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Textbook of

Hepato-gastroenterology
Textbook of
Hepato-gastroenterology

Editors

Mahmud Hasan Sheikh Mohammad Fazle Akbar


Chairman Principal Investigator
Bangladesh Medical Research Council Department of Medical Sciences
Former Vice Chancellor Toshiba General Hospital, Tokyo, Japan
Bangabandhu Sheikh Mujib Medical University Adjunct Professor
Former Chairman Faculty of Medical Sciences
Department of Gastroenterology State University of Bangladesh
Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh
Dhaka, Bangladesh

Mamun-Al-Mahtab
Associate Professor
Department of Hepatology
Bangabandhu Sheikh Mujib Medical University
Dhaka, Bangladesh

Foreword
Parveen J Kumar

The Health Sciences Publishers


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Textbook of Hepato-gastroenterology

First Edition: 2015

ISBN: 978-93-5152-378-9

Printed at
Dedicated to

Bangabandhu Sheikh Mujibur Rahman


Father of the Nation of the Peoples Republic of Bangladesh
None of us and nothing would have been here, had HE not been there!
CONTRIBUTORS

A Kadir Dokmeci Anil Arora


Professor Chairman
Department of Gastroenterology Department of Gastroenterology and Hepatology
Ankara University School of Medicine Ganga Ram Institute for Postgraduate
Ankara, Turkey Medical Education and Research
Sir Ganga Ram Hospital
New Delhi, India

Abhijit Chowdhury Arun J Sanyal


Professor and Head Professor and Chairman
Department of Hepatology Division of Gastroenterology
School of Digestive and Liver Diseases Hepatology and Nutrition
Institute of Post Graduate Virginia Commonwealth
Medical Education and Research University Medical Center - MCV Campus
Kolkata, West Bengal, India West Hospital, Richmond, USA

Ajay Duseja Ashish Kumar


Assistant Professor Associate Professor and Consultant Hepatologist
Department of Hepatology Department of Gastroenterology and
Post Graduate Institute of Medical Hepatology
Education and Research Ganga Ram Institute for Postgraduate
Chandigarh, India Medical Education and Research
Sir Ganga Ram Hospital, New Delhi, India

Ajesh Goyal AS Soin


Consultant Gastroenterology and Hepatology Chairman and Chief
Tagore Hospital Liver Transplant and Hepatobiliary Surgeon
Jalandhar, Punjab, India Medanta Institute of Liver Diseases and
Transplantation
Medanta- The Medicity
Gurgaon, Haryana, India

Amna Subhan Butt Axel Hsu


Assistant Professor Resident Specialist
Consultant Gastroenterologist Division of Gastroenterology and Hepatology
Department of Medicine Department of Medicine
Aga Khan University Hospital Queen Mary Hospital
Karachi, Pakistan Hong Kong

Andrew Vaillant Cassiano Ribeiro Pires


Vice President, Operations and Chief Scientific Gastroenterologist
Officer, REPLICor Inc. Member of the Medical Staff in Endoscopy Unit
Montreal, Canada of Azevedo, Lima State Hospital
Rio de Janeiro, Brazil
viii Textbook of Hepato-gastroenterology

Christopher A Wadsworth Gourdas Choudhuri


Senior Research Fellow Director and Head
St Marys Hospital Campus Department of Gastroenterology and Hepato-
Imperial College of London biliary Sciences
London, UK Fortis Medical Research Institute
Gurgaon, Haryana, India

Cihan Yurdaydin Govind K Makharia


Chief, Hepatology Institute Additional Professor
Professor of Gastroenterology Department of Gastroenterology and Human
Department of Gastroenterology Nutrition
University of Ankara Medical School All India institute of Medical Sciences
Ankara, Turkey New Delhi, India

Cristiane Alves Villela-Nogueira Hamama-tul-Bushra Khaar


Associate Professor Professor
Department of the Internal Medicine Department of Medicine
Hepatology Division Rawalpindi Medical College
School of Medicine Gastroenterologist and Hepatologist
Federal University of Rio de Janeiro Holy Family Hospital
Rio de Janeiro, Brazil Rawalpindi, Pakistan

Debashis Misra Hamizah Razlan


Resident Medical Officer cum Clinical Tutor Associate Professor
Division of Gastroenterology Consultant Gastroenterologist
School of Digestive and Liver Diseases Head of Gastroenterology Unit
Institute of Postgraduate Medical Education and Medical Department
Research, Kolkata, West Bengal, India Faculty of Medicine
University Kebangsaan Malaysia
Kuala Lumpur, Malaysia

Fazal Karim Izazul Haque


Associate and Head Assistant Professor and Head
Department of Hepatology Department of Hepatology
Sir Salimullah Medical College Mitford Hospital Comilla Medical College
Dhaka, Bangladesh Comilla, Bangladesh

Furqan Ahmed Javed Yakoob


Consultant Gastroenterologist and Hepatologist Assistant Professor
South City Hospital Department of Medicine
Karachi, Pakistan Aga Khan University
Karachi, Pakistan

GK Dhali Julio Cesar Aguilar


Professor and Head Head of Clinical Trials
School of Digestive and Liver Diseases Vaccine Division
Institute of Postgraduate Medical Department of Biomedical Research
Education and Research Center for Genetic Engineering and
Kolkata, West Bengal, India Biotechnology
Havana, Cuba
Contributors ix

Kaushal Kishor Prasad Mandish K Dhanjal


Additional Professor and Chief Consultant Obstetrician and Gynecologist
Division of GE Histopathology Honorary Senior Lecturer
In-Charge, Division of GE Enzymology Queen Charlottes and Chelsea Hospital
Department of Superspeciality of Imperial College Healthcare NHS Trust
Gastroenterology London, UK
Postgraduate Institute of Medical Education and
Research
Chandigarh, India

Khin Maung Win Mazhar Haque


Head Senior Lecturer, Department of Medicine
Department of Hepatology University of Queensland
Yangon GI and Liver Center Staff specialist Gastroenterologist
Yangon, Myanmar Mater Adult Hospital
Brisbane, Australia

Kshaunish Das Md Delwar Hossain


Associate Professor Head
Division of Gastroenterology Department of Gastroenterology
School of Digestive and Liver Diseases Combined Military Hospital
Institute of Postgraduate Medical Education Dhaka, Bangladesh
and Research
Kolkata, West Bengal, India

Mahesh Gupta Md Rabiul Hossain


Consultant Gastroenterologist Consultant Physician General
Kailash Group of Hospitals Bangladesh Armed Forces
New Delhi, India Dhaka, Bangladesh

Mamun-Al-Mahtab Mian Mashhud Ahmad


Associate Professor Professor and Senior Consultant
Department of Hepatology Department of Gastroenterology
Bangabandhu Sheikh Mujib Medical University LabAid Specialized Hospital
Dhaka, Bangladesh Dhaka, Bangladesh.

Man-Fung Yuen Moiss Copelman


Chairman, Gastroenterology and Hepatology Assistant Professor
and Li Shu Fan Medical Foundation in Medicine Department of Gastroenterology
Assistant Dean, Faculty of Medicine Postgraduate Course in the Medical and
The University of Hong Kong Rehabilitation Brazilian Institute (IBMR)
Chief, Division of Gastroenterology and Member of the Medical Staff
Hepatology Gastroenterology and Endoscopy Unit
Deputy Chief, Service and Honorary Consultant State University of Rio de Janeiro (Uerj)
Department of Medicine, Queen Mary Hospital Residency Supervisor
Hong Kong Digestive Endoscopy Program
Bonsucesso Federal Hospital
Rio de Janeiro, Brazil
x Textbook of Hepato-gastroenterology

Monjur Ahmed Om Parkash


Clinical Associate Professor of Medicine Senior Instructor
Division of Gastroenterology and Hepatology Consultant Gastroenterologist
Thomas Jefferson University Department of Medicine
Philadelphia, USA The Aga Khan University and Hospital
Karachi, Pakistan

Muhammad Umar Paisarn Vejchapipat


Principal Associate Professor and Head
Rawalpindi Medical College Pediatric Surgery Unit
Chief, Allied Hospitals, Rawalpindi Department of Surgery
Chief Gastroenterology and Chulalongkorn Hospital
Hepatology Division Bangkok, Thailand
Holy Family Hospital
Rawalpindi, Pakistan

Murat Saru Parimal Lawate


Professor Consultant Gastroenterologist
Department of Gastroenterology Department of Gastroenterology and
Acibadem University School of Medicine Endoscopy
Istanbul, Turkey Jehangir Hospital
Pune, Maharashtra, India

Mustafa Yakut P Karayiannis


Professor Professor
Department of Gastroenterology Department of Microbiology
Ankara University School of Medicine and Molecular Virology
Ankara, Turkey St Georges University of London
Medical School at University of Nicosia
Nicosia, Cypsus

Narendra Choudhary Premashis Kar


Consultant Hepatologist Director and Professor of Medicine
Medanta institute of Liver Transplantation and and Gastroenterologist
Regenerative Medicine Department of Medicine
Medanta- The Medicity Maulana Azad Medical College
Gurgaon, Haryana, India University of Delhi
New Delhi, India

Natalia Balbi Flores Punit Singla


Gastroenterologist Associate Consultant
Member of the Medical Staff in Endoscopy Unit Liver Transplant and Gastrointestinal Surgeon
of Getulio Vargas State Hospital Medanta Institute of Liver Diseases and
Rio de Janeiro, Brazil Transplantation
Medanta- The Medicity
Gurgaon, Haryana, India

Nurdan Tzn Rakesh Kochhar


Prefessor Professor
Department of Gastroenterology Department of Superspeciality of
Acibadem University Gastroenterology
Acibadem Kozyatagi Hospital Postgraduate Institute of Medical Education and
Istanbul, Turkey Research, Chandigarh, India
Contributors xi

Ramazan Idilman Sachin Gupta


Professor in Medicine Assistant Professor
Department of Gastroenterology Department of Gastroenterology
Ankara University Faculty of Medicine Laxmi Narayan Medical College and Hospital
Ankara, Turkey Bhopal, Madhya Pradesh, India

Ravi Mohanka Saeed Hamid


Senior Consultant The Ibn-e-Sina Chair and Professor
Hepatobiliary and Multiorgan Transplant Consultant Gastroenterologist
Surgeon Department of Medicine
Medanta Institute of Liver Diseases and The Aga Khan University and Hospital
Transplantation Karachi, Pakistan
Medanta- The Medicity
Gurgaon, Haryana, India

Roger W Chapman Salimur Rahman


Consultant Hepatologist Professor
John Radcliffe Hospital Department of Hepatology
Oxford University Hospitals Bangabandhu Sheikh Mujib Medical University
Oxford, UK Dhaka, Bangladesh

Rosmawati Mohamed Sanjay Govil


Consultant Hepatologist Senior Consultant
Department of Medicine HPB Surgery and Liver Transplantation
Faculty of Medicine Global Health City
University Malaya Chennai, Tamil Nadu, India
Kuala Lumpur, Malaysia

SM Wasim Jafri Saroj Kant Sinha


Ali Charan Professor of Medicine Additional Professor
(Gastroenterology) Department of Superspeciality of
Associate Dean Gastroenterology
Chairman, Department of Continuing Postgraduate Institute of Medical
Professional Education Education and Research
Aga Khan University Chandigarh, India
Karachi, Pakistan

Sabyasachi Ray Shahab Abid


Consultant Gastroenterologist Professor and Head
Peerless Hospital Section of Gastroenterology
Kolkata, West Bengal, India Department of Medicine
Aga Khan University
Karachi, Pakistan
xii Textbook of Hepato-gastroenterology

Shahid A Khan Taranjeet S Jolly


Senior Lecturer in Hepatology and Resident
Consultant Physician St Joseph Mercy Health System
St Marys Hospital Campus Livonia, USA
Imperial College of London
London, UK

Sheikh Mohammad Fazle Akbar Uday C Ghoshal


Principal Investigator Professor
Department of Medical Sciences Department of Gastroenterology
Toshiba General Hospital, Tokyo, Japan Sanjay Gandhi Postgraduate Institute
Adjunct Professor Lucknow, Uttar Pradesh, India
Faculty of Medical Sciences
State University of Bangladesh
Dhaka, Bangladesh

Shelley Haynes Vikas Singla


Consultant Obstetrician and Gynecologist Senior Resident
Southampon General Hospital All India Institute of Medical Sciences
Southampton, UK New Delhi, India

Shivaram Prasad Singh Voranush Chongsrisawat


Head Associate Professor
Department of Gastroenterology Department of Pediatrics
SCB Medical College Faculty of Medicine, Chulalongkorn University
Cuttack, Odisha, India Bangkok, Thailand
Simon D Taylor-Robinson YK Chawla
Professor of Translational Medicine Director
Clinical Dean, Faculty of Medicine Postgraduate Institute of Medial Education and
Department of Medicine Research
St Marys Hospital Campus Chandigarh, India
Imperial College London
London, UK

Sittisak Honsawek Yong Poovorawan


Professor Professor
Department of Biochemistry Center of Excellence in Clinical Virology
Faculty of Medicine Faculty of Medicine, Chulalongkorn University
Chulalongkorn Hospital Bangkok, Thailand
Bangkok, Thailand

Sony Sebastian Thazhath Zaigham Abbas


PhD Research Fellow Head
Discipline of Medicine Department of Hepatogastroenterology
University of Adelaide Sindh Institute of Urology and Transplantation
Adelaide, Australia Karachi, Pakistan

Sujay Ray Ziauddin Ahmed


Associate Professor Professor of Medicine
Division of Gastroenterology Drexel University College of Medicine
School of Digestive and Liver Disease Philadelphia, USA
Institute of Postgraduate Medical Education and
Research and SSKM Hospital
Kolkata, West Bengal, India
F or e w or d

It gives me great pleasure to write this Foreword. It takes great courage to embark on producing
a new textbook and tremendous hard work to fulfill this aim. It is a daunting task, and there
is absolutely no doubt that editing and authoring a new textbook is not for the faint-hearted
person. The idea has to be converted into practice. The design and format, listing appropriate
topics, searching for suitable authors, and producing guidelines and instructions for these
authors, and finally, when the chapters are written, there is the horrendous and daunting
task of editing! So why do it? Well, there are several reasons for wanting to take on this task,
but one of the most compelling ones is whether there is a need for such a textbook. The
editors have succeeded in this, as this new textbook has definitely filled a necessary gap.
Gastroenterology and hepatology are, relatively, new specialties despite the fact that the
diseases of these fields are highly prevalent in all populations throughout the world. There is a need for experts to tackle
the morbidity and mortality from these diseases. Alongside this, the changes in the practice of medicine are moving
rapidly with new therapies and novel surgical procedures. This requires all of us in the field to keep up-to-date with the
latest changes.
The book is divided into 46 chapters. The first half of the book deals with the diseases of esophagus, stomach, and
small and large intestines. The anatomy, pathophysiology, clinical presentation, and management are all covered in a
detailed and fairly consistent fashion. The second half of the book is devoted to liver disease. This starts with a chapter
on immunology giving the readers the facts that can be utilized for understanding disorders described later in the
book. There are useful chapters on viral hepatitis but also one covering coinfection with more than one virus. I was also
delighted to see a chapter on hepatitis virus control in developing countries, which is extremely practical and useful.
Some of the chapters cover highly specialized areas, such as liver disease in pregnancy, an often neglected topic. All
chapters describe the latest therapies and are also well referenced.
The book emanates from a team based in Bangladesh and Japan. The three editors are all distinguished and
experienced physicians. The contributors are mainly Asians, based also in Asia, and have practical knowledge of the
diseases in the local setting. Some of the contributors come from the west and Far-East giving the book an international
flavor. However, with the current rapidity of travel and transmission of diseases across a fast-dwindling distance, diseases
are much the same across the world, although they may differ in the numbers encountered in different countries.
The editors should be congratulated for having produced a new textbook on gastroenterological and liver disorders. It
would be a very useful textbook for trainees as well as for the practicing experienced gastroenterologists and hepatologists
to keep updated. I enjoyed reading it!

Parveen J Kumar cbe


Professor of Medicine and Education
Honorary Consultant Physician and Gastroenterologist
Barts and the London School of Medicine and Dentistry
Queen Mary, University of London UK
PREFACE

Diseases of the digestive system are common all over the world, more so in the developing countries, because of the
extra burden of infection with diverse organisms in all parts of the system. They present a challenge to the clinicians
specializing in this field and make the specialty more interesting. Since the early seventies of the last century, advances in
technology have enabled physicians to look into the hollow organs, initially via fiberoptic and later by videoendoscopy.
This has not only improved the accuracy of diagnosis of diseases but also has enabled clinicians to perform therapeutic
procedures previously undertaken at surgery. Advances in modalities of imaging by radiology, ultrasound and magnetic
resonance have extended the reach further.
Advances in technology continue in a manner that defies prediction. Specialists have a difficult task keeping
themselves up-to-date with the progress. It has become even more time-consuming to acquire the newer skills. In fact,
things have come to such a point that one can only acquire the necessary skills and experiences in a particular area.
Specialization in therapeutic endoscopy, endosonography, etc. has become inevitable. This trend is likely to continue.
The field has already been divided into various sectors depending on organ, such as liver, pancreas, colorectum.
Despite this state of affairs, training in the basics of digestive diseases remains mandatory for all aspiring specialists.
Furthermore, only a fraction of all patients are seen by the specialists, the vast majority being dealt with by general
physicians or general surgeons. These categories of doctors need to be aware of newer methods of diagnosis or treatment
available, even if they are not involved in its delivery.
Bearing all this in mind, the task of preparing a textbook on diseases of the liver and digestive system, which can cater
to the needs of all categories of doctors involved in the care of patients with diseases of these systems, has indeed become
difficult. The burden has been shared by many contributors, themselves reputable on their own right. Some degree of
duplication has been unavoidable despite the care taken to avoid this. We express our gratitude to all the contributors.
Among us, Mamun-Al-Mahtab has been the guiding spirit in all this, encouraging the contributors and urging them to
come up with their part of the book. He deserves all the appreciation for the success of this endeavor.
Many would argue that the need for another textbook on this subject is not clear. Yet, the fact remains that almost all
textbooks originate in the developed countries. The practice of this specialty in developing countries varies for a number
of reasons.
Firstly, the spectrum of diseases are different. Diseases of infection are still quite prevalent in many parts of the developing
world. Moreover, a number of diseases occur in developing countries which are only rarely, if ever, seen in the Western
world. One can cite the examples of tropical calcific pancreatitis and veno-occlusive disease of liver, among others.
Secondly, the paucity of diagnostic and therapeutic modalities makes the clinical approach to a patient somewhat
different in developing countries.
Thirdly, access to Western textbooks is limited in many areas of the developing world. The contributors have kept
these things in mind while preparing their part of the book.
The book is intended to the specialists and the general physicians to update their knowledge in this field and also to
the trainees to learn the stock of the trade. Our effort will be worthwhile if they find what they are looking for in this book.
It is, however, advisable to supplement the information from current journals, as the time frame of preparation of any
textbook of this kind does not allow for inclusion for the most recent advances.
The publishers have been very kind and supportive in their endeavors as they have to bear a great part of the burden
of collecting, coordinating and finalizing the manuscripts. No amount of thanks will do them justice.

