ‘protease activated receptor (PAR 2)’. If trypsin forms within the acini or in the duct, it attaches the PAR 2 receptor and because of this attachment, there is further activation of trypsinogen to trypsin. Therefore, the PAR 2 receptor is important in further activation of trypsinogen to trypsin if, by chance, there is a conversion of trypsinogen to trypsin in the ducts or the acini. If trypsin forms within the acini or the ductal system then SPINK 1 gets attached to the trypsin so that the trypsin gets inactivated. However, if some trypsin gets attached to the PAR 2 receptor it will result in further activation of trypsinogen to trypsin within the ducts or the acini. SPINK 2 gets attached to the other PAR 2 receptors blocking this pathway of further activation. Therefore this 56 amino acid structure is central to the blockage of this pathway of trypsinogen activation in the acini and duct. Normally there is a lot of PST 1 or SPINK 1 to inactivate trypsin. When there is an inappropriate activation of trypsinogen to trypsin in the ductal system, whatever the reason, even in the normal individual it will result in pancreatitis. On the other hand, if SPINK 1 is reduced or defective, then even with mild stimulation, the result will be the development of pancreatitis.[22, 23]

36.4 CLINICAL MANIFESTATIONS Geeverghese gave the classical description of CP and whenever one refers to chronic tropical calcifying pancreatitis, this is the description which comes to mind.[12] The study by Geeverghese was a hospital-based study which is quoted worldwide and describes CP as a serious illness with a male predominance. It typically starts in childhood and early adolescence, with the major clinical features being pain, insulin dependent diabetes mellitus, steatorrhea and pancreatic calcification in almost all patients. However, Balaji et al.,

572

Chapter 36 / CHRONIC PANCREATITIS

at the All India Institute of Medical Sciences, in a community based survey involving about 28,573 patients found that actually there was a female predominance in the community survey.[9] The diabetes was mild unlike the insulin-resistant diabetes in early childhood reported by Geeverghese et al. Also the mean age at onset was later. A major clinical feature of chronic calcific pancreatitis in India is abdominal pain. This leads to poor intake, weight loss and malnutrition resulting in a poor quality of life, loss of social function and finally addiction to narcotic analgesics. Chronic pain is incidentally the most important and the most relevant reason for subjecting these patients to surgery. Abdominal pain in CP has no characteristic diagnostic pattern. It is typically located in the epigastrium, radiating to the back and may be boring, deep or penetrating in character, and is sometimes associated with nausea and vomiting. Also, it is typically relieved on bending forward, is often nocturnal and ingestion of food aggravates the pain. The natural history of pain in CP is variable and incompletely understood. It is initially episodic but later becomes continuous. Fifteen percent of patients may be totally asymptomatic and may not have pain at all, but once pain develops it can, over a period of time, change in character, intensity and pattern. Unfortunately, there is no way to predict the pattern of pain of a given individual, but given the longitudinal follow-up of most of these patients, 50%–90% of all patients with CP will ultimately develop pain. Reports have suggested that abdominal pain in CP decreases with the passage of time, the so called the burn out effect. It was postulated that his may be related to the diffuse pancreatic calcification or oncoming endocrine and exocrine deficiency. But a recent longitudinal follow-up study has clearly shown that in spite of 10 years

of follow-up 60% of the patients continue to have significant pain. Probably the phenomenon of burn out is a myth.[1, 24, 25]

36.4.1 Steatorrhea Steatorrhea and weight loss occur only when the pancreatic secretions fall to less than 10%. It primarily occurs whenever there is either complete destruction of the acinar parenchyma or significant ductal blockage. Typically these patients have foul-smelling stools, 3 to 4 per day. Patients with pancreatic steatorrhea do not have cramps, and do not complain of excessive gas, the reason being the fact that carbohydrate metabolism is well preserved in CP as against the fat metabolism which is most commonly affected. Typically there may be more than 15 gm of fat per day in the stool when the patient is on a standard diet. Weight loss is seen and reported in almost all studies of CP. It is basically the effect of maldigestion and the loss of appetite which typically occurs at a time when the patient has significant pain. Whenever the weight loss is out of proportion to the loss of appetite, one must consider the development of an underlying malignancy.[26]

36.4.2 Diabetes Mellitus Diabetes mellitus, after pain and steatorrhea, is the third most cardinal manifestation of CP. It is the consequence of the long-standing pancreatitis as islets seem to be relatively resistant to destruction in CP. Patients with pancreatic diabetes were known to have brittle diabetes, the reason being that they have loss of alpha and beta cells. That, then, is the difference between pancreatic diabetes and juvenile onset diabetes. These patients do not have the compensatory glucagon release in response to hypoglycemia and hence, they are very prone to develop ketosis as well as hypoglycemia.[27]

Tropical Hepatogastroenterology

DIAGNOSIS OF CP

36.4.3 Cancer

36.5 DIAGNOSIS OF CP

Malignancy in CP has been documented in both prospective and retrospective studies. The presence of a proteinaceous plug in the pancreas cannot lead to development of malignancy. It is more likely to be related to chronic inflammation. Pain especially continuous in nature, weight loss and diabetes are more prominent features when a malignancy develops in CP, as against obstructive jaundice which is a cardinal symptom of pancreatic malignancy developing de novo. Patients who develop malignancy in CP are more likely to have the tumor in the body and tail region rather than the head. Once a malignancy develops, as is reported in about 2% to 6.8% of the patients with CP in studies from south India, the median survival is 11 months in spite of resection and chemotherapy. This indicates that these patients have a very poor outcome in spite of the therapy.[9, 26]

36.5.1 Pancreatic Function Tests

36.4.4 Chronic Pancreatitis in the West and in India Two-thirds of the Indian patients with CP are nonalcoholics. The disease predominantly affects young males. In fact, some reports from the south show that the mean age at presentation was 12.5 years. However, in a recent report from India the mean age of presentation was 38 years which was the same as published from the west. The basic difference is that CP not related to alcohol tends to present almost 10 years earlier than CP due to alcohol. The incidence of abdominal pain is almost the same as reported from the west. While diabetes mellitus is reported in about 23% of patients in the west with alcoholic CP, the figure is higher in India and is probably a function of duration of the disease.[12] The incidence of steatorrhea in our patients is similar to that reported from the west.

Part VIII / Pancreas

573

What, if any, is the role of laboratory tests in the diagnosis of CP? This was a common question in early 80s but for the last 10 years, this question has not appeared, and that possibly shows its value. The tests of pancreatic function can be the tests of structural abnormalities and tests of functional abnormalities. The tests of functional abnormalities can be the tests for endocrine function, which have never been used for diagnosis of CP. Tests of exocrine function, which may be direct stimulation tests and indirect tests, are of several types and include the Lunch test meal, fecal fat or Sudan III staining which is semiquantitative, chymotrypsin or elastase test in the stool, fluorescein dilaurate test, serum trypsinogen tests, and other tests like breath tests. None of them is very effective in making a diagnosis. Malabsorption occurs only when the functional capacity is reduced to 5% to 10% of normal, and these tests will become abnormal generally when a large amount of functional reserve has been lost.[28, 29] Is there a gold standard for the diagnosis of CP? The sensitivity and specificity of any test can only be measured if there is a gold standard. In case of CP, this gold standard is histology. However, the histological changes are not uniform and a small piece of tissue may not be adequate to make or refute a diagnosis of CP. Also, it is not possible to have tissue available to make a diagnosis in most cases. Can there be a substitute gold standard? This, possibly in case of CP, is adequate clinical follow-up. Patients with unclear tests of pancreatic function have not been adequately followed up for a long enough period to see whether or not these patients develop CP. But, in addition to specificity and sensitivity it is important for a clinician to consider the availability of a test prior to making

574

Chapter 36 / CHRONIC PANCREATITIS

it a gold standard for the diagnosis of any disease. The standard direct test is one which is a virtual gold standard.[30]

36.5.2 Direct Tests The tests are based on the principle that maximum volume bicarbonate and enzyme secretion are related to the functional mass of the pancreas. It is not true for the indirect test where a direct correlation is not there. The secretion is stimulated by constant intravenous infusion of two agents simultaneously, that is CCK and secretin. However, the problem begins after this. Both the stomach and duodenum have to be intubated. The stomach is intubated to remove the gastric secretions because they interfere with the ability to measure the volume and bicarbonate secretion from the pancreas. Low pH may also alter the pancreatic enzyme activity. A duodenal tube is required for two reasons. One is for infusion of a nonabsorbable marker such as cobalamin or polyethylene glycol, which allows quantitation of secretions without the needs of complete aspiration of secretions. The second reason is for the collection of pancreatic secretion for testing. One measures the volume bicarbonate and various enzymes in the secretions. The measurements are corrected for percentage of recovery. The test is 83% sensitive and 89% specific but false positive tests may occur in some patients of celiac sprue and diabetes mellitus. However, the relevant question is that, with so many of problems do we need these direct tests? These tests are performed hardly at any center in India. In most comparisons with pancreatography, direct hormonal stimulus tests appear to be slightly more sensitive for diagnosis of pancreatitis. The values of sensitivities range from 74% to 97% and specificity from 80 to 90%.[31–35] One must also realize abnormal function tests alone are not diagnostic for CP. In the Mayo Clinic

and the Lunenberg Clinic criteria scoring system the function tests do not appear at all. An abnormal secretin test does not meet the diagnostic criteria for CP in the Japan Pancreas Society criteria. In each of these diagnostic systems, CP is diagnosed by a single diagnostic imaging study, that is either typical CT scan or ERCP. In fact, now pancreatitis is being classified in 2 groups–one is a big duct disease where there is no role for the laboratory function test, the diagnosis is based only on imaging. These are the patients who have dilatation of pancreatic duct visible either on ultrasound, CT, or ERP. Functional abnormalities would be present and will be picked up in any indirect test. It is often due to alcohol abuse and the therapy focuses mainly on decompressing the dilated duct. In small duct disease there is no role for indirect tests. This is the only group where direct tests may have some value if they are available. There is a normal or near normal pancreatic duct, exocrine or endocrine insufficiency is very uncommon, the disease is most frequently idiopathic and the therapy focuses mainly on medical rather than surgical modalities.

36.5.3 Imaging in Chronic Pancreatitis Essentially, CP is a fibrotic disease and that is what we try to image. MR and MRCP are probably the best ways to look at ductal changes noninvasively. However, if one is looking for complications of CP like cysts and pseudocysts, ultrasound is the best modality, while for calcifications plain X-rays (Fig. 36.1), ultrasound and CT scan are useful. The problem comes when there are morphological changes within the gland; what should be done then? So far, CT scans seem to be the best, but MRI is probably as good or even better (Fig. 36.2). There are two unusual entities relevant from the imaging point of view. The first is autoimmune pancreatitis in which focal or diffuse pancreatic

Tropical Hepatogastroenterology

DIAGNOSIS OF CP

FIGURE 36.1 Plain X-ray of the pancreas showing calcification (arrows).

FIGURE 36.2 MR pancreatography showing a dilated, tortuous pancreatic duct (arrow) in a patient with chronic pancreatitis.

enlargement is seen and surprisingly, there is not much pancreatic atrophy or ductal dilatation. The peripancreatic region is always well defined, the

Part VIII / Pancreas

575

peripancreatic fat is usually always very well seen by whatever modality one chooses there is always presence of a peripancreatic rim of enhancement. Irrespective of the modality used, these features are seen and help make a diagnosis of autoimmune pancreatitis. The second is groove pancreatitis. It is a situation where one suspects CP clinically, and on imaging, there are changes which occur in the so-called groove, the groove between the duodenum and the common bile duct and the head of pancreas, while the rest of the pancreas is virtually normal. It is important to realize that this is a distinct entity as far as imaging is concerned. The pancreatic parenchyma is usually well preserved, and a sheet-like mass is seen in the groove. This is fibrous tissue and therefore does not enhance in the early arterial phase but enhances late. Routine findings in CP On CT scan pancreatic calcification, dilatation of the pancreatic duct and its side branches, and focal or diffuse atrophy may be observed. Other findings include focal pancreatic enlargement, biliary dilatation, and alteration in the peripancreatic fat or fascia, which is very different than that in autoimmune pancreatitis. Also, the complications of pancreatitis such as pseudocysts, pseudoaneurysms (Fig. 36.3), and thrombosis of adjacent blood vessels can be detected on CT scan. All these findings can be picked up on MRI also. There is no doubt in the fact that MRI with the current sequences is definitely as sensitive, in picking up all the changes of CP as CT scan. It is often debated whether there is a way to diagnose early chronic pancreatitis where the ductal changes are not yet visualized. Is there any way to diagnose CP on the enhancement pattern of the pancreatic parenchyma? Authors have attempted to look at the arterial signal intensity and the enhancement pattern at the peak arterial enhancement, and to see what the ratio is. If the arterial signal intensity is less than 1.7, there is high chance of CP. Again, this probably reflects that fibrosis is

576

Chapter 36 / CHRONIC PANCREATITIS

secretin would have shown just a normal pancreatogram. Authors have also looked at the fluid output into the duodenum in pancreatitis. On injection of secretin the fluid, which comes into the duodenum, is studied for density and the rate of rise of the density. This is analyzed to make a cutoff point that if the density in the duodenum, after injection of secretin, is beyond a certain level, then probably the pancreatic function is good, otherwise it is not so good and would support a diagnosis of CP. There is no standardization as yet, but is one of the areas of research as far as imaging in CP is concerned.[37, 39] FIGURE 36.3 A CT angiogram showing a pseudoaneurysm (AN) of the splenic artery in a patient with chronic pancreatitis (HA – hepatic artery, LRA and RRA – left and right renal arteries, SPL A – splenic artery). (Courtesy: Dr PK Mishra.)

occurring, and therefore while there will be no early arterial filling late arterial filling will take place and the arterial ratio will fall. However, this only has a sensitivity and specificity of 79% and 75% respectively.[36–38]

36.5.5 Endoscopic Ultrasound (EUS) (Fig. 36.4) EUS effectively looks at the same morphological changes. The changes in the ducts such as an irregular duct pattern, increasing duct caliber of the side branches, presence of dilated side branches, calculi, plugs, strictures and of course main branch disruption are picked up as are the parenchymal changes. However assessment of early changes in CP on endoscopic ultrasound is highly operator dependent. In a patient who was suspected to have CP, one can have a clear visualization of the pancreatic head and body, and a patient with

36.5.4 Secretin Studies In routine MRI one looks at the pancreatic tissue and tries to make a diagnosis. Maybe the ductal changes are there, but the MRI is not able to resolve them. Secretin has been used to increase secretion. All MRCPs are heavily weighted T2 sequences, based on the presence of fluid in the ductal systems, which one tries to image. By injecting secretin one can increase the fluid in the ducts and distend even the smaller side branches. This may help see the early changes. There is a progressive increase in signal intensity sometimes in the parenchyma and in the acinar filling in a patient who, without

FIGURE 36.4 Endoscopic ultrasound in a patient with chronic pancreatitis showing a dilated pancreatic duct (PD) on the left and a dilated common bile duct (CBD) on the right. (Courtesy: Dr SS Baijal.)

Tropical Hepatogastroenterology

DIAGNOSIS OF CP

early CP will show a honeycombing pattern with small cystic areas and some hyperechoic foci. This may be observed in a patient with recurring episodes of pain abdomen but no clear diagnosis of CP. The overall sensitivity of EUS is in picking up early chronic pancreatitis is about 85%, but the specificity is low at about 67%. Also EUS provides information about mass lesions and offers an opportunity for tissue sampling. It may pick up an etiological diagnosis of recurrent pancreatitis like small gallstones and may be helpful therapeutically as it can give guidance for drainage of pseudocysts and celiac plexus block. However it is not without pitfalls. It has a low specificity and false positive diagnosis have been made with EUS when done after acute pancreatitis and in elderly patients. Technically, it is a very demanding procedure and the cost of the equipment is high.[40–43]

36.5.6 Endoscopic Retrograde Cholangiopancreaticography (ERCP) In a situation where the entire pancreatic duct is outlined by calculi on a plain x-ray, one does not need any other tests, and an ERCP in such a case is certainly not required. ERCP basically shows up ductal changes in the main pancreatic duct and in the side branches. The changes may be diffuse or local, i.e., when they are confined to less than a third of the gland. When only the side branches are involved the CP is termed mild but when the main duct is involved the CP is moderate or severe. This implies marked or mild changes of CP and not mild pancreatitis or moderate pancreatitis. In a normal ERCP film the main duct is seen very well. If it is slightly dilated in the body region and the side branches seem slightly distended, but the ERCP looks normal otherwise, then there are probably minimal changes in CP. But one cannot be very sure in such a situation as

Part VIII / Pancreas

577

such changes may sometimes be seen in elderly and following acute pancreatitis. However, in a patient with recurrent episodes of pain, if on ERCP ductal dilatation were limited to the head and the uncinate process while the rest of the pancreatic duct is normal, it would be logical to make a diagnosis of localized CP confined to the uncinate process. The sensitivity of ERCP in picking up CP varies from 66% to 89% with a specificity of 89% to 100%. It can probably differentiate between alcoholic and idiopathic CP of tropics, because strictures are seen less often in tropical pancreatitis. In tropical pancreatitis one finds large stones and there is a smooth dilatation of the main duct. Whether these differences are specific is open to question. Another advantage of ERCP is that it gives an opportunity for doing some kind of therapeutic procedures in addition to the diagnosis. This is where ERCP scores over other tests we have discussed such as MRCP or other imaging modalities. If there are strictures or a ductal stone, one can do a sphincterotomy, basketing of the stones, and stenting. If one diagnoses pancreas divisum, therapy can be done in the same sitting in the form of a sphincterotomy of the minor papilla.[41, 44–46] However, there are also many problems with ERCP. There is no correlation with the severity or stage of the disease. There is also no definite correlation with the parenchymal dysfunction (either exocrine or endocrine) and it can result in complications like pancreatitis and sepsis. The incidence of pancreatitis in patients who have preserved parenchyma is more, and there is no additional information which we gain by a diagnostic ERCP in a patient with advanced CP. So, finally which test should be ordered in a given patient? In advanced CP there is no role for a diagnostic ERCP and imaging studies like ultrasound and CT and plain X-ray of

578

Chapter 36 / CHRONIC PANCREATITIS

the abdomen will pick up the diagnosis. Also if one does an ERCP in such patients it can lead to complications. In early CP an EUS as a first test, if it is available, is advisable; otherwise an ERCP or secretin MRCP, if available, should be done. 36.5.6.1 A practical approach to diagnosis in India

The first step should be a thorough history, which should include a history of pain suggestive of CP, history of alcohol and a family history of pancreatitis. One must also look for a history of diabetes, renal stones and steatorrhea. The next step after the history should be an X-ray of the abdomen. This is an important investigation in CP because it is inexpensive, riskfree, widely available, and can pick up calcification in different types of CP. The next imaging investigation should be an abdominal ultrasound, which again is freely available and can detect calcifications and ductal changes in the pancreas. It has a high sensitivity and specificity, but has problems whenever there is abdominal gas or artifacts. It is advisable to do a CT scan in these patients as well, because that would not only detect the abnormalities of the pancreas but also the adjoining organs, which tend to get affected. CT has a very high sensitivity and specificity, and there is consistency and reproducibility. The only disadvantage is the ionizing radiation, and it is more expensive. By and large the diagnosis would be made once you have these 3 modalities on a patient with CP. ERCP has a role in situations where a therapeutic procedure is simultaneously required, or when the ultrasound and CT scan does not show any evidence of CP and there is a suspicion of focal pancreatitis. Endoscopic ultrasound shown to be very useful in such a situation but is limited by the problem of availability and cost.

36.6 THE MECHANISM OF PAIN IN CHRONIC PANCREATITIS The pathway for transmission of pain from the pancreas is via the sympathetic fibers traveling along the splenic, hepatic and superior mesenteric arteries. The splanchnic nerves (greater and lesser) then transit the impulses to segments 5–10 of the spinal cord. The autonomic innervation of the upper abdominal viscera is primarily via the greater splanchnic nerve and this is the target for neurectomy in patients with intractable pain due to CP.

36.6.1 Neural Mechanisms Dense fibrosis, both pancreatic and peripancreatic, is a hallmark of the pathology of CP.[47] It is suggested that the mechanism for pain may be due to the entrapment of the sensory fibers in this fibrotic tissue. This has been refuted by others.[48] Another suggestion is that CP is associated with an increase in nerve diameter with a concomitant decrease in the area served by an individual nerve. Inflammatory cell infiltration with simultaneous ultrastructural changes of the nerves has been observed in patients with CP, and the possibility of loss of barrier function of the neural sheath has been suggested.[48] Keith et al.[49] noted the presence of eosinophilic infiltrates in the neural tissue and postulated the role of inflammatory mediators in causing the pain of CP. An increase in the levels of growth associated protein (GAP43), a marker of neuroplasticity, and of the sensory neurotransmitters substance P and calcitonin gene related peptide is seen in the enlarged nerves and intrinsic neurons of CP.[50, 51] This is further supported by the evidence that Neurokinin 1 receptor (NK-1R) expression is increased in CP.[52] However no co-relation between the severity of pain and perineural fibrosis or inflammation has been observed. The hypothesis that neural inflammation

Tropical Hepatogastroenterology

THE MECHANISM OF PAIN IN CHRONIC PANCREATITIS

is an important mechanism in the pathogenesis of pain in CP forms the basis for propagating resection as the preferred surgical treatment for CP.

36.6.2 Ductal and Parenchymal Pressures Increase in pancreatic interstitial and ductal pressure is certainly a major factor in the genesis of pain in CP. It has been observed that the intraductal pressures in patients with pancreatic disease are in the range of 18–48 mmHg as against 10– 16 mmHg in patients with a normal pancreas. Also, parenchymal pressure in patients with CP is higher (17–21 mmHg as against 3–11 mmHg in controls).[53–55] Dilatation of the pancreatic duct with an associated focal stenosis, stone occlusion or an increased intracystic pressure in a pseudocyst is usually but not always associated with pain in CP. Painless course with the same anatomic changes have been noted.[56, 57] In further proof of an association of increased pressure with pain, Ebbehoj et al.[58, 59] have demonstrated a fall in pancreatic tissue pressures after pancreaticojejunostomy or cystojejunostomy, which was also shown to be associated with pain relief in 12 of their 14 patients. Even in the background of a large volume of data the exact mechanism by which the increased pressures (ductal and interstitial) cause pain remains unresolved. While the above two are the main mechanisms postulated for the occurrence of pain in CP, additional factors that are thought to contribute are • Formation of pancreatic pseudocysts and necrosis of pancreatic tissue • Pain resulting from complications of CP (Table 36.2) • Pancreatic ischemia resulting from a decrease in pancreatic blood flow and local changes in parenchymal pH

Part VIII / Pancreas

579

TABLE fy 36.2 Anatomical abnormalities associated with pain in CP Intrapancreatic and extrapancreatic abnormalities associated with pain in chronic pancreatitis Intrapancreatic abnormalities • Pancreatic duct strictures (obstruction) • Pancreatic duct stones (obstruction) • Large pseudocysts (intracystic pressure, compression) • Pseudocysts with vascular involvement) (‘‘Hemosuccus pancreaticus’’) • Pancreatic abscess Extrapancreatic abnormalities • Ascites • Bile duct stenosis (cholestasis) • Duodenal stenosis • Maldigestion (bacterial overgrowth, meteorism)

• Persistence of alcohol abuse • Narcotic addiction and psychological factors

36.6.3 Natural Course of Pain in Chronic Pancreatitis Ninety percent of patients with alcoholic CP have pain as a prominent symptom. Amman et al.[1, 14, 24] have reported that 85% of their 145 patients had a lasting and spontaneous pain relief at a mean follow-up of 4.5 years. While the most severe pain is experienced in the early stages of the disease, sometimes even prior to clinical documentation of the disease, in the advanced stages the pain almost vanishes completely unless local complications occur.[1] It is important to rule out a nonpancreatic cause (such as peptic ulcer, cholestasis secondary to bile duct obstruction, narcotic addiction, etc.) of pain in patients who experience severe pain in advanced stages of alcoholic CP.

580

Chapter 36 / CHRONIC PANCREATITIS

It has been documented that abstinence from alcohol not only slows the progression of the disease,[60, 61] the pain severity decreases in almost 50% of patients.[62, 63]

36.6.4 Nonsurgical Treatment of Pain in CP 36.6.4.1 Pancreatic enzyme supplements

Normally, the presence of proteases in the duodenal lumen is associated with a negative feedback to the release of cholecystokinin. While it is accepted that a feedback mechanism exists in humans it is unresolved if this is active in true physiological conditions and not just experimental conditions.[64] It has been suggested that the exocrine deficiency in CP leads to an increased cholecystokinin mediated stimulation of the pancreas.[65] Therefore the administration of pancreatic enzymes, antagonists to cholecystokinin receptors or somatostatin should theoretically result in pain relief by preventing this over stimulation of the pancreas, lowering intraductal pressure and bringing the pancreas to rest.[66] However, this may me an oversimplification of the situation. Several studies have looked at pain relief resulting from supplementation of pancreatic enzyme supplements.[67–69] Slaff et al.[69] observed a 75% reduction in pain in patients with mild to moderate disease. They observed that young women with idiopathic CP responded the best, whereas there was no response in patients with severe disease and steatorrhea. In another study Haalgreen et al.[70] did not show benefit in pain relief with the use of pancrease in the form of microspheres. They attributed the failure to the release of active enzyme beyond the duodenum, which would not exert a negative feedback on pancreatic stimulation. Larger placebo

controlled studies[71, 72] have failed to show a significant improvement in pain control with the use of pancreatic enzyme supplements. Toskers et al.[73] in their study used octreotide in a dose of 200 micrograms given three times a day as a subcutaneous injection. Sixty-five percent of patients showed an over 25% improvement in pain while 35% of them also showed improvement with placebo. Thus there are several problems with the currently available data such as: • Use of various different enzyme preparations • High rates of response with placebo • The possibility of destruction of exogenous enzyme by gastric acid and/or pancreatic proteases • Lack of efficacy of enteric coated preparations In the absence of convincing data it is at present recommended that a short period of trial (2–3 months) may be given during which the patient must record his pain on a standard scale (such as the visual analogue scale). If there is no improvement in pain the enzyme supplements should be stopped.[6] 36.6.4.2 Nerve blocks in the treatment of pain in CP

Nerve blocks are simple and highly effective in providing pain relief in patients with pancreatic carcinoma. While they have been used in patients with CP,[74] the results are variable. The reported success rates vary from 50% to 100% but more importantly, the pain relief is short lived, lasting only a few months.[75, 76] Principles The aim is to interrupt the afferent sympathetic fibers that carry pain impulses from the pancreas to the brain. Injection of the drug behind the diaphragmatic crura results in ablation of the splanchnic nerves whereas injection in front

Tropical Hepatogastroenterology

SURGERY IN CP

581

Overall the results of nerve blocks in CP have been disappointing in contrast to the relatively promising results in pancreatic carcinoma, probably due to the following reasons:

FIGURE 36.5 X-rays showing the positioning of the needles for a percutaneous nerve block. (Courtesy: Dr Ashok Saxena.)

FIGURE 36.6 Thoracoscopic nerve block. The splanchnic nerve is visible under the parietal pleura and is about to be coagulated. (Courtesy: Dr AK Saha.)

of the crura or close to the celiac trunk ablates the celiac plexus (Fig. 36.5). The procedure involves injection of drugs such as alcohol (40 ml of 25%–50%) or local anaesthetics like lignocaine (15–20 ml of 0.25%) or bupivacaine (15–20 ml of 0.125%) at the level of the L-1 vertebra. The block is performed under radiographic or ultrasound guidance, contrast being injected prior to the drug to assess the site and spread of the drug. Blocks may also be carried out laparoscopically (Fig. 36.6)

Part VIII / Pancreas

• Survival in CP is longer than carcinoma thereby explaining the recurrence in pain after a few months. • Fibrosis results in loss of normal anatomy of the pancreatic and peripancreatic area in CP making diffusion of the injected drug difficult. • It is possible that the lysed sympathetic fibers may regenerate. Leung et al.[76] used a higher concentration of alcohol (75%) in an attempt to achieve better results. However the slightly better results were associated with an increased rate of complications. The complications that may occur following the nerve block procedure include, orthostatic hypotension, diarrhea, intercostal neuritis, root pain and problems with ejaculation. In a study from India. Desai[77] used the epidural injection of blood (10–15 ml) with bupivacaine (0.3 mg) at the T 8–9 or T 9–10 space with an 18/16G needle. They reported pain relief in all of their 12 patients over a period of six months. While encouraging results such as the above study continue to be reported the neuroablative and epidural injection procedures have not been very popular and at present can be recommended only as last resort procedures when other modalities have failed or are not feasible.

36.7 SURGERY IN CP The primary indication for surgery in CP is intractable pain when measures such as abstinence from alcohol, pancreatic enzyme supplements

582

Chapter 36 / CHRONIC PANCREATITIS

and analgesics have failed. Other indications for surgery are related to the secondary effects of the pancreatic inflammation and scarring on the organs in close relation to the pancreas. There may be compression or stricture formation in the distal bile duct or less commonly, the duodenum or the transverse colon. Damage to the pancreatic duct with subsequent leakage of pancreatic juice can present as pancreatic ascites or less frequently, as a pleural effusion. Recurrent pancreatic inflammation can result in a compression of the portal venous system and most frequently results in thrombosis of the splenic vein. Also damage to the blood vessel walls is known to result in the formation of pseudoaneurysms, which can cause massive hemorrhage. The indications for surgery in CP are listed in Table 36.3.

36.7.1 Surgery for Pain in Chronic Pancreatitis Pain is a leading symptom in chronic pancreatitis (CP), less than 10% cases of alcoholic chronic pancreatitis running a painless course.[1, 14, 24] Typically the pain is located in the upper abdomen with radiation to the back and ranges from mild to moderate to severe in intensity. Early in the course of CP, the pain free intervals are usually long. However, as the disease progresses they become shorter and the patient experiences frequent attacks of severe or a constant intractable pain, thus severely compromising the patients quality of life. There are two main theories regarding the genesis of pain in CP, the neural and the ductal/parenchymal pressure theory. These form the basis for the various operative procedures (Table 36.4) recommended for relieving pain in CP and have been discussed in the previous section.

TABLE fy 36.3 Indications for surgery in chronic pancreatitis • • • • • • • • •

Intractable pain Biliary obstruction Duodenal stenosis Colonic stricture Pancreatic duct stenosis Pseudocysts Pancreatic ascites Portal venous compression/thrombosis Pancreatic hemorrhage Suspicion of carcinoma

TABLE fy 36.4 Main operative procedures for the treatment of pain in CP Drainage procedures Lateral pancreaticojejunostomy (DuVal/Puestow/Partington-Rochelle) Frey’s procedure – Coring of the pancreatic head Beger’s procedure – Duodenum preserving pancreatic head resection Resectional procedures Pancreaticoduodenectomy (Whipple’s procedure) Pancreatectomy (distal /total)

36.7.1.1 Pancreaticojejunostomy

The aim of this procedure is to provide an alternative pathway to the pancreatic secretions in an attempt to reduce the pancreatic ductal pressure. Such a procedure was first used by Cattell in 1947[78] when he used a loop of jejunum to bypass the obstructed pancreatic duct in a patient with carcinoma of the pancreas. DuVal procedure In the initial years pancreaticojejunostomy, as applied to patients with CP, was performed by amputating the tail of the pancreas in addition to a splenectomy. The amputated tail was then anastomosed to a roux loop of jejunum to provide drainage to the pancreatic secretions (DuVal procedure). The initial reported results

Tropical Hepatogastroenterology

SURGERY IN CP

were encouraging and the pain was relieved in as many as 80% of patients.[79] The operation however had inherent shortcomings; ductal stenosis in CP is usually due to multiple strictures in the main pancreatic duct. Also, the small size of the pancreatic duct in the region of the tail of pancreas would not permit adequate drainage of pancreatic secretions. It was therefore, not surprising that the pain relief with this procedure was temporary.[80] Puestow I and II In an attempt to overcome the shortcomings of the DuVal procedure, Puestow and Gillesby put forth their modified procedure.[81] Recognizing the importance of multiple strictures in CP, they recommended that the entire main pancreatic duct be unroofed from the tail to the superior mesenteric and portal vein. As in the DuVal procedure the tail of the pancreas was amputated and a splenectomy done. The entire body and the tail of the pancreas was then implanted into the open end of a Roux loop of jejunum. Over time, it was recognized that resection of the pancreatic tail and splenectomy were not necessary for a good result. Partington and Rochelle[82] suggested this in their modification of the Puestow’s operation (Puestow II) and performed a side to side anastomosis with the pancreatic capsule. The stress should not be on a mucosa-to-mucosa anastomosis as this may lead an occlusion of the side branches of the pancreatic duct. This operation has been the basis for current day operations employed for the CP. Principles and technique of pancreaticojejunostomy Delineation of the pancreatic ductal anatomy is an essential step prior to a pancreaticojejunostomy. Traditionally endoscopic retrograde pancreaticography (ERP) has been the modality most commonly employed for this purpose. However, it is neither imperative nor is it always successful. Sharma et al.[83] in their series of 58 patients performed ERP in only 36 (62%)

Part VIII / Pancreas

583

patients. An advantage for which ERP has been recommended, is the possibility of obtaining additional information such as regarding pseudocysts. However, Sharma et al.[83] noted that it was inconclusive in 7 (19%) and had a direct bearing on the operative procedure carried out in only 15 (26%) of their 58 patients. Also, in the seven patients in whom the ERP, and the ductal dilatation was inconclusive, CT scan and USG picked up the ductal dilatation. Noninvasive modalities such as USG and CT scan can thus provide useful information diluting the role for an ERP. Magnetic resonance cholangiopancreaticography (MRCP) also has the advantage of being noninvasive, and provides a good delineation of the pancreatic ductal anatomy. Pancreaticography can also be performed at operation using a needle puncture or a transduodenal cannulation of the papilla of Vater.[84] A dilated ductal system is necessary to make a ductal drainage procedure technically feasible and successful. To achieve the same, most authors agree that the main pancreatic duct should be at least 7–8 mm in size. This size is however not imperative; adequate and successful drainage can be achieved with a ductal diameter of 5 mm.[83] To achieve good drainage the MPD should be opened from the pancreatic tail (1–2 cm from the splenic hilum) to the duct in the head of pancreas and the duct to the uncinate process should be included. The operative procedure entails a complete division of the gastrocolic omentum to provide a complete exposure of the pancreas. It is sometimes possible to feel the dilated pancreatic duct on the anterior surface of the pancreas or it may be identified by needle aspiration of pancreatic juice using a fine needle. Maneuvers such as division of the pancreatic tail or the anterior surface of the pancreas to identify the pancreatic duct are only infrequently required. After identification the duct must be opened along it’s length

584

Chapter 36 / CHRONIC PANCREATITIS

from the tail (1–2 cm from the splenic hilum) to the pancreatic head (to ensure drainage of the duct from the uncinate process). It is important to ensure adequate drainage of pancreatic secretions and all calculi should be meticulously removed. Bleeding vessels may need to be individually controlled, this being facilitated by the fibrosis that is characteristic of CP. After opening the MPD adequately, a Roux loop of jejunum is prepared and anastomosed to the anterior surface of the pancreas along it’s antimesenteric border ensuring that the blind end of the Roux loop lies adjacent to the tail of the pancreas. The anastomoses is performed using a delayed absorbable, interrupted suture. A second layer of interrupted sutures is made with the capsule of the gland if possible. Frey’s procedure (Fig. 36.7)[85] This modification of the lateral pancreatico-jejunostomy is based

FIGURE 36.7 Operative picture of a patient undergoing Frey’s procedure. The gastrocolic omentum has been cut. The stomach (S) is retracted upwards and the colon (C) downwards to expose the pancreas. A little dissection reveals the pancreatic duct (arrowhead), which is divided. The jejunum (J) will be opened and anastomosed to the ductal walls (arrows).

on the argument that when the pancreatic head is thick (> 3–4 cm), the Puestow II procedure may not provide adequate drainage to the pancreatic secretions. In addition to opening the duct in the body and tail of the gland (as in the Puestow II) the operation entails “coring” of the pancreatic head to remove areas of scarring and permit adequate decompression of the pancreatic head. Calculi, retention cysts and necrotic tissue in the head are removed. The bile duct and the superior mesenteric vein need to be protected and ensuring that a rim of 4–5 mm thick pancreatic tissue is left over these structures does this. To protect the bile duct a probe may be passed into the duct. Also, a rim of tissue of similar thickness should be left posteriorly to prevent leakage into the retroperitoneum. A Roux loop of jejunum is then anastomosed to the pancreas as in the Puestow II procedure. Beger’s operation (Fig. 36.8)[86] This operation also intends to provide adequate pain relief when the pancreatic head is replaced by an inflammatory mass. Unlike the Frey’s procedure where the tissue in the pancreatic head is “cored” out, in this operation a formal resection of the pancreatic head is done leaving a rim (about 5 mm) of pancreatic tissue along the C loop of the duodenum. It is recommended that the posterior capsule of the pancreas should be preserved. The residual end of the body of the pancreas is drained into the pancreatic head in an end-to-end fashion. Beger also recommends the drainage of the rim of the cavity resulting from resection of the pancreatic head in a side-to-side fashion with the same Roux loop of jejunum. Passing a metal probe into it through a supraduodenal choledochotomy protects the bile duct. Results of pancreaticojejunostomy The results of pancreaticojejunostomy have been variable (Table 36.5) and are difficult to interpret. Lack of uniformity in the procedures performed,

Tropical Hepatogastroenterology

SURGERY IN CP

585

FIGURE 36.8 Diagrammatic representation of Beger’s procedure. Note the cored-out head.

TABLE fy 36.5 Pain relief after pancreaticojejunostomy Reference

No. of patients

Duration of followup (months)

% Obtaining pain relief 39 35

Excellent Improved Total relief; only transient Excellent (no pain) or good (no narcotics, able to work despite some pain) Complete pain relief, no narcotics Partial relief; occasional narcotics (less than once/twice per week) Pain disappeared Pain alleviated Good; pain eliminated Fair; pain free, minor discomfort, no interference with life Fair, episodic pain needing analgesia but no hospitalization Complete relief Substantial relief Excellent Good

Jordan et al. (1977)

13

58∗ (12–123)

Taylor et al. (1981) Brinton et al. (1984) Warshaw (1985)

18 39 17

60 24–180 42∗ (6–120)

67 77

Surgerman et al. (1986) Sato et al. (1986)

20 4.3

35∗ 109∗

55 30

Bradley (1987)

46

69∗ (10–144)

91 09 28 38 34

Carter personal series (1992)

32

46

Sharma (1998)

58

6–120 (median 63)

Part VIII / Pancreas

45 28 41 38

Definition used

586

Chapter 36 / CHRONIC PANCREATITIS

inadequate follow-up, variation in the methods for the assessment of pain and variable indications for the surgery at different centers are some of the reasons for the same. It is, however, clear that over a period of time the results deteriorate and, patients who fail to abstain from alcohol or have been narcotic addicts are more likely to have recurrence of symptoms. The results of pancreaticojejunostomy may differ in patients with alcoholic pancreatitis as against nonalcoholic calcific pancreatitis. Sato et al.[87] in their report found that over a mean period of 9.1 years 56% of their patients with alcoholic pancreatitis had a good result as against patients with nonalcoholic pancreatitis where a good result was observed in 83% of patients over a similar duration of follow-up. While the immediate results of pancreaticojejunostomy for alcoholic pancreatitis may be good, the results have been observed to deteriorate with longer follow-up and at 5 years only 38%–60% continue to be pain free. However, other authors have found no correlation between the incidence of pain relief and the etiology of CP (alcoholic vs nonalcoholic).[88] Thomas et al.[89] and Sharma et al.[83] reported their results of lateral pancreaticojejunostomy performed exclusively in patients with nonalcoholic calcific pancreatitis. In the former, 77% of patients had good relief of pain at a median follow-up of 28 months while in the later series, 79% of patients had either a good or an excellent result. The operative mortality in most series has been low with 0% mortality also being reported (Table 36.6). The thickened and fibrosed pancreatic tissue holds sutures well allowing for secure anastomoses with the jejunum. However, the presence of splenic vein thrombosis with the resultant left sided portal hypertension can make the procedure troublesome. In the series reported by Sharma et al. operative mortality only occurred in patients

TABLE fy 36.6 Operative mortality after pancreaticojejunostomy Study Leger (1974)[90] White (1979)[91] Howard (1981)[92] Sugarman (1986)[93] Greeenlee (1990)[94] Hakaim (1994)[95] Sharma (1998)[83]

No. of patients

Operative mortality

45 55 42 20 100 50 58

2 (4%) 2 (4%) 1 (2%) 1 (5%) 4 (4%) 0 (0%) 4 (7%)

with portal hypertension due to a combination of blood loss from dissection of vascular adhesions and liver or renal Failure.[83] Frey’s and Beger’s procedures The presence of an inflammatory mass in the head of the pancreas poses a unique problem in about a third of patients with chronic pancreatitis. In this situation partial pancreaticoduodenectomy is the most commonly performed operation. However, this involves an unnecessary resection of the duodenum, distal stomach and the bile duct. Both, the Frey’s and the Beger’s procedure have been described to handle this specific situation, the aim being to provide adequate drainage with removal of cysts, stones and necrotic tissue in the enlarged head. In a series of 141 patients[96] who underwent the Beger’s procedure 77% patients had complete relief of pain. The hospital mortality was 0.7%. Deterioration in glucose metabolism was observed in only 10.1% of patients. Other authors have reported similar good results with the procedure and pain relief with the Beger’s procedure is around 80%.[97] The major argument against the Beger’s procedure has been that the procedure is technically difficult to perform and results in a high morbidity and mortality. However, Beger et al.[98] have reported their experience over 26 years in a recent analysis of 504 patients, 91.3% experiencing good

Tropical Hepatogastroenterology

SURGERY IN CP

and long lasting pain relief with operative mortality of only 0.8%. The authors conclude that in patients of CP with an inflammatory mass in the head of pancreas, DPPHR successfully treats the complications, relieves pain and may have a preventive role in terms of development of carcinoma – late carcinoma in the pancreatic head remnant developed in only 2 of their patients. They suggest that not only can DPPHR be performed successfully with a low morbidity and mortality, it also modifies the natural course of disease in terms of pain status, frequency of acute episodes of CP requiring hospital admission, late mortality and quality of life. Experience with the Frey’s procedure has been limited. As described previously it combines the advantages of a pancreaticojejunostomy with resection of the pancreatic head by “coring” out tissue from the thickened and chronically inflamed head of pancreas.[99] Izbicki et al.[100] compared the results of the two procedures in a randomized controlled trial, 22 patients underwent the Frey’s procedure while 20 patients underwent the Beger’s procedure. While there was no operative mortality in either group the morbidity was higher in the former (20% Beger, 9% Frey). In both groups, complications from adjacent organs were resolved definitely (90% Beger, 100% Frey) and the decrease in pain score was also similar (95% Beger, 94% Frey). Neither procedure led to a further deterioration in endocrine or exocrine function. 36.7.1.2 Pancreatectomy Distal pancreatectomy This may be subdivided into a less than 80% or an 80%–95% pancreatectomy. In the former the resection is limited to the tail, body, neck and only a small portion of the head of the gland. In the 80%–95% resection a

Part VIII / Pancreas

587

major portion of the head as well as the uncinate process is excised. Resection of the pancreatic tail constituted an important part of the drainage operations described by DuVal[80] and Puestow and Gillesby.[81] However, the aim was to facilitate the drainage operation rather than to resect diseased pancreatic tissue. One of the earliest reports of pancreatic resection came from Eliason and Welty,[101] who reported good pain relief in two of their three patients who underwent resection of the distal two-thirds of the pancreas. Frey and Child[102] reported further good results with the procedure and it became the most popular operation for chronic pancreatitis in the 1960s and 1970s.[103, 104] The procedure provided good results with significant pain relief being reported in 80% of cases.[103, 105] It was argued that with removal of the diseased pancreatic tissue it was immaterial whether the cause of pain was distention of the pancreatic tissue or neural in origin. Overall the results were as good as those reported with the drainage procedures. However, the two main reasons why distal pancreatectomy fell into disfavor was because of the unacceptably high incidence of exocrine and endocrine insufficiency[103, 105] (Table 36.7) and the development of better alternative surgical procedures.[99, 106] The place of distal pancreatectomy in the surgical management of CP is at present a limited one. In patients with disease limited to the body and tail of the gland and a small pancreatic duct (4 mm or less) there may be little option but to resort to a distal pancreatectomy. Frey et al.[99] have reported good pain relief in 7 of their 8 patients with an average follow-up of 3.5 years. They performed a 60% distal pancreatectomy in a select group of patients with CT scan and ERCP evidence of CP limited to the body and tail of the gland.

588

Chapter 36 / CHRONIC PANCREATITIS

TABLE fy 36.7 Effects of operations for chronic pancreatitis on exocrine and endocrine function in representative series. Figures in parenthesis refer to patients (%) requiring insulin to control diabetes mellitus Procedure

N

% Incidence of clinical

% Incidence of clinical

steatorrhea

diabetes mellitus

Preoperative

Postoperative

Preoperative

Late 1000 IU/ml) and protein (> 3 g/dl).[127] If the leak tracks anteriorly a massive ascites results, whereas, if it tracks posteriorly it may present in the form of a massive pleural effusion. While in 80% of cases the leak can be identified from an associated pseudocyst, in 10% it occurs directly from the pancreatic duct while in another 10% of cases the exact site of leak cannot be identified.[128] Overall the incidence of pancreatic ascites in CP ranges from 1% to 5% in different series.[74]

Tropical Hepatogastroenterology

REFERENCES

Most patients present with a history of progressive abdominal distension with associated abdominal pain and often are chronically ill and cachectic. Diagnosis is based on evaluation of the ascitic fluid and while the site of leak may be identified by ERCP, it is usually difficult to do so.[129] Most authors recommend a trial of conservative treatment of about 2 weeks which includes keeping the patient nil orally, reduction in pancreatic secretion by use of octreotide, large volume paracentesis and improvement in the nutritional status by the parenteral route. This approach is successful in 40%–60% cases.[128] If this fails surgery is indicated. If the ductal disruption is distal resection of the distal segment is recommended as the chances of recurrence are nil and mortality is low.[130] Internal drainage into a Roux loop of jejunum is indicated if the leak is in the head of the pancreas.[130] There are recent reports of successful treatment of

591

internal pancreatic fistulae with the use of pancreatic stents (Fig. 36.9) and follow-up over a period of up to 30 months has shown no recurrence.

FIGURE 36.9 (a) Plain X-ray of the abdomen showing a stent in the pancreatic duct. (b) An endoscopic view just after stent insertion. (Courtesy: Dr Nageshwar Reddy.)

REFERENCES [1] Ammann RW, Akvbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis, Longitudinal study of a mixed medicalsurgical series of 245 patients. Gastroenterology 1984;86:820–828. [2] Levy P, Milan C, Pignon JP et al. Mortality factors associated with chronic pancreatitis. Unidimensional and multidimensional analysis of a medical – surgical series of 240 patients. Gastroenterology 1989;96:1165–1172. [3] Nelson WH, Townsend C M Jr, Thompson JC. Operative drainage of the pancreatic duct delays functional impairment in patients with chronic pancreatitis. Ann Surg 1988;208:321–329. [4] Moossa AR, Lein B. The diagnosis of ‘early’ pancreatic cancer: the University of Chicago experience. Cancer 1981;47:1688–1697.

Part VIII / Pancreas

[5] Warshaw AL. Indications for surgical treatment in chronic pancreatitis. In:Beger HG, Buchler M, Ditshuneir H, Malfertheiner P(eds) Chronic Pancreatitis. Springer-Verlag, Berlin, 1990 p 395–399. [6] Lankisch PG, Banks PA. Pancreatitis. SpringerVerlag, Berlin, 1998. [7] Riela A, Zinsmeister AR, Melton LJ et al. Trends in the incidence and clinical characteristics of chronic pancreatitis. Pancreas 1990;5:727 (Abstract). [8] Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol 2003;38:315–26. [9] Balaji LN, Tandon RK, Tandon BN et al. Prevalence and clinical features of chronic pancreatitis in southern India. Int J Pancreatol 1994;15: 29–34.

592

Chapter 36 / CHRONIC PANCREATITIS

[10] Takebe T, Murashima Y, Suga T et al. A report on the epidemiology and the clinical features of the patients with chronic pancreatitis in Hokkaido District. Hokkaido Igaku Zasshi 1987;62: 461–8. [11] Kaushik SP, Vohra R, Verma R. Spectrum of pancreatitis at Chandigarh: a ten years experience. Indian J Gastroenterol 1983;2:9–11. [12] Geeverghese PJ. The etiology of pancreatitis. J Assoc Physicians India. 1971;19:413–5. [13] Almela P, Aparisi L, Grau F et al. Influence of alcohol consumption on the initial development of chronic pancreatitis. Rev Esp Enferm Dig 1997;89:741-6;747–52. [14] Ammann RW. Alcoholic chronic pancreatitis: its relation to alcoholic acute pancreatitis. Gastroenterol Clin Biol 1996;20:312–4. [15] Audrezet MP, Chen JM, Le Marechal C et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor geneto the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet 2002;10:100–6. [16] Threadgold J, Greenhalf W, Ellis I et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 2002;50: 675–81. [17] Balakrishnan V, Sauniere JF, Hariharan M et al. Diet, pancreatic function, and chronic pancreatitis in south India and France. Pancreas 1988;3: 30–5. [18] Kloppel G, Maillet B. Pathology of acute and chronic pancreatitis. Pancreas 1993;8:659–70. [19] Singh SM, Reber HA. The pathology of chronic pancreatitis. World J Surg 1990;14:2–10. [20] Bogomoletz WV. Duct destructive chronic pancreatitis. A new insight into the pathology of idiopathic nonalcoholic chronic pancreatitis. Gut 1997;41:272–3. [21] Madro A, Celinski K, Slomka M. The role of pancreatic stellate cells and cytokines in the development of chronic pancreatitis. Med Sci Monit 2004;10:RA166-70. Epub 2004 Jun 29.

[22] Friess H, Kleeff J, Buchler MW. Molecular pathophysiology of chronic pancreatitis–an update. J Gastrointest Surg 2003;7:943–5. [23] Freedman SD. New concepts in understanding the pathophysiology of chronic pancreatitis. Int J Pancreatol 1998;24:1–8. [24] Amman RW, B¨uhler H, M¨unch R et al. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic pancreatitis. Pancreas 1987;2: 368–3. [25] Lankish PG, Lohr-Happe A, Otto J et al. Natural course in chronic pancreatitis: pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993;54:148–55. [26] Chari ST, Mohan V, Jayanthi V et al. Comparative study of the clinical profiles of alcoholic chronic pancreatitis and tropical chronic pancreatitis in Tamil Nadu, south India. Pancreas. 1992;7:52–8. [27] Okuno G, Oki A, Kawakami F et al. Prevalence and clinical features of diabetes mellitus secondary to chronic pancreatitis in Japan; a study by questionnaire. Diabetes Res Clin Pract. 1990;10:65–71. [28] Amann ST, Bishop M, Curington C et al. Fecal pancreatic elastase 1 is inaccurate in the diagnosis of chronic pancreatitis. Pancreas 1996;13:226–30. [29] Arora A, Tandon RK. Fecal chymotrypsin assay in chronic pancreatitis. Trop Gastroenterol 1991;12:51. [30] Clain JE, Pearson RK. Diagnosis of chronic pancreatitis. Is a gold standard necessary? Surg Clin North Am 1999;79:829–45. [31] Kataoka K, Yamane Y, Kato M et al. Diagnosis of chronic pancreatitis using noninvasive tests of exocrine pancreatic function–comparison to duodenal intubation tests. Pancreas 1997;15: 409–15. [32] Katschinski M, Schirra J, Bross A et al. Duodenal secretion and fecal excretion of pancreatic elastase1 in healthy humans and patients with chronic pancreatitis. Pancreas 1997;15:191–200. [33] Hardt PD, Marzeion AM, Schnell-Kretschmer H et al. Fecal elastase 1 measurement compared with endoscopic retrograde cholangiopancreatography for the diagnosis of chronic pancreatitis. Pancreas 2002;25:e6–9.

Tropical Hepatogastroenterology

REFERENCES

[34] Lankisch PG, Schmidt I, Konig H et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency. Gut 1998;42: 551–4. [35] Lankisch PG. Function tests in the diagnosis of chronic pancreatitis. Critical evaluation. Int J Pancreatol 1993;14:9–20. [36] De Backer AI, Mortele KJ, Ros RR et al. Chronic pancreatitis: diagnostic role of computed tomography and magnetic resonance imaging. JBR-BTR 2002;85:304–10. [37] Zhang XM, Shi H, Parker L et al. Suspected early or mild chronic pancreatitis: enhancement patterns on gadolinium chelate dynamic MRI. Magnetic resonance imaging. J Magn Reson Imaging 2003;17:86–94. [38] Kusano S, Kaji T, Sugiura Y et al. CT demonstration of fibrous stroma in chronic pancreatitis: pathologic correlation. J Comput Assist Tomogr 1999;23:297–300. [39] Shimizu T, Suzuki R, Yamashiro Y et al. Progressive dilatation of the main pancreatic duct using magnetic resonance cholangiopancreatography in a boy with chronic pancreatitis. J Pediatr Gastroenterol Nutr 2000;30:102–4. [40] Bhutani MS. Endoscopic ultrasonography: changes of chronic pancreatitis in asymptomatic and symptomatic alcoholic patients. J Ultrasound Med 1999;18:455–62. [41] Buscail L, Escourrou J, Moreau J et al. Endoscopic ultrasonography in chronic pancreatitis: a comparative prospective study with conventional ultrasonography, computed tomography, and ERCP. Pancreas 1995;10:251–7. [42] Finet L, Deviere J, Cremer M. Endoscopic ultrasonography in chronic pancreatitis. Endoscopy 1994;26:750. [43] Kahl S, Glasbrenner B, Leodolter A et al. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002;55:507–11. [44] Hardt PD, Killinger A, Nalop J et al. Chronic pancreatitis and diabetes mellitus. A retrospective analysis of 156 ERCP investigations in patients

Part VIII / Pancreas

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53] [54]

[55]

[56]

593

with insulin-dependent and noninsulin-dependent diabetes mellitus. Pancreatology 2002;2:30–3. Lankisch PG, Seidensticker F, Otto J et al. Secretinpancreozymin test (SPT) and endoscopic retrograde cholangiopancreatography (ERCP): both are necessary for diagnosing or excluding chronic pancreatitis. Pancreas 1996;12:149–52. Lehman GA. Role of ERCP and other endoscopic modalities in chronic pancreatitis. Gastrointest Endosc 2002;56(6 Suppl):S237–40. Cooper MJ, Williamson RCN, Benjamin IS et al. Total pancreatectomy for chronic pancreatitis. Br J Surg 1987;74:912–915. Bockman DE, Buchler M, Malfertheiner P et al. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988;94:1459–1469. Keith RG, Saibil FG, Sheppard RH. Treatment of chronic alcoholic pancreatitis by pancreatic resection. Am J Surg 1989;157:156–162. Buchler M, Weihe E, Friess H et al. Changes in peptidergic innervation in chronic pancreatitis, Pancreas 1992;7:183–192. Di Sebastiano P, Fink T, Weihe E et al. Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis. Gastroenterology 1997:112: 1648–1655. Shrikhande SV, Friess H, di Mola FF et al. NK1 receptor gene expression is related to pain in chronic pancreatitis. Pain 2001;91:209–17. Bradley EL III. Pancreatic duct pressure in chronic pancreatitis Am J Surg 1982;144:313–316. Madsen P, Winkle K. The intraductal pancreatic pressure in chronic obstructive pancreatitis. Scan J Gastroenterol 1982;17:553–554. Okazaki K, Yamamoto Y, Kagiyama S et al. Pressure of papillary sphincter zone and pancreatic main duct in patients with alcoholic and idiopathic chronic pancreatitis. Int J Pancreatol 1988;3: 457–468. Jensen AR, Matzen P, Malchow-Moller A et al. (The Copenhagen Pancreatitis Study Group). Pattern of pain, duct morphology, and pancreatic function in chronic pancreatitis. Scand J Gastroenterol 1984;19:334–338.

594

Chapter 36 / CHRONIC PANCREATITIS

[57] Malfertheiner P, Buchler M, Staneseu A et al. Pancreatic morphology and function in relationship to pain in chronic pancreatitis. Int J Pancreatol 1987;1:59–66. [58] Ebbehoj N, Svendsen LB, Madsen P. Pancreatic tissue pressure:techniques and pathophysiologic aspects. Scand J Gastroenterol 1984;19: 1066–1068. [59] Ebbehoj N, Borly L, Madsen P et al. Pancreatic tissue pressure and pain in chronic pancreatitis. Pancreas 1986;1:556–558. [60] Sarles H. Chronic calcifying pancreatitis. Scand J Gastroenterol 1985;20:651–569. [61] Gullo L, Barbara L, Labo G. Effect of cessation of alcohol use on the occurs of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988;95:1063–1068. [62] Little JM. Alcohol abuse and chronic pancreatitis. Surgery 1987;101:357–360. [63] Hayakawa T, Kondo T, Slubata T et al. Chronic alcoholism and evolution of pain and prognosis in chronic pancreatitis. Dig Dis Sci 1989;34: 33–38. [64] Mossner J, Wresky HP, Back T. Does feedback regulation exist in chronic pancreatitis? In:Beger HG, Buchler M, Ditschuneit H, Malfertheiner P (eds) Chronic Pancreatitis. Springer, Berlin-Heidelberg, 1990;pp 198–209. [65] Andren-Sandbeg A. Theory and practice in the individualization of oral pancreatic enzyme administration for chronic pancreatitis. Int J Pancreatol 1989;5:Suppl:51–62. [66] Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332: 1482–90. [67] Owyang C. Negative feedback control of exocrine pancreatic secretion: role of cholecystokinin and cholinergic pathway. J Nutr 1994;124:Suppl: 1321S–1326S. [68] Dorbilla G. Management of chronic pancreatitis:focus on enzyme replacement therapy. Int J Pancreatol 1989;5:Suppl:17–29. [69] Staf J, Jacobson D, Tillman CR et al. Proteasespecific suppression of pancreatic exocrine secretion. Gastroenterology 1984;87:44–52.

[70] Halgren H, Thorsgaard Pedersen N, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol 1986;21:104–108. [71] Larvin M, McMahon MJ, Thomas WWEG et al. Creon (enteric coated pancreatin microspheres) for the treatment of pain in chronic pancreatitis. A double blind randomised placebo controlled crossover study. Gastroenterology 1991;100:A283 (abstr). [72] Malesci A, Gaia E, Fioretta A et al. No effect of long-term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis. Scand J Gastroenterol 1995;30:392–398. [73] Toskers PP, Forsmark CE, DeMeo MT et al. A multicenter controlled trial of octreotide for the pain of chronic pancreatitis. Pancreas 1993;8:774 abstract. [74] Bengtsson M, Lofstrom JB. Nerve block in pancreatic pain. Acta Chir Scand 1990;156:285–291. [75] Delhaye M, Hennart D, Bredas P et al. Steroid and alcohol coeliac plexus block in chronic pancreatitis. Eur J Gastroenterol Hepatol 1994;6: 552–558. [76] Leung JWC, Bowen-Wright M, Aveling W et al. Coeliac plexus block for pain in pancreatic cancer and chronic pancreatitis. Br J Surg 1983;70: 730–732. [77] Desai PM. Pain relief in chronic pancreatitis with epidural buprenorphine injection. Int J Gastroenterol 1997;16:12–13. [78] Cattell RB. Anastomosis of the duct of Wirsung: its use in palliative operations for cancer of the head of the pancreas. Surg Clin North Am 1947;27: 636–642. [79] Leger L, Lenriot JP, Lemaigre G. Five to twentyyear follow up after surgery for chronic pancreatitis in 148 patients. Ann Surg 1974;180: 185–191. [80] DuVal MK. Caudal pancreaticojejunostomy for chronic pancreatitis. Ann Surg 1954;140: 775–785. [81] Puestow CB, Gillesby WJ. Retrograde surgical drainage of the pancreas for chronic relapsing pancreatitis. Arch Surg 1958;76:898–907.

Tropical Hepatogastroenterology

REFERENCES

[82] Partington PF, Rochelle REL. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960;152:1037–1043. [83] Sharma AK, Pande GK, Sahni P et al. Surgery for nonalcoholic chronic pancreatitis. World J Surg 1998;22:236–9. [84] Cooper MJ, Willaimson RCN. The value of operative pancreatography. Br Surg 1983;70:577–580. [85] Frey CF, Smith GT. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987;2:701–707. [86] Beger HG, Buchler M. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis with inflammatory mass in the head. World J Surg 1990;14:83–87. [87] Sato T, Miyashita E, Matsuno S et al. The role of surgical treatment for chronic pancreatitis. Ann Surg 1986;203:226. [88] Brinton MH, Pellegrini CA, Stein SF et al. Surgical treatment of chronic pancreatitis. Am J Surg 1984;148:754–9. [89] Thomas PG, Augustine P, Ramesh H et al. Observations and surgical management of tropical pancreatitis in Kerala and southern India. World J Surg 1990;14:32–42. [90] Leger L, Lenriot JP, Lemaigre G. Five two twentyfive year follow up after surgery or chronic pancreatitis in 148 patients. Ann Surg 1974;180:185. [91] White TT, Slavatinek AH. Results of surgical treatment of chronic pancreatitis. Ann Surg 1979;189:217. [92] Howard JM. Surgical treatment of chronic pancreatitis; principles, applications, results. In Surgical Disease of the Pancreas. JM Howard, GI, Jordhan Jr., HA Reher, editors, Philadelphia, Lea & Febiger, 1987, p. 496. [93] Sugarman HJ, Barhart, GR, Newsome HH. Selected drainage for pancreatic, biliary and duodenal obstruction secondary to chronic fibrosis pancreatitis. Ann Surg 1986;203:558. [94] Greenlec HB, Prinz RA, Aranha GV. Long term results of side to side pancreaticojejunostomy for chronic pancreatitis. World J Surg 1990;14: 70.

Part VIII / Pancreas

595

[95] Hakim AG, Broughan TA, Hermann RE. Long term results of the surgical management of chronic pancreatitis. Am J Surg 1994;60:306. [96] Beger HG, Krautzberger W, Bittner R et al. Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery 1985;97:467–73. [97] Buchler MW, Friess H, Muller MW et al. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995;169: 65–9. [98] Beger HG, Schlosser W, Friess HM et al. Duodenum – Preserving head resection in chronic pancreatitis changes the natural course of the disease: a single center 26 year experience. Ann Surg 1999;230:512–523. [99] Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987;2:701–7. [100] Izbicki JR, Bloechle C, Knoefel WT et al. Comparison of two techniques of duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. Dig Surg 1994;11:331–7. [101] Eliason EL, Welty RF. Pancreatic calculi. Ann Surg 1958;127:150–157. [102] Fry WJ, Child CG III. Ninety-five percent distal pancreatectomy for chronic pancreatitis. Ann Surg 1965;162:543–519. [103] Frey CF, Child CG, Fry W. Pancreatectomy for chronic pancreatitis. Ann Surg 1976;184: 403–413. [104] Frey F. Role of subtotal pancreatectomy and pancreaticojejunostomy in chronic pancreatitis. J Surg Res 1981;31:361–370. [105] Eckhauser FE, Strodel WE, Knol JA et al. Near-total pancreatectomy for chronic pancreatitis. Surgery 1984;96:599–607. [106] Beger HG, Buchler M. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis with inflammatory mass in the head. World J Surg 1990;14:83–87. [107] Frey CF, Suzuki M, Isaji S et al. Pancreatic resection for chronic pancreatitis. Surg Clin North Am, 1989;69:499–528.

596

Chapter 36 / CHRONIC PANCREATITIS

[108] Keith RG, Saibil FG, Sheppard RH. Treatment of chronic pancreatitis by pancreatic resection. Am J Surg, 1989;157:156–162. [109] Mc Afee MK, van Heerden JA, Adson MA. Is proximal pancreatoduodenectomy with pyloric preservation superior to total pancreatectomy? Surgery 1989;105:307–351. [110] Trede M, Schwall G. The complications of pancreatectomy. Annals of Surgery 1979;190: 312–319. [111] Pliam MB, ReMine WH. Further evaluation of total pancreatectomy. Arch Surg 1975;110: 506–512. [112] Sato T, Yamauchi H, Miyashita E et al. Long-term follow up study on surgical treatment for chronic pancreatitis. In: Soto T, Yamauchi H (eds) Pancreatitis: its pathophysiology and clinical aspects. University of Tokyo Press, Tokyo, Japan, 1985, p 449–456. [113] Rossi RL, Rothschild J, Braasch JW et al. Pancreatoduodenectomy in the management of chronic pancreatitis. Arch Surg 1987;122: 416–420. [114] Gall FP, Gebhardt C, Zirnagibl H. Chronic Pancreatitis: results in 116 consecutive, partial duodenopancreatectomies combine with pancreatic duct occlusion. Hepatogastroenterology 1982;29:115–119. [115] Gall FP, Gebhardt C, Meister R et al. Severe chronic cephalic pancreatitis: use of partial duodenopancreatectomy with occlusion of the pancreatic duct in 289 patients. World J Surg 1989;13:809–817. [116] Stone WM, Sarr MG, Nagorney DM, McIlrath DC. Chronic Pancreatitis: results of Whipple’s resection and total pancreatectomy. Arch Surg 1988;123:815–819. [117] Howard JM, Zhang Z. Pancreaticoduodenectomy (Whipple resection) in the treatment of chronic pancreatitis. World J Surg 1990;14: 77–82.

[118] Hollands MJ, Little JM. Obstructive jaundice in chronic pancreatitis. Hepatobiliary Surgery 1989;1:263–270. [119] Morel P, Rohner A. Surgery for chronic pancreatitis. Surgery 1987;101:130–135. [120] Sarles H, Sahel J. Progress report:cholestasis and lesions of the biliary tract in chronic pancreatitis. 1978, Gut 19:851. [121] Wilson C, Auld CD, Schlinkert R et al. Hepatobiliary complications in chronic pancreatitis. Gut 1989;30:520–527. [122] Bornman PC, Kalvaria I, Girdwood AH et al. Clinical relevance of cholestasis syndrome in chronic pancreatitis- the Cape Town experience. In: Beger HG, Buchler M, Ditschuneit H, Malfertheiner P (eds) Chronic pancreatitis. Springer-Verlag, Berlin, 1990, p 256–259. [123] Bradley E L III, Salam AA. Hyperbilirubinaemia in inflammatory pancreatic disease. Ann Surg 1979;188:620–629. [124] Bradley EL, III: Long term results of pancreaticojejunostomy in patients with chronic pancreatitis. Am J Surg 1987;153:207. [125] Bradley E L III. Enteropathies. In: Bradley EL III (ed). Complications of Pancreatitis, Medical and Surgical Management. WB Saunders, Philadelphia, 1982. [126] Rignault D, Mine J, Moine D. Splenoportographic changes in chronic pancreatitis. Surgery 1968;63:571. [127] Donowitz M, Herstein MD, Spiro HM. Pancreatic ascites. Medicine 1974;53:183–95. [128] Weaver DW, Walt AJ, Sugawa G et al. A continuing appraisal of pancreatic ascites. Surg Gynecol Obstet 1982;154:845–8. [129] Sankaran S, Wait AJ. Pancreatic ascites: recognition and management. Arch Surg 1976;111: 430–34. [130] Neoptolemos JP, Winslet MC. Pancreatic ascites. In Beger HG, Buchler M, Ditschuneit H, Malfertheiner P (Eds) Chronic Pancreatitis. SpringerVerlag, Berlin 1990; Pg 269–79.

test

Tropical Hepatogastroenterology

Chapter

37 CANCER OF THE PANCREAS Deepak Govil, Saket Goel, and Sudhir Kumar

Cancer of the pancreas is one of the most aggressive tumors of the gastrointestinal tract. It is the third most common malignancy and the fourth leading cause of cancer-related mortality among all gastrointestinal cancers.[1, 2] Patients with pancreatic cancer usually present late due to vague symptoms initially. Hence, the majority of the patients have either a locally advanced or a metastatic disease at the time of presentation. Surgery is the only curative therapy. Although there are advances in improving the safety of pancreatic resections and critical care, there are only modest improvements in overall 5 year survival rates.[3]

higher rates are seen in the male urban populations of western and northern India.[5]

37.1 EPIDEMIOLOGY

37.1.1.1 Age

Approximately 150,000 worldwide and 40,000 in Europe die each year of pancreatic cancer.[4] It constitutes approximately 2% of newly reported malignancies in the US but it accounts for 5% of cancer deaths. The highest incidence rate is approximately 13 cases per 100,000 persons per year in black males in the United States. Most of the other countries have incidence rates of 8–12 cases per 100,000 persons per year. In India the incidence is 0.5–2.4 per 100,000 men and 0.2–1.8 per 100,000 women in most parts of it. Somewhat

37.1.1 Risk Factors Although 40% of pancreatic cancer cases are sporadic and not associated with any known risk factors, the rest of the patients have one or the other risk factor related to diet, environment or heredity. Common risk factors include smoking and dietary factors which may be responsible for approximately 30% and 20% cases respectively. Chronic pancreatitis and hereditary pancreatitis is seen in less than 10%. Other predisposing risk factors are:

The incidence of pancreatic cancer increases steadily with age; it is unusual in persons younger than 45 years. After the age of 50 years, the frequency of pancreatic cancer increases linearly. Advancing age is a risk factor for pancreatic cancer. Most patients are in the sixth to seventh decade. The median age at diagnosis is 65 years. 37.1.1.2 Sex

The male to female ratio for pancreatic cancer is 1.2–1.5:1. The incidence among females is 597

598

Chapter 37 / CANCER OF THE PANCREAS

increasing and the gender variation is gradually equalizing. 37.1.1.3 Smoking

It is the most common preventable environmental risk factor for pancreatic carcinoma. Nitrosamines in tobacco smoke are carcinogenic for the pancreas according to various animal studies. Cigarette smoking is associated with statistically significant increase in risk of cancer pancreas, approximately 2–4 fold above the non-smokers.[6, 7] It has a positive dose response, after a lag period of 20 years the risk of pancreatic cancer doubles. 37.1.1.4 Diet

The incidence of pancreatic cancer appears to be higher in people with increased calorie consumption, high fat and carbohydrate in diet.[8] The risk also increases with an increasing body mass index (BMI). A diet rich in fresh fruits and vegetables is associated with a lower risk of pancreatic cancer.[9] Alcohol consumption does not appear to be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis. 37.1.1.5 Diabetes mellitus

Numerous studies have examined the relative risk of pancreatic cancer in persons with diabetes mellitus.[10] Meta-analysis of 30 studies concluded that patients with long standing diabetes mellitus (at least 5-years) have a 2-fold increased risk of developing pancreatic carcinoma.[11] Other studies, on the contrary, show that abrupt onset of diabetes is more commonly an early symptom of pancreatic cancer rather than a causative influence. 37.1.1.6 Chronic pancreatitis

Long-standing chronic pancreatitis is a substantial risk factor for the development of pancreatic cancer. A multicenter study of more than 2000 patients

with chronic pancreatitis showed a 16-fold increase in the risk of developing pancreatic cancer. This risk increased linearly with time, with 4% of patients who had chronic pancreatitis for 20 years’ duration developing pancreatic cancer.[12] Patients with tropical calcifying pancreatitis appear to have significantly increased risk of pancreatic cancer.[13] There is 15–25 fold increased risk of pancreatic cancer in sporadic chronic pancreatitis.[14, 15] The prevalence of cancer of the pancreas in patients with chronic pancreatitis is 2.9%. The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. It is associated with genetic mutation on chromosome 7. The relative risk of pancreatic cancer in hereditary pancreatitis is increased more than 50-fold, and the cumulative risk rate of pancreatic cancer by age 70 years is 40%.[16] This cumulative risk increases to 75% in those families with a paternal inheritance pattern. 37.1.1.7 Familial factors

Familial background is an important risk factor for pancreatic cancer and affected families have a 5%– 10% higher incidence.[17] The inherited disorders that increase the risk of pancreatic cancer include hereditary pancreatitis, multiple endocrine neoplasia, hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis and Gardner syndrome, familial atypical multiple mole melanoma syndrome, von Hippel-Lindau syndrome, and germline mutations in the BRCA2 gene.[18] 37.1.1.8 Molecular biology

The molecular genetics of pancreatic adenocarcinoma has been well studied. Pancreatic cancer shows more mutations than any other malignancy. The techniques employed were karyotyping, comparative genomic hybridization and allelotyping.