Mahmud Hasan
Sheikh Mohammad Fazle Akbar
Mamun-Al-Mahtab
ac k no w l e d g m e nts

We extend our heartfelt thanks to our families, who sacrificed their share of our time allowing us to divert our attention
for this book.
We acknowledge all our contributors, who are global leaders in their respective fields and despite being so busy,
devoted their valuable time to contribute chapters to this book.
We also acknowledge Mr. Helal Uddin, who helped us with invaluable, but voluntary, secretarial support.
We thank our publisher Jaypee Brothers Medical Publishers (P) Ltd The Health Sciences Publishers for believing
in us.
Finally, we thank all the readers of this book for encouraging us by accepting our book.
CONTENTS

Chapter 1: Gastroesophageal Reflux Disease 1


Sujay Ray, Kshaunish Das, GK Dhali
Denition1; Epidemiology1; Pathogenesis4; Diagnosis5; Management8

Chapter 2: Carcinoma of Esophagus 17


Md Rabiul Hossain, Md Delwar Hossain
Epidemiology 17; Risk Factors 17; Biology and Genetics 18;
Clinical Presentation18; Complications19; Prognostic Factors19;
Investigations20; Treatment21; Prognosis23

Chapter 3: Peptic Ulcer Disease 25


Javed Yakoob, SM Wasim Jafri
Clinical Features25; Etiology26; Risk Factors27; Differential Diagnosis28;
Diagnosis29; Treatment29

Chapter 4: Peptic Ulcer Disease in AsiaPacific 31


Sony Sebastian Thazhath, Mazhar Haque
Prevalence31; Risk Factors31; Helicobacter pylori and Peptic Ulcer Disease in
Asia32; Nsaids and Peptic Ulcer Disease in the East 32; Racial and Regional
Differences in Peptic Ulcer Disease 32; Management of Peptic Ulcer Disease 32;
Management of Peptic Ulcer Bleed 33

Chapter 5: Functional Dyspepsia 35


Shahab Abid, SM Wasim Jafri
Rome Criteria for Functional Dyspepsia 35; Epidemiology 36;
Physiological Dysfunctions in Functional Dyspepsia 36;Symptoms and
Pathophysiological Mechanism-based Categorization of Functional Dyspepsia 37;
Etiologic Factors Associated with Functional Dyspepsia 38; Management 38;
Functional Dyspepsia and Quality of Life 41

Chapter 6: Gastric Cancer 43


Mian Mashhud Ahmad, Mamun-Al-Mahtab
Etiology 43; Pathology and Molecular Pathogenesis of Gastric Cancer 45;
Histologic Appearance 46; Clinical Features, Diagnosis, and
Staging of Gastric Cancer 47; Diagnosis 48; Treatment 51;
Further Research 57; Early Gastric Cancer 57
xx Textbook of Hepato-gastroenterology

Chapter 7: Malabsorption Disorders 61


Axel Hsu, Man-Fung Yuen
Epidemiology61; Pathophysiology61; Clinical Features62;
Differential Diagnoses 63; Diagnostic Workup 63; Management Plan 66

Chapter 8: Abdominal Tuberculosis 68


Zaigham Abbas
Risk Factors 68;Sites of Involvement 68; Pathogenesis 68;
Clinical Features71; Investigations71; Differential Diagnosis75;
Management75

Chapter 9: Inflammatory Bowel Disease 77


Vikas Singla, Govind K Makharia
Epidemiology77; Pathogenesis77; Extraintestinal Manifestations 81;
Diagnostic Criteria 81; Evaluation of Patients 82; Investigations for the
Diagnosis and Extent of the Disease 82; Assessment of the Activity of the
Disease 84; Assessment for the Extent of the Disease 85; Differential Diagnosis 85;
Natural History 86; Management 86; Fertility and Pregnancy 91;
Breastfeeding 92; Nutrition in Inflammatory Bowel Disease 92

Chapter 10: Irritable Bowel Syndrome 94


Monjur Ahmed
Pathophysiology94; Clinical Manifestations95; Physical Examination96;
Diagnostic Testing96; Differential Diagnosis97; Management97

Chapter 11: Colorectal Carcinoma 101


Kaushal Kishor Prasad, Saroj Kant Sinha, Rakesh Kochhar
Epidemiological Trends in Asia 101; Incidence of Colorectal Carcinoma in Asia 101;
Distribution According to Age and Sex 102; Right Shift in the Position of Colorectal
Cancer Lesions 103; Mortality Rate for Colorectal Cancer in Asia 103; Colorectal
Polypoid and Nonpolypoid Adenoma 103; Pathophysiology of Colorectal
Carcinoma 104; Molecular Biology: is it Different in Asians? 105; Inherited
Susceptibility to Colorectal Carcinoma 106; Molecular Genetics of Sporadic
Colorectal Carcinoma 108; Risk Factors 109; Clinical Features and
Diagnosis112; Management113; Treatment115

Chapter 12: Gastrointestinal Lymphomas 121


Moiss Copelman, Natalia Balbi Flores, Cassiano Ribeiro Pires
Gastric Lymphomas 121;Small Intestinal Lymphomas 125; Others Sites 128

Chapter 13: Gastrointestinal Stromal Tumor 132


Sony Sebastian Thazhath, Mazhar Haque

Histogenesis132; Epidemiology132; Clinical Features132; Imaging133;


Histology133; Immunohistochemistry133; Cytogenetics133; Kit-Negative
Contents xxi

Gists and Their Associations 134; Prognostic Value of Genetic Aberrations 134;
Risk Stratification 135; Treatment of Gastrointestinal Stromal Tumors 135

Chapter 14: Acute Diarrheal Diseases 138


Sabyasachi Ray
Definition138; Epidemiology138; Etiology138; Mechanisms139;
Bacteria140; Virus141; Parasites141; Prevention142; Management142

Chapter 15: Liver Immunology 145


Julio Csar Aguilar
Main Liver Cellular Types Related to the Immune Response 145; Biology of the
Liver Immune Response 147; Liver T-Cell Response and Potentialities for
Immunomodulating Vaccines 148; Toll-like Receptors and Innate Immunity
Activation within the Liver 149; Immunoprivileged Status of the Liver,
Toll-Like Receptors, and Immunomanipulations 150

Chapter 16: Inborn Errors of Bilirubin Metabolism 153


Cristiane Alves Villela-Nogueira
Clinical Approach to A Patient with Hyperbilirubinemia 153

Chapter 17: Hepatitis A and E Viruses 157


P Karayiannis
Hepatitis A Virus 157; Hepatitis E Virus 160

Chapter 18: Hepatitis B Virus 164


Narendra Choudhary, Ajay Duseja
Molecular Biology of the Hepatitis B Virus 164; Various Antigens and Antibodies of
Hepatitis B Virus 165; Genotypes of Hepatitis B Virus 165; Modes of Hepatitis B
Virus Transmission 165; Disease Manifestations of Hepatitis B Virus 165;
Pregnancy and Hepatitis B 172; Hepatitis B Virus and Hepatocellular Carcinoma 172;
Extrahepatic Manifestations of Hepatitis B Virus 173; Hepatitis B Vaccination 173;
Postexposure Prophylaxis 173; Coinfection with Hepatitis C Virus, Hepatitis D
Virus, and Human Immunodeficiency Virus 173

Chapter 19: Viral Factors and Host Immune


Response to Hepatitis B Virus 176
Andrew Vaillant
Acute Infection 176; Chronic Infection 179; Effect of Hepatitis B Viral
Components on Immune Function 179; Implications for Current and Future
Hepatitis B Virus Treatments 181

Chapter 20: Hepatitis C 184


Amna Subhan Butt, SM Wasim Jafri
Discovery of Novel Hepatitis C Virus 184; Global Burden of Hepatitis C 184;
Incidence 186; Risk Factors for Hcv Transmission 187; Population at Higher
xxii Textbook of Hepato-gastroenterology

Risk 188; Genotypes: Distribution Across the World 188; Pathogenesis and
Viral Characteristics 188; Clinical Characteristics and Natural History of the
Disease 189; Who should be Screened for Hepatitis C? 189; Diagnostic Workup 190;
Economic Burden of Hepatitis C 191; Treatment 191;Strategies to Prevent and
Control Hepatitis C 195; Challenges 195

Chapter 21: 
Emerging and Re-Emerging Factors about Hepatitis Virus
Control in Developing Countries 199
Sheikh Mohammad Fazle Akbar, Mamun-Al-Mahtab
Hepatitis A Virus 200; Hepatitis E Virus 200; Hepatitis B Virus 201;
Hepatitis C Virus 202

Chapter 22: Nonalcoholic Fatty Liver Disease 204


Taranjeet S Jolly, Arun J Sanyal
Epidemiology 204; Pathogenesis of Fatty Liver and Nonalcoholic Steatohepatitis 205;
Natural History of Disease 206; Clinical Features 206; Risk Factors for Advanced
Disease207; Diagnosis207; Management210

Chapter 23: Alcoholic Liver Disease 214


Hamizah Razlan, Rosmawati Mohamed
Disease Spectrum and Risk Factors 214; Pathogenesis 215; Diagnosis 215;
Prognosis 216; Therapy for Alcoholic Liver Disease 217

Chapter 24: Primary Sclerosing Cholangitis 220


Roger W Chapman
Epidemiology 220; Prevalence of Primary Sclerosing Cholangitis in Inflammatory
Bowel Disease 221; Etiology and Pathogenesis 221; Clinical Features 222;
Diagnosis 222; Management of Complications 223; Medical Treatment 225;
Prognosis 225; Hepatic Transplantation 225;Secondary Sclerosing Cholangitis 225

Chapter 25: Primary Biliary Cirrhosis 229


Nurdan Tzn, Murat Saru
Epidemiology 229; Etiology and Pathophysiology 230; Clinical Manifestations 231;
Diseases Associated with Primary Biliary Cirrhosis 232;Special Cases 232;
Diagnosis233; Patient Management and Treatment 234

Chapter 26: Autoimmune Hepatitis 239


Khin Maung Win
Epidemiology239; Classification239; Immunopathogenesis240;
Clinical Features242; Differential Diagnosis243; Diagnosis243; Treatment243

Chapter 27: Amebic Liver Abscess 248


Premashis Kar
Pathology248; Clinical Presentation248; Diagnosis249; Medical Therapy249;
Aspiration or Drainage of Abscess 250;Surgical Intervention 250; Long-term
Follow-up250; Prognostic Marker250
Contents xxiii

Chapter 28: Pyogenic Liver Abscess 251


Furqan Ahmed
Epidemiology251; Pathogenesis251; Clinical Manifestations252;
Microbiology252; Diagnosis253; Differential Diagnosis 253; Treatment253;
Complications255; Mortality255

Chapter 29: Hydatid Cyst of Liver 257


Fazal Karim, Salimur Rahman
Epidemiology257; Transmission258; Clinical Features258;
Complications 258; Diagnosis258; Treatment259; Prevention261

Chapter 30: Leptospirosis 262


Izazul Haque, Fazal Karim
Epidemiology262; Risk Factors262; Microbiology262; Pathogenesis263;
Clinical Manifestations 263; Differential Diagnosis 264; Laboratory Diagnosis 264;
Treatment265; Prognosis265; Prevention265

Chapter 31: Cirrhosis of Liver 267


Anil Arora, Ashish Kumar
Pathogenesis of Cirrhosis 268; Clinical Presentation 269; Diagnosis 269;
Treatment of Cirrhosis 272; Complications of Cirrhosis and its Management 273

Chapter 32: Ascites 280


Gourdas Choudhuri, Ajesh Goyal
Etiology280; Pathogenesis280; Evaluation and Diagnosis282; Physical
Examination 282; Definitions of some Commonly used Terms 285;
Complications285; Treatment of Ascites288; Refractory Ascites293; Prognosis295

Chapter 33: Hepatic Encephalopathy 297


Cihan Yurdaydin, Ramazan Idilman
Clinical Signs and Clinical Importance of Hepatic Encephalopathy 297; Diagnosis 298;
Minimal Hepatic Encephalopathy298; Pathogenesis299; Treatment300

Chapter 34: Hepatocellular Carcinoma 302


Sachin Gupta, YK Chawla
Epidemiology 302; Demographic Factors 302; Environmental Risk Factors 302;
Host Factors 304; Natural History of Hepatocellular Carcinoma 304;
Surveillance 305; Clinical Manifestations 305; Diagnosis and Staging 306;
Treatment307; Prevention310

Chapter 35: Portal Hypertension: Pathophysiology and Management 313


Debashis Misra, Abhijit Chowdhury
Portal Vein and Portal Hypertension 313;Etiology314;Pathophysiology of
Portal Hypertension in Cirrhosis 316; Clinical Sequelae of Portal Hypertension 317;
xxiv Textbook of Hepato-gastroenterology

Evaluation and Diagnosis 320; Treatment 321; Clinical Scenerios and the use of
Modalities 323; Failure of Initial Therapy and Salvage 325; Prophylactic
Therapies 326;Shunts and Surgery in Variceal Bleeding: Transjugular Intrahepatic
Portosystemic Stent 327

Chapter 36: Hepatorenal Syndrome 330


Ziauddin Ahmed
Definition 330; Pathogenesis 330; Estimation of Renal Function 330;
Clinical Presentation330; Incidence331; Precipitants331; Diagnosis331;
Differential Diagnosis331; Treatment332;Surgical Procedures332;
Prevention333; Prognosis333

Chapter 37: Drug-induced Liver Injury 335


Saeed Hamid, Om Parkash
Definition 335; Epidemiology 335; Types of Drug-induced Liver Injury 336;
Pathogenesis 337; Risk Factors for Idiosyncratic Variety of Drug-induced Liver
Injury 338; Clinical and Laboratory Features 339; Diagnosis 340;
Determinants of Prognosis in Drug-induced Liver Injury 342; Management and
Treatment343; Prevention344

Chapter 38: Acute Liver Failure 346


Shivaram Prasad Singh, Parimal Lawate
Definition 346;Subclassification of Acute Liver Failure 346; Etiology 347;
Pathophysiology 351; Clinical Features and Evaluation 351; Diagnostic
Evalulation in Acute Liver Failure 352; Management 352; Assessment of
Prognosis and Guidance for Liver Transplant Listing 356; Liver
Transplantation for Acute Liver Failure 358

Chapter 39: Biliary Atresia 359


Voranush Chongsrisawat, Sittisak Honsawek, Paisarn Vejchapipat, Yong Poovorawan
Pathogenesis 360; Diagnosis 361;Screening for Biliary Atresia 361;
Clinical Manifestations361; Investigations361; Management364

Chapter 40: Liver Diseases in Pregnancy 369


Shelley Haynes, Mandish K Dhanjal
Physiological Changes in Pregnancy 369; Hepatic Disorders Specific to
Pregnancy 369; Disorders not Specific to Pregnancy 376

Chapter 41: Liver Transplantation 379


Ravi Mohanka, Punit Singla, AS Soin
History and Evaluation 379; Indications for Liver Transplantation 380;
Indications for Liver Transplantation, Selection, and Prioritization for Organ
Allocation 381; Contraindications for Liver Transplantation 383; Recipient
Contents xxv

Evaluation and Preparation 383; Donor Evaluation and Preparation 385;


Surgical Technique 386; Innovative Strategies in Liver Transplantation 391;
Postoperative Management, Complications, and Outcomes 392

Chapter 42: Gallstone Disease 404


A Kadir Dokmeci, Mustafa Yakut
Risk Factors in Gallstone Formation 404; Genetic Factors in Gallstone Formation 405;
Bile Lipids and Cholesterol Gallstone Pathogenesis 406; Pigment Stones 407;
Diagnosis and Follow-up in Gallstone-related Diseases 408; Gallstone Diseases 409

Chapter 43: Cholangiocarcinoma 412


Christopher A Wadsworth, Simon D Taylor-Robinson, Shahid A Khan
Epidemiology and Prognosis 412; Risk Factors 412; Pathogenesis 413;
Histopathological Classification 413; Pathological Diagnosis 414;
Clinical Features 414; Laboratory Tests and Imaging 415;Screening for
Cholangiocarcinoma 419;Staging of Cholangiocarcinoma 419;
Treatment420; Published Guidelines423

Chapter 44: Acute Pancreatitis 426


Mahesh Gupta, Uday C Ghoshal
Definitions426; Etiology426; Pathophysiology430; Factors Determining the
Severity of Pancreatitis 431;Severity Assessment 432; Complications of
Acute Pancreatitis434; Management436; Diagnosis436; Treatment438

Chapter 45: Chronic Pancreatitis 442


Muhammad Umar, Hamama-tul-Bushra Khaar
Pathogenesis 442; Classification of Pancreatitis 445;Symptoms and Signs 448;
Complications of Chronic Pancreatitis 449; Diagnosis 450; Treatment 455

Chapter 46: Carcinoma Pancreas 466


Sanjay Govil
Pathogenesis466; Tumor Markers468; Imaging/Staging468; Treatment469

Index 473
1
cHAPTER

Gastroesophageal
Reflux Disease
Sujay Ray, Kshaunish Das, GK Dhali

DeFInition at least 3 times per week was 15.4%.9 Studies from china has
revealed a wide range of variation in prevalence of GERD. Hu
Gastroesophageal reflux disease (GERD) is a disorder in et al.10 demonstrated that only 4.8% of Chinese population had
which gastric contents reux recurrently into esophagus, GERD. On the other hand, Wong et al.11 in a study by telephone
causing troublesome symptoms and/or complications This contact,reported a prevalence of 29.8%.Thus Geographic
statement is similar to the Montreal denition. 1 The term differences in GERD prevalence are difficult to interpret, due to
troublesomeconnotes impairment of quality of life . different patient selectionand questionnaires used.12 In a study
in southern Iran, the prevalence of GERD was signifcantly
higher in rural and illiterate persons. 9 The relationship
EpidemIology between lower educational status and the prevalence of GERD
probably reflects the interaction of certain unhealthy lifestyle
Gastroesophageal reflux disease is a major clinical problem in habits or poor ability to modify such habits. Meucci et al.13
Western countries. found that patients with reflux-like and ulcer-like dyspepsia,
Several recent studies have suggested that the overall the prevalence of migraine headache did not differ from that
prevalence of reflux esophagitis (RE) in Western countries in controls, whereas a higher prevalence of migraine was noted
was around 1020%. 2 In contrast, GERD has traditionally in patients with dysmotility-like dyspepsia and in patients
been considered to be less common in Asian countries.3 But with nausea and vomiting alone. In the study by Aamodt
more recent studies suggest that the prevalence of GERD et al.14 higher prevalence of headache was found in individuals
in Asia is increasing in Japan, and the overall prevalence of with reflux, diarrhea, constipation, and nausea. They
RE among the adult population is around 16%. 4 While in suggested that headache sufferers commonly are predisposed
Taiwan, the prevalence of RE in patients evaluated for upper to gastrointestinal complaints. In a recent multicentric
gastrointestinal tract sympoms is 15%.5 study from India study showed that 8% of Indians reported
These results are similar to the findinngs reported in the symptoms of GER frequent or severe enough to be diagnosed
West. RE has been considered quite rare among Koreans. as GERD. The low prevalence could be attributed to genetic
However, recent studies have revealed that the incidence factors as Asians have a smaller parietal cell mass and a lower
is increasing in the Korean population. RE prevalence in acid output compared with Caucasians.The lower prevalence
subjects undergoing a routine check-up was reported to 2.36% of hiatus hernia and smaller body mass index in the Asian
in 19933 and 3.4% in 1997.6 In 1999, the prevalence of RE was population might also have accounted for the lower prevalence
found to be 5.3% in subjects with gastrointestinal symptoms. of GERD similar to that reported from the rest of south Asian
However in a recent study from Korea in 2009 the prevalence countries. H. pylori infection, common in Indian population,
of RE in male was 14.6% and the in female was only 4.7%.7 might also reduce the frequency of GERD by causing gastritis
According to univariate analysis, male sex, smoking history, and reduced acid secretion. Subjects with GERD were older,
total cholesterol >250 mg/dL, LDL cholesterol 160 mg/dL, more often female, frequently consulted doctors, and often
triglyceride 150 mg/dL, high BP, and fasting glucose 110 mg/ had overlapping functional lower GI symptoms. Frequency of
dL, were significant risk factors of RE.7 The prevalence rate of intake meat, fried food, fruit and spices was higher amongst
GERD in Qashgai migrating Nomads in sourthern Iran, defined subjects with GERD; also, meat, fried food, spice, aerated drink,
as reflux occurring at least one time per week in the preceding tea, coffee, and smoking were often associated with induction
year, was 33%.8 In a study from urban and rural population of of symptoms among subjects with GERD. On multivariate
southern Iran, the prevalence of refux symptoms occurring analysis, induction of symptoms of GERD following smoking
2 Textbook of Hepato-gastroenterology

and nonvegetarian foods was independently associated with words in the local language what heartburn means, i.e. a
GERD. Frequency of GERD was comparable in northern and burning discomfort arising from the epigastrium and rising
southern Indian population. (ISG Task Force Report -In Press). retrosternallyto clarify the term. Asian patients more easily
Assessment of health-related quality of life (HRQL) through understand acid regurgitation, meaning the experience of sour
the use of validated patient-completed questionnaires is or acidic uid in the mouth.
likely to provide a good indication of how troublesome Other symptomatic presentations are chest pain, belching,
gastroesophageal reux symptoms are. There are few nausea, dysphagia, early satiety, and epigastric pain, with or
studies assessing the relationship between HRQL and without typical reux symptoms. There was much discussion
symptoms of GERD in the general population using validated that Asian patients may not complain of the cardinal symptoms
questionnaires. 15 A population-based study in Malm, of heartburn and acid regurgitation, but instead complain of
Sweden showed that even mild reux symptoms on a weekly other upper gastrointestinal symptoms which may be more
basis were associated with a clinically meaningful reduction prominent. Noncardiac chest pain, is a common condition
in well-being,16 while another large survey of the Swedish among Asian patients.23,24 and may be a presenting feature
population (the Kalixanda study) found that daily or weekly of GERD. GERD symptoms among Asian patients are more
symptoms of heartburn and/or regurgitation substantially protean, and atypical symptoms may occur in the absence of
disrupted subjects everyday lives. 17 Similar results were heartburn and acid regurgitation (Table 1).
obtained in two recent studies in the USA.18,19 These studies
showed that the impact of GERD increased with symptom
frequency and severity in the general population. There are Spectrum
few data on the impact of GERD on HRQL in Asia generally. Symptomatic GERD is endoscopically manifested in three
One epidemiological study of GERD in Sanghai, East China, spectrumnonerosive reflux disease (NERD), consisting of
evaluated HRQL impairment in GERD subjects using a Chinese majority of around 60%, erosive esophagitis of around 35%,
version of the SF-3620 (Figs 1 and 2). and complicated GERD of 5%.Compliations of GERD are peptic
stricture, bleeding ulcer, Barretts esophagus, and esophageal
adenocarcinoma. NERD is dened as troublesome reux
Symptoms symptoms in the absence of esophageal mucosal damage on
Typical symptoms of reux are heartburn (retrosternal burning endoscopy. Barretts esophagus is the presence of columnar
sensation) and acid regurgitation. Heartburn, although lined epithelium suspected at endoscopy and proven by
an english term that has no equivalent in any of the Asian histology which requires the presence of intestinal metaplasia.
languages, is now thought to be increasingly understood The term Barretts esophagus has been loosely used, giving
by Asian patients.21,22 Doctors may still have to describe in rise to undue alarm and concern among doctors and patients.

Fig. 1: Health-related quality of life in subjects with and without GERD. Subjects with GERD,
(black bars); subjects without GERD, (white bars). GERD, gastroesophageal reux disease;
QOLRAD, Quality of Life in Reux and Dyspepsia. *P < 0.001;P = 0.003. P-values were
calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5
Gastroesophageal Reflux Disease 3

Fig. 2: Health status and well-being in subjects with and without GERD. Subjects with GERD, (black bars); subjects without GERD,
(white bars). BP, bodily pain; GERD, gastroesophageal reux disease; GH, general health; MH, mental health; PF, physical functioning;
RE, role-emotional;RP, role-physical; SF, social functioning; SF-36, 36-item short-form health survey; VT, vitality. *P < 0.001; P =
0.019. P-values were calculated by t-test. R. Wang et al. Digestive and Liver Disease. 2009;41:110-5

Table 1: Symptoms of gastroesophageal reflux disease Histological conrmation of columnar lined epithelium with
intestinal metaplasia in the denition of Barretts esophagus,
Typical symptoms Alarm symptoms
in addition to endoscopic diagnosis is important (Fig. 3).
Heartburn (pyrosis) Dysphagia Community-based studies identied older age and male
Acid regurgitation Gastrointestinal hemorrhage sex as risk factors for GERD symptoms.25,26 Endoscopy-based
Iron deficiency anemia studies have also revealed age and male sex as risk factors
Nausea and/or vomiting for ERD.27,28 Alcohol , smoking , BMI more than 25 and hiatus
Weight loss
hernia are important risk factors.29 Three reports from South-
east Asia identied Indian race as being a risk factor for
Family history of cancer
GERD.28,30

Fig 3: Spectrum of gastroesophageal disease


4 Textbook of Hepato-gastroenterology

The prevalence and incidence of GERD is increasing in comes into contact of lower esophageal mucosa during reflux
asian countries as revealed in many studies.31,32 Time trend episodes.The pathophysiological mechanisms of GERD in
studies have shown both an increase in symptoms of GERD33 Asian patients are similar to those in Western populations.
in the community, as well as an increase in the prevalence of Among the various motor dysfunction abnormalities of
esophagitis.34-40 esophagus, transient lower esophageal sphincter relaxation
The prevalence of Barretts esophagus and adenocarcinoma (TLESR) with excessive acid reflux is the single most important
of the esophagus, although lower than in the Western mechanism. 42 In patients with more severe GERD, hiatus
populations, is also increasing in Asia. The prevalence of hernia, impaired esophageal peristalsis and weak lower
Barretts esophagus is generally low in Asian patients and esophageal sphincter (LES) pressure play a more important
ranges from 0.9 to 2%.13,35 role in the pathogenesis.4244 However, it is intriguing to note
An isolated study, however, showed prevalence rates of up that rates of TLESR tend to be lower in both Asian GERD
to 6% of patients endoscoped, which was different from other patients and healthy volunteers compared to their Western
studies from the same region. A study based at the Singapore counterparts.42 Furthermore, the reported prevalence of hiatus
Cancer Registry has shown a signicant decrease in squamous hernia in Asian populations is substantially lower than those
cell carcinoma of the esophagus over 34 years and a numerical, reported in Western populations.45 Chang et al. reported that
but not statistically signicant, increase in adenocarcinoma of the prevalence of hiatus hernia was only 2.2% in the Taiwanese
the esophagus.41 general population. 21 In another study of patients with
dyspepsia, the prevalence of hiatus hernia was 49% in English
patients, but only 4% in Singaporeans, most of whom were
Pathogenesis Chinese, respectively. After adjusting for age and body mass
index (BMI), race remains an independent risk factor for hiatus
hernia.46 Furthermore, the prevalence of hiatus hernia has been
Pathophysiology reported as being lower in Asian GERD patients, ranging from
7 to 20% in NERD, and 20 to 30% in esophagitis.47,48 Further
Esophageal dysmotility and hiatus hernia studies are required to elucidate whether there are clear ethnic
The GERD results from imbalance between aggressive and differences in TLESR dysfunction and hiatus hernia, but the
protective factors which interact at lower esophageal mucosa apparent lower prevalence of these conditions could contribute
(Fig. 4). The protectve factors being lower esophageal sphincter to the lower prevalence of GERD and its complications in Asia.
which is supported by diaphragmatic crus, the esophageal
clearance, and esophageal tissue resistance. The aggressive
factors are the acid peptic secretion of stomach and bile which
Esophageal acid hypersensitivity
Esophageal acid hypersensitivity has been implicated in the
pathogenesis of heartburn symptoms, especially in NERD
patients.49 Psychological stress increases perception to low-
intensity stimuli in the esophagus and is perceived as heartburn
in NERD patients.50 It has been reported that NERD patients
have higher positive rates of the acid perfusion test compared
to those with erosive esophagitis, but results are conflicting.51,52

Obesity
The strong association between GERD and abdominal obesity
has been extensively reported in Western populations.53 Recent
studies also support a similar dose-response association
between GERD and BMI in Asians. Patients with reflux
esophagitis tend to have a higher BMI compared to NERD
patients and non-reflux controls.54,55 Recent studies have also
reported a positive association between metabolic syndrome
and GERD. Thus, hyperglycemia, hyperlipidemia, and high
blood pressure have all been shown to be independent risk
factors of esophagitis. 56 The underlying mechanism(s) of
Fig. 4: Pathogenesis of gastroesophageal disease
Gastroesophageal Reflux Disease 5

obesity-related GERD is/are unclear. It has been reported that Diagnosis


the prevalence of hiatus hernia increases with BMI, suggesting
that hiatus hernia may play a role in the development of GERD- Heartburn and regurgitation (or both) that occurs after meals
associated obesity.57 It has also been reported that BMI and are symptoms highly suggestive for GERD. Although the
waist circumference are significantly correlated with TLESR Montreal Consensus reported a high level of agreement on
and gastroesophageal pressure gradient in both asymptomatic this issue, but the denition of heartburn and the specicity
and GERD patients. This finding indicates that postprandial of the term for GERD had been studied mostly in Caucasian
LES dysfunction plays an important role in the pathogenesis populations, whereas the term heartburn carries different
of obesity related GERD.58 The rising problem of obesity may meanings to different parts in Asia.1
be one of the major contributing factors for the increasing There is lack of published data on the specicity and
prevalence of GERD in Asia. sensitivity of heartburn as a predictor of GERD in the Asia-
Pacic region so the term heartburn must be clealy described
and tested in different regions.
Role of H. pylori GERD symptoms do not predict the severity of esophagitis.
The role of H. pylori in GERD has been a controversial subject However, there is some correlation between the severity of
and a major area of substantial discrepancies between Asian symptoms and the presence and grade of esophagitis. 21,75
and Western studies. Most case-control and population-based Longer duration of symptoms, with increased frequency and
presence of symptoms at night, as well as in the daytime, are
studies tend to suggest a negative association between H.
features that are more likely to be associated with erosive
pylori infection and GERD in Asia. The prevalence of H. pylori
esophagitis (figs 5 and 6). This correlation has been established
infection in GERD patients ranges from 25 to 35%, which
in Caucasian GERD patients; about 3040% of patients are
is 2540% lower than that of the non-reflux population in
found to have ERD, with the remainder having NERD. In Asian
Asia.59,60 The negative association is more prominent in the
populations, the ratio of ERD to NERD is much lower and the
elderly,61 however, is only confined to patients with severe correlation of symptoms with erosive disease in this population
GERD in Western countries, especially for those infected has not been tested sufciently.
by more virulent cytotoxin-associated gene A (CagA+) Endoscopy should be done in patients with alarm
strains. 62-64 The prevalence of H. pylori is also inversely symptoms. But the sensitivity and specicity of alarm
related to the severity of GERD. The prevalence of H. pylori symptoms (like dysphagia, weight loss, and anemia)
in patients ranges from 20 to 33% for esophagitis 65, 66 and 0 varies on the denitions, duration of symptoms, and the
to 37% for Barretts esophagus.67 Furthermore, patients with population studied. Clinical diagnosis made by a physician
reflux esophagitis have lower rates of virulence for H. pylori on the basis of alarm symptoms is very specic (range,
infection compared to non-reflux controls.67, 68 Compared to 9798%), but it lacks sensitivity. 76 Urgent endoscopy in
cross-sectional prevalence studies, however, the results are patients with alarm symptoms results in a signicant yield
less consistent in H. pylori eradication studies for peptic ulcer of cancer (approximately 4% in one series) and of serious
patients.69, 70 These conflicting observations may be attributed benign disease, such as peptic ulcer, stricture, and severe
to different dominant patterns of H. pylori gastritis and acid esophagitis (13%).77 There are no published regional data
secretion between peptic ulcer patients and nonulcer patients on the correlation between alarm symptoms and peptic
in the general population. Changes in patients with duodenal stricture and esophagitis mainly because of the rarity of
ulcer and nonulcer dyspepsia are characterized by antrum- these in the Asia-Pacic region. In this region, patients
with alarm features more likely to have gastric rather than
predominant gastritis, hypergastrinemia, and relatively-
esophageal pathology due to the higher prevalence of peptic
preserved acid-secreting corpus mucosa. As a result, gastric
ulcer disease and gastric cancer in the region. Nevertheless,
acid hypersecretion is a common feature. 71,72 However,
alarm features suggest advanced malignancy. 78 In clinical
patients with gastric ulcer and gastric cancer are characterized
practice, expectation and anxiety of the patient is a major
by corpus-predominant gastritis or pangastritis, which is driver because any delay in the diagnosis of any pathologic
associated with profound destruction or even atrophy of acid- condition will lead to patient dissatisfaction.
secreting mucosa. These patients are characterized by gastric Patients with GERD symptoms for 5 years but no alarm
acid hyposecretion, while eradication of H. pylori is followed features should also undergo endoscopy to exclude Barretts
by rebound gastric acid hypersecretion. It has been reported esophagus. But the statement is irrelevant to Asia as there is a
that recovery of gastric acid secretion and the emergence of very low prevalence of Barretts esophagus and adenocarcinoma
reflux esophagitis occurs after H. pylori eradication in patients of the esophagus at present in this region. Due to the overlap of
with corpus gastritis and atrophic gastritis.73,74 upper gastrointestinal symptoms and the greater prevalence
6 Textbook of Hepato-gastroenterology

A B
Figs 5A and B: (A) One (or more) mucosal break, no longer than 5 mm (Grade A); (B) One (or more) mucosal break, more than 5 mm that
does not extend between the tops of mucosal folds (Grade B).
Source: Lundell et al. 1999, published with permission from professor G Tytgat and professor J Dent

A B
Figs 6A and B: (A) One (or more) mucosal break that is continuous. Between the tops of two or more mucosal folds, but which involves less than
75% of the circumference. (Grade C); (B) One (or more) mucosal break that involves at least 75% of the esophageal circumference (Grade D).
Source: Lundell et al. 1999, published with permission from professor G Tytga and professor J Dent
Gastroesophageal Reflux Disease 7

of peptic ulcer and gastric cancer in the region, the indication


for endoscopy is more often to exclude gastric pathology.
Every patient with GERD symptoms should undergo
endoscopy once in a lifetime.
The major reason to investigate a patient suffering from
symptoms of GERD is to detect Barretts esophagus. The highest
risk factor for development of Barretts esophagus is in white
men with chronic symptoms of GERD.79 However, the criteria to
select patients for screening of Barretts are not yet well dened
and it is recognized that persons with Barretts esophagus may A B C
be asymptomatc. Even within the Western population, this a Fig. 7: Endoscopic biopsy: (A) Normal mucosa; (B) Reflux esophagitis;
strategy of screening for Barretts esophagus is not uniformly (C) Eosinophilic esophagitis
accepted.80 Such a strategy is irrelevant to Asia at this time
because of its low prevalence.31,32 A recent direct comparative of basal cell layer to more than 15% of the thickness of the
study also found a lower prevalence of esophagitis (6% vs 27%) epithelium, (ii)an increase in height of the papilla to greater
and columnar-lined esophagus (1% vs 4%) in Asians compared than two third of thickness, (iii) presence of blood lakes at the
to Western patients. 81 In this region, the major reason for top of papilla, (iv) presence balloon cells, or (v) presence of
endoscopy is to diagnose or exclude gastric cancer or peptic inflammatory cells in epithelium or lamina propia (fig. 7).
ulcer. There is considerable debate regarding performance A negative ambulatory pH study off therapy helps exclude
of endoscopy at least once in patients with chronic upper GERD, if a PPI test fails.
gut symptoms, recognizing the difficulty of clinical diagnosis The test is considered positive if the total time for which
between GERD and peptic ulcer and the ability of endoscopy pH is <4 is >4.5% (fig. 8). However ambulatory pH testing
to provide or exclude a diagnosis and aid in tailoring therapy. is not widely available in Asia and is rarely done outside of
In one study, 18% of patients suffering from H. pylori-related major centers. Furthermore, there are few data on the test
peptic ulcers were misdiagnosed as GERD based on symptoms characteristics in Asian populations. For diagnostic purposes,
alone.82 As fear of gastric cancer is a major concern, endoscopy the need to have patients off PPIs when performing pH studies
should be performed early rather than later. Empiric use of was stressed. The likelihood of a positive test while on PPIs is
proton pump inhibitors (PPIs) is common prior to endoscopy low; the main role of the test with the patient on PPIs is for the
resulted increased risk of a false-negative H. pylori biopsy test, assessment of the adequacy of acid suppression in patients
so there is requirement to cease PPI prior to testing. Widespread with GERD who are not responding to therapy.
availability of endoscopy in many parts of the region favored Other diagnostic modalities are barium swallow and
endoscopic approaches over a noninvasive test. fluoroscopy and radionuclide scintigraphy, which are not
Symptomatic response to a trial of PPI is sufcient for commonly used tests. In a recent study from Delhi, when all
a presumptive diagnosis of GERD in a patient with typical the individual tests were compared against the gold standard
symptoms, in the absence of alarm symptoms. Although a of three or more positive tests, then as a single test, 24-hour
symptomatic response to a trial of PPI therapy has been used to pH monitoring had the best combination of sensitivity and
support a diagnosis of GERD in patients with typical symptoms, specificity.84
a meta-analysis revealed that the combined sensitivity and There is currently no established role for the use of narrow
specicity of this is only modest.83 As there is overlap of GERD band imaging (NBI), capsule endoscopy, and wireless pH
with the symptoms of peptic ulcer and the response of ulcer monitoring in the routine management of GERD in the Asia-
symptoms to PPI therapy, and the higher prevalence of ulcer Pacic region. However, these newer diagnostic modalities
in the region, such a strategy needs to be validated locally. require validation as research tools and for clinical practice. It
However, there is support for an empirical trial of PPI in those is recognized that they are not appropriate for routine clinical
with typical symptoms, particularly in the primary care setting. use in the region at present as the impact on diagnosis and
Histopathology also plays an important role in diagnosis of management and the cost effectiveness of these new tests
GERD and its complication. Barretts esophagus is defined as are yet to be determined. Nevertheless, NBI is considered a
presence of specialized intestinal metaplasia on histological potentially valuable tool in diagnosing GERD, in particular in
examination of biopsies taken from suspected areas (if patients with Barretts esophagus. Wireless pH monitoring has
present) above gastroesophageal junction. Biopsies are taken been shown to increase the diagnostic yield of GERD by 20%,85
from all four quadrants of distal 5 cm of the esophagus for in Caucasian population.
histopathologic diagnosis of GERD which require presence Diagnostic strategies in the Asia-Pacic region must take
of any of the following findings: (i) an increase in thickness consideration regarding the coexistence of GERD with other
8 Textbook of Hepato-gastroenterology

Fig. 8: Common pattern of24 hours esophageal pH monitoring. Upper panel showing physiologic
pattern of gastroesophageal reflux (GER) seen in healthy subject. Reflux is noted after meals (M) but
not while asleep(S). A reflux episode is defined when pH drops below 4.middle panel showing upright
reflux pattern with extensive GER during the day but not at night.Lower panel showing combined
pattern with GER during the day and night

common conditions like gastric cancer and peptic ulcer. Gastric infected with H. pylori. It is accepted to offer eradication therapy
cancer still accounts for nearly one million deaths worldwide prior to long-term PPI therapy in this setting.88 The decision to
annually, with much of this occurring in the region. There is test for and treat H. pylori infection in the context of reux must
immense difficulty in designing the management strategies be individualized based on patient factors including comorbidity,
in a large diverse region, where the prevalence and spectrum age, gastric histology, family history, and informed choice.
of GERD, peptic ulcer, and gastric cancer vary considerably.
The strategy for management of upper gut symptoms must
recognize that symptoms of GERD, peptic ulcer disease, and Management
functional dyspepsia frequently overlap, causing difficulty in
differentiating these conditions clinically. Goals of Therapy
H. pylori testing should be considered in patients presenting
with GERD symptoms in regions with a high prevalence of gastric Resolution of symptoms (symptoms no longer bothersome)
cancer or peptic ulcer disease. Symptoms were an imprecise way Healing of esophagitis or ulcer, if present. Prevent long-term,
of distinguishing between upper gastrointestinal conditions in etc. complications (ulcer, bleeding, Barretts esophagus,
Asia and that GERD may coexist. Peptic ulcer and gastric cancer stricture, etc.). Weight loss and elevation of head of bed could
have greater impact than GERD on morbidity and mortality. improve symptoms in GERD patient. There is insufficient data
There is evidence that benefits are gained by testing and treating to support other lifestyle modification recommendations.
H. pylori infection in the context of reducing symptoms, curing Lifestyle modifications are commonly used as first line of
ulcer disease, and reducing the risk of gastric cancer.86 H. pylori therapy in patients presenting with GERD-related symptoms.
does not cause or prevent reux disease and that eradication of They include weight loss, smoking cessation, avoidance of
this organism does not appreciably increase the risk of GERD postprandial recumbency for a period of at least 3 hours,
occurring.87 Long-term PPI therapy for GERD increases the risk of elevation of the head of the bed, avoidance of tight-tting
progression of gastric atrophy and intestinal metaplasia in those garments, and avoidance of large heavy meals as well as food
Gastroesophageal Reflux Disease 9

and drink that exacerbate GERD symptoms (e.g. spicy foods,


fatty meals, peppermint, chocolate, onions, citrus juices, and
carbonated beverages).89 However, for many patients lifestyle
modications are difficult to follow, very restrictive, and may
adversely affect the quality of life. In a recent systematic review
that evaluated the value of the different lifestyle modications
in GERD, the authors demonstrated that only weight loss and
elevation of the head of the bed are effective in improving
symptoms of GERD.90 Elevation of the head of the bed and left
lateral decubitus positioning improved the overall time pH
<4.0, and weight loss improved pH proles and GERD-related
symptoms. There was no evidence that lifestyle interventions,
such as dietary measures and tobacco or alcohol cessation were
effective in reducing esophageal acid exposure or ameliorating
GERD symptoms.90, 91 Fig. 9: Healing rates following up to 4 weeks of treatment with
PPIs are the most effective medical intervention for GERD. esomeprazole 40 mg (n = 1562) or pantoprazole 40 mg (n = 1589) by
Studies have shown repeatedly and consistently that PPIs are baseline Los Angeles (LA) grade of erosive esophagitis severity. Aliment
superior to histamine 2 receptor antagonists (H2RAs) in healing Pharmacol Ther. 2005;21:739-46
the esophageal mucosa and relieving GERD-related symptoms
of patients with ERD.9294
In a meta-analysis, the investigators demonstrated that with ERD, as compared to those with NERD. In one meta-
after 12 weeks of treatment, healing rates were 83.6% with analysis, response rates at 4 weeks were signicantly higher
PPIs, 51.9% with H2RAs, 39.2% with sucralfate, and 28.2% with for patients with ERD as compared to those with NERD (56%
placebo.95 In addition, treatment with PPIs resulted in healing vs 37%, P < 0.0001).98
rates of esophageal inammation and relief of GERD symptoms All PPIs are equally efficacious. In GERD/NERD/esophagitis
that were twofold higher than what was observed in patients 6 good quality systematic reviewsno clinically important
receiving H2RAs. Similarly, PPIs demonstrate superiority in differences in standard doses PPIs. Comparisons showing some
relieving heartburn symptoms in patients with NERD when degree of difference involved non-equivalent comparisons (e.g.
compared to H2RAs.96-98 high dose vs. standard dose). However with higher grades of
The superiority of PPIs over H2RAs in ERD is not esophagitis esomeprazole is more effective (Fig. 9).
limited to acute therapy but has also been demonstrated in High or double-dose PPI, as initial therapy, is no better than
maintenance studies over as long as 11 years.99 The symptoms standard daily dose therapy in the management of erosive
response rate to once daily PPI in randomized controlled esophagitis (fig. 10). Double-dose PPIs: step-up therapy for
trials has been shown to be signicantly higher in patients nonresponders to standard dose PPI can be used.