Tropical Hepatogastroenterology

PATHOPHYSIOLOGY

37.1.1.9 Genetics

The genes associated with cancer pancreas can be divided into 3 groups: (a) tumor suppressor genes (b) oncogenes (c) DNA mismatch repair genes. The tumor suppression genes inactivated frequently in cancer pancreas are p53, p16 and DPC4. They are located on the 17p, 9p and 18q chromosomes and are inactivated in 75%, 95%, and 50% cases with cancer pancreas respectively.[18] K-ras oncogene mutation is the most common genetic alteration and is found in 80%–100% of pancreatic cancers.[19] Most of these are mutations in codon 12. It can be detected in pancreatic juice, duodenal fluid, stool or blood. It is being considered for screening purpose as this mutation is an early event but it is also present in patients with chronic pancreatitis and smokers. It also has a prognostic value as its presence in patients with pancreatic cancer is associated with inoperable lesions and poorer prognosis after surgery.[20] Approximately 4% of pancreatic adenocarcinoma are characterized by the disorders of DNA repair genes.[21] This subgroup of patients may have a favorable prognosis compared to the typical adenocarcinoma without mutation in DNA repair genes. Although studies are underway, the genetic mutations associated with pancreatic adenocarcinoma are not yet clinically useful in screening or for diagnosing the disease. Various polypeptide growth factors and their receptors correlate with the biological behavior of the tumor when they are overexpressed.[22] These are EGFR (epidermal growth factor receptor), TGF b (transforming growth factor b), FGF (fibroblast growth factor) and IGF (insulin growth factor). Over-expression of EGFR is correlated with tumor

Part VIII / Pancreas

599

invasiveness, increased potential for metastasis and poorer prognosis.

37.2 PATHOPHYSIOLOGY Pancreatic cancers can arise from both the exocrine and endocrine portions of the pancreas. Of pancreatic tumors, 95% develop from the exocrine portion of the pancreas including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15%–20% occur in the body of the pancreas, and 5%–10% occur in the tail.[23] Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver, and less commonly to the lungs. It can also directly invade surrounding visceral organs such as the duodenum, stomach, and colon.

37.2.1 Histological Findings Of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. These are ill defined masses that frequently obstruct the distal bile duct and/or the main pancreatic duct. Histologically there are precursor lesions in the ducts or ductules that progress to infiltrating ductal carcinoma. Pancreatic cancer may progress from flat ductal lesions known as the pancreatic intraepithelial neoplasia (Pan IN 1A) to papillary duct lesions without atypia, followed by atypia, i.e., in situ carcinoma (Pan IN 3) and then to infiltrating adenocarcinoma.[24] Only 2% of tumors of the exocrine pancreas are benign. Less common histological appearances of exocrine pancreatic cancers include giant cell carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary

600

Chapter 37 / CANCER OF THE PANCREAS

TABLE fy 37.1 Characteristic features of cystic lesions of pancreas Type of neoplasm

Frequency (%)

Malignant potential

Serous cystadenoma Mucinous cystic neoplasm

32–40 10–45

No Yes

Microcystic (80%) Macrocystic

Intraductal papillary mucinous neoplasm (IPMN)

21–35

Yes

Mixed

192 ng/ml is associated with mucinous cysts compared to serous cystic lesions.[25] Patients can also develop tumors of the islet cells of the pancreas. These can be functionally inactive islet cell carcinomas or benign or malignant functioning tumors such as insulinomas,

Tumor markers

Mucin like antigen, CEA, CA 72–4, CA15–3 CEA, CA 72–4, Amylase CA 19-9

Prognosis Resection curative Resection curative

Excellent prognosis in absence of invasive carcinoma Dismal

glucagonomas, and gastrinomas. We would restrict ourselves to the exocrine tumors of the pancreas only.

37.3 CLINICAL FEATURES 37.3.1 History The initial symptoms are often quite nonspecific in the form of anorexia, malaise, nausea, upper abdominal discomfort and significant weight loss. High index of suspicion is the key for a physician to suspect the disease. Approximately one-third of the patients are diagnosed after 2 months of the onset of their symptoms. Epigastric dull aching pain often radiating to the back is the most common presenting symptom. Radiation to the back indicates retroperitoneal invasion and a poorer prognosis. The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless obstructive jaundice. Patients may come to medical attention before their tumors grow large enough to cause abdominal pain. Clinical jaundice can be appreciated when the total bilirubin reaches 2.5–3 mg%. However, darkening of urine, fading yellow color of stool and pruritus are often noticed by patients before clinical jaundice.

Tropical Hepatogastroenterology

INVESTIGATIONS

Weight loss may be related to anorexia and/or subclinical malabsorption from pancreatic exocrine insufficiency caused by pancreatic duct obstruction by the cancer. The new onset diabetes mellitus may be the first clinical presentation in approximately 10% of patients.[26] Depression, probably due to a delayed diagnosis and a dismal prognosis is frequently seen in these patients. Migratory thrombophlebitis (i.e., Trousseau sign) and venous thrombosis are also seen frequently in these patients.

37.3.2 Physical Examination The most common physical finding is icterus. Patients are in a poorly nourished stage, often cachexic and have marks of scratching all over the body. They may have hepatomegaly and a palpable gallbladder (i.e., Courvoisier sign). Patients with advanced disease have ascites and evidence of disseminated disease in the form of left supraclavicular lymphadenopathy (Virchow’s node) or a periumbilical Sister Joseph’s nodule.

37.4 INVESTIGATIONS 37.4.1 General Laboratory Studies Hematologic investigations reveal a normochromic anemia and sometimes thrombocytosis. Liver function tests show a cholestatic pattern in form of significantly elevated bilirubin (conjugated and total), alkaline phosphatase, gamma-glutamyl transpeptidase and a mild increase in aminotransferases. Hypoalbuminemia is also seen frequently.

37.4.2 Tumor Markers A number of tumor markers are found to be elevated in pancreatic cancer like CA 19-9, CA 242, CA 50, CA 494, SPAN-I, DUPAN-2. Amongst

Part VIII / Pancreas

601

these CA 19-9 (Carbohydrate antigen 19-9) is found to be the most useful for cancer pancreas. It is a Lewis blood group related mucin which has been extensively studied. It is at present the best available marker which has a role in supporting the diagnosis, and indicates recurrent or persistent disease postoperatively. The normal value is < 37 units/ml. The value of CA 19-9 also increases in certain benign conditions like biliary obstruction or benign pancreatic disease.[27] The accuracy for diagnosing cancer is higher (95%) if the value is > 200 units/ml. When combined with other investigative modalities like Ultrasound, CT scan or ERCP, the positive predictive value may approach 100%. This helps in taking decisions in patients where sometimes tissue diagnosis is either difficult or inconclusive. Preoperative high values are suggestive of a larger tumor with high chances of unresectability. Hence, measurement of CA 199 has a prognostic value as well.[28] It is useful in postoperative surveillance to indicate recurrence and identifying patients requiring aggressive adjuvant therapy. Molecular genetic markers like K-ras mutations appear promising to identify patients with pancreatic cancer early. This has been detected in patients with pancreatic cancer from their duodenal juice, endobiliary drainage tube fluid or stools.[29]

37.4.3 Imaging Studies 37.4.3.1 Ultrasound

Ultrasound of abdomen is the most useful and a simple screening test which gives us a lot of information in skilled hands. Apart from visualizing the pancreatic masses it can demonstrate intra- or extrahepatic biliary tract dilatation, distended gallbladder indicating the level of biliary obstruction. Extent of the disease can also be assessed by local extension of the lesion, enlarged lymph nodes, liver metastases and presence of ascites.

602

Chapter 37 / CANCER OF THE PANCREAS

not yet found favor probably due to the limited experience. On T1-weighted images, pancreatic adenocarcinoma appears as a hypointense pancreatic mass. Peripancreatic fat infiltration is best evaluated on T1-weighted images. On T2-weighted images pancreatic neoplasms are slightly isointense to hyperintense compared to the normal pancreas. As experience is gained, MR is likely to replace CT for pancreatic evaluation. FIGURE 37.1 CECT of the abdomen in a patient with pancreatic cancer. The picture shows an inhomogenously enhancing irregularly marginated mass (M) lesion involving the head of the pancreas (D - duodenum, L - liver).

37.4.3.2 CT scan (Computerized tomography)

Spiral CT and multidetector CT (MDCT) are the most advanced imaging modalities to diagnose and assess resectability of pancreatic cancer. Pancreatic cancer is seen as pancreatic enlargement or a hypodense lesion in the pancreas (Fig. 37.1). The accuracy for assessment of resectability is 70%–79% and unresectability is 96%. MDCT gives 3-dimensional display, CT angiography and detailed biliary and pancreatic duct anatomy. The preferred mode of pancreatic CT scanning is dual phase spiral CT scan.[30] Apart from assessing the primary tumor, CT is useful in evaluating the local extent of the lesion regarding neoplastic invasion or thrombosis of the adjacent major vessels, peripancreatic lymph nodes, retroperitoneal structures and distant spread to liver or ascites. Resection rates are higher in centers using high quality CT scan imaging. 37.4.3.3 MRI (Magnetic resonance imaging)

MRI along with MRCP and MR angiography may be helpful in evaluating these lesions, but this has

37.4.3.4 ERCP (Endoscopic retrograde cholangiopancreatography)

ERCP as a diagnostic tool for pancreatic neoplasms is gradually getting replaced by MRCP. ERCP is only indicated if a therapeutic intervention is planned. If the patient is identified to have disseminated disease with icterus, ERCP with stenting can be considered. ERCP findings provide only limited staging information, but ERCP does have the advantage of allowing for therapeutic palliation of obstructive jaundice with either a plastic or metallic biliary stent. 37.4.3.5 EUS (Endoscopic ultrasonography)

EUS uses a high-frequency ultrasonographic transducer on an endoscope, which is then positioned in the stomach or duodenum endoscopically to help visualize the pancreas. High-frequency ultrasonography (7.5– 12 MHz) can be used to produce very highresolution (submillimeter) images due to the proximity of the pancreas to the EUS transducer. It has proven to be the most sensitive and specific diagnostic test for pancreatic cancer including those smaller than 3 cm. An additional significant diagnostic advantage is EUS-guided fine needle aspiration, which allows for the simultaneous cytological confirmation of pancreatic carcinoma at the time of EUS diagnosis. It is sensitive for small pancreatic tumors and major vascular involvement.

Tropical Hepatogastroenterology

INVESTIGATIONS

It is less effective for lymph nodes and distant disease. Overall it has a sensitivity of 95% and specificity of 80%.[31] To date, studies show that EUS is approximately 70%–80% accurate for correctly staging pancreatic carcinoma. EUS is an operator dependent investigation, but has a good chance of detecting small lesions missed on other investigations. EUS has been found similar in predicting resectability when compared with CT scan. 37.4.3.6 PET (Positron emission tomography scanning)

PET uses the principle of increased metabolism of glucose by cancer cells compared to normal pancreatic cells. Hence it may be more useful in differentiating chronic pancreatitis from cancer and detecting lymph node metastases. Presently its use is limited due to high cost and poor availability.[32] 37.4.3.7 Laparoscopy

Occult metastatic disease missed on imaging in approximately 15%–25% patients change the decision for aggressive resection or palliation. These can be picked up on laparoscopy. Diagnostic laparoscopy detects unresectable disease in only 4%–13% of cases with potentially resectable lesions. Diagnostic laparoscopy is able to detect small liver and peritoneal metastases avoiding unnecessary laparotomy.[33] Patients who are deemed unresectable at the time of laparoscopy can undergo palliative biliary and/or gastric bypass procedures laparoscopically if required, and further minimize the morbidity of laparotomy. Laparoscopic ultrasound is also being evaluated to enhance pick up of these lesions. Although all these modalities are available today, but which is used in a particular institution depends largely on local availability and expertise with the procedure.

Part VIII / Pancreas

603

37.4.4 Preoperative Tissue Diagnosis Patients and their families usually want a definitive diagnosis prior to making major therapeutic decisions. The various means available to achieve this preoperatively are: 1. Percutaneous CT guided FNAC–it is controversial in potentially resectable lesions. 2. ERCP brushings – high specificity (98%) but poor sensitivity. 3. EUS guided FNAC – high specificity (98%) and sensitivity 86%–96%. How far should one go to get a preoperative tissue diagnosis especially when the radical procedure required for cure is extensive with its attendant morbidity and mortality, is a debatable issue. Although literature does not support the theory of intraperitoneal and tract seedlings with percutaneous fine needle aspiration cytology (FNAC), it is very difficult to actually sample the small lesions and to believe and change decision of resection if the biopsy only shows fibrosis or inflammation. The yield of CT-guided fine needle aspiration or biopsy findings is approximately 50%–85% in the lesions that are visible on CT. EUS-guided fine needle aspiration has proven to be the most effective means for making a definitive preoperative cytologic diagnosis of pancreatic carcinoma.[34] Using EUS-guided fine needle aspirations, a cytologic diagnosis can be made in 85%–95% of patients. The experience is limited and needs further evaluation before routine recommendation. In our experience, tissue diagnosis is not a must before resection. Resection can be planned on basis of supportive evidences, but in patients with advanced disease, we insist on getting a tissue diagnosis before starting any palliative treatment.

604

Chapter 37 / CANCER OF THE PANCREAS

TABLE fy 37.2 TNM classification of pancreatic cancer Tumor (T) Tx

Regional lymph nodes (N) Nx

T0

Primary tumor cannot be assessed No evidence of primary tumor

Tis

Carcinoma in situ

N1

T1

Tumor limited to the pancreas, 2 cm or smaller in greatest dimension Tumor limited to the pancreas, > 2 cm in greatest dimension Tumor extension beyond the pancreas (e.g., duodenum, bile duct, portal or superior mesenteric vein) Tumor involves the celiac axis or SMA

T2 T3

T4

N0

TABLE fy 37.3 Stage grouping for pancreatic cancer Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV

Distant metastasis (M)

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1-3, N1, M0 T4, Any N, M0 Any T, Any N, M1

37.4.5 Staging Accurate preoperative staging is important to determine resectability of the lesions. An attempt at resection should only be planned if we can offer a curative resection. Palliative resection does not offer any advantage to the patient other than adding to the morbidity. This is why only approximately 20% of these lesions are resectable. Cancer of the exocrine pancreas is staged according to the 2002 Union International Centre la Cancer (UICC) tumor, node, and metastases (TNM) classification (Tables 37.2 and 37.3).

Mx M0

Distant metastasis cannot be assessed No distant metastasis

M1

Distant metastasis

37.5 TREATMENT 37.5.1 General Principles The treatment of pancreatic cancer can be either curative or palliative depending on the stage of the disease. At present surgery is the only effective curative therapy although only 15%–20% of these patients present with surgically resectable disease. No survival benefit is achieved if the patient undergoes incomplete resection with positive tumor margins. The major goal of accurate preoperative staging for pancreatic cancer is to avoid performing a non-beneficial abdominal operation that entails a 6- to 8-week recovery period on a patient with a median survival of only 4–6 months. Patients with hyperbilirubinemia may sometimes need preoperative biliary drainage endoscopically before surgery.

37.5.2 Preoperative Biliary Drainage Preoperative biliary stenting does not offer any advantage and is associated with higher

Tropical Hepatogastroenterology

TREATMENT

605

intraoperative difficulties and postoperative complications.[35] It should be used selectively when the patient has cholangitis, the surgery is to be delayed due to some reasons, or if the patient is unfit.

37.5.3 Surgical Treatment The standard operation for carcinoma of the head of the pancreas is a pancreaticoduodenectomy (Kausch-Whipple procedure). This operation involves en bloc resection of the pancreatic head; the duodenum and proximal 10 cm of jejunum; the distal stomach; and the common bile duct along with the Gallbladder and cystic duct (Figs. 37.2 to 37.4). The standard Whipple’s procedure is still the commonest procedure for pancreatic cancer. Various modifications have been made.

FIGURE 37.3 Pancreaticoduodenectomy specimen (H - head pancreas, D - duodenum): In this specimen the duodenum has been cut open after surgery.

FIGURE 37.4 Diagram showing the reconstruction in the Whipple’s pancreaticoduodenectomy (HJ - hepaticojejunostomy, GJ - gastrojejunostomy, PJ - pancreaticojejunostomy). FIGURE 37.2 Pancreaticoduodenectomy: The extent of resection (shaded area) includes the gallbladder and distal bile duct, the distal stomach, the entire duodenum, the proximal jejunum, and the head of the pancreas.

Part VIII / Pancreas

37.5.3.1 PPPD (Pylorus preserving pancreaticoduodenectomy)

A more recent variation of the operation spares the pylorus, labeled as PPPD and allows for a more

606

Chapter 37 / CANCER OF THE PANCREAS

natural physiologic emptying of the stomach. PPPD as opposed to the standard Whipple’s does not offer any significant benefit in the clinical outcome in the short term or long term.[36] It is mainly surgeons, preference and experience that some centers routinely do PPPD than Whipple’s.

The other common complication is delayed gastric emptying. It occurs less frequently with the PPPD which is a preferred option at many centers.

37.5.3.2 Resections of portal/mesenteric vein

Liver, peritoneal, distant metastasis

Extended resections with excision of the portal or superior mesenteric vein have been shown to be safe but they do not have a survival benefit.[37, 38] It can be justified in a very small subgroup of patients with small locally invading lesions to achieve R0 resection. Venous involvement itself is a poor prognostic indicator. 37.5.3.3 Extended lymph node resection

Similarly extended lymph node resections may appear justified but do not provide any survival benefit.[39] Randomized and multicenter studies have shown no difference in the overall survival after PD with or without radical lymphadenectomies and hence are not recommended.[40] The operative mortality for PD in high volume centers is between 0% and 5%.[41] The concept of specialist and high volume centers has shown to make a difference in the outcome for these major and demanding procedures. The resectability rates are higher and the complications and mortality are reduced in such centers. The major cause of postoperative morbidity is the occurrence of pancreatic-enteric leaks leading to intra-abdominal abscess and pancreatic fistulae. In order to circumvent these problems many modifications of the originally described procedure have been tried with variable degrees of success. These include total pancreatectomy, isolated Roux loop pancreaticojejunostomies and duct to mucosa pancreatic anastomoses.

37.5.3.4 Features suggestive of irresectability

• Major venous encasement (> 2 cm, > 50% circumference) • Superior mesenteric, celiac or hepatic artery encasement The following features do not contraindicate resection • Continuous invasion of duodenum, stomach or colon, lymph node metastasis within the operative field • Minimal venous invasion, SMV, Splenic vein, PV, trifurcation, Gastroduodenal artery encasement • Age of the patient

37.5.4 Cancer of the Body and Tail of the Pancreas Patients with tumors of the body and tail of the pancreas have vague and nonspecific symptoms. They present with heaviness or pain in the epigastrium with gradual loss of weight and appetite. Sometimes these are detected on incidental evaluation. Diagnosis is supported by imaging and an image guided FNAC may be done to get a tissue diagnosis. Lesions in the tail of pancreas can be offered distal pancreatectomy with or without splenectomy. Subtotal or total pancreatectomy is required for patients with large lesions in the body of pancreas. Unfortunately majority of these patients present late, hence a curative resection is rarely possible.[42]

Tropical Hepatogastroenterology

TREATMENT

37.5.5 Somatostatin Analogues Somatostatin or octreotide administered before surgery may reduce the rate of major postoperative complications, particularly pancreatic fistulae. Majority of randomized controlled trials show a benefit and reduction in complication rates with the perioperative use of somatostatin analogues. The first dose of octreotide should be given 1 hour before surgery.[43, 44] Somatostatin analogues may also have a role in the treatment of established postoperative enterocutaneous pancreatic fistulae.[45]

37.5.6 Adjuvant Therapy The median survival of patients who undergo surgery alone, is 10–20 months with a high rate of local recurrence and distant metastasis.[46] Therefore all surgically treated patients including patients with tumor positive surgical margins are candidates for adjuvant therapy. No global consensus exists regarding adjuvant treatment. Chemoradiation involves the use of external beam radiotherapy along with 5-FU and is the subject of much debate and ongoing studies. There is some evidence to suggest that chemoradiation does not alter patient survival. Chemotherapy alone may have some benefit.[47] The ESPAC-I (European study group for pancreatic cancer) trial is the largest randomized trial for adjuvant therapy in pancreatic cancer. It showed a significantly improved survival after 5-FU based chemotherapy (21 months) compared to no chemotherapy group (15.5 months) but did not show any significant benefit in patients getting chemoradiation compared to no treatment. The most active chemotherapeutic agents for pancreatic cancer have been 5-fluorouracil (5-FU) and gemcitabine. Gemcitabine is becoming popular, as apart from the small survival benefit, this

Part VIII / Pancreas

607

also leads to reduction in pain and improvement in quality of life.[48] Neoadjuvant chemotherapy to downstage the tumor before surgery is not recommended. Chemoimmunotherapy Interferon alpha, interferon gamma and interleukin-2 in combination with chemotherapeutic agents like 5-FU, cisplatin, mitomycin and radiotherapy have recently been used with good results.[49, 50]

37.5.7 Biological Therapy Gene therapy aims at restoring tumor suppressor gene function or at inhibiting activated oncogenes. In immunomodulatory gene therapy the tumors are injected with vectors encoding genes for cytokines with antitumor activity. 37.5.7.1 Antiangiogenic therapy

Bevacizumab is an antivascular endothelial growth factor (VEGF) antibody which has been used as a single agent and also in combination with gemcitabine with promising results. Immunotherapy aims at achieving an antitumor response from the patient’s own immune system. Monoclonal antibodies such as cetuximab and trastuzumab are inhibitors of signal transduction. All these alternative approaches are still in the experimental stage and are not yet recommended for clinical application.

37.5.8 Nutritional Support Patients with pancreatic cancer are unable to take adequately due to abdominal pain, epigastric fullness, duodenal obstruction, cancer and opioid related anorexia. Pancreatic enzyme supplements help to maintain body weight.[51] Specific dietary supplements with high protein and calories and unsaturated fats help to reverse cachexia and improve the quality of life.[52]

608

Chapter 37 / CANCER OF THE PANCREAS

37.5.9 Palliative Therapy Palliative chemotherapy is offered to patients with symptomatic and locally advanced (surgically unresectable) or metastatic disease. Gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms and also confers a modest survival advantage over treatment with 5-FU. Palliation is required for pain, biliary obstruction and gastric obstruction. 37.5.9.1 Pain

Pain occurs due to invasion of the celiac and mesenteric nerve plexus. Narcotic analgesics should be used early and in adequate dosages. Morphine is considered the gold standard. Combining narcotic analgesics with tricyclic antidepressants or antiemetics can sometimes potentiate their analgesic effects. Use of longer-acting dosage forms such as fentanyl transdermal patches can further simplify therapy. When oral and transdermal routes of administration no longer provide adequate relief, the use of parenteral therapy should be considered. Patient-controlled analgesia, utilizing continuous infusions, bolus doses or both can provide rapid relief of pain while drastically reducing total narcotic requirements for acceptable pain management. Neurolysis of the celiac ganglia (Neurolytic celiac plexus block) may provide significant long-term pain relief in patients with refractory abdominal pain. This can be performed either transthoracically or transabdominally under CT or USG guidance (EUS-guided transgastric injection). If the patient is being operated for palliative bypass, celiac plexus block should be given using 50% alcohol intraoperatively. Radiation therapy for pancreatic cancer can palliate pain but does not affect the patient’s survival. This may be useful in patients with bony metastases.

Pain from the obstruction of the pancreatic or biliary ducts may be relieved by endoscopic decompression with plastic or metallic stents. 37.5.9.2 Jaundice

Biliary obstruction from pancreatic cancer is usually best palliated by the endoscopic placement of plastic or metal stents. The more expensive and permanent metallic stents appear to have a longer period of patency and are preferable in patients with an estimated lifespan of more than 3 months. Plastic stents although are easy to insert and associated with low cost, but usually need to be replaced every 3–4 months due to frequent blockage. Patients who have locally small lesions with invasion, not amenable to curative resection but no distant metastases are candidates for surgical biliary decompression, either by choledochojejunostomy or cholecystojejunostomy. Drainage of the bile duct is preferable to the gallbladder due to higher risk of recurrent jaundice with blockage of the cystic duct. These procedures can be done when patient is operated and assessed to be unresectable. They may also be offered in well preserved and fit patients where endoscopic palliation is not available or possible.

37.5.10 Duodenal Obstruction Approximately 5% of patients develop duodenal obstruction secondary to pancreatic carcinoma. Patients found to have unresectable disease at operation can be palliated with a gastrojejunostomy. An endoscopic placement of a self-expanding duodenal stent may be preferred for patients who are poor operative candidates. When pancreatic resection is contraindicated or unsuccessful and the patient is taken up for a biliary bypass, a gastric drainage

Tropical Hepatogastroenterology

PREVENTION

procedure should be performed prophylactically to prevent duodenal obstruction that may occur later.

37.5.11 Management Algorithm (Fig 37.5) Patients suspected of having pancreatic carcinoma are initially evaluated with abdominal ultrasonography. Further management varies from institution to institution depending on local expertise and interest. Patients with pancreatic mass observed on abdominal US need to have more definitive imaging studies. This can be done using high-quality thin-cut CT scanning with dual phase contrast and/or by endoscopic ultrasonography. If a pancreatic mass is confirmed on EUS images EUS-guided fine needle aspiration can be performed to confirm the disease cytologically. At the same time, the patient is staged using CT/EUS to determine resectability potential. Patients thought to have resectable tumors can be planned for operative intervention. If tumors are deemed unresectable based on CT/EUS findings and the patients have obstructive jaundice, therapeutic stent placement can be done with ERCP at the same endoscopy sitting.

609

If patients have obvious hepatic metastatic disease based on initial US or CT findings, they should undergo a CT- or US-guided biopsy of one of the liver metastases and then proceed to palliative therapy. Patients with unresectable disease are offered chemotherapy for their disease. In institutions without EUS and EUS-guided fine needle aspiration capabilities, spiral CT scanning with CTguided pancreatic fine needle aspiration or biopsy plays the central role in evaluation. ERCP is also used frequently for evaluating patients with jaundice or patients with possible pancreatic masses based on findings from imaging modalities if EUS is not available. The most difficult clinical situation to diagnose pancreatic carcinoma is in the patient with underlying chronic pancreatitis. Here, all of the above imaging studies may not help differentiate between pancreatic carcinoma and chronic pancreatitis. Even tumor markers can be elevated in patients with chronic pancreatitis. In these patients, one must often combine multiple imaging modalities, close clinical follow-up, serial imaging studies, and occasionally empiric resection to diagnose an underlying pancreatic carcinoma. The only therapy that has definitively been shown to increase the survival of patients with pancreatic cancer is surgical resection. For patients with disease not amenable to curative resection, little has been shown to impact survival significantly.

37.6 PREVENTION

FIGURE 37.5 Algorithm for the management of pancreatic cancer.

Part VIII / Pancreas

Smoking is the most significant reversible risk factor for pancreatic cancer. Estimates indicate that smoking accounts for up to 30% of cases of pancreatic cancer. A diet high in caloric intake and low in fresh fruits and vegetables increases the risk of pancreatic cancer. Alcohol consumption does not

610

Chapter 37 / CANCER OF THE PANCREAS

increase the risk of pancreatic cancer unless it leads to chronic pancreatitis.

• No perineural or vascular invasion • Negative retroperitoneal margin along SMA.

37.7 PROGNOSIS 37.8 SUMMARY The mean survival for patients with unresectable disease remains 4–6 months, with a 5-year survival rate of less than 5%. The median survival for patients who undergo successful resection (only 20% of patients) is approximately 12–19 months, with a 5-year survival rate of 15%–20%. Although discouraging, these results are still markedly better than those for patients with unresectable pancreatic carcinoma.

37.7.1 Favorable Prognostic Factors • • • •

Negative resection margins Negative lymph node status Well or moderately differentiated tumor Small primary tumor < 2 cm

The outlook for patients with pancreatic cancer is bleak given the limited success of currently available treatment options. The vast majority of patients have advanced, incurable disease at the time of diagnosis, and no significant increase in survival has been demonstrated using the available treatment modalities. Early identification of disease through advances in the use of tumor markers and other genetic testing is needed to significantly improve survival. Continued research into the development and use of newer agents is essential to improve patient outcomes. The use of palliative and supportive therapies should be maximized to improve the quality of life for these patients.

REFERENCES [1] Boring CC, Squires TS, Tong T et al. Cancer statistics 1994. CA Cancer J Clin 1994;44:7–26. [2] American Cancer Society. Cancer facts and figures 2005. Atlanta, GA: Amer Cancer Society 2005. [3] Jemal A, Murray T, Samuels A et al. CA Cancer J Clin 2003;53:5–26. [4] Freiss H, Kleef J, Fischer L et al. Surgical standard therapy for cancer of the pancreas. Chirurg 2003;74:183–90. [5] Dhir V, Mohandas KM. Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Ind J Gastroenterol 1999;18:24–8. [6] Gold EB. Epidemiology of and risk factors for pancreatic cancer. Surg Clin North Am 1995;75: 819–843. [7] Richie JP, Carmella SG, Muscat JE et al. Differences in the urinary metabolites of the tobacco-

[8]

[9] [10]

[11]

specific lung carcinogen 4-(methylnitrosamino)1-butanone in black and white smokers. Cancer Epidemiol Biomarkers Prev 1997;6: 783–790. Gold EB, Goldin SB. Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin North Am 1998;7:67–91. Howe GR, Burch JD. Nutrition and pancreatic cancer. Cancer Causes Control 1996;7:69–82. Silverman DT, Schiffman M, Everhart J et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 1999;80: 1830–1837. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995 May 24–31;273:1605–9.

Tropical Hepatogastroenterology

REFERENCES

[12] Lowenfels AB, Maisonmeuve P, Cavallini G. Pancreatitis and the risk of pancreatic cancer: International pancreatitis study group. N Eng J Med 1993;328:1433–1437. [13] Chari ST, Mohan V, Pitchumoni CS et al. Risk of pancreatic carcinoma in tropical calcifying pancreatitis: an epidemiologic study; Pancreas 1994;9: 62–66. [14] Howes N, Neoptolemos JP. Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis. Gut 2002;51:765–766. [15] Malka D, Hammel P, Maire F et al. Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–852. [16] Howes N, Wong T, Greenhalf W. Pancreatitis cancer risk in hereditary pancreatitis in Europe. Digestion 2000;61:300. [17] Tersmette AC, Peterson GM, Offerhaus GJ et al. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001;7: 738–744. [18] Hruban RH, Peterson GM, Ha PK et al. Genetics of pancreatic cancer: from genes to families. Surg Oncol Clin N Am 1998;7:1–23. [19] Rozenblum E, Schutte M, Goggins M et al. Tumour suppressive pathways in pancreatic carcinoma. Cancer Res 1997;57:1731–4. [20] Yamada T, Nakamori S, Ohzato H et al. Detection of K-ras gene mutation in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinico-pathological features. Clin Cancer Res 1998;4:1527–1532. [21] Goggins M, Offerhaus GJ, Hilgers W et al. Pancreatic adenocarcinoma with DNA replication errors (RER+) are associated with a characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggesting RER+. Am J Pathol 1998;152: 1501–7. [22] Korc M. Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 1998;7:25–41. [23] Wilentz RE, Hruban RH. Pathology of cancer of the pancreas. Surg Oncol Clin N Am 1998;7: 43–65.

Part VIII / Pancreas

611

[24] Hruban RH, Adsay NV, Albore-Saavedra J et al. Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25:579–586. [25] Brugge WR, Lewandrowski K, Lee-Lewandrowsky E et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–1336. [26] Cujik J, Babiker AG. Pancreatic cancer, Diabetes Mellitus and gall bladder disease. Int J Cancer 1989;43:415–421. [27] Ritts RE, Pitt HA. CA 19-9 in pancreatic cancer. Surg Oncol Clin N Am 1998;7:93–101. [28] Beretta E, Malesci A, Zerbi A et al. Serum CA-19 in the post surgical followup of patients with pancreatic cancer. Cancer 1987;60:2428–2431. [29] Caldas C, Hahn SA, Hruban RH et al. Detection of K-ras mutations in the stools of the patients with pancreatic adenocarcinoma and pancreatic ductal mucinous cell hyperplasia. Cancer Res 1997;54:3568–73. [30] Diehl SJ, Lehmann KJ, Sadick M et al. Pancreatic cancer: value of dual phase helical CT in assessing respectability. Radiology 1998;206: 373–378. [31] Glasbrennar B, Schwarz M, Pauls S et al. Prospective comparison of endoscopic ultrasound and ERCP in the preoperative assessment of masses in the pancreatic head. Dig Surg 2000;17:468–474. [32] Sendler A, Avril N, Helmberger H et al. Preoperative evaluation of pancreatic masses with PET using 18Ffluorodeoxyglucose: diagnostic limitations. World J Surg 2000;24:1121–1129. [33] Conlon KC, Dougherty E, Klimstra DS et al. The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg 1996;223:134–140. [34] Raut CP, Grau AM, Staerkel GA et al. Diagnostic accuracy of EUS guided FNA in patients with presumed pancreatic cancer. J Gastrointest Surg 2003;7:118–126. [35] Sewnath ME, Karsten TM, Prins MH et al. A meta-analysis of the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2002;236:17–27.

612

Chapter 37 / CANCER OF THE PANCREAS

[36] Tran K, Smeenk H, van Eijck C et al. PPPD versus standard Whipple’s procedure: a randomized multicenter study of 170 patients with pancreatic or periampullary tumours. Ann Surg 2004;240: 738–745. [37] Takahashi S, Ogata Y, Tsuzuki T. Combined resection of pancreas and portal vein for pancreatic cancer. Br J Surg 1994;81:1190–1193. [38] Nagakawa T, Konishi I, Ueno K et al. Extended radical pancreatectomy for carcinoma of the head of pancreas. Hepatogastroenterology 1998;45: 849–845. [39] Yeo CJ, Cameron JL, Sohn TA et al. PD with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: comparison of morbidity and mortality and short term outcome. Ann Surg 1999;229:613–622. [40] Pedrazzoli S, Dicarlo V, Dionigi R et al. Standard versus extended lymphadenectomy associated with PD in surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective randomized study. Lymphadenectomy study group. Ann Surg 1998;228:508–517. [41] Cameron JL, Pitt HA, Yeo CJ et al. One hundred and forty five consecutive pancreaticoduodenectomies without mortality. Ann Surg 1993;217:430–438. [42] Burcharth F, Trillingsgard J, Oslen SD et al. Resection of cancer of the body and tail of pancreas. Hepatogastroenterology 2003;50:563–566. [43] Buchler M, Friess H, Klempa I et al. Role of Octreotide in the prevention of postoperative complications following pancreatic resection. Am J Surg 1992;163:125–130. [44] Gouillat C, Chipponi J, Baulieux J et al. Randomised controlled multicenter trial of somatostatin

[45]

[46] [47]

[48]

[49]

[50]

[51]

[52]

infusion after pancreato-duodenectomy. Br J Surg 2001;88:1456–1462. Li-Ling J. Irving: Somatostatin and Octreotide in the prevention of postoperative pancreatic complications and the treatment of enterocutaneous pancreatic fistulas: A systematic review of randomized trials. Br J Surg 2001;88:190–199. Gudjonsson B. Cancer of Pancreas: 50 years of surgery. Cancer 1987 Nov 1;60:2284–303. Neoptolemos JP, Stocken DD, Dunn JA. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001 Nov 10;358(9293):1576–85. Burris HA III, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13. Regional targeting chemoimmunotherapy in patients undergoing pancreatic resection in an advanced stage of their disease: a prospective randomized study. Ann Surg 2002 Dec;236:806–13. Picozzi VJ, Kozarek RA, Traverso LW. Interferonbased adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2003 May;185:476–80. Bruno MJ, Haverkort EB, Tijssen GP et al. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region. Gut 1998;42: 92–96. Wigmore SJ, Barber MD, Ross JA et al. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2000;36: 177–184.

test

Tropical Hepatogastroenterology

x

Part IX Parasitic Diseases

38 39 40

Intestinal and Extraintestinal Amebiasis Hydatid Cyst of the Liver Schistosomiasis

615 629 641

“This page intentionally left blank"

xx

Chapter

38

INTESTINAL AND EXTRAINTESTINAL AMEBIASIS MP Sharma and Vineet Ahuja

38.1 INTRODUCTION Intestinal protozoa have gained importance following increasing travel and growing numbers of immunosuppressed people. Protozoans that infect the gastrointestinal tract include Entameba histolytica, Giardia lamblia, and the spore forming parasites Cryptosporidia, Cyclospora, Isospora and Microsporidia. Of these, Entameba histolytica is one of the most prevalent intestinal protozoa in developing countries.

38.2 MICROBIOLOGY Amebiasis is the infection of the gastrointestinal tract by Entameba histolytica, a parasite that invades the intestinal mucosa and often spreads to other organs, particularly the liver.

38.2.1 Biology and Life Cycle E. histolytica exists in either trophozoite or cyst form. 38.2.1.1 Trophozoite

This is the motile form of Entameba. It is strongly affected by changes in temperature, pH, osmolarity, and redox potential. Actively motile amebas

are elongated whereas resting trophozoites tend to be spherical. The cell surface has numerous openings that correspond to the micropinocytic vesicle. The plasma membrane is covered by a uniform surface coat composed of glycoproteins. The binding of the lectin concanavalin A to the surface of the trophozoite suggests a high content of sugar residues. Interaction of the trophozoite plasma membrane with specific ligands induces a redistribution of surface components. This suggests that evasion of humoral immune response may be occurring through a sliding mechanism that involves both actin and myosin, regulated by calmodulin and a myosin light chain kinase. The cytoplasm of the trophozoite is characterized by the absence of mitochondria, Golgi apparatus, rough endoplasmic reticulum, centrioles, and microtubules. Instead, the cytoplasm contains abundant vacuoles.[1–3] 38.2.1.2 Cyst

The inability to encyst in axenic cultures has led to less extensive data on cysts of E. histolytica. The cysts are round or oval hyaline bodies, surrounded by a refractile wall composed of fibrillar material. The plasma membrane invaginates deeply to form polyribosomes, vacuoles and organelles containing dense fibrogranular material. Staining 615

616

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

with iron hematoxylin makes the cytoplasm appear vacuolated with numerous glycogen deposits that decrease in size and number as the cyst matures. Iodine stains allow the clear visualization of one to 4 small nuclei.[4] There are distinct species of Entameba that are morphologically identical. The existence of a species complex was first suggested in studies in which zymodemes (patterns of electrophoretic mobility of certain parasitic isoenzymes) were analyzed. Distinctive zymodemes were associated with symptomatic invasive disease or with asymptomatic carrier states. Further research with RNA and DNA probes clearly indicated two separate species–E. histolytica and E. dispar. Numerous antigenic differences between the two have been demonstrated. Distinct epitopes present on the 170 kDa heavy subunit of the galactose inhibitable adherence lectin, an important surface adhesin, and a highly conserved antigen are all found in E. histolytica but not in E. dispar. Monoclonal antibody probes have been used to differentiate between the two species. E. histolytica and E. dispar are morphologically indistinguishable from one another. The presence of ingested erythrocytes correlates positively with the presence of E. histolytica and not of E. dispar.[5, 6] E. dispar also colonizes the human gut but has no pathogenic potential.[7–10] The acceptance of E. dispar as a distinct but closely related protozoan species has had major implications for the epidemiology of amebiasis, since most asymptomatic infections are now attributed to this noninvasive ameba. 38.2.1.3 Life cycle

Man acquires infection by ingestion of the cyst form which is resistant to the acidic pH of the stomach. Excystation occurs in small bowel, with division of the mature quadrinucleated cyst into

four and then eight trophozoites by nuclear and cytoplasmic division. The trophozoites move to, and colonize in, the large bowel, where they feed on bacteria and cellular debris. If luminal conditions are unfavorable, the trophozoites may encyst. The cysts are excreted and remain viable for weeks or months. Trophozoites excreted during episodes of acute colitis rapidly degenerate and do not transmit infection. Infection results from ingestion of cyst in contaminated food or water.

38.3 EPIDEMIOLOGY The main reservoirs of E. histolytica are humans. It is estimated that 10% of the world’s population is infected by E. dispar or E. histolytica. E. dispar infection is approximately 10 fold more common than E. histolytica infection. Symptomatic invasive amebiasis develops in 10% of individuals with E. histolytica infection. Therefore, disease will develop in only one of 100 asymptomatic individuals whose stool microscopy shows Entameba. High rates of amebic infection are seen in the Indian subcontinent, in Southern and Western Africa, in the Far East and in areas of South and Central America.[11, 12] Asymptomatic E. histolytica infection results in a humoral immune response and consequent production of serum antibodies. E. dispar infection does not lead to a positive serology. There is a clear correlation between high seroprevalence, low socioeconomic and educational levels and inadequate housing conditions. Patients with a high mortality from invasive amebiasis, though not necessarily at increased risk of infection, include malnourished individuals, children younger than one year, pregnant women, and individuals receiving steroid therapy. No controlled studies have shown that people with the acquired immunodeficiency syndrome (AIDS) are more likely to develop invasive amebiasis or

Tropical Hepatogastroenterology

INTESTINAL AMEBIASIS

more fulminant disease, and E. dispar appears unable to cause invasive disease in this population too.[13, 14]

38.4 INTESTINAL AMEBIASIS 38.4.1 Pathogenesis The powerful lytic activity, responsible for the name of the parasite, has inspired efforts aimed at understanding the pathogenesis of invasive amebiasis. Intestinal invasive amebiasis is associated with amebic ulcerative colitis, toxic megacolon, ameboma, or amebic appendicitis. 38.4.1.1 Ulcers

Typical intestinal ulcers are found in the cecum, sigmoid colon, and rectum. These ulcers are characteristically shallow with broad elevated margins and are filled with fibrin.[15] The late invasive lesion with deep ulceration corresponds to the description of the flask ulcer described in the classical 1891 monograph of Councilman and Cafleur.[16] The mucosal ulcer extends deep into a larger area of the submucosa, which seems to be particularly susceptible to the lytic action of the parasite, and produces abundant microhemorrhages. Cell infiltration around invading amebas leads to rapid lysis of inflammatory cells and tissue necrosis. Thus acute inflammatory cells are seldom found in biopsy samples or in scrapings of rectal mucosal lesions. 38.4.1.2 Molecular events

Human colonic mucin effectively prevents the binding of E. histolytica to target cells in vitro by inhibiting the galactose and N-acetyl D galactosamine (Gal-Gal-Nac) adherence lectin of the parasite.[17, 18]

Part IX / Parasitic Diseases

617

The highly glycosylated colonic mucin could be the target of glycosidic cleavage by the parasite. Glycosidase activities detected in E. histolytica include glucosidase, galactosidase, mannosidase, fucosidase, xylosidase, glucuronidase, hyaluronidase, and others.[19, 20] As the trophozoites do not secrete glycosidases, their activity on intestinal mucus may be mostly due to the liberation of enzymes from lysed trophozoites. Histologically, three consecutive events occur at this stage: a focal superficial erosion of the mucosa, small glandular foci of microinvasion and mild to moderate infiltration of lamina propria. These changes result from a cellular interplay of adhesion, a contact dependent ‘hit and run’ damage to the plasma membrane of effector cells, and phagocytosis with intracellular degradation of ingested cells. The adhesion and cytolytic events depend on three types of molecules: lectins, amebapores, and proteases. Adhesion of the parasite occurs mainly through a surface Gal-Gal-Nac which binds to exposed terminal Gal-Gal-Nac residues of target cell glycoprotein.[21] The amebapores of E. histolytica, small but potent peptides, destroy ingested bacteria that serve as the main nutrients for the parasite in the otherwise nutrient scarce colonic environment.[22] During their passage to deeper layers of the intestine, trophozoites must lyse surrounding cells and degrade the extracellular matrix components of the colonic mucosa. This stage of the lesion is characterized by continuing lysis of cells, penetration through locomotion and proteolytic degradation of the extracellular matrix. Cystine proteases are the most abundant proteases in the parasite. Amebic cysteine proteases are active against a variety of substrates and increased activity has been reported in clones of high virulence.[23] (Navarro-Garcia et al. 1995) Of the extracellular matrix components that E. histolytica encounters during colonic invasion,

618

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

laminin, collagen type I and IV and fibronectin are good targets for amebic histolysin, ERCP5 membrane bound protease, and the neutral 56 kDa protease. At least five roles for cysteine proteinases can be envisioned during infection–(i) aiding attachment by degrading mucus and debris overlying the intestinal mucosa, (ii) aiding penetration of host tissue by digesting extracellular matrix, (iii) degrading host proteins to circumvent the immune response, (iv) activating host cell proteolytic cascades such complement, and (v) aiding dissemination to produce metastatic lesions.[24] 38.4.1.3 Immunology

IgA and IgE antibodies appear, after an unknown time, following infection with E. histolytica. Invasive intestinal amebiasis causes a transient local secretory response, followed by an increase in systemic antibodies.[25] The protective role of secretory IgA (and IgE) in amebiasis has not been established. High titers of antibodies tend to appear early in the disease. They persist after invasive amebiasis is cured, in patients whose subclinical amebiasis is cured, and in patients whose subclinical amebic infection is controlled. The detection of antibodies depends on the sensitivity of the test used. Thus, if antibodies are measured by the sensitive indirect hemagglutination test (IHA) or by enzyme linked immunosorbent assays (ELISA) they can be detected for more than three years after an invasive amebic episode in the absence of any recurrent infection. Immunologists are unraveling interesting mechanisms of parasite modulation of the host immune response. The main targets of this modulation appear to be neutrophils and macrophages, which although recruited at the site of the lesion, are unable to abort infection.[26] The parasite develops resistance to complement, and a mechanism for capping and shedding of surface antigens, so

that antibodies do not protect the host. Persons with elevated antibody titers nevertheless have a high rate of re-infection. Evidence of systemic cell mediated immunity in amebiasis has been confirmed by–(i) in vivo delayed hypersensitivity skin reactions and (ii) in vitro lymphokine blastogenic response, leukocyte adherence inhibition and lymphocytotoxic assays. Many patients however fail to react to delayed skin tests with amebic antigens during the early stages of the disease apparently due to a state of specific unresponsiveness. The presence of malnutrition in over 90% of cases of amebic liver abscess, and the significantly increased HLA-DR3 antigen levels found in Mexican patients with amebic liver abscess, both suggest that T cell mediated suppression is a factor in invasive amebiasis.[27, 28]

38.4.2 Clinical Features (Table 38.1) The term amebiasis includes all cases of human infection with E. histolytica. Only a proportion

TABLE fy 38.1 Clinical syndromes associated with E. histolytica infection • Intestinal amebiasis • Asymptomatic cyst passers • Acute amebic colitis – Mucosal disease – Transmural disease – Ulcerative postdysenteric colitis • Appendicitis • Ameboma • Amebic stricture • Extraintestinal amebiasis – Amebic liver abscess – Perforation and peritonitis – Pleuropulmonary amebiasis – Amebic pericarditis – Cutaneous amebiasis

Tropical Hepatogastroenterology

INTESTINAL AMEBIASIS

of cyst releasing individuals experience symptoms caused by the penetration of the parasite into the tissues, termed “invasive amebiasis”. The large group of infected asymptomatic individuals previously described as having ‘luminal amebiasis’ is thought to be composed mainly of E. dispar carriers.

619

TABLE fy 38.2 Surgical complications of intestinal amebiasis • • • • • •

Fulminant colitis Toxic dilatation Necrosis Perforation Bleeding Stricture

38.4.2.1 Intestinal amebiasis

There are 4 clinical forms of invasive intestinal amebiasis: acute dysentery, fulminant colitis, amebic appendicitis, and ameboma of the colon. Patients with acute amebic dysentery present with a 1 to 2 week history of abdominal pain, tenesmus, and frequent loose, watery stools containing blood and mucus. Despite the presence of mucosal ulcerations and occult blood in stools, leucocytes may not be found in feces because of the lytic activities of the parasites. Endoscopy may show the characteristic appearance of the punctate, hemorrhagic ulcers dispersed throughout a normal appearing mucosa.

38.4.3 Surgical Complications (Table 38.2) Fulminant colitis is a marked and extensive involvement of the colon, and presents with severe bloody diarrhea, fever, and diffuse abdominal tenderness of rapid onset. It may progress to toxic dilatation, perforation, and gangrene. Fulminant colitis is an unusual but serious complication of amebic dysentery, and has been reported in 3%– 5% of autopsies in patients who die of amebiasis. The disease may be so fulminant that only 25% of adults with colonic perforation evident at laparotomy present with a rigid abdomen.[29] An ameboma is a mass associated with bowel amebiasis, and develops in up to 5% of patients with amebic dysentery. They may be

Part IX / Parasitic Diseases

fibrolipomatous masses involving the entire thickness of the bowel wall, or masses associated with phlegmon formation near a deeply penetrating ulcer.[29] An ameboma may form the apex of an intussusception. Gastrointestinal bleeding is not uncommon in amebic colitis. However, massive hemorrhage is distinctly rare. Amebic proctocolitis accounts for about 5% of cases of lower gastrointestinal bleeding. Large bowel strictures are rare complications seen in fewer than 1% of cases of intestinal amebiasis. They are most often described in the anus, rectum, or rectosigmoid. Amebiasis causing appendicitis has also been described. Clinical features are those of acute appendicitis, although chronic right iliac fossa pain may occur.

38.4.4 Diagnosis A definitive diagnosis of invasive intestinal amebiasis is made by demonstration of E. histolytica parasite in the stool. These amebas may have ingested red blood cells (hematophagus trophozoites). 38.4.4.1 Stool specimen

E. histolytica cysts may remain viable for some time in unpreserved stools while trophozoites are labile and remain in stool for about 30 minutes.

620

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

The diagnostic yield is better if the specimen is collected over a period of 3 days or longer. For examination of a stool specimen, an iodine stained smear as well as a concentration test should be done. Microscopy does not distinguish between E. dispar and E. histolytica. Isoenzyme electrophoresis is available in a few laboratories only. Monoclonal antibodies that distinguish between pathogenic and nonpathogenic species are being used in antigen capture ELISA assays that will be very useful. Charcot Leyden crystals are associated with amebiasis but are not specific for it. 38.4.4.2 Sigmoidoscopic examination

Typical ulcers with normal intervening mucosa are often visualized. Scrapings may be obtained from the ulcer edge for immediate examination. 38.4.4.3 Serology

Serum antibodies to amebas develop only during E. histolytica infection and not during E. dispar infection. The absence of serum antibodies to E. histolytica after 1 week of symptoms is a strong evidence against the diagnosis of invasive amebiasis of the colon or liver. Serum antibodies to amebas are detected in 85%–95% of all patients who present with invasive amebiasis or liver abscess. However, as antibodies persist for many years, ELISA or IHA cannot differentiate acute from remote infection in areas of high endemicity. Purified native and recombinant parasitic antigens have been utilized in serological studies with good results. More than 95% of the patients with amebic liver abscess have serum antibodies to the 170 kDa subunit of the galactose inhibitable adherence lectin. This antigen is highly specific for differentiating acute phase serum from convalescent phase serum in areas of high endemicity.

38.4.4.4 Newer methods

Newer diagnostic strategies involve detection of protein antigens in feces or serum by monoclonal antibodies, and detection of parasitic DNA by use of nucleotide probes and PCR amplification. A commercial ELISA kit has recently been developed for clinical use; it uses monoclonal antibodies directed against an amebic adherence lectin and accurately differentiates the true pathogen E. histolytica from E. dispar.[30]

38.4.5 Treatment 38.4.5.1 Uncomplicated amebiasis

Amebicidal drugs (Table 38.3) may be classified into 3 groups: luminal, tissue and mixed amebicides. Diiodohydroxyquin, diloxanide furoate, and paromomycin are luminal amebicides. The amebicides effective in tissues are emetine and dehydroemetine, which act in the liver and intestinal wall, and chloroquine, which acts only in the liver. Emetine and dehydroemetine are currently not used because of their cardiotoxicity. Amebicides effective in both tissues and the intestinal lumen include the nitroimidazole derivatives– metronidazole, tinidazole and ornidazole. They

TABLE fy 38.3 Pharmacotherapy for E. histolytica infection in adults Intraluminal infection

Invasive colitis Amebic liver abscess

Diloxanide furoate 500 mg tid × 20 days Paromomycin 30 mg/kg/day × 10 days (3 divided doses) Iodoquinol 650 mg tid × 20 days Metronidazole 800 mg tid × 5 days Tinidazole 1 g bd × 3 days Metronidazole 800 mg tid PO × 10 days (500 mg qid IV)

Tropical Hepatogastroenterology

AMEBIC LIVER ABSCESS

are the drugs of choice in invasive amebiasis. Oral or intravenous metronidazole or tinidazole also leads to rapid clinical improvement of amebic liver abscess.[31] This drug should be followed by a luminally active drug.

621

N-acetyl D-galactosamine inhibitable lectin and the 29 kDa cysteine rich antigen.[32]

38.5 AMEBIC LIVER ABSCESS 38.5.1 Extraintestinal Amebiasis

38.4.6 Surgical Complications Fulminant colitis needs colectomy. Abdominal distension in unresponsive amebic colitis is an absolute indication for surgery. Localized dilatation and necrosis may be treated by segmental colectomy. More extensive disease requires total colectomy, with ileostomy and distal mucous fistula: a primary colorectal anastomosis is usually unsafe. The mortality in extensive fulminant colitis approaches 80%.[29] Amebomas are treated conservatively. Surgery is indicated if malignancy cannot be excluded, and if perforation or obstruction develops. Massive hemorrhage may need resection. The protocol is further described in the chapter “Lower Gastrointestinal Bleeding”. Amebiasis as a cause for appendicitis is usually diagnosed after appendectomy. The presence of amebic colitis worsens the results of appendectomy, and cecal blow-out, fistula formation, and amebiasis cutis may develop. Anal strictures may respond to dilatation. Severe strictures call for surgical resection, as do those where malignancy cannot be excluded.

Syndromes of extraintestinal amebiasis include amebic liver abscess, and liver abscess involving the pleura, lung, pericardium or peritoneum, brain abscess, and skin, and, rarely, genitourinary disease. Lesions in the lung and brain are complications of amebic liver abscess. Genital amebiasis is rare and is probably sexually transmitted.[29] Amebic liver abscess is the most common form of extraintestinal amebiasis. It is an inflammatory space occupying lesion of the liver caused by E. histolytica. The diagnosis of this condition has undergone major changes after the advent of advances in imaging and molecular biology techniques. This has also enabled a reappraisal of the disease with recognition of the wide variety of clinical presentations and multitude of complications.

38.5.2 Epidemiology The incidence of ALA varies between 3% and 9% of all cases of amebiasis.[33] In India, ALA is endemic. A liver abscess accounts for about 0.2% of hospital admissions and for about 75% of all liver abscesses.[29]

38.5.3 Clinical Features 38.4.7 Vaccine Recombinant peptides of three E. histolytica antigens show promise for prevention of experimental amebic liver abscess: the serine rich E. histolytica protein (SREHP) the 170 kDa subunit of the

Part IX / Parasitic Diseases

The classical description of an ALA needs to be modified due to a large number of patients who present with variants.[34, 35] Long-term follow-up of patients has helped in identifying the factors affecting the healing pattern. Separation of patients

622

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

at high risk is of clinical relevance so that more aggressive treatment can be instituted. Amebic liver abscess occurs most commonly in the age group of 20 to 45 years and has been noted infrequently at the extremes of age. It is seven to nine times more common in males. ALA may present as an acute process or as a chronic indolent disease. It is classified by the duration of illness and severity into – Acute Chronic

Acute benign Acute aggressive Chronic benign Chronic accelerated

Most patients present with an acute illness symptomatic for less than two weeks. The main presenting symptoms are abdominal pain, fever, and anorexia. Abdominal pain is usually moderate and localized to the right upper quadrant or to the epigastrium. Diffuse abdominal pain, pleuritic chest pain, and radiation of right upper quadrant pain to the right shoulder are not uncommon. Epigastric pain is commonly seen in left lobe abscesses. Fever is of moderate degree in most instances, while high fever with chills is suggestive of secondary bacterial infection. Cough, with or without expectoration and pleuritic chest pain, is also seen in ALA. During the course of illness one-third of the patients may develop clinical jaundice. Severe icterus is usually due to a large abscess, or multiple abscesses, or to an abscess situated at the porta hepatitis.[36] Jaundice raises diagnostic problems and brings in the possibilities of intrahepatic obstruction or viral hepatitis. Diarrhea and weight loss are not uncommonly seen. Unfortunately, diarrhea is such a common complaint in the tropics that it may not be given adequate consideration by the patient.

Tender hepatomegaly is detected in up to 80% of patients. The liver surface is generally smooth. Intercostal tenderness and bulging of the intercostal spaces may occur in large right lobe abscesses. Complications such as rupture into the pleura or peritoneal cavity may alter the clinical features. Upper abdominal guarding and rigidity is seen in a minority of cases with features of generalized peritonitis. However, it is the protean manifestations of the variants that may be a source of consternation to the clinician. Toxemia, deep jaundice, and encephalopathy may develop, particularly in patients with multiple abscesses. Toxemia is suggestive of an added bacterial infection leading to a more severe disease. E. coli and Klebsiella are the commonly cultured organisms. These patients present with a clinical picture indistinguishable from hepatic encephalopathy due to acute hepatocellular failure. Hepatic encephalopathy in ALA patients possibly results from a combination of right hepatic vein occlusion, pylephlebitis, and occlusion of several portal vein radicals.[37–39] Ascites developing in patients with ALA suggests the development or presence of inferior vena cava obstruction; and cough with copious expectoration suggests rupture into the communication with the right lower lobe bronchus. 38.5.3.1 Variants[35]

ALA usually occurs in the right lobe of the liver and is solitary (30%–70%).[40] Unusual presentations include multiple lobe abscesses, left lobe abscesses, abscesses presenting as compressive lesion, and abscesses rupturing into viscera. These are clinically important due to the curable nature of this disease and potentially fatal outcome in untreated abscesses.

Tropical Hepatogastroenterology

AMEBIC LIVER ABSCESS

38.5.4 Multiple Liver Abscesses Fifteen percent of patients may have multiple abscesses. They are more likely to present with fever, toxemia, deep jaundice, and encephalopathy. 38.5.4.1 Left lobe abscess

Thirty-five per cent of ALA patients will have a left lobe abscess.[41] Half of these have associated lesions in the right lobe while the remainder have solitary left lobe abscesses. These patients have a longer duration of symptoms (3–4 weeks), and fever is less commonly observed as compared to right lobe abscesses. The patient may present with a large epigastric mass with minimal movement on respiration. Clinicians have often confused it with a pseudocyst of the pancreas. The patient also has weight loss with poor hepatic localization of symptoms. Complications like peritonitis and toxemia are significantly more common in left lobe abscesses. Needle aspiration may be more rewarding in combination with antiamebic drugs. A high index of suspicion and early diagnosis are important for proper management.

623

cavity is usually associated with shock and generalized peritonitis, and may occur in up to 7% of cases. Rupture into the colon and biliary tree has also been reported.[33] A subhepatic collection may also be localized and walled off. Such presentations have, however, been rare and form a small number of cases in any series in ALA. The above clinical patterns have been described more frequently with the routine availability of ultrasound and serological assays. These clinical variants are important because of their therapeutic and prognostic significance. The best outcomes occur in patients with a solitary abscess.

38.5.5 Diagnosis Ultrasound is very useful for the diagnosis of amebic liver abscess. Classically, the abscess appears as a nonhomogeneous hypoechoic round or oval mass with well defined borders. (Fig. 38.1) Complete sonologic resolution of an amebic liver abscess may take up to two years. Occasionally, percutaneous diagnostic needle aspiration may be needed to differentiate between an amebic and pyogenic liver abscess.

38.5.4.2 Compression lesions

A posteriorly located ALA in the right lobe may present as inferior vena cava obstruction or hepatic outflow obstruction.[39] This is suggested by bilateral pedal edema, ascites, visible veins on anterior and posterior abdominal wall, along with clinical, radiological and serological features of ALA. These features disappear after aspiration of the abscess. 38.5.4.3 Extension of the abscess

Leakage of the abscess may occur into the pleural cavity, with empyema thoracis. Intra-abdominal extension following perforation into the peritoneal

Part IX / Parasitic Diseases

FIGURE 38.1 Ultrasound picture of a patient with an amebic liver abscess. Note the slightly irregular walls of the abscess (A).

624

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

rarely, and used in seriously ill patients when the risk of failure of therapy is unacceptable. The response to antiamebic drugs is usually evident within 48–72 hours with the subsidence of toxemia, abdominal pain, anorexia, jaundice, guarding and tenderness in the Right hypochondrium, and hepatomegaly. 38.5.6.2 Aspiration or drainage of abscess (Table 38.4) FIGURE 38.2 CT scan showing a liver abscess in the right lobe.

Detection of amebic lectin antigen in serum samples from patients with amebic liver abscess is also more than 95% sensitive if used prior to treatment with metronidazole. The CT scan shows the liver abscess well, but is infrequently required. (Fig. 38.2)

38.5.6 Treatment 38.5.6.1 Medical therapy

Medical therapy may be instituted using either a single agent or a combination of drugs for the extraluminal parasite. Nitroimidazoles including metronidazole are effective in over 90% of cases. Therapy should continue for at least 10 days. Relapses have been reported with this duration of therapy and the drug may need to be administered for up to 3 weeks. The dose of metronidazole is 40 mg/kg/day in divided dosages. Tinidazole has been used in a dose of 1.2 g per day for 7 days, but this dosage has not been firmly established. Chloroquine, emetine, and dehydroemetine have been used. Singleagent therapy with metronidazole yields excellent results. The alternative toxic drugs are indicated

Routine aspiration of liver abscess is not indicated for diagnostic or therapeutic purposes.[42] A combination of ultrasonographic finding with a positive serology in the appropriate clinical setting is adequate to start drug therapy. Aspiration is indicated in patients with lack of clinical improvement in 48–72 hours, those with left lobe abscess, where ultrasonography shows a very thin rim of liver tissue around the abscess (< 10 mm), and in seronegative abscesses to exclude pyogenic abscess.[43] The aspirate is anchovy-sauce type in half of the patients. The chocolate color is due to admixture of blood with liver tissue. Antiamebic therapy alone is as effective as routine needle aspiration combined with anti-amebic therapy in the treatment of patients with uncomplicated amebic liver abscess.[44, 45] Percutaneous catheter drainage of a liver abscess has been infrequently evaluated.[46, 47] Like aspiration, it is done under ultrasound guidance, usually with a 10F or 12F catheter. It offers quicker relief of pain and fever than medical therapy alone.

TABLE fy 38.4 Indications of aspiration in liver abscess • • • •

Lack of clinical improvement Left lobe abscess Thin rim of liver tissue around the abscess Seronegative abscesses

Tropical Hepatogastroenterology

SEXUALLY TRANSMITTED AMEBIASIS

However, complications such as bile leak, hemorrhage, and secondary infection occur in about 15% of patients, and therefore repeated aspirations may be preferable. 38.5.6.3 Surgical therapy [29]

Open surgical drainage is infrequently required. Relative indications include the large abscess with a poor yield on needle aspiration, clinical deterioration despite aspiration, and repeated symptomatic recurrences after aspiration. Rupture into the peritoneal cavity is an absolute indication. The approach to the liver is usually transperitoneal. At surgery, the abscess is opened and the contents sucked out. Patients with intraperitoneal rupture require a laparotomy and peritoneal toilet. Rupture into the lung or pericardium is treated as for other causes of empyema and pyopericardium. Surgical mortality may be high in very sick patients. 38.5.6.4 Long-term follow-up

After clinical cure, patients show few symptoms. Sonographic follow-up demonstrates evidence of persistent hypoechoic lesion.[48] The mean time for disappearance of the sonographic abnormality is 6–9 months. Relapses are very uncommon and the sonographic abnormality does not warrant continued therapy. The patterns of resolution that have been seen on sonographic follow-up include: type I, where complete disappearance of the cavity occurs within 3 months (29.8%); type II, where a rapid reduction till 25% of the original cavity size and then a delayed resolution occurs (5.9%). Factors influencing healing time include the size of abscess cavity at admission, hypoalbuminemia and anemia. In multiple abscesses the type of

Part IX / Parasitic Diseases

625

clinical presentation, nature of therapy, number or location of abscesses, and time for clinical resolution are similar to those of solitary abscesses, and the number of abscesses does not significantly influence the healing patterns or rates. The total abscess volume of all the cavities is the most important factor that influence resolution time in multiple abscesses. Clinical resolution does not correlate with ultrasonographic resolution, and clinical criteria rather than ultrasonography should monitor the result of therapy.

38.5.7 Prognosis There are two major categories of patients with ALA: those with a good prognosis and those with a poor prognosis (Table 38.5). These groups can be easily identified by evaluation of clinical, biochemical and sonographic criteria. Bilirubin > 3.5 mg/dL, encephalopathy, volume of abscess cavity, and hypoalbuminemia (serum albumin level < 2.0 g/dL) are independent risk factors for mortality.[49] The duration of symptoms and the type of treatment do not influence mortality.

38.6 SEXUALLY TRANSMITTED AMEBIASIS Amebiasis can also be classified as a sexually transmitted disease. Most homosexual men with amebiasis are asymptomatic, and invasive disease in this group is extremely rare.[50]

TABLE fy 38.5 Poor prognostic markers in amebic liver abscess • • • •

Bilirubin > 3.5 mg/dL Encephalopathy High volume Hypoalbuminemia

626

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

Penile amebiasis is rare.[51] Homosexual men have a higher risk of acquiring the lesion. Amebic ulcers resemble cutaneous lesions arising from squamous cell carcinoma, chancroid, primary syphilis, granuloma inguinale, and many other causes. An amebic ulcer should be suspected in a patient with balanoposthitis that resists antibiotic therapy. Biopsy is essential to confirm the diagnosis. Metronidazole and emetine are still the drugs of choice. This diagnosis should especially be considered in

lesions detected in patients who practice anogenital sex or those who are immunocompromised. E. histolytica is a common commensal in the homosexual population. In the absence of invasive disease, treatment of persons passing cysts has little benefit. Unlike tuberculosis, cytomegalovirus infection, Pneumocystis carinii pneumonia and toxoplasmosis, the frequency or severity of invasive amebiasis is not increased in patients with AIDS.[52]

REFERENCES [1] Espinosa-Cantellano M et al. Entamoeba histolytica: Mechanism of surface receptor capping. Exp Parasitol 1994;79:424–35. [2] Martinez-Palomo A. Biology of Entamoeba histolytica, amebiasis, ed Martinex-Palomo A, Elsevier, Amsterdam, 1986;11–43. [3] Martnez-Palomo A. Parasitic amebas of the intestinal tract,. In: Kreier JP, Baker JT (Editors), Parasitic Protozoa, eds Kreier JP, Baker JT, Academic Press, San Diego 1993;65–141. [4] Gonzalez-Robles A et al. The fine structure of Entamoeba histolytica processed by cryo-fixation and cryosubstitution. Arch Med Res 1992;23: 73–6. [5] Horstmann RD et al. Recent progress in the molecular biology of Entamoeba histolytica. Trop med Parasitol 1992;43:213–8. [6] Ravdin JI. Entamoeba histolytica (amebiasis). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practices of infectious diseases. 4th ed. New York: Churchill Livingstone. 1994;2395–408. [7] Anonymous. Entamoeba taxonomy. Bull W.H.O. 1997;75:291–292. [8] Clark CG. Entamoeba dispar, an organism reborn. Trans R Soc Trop Med Hyg 1998;92:361–364. [9] Diamond LD et al. A redescription of Entamoeba histolytica Schaudinn, 1903 (amended Walker,

[10]

[11]

[12]

[13] [14]

[15]

[16] [17]

1911) separating it from Entamoeba dispar Brumpt. J Eukaryot Microbil 1925;40:340–344. Martinez-Palomo A. Amoebiasis: new understanding and new goals. Parasitol Today 1998;14: 1–3. Roche J. Prevalence of intestinal parasite infections with special reference to Entamoeba histolytica on the island of Bioko (Equatorial Guinea). Am J Trop Med Hyg 1999;60:257–262. Haque R. Prevalence and immune response to Entamoeba histolytica in preschool children in an urban slum of Dhaka, Bangladesh. Am J Trop Med Hyg 1999;60:1031–1034. Reed SL. Entamoeba histolytica infection and AIDS. Am J Med 1991;90:269–271. Germany Y. Etiologies of acute persistent, and dysenteric diarrhoeas in adults in Bangui, Central African Republic in relation to human immunodeficiency virus serostatus. Am J Trop Med Hyg 1998;59:1008–1014. Prathap K. The histopathology of acute intestinal amebiasis. A rectal biopsy study. Am J Pathol 1970;60:229–245. Councilman WG. Amebic dysentery. Johns Hopkins Hosp Rep 1891;2:395–548. Chadee KWA. Binding and internalisation of rat colonic mucins by the galactose/N-acetyl

Tropical Hepatogastroenterology

REFERENCES

[18]

[19] [20]

[21]

[22]

[23]

[24]

[25] [26]

[27]

[28]

[29]

[30]

D-galactosamine adherence lectin of E. histolytica. J Infect Dis 1988;158:398–406. Gottke MU et al. Functional heterogeneity of colonic adenocarcinoma mucins for inhibition of Entamoeba histolytica adherence to target cells. J Eukaryot Microbiol 1998;45:17S–23S. Muller FW et al. Secretory hydrolases of E. histolytica. J Exp med 1982;155:42–51. Spice WM et al. The effects of Entamoeba histolytica lysates on human colonic mucins. J Eukaryot Microbiol 1998;45:24S–27S. Petri WA. Subunit structure of the galactose and N-acetyl-D-galactosamine-inhibitable adherence lectin of Entamoeba histolytica. J Biol Chem 1989;264:3007–3012. Leippe MS. Pore-forming peptide of pathogenic Entamoeba histolytica. Proc Natl Acad Sci USA 1991;88:7659–7663. Navarro-Garcia FL. Entamoeba histolytica: increase of enterotoxicity and of 53 and 75-kDa cysteine proteinases in a clone of higher virulence. Exp Parasitol 1995;80:361–372. Espinose Castellano M. Pathogenesis of Intestinal amoebiasis : from Molecules to disease. Clin Microbiol Review 2000;13:318–331. Kelsall BL et al. Degradation of human IgA by Entamoeba histolytica. J Infect Dis 1993;168:1319–22. Que X et al. Cysteine proteases and pathogenesis of amebiasis. Clin Microbiol Review 2000;13: 196–206. Salata RA et al. Patients treated for amebic liver abscess develop a cell mediated immune response effective in vitro against Entamoeba histolytica. J Immunol 1986;136:2633–9. Salata RA et al. The role of gamma interferon in the generation of human macrophages and T lymphocytes cytotoxic for Entamoeba histolytica. Am J Trop Med Hyg 1987;37:72–8. Chaudhary A. Amebiasis. In: Sood S, Krishna A (Editors), Surgical Diseases in Tropical Countries, Jaypee Brothers, New Delhi, 1995, p 1–10. Haque R et al. Diagnosis of amebic liver abscess and intestinal infection with the TechLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol 2000;38:3235–3239.

Part IX / Parasitic Diseases

627

[31] Irusen EM. Asymptomatic intestinal colonization by pathogenic Entamoeba histolytica in amebic liver abscess: prevalence, response to therapy and pathogenic potential. Clin Infect Dis 1992;14: 889–93. [32] Stanley Jr SL. Progress towards an amebiasis vaccine. Parasitol Today 1996;12:7–14. [33] Peters RS, Gitlin N, Libke RD. Amebic liver diseases. Ann Rev Med 1982;32:161–74. [34] Sharma MP, Ahuja V. Amoebic liver abscess: clinician’s perspective. Bombay Hosp J 1997;39:615–9. [35] Sharma MP, Dasarathy S, Sushma S et al. Variants of amebic liver abscess. Arch Med Res 1997;28: S272–73. [36] Data DV, Saha S, Singh SA et al. The clinical pattern and prognosis of patients with amebic liver abscess and jaundice. Am J Dig Dis 1973;18:883–98. [37] Kapoor OP, Joshi R. Multiple amoebic liver abscess. A study of 56 cases. J Trop Med Hyg 1992;75: 4–6. [38] Sakltzmann DA, Smithline N, Davis JR. Fulminant hepatic failure secondary to amebic abscesses. Am J Dig Dis 1978;23:561–7. [39] Sharma MP, Sarin SK. Inferior vena caval obstruction due to amoebic liver abscess. J Assoc Physicians India 1990;30:243. [40] Sharma MP, Sarin SK. Amoebic liver abscess in a north Indian hospital – current trends. Br J Clin Pract 1987;41:789–93. [41] Sharma MP, Sarin SK, Acharya SK. Left lobe amebic abscess of liver – A distinct clinical entity. J Assoc Physicians India 1984;32:477. [42] Sharma MP, Rai RR, Acharya SK. Needle aspiration in amoebic liver abscess. Br Med J 1989;299: 1309–9. [43] Dela Rey Nel J, Simjee AE, Patel A. Indication for aspiration of amoebic liver abscess. S Afr Med J 1989;75:373–6. [44] Sharma MP, Dasarathy S. Amoebic liver abscess. Trop Gastroenterol 1993;14:3–9. [45] Sharma MP, Ahuja V. Management of amebic liver abscess. Arch Med Res 2000;31:S4–5. [46] Singh HP, Kashyap A. A comparative evaluation of percutaneous catheter drainage for resistant amoebic liver abscesses. Am J Surg 1989;158:58–62.

628

Chapter 38 / INTESTINAL AND EXTRAINTESTINAL AMEBIASIS

[47] Arora P. Comparison of conservative therapy and percutaneous catheter drainage in amebic liver abscesses: a prospective, randomized clinical trial. Thesis for MS, University College of Medical Sciences, Delhi 1995. [48] Sharma MP, Dasarathy S, Sushma S et al. term follow up of amoebic liver abscess: clinical and ultrasound patterns of resolution. Trop Gastroenterol 1995;16:24–8. [49] Sharma MP, Dasarathy S, Verma N et al. Prog-

nostic markers in amebic liver abscess: a prospective study. Am J Gastroenterol 1996;91: 2584–8. [50] Cimerman S et al. Enteric parasites and AIDS. Sao Paulo Med J 1999;117:266–73. [51] Hejase MJ et al. Amebiasis of the penis. Urology 1996;48:151–4. [52] Jessurun J. The prevalence of invasive amebiasis is not increased in patients with AIDS. AIDS 1992;6:307–9.

Tropical Hepatogastroenterology

Chapter

39 HYDATID CYST OF THE LIVER Anil K Agarwal, Shivendra Singh, and K Rajkumar

39.1 INTRODUCTION Hydatid disease (Hydatidosis, Echinococcosis) is a zoonosis caused by the larval stage of Taenia Echinococcus. Humans are the accidental intermediate hosts. Echinococcus granulosus causes cystic hydatid disease while E. multilocularis causes alveolar echinococcosis. Two other species, E. oligarthrus and E. vogeli, occur rarely in humans. Cystic hydatid disease is discussed in this chapter.[1, 2]

39.2 EPIDEMIOLOGY Echinococcus granulosus lives in the small intestine of dogs and other carnivores. Infection with Echinococcus granulosus occurs worldwide. The disease occurs more commonly in sheep raising areas, but the distribution is wide, as the dog, the definitive host, is common all over the world. Echinococcosis is endemic in Mediterranean countries, Middle and Far East, South America, Australia, New Zealand and East Africa. The larval (cystic) stage of the parasite produces disease in humans as well as in animals such as sheep, cow, goat, camel, buffalo and horse. These act as intermediate hosts. Definitive hosts are dogs. The most common domestic linkage is dog-sheep. Humans are accidental intermediate

hosts and contact disease from dogs. The disease is not transmitted from person to person, or from one intermediate host to another.

39.3 LIFE CYCLE OF E. GRANULOSUS The tapeworm lies in the terminal ileum of the definitive host attached to the villi. The adult tapeworm has a head (scolex), neck, and 3–5 segments. Its length is 3–6 mm. The last or gravid segment is disproportionately large and contains about 5000 eggs. During the life of the adult tapeworm this segment detaches from the worm and disintegrates in the alimentary tract of the definitive host releasing the eggs with the dog’s feces. The eggs are very resistant to physical agents. These eggs are the ingested by the intermediate host such as sheep while grazing. Humans are accidental intermediate host, getting infected by direct contact with the dogs or indirectly by food, water, or contaminated objects. Direct contact in childhood is the most common route. Humans represent the end stage of the parasitic life cycle. In the duodenum the eggs hatch and the oncosphere or hexacanth (boring) embryo penetrates the mucosa using its hooklets and reaches the blood vessel. Through the blood stream it can reach anywhere in the body, but most frequently it gets lodged in liver. In the liver/lung it develops its 629

630

Chapter 39 / HYDATID CYST OF THE LIVER

larval stage (hydatid cyst). Development of the fully mature metacestode (i.e., hydatid cyst) may take several months to years. Dog gets infected by ingesting viscera of dead animals containing fertile cysts with viable protoscolices. The adult tapeworm develops from ingested protoscolices in 5–6 weeks. This cycle with one definitive and one intermediate host is the sexual cycle and the resulting disease in humans or animals is named primary echinococcosis. There is an asexual, minor cycle where the new hydatid cyst develops from any element of the larval stage of the parasite in the same intermediate host. This disease in humans is known as secondary echinococcosis.

39.3.1 Development in the Intermediate Host (Humans) In the duodenum, bile salts activate the oncosphere which then penetrates the mucosa and enters into the portal vein and reaches the liver. If the Kupffer cells of liver do not destroy the oncosphere it penetrates the hepatic veins, and the larval stage can then develop practically in any organ. A small hydatid follicle may be identified within 12 hours of infestation. If the parasite survives the hydatid cyst becomes visible to the naked eyes by the 3rd week. Growth is usually even, giving its usual spherical shape. The cyst generally increases by about 1 mm in diameter per month. Central hydatid cysts have a slower growth rate as compared to superficially located cysts because of surrounding high pressure liver parenchyma. By five months the main adventitious capsule is produced from host liver tissue forms. This is known as ‘pericyst’. The outer layer of pericyst is formed of atrophic liver cells. The fully developed cyst wall has two layers – an outer laminated membrane or ectocyst and an inner germinal membrane or endocyst. The

laminated membrane is bluish-white, shiny, gelatinous and about 5 mm thick. It is a very efficient barrier for bacteria. The germinal membrane is 10– 25 microns thick and not visible to naked eyes. It is responsible for the production of the crystal clear hydatid fluid, the ectocyst, brood capsules, scolices, and the daughter cysts. The germinal membrane forms small cellular masses which give rise to brood capsules in which the future worm develops. Many small brood capsules and freed protoscolices released into the fluid of the original cyst, together with calcareous bodies, form ‘hydatid sand’. Hydatid sand may contain about 400,000 scolices in 1 ml of fluid. Death of hydatid cyst occurs when germinal layer degenerates and production of laminated membrane ceases. Hydatid fluid gets absorbed and cyst wall gets calcified. But not every calcified cyst is dead.

39.4 CLINICAL FEATURES Hydatid disease presents as one or more welldelineated spherical primary cysts, most often in liver, followed by lungs. However, it has been reported in several organs – both intra and extraabdominal such as in the kidney, spleen, brain, heart, bone, and pancreas. Most patients have a single organ involvement; however, the simultaneous involvement of 2 or more organs occurs in 10% to 15% of patients. Liver is involved in over 90% of cases, with the right lobe being more commonly affected. The isolated involvement of extrahepatic sites is uncommon, but seen. We recently managed two patients presenting with isolated splenic hydatid. A simple, uncomplicated liver hydatid remains clinically latent for long time. The latency period may vary from months to years; often the cyst may be detected on ultrasonic imaging for nonspecific/unrelated symptoms. Symptoms usually

Tropical Hepatogastroenterology

COMPLICATIONS

appear due to size, or when some complication in the form of cyst-biliary communication, infection in the cyst, or pressure on the adjacent viscera occurs. The most common presentation is a dull aching right upper quadrant pain, and occurs in 60% of patients. Other presentations include dyspepsia (38%), nausea, vomiting (22%), jaundice (8–15%), fever (8%), and generalized pruritus (3%). Around 15%–25% of patients are asymptomatic.[3] On clinical examination, hepatomegaly is seen in 65% of patients. A pulmonary hydatid may present with chronic cough, hemoptysis, pneumothorax, pleuritis, lung abscess, and parasite lung embolism. Occasionally, compression of the portal pedicle or hepatic vein can result in atrophy-hypertrophy or a Budd-Chiari syndrome respectively. Hydatids in other sites such as heart, brain, or bone present with symptoms arising due to pressure and complications. Virtually no site in the body is immune to cystic hydatid disease.

39.5 COMPLICATIONS 39.5.1 Infection This generally occurs after a breach in the laminated membrane. The breach is usually associated with biliary communication.[4] This is followed by secondary invasion by pyogenic organisms. It then presents as pyogenic abscess, and the parasite dies. The incidence of infected hydatid cyst is 11%– 27%.[5] The infected cyst is usually defined as a symptomatic cyst presenting with signs of infection, pus at operation, and positive culture. The most frequently isolated organism is E. coli.

39.5.2 Rupture (Internal/External) Enlargement in the hydatid cyst causes compression of surrounding hepatocytes leading to their

Part IX / Parasitic Diseases

631

atrophy and fibrosis. Cysts grow along the path of least resistance and finally the cyst can rupture. Rupture can be of two types. In obscure rupture there is only endocyst rupture and the contents are retained inside the pericyst. In communicant rupture, the contents enter into the biliary tree or bronchial tree. As the cyst enlarges it causes compression of intrahepatic or extrahepatic bile ducts leading to an increase in the intraductal pressure. This causes horizontal or longitudinal fissures in the bile duct wall. Bile leaks through these breaches, and collects outside the laminated membrane. This is known as ‘internal rupture’. If the pressure increases further, the cyst ruptures into the biliary tract. This is known as ‘external rupture’. Rupture into the biliary tree can be occult or silent with no obvious bile duct communication. In these, bile leaking through the eroded small bile ductules seeps into the cyst through the cracks in the laminated membrane. Around 90% of cyst-bile duct ruptures are silent. Rupture into biliary tract is characterized by a triad of biliary colic, recurrent jaundice, and cholangitis, with the passage of germinative membranes in the feces. This can also cause anaphylaxis, though more frequently it presents with urticarial rash and pruritus. The incidence of rupture into the biliary tract is 5%–25%.[6] The incidence of diaphragmatic or transdiaphragmatic thoracic involvement is 0.6%– 16%.[7] Free rupture may occur into peritoneal, pleural or pericardial cavity. The incidence of free peritoneal rupture is 1%–4%.[8, 9] It can occur spontaneously due to high intracystic pressure or due to minor trauma. Intraperitoneal rupture can present as acute abdomen or anaphylactic shock, or it may remain silent and present years later with disseminated abdominal hydatidosis. This phenomenon is called secondary echinococcosis.

632

Chapter 39 / HYDATID CYST OF THE LIVER

39.6 DIAGNOSIS The diagnosis is often made by typical imaging with the aid of serology. Sonography is usually the primary investigation performed. Typical ultrasound characteristics when present may be virtually diagnostic. However, often the other cystic lesions of the liver cannot be excluded on ultrasound imaging.

39.6.1 Ultrasound The ultrasound is useful to characterize and confirm the cystic nature of the lesion. It can demonstrate daughter cysts within the main cyst. In patients with jaundice due to hydatid membranes blocking the biliary tree, ultrasonography may be helpful in differentiating membranes from stones.[10] Gharbi and coworkers[11] classified liver hydatid cysts into 5 types based on ultrasound findings. These types are supposed to correspond to the various evolutionary stages of hydatid cyst. This classification is also useful in planning the treatment. Type I : Pure fluid collection Type II : Fluid collection with split wall Type III : Fluid collection with septa Type IV : Heterogenous appearance Type V : Reflecting thick walls An alternative classification is that described by Weil.[12] Type I – Simple Hydatid cyst. (Weil defined a cystic lesion with a clearly defined cyst wall.) Hydatid sand characterized by hyperechogenic foci floating freely in the cyst fluid might be present. These cysts can also have budding signs on the germinal layer. Type II – Rosette appearance – due to multiple daughter cysts.

Type III – Solid or semisolid appearance – as the cyst is filled with an amorphous mass. At this stage it can be confused with tumor, liver abscess, or hemangioma. The presence of cyst wall calcification and hypoechoic lacunar structures in the matrix helps in differentiating. Type IV – Completely calcified cyst – eggshell appearance on ultrasound. Ultrasonography also gives the localization of the cyst and its relation with important vascular biliary structures, though this is better assessed on CECT. Dilated bile ducts can be seen in 5%– 7% and daughter cysts in the CBD is seen in 2%–5%.

39.6.2 CECT/MRI CT is the best investigation to assess the site and its relation with the major vascular and biliary channels which would be helpful in treatment planning. Daughter cysts and exogenic vesiculation are also better seen, which is important during surgery to prevent any recurrence. The density of the cyst contents gives an idea about cyst vitality. MR gives almost all the information that CT gives. Additionally, it can detect the hydatid membranes in the bile duct on MRCP images. It is more useful in skeletal, vertebral, and cardiac hydatidosis.[13]

39.6.3 ERCP It has both a diagnostic and therapeutic role in patients of hydatid cysts with suspected cystbiliary communication. Cyst-biliary communication can be demonstrated by ERCP;[14] and ERCP can be therapeutic in patients with obstructive jaundice due to membranes in the bile duct or if the patient is having cholangitis.[15] The following are the indications of ERCP (with or without endoscopic papillotomy or stenting):

Tropical Hepatogastroenterology

MANAGEMENT

A. Preoperative 1. If hydatid membranes are suspected in the bile duct 2. Cholangitis B. Postoperative 1. Hydatid debris in the bile duct is present 2. Biliary fistula 3. Postoperative jaundice 4. Suspected caustic sclerosing cholangitis

39.6.4 Immunological Tests The older Casoni’s intradermal test and intracutaneous Pontan test have low sensitivity (60%– 70%) as well as low specificity due to high false positive reactions.[16] The newer serological tests such as immunofluorescence assay, indirect hemagglutination, immunoelectrophoresis, complement fixation, latex agglutination, enzyme-linked immunosorbent assay (ELISA) or co-electrosyneresis with antigen 5 identification confirm the diagnosis in 80%–96% of patients with liver hydatid. The main drawback of the serological tests is low specificity, as there are frequent false positive results in patients with malignancies, cirrhosis, or the presence of anti-P1 antibodies.[17] These tests are also less sensitive for extrahepatic cysts. ELISA has a high specificity and accuracy independent of disease stage and site of cyst.[18] Serological tests are of little benefit in the follow-up of the patients after surgery or medical treatment as they remain positive for long, 6– 12 months after successful treatment of the disease. Complement fixation and radioallergosorbent test (RAST) become negative within 1 year, and may be used in follow-up.[19, 20] Human basophil degranulation test also has high sensitivity (87%), and becomes negative after 1 week of surgery.[21] Aspiration cytology appears to be particularly helpful in the detection of pulmonary, renal, and

Part IX / Parasitic Diseases

633

other extrahepatic lesions for which imaging techniques and serology are not diagnostic.

39.7 MANAGEMENT Management guidelines were laid out in the OIE and WHO manual on Echinococcosis published in 2001.[22] The mainstay of treatment of Hydatid disease is surgical or radiologic-guided intervention. Medical therapy alone is used in cases unsuitable for these interventions, or as an adjunct to prevent recurrence.

39.7.1 Medical Treatment Medical treatment alone is not the preferred treatment modality. It is often used as an adjunct to surgical/radiological management in the preoperative/periprocedure period to reduce the risk of recurrence resulting from accidental spillage. It is also used in small cysts in inaccessible regions inappropriate for other interventions or in patients unsuitable for intervention either on temporary (such as pregnancy) or on long term basis (comorbidity). The indications of medical treatment are: 1. Widely disseminated disease/multiorgan involvement 2. Poor surgical risk patients with localized disease 3. Small, unilocular, asymptomatic, inaccessible (lying deep in the parenchyma < 4 cm) Medical therapy is used in conjunction with other interventional treatment: Patients with spontaneous rupture of cyst Patients with intraoperative spillage As pre-op and post-op prophylaxis Drugs used for medical therapy include 1. Benzimidazole group – mebendazole, albendazole, flubendazole

634

Chapter 39 / HYDATID CYST OF THE LIVER

2. Praziquantel (Isoquinoline) 3. Newer drugs (a) Immune stimulants (b) Trans-2-phenoxy cyclohexolol ethers – these inhibit both in-vitro and in-vivo E-multilocularis. The combination of albendazole and praziquantel is the most effective, and is the drug treatment of choice. 39.7.1.1 Efficacy

Some authors have reported a high response rate with albendazole, with disappearance of the cyst in 50% of patients. In others it causes shrinkage, with cyst wall and intracystic changes. However, the recurrence rate is about 30%.[23] Medical treatment is most effective in pulmonary hydatid, followed by liver disease. It is ineffective for disease of the bone, brain, eye, and other sites. Large cysts which have an intact laminated membrane and are capable of endogenous vesiculization are more resistant to the drugs than small cysts with a thin pericyst. The following are the drawbacks of medical treatment: 1. It is not possible to assess the viability of cyst before treatment 2. It is unclear that decrease in cyst size indicates death of parasite 3. Serological tests are also not good for assessing response 4. The natural history is unpredictable. 39.7.1.2 Mechanism of action

Benzimidazoles kill the larval stage of both E. granulosus and E. multilocularis by limiting their cellular glucose uptake and lowering the glycogen level. They cause death of germinal

membrane cells, and the cyst loses its ability to maintain homeostasis and integrity. Albendazole is the only drug that is ovicidal, larvicidal, and vermicidal. In the body, it is converted into 3 metabolites – albendazole sulfoxide, albendazole sulfone, and albendazole 2-aminosulfone. Albendazole is better absorbed than mebendazole because its metabolite albendazole sulfoxide is more consistently absorbed. Praziquantel is effective both in-vitro and invivo, but most data at present are in-vitro or animal studies. Praziquantel combined with albendazole is more effective than either drug used alone. Praziquantel causes two effects. At lowest effective concentration it causes increased muscular activity followed by contraction and spastic paralyses. At a slightly higher concentration it causes vacuolization and vesiculation of the tegument. Praziquantel is a very effective scolicide but has limited activity on the germinal layer. Therefore, it may be useful in prophylaxis around the time of surgery or other time of spillage. Praziquantel, 50 mg/kg daily for 4 weeks, followed by 3 doses per week for two months in combination with albendazole is very effective, and has a quicker response than albendazole alone. It causes a rapid decrease in size and destruction of the cyst wall, intracystic changes and disappearance of some of the cyst in a relatively short period of treatment. 39.7.1.3 Dosage

Mebendazole is to be given 20–50 mg/kg in three divided doses for 21–30 cycle for a minimum of three months and it may be increased to one year. For albendazole, WHO has recommended three, 28 days course of 10 mg/kg/day in 2 divided doses separated by 2 weeks interval. Efficacy is higher in 3 months course as compared to 1 month treatment, as measured by cyst nonviability (94% vs. 72%) and membrane disruption (94% vs. 58%).

Tropical Hepatogastroenterology

MANAGEMENT

39.7.1.4 Side effects and toxicity

Mebendazole causes nausea, vomiting, alopecia, hepatitis, glomerulonephritis, neutropenia, pruritus, low-grade fever, and urticaria. Gastrointestinal side effects are fewer if the drug is given with meals. Treatment should not be stopped due to this as these usually disappear with 1–2 weeks of treatment. It is teratogenic in first trimester, but it can be given in second and third trimesters. Albendazole causes fewer side effects. It causes increase in liver transaminases in 16% of patients, hepatotoxicity (jaundice) in 5%, fever (5%), alopecia (3%), and leucopenia (2%). 39.7.1.5 Follow-up protocol for medical management

Liver function tests and counts should be done every two weeks. If there is any abnormality, albendazole should be stopped for 3 weeks and then started again. Abdominal ultrasound or CECT should be done every three months. Parameters of radiological evaluation are status of germinal membrane and presence of calcification. The collapse of membrane and/or detection of calcification are signs of good response to medical treatment. Despite four courses over a three-months period, if the germinal membrane remains intact and no calcification occurs, surgery is indicated. No change in size of cyst is expected for at least 1.5–2 years.

635

Radical en bloc resection and excision is possible in 50% to 85% cases (78.5% in our series) and can be performed with little mortality and acceptable morbidity. The various surgical procedures described and practiced for hydatid cyst include: I. Open surgical procedures 1. Conservative parenchyma-sparing techniques: Cyst evacuation + management of residual cavity with various techniques (a) (b) (c) (d) (e)

Drainage Omentoplasty Capitonnage Introflexion Marsupialization

2. Total cystopericystectomy – closed/open 3. Hepatic resection II. Laparoscopic surgical procedure 1. Cyst drainage 2. Cystopericystectomy 3. Hepatic resection Perioperative albendazole or mebendazole is indicated for reducing the risk of secondary echinococcosis after the operation and should begin at least 4 days before surgery (we prefer to give 2 weeks preoperatively) and be continued at least 1 month or preferably 3 months.

39.7.2 Surgical Treatment

39.7.2.1 Open surgical procedures

Surgery remains the mainstay in the treatment of hepatic hydatid disease. Cystectomy and pericystectomy are effective therapies with a very low risk of recurrence in long term studies. Formal hepatic resection is reserved for a single lesion occupying most of the liver lobe or segment or for multiple lesions in a lobe or segment of the liver.

The choice of surgical technique depends on the site, size, type of cyst, presence of biliary communication, and the surgeon’s expertise.[24] The primary debate is between performing more conservative drainage procedures versus more radical ‘en bloc’ resection of the entire cyst either as cystopericystectomy or formal

Part IX / Parasitic Diseases

636

Chapter 39 / HYDATID CYST OF THE LIVER

resection of the affected segments of the liver. Conservative surgery consists of following steps – decompression and evacuation of cyst contents, sterilization of the cyst, management of biliary communication, if present, and management of the remaining cyst cavity. In this procedure, the abdomen is packed with pads soaked in scolicidal agent like betadine around the cyst to decrease the risk of peritoneal soilage and contamination. The cysts are aspirated in a closed system using an angiocath needle for a univesicular cyst, suction trocar for univesicular cysts and multivesicular cysts with a few daughter cyst, and cone – freezing/suction for multivesicular cyst. Scolicidal agents are injected into the cyst cavity. The various scolicidal agents in use are hypertonic saline 10%–15%, sodium hypochlorite 0.5%, formalin, chlorhexidine, cetrimide 0.5%, and 3% hydrogen peroxide. If there is any bile staining suggesting biliary communication, formalin should not be used since it is associated with the risk of sclerosing cholangitis. Betadine, 70%–95% ethanol, or 15%– 20% hypertonic saline are safer. Intraoperative use of scolicidal agents ensures the inactivation and clearance of the parasite. The cyst cavity may be closed by omentoplasty. Capitonnage is preferred by some authors if the cyst is deep. In this cyst wall is infolded into the depth of cyst wall with successive layer of sutures. It should not be used if the cyst wall is rigid and calcified.[25, 26] Marsupialization was used in past for infected cysts, but at present, it is not recommended due to its high complication rate. The recurrence rate following conservative surgical procedures ranges between 10% and 30%.[27] Resectional procedures Total cystopericystectomy was first described in 1930s. It can be done with either an open or closed method. In the closed method, en-bloc pericystectomy is performed. In

the open technique, the cyst contents are evacuated, and then pericystectomy is done. Total cystopericystectomy is technically demanding but it causes cavity disappearance and prevents relapse of disease and secondary inflammatory complications.[28, 29] It also has advantage of identifying exogenous daughter cysts but is to be avoided for cysts impinging on the major hepatic veins, IVC, and cysts close to the liver hilum. Closed cystopericystectomy creates no residual adventitia, eliminates the need of scolicidal agents and avoids biliary fistula, but needs more expertise in hepatic surgery.[26] Open cystopericystectomy is preferred when the cyst wall is thin and there is risk of impending rupture, and when major vascular structures are found during closed cystopericystectomy.[30] Liver resection has been advocated for a selected group of patients such as when the cyst has destroyed an entire lobe or segment, or when cyst – biliary fistula draining zones need to be formatted, or when other conservative techniques have failed. In such cases, a typical left or right hepatectomy or segmentectomy can be done.[31] It is more commonly performed in cases where the hydatid cyst occupies most of the left lateral segments II and III. (Fig. 39.1) Radical or ‘en bloc’ excision of the hydatid cyst in the form of total cystopericystectomy or liver resection is the most effective treatment for hepatic hydatid disease. It has the distinct advantage of minimal or no risk of recurrence, obviates the need to deal with any residual cavity, and obviates the need for postoperative antihelminthic agents. In a recent analysis of 232 patients, Puliga et al.[32] reported a low mortality, a significant reduction in biliary fistula rate and overall morbidity with a zero recurrence in the radical surgery group. Similar results were reported by Buttenschoen[33] in a meta-analysis. However, not all cases are suitable for radical surgery. In our series, radical excision

Tropical Hepatogastroenterology

MANAGEMENT

FIGURE 39.1 CT scan of the liver showing a hydatid cyst in the right lobe.

was feasible in 78.5% of patients. Unsuitable cases include unfavorable location, proximity to major vascular structures, proximity to right sectoral pedicle, communication with a major bile duct, and cyst in a cirrhotic liver. Therefore, considering the benign nature of the disease, in situations where higher morbidity is anticipated with radical excision of a hepatic hydatid, one should resort to more conservative options. Radical ‘en bloc’ excision of hepatic hydatid is a safe procedure in centers routinely performing hepatobiliary surgery, and should be the preferred approach. However, all cases are not suitable for complete excision with radical surgery, and the surgical procedure needs to be tailored to individual patient. 39.7.2.2 Laparoscopic surgery

Laparoscopic management of hydatid cyst is gaining popularity in recent years, though there is no level I evidence supporting it over conventional open surgery. Laparoscopic treatment includes cyst evacuation with drainage/omentoplasty and also total cystopericystectomy. However, most of

Part IX / Parasitic Diseases

637

the case series have reported predominantly cyst evacuation only. Technically, the steps are the same as in open conservative surgery. The most important disadvantage is the lack of precautionary measures to prevent spillage under high intraabdominal pressures due to pneumoperitoneum, as the initial puncture into the cyst is less well controlled than in open surgery. Also, the rest of the peritoneal cavity can not be as effectively separated from the cyst area using sponges soaked in scolicidal agent. Bickel et al.[34] have suggested that pneumoperitoneum is beneficial in preventing spillage, while others suggest that decrease in intraabdominal pressure helps in preventing spillage.[35] This is why initial cyst puncture and aspiration of cyst fluid is the most difficult part of laparoscopic procedure.[36] Some authors have suggested fixing the cyst to the abdominal wall using special umbrella trocar and suction with a specific suction device, to prevent spillage.[37] Bickel et al.[34] have proposed filling the right subphrenic space with scolicidal agent and combining it with a Trendelenburg position to lessen the consequences of inadvertent spillage. They use a transparent cannula and vacuum for complete fluid evacuation. The tip of the device is adhered firmly to the cyst wall to prevent spillage in the peritoneal cavity. Indications of laparoscopic approach have increased with time. Presently, the exclusion criteria are deep intraparenchymal cyst, cyst situated close to IVC posteriorly, more than 3 cysts, and cysts with thick and calcified walls.[38, 39] Conversion to open surgery might be needed due to poor exposure, unsatisfactory access, intraoperative bleeding and biliary communication. Biliary communication can also be dealt laparoscopically by choledochotomy, irrigation, and T-tube drainage. In some such situations, the cyst can be dealt with laparoscopically and if biliary communication is present, it can be dealt

638

Chapter 39 / HYDATID CYST OF THE LIVER

later by ERCP with or without sphincterotomy or stenting.[40, 41] Even though several laparoscopic series have reported lower mortality and morbidity rate, shorter hospital stay and lower short term recurrence rate than open surgery,[29, 31, 34, 37, 38, 42] there are no randomized controlled trials comparing both the approaches. The better results in laparoscopic surgery might be due to strict selection criteria for laparoscopic surgery. However, considering the definite advantage of ‘resectional surgery’ in reducing the incidence of long term recurrence in comparison to the ‘drainage procedure’, it would be appropriate to perform laparoscopic drainage procedures only in cases otherwise unsuitable for ‘en bloc’ cyst excision (cystopericystectomy/liver resection) either laparoscopic or open.

39.7.3 Percutaneous Management (PAIR) Because of risks of peritoneal spillage, dissemination and anaphylactic shock, percutaneous aspiration was initially considered contraindicated. However, with the development of fine needles and catheters, advancement in imaging techniques, and use of an intercostal, intrahepatic approach, percutaneous aspiration is being increasingly used. Percutaneous aspiration can be done under ultrasound or CT guidance. After initial cyst puncture contents are aspirated and contrast is injected to opacify the cyst. A scolicidal agent is injected. The catheter is then clamped for 30 minutes followed

by another infusion of betadine; this catheter is left for continuous drainage.[43–46] Percutaneous management is indicated for type I – II cysts, some type III cysts that do not have undrainable solid or thick debris, suspected fluid collections, and infected hydatid cysts. Percutaneous aspiration, injection and reaspiration (PAIR) of types I and II hydatid liver cysts is effective and safe in the long-term and is the preferred modality in centers with available expertise. Also, percutaneous treatment might be preferred in high surgical risk patients, pregnant patients, and patients with multiple or disseminated cysts. A percutaneous approach is contraindicated if there is biliary communication or intraperitoneal rupture of the cyst. For uncomplicated type I and II cysts several workers have now generated evidence to support it as the optimal treatment, with recurrence rates of 0%–4%.[46, 47] The overall complication rates vary between 15% and 40%. Major complications such as anaphylactic shock range from 0.1% to 0.2% and minor complications vary between 10% and 30%. The overall mortality reported is 0.9%–2.5%.[16] Percutaneous approach is a safe and reliable option for well selected patients in type I and II cysts. A meta-analysis of percutaneous drainage has shown minimal complication and immediate relief of symptoms with no recurrence during 33 months of follow-up.[48] However, the PAIR technique requires a skilled interventional radiologist performing the procedure in an appropriately selected case.

Tropical Hepatogastroenterology

REFERENCES

639

REFERENCES [1] Kew MC. Hepatic tumors and cysts. In: Feldman M, Scharschmidt BF, Sleisenger MH (eds) Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 6th edition, WB Saunders Co, Philadelphia, 1998, p 1381. [2] Gonzalez AE, Moro PL, Garcia HH. Cystic hydatid disease (Echinococcus granulosus). In Warrell DA, Cox TM, Firth JD, Benz Jr JD (editors), Oxford Textbook of Medicine, 4th edition, Oxford University Press, 2003. [3] Little JM. Hydatid disease at Royal Prince Alfred Hospital, 1964 to 1974. Med J Aust 1976;1: 903–908. [4] Lowenthal J, Way LW. Echinococcosis. In: Surgery of the gallbladder and bile ducts. Way L, Pellegrini CAP(eds) WB Saunders Company, Philadelphia. 1987:557–568. [5] Akinoglu A, Bilgin I, Erkocak EU. Surgical management of hydatid disease of liver. Can J Surg 1985;28:171–174. [6] Lygidakis N J. Diagnosis and treatment of intrabiliary rupture of hydatid cyst of the liver. Arch Surg 1983;118:1186–89. [7] Gomez R, Moreno E, Loinaz C et al. Diaphragmatic and transdiaphragmatic thoracic involvement in hepatic hydatid disease: surgical trends and classification. World J Surg 1995;19:714–719. [8] Al-hashmi H M. Intrabiliary rupture of hydatid cyst of liver. British J Surgery 1971;58: 228–232. [9] El-mufti M. Surgical management of hydatid disease. Butterworth, London 1989;p1–55. [10] Biggi E, Derchi L, Cicio GR, Valente M. Sonographic findings of hydatid cyst of the liver ruptured into biliary ducts. J Clin Ultrasound 1979;7: 381–382. [11] Gharbi HA, Hassine W, Brauner MW et al. Ultrasound examination of the hydatid liver. Radiology 1981;139:459–463. [12] Weill SF. Ultrasound diagnosis of digestive diseases. Springer-Verlag, Berlin 1990:221–235.

Part IX / Parasitic Diseases

[13] Urbanyi B, Rieckmann C, Hellberg K et al. Myocardial echinococcosis with perforation into the pericardium. J Card Surg 1991;32:534–538. [14] Moreira Vicente VF, Merono Garcia E, Simon Marco MA. Endoscopic retrograde cholangiography and complicated hepatic hydatid cyst in the biliary tract. Endoscopy 1984;16:124–126. [15] Cottone M, Amuso M, Cotton PB. Endoscopic retrograde cholangiography in hepatic hydatid disease. Br J Surg 1978;65:107–108. [16] Schantz PM, Ortiz Valqui RE, Lumreras H. Nonspecific reactions with the intradermal test for hydatidosis in persons with other helminth infections. Am J Trop Med Hyg 1975;24:849–852. [17] Gottstein B. Serodiagnosis of echinococcosis. Echinomed 1992;3:3–4. [18] Babba H, Messedi S, Masmoudi S et al. Diagnosis of human hydatidosis: comparison between imagery and six serological techniques. Am J Trop Med Hyg 1994;50:64–72. [19] Lass N, Laver Z, Lengy J. The immunodiagnosis of hydatid disease: postoperative evaluation of the skin test and four serological tests. Annals of Allergy 1973;31:430–436. [20] Sorice F, Delia S, Vullo V et al. Sensitivity and specificity of the RAST (radioallergosorbent test) in biological diagnosis of the hydatidosis. Annali Sclavo 1979;21:800–815. [21] Huguier M, Leynadier F, Houry S et al. Human basophil degranulation test in liver hydatidosis. Digestive Diseases and Sciences 1987;32: 1354–1357. [22] Pawlowski ZS, Eckert J, Vuitton DA, et al. Echinococcosis in humans: clinical aspects, diagnosis & treatment. In: Eckert J et al., eds WHO/ OIE Manual on echinococcosis in humans and animals. Paris WHO/OIE; 2001:20–71. [23] Yasawy MI, Alkarawi FA, Mohammed ARE. Prospects in medical management of Echinococcus granulosus. Hepatogastroenterology 2001;48: 1467–1470.

640

Chapter 39 / HYDATID CYST OF THE LIVER

[24] Demirici S, Eraslan S, Anadol E et al. Comparison of the results of different surgical techniques in the management of hydatid cyst of the liver. World J Surg 1989;13:88–90. [25] Utkan NZ, Canturk NZ, Gonullu Y et al. Surgical experience in radical surgical treatment of hepatic hydatid cysts. Hepatogastroenterology 2001;48: 203–7. [26] Magistreli P, Masetti R, Coppola R. Surgical treatment of hydatid disease of liver: a 20-year experience. Arch Surg 1991;126:518–522. [27] Casado AO, Gonzalez ME, Segurola LC. Results of 22 years experience in radical surgical treatment of hepatic hydatid cysts. Hepatogastroenterology 2001;48:235–243. [28] Abbas M, Nafeh AI, Youssef YF et al. Conservative versus radical surgery for treatment of uncomplicated hepatic hydatid cysts. J Egypt Soc Parasitol 2006;36:559–76. [29] Cirenei A, Bertoldi I. Evolution of surgery for liver hydatidosis from 1950 to today. World J Surg 2001;25:87–92. [30] Moreno G, Rico S, Martinez B et al. Results of surgical treatment of hepatic hydatidosis: current therapeutic modifications. World J Surg 1991;15: 254–263. [31] Gollackner B, Langle F, Auer H et al. Radical surgical therapy of abdominal cystic hydatid disease: factors of recurrence. World J Surg 2000;24: 717–721. [32] Puliga A, Sulis R, Pala M et al. Surgical treatment of hydatid liver cysts: 20 more years of experience. Chir Ital 2003;55:533–40 (Abs). [33] Buttenschoen K, Carli Buttenschoen D. Echinococcus granulosus infection: the challenge of surgical treatment.Langenbecks Arch Surg 2003;388: 218–30. [34] Bickel A, Loberant N, Singer-Jordan J et al. The laparoscopic approach to abdominal hydatid cysts. Arch Surg 2001;136:789–795. [35] Klinger PJ, Gadenstatter M, Schmid T et al. Treatment of hepatic cysts in the era of laparoscopic surgery. Br J Surg 1997;84:438–444.

[36] Saglam A. Laparoscopic treatment of liver hydatid cysts. Surg Laparosc Endosc 1996;6:29–33. [37] Seven R, Berber E, Mercan S et al. Laparoscopic treatment of hepatic hydatid disease. Surgery 2002;28:36–40. [38] Ertem M, Yras C, Karahasanoglou T et al. Laparoscopic approach to hepatic hydatid disease. Dig Surg 1998;15:333–336. [39] Mompean JAL, Paricio PP, Campas RR et al. Laparoscopic treatment of a liver hydatid cyst. Br J Surg 1993;80:907–908. [40] Alper A, Emre A, Acarli K et al. Laparoscopic treatment of hepatic hydatid disease. J Laparoendosc Surg 1996;6:29–33. [41] Tekant Y, Bilge K, Acarli K et al. Endoscopic sphincterotomy in the treatment of postoperative biliary fistulas of hepatic hydatid disease. Surg Endosc 1996;10:901–911. [42] Ertem M, Karanasoglu T, Yavuj N et al. Laparoscopically treated liver hydatid cysts. Arch Surg 2002;137:1170–1173. [43] Bosanac ZB, Lisanin L. Percutaneous drainage of hydatid cyst in the liver as primary treatment: Review of 52 consecutive cases with long term follow up. Clin Radiol 2000;55:839–848. [44] Akhan O, Ozmen MN, Dincer A et al. Liver hydatid disease: Long term results of percutaneous treatment. Radiology 1996;198:259–264. [45] Men S, Hekimoglou B, Yecesoc C. Percutaneous treatment of hepatic hydatid cysts: an alternative to surgery. N Engl J Med 1997;337:881–887. [46] Khuroo MS, Zargar SA, Mahajan R. Echinococcus granulosus cysts in the liver: Management with percutaneous drainage. Radiology 1991;180: 141–145. [47] Xiaozhi W. Clinical treatment of hepatic and abdominal hydatidosis with percutaneous puncture drainage and curettage (report of 869 cases) Chin J Parasitol Parasitic Dis 1994;12:285–287. [48] Kohlhaufl M. Percutaneous ultrasound guided fine needle puncture of parasitic liver cysts: Risks and benefits. Ultraschall Med 1995;16: 218–223.

Tropical Hepatogastroenterology

Chapter

40 SCHISTOSOMIASIS Kaushal Madan and Subrat Kumar Acharya

Schistosomiasis is a chronic illness caused by a trematode which can last long in the veins. It is also called Bilharziasis, after Theodor M Bilharz, who first described it in humans. Different species cause disease in different parts of the world (Table 40.1). In endemic areas, the morbidity and economic burden is enormous. There are five species of human schistosomes. These are Schistosoma mansoni, S. japonicum, S. haematobium, S. mekongi, and S. intercalatum. S. haematobium resides in the vesicular venous plexus. The others reside in the portomesenteric vasculature. S. mansoni and S. japonicum cause hepatosplenic disease.

TABLE fy 40.1 Geographical and anatomical localization of human schistosomiasis Species

Geographical localization

S. mansoni

Middle east, Africa, South America S. japonicum Japan, China, Philippines S. mekongi Southeast Asia S. intercalatum Central Africa S. haematobium Middle east, Africa

Vascular localization Inferior mesenteric vein Superior mesenteric vein Mesenteric Mesenteric Vesicular plexus

venous beds. There, for decades, they continue to produce eggs.[1]

40.1 LIFE CYCLE OF SCHISTOSOMES

40.2 PATHOPHYSIOLOGY

The female worm passes the eggs, which the human excretes in the stools. The eggs hatch in water. Here the larvae seek the intermediate host, the fresh water snails. Inside the snail hosts, they develop into the infective stage for humans, the free-swimming cercariae. The cercariae can penetrate human skin and transform into immature worms or schistosomula. They pass through the systemic and pulmonary circulations several times over a period of 5–6 weeks. At the end of this time they transform into adult worms which finally localize as male and female pairs in the mesenteric

How do the worms preferentially colonize the mesenteric venules? The exact mechanism is uncertain. Shaker et al recently showed that a 2 to 50 kDa fraction of the human portal serum stimulated cell proliferation in immature and developing schistosomula. This response did not occur with peripheral venous serum. The inference is that human portal serum contains a growth factor for developing schistosomula.[2] Once in the mesenteric venous bed, the adult worms produce a huge load of eggs. The eggs either stay in the intestinal wall and elicit a granulomatous response or erode 641

642

Chapter 40 / SCHISTOSOMIASIS

FIGURE 40.1 Photomicrograph of hepatic schistosomiasis. (Courtesy: The DPDx Team, Division of Parasitic Diseases, Centers for Disease Control and Prevention.)

through the intestinal wall and get excreted in the feces. The eggs may get carried through the portal venous system to the smallest portal venules in the liver. In the liver, the eggs incite a granulomatous fibrotic reaction to the secreted products. This leads to the formation of characteristic schistosome egg granuloma in the portal tracts (Fig. 40.1), which in later stages leads to severe fibrosis. The hepatic fibrosis is so aggressive that it gives a gross appearance of clay pipes thrust through the liver. This type of fibrosis is termed pipe stem fibrosis or Symmers fibrosis.[3]

40.2.1 Immunology of Hepatic Inflammation/Fibrosis in Schistosomiasis The immunologic process and their regulatory elements vary according to the stage of the disease. In the early stage of hepatic involvement, the antigenic products secreted by the schistosomal eggs incite a predominant Th1 type response. This phase is characterized by infiltration by mononuclear cells leading to formation of highly cellular egg granulomas. Along with this, collagen deposition is also initiated. As the egg deposition continues

further, there is modulation of the inflammatory response. Over time, the Th1 type response changes to Th2 type of response with reduction in the intensity of inflammation. The size of the granulomas reduces as they become less cellular. The cellular elements also change from being predominantly mononuclear to eosinophilic. There is increased and progressive collagen deposition, which continues and assumes the characteristic pipe stem morphology depending upon the burden of eggs. Experimental studies show that if the Th2 response is inhibited the Th1 dependent formation of large granulomas continues, and there is severe hepatic lobular inflammation that may even be fatal.[4] A similar scenario occurs in animals which lack Th2 cytokines (IL-10 knockout mice). In these animals, there is formation of large noncohesive granulomas along with severe lobular inflammation.[5] In advanced disease, there is deposition of dense collagen in the portal tracts. This leads to massive fibrotic expansion of the portal tracts which is visible grossly as well as ultrasonographically. Products produced both by the schistosome eggs and the developing granulomas stimulate fibrogenesis. In egg granulomas, CD4+ lymphocytes and fibroblasts produce fibrosin–a fibrogenic cytokine. It stimulates fibroblast proliferation and increased collagen biosynthesis.[6] Although there is dense hepatic periovular fibrosis around the portal tracts, there is no destruction of normal hepatic architecture (unlike cirrhosis). Therefore, this form of fibrosis is usually reversible after parasitologic cure. Genetic factors may influence severity (Table 40.2).[7, 8]

40.3 CLINICAL FEATURES The clinical features are those of a presinusoidal portal hypertension due to an intrahepatic lesion

Tropical Hepatogastroenterology

CLINICAL FEATURES

TABLE fy 40.2 Evidence that genetic factors may influence severity • In patients with severe fibrosis, there is increased frequency of a co-dominant gene linked to the IFN-gamma receptor (IFN-γ R1) gene on chromosome 6 • IFN-γ is a strong antifibrogenic cytokine. IFN-γ polymorphisms are associated with severe schistosomal hepatic fibrosis • IFN-γ + 2109 A/G polymorphism is associated with an increased risk of developing fibrosing schistosomal disease

around the portal tracts. The features are similar to those of noncirrhotic portal fibrosis or idiopathic portal hypertension. Patients in endemic areas have one or more episodes of upper gastrointestinal bleeding associated with passive congestive splenomegaly. They have no signs of liver cell failure (jaundice, ascites, encephalopathy after bleed). Even in the absence of bleed, patients may have prominent splenomegaly presenting as a left upper quadrant lump with or without features of hypersplenism. Growth retardation occurs in children, and is only partially reversible even after parasitological cure.[9] In schistosomiasis, there is an increased incidence of Staphylococcus aureus liver abscesses as well as of chronic salmonella bacteremia. Salmonellae may become sequestered in the integument of the adult worm, and permanent cure may require eradication of the schistosomal infection.[10] Patients with chronic hepatosplenic schistosomiasis are also at an increased risk of developing of spleen. Among patients who undergo splenectomy for hepato-splenic schistosomiasis 1% has follicular lymphoma of the spleen.

Part IX / Parasitic Diseases

643

40.3.1 Schistosomiasis and Hepatitis Areas where schistosomiasis is endemic also have a high prevalence of viral hepatitis B and C. Hepatitis C virus (HCV) is the most common cause of chronic liver disease in Egypt. The prevalence of anti-HCV antibodies is 10 times higher in Egypt than in US or Europe. Chronic hepatitis C (CHC) and schistosomal liver disease may often coexist. Although coinfection is not as prevalent as would be expected from the high individual incidences, coinfection may affect the natural course. There is increased clustering of schistosomiasis and chronic hepatitis C in the members of the same household. This has been related to the mass treatment programmes which utilized parenteral injections of tartar emetic. The use of unsterilized injections led to an increased transmission of this viral infection among the population infested with the schistosomes.[11, 12] Another reason for the increased incidence of parenterally transmitted viruses among patients with schistosomiasis is the increased exposure to blood and blood products during episodes of variceal hemorrhage. Patients coinfected with the two pathogens usually have a severe illness. They usually have decompensated cirrhosis. The complications of cirrhosis are more frequent and more severe in patients with CHC who also have schistosomal liver disease, although the activity of CHC as evidenced by ALT levels and HCV RNA levels is lower among such patients.[13] Kamal et al compared clinical, virological, and histological features among patients who had either disease alone, with those who had both. They showed that 48% of coinfected patients had Child’s C cirrhosis, as compared to 15% who had only CHC. The histological stage and grade of the disease was also higher among coinfected patients. The mortality rate was 48%, 12%, and 3% among coinfected

644

Chapter 40 / SCHISTOSOMIASIS

patients, CHC patients, and schistosomal liver disease patients respectively.[14] The management of CHC in such patients remains the same although the response of hepatitis C to interferon therapy in coinfected patients is poor.[15]

assay has been developed. This has a high sensitivity for detection of both acute and chronic illness but is also positive in 13.3% of cases of paragonimiasis.[18]

40.4 DIAGNOSIS

Ultrasonography is the preferred investigation for the diagnosis of advanced hepatic fibrosis. It can easily pick up the broad bands of periportal fibrosis that are so characteristic of this disease. The typical lesion described is one of highly echogenic fibrotic bands forming a network-like mosaic pattern or ‘coarse reticular pattern’. This pattern has been described mainly for S. japonicum but not for S. mansoni or S. haematobium. Other findings are periportal fibrosis and septum-like bands extending to the liver surface.[19, 20] Ultrasonography can also be used for monitoring the response to therapy as the degree of fibrotic expansion of portal tracts reduces after parasitological cure. It can also be used for epidemiological purposes for detecting the burden of schistosomal liver disease in the community.[21] MRI picks up periportal changes as well as septa. On T1-weighted images of periportal zones, the T1-weighted images are strongly enhanced after injection of Gd-DTPA. On T2-weighted images, the periportal zones appear as high signal bands throughout the liver suggesting periportal inflammatory changes with edema.[22] Septa are seen as linear abnormalities, with low signal intensity on T1-weighted images and with high intensity on T2-weighted images.[23]

40.4.1 Stool Examination Stool examination demonstrating schistosome eggs is an indicator of active disease. The severity of the disease correlates with the level of fecal egg output. Egg output in stools tends to decrease and disappear after parasitological cure is achieved, and therefore can be used to monitor the response to therapy. Rectal biopsy specimens can also be used to detect eggs if stool examinations are negative. If the egg load in stool is low, a rectal biopsy with tissue oogram is a more sensitive technique for detection of schistosome eggs.[16] The sensitivity of stool examination is 88%–94% when the egg load is more than 5000 eggs per gram of rectal tissue, but only 22%–34% when the oogram shows a load of less than 1000 eggs per gram of rectal tissue.

40.4.2 Serology ELISA can be used for detection of schistosomiasis for epidemiological purposes, but it does not differentiate between active and treated infection. For this reason it can not be used to monitor response to therapy. Recently, however, a new ELISA utilizing RP 26 schistosomal protein showed promise in differentiating between acute and chronic infection. It had an excellent specificity, was positive in 89% of patients in the acute phase, and was only 26% positive in the chronic phase.[17] A new dye immunofiltration

40.4.3 Imaging

40.5 MANAGEMENT Management is directed at eradication of the parasite with pharmacological treatment, and management of portal hypertension, if it exists.

Tropical Hepatogastroenterology

MANAGEMENT

40.5.1 Medical Management Several pharmacological agents have been used for the treatment of schistosomiasis. By far the most commonly used and the most effective drug is praziquantel. It produces parasitological cure rates of more than 90%. It is given orally in a dose of 60 mg/kg body weight given in three divided doses over 8 hours.[16] For mass treatment programmes, a single dose of 40–50 mg/kg body weight has been used in endemic areas. Praziquantel is a part of mass treatment programs in endemic areas. Another drug which has been used for mass treatment programmes in areas of Africa and South America is oxamniquine. It is less effective.[16] Unfortunately, the dependence on praziquantel has been responsible for the failure of schistosomiasis control programmes. One reason is that praziquantel is less effective against developing schistosomula. This problem can be tackled by giving repeated doses of praziquantel after intervals of a few weeks. Such a strategy has been used for the treatment of S. haematobium, where praziquantel was used in a dose of 40 mg/kg body weight, repeated 4 weeks later, and then a third dose was given in those whose urine was positive for eggs even after the second dose.[24] However, the WHO has proposed a dual strategy for long term schistosomiasis control. This strategy involves morbidity control in endemic zones using chemotherapy, and utilizing preventive measures focused on clean water, adequate sanitation, and health education.[25] Based on the above guidelines recently, a schistosomiasis control initiative (SCI) has been started in Uganda from March 2003. One other way of dealing with the problem of relative inactivity of praziquantel against schistosomula is by combining praziquantel with an agent that is effective against the developing stages of the parasite. One such unique agent is artemether, one of the artemisinins. Use of

Part IX / Parasitic Diseases

645

artemether, which has strong activity against schistosomula, complements the stage specific susceptibility of praziquantel.[26, 27] Rabbits in whom 7–14 days old schistosomula and 42 days old adult worms were simultaneously present, were randomized to receive either praziquantel, artemether alone, or praziquantel plus artemether. The total worm burden reduction was 28%–66%, 44%– 56%, and 79%–92% respectively in the three groups.[28] Thus the simultaneous use of praziquantel and artemisinins may have superior cure rates than either of the drugs alone. Another nonsurgical form of therapy in patients with hepatosplenic schistosomiasis is endotherapy for variceal bleeding, which is common in such patients.[29] The role of beta-blockers in reducing the portal pressure in schistosomal portal hypertension is controversial. A large study, using up to 160 mg of propranolol, demonstrated a reduction of 40% in mortality at 2 years among patients with schistosomal portal hypertension when compared to placebo.[30] However, another study showed that propranolol did not reduce the portal pressure in this disease.[31]

40.5.2 Reversibility of Schistosomal Hepatic Fibrosis There is experimental and human data to prove that once the parasitologic cure is achieved, histological fibrosis seen around the periovular granulomas is reversible. Since there is no distortion of hepatic parenchyma due to schistosomal fibrosis, the reversal of fibrosis would mean reversal of portal hypertension also. Three years after a mass praziquantel therapy programme in Madagascar, the prevalence of splenomegaly reduced significantly, and there was ultrasonographic evidence of reduction in periportal fibrosis from 28% to 10.3%.[32] This was also demonstrated in a mouse model

646

Chapter 40 / SCHISTOSOMIASIS

infected with S. japonicum. The rate of collagenolysis increases, collagen biosynthesis decreases, and the total collagen content in fibrotic hepatic scars decreases significantly after the cure of S. japonicum infection in the mice model.[33]

40.5.3 Future Therapies for Schistosomiasis The major cause of schistosomal morbidity is the immune mediated inflammatory liver injury. If the immune response can be modulated, it may lead to reduction in hepatic fibrosis. Downregulation of the Th2 dependent granulomatous response can result in reduced hepatic fibrosis in animal models of schistosomiasis. Czaja in 1989 showed that weekly intramuscular injections of IFN-γ 4 weeks after the initial infection resulted in significantly reduced fibrogenic response in the mice.[34] Treatment of S. japonicum-infected mice with anti-IL-4 (Th2 cytokine) resulted in reduced hepatic fibrosis at ten weeks. At the same time in these animals the periovular granulomas were larger than in the controls, because of uninterrupted Th1 response.[35] In mice, intraperitoneal vaccination with the Th1 cytokine IL-12 along with schistosome eggs favors a predominantly Th1 response with reduced Th-2 dependent granulomatous response and significantly reduces fibrosis.[36] Abdel-Aaty showed that using IL-12 as an adjuvant to SWAP (soluble worm antigen preparation) vaccine resulted in marked reduction in granuloma formation as well as absence of fibrosis in mice.[37]

40.5.4 Surgical Management Surgical management of hepatic schistosomiasis involves surgery for complications of portal hypertension. The principles of surgery for schistosomal portal hypertension remain the same as those for any other form of presinusoidal portal hypertension. There has been one large randomized

controlled trial comparing three forms of surgery for this disease.[38] This study compared a proximal splenorenal shunt, distal splenorenal shunt, and splenectomy with devascularization among 94 patients with schistosomal portal hypertension. The authors found a trend towards more patient satisfaction as well as a reduced number of complications after splenectomy and devascularization as compared with shunt surgeries. In this study the mortality rates were 42.9%, 14.8%, and 7.1% for proximal splenorenal, distal splenorenal shunt, and splenectomy with devascularization respectively. Partial splenectomy has also been used as an alternative to total splenectomy. It takes away most of the congestive spleen leaving behind a small functional portion of the spleen.

40.6 PREVENTION OF SCHISTOSOMIASIS: VACCINE DEVELOPMENT Even though effective antihelminthic treatment and snail eradication programmes exist, the discovery of an effective vaccine still remains the most potentially powerful means of control for this disease. A lot of research is being directed towards formulation of a viable schistosomal vaccine. A number of trials in animals have shown that vaccines derived from inactivated cercariae or schistosomal antigens confer 30%–50% protection in terms of reduced worm burden and reduced fecundity in the immunized animals.[39, 40] Egypt’s schistosomiasis vaccine development programme (SVDP) focuses on two S. mansoni antigens–paramyosin, and a synthetic peptide containing multiple antigen epitopes of the schistosoma triose phosphatase isomerase enzyme. Siddiqui et al. have used the large subunit of Calpain or Sm-p80 antigen. This antigen plays

Tropical Hepatogastroenterology

CONCLUSION

a pivotal role in surface membrane biosynthesis in schistosomes. Surface membrane renewal is a major phenomenon employed by helminths to evade the host immune system. Therefore, an immune response directed against Sm-p80 should make the parasite susceptible to immune clearance from the host. Using a DNA vaccine containing plasmids encoding IL-2 & IL-12 along with the antigen Sm-p80, 57%, and 45% protection was conferred respectively among immunized mice.[41]

647

40.7 CONCLUSION Perhaps no other parasitic disease has so enlightened the medical community on immunology, hepatic inflammation, hepatic fibrogenesis, and lessons on disease control as schistosomiasis. This disease also has a deep impact on the economy and development in the endemic countries because of the immense morbidity and the sheer burden of the population involved. A global effort is required for an effective control of this problem.

REFERENCES [1] Warren KS. The kinetics of hepatosplenic schistosomiasis. Semin. Liver Dis. 1984; 4: 293–300. [2] Shaker YM, Wu CH, El-Shobaki FA et al. Human portal stimulates cell proliferation in immature schistosoma mansoni. Parasitology 1998; 117: 293– 299. [3] Symmers WSC. Note on a new form of liver cirrhosis due to the presence of ova of bilharzia haematobium. J Pathol Bacteriol 1904; 9: 237–239. [4] Rutitzky LI, Hernandez HJ, Stadecker MJ. Th1polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc. Natl. Acad Sci USA 2001; 98: 13243–13248. [5] Sadler CH, Rutitzky LI, Stadecker MJ et al. IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur J Immunol 2003; 33: 880–8. [6] Wyler DJ. Fibrosin, a novel fibrogenic protein: discovery, cloning and implications for fibrotic disorders. Int Arch Allergy Immunol 1996; 111: 326–329. [7] Dessein AJ, Hillaire D, Elwali NE et al. Severe hepatic fibrosis in schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 1999; 65: 709–21.

Part IX / Parasitic Diseases

[8] Chevillard C, Moukoko CE, Elwali NE et al. IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). J Immunol 2003;171:5596–601. [9] Olds GR, Olveda R, Wu G et al. Immunity and morbidity in schistosomiasis japonicum infection. Am J Trop Med Hyg 1996; 55: 121–126. [10] Lambertucci JR, Rayes AA, Serufo JC et al. Pyogenic abscesses and parasitic diseases. Rev Inst Med Trop Sao Paulo 2001; 43: 67–74. [11] Rao MR, Naficy AB, Darwish MA et al. Further evidence for association of hepatitis C infection with parenteral schistosomiasis treatment in Egypt. BMC Infect Dis 2002; 2: 29. [12] Frank C, Mohamed MK, Strickland GT et al. The role of parenteral anti-schistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 2000; 355: 887–891. [13] Gad A, Tanaka E, Orii K et al. Relationship between hepatitis C virus infection and schistosomal liver disease:not simply an additive effect. J Gastroenterol 2001;36:753–8. [14] Kamal S, Madwar M, Bianchi L et al. Clinical, virological and histopathological features: longterm follow-up in patients with chronic hepatitis C co-infected with S. mansoni. Liver 2000;20:281–9.

648

Chapter 40 / SCHISTOSOMIASIS

[15] El-Shazly Y, Abdel-Salam AF, Abdel-Ghaffar A et al. Schistosomiasis as an important determining factor for the response of Egyptian patients with chronic hepatitis C to therapy with recombinant human alpha-2 interferon. Trans R Soc Trop Med Hyg 1994;88:229–31. [16] Ferrari ML, Coelho PM, Antunes CM et al. Efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infection: a controlled trial. Bull World Health Organ 2003;81:190–6. [17] Makarova E, Goes TS, Marcatto AL et al. Serological differentiation of acute and chronic schistosomiasis using schistosoma mansoni recombinant protein RP26. Parasitol Int 2003;52: 269–279. [18] Xiang X, Tianping W, Zhigang T. Development of a rapid, sensitive, dye immunoassay for schistosomiasis diagnosis: a colloidal dye immunofiltration assay. J Immunol Methods 2003;280: 49–57. [19] Ohmae H, Sy OS, Chigusa Y et al. Imaging diagnosis of schistosomiasis japonica–the use in Japan and application for field study in the present endemic area. Parasitol Int 2003;52:385–93. [20] Chou YH, Chiou HJ, Tiu CM et al. Duplex Doppler ultrasound of hepatic Schistosomiasis japonica: a study of 47 patients. Am J Trop Med Hyg 2003;68:18–23. [21] King CH, Magak P, Salam EA et al. World Health Organization. Measuring morbidity in schistosomiasis mansoni: relationship between image pattern, portal vein diameter and portal branch thickness in large-scale surveys using new WHO coding guidelines for ultrasound in schistosomiasis. Trop Med Int Health 2003;8:109–17. [22] Willemsen UF, Pfluger T, Zoller WG et al. MRI of hepatic schistosomiasis mansoni. J Comput Assist Tomogr 1995;19:811–3. [23] Monzawa S, Ohtomo K, Oba H et al. Septa in the liver of patients with chronic hepatic schistosomiasis japonica: MR appearance. AJR Am J Roentgenol 1994;162:1347–51. [24] N’Goran EK, Gnaka HN, Tanner M et al. Efficacy and side-effects of two praziquantel treatments against Schistosoma haematobium infection, among

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

schoolchildren from Cote d’Ivoire. Ann Trop Med Parasitol 2003;97:37–51. Asaolu SO, Ofoezie IE. The role of health education and sanitation in the control of helminth infections. Acta Trop 2003;86:283–94. N’Goran EK, Utzinger J, Gnaka HN et al. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am J Trop Med Hyg 2003;68:24–32. Xiao S, Tanner M, N’Goran EK et al. Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mansoni and haematobia. Acta Trop 2002;82:175–81. Shuhua X, Jiqing Y, Jinying M et al. Effect of praziquantel together with artemether on Schistosoma japonicum parasites of different ages in rabbits. Parasitol Int 2000;49:25–30. Gasim B, Fedail SS, Musaad AM et al. Endoscopic sclerotherapy for bleeding oesophageal varices: experience in Sudan. Trop Gastroenterol 2002;23:107–9. el Tourabi H, el Amin AA, Shaheen M et al. Propranolol reduces mortality in patients with portal hypertension secondary to schistosomiasis. Ann Trop Med Parasitol 1994;88:493–500. Mies S, Neto OB, Beer A Jr et al. Systemic and hepatic hemodynamics in hepatosplenic Manson’s schistosomiasis with and without propranolol. Dig Dis Sci 1997;42:751–61. Boisier P, Ramarokoto CE, Ravaoalimalala VE et al. Reversibility of Schistosoma mansoni-associated morbidity after yearly mass praziquantel therapy: ultrasonographic assessment. Trans R Soc Trop Med Hyg 1998;92:451–3. Dunn MA, Cheever AW, Paglia LM et al. Reversal of advanced liver fibrosis in rabbits with Schistosomiasis japonica. Am J Trop Med Hyg 1994;50:499–505. Czaja MJ, Weiner FR, Takahashi S et al. Gammainterferon treatment inhibits collagen deposition in murine schistosomiasis. Hepatology 1989;10:795– 800. Cheever AW, Finkelman FD, Cox TM. Antiinterleukin-4 treatment diminishes secretion of Th2 cytokines and inhibits hepatic fibrosis in

Tropical Hepatogastroenterology

REFERENCES

murine schistosomiasis japonica. Parasite Immunol 1995;17:103–9. [36] Wynn TA, Cheever AW, Jankovic D et al. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 1995;376:594–6. [37] Abdel-Aaty HE, Ramadan NI, Mahmoud MS et al. Role of recombinant interleukin-12 as an adjuvant on vaccine-induced immunity in murine Schistosoma mansoni infection. J Egypt Soc Parasitol 1999;29:1–11. [38] Raia S, da Silva LC, Gayotto LC et al. Portal hypertension in schistosomiasis: a long-term follow-up of a randomized trial comparing three types of surgery. Hepatology 1994;20:398–403.

test

Part IX / Parasitic Diseases

649

[39] Pearce Ej, James SL, Hieny S et al. Induction of protective immunity against schistosoma mansoni by vaccination with schistosome paramyosin (Sm 97), a non surface parasite antigen. Proc Natl Acad Sci USA 1988;85:5678–5682. [40] Soisson LM, Masterson CP, Tom TD et al. Induction of protective immunity in mice using a 62-kDa recombinant fragment of a schistosoma mansoni surface antigen. J Immunol 1992;149:3612–3620. [41] Siddiqui AA, Phillips T, Charest H et al. Enhancement of Sm-p80 (large subunit of calpain) induced protective immunity against schistosoma mansoni through co-delivery of interleukin-2 and interleukin12 in a DNA vaccine formulation. Vaccine 2003;21:2882–2889.

“This page intentionally left blank"

xx

Part X Special Topics

41 42 43 44 45 46 47 48

Abdominal Tuberculosis Diarrhea in Children Nonvariceal Upper Gastrointestinal Tract Bleeding Lower Gastrointestinal Bleeding Hepatorenal Syndrome Hepatic Encephalopathy Ascites in Cirrhosis Malignant Liver Tumors

653 678 703 722 738 746 755 761

“This page intentionally left blank"

xx

Chapter

41 ABDOMINAL TUBERCULOSIS AK Jain

Abdominal tuberculosis is one of the earliest known diseases to the mankind. The earliest description (Law of Manu, 1000 BC) was based on clinical observations and the famous Greek physician Hippocrates (4th Century BC). Ancient descriptions recognized diarrhea as a mortal symptom in patients with pulmonary tuberculosis.[1] The disease has a worldwide distribution and remains prevalent in developing countries despite extensive vaccination programmes and use of antitubercular drugs for over four decades. In the west, an improved standard of living and the effective use of chemotherapy had resulted in a marked decline in tuberculosis prevalence, but in recent years there has been a resurgence of the disease.[2–4] This has occurred due to the advent of HIV infection; in these patients there is a high frequency of extrapulmonary involvement and rise of multidrug resistant (MDR) tuberculosis.

41.1 CHANGING PROFILE OF TUBERCULOSIS Snider and Roper in 1992 described the changing profile of tuberculosis as a consequence of HIV infections.[5] Extrapulmonary manifestations are seen in nearly 50% of HIV coinfected persons but in only 10%–15% of non-HIV infected subjects. In the United States peritoneal tuberculosis

is presently the sixth most common site of extrapulmonary involvement. HIV-infected intestinal tuberculosis subjects, as compared to non-HIVinfected patients, more frequently had fever with chills (100% vs 33%) and diarrhea (80% vs 25%). There was no difference in the frequency of other presenting features like abdominal pain, weight loss, and gastrointestinal bleed.[4]

41.2 EPIDEMIOLOGY 41.2.1 World An estimated two billion people (one-third of the world’s population) are infected with Mycobacterium tuberculosis, and 80–100 million people have the disease with 10 million new cases occurring every year. Tuberculosis is the commonest cause of death due to a single infectious agent resulting in 3 million deaths (a quarter of total avoidable deaths) world wide.[2, 4, 6]

41.2.2 India India is a low incidence and high prevalence country. There are about 400 million infected cases in India, with active tuberculosis in 12 to 15 million, resulting in 0.5 to 0.7 million deaths every year.[3, 7] A group of workers from Mumbai 653

654

Chapter 41 / ABDOMINAL TUBERCULOSIS

reported a 16.6% HIV seroprevalence in abdominal tuberculosis as compared to 1.4% in voluntary blood donors and 6.9% in pulmonary tuberculosis.[8] In HIV seropositive abdominal tuberculosis cases there was higher prevalence of lymphatic and hepatic involvement.[8] Epidemiological data on the prevalence of intestinal tuberculosis in India is scarce. A clinicoradiological study reveals that 0.8% of all the hospital admissions in India are due to tuberculosis.[9] The incidence of tuberculosis in an emigrant Asian population in UK is an estimated 36 per 1,00,000, and 0.43 per 1,00,000 in the native UK population.[10] Unselected autopsy studies from India report a 0.2% to 5.1% prevalence.[11, 12] An autopsy study from KEM Hospital, Mumbai reported a prevalence of 1.4% for intestinal tuberculosis and 7.1% for pulmonary tuberculosis.[12] The prevalence of intestinal involvement is related to the severity of pulmonary disease. The frequency of intestinal involvement in clinical[13] and autopsy studies[14, 15] respectively is 1% and 5%– 8% in cases with minimal pulmonary lesions, 4.5% and 14%–18% in moderately advanced disease, and 24.7% and 51%–60% in far advanced disease. Still, in about three-quarters of subjects, intestinal disease is primary, i.e., without any evidence of pulmonary disease.[16, 17] A recent study using DNA sequencing has established that nearly half of the cases with abdominal tuberculosis are due to reinfection[18] rather than reactivation of infection acquired several years ago (Table 41.1). In the present description the term “abdominal tuberculosis” implies tuberculosis of the digestive system, i.e., gastrointestinal tract including esophagus and anorectum, draining mesenteric lymph nodes, peritoneum, and digestive viscera like liver, biliary tract, and pancreas. The various sites of involvement reviewed recently[19] (eight studies: 817 cases) were peritoneal 37.6%, gastrointestinal 56.9% (esophagus

TABLE fy 41.1 Severity of pulmonary disease and frequency of intestinal involvement Severity of pulmonary lesions Minimal pulmonary lesion Moderately advanced lesions For advanced to Fatal disease

Frequency of intestinal involvement Clinicoradiologic[13]

Autopsy[14, 15]

1%

5%–8%

4.5%

14%–18%

24.7%

51%–80%

0.2%, stomach 1%, duodenum 1%, small bowel 27%, ileocecal area 22.9%, appendix 0.4% and colon and rectum 9.2%). Hepatobiliary tuberculosis was not included in these studies due to infrequent clinical manifestations of liver involvement, though on histology and autopsy studies liver involvement is frequent and varies with the state of pulmonary or systemic infection varying from 0% to 93% (average 21%) hepatic involvement in pulmonary, 12%–93% (average 74%) in extrapulmonary, and 25%–100% (average 50%) in miliary tuberculosis.[20, 21]

41.3 PATHOGENESIS The precise mode of involvement of intestines by tuberculosis remains poorly understood. Primary infection of gastrointestinal tract occurs through ingestion of contaminated milk or food. It is rare in India due to boiling of milk before consumption as well as in the west due to practice of milk pasteurization. Primary intestinal tuberculosis has been defined as “gastrointestinal involvement in the absence of clinically apparent pulmonary infection”. Secondary infection of gut results from a focus elsewhere in the body. The following are the

Tropical Hepatogastroenterology

PATHOGENESIS

routes of spread to the gut – (i) Hematogenous spread from active pulmonary or miliary tuberculosis. The importance of intestinal seeding by silent bacteremia is suggested by the result of a recent study, where all the 8 cases with pulmonary tuberculosis had evidence of M. tuberculosis infection in monocytes of the peripheral blood.[22] (ii) Swallowing of infected sputum by patients of open or active pulmonary tuberculosis. The lipid-laden mycobacterial cell wall is relatively acid resistant and allows organisms to reach and invade the bowel wall. (iii) Contiguous spread from adjacent organs like the female genital tract may be the source of intestinal involvement in some cases. Organism on reaching the intestines lodge at the sites of physiological stasis, abundant lymphoid tissue (Peyer’s patches), and at sites of light rate of absorption and low digestive activity, thereby permitting intimate contact of organism with mucosa. Thus, lesions are most common in the ileocecal area and ileal regions. Predilection of ileocecal involvement may also relate to rate of M. cells in Peyer’s patches in antigen-sampling of intestinal contents. BCG is selectively taken up by M. cells in and transported to antigen-processing cells in Peyer’s patches without any evidence of epithelial inflammation. In the early stages of intestinal tuberculosis similar histologic changes occur, i.e., involvement confined to lymphoid tissue with minimal involvement of epithelium.[23] Subsequently, inflammation extends throughout the submucosa. Ultimately, the epithelial layer above the Peyer’s patch may ulcerate resulting in the typical appearance of ulcerative tuberculosis. An important factor in the pathogenesis of the ulcer is mucosal ischemia due to tuberculous endarteritis. Often proliferative type of lesions develop. Whether ulcerative or hypertrophic type of lesions develop, it is probably related to host’s reaction and virulence of the bacilli.

Part X / Special Topics

655

41.3.1 Pathologic Appearance The characteristic morphologic appearances are either ulcerative, hypertrophic, or ulcerohypertrophic. In the ulcerative type, ulcers are transverse and usually circumferential probably as a result of coalescence of multiple smaller ones. These usually have undermined or everted edges. There is edema and induration of the disease segment, with serosal seeding with tubercular nodules (Fig. 41.1) and increase in serosal fat.

FIGURE 41.1 Ileal tuberculosis. The upper picture shows typical tubercles on the surface (arrow) (the picture was taken after the resection and anastomosis). This 30-year-old woman had a stricture, which on opening showed an ulcer at the site of the bowel narrowing (arrowhead). The ileum proximal (P) to the stricture is dilated as compared to the distal (D) ileum.

656

Chapter 41 / ABDOMINAL TUBERCULOSIS

TABLE fy 41.2 Pathologic differentiation between intestinal tuberculosis and Crohn’s disease Features Gross appearance Anal lesions, internal fistulae Miliary nodules on serosa Length of stricture Perforation Ulcers: Location axis Microscopic appearance Granulomas: Presence - Size and shape - Caseation - Presence of caseation in lymph node when absent in intestine - Surrounding fibrosis, hyalinization & inflammatory cells at periphery Submucosal widening, fissures & transmural follicular hyperplasia Fibrosis in muscularis propria & epithelial regeneration

Tuberculosis

Crohn’s disease

Rare Common Usually < 3 cm Uncommon Circumferential Transverse

Frequent (Fig. 41.2) Rare Usually long Rare On mesenteric attachment Longitudinal/Serpiginous

Almost always Large & confluent Usually present Usually present

75% Small & discrete Usually absent Always absent

Common

Rare

Generally absent

Generally present

Generally present

Uncommon

Adapted from Prakash and Tandon[24]

Crohn’s disease, an inflammatory disease involving almost same intestinal sites and presenting as ulcerative lesions, as granulomas sometimes may create problems in diagnosis. Tandon and Prakash[24] described the characteristic differentiating features between the intestinal lesions of tuberculosis and Crohn’s disease (Table 41.2). The hypertrophic form is characterized by extensive inflammation and fibrosis in the submucosa and serosa. Adherence of bowel mesentery and lymph nodes results in a mass. Sometimes, there may be an exophytic mass lesion from mucosal surface. The lumen of the bowel is compromised and stricture formation results both from ulcerative and hypertrophic forms of the disease. Ulceroproliferative lesions are more frequent than proliferative lesions. Sometimes diffuse

granulomatous inflammatory lesions may occur involving the small bowel (diffuse enteritis) or involving the colon (diffuse colitis). Later these lesions may mimic ulcerative colitis and may be difficult to be precisely recognized on colonoscopic appearance alone. However, histology is usually helpful. Rare manifestations are fistula formation (enteroenteric/colic or enterovesical/vaginal) or formation of enteroliths.