Fig. 10: Result of studies showing comparison between Standard vs double dose PPIno
difference in healing of esophagitis or symptom relief
10 Textbook of Hepato-gastroenterology

H2RAs and antacids are useful in treating episodic in NERD patients have lasted only 4 weeks. The studies were
heartburn. H2RAs and antacids are commonly used for designed with the assumption that 4 weeks are sufcient to
episodic heartburn, primarily for postprandial heartburn. assess symptom improvement as opposed to esophageal
The perception of heartburn serves as a trigger for medication mucosal healing, which requires more than 4 weeks of PPI
use, and the expectation is an immediate symptom relief that therapy. This arbitrary time frame is unlikely to provide
PPIs are unlikely to provide. The onset of action of antacids the full symptomatic response rate of patients with NERD
on esophageal acid concentration is 30 min after dosing and undergoing PPI treatment. A systematic review of the
inhibition persists for 1 hour. 100 However, studies reported literature, revealed a trend in increased therapeutic gain
that effective heartburn relief can be achieved 19 min after for NERD patients throughout the 4 weeks, suggesting that
consumption. 101 In contrast, H2RAs have been shown to a 4-week follow-up evaluation alone may be insufficient to
provide symptom relief within 30 min of dosing that can last show the full therapeutic gain in this patient population.98
up to 12 hours.102 ERD patients will require a minimum of 48 weeks of initial
When consumed 30 min prior to a meal, H2RAs are effective continuous therapy with a PPI. Therapeutic studies in
in completely or partially preventing postprandial heartburn.103 patients with ERD have almost always lasted 8 weeks. Healing
There is some evidence to suggest that simultaneous rates in those receiving PPI once daily for 8 weeks ranged
consumption of both an H2RA and an antacid provides better from 8596%, regardless of the PPI that was used and the
control of heartburn symptoms, when compared to the clinical underlying severity or ERD.108-111
effect of each one of these products alone. 100 On-demand However, patients with severe grades of ERD demonstrated
treatment with H2RAs has been shown to be safe and effective higher PPI failure rates as compared to those with mild-to-
in GERD patients. In one study, ranitidine 75 mg daily was moderate disease after 8 weeks of treatment.107
consumed on demand (up to three times daily) as compared In one study, patients were randomized to either
to placebo in patients with uninvestigated GERD.104 The study omeprazole 20 mg once daily versus esomeprazole 40 mg
revealed that 3841% of those receiving H2RAs reported relief once daily.112 The failure rate in those with Los Angeles grade
of at least 75% of heartburn episodes during the study period A was 9.6% and 6.6%; grade B, 28.7% and 10.6%; grade C,
as compared to 28% on placebo. 29.6% and 12.8%; and grade D 26.2% and 20%, respectively.
The use of prokinetic agents either as monotherapy or Patients with lower grades of ERD are likely to heal earlier,
adjunctive therapy to PPIs may have a role in the treatment of and thus 4 weeks of treatment could be sufcient. This is
GERD in Asia. Several recent studies have demonstrated the particularly important in the Asian context where generally
value of prokinetic agents in GERD management. Itopride, a patients are less likely to develop severe ERD, specically
dopamine D2 antagonist with antiacetylcholinesterase effect, Los Angeles grades C and D, as compared to their Western
has been recently evaluated in patients with an abnormal counterparts.32 The rate of symptom resolution in patients
pH test and mild ERD. After 30 days of treatment in an open with ERD is commonly 515% lower when compared
label study design, itopride signicantly reduced the extent to esophageal mucosal healing rate after 8 weeks of
of esophageal acid exposure and improved GERD-related treatment.108-112 This clearly suggests that a small portion of
symptoms as compared to baseline values.105 Mosapride, a the patients with ERD will continue to report GERD-related
newly developed 5-HT4 agonist, has been shown to increase symptoms despite complete esophageal mucosal healing. In
the rate of complete esophageal bolus transit and enhances a meta-analysis of 43 therapeutic trials in ERD, the authors
esophageal bolus transit in normal controls.106 In one study reported an overall 65% healing rate of esophageal mucosa
from India, 68 patients suffering from heartburn twice a week after 4 weeks, 80% after 8 weeks, and 84% after 12 weeks of
were randomized to either pantoprazole 40 mg twice daily or treatment with PPI once daily.
pantoprazole 40 mg twice daily plus mosapride 5 mg thrice PPIs provided a healing rate of 11.7% per week and complete
daily for a period of 8 weeks.107 The investigators found that heartburn relief at a rate of 11.5% per week. The meta-analysis
the PPI + mosapride regimen provided signicantly better demonstrated that 12 weeks of treatment with PPI once a
symptom control in patients with ERD as compared to the day provided only a modest increase in the healing rate as
PPI alone. However, there was no difference between the two compared to 8 weeks of treatment in patients with ERD.
therapeutic arms in ERD healing rates or symptomatic response O n - d e ma n d t h e rapy i s a n ap p ro p r i at e o n g o i n g
of subjects with NERD. Further studies using the new prokinetic management strategy in NERD patients. Several alternative
agents are needed, but those that are currently available therapeutic strategies have been proposed for patients
demonstrate little efcacy as sole therapy or in combination with NERD. The one that has been studied the most is
with a PPI in subsets of patients with GERD. on-demand therapy dened as PPI consumption (up to
NERD patients will require a minimum of 4 weeks of initial once daily) when needed and for the duration desired.
continuous therapy with a PPI. Almost all therapeutic trials This patient-driven therapeutic strategy has been shown
Gastroesophageal Reflux Disease 11

to be clinically efcacious and cost effective. On-demand antireux surgery is highly predictive of clinical success.132 In
therapy is attractive to patients because it provides their addition, several cost-effectiveness analyses have revealed
input into their own management, addresses concerns that medical therapy is significantly less costly than antireux
about chronic ingestion of PPIs, and offers personal cost surgery.134
savings. Studies have also demonstrated that patients are Thus, only in GERD patients who wish to discontinue
commonly consuming PPIs in an on-demand fashion despite maintenance of medical treatment, surgery by a fully trained
instructions to take their medications on a daily basis.113 Many and highly experienced surgeon is recommended. Endoscopic
studies have assessed the value of on-demand PPI therapy treatment of GERD should not be offered outside well-designed
as a maintenance strategy in patients with NERD.114-120 These clinical trials
studies commonly followed a similar design. Patients who
responded to an acute treatment (4 weeks) with a daily PPI
were then randomized to either placebo or PPI for a period
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Gastroesophageal Reflux Disease 15

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placebo. Aliment. Pharmacol. Ther. 1998;12:909-17. 119. Tsai H, Chapman R, Shepherd A et al. Esomeprazole 20 mg
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patients with mild GERD: a pilot study. World. J. Gastroenterol. lansoprazole 15 mg in the long-term maintenance of endoscopy-
2005;11:4210-4. negative gastro-oesophageal reux patients: the COMMAND
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motility and bolus transit in asymptomatic volunteers. J. Clin. 120. Ponce J, Arguello L, Bastida G, Ponce M, Ortiz V, Garrigues V. On-
Gastroenterol. 2006;40:286-92. demand therapy with rabeprazole in nonerosive and erosive
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therapy of gastroesophageal reux disease: a randomized trial. 2004;49:931-6.
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patients with reux esophagitis: comparative study of omeprazole, pump inhibitors in patients with non-erosive reux disease.
lansoprazole and rabeprazole. J. Gastroenterol. Hepatol. Pharmaeconomics. 2005;23:1031-41.
2003;18:1392-8. 122. Wahlqvist P, Junghard O, Higgins A, Green J. Cost effectiveness
109. Richter J, Bochenek W. Oral pantoprazole for erosive esophagitis: a of proton pump inhibitors in gastro-oesophageal reux disease
placebo-controlled, randomized clinical trial. Am. J. Gastroenterol. without oesophagitis. Pharmaeconomics. 2002;20:267-77.
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Lansoprazole Group. Am. J. Gastroenterol. 1996;91:1749-57. 125. Lafullarde T, Watson D, Jamieson G, Myers J, Game P, Devitt
112. Richter J, Kahrilas P, Johanson J et al. Efcacy and safety of P. Laparoscopic Nissen fundoplication. Arch. Surg. 2001;136:
esomeprazole compared with omeprazole in GERD patients 180-4.
with erosive esophagitis: a randomized controlled trial. Am. 126. Lundell L, Miettinen P, Myrvold H et al. Continued (5-year) follow-
J.Gastroenterol. 2001;96:656-65. up of a randomized clinical study comparing anti-reux surgery
113. Hungin A, Rubin G, OFlanagan H. Factors inuencing compliance and omeprazole in gastroesophageal reux disease. J. Am. Coll.
in long-term proton pump inhibitor therapy in general practice. Surg. 2001;192:172-81.
Br. J. Gen. Pract. 1999;49:463-4. 127. Spechler S, Department of Veterans Affairs Gastroesophageal
114. Pace F, Pallotta S, Bianchi Porro G. On-demand proton pump Reux Disease Study Group. Comparison of medical and surgical
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disease. Dig. Liver. Dis. 2002;34:870-7. veterans. N. Engl. J. Med. 1992;326:786-92.
115. Scholten T, Dekkers C, Schtze K, Krner T, Bohuschke M, Gatz G. 128. Madan A, Minocha A. Despite high satisfaction, majority of gastro-
On-demand therapy with pantoprazole 20 mg as effective long- oesophageal reux disease patients continue to use proton pump
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the ORION trial. Digestion. 2005;72:76-85. 2006;23:601-5.
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Systematic review: the efcacy of intermittent and on-demand term outcomes after Toupet Fundoplication. J. Clin. Gastroenterol.
therapy with histamine H2-receptor antagonists or proton pump 2002;34:509-15.
16 Textbook of Hepato-gastroenterology

130. Spechler S, Lee E, Ahnen D et al. Long-term outcome of medical 133. Kozarek R, Low D, Raltz S. Complications associated with
and surgical therapies for gastroesophageal reux disease. JAMA. laparoscopic anti-reux surgery: one multispecialty clinics
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of choice for gastro-oesophageal reux disease. Gut. 2002;51:472-4. of the cost-effectiveness of surgical versus medical therapy
132. Soot S, Eshraghi N, Farahmand M et al. Transition from open in patients with gastroesophageal reux disease: the value
to laparoscopic fundoplication: the learning curve. Arch. Surg. of long-term data collection. Am. J. Gastroenterol. 2004;99:
1999;134:278-81. 1023-8.
2
cHAPTER

Carcinoma of
Esophagus
Md Rabiul Hossain, Md Delwar Hossain

INTRODUCTION RISK FACTORS


Worldwide, esophageal cancer is the sixth leading cause of Many factors are responsible for the development of
death from cancer. There were 7,966 people diagnosed with esophageal cancer (Table 1). It varies with the types of
esophageal cancer in the UK in 2007, with twice as many cases carcinoma. Cigarette smoking and alcohol consumption are
occurring in men as in women. Squamous cell carcinoma the most important predisposing factors for esophageal cancer
(SCC) is the most common esophageal carcinoma worldwide. in developed countries, particularly for SCC. The carcinogenic
Adenocarcinoma is less common (<15%) esophageal cancer. effects are more pronounced for SCC. The mechanism of
Small cell carcinoma of esophagus is very rare. Approximately carcinogenesis is obscure. It is postulated that many tobacco-
15% of esophageal cancers arise in the upper one-third, derived chemicals, such as nitrosamines may initiate the
50% in the middle-third and 35% in the lower-third, and
gastroesophageal junction. Table 1: Risk factors for esophageal carcinoma

Squamous cell carcinoma


Chronic tobacco use
EPIDEMIOLOGY Heavy alcohol consumption
The incidence of carcinoma differs significantly by geographic History of radiation therapy
regions, race, sex, and also types. The rates can vary between Chronic esophagitis (most common in Asia and Africa)
regions in a given country due to environmental and possibly Chronic stricture
nutritional factors. The disease predominantly affects older age
Tylosis
groups with the peak incidence between 60 and 70 years of age. In
Plummer-Vinson syndrome
low-risk countries, male-to-female ratio of cases is usually 3:4.1,
but it is nearly equal in high-risk countries. For SCC worldwide, Achalasia
the highest risk populations (incidence rate >100 cases per Dietary deficiency of carotene, vitamins C, E and riboflavin, selenium and
100,000 inhabitants/year) are found in north central China, zinc
northeastern Iran and the intervening central Asian countries Low intake of fruits and vegetables
sometimes collectively called the Central Asian esophageal High intake of red meat and nitrate-containing foods
cancer belt. Intermediate-risk populations with incidence rates Consumption of hot beverages
approximately 2050 cases per 100,000 inhabitants per year are
Adenocarcinoma
found in eastern and southern Africa, southern Brazil, Uruguay,
Barretts esophagus and gastroesophageal reflux disease
northern Argentina, and northwest France. Most of the world
is considered low risk with the incidence rates less than 10 Obesity
cases per 100,000 inhabitants per year. By far, SCC is the most Cigarette smoking
common esophageal cancer worldwide and adenocarcinoma Alcohol consumption
accounts for less than 15% of all esophageal cancers. Over the Scleroderma
last two decades, the incidence of adenocarcinoma has risen
History of colon cancer
sharply particularly among white males, although SCC remains
Medications: theophylline and -agonists (long-term use >5 years)
the predominant cell type among African Americans.
18 Textbook of Hepato-gastroenterology

favorable indicator of risk for digestive tract neoplasms in this


population.

BIOLOGY AND GENETICS


The progression from basal cell hyperplasia and dysplasia to
the development of invasive SCC is variable and may be of long
duration. The premalignant stages may persist for 20 years or
more. Alterations of oncogenes, tumor suppressor gene and
deoxyribonucleic acid (DNA) mismatch repair genes play a
role in the genesis of SCC of esophagus like in other cancers
of the digestive tract. Cyclin D1 is overexpressed in many
cancers and in up to 50% of esophageal SCC. Overexpression
is associated with a poor prognosis.
The p53 gene is mutated in up to 70% of esophageal cancers.
Inherited germline mutations of the E-cadherin gene lead to
loss of E-cadherin expression that causes increased activation
of other genes, such as cyclooxygenase-2 (COX-2) and c-myc
Fig. 1: Barretts esophagusrisk for esophageal carcinoma
that may induce proliferation.
Abnormal variants of interleukin-1 gene are associated with
esophageal carcinoma or act as promotional agents. Barretts an increased risk of development of cancer of gastric cardia.
esophagus is the most important risk factor for esophageal So, these genes may make possible screening of individuals
adenocarcinoma (Fig. 1). It is a premalignant lesion that with intestinal metaplasia of the esophagus. Furthermore,
results from gastroesophageal reflux disease (GERD) in which anti-inflammatory drugs, such as cyclooxygenase inhibitors
the squamous epithelium of the distal esophagus is replaced may provide a means of medical intervention.
by intestinal type columnar epithelium. The lifetime risk of
esophageal carcinoma in Barretts esophagus is estimated to
be 5%. In addition to this, GERD is an independent risk factor CLINICAL PRESENTATION (TABLE 2)
for esophageal adenocarcinoma.
Dysphagia
Decreased Risk for Esophageal Progressive dysphagia (90%) is the most common
presentation of esophageal cancer leading to its diagnosis. A
Carcinoma patient may not manifest dysphagia until the lumen is more
The risk appears to be less in patients using aspirin or related than 5060% obstructed by the tumor mass by stretching the
drugs (NSAIDs). The role of Helicobacter pylori in progression smooth muscle due to lack of serosal layer. Initially, there is
to esophageal adenocarcinoma is still uncertain, but on the dysphagia to solid and later on for both solid and liquid.
basis of population data, it may carry a protective effect. It
is postulated that H. pylori induces chronic gastritis, which Table 2: Signs and symptoms of esophageal carcinoma
is a risk factor for reflux, which in turn is a risk factor for Dysphagia (most common)solids then liquids
esophageal adenocarcinoma. Odynophagia
According to the National Cancer Institute, diets high
Back pain and chest pain
in cruciferous (cabbage, broccoli/broccolini, cauliflower,
brussel sprouts), and green and yellow vegetables and fruits Anorexia
are associated with a decreased risk of esophageal cancer. Weight loss
Moderate coffee consumption is associated with a Regurgitation
decreased risk. Hoarseness/voice change
According to one Italian study of diet surveys completed by Aspiration/cough/recurrent pneumonia
5,500 Italiansa study which has raised debates questioning
Anemia
its claims among cancer researchers cited in news reports
about it, eating pizza more than once a week appears to be a Hematemesis
Carcinoma of Esophagus 19

Odynophagia Clinical Stage


Odynophagia (50%) is the second most common presenting The new system recognizes five major prognostic stages from
symptom of esophageal cancer. It may be due to an ulcerated stage 0 to stage IV of tumor extent and tumor stage based on
area in the tumor or mediastinal involvement. But constant local invasion, nodal involvement and presence of metastases
pain in the mid back or mid chest is the typical presentation (Table 3). The 5-year survival rates associated with the tumor
of mediastinal invasion. invasion (T1 to T4) are approximately 80%, 45%, 25% and less
than 20%, respectively.

Anorexia and Weight Loss


Table 3: American Joint Committee on Cancer (AJCC) TNM staging
Up to 75% of patients have experienced anorexia and weight system for esophageal cancers (1997 revision)
loss when they seek medical attention.
Primary tumor infiltration (T)

Gastrointestinal Bleeding and Anemia TX Primary tumor cannot be assessed

T0 No evidence of primary tumor


Overt gastrointestinal bleeding as manifested by hematemesis
or melena rarely occur. But anemia is more common due to Tis Carcinoma in situ
subclinical bleeding. Hoarseness of voice, severe cough and T1 Tumor limited to mucosa/submucosa
recurrent pneumonia may present. T2 Tumor involving muscularis propria

T3 Involvement of adventitia, no extraesophageal involvement

COMPLICATIONS Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed


Pulmonary complications: Dyspnea, chronic cough,
N0 No nodal involvement
aspiration and postobstructive pneumonia, lung abscess,
esophagoairway fistula, pleural effusion, and halitosis N1 Regional nodes involved
Cardiovascular complications: Hemorrhage from the Distant metastasis (M)
aorta, arrhythmias, conduction abnormalities, and
MX Distant metastases cannot be assessed
pericardial effusion
M0 No distant metastases

M1 Distant metastases for tumors of the lower thoracic esophagus


PROGNOSTIC FACTORS

M1a Metastases in celiac nodes
M1b Other distant metastases
Tumors of the mid-thoracic esophagus
Radiographic Endoscopic M1a Not applicable
M1b Nonregional lymph nodes and/or other distant metastasis
Tumors measuring less than 5 cm are often confined to the Tumors of the upper thoracic esophagus
esophageal wall, whereas only 10% of those measuring greater M1a Metastases in cervical nodes
than 5 cm are localized. The presence of metastases is a poor M1b Other distant metastases
prognostic sign and is a contraindication to surgery. The AJCC stage groupings
presence of transmural invasion into adjacent organs, such Stage 0 Tis N0 M0
as pericardium or trachea is associated with poor prognosis.
Stage I T1 N0 M0
Evidence of lymph node involvement is also associated with a
poor overall 5-year survival (5%). Stage IIA T23 N0 M0

Stage IIB T12 N1 M0

Pathologic Stage III T3 N1 M0

The prognosis of any malignancy depends on the histologic T4 Any N M0


type and grade, and clinical stage. The vast majority of Stage IV Any T Any N M1
esophageal cancer are either SCC or adenocarcinoma. The Stage IVA Any T Any N M1a
overall prognosis of a poorly differentiated tumor is worse
Stage IVB Any T Any N M1b
than that of a well-differentiated tumor.
20 Textbook of Hepato-gastroenterology

INVESTIGATIONS
Radiography
Chest X-ray
Posteroanterior (PA) and lateral chest radiography is indicated
in patients with chronic cough and in case of abnormal
chest findings on auscultation to demonstrate pulmonary
metastases, pneumonia or esophagorespiratory fistula.

Barium Swallow Radiography


It is indicated in selected patients and details high-grade
stenosis, obstruction, and fistulas (Fig. 2).
Fig. 3: CT with contrast axial image revealing esophageal carcinoma
Computed Tomography
Computed tomography scanning of the chest and upper
abdomen is indicated to assess the lymph nodes, and
pulmonary and hepatic metastases. The primary tumor
is seen as low density mass. The length and extent can be
assessed as well. Magnetic resonance imaging can assess but
has no advantages over CT scan (Fig. 3).