41.4 CLINICAL FEATURES The clinical features of abdominal tuberculosis are nonspecific and insidious in onset, but the presentation is sometimes acute. The disease affects all age groups, but is commonest in young adults in the third and fourth decades of life.

Tropical Hepatogastroenterology

CLINICAL FEATURES

657

TABLE fy 41.3 Symptoms and signs

FIGURE 41.2 Ileocolic fistula in a patient with Crohn’s disease. The patient presented with intestinal obstruction, and underwent surgery. The upper illustration shows a small segment of distal ileum (Di) adherent to the ascending colon, where a tight stricture (S) had formed a few centimeters distal to the cecum (C). The region of the stricture is better seen in the second illustration. At the site of the stricture there was an ileocolic fistula. The lower picture shows this fistula, posterior view; the terminal ileum (Ti) is on the lower left, the mucosa of the ascending colon is on the right, communicating at the site of the stricture with the mucosa of the distal ileal segment (Di). The distal ileal segment was resected along with the right colon. The white arrowheads point to the stapled edges. H = hepatic flexure.

Part X / Special Topics

Abdominal symptoms and signs Abdominal pain 77%–94% Abdominal distension 28%–45% Vomiting 33%–74% Borborygmi 26%–50% Amenorrhea 12%–36% Diarrhea 11%–48% Constipation 12%–46% Hematochezia 02%–13% Ascites 19%–60% Abdominal mass 17%–45%

(86%) (37%) (46%) (35%) (23%) (22%) (24%) (4%) (37%) (33%)

Other symptoms Weight loss Fever Anorexia Pulmonary

(63%) (61%) (48%) (19%)

35%–87% 29%–100% 10%–100% 4%–51%

Studies from the West report an equal prevalence in both sexes but a female predominance of about two times has been reported in various studies from India.[16, 25] The duration of the disease at the time of presentation can vary from a month to a year in most of the patients. These patients present with constitutional symptoms, abdominal symptoms, and sometimes symptoms related to the involvement of other organs and sites. Constitutional symptoms in the form of fever, malaise, night sweats, anorexia, and weight loss are noted in over 50% of the subjects. The clinical features are listed in Table 41.3 and were compiled recently based on observations in 8 studies from India and 6 from other countries.[19] Pulmonary symptoms are noted in one-fifth and amenorrhea in a quarter of female subjects. Abdominal pain can be anywhere in abdomen or may be diffuse all over the abdomen though more frequently described in the right lower quadrant. Pain, many a times, is crampy or colicky in nature and is present in all the patients irrespective of the presence or absence of bowel obstruction. It

658

Chapter 41 / ABDOMINAL TUBERCULOSIS

is a dominant symptom with acute presentation like bowel obstruction and bowel perforation. In peritoneal or ascitic type, pain has been infrequent and if present, is mostly dull aching and diffuse. Diarrhea had been previously regarded as a common symptom in intestinal TB but is noted less frequently. Many factors contribute to its pathogenesis; one of the important factors is diffuse enteritis or ulcerations. The generalized inflammatory response in intestine and subsequent effects of cytokines, leukotrienes, and prostaglandins on fluid and electrolyte transport can result in diarrhea. Occasional case report of active chloride secretion[26] has been observed in endoscopically normal appearing terminal ileum. Secondary diarrhea can also be the result of bile salt malabsorption as the disease predominantly affects the terminal ileum. Bacterial overgrowth proximal to stricture, and malabsorption state are other important contributory factors. Short bowel syndrome with or without enteroenteric fistulae is now infrequent development but can also contribute to diarrhea if present. Motility disturbance in nonstricture bowel has also been proposed but it has not been evaluated adequately. Constipation has been observed in one fourth of cases but is more frequent in patients undergoing surgical treatment (41%–67%)[17] suggesting it to be a manifestation of obstruction. Involvement of proximal gut is an infrequent the esophageal involvement can manifest with dysphagia and gastroduodenal tuberculosis with feature of gastric outlet obstruction and rarely, hematemesis. On examination, there are no pathognomonic signs. Most patients appear sick, poorly nourished and febrile. Associated pulmonary tuberculosis has been noted less frequently in developing world (India 16%, Iraq 10%) but more frequently from developed nations (USA 71%, Japan 52% UK 52%).[16] Clinically evident tuberculosis of other sites can be a rare accompaniment. Classical

TABLE fy 41.4 Clinical presentation Presentation Nonobstructive and vague Ascites Abdominal masses Obstruction Perforation Bleeding per rectum Malabsorption

Range

Average

25%–38%

29%

19%–60% 17%–45% 15%–35% 1%–10% 2%–13% Up to 20%

37% 33% 21% 3% 4% 14%

doughy consistency of abdomen (due to extensive fibro-adhesive inflammation) is infrequent and is nonspecific. Abdominal tenderness is frequently present in the right lower quadrant. Palpable mass may be observed in 17%–45% of subjects. Visible bowel loops or features of obstruction (21%), free fluid in peritoneal cavity (33%) (sometimes the fluid collection may be loculated) are other features observed. Although these clinical features are protean (Table 41.3), these manifest in different modes of presentation which has been recently reviewed and listed in Table 41.4 based on observation in 8 large series from India and 6 reports from elsewhere.[19]

41.5 DIAGNOSTIC CRITERIA The diagnosis of abdominal tuberculosis can be established on fulfillment of one of following criteria: 1. Isolation or demonstration of mycobacteria 2. Mycobacterial DNA/RNA demonstration 3. Caseating granuloma/Noncaseating granuloma with Langhan’s giant cells 4. Noncaseating granuloma or characteristic radiologic features or characteristic laboratory

Tropical Hepatogastroenterology

DIAGNOSTIC APPROACH

findings or serologic positivity with response to antitubercular therapy. Probable tuberculosis has been considered when there is response to antitubercular therapy in clinicoradiologically suspected patients (Logan’s criteria).[27]

41.6 DIAGNOSTIC APPROACH 41.6.1 Ascitic Presentation • Ascitic Fluid – Exudative: Protein > 2.5 gm/dl; Serum ascites albumin gradient < 1.1 – Adenosine Deaminase (> 32 IU/L); γ Interferon (> 3.2 U/ml) – Mycobacteria, Mycobacterial antigen or DNA • Laparoscopy and Biopsy:- Tubercular granuloma, Mycobacteria or its DNA

41.6.2 Masses, Obstruction, Nonobstructive, and Vague Presentation • Supportive – Radiology/Imaging/Serology • Confirmatory – Tissue studies for:- Tubercular granuloma, Mycobacteria or its DNA

659

41.7.1 Supportive Diagnostic Aids (a) Hematology: Hematological changes are nonspecific and only correlate with a chronic infective process in the body. Raised ESR has been noted in over 90% of the patients and blood counts usually do not reveal any abnormality, although relative lymphocytosis is seen in one-third of cases.[16] (b) Mantoux test: Mantoux test is positive in over 70% of cases, but the high prevalence of Mantoux positively in developing countries (60%) limits its usefulness. Hence neither the Mantoux result is helpful for diagnosis, nor does a negative result exclude the possibility of intestinal tuberculosis. False negative results are often seen in the elderly, undernourished, immunosuppressed patients, and in patients with disseminated disease. (c) Radiology: Plain abdominal X-rays often show presence of ascites, or distended bowel loops with fluid levels on erect film. Plain X-rays in abdominal tuberculosis reveal fluid and gas level in half of the cases with obstructive variety and no positive findings in nonobstructive type. Calcified lymph nodes were noted in 6% and gas under diaphragm in 4% of cases.[28] Occasionally, enteroliths have also been seen. 41.7.1.1 Barium contrast radiography

41.7 DIAGNOSTIC AIDS Since the clinical presentation is nonspecific, one has to rely upon the available investigative modalities. Most of the cases can be established by available methods; seldom is laparotomy required for diagnosis. The available diagnostic aids can be classified into two categories, i.e.,: A. Supportive B. Confirmatory

Part X / Special Topics

There are no pathognomonic roentgenographic signs of intestinal tuberculosis on barium film but certain features are suggestive of this disease. The earliest small bowel manifestations are disturbances in motility resulting in accelerated transit time, and hypersegmentation and flocculation of barium. Diseased small bowel may show scalloping, spicule formation, and thickening of the mucosal folds. The later findings are stricture with proximal dilatation (27%–41%), deformed

660

Chapter 41 / ABDOMINAL TUBERCULOSIS

and pulled up cecum (7%–29%), ulcers (6%–9%), masses (7%–16%), and enteroliths (< 1%). These radiological features have positivity in only half of the cases.[25, 28, 29] Moreover, even these features lack specificity as similar features are often noted in lymphoma, carcinoma, Crohn’s disease, ameboma, ischemic colitis, and periappendiceal abscess. Characteristically described signs like Sterlin’s sign (lack of barium in the involved segment), string sign (a sustained narrow stream of barium in the small bowel), and Fleischner’s sign (gaping of IC valve) are rare and not pathognomonic. Barium contrast is still useful in assessment of intestinal lesions and localizing the site of involvement in intestinal tuberculosis. Small bowel enema or enteroclysis further improves the diagnostic yield (Fig. 41.3). In our experience, it

gave a positive result in 73% (single contrast study 60%) and excluded false positive barium follow through findings in 5% (unpublished data). Comparative studies in abdominal tuberculosis are lacking though available in Crohn’s disease suggesting a better yield with enteroclysis (Fig. 41.4). Barium enema has also been used as lesions usually involve the ileocecal junction and adjoining colon. In a Double Contrast Barium Enema (DCBE) study on 25 established cases of colonic tuberculosis,[30] examination revealed characteristic findings in 16 patients in the form of ulcers (64%), polypoid lesions (5%), and ileocecal valve changes like deformity, thickening, and shortening of the involved segment (88%). In three (12%) patients the study revealed a mass lesion, and lymphoma and carcinoma could not be excluded. The remaining two (24%) had either normal or equivocal appearance. 41.7.1.2 Ultrasonography

FIGURE 41.3 Small bowel enema in a patient with an ileal stricture (white arrow). The tube through which contrast is administered is visible towards the left of the picture.

Ultrasound in peritoneal tuberculosis can reveal involvement of the peritoneal cavity, mesentery, or omentum. Peritoneal involvement is in the form of free fluid (20%–30%), rarely loculated ascites and focal ascites, and peritoneal thickening (12% to 91%). Free fluid can be clear fluid (52%–64%), and complex fluid with debris and septa (38%–48%). Focal ascites is an interloop fluid collection which appears as “club sandwich sign”. Mesenteric involvement is the earliest sign noted in 60%–100% of subjects and is the form of mesenteric thickening (≥ 15 mm) and mesenteric lymphadenopathy.[35] Matted and fixed bowel loops arranged around thickened mesentery stand out as spokes radiating from centre (Stellate sign.) Omental involvement has been noted in 5%– 18% and is in the form of omental thickening and matted bowel loops which may result in clinically palpable masses. Mesenteric thickening

Tropical Hepatogastroenterology

DIAGNOSTIC AIDS

661

FIGURE 41.4 Ileocecal lesions. (a) A patient with ileocecal tuberculosis. (b) The patient had Crohn’s disease.

with mesenteric lymphadenopathy is the earliest sonographic sign of abdominal tuberculosis noted even before intestinal involvement.[35] The mesenteric thickening can also be seen in portal hypertension (without lymphadenopathy) and lymphoma (with retroperitoneal lymphadenopathy). Mesenteric thickening has been considered as a reliable parameter to evaluate the course of therapy as mesenteric lymphadenopathy is the first to regress (as early as two weeks), and thickening is the last to regress. In cases presenting with abdominal masses and abdominal lymphadenopathy, ultrasound can reveal the site of involvement, and can provide tissue diagnosis by guiding fine needle aspiration biopsy (FNAB) (Fig. 41.5). Mesenteric, para-aortic, peripancreatic, and celiac nodes are common sites affected but the sole involvement

Part X / Special Topics

FIGURE 41.5 A large lymph node in the ileal mesentery. While lymphadenopathy is common in abdominal tuberculosis, very large nodes are unusual.

662

Chapter 41 / ABDOMINAL TUBERCULOSIS

of retroperitoneal lymph nodes is infrequent. Nodes appear as hypoechoic and heterogeneous with central lucency (41%–64%).[32, 33] FNAB had a sensitivity of 76% in confirming tubercular pathology in abdominal lymph nodes. There was no false positivity and no complications.[36] Bowel involvement on US appears as concentric wall thickening whereas in Crohn’s disease, the bowel shows thickening on the mesenteric border, and in malignancy a variegated appearance. However, asymmetrical thickening of the medial wall of the cecum and ileocecal valve has also been described in tuberculosis.[37] Since the lesions are predominantly on ileocecal region and ascending colon, lesions are in the subhepatic region and appear as “pseudokidney” sign. US guided FNAB from colonic mass lesions (colonoscopic biopsy equivocal finding) could identify tubercular granuloma in 2 of the 3 cases.[36] 41.7.1.3 CT scan

CT studies[29, 38] report intestinal involvement in 35%–50% of patients. The involvement is nodal in 54%–90% (nodal alone in 11%–45%), and peritoneal in 26%–54% (peritoneal alone in 22%). CT can detect clinically unsuspected nodes and ascites.[39] Bowel loops forming a mass are observed in 14%. The distinguishing features of tubercular nodes vs. lymphomatous involvement on CT were evaluated recently in a study on 26 cases of abdominal tuberculosis and 43 lymphoma subjects.[40] Retroperitoneal nodes alone were rarely involved in tuberculosis. Lower paraaortic lymph nodes were rarely involved in tubercular patients (5%) but invariably involved in lymphoma subjects (90%) and also in disseminated tuberculosis (80%). However, in disseminated tuberculosis mesenteric lymph nodes were also involved (80%) but less frequently so in lymphoma (20%). Moreover, tubercular abdominal lymph

nodes in contrast to lymphomatous lymph nodes revealed peripheral enhancement more frequently (88% vs. 2%) and multilocular appearance (65% vs. 9%) in contrast enhanced study. Hypodense centers and enhancing rims occurred in 40%– 70% of abdominal tuberculosis patients. Other CT pattern of lymph node morphology include:[41] 1. Conglomerate mixed density nodal masses. 2. Enlarged nodes of homogenous density most often associated with low density nodes at other sites 3. Increased number (> 3 in one CT section) of normal size or mildly enlarged mesenteric nodes of homogenous density. 4. Nodal calcification. Identification of site of lesion was possible using CT in 60% of subjects. However, the positivity was only 50% with characteristic barium findings but 80% with inconclusive barium findings.[29] This implies that barium contrast and CT are complimentary to each other. CT findings appear to be quite sensitive but lack a high degree of specificity as on rare occasions the CT appearance may be indistinguishable from neoplastic lesions, pyo- or hemoperitoneum. Peritoneal involvement on CT[29, 38] manifests as high density ascites (due to high protein and cellular contents) and a uniformly thickened peritoneum causing peritoneal enhancement. Intestinal tuberculosis on CT[37] appears as concentric mural thickening (occasionally eccentric) of the ileocecal region mainly of the medial cecal wall along with concomitantly enlarged hypodense lymph nodes in the adjacent mesentery. 41.7.1.4 Serodiagnosis

Histologic and bacteriologic methods often present problems of access to disease site and poor yield. ELISA in abdominal tuberculosis had a specificity

Tropical Hepatogastroenterology

DIAGNOSTIC AIDS

663

TABLE fy 41.5 Biochemical markers in tuberculosisy

Ascitic ADA

Indian studies Europe/Africa

Serum ADA Gamma interferonAscites, mycolic acid, SCFA, CA-125, etc. ∗ Average

Sensitivity

Specificity

89%–100% (92%) 83%–95% (93%) 100% 98%–100% –

81%–97% (90%) 96%–100% (985) 95% 98%–100% –

figures shown in parenthesis

of over 90%, and a sensitivity of about 80% in various studies using purified and semipurified antigen.[42, 43] A Competition ELISA using monoclonal antibody TB-72 against 38 kDa protein gave encouraging results.[44] Danel and coworkers developed a test system with 100% sensitivity using DA 5 antigen.[45] It gave a sensitivity of 89% in China but only 49% in Cleveland. This may be due to antigenic variability among different racial groups. ELISA lacks sensitivity in HIV infected cases due to failure of the humoral response. ELISA fails to distinguish between active and past infection as titers are often in the positive range in half of the cases after a year of chemotherapy. The soluble antigen fluorescent antibody (SAFA) test in the diagnosis of abdominal tuberculosis has results comparable to ELISA.[46] Radioimmunoassay has also been evaluated for diagnosis of abdominal tuberculosis, but the yield is lower [47, 48] (sensitivity of 53%–56% and specificity of 86%–97%). Serologic techniques have also been employed for the detection of antigen[49, 50] in the ascitic fluid which is being discussed subsequently. 41.7.1.5 Biochemical markers of tuberculosis (Table 41.5)

Adenosine deaminase (ADA) is an enzyme found in the cell surface of lymphocytes (particularly T lymphocytes) and macrophages. Activation of

Part X / Special Topics

T lymphocytes in response to the cell-mediated immune reaction to mycobacterial antigen causes elevation of ADA levels. ADA has been studied mostly in serous fluids. In addition, there are reports in the serum levels as well. ADA estimation in ascitic fluid has been found to be highly useful in the diagnosis of the ascitic form of tuberculosis. A sensitivity approaching almost 100%[51–53] has been noted in Indian studies, with a specificity of 95%–97%[51–53] in most studies, except in one study showing a sensitivity of 81%.[44] A comparable yield has been noted in studies from Spain[55] and South Africa,[56] revealing a sensitivity of 83%–95% and a specificity of 96%– 100%. Recently, serum ADA values have also been evaluated for the diagnosis of tuberculosis in children.[57] This study included 51 cases of tuberculosis involving various sites. Fifteen of these had disseminated tuberculosis, and 4 had abdominal tuberculosis. Serum ADA values of ≥ 42 IU/L and lysozymes ≥ 20 were noted in all patients with tuberculosis. A high serum concentration of ADA isoenzyme 2 was observed in tuberculosis, infectious mononucleosis, T cell leukemia, and multiple myeloma, whereas ADA isoenzyme-1 rise was noted in hematological malignancy.[58]

41.7.2 Confirmatory Modalities A definite evidence of tubercular pathology can be demonstration of mycobacteria, classical

664

Chapter 41 / ABDOMINAL TUBERCULOSIS

tubercular granulomas, and/or detection of mycobacterial nucleic acids in the tissue samples. Each of these modalities has its own merits and demerits when applied to the diagnosis of abdominal tuberculosis. Still, these are useful in a large proportion of subjects and are employed for diagnosis. Gamma interferon in ascitic fluid is another useful marker for the diagnosis of tuberculosis.[59] It is secreted by antigen-triggered CD lymphocytes. The diagnostic yield of Gamma interferon is comparable to ADA estimation. The only advantage is its usefulness in HIV coinfected cases where ADA is usually negative. However, in a recent study from Durban, South Africa,[60] ADA-T (total), ADA-2 isoenzyme and gamma interferon were prospectively evaluated in HIV seropositive and seronegative patients with tubercular peritonitis. It was observed that ADA (T) and ADA-2 activities were significantly elevated above the control values in both the HIV seropositive and seronegative groups. Tuberculostearic acid (TBSA) is a cell wall fatty acid which can be estimated precisely using gas chromatography and mass spectrometry. This has proven to be a rapid and sensitive method for the diagnosis of tubercular meningitis,[61] and has been evaluated in other forms of tuberculosis including tubercular peritonitis. The test is expensive and requires technical expertise, but a monoclonal antibody for detection of TBSA is underdevelopment. This might provide a rapid and simple method of detection of TBSA in serous fluids. Isolated case reports of elevated serum CA125 and increased peritoneal uptake of Gallium– 67 have been advocated as useful modalities for the diagnosis of peritoneal tuberculosis. However, there are insufficient large-scale studies.

ing the diagnosis, as the mycobacterial isolation results are delayed and the efficacy poor. In recent times, the availability and advances in endoscopic techniques have simplified access to disease sites enabling inspection and tissue sampling. However, many-a times lesions are minimal and nonspecific in the bowel (even in resected tissues), and classical caseating granulomas are present only in the lymph nodes limiting the usefulness of endoscopic biopsies. In mass lesions, percutaneous fine needle aspiration biopsy (FNAB) is valuable. Often, early laparotomy has been advocated for early and more precise diagnosis. Since laparotomy carries the mortality rate of 3%–12%[62] in patients with tubercular peritonitis, it should be only be considered if all other diagnostic modalities have failed or if a surgical reconstruction is needed.

41.7.2.1 Histologic diagnosis

41.9 ENTEROSCOPY

The presence of tubercular granulomas in the biopsy sample remains the mainstay for establish-

Although enteroscopy and biopsy are theoretically attractive for establishing the diagnosis of

41.8 UPPER GI ENDOSCOPY Upper GI endoscopy has been used whenever lesions are suspected in the upper gastrointestinal tract. Endoscopic biopsies usually establish the diagnosis,[63, 64] although esophageal and gastric involvement in tuberculosis is rare. Endoscopic brush cytology and aspiration cytology from unsuspected esophageal lesions (228) revealed tubercular granulomas in 8 (3.5%) and mycobacteria in 5 (2.2%).[65] Six of these unsuspected cases had superficial erosions only. There were stricture and mass in one case each.[65] Duodenal involvement is usually visualized on endoscopy, but biopsies have a low yield as often the characteristic histologic lesions are in the surrounding lymph nodes.[66]

Tropical Hepatogastroenterology

LAPAROSCOPY

intestinal tuberculosis as nearly half of intestinal lesions are in small bowel, these remain an experimental tool. Among various types of enteroscopic techniques (push enteroscopy, Sonde enteroscopy, and intraoperative enteroscopy) Sonde enteroscopy appears the most promising for total small bowel examination. In a report using push enteroscopy the histological diagnosis could be established in a case of distal jejunal tuberculosis.[67]

41.10 LAPAROSCOPY In exudative peritoneal tuberculosis presenting as ascites laparoscopy has been found the most useful and safe in providing inspection diagnosis and obtaining tissues samples for histologic and/or bacteriologic confirmation. In the fibroadhesive form of tuberculosis, which is infrequent (0–12%), the procedure is relatively difficult, the success rate is low, and complications are more frequent. The diagnostic yield of laparoscopy in 385 cases with ascitic form of presentation and 22 cases with fibroadhesive form in 8 studies[52, 68–74] is summarized below in Table 41.6.

TABLE fy 41.6 Laparoscopy in peritoneal tuberculosis

Success rate of laparoscopy Diagnosis on inspection Histological diagnosis Mycobacterial isolation Major complications

Ascitic (385)

Fibroadhesive (22)

100%

68%

75%–100% (93%)

90%

53%–100% (90%)

77%

37%–75% (70%)

–

0%–10% (2%)

15%

Part X / Special Topics

665

Characteristic laparoscopic findings include multiple yellow white miliary nodules (3–5 mm) diffusely distributed over the visceral and parietal peritoneum, adhesions, erythematous patches, thickened and hyperemic peritoneum, and ascites. Other diseases that may mimic tubercular lesions but may be diagnosed by laparoscopic biopsies are carcinomatosis peritonei, lymphoma, sarcoidosis, starch peritonitis, and rarely Crohn’s disease. Laparoscopy guided peritoneal biopsy has superior and consistent yields whereas blind percutaneous biopsy, though a simple technique, provides variable diagnostic yield[75, 76] and is not without risk.[77] Mini-laparotomy for peritoneal biopsy has been preferred by some clinicians. This may be diagnostic if laparoscopy is inconclusive. Earlier studies recommended laparotomy for the diagnosis of peritoneal tuberculosis[78] but a mortality of up to 12%[79, 80] has been reported, which does not favor its use.

41.11 COLONOSCOPY In nearly half of the patients of intestinal tuberculosis the lesions are in the terminal ileum, cecum, or colon, which are easily accessible by colonoscopy. Still, colonoscopy remains underutilized for the diagnosis of intestinal tuberculosis. Colonoscopic features[81–89] noted in 9 studies on 394 colonic tuberculosis subjects are listed in Table 41.7. Gross features like circumferential ulcer, a single transverse ulcer with uneven base, pseudopolyps, strictures, edematous and deformed ileocecal valve, nodules, and pouch formation due to multiple fibrous bands are characteristic but not diagnostic of intestinal tuberculosis. In a recent study of 60 subjects,[87] the sensitivity of these features in suspecting the diagnosis was 90%, but the specificity of these features was only 48%, as 52% of these patients with these features had

666

Chapter 41 / ABDOMINAL TUBERCULOSIS

TABLE fy 41.7 Colonoscopic features (9 studies: 394 cases) Ulcers Nodules IC value deformity Strictures Polypoid lesion Fibrous band Segmental >One site Diffuse Histology positive ∗ Average

70%–93% 51%–100% 27%–55% 7%–44% 6%–55% 0%–8% 8%–26% 10%–58% 0%–18% 38%–80%

(80%) (71%) (47%) (24%) (18%) – (19%) (29%) (5%) (60%)

figures in parenthesis

alternative diagnosis like IBD, lymphoma, carcinoma, typhoid fever, colonic polyp, and amebic colitis. Although these features are nonspecific, they are most useful in suspecting the diagnosis and obtaining tissue samples for histologic diagnosis as well as for mycobacterial isolation and mycobacterial DNA detection. The overall diagnostic yield of colonoscopic biopsies in various studied has been found to be 60% (Table 41.6). Five recent studies consisting of 233 cases[84, 85, 87–89] gave histological details in patients in undergoing colonoscopy. The typical granuloma with Langhan’s giant cells was observed in 31% (17%–48%), and collections of epithelioid cells (without Langhan’s giant cells) suggestive of tuberculosis were recorded in another 36% (21%–59%). In nearly onethird (20%–62%) of patients histology remained equivocal towards diagnosis as only nonspecific changes were observed. In addition, colonoscopic biopsy samples have been utilized for the detection of mycobacteria and mycobacterial DNA. The yield of these techniques has been discussed subsequently (Table 41.7). The histologic yield of colonoscopic biopsy has improved with deeper biopsies (as granulomas are located in the submucosa) and multiple biopsies

TABLE fy 41.8 Bacteriologic yield of colonoscopic biopsies Fresh tissue smear (318 cases in 6 studies) Fixed tissue histology[82, 87, 88] (63 cases in 3 studies) Tissue culture[82, 83, 88] (184 cases in 6 studies)

0%–32%

(6%)

36%–100%

(58%)

0%–40%

(14%)

especially from the edge of ulcers and deeper parts of ulcer bed (Table 41.8). Biopsies from nodular lesions had poorer histological positivity (25%) than those from an ulcer edge (60%).[83] Hence, for assessment of nodular lesions, colonoscopic needle aspiration has been advocated. The aspirates obtained can be evaluated for cytology, bacteriology and mycobacterial DNA detection.[90, 91]

41.12 BACTERIOLOGIC DIAGNOSIS Demonstration of Mycobacterium tuberculosis in clinical samples is the most convincing evidence for tuberculosis. The various techniques applied include smear examinations, culture, and guinea pig inoculation.

41.12.1 Smear Examination Microscopy gives positive results whenever 5,000– 10,000 bacteria per ml are present in clinical samples. Since many a times such a high concentration of bacteria is not present in clinical samples of abdominal tuberculosis patients, the yield of smear examination is poor (0%–32%), particularly when using conventional staining procedures like Ziehl–Neilson staining. Recently, fluorochrome staining methods (Auramine and Rhodamine) have been applied with improved results for better yield. These techniques are simple rapid and inexpensive.

Tropical Hepatogastroenterology

MOLECULAR METHODS OF DIAGNOSIS

41.12.2 AFB on Histology Mycobacterial detection has been attempted in only few studies[82, 87, 88] and the positivity (36%– 100%) had been better than the smear studies (Table 41.8)

41.12.3 Culture Mycobacterial isolation on culture of the biopsy samples has been low with variable yield (0%– 48%) in various studies (Table 41.8). Moreover, it takes more than 4 weeks using conventional media. However, in recent times use of rapid culture techniques (Bactec, Septicheck and microcolony) have provided results in 2 weeks. The bacteriological yield using various techniques has also been evaluated in relation to the histological type of lesion in resected tissues and colonoscopy biopsies.[88]

41.13 MOLECULAR METHODS OF DIAGNOSIS Detection of mycobacterial nucleic acid in the clinical samples is a recent concept in the diagnosis of tuberculosis. Mycobacterial DNA sequence can be identified by DNA probes and is species specific. Positive results require 10 bacilli/ml.[7] Hence, the yield is often poor in clinical samples. To overcome this limitation the polymerase chain reaction (PCR) has been applied to amplify the DNA content more than a million fold. Recently, RNA amplification[49] has also been utilized for mycobacterial detection but clinical studies are limited. Most of the studies of PCR and DNA detection are on respiratory secretion, serious effusion, paraffin fixed tissue sections and fresh tissue homogenates from extraintestinal tuberculosis samples. Studies are available on intestinal and peritoneal tuberculosis with promising results.[88, 91–94]

Part X / Special Topics

667

41.13.1 PCR in Abdominal Tuberculosis Most of the studies on intestinal tissue samples are case reports. Recently in 3 studies,[88, 92, 93] 90 abdominal tuberculosis samples and 48 negative controls have been evaluated obtained on endoscopic and operative biopsies. Oligonucleotides derived from the IS6110 sequence which is repeated in M. tuberculosis chromosome and is highly specific for the M. tuberculosis complex, was used as a primer. In histologically confirmed tuberculosis cases, the PCR positivity was 61% and in 2 cases with nonspecific histology PCR gave a positive result. 94% PCR positivity was noted in the mycobacterial positive group and 60% in the mycobacterial negative group. In liver biopsies, all the culture positive cases had PCR positivity as well, and an overall PCR sensitivity of 58% when the tuberculosis was the most likely diagnosis and had a 96% specificity. The PCR positivity on resected tissues was 85% but only 50% on endoscopic biopsies. However, the PCR yield was superior to mycobacterial detection (75% vs. 44%).

41.14 HEPATIC TUBERCULOSIS The liver can be involved in pulmonary, extrapulmonary, and miliary tuberculosis. Histologic changes of tuberculosis has been identified in 21% (0%–93%) of pulmonary tuberculosis, 74% (12%–93%) of extraintestinal tuberculosis and 50% (25%–100%) of miliary tuberculosis in a meta-analysis of 23 studies involving 1111 cases, conducted by Lewis and Zimmerman.[20] In a recent report from India, 63% of pulmonary and extrapulmonary tuberculosis subjects and 46% of pyrexia of unknown origin cases had histologic evidence of hepatic tuberculosis.[21] A variety of hepatic lesions have been recognized. These are[95]

668

Chapter 41 / ABDOMINAL TUBERCULOSIS

I. Diffuse form of hepatic tuberculosis:1. Miliary tuberculosis of liver is the most common (50%–80%) in fatal tuberculosis cases. It is mostly the part of a generalized miliary tuberculosis. It has no signs and symptoms relevant to the liver. 2. Tuberculous hepatitis (granulomatous disease) is an uncommon manifestation and only case reports are available. It presents with unexplained fever, mild jaundice and/or hepatomegaly in some cases. Hepatic histology shows caseating granulomas. Occasionally, fulminant hepatic failure has been reported. II. Localized form of hepatic tuberculosis has been observed in 14% of all hepatic tuberculosis cases. It can be: 1. Focal or nodular form which includes tuberculomas and tubercular abscess. 2. Tubular form involves intrahepatic ducts and often referred to as hepatobiliary tuberculosis. It can manifests as obstructive jaundice, more frequently due to enlarged nodes surrounding the bile ducts, and less frequently due to lesions involving ductal epithelium resulting in bile duct strictures.

41.14.1 Pathogenesis Hematogenous spread usually through the hepatic artery and sometimes through the portal vein (particularly in gastrointestinal tuberculosis) results in hepatic involvement. The liver can also be involved through lymphatics, or direct rupture of a tubercular lymph node in the portal vein; still rarely hepatic tuberculosis may be primary (without any lesions elsewhere).

41.14.2 Clinical Presentation Most of these patients (based on 4 studies involving 467 patients)[96–99] are in the second decade with male predominance ((M:F = 2 : 1). Patients with localized tuberculosis present usually between 30– 50 years of age. The usual presenting symptoms are abdominal pain in 53% (45%–66%), fever in 84% (63%–90%), weight loss in 70%(55%–75%), jaundice in 20% (11%–35%), hepatomegaly in 92% (80%–96%), nodular liver mimicking tumor in 55%, tender liver mimicking abscess in 47% (36%–60%), and splenomegaly in 44% (25%– 57%). Patients with the localized form of tuberculosis had pain in only in 15%. Nearly half of the patients with a tubercular lesion in the liver did not have any symptoms suggestive of liver disease. The most consistent abnormality was rise in alkaline phosphatase (75%–80%). It was observed in almost in all jaundice cases and in only 6% nonjaundiced subjects. Transaminases were elevated in 56% (35%–70%), (> 90% of jaundice cases and < 5% nonjaundice cases.) Altered albumin:globulin ratio has been found in 85% (63%–95%. Although liver biochemistry is deranged in most cases, it is not diagnostic.

41.14.3 Diagnosis It requires high degree of suspicion in endemic areas in patients presenting with right hypochondriac pain, hepatomegaly, nodular liver of long duration (> 1 year), pyrexia and jaundice, particularly in a setting of tuberculosis elsewhere in the body. Abnormal hepatic biochemistry is usually nonspecific imaging and guided biopsies are helpful in establishing the diagnosis. 41.14.3.1 Imaging techniques

Radiolabeled isotope scan has largely been replaced by US and CT scan.

Tropical Hepatogastroenterology

TREATMENT

US shows hypoechoic lesions, and complex masses with calcification. The differentiation from neoplastic lesions is often unless guided liver biopsy is performed.[100–102] The dilated intrahepatic ducts can also be noted if biliary channels are involved. CT reveals solitary or multiple focal masses due to a large tuberculoma or cold abscess.[100–102] The possibility of malignancy can only be excluded only on CT guided biopsy or aspiration cytology. 41.14.3.2 Liver biopsy

Percutaneous blind liver biopsy is useful in miliary form of hepatic involvement which is the commonest form of hepatic lesion and is often missed because most of these patients do not have symptoms of liver disease. Guided liver biopsies (US/CT/laparoscopic guidance) have been found to be the most useful procedure in the diagnosis of localized hepatic tuberculosis (almost 100% diagnostic yield compared to 67% yield on blind biopsy).[95] Histology usually reveals granulomas which are confluent and large but central caseation is present only in 67% (30%–83%).[95] Noncaseating tubercular granuloma needs to be differentiated from hepatic granuloma due to other causes like brucellosis, Hodgkin’s disease, Coccidioidomycosis, drugs, etc. Liver biopsy specimens have been utilized for AFB detection using smear examination and culture techniques with an isolation rate of 16% (7%–59%).[96, 97, 99] 41.14.3.3 Laparoscopy

Laparoscopy was widely utilized for visualization of lesion and obtaining tissue samples in presonographic era. Nowadays, it is less frequently utilized. Diagnosis of tubercular granuloma on gross laparoscopic appearance could be correctly

Part X / Special Topics

669

made in 92% of 55 cases.[96] Characteristic lesions are chalky white and irregular nodules of varying sizes. Laparoscopic guided biopsy could establish diagnosis in all of them. 41.14.3.4 ERCP/PTC

It is employed in the diagnosis of biliary tuberculosis, particularly in cases showing intrahepatic biliary ductal dilatation on US. PTC in cases with obstructive jaundice in hepatobiliary tuberculosis revealed site of obstruction at porta hepatis in 75% (57%–86%)[96, 103] and at the distal CBD (14%).[103] Cholangiographic appearances failed to discriminate between tuberculosis and neoplastic lesions; however calcification favors tuberculosis. ERCP revealed hilar obstruction in 67% (61%–82%), CBD abnormality in the form of dilation and constriction in 24% (19%–36%) and intrahepatic ductal abnormality was seen in 23%.

41.15 TREATMENT Abdominal tuberculosis usually responds to medical treatment with standard antitubercular drugs. According to WHO guidelines intestinal and peritoneal tuberculosis has been considered as severe disease and nodal tuberculosis as less severe involvement, based on long term morbidity and acute threat to life. Anti tubercular treatment recommended for seriously ill patients with severe involvement is the same as smear positive pulmonary tuberculosis, and treatment for less severe forms are same as smear negative pulmonary tuberculosis (Table 41.9).[104–110] Contrary to published recommendations, many a times, physicians administer prolonged therapy for abdominal tuberculosis. However, little microbiological and pharmacologic basis exists for this practice.[111] The bacillary burden in extrapulmonary tuberculosis and particularly in abdominal

670

Chapter 41 / ABDOMINAL TUBERCULOSIS

TABLE fy 41.9 Treatment of tuberculosisy Tuberculosis treatment category

I

II III

Tuberculosis patient

Treatment regiment

Seriously ill intestinal and peritoneal tuberculosis (also applicable to smear positive pulmonary tuberculosis) Treatment failure/return after drug default Nodal tuberculosis (also applicable to smear negative pulmonary tuberculosis

tuberculosis is much lower than in cavitatory pulmonary disease (10[8] bacilli in a 2.5 cm cavity). Penetration of antitubercular drug in intestines and peritoneal tissues is adequate, and clinical trials have shown the effectiveness of standard 12 month regimen, short course therapy as well as intermittent regimen. Balasubrahmaniam and co workers[112] in a randomized trial on 193 patients with abdominal tuberculosis had favorable response in 99% with short course therapy (isoniazid and rifampicin daily for 6 months supplemented by ethambutol daily in the initial two months) and in 97% of cases using standard one year regimen (isoniazid and ethambutol daily for one year supplemented by streptomycin daily in initial 2 weeks). Though the end point of therapy and satisfactory outcome or cure is difficult to define in abdominal tuberculosis, still both the above regimens were found to have comparable outcome on the basis of clinical improvement, and absence of relapse on 5 years follow-up suggesting adequacy of treatment given. The usefulness of intermittent regimens were evaluated in the management of extrapulmonary tuberculosis including abdominal tuberculosis by the Chennai group.[113] They were as effective as the short course daily regimen. Similar

Initial phase (2 months) (Daily or 3 days per week)

Continuation phase (4 months)

2EHRZ (SHRZ)

6HE 4HR

reports of high success with the short course regimen and intermittent therapy in extrapulmonary tuberculosis (which included cases with abdominal involvement) are available from elsewhere as well.[114–116] These clinical trials confirm that the medical therapy of abdominal tuberculosis is no different from that of pulmonary tuberculosis or other form of extrapulmonary tuberculosis. Presently, the six months short course regimen is used most often. These patients require careful monitoring for compliance and complications as more frequent side effects (26% as compared to 13% with the standard 1-year regimen) have been reported. Though these side effects resulted in interruptions in treatment, they rarely require change in regimen (8% with six months therapy and 5% with one year regimen).[117]

41.15.1 Special Situations 41.15.1.1 HIV coinfection

In patients having HIV coinfection a short course regimen is usually effective (better than standard one year regimen),[118] though some times if response is suboptimal the treatment may have to be prolonged. Rifampicin is a microsomal enzyme

Tropical Hepatogastroenterology

TREATMENT

inducer and shortens the half-life of HIV protease inhibitor drugs. These patients instead, may be given rifabutin (15 mg/day). 41.15.1.2 Hepatic disease

Isoniazid, rifampicin, and pyrazinamide are potentially hepatotoxic drugs. Hence, in patients with severe hepatic disease these are to be used with caution and under close monitoring. Pyrazinamide may best be avoided in these situations. Rifampicin potentiates the hepatotoxicity of isoniazid. Hence, coadministration may be hazardous in severe hepatic dysfunction. If isoniazid and rifampicin therapy is mandatory, these may be administered under close supervision.[119] If in the initial phase isoniazid, streptomycin, and ethambutol have been used (without rifampicin) the continuation phase is to be prolonged to one year. If a patient with tuberculosis develops acute viral hepatitis (rare event) it is better to withhold treatment till viral hepatitis resolves and transaminases become normal. However, if treatment is mandatory then a combination of streptomycin, ethambutol, and ciprofloxacin is preferred till resolution of viral hepatitis. 41.15.1.3 Pregnancy

Most antitubercular drugs are safe for use in pregnancy with the exception of streptomycin, which causes ototoxicity to the fetus. Doses and durations of the recommended regimen remain same. 41.15.1.4 Multiple drug resistant (MDR) tuberculosis

MDR strains are encountered with increasing frequency since the 1990s due to failure of retreatment regimens, and the resistance is usually acquired. Primary resistance due to infection with MDR strain is a rare phenomenon. The impact on the epidemiology of abdominal tuberculosis largely

Part X / Special Topics

671

remains unknown. Moreover, many a times it is not possible to precisely identify the MDR strains in abdominal tuberculosis. If drug resistant tuberculosis is suspected, drug sensitivity results are not available and retreatment regimens (category-II; Table 41.9) have failed, use at least three new drugs (not used before like kanamycin, ethionamide, ofloxacin and pyrazinamide) for 3–4 months and two best tolerated drugs (ethionamide and ofloxacin) for 18 months in continuation phase. In isoniazid resistant but rifampicin sensitive strains, standard retreatment regimen (category–II ; Table 41.9) may be used but isoniazid and streptomycin may be omitted in the initial phase treatment. If there is resistance to all first line drugs, the physician may advise, for two years, one injectable and any three of the following: PAS, quinolones, ethionamide, and cycloserine.[119]

41.15.2 Adjuvants to Antitubercular Therapy 41.15.2.1 Corticosteroids

Corticosteroid administration for the first few weeks may be beneficial only in miliary tuberculosis with toxemia and in adrenal insufficiency. Often steroids have been used in abdominal tuberculosis on the assumption that they decrease the fibrosis during healing, and reduce the chances of stricture formation or obstruction.[110] However, this could not be substantiated in most of the studies ([111–113] ). Singh and associates advocated the use of steroids as they recorded late development (15 to 2.5 years later) of intestinal obstruction in 3 out of 23 subjects who did not receive steroid treatment, and in none of those who received steroid. However, the study was not blind and results were statistically insignificant.[117] Moreover, in Anand’s series[115] as well as in Dutt’s study,[108]

672

Chapter 41 / ABDOMINAL TUBERCULOSIS

patients of intestinal tuberculosis did well without use of corticosteroids.

41.15.3 Surgery Surgery is indicated only in the presence of complications like obstruction, perforations, fistulae, massive bleed, and when the diagnosis is uncertain. However, recent evidence suggests that some strictures and fistulae will respond to medical therapy alone.[116, 117] Experience about improvement in strictures is more convincing. Anand and coworkers[115] treated 39 patients with symptoms of bowel obstruction using medical therapy. At the end of one year 91% showed clinical improvement, 70% had complete resolution of radiological abnormality, and surgery was required only in 3 cases (8%). Predictors of surgical intervention were long stricture (> 12 cm) and multiple areas of involvement. Bhansali in the early Seventies[118] advocated conservative treatment even

for intestinal obstruction if the patients were stable, to avoid the high mortality of emergency surgery. Most patients improved with conservative treatment alone and elective surgery (2–4 weeks later) was required only in a few. The principle of surgery is to conserve as much bowel as possible. Hence, stricturoplasty is the preferred surgery even for multiple strictures.[119] However, short segment bowel resection and primary anastomosis may be done when multiple lesions are present in a relatively short segment or with very tight strictures.[120] By pass procedures were popular in the prechemotherapy era. Now a days, these are avoided as they may result in blind loops, malabsorption, and even perforation.[120] Presently, bypass procedures should only be reserved for obstructing duodenal lesions. Perforations are best treated with resection and anastomosis as simple closure of the lesion is often associated with high incidence of reperforation and fistulization[121]

REFERENCES [1] Brown L, Sampson HL. Intestinal tuberculosis: Its Importance, Diagnosis and Treatment. New York: Lea & Febiger, 1926. [2] Raviglione MC, Snider DE Jr, Kochi A. Global epidemiology of tuberculosis: Morbidity and mortality of world wide epidemic. JAMA 1995;273: 220–26. [3] Grzybowski S. Epidemiology of Tuberculosis with particular reference to India. Indian J Tuberc 1995; 42:195–200. [4] Marshall JB. Tuberculosis of gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88: 989–999. [5] Snider DE Jr., Roper WL. The New Tuberculosis. N Eng J Med 1992;326:703–05. [6] Sudre P ten-Dom-G, Kochi A. Tuberculosis: A Global overview of the situation today. Bull

WHO 1992;70:142–59. [7] Tripathi SP. “Can we control tuberculosis in India by the year 2000? In: “Can we control tuberculosis in India by the year 2000?” Proceedings of the symposium held in Bangkok Thailand, November 1–4, 1993. Excerpta Medica 1994;17–19. [8] Rathi PM, Amarapurkar DN, Parikh SS et al. Impact of human immuno deficiency virus infection on abdominal tuberculosis in Western India. J Clin Gastroenterol 1997;27:43–48. [9] Chuttani HK. Intestinal tuberculosis. In: Card WL, Creamer B. editors. Modern trends in Gastroenterology, 4. Butterworth, London 1970;309–32. [10] Klimach OE, Ormerod LP. Gastrointestinal tuberculosis: A retrospective review of 109 cases in district general hospital. Q J Med 1985;56: 569–578.

Tropical Hepatogastroenterology

REFERENCES

[11] Garlick FH, Kurvilla J. Intestinal Tuberculosis. J Assoc Phys India 1965;13:493. [12] Pimparkar BD, Donde UM. Intestinal tuberculosis: Clinical and radiological studies. J Assoc Phys India 1974;22:205–217. [13] Mitchell RS, Bristol LJ. Intestinal tuberculosis: An analysis of 346 cases diagnosed by routine intestinal radiography on 5529 admissions for pulmonary tuberculosis 1929–1949. Am J Med Sci 1954;227:241–249. [14] Blumber A. Pathology of intestinal tuberculosis. J Lab Clin Med 1928;13:405–412. [15] Ukil AC. Early diagnosis and treatment of intestinal tuberculosis. Indian Med Gaz 1942;77:613. [16] Haddad FS, Ghossain A, Sawaya E et al. Abdominal tuberculosis. Dis Colon Rectum 1987;30: 724–735. [17] Bhansali SK. The challenge of abdominal tuberculosis in 310 cases. Indian J Surg 1978;4065–77. [18] Small PM, Hopewell PC, Singh SP et al. The epidemiology of tuberculosis in San Francisco: A population based study using conventional DNA molecular methods. N Engl J Med 1994;330: 1703–1709. [19] Jain AK. Diagnosis of abdominal tuberculosis. Gastroenterol Today 1998;2:20–26. [20] Lewis JH, Zimmerman HJ. Tuberculosis of the liver and biliary tract. In: Schlossberg D, ed. Tuberculosis and nontubercular mycobacterial infection, 4th ed. WB Saunders, 1999:238–263. [21] Gupta S, Meena HS, Chopra R. Hepatic involvement in abdominal tuberculosis. J Assoc Physicians India 1993;41:20–22. [22] Schluger N, Condos R, Lewis S et al. DNA amplification using polymerase chain reaction in blood of patients with pulmonary tuberculosis. Lancet 1994;344:232–233. [23] Abrams JS, Holden WD. Tuberculosis of gastrointestinal tract. Arch Surg 1964;89:282–93. [24] Tandon HD, Prakash A. Pathology of intestinal tuberculosis and its distinction from Crohn’s disease. Gut 1972;13:260–9. [25] Singh V, Jain AK, Aggrawal AK et al. Clinicopathological profile of abdominal tuberculosis. Br J Clin Pathol 1995;49:22–24.

Part X / Special Topics

673

[26] Davis GR, Corbett DB, Krejs GJ. Ileal chloride secretion as a cause of secretory diarrhoea in a patient with primary intestinal tuberculosis. Gastroenterology 1979;76:829–35. [27] Logan VSD. Anorectal tuberculosis. Proc R Soc Med 1969;62:27–30. [28] Das P, Shukla HS. Clinical diagnosis of abdominal tuberculosis. B J Surg 1976;63:941–46. [29] Suri S, Kaur H, Wig JD et al. CT in abdominal tuberculosis comparison with barium studies. Indian JR Imaging 1993;3:237–242. [30] Han JK, Kim SH, Choi BI et al. Tuberculous colitis: Findings at double contrast barium enema examination. Dis Colon Rectum, 1996;39:1204–9. [31] Akhan O, Demirkazik FB, Demirkazik A et al. Tuberculosis peritonitis ultrasound diagnosis. J Clin Ultrasound 1990;18:711–714. [32] Ganesan S, Inderajit IK. US-in abdominal lymph node tuberculosis. India J R Imaging 1993;3: 231–236. [33] Agrawal AK, Budhraja A, Gupta S et al. Ultrasonography in intestinal tuberculosis. Indian J Gastroenterol 1993;12(suppl):A65. [34] Demurkazck FB, Akhan O, Ozmen et al. US and CT findings in diagnosis of tubercular peritonitis. Acta Radiol 1996;37:517–20. [35] Jain R, Sawhney S, Bhargava DK et al. Diagnosis of abdominal tuberculosis: Sonographic findings in patients with early disease. AJR 1995;165: 1391–95. [36] Gupta S, Rajak CL, Sood BP et al. Sonographically Guided Fine Needle Aspiration Biopsy of Abdominal Lymph Nodes. Experience in 152 patients. J Ultrasound Med 1993:135–139. [37] Batra A, Gulati MS, Sharma D et al. Sonographic appearances in abdominal tuberculosis. J Clin Ultrasound 2000;28:233–45. [38] Hulnick DH, Megibow AJ, Naidich DP et al. Abdominal tuberculosis: CT evaluation. Radiol 1985;157:199–204. [39] Lam KN, Rajasoorya C, Mah PK et al. Diagnosis of tuberculous peritonitis. Singapore-Med-J 1999;40:601–4. [40] Yang ZG, Min PQ, Sone S HE ZY Liao ZY et al. Tuberculosis versus Lymphoma in the abdominal

674

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

Chapter 41 / ABDOMINAL TUBERCULOSIS

lymph nodes: Evaluation with contrast enhanced CT. AJR 1999;172:619–623. Suri S, Gupta S, Suri R. Computed Tomography in abdominal tuberculosis. Br J Radiol 1999;72: 92–98. Jain AK, Lal RK, Gupta S et al. Enzyme linked immunosorbent assay (ELISA) in gut tuberculosis. Indian J Gastroenterol 1986;5:175–177. Bhargava DK, Dasrathy S, Kushwaha AKS et al. Evaluation of enzyme linked immunosorbent assay using mycobacterial saline extract for serodiagnosis of abdominal tuberculosis. Am J Gastroenterol 1992;87:105–108. Wilins LGL, Ivangi J. Potential value of serology for diagnosis of extrapulmonary tuberculosis. Lancet 1990;336:641–644. Daniel TM, Debanne. The serodiagnosis of tuberculosis and other mycobacterial disease by enzyme linked immunoassay. Am Rev Respir Dis 1987; 135:1137–1151. Chawla TC, Sharma P, Kiran U et al. Serodiagnosis of intestinal tuberculosis by enzyme immunoassay and soluble antigen fluorescent antibody tests using a saline extracted antigen. Tubercle 1986;67: 55–60. Winter WD, Cox RA. Serodiagnosis of tuberculosis by radioimmunoassay. Am Rev Resp Dis 1981;124:582–585. Zeiss CR, Radin RC, William JE et al. Detection of immuno globulin G antibody to purified protein derivative in patients with tuberculosis by radio immuno assay and enzyme linked immunosorbent assay. J Clin Microbiol 1982;15:93–96. Kox LFF. Tests for detection and identification of mycobacteria. How they should be used? Respir Med 1995;789:399–405. Wadee AA, Boting L, Reddy SG. Antigen capture assay for detection of 43 kd Myc tuberculosis antigen. J Clin Microbiol 1990;28:2786–91. Bhargava DK, Nijhavan S, Gupta M. Adenosine Deaminase and tuberculosis peritonitis. Lancet 1989;1:1260–1261. Dwivedi M, Misar SP, Misra V et al. Value of adenosine deaminase in diagnosis of tuberculosis ascites. Am J Gastroenterol 1990;85:1123–5.

[53] Gulati S, Jain AK, Dixit VK et al. Diagnosis of tuberculous ascitis. Is adenosine deaminase estimation helpful? Indian J Gastroenterol 1994;13(suppl):A53. [54] Kaur A, Basha A, Ranjan M et al. Poor diagnostic value of adenosine deaminase in pleural, peritoneal and CSF in tuberculosis. Ind J Med Res (A) 1992;95:270–77. [55] Fernandez Radioguez CM, Perez Arguelles BS, Ledo L et al. Ascites adenosine deaminase activity is decreased in tuberculosis ascites with low protein content. Am J Gastroenterol 1991;86: 1500–1503. [56] Voight MD, Trey C, Lombard C et al. Diagnostic value of ascites adenosine deaminase in tuberculosis peritonitis. Lancet 1989;1:751–754. [57] Misra OP, Yasaf S, Ali Z et al. Adenosine deaminase activity and lysozyme levels in children with tuberculosis. J Trop Pediatr 2000;46:175–8. [58] Kurata N. Adenosine deaminase (Japanese, English Abstract). Nippon-Rinsho 1995;53:1178– 83. [59] Sathar MA, Sinjee AE, Coovadia YM et al. Ascitic fluid γ interferon concentration and adenosine deaminase activity in tuberculosis peritonitis. Gut 1995;16:419–422. [60] Sathar MA, Ungerer JP, Lockhat F et al. Elevated adenosine deaminase activity in patients with HIV and tuberculous peritonitis. Eur J Gastroenterol Hepatol 1999;11:337–41. [61] French GL, Teoch R, Chan CY et al. Diagnosis of tuberculois meningitis by detection of tuberculosis acid in cerebrospinal fluid. Lancet 1987;2: 117–19. [62] Khuru GA, Payne CR, Harvey DR. Tuberculosis of peritoneal cavity. Br J Surg 1979;65:808–11. [63] Lin OS, WK SS, Yeh KT. Isolated gastric tuberculosis of the Cardia. J Gastroenterol Hepatol 1999;14:258–61. [64] Alatas F, Ozdemir N, Isiksoy S et al. An unusual case of esophageal tuberculosis in an adult. Respiration 1999;66:88–90. [65] Jain S, Kumar N, Das DK et al. Esophageal tuberculosis. Endoscopic cytology as a diagnostic tool. Acta Cytol 1999;43(6);1085–90.

Tropical Hepatogastroenterology

REFERENCES

[66] Gupta SK, Jain AK, Gupta JP et al. Duodenal tuberculosis. Clin Radiol 1988;39:159–161. [67] Artru P, Lavergne SA, Joly F et al. Isolated jejunal tuberculosis mimicking Crohn’s disease. Diagnosis by push videoenteroscopy (Abstract:Medline 2000–01). Gastroenterol Clin Biol 1999;23: 1086–9. [68] Bhargava DK, Shriniwas, Cropra P et al. Peritoneal tuberculosis: Laparoscopic patterns and its diagnostic accuracy. Am J Gastroenterol 1992;87: 109–111. [69] Manohar A, Simjee AF, Haffejee AA et al. Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period. Gut 1990;31:1130–32. [70] Mimica M. Usefulness and limitations of laparoscopy in the diagnosis of tubercular peritonitis. Endoscopy 1992;24:588–91. [71] Menzies RI, Alsen H, Fitzgerald JM et al. Tuberculous peritonitis in Lesotho. Tubercle 1986;67: 47–54. [72] Amarapurkar DN, Kalro RH, Desai HG. Peritoneoscopy in diagnosis of ascites. J Assoc Phys India 1991;39;933–35. [73] Jorge AD. Peritoneal tuberculosis. Endoscopy 1984;16:10–12. [74] Geake TMS, Spitaels JM, Moshal MJ et al. Peritoneoscopy in the diagnosis of tuberculous peritonitis. Gastrointest Endosc 1981;27:66–68. [75] Levine H. Needle biopsy of tuberculosis peritonitis. Am Rev Respir Dis 1968;97:889–94. [76] Sherman S, Rohwedder JJ, Ravi Krishnan KP et al. Tuberculosis enteritis and peritonitis. Arch Intern Med 1980;140;506–8. [77] Bastani B, Sharistzadeh MR, Dehdashti F. Tuberculous peritonitis. Report of 30 cases and review of the literature. Q J Med 1985;56:549–57. [78] Lischora GE, Lee YTM, Baria PJ. Exploratory laparotomy for diagnosis of tuberculous peritonitis. Surg Gynaecol Obstet 1989;169;299–302. [79] Dineen P, Homan WP, Grafe WR. Tuberculous peritonitis 43 years experience in diagnosis and treatment. Ann Surg 1976;184:717–22.

Part X / Special Topics

675

[80] Karney WW, O’Donoghue JM, Ostrow JH et al. The spectrum of tuberculous peritonitis. Chest 1977;72:310–15. [81] Kalvaria I, Kottler RE, Marks IN. The role of colonoscopy in diagnosis of tuberculosis. J Clin Gastroenterol 1988;10:516–23. [82] Pettengell KE, Pirie D, Simjee AE. Colonoscopic features of early intestinal tuberculosis: Report of 11 cases. S Afr Med J 1991;79: 279–80. [83] Bhargva DK, Kushwaha AK, Dasrathy S et al. Endoscopic diagnosis of segmental colonic tuberculosis. Gastrointest Endosc 1992;38:571–72. [84] Shah S, Thomas V, Mathan M et al. Colonoscopic study of 50 patients with colonic tuberculosis. Gut 1992;33:347–51. [85] Singh V, Kumar P, Kamal J et al. Clinicocolonoscopic profile of colonic tuberculosis. Am J Gastroenterol 1996;91:565–68. [86] Dixit VK, Bhatt JP, Jain AK et al. Large bowel tuberculosis: Pattern of involvement on colonoscopy. Indian J Gastroenterol 1996;15 (suppl 1):A33. [87] Hasiao TJ, Wong JM, Shieh M et al. Colonofiberoscopic diagnosis of intestinal tuberculosis. J Formos Med Assoc 1998;97:21–5. [88] Misra SP, Misra V, Dwivedi M et al. Colonic tuberculosis: Clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 1999;14:723–29. [89] Kim KM, Lee A, Choi KY et al. Intestinal tuberculosis: Clinicopathologic Analyses and Diagnosis by Endoscopic biopsy. A J Gastroenterol 1998;93: 606–609. [90] Kochhar R, Rajwanshi A, Goenka MK et al. Colonoscopic fine needle aspiration cytology in the diagnosis of ileocecal tuberculosis. Am J Gastroenterol 1991;86:102–04. [91] Anand BS, Schneider FE, El-Zaatari FAK et al. Diagnosis of intestinal tuberculosis by polymerase chain reaction on endoscopic biopsy specimens. Am J Gastroenterol 1994;89: 2248–49. [92] Huatian G, Qin O, Hong B et al. Value of Polymerase Chain Reaction Assay in diagnosis

676

[93]

[94]

[95] [96] [97]

[98] [99]

[100]

[101]

[102]

[103]

[104] [105]

Chapter 41 / ABDOMINAL TUBERCULOSIS

of intestinal tuberculosis and differentiation from Crohn’s disease. Chin Med J 1994;107:215–20. Moatter T, Mirza S, Siddiqui MS et al. Detection of mycobacterium tuberculosis in paraffin embedded intestinal tissue specimen by Polymerase Chain Reaction: Characterisation of IS6110 element negative strain. J Pak Med Assoc 1998;48:174–8. Diaz ML, Herrera T, Lopez-Vidal Y et al. Polymerase chain reaction for the detection of mycobacterium tuberculosis DNA in tissue and assessment of its utility in the diagnosis of hepatic granulomas. J Lab Clin Med 1996;127:359–A. Alvarez SZ. Hepatobiliary tuberculosis. J Gastroenterol Hepatol 1998;13:833–839. Alvarez SZ, Carpio R. Hepatobiliary tuberculosis. Dig Dis Sci 1983;28:193–200. Essop AR, Posen JA, Hodkinson JH et al. Tuberculous hepatitis. A Clinical review of 96 cases. Q J Med 1984;53:465–77. Hersch C. Tuberculosis of the liver. A study of 200 cases. S Afr Med J 1964;38:857–63. Maharaja B, Leary WP, Pudifin DJ. A prospective study of hepatic tuberculosis in 41 black patients. Q J Med 1987;63:517–22. Chan HS, Pang J. Isolated giant tuberculoma of the liver detected by CT. Gastrointest Radiol 1989;14:305–07. Barauner M, Buffard MD, Jeantils V et al. Sonography and computed tomography of microscopic tuberculosis of the liver. J Clin Ultrasound 1989;17:563–8. Epstein BM, Leibowitz CB. Ultrasonographic and computed tomographic appearance of focal tuberculosis of the liver. S Afr Med J 1987;71:461–2. Maglinte DT, Alvarez SZ, Ng AC et al. Patterns of calcification and cholangiographic findings in hepatobiliary tuberculosis. Gastrointest Radiol 1988;13:331–5. Barnes PF, Barrows SA. Tuberculosis in 1990s. Ann Intern Med 1993;119:400–410. Balasubramanian R, Nagarajan M, Balambal R et al. Randomised controlled clinical trial of short course chemotherapy in abdominal tuberculosis: a five year report. Int J Tuberc Lung Dis 1997;1: 44–51.

[106] Balasubramanian R, Sivasubramanian S, Vijayan VK et al. Five year results of a 3-month and two 5-month regimens for the treatment of sputumpositive pulmonary tuberculosis in south India. Tubercle 1990;71:253–8. [107] Monie RD, Hunter AM, Rocchiccioli KI et al. Management of extrapulmonary tuberculosis (excluding miliary and meningeal) in South and West Wales (1976–78). Br Med J 1982;285:415– 418. [108] Dutt AK, Stead WW. Short Course Chemotherapy for extrapulmonary tuberculosis. Nine years experience. Ann Intern Med 1996;104:7–12. [109] Chhn DL, Catlin BJ, Peterson KL et al. A 62dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis: A twice-weekly, directly observed and cost-effective regimen. Ann Intern Med 1990;112:407–15. [110] Balasubramanian R, Ramchandran R, Joseph P et al. Interim Results of a Controlled clinical study of abdominal tuberculosis. Ind J Tub 1989;36: 117–121. [111] WHO. HIV Infection and Tuberculosis. In: Treatment of Tuberculosis - Guidelines for National Programmes. 2nd edition. Jeneva, Switzerland: WHO 1997:45–48. [112] Balasubramanian R, Ramachandran R. Management of nonpulmonary forms of tuberculosis: review of TRC studies over two decades. Indian J Pediatr 2000;67(2 Suppl):S34–40. [113] Findlay JM. Medical management of gastrointestinal tuberculosis. J Soc Med 1982;75:583–4. [114] Borhanmanesh F, Hekmat K, Vaezzadeh K et al. Tuberculous peritonitis: Prospective study of 32 cases in Iran. Ann Intern Med 1972;76:567–72. [115] Aguado JM, Pons F, Casafont F et al. Tuberculous peritonitis: A study comprising cirrhotic and noncirrhotic patients. J Clin Gastroenterol 1990; 550–54. [116] Wolfe JHN, Behn AR, Jackson BT. Tuberculous peritonitis and role of diagnostic laparoscopy. Lancet 1979;1:852–3. [117] Singh MM, Bhargava AN, Jain KP. Tuberculous peritonitis: An evaluation of pathogenetic mecha-

Tropical Hepatogastroenterology

REFERENCES

nisms, diagnostic procedures and therapeutic measures. N Engl J Med 1969;281:1091–94. [118] Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antituberculous treatment. Gut 1988;29:62–9. [119] Lee JH, Shin DH, Kang KW et al. The medical treatment of a tuberculous tracheoesophageal fistula. Tubercle Lung Dis 1992;73: 177–179. [120] Conjalka MS, Usselman J. Successful medical treatment of a tuberculosis B-E fistula. Mt Sinai J Med 1980;47:283–284.

test

Part X / Special Topics

677

[121] Bhansali SK. Abdominal tuberculosis. Experiences with 300 cases. Am J Gastroenterol 1972;67:324–37. [122] Katariya RN, Sood S, Rao PG et al. Stricture-plasty for tubercular strictures of the gastrointestinal tract. Br J Surg 1977;64:496–8. [123] McGee GS, Lester WF, Potts J et al. Gastrointestinal tuberculosis resurgence of an old pathogen. Am Surg 1989;55:16–19. [124] Aston NO, deCosta AM. Tuberculosis perforation of the small bowel. Postgrad Med J 1985;61: 251–252.

Chapter

42 DIARRHEA IN CHILDREN Pankaj Vohra

The incidence of diarrhea has decreased over the past 1–2 decades in developing nations.[1, 2] However, it still remains an important cause of morbidity and mortality in children under 5 years of age.[3, 4] Children in the tropics continue to suffer about 3 episodes of diarrhea per year.[5]

TABLE fy 42.1 Classification of diarrhea based on duration of illness Acute diarrhea Persistent diarrhea Chronic diarrhea

42.1 DEFINITION Diarrhea refers to stool that contains more water than usual. This would either result in loose stools or more frequent stools. However, for accurately defining diarrhea, the weight of the stool should be more than 10 gram/kg/day in an infant[6] and more than 200 gm/day in an older child (or an adult).[7] In practice, the definition used most often is 3 or more loose or watery stools in a 24 hour period.[8] It is important to remember that it is the consistency of the stool rather than the number of stools that is important. Frequent passage of normal stools is not diarrhea. Diarrhea may be accompanied by nausea, vomiting, cramps, fever, tenesmus, and shock. Diarrhea in the newborn period and early infancy is more difficult to define as there is a wide normal range of frequency of stools. In addition, the stools are often semi-formed, especially if the baby is on breast milk. Hence, to define diarrhea in this age group there must be a change noted in 678

Less than 14 days, usually infectious, may be bloody 14 days or more, onset like acute diarrhea, may be bloody More than 14 days, subacute onset, may be bloody

the stool pattern or consistency. The mother is often able to report the change in the stool pattern. Dysentery is described as the presence of gross blood in the stools. The dysentery syndrome consists of fever, abdominal cramps, and presence of blood and pus in the stools.

42.2 CLASSIFICATION The classification of diarrhea based on duration of illness is shown in Table 42.1. This is an arbitrary definition used by World Health Organization and validated by mortality data.[9] This classification is important for two reasons. One, the etiopathogenesis of chronic diarrhea is very different from that of acute and persistent diarrhea. Second, the duration of illness has a major impact on morbidity and mortality in children. The case fatality rate for acute watery diarrhea is 0.56%, while it is 4.27% for dysentery, 11.94% for

ETIOLOGY

679

TABLE fy 42.2 Etiology of diarrhea in different age groups Acute Common

Chronic Uncommon

Common

Uncommon

• Postviral enteritis

• Cow milk protein allergy • Hirschsprung’s disease • Immunodeficiency including HIV • Cystic fibrosis • Intractable diarrhea of infancy • Giardia infection • Inflammatory bowel disease • Irritable bowel syndrome (Toddlers diarrhea) • Giardia infection • Inflammatory bowel disease • Lactose intolerance • Sorbitol ingestion

Infant

• Infectious • Secondary lactose intolerance

• Systemic

Toddler

• Infectious • Secondary lactose intolerance

• Systemic disease# • Drugs∗

• Celiac disease

Adolescent

• Infectious

• Food poisoning • Drugs∗

• Irritable bowel syndrome • Celiac disease • Constipation

# Systemic

disease#

disease – Pneumonia, otitis media, sepsis, etc. ∗ Drugs – Usually antibiotics

nondysentery persistent diarrhea (PD), and 21.1% dysenteric persistent diarrhea.[10] Hence, persistent invasive type of persistent diarrhea has a high mortality rate.[11] The major morbidity of acute watery diarrhea is dehydration while for recurrent and persistent diarrhea it is malnutrition and stunted growth.[12]

Constipation and encopresis may be mistaken for chronic diarrhea. Persistent diarrhea, as discussed later, begins as an acute infectious diarrhea but because of several possible reasons persists for 14 days or more.

42.3 ETIOLOGY The etiology of diarrhea is different in various age groups. The more frequent causes are shown in Table 42.2. Rarer causes of diarrhea that should be kept in mind for a particular child include immunodeficiency, like common variable immunodeficiency, food allergy, autoimmune enteritis, eosinophilic enteritis, short gut syndrome, microvillous inclusion disease, secretory tumors, congenital transporter defects, laxative abuse, factitious diarrhea, and Munchausen’s syndrome. Tropical sprue remains an ill-defined entity in children.

Part X / Special Topics

42.3.1 Acute Diarrhea Most acute diarrheas encountered in developing countries are infectious. The common infectious causes are shown in Table 42.3. 42.3.1.1 Etiology Viruses

Rotavirus Rotavirus is the leading cause of severe diarrhea in children under the age of 5 years in developed nations resulting in estimated

680

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.3 Common infectious causes of acute diarrhea Etiology

Infantile diarrhea[13]

Diarrhea under

25% positive of age of 4 years[14] total 780 specimens N = 204 Rotavirus Shigella Salmonella Vibrio Cryptosporidium Aeromonas Candida Enteroaggregative E. coli Enterotoxigenic E. coli Enteropathogenic E. coli Campylobacter jejuni Yersinia Amoeba Giardia

19.5% 20.9% 22.9% 4.5% 6.47% 15.9% 3.9% 4.98%

20% 2.9% 2.5% – – – – –

–

23%

–

7.8%

–

10%

– – –

0.5% 1.5% 3.9%

600,000 deaths each year.[15] However, in India it makes up 9%–20% of all diarrhea in the community and about 30%–35% in hospitalized children.[16, 17] Rotavirus is spread via the feco-oral route and only a few virions are needed to infect an individual. The virus is found in the stool prior to start of the illness and for several days after the child is better. The virus can survive on hands, hard surfaces, water for prolonged periods of time.[18] Rotavirus diarrhea can last 3–8 days. The virus damages the tips of the villi in the small bowel causing blunting of villi. The tips of the villi have enterocytes involved in the digestion and absorption. The enterocytes in the crypts

are immature and involved in secretion of fluid – hence, there is malabsorption of food as well as active secretion. As lactose is broken down to glucose and galactose at the brush border membrane, lactose malabsorption occurs. This is transient but may become clinically significant in a subset of patients. The most common age group affected is 3 months to 24 months. Children less than 3 months are protected by breast feeding as well as antibodies acquired transplacentally. The incubation period is 24–48 hours. The illness often starts with fever and vomiting and this phase usually lasts about 24–48 hours. The diarrhea usually begins on the 2nd day of illness and the mean duration is 3–8 days. The illness is severe in infants and in those who already have a compromised gut. Most hospitalizations due to dehydration secondary to Rotavirus infections occur in the less than 1-year age group. Immunocompromised hosts may develop chronic rotavirus infections.[19] Dehydration is the single most important complication of viral diarrhea. The most common morbidity associated with rotavirus diarrhea is dehydration. Assessment of dehydration is shown in Table 42.4.[20] Diagnosis can be made by ELISA or latex agglutination on stool to look for rotavirus specific antigens. In practice this is rarely required. Treatment is essentially to prevent and treat dehydration (Table 42.4). There is no antiviral agent available. Other viruses Norwalk virus, the most well known calcivirus usually causes outbreaks of illness in older children or adults in a school or ship setting.[21] The virus is usually spread by

Tropical Hepatogastroenterology

ETIOLOGY

681

TABLE fy# 42.4 Assessment of dehydration in children with diarrhea# Severe dehydration

Some dehydration

Any two of the following signs if present: • Lethargy or unconsciousness • Sunken eyes • Skin pinch goes back very slowly (2 seconds or more) • Not able to drink or drinks poorly

Any two or more of the following: • Restless or irritable • Sunken eyes • Thirsty and drinks eagerly • Skin pinch goes back slowly

Treatment plan C

Treatment plan B

# World

No dehydration Does not have two or more of the following: • Restlessness/irritability • Lethargy or unconsciousness • Not able to drink or drinks poorly • Thirsty and drinks eagerly • Sunken eyes • Skin pinch goes backs slowly or very slowly Treatment plan A

Health Organization guidelines

contaminated food and water and rarely, by the airborne route. The illness has an incubation period of 24–48 hours and lasts for about 3 days. It is characterized by intense vomiting similar to food poisoning by Staphylococcus aureus or Bacillus cereus. Enteric adenovirus strains 40 and 41 are known to produce gastroenteritis. Adenovirus infections are atypical due to its long incubation period and prolonged course of diarrhea that could last for 10–14 days.[22] Children with adenovirus infections may have respiratory symptoms preceding the diarrhea. The illness produced by astrovirus is similar to rotavirus except that it is less severe and causes diarrhea for 1–3 days in most individuals.[23] Treatment is supportive.

pathogenic or not. Five well-characterized forms of the diarrheagenic E. coli are shown in Table 42.5. Enterotoxigenic E. coli is amongst the common causes of acute diarrhea in India.[24] All diarrheagenic strains of E. coli are transmitted by the feco-oral route from a patient, asymptomatic carrier or through contaminated food and water except E. coli O157:H7. The incubation period of E. coli related diarrhea varies from 6 hours to 10 days.