Endoscopy
Upper gastrointestinal endoscopy allows direct visualization
of the esophagus as well as tissue sampling to confirm the
diagnosis (Fig. 4). It allows accurate characterization of
tumors configuration, length and localization. At least six
biopsy samples should be taken from a non-necrotic area to
yield an accuracy approaching 100%. Brush cytology may be
used as a complementary technique.
Fig. 4: Endoscopic view of esophageal carcinoma

Investigations for Staging


Computed tomography and MRI are highly effective in
identifying solid organ metastases when these lesions are
larger than 510 mm (Fig. 3). For metastases detection by CT
scan, the accuracy is 6090% with overall sensitivity from 41
to 62% and specificity from 63 to 83%.

Positron Emission Tomography


Positron emission tomography (PET) is a noninvasive
procedure to detect distant metastases with a sensitivity of
88%, specificity of 93%, and accuracy of 91%. In one study
Fig. 2: Barium swallow of the esophagus showing irregular filling that compared PET with CT and endoscopic ultrasonography
defects suggestive of esophageal carcinoma (EUS) for local lymph node (LN) disease, the sensitivity of PET
Carcinoma of Esophagus 21

A B
Figs 5A and B: (A) Endoscopy and (B) radial ultrasound revealing submucosal esophageal tumor

was lower than that of EUS (33% vs 81%), but the specificity Primary Therapy
may have been higher (87% vs 67%).
Surgery
Endoscopic Ultrasonography General considerations: Patients in the subgroup with
limited local spread (T1T2) and no regional lymph node
It is the most accurate in identifying T3 or T4 stage. Overall
involvement are potentially curable by surgery. Resectable
EUS nodal staging is less accurate. Endoscope ultrasound-
tumors are characterized by the absence of extension into
guided fine-needle aspiration has significantly improved the mediastinal structures and the absence of nodal or organ
diagnosis of malignant adenopathy (Figs 5A and B). metastases. Prior to surgery, the patient should have sufficient
cardiopulmonary reserve. Forced expiratory volume (FEV1)
should be 2 L or more. Resting ejection fraction of less than
TREATMENT 40% is an ominous finding.
Surgical approach: The surgical options available for
Esophageal carcinoma is a treatable disease, but it is rarely
esophageal tumor resection include:
curable. Whether the patient is a candidate for major curative
Transhiatal: It is currently the preferred surgical approach.
surgery is to be determined first before going to start treatment.
Combined right thoracic and abdominal (Ivor Lewis)
Unfortunately, over 60% patients with esophageal carcinoma Left thoracoabdominal
are not candidates for surgery at the time of presentation due En bloc, either two field- or three field-resection remains
to advanced stage of the disease or significant comorbidity. the definitive surgical cure for esophageal cancer (field
Primary treatment modalities include: oneceliac and splenic nodes, field twoinfracarinal
Surgery alone posterior mediastinal nodes, field threeupper
Chemotherapy with radiation therapy mediastinal and cervical nodes).
Combined modality therapy (chemotherapy + surgery,
chemotherapy and radiation therapy + surgery) is under
clinical evaluation Combination Therapy
Endoscopic mucosal resection (EMR) and or photodynamic It is alternative to surgery. Definitive radiation therapy in
therapy in selected patients with superficial carcinoma is combination with chemotherapy (fluorouracil and mytomycin)
also under evaluation. is used for treatment.
22 Textbook of Hepato-gastroenterology

Treatment of Superficial Esophageal Cancer Chemical sclerosant injection: Absolute alcohol is the
most widely used sclerosant chemical agent
Endoscopically Photodynamic therapy (PDT): It has been successful in
EMR reducing tumor bulk and in opening the lumen in patients
Laser therapy with complete obstruction. It also acts as a salvage therapy
Argon plasma coagulation (APC) in patient with stents failure due to tumor ingrowth
Photodynamic therapy. or overgrowth. It is done by intravenous injection of a
photosensitive chemical, porfimer sodium (Photofrin),
at a dose of 2 mg/kg body weight followed by exposure of
Palliation Therapy red light at a wave length of 630 nm to tumor resulting in
Palliative therapy remains the mainstay of treatment options necrosis of the tumor
for incurable esophageal carcinoma with what the majority of Monopolar and bipolar electrocautery: It is rarely used
patients present. The following palliative therapy options are now a days
available. Argon plasma coagulation: It uses ionized argon gas to
convey electrical energy to achieve thermal desiccation
of the tumor tissue. But it is less effective in relieving
Radiation Therapy dysphagia in advanced esophageal cancer
Neodymium:yttrium-aluminium-garnet (Nd:YAG):
External beam radiation therapy alone provides reasonable
Nd:YAG laser relieves dysphagia by coagulating and
palliation for esophageal cancer. Radiotherapy achieves
vaporizing the malignant tissue under endoscopic control.
palliation of dysphagia in 7090% of patients. Combination of
Multiple laser sessions are required to improve dysphagia.
external beam radiation with intraluminal irradiation using
The requirement for the laser therapy are as follows:
cobalt-60, cesium-137 or iridium-192 is possible to increase
Growth should be exophytic or polypoid
the dose of radiation to the tumor, and it is promising both in
Preferably, it will be located in the straight segment of
median and 5-year survival.
esophagus
Contraindication to radiotherapy: Mass shorter than 5 cm.
Tracheal or bronchial involvement
Endoscopic mucosal resection: EMR or mucosectomy is used
Cervical esophageal location of the tumor
to treat superficial flat and polypoid neoplasm of the mucosa
Stenosis.
of gastrointestinal tract. Long-term studies show that EMR
outcomes are similar to those of surgery to the treatment,
Chemotherapy particularly in early gastrointestinal cancers. Different EMR
techniques are as follows:
Single agents: The clinical response rates (510%) and Injection and snare cautery
duration response (24 months) of any single agent of any Injection with precut
class of chemotherapy are poor. EMR with cap
Combination chemotherapy: It is superior to single agent EMR with band ligation.
chemotherapy in the management of esophageal cancer. It is indicated:
In general, the cisplatin-based combination chemotherapy When the lesion is superficial lesion
(commonly used) has yielded a response rate of 2535%. No evidence of lymph node metastasis
To date, there is no role of single agent or combination Bleeding, perforation and necrosis are the major
chemotherapy as an adjuvant to surgery. complications.
The commonly employed modalities of EMR include strip
biopsy, double-snare polypectomy, resection with combined
Endoscopic Therapy use of highly concentrated saline and epinephrine, and
Dilation: Esophageal dilation is commonly done by resection using a cap.
expandable balloons through-the-scope or wire-guided Esophageal prostheses: The prostheses (stents) are inserted
polyvinyl bougies under fluoroscopy. endoscopically under fluoroscopic guidance and provide
Ablation: The available options for tumor ablation are as relief of dysphagia effectively. At present, self-expanding
follows: metallic stents (SEMS) covered/uncovered are widely used
Carcinoma of Esophagus 23

chemotherapy and as an adjunct to other palliative measures.


Enteral access is achieved surgically (gastrojejunostomy),
endoscopically [percutaneous endoscopic gastrostomy
(PEG), direct percutaneous jejunostomy or PEG with a jejunal
feeding tube extension] or radiologically.

PROGNOSIS
Despite the widespread use of different modalities of
treatment, the reported overall 5-year survival rates are at
best 1015%. Delayed presentation, rapid intramural invasion
and distant metastases are responsible for poor prognosis.
The patients with early stage of disease carry better prognosis.
The 5-year survival rate is greater than 40% in a patient with
T1 or T2 disease without nodal involvement, but it is less than
25% for patients with T3 or T4 lesion.
Stage 0, I, and III tumors are resectable for cure and 5-year
survival is greater than 85%, 50% and 40%, respectively. On
the other hand, stage IV tumors are considered incurable and
nonresectable. Nodal involvement has prognostic impact and
Fig. 6: Self-expanding metallic stents used for the palliation of
esophageal carcinoma it is independent of the T classification. The 5-year survival is
over 70% for N0 disease, but for N1 disease it is near to 40%.

(Fig. 6). Covering the stent with a polymer sheet effectively


reduces tumor ingrowth and provides for treatment of
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The Wallstent II (Microvasive, Boston Scientific, Inc, in white males. Cancer. 2001;92(3):549-55.
Natick, Mass) 2. Cancer research UK. Oesophageal cancer incidence statistics.
The Flamingo, Wallstent [online]. Available from http://www.cancerresearchuk.org/
The Ultraflex stent (Microvasive, Boston Scientific, Inc, cancer-info/cancerstats/types/oesophagus/incidence/uk-
Natick, Mass) oesophageal-cancer-incidence-statistics. [Accessed January,
The Z stent (Cook medical, Inc, Winston-Salem, NC). 2013].
3. Corley DA, Kerlikowske K, Verma R, et al. Protective association of
Other than the SEMS, the Polyflex (Boston Scientific, Inc,
aspirin/NSAIDs and esophageal cancer: a systematic review and
Natick, Mass) is a completely covered self-expanding non-
meta-analysis. Gastroenterology. 2003;124:47-56.
metallic (plastic) stent recently introduced. It is approved 4. EII C, May A, Gossner L, et al. Endoscopic mucosal resection of
by the Food and Drug Administration (FDA) for palliation of early cancer and high-grade dysplasia in Barretts oesophagus.
malignant dysphagia. Gastroenterogy. 2000;118:670-7.
Major complications of SEMS placement include tumor 5. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med.
ingrowth or tumor overgrowth (520%), which can be treated 2003;349:2241-52.
effectively with laser or thermal contact therapy, stent 6. Heath EI, Limburg PJ, Hawk ET, et al. Adenocarcinoma of the
migration (10%) and chest pain. Other complications are food esophagus: risk factors and prevention. Oncology (Williston
impaction, bleeding, and reflux esophagitis. Park). 2000;14(4):507-14.
7. Koshy M, Esiashvilli N, Landry JC, et al. Multiple management
modalities in esophageal cancer: epidemiology, presentation
Enteral Nutrition and progression, work-up and surgical approaches. Oncologist.
2004;9(2):137-46.
Enteral nutrition support may be indicated in an attempt to 8. Ku GY, Ilson DH. Preoperative therapy for esophageal cancer.
improve functional status before and after surgery, during Gastroenterol Clin North Am. 2009;38(1):135-52.
24 Textbook of Hepato-gastroenterology

9. Lagergren J, Bergstrm R, Lindgren A, et al. Symptomatic [online]. Available from http://guidance.nice.org.uk/IPG206


gastroesophageal reflux as a risk factor for esophageal [Accessed January, 2013].
adenocarcinoma. N Engl J Med. 1999;340(11):825-31. 13. Pisani P, Parkin DM, Bray F, et al. Estimates of the worldwide
10. Lepage C, Rachet B, Jooste V, et al. Continuing rapid increase mortality from 25 cancers in 1990. Int J Cancer. 1999;83:
in esophageal adenocarcinoma in England and Wales. Am J 18-29.
Gastroenterol. 2008;103(11):2694-9.
14. Radu A, Wagnires G, van den Bergh H, et al. Phtodynamic
11. Narahara H, Lishi H, Tatsuta M, et al. Effectiveness of endoscopic
therapy of early squamous cell cancers of the esophagus.
mucosal resection with submucosal saline injection technique
for superficial squamous carcinomas of the esophagus. Gastrointest Endosc Clin N Am. 2000;10(3):439-60.
Gastrointest Endosc. 2000;52:730-4. 15. Systemic review of the staging performance of 18F-fluorod
12. NICE Interventional Procedural Guideline. (2007). Palliative eoxyglucose position emission tomography in esophageal
photodynamic therapy for advanced oesophageal cancer. cancer. J Clin Oncol. 2004;22:3805-12.
3
cHAPTER

Peptic Ulcer Disease

Javed Yakoob, SM Wasim Jafri

INTRODUCTION drugs suggest the role of acid in this process. GU is associated


with severe abdominal pain associated with meals that is
Peptic ulcers (PUs) are mucosal breaks in the gastric or infrequently relieved by food or antacids.
small intestinal mucosa that extend through the muscularis Epigastric discomfort described as a vague or cramping
mucosa. In contrast to erosions, which are small and is experienced in two-thirds of the patients that may localize
superficial mucosal lesions, PU varies in size from 5 mm to in the upper quadrants or the hypochondrium. It may also
several centimeters. The term PU is used to group together be associated with burning pain that may radiate to the
chronic duodenal ulcer (DU) and chronic benign gastric ulcer back. Symptomatic periods lasting weeks are associated
(GU). A precise diagnosis of either DU or GU is required to with similar to longer duration symptom-free periods is
manage them clinically as separate though related diseases. characteristic of DUs. The reliance on symptoms alone may
PU is an important cause of morbidity and increased result in overdiagnosis of nonulcer dyspepsia (NUD) and will
healthcare costs. They can progress to complete resolution miss PUs in patients.
without treatment or complications, such as bleeding and The classic symptoms of acid dyspepsia relieved with food
perforation with considerable morbidity and mortality. occur in only about 50% of patients with DU. An increase in
Those experiencing ulcer complications are at risk of further appetite or weight gain, indigestion associated with particular
complications. Those with history of delayed ulcer healing dietary food resulting in anorexia, weight loss and fatty food
are likely to experience early recurrence. These recurrences intolerance is reported in approximately 20%. In 2060%,
are usually associated with active Helicobacter pylori (H. DU pain may be described as heartburn or irritable bowel
pylori) infection, intake of nonsteroidal anti-inflammatory syndrome like crampy abdominal pain associated with
drugs (NSAIDs), etc. Eradication of H. pylori infection alters altered bowel habit. Silent asymptomatic PU was detected on
the incidence of ulcer relapse. A meta-analysis of 14 studies screening endoscopy in 11% of 6,457 subjects.1
demonstrated recurrence of DUs followed in less than 10% Also, 2050% of complicated asymptomatic ulcers are
who had documented H. pylori eradication compared to 65 presented in elderly patients and individuals on NSAIDs.
90% in those who did not have H. pylori eradicated. Mechanism of PU symptoms is unclear. Some patients with
DU are known to develop symptoms when the ulcer crater is
exposed to acid. The secretory rates and concentration of acid
CLINICAL FEATURES in DU patients are similar to that of asymptomatic patients
and in controls. Often there is no correlation between the
Symptoms presence of an active ulcer and symptoms. Symptoms may
persist in 40% of patients with endoscopically healed ulcers,
The symptoms vary from nausea, vomiting, epigastric pain, while 1544% with an ulcer crater may be symptom-free.
postprandial belching, bloating, anorexia and early satiety. Absence of symptoms does not guarantee ulcer healing is
Clinical assessment has poor predictive value for the specific complete, nor does the persistence of symptoms predict the
diagnosis found upon endoscopy. The classic symptoms presence of an ulcer crater. In some cases, this sensitization
of DU occur when acid is in excess. Symptoms also occur to acid is related to an ulcer crater or secretion of an excess
late at night when the circadian acid secretion is maximal. acid, but it may also occur in grossly normal mucosa with
Symptoms relieved by food, antacids, and acid-reducing physiologic levels of acid secretion.
26 Textbook of Hepato-gastroenterology

Clinical Signs Nonsteroidal Anti-inflammatory Drugs


The physical examination is often normal and unreliable. Nonsteroidal anti-inflammatory drugs act by inhibiting
Some patients may exhibit epigastric tenderness to deep prostaglandin synthesis that affect the amount of gastric
palpation. Hematemesis or occult blood may be detected in acid generated, integrity of the mucosal barrier, amount of
the setting of bleeding ulcers. Tachycardia and orthostatic bicarbonate and glutathione generated and rate of mucosal
hypotension may be found in patients with significant blood flow.
bleeding or dehydration, while rigid abdomen with diffuse
tenderness may reflect ulcer perforation with peritonitis.
Rarely, a distended abdomen or a succession splash can be Gastric Acid Hypersecretion
noted in patients with an ulcer-associated outlet obstruction. Although only a small proportion of DU patients have acid
The majority of DUs develop in the bulb or pyloric channel. hypersecretion, high normal or modestly elevated values
Patients with DUs tend to have a younger age of onset, often appear to be associated with DU. Among H. pylori-positive
between 30 years and 55 years. In the stomach, most benign subjects with DU, the drive for acid secretion that includes
ulcers are found in the antrum and lesser curvature of the H. pylori-dependent hypergastrinemia reverses following
stomach at the junction of the body and antrum. GUs often cure of the infection.3 Relative hypergastrinemia is seen
occur among patients between the ages of 55 years and 70 in H. pylori-infected subjects are due to suppression of
years with a peak incidence in the sixth decade. somatostatin. The abnormality in acid secretion seen in
DU subjects is linked to the host predisposition rather than
H. pylori infection. The defective regulation of acid secretion
ETIOLOGY in DU is related to impaired control of inhibitory mechanisms
and can be seen in people without DU. The abnormalities in
Multiple factors are involved in the pathophysiology of most gastrin, somatostatin and acid secretion normalizes within
PUs. Primary malfunction of gastric secretory, defense or 1 year of H. pylori eradication.
repair mechanisms are uncommon causes of ulcer. Most A higher basal and pentagastrin-stimulated acid secretion
ulcers are associated with H. pylori infection and NSAIDs was described in patients with recurrent ulcers following
intake. successful H. pylori eradication compared to patients without
recurrent ulcers. Among H. pylori-negative subjects, a subset
has acid hypersecretion without hypergastrinemia. Another
Helicobacter pylori study with non-H. pylori, non-NSAID DU found increased
H. pylori affects gastric acid secretion, gastric metaplasia, gastrin response to a meal and increased peak gastric acid
immune responses and mucosal defense mechanisms. secretion. Some subjects with non-H. pylori, non-NSAID
Two virulence markers of H. pylori strains that include the hypersecretion may have a component of muscarinic-
cytotoxin-associated gene A (cagA) and the vacuolating dependent, vagal hyperactivity. In the absence of H. pylori or
cytotoxin (vacA) have been found to be associated with distinct gastrinoma, fasting hypergastrinemia is only rarely found in
gastroduodenal disorders. Various studies demonstrated an hypersecretory DU patients, sometimes linked to antral G-cell
association between the presences of cagA antibodies and hyperfunction. Increased acid secretion is an important factor
PU and gastric carcinoma. The gene encoding vacA is present in some patients with ulcer recurrences following successful
in all H. pylori strains; however, the activity of this cytotoxin H. pylori eradication and in some patients with non-H. pylori,
is dependent on its allelic type is positive in only 4060% of non-NSAID DU.
patients with PU disease and in only 30% of H. pylori strains
isolated from patients with chronic gastritis. In a recent study,
cagA was found associated with GU in 20 (63%) (p = 0.04), Duodenum
DU in 23 (72%) (p = 0.003) and GC in 29 (73%) (p = 0.001) The majority of DU patients have impaired duodenal
compared to NUD in 51 (42%). The vacA allele s1am1 was bicarbonate secretion, which is H. pylori-dependent, since
associated with GU in 23 (72%) (p = 0.001), DU in 17 (53%) cure of the infection reverses the defect. The increased gastric
(p < 0.001) and GC in 23 (58%) (p = 0.003) compared to NUD acid secretion with reduced duodenal bicarbonate lowers
in 38 (32%), while vacA s1bm1 was associated with GU in 9 duodenal pH and promotes development of gastric metaplasia
(28%) (p = 0.001), DU in 12 (37%) (p < 0.001) and GC 11 (28%) in the duodenum. Areas of gastric metaplasia infected by
(p < 0.001) compared to NUD in 13 (11%), respectively.2 H. pylori results in duodenitis and enhances the susceptibility
Peptic Ulcer Disease 27

to acid injury and DU. In patients with endoscopy-negative, Twin studies provide evidence for genetic predisposition
NUD has described duodenal colonization by H. pylori as a to PU independent of predisposition to H. pylori infection.
highly significant predictor of the subsequent development There is a high concordance of a self-reported ulcer history
of DU. In gastrinoma patients, there is an excess gastric in monozygotic compared to dizygotic twins. Another twin
acid secretion, which is associated with prominent gastric study also concluded that genetic factors were linked to DU,
metaplasia in the duodenum. independent of environmental variables. A study described a
family in which PU was linked to elevated serum pepsinogen
group A in the absence of H. pylori infection. Blood groups
Gastric Ulcer O and A, the Lewis phenotype Le (a + b-), and nonsecretors
A GU occurring in the stomach proximal to the distal antrum of ABH, in particular, have an increased risk of DU. However,
and prepyloric region is usually associated with low-normal other studies did not show any association of blood group O
acid secretion associated with a low-normal parietal cell with H. pylori infection or with PU.
mass. These findings correspond to the encroachment of
oxyntic mucosa by advancing inflammation and oxyntic
gland atrophy.4 In contrast to GU involving the gastric body,
Factors that Influence the Course of
patients with ulcers in the distal antrum or GU associated Peptic Ulcer
with concurrent DU have normal or even increased levels of
A number of risk factors potentially impact the rate of ulcer
acid secretion.
healing, complications, and the tendency for recurrence.