Bacteria

Vibrio Cholera is caused by Vibrio cholerae, a gram negative motile bacteria with many serogroups. Many serogroups have been known to cause diarrhea; however, it is only the serogroups 01 and 0139 that have caused epidemics. V. parahemolyticus causes a less intense diarrhea but it could be bloody. Pathogenesis requires colonization followed by elaboration of a toxin.

Escherichia coli E. coli is a commensal in the gastrointestinal tract. However, there are several subtypes of diarrhea producing E. coli that have been identified by serotyping for the somatic (O) and flagellar (H) antigens. Hence, in the absence of typing it is not possible to know from a routine stool culture, whether the E. coli grown is

Part X / Special Topics

Treating a child with antibiotics on the basis of stool culture report of E. coli is not recommended. Treatment of E. coli diarrhea is supportive.

682

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.5 Forms of diarrheagenic E. coli Type

Epidemiology

Mechanism of diarrhea

Enterotoxigenic E. coli (ETEC)

Watery diarrhea in infants and children; LT (heat labile toxin) similar to cholera toxin

Enteropathogenic E. coli (EPEC)

Acute and chronic watery diarrhea in infants and children, malnutrition may occur in the chronic form especially in young infants[25] Cause of persistent diarrhea

Enteroaggregative E. coli (EAEC) Enteroinvasive E. coli (EIEC)

Enterohemorrhagic E. coli (EHEC)

Bloody or nonbloody acute diarrhea producing fever, abdominal cramps, tenesmus; difficult to distinguish from Shigella Hemorrhagic colitis usually starting with fever, cramps and watery diarrhea, may go on to hemolytic uremic syndrome; duration of illness variable; uncommon pathogen in developing nations; usually spread from improperly cooked meats; afebrile bloody diarrhea is another manifestation; E. coli O157:H7 subtype is the most well recognized

Cholera is spread by ingestion of contaminated water and food. Human to human spread rarely occurs. The disease usually starts abruptly after an incubation period of a few hours to 5 days and can last for 3 days. Stools are painless, voluminous, and without fever or cramps. It may cause severe dehydration very quickly along with hypokalemia, metabolic acidosis, and hypovolemic shock. The stools of cholera are typically described as ricewater stools (watery and colorless with flecks of mucus). Diagnosis can be easily made by a hanging drop preparation. Special media are needed for culturing the bacteria. Treatment of cholera is similar to other causes of watery diarrhea except that antibiotics play an important role here to decrease the duration and severity of disease (Table 42.11). Administration of antibiotics to contacts prevents secondary cases.

Colonization of the small bowel and enterotoxin resulting in secretion of water and electrolytes Adherence and effacement of brush border Adherence Invasion of mucosa, similar to Shigella

Shiga like cytotoxin production

Shigella Shigella is responsible for 10%–15% of all diarrhea in children and is the most frequent cause of bloody diarrhea. Shigella invades and multiplies within the epithelial cells of the colon causing necrosis and development of ulcers. The cell wall lipopolysaccharide and elaboration of the cytotoxic Shiga toxin is responsible for the illness. Only 10 organisms are adequate to cause illness. Human to human spread and secondary cases to householders is common. Shigella has 4 distinct serogroups – S. flexneri and S. dysenteriae are the most common – the latter causing the most severe disease. Shigella might cause fever with watery diarrhea, dysentery with fever, cramps, tenesmus and colitic type of stools that are small, bloody and mucoid. The incubation period is 1–2 days. Prolonged bloody diarrhea that is not responding to standard antibiotics is one manifestation of hemolytic uremic syndrome due to Shigella.[26] In malnourished and

Tropical Hepatogastroenterology

ETIOLOGY

immunocompromised hosts, bacteremia may occur with increased morbidity and mortality. Diagnosis of Shigella can be made on stool culture. However, it is the gross examination of the stool that should lead to starting specific antibiotic therapy. Stools on routine examination reveal sheets of pus cells. Treatment is primarily by antibiotics (see Table 42.11). Antidiarrheals are contraindicated. Campylobacter jejuni C. jejuni causes about 10% of all diarrhea and is more common in children less than 2 years of age. C. jejuni invades the terminal small intestine and colon by producing a cytotoxin and enterotoxin. The clinical syndrome is primarily of low-grade fever with watery stools. In one third of cases, stools become bloody after a day or two. Abdominal pain and tenderness may be common and can be mistaken for acute appendicitis. The disease is self-limiting and lasts about 5– 7 days. Antibiotic therapy may shorten the course of disease by 1 day if started early. Nontyphoidal Salmonella species Nontyphoidal Salmonella species (e.g., S. typhimurium) cause about 10% of all cases of acute diarrhea. There are several hundred species of Salmonella of which only about 10 make up most of the cases. The disease occurs due to invasion of the small intestine. The infection usually comes from food typically poultry, egg, milk and meat. Human to human spread by the feco-oral route is common. The disease usually starts with nausea and vomiting after an incubation period of 8–48 hours. This is followed by acute watery diarrhea with fever and cramps. Dysentery occurs in about 20% of cases. The disease is self-limiting and lasts about 3–5 days.

Part X / Special Topics

683

Diagnosis is made by stool culture. Antibiotic usage is controversial and may actually prolong the excretion of the bacteria. It is, however, indicated for use in infants, malnourished children, evidence of systemic illness, and immunocompromised hosts. Clostridium difficile C. difficile is amongst the most common causes of nosocomial diarrhea as well as antibiotic associated diarrhea. The disease can occur anytime up to 6 weeks after hospitalization or use of antibiotics. It is, however, not the cause of all antibiotic related diarrhea, especially if the diarrhea is mild. The most commonly used antibiotics implicated in development of C. difficile related diarrhea are penicillins, clindamycin, and cephalosporins. C. difficile diarrhea can occur 6 weeks after stopping antibiotics. C. difficile often result in colonization in newborns in the nursery but perhaps due to lack of receptors for the toxin it rarely causes disease in this age group.[27] The disease results from the production of two toxins – Toxin A (enterotoxin) and Toxin B (cytotoxin). The illness produced by this organism can range from mild diarrhea to fulminant colitis with pseudomembrane formation. It can produce a fatal illness in immunocompromised hosts and children with Hirschsprung’s disease, and it may precipitate relapses in children with inflammatory bowel disease. In most patients, the rectum and sigmoid are involved. Diagnosis requires the demonstration of the presence of cytotoxin (Toxin B) in the stool. A tissue cell culture assay is the gold standard but it is difficult and expensive to perform. Hence, Toxin B is identified by enzyme-linked immunoassay. Stool culture (false positive) and evaluating for toxin via latex agglutination (false negative) are

684

Chapter 42 / DIARRHEA IN CHILDREN

not accurate.[28] Sigmoidoscopy in sick children or those with severe bloody diarrhea may reveal pseudomembranes. C. difficile infection on histology is suspected by seeing clumps of neutrophils, fibrin, and mucus exudates from microulcerations that appear like volcanoes. The mainstay of therapy of C. difficile diarrhea is stopping antibiotics, if feasible. This may be the only therapy needed. However, specific antibiotics (see Table 42.11) are required if the child is toxic, if there is severe colitis, or if the diarrhea persists after stopping the implicated antibiotic. Relapse of the colitis occurs in 10%– 15% of cases and usually responds to the alternate antibiotic. Cholestyramine is used to bind the toxin. For relapsing disease, Lactobacillus GG and Saccharomyces boulardii have been found to be valuable.[29, 30] Protozoa

Giardia Giardia lamblia is a common pathogen all over the world with an increased prevalence noted in developing countries especially in areas of crowding.[31] However, it is an uncommon cause of acute diarrhea in our children constituting less than 5% of all cases. It usually spread by contaminated food, water, and from person to person. Pathogenesis of giardiasis is not clear. It usually causes upper abdominal pain with persistent or chronic diarrhea along with bloating and flatulence. It may also cause acute diarrhea and malabsorption. Diagnosis is made by finding the giardia trophozoites in stool. Three stools samples should be examined to make the diagnosis. Giardia antigen can also be detected in the stool. Ameba Entameba histolytica is a rare cause of diarrhea (bloody or nonbloody) in children.

The protozoa invade the colonic epithelium resulting in persistent mild diarrhea, or fulminant dysentery. Diagnosis requires the identification of hematophagous trophozoites. Amebic serology is unreliable though may be positive in half the patients with invasive diarrhea. Cryptosporidium Cryptosporidium parvum is a common pathogen resulting in acute watery diarrhea.[32] The diarrhea may persist for 1–20 days with a mean of 10 days. Abdominal pain, fever, and anorexia might accompany the infection. Even though the child gets clinically better, the organism may continue to be excreted for a few weeks more. This organism is spread by the feco-oral route. The protozoa attach to the enterocyte resulting in fluid loss and malabsorption. In immunocompromised hosts, cryptosporidiosis may cause particularly severe chronic diarrhea that is very difficult to eradicate. Besides chronic diarrhea, malnutrition and dehydration may occur. Small intestinal cause of diarrhea results in voluminous stools while a colonic cause of diarrhea often results in frequent small volume stools or dysentery with tenesmus. The diagnosis is made by finding oocysts in the stool by using the modified Kinyoun acidfast stain technique. A direct immunofluorescent stain for identifying oocysts and enzyme linked immunoassay for detecting antigen in the stool is also available in some laboratories. The parasite may be visualized in duodenal biopsies as well. Treatment is supportive in immunocompetent children and by and large ineffective in immunocompromised children.

Tropical Hepatogastroenterology

ETIOLOGY

TABLE fy 42.6 Helminthic causes of diarrheay Trichuris trichiura (Whipworm) Strongyloides stercoralis (Strongyloidiasis) Hymenolepsis nana (Dog tapeworm)[34]

Dysentery, rectal prolapse Malabsorption, larva currens

685

Food poisoning can also occur due to ingestion of certain types of mushrooms, shellfish, and some other types of fish. 42.3.1.3 Laboratory features

Malabsorption

Naked eye examination of stool is informative.

Helminths Helminthiasis is common all over the world. However, since the worms tend to live in the lumen of the intestinal tract and eat on the intestinal contents, diarrhea is usually not such a problem except in some situations, e.g., when invasion of the mucosa occurs or the ‘worm’ is attached to the intestinal mucosa (Table 42.6). In the majority of cases, the diagnosis is made by identifying the egg, larva or the worm itself in the stool.[33] 42.3.1.2 Food poisoning (Table 42.7)

The term food poisoning suggests a commonsource outbreak of a disease after ingestion of specific food items. It occurs most often due to some bacteria or their toxins and result in a noninflammatory type of gastrointestinal infection. Usually, the possible etiology of food poisoning is suspected by the incubation period and type of the illness produced as shown below.

Stool examination and culture are not necessary in all cases of acute diarrhea. For a meaningful stool examination, the stool must be collected properly. In a child with watery diarrhea, it is best to collect the stool sample in the laboratory itself. This may be done by passing a lubricated 8–10F nasogastric tube 5 inches into the rectum and aspirating the liquid stool with a 20 ml syringe.[36] Stool may need to be examined for pus cells, fat globules, pH, reducing sugars, ova and parasite, occult blood and other specialized tests including Gram stain, hanging drop, stool electrolytes, C. difficile toxin, and stool culture. Modified acid-fast stain is required to detect Cryptosporidium and Isospora belli. A recently developed test for evaluating invasive diarrhea is to look for fecal lactoferrin; however, this may not be very useful in developing nations.[37, 38]

TABLE fy 42.7 Different forms of food poisoning Onset of illness Less than 6 hours of ingestion Onset between 8 and 16 hours of ingestion Onset beyond 16 hours of ingestion

Part X / Special Topics

Manifestation of disease Vomiting, diarrhea, cramps Diarrhea and cramps Diarrhea

and

Etiology Staphylococcus aureus, Bacillus cereus; preformed toxins Clostridium perfringens, B cereus; Ingestion of heat resistant spores Enterotoxigenic E. coli,[35] Vibrio, Salmonella

686

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.8 Prevention and treatment of dehydration Treatment plan A

• Provision of normal fluid requirement plus replacement of ongoing losses with home based fluids, e.g., water, lemon water, soups, coconut water, curd water along with food to provide oral rehydration therapy • Sugar salt solution, rice water, dal or dal water with salt, buttermilk with salt, soups with salt • WHO Low osmolar ORS given as 50–100 ml per loose stool for infants less than 2 years and 100–200 ml per loose stool for children more than 2 years

Treatment plan B (initiate in health care facility)

• Fluid for rehydration, provision of normal daily fluid requirement, and replacement of ongoing losses • Replacement is by providing WHO low osmolar ORS 75 ml/kg over first 4 hours • After 4 hours signs of dehydration should disappear and ongoing losses to be replaced at the rate of 10–20 ml/kg/loose stool

Treatment plan C

• Intravenous fluids started at 30 ml/kg ringer lactate over 1 hour followed by 70 ml/kg in 5 hours for children less than 12 months old, and in half the time for children above the age of 12 months • The above can be repeated if the pulse volume is not adequate • WHO ORS should be started as soon as feasible (even while the intravenous fluids are going on) • WHO ORS will correct hyponatremia or hypernatremia if present in most of the situations

If the measured fecal osmolality is more than double the sum of sodium and potassium, osmotic diarrhea is suspected. In secretory diarrhea, doubling the stool sodium and potassium will approximate the stool osmolality.

Stool culture is often overemphasized. It is important to remember that most laboratories are not able to type the E. coli and hence, a stool culture report of E. coli has little relevance. Stool should be plated within 2 hours or kept at 4◦ C till it can be plated. Most laboratories use the MacConkey’s agar, SS agar, and blood agar for culturing stool. Campylobacter requires a selective growth media and incubation at 42◦ C in a microaerophilic environment. Enterohemorrhagic E. coli O157:H7 requires sorbitol MacConkey’s agar for isolation and identification.[39] TCBS (Thiosulfate citrate bile salts) agar is required for culturing Vibrio. However, when cholera is suspected, a hanging

drop examination usually suffices. Rapid enzyme immunoassays and latex agglutination are used to detect C. difficile Toxin B, though the most reliable test is a cytotoxin assay (tissue culture) for Toxin B. Isolation of C. difficile in culture has a high false positivity rate. Rotavirus, adenovirus, astrovirus, and Norwalk virus can be detected by a rapid latex agglutination assay of the stool. 42.3.1.4 Treatment

Established treatment protocols for most acute diarrhea is limited to oral rehydration therapy, zinc supplementation, and, in certain specific situations, antibiotics. Oral rehydration therapy includes fluid therapy and feeding. Fluids used in diarrhea are either home based fluids or oral rehydration salt solution. Low osmolar ORS Conventional WHO ORS is a very effective solution for prevention and treatment of diarrhea of all types when used appropriately. However, due to a high osmolar

Tropical Hepatogastroenterology

ETIOLOGY

load (311 mosm/l) and high sodium concentration (90 mmol/L) there have been some concerns with it.[40] 1. The sodium in the ORS matched that of stool sodium in toxin mediated diarrheas which was higher than other more common forms of diarrhea and hence, there was risk of hypernatremia. Also it provided more sodium to children with severe malnutrition especially if they were edematous and hence, could potentially cause heart failure. 2. Some children who would malabsorb glucose would worsen their dehydration due to the high concentration of glucose. 3. A low osmolar ORS was found to be more effective in both sodium and water absorption. Hence, WHO and Indian Academy of Pediatrics National Task Force on Management of diarrhea recently has recommended a reduced osmolarity ORS (245 mosml/L) containing 75 mmol/L of sodium (Table 42.9).[41] This ORS has a few advantages: 1. Improved efficacy – less unscheduled intravenous fluid requirement, less stool output and reduced vomiting in children with noncholera diarrhea. 2. In cholera, a marginal increase in the incidence of asymptomatic hyponatremia has been noted in adults.

687

There is adequate data from India and other parts of the world regarding improved efficacy of this fluid in diarrhea. It is now the preferred fluid for prevention and treatment of diarrhea. Low osmolar ORS is currently the most appropriate fluid for prevention and treatment of dehydration.

In the majority of cases (except cholera and bloody diarrhea) no antibiotic or antimicrobial is required. Zinc is an established adjunct to oral rehydration for management of acute diarrhea. Two times the RDA of zinc supplementation (10 mg/day for 14 days to children less than 6 months, and 20 mg/day for children more than 6 months of age) reduces the duration of diarrhea, frequency of stools and the proportion of cases lasting more than 7 days.[42] Antibiotics and antimicrobials have a limited role in acute diarrhea.[43] The indications for using antibiotics (Table 42.10) and the drugs of choice for different conditions are listed (Table 42.11). All dysentery should be treated as for Shigella infection unless another specific cause is found. Currently there is not enough data to recommend probiotics or antisecretory drugs like

TABLE fy 42.9 Composition of standard WHO ORS with the new recommended ORS

Glucose Sodium Potassium Chloride Citrate

Standard WHO ORS (mmol/L)

Low osmolar ORS (mmol/L)

111 90 20 80 10

75 75 20 65 10

Part X / Special Topics

TABLE fy 42.10 Indications of antibiotics in acute diarrhea • • • • •

Dysentery Cholera Presence of severe malnutrition Preterm or small for date infant Evidence of systemic infection

688

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.11 Indications and preferred antimicrobials in children with diarrhea Severe malnutrition Evidence of systemic infection Preterm or small for date infants Cholera

Shigella

Campylobacter Clostridium difficile Protozoa* Giardia lamblia Entamoeba histolytica Helminth* Trichuris trichiura Strongyloides stercoralis Hymenolepsis nana ∗ Rare

Penicillin plus aminoglycoside

Trimethoprim-Sulfamethoxazole 5 mg/kg/dose (trimethoprim equivalent) twice daily for 3 days OR Tetracycline 50/mg/kg/day in 4 divided doses for 3 days in children above 7 years of age OR Erythromycin/Furazolidone/Azithromycin[46] may also be used Trimethoprim-Sulfamethaxazole 5 mg/kg/dose (trimethoprim equivalent) twice daily for 5 days OR Ampicillin 25 mg/kg/dose 4 times daily for 5 days OR Nalidixic acid 15 mg/kg/dose 4 times daily for 5 days OR Cefuroxime/cefixime/ceftriaxone/ciprofloxacin Macrolide antibiotics (useful if given within 4 days of onset of illness) Metronidazole (oral or intravenous), vancomycin (oral), lactobacillus GG Metronidazole 15 mg/kg/day in 3 divided doses for 5 days Metronidazole 30 mg/kg/day in 3 divided doses for 5 days Mebendazole Thiabendazole Praziquantel

in children

Racecadotril in acute diarrhea.[44] Antidiarrheals are unsafe in children and should not be used. Antiemetics (Domperidone) are useful in children with severe vomiting.

faster and decreases risk of prolonged diarrhea as well as development of malnutrition.[45]

Evaluation of a child with acute gastroenteritis is a good opportunity for the healthcare provider to inculcate good hygiene and impart education for treatment and prevention of further infections.

In persistent diarrhea the initial insult is probably infectious (viral).

Feeding is an important component of the therapy of acute diarrhea. Breast-feeding must continue during the rehydration phase, and in those infants and children who are on animal milk it must be started soon after rehydration is complete. The child must be fed a normal diet including milk usually with a cereal. Feeding helps the gut to recover

42.3.2 Persistent Diarrhea

Diarrhea that begins acutely but continues for more than 2 weeks is referred to as a persistent diarrhea. This condition is unique to developing countries.[47] Persistent diarrhea is very important as it is responsible for almost 36%–56% of all diarrheal deaths. It is estimated that approximately 10% of all acute diarrhea in India goes on to persistent diarrhea and this is much more so in children less than 2 years of age.[48] Factors that increase the risk of persistent diarrhea include malnutrition

Tropical Hepatogastroenterology

ETIOLOGY

(and persistent diarrhea often makes malnutrition worse), micronutrient deficiency especially those of zinc and Vitamin A, transient impairment of cell mediated immunity, lack of exclusive breast feeding especially in the first four months, and infection with enteroaggregative Escherichia coli, Salmonella, and Cryptosporidium.[12, 49] A recent episode of diarrhea increases the risk of persistent diarrhea.[50] Hence, the pathogenesis of persistent diarrhea includes persistent infection, malabsorption of carbohydrates and fat, and rarely milk protein allergy. Malnutrition is worsened on account of malabsorption, and reduced energy intake. Reduced caloric intake may be a result of anorexia or poor advice from the healthcare worker. Development of persistent diarrhea also increases the risk of dying in the next illness because of an increase in the risk of developing another bout of persistent diarrhea and worsening malnutrition. The systemic infections most commonly encountered in persistent diarrhea are urinary tract infection, pneumonia, sepsis, and otitis media. Most children with persistent diarrhea have several loose stools daily (it could be bloody in some children). The hydration status is, however, usually normal. Malnutrition is often evident and examination of the tongue is useful to asses for dehydration. The presence of an underlying infection should be suspected if there is fever or hypothermia, severe anorexia, inability to drink, abdominal distension, lethargy, or evidence of pneumonia, and otitis media. The management of persistent diarrhea is relatively simple and is outlined below. 42.3.2.1 Initial evaluation and urgent management

1. Resuscitation if needed. 2. Assessing and management of dehydration.

Part X / Special Topics

689

3. Correcting hypothermia. 4. Management of electrolyte imbalance and hypoglycemia especially in a malnourished child. 5. Assessment and management of a nongastrointestinal infection therapy. Detailed assessment of each of the above is beyond the scope of this chapter. 42.3.2.2 Feedings[51]

The aim of feeding should be to provide energy dense and reduced lactose food to the child in the form of frequent small feeds. Depending upon the lactose tolerance of the child a progressively decreasing amount of lactose may have to be tried. Examples of such feeds are shown in Table 42.12. Children with persistent diarrhea may be managed on an outpatient basis. However, children who need to be managed in the hospital include those who appear sick or infected, have severe dehydration, are malnourished, or are less than 4 months old and are not being breast fed. These children would also qualify to get parenteral antibiotics. 42.3.2.3 Micronutrients[51]

One of the suggested possible causes of development of persistent diarrhea in a child is decreased levels of micronutrients that are involved in maintaining and repair the intestinal tissue. Hence the recommendation is to use twice the Recommended Daily Allowance of vitamins and minerals for 2– 4 weeks in all children with persistent diarrhea. Of all the micronutrients, the following appear to be the most important: 1. Zinc – 20 mg/day for 2 weeks in children beyond 6 months of age; in less than 6 months give 10 mg/day

690

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.12 Recommended feeding in persistent diarrhea Type of diet

Comments

Diet A – Limited lactose intake • Animal milk 50–60 ml/kg/day = 2–2.5 g/kg/day lactose preferably with cereal • Add fat to milk cereal mix in order to increase caloric density and reduce total lactose intake • 6–7 feeds per day • 100 kcal/kg/d – increase to 150 kcal/kg/d for catch up growth • Breast feeding should continue ad lib

Adequate therapy in over 75% of children with persistent diarrhea. Trial of this therapy can be for 7 days though if there is no response in 1–2 days Diet B should be initiated. For the first 48 hours, anorexia may be present and nasogastric tube feeds may be needed. Children with severe anorexia must be evaluated thoroughly for an underlying infection

Diet B – Lactose free diet, reduced starch • No milk in diet; starch reduced and replaced partially by glucose to increase digestibility without significant increase in osmolarity • Protein source is egg white or chicken

Go to Diet B if child has failed to respond in 1 week, i.e., failed to gain weight by day 7 of Diet A or persistence of diarrhea or re-appearance of dehydration any time on Diet A

Diet C – Monosaccharide diet • Protein and glucose based diet • Oil provides energy

Five to ten percent of children with persistent diarrhea will fail diet B (by the same criterion as above). In children not tolerating glucose, parenteral nutrition may need to be provided

2. Vitamin A – a. < 8 kg – 100,000 units one time b. > 8 kg – 200,000 units one time In malnourished children, potassium and magnesium supplements are also needed along with other micronutrients as their bodies are depleted of these two minerals.

However, due to cost constraints these are not practical in most situations. The outcome of persistent diarrhea is usually good if the nutritional and micronutrient status of the child can be improved. A child seen with persistent diarrhea is a good opportunity for intervention by the health care provider for overall betterment of the child’s health.

42.3.2.4 Ancillary therapy

42.3.3 Chronic Diarrhea

1. Antibiotics – The role of using antibiotics in all children with persistent diarrhea is not necessary except in situations listed in Table 42.10. 2. Probiotics – Currently, there are no studies to suggest any benefit of probiotics in persistent diarrhea. 3. Commercial formula – A predigested formula with limited or no lactose would be useful.

Chronic diarrhea in infants is uncommon but troublesome. It often requires special investigations and treatment at a center experienced to handle such problems. Chronic diarrhea in infancy often leads to malnutrition and poor growth and development. Some of the common causes of chronic diarrhea in infants are discussed in Table 42.13. Discussion about each of the causes of chronic diarrhea is beyond the scope of this article. Three

Tropical Hepatogastroenterology

ETIOLOGY

691

TABLE fy 42.13 Common causes of chronic diarrhea in infants and their characteristicsy Postinfectious enteritis

Milk protein allergy

Hirschsprung’s disease

Common problem in developing nations, may result from transient secondary lactose intolerance, or even transient allergy – similar to persistent diarrhea and may be difficult to distinguish except that persistent diarrhea starts acutely Duodenal biopsy – Shows variable villus damage, inflammation and increased mitosis in the crypts, not characteristic Diagnosis – Elimination of other causes, history suggestive of an infectious origin of the disease; response to low lactose feed Treatment – Low lactose feeds, increased fat in diet, breast feeding ad lib if continuing, replacement of electrolytes, vitamins and minerals; parenteral nutrition for short term duration may be needed; treatment based on therapy for persistent diarrhea More common in developed nations but probably under-recognized in developing nations; usually diarrhea sets in after a few weeks of ingesting cow milk; small bowel involvement leads to nonbloody diarrhea and malabsorption; colitis (bloody stools) may occur with or without the small bowel disease Duodenal biopsy – Shows increased eosinophils along with blunting of villi, and generalized inflammation: colonic biopsy shows increased inflammation with eosinophils Diagnosis – Removal of the offending agent, i.e., cow milk protein eliminates the diarrhea and occurs with rechallenge Treatment – Cow milk protein free diet for 1-3 years. Most children will do well on soya based formula – however, as 30%–40% of infants with cow milk protein allergy also have soy protein allergy, a protein hydrolysate formula will be required. Hirschsprung’s disease characteristically causes constipation – however, chronic diarrhea or severe enterocolitis in an infant must make us think of Hirschsprung’s especially if there is a history of constipation as it has a high mortality rate if not treated aggressively. Diagnosis – High index of suspicion; history of constipation or delayed passage of meconium, family history and rectal examination suggestive of Hirschsprung’s. Treatment – Broad-spectrum antibiotics with fluid replacement; specific therapy for Hirschsprung’s.

other causes of chronic diarrhea – Celiac disease, human immunodeficiency virus disease and diarrhea, and Inflammatory bowel disease are discussed in detail. 42.3.3.1 Celiac disease

Celiac disease is a common disorder and makes up about two-thirds of all cases of chronic diarrhea in Indian children. Etiopathogenesis Celiac disease is an immunological disease. The pathogenesis of celiac disease is an-interplay between the genetic makeup, the allergen (gluten), and some hitherto unknown

Part X / Special Topics

Celiac disease results from a permanent allergy to gluten in some genetically predisposed individuals. trigger.[52] Gluten is a common term for certain alcohol-soluble proteins known as prolamins. These are found in wheat (gliadin), rye (secalin) and barley (hordein). It is a permanent and inappropriate intestinal T-cell activation that leads to disease. It is proposed that an earlier exposure of gluten during infancy in a genetically predisposed individual will increase the likelihood of celiac disease, though this is yet to be proven.

692

Chapter 42 / DIARRHEA IN CHILDREN

Genetics The genetic makeup most often associated with celiac disease is the presence of heterodimer or homodimer of the class II antigens HLA DQ 2 and HLA DQ 3. In the absence of these two genetic markers the likelihood of having celiac disease is negligible. Hence, this is a good test to perform in unclear cases or to determine if a sibling is at risk of developing the disease. Mechanism of disease The proposed pathogenesis of Celiac disease is shown below.

Gluten

−−−−−−−−→ Tissue Transglutaminase

Deaminated gluten | | | HLA DQ 2 or | ↓ HLA DQ 3

Deaminated glutenHLA DQ 2 or DQ 8 complex | | Complex detected as || foreign by T cells ↓ Destruction of mucosa The proposed mechanism cannot explain all the clinical symptoms associated with celiac disease. However, the most important and consistent feature of the disease (even if not clinically apparent) is damage to the villi. It is yet not clear why in some of the genetically predisposed individuals the ubiquitous enzyme tissue transglutaminase deaminates the gluten in the first place though there is some evidence that an adenovirus infection may induce it to do so.[53] Clinical features The clinical features (Table 42.14) can broadly be divided into two main groups – intestinal and extraintestinal. It is important to remember that even the patients with

extraintestinal disease with no clinical evidence of intestinal disease will have microscopic changes of the small intestine. In fact, 75% of individuals with dermatitis herpetiformis (the classical skin disease associated with Celiac disease) have small bowel villous atrophy while the rest have minor mucosal changes. Unexplained persistent iron deficiency anemia may be due to celiac disease. In developing countries, the disease manifests itself primarily with intestinal disease while in the West a large number of cases present with extraintestinal disease. Hence, it may be expected that in the future, even in India, many more children will present with extraintestinal manifestations, including short stature, and delayed puberty. Celiac disease must be suspected if the child has unexplained anemia or is inappropriately underweight (even in the absence of intestinal symptoms). Celiac disease is more common in children with Down’s syndrome, IgA deficiency, Type 1 diabetes mellitus (3%–5% of new cases), and with other autoimmune diseases including thyroiditis. Age at diagnosis is variable and the condition has been diagnosed in adults as well. TABLE fy 42.14 Clinical features of celiac diseasey Intestinal

Extraintestinal

Nonbloody diarrhea Bloating Failure to thrive Constipation Irritability Recurrent abdominal pain Aphthous ulcers

Isolated short stature Iron deficiency anemia Delayed puberty Rickets Cryptogenic cirrhosis Seizures Occipital calcification Dermatitis herpetiformis Osteoporosis, osteopenia Dental enamel defects

Tropical Hepatogastroenterology

ETIOLOGY

Diagnosis The diagnosis of celiac disease is relatively easy provided it is suspected. The gold standard remains duodenal biopsy.[54] The mucosa of the duodenum may reveal villous broadening and flattening, increased crypt-villous ratio secondary to crypt hyperplasia, lymphocyte infiltration, and increase in intraepithelial cells. Total villous atrophy is very suggestive of celiac disease. However, mild or moderate villous damage can be seen in celiac disease as well as other conditions like Giardiasis, postviral enteritis, cow-milk allergy, malnutrition, bacterial overgrowth, and autoimmune enteropathy. Hence, if the villous atrophy is not complete other diagnoses may need to be considered. However, if the clinical picture is consistent and there is rapid improvement in the child’s condition after withdrawal of gluten the diagnosis is confirmed. Usually a second biopsy (performed after the child has been off gluten for 2 years) is not required except in certain circumstances listed below.

1. Diagnosis made in a child under the age of 2 years. 2. Improvement not satisfactory on a gluten free diet. 3. Possibility of another diagnosis like cow milk protein allergy present. 4. Gluten withdrawal prior to the first endoscopy and hence, initial biopsy not typical. Very rarely, is a third biopsy required (biopsy done after ingestion of gluten for 3 months or when symptoms reappear). This biopsy confirms the disease if there is destruction of villi after addition of gluten. If the villi are normal, an alternative diagnosis must be considered. Serology Several advances have been made in the serological diagnosis of celiac disease. Antigliadin antibody (IgA and IgG) are now rarely used for screening and diagnosis of celiac disease.

Part X / Special Topics

693

This is because of the unacceptable rates of false negative and false positive results. The main utility of the IgG antigliadin antibody test is when IgA deficiency is present. Most of the newer and more sensitive and specific tests available currently in the country are IgA based and hence, may be falsely negative. Tissue transglutaminase antibody and antiendomysial antibody have sensitivity and specificity of about 95%. Antibody to tissue transglutaminase enzyme (human antigen), an ELISA test has become the gold standard for all serological tests. This is a relatively cheap and easily reproducible test. However, the test most often used in the past was antiendomysial antibody (IgA). It has a sensitivity and specificity exceeding 96% and similar to tissue transglutaminase antibody. The problem with the antiendomysial antibody test is that it is an immunofluorescence test making interpretation more difficult. However, because of their high sensitivity and specificity it is a good screening test as well as a good adjunct to the duodenal biopsy. Family work-up Once a diagnosis of celiac disease is made in a child it is important to investigate other siblings as the disease is found in approximately 10% of first-degree relatives. These individuals may be asymptomatic (latent celiac disease). Serological tests have a higher incidence of false negative results infants. Testing for HLA markers would be another way to determine if an asymptomatic child is at risk of developing celiac disease. Routine screen would include an antiendomysial antibody along with total IgA level. If the antibody is negative with a normal IgA level it is unlikely that the child has celiac; however, if the antibody is negative with low IgA levels it

694

Chapter 42 / DIARRHEA IN CHILDREN

could be a false negative one. In this situation, IgG antigliadin antibody should be done and if positive, a duodenal biopsy carried out. Treatment Treatment of celiac disease is simple and yet difficult to carry out. Treatment consists of life-long and total elimination of gluten from the diet, i.e., no wheat, rye and barley. Oats was also previously included in the list but it is now apparent that oats can be consumed without any adverse affects. If gluten continues to be ingested (knowingly or accidentally), besides the original disease returning, there is a likelihood of developing small bowel lymphoma.

Key messages • Celiac disease is common in India • Presentation is varied • There is a higher incidence of celiac disease in children with insulin dependant diabetes mellitus and other autoimmune diseases • Gold standard of diagnosis is duodenal biopsy though serology is helpful in screening and confirming disease • Do not stop gluten prior to diagnosis • Therapy is life long and no gluten intake is permitted. The initial treatment of celiac disease will also depend upon the presentation. Most children in India are malnourished and will require multivitamin, and multimineral supplements for the first 2 months. Lactose may have to be limited as well initially. Bacterial overgrowth may also hamper response to therapy.[55] However, children with celiac disease recover quickly when the offending agent is removed from the diet with resumption of growth and pubertal development, and improvement of anemia, if present.

It is important to keep reinforcing the child (specially during the teenage years) and the family, the need to continue to eliminate gluten from the diet to prevent relapse. Therapy of celiac disease is the most successful if the whole family participates to avoid gluten intake. To help these children not feel deprived, several gluten free off the shelf products are being marketed in India. 42.3.3.2 Human immunodeficiency virus disease and diarrhea

HIV disease is a worldwide phenomenon. There is expected to be an explosion of cases of HIV in the developing countries including India in the coming decade. There are many presentations of HIV in children but one of the more common ones involves the gastrointestinal tract. In fact, some of the gastrointestinal presentations along with confirmation of presence of HIV in the child constitute the AIDS syndrome.[56] The gastrointestinal manifestations of HIV are numerous and include diseases of the gastrointestinal tract, liver, pancreas and oral cavity. Growth failure is an important component of the disease and occurs from a multitude of reasons.[57, 58] A child with chronic diarrhea and failure to thrive without any other obvious cause should be investigated for HIV. Diarrhea is the most common gastrointestinal manifestation of HIV infection. In fact, most children go on to get gastrointestinal tract involvement as their immunity wanes with time.[59] This often leads to malabsorption and weight loss especially if the small gut is involved. Medications, e.g., protease inhibitors are the second most common cause of diarrhea in children with HIV. Mycobacterium tuberculosis remains a common problem in HIV in developing countries.[60] Lactose intolerance may also contribute to diarrhea.

Tropical Hepatogastroenterology

ETIOLOGY

Evaluating diarrhea in children with HIV includes the following steps: 1. Complete history and physical examination to determine nutritional status, current medications, type of stool (bloody or nonbloody, small bowel versus large bowel, evidence of malabsorption), presence or absence of systemic disease, duration of diarrhea, pain, previous gastrointestinal infection or diarrhea, improvement with elimination of lactose, and the immune status of the child. 2. Multiple stools examinations for including routine, microscopy, pH, reducing sugars, occult blood, fat globules, stool culture, special stain for Microsporidia and Cryptosporidium, stool culture, and C. difficile toxin assay. 3. Blood investigations including blood culture, evidence of systemic infection, immune deficiency status (CD4 counts). 4. Endoscopy – upper and/or lower with biopsy with special stains including for electron microscopy as indicated. It is important to remember that unlike adults where usually the opportunistic organisms are involved, in children ‘routine’ organisms can be involved and result in severe or protracted disease. However, some causes of diarrhea are relatively unusual in HIV infected children (Table 42.15). In case of acute diarrhea in a child on intensive retroviral therapy and with CD4 counts above 500, management is similar to other children. However, if there is inadequate retroviral therapy or the CD4 counts are less than 400, the patient should be started on metronidazole and ciprofloxacin. In case of unsatisfactory response and inability to detect an organism on repeated stool examinations, co-trimoxazole should be added.[61] Once the

Part X / Special Topics

695

TABLE fy 42.15 Unusual infective causes of diarrhea in children with HIV • Mycobacterium tuberculosis, M. avium-intracellulare • Entamoeba histolytica, Giardia, Cryptosporidium, Isospora, Microsporidia • Cytomegalovirus, Herpes • Candida, Cryptococcus

TABLE fy 42.16 Specific management of identified pathogens Pathogen Campylobacter Clostridium difficile Cryptosporidium Cytomegalovirus Herpes Isospora belli Microsporidia Mycobacterium avium intracellulare Salmonella

Treatment Erythromycin Metronidazole or vancomycin Nitazoxanide, azithromycin, clarithromycin, paramomycin Ganciclovir, foscarnet Acyclovir Co-trimoxazole Albendazole, metronidazole Clarithromycin or azithromycin with ethambutol and/or rifampicin followed by maintenance therapy Fluoroquinolones, co-trimoxazole

cause is identified, specific therapy if available should be used (Table 42.16). If the etiology is not clear, despite noninvasive and invasive investigations, HIV itself may be responsible for diarrhea. Symptomatic therapy may be required in majority of cases (Table 42.17). It is recommended that patients with HIV are managed in conjunction with a team of doctors experienced in managing immunocompromised children. Effective antiretroviral therapy along with maintenance of nutritional status is the cornerstone of therapy for children with HIV and diarrhea.[62, 63]

696

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.17 Supportive Rx of diarrhea in children with HIV infection Antisecretory agent

Somatostatin

Non-narcotic agents

Fiber, probiotics, prebiotics, diphenoxylate, loperamide Morphine, codeine

Narcotics Nutritional support

Supplemental feeds, tube feeding, parenteral nutrition

Key messages • Recurrence of disease is common with same or different pathogen. • Multiple pathogens, lactose intolerance plus drugs may be involved at the same time in a given child. • Bacterial overgrowth may contribute to the illness. • Malabsorption and weight loss worsens overall outcome. • In many cases no identifiable pathogen can be determined and hence treatment is symptomatic. • Maintaining or improving the nutritional status of the child is important for overall management • Effective antiretroviral paramount.

therapy

is

42.3.3.3 Inflammatory bowel disease

Inflammatory bowel disease (IBD) is an uncommon problem in children in our country. In fact, it is uncommon under the age of 5 years even in communities where IBD is common. In almost 15% of the cases, a positive family history is present. The more common type of inflammatory bowel disease seen in our country in children is ulcerative

colitis. Both forms of IBD, ulcerative colitis and Crohn’s disease are idiopathic with some evidence to show that they occur due to a disordered immune mechanism.[64] The common manifestations of ulcerative colitis include chronic diarrhea that is usually bloody along with abdominal pain and cramps. Distal ulcerative colitis (proctitis) may present with constipation and presence of blood on the stool. Weight loss and growth failure are uncommon in ulcerative colitis. Oral ulcers, previously thought to be found only in Crohn’s disease, are common in ulcerative colitis and often reflect colonic activity. Ulcerative colitis may also present as a fulminant colitis and toxic megacolon, and more rarely, perforation. Crohn’s disease on the other hand has protean manifestations not only because the entire GI tract can be involved but also because of the nature of the disease. Recurrent abdominal pain, diarrhea, blood in the stool, recurrent perianal abscess, peritonitis, prolonged fever, weight loss, growth failure and delayed sexual maturation are some of its manifestations. Upper gastrointestinal symptoms are also common in Crohn’s disease and include oral ulcers, esophagitis, gastritis, and gastric ulcer. Small bowel disease may also occur and this could result in malabsorption. The physical findings usually reveal aphthous stomatitis, clubbing, anemia, perineal skin tags, and abscesses in Crohn’s disease. In both conditions, the abdomen may be tender, distended or a lump may be felt. Extraintestinal manifestations (EIM) of inflammatory bowel disease may appear before the intestinal disease, or along with it, or several years later. Overall extraintestinal manifestations are seen more often with Crohn’s disease (especially colonic disease) rather than ulcerative colitis. Extraintestinal manifestations are of different types and fall into the following 4 categories:[65]

Tropical Hepatogastroenterology

ETIOLOGY

697

TABLE fy 42.18 Extraintestinal manifestations of IBDy Joints • Arthralgia is more common than arthritis and can involve up to 25% of children • Arthritis in nondestructive and usually involves large joints • Peripheral arthritis is related to GI disease activity and usually responds to therapy for the GI disease • Central arthropathy – spondyloarthritis and sacroilitis is less common, often occurs in patients with HLA B27 and is not related to GI disease Hepatobiliary disease • Occurs in 5%–10% of patients • Fatty liver (nutrition or drug related), hepatitis (autoimmune or drug related), cholangitis, cirrhosis, liver abscess may occur • Liver disease is seen more often in ulcerative colitis especially if antineutrophil cytoplasmic antibody is positive • Primary sclerosing cholangitis is the most aggressive EIM and may cause end stage liver disease 5–10 years Eye disease • Rare in children • Uveitis is most common and may remain asymptomatic Osteoporosis • Osteoporosis is common and occurs due to multiple reasons including low nutrient intake, less physical activity and drugs • Osteoporosis can present with pain, fractures, aseptic necrosis of the hip Skin manifestations • Pyoderma gangrenosum and erythema nodosum may occur

1. Those that are directly related to the intestinal disease activity and often respond to the therapy for the intestinal disease, e.g., peripheral arthritis. 2. Those that are independent of the intestinal disease activity and do not respond to the therapy for the gastrointestinal disease, e.g., hepatobiliary disorders. 3. Those related to the diseased bowel per se, e.g., renal stones. 4. Iatrogenic – e.g., drug related pancreatitis.

mucosa or surgically resected specimens. However, the diagnosis should be suspected on the clinical picture, laboratory data, Stool examination (especially occult blood), barium examinations, endoscopy, ultrasound, white cell scans, CT scan, etc. The important differential diagnosis of inflammatory bowel disease in our country remains infectious colitis, antibiotic associated diarrhea, tuberculosis, celiac disease, and tropical enteropathy. Occasionally, amebic colitis may masquerade as IBD, i.e., nonresponse to conventional antiamebic therapy and colonoscopy would be required to confirm the diagnosis.

The common EIMs are listed in Table 42.18. Diagnosis Diagnosis of inflammatory bowel disease can be made only on histology of the intestinal

Part X / Special Topics

Treatment Treating a child with inflammatory bowel disease is complex due to several reasons as shown in Table 42.19.[66]

698

Chapter 42 / DIARRHEA IN CHILDREN

TABLE fy 42.19 Factors making IBD a complex problem in childreny • Delay in diagnosis, as is it an under-recognized condition • Delayed growth and development, malnutrition, delayed puberty affects physical and mental development of the child • School days lost due to relapses • Increased risk of malignancy with increasing duration of disease • Extraintestinal manifestations may become severe and necessitate special therapy, e.g. liver transplantation for cirrhosis secondary to sclerosing cholangitis • Medications are expensive, have numerous side effects, often not available as liquid preparations • Use of steroids worsens growth failure, while immunosuppression increases risk of infections and may mask serious complications like abdominal abscess • Effects of long-term use of newer agents not clear in children • Restricted diets not accepted by children • Multiple hospitalizations and surgeries and overall poor quality of life results in major psychological problems • High cost of chronic illness including mental cost borne by the whole family

TABLE fy 42.20 Overview of therapy of children with inflammatory bowel disease Ulcerative colitis Drugs • Sulfasalazine • 5-amino salicylic acid • Corticosteroids (systemic or local) • 6-Mercaptopurine, azathioprine, methotrexate Surgery • Total proctocolectomy Nutrition • Parenteral nutrition in case of fulminant colitis

Crohn’s disease • Sulfasalazine • 5-amino salicylic acid • Corticosteroids (systemic or local) • Antibiotics • 6-Mercaptopurine, azathioprine, methotrexate • Infliximab • Limited resections • Stricturoplasty • Abscess drainage • Parenteral nutrition to heal fistulas • Protein hydrolysate formulas

An overview of therapy of inflammatory bowel disease is shown in Table 42.20.[67] Ideally,

the pediatrician along with a pediatric gastroenterologist should provide care to a child with inflammatory bowel disease. For all children with inflammatory bowel disease: 1. Education of the family regarding the disease including it’s chronic course is crucial 2. Regular follow up for assessing disease activity, extraintestinal manifestations, drug related toxicity, physical examination especially weight and height of the child 3. Regular assessment of school related activities 4. Providing a broad long-term outlook for the child specifically addressing growth failure and delay in puberty 5. Psychological evaluation of the child and family if necessary 6. Surveillance for carcinoma should begin after 10 years of disease It is important to limit the use of corticosteroids in inflammatory bowel disease as much as possible due to multiple side effects including growth failure. Use of immunosuppression, though steroid

Tropical Hepatogastroenterology

PREVENTION OF DIARRHEA

sparing, should not be taken lightly and all possible information about the drug should be provided to the family prior to its usage. Surgery remains the therapy of last resort especially in Crohn’s disease. Key messages • All chronic diarrhea especially bloody or associated with growth failure needs special investigations to rule out noninfectious causes. • Pyrexia of unknown origin may be related to diseases of the gut • Bloody diarrhea should not be treated with repeated courses of antibiotics or antiprotozoal as it may be inflammatory • Endoscopy may be needed in selected patients with diarrhea.

699

1. Hand washing – after defecating and prior to touching any food – while preparing, cooking or eating. 2. Provision of potable water 3. Provision of vitamin A[68] 4. Provision of zinc in the diet [69, 70] 5. Breast feeding – for 6 months has resulted in reduction of infectious diarrhea.[71] 6. Use of latrines 7. Measles vaccine[72] 8. Education[73] Cholera vaccine and rotavirus vaccine are currently not available but are under development or review. Some of the above have resulted in significant decrease in diarrhea morbidity and mortality in India and other developing nations.[74]

42.4 PREVENTION OF DIARRHEA

ACKNOWLEDGEMENT

Prevention of diarrhea implies prevention of diarrhea of infectious origin, i.e., acute or persistent diarrhea. Some of the practices that could be employed to control infectious diarrhea include the following:

I am grateful to Dr. Shinjini Bhatnagar, Senior Scientist, Center for Diarrheal Disease Research, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi for her invaluable suggestions.

REFERENCES [1] Farthing MJ. Diarrhea: a significant worldwide problem. Int J Antimicrob Agents 2000;14: 65–69. [2] WHO-State of the world’s children, 1998–1997, Geneva. WHO 1987:75. [3] Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global burden of Disease study. Lancet 1997; 349(9061):1269–76. [4] WHO – State of the World’s children 2001. WHO 2001:68. [5] Bern C, Martines J, De Zoysa I et al. Magnitude of the global problem of diarrheal diseases: An update. Bull WHO 1992;70:705–714.

Part X / Special Topics

[6] Rhoads JM, Powell DW. Diarrhea. In: Walker WA, Durie PR, Hamilton JR eds. Pediatric Gastrointestinal disease, Toronto: B C Decker 1991. [7] Davies GJ, Crowder M, Reid B et al. Bowel function measurements of individuals with different eating patterns. Gut 1986;27:164–169. [8] WHO. The treatment and prevention of diarrhoea: Practical guidelines, 2nd Edition, WHO, Geneva, 1990. [9] Bhandari N, Sazawal S, Clemens JD et al. Association between diarrheal duration and nutritional decline: implications for an empirically validated

700

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

Chapter 42 / DIARRHEA IN CHILDREN

definition of persistent diarrhea. Indian J Pediatr 1994;61:559–566. Bhandari N, Bhan MK, Sazawal S. Mortality associated with acute watery diarrhea, dysentery and persistent diarrhea in north India. Acta Pediatr 1992:81 Suppl 381:3–6. Dutta P, Mitra U, Raisaily R et al. Assessing the cause of in-patient pediatric diarrheal deaths: an analysis of hospital records. Indian Pediatr 1995:32:313–321. Bhan MK, Bhandari N, Bhatnagar S et al. Epidemiology and management of persistent diarrhea in children of developing countries. Indian J Med Res 1996; 104:103–114. Ballal M, Shivananda PG. Rotavirus and enteric pathogens in infantile diarrhea in Manipal, south India. Indian J Pediatr 2002;69:393–396. Arora NK, Raj P, Stintzing G et al. Etiologic role of enterotoxigenic Escherichia coli & rotavirus in acute diarrhea in Delhi children. Indian J Med Res 1987;85:604–7. Glass RI, Bresee JS, Parasher U et al. Rotavirus vaccines at the threshold. Nature Med 1997;3: 1324–1325. Nath G, Singh SP, Sanyal SC. Childhood diarrhea due to rotavirus in a community. Indian J Med Res 1992;95:259–262. Phukan AC, Patgiri DK, Mahanta J. Rotavirus associated acute diarrhea in hospitalized children in Dibrugarh, north east India. Indian J Pathol Microbiol 2003;46:274–8. Czachor JS, Herchline TE. Infectious diarrhea in immunocompetent hosts: Part 1. Bacteria, Viruses and Parasites. Hosp Physician 1996;10–17. Thomas PD, Pollok RC, Gazzard BG. Enteric viral infections as a cause of diarrhea in the acquired immunodeficiency syndrome. HIV Med 1999;1: 19–24. WHO. The treatment of diarrhea: A manual for physicians and other senior health workers. Geneva, WHO 1995. Girish R, Broor S, Dar L et al. Food-borne outbreak caused by a Norwalk like virus in India. J Med Virol 2002;67:603–607.

[22] Raj P, Bhandari N, Bhan MK. Enteric adenoviruses in childhood diarrhea. Indian J Pediatr 1988;55: 825–828. [23] Singh PB, Sreenivasan MD, Pavri KM. Viruses in acute gastroenteritis in children in Pune, India. Epidemiol Infect 1989;102:345–353. [24] Sen D, Ganguly U, Saha MR et al. Studies on Escherichia coli as a cause of acute diarrhea in Calcutta. J Med Microbiol 1984;17:53–58. [25] Vaishnavi C, Ray P, Thapa BR et al. Enteropathogenic Escherichia coli isolates in Pediatric diarrhea. Trop Gastro 2000;21:35–36. [26] Srivastava RN, Moudgil A, Bagga A et al. Hemolytic uremic syndrome in children in northern India. Pediatr Nephrol 1991;5:284–288. [27] Vaishnavi C. Antibiotic associated diarrhea and enterocolitis. Trop Gastroenterol 1997;18:145–148. [28] Meyers S. Treatment of Clostridium difficile infection. Mt Sinai J Med 1995;62:183–187. [29] Gorbach S, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet 1987;2:1519. [30] McFarland LV, Surawicz CM, Greenberg RN et al. A randomized placebo controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271:1913–1918. [31] Ali SA, Hill DR. Giardia intestinalis. Curr Opin Infect Dis 2003;16:453–460. [32] Kaur N, Diwan N. Cryptosporidosis in north Indian children. Indian J Med Sci 1995;45:143–5. [33] Kenney RT. Parasitic causes of diarrhea. Pediatr Ann 1994;23:414–422. [34] Mirdha BR, Samantray JC. Hymenolepsis nana: a common cause of pediatric diarrhea in urban slum dwellers in India. J Trop Pediatr 2002;48:331–334. [35] Malik SV, Khanna PN. Enterotoxigenic Escherichia coli outbreak with choleragenic syndromes of gastroenteritis. J Commun Dis 1989;21:313–317. [36] Hay WW, Hatward AR, Levin MJ et al. (Eds.) Current Pediatric Diagnosis & Treatment (14th ed.). Stamford Connecticut: Appleton & Lange, 1999. [37] Choi SW, Park CH, Silva TM et al. To culture or not to culture: fecal lactoferrin screening for

Tropical Hepatogastroenterology

REFERENCES

[38]

[39] [40] [41]

[42]

[43] [44]

[45]

[46]

[47]

[48]

[49]

[50]

inflammatory bacterial diarrhea. J Clin Microbiol 1996;34:928–932. Gill CJ, Lau J, Gorbach SL et al. Diagnostic accuracy of stool assays for inflammatory bacterial gastroenteritis in developed and resource poor countries. Clin Infect Dis 2003;37:365–375. Hoshiko M. Laboratory diagnosis of infectious diarrhea. Pediatr Ann 1994;23:570–574. Bhan MK. Current concepts in management of acute diarrhea. Indian Pediatr 2003;40:463–476. WHO expert consultation on ORS formulation, New York, July 2001. www.rehydrate.org/ors/expert-consultation.html Bhatnagar S, Bahl R, Sharma PK et al. Zinc with oral rehydration therapy reduces the stool output and duration of diarrhea in hospitalized children: a randomized control trial. J Ped Gastro Nutr 2004;38:34–40. Alam NH, Ashraf H. Treatment of infectious diarrhea in children. Pediatr Drugs 2003;5:151–165. Bhan MK, Bhatnagar S. Racecadotril – Is there enough evidence to recommend it for treatment of acute diarrhea? Indian Pediatr 2004;41: 1201–1204. Duggan C, Nurko S. “Feeding the gut”: The scientific basis for continued enteral nutrition during acute diarrhea. J Pediatr 1997;131:801–808. Sarkar D, Singharoy A, Bhattacharya SK. Azithromycin in the treatment of cholera in children. Acta Pediatr 2003;92:676–678. Black RE. Persistent diarrhea in children of developing countries. Pediatr Inf Dis J 1993;12: 751–761. Bhan MK, Bhandari N, Sazawal S et al. Descriptive epidemiology of persistent diarrhea among young children in rural northern India. Bull WHO 1989;67:281–288. Bhan MK, Khushoo V, Sommerfelt H et al. Enteroaggregative Escherichia coli and Salmonella associated with nondysenteric persistent diarrhea. Pediatr Infect Dis J 1989;8:499–502. Sazawal S, Bhan MK, Bhandari N et al. Evidence for recent diarrheal morbidity as a risk factor for persistent diarrhea: a case control study. Int J Epidemiol 1991;20:540–545.

Part X / Special Topics

701

[51] Guidelines for management of diarrhoea in children. Bhan MK, Bhatnagar S, eds. Bhumica, New Delhi 2000. [52] Maki M, Collin P. Coeliac disease. Lancet 1997;349:1755–1759. [53] Lahdeaho ML, Parkkonen P, Reunala T et al. Antibodies to E1b protein derived peptides of enteric adenovirus type 40 are associated with celiac disease and dermatitis herpetiformis. Clin Immunol Immunopathol 1993;69:300–305. [54] Marsh MN, Crowe PT. Morphology of the mucosal lesion in gluten sensitivity. Baillieres Clin Gastroenterol 1995;9:273–293. [55] Ghoshal UC, Ghoshal U, Misra A et al. Partially responsive celiac disease resulting from small intestinal bacterial overgrowth and lactose intolerance. BMC Gastroenterol 2004;4:10. [56] 1997 Red Book: Report of the committee on Infectious diseases, American Academy of Pediatrics. Peter G, Ed. 24th Edition, pg. 279–304. [57] Karande S, Bhalke S, Kelkar A et al. Utility of clinically directed selective screening to diagnose HIV infection in hospitalized children in Bombay, India. J Trop Pediatr 2002;48:149–155. [58] Agostoni C, Riva E, Gianni ML et al. Anthropometric indicators of human immunodeficiency virus infection in infants with early and late symptoms in the first months of life. Eur J Pediatr 1998;157:811–813. [59] Madhivanan P, Mothi SN, Kumarasamy N et al. Clinical manifestations of HIV infected children. Indian J Pediatr 2003;70:615–620. [60] Lanjewar DN, Anand BS, Genta R et al. Major differences in the spectrum of gastrointestinal infections associated with AIDS in India versus the West: An autopsy study. Clin Infec Dis 1996;23:482–485. [61] Bhatnagar S, Bhandari N, Mouli UC et al. Consensus statement of IAP National Task Force: Status report on management of Acute diarrhea. Indian Pediatr 2004;41:335–347. [62] Stewart GJ, Kunanusont C, Phanuphak P et al. Managing HIV with limited medical resources. In Managing HIV. Eds Greame Stewart, Australasian Publishing Company Ltd, 1997.

702

Chapter 42 / DIARRHEA IN CHILDREN

[63] Rongkavilit C, Asmar BI. Antiretroviral drugs in Pediatrics. Indian J Pediatr 2001;68:641–647. [64] Kirschner BS. Ulcerative colitis and Crohn’s disease in children. Gastroenterol Clin N Am 1995;24: 99–117. [65] Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994;19:7–21. [66] Vohra P. Inflammatory bowel disease. Indian J Pediatr, 2000;67:747–756. [67] Grand RJ, Ramakrishna J, Calenda KA. Inflammatory bowel disease in the pediatric patient. Gastroenterol Clin N Am 1995;24:613–632. [68] Chowdhury S, Kumar R, Ganguly NK et al. Effect of Vitamin A supplementation on childhood morbidity and mortality. Indian J Med Sci 2002;56:259–64. [69] Bhutta ZA, Black RE, Brown KH et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: Pooled analysis of randomized controlled trials. Zinc Investigators’ Collaborative Group. J Pediatr 1999;135: 689–697.

[70] Sur D, Gupta DN, Mondal SK et al. Impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight infants in Kolkata, India: a randomized, double-blind, placebo-controlled, community based study. Pediatrics 2003;112: 1327–1332. [71] Bhandari N, Bahl R, Mazumdar S et al. Effect of community based promotion of exclusive breast feeding on diarrheal illness and growth: a cluster randomized controlled trial. Lancet 2003;361: 1418–23. [72] Aaby P, Bhuiya A, Nahar L et al. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol 2003;32:106–116. [73] Mangala S, Gopinath D, Narasimhamurthy NS et al. Impact of educational intervention on knowledge of mothers regarding home management of diarrhea. Indian J Pediatr 2000;68:393–397. [74] Bhattacharya SK. Progress in the prevention and control of diarrhoeal diseases since Independence. Natl Med J India 2003;16 (Suppl 2):15–19.

test

Tropical Hepatogastroenterology

Chapter

43

NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING Manisha Dwivedi and SP Misra

Acute upper gastrointestinal (UGI) hemorrhage manifests as hematemesis and/or melena, and occasionally as hematochezia with brisk bleeding. Nearly 80% of patients stop bleeding without specific intervention. The remaining 20% are important: a major artery is eroded and management skills are needed to stop bleeding, prevent rebleeding, and improve survival. The three common causes of UGI hemorrhage in India are variceal, peptic ulcer bleeding, and erosive mucosal disease. In the west, peptic ulcers account for more than 50% of UGI bleeding;[1–3] in India, variceal bleeding is the most frequent cause. The various causes of UGI bleeding are depicted in Table 43.1.

43.1 MEDICAL HISTORY AND PHYSICAL EXAMINATION After ensuring hemodynamic stability, a directed history and physical examination is performed keeping in mind the common causes of UGI bleeding. A history of syncope, diaphoreses, and light headedness signify significant blood loss. A past history of dyspepsia and upper abdominal pain may suggest diagnosis of ulcer disease. The physician must ask about aspirin or nonsteroidal anti-inflammatory drug intake, alcohol intake, or cigarette smoking. A past history of coma, pedal edema, abdominal distension, prolonged diuretic

TABLE fy 43.1 Causes of nonvariceal UGI bleeding (Figs. 43.1 and 43.2) Common

Uncommon

Duodenal ulcer Gastric ulcer Erosions

Dieulafoy lesion A–V malformations Angiodysplasia

Mallory–Weiss tear Esophagitis

Water melon stomach Aortoduodenal fistula Hemobilia

Neoplastic Hemosuccus pancreaticus

Iatrogenic Polypectomy Papillotomy Mucosal resection Papillectomy Stricture dilation Transmural procedures

Pseudoaneurysms Diverticula Ectopic pancreatic tissue

intake, or jaundice may point towards variceal bleeding. Vomiting and retching before bleeding suggest a Mallory–Weiss tear. The priority is to ensure hemodynamic stability after an episode of GI bleeding. Supine hypotension is preceded by orthostatic hypotension, which means a fall in systolic blood pressure by 20 mmHg and a fall in diastolic blood pressure by more than 10 mmHg, with an increase in pulse rate of more than 20 beats per minute on standing.[4, 5] 703

704

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

FIGURE 43.1 Mallory–Weiss tear.

A tachycardia of more than 120 beats per minute and a systolic blood pressure of less than 100 mmHg signify an acute loss of 20% of the blood volume. Exceptional situations may occur. For example, young patients may remain normotensive in spite of massive bleeding due to intense vasoconstriction[6] and elderly diabetics may exhibit orthostatic hypotension even with loss of small amounts of blood. Massive blood loss may present as shock with a weak thready pulse and a cold clammy skin. A quick physical examination should be done to see for features of liver cell failure and portal hypertension in the form of fetor hepaticus, asterixis, altered sensorium, icterus, spider angiomas, gynecomastia and testicular atrophy in males, palmer erythema, clubbing Dupuytren’s contracture, caput medusae, splenomegaly, and ascites. If these are present variceal bleeding is the first diagnosis. Epigastric tenderness is a feature of peptic ulcer or erosive mucosal disease. Guarding and rigidity of the abdominal wall occur in cases of perforation of a peptic ulcer. In cases of UGI bleeding, the bowel sounds are exaggerated due to the presence of blood in the intestine.

43.2 LABORATORY TESTING

FIGURE 43.2 Upper gastrointestinal endoscopy showing a lesion with an ulcerated tip. The patient was bleeding profusely from this point. Resection and biopsy showed that this was ectopic pancreatic tissue, a rare cause of upper gastrointestinal bleeding.

The hematocrit values effectively reflect the amount of bleeding 24–72 hours after the initial hemorrhage, due to redistribution of fluid from the extravascular to the intravascular space.[7] The blood urea nitrogen (BUN) and creatinine are raised after UGI bleeding due to volume depletion and intestinal absorption of proteins in the blood. A highly elevated BUN to creatinine ratio suggests UGI bleeding.[8] Coagulation parameters should be determined, and fresh frozen plasma transfused to correct the altered profile if necessary.

Tropical Hepatogastroenterology

INITIAL MANAGEMENT

Severe blood loss may lead to intracellular hypoxia resulting in systemic acidosis and elevated serum lactate levels. In elderly patients presenting with shock, syncope, or other evidence of hypoperfusion, the possibility of myocardial infarction should be excluded by creatinine kinase estimation.[9] A liver function test profile should be estimated.

43.3 INITIAL MANAGEMENT 43.3.1 Nasogastric Aspiration The emergency medical officer should do a gastric lavage with 200 ml of water at room temperature after passing a nasogastric (NG) tube. Lavage with ice cold water should be avoided as it is uncomfortable, lowers core body temperature and may have a deleterious effect on GI bleeding. The quality of the aspirate determines the aggressiveness of the management approach in the patient. Coffeeground material or a frankly bloody aspirate will confirm UGI bleeding. However, it should be kept in mind that nearly 50% of patients with duodenal bleeding may have a clear aspirate due to insufficient blood having refluxed through the pylorus into the stomach.[10, 11] On the other hand, UGI bleeding may also be intermittent. Red blood in the gastric aspirate and rectum signifies rapid bleeding, and has a 30% mortality[12, 13] as compared to 9% mortality in patients who have altered blood in the aspirates and melanotic stools.[14]

43.3.2 General Measures The airway is protected in a drowsy or comatose patient to prevent aspiration. A Foley’s catheter is passed to monitor the urine output in a patient who is hemodynamically unstable. The patient should be nil orally so that endoscopy may be done, or surgery performed if needed. Antacids should not

Part X / Special Topics

705

be administered as they obscure the endoscopic view.

43.3.3 Fluid Replacement Fluid replacement is titrated to the patient’s needs. Two large bore, 16–18 gauge intravenous catheters are placed, preferably in the same arm, in a patient who is actively bleeding and needs quick replenishment of the intravascular volume.[4] A central venous pressure catheter may help estimate intravascular volume, though this is not uniformly needed. Vasopressors should not be administered before replenishing the intravascular volume as this may increase end-organ ischemia.[15, 16] Patients with congestive heart failure and/or renal failure or cirrhosis may benefit by placing a pulmonary artery Swan–Ganz catheter to titrate volume expansion and avoid pulmonary edema due to aggressive volume expansion.[17, 18]

43.3.4 Transfusion Requirements These are governed by various factors like patient’s age, other comorbid conditions, cardiovascular status, the baseline and current hematocrit level, and the rate of bleeding. Patients with rapid ongoing bleeding, bleeding associated with hemodynamic compromise or those with rebleeding should be transfused blood. Though young healthy patients tolerate moderate anemia well, elderly patients may develop myocardial ischemia with the same hematocrit level. A hematocrit level more than 28% is desirable to prevent myocardial ischemia in the elderly.[19] Transfusion of one unit of packed erythrocytes raises the hematocrit by 3.5 units.[20, 21] A study showed that aggressive transfusion in patients with portal hypertension increased the risk of rebleeding.[22] In such patients, it is preferable to transfuse blood if the

706

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

hemoglobin is less than 8 gm/dl or if the patient is in shock. To prevent the infectious complications of blood transfusion, blood should only be transfused in ongoing bleeding, if the patient is in shock, or if the postbleed hemoglobin is less than 8 gm/dl. Otherwise, replenishing the intravascular volume with normal saline infusions should suffice. Multiple blood transfusions can result in hypocalcemia due to citrate contained in the transfused blood.[23] Platelet transfusions should be given if platelet counts are less than 50, 000/mm3 with active bleeding.[24] Blood is transfused slowly to provide time for cardiovascular compensation,[25, 26] unless the patient is actively bleeding or is in shock.

43.3.5 Acid Suppressive Therapy This should be administered intravenously as intraluminal acid neutralization promotes mucosal hemostasis. Intravenous H-2 receptor antagonists are rarely associated with mental confusion, bradycardia, hypotension, negative inotropic effects and reversible elevation of liver enzymes. Khuroo et al[27] in a randomized controlled trial of 220 patients showed that oral administration of 40 mg of omeprazole twice a day reduced rates of further bleeding, blood transfusions, surgery, and mortality when compared to placebo. However, oral omeprazole may have an inconsistent absorption, so an intravenously administered drug is preferred. Intravenous proton pump inhibitors have a more potent acid suppressing capability than H2receptor antagonists.[28] The studies suggest that the effect of omeprazole on severe bleeding from an eroded major artery may not be much, but its routine use in patients with upper GI bleeding is advocated as it starts the ulcer healing process at an early stage and has few adverse effects. Somatostatin and its analogue octreotide inhibit acid secretion and decrease splanchnic blood flow. Two meta-analyses showed that somatostatin, but

not octreotide had a primary hemostatic role and reduced the need for surgical intervention.[29, 30] However, a closer scrutiny of the various trials reveals that many studies were small, with variable inclusion criteria. In another study, Somerville et al randomized 630 actively bleeding patients to receive somatostatin (bolus of 250 mg followed by 250 micrograms daily for 72 hours) or a placebo, and reported no significant difference in re-bleeding, operation rate, and mortality.[31] Therefore, the consensus today is that somatostatin should not be routinely used in nonvariceal UGI bleeding till its efficacy is unequivocally proved by larger studies.

43.4 ENDOSCOPIC MEANS OF HEMOSTASIS (Table 43.2) In the past three decades, advances in endoscopic instrumentation and technology have transformed endoscopy from being largely passive and cognitive to actively interventional. Today nearly 90% of UGI bleeding can be managed endoscopically.[3] However, there is a word of caution. The therapeutic endoscopist should realize the limits of endoscopic intervention and should not persist in

TABLE fy 43.2 Methods of endoscopic hemostasis Injection

Thermal

Epinephrine Ethanol Ethanolamine Polidocanol

Heater probe BICAP Nd:YAG Laser Argon plasma coagulation Microwave

Hypertonic saline Thrombin Fibrin Histacryl

Mechanical Hemoclip Endoloop Bands

Tropical Hepatogastroenterology

ENDOSCOPIC MEANS OF HEMOSTASIS

trying to achieve endoscopic hemostasis when it has a low probability of success (Table 43.3) For endoscopic hemostasis, an endoscope with a working channel of 3.7 or 4.2 mm is preferred. As all the water instilled through the working channel has to be removed, excessive flushing should be avoided. Bleeding from peptic ulcer usually stops spontaneously in 70%–80% of cases.[3] The Forrest classification is used to predict the further course of ulcer bleeding and management (Table 43.4). Adherent clots should be washed off to look for underlying blood vessels. Epinephrine (1;20,000 dilution) should be injected into the base of the ulcer to see the site better. Once a blood vessel is identified the further management will depend on the modalities of endoscopic hemostasis available at a particular centre and the expertise of the endoscopist.

TABLE fy 43.3 Limitations of endoscopic treatment Situation

Explanation

Large deep ulcers Major vascular injury like aortoenteric poor fistula, pseudoaneurysmal bleed, etc. Technically difficult sites

Usually erosion of a major vessel Massive bleeding makes visibility and methods ineffective High lesser curve, posterior wall of D1

TABLE fy 43.4 Endoscopic stigmata of bleeding ulcers Forrest type III II-C II-B II-A I

Prevalence (%)

Rebleed

42 20 17 17 18

5 10 22 43 55

Clean base Flat spot Adherent clot Visible vessel Active bleeding

(A: Spurting; B: Oozing)

Part X / Special Topics

707

43.4.1 Argon Plasma Coagulation This is a recently introduced endoscopic modality to stop superficial bleeding from the GI tract by thermal mearrs.[32] The procedure is based upon coagulation through a jet of argon gas. This is very effective in the management of gastric antral vascular ectasia and postsphincterotomy bleeds. Argon beam coagulation has an efficacy comparable to heater probe therapy for ulcer hemostasis.[32]

43.4.2 Endoscopic Injection Therapy for Bleeding Peptic Ulcer This is an effective therapeutic modality for bleeding from peptic ulcers, Mallory–Weiss tears and Dieulafoy’s lesions. Crafoord and Frenckner, two Swedish otolaryngologists, described the first case of injection therapy for UGI hemorrhage in 1939.[33] The bleeding site is localized under vision and bleeding checked, without exposing the patient to the hazards of anesthesia or surgery. The technique is simple, easy to master, requires no costly equipment and can be performed even at peripheral centers. After resuscitation, to ensure hemodynamic stability, or even in the case of ongoing upper gastrointestinal bleeding, the patient undergoes gastric lavage with water to remove blood clots from the stomach. Using a flexible needle injector, inserted through the biopsy channel of the endoscope, 0.5 ml aliquots of the sclerosant are injected by multiple punctures into and around the bleeding point under vision until hemostasis is achieved. Repeat endoscopy is performed after 24 hrs to see if complete hemostasis has occurred. Repeated injections may be needed in about 10– 20% of patients who are rebleeding.[34, 35] The agents used for injection therapy are hypertonic saline, adrenaline I:10,000, polidocanol, absolute alcohol, thrombin, sodium tetradecyl sulphate and dextrose 50% in water.

708

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

Japanese workers started the use of ethanol as an injectant in the 1970s, when they tried to destroy neoplastic lesions of the stomach via the endoscope. Initially, alcohol was combined with a necrotizing agent.[36–38] However, it was the pioneering work of Asaki[39] and Sugawa[40] that firmly established alcohol as a very effective injectant to check gastrointestinal bleeding. Asaki[39] injected 332 patients with UGI bleeding and achieved hemostasis in 99%. The rebleeding rate was 10% and the perforation rate was less than 1%. Hajiro[41] achieved an initial hemostasis rate of 62%. Rebleeding occurred in 25% of cases. The largest series from the United States is that of Sugawa et al[40] who used 0.1–0.2 ml of 98% ethanol per injection at three or four sites surrounding the bleeding vessel. Hemostasis was achieved in 29 of the 33 patients and no complications occurred. Soehendra first used sclerosants to inject nonvariceal gastrointestinal sites of bleeding.[42] In a study of 50 patients bleeding from peptic ulcers he used 5–10 ml of 1:10,000 adrenaline with 3– 5 ml of 1% polidocanol and achieved hemostasis in 16 of 22 patients bleeding from spurting vessels within ulcers with a single endoscopic procedure. The six remaining cases needed a second injection to check bleeding. Hemostasis was achieved after a single injection in 27 of 28 patients, and after a second injection in one patient oozing blood.[43] No perforations were reported. Wordehoff and Gross treated 36 patients with a high operative risk achieving hemostasis in 92% of patients using I% polidocanol alone.[44] Lin and co-workers[45] observed that normal saline, 3% saline, 50% dextrose in water, and absolute alcohol had comparable efficacy in checking active bleeding, in patients with a visible vessel in the ulcer base. In another prospective randomized trial of epinephrine and epinephrine plus alcohol for injection of bleeding ulcers, it was shown that additional injection of alcohol after endoscopic

epinephrine injection conferred no added advantage in achieving hemostasis.[46] Panes et al [47] showed injection of epinephrine followed by polidocanol to be effective in patients with active bleeding amongst those having a visible vessel in the ulcer base. Two other studies concluded that endoscopic ethanol injection therapy achieved ultimate hemostasis and prevented recurrent bleeding in patients with gastric ulcers and nonbleeding visible vessels.[48, 49] Complications of injection sclerotherapy occur in the form of extension of ulcer and perforation, especially when alcohol is used. Injection of adrenaline submucosally in the stomach or duodenum is less likely to cause cardiovascular side effects because catecholamines have a significant first pass extraction in the liver.[50] It was hypothesized that the efficacy of achieving hemostasis by injection therapy may be partly related to the volume of the sclerosant itself.[51] However, in an experimental study on dogs, it was seen that submucosal injection of adrenaline in bleeding gastric ulcers stopped the bleeding, while injection of an inert carrier substance had no effect.[52] Absolute alcohol is known to cause dehydration and fixation of the exposed blood vessel and the surrounding tissue. Later, local thrombosis results from vasoconstriction, vascular wall degeneration, and endothelial destruction. Several other controlled trials have shown a beneficial effect of endoscopic injection therapy.[53–55]

43.4.3 Mechanical Means of Hemostasis These methods of achieving hemostasis are in the form of resnaring the stalk after polypectomy for pedunculated polyps of the UGI tract, using balloons to cause tamponade to check bleeding from ulcers, erosions or tears in the distal esophagus, pylorus or duodenum, and the use of hemoclips, bands and detachable snares.

Tropical Hepatogastroenterology

ENDOSCOPIC MEANS OF HEMOSTASIS

Japanese workers first used hemoclips to arrest UGI hemorrhage.[51] Staple-line clips which can be delivered to the site of bleeding via the endoscope have been used.[56] These clips were first devised by Hayashi in 1971. He achieved hemostasis in 23 of 25 patients bleeding from gastric ulcers and 3 of 4 from duodenal ulcers. The Sakura J-clip was developed later and used to achieve hemostasis in 22 of 24 bleeding gastric ulcers by Hachisu.[56] Mechanical methods of hemostasis have improved recently with the introduction of improved applicators. Today clips can be applied quickly and effectively, without any tissue injury. Sohendra et al used clips in 350 patients, 140 of which had active arterial bleeding. The rates of re-bleeding and surgery were less than 10%. He reported no complications related to the procedure.[57] Workers in Japan used hemoclips in 10 critically ill patients with 100% success.[58] Clips were compared to injections by Nagasu in a retrospective study where the rates of hemostasis were reported as 100% and 84% respectively. After injections, 3 patients had deep ulcers and one perforation was reported, as compared to no complications with the use of clips.[59] In another Japanese study comparing clips with injections, similar rates of primary hemostasis and mortality were reported, though the re-bleeding rates, transfusion requirements, and hospital stay were significantly decreased by the use of clips.[60] Chung et al in a randomized trial of hemoclip, hypertonic saline epinephrine, and a combination, found improvement by the use of clips regarding hemostasis, re-bleeding rate, complications and need for emergency surgery.[61] Bands and loops have proved effective in checking bleeding from Mallory–Weiss tears, polypectomy stumps, Dieulafoy’s lesions, and even gastric varices.[62] Two patients with bleeding gastric ulcers were successfully treated by the use of a motor-rotated 1.5 cm wire helix made of biocompatible steel by Escourrou et al.[63]

Part X / Special Topics

709

43.4.4 Endoscopic Electrocoagulation (EC) This may be monopolar, bipolar, or multipolar. In monopolar electrocoagulation, the current passes from a point source to a remotely placed ground plate during which electrical energy is quickly diffused. In bipolar EC the current density is concentrated at the current tip because tissue contact completes a circuit between two areas, a few millimeters apart. This limits the depth of tissue injury and perforation. Studies using monopolar EC showed a significant benefit in favor of the treatment group in terms of recurrent bleeding and emergency surgery.[64, 65] However, monopolar EC has the disadvantage of causing greater tissue injury than multipolar EC. Also, in the animal model, the vessel erosion caused by monopolar EC interfered with coagulation of arteries more than 0.5 mm in diameter and induced bleeding.[64] Multipolar EC (BICAP) consists of six longitudinally placed electrodes on the probe with a central irrigation port to wash blood clots. This is an effective modality to check rebleeding and to decrease the need for emergency surgery in patients with bleeding peptic ulcers, with a visible vessel. It has the advantage of being portable and causing less tissue damage than laser treatment. Forceful application of the probe to the ulcer base increases the hemostatic efficacy.[66] Application of EC for a longer period and use of a larger probe (3.2 mm as compared to 2.3 min) covering a larger surface area increases the efficacy without increasing the depth of tissue injury.[67] Multipolar EC is less expensive than Nd-YAG laser and has proved more efficacious in coagulating canine arteries of 0.5–2 mm diameter,[68] similar to the size of visible vessels in bleeding peptic ulcers.[69] However, multipolar EC has the disadvantage that it may induce bleeding in nearly 20% of the patients.[70] In the majority, however, hemorrhage can be controlled by continued

710

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

coagulation, but an occasional patient may need surgery. Perforation has also been reported after multipolar EC.[71] The BICAP was found to check bleeding effectively in 83%–100% of patients bleeding from peptic ulcers.[72–76] In a controlled trial by Laine multipolar EC could reduce transfusion requirements, hospital stay and mortality significantly.[77]

and safer than the Nd-YAG laser. Storey[84] found the heater probe to be more effective in checking bleeding from gastric than duodenal ulcers. The overall success rate in achieving hemostasis was 90%. Recent studies comparing the heater probe and ethanol injection found both to be equally effective in checking nonvariceal upper gastrointestinal hemorrhage.[85, 86]

43.4.5 Heater Probe

43.4.6 Laser

The heater probe is a transendoscopic thermal device which is relatively inexpensive and portable. It produces vessel coagulation with less tissue erosion than the other currently available thermal devices.[78, 79] It has an internal silicon chip controlled heating element linked to a computerized power source. Thermal energy is transferred by conduction through the probe tip at variable energy settings (5–30 Joules), each delivered as a 7 second pulse. The probe tip is Teflon coated, which reduces tissue adherence. The probe, through its proximal water port, allows continuous washing during tamponade which helps in assessing hemostasis. On an average, about seven applications per patient, delivered at a 25-J setting are needed to stop bleeding.[80] The advantage of the heater probe is its powerful washing facility, which improves visibility and allows accurate targeted therapy. It produces co-aptive coagulation and can be activated tangentially allowing better access to difficult areas. In the study by Jensen et al [81] and a recent Chinese study[82] significant benefits were noted with the heater probe, while another study reported borderline significance for re-bleeding, but no improvement in any other parameter.[80] Johnston et al achieved hemostasis in 95% of patients who presented with severe bleeding from peptic ulcers, using a heater probe.[83] In the same study, they concluded that the heater probe is more effective

Using an animal model it was shown that both neodymium–yttrium aluminium-garnet (NdYAG) laser and the argon laser [87, 88] could stop bleeding from peptic ulcers effectively and safely. Uncontrolled studies[87–89] showed that laser therapy could check gastrointestinal bleeding in humans. Later a controlled study also showed beneficial effects.[90] Rutgeerts and co-workers, however, found that the mortality rates were not influenced after Nd-YAG laser treatment, although there was a reduction in the rate of re-bleeding and in the need for surgery.[91] 43.4.6.1 Technique

Earlier, a triaxial quartz Nath fiber was introduced through the biopsy channel of the therapeutic gastroscope for transmission of laser power. Later, a flexible fiber with co-axial carbon dioxide jet became available. This could be introduced into the biopsy channel of any gastroscope. Short laser pulses (0.55 or I second) with power settings of 70–80 Watts are applied. The duration of the pulses is limited electronically. The lesions are cleaned with water before the laser is used. In high risk patients, intubation and general anesthesia may be used to prevent pulmonary complications. Keifliaber,[92] collating the entire international experience regarding endoscopic therapy for UGI bleeding, reported that bleeding could be checked

Tropical Hepatogastroenterology

MANAGEMENT OF SITE SPECIFIC BLEEDING

in 84% of patients treated with argon laser and 90% cases treated with Nd-YAG laser. The efficacy and safety of laser therapy for gastrointestinal hemorrhage has been reported in various controlled trials.[93–96] Trudeau[97] showed that Nd-YAG laser therapy reduced rebleeding, the need for urgent surgery, and improved the survival of patients with endoscopic stigmata of recent bleeding at ulcer base. A meta-analysis of all laser prospective controlled trials showed significant benefit in terms of the need for urgent surgery and mortality.[1] The laser equipment had a limited use in the past because of the expense, not being portable, needing considerable expertise, and because of some risk of perforation due to transmural injury. However, portable laser equipment is available now at a lower cost and this may permit a more widespread use of the modality.

43.5 MANAGEMENT OF SITE SPECIFIC BLEEDING 43.5.1 Peptic Ulcer Disease Peptic ulcer remains the commonest cause of upper gastrointestinal bleeding in the west accounting for 27%–40% of all bleeding episodes.[98] Duodenal ulcers are more common then gastric ulcers, but both varieties bleed with equal frequency.[99] In nearly 75% of cases, peptic ulcer bleeding, stops without therapeutic intervention. However, recurrent bleeding is associated with most instances of mortality.[100] Factors predicting rebleeding and mortality are age greater than 60 years, shock at admission, coagulopathy, active pulsatile bleeding, and concomitant cardiac disease.[4] Endoscopic hemostasis should be tried at the time of initial diagnostic endoscopy when peptic ulcer is diagnosed to be the cause of significant bleeding. Adjunctive medical therapy with

Part X / Special Topics

711

proton-pump inhibitors appears to be effective in decreasing re-bleeding from ulcer with an overlying blood clot or nonbleeding visible vessel.[102] Transcatheter angiographic embolization of the bleeding artery responsible for ulcer hemorrhage has a role in patients who fail at endoscopic methods of control or who are poor surgical candidates.[103] Randomized controlled trials comparing endoscopic therapy with traditional medical or surgical therapy for UGI bleeding from peptic ulcer with a nonbleeding visible vessel at endoscopy showed that endoscopic hemostatic therapy is associated with significantly less ulcer bleeding, transfusion requirements, and the need for emergency surgery.[114] The utility and limitations of endoscopic means of hemostasis should be understood while managing patients bleeding from peptic ulcers. Endoscopic interventions are effective in 95% of patients with actively bleeding peptic ulcers or ulcers with nonbleeding visible vessels. Rebleeding occurs in 4%–10% patients and 5%– 10% die. In two studies that analyzed factors predicting therapeutic failure of endoscopic hemostasis, ulcers > 2 cm and active bleeding at endoscopy were independent predictors of failure.[105, 106] 43.5.1.1 H. pylori and peptic ulcer bleeding

The discovery of H. pylori in 1993 revolutionized the management of peptic ulcers changing the life history of ulcer from a disease with remissions and relapses to one that could be completely cured. Anti-H. pylori therapy should be given to all patients with peptic ulcer bleeding to prevent rebleeding and recurrence of ulcer disease.[107, 108] Proton pump inhibitors started being used in 1989 and were found to heal gastritis, duodenitis, erosions, and nearly all ulcers. They are strongly recommended to be used concomitantly with nonsteroidal anti-inflammatory drugs or aspirin to prevent ulcer recurrence and complications.[109]

712

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

43.5.2 Hemorrhagic Gastritis The superficial ulcerations associated with hemorrhagic gastritis usually do not manifest as life-threatening hemorrhage.[110] However, when coagulopathy accompanies cirrhosis and portal hypertension, mucosal bleeding can be brisk and refractory to all measures except those that decrease portal venous pressure.[111] Endoscopic therapy maybe useful for multiple punctate bleeding sites, but with diffuse mucosal hemorrhage selective intra-arterial infusion of vasopressin may control bleeding in nearly 75% of cases.[111] Recently, argon plasma coagulation with its ability to coagulate superficially has proved useful in checking bleeding from superficial lesions. In the rare case when surgery is needed to check bleeding in diffuse gastritis, total gastrectomy is the most effective procedure, though it carries a high morbidity and mortality. Surgical intervention should be the last resort in hemorrhagic gastritis because it has a mortality of 40%–55%.[111]

43.5.3 Mallory–Weiss Tears This accounts for bleeding in nearly 15% of upper gastrointestinal hemorrhage and is associated with coughing, retching, vomiting, or straining. Bleeding is usually mild except in 3%–4% cases where, due to presence of portal hypertension in cirrhotic patients the bleeding may be exsanguinating and may contribute to mortality. The tear may be entirely in the stomach, and in the majority of patients endoscopic means of hemostasis such as sclerotherapy, banding or hemoclip application are effective in cases with active bleeding, protuberant vessel or clot overlying the tear.[112, 113] However, in another study where endoscopic hemostasis was attempted in patients with Mallory–Weiss tears, 24% followed a complicated course. In these patients, a low hematocrit at admission and active

bleeding at endoscopy were important factors accounting for the complications.[114] Re-bleeding is rare after intervention.

43.5.4 Dieulafoy’s Lesion Dieulafoy’s lesion is a vascular malformation typically occurring in the proximal gastric corpus. It is prone to ulceration and upper gastrointestinal hemorrhage. Due to the large size of the sub-mucosal artery, the bleeding is brisk and life threatening. The typical lesion is seen on the lesser curvature within 6 cm of the gastroesophageal junction.[115] In this condition, an erosion is present in the mucosa overlying the aberrant large caliber submucosal artery, with focal necrosis and rupture of the artery at the base of the erosion. When an experienced endoscopist fails to identify a bleeding site in the setting of massive upper gastrointestinal bleeding Dieulafoy’s disease should be considered. Stark et al [116] showed that the majority of patients with this disease were elderly men. Multiple endoscopies were needed in 37% of cases to detect the source of bleeding. The lesions were seen in the proximal stomach in 79% and in the duodenal bulb in 21% of patients. Endoscopic therapy to check bleeding in the form of epinephrine injection followed by heater probe coagulation was successful in 95% of patients. One patient each needed bipolar coagulation and Nd:YAG laser photocoagulation. Asaki et al [117] reported successful endoscopic therapy in 98% of 45 patients treated with ethanol injection sclerotherapy. Histacryl glue has also been used successfully to check bleeding from these lesions.[118] Recently, banding and the use of hemoclips has been shown to be very effective in producing hemostasis in Dieulafoy ulcer bleeding.[62] In case of failure of endoscopic means of hemostasis, surgical wedge resection of the ulcerated vascular lesion is the safest course.[119]

Tropical Hepatogastroenterology

RISK ASSESSMENT IN UGI BLEEDING

Alternatively, with endoscopic guidance, laparoscopic ligation of the feeding vessel may be done.

43.5.5 Angiodysplasia These lesions account for UGI bleeding in 2%–4% cases. Usually they are seen in elderly patients with chronic renal failure or aortic stenosis.[120] However, in hereditary hemorrhagic telangiectasia, the lesions are congenital.[121] The lesions are usually less then 1 cm, multiple and present with occult blood loss. The argon plasma coagulator is very effective in checking bleeding from these small superficial lesions.

43.6 RISK ASSESSMENT IN UGI BLEEDING The mortality of UGI bleeding has stood stubbornly at 10%–15% over the last fifteen years, in spite of the revolution in the endoscopic means of hemostasis which has taken place. Closer scrutiny shows that there is a general shift in the mean age of the patients presenting with UGI bleeding.[122] This offsets the advantage of better means of endoscopic hemostasis. The risk of re-bleeding after endoscopic hemostasis is around 20%–25%, irrespective of the endoscopic modality used in management. Apart from the age and comorbidity, it is the re-bleeding which determines the outcome of UGI bleeding. Rockall estimated that the mortality with UGI bleeding rises to 40%–50% with a high risk score and re-bleeding.[123, 124]

43.7 SECOND LOOK ENDOSCOPY This should be carried out after endoscopic hemostasis as it decreases rebleeding and mortality. Villanueva et al performed second look

Part X / Special Topics

713

endoscopy after 24 hours and retreated if necessary.[125] This reduced the re-bleeding from 15% to 8% and mortality from 4% to 2%. They concluded that immediate endoscopic retreatment of early recurrent bleeding nearly always results in definitive hemostasis. Lau and co-workers reported a higher morbidity after surgical treatment of rebleeding as compared to endoscopic management.[126]

43.8 INTERVENTIONAL RADIOLOGY Despite the improvements in endoscopic accessories and fiberoptic endoscopes, a subset of patients with UGI bleeding need radiology for diagnosis and therapy (Table 43.5). These cases are best managed by a team approach including a radiologist, gastroenterologist, and surgeon. UGI endoscopy is normal in 10% cases of UGI bleeding.[127] Radiological techniques are specially useful for bleeding beyond the ligament of Treitz. Enteroscopy is available only at tertiary centres, needs considerable expertise, and has a moderate sensitivity. A preoperative angiography greatly reduces the morbidity and mortality of surgery for GI bleeding, when preoperative endoscopy is normal.[128] Endoscopic means of hemostasis may fail in 10%–20% cases.[129, 130] In this situation, interventional radiology may be a nonoperative means to

TABLE fy 43.5 Conditions where radiology is needed in diagnosis and treatment of UGI bleeding • • • •

When bleeding site is obscure-endoscopic evaluation normal Massive bleeding Bleeding refractory to endoscopic treatment Bleeding associated with mass

714

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

check bleeding. Radionuclide scanning with technetium 99 m (Tc-99 m) sulfur colloid or Tc99 m labeled erythrocytes is used to localize mild to moderate intermittent bleeding. Superselective angiographic catheterization and microcoil embolization are used to diagnose and treat acute UGI bleeding. The minimal bleeding rate for angiographic detection is approximately 0.5 ml/minute; however, the optimum sensitivity of angiography is when the bleeding rate is 1 ml/minute, equivalent to 3 units/day.[131] Angiography is best postponed when bleeding has stopped. Angiography may be bypassed and the patient sent directly to surgery for massive bleeding especially when the patient is in shock. Angiography is particularly useful in identifying angiodysplasia, pseudoaneurysms associated with pancreatitis or pancreatic pseudocysts, and early postoperative upper gastrointestinal bleeding.[132] Therapeutic angiography is the procedure of choice in the frail, severely ill patient who is a poor surgical risk but is also offered to all acute GI bleeders who continue to bleed after therapeutic endoscopy. It is particularly indicated when active bleeding is seen during angiography as contrast extravasations. Selective intra-arterial vasopressin may be used before arterial embolization. Arterial embolization is safe in the UGI tract due to the rich arterial collateral supply.[133] The entire arterial supply to an area of hemorrhage is evaluated angiographically before embolization so that even collateral vessels feeding the area of hemorrhage may be embolized. The catheter is positioned as close to the site of extravasation as possible for embolization. The embolic materials currently considered most efficacious are microcoils, either alone or with gelatin sponge pledgets or polyvinyl alcohol particles (diameter 355 to 500 microns).[134] For successful embolization, trained interventional

radiologists and state of the art radiological equipment is needed. Complications of embolotherapy are gastric necrosis, duodenal stricture, splenic abscess, gangrenous cholecystitis, pancreatitis, pancreatic necrosis, and liver necrosis.[135–138]

43.9 SURGICAL INTERVENTION IN UGI BLEEDING The indications for surgical intervention in peptic ulcer bleeding are (1) severe hemorrhage unresponsive to initial resuscitative measures, (2) failure or unavailability of endoscopic or other nonsurgical therapies to control persistent or recurrent bleeding, and (3) perforation or obstruction as a complication of peptic ulcer.[140] Nearly 10%–12% patients with acute ulcer hemorrhage still need surgical intervention to achieve hemostasis.[140] This carries a mortality of 15%– 25%,[141, 142] The type of surgery carried out for peptic ulcer bleeding depends on the location, size and anatomy of ulcer as well as the age and condition of the patient. Suture ligation of the bleeding artery together with some form of vagotomy is indicated for duodenal ulcer hemorrhage. The various operations carried out for duodenal ulcer bleeding include the following: 1. Truncal vagotomy, duodenotomy with suture ligation of the bleeding ulcer, and a drainage procedure (gastrojejunostomy or pyloroplasty) 2. Truncal vagotomy and antrectomy with resection or suture ligation of ulcer Bleeding gastric ulcer is most often managed surgically by distal gastrectomy that includes the ulcer.[143] The various operative interventions carried out are as follows:

Tropical Hepatogastroenterology

REFERENCES

1. Truncal vagotomy and gastrojejunostomy/ pyloroplasty with wedge excision of ulcerbearing gastric wall 2. Truncal vagotomy and antrectomy, with wedge excision of ulcer if not included in the antrectomy 3. Distal gastrectomy to include ulcer with or without truncal vagotomy

715

4. Wedge excision of ulcer. Pyloric channel and prepyloric ulcers warrant vagotomy as they are associated with hypersecretory states as duodenal ulcer patients.[143] Laparoscopic wedge resection of a greater curve gastric ulcer can be accomplished and is helped by intraoperative localization of the ulcer site.

REFERENCES [1] Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331:717–27. [2] Silverstein FE, Gilbert DA, Tedesco FJ et al. The national ASGE survey on upper gastrointestinal bleeding. Gastrointest Endosc 1981;27:73–103. [3] Fleischer D. Endoscopic haemostasis in nonvariceal bleeding. Endoscopy 1992;24:58–63. [4] Lieberman D. Gastrointestinal bleeding: Initial management. Gastroenterol Clin North Am 1993; 22:723–736. [5] Talbot–Stem JK. Gastrointestinal bleeding. Emerg Med Clin North Am 1996;14:173–184. [6] Abou–Khalil B, Scalea TM, Trooskin SZ et al. Hemodynamic responses to shock in young trauma patients: Need for invasive monitoring. Crit Care Med 1994;22:633–639. [7] Ebert RV, Stead EA Jr, Gibson JG Jr. Response of normal subjects to acute blood loss, with special reference to the mechanism of the restoration of blood volume. Arch Intern Med 1941;68:578–590. [8] Richards RJ, Donica MB, Grayer D. Can the blood urea nitrogen/creatinine ratio distinguish upper from lower gastrointestinal bleeding? J Clin Gastroenterol 1990;12:500–4. [9] Cappell MS. A study of the syndrome of simultaneous acute upper gastrointestinal bleeding and myocardial infarction in 36 patients. Am J Gastroenterol 1995;90:1444–9. [10] Cuellar RE, Gavaler JS, Alexander JA et al. Gastrointestinal tract hemorrhage: The value of a

Part X / Special Topics

[11]

[12] [13]

[14]

[15]

[16]

[17] [18]

[19]

nasogastric aspirate. Arch Intern Med 1990;150: 1381–4. Gilbert DA, Silverstein FE, Tedesco FJ et al. The national ASGE survey on upper gastrointestinal bleeding: 111. Endoscopy in upper gastrointestinal bleeding. Gastrointest Endosc 1981;27:94–103. Hawkey CJ. Nonsteroidal anti-inflammatory drugs and peptic ulcers. BMJ 1990;300:278–84. Laine L. Multipolar electrocoagulation in the treatment of active upper gastrointestinal tract hemorrhage. N Engl J Med 1987;316:1613–7. Kankaria AG, Fleischer DE. The critical care management of nonvariceal upper gastrointestinal bleeding. Crit Care Clin 1995;11:347–68. Cappell MS. Intestinal (mesenteric) vasculopathy: I. Acute superior mesenteric arteriopathy and venopathy. Gastroenterol Clin North Am 1998;27:783–825. Levinsky RA, Lewis RM, Bynum TE et al. Digoxin induced intestinal vasoconstriction. Circulation 1997;52:130–36. Ermakov S, Hoyt JW. Pulmonary artery catheterization. Crit Care Clin 1992;8:773–804. Kruskall MS, Mintz PD, Johnston MFM et al. Transfusion therapy in emergency medicine. Ann Emerg Med 1988;17:327–8. Hogue CW, Goodnough LT, Monk TG. Preoperative myocardial ischemic episodes are related to hematocrit levels in patients undergoing radical prostatectomy. Transfusion 1998;38:924–31.

716

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

[20] Lichtenstein Dr, Berman MD, Wolfe MM. Approach to the patient with acute upper gastrointestinal hemorrhage. In Taylor MB, Gollan JL, Steer ML et al (eds) Gastrointestinal Emergencies, ed 2. Baltimore, Williams & Wilkins 1997; pp 99–129 [21] Wiesen AR, Hospenthal DR, Byrd JC et al. Equilibration of hemoglobin concentration after transfusion in medical inpatients not actively bleeding. Ann Intern Med 1994;121:278–280. [22] Blair SD, Janvrin SB, McCollum CN et al. Effect of early blood transfusion on gastrointestinal hemorrhage. Br J Surg 1986;73:783–785. [23] Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfusion. Transfusion Med Rev 1988;2:76–94. [24] Conteras M. Final statement from the consensus conference on platelet transfusion. Transfusion 1998;38:796–797. [25] Marriott HL, Kekwick A. Volume and rate in blood transfusion for the relief of anaemia. BMJ 1940;1:1043–1046. [26] Snyder EL. Transfusion reactions. In Hoffman R, Benz EJ Jr, Shattil SJ et al (eds): Hematology: Basic Principles and Practice, et 2. New York, Churchill Livingstone, 1995, pp 2045–2053. [27] Khuroo MS, Yatto GN, Javid G et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997;336:1054–8 [28] Lin HJ, Lo WC, Lee FY et al. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998;158: 54–58. [29] Jenkins SA, Poulianos G, Goraggio F et al. Somatostatin in the treatment of non variceal upper gastrointestinal bleeding. Dig Dis Sci 1998;16: 214–24. [30] Imperiale TF, Birgisson S. Somatostatin or octreotide compares with H2 antagonists and variceal upper gastrointestinal haemorrhage: a metaanalysis. Ann Intern Med 1997;127:1062–71.

[31] Sommerville KW, Henry DA, Davies JG et al. Somatostatin in treatment of haematemesis and melena. Lancet 1985;1:130–2. [32] Kipolletta L, Bianco MA, Rotondano G et al. coagulator and heater probe in the endoscopic treatment of major peptic ulcer bleeding. Gastrointest Endosc 1998;48:191–5. [33] Crafoord C, Frenckner P. New surgical treatment of varicose veins of the oesophagus. Acta Otolaryngol 1939;27:422–9. [34] Chung SCS, Leung JWC, Steele RJC et al. Endoscopic injection of adrenaline for actively bleeding ulcers: A randomised trial. Br Med J 1988;296:1631–3. [35] Chiozzini G, Bortoluzzi F, Pallini P et al. Controlled trial of absolute ethanol Vs. epinephrine as injection agent in gastroduodenal bleeding. Gastroenterology 1989;96:A86. [36] Ujiie T, Ikeda S. Studies on intramural stomach injections under direct gastrofiberscope observation. Proceedings of the Second World Congress of Gastrointestinal Endoscopy in Rome and Copenhagen. Italy Piccin Medical 1970; 197–202. [37] Akasaka Y, Kawai K, Toriic S et al. Endoscopical local injection method for cancer and polypous lesion. J Kyoto Prefect Univers Med 1972;81: 365–82. [38] Otani T, Tatsuka T, Kanamaru K et al. Intramural injection of ethanol under direct vision for the treatment of protuberant lesions of the stomach. Gastroenterology 1975:69:123–9. [39] Asaki S. Tissue solidification in coping with digestive tract bleeding. Hemostatic effect of local injection of 99.5% alcohol. Tohoku J Exp Med 1981:134:223–7. [40] Sugawa CH, Fujita Y, Ikeda T et al. Endoscopic haemostasis of bleeding of the upper gastrointestinal tract by local injection of ninety–eight percent dehydrated ethanol. Surg Gynecol Obstet 1986;162:159–63. [41] Hajiro K. Japanese experience with local injection and hemoclips. Symposium on Endoscopy in Upper GI Bleeding. The XII International Gastroenterology Congress. The V European

Tropical Hepatogastroenterology

REFERENCES

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

Gastrointestinal Endoscopy Congress. Lisbon, September 1984. Soehendra N, Knipper A. Endoskopische Unterspritzung zur Blutstillung in Verdauunngstrakt. Dtsch Med Wochenschr 1977;102:1688. Soehendra N. Results in sclerosing of bleeding ulcers. Workshop Traunstein. European Laser Association. Traunstein, Germany, November 1984. Wordehoff D, Gross E. Endoscopic haemostasis by injection-therapy in high risk patients. Endoscopy 1982;14:196–9. Lin HJ, Huang ZC, Wang YC et al. Endoscopic injection for arrest of peptic ulcer hemorrhage: A prospective, randomized controlled trial. Gastroenterology 1990;78:A78. Chung SCS, Leong HT, Chen ACW et al. Epinephrine or epinephrine plus alcohol for injection of bleeding ulcer. Gastrointest Endosc 1996; 43:591–595. Panes J, Viver J, Forne M et al. Controlled trial of endoscopic sclerosis in bleeding peptic ulcers. Lancet 1987;2:1292–8. Koyama T, Fujimoto K, Iwakiri R et al. Prevention of recurrent bleeding from gastric ulcer with a nonbleeding visible vessel by endoscopic injection of absolute ethanol: a prospective, controlled trial. Gastrointest Endosc 1995;42:128–31. Koyama T, Fujimoto K, Iwakiri R et al. Endoscopic injection of absolute ethanol achieves ultimate haemostasis in bleeding caused by peptic ulcer. Digestive Endoscopy 1984;6:34–8. Leveen HH, Diag C, Falk C et al. A proposed method to interrupt gastrointestinal bleeding: preliminary report. Ann Surg 1972;175:459–69. Rutgeerts P, Geboes K, Vantrappen G. Experimental studies of injection therapy for severe nonvariceal bleeding in dogs: a prospective randomized trial. Gastroenterology 1989;98:610–21. Chung SCS, Leung JWC, Galvrna M et al. The effect of submucosal adrenaline on blood loss from standard bleeding ulcers. Gut 1987;128:A 1402. Rutgeerts P, Vantrappen G, Broeckaert L et al. Comparison of endoscopic polidocanol injection

Part X / Special Topics

[54]

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64]

717

and YAG laser therapy for bleeding peptic ulcers. Lancet 1989;1:1164–66. Rutgeerts P, Gevers AM, Hiele M et al. Injection therapy for prevention of rebleeding from peptic ulcers with protruding vessel: Which method is best? Gastroenterology 1990;98;Al 15. Rajgopal C, Palmer KR. Endoscopic injection sclerosis: Effective treatment for bleeding peptic ulcer. Gut 1991;32:727–9. Hayashi J. The study of endoscopic staunching clips for bleeding of the exposed vessel end of the ulcer. In: Endoscopic surgery. Okabe M, Honda T, Oshiba S. eds. New York: Elsevier. 1984; 117–24. Soehendra N. Endoscopic management of nonvariceal upper gastro intestinal bleeding. In: Therapeutic endoscopy at the end of this millennium Calcutta Art Printing House. Ed. Goenka MK, Das K. 1999;45–53. Ohta S, Yukioka T, Ohta S. Hemostasis with endoscopic hemoclipping for severe gastrointestinal bleeding. Endoscopy 1993;25:167–70. Nagasu N, DiPalma JA. Bleeding ulcer: inject or clip? Am J Gastroenterol 1998;93:1998. Nagayama K, Tazawa J, Sakai Y et al. Efficacy of endoscopic clipping for bleeding gastroduodenal ulcer: comparison with topical ethanol injection. Am J Gastroenterol 1990;94:2897–2901. Chung IK, Ham JS, Kim HS et al. Comparison of the hemostatic efficacy of the endoscopic hemoclip method with hypertonic saline-epinephrine injection and a combination of the two for the management of bleeding peptic ulcers. Gastrointest Endosc 1999;49:13–18. Yamaguchi Y, Yamato T, Katsumi N et al. Short term and long term benefits of endoscopic hemoclip application for Dieulafoy’s lesion in the upper G.I. tract. Gastrointest Endosc 2003;57: 653–6. Escourou J, Delvaux M, Buscail L et al. First clinical evaluation and experimental study of a new mechanical suture device for endoscopic hemostasis. Gastrointest Endosc 1990;36:494–7. Freitas D, Donto A, Monteiro JG. Controlled trial of liquid monopolar electro-coagulation in

718

[65]

[66] [67]

[68]

[69]

[70]

[71]

[72]

[73] [74]

[75]

[76]

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

bleeding peptic ulcers. Am J Gastroenterol 1985; 80:853–7. Moeto M, Zabalan M, lbranez S et al. Efficacy of monopolar electrocoagulation in the treatment of bleeding gastric ulcer: a controlled trial. Endoscopy 1987;19:54–56. Siegel B, Hathe FL. Physical factors in electrocoaptation of blood vessels. Arch Surg 1967;95:54–58. Morris DL, Brearley S, Thompson H et al. A comparison of the efficacy and depth of gastric wall injury with 3.2 and 2.3 mm bipolar probes in canine arterial haemorrhage. Gastrointest Endosc 1985;31:361–3. Johnston JH, Jensen DM, Anth D. Experimental comparison of endoscopic ytrriurn – alumuniumgarnet laser, electrosurgery and heater probe for canine gut arterial coagulation: importance of compression and avoidance of erosion. Gastroenterology 1987;92:1101–8. Swain CP, Storey DW, Bown SG et al. Nature of the bleeding vessel in recurrently bleeding gastric ulcers. Gastroenterology 1986;90:595–608. Laine L. Multipolar electrocoagulation in the treatment of peptic ulcers with nonbleeding visible vessels. A prospective, controlled trial. Ann InternMedicine 1989;110:510–514. Brearley S, Morris DL, Hawker PC et al. Preendoscopic bipolar diathermy coagulation of visible vessels using a 3.2 mm. probe-a randomized clinical trial. Endoscopy 1987;19:160–3. Jensen DM, Machicado GA, Silpa ML. Argon laser vs. heater probe or BICAP for control of severe ulcer bleeding. Gastrointest Endosc 1984; 30:134. Jessen K. BICAP control of UGI bleeding. Z Gastroenterol 1983;21:268–71. Hajiro K, Yamamoto H, Matsui H et al. Endoscopic bipolar electrocoagulation in upper gastrointestinal bleeding. Endoscopy 1984;16:6–9. Donahue PE, Moberhan S, Layder TJ et al. Endoscopic control of upper gastrointestinal hemorrhage with a bipolar coagulation device. Surg Gynecol Obstet 1984;159:113–8. Winkler WP, Comer G, McCray RS. Initial experience with BICAP multipolar probe electrocautery

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

in the control of upper gastrointestinal hemorrhage.Gastrointest Endosc 1983;29:169. Laine L. Multipolar electrocoagulation in the treatment of active upper gastrointestinal haemorrhage: a prospective controlled trial. N Engl J Med 1987;316:1613–7. Protel RL, Rubin CE, Auth DC et al. The heater probe: a new endoscopic method for stopping massive gastrointestinal bleeding. Gastroenterology 1978;74:257–62. Swain CP, Mills TN, Shemesh E et al. Which electrode? A comparison of four endoscopic methods of electrocoagulation in experimental bleeding ulcers. Gut 1984;25:1424–43. Fullerton GM, Birnie GG, Macdonald A et al. Controlled trial of heater probe treatment in bleeding peptic ulcers. Br J Surg 1989;76:541–4. Jensen DM, Dovacs TOG, Freeman M et al. A multicenter randomized prospective study of gold probe versus heater probe for haemostasis of very severe ulcer or Mallory–Weiss bleeding. Gastroenterology 1991;100:A92. Lin HJ, Lee FY, Kang WM et al. Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer haemorrhage: A prospective, randomized controlled trial. Gut 1990;31:753–7. Johnston JH, Sones JQ, Long BW et al. Comparison of the heater probe and YAG laser in endoscopic treatment of major bleeding from peptic ulcers. Gastrointest Endosc 1985;31: 175–81. Storey DW. Endoscopic control of peptic ulcer haemorrhage using the heater probe. Gut 1983;24: A967. Saeed ZA, Winchester CB, Patrice RN et al. A scoring system to predict rebleeding after endoscopic therepy in nonvariceal upper gastrointestinal haemorrhage, with a comparison of heat probe and ethanol injection. Gastrointest Endosc 1983;88: 1842–1849. Liach J, Bordas JM, Salmeron JM et al. A prospective randomized trial of heater probe thermocoagulation versus injection therapy in peptic ulcer haemorrhage. Gastrointest Endosc 1986;43:117–20.

Tropical Hepatogastroenterology

REFERENCES

[87] Kiefliaber P, Nath G, Moritz K. Endoscopical control of massive gastrointestinal haemorrhage by irradiation with a high power neodymium. YAG laser. Prog Surg 1977;15:140–55. [88] Silverstein FE, Portall RL, Gubert DA et al. Argon vs neodymium-YAG laser photocoagulation of experimental canine gastric ulcer. Gastroenterology 1979;77:419–26. [89] Lawrence BH, Vallon AG, Cotton PB et al. Endoscopic laser photocoagulation for bleeding peptic ulcers. Lancet 1980;I:124–5. [90] Vallon AG, Cotton PB, Laurence BM et al. Randomized trial of endoscopic laser photocoagulation in bleeding peptic ulcer. Gut 1981;22:228–33. [91] Rutgeerts P, Vantrappen G, Broecbaert L et al. Controlled trial of YAG laser treatment of upper digestive haemorrhage. Gastroenterology 1992;83:410– 416. [92] Kiefhaber P. International experience with LASERs for gastrointestinal bleeding. Proceedings of the International Laser Congress. Detroit, 1979. [93] Swain CP, Storey DW, Northfield TC, et al. Controlled trial of argon laser photocoagulation in bleeding peptic ulcers. Lancet 198 1;ii:1313–6. [94] Escourrou J. NdYAG laser therapy for acute gastrointestinal haemorrhage. In: Atsumi, Nimsakul, eds. Laser. Tokyo: Intergroup Corp. 1981. [95] Ihre T, Johansson C, Seligsson U et al. Endoscopic YAG laser treatment in massive UGI bleeding. Scand J Gastroenterol 1981;16:633–40. [96] Fleischer D. Endoscopic laser therapy for upper gastrointestinal tract disease. Surg Dig Dis 1983;1:42–53. [97] Rudeau W, Siepler JK, Ross K et al. Endoscopic neodymium: YAG laser photocoagulation of bleeding ulcers with visible vessels. Gastrointest Endosc 1985;31:138–44. [98] Steffes C, Fromon D. The current diagnosis and management of upper gastrointestinal bleeding. Adv Surg 1992;25:331–61. [99] Sugawa C, Steffas CP, Nakamawra R et al. Upper GI bleeding in an urban hospital. Ann Surg 1990;212:521–6.

Part X / Special Topics

719

[100] Lau JY, Sung JJ, Lam YH et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999;340:751–756. [101] Wara P. Endoscopic prediction of major rebleeding – a prospective study of stigmata of haemorrhage in bleeding ulcer. Gastroenterology 1985;88:1209–14. [102] Lin HJ, Lo WC, Lee FY et al. A prospective randomized prospective trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998;158:54–58. [103] Hamlin JA, Peterson B, Keller PS et al. Angiographic evaluation and management of nonvariceal upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am 1997;7:703–16. [104] Rockall TA, Logan RFA, Devlin HB et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–321. [105] Wong SK, Yu LM, Lau JY et al. Prediction of therapeutic failure after adrenaline injection plus heater probe treatment in patients with bleeding peptic ulcer. Gut 2002;50:322–325. [106] Chung IK, Kim EG, Lee MS et al. Endoscopic factors predisposing to re-bleeding following endoscopic hemostasis in bleeding peptic ulcers. Endoscopy 2001;33:969–975. [107] Labenz J, Borsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J Gastroenterol 1994;89: 1785–8. [108] Lai KC, Hui WM, Wong WM et al. Treatment of Helicobacter pylori in patients with duodenal ulcer hemorrhage – a long term randomized, controlled study. Am J Gastroenterol 2000;95:2225–32. [109] Lai KC, Lam SK, Chu KM et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033–8. [110] Peterson WL, Laine L. Gastrointestinal bleeding. In Sleisenger MH, Fordtran JS(eds): Gastrointestinal Disease. Philadelphia, WB Saunders, 1993.

720

Chapter 43 / NONVARICEAL UPPER GASTROINTESTINAL TRACT BLEEDING

[111] Johansen K, Helton WC. Efficacy of selective splanchnic arteriography and vasopressin perfusion in diagnosis and treatment of gastrointestinal hemorrhage. Am J Surg 1976;131:481–84. [112] Bharucha AE, Gostout CJ, Balm RK. Clinical and endoscopic risk factors in the Mallory–Weiss syndrome. Am J Gastroenterol 1997;92:805–8. [113] Dwivedi M, Misra SP. Mallory–Weiss Syndrome: Clinical features and management JAPI 1999;47:397–399. [114] Kortas DY, Haas LS, Simpson WG et al. Mallory– Weiss tear: predisposing factors and predictors of a complicated course. Am J Gastroenterol 2001; 96:2863–2865. [115] Vekdhuyzen Van Zanten SJO, Bartelsman JFWM, Schipper MEI et al. Recurrent massive hematemesis from Dieulafoy vascular malformations – a review of 101 cases. Gut 1986;27:213. [116] Stark ME, Gostout CJ, Balm RK. Clinical features and endoscopic management of Dieulafoy’s disease. Gastrointest Endosc 1992;38;545–550. [117] Asaki S, Sato H, Nishimura T et al. Endoscopic diagnosis and treatment of Dieulafoy’s ulcer. Toboku J Exp Med 1988;154:135–41. [118] Loperfido S. Endoscopic haemostasis of gastric bleeding from Dieulafoy’s ulcer with histoacryl. Endoscopy 1989;21:199–200. [119] Bech–Knudsen F, Toftgaard C. Exulceratio simplex Dieulafoy. Surg Gynecol Obstet 1993;176: 139–43. [120] Gilmore PR. Angiodysplasia of the upper gastrointestinal tract. J Clin Gastroenterol 1988;10:386–97. [121] Steffes C, Fromm D. The current diagnosis and management of upper gastrointestinal bleeding. Adv Surg 1992;25:31–61. [122] Rockall TA, Logan RF, Devlin HB et al. Incidence of and mortality from acute upper gastrointestinal hemorrhage in the United Kingdom. Steering committee and members of the national audit of acute upper gastrointestinal hemorrhage. BMJ 1995;311:222–226. [123] Rockall TA, Logan RFA, Devlin HB et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–321.

[124] Tockall TA, Logan RFA, Devlin HB et al. Selection of patients for early discharge or outpatient care after acute upper gastrointestinal hemorrhage. Lancet 1996;347:1138–1140. [125] Villanueva C, Balanzo J, Torras X et al. Value of second-look endoscopy after injection therapy for bleeding peptic ulcer: a prospective and randomized trial. Gastrointest Endosc 1994;40: 34–39. [126] Lau JY, Sung JJ, Lam YH et al. Endoscopic retreatment compared with surgery in-patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. NEJM 1999;340:751–6. [127] Lieberman D. Gastrointestinal bleeding: Initial management. Gastroenterol Clin North Am 1993;22:723–726. [128] Retzlaff J, Hagedorn A, Bartholomen L. Abdominal exploration for gastrointestinal bleeding of obscure origin. JAMA 1961;177:104–107. [129] Hajiro K, Yamamoto H, Matsui H et al. Endoscopic bipolar electrocoagulation in upper gastrointestinal bleeding. Endoscopy 1984;16:6–9. [130] Kovacs TOG, Jensen DM. Therapeutic endoscopy for nonvariceal upper gastrointestinal bleeding. In Taylor MB, Gollan JL, Steer ML et al (eds): Gastrointestinal Emergencies, ed 2. Baltimore, Williams & Wilkins, 1997, pp 181–198. [131] Porter DH, Kim D. Angiographic intervention in upper gastrointestinal bleeding. In Taylor MB, Gollan JL, Steer ML et al (eds): Gastrointestinal Emergencies, et 2. Baltimore, Williams & Wilkins, 1997, pp 163–180. [132] Valji K. Vascular and Interventional Radiology. Philadelphia, WB Saunders, 1999. [133] Ledermann HP, Schoch E, Jost R et al. Superselective coil embolization in acute gastrointestinal hemorrhage: Personal experience in 10 patients and review of the literature. J Vasc Interv Radiol 1998;9:753–760. [134] Rosch RJ, Sanchez G. Angiographic diagnosis and management of gastrointestinal hemorrhage: Current concepts. Radiol Clin North Am 1994;32: 951–967. [135] Goldman ML, Land WC Jr, Bradley EL et al. Transcatheter therapeutic embolization in the

Tropical Hepatogastroenterology

REFERENCES

[136]

[137]

[138]

[139]

management of massive upper gastrointestinal bleeding. Radiology 1976;120:513–521. Lang EK. Transcatheter embolization in management of hemorrhage from duodenal ulcer: Long term results and complications. Radiology 192;182:703–707. Bell SD, Lau KY, Sniderman KW. Synchronous embolization of the gastroduodenal artery and the inferior pancreaticoduodenal artery in patients with massive duodenal hemorrhage. J Vasc Interv Radiol 1995;6:531–536. Hidalgo F, Narvaez JA, Rene M et al. Treatment of hemobilia with selective hepatic artery embolization. J Vasc Interv Radiol 1995;6:793–798. Stabile BE. Current surgical management of duodenal ulcers. Surg Clin North Am 1992;72:335–38.

test

Part X / Special Topics

721

[140] Rockall TA. Management and outcome of patients undergoing surgery after acute upper gastrointestinal haemorrhage. Steering Group for the national audit of acute upper gastrointestinal hemorrhage. J R Soc Med 1998;91:519–21. [141] Kubba AK, Choudari C, Rajgopal C et al. The outcome of urgent surgery for major peptic ulcer haemorrhage following failed endoscopic therapy. Eur J Gastroenterol Hepatol 1996;8:1175–8. [142] Qvist P, Arnesan KE, Jacobsen CD et al. Endoscopic treatment and restrictive surgical policy in the management of peptic ulcer bleeding: Five years’ experience in a central hospital. Scand J Gastroenterol 1994;29:569–76. [143] Jordon PH Jr. Surgery for peptic ulcer disease. Curr Prob Surg 1991;28:265.

Chapter

44 LOWER GASTROINTESTINAL BLEEDING Girish SP and PK Mishra

Lower gastrointestinal (LGI) bleeding is bleeding that originates beyond the ligament of Treitz. Even though the incidence is much less compared to upper gastrointestinal (GI) bleed, it is not uncommon in general practice. Most patients with LGI bleed have a self limiting course but 10%–25% of patients may have continued bleeding requiring surgical intervention, and may have considerable morbidity and mortality. The spectrum of lesions causing lower gastrointestinal hemorrhage shows marked geographic variation. Prompt assessment and resuscitation is the initial management goal followed by definitive investigation and treatment. Unlike upper GI bleeding, the preoperative localization of source of bleed is the key to successful management. The following review describes the broad outline of management of LGI bleeding, its etiology, and evaluation. It highlights the differences in the western and Indian reports in terms of etiology, distribution of source of bleeding, and management principles.

44.1 INCIDENCE AND EPIDEMIOLOGY There is no population based study that describes the true overall incidence of LGI bleeding. In hospital based studies, the incidence is about 1% of the hospital admissions. Vernava and colleagues 722

reported in their review of 17, 941 patients that patients with lower GI bleeding comprised only 0.7% of all hospital admissions.[1] There are few Indian studies reporting on the incidence in adults as well as in children.[2, 3] In a study from Delhi, there were only 90 patients needing surgery over a period of 17 years. In another study from three army hospitals, there were 91 patients from an 11year experience. With the above data it is difficult to come to a conclusion on the Indian incidence of the disease. However, these studies highlight the difference in presentation and need for different management protocol for this disease in the Indian patients compared to the west. The average age of presentation of LGI bleed in western population is 70 years but in the Indian population, it is about 40 years.

44.2 ETIOLOGY The causes of LGI bleeding vary in different parts of the world (Table 44.1). They also vary in different age groups. The causes can be broadly classified into anatomical, vascular, inflammatory, and neoplastic. More commonly, etiologies are classified according to the frequency of occurrence. The small bowel as a source of bleeding accounts for less than 3%–5% of lower GI bleeding, but because of its length

ETIOLOGY

723

TABLE fy 44.1 Causes of LGI bleeding Systemic • Coagulopathy • Drugs-Anticoagulants, NSAIDs • Henoch–Schonlein purpura • Hereditary hemorrhagic telangiectasia Localized • Angiodysplasia • Aortoenteric/Aortocolic fistula • Colonic duplications • Diverticulosis • Endometriosis • Fissures • Hemangioma • Hemorrhoids • Ischemic enteritis/colitis • Idiopathic ulcers • Intussusception • Inflammatory bowel disease • Infection-Tuberculosis, typhoid, amoebiasis • Meckel’s diverticulum • Nonspecific proctitis • Polyps and polypectomy • Radiation enteritis • Solitary rectal ulcer syndrome • Tumors-Carcinoma, sarcoma, carcinoid, lymphoma • Varices

and diagnostic inaccessibility, it forms the most difficult site to diagnose and treat (Figs. 44.1– 44.4). The common causes of lower GI bleeding in infants, children, and adolescents differ from those found in adults (Table 44.2). In India the common causes of LGI bleeding are different. Bleeding occurs in a younger population.[4] The most common causes are given in Table 44.3. The single commonest cause of lower gastrointestinal bleeding is colitis and ulceration, often

Part X / Special Topics

FIGURE 44.1 Ileal inflammatory mass cause lower gastrointestinal bleeding. The mass was discovered on operative enteroscopy.

nonspecific. Table 44.4 lists a retrospective review by Bhargava et al. from Delhi. In comparison to the West, in the Indian experience, patients are younger; most lesions can be localized and involve the right colon, mortality is lower and re-bleed rate is only 4% after surgery.[2] Diverticulosis is a common cause of LGI bleeding. A diverticulum is a sac-like protrusion of the colonic wall. The prevalence of diverticular disease is age-dependent, increasing from less than 5% at age 40, to 30% by the age 60, and to 65% by the age of 85 years. The high prevalence of the disease in western population explains why diverticulosis is the most common cause of LGI bleeding in the western population. Diverticular bleeding typically occurs in the absence of diverticulitis. Colonic angiodysplasias are arteriovenous malformations located in the cecum and ascending colon. Colonic angiodysplasias are acquired lesions affecting persons older than 60 years. These lesions are composed of clusters of dilated vessels, mostly veins, in the colonic mucosa and submucosa. Colonic angiodysplasias are believed

724

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

FIGURE 44.2 (a) This 28-year-old patient, known to have extrahepatic portal hypertension, had severe lower gastrointestinal hemorrhage. She had undergone splenectomy in childhood. She had esophageal varices, which were not bleeding: the obvious conclusion was ectopic variceal hemorrhage requiring surgery. The procedure done was a jugular vein interposition mesocaval shunt joining the superior mesenteric vein (arrowheads) with the inferior vena cava (arrow). She continued to bleed despite a patent shunt as shown by a Doppler study. At reoperation and operative enteroscopy, the surgeons discovered an ileal varix bleeding at the time of surgery. (b) The varix (arrow) still bleeding in the resected specimen. The bleeding stopped after the second procedure.

FIGURE 44.3 Bleeding nonspecific ulcers. Both patients had profuse lower gastrointestinal hemorrhage. Nonspecific ulcers may be multiple or single, superficial [as in (a)], or deep. (b) The ulcer associated with a stricture.

Tropical Hepatogastroenterology

ETIOLOGY

725

TABLE fy 44.3 Common causes of LGI bleeding in India • • • • • • • • • • • • •

FIGURE 44.4 Polyp in the colon causing a moderate lower gastrointestinal bleed. It was removed during colonoscopy. TABLE fy 44.2 Common causes of LGI bleeding at different ages A. Adolescent and young • Meckel’s diverticula • Inflammatory bowel disease B. Up to 60 yrs of age • Diverticulosis • IBD C. Above 60 yrs of age • Angiodysplasia • Diverticulosis

to occur as a result of chronic, intermittent, lowgrade obstruction of submucosal veins as they penetrate the muscular layer of the colon. The characteristic angiographic findings are clusters of small arteries during the arterial phase of the study, accumulation of contrast media in vascular tufts, early opacification, and persistent opacification due to the late emptying of the draining veins.

Part X / Special Topics

Nonspecific colitis and ulcers Enteric ulcers Polyps Cancer Tuberculosis Amebic ulcers Rectal varices Radiation colitis Ischemic colitis Vascular malformation Diverticulosis Right sided ulcerative colitis Pseudopancreatic cyst communicating with the descending colon

TABLE fy 44.4 Frequency of different causes of lower gastrointestinal bleeding in 90 cases[4] • • • • •

Nonspecific colitis and ulcers (58%) Polyps (19%) Cancer (10%) Rectal varices (4%) Tuberculosis (3%)

Ulcerative colitis causes bloody diarrhea in most cases. In up to 50% of patients with ulcerative colitis, mild-to-moderate lower GI bleeding occurs, and approximately 4% of patients with ulcerative colitis have massive hemorrhage. Lower GI bleeding in patients with Crohn’s disease is not as common as in patients with ulcerative colitis; 1%–2% of patients with Crohn’s disease may experience massive bleeding. The frequency of bleeding in patients with Crohn’s disease is significantly more common with colonic involvement than with small bowel involvement alone. Ischemic colitis, the most common form of ischemic injury to the digestive system, frequently involves the watershed areas, including the splenic

726

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

flexure and the rectosigmoid junction. In most cases, the precipitating event cannot be identified. Colonic ischemia is a disease of the elderly and is commonly observed after the sixth decade of life. Ischemia causes mucosal and partial-thickness colonic wall sloughing, edema, and bleeding. Ischemic colitis is not associated with significant blood loss or hematochezia, although abdominal pain and bloody diarrhea are the main clinical manifestations. Colorectal adenocarcinoma causes occult bleeding, and patients usually present with anemia. The incidence of massive bleeding due to colorectal carcinoma varies from 5% to 20% in different series. Postpolypectomy hemorrhage occurs up to 1 month following colonoscopic resection. The reported incidence is between 0.2 and 3%. Benign anorectal disease (e.g., hemorrhoids, anal fissures, anorectal fistulas) can cause intermittent rectal bleeding. Massive rectal bleeding due to benign anorectal disease has also been reported. Patients who have rectal varices with portal hypertension may develop painless massive lower GI bleeding; therefore, examining the anorectum early in the workup is important. Note that the discovery of benign anorectal disease does not exclude the possibility of more proximal bleeding from lower GI tract. Nonspecific colon ulcers occur in all age groups, predominantly 40 to 60 years, with a slight female sex predilection. The main clinical manifestations include abdominal pain mimicking appendicitis (50%), lower gastrointestinal hemorrhage (33%), perforation (19%), and abdominal mass (16%). The usual location of the ulcers is the cecum and ascending colon (67%), and less commonly the transverse colon, the hepatic and splenic flexures (18%), and descending and sigmoid colon (15%). The diagnosis is best estab-

lished by colonoscopy. Nonoperative conservative management is probably indicated in uncomplicated cases, with follow-up colonoscopic studies, to ensure complete healing. The etiology of this condition is still unknown.[6] Colonic tuberculosis, although rare in the West, is not an uncommon disease in developing countries. The clinical manifestations and radiological appearance of the disease are nonspecific. Abdominal pain, fever, anorexia, weight loss, and diarrhea are the common symptoms. Colonoscopy is very useful in diagnosing patients with colonic tuberculosis. The colonoscopic features consist of ulcers, nodules, deformed cecum and ileocecal valve, strictures, and polypoid lesions. Segmental tuberculosis and lesions simulating carcinoma are also seen occasionally. Histological examination of the colonic biopsy specimens shows well-formed, noncaseating granulomas in a small percentages of patients. Collections of loosely arranged epithelioid cells and chronic nonspecific inflammatory changes are seen more commonly. Patients respond well to antitubercular treatment. Surgical intervention may be needed in 5%–10% of patients, who present with obstruction or massive colonic bleeding.[7] Small bowel sources of LGI bleeding are less common (Figs. 44.1–44.3). Intestinal bleeding in typhoid fever is typically occult; massive bleeding is uncommon and usually occurs from the ulcers in the distal ileum or proximal colon. The most commonly involved areas are the terminal ileum (100%), followed by the ileocecal valve (57%), the ascending colon (43%), and the transverse colon (29%). The left colon is usually normal. The most common colonoscopic findings include multiple variable-sized punched-out ulcers with slightly elevated margins, and several edematous hyperemic mucosal patches with hemorrhagic spots or shallow erosions.[8]

Tropical Hepatogastroenterology

EVALUATION AND RESUSCITATION

44.3 EVALUATION AND RESUSCITATION The myriad nature of severe bleeding and its variable presentation leads to limitations with the common treatment strategies. To manage LGI bleeding, it is useful to stratify patients based on the severity of hemorrhage. Lower GI bleeding can manifest in different ways. According to clinical manifestation it has been classified broadly into four overlapping categories for the purposes of management. 1. 2. 3. 4.

Minor self-limiting Chronic intermittent Massive intermittent Massive ongoing.

The first category includes 75%–90% of patients and is characterized by minor bleeding that resolves with conservative therapy. The second category is comprised of patients with chronic intermittent bleeding. The etiology of bleeding in this group is often elusive and probably needs extensive investigation before deciding the management plan. The third group has episodes of severe, lifethreatening bleeding with hemodynamic stability in between the episodes. Because of the inconsistent nature of bleeding in this group, technetium (Tc)-99 m red blood cell scans are useful prior to angiography. Alternatively, urgent colonoscopy (with or without colonic purge) may play a diagnostic and therapeutic role in this group. The fourth category comprises patients with continual active bleeding. These patients may be hemodynamically unstable and need urgent therapeutic intervention before extensive investigations for knowing the actual source. The patient who presents with acute lower gastrointestinal hemorrhage may complain of passing bright red blood per rectum, dark blood with clots, or, less commonly, melena. Pallor, fatigue, chest

Part X / Special Topics

727

pain, palpitations, dyspnea, tachypnea, tachycardia, postural changes, or syncope are suggestive of hemodynamic compromise. Resuscitation should take place simultaneously with the initial evaluation of the patient. Associated symptoms may provide clues to the source of the bleeding. Lower gastrointestinal bleeding is usually painless. A history of abdominal pain, weight loss, fever, diarrhea, vomiting, or partial small intestinal or colonic obstruction are important findings in the differential diagnosis of inflammatory, infectious, or malignant lesions. The patient’s age, medical history, and medication history (e.g., anticoagulants, NSAID) may be useful in analyzing the cause of bleeding. Colonic diverticula or angiodysplasia are more likely to be a cause of lower gastrointestinal bleeding in a person over 70 years of age. Similarly, a history of pelvic radiation therapy (for prostatic or gynecologic malignancy) may point to radiation proctitis as a cause of rectal bleeding. This may occur anywhere from 9 months to 4 years after radiation therapy. Patient assessment should include careful cardiac, pulmonary, abdominal, and rectal examinations. A digital rectal examination is helpful in excluding anorectal pathology as well as confirming the patient’s description of the appearance of the stool. The presence of coagulopathy [international normalized ratio (INR) > 1.5] or thrombocytopenia (< 50000/μL) should prompt correction with transfusion of fresh frozen plasma or platelets respectively. Blood transfusion requirement is determined by the rate of bleeding and is also influenced by the presence of comorbid conditions such as coronary artery disease, cirrhosis, or chronic obstructive pulmonary disease. Orthostatic hypotension, a transfusion requirement of more than two units of packed red blood cells, or a continued active bleeding requires admission to an intensive

728

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

care unit for close observation. During a bleeding episode, persistent hemodynamic instability despite aggressive resuscitation efforts warrants intervention. Other than the removal of possible etiologic causes (e.g., NSAIDs) and correction of coagulopathy, there are a few specific medical therapies aimed directly at the management of lower gastrointestinal bleeding. Empiric hormonal therapy (estrogen) to control gastrointestinal bleeding of obscure origin thought to be caused by colonic angiodysplasia is controversial and may be ineffective. There is no evidence to support the initial use of octreotide or other systemically administered drugs in the management of lower gastrointestinal bleeding. In radiation proctitis, vascular telangiectasia and nonhealing mucosal ulceration caused by an underlying obliterative arteritis may lead to severe recurrent hemorrhage. The nonendoscopic management of bleeding secondary to radiation proctitis includes the use of sucralfate or formalin enemas. Sucralfate is a highly sulfated polyanionic disaccharide. Its postulated mechanisms of action include stimulation of epithelial healing and formation of a protective barrier. The strongest evidence for the use of sucralfate enemas comes from a prospective randomized, doubleblind, controlled trial of 37 patients in which anti-inflammatory drugs were compared with rectal sucralfate and a single prospective study of rectal sucralfate. Formalin may sclerose and seal fragile neovasculature in radiation-damaged tissues, thereby preventing further bleeding. Application of formalin directly to the mucosa produces local chemical cauterization and can stop bleeding by sealing the neovascularized telangiectatic spots and ulcers. Either a 3.6% formalin solution or 4% formalin solution is used for irrigation. An alternative method is the direct application of gauze soaked in formalin (4% or 10%).

However, when the source of massive LGI bleed is unknown, apart from the resuscitation patients need simultaneous intervention for diagnosis of the bleeding source and possible control of bleeding as early as possible. There are no standard general guidelines for the management of LGI bleeding, and most institutions follow their own protocols.

44.3.1 Endoscopy Overall upper endoscopy, push enteroscopy, and colonoscopy are considered safe in an emergency, even in elderly patients with gastrointestinal bleeding.[9] Still, the risk of endoscopy in an emergency setting (compared to the elective) may be high, due to a poor general condition, unknown comorbid status, and poor preparation for the procedure.[10] The risks may be minimized through adequate preparation of the patient before the procedure and by appropriate sedation and monitoring during the endoscopy. The monitoring of sedated patients undergoing gastrointestinal endoscopic procedures includes recording of the heart rate, blood pressure, respiratory rate, and oxygen saturation. Electrocardiographic (ECG) monitoring is advisable in high-risk patients, although improved outcomes with such monitoring have not been shown conclusively in controlled trials. Supplemental oxygen administration should be considered mandatory, especially in patients with impaired pulmonary function or patients in whom a prolonged or complex procedure is anticipated. Care must be taken to avoid suppression of the hypoxic ventilatory drive, which can lead to profound hypercapnia.

44.3.2 Upper GI Endoscopy Diagnostic endoscopic studies should be undertaken only after the patient has been hemodynami-

Tropical Hepatogastroenterology

EVALUATION AND RESUSCITATION

cally resuscitated. Nasogastric (NG) lavage before upper endoscopy is advised if there is low suspicion of an upper gastrointestinal source but may be misleading if only clear fluid without bile returns. If blood, clots, or coffee-ground material is present in the NG aspirate, upper endoscopy must be performed to exclude an upper gastrointestinal source as the cause of the hematochezia. For patients with severe hematochezia and hypovolemia, an upper gastrointestinal source will be found in 10%–15% of patients.[11]

44.3.3 Diagnostic Colonoscopy A lower endoscopic study is an established diagnostic procedure of choice in the setting of acute lower gastrointestinal hemorrhage. If sigmoidoscopy is selected as the initial endoscopic approach, it should only be considered diagnostic if an actively bleeding lesion is visualized. However, many endoscopists prefer to perform a total colonoscopy as the initial evaluation. Previously, it was thought that colonoscopy in patients with severe hematochezia is impractical because of inadequate visualization, but now colonoscopy is considered feasible after rapid cleansing. The diagnostic accuracy of colonoscopy ranges from 72% to 86% in patients with lower gastrointestinal bleeding.[11] In contrast, Indian studies have shown a much lower rate of success in this setting. Anand et al. reviewed 91 patients with massive lower gastrointestinal bleeding; the diagnosis was made in only 36 patients on fiber-optic colonoscopy done during active bleeding.[3] At colonoscopy, angiodysplasias are recognized by their characteristic appearance as red, flat, fern-like lesions consisting of ectatic blood vessels that appear to radiate from a central feeding vessel. They may have a diameter of 2–10 mm. A pale mucosal halo may be seen around the lesion. When the colon is examined completely, the

Part X / Special Topics

729

sensitivity of colonoscopy for detecting angiodysplasia exceeds 80%. Colonic angiodysplasias are the most common in cecum and proximal ascending colon (54%), followed by sigmoid colon (18%) and rectum (14%). Other diseases with specific diagnostic features at colonoscopy include NSAID-related disease, ischemic colitis, and radiation colitis. Colonic ulcers caused by NSAIDs are often sharply demarcated with a predilection for the terminal ileum and proximal colon, where pills may reside for a longer period of time than in other segments of the bowel. The development of diaphragm-like strictures is pathognomonic of NSAID injury. These strictures are typically multiple in number, with normal intervening mucosa. Nonocclusive colonic ischemia most commonly involves the watershed areas: splenic flexure, right colon, or rectosigmoid junction. In patients with ischemic colitis, sigmoidoscopy reveals ulceration of the colonic mucosa with the exception of the rectum in most cases. Histology reveals necrosis, nonacute, and chronic inflammatory changes as seen in inflammatory bowel disease. Radiation proctitis typically demonstrates characteristic telangiectasias at colonoscopy. Colonoscopy performed in an emergency (within 12 hours of admission) is safe and effective.[12] Early intervention, particularly for massive hemorrhage, may improve the diagnostic and therapeutic outcome and prevent the need for surgical intervention. In addition, early colonoscopic evaluation may reduce the duration of hospitalization and lower overall costs per patient. In fact, time to colonoscopy has been shown to be an independent predictor of the length of hospital stay. In a wide spectrum of patients with lower gastrointestinal bleeding, the reduction in the length of hospital stay was shown to relate primarily to improved diagnostic yield rather than therapeutic intervention.

730

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

There is no uniform agreement regarding the need for a colonic purge prior to colonoscopy in a patient with active lower gastrointestinal bleeding. If it is prescribed, extra effort of the nursing staff and patient is required to ensure a successful cleansing. A sulfate or polyethylene glycol (PEG) based solution is administered orally. The dose can be repeated every 4–6 hours if further purge is necessary. Occasionally, patients with chronic kidney disease may require dialysis after purging, and those with severe congestive heart failure may require diuresis. However, complication rates are low with PEG-based solutions. Only an experienced endoscopist should perform colonoscopy in an actively bleeding patient with an unprepared colon, because the risk of colonic perforation may be increased in this setting.

44.3.4 Radiography The role of double-contrast barium enema (DCBE) in the evaluation of lower gastrointestinal bleeding is decreasing. In addition to the suboptimal quality of DCBE, patients often prefer colonoscopy. However, plain abdominal radiography should be performed prior to colonoscopy if bowel perforation or obstruction is suspected. Radiologic evidence of thumb printing is indicative of transmural injury to the colon as a result of ischemic or infectious colitis. The role of multidetector computed tomography (MDCT) is evolving.[13] Apart from its role in detecting the mass lesion, the property of high resolution and speed of the machine can be utilized to obtain images mimicking arteriography in detecting the bleeding point. This may predict the treatment potential of arteriographic intervention. MDCT is highly sensitive and specific for the diagnosis of colonic angiodysplasia. Bleeding rates < 0.4 ml/min are detectable on MDCT. Several

small retrospective reports have reported an accuracy rate of 54%–79% for localizing large bowel bleeding.[13]

44.3.5 Radionuclide Imaging Evaluation with radionuclide imaging or with angiography may be appropriate in patients with massive hemorrhage that precludes colonoscopy or in patients in whom a bleeding source is not identified on colonoscopy. Radionuclide imaging detects active bleeding at rates of 0.1–0.5 ml/minute and is more sensitive than angiography but less specific than endoscopic or angiographic study.[14] Either technetium sulphur colloid or (99mTc) pertechnetate-labeled red blood cells can be used. The disadvantage of using pertechnetate-labeled red blood cells is the persistence of background activity in blood vessels and the blood pool throughout the study, thereby theoretically increasing the threshold for the amount of bleeding needed for detection. In contrast, technetium sulphur colloid, which completely clears the blood pool by 10–15 min after injection, is easier to detect because background activity is absent. Although imaging with technetium sulphur colloid can detect a bleeding rate as low as 0.1 ml/minute, the short half-life of the colloid within the vascular system requires active bleeding at the time the radionuclide is present in the intravascular space. Therefore, for evaluation of episodic lower gastrointestinal bleeding, imaging following injection of pertechnetate-labeled red blood cells is preferred. It can be performed at 30-minute intervals for up to 24 hours if necessary, thereby allowing detection of intermittent bleeding. Radionuclide imaging is well tolerated by patients but is limited by highly variable accuracy rates for localizing bleeding ranging from 24 to 91%.[15] A bleeding scan study may be done while the patient has ongoing hematochezia and imaging can

Tropical Hepatogastroenterology

EVALUATION AND RESUSCITATION

be repeated over the next 24 hours, because the labeled red blood cells stay in the vascular space for at least 24 hours. However, the patient must have active bleeding when the image is taken in order to demonstrate extravasation. Whereas early scans (< 4 hours after baseline) may be helpful in localizing the bleeding site, delayed scans are less efficient in localizing the bleeding site. Therefore, early-bleeding scans (i.e., at baseline and up to 1–4 hours later, before or after the patient starts the oral purge prior to colonoscopy) are recommended in patients who are hospitalized for severe, ongoing hematochezia. Even if the bleeding scan is positive, a confirmatory test such as colonoscopy, angiography, or push enteroscopy is recommended before emergency surgery is considered. Radionuclide imaging is generally performed before angiography. In addition to its role in determining which patients are bleeding sufficiently to warrant an angiographic study, localization of the bleeding source by radionuclide imaging may allow a more selective angiographic study thereby decreasing the contrast dye load. Radionuclide screening appears to increase the diagnostic yield of arteriography by screening out patients who are not actively bleeding at the time of the examination, thus sparing them the risks and costs of a nondiagnostic arteriographic study. Hemodynamically stable patients with severe but intermittent bleeding should be evaluated with pertechnetate red blood cell scanning. A positive red blood cell diagnosis should necessitate an urgent angiography which should be performed within 1 hour of positive scintigraphy, day or night. Patients who are hemodynamically unstable with severe unremitting bleeding should forego nuclear scintigraphy and instead undergo resuscitation and angiography as soon as possible.[16]

Part X / Special Topics

731

44.3.6 Angiography Angiography is performed only if there is a gastrointestinal bleeding rate of at least 1 ml/minute for accurate detection of extravasation of contrast into the bowel lumen. Unfortunately, bleeding is frequently intermittent and may occur at a lower rate, thereby limiting the detection of the causative lesion. Indirect evidence of a bleeding lesion suggests but does not confirm a potential bleeding site. The examination is not definitive unless extravasation of contrast into the lumen is observed. The overall yield of angiography for the detection of a gastrointestinal bleeding source ranges from 40% to 78%.[17] Angiography remains the gold standard for the diagnosis of angiodysplasia. Following injection of contrast, angiodysplasias are recognized by ectatic slowemptying veins, vascular tufts, or small veins that fill early. The advantages of angiography include the lack of requirement for bowel preparation, ability to localize the bleeding source, and possibility of therapeutic intervention in some cases. The study can be performed without a colonic purge or while a purge is being administered. Hemostasis can be achieved by intra-arterial infusion of vasopressin or arterial embolization via the angiographic catheter. Intra-arterial infusion of vasopressin is successful in controlling gastrointestinal hemorrhage in up to 91% of patients. Unfortunately, bleeding recurs in up to 50% of patients after cessation of the vasopressin infusion. Vasopressin infusion is labor-intensive, requiring admission to the intensive care unit for most of the patients. It also causes important side effects including abdominal pain, and is contraindicated in patients with clinically significant coronary artery disease. A longer-acting synthetic vasopressin analogue (terlipressin) has been used successfully

732

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

as a single bolus intra-arterial injection to stop lower gastrointestinal bleeding. Transcatheter embolization is a more definitive means of controlling hemorrhage than intraarterial infusion of vasopressin.[18] Initial studies reported bowel infarction that ranged from 13% to 33% after embolization of proximal vessels. These complications deterred enthusiasm for the technique, favoring local vasoconstrictive therapy (i.e., vasopressin infusion) despite serious disadvantages. However, the availability of microcatheters led to the development of microcatheter embolization using microcoils, gelfoam, and polyvinyl alcohol particles. With this advancement, studies have shown significant clinical success (cessation of bleeding) between 44% and 91% without major ischemic complications. The advantages of embolization include immediate cessation of bleeding without the need for prolonged infusions or management of an indwelling arterial catheter. The side effects of vasopressin are also avoided. Angiography should be reserved for the patient who has massive bleeding that precludes colonoscopy, has persistent or recurrent bleeding, or has undergone a colonoscopy that has failed to identify the bleeding source. The endoscopic and angiographic examinations are complementary to each other, and the order in which the investigations are undertaken often depends on local availability and expertise.