RISK FACTORS Smoking


Studies found that smoking facilitated development of PU
Familial Aggregation disease.11 PUs in smokers are difficult to treat and have a
Studies have recognized a polygenic inheritance pattern higher rate of recurrence. In a prospective study, the ulcer
in families with history of PU disease (PUD). First-degree risk progressively increased with number and years of
relatives of patients with GU have a threefold increase in the cigarette smoking. The evidence supports an association
prevalence of GU but not DU, while patients with DU have a between smoking and PUD in H. pylori-infected subject.
threefold increase in the prevalence of DU but not GU. However, smoking does not appear to be a risk factor for ulcer
relapse once H. pylori have been eradicated. Smoking also
did not influence recurrence of the H. pylori infection, which
Genetic Factors was observed in 4.8 and 4.4% of smokers and nonsmokers,
respectively. As an example, smoking and chronic nicotine
Host factors appear to be important in predisposing to H.
treatment stimulated basal acid output to a greater extent in
pylori infection and to disease outcomes, such as DU and
smokers with DU history compared to smokers without a DU
gastric cancer. Genetic polymorphism related to synergy
history.12
between host [tumor necrosis factor (TNF)- promoter]
and bacterial (induced by contact with epithelium, or the
iceA1 gene) factors have been related to DU in children.5 Nonsteroidal Anti-inflammatory Drugs
Host polymorphisms involving the cytokine interleukin
(IL)-1- are linked to DU probably related to effects of H. Nonsteroidal anti-inflammatory drugs are responsible for the
pylori-associated inflammation and acid secretion.6,7 Host majority of PUs not caused by H. pylori. These are associated
polymorphisms in TNF- were associated with increased with an increased risk of complications. NSAIDs cause de
risk for GU and gastric cancer, but not DU in Japanese novo PUs and exacerbate underlying PUD due to H. pylori.
population.8 Other studies have been negative for both factors In a study, NSAID histories of 494 patients with PUD were
in DU.9 One study involving 200 patients with DU and GU compared with 972 matched controls. The odds ratio for the
and 342 healthy controls found that the TGFB1+869(*) C/C development of GU and DU was 5.9 and 4.9, respectively for
genotype was associated with reduced risk of developing NSAID users compared to controls. The odds ratio for the
DU.10 Genetic polymorphism relating to cyclooxygenase-1 development of hemorrhage complicating a PU was 5.2, as
(COX-1) and prostaglandin production demonstrated was the risk of perforation. NSAIDs are also responsible for
T1676C COX-1 polymorphism associated with GU in non- a significant number of PUs that is refractory to conventional
NSAID users and with both GU and DU in NSAID users. therapy.
28 Textbook of Hepato-gastroenterology

Alcohol Functional Dyspepsia


Alcohol also stimulates acid secretion. In high concentrations Dyspepsia commonly encountered in primary care and
it damages the gastric mucosal barrier and induces acute gastroenterology practice is also known as functional
gastric mucosal lesions that are characterized by mucosal (idiopathic) or NUD. It is described as chronic recurrent
hemorrhages. Alcohol abuse interferes with patient abdominal pain or discomfort centered in the upper abdomen;
compliance and ulcer healing. a duration of greater than or equal to 4 weeks with symptoms
25% of the time (i.e. on 7 days or more) in the absence of clinical,
biochemical, endoscopic or ultrasonographic evidence of
Diet any known organic disease to explain the symptoms (i.e.
Fried fat rich foods, drinks and spices cause dyspepsia; acid-peptic, neoplastic disease of the stomach, esophagus or
however, there are no convincing data that these specific foods duodenum, pancreas or hepatobiliary system), and no history
can cause or reactivate PUs. DU is much more common in the of major gastric or intestinal surgery.
rice-eating southern regions of India compared to the wheat-
eating northern regions.13 A study described low consumption
of chili peppers by DU patients compared to controls,
Gastric Carcinoma
protected against mucosal damage. High consumption of Gastric malignancy may be associated with chronic dyspepsia,
fruits and vegetables, dietary fiber and vitamin A reduced particularly in patients over 4555 years of age and in those
risk of ulcer disease. Coffee-stimulated acid secretion and with alarm symptoms, e.g. unintended weight loss, bleeding,
produced dyspepsia, which often resulted from enhanced anemia, dysphagia, odynophagia, hematemesis, a palpable
esophageal reflux. However, coffee consumption is not a risk abdominal mass or lymphadenopathy, persistent vomiting,
factor for ulcer disease, although increased consumption unexplained iron deficiency anemia, family history of
may be associated with H. pylori infection. Food intolerances upper gastrointestinal cancer, previous gastric surgery and
common in patients with PU disease may reflect sensitivities jaundice. Early gastric cancer is usually asymptomatic or
to substances in foods. Milk because of its calcium and has few associated symptoms. It can present with dyspepsia
protein content stimulates more acid secretion than it indistinguishable from PU. A new onset of symptoms or a
buffers and is not an effective antacid. Human milk contains recent change in pattern should raise concern over possible
protective factors including growth factors, surface active neoplasia. In a recent review of presenting symptoms epigastric
phospholipids and prostaglandin E2. Thus, it is possible that pain or dyspepsia similar to PU was present in 6590%, nausea
milk has antiulcer actions that override the stimulation of and/or vomiting in 640% and anorexia in 1240%. Alarm
acid secretion. signs or symptoms suggestive of invasive disease, such as
anemia or weight loss, occurred less frequently (515% and
440%, respectively). Other neoplastic processes can mimic
Psychologic Factors PUs, presenting with dyspepsia or ulcers, such as gastric
Poorly tolerated stress or depressive symptoms increased lymphoma, leiomyosarcomas, primary gastric and metastatic
the risk of ulcer development over the next 915 years. Work- malignant melanoma and metastatic renal cell carcinoma.
related stress, social problems and post-traumatic stress
disorder are predictive of subsequent ulcer disease. PU
complications become much more prevalent during periods
Drug-induced Dyspepsia
of natural disaster. Stress, anxiety and depression are known Many drugs are known to cause dyspepsia, epigastric distress,
to impair healing and to promote relapse of ulcers. nausea or vomiting. These include NSAIDs, with or without
ulceration, theophylline and digitalis. Caffeine, coffee,
alcohol and smoking can also contribute to symptoms.
DIFFERENTIAL DIAGNOSIS
Disorders that cause symptoms in the upper abdomen and Infiltrative or Granulomatous Diseases
ulcerative lesions of the stomach and duodenum include the Infiltrative or granulomatous diseases can present with
following: dyspepsia and occasionally ulceration. Involvement of
Peptic Ulcer Disease 29

the stomach is the most common site of sarcoidosis in the Biopsy specimen sent for histologic examination is stained
gastrointestinal tract, almost always occurring in association with hematoxylin and eosin, modified Giemsa, Warthin-
with pulmonary disease. Ulceration resembling PUD Starry or Genta staining for H. pylori infection. The presence
can occur with or without enlargement of mucosal folds. of polymorphonuclear leukocytes in inflamed gastric tissue
Eosinophilic granuloma and Wegeners granulomatosis can is suggestive of H. pylori gastritis. Culture of H. pylori from
have similar presentation. Hypertrophic gastritis (including biopsy samples has a specificity of 100% if results are positive,
Mntriers disease) may present with dyspeptic symptoms. but it is not routinely performed. Culture is difficult and is
Crohns disease of the stomach or duodenum may produce usually performed to determine antibiotic susceptibilities
symptoms and a radiographic appearance that mimics PU. for patients who fail to respond to second-line eradication
Isolated gastroduodenal Crohns may produce radiographic therapy. Urea breath test (UBT) based on detecting H. pylori-
abnormalities that are usually present in distal portions of the derived urease activity in the stomach and stool antigen test
duodenum and the small intestine. using polyclonal anti-H. pylori capture antibody adsorbed
to microwells are also used for the diagnosis of H. pylori
infection. It is generally recommended to wait for 4 weeks
Infections after completing eradication therapy to confirm successful
Gastric and duodenal tuberculosis can present with mucosal cure. Proton pump inhibitors (PPIs) should be withheld for
ulceration. It is difficult to diagnose in the absence of a 24 weeks and antibiotics and bismuth compounds for 4
negative acid-fast stain and caseating granulomas, which are weeks prior to testing for H. pylori infection.
often submucosal, are not demonstrated in the superficial For patients on PPIs, the diagnostic yield of RUT and
gastric biopsies obtained at endoscopy. Other infections also histology was reduced from both the gastric antrum and
associated with chronic ulcer and abdominal pain includes body. In these patients, polymerase chain reaction for H.
Mycobacterium avium intracellulare, strongyloidiasis pylori is more sensitive than RUT and histology.15
and giardiasis. Giardiasis may produce upper abdominal
discomfort, nausea, diarrhea and sometimes anorexia and
malabsorption.14 Dyspeptic symptoms may persist over TREATMENT
months associated with periods of diarrhea lasting a few days.
There are more effective medications for the suppression of
stomach acid. They relieve symptoms and allow ulcers to heal.
Duodenal Tumors If an ulcer is associated with aspirin or other NSAID, avoiding
Duodenal carcinoma or localized lymphoma may present them prevent ulcer recurrence. There are several antibiotic
with gastrointestinal bleeding or as benign ulcer. They are regimes available to treat H. pylori infection and cure ulcers.
uncommon and most cases present as a mass lesion rather Younger patients with symptoms suggestive of
an ulcer. functional dyspepsia without alarm symptoms are
often treated with antacids or H2 antagonists before
esophagogastroduodenoscopys undertaken. Patients on
NSAIDs may also be prescribed a prostaglandin analog
DIAGNOSIS (misoprostol) to prevent PUs. When H. pylori infection is
Definitive diagnosis of PUs can be made with upper present, combinations of two antibiotics (e.g. clarithromycin
endoscopy. Endoscopy has a much higher diagnostic and amoxicillin or metronidazole) and one PPI are
yield than barium contrast radiology and enables biopsy commonly used. In triple therapy failures, three antibiotics
specimens to be obtained for evaluation of H. pylori infection (e.g. amoxicillin + clarithromycin + metronidazole) are used
and underlying malignancy. Up to 5% GUs are malignant; together with a PPI and sometimes with bismuth compound.
biopsy is recommended from the ulcer margin. A follow- First-line therapy for uncomplicated cases consists of
up endoscopy is scheduled 12 weeks after starting acid amoxicillin + clarithromycin + PPI. In a recent study of
suppressive medications to document complete healing. GUs triple therapy with esomeprazole 20 mg, amoxicillin 1g and
greater than 3 cm in size and those associated with a mass clarithromycin 500 mg twice a day for 10 days were prescribed
are more likely to be malignant. Actively bleeding or ulcers to 111 patients with a mean age of 46 16 years and 14C UBT
at risk of rebleeding can be treated during endoscopy with repeated 4 weeks after treatment. The mean age of treatment
hemostasis therapy. In patients undergoing endoscopy, an failure was 39 14 years compared to 48 16 years with
antral biopsy can be obtained for rapid urease test (RUT), eradication (P = 0.002). Treatment failure was associated
which has sensitivity of 89100% and specificity of 92100%. with a younger mean age; collagen-like region-related point
30 Textbook of Hepato-gastroenterology

mutations in the 23S rRNA gene of H. pylori and vacA s1a and 4. Malaty HM, Graham DY, Isaksson I, et al. Are genetic influences
m1 alleles associated with cagA negativity.16 on peptic ulcer dependent or independent of genetic influ
In another study, H. pylori isolates resistance rate noted to ences for Helicobacter pylori infection? Arch Intern Med. 2000;
clarithromycin was 33%, metronidazole 48% and amoxicillin 160(1):105-9.
2%. Clarithromycin resistance was seen in 30 H. pylori 5. Wilschanski M, Schlesinger Y, Faber J, et al. Combination of
Helicobacter pylori strain and tumor necrosis factor-alpha
isolates, 20 (67%) from patients with NUD, six (20%) with GU
polymorphism of the host increases the risk of peptic ulcer disease
and four (13%) with DU. Triple therapy failure was associated
in children. J Pediatr Gastroenterol Nutr. 2007;45(2):199-203.
with clarithromycin resistance in 28 (93%) (P < 0.001). It was 6. Furuta T, El-Omar EM, Xiao F, et al. Interleukin 1beta
associated with A2142G mutation in 20 (67%; P < 0.001), polymorphisms increase risk of hypochlorhydria and atrophic
A2143G mutation in 12 (40%; P < 0.001) and A2142C mutation gastritis and reduce risk of duodenal ulcer recurrence in Japan.
in five (17%; P = 0.003).17 Gastroenterology. 2002;123(1):92-105.
In the absence of H. pylori infection, PPIs are often used 7. Garcia-Gonzalez MA, Lanas A, Savelkoul PH, et al. Association of
in high doses for long-term. Treatment of H. pylori relieves interleukin 1 gene family polymorphisms with duodenal ulcer
symptoms and leads to eventual healing of DUs. Eradication disease. Clin Exp Immunol. 2003;134(3):525-31.
of H. pylori infection must be documented when a decision 8. Sugimoto M, Furuta T, Shirai N, et al. Different effects of
has been made to treat it. Recurrence of infection requires polymorphisms of tumor necrosis factor-alpha and interleukin-1
beta on development of peptic ulcer and gastric cancer. J
retreatment if necessary with other antibiotics. For this H.
Gastroenterol Hepatol. 2007;22(1):51-9.
pylori sensitivities to commonly used antibiotics must be
9. Garcia-Gonzalez MA, Strunk M, Piazuelo E, et al. TGFB1 gene
known. Since the widespread use of PPIs, surgical procedures polymorphisms: their relevance in the susceptibility to
like highly selective vagotomy for uncomplicated PUs Helicobacter pylori-related diseases. Genes Immun. 2006;7(8):
became obsolete. Perforated PUs requires surgical repair. 640-6.
Most bleeding ulcers are treated with either cautery, injection 10. Arisawa T, Tahara T, Shibata T, et al. Association between promoter
or clipping. PUs generally heal within 13 months. Smoking polymorphisms of nuclear factor-erythroid 2-related factor 2
and use of alcohol or NSAIDs are known to inflame the gene and peptic ulcer diseases. Int J Mol Med. 2007;20(6):849-53.
stomach and duodenal mucosa leading to failure of the ulcer 11. Rosenstock S, Jrgensen T, Bonnevie O, et al. Risk factors
to heal. Use of nonprescription medications that include for peptic ulcer disease: a population based prospective
some NSAIDs including aspirin, ibuprofen and naproxen is cohort study comprising 2416 Danish adults. Gut. 2003;52(2):
186-93.
an important cause. In other cases, some H. pylori bacteria
12. Maity P, Biswas K, Roy S, et al. Smoking and the pathogenesis
are resistant to prescribed antibiotics. In rare cases, refractory
of gastroduodenal ulcerrecent mechanistic update. Mol Cell
ulcers (fail to heal) may be the result of Crohns disease or Biochem. 2003;253(1-2):329-38.
cancer or gastrinomas leading to extreme overproduction of 13. Tovey FI, Hobsley M, Kaushik SP, et al. Duodenal gastric metaplasia
gastric acid. and Helicobacter pylori infection in high and low duodenal ulcer
prevalent areas in India. J Gastroenterol Hepatol. 2004;19(5):497-
505.
REFERENCES 14. Yakoob J, Jafri W, Abid S, et al. Giardiasis in patients with
dyspeptic symptoms. World J Gastroenterol. 2005;11(14):
1. Lu CL, Chang SS, Wang SS, et al. Silent peptic ulcer disease: 6667-70.
frequency, factors leading to silence, and implications regarding 15. Yakoob J, Jafri W, Abbas Z, et al. The diagnostic yield of various
the pathogenesis of visceral symptoms. Gastrointest Endosc. tests for Helicobacter pylori infection in patients on acid-reducing
2004;60(1):34-8. drugs. Dig Dis Sci. 2008;53(1):95-100.
2. Yakoob J, Abid S, Abbas Z, et al. Distribution of Helicobacter pylori 16. Yakoob J, Jafri W, Abbas Z, et al. Risk factors associated with
virulence markers in patients with gastroduodenal diseases in Helicobacter pylori infection treatment failure in a high prevalence
Pakistan. BMC Gastroenterol. 2009;9:87. area. Epidemiol Infect. 2010;7:1-10.
3. Hirschowitz BI, Lanas A. Atypical and aggressive upper 17. Yakoob J, Abid S, Abbas Z, et al. Antibiotic susceptibility patterns
gastrointestinal ulceration associated with aspirin abuse. J Clin of Helicobacter pylori and triple therapy in a high-prevalence
Gastroenterol. 2002;34(5):523-8. area. Br J Biomed Sci. 2010;67(4):197-201.
4
cHAPTER

Peptic Ulcer Disease in


AsiaPacific
Sony S Thazhath, Mazhar Haque

INTRODUCTION AND PREVALENCE the GU group and five deaths in the DU group. However, a 10-
year experience on children and adolescents from Hong Kong
Peptic ulcer can be described as a breach in the mucous from 1996 to 2006 had contrasting findings with 75% of UGIB
membrane, which lines parts of the alimentary tract exposed cases attributed to DUs, with H. pylori infection implicated in
to digestive juices, such as esophagus, stomach, duodenum, majority of them. There was a male predominance at a ratio of
jejunum, and parts of ileum. Peptic ulcer disease (PUD) tends 2.6:1.
to have a chronic remitting course with poor correlation
between symptoms and severity of the disease, which
limits the ability to accurately document its incidence and RISK FACTORS
prevalence. A rural Chinese random endoscopic survey on
2,423 subjects showed a prevalence of 9.3%, of which 5.7% Nonsteroidal anti-inflammatory drugs and H. pylori infection
were duodenal ulcers (DUs), 3.4% were nonmalignant gastric account for the majority of peptic ulcer bleeds. Both these
ulcers (GUs), and 0.2% were concurrent GUs and DUs. In are more prevalent in the elderly population who are least
comparison, a Western study from Sweden showed PUD able to tolerate ulcer complications. Other causes of peptic
prevalence of only 4.1% with a 1:1 ratio between GU and DU. ulcer include gastric malignancies, lymphomas, eosinophilic
A downward trend in the prevalence of DUs in South Korea gastroduodenitis, systemic mastocytosis, radiation damage,
has been noted from 1994 to 1995 and from 2004 to 2005, burns (Curlings ulcer) and severe systemic disease (stress
whereas GUs showed a rising trend. The investigators attribute ulcer). Anastomotic ulcer after subtotal gastric resection is
the reduction of DU prevalence to the widespread efforts well known as is the Cameron ulcer where a hiatus hernia
at Helicobacter pylori eradication; and the increase in GU passes through the diaphragmatic hiatus.
prevalence to the increasing use of aspirin and nonsteroidal Helicobacter pylori infection itself can account for a
anti-inflammatory drugs (NSAIDs). Another similar study 1.8-fold increase in the risk of DU development. The risk
involving retrospective analysis of the endoscopic records of ulcer formation is increased substantially when NSAID
from a busy South Indian tertiary referral center between the users are infected with H. pylori. Though cyclooxygenase-2
years 1989 and 2004 showed a decreasing trend of endoscopic (COX-2) inhibitors are known to carry lower risk of PUD
diagnosis of GUs as well as DUs, which were attributed to and its complications as compared to nonselective NSAIDs,
improving sanitation and hygiene along with widespread use concurrent use of nonselective NSAIDs or COX-2 inhibitors
of proton pump inhibitors (PPIs) and treatment of H. pylori with aspirin increase the incidence of PUD (more commonly
infection. GUs) as compared with using aspirin alone. Another widely
Although chronic ulcers can be asymptomatic, upper used medication implicated in the causation of peptic ulcer
gastrointestinal bleeding (UGIB) is the most frequent and is glucocorticoids. However, if used alone, it does not seem
severe complication of PUD. In Korea, the incidence of peptic to increase the risk of ulcer formation. Other reported risk
ulcer bleed was 22.1 per 100,000 during 20062007, and the factors for the development of PUD include use of antiplatelet
age-specific incidence rate and 30-day mortality showed a agents, Helicobacter heilmannii, cytomegalovirus infections,
rising trend with advancing age. In a recent observation in Behcets disease, Zollinger Ellison syndrome, Crohns disease
Australia, over a period of about 4 years from 2004 to 2008 and cirrhosis with portal hypertension.
on 265 bleeding peptic ulcer cases, the mean age of patients Idiopathic PUD is also well described and multiple DUs are
was 71 years (SD = 15). Gastric ulcers (n = 146) outnumbered more frequently seen in this group. With increasing rates of H.
DUs (n = 119) and melena was the most common presenting pylori treatment, a disproportionate rise in the incidence of
complaint. The overall mortality was 3.4% with four deaths in idiopathic bleeding peptic ulcer has been noted in Hong Kong
32 Textbook of Hepato-gastroenterology