44.3.7 Small Bowel Evaluation A small bowel evaluation may be necessary to find out the cause of bleeding when both upper gastrointestinal (UGI) endoscopy and colonoscopy results are negative. Evaluation of the entire small bowel is the most tedious step in the diagnostic work up of GI bleed. Usually the source of bleeding is found in the proximal small bowel or distal

two feet of ileum. These sites can be visualized by push enteroscopy and ileoscopy. When examination of the remaining small bowel is desired video capsule endoscopy provides imaging of the entire small bowel. The recent double tube endoscope provides advantage of accurate localization and possible local therapy. Video capsule endoscopy reportedly identifies the bleeding source in 55%– 65% of the examined patients with gastrointestinal bleeding. In the Indian setting it is expensive and the experience is limited. A radionuclide scan for a Meckel’s diverticulum may be appropriate in young patients presenting with otherwise unexplained lower gastrointestinal bleeding.

44.4 THERAPEUTIC COLONOSCOPY Colonoscopy provides the therapeutic advantages similar to UGI endoscopy, and the applications for LGI bleeding are similar. Most principles used such as stigmata of hemorrhage and predictors of recurrent hemorrhage are similar to those applied for UGI hemorrhage from ulcers. For most actively bleeding lesions or those with adherent clots in the colon, a combination of adrenaline injection and thermal coagulation (with a bipolar or heater probe) is recommended. (The exceptions are active bleeding in association with hemangiomas and internal hemorrhoids.) This recommendation is supported in part by demonstration of the safety of colonic endotherapy in experimental animals.[19] Colonic diverticular bleeding is amenable to hemostasis with adrenaline injection therapy, bipolar coagulation, or both. Less frequently employed methods for controlling diverticular bleeding include endoscopic band ligation and placement of hemoclips. The endoscopic treatment of colonic angiodysplasia is performed with contact thermal probes. To prevent brisk bleeding from angiodysplasia when contact electrocautery is performed,

Tropical Hepatogastroenterology

SURGERY

large angiodysplasia should be cauterized. Injection therapy with sclerosing agents, such as ethanolamine, has also been described for control of bleeding from colonic angiodysplasia, but is not widely employed. Argon plasma coagulation, a noncontact method, has been used increasingly for the treatment of bleeding colonic angiodysplasia.[20] Extra care must be taken when treating lesions in the cecum to avoid perforation. Postpolypectomy bleeding is the most frequent complication of colonoscopy performed for polypectomy, and accounts for approximately 2%– 8% of cases of acute LGI bleeding. Massive bleeding that occurs at the time of polypectomy (early postpolypectomy bleeding) is typically arterial in nature and results from inadequate hemostasis of the blood vessel in the polyp stalk. Reduction in the risk of early postpolypectomy bleeding can be achieved by the use of blended, rather than pure cutting, electrocautery currents in the polypectomy snare. Delayed bleeding may occur up to 15 days after polypectomy and are likely to be a result of the sloughing of the eschar at the polypectomy site. Delayed bleeding is usually self-limited and resolves with supportive care in more than 70% of cases. The lower gastrointestinal bleeding from radiation proctitis needs endoscopic coagulation. It is recommended to coagulate focal bleeding telangiectasias rather than the entire friable mucosa. Several treatment sessions are often required. Scarring and re-epithelization with more normal tissue tend to occur over time. More recently, argon plasma coagulation has gained popularity for the management of lower gastrointestinal bleeding related to radiation proctitis. Some of the more recent developments in endoscopic hemostasis (e.g., endoscopic band ligation, endoscopic clipping, and argon plasma coagulation) have been applied to the management of

Part X / Special Topics

733

other sources of lower gastrointestinal bleeding (e.g., bleeding colonic varices, bleeding rectal Dieulafoy’s lesion).

44.5 SURGERY Surgical treatment of LGI bleed can be considered in two separate scenarios. One in which it is indicated as emergency life-saving intervention, and the second is in chronic slow intermittent bleeding in which a focal lesion has been identified. Most patients with severe lower gastrointestinal bleeding and even those with prolonged bleeding will not require surgery. Most have intermittent bleeding or can be controlled with nonsurgical therapies, including endoscopic, angiographic, or proctoscopic techniques (bleeding from hemorrhoids). Surgical intervention is required when hemodynamic instability persists despite aggressive resuscitation, the blood transfusion requirement is greater than 6 units, or severe bleeding recurs. Surgical intervention for lower gastrointestinal bleeding is necessary in 18%–25% of patients who require blood transfusion.[21, 22] The other indication for urgent surgery is nonocclusive colonic ischemia, particularly in patients with renal failure or severe atherosclerosis. These patients have a fulminant course and unless surgery is performed to remove the septic foci, have a very high mortality. The absence of colonic infarction does not ensure a favorable outcome and some patients who are felt to be candidates for nonoperative therapy have a substantial mortality rate. In the emergency setting every attempt should be made to stabilize the patient and to localize the cause of bleeding. Otherwise the outcome is poor. After initial resuscitation, a search for the cause of bleeding should be undertaken in order to diagnose the bleeding point precisely. Following accurate localization by angiogram, bleeding

734

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

can be temporarily controlled with either angiographic embolization or vasopressin infusion. Segmental bowel resection is performed in the next 24–48 hours following correction of the patient’s physiologic parameters which include hypotension, hypothermia, acute hemorrhagic anemia, and deficient coagulation factors. In a certain minority of patients an emergency operation before any diagnostic study may be the only life saving measure, which is thoroughly justified.[23] While performing surgery adequate blood products should be available, and hypothermia should be avoided. Expert anesthetist should ensure placement of all invasive monitoring. The abdominal cavity is explored through a midline vertical incision. The abdomen is meticulously explored to give a clue to the site of bleeding in case it is not localized preoperatively. Small and large bowel and the mesentery are inspected and palpated for any tumors, polyps, ulcers, or vascular malformations. Transillumination may help in locating vascular malformations. A search is made for signs of tuberculosis, Meckel’s, strictures or enteric ulcers. If the bleeding point is not diagnosed per-operatively, an intraoperative surgeonguided enteroscopy and colonoscopy should be performed in order to locate the precise bleeding point. The presence of an endoscopist is an advantage for performing intraoperative endoscopic evaluation. The colonoscopy can be performed with surgeon’s guidance. If the colonoscopy cannot identify any source of bleeding the same colonoscope can be used for enteroscopy by making an enterotomy close to ileocecal junction. The enteroscopic examination should be performed while introducing the scope, otherwise the manipulation can cause mucosal tears and false impressions. By these maneuvers if the source of bleeding is identified the treatment is simple resection of the affected segment.

Surgery depends on the site of bleeding. The most common site in the emergency setting is the colon and it requires some form of segmental resections after identification of the source of bleeding. It has been well documented that segmental resection after identifying the source of bleeding has the best outcome in terms of rebleeding rate and mortality, which is about 0%–15% and 0%–22% respectively.[24] The controversy in treatment is when the source of bleeding is still not identifiable. The most common source of bleeding is the left colon, probably due to diverticular disease in western series; hence many authors advocate a blind left hemicolectomy. The blind resections carry a high rebleeding rate of nearly 50% with increased mortality.[25] With this background it is safer to perform subtotal colectomy which has 0% rebleeding and 9% mortality.[25] Blind segmental resections should be avoided, if possible. Studies show that in an emergency it has high morbidity rate up to 83%, and a mortality rate up to 60%.[26] It is always advisable to exert in identifying the source of bleeding either preoperatively or peroperatively for a better out come. When preoperative identification is successful in localizing the bleeding site, limited intestinal resection has resulted in significantly lower morbidity rates than did surgery in historic controls without localization (8.6% vs. 37%).[27] When there are no facilities for intraoperative endoscopy it may be safer to perform subtotal colectomy with inspection of terminal ileum and performing either an ileorectal anastomosis or ileostomy and mucus fistula. In India, a retrospective study from Delhi demonstrated low morbidity and rebleeding from blind right hemicolectomy in their 19 patients (n = 90) where localization of bleeding site was not possible. The most common cause of bleeding in their patients was from nonspecific ulcers in the right colon and the adjoining ileum which could

Tropical Hepatogastroenterology

SURGERY

be demonstrated in 14/19 of these patients. In this study left colonic lesions were easily identified on colonoscopy and treated accordingly.[2] As far as possible, intraoperative endoscopy should be done to localize the site of bleeding. Patients with chronic intermittent bleeding without a known source or diagnosis should undergo elective mesenteric angiography, upper and LGI endoscopy, isotope scan, upper GI endoscopy, small bowel series, and enteroclysis. Elective evaluation of the entire GI tract may identify uncommon lesions and undiagnosed arteriovenous malformations. If the source is not identified and the patient continues to have symptoms, they should undergo exploratory laparotomy similar to emergency surgery. The advantage in elective situations is that the patient’s general condition is stable; hence, surgeon has enough time to evaluate the bowel thoroughly. The surgery depends on the intraoperative findings. Very rarely, surgeon needs to do blind subtotal colectomy with ileorectal anastomosis.

44.5.1 Complications Patients who have had surgery of the lower GI tract are prone to the development of complications. The most common early postoperative complications are intra-abdominal or anastomotic bleeding, ileus, mechanical small bowel obstruction, intra-abdominal sepsis, localized or generalized peritonitis, wound infection and/or dehiscence, Clostridium difficile colitis, pneumonia, urinary retention, urinary tract infection, deep venous thrombosis, and pulmonary embolus. Intra-abdominal sepsis following surgery is a life-threatening complication and requires aggressive treatment. Systemic comorbidity (e.g., severe blood loss and shock, poor bowel preparation, irradiation, diabetes, malnutrition, and hypoalbuminemia) may adversely affect anastomotic heal-

Part X / Special Topics

735

ing. Changes in anatomy and physiology of the large bowel, high bacterial content, improper operative technique, tension, and ischemia can cause anastomotic leak associated with abscess and intraabdominal sepsis. This condition requires either laparotomy (if the sepsis is generalized) or percutaneous drainage (if the sepsis is localized). Delayed complications usually occur more than a week after surgery. The most common delayed complications are anastomotic stricture, incisional hernia, and incontinence.

44.5.2 Morbidity and Mortality The overall operative mortality rate for emergency surgery for lower gastrointestinal bleeding is 10% despite improved methods to localize the bleeding site that permit segmental rather than subtotal colectomy. Age and comorbidity are important risk factors for postoperative mortality. The postoperative mortality rate in patients who undergo surgery for colorectal cancer increases with age (3.7% in patients aged 70–79 years, 9.8% in patients aged 80 to 89 years, and 12.9% in those over 89 years.)[26] The blind segmental resection of the colon or segmental resections based solely on tagged red blood cell scan localization are associated with substantial rates of rebleeding (as high as 33%) and mortality (33%–57%).[28] Subtotal colectomy in an emergency is associated with a low rebleeding rate (3%), an acceptable average morbidity (32%), though significant mortality (19%) rates. Limited segmental resections after preoperative localization of bleeding have the lowest morbidity (5%–10%) and rebleeding rates (1%–3%). Right or left hemicolectomies have been advocated on the basis of institutional experiences but need to be evaluated carefully. Present data supports the importance of an aggressive approach to preoperative localization of the bleeding source.

736

Chapter 44 / LOWER GASTROINTESTINAL BLEEDING

The type of resection also depends on surgeon’s experience and locally prevalent cause of bleeding.

44.6 CONCLUSION Although not as common as upper gastrointestinal bleeding, lower gastrointestinal bleeding can be associated with substantial morbidity and mortality. Recent advances have improved the endoscopic, radiologic, and surgical management of patients with lower gastrointestinal bleeding. With increased access to urgent endoscopy, the diagnostic and therapeutic colonoscopy can be expected to play an increasing role in the management of acute

lower gastrointestinal bleeding. Surgical intervention may be life saving in a proportion of patients. Experience and proper planning are required to achieve an excellent outcome. Limited segmental resection based on pre- or peroperative localization of the source is most important for a favorable outcome. Blind segmental resections are to be avoided in view of a high rebleeding rate, morbidity, and mortality. Subtotal colectomy, right or left hemicolectomy has been advocated in the situation where localization of bleeding has not been possible. This decision is based on local experience and remains controversial. Thus pre- or peroperative localization of bleeding is the key to achieve a good outcome.

REFERENCES [1] Vernava AM, Longo WE, Virgo KS: A nationwide study of the incidence and etiology of lower gastrointestinal bleeding. Surg Res Commun 1996;18: 113–120. [2] Govil D, Sahni P. Lower Gastrointestinal Haemorrhage. GI Surgery Annual 1994;93–103. [3] Anand AC, Patnaik PK, Bhalla VP et al. Massive lower intestinal bleeding–a decade of experience. Trop Gastroenterol 2001;22:131–4. [4] Bhargava DK, Rai RR, Chopra P. Colonoscopy for investigation of unexplained rectal bleeding in a tropical country. Gastroenterol Jpn 1990;25:781–5. [5] Bhargava DK, Rai RR, Dasarathy S et al. Colonoscopy for unexplained lower gastrointestinal bleeding in a tropical country. Trop Gastroenterol 1995;16:59–63. [6] Misra SP, Misra V, Dvivedi M et al. Colonic tuberculosis: clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 1999;14: 723–9. [7] Ona FV, Allende HD, Vivenzio R et al. Diagnosis and management of nonspecific colon ulcer. Arch Surg 1982;117:888–94.

[8] Lee JH, Kim JJ, Jung JH et al. Colonoscopic manifestations of typhoid fever with lower gastrointestinal bleeding. Dig Liver Dis 2004;36:141–6. [9] Arrowsmith JB, Gerstman BB, Fleischer DE et al. Results from the American Society for Gastrointestinal Endoscopy/U.S. Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991;37:421–7. [10] Quine MA, Bell GD, McCloy RF et al. Prospective audit of upper gastrointestinal endoscopy in two regions of England: safety, staffing, and sedation methods. Gut 1995;36:462–7. [11] Jensen DM, Machicado GA. Diagnosis and treatment of severe haematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988;95:1569–74. [12] Chaudhry V, Hyser MJ, Gracias VH et al. Colonoscopy: the initial test for acute lower gastrointestinal bleeding. Am Surg 1998;64:723–8. [13] Tew K, Davies RP, Jadun CK et al. MDCT of acute lower gastrointestinal bleeding. AJR Am J Roentgenol 2004;182:427–30.

Tropical Hepatogastroenterology

REFERENCES

[14] Dusold R, Burke K, Carpentier W et al. The accuracy of technetium-99m-labeled red cell scintigraphy in localizing gastrointestinal bleeding. Am J Gastroenterol 1994;89:345–8. [15] Imbembo AB RW. Diverticular disease of the colon. In: Sabiston D, ed. Textbook of Surgery, 14th ed. New York: Churchill Livingstone, 1992:910. [16] Gunderman R, Leef J, Ong K et al. Scintigraphic screening prior to visceral arteriography in acute lower gastrointestinal bleeding. J Nucl Med 1998;39:1081–3. [17] Koval G, Benner KG, Rosch J et al. Aggressive angiographic diagnosis in acute lower gastrointestinal haemorrhage. Dig Dis Sci 1987;32:248–53. [18] Gordon RL, Ahl KL, Kerlan RK et al. Selective arterial embolization for the control of lower gastrointestinal bleeding. Am J Surg 1997;174: 24–8. [19] Jensen DM. Endoscopic diagnosis and treatment of severe haematochezia. Tech Gastrointest Endosc 2001;3:178–84. [20] Wahab PJ, Mulder CJ, den Hartog G et al. Argon plasma coagulation in flexible gastrointestinal endoscopy: pilot experiences. Endoscopy 1997;29:176–81. [21] Field RJ Sr, Field RJ Jr, Shackleford S. Total abdominal colectomy for control of massive lower

test

Part X / Special Topics

[22]

[23]

[24]

[25]

[26]

[27]

[28]

737

gastrointestinal bleeding. J Miss State Med Assoc 1994;35:29–33. Milewski PJ, Schofield PF. Massive colonic haemorrhage - the case for right hemicolectomy. Ann R Coll Surg Engl 1989;71:253–9. Klas JM RD. Surgical options in lower gastrointestinal bleeding. Semin Colon Rectal Surg 1997;141:478–81. Drapanas T, Pennington DG, Kappelman M et al. Emergency subtotal colectomy: the preferred approach to management of massively bleeding diveticular disease. Ann Surg 1979;177:519–526. Farner R, Lichliter W, Kuhn J et al. Total colectomy versus limited colonic resection for acute lower gastrointestinal bleeding. Am J Surg 1999;178: 587–91. Bender JS, Wiencek RG, Bouwman DL. Morbidity and mortality following total abdominal colectomy for massive lower gastrointestinal bleeding. Am Surg 1991;57:536-40. Uden P, Jiborn H, Jonsson K. Influence of selective mesenteric arteriography on the outcome of emergency surgery for massive, lower gastrointestinal hemorrhage. A 15- year experience. Dis Colon Rectum 1986;29:561–6. Parkes BM, Obeid FN, Sorensen VJ et al. The management of massive lower gastrointestinal bleeding. Am Surg 1993;59:676–8.

Chapter

45 HEPATORENAL SYNDROME AC Anand

Oliguric renal failure is a common complication seen in patients hospitalized with advanced liver disease.[1] There are many causes of renal dysfunction along with simultaneous hepatic dysfunction. One of these is the hepatorenal syndrome (HRS). HRS is a functional renal failure in the setting of cirrhosis with a normal renal histology and the absence of any intrinsic renal disease. Simultaneous renal and hepatic dysfunction may also be due to systemic diseases affecting both the liver and the kidneys; various causes of acute renal failure in cirrhosis such as severe dehydration, shock, or nephrotoxic drugs. Less often, some intrinsic renal parenchymal disease such as glomerulonephritis may be associated with alcoholic cirrhosis or cirrhosis due to hepatitis B.[2–6] Causes of combined severe hepatic and renal dysfunction are depicted in Table 45.1.

biliary surgery or hepatic trauma.[8–11] However, with time, HRS has been redefined, and it is now used to describe the renal failure seen in patients with liver failure in the absence of renal pathology. In 1956, Hecker and Sherlock [12] gave a detailed description of patients with liver disease associated with renal failure characterized by lack of proteinuria and very low urinary sodium excretion.

45.2 INCIDENCE The annual incidence of HRS in patients with ascites is approximately 8%. In a follow-up study of cirrhotic patients with ascites, development of renal failure occurred in 18% and 39% of the patients at 1 year and at 5 years, respectively, with a median survival of 1.7 weeks or 90% mortality at 10 weeks.[13]

45.1 HISTORICAL PERSPECTIVE OF HRS 45.3 DIAGNOSTIC CRITERIA The association between decompensated cirrhosis and oliguric renal failure was recognized by Flint in 1863.[7] He showed that in most of the cases, renal failure in cirrhosis occurred in absence of significant histological changes in kidney at postmortem examination. The term hepatorenal syndrome (HRS) was originally used by surgeons to refer to the occurrence of renal failure following 738

The diagnostic criteria for HRS were proposed by the international Ascites Club consensus conference.[14] These are shown in Table 45.2. All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not necessary for the diagnosis, but provide supportive evidence.

CLASSIFICATION

739

TABLE fy 45.1 Causes of simultaneous liver and renal dysfunction Infections Toxins Neoplasms Collagen vascular disease Congenital Cardiac/Vascular Miscellaneous

Sepsis, leptospirosis, malaria, cytomegalovirus Methoxyflurane, carbon tetrachloride, tetracyclines, phosphorus Metastatic, hypernephroma Systemic lupus erythematosus, polyarteritis nodosa Polycystic kidney disease, sickle cell anemia, Wilson’s disease Inferior vena cava thrombosis, congestive cardiac failure Amyloidosis, HELPP syndrome, Reye’s syndrome, glomerulonephritis associated with hepatitis B, and IgA nephropathy associated with alcoholic cirrhosis, nephrotoxic drugs, radiocontrast agents in cirrhosis

Hepatorenal syndrome Prerenal causes of acute renal failure in cirrhosis

Gastrointestinal bleeding, renal losses, sepsis, shock

TABLE fy 45.2 International ascites club’s diagnostic criteria of hepatorenal syndrome Major criteria

Additional criteria

• Chronic or acute liver disease with advanced hepatic failure and portal hypertension. • Low glomerular filtration rate, as indicated by serum creatinine of > 1.5 mg/dl or 24-h creatinine clearance < 40 ml/min. • Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal or renal fluid losses∗ . • No sustained improvement in renal function∗∗ following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline. • Proteinuria < 500 mg/dl and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease. • Urine volume < 500 ml/d • Urine sodium < 10 mEq/L • Urine osmolality > plasma osmolality • Urine red blood cells < 50 per high power field • Serum sodium concentration < 130 mEq/L

∗ Significant

renal fluid losses (weight loss < 500 g/d for several days in patients with ascites without peripheral edema or 1, 000 g/d in patients with peripheral edema). ∗∗ (decrease in serum creatinine to 1.5 mg/dl or less or increase in creatinine clearance to 40 ml/min or more)

45.4 CLASSIFICATION There are two clinical patterns of HRS in patients with cirrhosis. 1. Type 1 HRS is characterized by rapidly progressive decline of renal function. This type of HRS is defined as a doubling of the initial serum

Part X / Special Topics

creatinine to a level greater than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 ml/min in less than 2 weeks. 2. Type 2 HRS is characterized by a less severe and nonprogressive reduction of glomerular filtration rate. Ascites is the main clinical problem.

740

Chapter 45 / HEPATORENAL SYNDROME

45.5 PATHOGENESIS HRS occurs in the setting of advanced cirrhosis. Several theories have been proposed to explain the development renal dysfunction in HRS. The pathophysiological hallmark of HRS is hypoperfusion of the kidney due to vasoconstriction of the renal circulation and decreased renal flow as a result of systemic vasodilatation.[15–22] The renal vasoconstriction may be multifactorial, involving disturbances in the circulatory function and activity of systemic and renal vasoactive mechanisms. The three main renal function abnormalities seen in cirrhosis are sodium retention, impaired free water excretion, and decreased renal perfusion and GFR.[23] The main consequences of these three are ascites, dilutional hyponatremia, and HRS respectively.[24] The first renal function abnormality in cirrhosis is a reduced ability to excrete sodium. Initially, the arterial vasodilatation is inadequate to stimulate the renin-angiotensin-aldosterone and sympathetic nervous systems. However, it activates an unknown sodium-retaining mechanism.[25] With increasing circulatory dysfunction, the renin-angiotensinaldosterone and sympathetic nervous systems are activated. Aldosterone increases sodium resorption from the distal and collecting tubules. The sympathetic nervous system activity increases sodium resorption from the proximal tubule, loop of Henle, and the distal tubule. Angiotensin II and noradrenalin have a vasoconstrictor effect on the renal vasculature, and their effect is balanced by increased renal production of prostaglandins (which have a vasodilatory effect) nitric oxide, and natriuretic peptides. The ADH causes reduced ability to secrete free water and hyponatremia. Cirrhosis is associated with marked vasodilatation of the splanchnic arterial circulation related to an increased splanchnic production of vasodila-

tor substances, particularly nitric oxide. This splanchnic arterial vasodilatation leads to arterial underfilling in the systemic circulation.[9, 10] As a result of this systemic arterial underfilling, homeostatic mechanisms are activated including renin-angiotensin and sympathetic nervous systems. In the early phases of decompensated cirrhosis, renal perfusion is maintained within normal levels because of an increased synthesis of renal vasodilator factors (mainly prostaglandins). In later phases of the disease, renal perfusion cannot be maintained because the marked systemic arterial underfilling causes this increased activity of the vasoconstrictor systems, activation of vasoconstrictor systems, and/or decreased formation of renal vasodilator factors. This causes reduction in renal perfusion and glomerular filtration rate (GFR) leading to the development of HRS.

45.6 PRECIPITATING FACTORS All patients with severe liver dysfunction do not develop HRS. The liver dysfunction is an important background factor or “first hit”. An additional precipitating factor or “second hit” is required to initiate HRS.[22] Type I HRS usually occurs after a precipitating cause like gastrointestinal hemorrhage, spontaneous bacterial peritonitis, severe bacterial infection, superimposed hepatitis, or large volume paracentesis without volume expansion.[26–30]

45.7 CLINICAL AND LABORATORY FINDINGS HRS occurs in the setting of advanced cirrhosis, and the patients have complications and clinical features of the latter. Blood pressure is usually low due to reduced systemic vascular resistance. Investigations show a rise in blood urea and serum

Tropical Hepatogastroenterology

APPROACH TO A PATIENT WITH HRS

creatinine. In type I HRS, there is doubling of serum creatinine to a level greater than 2.5 mg/dl in less than 2 weeks. Patients who do not have such a rapid decline of renal function are considered to have type II HRS. The major manifestation of patients with type II HRS is refractory ascites, while that of type I HRS is severe renal failure. Hyponatremia is almost universal.

45.8 APPROACH TO A PATIENT WITH HRS When a patient with advanced liver disease has azotemia HRS should be suspected. However, the diagnosis of HRS should always be made after the exclusion of other causes of renal failure in cirrhosis.[14] A history of nephrotoxic drugs, gastrointestinal bleeding, excessive gastrointestinal or renal fluid losses may point to an alternative etiology. Even in the absence of obvious losses, the patient’s renal function should be reassessed after diuretic withdrawal and volume expansion with 1.5 liters of normal saline. If hypotension was present before the onset of renal failure, the patient is likely to have acute tubular necrosis. The patient needs to be evaluated for infection including leucocyte count, blood cultures, and ascitic fluid analysis to rule out spontaneous bacterial peritonitis. The presence of proteinuria or hematuria points to a glomerular pathology which may occur in HBV and HCV infection or in alcoholic cirrhosis.[31]

45.9 MANAGEMENT OF HRS HRS was considered to be an incurable terminal event in cirrhosis and drug therapy was considered ineffective. However, with liver transplantation providing a cure, a number of trials of medical therapy have been carried out showing improvement in a renal function and prolonging survival as a bridge

Part X / Special Topics

741

to transplantation. The rationale of the various therapeutic modalities based on the pathophysiology is depicted in Fig. 45.1. The various treatment modalities in HRS have been shown in Table 45.3.

45.9.1 Vasoconstrictors Vasoconstrictor drugs cause vasoconstriction of the splanchnic vessels, thereby improving renal perfusion and suppressing renal vasoconstrictor activity. The drugs which have been used include vasopressin analogues (Terlipressin/Ornipressin) and the α-adrenergic drugs (norepinephrine/ midodrine). Ornipressin is associated with intestinal ischemia in one third of the patients.[32, 33] Terlipressin has a lower incidence of ischemic side effects and been used in a dose of 0.5– 2.0 mg 4–6 hourly as an intravenous bolus.[34–37] Norepinephrine has been used in a dosage of 0.5–3.0 mg/hr infusion.[38] Midodrine is an oral α-adrenergic agonist and has been shown to be effective along with albumin and octreotide (to suppress glucagons) in a small number of patients.[39]

45.9.2 Albumin Infusion along with Vasopressor Gines et al. have assessed whether albumin is necessary in the treatment of HRS along with vasopressors. They showed that both the components are important as HRS does not reverse with vasoconstrictors or plasma expansion when given alone.[40]

45.9.3 Transjugular Intrahepatic Portocaval Shunt (TIPS) The rationale for the use of TIPS is that the portal hypertension is the initiating event in HRS and TIPS results in a fall in portal pressure. In this

742

Chapter 45 / HEPATORENAL SYNDROME

FIGURE 45.1 Pathogenesis and treatment strategies of the hepatorenal syndrome. (MARS – molecular adsorbent and recirculating system, RAAS – renin-angiotensin aldosterone system, SNS – sympathetic nervous system, ADH – antidiuretic hormone, PG – prostaglandins, NO – nitric oxide).

procedure, a stent is inserted between the portal and hepatic veins by a transjugular approach. There

are several reports of efficacy of TIPS in reversal of HRS.[41–43] However TIPS may be contraindicated

Tropical Hepatogastroenterology

PROGNOSIS

TABLE fy 45.3 Treatment modalities in HRSy 1. Vasoconstrictors (a) Vasopressin analogues: terlipressin, ornipressin (b) α-adrenergic drugs: Norepinephrine, midridone 2. Albumin infusion along with vasopressor 3. TIPS 4. Liver transplantation 5. Others: (a) Hemodialysis (b) Molecular adsorbent recirculating system (MARS) (c) Antioxidants: N-acetylcysteine (d) Endothelin antagonists (e) Renal vasodilators: dopamine, prostaglandins

743

45.9.5 Other Treatment Modalities The other treatment modalities which have been tried include hemodialysis, Molecular Adsorbent Recirculating System(MARS), antioxidants like N-acetylcysteine, endothelin antagonists, and renal vasodilators like dopamine and prostaglandins. While conventional therapy does not appear to be effective in HRS,[45] MARS appears to have the potential to act as a bridgeto-transplantation.[46]

45.10 PROGNOSIS in the presence of encephalopathy and advanced liver disease.

45.9.4 Liver Transplantation Liver transplantation is the ideal treatment for HRS and medical management of HRS prior to transplantation reduces the morbidity and mortality.[44]

Patients with type-2 HRS have a poorer short-term prognosis as compared to patients with type I HRS. Patients with type-2 HRS have a survival rate of 50% and 20% at 5 months and 1 year after the onset of the renal failure respectively.[24] The prognosis of patients with type-1 HRS is extremely poor, with 80% of patients dying in less than 2 weeks after the onset of HRS.[13]

REFERENCES [1] Gines P, Rodes J. Clinical disorders of renal function in cirrhosis with ascites. In: Arroyo V, Gines P, Rodes J, Schrier RW, eds. Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis, and treatment. Malden: Blackwell Science, 1999; 36–62. [2] Briglia AE, Anania FA. Hepatorenal syndrome. Definition, pathophysiology, and intervention. Crit Care Clin 2002;18:345–73. [3] Eckardt KU. Renal failure in liver disease. Intensive Care Med 1999;25:5–14. [4] Moreau R. Hepatorenal syndrome in patients with cirrhosis. J Gastroenterol Hepatol 2002;17: 739–47.

Part X / Special Topics

[5] Hoefs JC. Hepatorenal syndrome. In Haubrich WS, Schaffner F, eds. Bockus’ Gastroenterology 5th ed. WB Saunders Company, 1995: 2023–34. [6] Sanyal A. J. Hepatorenal syndrome. J Gastroenterol Hepatol 2002;17(Suppl 3) S248–S252. [7] Flint A. Clinical report on hydro-peritoneum based on an analysis of forty-six cases. Am J Med Sci 1863; 45:306–339. [8] Helwig FC, Schutz CB. A liver kidney syndrome. Clinical pathological and experimental studies. Surg Gynecol Obstet 1932;55:570–580. [9] Orr TG, Helwig FC. Liver trauma and the hepatorenal syndrome. Ann Surg 1939;110:683–92.

744

Chapter 45 / HEPATORENAL SYNDROME

[10] Wilensky AO. Occurrence, distribution and pathogenesis of so called liver death and/ or hepatorenal syndrome. Arch Surg 1939;38: 625–91. [11] Heyd CG. Liver deaths in surgery of the gallbladder. JAMA 1931;97:1847–48. [12] Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure. Lancet 1956;2: 1221–25. [13] Gines A, Escorsell A, Gine’s P et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993;105:229–236. [14] Arroyo V, Gines P, Gerbes AL et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164–76. [15] Ring-Larsen H. Renal blood flow in cirrhosis: relation to systemic and portal hemodynamics and liver function. Scand J Clin Lab Invest 1977;37: 635–42. [16] Epstein M, Berck, Hollemberg NK et al. Renal failure in the patient with cirrhosis: the role of active vasoconstriction. Am J Med 1970;49:175–85. [17] Kew MC, Brunt PW, Varma RR. Renal and intrarenal blood flow in cirrhosis of the liver. Lancet 1971;2:504–10. [18] Schroeder ET, Shear L, Sancetta SM et al. Renal failure in patients with cirrhosis of the liver: evaluation of intrarenal blood flow by para-aminohippurate extraction and response to angiotensin. Am J Med 1967;43:887–96. [19] Platt JF, Marn CS, Baliga PK et al. Renal dysfunction in hepatic disease: early identification with renal duplex Doppler US in patients who undergo liver transplantation. Radiology 1992;183:801–6. [20] Cardenas A, Uriz J, Gines P et al.“Hepatorenal syndrome.” Liver Transpl. 6.4 Suppl 1 (2000):S63–S71. [21] Bataller R, Sort P, Gines P et al. Hepatorenal syndrome: definition, pathophysiology, clinical features and management. Kidney Int. 1998;53 (Suppl 66):S47–S53. [22] Wong F, Blendis L. New challenge of hepatorenal syndrome: prevention and treatment. Hepatology 2001;34:1242–51.

[23] Arroyo V, Guevara M and Gines P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology 2002;12:1658–76. [24] Arroyo V, Colmero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003; 38:S 69–89. [25] Arroyo V, Jime’nez W. Complications of cirrhosis. Renal and circulatory dysfunction lights and shadows in an important clinical problem. J Hepatol 2000;32:157–170. [26] Sort P, Navasa M, Arroyo V et al. Effect of plasma volume expansion on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341: 403–09. [27] Follo A, Llovet JM, Navasa M et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20:1495–01. [28] Gin`es P, Tit´o Ll, Arroyo V et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493–502. [29] Del Olmo JA, Pena A, Serra MA et al. Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis. J Hepatol 2000;32:19–24. [30] Cardenas A, Gines P, Uriz J et al. Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors and short-term prognosis. Hepatology 2001;34:671–6. [31] Gines P, Guevara M, Arroyo V et al. Hepatorenal syndrome. Lancet. 2003;362:1819–27. [32] G¨ulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type I with ornipressin and dopamine. Hepatology 1999;30:870–75. [33] Guevara M, Gin`es P, Fern´andez-Esparrach G et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998;27:35–41. [34] Halimi C, Bonnard P, Bernard B et al. Effect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicentre

Tropical Hepatogastroenterology

REFERENCES

[35]

[36]

[37]

[38]

[39]

[40]

pilot study. Eur J Gastroenterol Hepatol 2002;14: 153–58. Moreau R, Durand F, Poynard T et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002;122:923–30. Uriz J, Gin`es P, C´ardenas A et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000;33: 43–48. Ortega R, Gin`es P, Uriz J et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002;36:941–48. Duvoux C, Zanditenas D, Hezode C et al. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study. Hepatology 2002;36:374–80. Angeli P, Volpin R, Gerunda G et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999;29:1690–1697. Gines P, Ortega R, Uriz J et al. Effect of terlipressin administration with and without albumin in hepatorenal syndrome (HRS) (abstract). A phase-II study. Hepatology 2001;34:186A.

test

Part X / Special Topics

745

[41] Guevara M, Gine’s P, Bandi JC et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology 1998;28:416–422. [42] Alam I, Bass NM, LaBerge JM et al. Treatment of hepatorenal syndrome with the transjugular intrahepatic shunt (TIPS). Gastroenterology 1995;108:A1024. [43] Brensing KA, Textro J, Perz J et al. Long-term outcome after transjugular intrahepatic portosystemic stent-shunt in nontransplant patients with hepatorenal syndrome: a phase II study. Gut 2000;47: 288–295. [44] Restuccia T, Guevara M, Gin`es P et al. Impact of pretransplant treatment of hepatorenal syndrome with vasopressin analogues on outcome after liver transplantation: a case-control study. J Hepatol 2003;38:69A (abstract). [45] Wilkinson SP, Weston MJ, Parsons V et al. Dialysis in the treatment of renal failure in liver disease. Clin Nephrol 1977;8:287–292. [46] Mitzner SR, Stange J, Klammt S et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective randomized, controlled clinical trial. Liver Transpl 2000;6:277–286.

Chapter

46 HEPATIC ENCEPHALOPATHY AC Anand

Hepatic (portosystemic) encephalopathy (HE) includes a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction or portal-systemic shunting. Diagnosis depends on exclusion of other known brain diseases.[1] The commonest change is reversible alteration in sensorium (Table 46.1).

(b)

(c)

46.1 CLINICAL FEATURES The diagnosis of HE is easy if the background liver disease is recognized. In addition to the symptoms and signs of hepatocellular dysfunction, one may recognize precipitating events.[2] These events include use of sedatives, volume or electrolyte disturbance (e.g., diuresis, diarrhea, vomiting, paracentesis, hemorrhage), stress such as surgery or infection, an alcoholic binge, constipation, and increased dietary protein intake in the presence of portosystemic shunting (Table 46.2). The clinical picture[2, 4–6] includes the following: (a) Altered consciousness, often beginning with inversion of sleep rhythm. During the day, the patient appears excessively drowsy and is unable to sleep at night. There is reduction of spontaneous movement, a fixed stare, apathy, and slowness of response in early signs. 746

(d)

(e)

(f)

(g)

Further deterioration to stupor can be graded (Table 46.2). Psychiatric and personality changes, which are common and include childishness, irritability, and loss of concern for family suggesting frontal lobe involvement. Patients are usually co-operative, and frequently euphoric. Speech that is slow, slurred, and monotonous. Dysphasia becomes marked as encephalopathy progresses and is always combined with perseveration. Intellectual deterioration, including mental confusion, visual spatial agnosia, and constructional apraxia. Patients may micturate and defecate in inappropriate places. Fetor hepaticus, a sour, fecal smell in the breath, that may occur due to volatile substances such as mercaptans normally formed in the stool by bacteria. ‘Flapping’ tremor or asterixis, which can be elicited by asking the patient to out-stretch his arms and fingers and keep them hyperextended at the wrists. The rapid flexion-extension movements at the metacarpophalangeal and wrist joints indicate asterixis. It is not specific for hepatic precoma, and can also be observed in uremia, and respiratory failure. Exaggeration of deep tendon reflexes. Increased muscle tone is present and sustained

DIFFERENTIAL DIAGNOSIS

747

TABLE fy 46.1 Types of hepatic encephalopathy Classification

Nomenclature

Type A

∗ Acute

Type B

∗ In patients with portosystemic bypass with no intrinsic liver disease Acute episode in course of chronic liver disease. Can be episodic, spontaneous or recurrent Persistent Can be mild severe or treatment dependent Subclinical hepatic encephalopathy

Type C

∗ patients

hepatic failure

Extrahepatic

Neurologic

portosystemic shunting

manifestations

Absent

Specific features

Acute confusional state to coma Relapsing episodes and persistent abnormalities

Complication of acute hepatitis Secondary to surgical portosystemic shunts

Variable

Acute confusional state to coma

Often a precipitating cause is present

Severe

Persistent cognitive or motor abnormalities

Variable

Asymptomatic

Generally related to surgically induced shunts Minor personality changes, abnormal psychometric tests

Large portosystemic shunts, either surgical or TIPS

may not have any preexisting liver disease

ankle clonus is often associated with rigidity. During coma, patients become flaccid and lose their reflexes. The plantar responses are usually flexor, becoming extensor in deep stupor or coma. HE can be of several types (Table 46.1) and grades of severity (Table 46.3). The onset of clinical encephalopathy may be acute or insidious. The syndrome may appear spontaneously, due to deterioration in liver functions or, more commonly, be precipitated by additional factors that affect hepatic or cerebral function directly or indirectly, or by increasing the portal-collateral flow. The clinical course fluctuates, and frequent observation of the patient is necessary. Between 15% and 60% of apparently normal patients with cirrhosis and/or portasystemic shunts with no clinical encephalopathy fail psychometric tests, have poor verbal skills and abnormal EEG. Subtle changes in behavior may be noticeable to the

Part X / Special Topics

spouse during this phase. This state has been called ‘subclinical encephalopathy’. Chronic encephalopathy often complicates extensive portal-systemic shunting, which can be spontaneous or iatrogenic, i.e., surgical or after transjugular intrahepatic portosystemic shunting (TIPS). Fluctuations in encephalopathy may be seen depending on the dietary protein intake and other precipitating events. Rarely one may see acute psychiatric states presenting as delirium or hypomania. Gastroenterologists have also described hepatocerebral degeneration[7] with associated myelopathy, presenting as paraplegia. Chronic cerebellar and basal ganglia signs with Parkinsonism may on rare occasions develop after years of chronic hepatic encephalopathy.

46.2 DIFFERENTIAL DIAGNOSIS One should keep in mind hyponatremia, other metabolic encephalopathies, acute alcoholism,

748

Chapter 46 / HEPATIC ENCEPHALOPATHY

TABLE fy 46.2 Precipitating factors for hepatic encephalopathy Precipitating factor Gastrointestinal bleeding

Mechanism of action

Effect facilitated by associated

Hepatic hypoperfusion, deterioration in liver function

Infection

Blood is a large protein meal

Anemia

Hypokalemia Azotemia

Increased ammonia generation Increased ammonia generation

– –

Dehydration, diarrhea, vomiting

Hepatic hypoperfusion, deterioration in liver function Hypokalemia, azotemia and dehydration

Hypokalemia, azotemia

Acute hepatitis

Liver injury Activation of cytokines may enhance effect of neurotoxins

Use of paracetamol/other hepatotoxic drugs during prodromal period

Sepsis

Protein catabolism, increase in blood ammonia level Activation of cytokines may enhance effect of neurotoxins Stress of surgery, blood loss, and ‘shock’ lead to hepatic hypoperfusion Ammonia generation by enteric flora

Azotemia

Increased ammonia production Acute intoxication, impairment of hepatic function Activation of inhibitory neurotransmission, further impairment of cerebral function. Prolonged action as hepatic detoxification is ineffective

Animal protein poorly tolerated Other substance abuse

Diuretics or large volume paracentesis

Surgery Constipation Large protein intake Acute alcoholism Psychoactive drugs such as Opiates, benzodiazepines and barbiturates

Wernicke’s encephalopathy due to malnutrition and alcoholism, hepatolenticular degeneration (Wilson’s disease), and latent functional psychoses, such as depression or paranoia, when a diagnosis of HE is considered.

46.3 INVESTIGATIONS Liver functions are often deranged. The cerebrospinal fluid is usually clear and under normal pressure. It may show raised protein concentration,

Hypovolemia leading to changes in hepatic circulation and hypotension may contribute.

Arterial hypotension Anesthetics hepatotoxicity –

–

but the cell count is normal. Glutamic acid and glutamine may be increased. Electroencephalography (EEG) shows a bilateral synchronous slowing of the wave frequency (with an increase in wave amplitude) from the normal alpha rhythm of 8– 13 cycles per second (Hz) down to the delta range of below 4 cycles per second. The change starts in the frontal or central region and progresses posteriorly. EEG changes occur very early even before psychiatric or biochemical disturbances. Similar changes have also been seen in uremia,

Tropical Hepatogastroenterology

PATHOLOGY

749

TABLE fy 46.3 The clinical grades of hepatic encephalopathy Grade of

Features

encephalopathy Subclinical I

II III IV

Diagnosed only by psychometry and EEG recording Trivial lack of awareness, mild confusion, euphoria, anxiety or depression, shortened attention span, slowing of ability to perform mental tasks (addition/subtraction), Reversal of sleep rhythm Drowsiness, lethargy or apathy, obvious personality changes, inappropriate behavior, intermittent disorientation of time (and place) and lack of sphincter control Somnolent but reusable by noxious stimuli, disorientation of time and place, marked confusion and disorientation. Coma with no response to painful noxious stimuli

chronic respiratory failure, vitamin B12 deficiency, and hypoglycemia. Evoked potentials abnormalities also occur early, but are at best a research tool. CT scans often show cerebral atrophy and sometimes cerebral edema.[8] On T2 weighted MRI images, there is increased signal in the basal ganglia in cirrhotic patients possibly due to the deposition of manganese. Magnetic resonance spectroscopy may reveal changes in intracellular glutamine.

46.4 PATHOLOGY Cerebral edema is apparent in about half of the patients on gross examination. Microscopically, astrocyte proliferation with enlargement of nuclei, prominent nucleoli, margination of chromatin, and accumulation of glycogen can be seen (Alzheimer type 2 astrocytosis).[9, 10] These changes are common in the cerebral cortex and basal ganglia. In chronic encephalopathy, one may notice hepatocerebral degeneration consisting of cortical thinning with loss of neurons in the cortex, basal ganglia, cerebellum, and demyelination in the pyramidal tracts.

Part X / Special Topics

46.5 PROGNOSIS The prognosis depends on the extent of liver cell failure. The best prognosis occurs in patients with chronic HE and relatively good liver function combined with a precipitating event. It is worst in those with acute hepatitis. In cirrhosis, the outlook is poor if the patient has ascites, jaundice, a low serum albumin level, and if encephalopathy has appeared without a precipitating factor – all indicative of advanced liver failure. The survival probability in cirrhotic patients after the first episode of acute HE is 42% at 1 year and 23% at 3 years.[1–3]

46.6 PATHOGENESIS (Fig. 46.1) The basic abnormality is a failure of liver to clear gut-derived neurotoxic or neuroactive substances either due to hepatocellular failure, or to portosystemic shunting. The most likely source of such substances is intestinal bacteria.[11–14] A summary of some such substances is outlined in Table 46.4. Brain dysfunction is associated with a low-grade chronic glial edema with subsequent alterations of glioneuronal communication. Factors such as ammonia, benzodiazepines, and inflammatory cytokines cause astrocyte swelling;

750

Chapter 46 / HEPATIC ENCEPHALOPATHY

diazepines, and inflammatory cytokines. Therefore heterogeneous conditions (e.g., bleeding, electrolyte disturbances, sedatives, infections) precipitate HE in the cirrhotic patient. Noncirrhotics may tolerate such precipitating factors without developing HE symptoms because their osmolyte systems for counteraction of cell swelling are not exhausted. In cirrhosis, however, organic osmolytes are largely depleted in order to compensate for glial glutamine accumulation and there may be little room for action of these volumeregulatory mechanisms against further challenges of cell volume.

46.7 TREATMENT 46.7.1 General Measures FIGURE 46.1 Pathogenesis of hepatic encephalopathy. Brain dysfunction is multifactorial and is caused by chemicals produced in gastrointestinal tract by gut bacteria (2) acting on nitrogenous material (1) provided by proteins. The toxic chemicals and false neurotransmitters (3) so produced cannot be detoxified by a liver with poor function (4a), or bypass liver due to portosystemic shunting of blood (4b) (BZP - benzodiazepines).

this activates osmosignaling cascades, protein modifications, altered gene expression, and altered neurotransmission. Investigators have identified several proteins that are nitrated in response to ammonia, benzodiazepines, and hypo-osmotic astrocyte swelling or inflammatory cytokines; among these are glutamine synthetase and the peripheral type benzodiazepine receptor. Nitration of critical tyrosine residues in glial proteins may play an important role. Astrocyte swelling is induced not only by ammonia[15] but also by hyponatremia, benzo-

Patients of HE are hospitalized for intensive supervision of the vital functions, volume, electrolytes, and acid-base status as well as for an efficient control of caloric administration.

46.7.2 Control of Precipitating Factors One of the first steps is the identification and treatment of the precipitating factors. Measures include control of bleeding, discontinuation of the precipitating drugs, and antibiotic treatment of infections such as spontaneous bacterial peritonitis or septic conditions.[16]

46.7.3 Caloric and Protein-administration, Enemas Cornerstone of the treatment of HE is the control of protein ingestion. It deserves primary attention because excessive dietary protein is the single most common precipitant of chronic and relapsing HE. Protein-restriction to 30 or even < 20 g per day often improves an existing HE. While a restriction of protein intake is beneficial for HE a negative

Tropical Hepatogastroenterology

TREATMENT

751

TABLE fy 46.4 Summary of some of the chemicals thought to be involved in pathogenesis of hepatic encephalopathy Substance Ammonia produced by urea-splitting bacteria and the small intestinal flora and high protein meal and by metabolism of glutamine by small intestinal mucosa. GABA Short-chain fatty acids Mercaptans

Manganese

Aromatic amino acids versus branched chain amino acids

Glutamate Serotonin Dopamine

Comments Ammonia blocks chloride channels, thereby impairing postsynaptic inhibition. It causes up-regulation of peripheral benzodiazepine receptors and enhances the synthesis of neurosteroids, resulting in agonist effects on GABA neurotransmission. It also downregulates glutamatergic synaptic uptake causing increase in brain glutamine. Increase in plasma levels and disturbance in GABAergic neurotransmission reported, however, GABA levels are not increased in CNS. Synergetic effects with ammonia however, plasma levels do not correlate with grade of HE. Act synergistically with other toxins, particularly ammonia, fatty acids and phenols. However, plasma levels found in HE are not neurotoxic nor do they correlate with grade of HE. Blood and brain concentrations of manganese are increased in chronic liver failure due to portal-systemic shunting. Exposure of astrocytes to manganese produces Alzheimer type 2 changes as seen in hepatic encephalopathy. (a) Increase in plasma levels found in HE. Amines generated either by bacterial action in the colon or by altered cerebral metabolism of precursors may inhibit dopamine and catecholamine-mediated cerebral neurotransmission. (b) Decarboxylation of some amino acids in the colon leads to the formation of p-phenylethanolamine, tyramine and octopamine, so-called false neurotransmitters. (c) Plasma aromatic amino acids, tyrosine, phenylalanine and tryptophan, are increased in patients with liver disease probably due to failure of hepatic deamination. (d) The branched-chain amino acids, valine, leucine and isoleucine are decreased, perhaps due to increased metabolism by skeletal muscle and kidneys secondary to the hyperinsulinemia of chronic liver disease. The two groups of amino acids compete for uptake into the brain. (e) An increase in phenylalanine level in the brain leads to inhibition of DOPA production and the formation of false neurotransmitters such as phenylethanolamine and octopamine. There is decrease in total brain glutamate, increase in extracellular glutamate, decrease in glutamate transporters and decrease in glutamate receptors. Increase in the metabolism of serotonin has been reported. In HE decrease of dopamine receptors, increase in degradation of DOPA, and improvement of extrapyramidal signs with DOPA have been reported.

nitrogen balance must be avoided as it may aggravate corresponding muscle wasting and hyperammonemia. Therefore, as soon as encephalopathy is controlled, a gradual increase of the protein admin-

Part X / Special Topics

istration to at least 1 g/kg bodyweight per day is necessary.[17, 18] Blood protein and meat proteins are more ammoniagenic than dietary vegetable protein.[19]

752

Chapter 46 / HEPATIC ENCEPHALOPATHY

One can eliminate ammonia (and some other gut-derived neurotoxins) by acidification of the gut lumen and trapping ammonia with nonabsorbable disaccharides such as lactulose. This can also be done by lactulose enemas. Catharsis by high enemas as well as total gut wash-outs favorably affects HE by removing bacteria, ammonia and toxincontaining substances from the gut. Other disaccharides such as lactose or lactilol act similarly.

46.7.4 Pharmacotherapy Due to the reversibility and the episodic character of the HE a high incidence of spontaneous improvements in existing HE can be expected in the natural course of disease. Randomized, controlled clinical studies are lacking for evaluation of pharmacological effects of most drugs (Table 46.5). The majority of the drugs used in TABLE fy 46.5 Current status of different treatments of HE Reasonable evidence of efficacy

Unconfirmed efficacy/ Large controlled trials lacking

Elimination of precipitating factors Protein restriction Vegetable protein Lactulose enemas L-ornithine-L-aspartate Oral branched-chain amino acids Transplantation

Oral lactulose Neomycin Lactobacillus Metronidazole Rifaximin Levodopa Bromocriptine Flumazenil Ornithine-ketoglutarate Sodium benzoate Zinc H. pylori eradication Intravenous branched-chain amino acids

the treatment of HE are primarily directed at the reduction or elimination of the increased neurotoxic ammonia. 46.7.4.1 Reduction of intestinal ammonia generation

The intestinal ammonia production and the action of toxins can be reduced by the elimination of the bacterial flora in the gut. For many years, the only therapy other than protein restriction was the administration of nonabsorbable antibiotic agent, Neomycin. Within the past few years, randomized clinical trials of metronidazole or nonabsorbable antibiotics such as rifaximin or vancomycin have found them to be as effective as neomycin. Nonabsorbable antibiotics such as neomycin, paromomycin, rifaximin, or vancomycin should not be administered for a longer period than 7 days. Complications may occur in form of diarrhea as well as nephrotoxicity, due to absorption of around 3% of drug. Absorbable antibiotics such as ampicillin may also be useful in HE and even better than metronidazole. 46.7.4.2 Enhancing the ammonia— detoxifying capacity of the liver

L-ornithine-L-aspartate (OA) administration can improve mental state, reduce hyperammonemia[20] and improve psychometric test results. Lornithine-L-aspartate provides critical substrates for both ureagenesis and glutamine synthesis, the two primary pathways of ammonia detoxification. The reduced glutamine synthetase activity in cirrhotics can be improved by OA administration. Additionally, stimulation of the extrahepatic ammonia-detoxifying capacity may be induced by OA treatment. Due to the short half-life of about 40 minutes, oral OA must be offered three times daily to induce an acceptable ammonia reduction.

Tropical Hepatogastroenterology

REFERENCES

Benzoic acid and phenylacetic acid are two substances which incorporate ammonia into hippuric acid and phenylacetyl glutamine, respectively. These products result in large decrements in blood ammonia concentration. Randomized clinical trials have compared sodium benzoate with lactulose.[21] Although it has been known for many years that serum zinc levels are often reduced in patients with alcoholic cirrhosis, the association of hypozincemia and HE has only recently been recognized. Because zinc is a component of carbamoyl phosphate synthetase, decreased zinc concentrations may contribute to decreased urea synthesis and increasing ammonia levels in cirrhotics.[22] The effectiveness of a zinc-substitution on the HE symptoms is controversial.

753

such as L-dopa or a dopamine-agonist such as bromocriptine can improve levels of consciousness in cirrhotic patients with hepatic encephalopathy. 46.7.4.4 Inhibition of GABA-receptors

Due to the increased benzodiazepine receptors as well as simultaneously increased benzodiazepine levels in the brain of patients with HE, there is a strong rationale for the administration of benzodiazepine receptor-antagonists such as Flumazenil. Flumazenil can improve level of consciousness, in patients with manifest, comatose and precomatose forms of HE but shows no influence on the mortality of the patients. The use for routine treatment of HE is doubtful.[24]

46.7.5 Other Treatments 46.7.4.3 Reduction of extraintestinal ammonia formation and of false neurotransmitters

Supplementation with branched chain amino acids (BCAA), both orally and intravenously, has been evaluated extensively in the management of both acute and chronic HE.[23] Amino acid mixtures with high concentrations of BCAA and low or lacking concentrations of aromatic amino acids administered orally improve patients with HE. The administration of a neurotransmitter precursor

The possibility of liver transplantation in selected cases seems to be the best proven option in the therapy of HE.[25] On the basis of recent publications, this option should already be considered after the appearance of a first coma-episode. Helicobacter pylori infection in patients with liver cirrhosis seems to be associated with a higher risk of hyperammonemia after a defined protein load.[26] Helicobacter pylori eradication may reduce the risk for HE in individual H. pylori-infected cirrhotics.

REFERENCES [1] Ferenci P, Lockwood A, Mullen K et al. Hepatic encephalopathy-definition, nomenclature, diagnosis and quantification: Final report of the working party at 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21. [2] Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001;96:1968–76.

Part X / Special Topics

[3] Das A, Dhiman RK, Saraswat VA et al. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 2001;16:531–6. [4] Saxena N, Bhatia M, Joshi YK et al. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and

754

[5] [6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14] [15]

[16]

Chapter 46 / HEPATIC ENCEPHALOPATHY

prediction of overt encephalopathy. Liver 2002;22: 190–7. Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis. Drugs 2000;60:1353–70. Watanbe A. Portosystemic encephalopathy in noncirrhotic patients: classification of clinical types, diagnosis and treatment. J Gastroenterol Hepatol 2000;15:969–74. Burkhard PR, Delavelle J, Du Pasquier R et al. Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003;60:521–8. Genovese E, Maghnie M, Maggiore G et al. MR imaging of CNS involvement in children affected by chronic liver disease. Am J Neuroradiol 2000; 21:845–51. Norenberg MD. Astrocytic–ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16: 245–53. H¨aussinger D, Schliess E. Osmotic induction of signalling cascades: role in regulation of cell function. Biochem Biophys Res Commun 1999;255: 551–5. Butterworth RF. Complications of cirrhosis. III. Hepatic encephalopathy. J Hepatol 2000;32: 171–80. Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999; 31:771–6. H¨aussinger D. Pathogenesis and treatment of chronic hepatic encephalopathy. Digestion 1998;59 (Suppl. 2):25–7. Ferenci P. Pathophysiology of hepatic encephalopathy. Hepatogastroenterology 1991;38:371–6. Norenberg MD. Astrocytic–ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16: 245–53. Riordan S, Williams R. Treatment hepatic encephalopathy. N Engl J Med 1997;337:473–8.

[17] Uribe M, Conn HO. Dietary management of portal systemic encephalopathy. In: Hepatic Encephalopathy: Syndromes and Therapies. Conn HO, Bircher J, eds. East Lansing, Michigan: Medi-Ed Press 1993;331–50. [18] Plauth M, Merli M, Kondrup J et al. ESPEN Guidelines for nutrition in liver disease and transplantation. Clin Nutr 1997;16:43–55. [19] Amodio P, Caregaro L, Patteno E et al. Vegetarian diets in hepatic encephalopathy: facts or fantasies? Dig Liver Dis 2001;33:492–500. [20] Rose C, Michalak A, Rao KV et al. 1-ornithineL-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 1999;30:636–40. [21] Sushma S, Dasarathy S, Tandon RK. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double blind randomized trial. Hepatology 1992;16:138–44. [22] Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long term treatment. Eur J Med 1993;2:414–16. [23] Eriksson LS. Branched-chain amino acids in the treatment of hepatic encephalopathy. In: Hepatic Encephalopathy. Syndromes and Therapies. Conn HO, Bircher J, eds. East Lansing, Michigan: MediEd Press, 1993;351–61. [24] Goulenok C, Bernard B, Cadranel JF et al. Flumazenil versus placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther 2002;16:361–72. [25] Bustamante J, Rimola A, Ventura P-J et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–5. [26] Wiedmann B, Klauk S, Kircheis G et al. The influence of the Helicobacter pylori infection on ammonia levels and psychometric test results in cirrhotic patients with hepatic encephalopathy. Gastroenterology 1997;112:1415.

Tropical Hepatogastroenterology

Chapter

47 ASCITES IN CIRRHOSIS AC Anand

Ascites in cirrhosis is common and develops in almost half of the cases over a 10 year follow up.[1] Some cirrhotics may have an additional cause for ascites, such as (10%), cardiac failure (3%), tuberculosis (2%), and pancreatitis (1%).[2] The development of ascites in cirrhosis is a marker for decompensation and increased mortality.

47.1 CLINICAL FEATURES Patients often notice increasing size of the abdomen or tightness of clothes. Some may complain of a stretching or pulling sensation in flanks. Clinical examination may reveal stigmata or chronic liver disease, minimal pedal edema, eversion of the umbilicus, fullness in the flanks, shifting dullness, and fluid thrill. Umbilical and inguinal hernias are common (Fig. 47.1). Even in asymptomatic patients, a minimal amount of fluid in peritoneal cavity can be visualized by ultrasound scanning.

47.2 PATHOGENESIS OF ASCITES IN CIRRHOSIS Several factors contribute to the development of ascites in cirrhosis. Hypoalbuminemia, increased hepatic and splanchnic lymph formation due to portal hypertension, renal retention of sodium, and

FIGURE 47.1 A large umbilical hernia in a cirrhotic patient with ascites. In time, the overlying skin thins and may necrose. Irreducibility is not uncommon. Patients require surgery, preferably under local anesthesia with sedation, under cover of adequate plasma to control the coagulopathy.

systemic vascular changes are all involved to varying degree. Different theories have been proposed to explain the initiating event for ascites in cirrhosis. These include the ‘underfill’, ‘overflow’ and the ‘forward’ theories.[3]

47.2.1 The Underfill Theory According to this theory, the increased resistance to flow in hepatic sinusoids leads to retrograde rise in 755

756

Chapter 47 / ASCITES IN CIRRHOSIS

hydrostatic pressure in the hepatic and splanchnic circulation.[4] This causes increased filtration of fluid in the interstitial space. With increasing portal pressure, the capacity of the lymphatic system to drain the excess fluid is overwhelmed resulting in ascites. The hypovolemia due to the formation of ascites triggers sodium and water retaining mechanisms.

47.2.2 The Overflow Theory According to this theory, in advanced cirrhosis, a sodium retaining signal is released resulting in salt and water retention and increase in plasma volume. An overflow fluid exudation and ascites are result of this fluid accumulation.[5] However, it has been shown that the systemic vascular resistance is underfilled and not overfilled as postulated.[6]

47.2.3 Forward Theory The currently accepted theory is the forward theory, which proposes that the initiating event for the formation of ascites is splanchnic arterial vasodilation.[6] Sinusoidal portal hypertension leads to the development of splanchnic arterial vasodilation related to an increased splanchnic production of vasodilator substances, particularly nitric oxide. This splanchnic arterial vasodilation leads to the formation of ascites by systemic arterial underfilling leading to the activation of the homeostatic sodium retaining mechanisms including the renin-angiotensin axis and sympathetic nervous system. Along with sodium retention, there is also water reabsorption due to nonosmotic secretion of argentine-vasopressin (AVP). Besides, the arterial vasodilation also impairs splanchnic microcirculation leading to increased permeability and leakage of fluids into the abdominal cavity. In later stages of cirrhosis, there is renal vasoconstriction

FIGURE 47.2 Pathogenesis of ascites in cirrhosis (ADH - antidiuretic hormone, RAAS - renin-angiotensin aldosterone system, SNS - sympathetic nervous system).

precipitated by extreme underfilling of the arterial circulation. The pathogenesis of ascites in cirrhosis is depicted in Fig. 47.2.

47.3 DEFINITIONS Grade I ascites is ascites detected only on ultrasound examination. Grade II ascites is moderate ascites causing symmetrical distension of the abdomen. Grade III ascites is tense ascites causing marked abdominal distension.[7] Refractory ascites was defined in 1996 by the International Ascites Club as ascites that cannot be mobilized, or the early recurrence of which cannot be satisfactorily prevented by medical therapy.[8]

Tropical Hepatogastroenterology

EVALUATION OF ASCITES

757

TABLE fy 47.1 Diagnostic criteria for refractory ascites Failure to decrease ascites to Grade I with Intensive diuretic treatment (Spironolactone 400 mg/day + Furosemide 160 mg/day) Sodium restriction (< 90 mmol/day or < 5.2 gm salt/day) Treatment duration of at least one week Lack of response Low weight loss (< 800 g/day during last 4 days) Urinary sodium output 100% to a value > 2 mg/dL) Diuretic-induced hyponatremia (↓ in serum sodium by 10 mmol/L to a serum sodium of < 125 mmol/L) Diuretic induced hypokalemia (< 3 mmol/L) Diuretic induced hyperkalemia (> 6 mmol/L)

Refractory ascites includes diuretic resistant and diuretic intractable ascites. Diuretic-resistant ascites is resistant ascites due to lack of response to dietary sodium resistance and intensive diuretic treatment. Diuretic-intractable ascites is resistant ascites due to development of diuretic-induced complications that preclude the use an effective diuretic dosage. The criteria for refractory ascites are depicted in Table 47.1.[7, 8]

cell count more than 250/ml suggests spontaneous bacterial peritonitis. In case other etiologies are suspected, then appropriate investigations like ascitic fluid amylase, adenosine deaminase, and ascitic cell morphology for malignant cells are done. Finally, in patients with cirrhotic ascites appropriate investigations are required to look for the etiology of cirrhosis and to rule out hepatocellular carcinoma, if indicated.

47.4 EVALUATION OF ASCITES

The treatment modalities available for management of ascites and the suggested approach are depicted in Table 47.2 and Fig. 47.3 respectively.

All patients with ascites should be investigated for evidence of portal hypertension on ultrasound abdomen and endoscopic evidence of varices. Ascitic fluid examination should be carried out, including the serum ascites albumin gradient (SAAG), cytology, biochemistry, and culture. SAAG (i.e., serum albumin – ascitic fluid albumin concentration) ≥ 1.1 g/L is 97% accurate in diagnosing portal hypertension as a cause of the ascites.[9] Ascitic fluid polymorphonuclear

Part X / Special Topics

47.5 TREATMENT MODALITIES

47.5.1 Dietary Salt Restriction Dietary salt should be moderately restricted to 90 mmol/day (5.2 g/day).[7] Reducing dietary salt intake to 60–90 mEq/day leads to mobilization of ascitic fluid 10%–15% of the patients.[1, 10] While a majority of cases will require diuretics, sodium

758

Chapter 47 / ASCITES IN CIRRHOSIS

TABLE fy 47.2 Treatment modalities in the management of ascites • Sodium restriction • Diuretics Aldosterone antagonists: spironolactone, canrenoate Other K+ sparing diuretics: Amiloride, triamterene Loop diuretics: Furosemide • Therapeutic paracentesis • Aquaretics • Transjugular intrahepatic portasystemic shunt (TIPS) • Peritoneovenous shunts • Liver transplantation

sparing diuretics (Amiloride, Triamterene) and the loop diuretics (Furosemide). Unlike its effect in healthy persons, in patients with cirrhotic ascites spironolactone is more effective than furosemide.[12] Spironolactone is used in an initial dose of 100 mg/day increasing up to 400 mg/day. Furosemide addition is done starting at 40 mg/day (in combination with 100 mg/day of Spironolactone), increasing up to a maximum of 160 mg/day. The aim of diuretic therapy is to achieve a weight loss of 0.3–0.5 kg/day in patients without edema and 0.5–1.0 kg/day in patients with edema.[13] While water restriction appears logical in patients with dilutional hyponatremia, this may exacerbate the hypovolemia in cirrhosis.

47.5.3 Aquaretics Aquaretics are drugs that interfere with the renal effects of ADH and inhibit water reabsorption from the collecting tubules without affecting sodium excretion. There are two types of aquaretic agents: κ-opioid agonists and vasopressin V2 receptor antagonists. Aquaretic drugs like niravoline and appear to be agents of promise in treatment of water retention and dilutional hyponatremia in cirrhosis.[14]

47.5.4 Therapeutic Paracentesis FIGURE 47.3 Approach to management of ascites (LVP - large volume paracentesis, TIPS - transjugular intrahepatic portosystemic shunt).

restriction is important as it reduces diuretic requirement.[11]

47.5.2 Diuretics The diuretics include the Aldosterone antagonists (spironolactone, canrenoate), the other K+

Therapeutic paracentesis is used to treat refractory ascites, and to give rapid relief in patients with tense ascites. Studies have shown that paracentesis is more effective than diuretics in resolution of ascites and decreasing the duration of hospitalization.[15, 16] Total large volume paracentesis is as safe and as effective as repeated paracentesis.[17] Therapeutic paracentesis without albumin infusion is associated with a higher incidence of side effects than when albumin is given.[18] In the presence of peripheral edema, a single

Tropical Hepatogastroenterology

PROGNOSIS

759

paracentesis of up to 5 liters without albumin infusion may not be associated with short term hemodynamic dysfunction.[19] A larger amount of ascitic fluid removal, especially if there is no peripheral edema, should be associated with volume replacement as these patients may develop postparacentesis hypovolemia, hyponatremia, and renal impairment. The choice of volume expanders includes human albumin and the synthetic plasma expanders such as dextran 70, dextran 40 or polygeline. While some studies have shown similar efficacy Gines et al have shown that albumin is better than dextran70 or Polygeline in preventing postparacentesis circulatory dysfunction.[20] Since postparacentesis circulatory dysfunction develops late, volume expansions should be given after paracentesis has been completed. If ascitic fluid removed is more than 5 liters, albumin should be given in a dose of 8 gm/l of ascitic fluid removed. In case the paracentesis is less than 5 liters, a synthetic plasma substitute may be used.[7]

from the hepatic vein through the liver to the portal vein. By decreasing the portal pressure it decreases the splanchnic arterial vasodilation and it improves arterial underfilling. Hepatic encephalopathy is the most important complication and may occur in a third of patients undergoing TIPS.[21, 22]

47.5.5 Transjugular Intrahepatic Portasystemic Shunt (TIPS)

47.6 PROGNOSIS

In TIPS, the portal system is decompressed by radiological placement of a flexible metallic stent

47.5.6 Peritoneovenous Shunt Peritoneovenous shunts including the LeVeen the Denver Shunt were specifically designed for the treatment of refractory ascites. However, due to its complications, peritoneovenous shunting has little role in management of refractory ascites.

47.5.7 Liver Transplantation Since the prognosis of patients with ascites is poor, all patients with ascites should be considered as candidates for liver transplantation.

Patients with cirrhotic ascites have mortality rates of approximately fifty percent in two years.[23]

REFERENCES [1] Gines A, Quintro E, Arroyo V et al. Compensated cirrhosis: Natural history and prognostic factors. Hepatology 1987;7:122–28. [2] Reynolds TB. Ascites. Clin Liver Disease 2000;4:15–68. [3] De Franchis R, Salerno F. Pathogenesis of ascites and resistance to therapy. J Gastroenterol Hepatol 2002;17:S242–S247. [4] Witte CL, Witte MH, Dumont AE. Lymph imbalance in the genesis and perpetuation of ascites

Part X / Special Topics

syndrome in hepatic cirrhosis. Gastroenterology 1980;78:1059–68. [5] Lieberman FL, Denison EK, Reynolds TB. The relationship of plasma volume, portal hypertension, ascites, and renal sodium retention in cirrhosis: the overflow theory of ascites formation. Ann N Y Acad Sci 1970;170: 202–7. [6] Schrier RW, Arroyo V, Bernardi M et al. Peripheral arterial vasodilation hypothesis. A proposal for the

760

[7]

[8]

[9]

[10] [11]

[12]

[13]

[14]

[15]

Chapter 47 / ASCITES IN CIRRHOSIS

initiation of sodium and water retention in cirrhosis. Hepatology 1988;8:1151–57. Moore KP, Wong F, Gines P et al. The management of ascites in cirrhosis: Report on the consensus conference of the international Ascites club. Hepatology 2003;38:258–66. Arroyo V, Gines P, Gerbes AL et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164–76. Runyon BA, Montano AA, Akriviadis EA et al. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992;117:215–220. Gerbes AL. Medical treatment of ascites in cirrhosis. J Hepatol 1993;17(Suppl. 2):S4–S9. Gauthier A, Levy VG, Quinton A et al. Salt or no salt in the treatment of cirrhotic ascites: a randomized study. Gut 1986;27:705–709. Perez-Ayuso RM, Arroyo V, Planas R et al. Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin–aldosterone system. Gastroenterology 1983;84:961–968. Arroyo V, Colmero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38:S69–89. Gadano A, Moreau R, Pessione F et al. Aquaretic effects of niravoline, a κ-opioid agonist, in patients with cirrhosis. J Hepatol 2000;32:38–42. Gines P, Arroyo V, Quintero E et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 1987;93:234–341.

[16] Salerno F, Badalamenti S, Incerti P et al. Repeated paracentesis and iv albumin infusion to treat tense ascites in cirrhotic patients. A safe alternative therapy. J Hepatol 1987;5: 102–108. [17] Tito L, Gines P, Arroyo V et al. Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology 1990;98:146–151. [18] Gines P, Tito L, Arroyo V et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493–1502. [19] Peltekian KM, Wong F, Liu PP et al. Cardiovascular, renal and neurohumoral responses to a single large volume paracentesis in patients with cirrhosis and diuretic resistant ascites. Am J Gastroenterol 1997;92:394–99. [20] Gines A, Fernandez-Esparrach G, Monescillo A et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 1996;111:1002–1010. [21] Rossle M, Ochs A, G¨ulberg V et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 2000;342:1701–1707. [22] Sanyal AJ, Freedman AM, Shiffman ML et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology 1994;20: 46–55. [23] D’Amico G, Morabito A, Pagliaro L et al. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986;31: 468–75.

Tropical Hepatogastroenterology

Chapter

48 MALIGNANT LIVER TUMORS Anil K Agarwal, Shivendra Singh, and Sanjoy Mandal

Malignant tumors of the liver can be either primary or metastatic. Metastatic tumors form the most common tumors of the liver. Of the primary malignant liver tumors, hepatocellular carcinoma is the most common (Table 48.1).

48.1 HEPATOCELLULAR CARCINOMA Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte. HCC frequently arises in the setting of cirrhosis, appearing 20– 50 years following the initial insult to the liver. However, 25% of patients have no history or risk

TABLE fy 48.1 Malignant tumors Primary • Hepatocellular carcinoma • Cholangiocarcinoma • Hepatoblastoma • Angiosarcoma • Epithelioid hemangioendothelioma • Infantile hemangioendothelioma • Embryonal sarcoma • Leiomyosarcoma Secondary/metastatic • Colorectal • Neuroendocrine • Noncolorectal non-neuroendocrine

factors for the development of cirrhosis. The extent of hepatic dysfunction limits treatment options, and patients usually die of liver failure. Hopefully, a major impact on incidence of HCC will be achieved through the current vaccination strategies for hepatitis B virus (HBV) infection and the systematic screening of blood donations for hepatitis B and C virus. However, because the latency period from infection to HCC development is very long, years may pass until the incidence of HCC decreases as a result of these interventions.

48.1.1 Epidemiology The highest incidence is seen in south-east Asian countries like Taiwan, China, Singapore, Hong Kong, and in tropical Africa.[1] In these countries the incidence is higher than 20 per 1,00,000 population. Europe, North America, Australia and countries like India have a low incidence. In the west, the incidence is about 1–3 per 1,00,000 population.[2, 3] Migrant populations generally acquire the incidence profile of the local population.[3, 4]

48.1.2 Risk Factors and Etiology The most consistent etiologic association is with persistent HBV infection. The relative risk of 761

762

Chapter 48 / MALIGNANT LIVER TUMORS

developing HCC in HBV infection is about 200 fold greater than normal. The development of HCC requires a persistence of virus infection like in the form of chronic HBV carrier state.[5] The risk of becoming a carrier is much higher if the infection is acquired at birth or early childhood. Infection in adults has a lower risk. The risk is about 40% in those infected in childhood in comparison to 10% among those infected as adults.[5, 6] The genome of human HBV does not contain oncogenes and it probably exerts its effect on hepatocarcinogenesis through transactivation and transregression of cellular genes or factors by HBV related gene product. Integration of viral DNA may also be responsible for hepatocarcinogenesis in HBsAg negative patients. Thus, the absence of HBV DNA in serum and HBsAg negativity do not rule out HBV infection being a contributory factor of hepatocarcinogenesis in a particular patient. Patients with HBsAg seropositive chronic HBV infection have a 70-fold relative risk of HCC as compared to seronegative patients. Even HBsAg negative cases of HCC often exhibit immunologic or PCR evidence of past or present HBV infection.[7] Hepatitis C virus infection is another important cause of chronic liver disease and HCC. Antibodies to HCV are seen in 76% of cases of HCC in Japan, Italy, and Spain, whereas in USA they are seen in 36% of cases of HCC. HCC in HCV infection can develop in noncirrhotics also. Patients with chronic hepatitis C have a 2.7-fold increased risk of HCC compared to patients suffering from chronic hepatitis B. The incidence of HCC in HCV carriers is 20% as compared to 5% in HBV carriers.[8] Aflatoxin is derived from the fungi Aspergillus flavus and A. parasiticus. The fungi produce toxins that are designated as B1, B2, G1, and G2. Among these aflatoxins, B1 is the most hepatotoxic. The intake of aflatoxins, has correlated with the development of HCC, especially in China.[9]

These fungi grow rapidly on grains, peanuts, and on food products stored in humid tropical and subtropical conditions. Chronic alcohol abuse and smoking have also been implicated as causative factors in low incidence areas. Cirrhosis of any cause has been known to predispose to HCC especially those with large nodules and thin stromas.[10] Rarely, HCC is associated with hemochromatosis, Wilson’s disease, hereditary tyrosinemia, type I glycogen storage disease, hepatic porphyria, biliary atresia, α-antitrypsin deficiency, and BuddChiari syndrome.[1] Thorotrast, which was used as an angiographic contrast medium in the past, is associated with angiosarcoma in the west, and with both HCC and cholangiocarcinoma in Japan.[11] Chemicals such as nitrites, hydrocarbons, solvents, organochlorine, pesticides, primary metals, and polychlorinated biphenyls have also been shown to increase the risk for HCC.

48.1.3 Pathophysiology HCC is a malignant tumor of hepatocellular origin. It develops in patients with risk factors that include alcohol abuse, viral hepatitis, and metabolic liver disease. It can occur rarely in patients with normal liver parenchyma. Grossly, HCC can undergo hemorrhage and necrosis because of a lack of fibrous stroma. Vascular invasion, particularly of the portal system, is common. Invasion of the biliary system is less common. Aggressive HCC can cause hepatic rupture and hemoperitoneum. There are three growth patterns of HCC– • Solitary mass – Often large • Multifocal or nodular pattern – Multiple nodules • Diffuse – Multiple, small foci scattered diffusely throughout the liver

Tropical Hepatogastroenterology

HEPATOCELLULAR CARCINOMA

Okuda has classified HCC based on pattern of growth and spread into expanding, spreading, diffuse and indeterminate types. Microscopically, cells resemble normal hepatocytes and can be confused with cells of hepatic adenoma. Tumors that are more differentiated can produce bile. The histology is quite variable ranging from well-differentiated tumors to anaplastic tumors. The fibrolamellar subtype is associated with a better prognosis for survival possibly because it is usually not associated with cirrhosis and is more likely to be resectable. The presence of intracellular bile or staining for AFP may be helpful in distinguishing HCC from other hepatic malignancies (cholangiocarcinoma). HCC can produce alpha-fetoprotein (AFP) as well as other serum proteins. WHO has classified HCC into trabecular, pseudoglandular, compact, and scirrhous pattern.

48.1.4 Clinical Presentation HCC tends to occur in the elderly in low incidence areas, while in high incidence areas it is seen to affect patients early in their adult life. It is seen more commonly in males in both high and low incidence areas. The male to female ratio is 4–8:1. HCC presents late in its natural history mainly because of lack of symptoms in the early stages of its evolution. The large functional reserve of the liver, the large size and position of the liver behind the costal cartilage all cause delay in clinical presentation. Patients most often present with a triad of complaints of right upper quadrant pain, weight loss, and mass. Other symptoms are anorexia, lethargy, and nausea. The most common symptom is right upper quadrant pain while the most common sign is hepatomegaly. Other signs are vascular bruit and rub which may be seen in around 20% of cases. Hepatic decompensation is another mode

Part X / Special Topics

763

of presentation with patients developing refractory ascites and jaundice. Symptoms like tremors and frank encephalopathy are less common. Cutaneous stigmata of chronic liver disease may be present. Jaundice as presenting symptom of HCC occurs in 20% to 40% of patients with the primary cause being hepatic insufficiency.[12] The incidence of obstructive jaundice is about 5% to 10%. Obstructive jaundice in these patients is of three types: Type I: Intraluminal obstruction by tumor thrombus. Many of these tumors are resectable. Type II: Obstruction due to hemobilia Type III: Jaundice in these patients is due to extraluminal bile duct compression as a result of tumor invasion or encasement or lymph node involvement. These patients generally have unresectable disease and are best palliated. About 10% of the patients present with symptoms of GI bleed, which is most often a consequence of variceal bleed secondary to portal hypertension due to the underlying chronic liver disease. Less frequently it is due to portal vein invasion by the tumor or direct invasion of the bowel by the tumor. Rare modes of presentation have included tumor rupture with massive intraperitoneal bleed and shock, Budd–Chiari syndrome, hemobilia, jaundice due to tumor thrombus in the bile duct or external compression of the bile duct, and paraneoplastic symptoms (pyrexia of unknown origin, hypercalcemia, hypoglycemia, and others).

48.1.5 Investigations The approach to a patient with suspected HCC initially involves confirmation of the diagnosis followed by assessment of the extent of the disease both in the liver and outside. Assessment of functional reserve of the liver and the general

764

Chapter 48 / MALIGNANT LIVER TUMORS

condition of the patient is an important guide for management of such a patient. Assessment is done for suitability to withstand a major resection and to determine the adequacy of the residual functional liver volume. Investigations are aimed at imaging of the liver to assess the lesions – site, size, number, extent, and to evaluate any evidence of distant spread. The quantitative as well as qualitative assessment of the liver is required to determine the extent of liver resection that can be safely performed. To this end, one may need biopsy of the nontumor area to assess the extent of fibrosis/cirrhosis. The presence and the extent of portal hypertension in cirrhotics are ascertained. The patients’ overall suitability to withstand a surgical resection in terms of physical status, comorbidity, and residual functional reserve are evaluated. Ultrasound of the abdomen forms the initial investigating tool. The tumors are seen as space occupying lesions that are hyperechoic when small, becoming heterogeneous with enlargement.[13–16] The nodular type of HCC can be easily differentiated from metastasis and hemangioma if characteristic findings are present of thin halo with lateral shadows with posterior echo enhancement and mosaic or nodule in nodule pattern. Invasion into the portal and hepatic veins is seen as echogenic foci with signal voids on Doppler. Most HCC are hypervascular, which is demonstrated at the periphery of the tumor on Doppler. In a background of cirrhotic liver the HCC appear as well-defined foci since most regenerating nodules are inapparent. Detection of the diffuse form of HCC is difficult on ultrasound, and CT or MRI may be more useful in this regard. In particular, small hyperechoic masses seen on US require further evaluation since they can represent hemangioma (most commonly), metastatic disease, or, less likely, HCC. Further imaging with CT or MRI during dynamic contrast enhancement shows the

FIGURE 48.1 Primary hepatoma. The CT scan of the upper abdomen shows a large mass in the right lobe of the liver.

typical, peripheral, nodular contrast enhancement pattern of hemangioma. In at-risk populations, this has been used as a screening tool, though with mixed results.[17–19] The CT scan (Fig. 48.1) provides a more accurate picture and extra information. On plain CT scans HCC masses appear as hypodense lesions relative to the liver parenchyma except in fatty livers. The fibrous capsule of HCC appears as a thin hypodense band surrounding the tumor. Calcification is seen in less than 10% of patients.[20] Since the HCC are primarily supplied by the hepatic artery, it appears hyperdense in the arterial phase of contrast injection and hypo or isodense lesion surrounded by enhancing fibrous capsule in the portal phase. Imaging during the arterial phase can also detect arterioportal shunting and portal vein thrombi where there has been portal vein invasion. Portal vein invasion occurs in up to 44% of patients while hepatic vein and IVC invasion is seen in 5%. However, these characteristic findings are not evident in small, well-differentiated HCC,

Tropical Hepatogastroenterology

HEPATOCELLULAR CARCINOMA

since it is usually hypovascular and less frequently associated with a fibrous capsule. Detection of small HCC is increased by Lipiodol CT. In this, CT scans are taken 2–3 weeks after injection of lipiodol through the hepatic artery. For early HCC, MRI may be more sensitive. Extrahepatic spread of HCC is seen in 70% of patients, and the most common site among these is the lymph nodes in the hepatoduodenal ligament, which may be seen in 25%. Hematogenous metastases are seen most commonly in the lungs (47.6%). Other sites of metastases are adrenals (8.3%), bones (5.6%), gastrointestinal tract (4.7%), gallbladder (3.5%), and pancreas (3%). Also important is CT volumetry in which the amount of functional liver volume that is to be left behind is assessed. A close correlation has been seen with indocyanine green (ICG) testing (described below).[21] In the setting of an abnormal liver with elevated AFP, a vascular mass or a large necrotic mass in the liver strongly suggests HCC. However, other hepatic lesions both benign and malignant can mimic HCC on CT. MRI or nuclear imaging can assist in this differentiation. In addition, cirrhotic nodules cannot be differentiated reliably from small HCCs. Since the success of therapy depends on early detection of HCC, the distinction is important. MRI can assist this. Even the best CT scanner may have difficulty in detecting small lesions especially if, a good quality, triphasic scanning is not performed. Prospective detection rates of patients with tumors and of tumor nodules were reported as 59% and 37% respectively, in a large series with pathologic correlation.[22] On MRI, HCCs are hypointense on T1 and hyperintense on T2-weighted images but welldifferentiated HCC are hyperintense on T1 due to the presence of intracellular lipid. Fibrolamellar

Part X / Special Topics

765

HCC may have a central scar that is hypointense on both T1 and T2-weighted images. Gradient echo MRI and other flow techniques can identify vascular invasion quite accurately. MR with gadolinium is more sensitive than helical CT especially for small HCC. MRI can also help in differentiating cirrhotic nodules from HCC; if the mass is bright on T2-weighted images, it is HCC until proven otherwise. If the mass is dark on T1- and T2-weighted images, it is a siderotic regenerative nodule or siderotic dysplastic nodule. If the mass is bright on T1-weighted images and dark or isointense on T2-weighted images, it is a dysplastic nodule or low-grade HCC.[23–25] Gadolinium-enhanced MRI typically demonstrates that HCCs densely enhance, usually in the arterial phase and particularly if they are small. A lesion showing arterial enhancement is most likely HCC. However, dysplastic nodules and less likely regenerative nodules can show similar enhancement. The degree of enhancement varies particularly with the degree of necrosis in larger tumors. One should look carefully for enhancement in small portions of tumor. (In addition, a “flash filling” hemangioma can have rapid arterial enhancement but could be differentiated by lack of washout on delayed images). Presently the role of angiography in evaluation of HCC is very limited as most informations are readily available on other imaging modalities. On angiography, these tumors characteristically appear as hypervascular lesions with a bizarre circulation. Portal vein invasion and arterioportal shunt may be seen. Tumors which are unresectable may require angiography as a part of chemoembolization or other ablative therapy. On gallium scan, up to 90% of HCCs demonstrate uptake of radiopharmaceutical Gallium. It may help distinguish regenerating nodules of cirrhosis from HCC since regenerating nodules

766

Chapter 48 / MALIGNANT LIVER TUMORS

typically do not label with gallium. On liver-spleen scan, a sulfur-colloid study typically demonstrates an area of decreased labeling in HCC. The radiologist should look for signs of cirrhosis, such as heterogeneous labeling of the liver with a large spleen and colloid shift to the bone marrow. Prominent left and caudate lobes of the liver also are signs of cirrhosis. A “cold” defect in the liver with signs of cirrhosis strongly suggests HCC. A hepatobiliary scan can show labeling of HCC due to the presence of hepatocytes. HCC may have no uptake initially but may show delayed uptake as the rest of the normal liver clears. This is related to malignant hepatocytes, which are hypofunctional relative to normal hepatocytes. Positron emission tomography with fluorodeoxyglucose (FDG PET) is more useful in assessing the degree of differentiation and in staging moderately and poorly differentiated tumors than in primary lesion detection. Sensitivities of FDG PET for the detection of HCC range from 50%–70%. This limited sensitivity is due to the low level of FDG uptake in well-differentiated tumors. However, FDG PET may be superior to CT in detecting extrahepatic spread. On gallium scan, the liver normally labels early and may obscure labeling of HCC. Differential diagnoses of a mass that shows labeling in the liver include other types of malignancy and infection. Though tissue diagnosis can be made by ultrasound or CT guided FNAC or core biopsy, it is not recommended in most cases as there is definite risk of dissemination of tumor cell and bleeding.[1] A tissue diagnosis is warranted in a patient who is not a candidate for surgery and in patients where the diagnosis is in sufficient doubt that performing a biopsy would alter the plan of management. A chest X-ray should be performed to rule out any lung metastasis. In view of the low diagnostic yield a CT of the chest, brain or bone scan in not mandatory.

A complete blood count including platelet count, renal and hepatic function tests, coagulation profile, ECG should be carried out. Also required are viral markers for HBV and HCV. Alpha-fetoprotein levels are elevated in more than 90% of patients. A level of > 500 ng/dl is considered to be HCC until proven otherwise. The half life of AFP is 6 days and hence, it is also a marker of residual disease following resection. A rapid decline in levels is an indicator of complete resection while a slower than expected fall in the level indicates residual disease. Another tumor marker for HCC in PIVKA-II (Protein induced by absence of vitamin K or by antagonist II). It is raised in 55%–62% of cases. Upper gastrointestinal endoscopy is performed to rule out the presence of varices which is an indicator of portal hypertension. The presence of portal hypertension has a bearing on the management plan. A normal liver can tolerate up to 75% to 80% resection while in a cholestatic liver the figure is approximately 60%.[26] In cirrhotic patients the amount of liver that can be resected depends upon the extent of underlying liver damage.[27, 28] Hence, it is of prime importance to assess the functional reserve of the remnant liver volume. This can be carried out by an array of clinical, biochemical and radiological parameters. It is also a well known fact that the liver after resection regenerates back to its normal size in about 2 weeks time. The preoperative bilirubin has been suggested as the single most important prognostic indicator and a two fold increase in the serum bilirubin (> 2 mg/dl) has been reported to be an absolute contraindication for liver resection in cirrhotic patients.[29] If the bilirubin level is 1.5 to 1.9 mg/dl only enucleation is indicated while for level ranging from 1.1 to 1.4 mg/dl limited resection is recommended. A major resection can be done when the bilirubin is ≤ 1 mg/dl. The preoperative level of SGPT (ALT)

Tropical Hepatogastroenterology

HEPATOCELLULAR CARCINOMA

TABLE fy 48.2 Pugh–Child’s grading of cirrhosis Measurements

1 point

2 points

3 points

Bilirubin (μmol/l) PT∗ prolongation(s) Albumin(mg/dl) Ascites

17–34 1–3 > 3.5 None

35–50 4–6 2.8–3.4 Mild

Encephalopathy

None

Grade 1 or 2

> 50 >6 < 2.8 Moderate to severe Grade 3 or 4

Child’s A: 5–6 points; B: 7–9 points; C: 10–15 points ∗ Prothrombin time

has been an indicator of morbidity and mortality in this group of patients.[30] However, reports to the contrary are also available.[27] A number of scoring systems are available and the Pugh–Child’s scoring system is the most accepted one (Table 48.2). In Child’s grade A the cirrhosis is compensated, in grade B it is decompensating while in grade C it is decompensated. Liver resection is generally offered to most of grade A and B patients. Of the dynamic tests to assess liver function, indocyanine green retention at 15 minutes (ICG R15) has been the most preferred one. When the ICG R15 is < 10% a major resection with resection of 1/2 or more of the liver (right hepatectomy, extended right or left hepatectomy) can be safely performed. If the level is 10% to 19%, resection of 1/3rd of the liver is the recommended safe limit (left hepatectomy, right anterior or posterior segmentectomy). For levels 20% to 29%, resection of 1/6th of the liver is possible (segmentectomy), and when the level is ≥ 30%, enucleation is recommended. Among the radiologic investigations CT volumetry is most widely used and has been to correlate well with the ICG R15 test.[31] Others have used redox tolerance index,[32] and laparoscopy to assess the remnant liver volume. Staging laparoscopy has been widely used for staging the disease.[33]

Part X / Special Topics

767

48.1.6 Staging The American Joint Committee on Cancer (AJCC) has designated TNM stages for liver cancer as follows:[34] 48.1.6.1 TNM definitions

Primary tumor (T) TX: T0: T1: T2: T3:

T4:

Primary tumor cannot be assessed No evidence of primary tumor Solitary tumor without vascular invasion Solitary tumor with vascular invasion or multiple tumors none more than 5 cm Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum

Regional lymph nodes (N) NX: N0: N1:

Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis

[The regional lymph nodes are the hilar (i.e., those in the hepatoduodenal ligament, hepatic, and periportal nodes). Regional lymph nodes also include those along the inferior vena cava, hepatic artery, and portal vein. Any lymph node involvement beyond these nodes is considered distant metastasis and should be coded as M1. Involvement of the inferior phrenic lymph nodes should also be considered M1.] Distant metastasis (M) MX: M0: M1:

Distant metastasis cannot be assessed No distant metastasis Distant metastasis

768

Chapter 48 / MALIGNANT LIVER TUMORS

[Metastases occur most frequently in bones and lungs. Tumors may extend through the capsule to the adjacent organs (adrenal glands, diaphragm, and colon) or may rupture causing acute hemorrhage and peritoneal carcinomatosis.] The T classification is based on the results of multivariate analyses of factors affecting prognosis after resection of liver carcinomas. The classification considers the presence or absence of vascular invasion (as assessed radiographically or pathologically), the number of tumor nodules (single vs multiple), and the size of the largest tumor (≤ 5 cm vs > 5 cm). For pathologic classification, vascular invasion includes gross as well as microscopic involvement of vessels. Major vascular invasion (T3) is defined as invasion of the branches of the main portal vein (right or left portal vein; this does not include sectoral or segmental branches), or as invasion of one or more of the 3 hepatic veins (right, middle, or left). Multiple tumors include satellitosis, multifocal tumors, and intrahepatic metastases. Invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum is considered T4. The stage groupings are defined as follows: AJCC Stage Stage Stage Stage Stage Stage

Stage groupings I-T1, N0, M0 II-T2, N0, M0 IIIA-T3, N0, M0 IIIB-T4, N0, M0 IIIC-Any T, N1, M0 IV-Any T, any N, M1

48.1.7 Management Patients who have resectable disease and who are otherwise candidates for surgery should undergo curative resection of the tumor since surgical resection provides the best chance of cure. Studies have

shown that most of the Child’s A patients and Child’s B who are otherwise fit candidates should undergo surgical resection of the lesion. Palliative therapy should be reserved for the Child’s C patients. Patients who have a small size of remnant liver are candidates for portal vein embolization of the involved liver. This induces hypertrophy of the normal liver thus extending the limits of resections.[35] Large tumors can be down staged by means of transarterial chemoembolization,[36] systemic chemotherapy, radiotherapy, hepatic artery ligation, or transarterial instillation of Yttrium 90 microspheres.[37] The main drawbacks with these approaches are limited response and unpredictability of the response. 48.1.7.1 Surgical resection

As discussed earlier the selection of the patients for resection is based on size and number of lesions, the presence of ascites, extrahepatic metastasis, or main portal vein thrombosis. The type of resection is guided by overall liver functional status as indicated by Child’s score and other tests for assessment of functional reserve of liver, especially ICG clearance test (Fig. 48.2). The Barcelona Clinic Liver Cancer (BCLC) treatment schedule restricts resection to single asymptomatic HCC in patients with preserved liver function.[38] Llovet has proposed portal pressure (clinically relevant portal pressure being defined as presence of hepatic vein pressure gradient > 10 mmHg, esophageal varices, or splenomegaly with platelet count < 100, 000), and serum bilirubin as the best parameters to select patients for resection. They have advocated resection for patients without clinically relevant portal hypertension and normal serum bilirubin.[39] Surgical resection involves partial resection of the liver. Here, an anatomical resection (Fig. 48.3)

Tropical Hepatogastroenterology

HEPATOCELLULAR CARCINOMA

769

FIGURE 48.2 Algorithm for the management of hepatocellular carcinoma.

is considered more appropriate than a nonanatomical resection since there are more chances of obtaining a clear surgical margin, less blood loss,

Part X / Special Topics

and less incidence of damage to the structures of the remnant liver. Since HCC involves invasion of the portal vein and retrograde dissemination,[40]

770

Chapter 48 / MALIGNANT LIVER TUMORS

FIGURE 48.3 Hepatectomy specimen after resection for a right lobe tumor.

a curative resection should include the entire parenchyma being supplied by that branch of portal vein. Surgical resection should aim to remove all possible tumor tissue including satellite nodules. The use of intraoperative USG is very useful since it helps in delineating not only the tumor margin but also the vasculature. Its usefulness is paramount in cirrhotic livers where small tumors may not be visible and are difficult to palpate. It may also pick up tumors which were previously not detected.[41] Intraoperative USG has been shown to change the surgical management in 18% of cases.[42] A surgical margin of 1 cm is essential during resection. The various types of resections used are: 1. Enucleation 2. Segmentectomy 3. Bisegmentectomy (2 and 3, 6 and 7, 5 and 8, etc.) 4. Formal right (5,6,7, and 8) or left hepatectomy (2, 3, and 4 with or without 1) 5. Extended right hepatectomy/right trisegmentectomy (4,5,6,7,8 with or without 1) or extended left hepatectomy (1, 2, 3, 4, 5, 7, and 8)

Postoperative complications include bleeding, bile leak, collection/abscess, liver failure, chest infection, and other chest complications, and wound infection. In the postoperative period, the liver function tests and other parameter like prothrombin time are monitored. A gradual normalization of the parameters is a good sign that the liver is recovering. On the other hand, a rising or static bilirubin and enzyme levels are ominous signs. With good intensive supporting care, most patients would have a good outcome. The perioperative mortality has currently come down to approximately 5% in most large centers.[43–45] Overall postresection 1 year, 3 year, and 5 year survival is 58%–100%, 28%–88%, and 19%–26% respectively. 48.1.7.2 Liver transplantation

Orthotopic liver transplantation for resectable or unresectable HCC in the setting of cirrhosis may be feasible for small, solitary, well-staged lesions; however, the prognosis for long-term survival is poor (20%–30%). The limited availability of organs and long wait times make this an unrealistic option for most patients. However, transplantation has the potential to treat both the HCC and concomitant end-stage liver insufficiency secondary to cirrhosis. Prognosis for survival is better in patients diagnosed with HCC as an incidental finding in the resected liver after transplantation for another cause (mainly end-stage liver insufficiency). Tumors which are single and < 5 cm or multiple < 3 in number and < 3 cm, fibrolamellar tumors, and neuroendocrine tumors have a better prognosis with transplantation. Adverse prognostic indicators are advanced disease, involvement of the resected margin, vascular invasion and bilobar disease. Recently the BCLC has extended criteria for liver transplantation to single HCC

Tropical Hepatogastroenterology

HEPATOCELLULAR CARCINOMA

< 7 cm, 3 nodules < 5 cm, or 5 nodules < 3 cm and after partial response to any treatment lasting > 6 months that achieves the conventional criteria for liver transplant.[39] It has been calculated that liver transplantation offers survival benefit from 1–4.7 years depending on treatment related survival rates. If the waiting period exceeds 6–10 months the increase in life expectancy provided by transplantation is overwhelmed by the risks that patient faces while waiting for liver transplantation.[46] If the waiting period is more than 6–10 months, one should consider liver resection if the tumor is unilobar and the patient has reasonable underlying liver synthetic function. Otherwise local ablative therapy or Transarterial chemoembolization (TACE) is preferable while waiting. The recurrence after liver transplant is high and many have used chemotherapy and radiotherapy in combination to help improve the outcome.[47] 48.1.7.3 Resection vs transplantation for patients otherwise eligible for transplant

Though recurrence free survival and overall survival is better with liver transplantation than resection, because of donor shortage and donor risk in related liver transplantation many centers especially in South–east Asia and Japan are doing resection at first, and if there is recurrence later, it is dealt with salvage liver transplantation.[48, 49] 48.1.7.4 Percutaneous ethanol injection (PEI)

This is performed under USG guidance. Absolute alcohol causes cellular dehydration, coagulative necrosis and vascular thrombosis. Indications for PEI are

Part X / Special Topics

771

1. HCC < 3 cm[50] 2. 3 tumors or fewer 3. Patients who are not candidates for surgery – Child’s C and some Child’s B 4. Recurrence following surgery Contraindications for the procedure are 1. Gross ascites 2. Bleeding tendency 3. Obstructive jaundice Results have been mixed with nonrandomized trials showing good results[51, 52] while most randomized studies have failed to show any significant improvement.[53] 48.1.7.5 Hepatic artery embolization

This can be carried out by angiographic means or during open surgery when the hepatic artery or its main branches are ligated. However, there is rapid development of collateral vessels within 1 week. Occlusion should preferably be carried out by angiographic methods since more peripheral arteries can be blocked, there is less morbidity, and since the occlusion is not permanent the vessel can be reutilized for repeat embolization or chemotherapy infusion. Side effects include pain, fever, nausea, and transient rise of enzymes. Though there is good symptom control associated with the procedure there is no prolongation in survival.[54–56] 48.1.7.6 Transarterial chemotherapy

Since HCC’s derive most of their blood flow from the hepatic artery, it is believed that injection of the chemotherapeutic drugs into the artery will achieve high levels of drug concentration in the tumor with associated less systemic toxicity. Drugs commonly used are 5-FU, 5-FUDR, cisplatin, doxorubicin,

772

Chapter 48 / MALIGNANT LIVER TUMORS

etc, since these have a high hepatic extraction and short plasma half-life.[57] This procedure requires placement of an angiographic catheter under fluoroscopic guidance or open placement of an implantable arterial port. 48.1.7.7 Transarterial chemoembolization (TACE)

This approach is based on the particle embolization (cellulose, microspheres, lipoidal, Gelfoam) and intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) into the hepatic artery providing blood supply to the tumor. The remainder of the liver may be spared because it depends primarily on the portal vein for its blood supply. Morbidity is greatly dependent on the extent of cirrhosis as judged by serum bilirubin and albumin, as well as on portal vein patency. Other similar procedures have included transarterial chemotherapy, lipiodolization, and embolization. Better response rates have been obtained with some of these later procedures but there has been higher incidence of liver failure. Response rates as high as 60%–80% have been reported in selected groups of patients; however, no clear impact in overall survival has been demonstrated. Contraindications have included: 1. 2. 3. 4.

Main portal vein thrombosis Marked arteriovenous shunting Poor liver function Very large tumors where the results have been poor

Side effects have included fever, abdominal pain, nausea, vomiting, cholecystitis, pancreatitis, gastroduodenal ulcerations and massive liver necrosis and liver failure.

48.1.7.8 Radiofrequency ablation

This method involves use of a radiofrequency current from a generator which generates heat and leads to tissue destruction. An optimum temperature of 80◦ C to 100◦ C is required for adequate results, though the charring and desiccation of tissues around the needle leads to increase in resistance and tissue impedance thus decreasing the flow of current. Indications: 1. Patients with 4 or less small (< 5 cm) tumors (HCC or colorectal tumors) 2. Patients who are not otherwise candidates for surgery (poor general condition, cirrhosis, tumor location prohibiting surgical resection, recurrent disease) 3. Patients with small tumors who are candidates for liver transplantation Contraindications are extrahepatic disease, life expectancy < 6 m, other malignant disease, severe liver insufficiency, portal hypertension, pregnancy, < 18 years age, refractory coagulopathy, tumors > 5 cm (relative contraindication), > 4 tumors (relative), tumor adjacent to major vessel or viscera (relative). 48.1.7.9 Transarterial radioembolization

Radiation therapy is limited by dose-related radiation hepatitis which precludes the administration of doses effective for tumor eradication. Doses of 2500 cGy may be used for palliative measures. The other option has been to use Yttrium 90 microsphere or lipiodol-iodine-131 injected into the hepatic artery. Success has been limited. 48.1.7.10 Systemic chemotherapy

To date, chemotherapy for HCC has shown unsatisfactory results. This may be caused by the universal

Tropical Hepatogastroenterology

FIBROLAMELLAR HCC

expression of the multidrug resistance gene protein on the surface of the malignant cells leading to active efflux of chemotherapeutic agents. The most active drugs tested include doxorubicin, cisplatin, and fluorouracil. Response rates are well under 10% and treatment shows no clear impact on overall survival. Combination chemotherapy does not add any benefit to single-agent chemotherapy. To date, interferon and other biologic agents have been ineffective. 48.1.7.11 Immunotherapy

Interferons have been used but with limited results. 48.1.7.12 Hormonal therapy

Tamoxifen which is an antiestrogenic compound has been used in a number of studies but response has been low.

48.1.8 Survival and Prognosis Prognostic factors associated with long term survival are size of the tumor, cirrhosis, infiltrative growth, vascular invasion, TNM stage, multiple tumors, lymph node metastasis, and margin < 1 cm.[58–61] After adequate resection the 1, 3, and 5 year survival has ranged between 70% to 90%, 40% to 70% and 10% to 30% respectively.[44, 62, 63]

48.2 FIBROLAMELLAR HCC This is a less aggressive tumor seen in young adults without any evidence of chronic liver disease and carries a good prognosis. Serum AFP is usually normal. On CT it is sharply demarcated from the surrounding liver tissue and may contain a central scar. Central calcifications may also be seen in half of the patients. MRI is considered to be the best diagnostic test. It shows a low attenuation on T1, while on T2 a heterogeneous high signal with

Part X / Special Topics

773

a hypodense scar is seen. It should be noted that the scar of FNH is hyperdense. These patients like in other liver tumors should undergo aggressive resection as the long term prognosis is much better than in conventional HCC patients.

48.3 INTRAHEPATIC CHOLANGIOCARCINOMA This is an uncommon tumor and is seen in association with primary sclerosing cholangitis, biliary atresia, hepatolithiasis, and liver flukes. These tumors tend to invade the portal vein and hepatic vein in 32% and 14% cases respectively. On ultrasound the tumor is hyperechoic. On CT it is seen as a hypodense mass with minimal enhancement mainly in the periphery on delayed images.[64] On MR the tumor is hypointense on T1 and mild to moderately hyperintense on T2 images.[65] A scar if present is hyperintense on T2. Since the tumor is hypovascular angiography is not useful.

48.4 LIVER METASTASES These are 20 times more common than primary tumors of the liver. The metastases most often found are from the stomach, gallbladder, colon, rectum, pancreas, lung, and breast. Metastases from colon, pancreas, and ovary may be cystic. Mucinous colorectal tumors, metastases from the stomach, pancreas, breast, and ovaries may be calcified. Diffuse metastases can be seen with melanoma, lymphoma, lung, and breast, and can be difficult to detect. Tumors originating from neuroendocrine lesions (islet cells, thyroid, carcinoid, melanoma, pheochromocytoma), kidney, breast, and sarcoma are hypervascular, while those from the colon, stomach, lung, pancreas, esophagus, gallbladder, and urinary bladder are hypovascular. Most secondaries have a low

774

Chapter 48 / MALIGNANT LIVER TUMORS

attenuation on NCCT while on CECT they have a variable appearance. Some hypervascular metastases may only be visualized on NCCT since they become isodense after contrast injection. CT arterial portography is considered the gold standard for assessing the number and distribution of hepatic metastases in the peroperative setting. On MR metastases are hypointense on T1 with the exception of melanoma which is exceptionally bright. On T2 the images show moderate hyperintensity. With gadolinium there is enhancement. MR is better than CT in detecting diffuse metastasis. Though USG is used mainly as a screening tool for detecting metastasis, intraoperative USG is considered one of the best modalities for detecting these tumors. Angiography has very little role in these tumors. Hypervascular tumors show neovascularization on angiography while hypovascular tumors show displacement of vessels. CT is considered the best initial test for detection of liver metastasis, while CT AP is the most accurate preoperative test. A percutaneous guided biopsy is indicated if surgery is not contemplated. Roughly 15% to 25% of patients with colorectal carcinoma present with synchronous liver metastases while another 20% present with metachronous lesions.[66, 67] A quarter of these are candidates for liver resection.[68] Thus overall 5 to 10% of patients will undergo liver resection.[69, 70] The most important prognostic factor is the completeness of resection (R0). In patients who have undergone an R0 resection the factors which indicate an adverse prognosis are age of more than 50 years,[71] location of the tumor in the rectum,[72, 73] mesenteric lymph node metastasis,[74, 75] poor differentiation,[72] multiple lesions,[76, 77] satellite lesions,[72, 78] size of the

tumor,[74, 79] percentage of liver replaced by the tumor,[80] metachronously detected lesions,[72] synchronous resection,[81] higher operative blood loss, and intraoperative transfusion.[82, 83] Of these entire factors the presence of satellite lesions is important. Satellite lesions are defined as tumor in the same segment or less than 2 cm from the larger nodule and with a diameter of less than 50% and less than 4 cm even if associated with a giant lesion. This generally indicates a higher potential for vascular spread. General contraindications to liver resection in these groups of patients are.[84] 1. Presence of 4 or more metastasis 2. Extrahepatic disease 3. Resection margin of less than 1 cm These criteria have been significantly diluted in many circumstances with many resecting tumors with solitary lung metastasis, with contiguous extrahepatic disease and negative margins but less than 1 cm. Thus, the absolute criteria for exclusion are inability to achieve R0 resection and distant extrahepatic disease. With regards to the time of resection many authors would wait for a few weeks to months to give a ‘test of time’ to the tumor with a belief that it is unlikely that the tumor is going to become unresectable during this period. Most liver resection can be carried out simultaneously with a right sided colon resection, while for left sided resections removal of up to 2 segments is feasible. For major resections it better to defer the liver resection.

48.4.1 Surgical Management In view of the high incidence of positive margins with nonanatomical resection, a wedge resection is recommended for tumors less than 2 cm in

Tropical Hepatogastroenterology

MALIGNANT TUMORS IN CHILDREN

size, at the edge of the liver, or as a supplement to major liver resection for removal of multiple tumors in the presence of cirrhosis or very fatty liver. In case of recurrent tumors a repeat resection if feasible should be performed, otherwise adjuvant therapy can be used. In case of liver metastasis in neuroendocrine tumors resection is indicated if 1. R0 resection is deemed feasible 2. Medical management has failed and a palliative debulking is required and at least 90% tumor removal is possible.[77] In all other tumors with metastasis to the liver resection is generally not recommended.[85]

48.5 MALIGNANT TUMORS IN CHILDREN The most common malignant liver tumor in children is hepatoblastoma (58%), followed by hepatoma (33%) and sarcomas (9%). The median age at presentation with hepatoblastoma is 18 months with most cases occurring

775

before 3 years age.[86] Hepatoblastoma has been known to be associated with familial polyposis,[87] Gardner’s syndrome,[88] Beckwith–Wiedemann syndrome,[89] trisomy,[90] low birth weight,[91] cleft palate, and cardiac and renal abnormalities. It is not associated with hepatitis or any other viral infection. Most children present with an asymptomatic abdominal mass. Pain, irritability, GI disturbance, fever, and pallor may occur in minority of cases. Rarely, presentation may be associated with rupture and intraperitoneal bleed or sexual precocity. Other features have included hepatomegaly, anemia, thrombocytosis, and raised AFP. A marked posttreatment fall in AFP levels correlates with good survival. Investigations include ultrasound abdomen, CECT, and MRI. These are chemosensitive tumors and respond well to cisplatinum, 5-FU, doxorubicin, and vincristine which are the recommended drugs. Chemotherapy can be give either as a neoadjuvant setting or following resection. Surgical resection of the primary tumor is a necessity even in the presence of metastatic disease.

REFERENCES [1] Leong ASY, Liew CT. Epidemiology, risk factors, etiology, premalignant lesions and carcinogenesis. In: Leong ASY, Leiw CT, Lau JWY, Johnson PJ (eds) Hepatocellular carcinoma. Diagnosis, investigation and management. Arnold, London 1999:1–17. [2] Munoz N, Linsell A. Epidemiology of primary liver cancer. In: Correa P, Haenzel W (eds) Epidemiology of cancer in digestive tract. Nijhoff, The Hague 1982:161–195. [3] Rustgi VK. Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 1987;16: 545–551.

Part X / Special Topics

[4] Lau JYN, Lai CL. Hepatocarcinogenesis. Trop Gastroenterol 1990;11:9–24. [5] Beasley RP, Hwang LY. Epidemiology of hepatocellular carcinoma. In: Vyas GH, Dienstag JL, Hoofnangle JH. Viral hepatitis and liver disease, New York: Grune & Stratton 1984:209–224. [6] Melnick JL. Hepatitis B virus and liver cancer. In: Philips LA (ed) Viruses associated with human cancer. Marcel Dekker, New York 1983: 337–367. [7] Rabe C, Pilz T, Klostermann C et al. Clinical characteristics and outcome of a cohort of 101 patients with

776

[8]

[9] [10]

[11]

[12]

[13] [14]

[15]

[16]

[17]

[18]

[19]

[20]

Chapter 48 / MALIGNANT LIVER TUMORS

hepatocellular carcinoma. World J Gastroenterol 2001;7:208–15. Rocken C, Carl-McGrath S. Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis 2001;19:269–78. Yu SZ. Primary prevention of hepatocellular carcinoma. J Gastroenterol Hepatol 1995;10:674–682. Shikata T. Primary liver carcinoma and liver cirrhosis.In: Okuda K, Peters RL (eds) Hepatocellular carcinoma, John Wiley, New York 1976:53–68. Okuda K, Kojiro M, Okuda H. Neoplasms of the liver. In: Schiff L, Schiff ER (eds) Diseases of the liver, 7th ed. JB Lippincott Co, Philadelphia 1993:1226–1236. Kew MC, Geddes EW. Hepatocellular carcinoma in rural Southern African Blacks. Medicine 1982;61:98–108. Itai Y, Ohtomo K, Ohnishi S et al. Ultrasonography of small hepatic tumors. Radiat Med 1987;5:14–9. Buscarini L, Di Stasi M, Buscarini E et al. Clinical presentation, diagnostic work-up and therapeutic choices in two consecutive series of patients with hepatocellular carcinoma. Oncology 1996;53: 204–9. Ishiguchi T, Shimamoto K, Fukatsu H et al. Radiologic diagnosis of hepatocellular carcinoma. Semin Surg Oncol 1996;12:164–9. Toyoda H, Kumuda T, Nakano S et al. Significance of tumor vascularity as a predictor of long-term prognosis in patients with small hepatocellular carcinoma treated by percutaneous ethanol injection therapy. J Hepatol 1997;26:1055–62. Khakoo SI, Grellier LF, Soni PN et al. Etiology, screening, and treatment of hepatocellular carcinoma. Med Clin North Am 1996;80:1121–45. Bottelli R, Tibballs J, Hochhauser D et al. Ultrasound screening for hepatocellular carcinoma (HCC) in cirrhosis: the evidence for an established clinical practice. Clin Radiol 1998;53:713–6. Larcos G, Sorokopud H, Berry G et al. Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation. AJR Am J Roentgenol 1998;171:433–5. Freeny PC, Baron RL, Teefey SA. Hepatocellular carcinoma: reduced frequency of typical findings

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

with dynamic contrast-enhanced CT in a non-Asian population. Radiology 1992;182:143–8. Okamoto E, Kyo A, Yamanaka N et al. Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function. Surgery 1984;95:586–92. Peterson MS, Baron RL, Marsh JW Jr et al. Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 2000;217:743–9. Kelekis NL, Semelka RC, Worawattanakul S et al. Hepatocellular carcinoma in North America: a multi-institutional study of appearance on T1weighted, T2-weighted, and serial gadoliniumenhanced gradient-echo images. AJR Am J Roentgenol 1998;170:1005–13. Ebara M, Ohto M, Shinagawa T et al. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis – A study of 22 patients. Gastroenterology 1986;90: 289–298. Yoshimitsu K, Honda H, Jimi M et al. Correlation of three-dimensional gradient echo dynamic MR imaging with CT during hepatic arteriography in patients with hypervascular hepatocellular carcinomas: preliminary clinical experience. J Magn Reson Imaging 2001;13:258–62. Bismuth H, Houssin D, Mazmanian G. Postoperative liver insufficiency: prevention and management. World J Surgery 1983;7:505–510. Tanabe G, Sakamoto M, Akazawa K et al. Intraoperative risk factors associated with hepatic resection. Br J Surg 1995;82:1262–1265. Vauthey JN, Klimstra D, Franceschi D et al. Factors affecting long term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg 1995;169:28–34. Hasegawa, Yamazaki S, Makuuchi M et al. Hepatectomies pour hepatocarcinome sur foie cirrhotique: schemes decisionnels et principes de reanimation peri-operatoire. Experience de 204cas. Journal de Cirurgie 1987;124:425–431.

Tropical Hepatogastroenterology

REFERENCES

[30] Noun R, Jagot P, Farges O et al. High preoperative serum alanine transferase levels: effect on the risk of liver resection in Child grade A cirrhotic patients. World J Surgery 1997;21:390–394. [31] Okamoto E, Kyo A, Yamanaka N et al. Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function. Surgery 1984;95:586–592. [32] Mori K, Ozawa K, Yamamoto Y et al. Response of hepatic mitochondrial redox tolerance test as a new prediction of surgical risk in hepatectomy. Ann Surg 1990;211:438–446. [33] Lo CM, Lai EC, Liu CL et al. Laparoscopy and laparoscopic ultrasonography avoid exploratory laparotomy in patients with hepatocellular carcinoma. Ann Surg 1998;227:527–532. [34] Greene FL, Page DL, Fleming ID et al. (editors). AJCC Cancer Staging Manual (6th Edition), Springer, 2002. [35] Nagino N, Nimura Y, Kamiya J et al. Selective percutaneous transhepatic embolisation of the portal vein in preparation for extensive liver resection: the ipsilateral approach. Radiology 1996;200: 559–563. [36] Fan J, Tang ZY, Yu YQ. Improved survival with resection after transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma. Digestive Surgery 1998;15:674–678. [37] Lau WY, Ho S, Leung TW et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intra-arterial infusion of 90 yttrium microspheres. Int J Radiat Oncol Biol Phys 1998;40:583–592. [38] Bruix J, Llovet JM. Prognostic assessment and evaluation of the benefits of treatment. J Clin Gastroenterol 2002 Nov-Dec;35(5 Suppl 2):S138–42. [39] Llovet JM, Fuster J, Bruix J. Prognosis of hepatocellular carcinoma. Hepatogastroenterology 2002;49:7–11. [40] Makuchi M, Hasegawa H, Yamazaki S. Ultrasound guided subsegmentectomy. Surg Gynecol Obstet 1985;161:346–350. [41] Gozzetti G, Mazziotti A, Cavallari A et al. Clinical experience with hepatic resections for hepatocellular

Part X / Special Topics

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

777

carcinoma in patients with cirrhosis. Surg Gynecol Obstet 1988;166:503–10. Lau WY, Arnold M, Leung NW et al. Hepatic intra-arterial lipiodol ultrasound guided biopsy in the management of hepatocellular carcinoma. Surg Oncol 1993;2:119–124. Kawasaki S, Makuuchi M, Miyagawa S et al. Results of hepatic resection for hepatocellular carcinoma. World J Surg 1995;19:31–34. Takenaka K, Kawahara N, Yamamoto K et al. Results of 280 liver resections for hepatocellular carcinoma. Arch Surg 1996;131:71–76. Nadig DE, Wade JP, Fairchild RB et al. Major hepatic resection. Indications and results in a national hospital system from 1988 to 1992. Arch Surg 1997;132:115–119. Wong LL. Current status of liver transplantation for hepatocellular cancer. Am J Surg 2002;183: 309–16. Cherqui D, Piedbois P, Pierga JY et al. Multimodal adjuvant treatment and liver transplantation for advanced hepatocellular carcinoma – a pilot study. Cancer 1994;73:2721–2726. Cha CH, Ruo L, Fong Y et al. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003;238:315–21. Poon RT, Fan ST, Lo CM et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg 2002;236:602–11. Vilana R, Bruix J, Bru C et al. Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology 1992;16:354–357. Ebara M, Kita K, Yoshikawa M et al. Percutaneous ethanol injection for patients with small hepatocellular carcinoma. In: Tobe T, Kameda H, Okudaira et al (eds) Primary liver cancer in Japan. Springer–Verlag, Tokyo 1992:291–300. Isobe H, Sakai H, Imari Y et al. Intratumor ethanol injection therapy for solitary minute hepatocellular carcinoma. A study of 37 patients. J Clin Gastroenterol 1994;18:122–126. Mathurin P, Rixe O, Carbonell N et al. Overview of medical treatments in unresectable hepatocellular

778

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

Chapter 48 / MALIGNANT LIVER TUMORS

carcinoma – an impossible meta-analysis. Aliment Pharmacol Ther 1998;12:111–126. Plengavanit U, Chearanai O, Sindhvananda K et al. Collateral arterial blood supply of the liver after hepatic artery ligation. Angiographic study of 20 patients. Ann Surg 1972;175:105–110. Coldwell DM, Mortimer JE. Hepatic artery embolization in the treatment of hepatic malignancies. Regional Cancer Treatment 1991;3:298–301. Ahrar K, Gupta S. Hepatic artery embolization for hepatocellular carcinoma: technique, patient selection, and outcomes. Surg Oncol Clin N Am 2003;12:105–26. Civalleri D. Methoda to enhance the efficacy of regional chemotherapeutic treatment of liver malignancies. In: Civalleri D (ed) An update on regional treatment of liver cancer. Wells Medical Press: London;1992:17–34. Lehnert T, Otto G, Herfarth C. Therapeutic modalities and prognostic factors for primary and secondary tumors. World J Surg 1995;19:252–263. Iwatsuki S, Starzl T, Sheahan DG et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214:221–228. Yamanaka N, Okamoto E, Toyosaka A et al. Prognostic factors after hepatectomy for hepatocellular carcinoma. A univariate and multivariate analysis. Cancer 1990;65:1104–1110. Ringe B, Pichlmayr R, Wittekind C et al. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg 1991;15:270–285. Okuda K, Obata H, Nakajima Y et al. Prognosis of hepatocellular carcinoma. Hepatology 1984;4: S3–S6. Tsuzuki T, Sugioka A, Vdeda M et al. Hepatic resection for hepatocellular carcinoma. Surgery 1990;107:511–20. Lacomis JM, Baron RL, Oliver JH 3rd et al. Cholangiocarcinoma: delayed CT contrast enhancement patterns. Radiology 1997;203:98–104. Hamrick–Turner J, Abbitt PL, Ros PR. Intrahepatic cholangiocarcinoma: MR appearance. AJR Am J Roentgenol 1992;158:77–9.

[66] Jatzko G, Wette V, Muller M et al. Simultaneous resection of colorectal carcinoma and synchronous liver metastases in a district hospital. Int J Colorectal Dis 1991;6:111–4. [67] Scheele J, Stangl R, Schmidt K et al. Recurrent tumor after R0 resection of colorectal liver metastases. Incidence, resectability and prognosis. Chirurg 1995;66:965–73. [68] Wagner JS, Adson MA, Van Heerden JA et al.The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–8. [69] Fortner JG, Silva JS, Golbey RB et al. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection. Ann Surg 1984;199:306–16. [70] Miyazaki M, Ito H, Nakagawa K et al. Aggressive surgical resection for hepatic metastases involving the inferior vena cava. Am J Surg 1999;177:294–8. [71] Hardy KJ, Fletcher DR, Jones RM. One hundred liver resections including comparison to nonresected liver-mobilized patients. Aust N Z J Surg 1998;68:716–21. [72] Scheele J, Altendorf-Hofmann A, Stangl R et al. Surgical resection of colorectal liver metastases: Gold standard for solitary and radically resectable lesions. Swiss Surg 1996;Suppl 4:4–17. [73] Elias D, Cavalcanti de Albuquerque A, Eggenspieler P et al. Resection of liver metastases from a noncolorectal primary: indications and results based on 147 monocentric patients. J Am Coll Surg 1998;187:487–93. [74] Fong Y, Sun RL, Jarnagin WR et al. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229:790–800. [75] Nuzzo G, Giuliante F, Giovannini I et al. Resection of hepatic metastases from colorectal cancer. Hepatogastroenterology 1997;44:751–9. [76] Irie T, Itai Y, Hatsuse K et al. Does resection of small liver metastases from colorectal cancer improve survival of patients? Br J Radiol 1999;72:246–9. [77] Scheele J, Altendorf-Hofmann A. Tumor implantation from needle biopsy of hepatic metastases. Hepatogastroenterology 1990;37:335–7.

Tropical Hepatogastroenterology

REFERENCES

[78] Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992;216:493–504. [79] Rees M, Plant G, Bygrave S. Late results justify resection for multiple hepatic metastases from colorectal cancer. Br J Surg 1997;84:1136–40. [80] Doci R, Gennari L, Bignami P et al. Morbidity and mortality after hepatic resection of metastases from colorectal cancer. Br J Surg 1995;82:377. [81] Jenkins LT, Millikan KW, Bines SD et al. Hepatic resection for metastatic colorectal cancer. Am Surg 1997;63:605–10. [82] Gall FP, Scheele J, Altendorf A. Typical and atypical resection techniques of hepatic metastases. Recent Results Cancer Res 1986;100:212–20. [83] Scheele J. Segment-oriented liver resection. Principles–technic—status. Chirurg 1989;60: 251–65. [84] Ekberg H, Tranberg KG, Andersson R et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986;73:727–31. [85] Foster JH. Survival after liver resection for secondary tumors. Am J Surg 1978;135:389–94.

Part X / Special Topics

779

[86] Exelby PR, Filler RM, Grosfeld JL. Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey–1974. J Pediatr Surg 1975;10: 329–37. [87] Hughes LJ, Michels VV. Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 1992;43:1023–5. [88] Hartley AL, Birch JM, Kelsey AM et al. Epidemiological and familial aspects of hepatoblastoma. Med Pediatr Oncol 1990;18:103–9. [89] Vaughan WG, Sanders DW, Grosfeld JL et al. Favorable outcome in children with Beckwith– Wiedemann syndrome and intra-abdominal malignant tumors. J Pediatr Surg 1995;30:1042–4. [90] Bove KE, Soukup S, Ballard ET et al. Hepatoblastoma in a child with trisomy 18: cytogenetics, liver anomalies and literature review. Pediatr Pathol Lab Med 1996;16:253–62. [91] Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a chance? J Pediatr 1997;130: 557–60.

Chapter

0 Index 6-mercaptopurine, 200 Abdominal tuberculosis, 653 Achalasia cardia, 82 Acid secretion, 98 Acid suppressive therapy, 706 Acute diarrhea, 677, 679 Acute hepatic failure, 276, 279 Acute hepatic necrosis and renal failure, 345 Acute hepatitis, 276, 279, 329, 336 Acute liver failure definitions, 425 Acute pancreatitis, 539 Acute variceal bleeding, 381 Acute viral hepatitis, 268, 269 Adenocarcinoma, 8, 726 Adenomas, 214, 341 tubular adenomas, 214 tubulovillous adenomas, 214 villous adenomas, 214 Adenomatous polyps, 225 Adjuvant chemotherapy, 234 Adjuvant therapy, 507 Advanced gastric cancer, 134 Aeromonas, 171 Aflatoxin-B1, 349 aspergillus flavus, 349 Air contrast barium enema, 217 Alagille syndrome, 254 Albumin infusion, 737, 741 Alpha 1 antitrypsin deficiency, 256 Ambulatory pH monitoring, 68 Amebiasis, 615 Amebic liver abscess, 614, 621 aspiration or drainage of abscess, 624 clinical features, 614, 621 780

diagnosis, 614, 623 epidemiology, 614, 621 left lobe abscess, 623 treatment, 614, 624 variants, 622 Aminosalicylates, 196, 199 5-aminosalicylic acid (5-ASA), 199 Angiodysplasia, 713, 723 Angiography, 395, 721, 731 Anomalous pancreaticobiliary junction, 517 Antibiotics, 196, 201, 538, 553 Antioxidants, 226 Anti–Saccharomyces cerevisiae antibodies, 199 Aquaretics, 754, 758 Argon beam coagulation, 707 Ascaris lumbricoides (roundworm), 180 Ascites, 376 Ascites in cirrhosis, 755 Aspergillosis, 166, 188 Asthma and gastroesophageal reflux, 56, 65 Astrovirus, 175 Atrophy-hypertrophy, 529 Autoimmune gastritis, 127 Autoimmune hepatitis, 363 antinuclear antibodies, 363 drugs, 363 Epstein Barr virus, 363 smooth muscle, 363 Azathioprine, 200 Bacillus cereus, 168 Bacterial food poisoning, 167 Bacterial infections, 167 Bacteriologic diagnosis, 666 AFB on histology, 667 culture, 667

Index

smear, 666 Banti’s syndrome, 388 Barium meal examination, 139 Barium swallow, 10 Barrett’s esophagus, 58 Barrett’s metaplasia, 6 Beger’s operation, 584 Bile duct strictures, benign, 528 classification, 527, 528 iatrogenic injury, 528 incidence, 527, 528 Benign anorectal disease, 726 Benign colorectal tumors, 213 Benign tumors of the stomach, 116 Bile duct adenoma, 459 Bile duct paucity, 242, 253 Biliary atresia, 242, 251 Kasai portoenterostomy, 251 Biological agents, 196, 202 infliximab, 202 RDP58, 202 visilizumab, 203 Biological staging, 16 Bleeding, 110 Bone scan, 16 Borrmann’s classification, 133 Botulinum toxin, 81, 87 Brachytherapy, 25 Breast milk jaundice, 242, 244 Bronchoscopy, 14 Brucellosis, 353, 358 Budd-Chiari syndrome veno-occlusive disease (VOD), 413 Caliciviruses, 174 Calcium channel blockers, 87 Cancer of the pancreas, 597 Capillaria philippinensis, 182 Carbon tetrachloride poisoning, 345 lipid peroxidation, 345 Carcinoembryonic antigen, 231 Carcinoma of the stomach, 126 Celiac disease, 691 Chemoradiotherapy, 26 Chemotherapy, 26, 145, 233

Part / xx

781

capecitabine, 234 fluorouracil (5-FU), 233 irinotecan, 234 oxaliplatin, 234 Cholangiocarcinoma, 484, 500 Choledochal cyst, 514 Cholesterol supersaturation, 473 Chronic diarrhea, 677, 690 Chronic hepatitis, 272, 329, 339 hepatitis B, 268, 273 hepatitis C, 268, 274 hepatitis D, 268, 275 HGV and TTV, 268, 275 Chronic infection, 293 Chronic pancreatitis, 566 Cirrhosis of the liver, 375 Classification Alonso-Lej, 514 Caroli’s disease, 515 Todani, 514 hepatotoxins, 329, 334 Clostridium perfringens, 168 Coexistent gastric and esophageal injury, 37, 42 Coagulation disorders, 377 Colitis, 723 Colonic obstruction, 590 Colonic resection, 218 Colonic tuberculosis, 726 Colorectal cancer (CRC), 221 Complications of peptic ulcer requiring surgery, 96, 109 Composition of gallstones, 469 cholesterol, 469 pigment stones, 469 Conjugated hyperbilirubinemia, 242, 245 Contrast enhanced computed tomography, 125, 139 Copper toxicity, 347 Corrosive injuries of the stomach, 37, 50 Corrosive strictures, 39 Corticosteroids, 37, 44, 196, 200 Cough and GER, 56, 65 Crigler–Najjar syndrome, 242, 245 Cryptosporidia, 178 Cyclospora cayetanensis, 178 Cyclosporine, 201 Cystadenoma biliary, 449, 460

782

Index

Cystenterostomy, 521 Cyst-biliary communication, 632 Cyst excision, 521 Cytology, 492 Development, 539 Diagnosis of drug hepatotoxicity, 329, 331 Diagnosis of H. pylori infection, 101 Dietary fiber, 213 Dieulafoy’s lesion, 712 Dilatation, 27, 37, 45 balloon dilators, 45 Savary-Gilliard bougies, 45 Diphyllobothrium latum (fish tapeworm), 166, 185 Diverticulosis, 723 Dopamine agonist L-dopa, 384 Drug therapy for prevention of bleeding, 382 isosorbide 5-mononitrate, 382 isosorbide dinitrate, 382 propranolol, 382 Drug-induced cholestasis, 329, 337 chlorpromazine (CPZ), 338 cholestasis with bile duct injury, 338 cholestasis with hepatitis, 338 macrolides, 338 Drugs, 227, 543 hormone replacement therapy, 227 NSAIDs, 227 Duodenal stenosis, 590 Duodenal ulcer, 98 DuVal, 582 Dysplasia/carcinoma sequence, 3 D-Xylose test, 163 Early gastric cancer, 133 Japanese classification, 134 Echinococcus granulosus, 629 Electrocoagulation, 709 Encephalopathy, 746 Endoscopic means of hemostasis, 706 Endoscopic therapy for GERD, 56, 73 endoscopic sewing, 73 injection of nonabsorbable polymer (enteryx), 73 radiofrequency application, 73 Endoscopic ultrasound, 15, 576 Entameba histolytica, 615

Enteric adenovirus 40 and 41, 174 Enteropathogens, 158 Enteropathogenic Escherichia coli, 169 Enterotoxigenic Escherichia coli, 168 Environmental factors, 128, 225 Enzyme supplements, 580 Epidemic hepatitis E, 322 Epstein Barr virus infection, 129 ERCP, 577 Esophageal balloons, 88 Esophageal cancer, 3 Esophageal carcinoma, 3 risk factors, 4, 470, 541, 596, 597 alcohol, 542 gallstone, 541 pancreatic cancer, 542 Paterson–Kelly syndrome, 6 Plummer–Vinson syndrome, 6 Tylosis, 6 Zenker’s diverticulum, 6 Esophagectomy, 18 Esophagogastric junction, 59 Extraesophageal presentations of GERD, 56, 64 Extrahepatic portal venous obstruction (EHPVO), 404 Familial adenomatous polyposis, 127 attenuated adenomatous polyposis coli (AAPC), 223 Familial polyposis coli (FPC), 215 Familial stomach cancer syndrome, 127 Fasciolopsis buski (giant intestinal fluke), 166, 186 Fecal occult blood testing, 227 Flumazenil, 384 Focal nodular hyperplasia, 453 Follicular lymphoma, 643 Food poisoning, 685 Frey’s procedure, 584 Fulminant hepatic failure, 291 Fundic gland polyps, 117 Galactosemia, 257 Gallbladder cancer, 478 Gallbladder cancer and cholangiocarcinoma gallbladder cancer (GBC), 485 Gallbladder hypomotility, 474 Gastric endocrine tumors, 115, 120 carcinoids, 120

xx

Index

gastric carcinoids, 120 multiple endocrine neoplasia, 121 neuroendocrine, 120 tumors, 120 Zollinger–Ellison syndrome, 121 Gastric polyps, 115, 116, 127 adenomatous, 127 hyperplastic, 127 Gastric resection, 109 Gastric ulcer, 98 Gastroduodenoscopy, 139 Gastroesophageal flap valve, 56, 62 Gastroesophageal reflux disease (GERD), 57 Barrett’s esophagus, 57 esophagitis, 57 Gastrointestinal stromal cell tumors, 115, 119 c-Kit (CD117), 119 interstitial cells of Cajal, 119 transmembrane protein, 119 Genetic changes, 222 Genetic factors, 99 Genetics of esophageal carcinoma, 7 Genome, 288 Genomic organization, 260–264 Giardia duodenalis, 176 Giardia lamblia, 176 Gilbert’s syndrome, 242, 244 Goseki classification, 133 Gut decontamination, 538, 554 H2 receptor antagonists, 69 H. pylori, 97, 98 gastric metaplasia, 99 hypergastrinemia, 98 Heater probe, 710 Helicobacter pylori, 128 Helminths, 685 Hemangioma, 449, 461 Hematogenous, 137 Hemolytic anemia, 242, 243 Hemorrhagic gastritis, 712 Hepatic adenoma, 450 multiple hepatic adenomas, 451 oral contraceptive (OC), 450 Hepatic drug toxicity, 330

Part / xx

783

troglitazone, 330 Hepatic encephalopathy, 376, 378 Hepatic fibrosis, 329, 340 Hepatic granulomas, 354 Hepatic hemangiomatosis, 462 Hepatic tuberculosis, 667 Hepatitis A infection, 277 Hepatitis A virus, 260, 261 infectious hepatitis, 261 Hepatitis B and C coinfection, 297 Hepatitis B and D coinfection, 297 Hepatitis B vaccine, 301 Hepatitis B virus, 260, 262, 286 Hepatitis C virus, 260, 263 non-A, non-B hepatitis (NANBH), 263 Hepatitis D virus, 301 Hepatitis delta virus (HDV), 260, 264 Hepatitis E, 321 Hepatitis E virus, 260, 264 Hepatitis G virus, 260, 265 Hepatitis C, 311 Hepatocellular carcinoma, 298, 341 Hepatoportal sclerosis, 388 Hepatopulmonary syndrome, 379 Hepatorenal syndrome, 379, 738 Herbal drug toxicity, 350 Chelidonium majus, 351 Heliotropium eichwaldii, 351 kava kava, 351 Piper methysticum, 351 Teucrium chamaedrys, 351 Hereditary nonpolyposis colon cancer (HNPCC), 127, 224 Heterophyes heterophyes, 186 Hiatal hernia, 56, 62 Histoplasmosis, 166, 187 History, 97 HIV, 175 Hookworm, 181 Human immunodeficiency virus disease and diarrhea, 694 Hydatid cyst of the liver hydatid disease, 629 percutaneous management (PAIR), 628, 638 Hymenolepsis nana (dwarf tapeworm), 166, 185

784

Index

Hyperplastic polyps, 117, 214 Hypothyroidism, 242, 244 Idiopathic portal hypertension, 388 Imaging, 449, 454, 457–459, 462, 484, 502, 574 Imaging of adenomas, 452 Inflammatory bowel disease, 225, 696 Interferon, 315 Intestinal amebiasis, 614, 617 clinical features, 614, 618 diagnosis, 614, 619 pathogenesis, 614, 617 surgical complications, 614, 619, 621 treatment, 614, 620 vaccine, 614, 621 Intestinal metaplasia, 127 Intracranial pressure monitoring, 434 Intravenous glycyrrhizin, 448 Ischemic colitis, 725 Isospora belli, 177 Jamaican vomiting sickness, 347 blighia sapida, 347 Reye’s syndrome, 347 Japanese staging system, 139 Jaundice in the infant, 243 Juvenile polyps, 216 Laboratory diagnosis of granulomatous liver disease, 353, 356 Laboratory features, 685 Laryngitis and GER, 56, 66 Laser therapy, 29 Lauren classification, 133 Leiomyomas, 115, 118 Leprosy, 353, 358 LES, 59 Li Fraumeni syndrome, 127 Lipomas, 115, 122 Lipogranuloma, 356 Lithostathine, 568 Liver adenomatosis, 451 Liver biopsy, 329, 332 Liver histology, 294 chronic active hepatitis, 294 chronic persistent hepatitis, 294

Liver transplantation, 370, 385, 412, 419, 424, 439, 754, 759 LKM antibodies, 365 Long-term prevention of variceal bleeding, 381 L-ornithine-L-aspartate, 384 Los Angeles endoscopic grading scheme, 67 Los Angeles system, 67 Low osmolar ORS, 686 Lower esophageal sphincter, 59 Lower gastrointestinal (LGI) bleeding, 722 Lymphoma, 353, 359 fungal granulomas, 359 primary biliary cirrhosis, 359 Malignancy in CP, 573 Malignant change, 37, 43 Malignant colorectal tumors, 221 MALT (mucosa-associated lymphoid tissue) lymphoma, 102 Mallory–Weiss tears, 703, 712 Management of hepatic drug toxicity, 329, 342 Manometric examination, 81, 85 Margosa oil syndrome, 347 azadirachta indica, 347 Mechanism of pain, 578 Mechanisms of drug hepatotoxicity, 329, 333 Membranous obstruction, 414 Metagonimus yokogawai, 186 Methylene diamine, 348 Microhamartomas biliary, 458 Microsporidia, 179 Microvesicular steatosis, 347 Ming classification, 133 Mirizzi’s syndrome, 486 Molecular adsorbent recirculating system (MARS), 440 Mulligan classification, 133 Multifocal atrophic gastritis, 128 Multiple drug resistant (MDR) tuberculosis, 671 Multiple FNH syndrome, 454 Mycotic infections, 166, 187 Myenteric plexus, 82 Nagayo-Komagome classification, 133 NCPF, 388 NCPF in children, 396 NCPF in pregnancy, 397

xx

Index

Neonatal cholestasis, 242, 246 Neonatal hemochromatosis, 242, 247 Cytomegalovirus – PCR, 248 ECHO virus, 248 Niemann pick type C, 248 Parvovirus B 19, 248 Neonatal hepatitis, 242, 252 Neonatal liver failure, 242, 246 Neoplastic polyps, 116 adenomas, 116 adenomatous polyps, 116 Nerve blocks, 580 Neural mechanisms, 578 ductal pressure, 579 pancreatic interstitial, 579 Neuroendocrine carcinomas, 122 Nodular regenerative hyperplasia, 456 Noncirrhotic portal fibrosis, 388 Nonerosive reflux disease (NERD), 57 Nonspecific colon ulcers, 726 Nonsteroidal anti-inflammatory drugs, 99 Nonsurgical treatment, 565, 580 Nontyphoid salmonellosis, 173 Nonulcer dyspepsia, 97, 106 NSAIDs, 104 Nucleating and antinucleating factors, 474 Nucleoside analogues, 299 famciclovir, 300 lamivudine, 299 Nutrition, 548 Nutritional theory, 154, 158 Oligoganglionosis, 518 Orthotopic liver transplantation, 507 Osmotherapy, 435 Overflow theory, 754, 756 Pain, 572 Pancreatectomy, 587 Pancreaticoduodenectomy, 588 Papillomatosis biliary, 449, 461 Paracentesis, 383 Paraneoplastic syndromes, 138 Paraquat, 348 Patterns of gastric cancer spread, 136 Peptic ulcer, 97

Part / xx

785

Peptic ulcer disease, 711 Percutaneous transhepatic portography (PTP), 394 Perinuclear-staining antineutrophil cytoplasmic antibodies, 199 Peritoneovenous shunt, 754, 759 Peutz-Jegher syndrome, 127 Phases of HBV infection, 289 lifecycle of HBV, 289 Phosphorus poisoning, 346 Photodynamic therapy, 28 Phyllanthus amarus, 300 Physiological cholestasis, 242, 246 Physiological jaundice of the newborn, 242, 243 Pleural effusion, 590 Pneumatic dilatation, 81, 88 Polychlorinated biphenyls, 350 Polycystic liver disease, 457 Polypectomy, 218 Porphyria cutanea tarda, 350 Portal hypertension, 376, 529, 642 Portal vein embolization (PVE), 507 Portal vein thrombosis (PVT), 404 Portal venous obstruction, 590 Positron emission tomography, 14 Postexposure prophylaxis, 276, 282 Postoperative surveillance, 235 Postpolypectomy, 726 Pouchitis, 196, 208 Preexposure prevention, 276, 281 Preoperative biliary drainage, 505, 596, 604 Preoperative work up, 484, 502 Pro-motility therapy, 56, 70 Probiotics, 196, 202 Prognosis of chronic HBV infection, 296 Progressive familial intrahepatic cholestasis 1 (PFIC 1), 255 Prothrombotic diseases, 414 Proto-oncogenes, 131 Bcl-2, nm-23, 132 c-met gene, 131 Cyclo-oxygenase-2 (COX-2) enzymes, 132 EGFR/k-sam, 132 erbB-2(HER-2/neu), 131 matrix metalloproteinases, 132 vascular endothelial growth factor, 132

786

Index

Proton pump inhibitors, 69 Pseudosclerosing cholangitis, 406 Puestow I and II, 583 Pyloric stenosis, 110 Pyloromyotomy, 22 Pyloroplasty, 22 Pylorus preserving pancreaticoduodenectomy, 605 Radiation therapy, 233 Radiography, 721, 730 Rectal cancer, 221 Refractory ulcer, 105 gastrinoma, 105 Rotavirus, 173 Salmonella species, 171 Sarcoidosis, 353, 358 Schistosomiasis, 353, 360, 641 Screening for colorectal neoplasia, 227 Second look endoscopy, 713 Secretin studies, 576 Self-expanding metallic stents, 28 Serologic markers of HBV infection, 291 hepatitis B core antigen, 291 hepatitis B e antigen, 292 hepatitis B surface antigen, 291 Sildenafil, 87 Simple hepatic cysts, 458 SLA antibodies, 365 Somatostatin analogues, 596, 607 SPINK 1, 571 Splenoportovenography (SPV), 393 Splenorenal shunt, 409 Spontaneous bacterial peritonitis, 378 Spontaneous shunts, 396 Sporadic hepatitis E, 322 Spore-forming protozoas, 177 Spread of the virus, 276, 277 Squamous cell, 7 Staphylococcus aureus infections, 167 Steatorrhea, 572 Steatosis, 329, 340 Stents, 37, 44 Stronger neo-minophagen C (SNMC), 301 Strongyloides stercoralis, 181 Subacute hepatic failure, 293

definition, 444, 445 Sulfasalazine, 199 Surgery for ulcerative colitis, 196, 206 Surgery in CP, 565, 581 Surgical myotomy, 81, 89 Taenia saginata (beef tapeworm), 166, 184 Taenia solium (pork tapeworm), 166, 184 Thrombolysis, 417 TIPS, 412, 418, 737, 741 Toxic liver injury, 344 Toxic mushroom ingestion, 346 Amanita phalloides, 346 amatoxins, 346 Toxic oil syndrome, 348 Toxins, 543 Transabdominal (open) cardiomyotomy, 90 Transjugular intrahepatic portosystemic shunts (TIPS), 383 Transthoracic (open) cardiomyotomy, 90 Trichinella spiralis, 166, 183 Trichostrongylus, 183 Trichuris trichiura (whipworm), 182 Tropical chronic pancreatitis (TCP), 569 Tropical malabsorption, 155 tropical enteropathy, 155 tropical sprue, 155 TT virus, 260, 265 Tuberculoma, 358 Tumor suppressor genes, 131 β-catenin, 131 APC, 131 LKB1 (STK11), 131 smad genes, 131 Ulcerative colitis, 197, 725 Ultrasonography, 139 Unconjugated hyperbilirubinemia, 242, 243 Underfill theory, 754, 755 Upper GI endoscopy, 721, 728 Ursodeoxycholic acid, 276, 281 V. cholerae, 170 Vibrio cholerae Non-O1, 171 V. parahemolyticus, 170

xx

Index

Vagotomy and drainage, 108 Vascular disorders, 329, 341 nodular hyperplasia, 341 peliosis hepatis, 341 Veno-occlusive disease, 348 heliotropium, 348 senecio jacobaea, 348 Vibrio species, 169

Part / xx

Vinyl chloride, 350 Viral hepatitis, 643 Virology, 287, 301, 311, 320, 321 Virtual colonoscopy, 217 Xanthogranulomatous cholecystitis, 478, 486 Yusho incident, 350

787