and South Korea. In Australia, non-H. pylori, non-NSAID RACIAL AND REGIONAL DIFFERENCES
related PUD (idiopathic) was found to be prevalent in younger
age groups as compared to NSAID-induced counterparts. IN PEPTIC ULCER DISEASE
In India, this group consisted more of patients with GUs
Chinese population has less parietal cell mass as compared to
than DUs.
the Caucasians, which may account for the increased efficacy
of PPIs. Genetic variations can also moderately influence the
liability to acquire PUD and H. pylori infection independent
HELICOBACTER PYLORI AND PEPTIC of each other. Regional variations in the dietary habits could
ULCER DISEASE IN ASIA be yet another factor. This is based on the observations of
increased DU prevalence in the rice-eating areas of India
Prevalence rate of H. pylori is higher in Asian countries as and China as compared to the non-rice eating or less rice-
compared to the West, which could be at least partly attributed eating areas. The physiological basis for such a difference is
to the lower socioeconomic status of majority of the Asian unknown.
population and probably to some cultural practices. In recent
years, improvement in hygienic practices has resulted in a
decline in the rate of infection. The overall prevalence of H. MANAGEMENT OF PEPTIC ULCER
pylori was 80% in one of the South Indian hospital study of
500 patients. In this study, clean water index (CWI) was the DISEASE
most significant contributor. In rural China, mother-to-child
In Asians requiring long-term use of NSAIDs, prior
transmission of H. pylori may be facilitated by some cultural
eradication of H. pylori helps to prevent the occurrence
practices, such as sharing the same bed, eating from the same
of PUD and UGIB. Those already on NSAIDs and with
bowl, using the same chopsticks and feeding infants by pre-
past history of PUD will benefit from switching to a COX-
chewing their food. An Australian population-based study
2 selective NSAID (if they were on a nonselective NSAID)
reported a low prevalence rate of 18%, which is significantly
and will additionally require PPIs. In aspirin users with
less even compared to Western observations, highlighting the
high gastrointestinal bleeding risk, cotherapy with a PPI
association of socioeconomic status and H. pylori prevalence.
is recommended instead of switching to clopidogrel.
However, despite relatively poor socioeconomic condi-
Prophylactic PPI is also recommended in patients receiving
tions, Indonesia has a low prevalence rate for H. pylori. In
dual antiplatelet therapy with aspirin and clopidogrel.
Malaysia, prevalence rates as low as 11.929.2% were noted in
However, in vitro studies show that some PPIs reduce the
Malays and as high as 49.452.3% in Indians; those with Chi-
antiplatelet activity of clopidogrel by inhibiting CYP2C19,
nese ethnicity had an intermediate prevalence rate of 26.7
a hepatic cytochrome P450 enzyme. In slow metabolizers
57.5%. This racial difference cannot be explained by environ-
of clopidogrel due to genetic polymorphisms of CYP2C19,
mental effects or by the differences in socioeconomic status.
this effect could potentially be clinically significant,
It appears reasonable to speculate the possibilities of yet un-
although not conclusively proven. CYP2C19*2 and *3
known host mechanisms of resistance against H. pylori. Re-
variants are the most common loss-of-function alleles of
gional variations in the interplay between host factors, such
CYP2C19. In Caucasians, CYP2C19*3 allele is very rare,
as interleukin-1 gene cluster polymorphisms and the viru-
but it is very common in East Asians, especially in Chinese
lence factors of H. pylori are being increasingly recognized.
populations (710%). CYP2C19*2 allele frequencies in
different populations are reported as follows: Mexican
Americans (9.7%), Caucasians (12.7%), African Americans
NSAIDs AND PEPTIC ULCER DISEASE IN (18.2%), and Chinese (29%). This would mean that there
THE EAST could be a considerable variation in the drug effects based
on genetic polymorphism of the enzyme, which could
The prevalence of GUs in patients on NSAIDs was found to adversely affect the Asians compared to the Western
be similar in Japanese population when compared to the population. So far, prospective data are not available in
Western studies. But meta-analyses of randomized, placebo- this regard and conclusive evidence is lacking to ascertain
controlled trials of low-dose aspirin suggest the possibility if pharmacogenomic assessment of individual patients will
that the risk of major GI bleeding from the use of low-dose help to tailor therapy. Current approach is to assess both the
aspirin may possibly be higher in Japanese populations as gastrointestinal and cardiovascular risks to decide about
compared to their Western counterparts; the reason for such the need for combination therapy, including clopidogrel
a difference is unclear. and PPI.
Peptic Ulcer Disease in AsiaPacific 33

To diagnose H. pylori infection, 13C or 14C urea breath tests angiographic embolization may be attempted to achieve
and monoclonal stool antigen tests are preferred over the hemostasis, although the efficacy of this method is yet not
less accurate serology as noninvasive diagnostic methods; conclusively proven.
although in cases of UGIB, histology is preferred. First-
line treatment for H. pylori eradication in Asian population
includes PPI, amoxicillin and clarithromycin for 7 days. SUMMARY
Alternatively, sequential therapy with 5-day dual therapy (20
mg of rabeprazole and 1 g of amoxicillin twice daily) followed Peptic ulcer disease and its complications continue to be a
by a 5-day triple therapy (20 mg of rabeprazole, 500 mg of significant burden to the health systems around the world
clarithromycin and 500 mg of metronidazole twice daily) has despite increasing awareness about the etiologies and
also shown good results. However, rising trend of antibiotic declining prevalence of H. pylori. Management strategies
resistance especially to clarithromycin and metronidazole as need to be tailored to suit the economic limitations and
seen in many Asian populations could be an impediment to drug resistance patterns as well as the racial, cultural and
eradication of H. pylori. In such situations, bismuth-based dietary diversity of different parts of the Asia-Pacific. More
quadruple therapy (for 10 days) or triple therapy with at robust studies are needed to identify the best approach in
least one antibiotic different from the previously tried one or the resource-limited healthcare facilities of the developing
with addition of levofloxacin (for 10 days) or rifabutin (for 10 world.
days) can be tried as salvage therapy. If the salvage therapy
is ineffective due to suspected inefficacy of PPIs (possibly
from activating polymorphisms of CYP2C19, which is less BIBLIOGRAPHY
common in the East compared to the West), increasing its
dose or changing the choice of the PPI is more pragmatic than 1. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010
upfront diagnostic genotyping, considering the cost involved expert consensus document on the concomitant use of proton
and the limited availability of these tests in Asian settings. pump inhibitors and thienopyridines: a focused update of the
Smoking facilitates PUD. Smoking cessation is shown to ACCF/ACG/AHA 2008 expert consensus document on reducing
the gastrointestinal risks of antiplatelet therapy and NSAID use.
be associated with better outcomes of H. pylori eradication
Am J Gastroenterol. 2010;105:2533-49.
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hygiene and water source on the prevalence and transmission
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3. Aro P, Storskrubb T, Ronkainen J, et al. Peptic ulcer disease in
Endoscopic treatment is the mainstay of management of a general adult population: the Kalixanda study: a random
major peptic ulcer bleeds. In the Asian setting, Blatchford population-based study. Am J Epidemiol. 2006;163:1025-34.
score is preferred over pre-endoscopic Rockall score to assess 4. Bae S, Kim N, Kang JM, et al. Incidence and 30-day mortality of
the need for endoscopic intervention. Use of pre-endoscopic peptic ulcer bleeding in Korea. Eur J Gastroenterol Hepatolol.
high-dose PPIs in order to downgrade the gastrointestinal 2012;24:675-82.
5. Bardou M, Barkun AN. Preventing the gastrointestinal adverse
hemorrhage helps cover for the delay in instituting definitive
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endoscopic treatment, which is often the case in rural Asia
identification to risk factor intervention. Joint Bone Spine.
with limited medical facilities. Although not supported with 2010;77:6-12.
enough evidence, it is recommended that whenever possible, 6. Chan FK, Lanas A, Scheiman J, et al. Celecoxib versus omeprazole
endoscopic intervention should be undertaken within the and diclofenac in patients with osteoarthritis and rheumatoid
first 24 hours of UGIB, and in severe cases with hemodynamic arthritis (CONDOR): a randomised trial. Lancet. 2010;376:
instability, urgent endoscopy should be attempted as long 173-9.
as there are no interfering comorbidities. Patients with 7. Cherian JV, Somasundaram A, Ramalingam S, et al. Peptic ulcer
high cardiovascular risk profile who ceased aspirin due to disease in Indiaa 16 year trend analysis. Trop Gastroenterol.
UGIB may be encouraged to restart aspirin in 35 days after 2010;31:260-5.
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high-dose oral or intravenous PPI may be used to reduce
9. Choi YJ, Kim N, Lim J, et al. Accuracy of diagnostic tests for
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treatment fails and the patient is not suitable for surgery, Helicobacter. 2012;17:77-85.
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Consensus Guidelines for Helicobacter pylori infection. J pylori infection and gastric cancer: an 8-year hospital based
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disease in the US population. Dig Dis Sci. 2010;55:66-72. eradication. J Gastroenterol Hepatol. 2008;23:1163.
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5
cHAPTER

Functional Dyspepsia

Shahab Abid, SM Wasim Jafri

INTRODUCTION three categories of dyspepsia: (i) dyspepsia with an


identified cause that, if treated, led to improvement, such as
Dyspepsia is a very common clinical condition, which is chronic peptic ulcer disease, reflux esophagitis, malignancy
frequently encountered in daily practice of gastroenterologists or hepatobiliary disease; (ii) dyspepsia with identified
as well as general physicians. The term dyspepsia is abnormalities of uncertain significance like H. pylori infection
derived from Greek language, which means upset stomach and gastroparesis, and (iii) dyspepsia with no explanation
or indigestion. In the early 18th century, dyspepsia was identified. The term FD was used for dyspepsia with
classified into dietary, moral, or nervous dyspepsia. An identified underlying mechanisms of uncertain significance
increase awareness and rapid surge in research was observed or dyspepsia for which no explanation was available.
following the rediscovery of Helicobacter pylori (H. pylori) by The definition of FD was further elaborated by splitting
Barry Marshall and Robin Warren as a cause of peptic ulcer it into three subgroups: (i) ulcer-like dyspepsia with
disease in the early 1980s. predominant pain symptoms localized to the upper abdomen,
Functional dyspepsia (FD) is a heterogeneous disorder relieved by taking food, antacid, H2 receptor antagonist
whose etiology is largely unknown. Several etiopathogenetic (H2RA) or proton pump inhibitors (PPIs), (ii) dysmotility-like
mechanisms have been investigated, but FD remains a dyspepsia where three or more of the following symptoms
diagnosis of exclusion. Likewise its treatment is not yet early satiety, nausea, recurrent retching or vomiting, bloating
established, and it has an unpredictable course, which overlaps without visible distension or abdominal discomfort are often
with irritable bowel syndrome (IBS) or reflux disease at time. aggravated by food. The latter subgroup excludes abdominal
pain as the predominant symptom, and (iii) unspecified FD.
It was also defined that the symptoms should be present for at
ROME CRITERIA FOR least 3 months.
FUNCTIONAL DYSPEPSIA
In parallel to the classification of psychological disorder Rome II Criteria
(Diagnostic and Statistical Manual of Mental Disorders), In 1999, the Rome committee partially changed the criteria
the Rome process is an international effort to organize for dyspepsia, although the definition of dyspepsia was not
gastrointestinal (GI) symptoms of unknown etiology and to altered. The main focus of Rome II was to align one specific
group them into various groups collectively called functional predominant symptom with underlying Rome I based
gastrointestinal disorders (FGID). This latter includes IBS, subgroups of FD. Main purpose of this change was to target the
FD and several other functional disorders of the GI tract. The predominant symptom. In additions Rome II also modified
Rome criteria are issued after passing through a consensus the duration of symptoms by stating that the symptoms had
process using the Delphi technique. to be present for at least 12 weeks over a 12-month period,
which need not to be consecutive.
Rome I Criteria Both Rome I and II criteria for FD received disagreement.
It was argued that FD patients were frequently unable to
In 1991, the Rome committee defined dyspepsia as persistent distinguish abdominal pain from discomfort. Moreover, it was
or recurrent abdominal pain or abdominal discomfort noted the word predominant symptom (in Rome II) was
centered in the upper abdomen. Rome I criteria identified unclear. Furthermore, subgrouping of patients on the basis
36 Textbook of Hepato-gastroenterology

of symptoms could not be correlated well with underlying EPIDEMIOLOGY


pathophysiological mechanisms. The duration and time
course specification for dyspepsia also thought to be clumsy. There is a wide variation in the prevalence estimates for FD.
It ranges from 7 to 63% in one study; while in another study,
it was 2.541%. This wide range of prevalence is probably due
Rome III Criteria to variability in the definition of dyspepsia used in various
Several changes were made in FD definition and subgroups papers.
by Rome III committee in 2006. An elaborative localization of A recently published population-based study showed that
the pain in the epigastric area has been described. The term FD was present in 11% of the Italian general population. The
abdominal discomfort was abandoned and the key concept same study also documented the existence of two distinct
was replaced by the terms postprandial fullness and early subgroups of FD (as defined in Rome III) in the general
satiety. Predominant symptom-based subgroups of FD were population.
replaced by placing symptoms into new categories. The term Natural history of FD is largely unknown because of
functional dyspepsia was abandoned for research purposes heterogeneity of its symptoms fluctuation in predominant
in favor of a more detailed classification of functional symptoms over a period of time and conservable overlap
gastroduodenal disorders. Rome III-based criteria for FD is with other FGIDs. Studies have demonstrated both short-
given in Table 1. term and long-term fluxes of dyspeptic symptoms with
gastroesophageal reflux disease and IBS. A Swedish study
noted some symptom fluctuation in the shorter-term, but
Table 1: Rome III criteria for functional dyspepsia
troublesome GI complaints remained stable in approximately
Symptoms 90% of subjects over a period of 16 months.
At least 3 months with onset at least 6 months previously A 40% prevalence of FGID was observed in a Japanese
One or more of the following: study with overlapping functional bowel disorders. In
Bothersome postprandial fullness Malaysia, dyspepsia has been reported in up to 15% of rural
Early satiation and 25% of urban population.
Epigastric pain
Epigastric burning
No evidence of structural disease (including upper endoscopy that is
likely to explain the symptoms)
PHYSIOLOGICAL DYSFUNCTIONS IN
1.Epigastric pain syndrome: FUNCTIONAL DYSPEPSIA
Pain or burning localized to the epigastrium of at least moderate
severity and at least once per week There is no uniform pattern of pathophysiological
Pain is intermittent abnormalities found in all FD patients. Various mechanisms
Pain is not generalized or localized to other abdominal or chest have been described (Table 2). Functional abnormalities
regions
have been identified at gastroduodenal region while there
Pain is not relieved by defecation or passage of flatus
Pain does not fulfill criteria for gallbladder or sphincter of Oddi is growing evidence of deranged biochemical abnormalities
disorders and cortical dysfunction in a subset of FD patients.
Supportive criteria:
Pain may be of a burning quality but without a retrosternal
component
Pain is commonly induced or relieved by ingestion of a meal, but
may occur while fasting
Pain may coexist with postprandial distress syndrome. Table 2: Pathophysiologic mechanisms of functional dyspepsia
2.Postprandial distress syndrome:
Visceral hypersensitivity (Fat, H+, wall distension, etc.)
Bothersome postprandial fullness, occurring after ordinary sized
meals, at least several times per week Decreased fundic accommodation
Early satiation that prevents finishing a regular meal at least several Delayed gastric emptying/antral hypomotility
times per week.
Supportive criteria Inflammation [bacteria (H. pylori), virus, etc.]
Upper abdominal bloating, postprandial nausea or excessive Vagal neuropathy
belching can be present
Duodenal hypersensitivity
May coexist with epigastric pain syndrome.
Small bowel dysmotility
Source: Adapted from Rome III criteria
Functional Dyspepsia 37

Impaired Gastric Emptying Other Evolving Pathogenetic


Relationship between impaired gastric emptying and FD Mechanisms for Functional Dyspepsia
symptoms groups remains controversial. While several
Bacterial gastroenteritis leading to persistent symptoms
studies have demonstrated delayed gastric emptying in
after the treatment of infection
2050% of patients with FD, a meta-analysis of 17 studies
Untreated celiac disease is associated with intestinal
evaluating a total of 868 patients with dyspepsia and 397
inflammation proximal gut motility dysfunction.
controls, a delayed gastric emptying was observed in 40
Interestingly it was found that a gluten-free diet in these
patients with FD. In a subset of patients with FD, rapid gastric
patients normalized gastric emptying rate
emptying has also been observed.
Food intolerance has been debated for a long time as
a factor causing FD. In patients with food intolerance,
Increased Visceral Hypersensitivity ingestion of a meal is associated with a rise in dyspeptic
symptoms, which is significant within 15 minutes after the
Increased perception of visceral stimuli has been considered start of the meal, and which persists for at least 4 hours
as one of the major pathophysiological mechanisms in FGID. postprandially. The underlying mechanism is unclear but
Studies have demonstrated that a subset of patients with sensorimotor dysfunction is a likely possibility
FD have enhanced sensitivity to isobaric gastric distension. Autonomic dysfunction notably impaired vagal activity
The exact site of hypersensitivity generated in these patients has also been implicated in the pathogenesis of FD
is however unknown. Two possible sites for generating Recently, the role of eosinophils and mast cells in the
hypersensitivity in these patients are the central nervous intestinal functional disease has been a subject of
system (CNS) and enteric nervous system (ENS) especially considerable debate. Eosinophils and mast cells are an
visceral afferents. important link between innate and adaptive immunity,
Several receptors have been identified as potential targets and are important in allergic T-helper type 2 inflammation.
for future drug development which are potentially responsible Eosinophils may give rise to symptoms due to release
to bring visceral hypersensitivity. These include transient of preformed cytokine proteins, which trigger neural
potential receptor vanilloid type I, voltage-gated sodium excitation, muscle spasm, and pain.
channels, adenosine triphosphate (ATP), acid-sensing ion
channels, protease-activated receptor-2, cannabinoid,
prostaglandin, tachykinin and 5-hydroxytryptamine (5-HT) SYMPTOMS AND
receptors.
PATHOPHYSIOLOGICAL MECHANISM-
BASED CATEGORIZATION OF
Impaired Gastric Accommodation
FUNCTIONAL DYSPEPSIA
Gastric accommodation is a receptive relaxation of primarily
gastric fundus after taking a meal, a vagus nerve-mediated In order to facilitate treatment in patients with FD, attempts
reflex. This reflex relation of stomach increases the gastric were made to classify symptoms into groups based upon
volume, which facilitates accumulations of a meal and underlying pathophysiological mechanism. Unfortunately,
enables the stomach to handle intragastric volumes in clinical practice, this classification showed great overlap
without a proportional increase of intragastric pressure. It is between subclasses. Moreover, a detailed analysis has
speculated that impaired accommodation of the proximal revealed that the predominant symptom does not reliably
stomach during and after the ingestion of a meal may be identify pathophysiological subsets.
accompanied by increase in intragastric pressure, which In a slightly different approach, pathophysiology-based
activates mechanoreceptors in the gastric wall, thus, inducing subgroups of FD were formed, and an attempt was made to fit
dyspeptic symptoms. Using a barostat, impaired gastric various symptoms into such groups. A study has demonstrated
accommodation was demonstrated in 40% of patients with FD association between delayed gastric emptying and symptoms
who presented with symptoms of early satiety and weight loss. of fullness, nausea, and vomiting. Likewise an association
Other tests, which can measure the gastric volume include was also found between impaired fundic accommodation
single photon emission computed tomography, three- and early satiety and weight loss. A recent study on a large
dimensional ultrasound and magnetic resonance imaging. group of patients with FD in a tertiary care setting performed
All these evolving techniques are promising alternatives to factor analysis of symptom patterns. This study showed that
Barostat, as these are noninvasive techniques for measuring the presence of weight loss was strongly associated with early
gastric accommodation. satiety and also with nausea and vomiting.
38 Textbook of Hepato-gastroenterology

An alternate to GI symptom-based Rome criteria for the MANAGEMENT


diagnosis of FD has been suggested recently. This alternative
for Rome III was based upon a cluster analysis approach. In Functional dyspepsia is a diagnosis of exclusion; therefore,
this study, it has been documented that anxiety, depression, it is essential to exclude serious potentially treatable causes.
and somatization are the most important variables along with A list of organic causes is given in Table 3 that indicates that
gastroduodenal symptom-based clusters of FD to define the the causes of dyspeptic symptoms are not only associated
subgroups of patients with FD. with upper GI diseases but also include liver and gallbladder
pathologies. There is a long list of medicines, which also
cause dyspeptic symptoms. A practical approach to a patient
ETIOLOGIC FACTORS ASSOCIATED with dyspeptic symptoms is given in Figure 1. Several
physiological tests are now available to evaluate the proximal
WITH FUNCTIONAL DYSPEPSIA gut dysfunction. These tests can assess the gastric emptying

Genes
Certain genetic polymorphism was found to be associated
Table 3: Differential diagnosis of dyspepsia
with increased susceptibility to FGIDs. Homozygous GNB3
825C carrier status was identified to be associated with 1. Functional (nonulcer) dyspepsia 16. Systemic disorders
unexplained predominantly upper abdominal symptoms. 2. Peptic ulcer disease Diabetes mellitus
Recently, Japanese study found an association of IL-17F and 3. Reflux esophagitis Thyroid and parathyroid
MIF gene polymorphisms with the development of FD in H. disorders
pylori-infected patients. 4. Gastric or esophageal cancer Connective tissue disease
5. Abdominal cancer, especially
Psychosocial Disorders pancreatic cancer
6. Biliary tract disease 17. Drugs:
Patients with FD have demonstrated a high score on
7. Carbohydrate malabsorption: Acarbose
psychomotor scale compared to normal individuals.
Lactose Alcohol
Psychosocial stress, mood symptoms, and coping style
Sorbitol Antibiotics, oral (e.g.
diversity are the major predictors of FD. A recent population- Fructose erythromycin)
based study found that anxiety was linked to uninvestigated Mannitol Bisphosphonates
dyspepsia and FD. The same study, however, did not find Corticosteroids
depression as an associated factor in patients with FD. Iron
8. Gastroparesis Metformin (glucophage)
9. Hepatoma Miglitol (glyset)
Helicobacter pylori and Functional
10. Infiltrative diseases of the stomach Nonsteroidal anti-
Dyspepsia inflammatory drugs, including
cyclooxygenase-2 inhibitors
The relationship between H. pylori infection and symptoms of
Crohns disease Opiates
FD is not yet established. Studies have not shown consistency
Sarcoidosis
between the frequency and severity of symptoms in FD
11. Intestinal parasites: Orlistat (xenical)
patients with the H. pylori status. Additionally, the effects of
eradication of H. pylori on epigastric symptoms of dyspepsia Giardia species Potassium chloride
Strongyloides species Theophylline
are arguable. A Cochrane meta-analysis suggested a small
but significant beneficial effect of eradicating H. pylori on 12. Ischemic bowel disease
symptoms associated with FD. The influence of H. pylori on 13. Medication effects
the pathogenesis and symptom generation in patients with 14. Metabolic disturbances:
FD remains unclear. Therefore, it is debatable whether H. Hypercalcemia
pylori-associated FD is different disease as compared to FD Hyperkalemia
without H. pylori infection. 15. Pancreatitis
Functional Dyspepsia 39

Table 4: Pathophysiological tests for the assessment of functional


dyspepsia

Test Indication
13C octanoic acid Gastric emptying
Scintigraphy Gastric emptying
SPECT Gastric accommodation
Barostat Gastric accommodation and sensations
Ultrasound Gastric accommodation and emptying
MRI Gastric accommodation and emptying
Electrogastrography Gastric myoelectric activities
Antroduodenal motility Motility study of stomach and small intestine
SmartPill Gastric emptying and transit time
Satiety drinking test Gastric sensations and accommodation
Abbreviations: SPECT, single photon emission computed tomography; MRI,
magnetic resonance imaging

Table 5: Functional dyspepsia treatment options and their benefits

Significant clinical benefits


Helicobacter pylori eradications
Protonpump inhibitors
H2 blockers
Prokinetics (metoclopramide)
Probable clinical benefits:
Tegaserod (5-HT4 partial agonist)
Alternative therapies:
Hypnosis
Psychological therapies
Iberogast (herbal extract STW 5)
Chinese herbal medicine
Japanese herbal medicine

Fig. 1: Approach to a patient with dyspeptic symptoms No benefits:


Mucosal protecting agents
Itopride (D2 antagonist, acetylcholinesterase inhibitor)

rate, gastric accommodation, and sensation. Additional tools, information is available about the role of dietary modification,
such as antroduodenal manometry and electrogastrography such as ingestion of low fat diet and small frequent meals and
can be applied to understand the myoelectrical disturbances its actual benefit in FD patients symptoms improvement.
in the proximal gut. However, the practical usefulness of these Various treatment options and their clinical usefulness are
tests is limited beyond the scope of experimental studies and summarized in Table 5.
evaluation of disease process. A list of such tests is given in
Table 4.
Acid Suppression and Neutralization
Treatment Options for Patients with Empiric acid suppression with H2RAs or PPIs is likely superior
to placebo in the treatment of FD. Most recent meta-analysis
Functional Dyspepsia of 10 randomized controlled trails (RCTs) evaluating 3,347
A strong physicianpatient relationship is of utmost participants demonstrated an average 34% response to PPI
importance in treating individual patient with FD so that as compared to 25% response to placebo. Overall, there was
reassurance and education may be provided. Very little a statistically significant benefit of PPI over placebo with
40 Textbook of Hepato-gastroenterology

number needed to treat was 10. Likewise 12 RCTs compared Erythromycin which is a motilin agonist stimulates gastric
H2RAs (ranitidine or famotidine) with placebo assessing 2,183 and duodenal motility by acting on smooth muscles and
participants. Overall 54% symptoms improvement was noted enteric nerves. Erythromycin may promote gastric emptying
as compared to 40% placebo response and number needed but does not improve dyspeptic symptoms, and there are
to treat was 7. issues of tachyphylaxis.
Symptom intensity can be reduced significantly by
antacids as well. In a randomized placebo controlled study
using a combination of simethicone, activated charcoal and Antidepressants
magnesium oxide showed significantly more effectiveness It is plausible that selective serotonin reuptake inhibitors
as compared to placebo in relieving dyspeptic symptoms. (SSRI) might be useful in patients with FD. SSRI increase the
Similarly, bismuth compounds have demonstrated same amount of serotonin within the synapse by inhibiting the
beneficial effects on symptoms in patients with FD. serotonin reuptake transporter in both the CNS and ENS. This
However, mucosal protective agents (such as sucralfate and increased availability of serotonin to the enteric nerves may
misoprostol) did not show any significant improvement in lead to alteration in sensorimotor functions of the gut. Almost
dyspepsia symptoms. no data regarding the efficacy of SSRIs in the treatment of
patients with FD exist. Studies are underway to assess the
effects of SSRIs on visceral sensation and clinical symptoms
Helicobacter pylori Eradication in in patients with FD.
Functional Dyspepsia Tricyclic antidepressants (TCA) block serotonin and
norepinephrine reuptake pumps. Hence, TCA have the
A Cochrane meta-analysis has shown a small but significant
potential to stimulate serotonin and noradrenergic neurons,
benefit from eradication of H. pylori in patients with FD
and thus affect sensorimotor functions of the gut as well
that will reduce the risk of symptoms by 10% and number
as analgesic pathways. Very few studies with TCAs in the
needed to improve the condition of one patient is 14. A test
treatment of FD have been completed. Amitriptyline, a TCA
and treatment policy for eradication of H.pylori is, therefore,
has shown decreased perception of symptoms as compared
recommended for patients with uninvestigated dyspepsia
to placebo in patients with FD but it was not associated with
when there are no alarming features, especially in areas,
decreased perception to gastric distension.
where H. pylori prevalence is 20% or higher.

Prokinetics in Functional Dyspepsia Other Agents for Treatment of


Usefulness of prokinetics in treatment of FD symptoms is
Functional Dyspepsia
doubtful and the experience is very limited. Domperidone This includes opioid, neurokinin and vanilloid receptors
and metoclopramide are two commonly used drugs from and drugs that target receptors involved in pain perception.
prokinetics; former is a D2 antagonist which acts peripherally All these agents are modifiers of visceral hypersensitivity
to increase antral motility, while latter acts centrally. One trial a key mechanism in patients with FD. These are under
comparing metoclopramide and domperidone demonstrated development and yet no conclusive data is available to
no significant difference in side effects. support their use at present. Recently, the analgesic effects
Some emerging prokinetic agents include itopride, which of the gamma-aminobutyric acid type-B (GABAB) receptor
is D2-receptor antagonist with acetylcholinesterase inhibitory agonist, baclofen, has shown pain attenuation in a rodent
and low central activities. However, the clinical usefulness of model of FD, which provide the basis for clinical trials of this
itopride in FD patients is debated. drug in FD patients.
Tegaserod is a 5-HT4 partial agonist found to accelerate
gastric emptying and improvement in symptoms. This drug
has been withdrawn from the market because of increase Alternate Medicines
cardiovascular ischemic side effects. Transcutaneous electroacupuncture has shown marked
Triptans (notably sumatriptan) which relaxes the gastric improvement in dyspepsia symptoms with possible
fundus is a 5-HT1 B/D receptor agonist and was found to mechanism that may be associated with increase in high
increase perception threshold in healthy volunteers and frequency of heart rate variability and the modulation of
decrease sensitivity to gastric distension. neuropeptide.
Functional Dyspepsia 41

Likewise hypnotherapy and psychotherapy in randomized 8. Bolling-Sternevald E, Aro P, Ronkainen J, et al. Do gastrointestinal
trials showed some improvement in dyspepsia symptoms. symptoms fluctuate in the short-term perspective? The
Cochrane review evaluating the impact of psychological Kalixanda study. Dig Dis. 2008;26(3):256-63.
therapies concluded that there was insufficient evidence to 9. Bouin M, Lupien F, Riberdy M, et al. Intolerance to visceral
confirm the efficacy of psychological intervention despite distension in functional dyspepsia or irritable bowel syndrome:
an organ specific defect or pan intestinal dysregulation?
good results in individual studies.
Neurogastroenterol Motil. 2004;16(3):311-4.
Herbal medicines, such as rikkunshito and Chinese herbal
10. Brook RA, Kleinman NL, Choung RS, et al. Functional dyspepsia
medicine, xiaoyao showed effects on gastric sensorimotor impacts absenteeism and direct and indirect costs. Clin
function and dyspeptic symptoms. Similarly, Iberogast, a Gastroenterol Hepatol. 2010;8(6):498-503.
herbal extract, showed its efficacy in FD in a placebo-controlled 11. Chey WD, Wong BC, Practice Parameters Committee of the
study. However, lack of standardization and identification of American College of Gastroenterology. American College
the active ingredients are its major limitations. of Gastroenterology guideline on the management of
Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):
1808-25.
FUNCTIONAL DYSPEPSIA AND 12. Coffin B, Bortolloti C, Bourgeois O, et al. Efficacy of a simethicone,
activated charcoal and magnesium oxide combination
QUALITY OF LIFE (Carbosymag) in functional dyspepsia: results of a general
practice-based randomized trial. Clin Res Hepatol Gastroenterol.
Functional dyspepsia has a significant impact over quality 2011;35(6-7):494-9.
of life and burden on healthcare facilities of the society. A 13. De la Roca-Chiapas JM, Sols-Ortiz S, Fajardo-Araujo M, et al.
Swedish population-based study has shown its significant Stress profile, coping style, anxiety, depression, and gastric
impacts on all main domains describing physical, mental emptying as predictors of functional dyspepsia: a case-control
and social aspects of health-related quality of life in general study. J Psychosom Res. 2010;68(1):73-81.
population. A retrospective analysis of payroll data has shown 14. Delgado-Aros S, Camilleri M, Cremonini F, et al. Contributions
significantly greater costs (both direct and indirect) and lower of gastric volumes and gastric emptying to meal size and
productivity than employees without FD. postmeal symptoms in functional dyspepsia. Gastroenterology.
2004;127(6):1685-94.
15. El-Serag HB, Talley NJ. Systemic review: the prevalence and
clinical course of functional dyspepsia. Aliment Pharmacol Ther.
BIBLIOGRAPHY 2004;19(6):643-54.
16. Ford AC, Thabane M, Collins SM, et al. Prevalence of uninvestigated
1. Akbar A, Walters JR, Ghosh S. Visceral hypersensitivity in irritable
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bowel syndrome: molecular mechanisms and therapeutic
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2. Ang D. Measurement of gastric accommodation: a reappraisal 17. Goh KL. Clinical and epidemiological perspective of dyspepsia
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4. Aro P, Talley NJ, Ronkainen J, et al. Anxiety is associated with 19. Hsu YC, Liou JM, Yang TH, et al. Proton pump inhibitor versus
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6. Bassotti G, Villanacci V, Mazzocchi A, et al. Antroduodenojejunal 21. van Lelyveld N, Linde JT, Schipper M, et al. Candidate genotypes
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23. Liu S, Peng S, Hou X, et al. Transcutaneous eletroacupuncture 34. Suzuki H, Inadomi JM, Hibi T. Japanese herbal medicine in
improves dyspeptic symptoms and increases high frequency functional gastrointestinal disorder. Neurogastroenterol Motil.
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Neurogastroenterol Motil. 2008;20(11):1204-11. 35. Suzuki H, Matsuzaki J, Hibi T. What is the difference between
24. Lunding JA, Nordstrm LM, Haukelid AO, et al. Vagal activation by Helicobacter pylori-associated dyspepsia and functional
sham feeding improves gastric motility in functional dyspepsia. dyspepsia? J Neurogastroenterology Motil. 2011;17(2):124-30.
Neurogastroenterol Motil. 2008;20(6):618-24. 36. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of
25. Mazzoleni LE, Sander GB, Francesconi CF, et al. Helicobacter functional dyspepsia. Gastroenterology. 2004;127(4):1239-55.
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Intern Med. 2011;171(21):1929-36. pathophysiological correlates of weight loss in tertiary referred
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28. Mearin F, Prez-Oliveras M, Perell A, et al. Dyspepsia and 39. Tahara T, Arisawa T, Shibata T, et al. 779 TC of CCK-1 intron 1 is
irritable bowel syndrome after a Salmonella gastroenteritis associated with postprandial syndrome (PDS) in Japanese male
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2005;129(1):98-104.
40. Talley NJ, Locke GR, Lahr BD, et al. Functional dyspepsia,
29. Nakajima S. The spectra of functional gastrointestinal disorders
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41. Talley NJ, Tack J, Ptak T, et al. Itopride in functional dyspepsia:
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30. Pilichiewicz AN, Horowitz M, Holtmann GJ, et al. Relationship
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between symptoms and dietary patterns in patients with
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6
cHAPTER

Gastric Cancer

Mian Mashhud Ahmad, Mamun-Al-Mahtab

introduction Helicobacter pylori


Gastric cancer (cancer of the stomach) is a disease in which Helicobacter pylori is a gram-negative bacterium, which has
malignant cells arise in the tissues of the stomach. Since most been etiologically linked with gastric cancer in numerous
malignant tumors of the stomach are epithelial in origin, ecologic, cohort, and case-control studies over the last
the overwhelming majority of cancers of the stomach are 2 decades. The strongest evidence to support the role of
adenocarcinoma and most of the routine statistics about H. pylori in gastric cancer development comes from
gastric cancer refer to this histological entity. Worldwide, prospective cohort studies. A pooled analysis of data from 12
there are currently over 900,000 new diagnoses of gastric prospective cohort studies demonstrated a sixfold elevation
cancer each year making this the third and fifth most common in risk occurring after 10 years of follow-up. More recent
form of cancer in males and females, respectively. evidence indicates that the use of more sensitive methods
Incidence rate in males is approximately double than those to detect H. pylori infection results in substantially higher
in females. The consistency of this difference has never been risk estimates for gastric cancer. Although there are a variety
adequately explained, although theories have been advanced of proposed mechanisms whereby H. pylori infection may
in which female sex-specific hormones may play a protective increase the risk of gastric cancer, it is thought that the
role. The incidence rate of gastric cancer increases with age, primary mode of action is through the induction of long-term
and the cancer is relatively rare in males or females under 45 chronic inflammation. Relatively few studies have examined
years. Most patients are between 60 years and 80 years old at the joint effects of both H. pylori infection and diet as causes
diagnosis. There is a tenfold variation in incidence between of gastric cancer suggesting that H. pylori infection may act as
the highest risk populations and lowest risk populations and an effect modifier for dietary risk factors. The role of H. pylori
rates are notably high in East Asia, South Asia, South America, in the etiopathogenesis of gastric cancer is discussed further
and Eastern Europe. Incidence rate in most populations have in the chapter.
been declining substantially over several decades. However,
proximal cardia cancers have been found to be increasing
Dietary Factors
in incidence in some populations compared with noncardia
cancer. Many studies, including a recent meta-analysis of studies
investigating the interactions between dietary factors and
the development of gastric cancer concluded that a diet high
ETIOLOGY in fruit and vegetables reduces the risk of developing gastric
cancer. There are many potential mechanisms through
which a diet high in fruit and vegetables may be protective
Common Identified Risk Factors against cancer, what the active component is in the case of
The main identified environmental risk factors for gastric stomach cancer is not clear yet. One possibility is related
cancer are Helicobacter pylori infection and various dietary to the antioxidant capacity of fruit and vegetables, which is
exposures associated with at least sixfold risk of cancer. related to the content of beta-carotene, alpha-tocopherol,
Evidence relating to the etiology of gastric cancer to and vitamin C content. Infection with H. pylori is known to
Helicobacter pylori infection, dietary factors, smoking, substantially reduce the bioavailability of vitamin C leading
occupation, physical activity, and anthropometry is discussed to reduced plasma vitamin C concentrations. This lower
here. vitamin C may be in itself a potential causative factor in the
44 Textbook of Hepato-gastroenterology

development of gastric cancer. A randomized controlled However, the use of nonsteroidal anti-inflammatory drugs
trial in which the treatment of patients at high risk of gastric has been suggested to reduce the risk of stomach cancer.
cancer with a combination of vitamin C, beta-carotene and
H. pylori eradication had successfully promoted the regression
of premalignant lesions. There has been a considerable Occupation
epidemiological research focus on the effects of vegetables Occupational factors have been regarded as playing a
from the Allium family (onions, garlic, leeks). A recent meta- smaller part in the etiology of gastric cancer than dietary
analysis on the effects of garlic intake found a risk estimate and other environmental exposures. Excess risks have been
of 0.53 (95% CI: 0.31, 0.92) associated with high levels of found for several occupational groups, including miners
consumption, indicating a protective effect. and quarryman, farmers, fishermen, masonry and concrete
A possible increase in risk of gastric cancer associated with worker, machine operators, nurses, food industry workers,
alcohol intake has been suggested from a meta-analysis of cooks, launderers and dry cleaners.
number of cohort and case-control studies of gastric cancer
and reported a pooled relative risk of 1.3 for a high intake
of alcohol (100 g/day) but on the basis of the significant Anthropometry
heterogeneity observed between studies, the authors Whilst measures of obesity are generally positively related
concluded that it was not possible to infer causality from these to the risk of cancer, for stomach cancer there is a lack of
data. What is clear that in direct contrast to the cardiovascular epidemiological literature. However, some recent prospective
system, there is less evidence that moderate consumption studies suggested that risk of cancer occurring in the cardia or
of alcoholic beverages has beneficial health effects on the proximal region of the stomach somewhat elevated in obese
stomach. individuals.
Evidence that salt intake is inversely associated with the risk
of stomach cancer has accumulated over many decades. The
mechanism of action of salt on gastric cancer risk is thought Physical Activity
to be via irritation of the stomach lining and ultimately the
Relatively few studies have examined the relationship
development of atrophic gastritis, and this is also thought to
between the physical activity and stomach cancer. A
occur with H. pylori infections, the effects of salt intake may
prospective cohort study of Japanese residents of Hawai
be readily confounded by the lack of adjustment for infection.
found an elevated risk of stomach cancer associated with
Adverse effects of cured or salted meat and fish are thought
highest levels of both recreational and occupational physical
to be linked to the N-nitroso model of gastric carcinogenesis,
activity when compared with mostly sedentary activity levels.
a process inhibited by vitamin C in gastric juice. In the
One recent population-based case-control study found no
stomach nitrites are mainly derived from food and water
significant association for cancer of the gastric cardia with
sources. Despite continuing concern that the formation of
occupational activity.
nitrosamines from dietary precursors may be casually related
to gastrointestinal cancer, the epidemiological literature has
failed to support this link with any degree of conviction. Practice Points
Despite a worldwide decline in incidence of gastric
Smoking cancer, it remains as a major malignant disease in many
populations
Both cohort and case-control studies have found a causal role Helicobacter pylori is an established cause of gastric cancer
of tobacco smoking in the development of gastric cancer. The High intake of fruit and vegetables has been associated
worldwide estimated attributable risk of smoking was 11% with reduced risk of gastric cancer although recent data
derived from a meta-analysis of smoking and stomach cancer. have failed to confirm this relationship. Adherence to
recommendations to consume at least five portions of
fruits and vegetables daily remains, strongly advisable
Medical Conditions There is no evidence that antioxidant vitamin supplements
Pernicious anemia and prior experience of gastric surgery are useful in the prevention of gastric cancer
have been suggested to increase the risk of stomach cancer. Smoking contributes to the risk of gastric cancer.
Gastric Cancer 45

PATHOLOGY AND MOLECULAR event in DGCA is loss of expression of E-cadherin, a key cell
surface protein for establishing intercellular connections
PATHOGENESIS OF GASTRIC CANCER and maintaining the organization of epithelial tissues.
Biallelic inactivation of the gene encoding E-cadherin, CDH1,
Several classifications of gastric cancer (GCA) have been
can occur through germline or somatic mutation, allelic
proposed in the past decades by WHO, Ming, Mulligan and
imbalance events (e.g. loss of heterozygosity) or epigenetic
Lauren. The most successful and currently widely used
silencing of gene transcription through aberrant methylation
classification was presented by Lauren in 1965 depending on
the microscopic morphology alone. There are two main cancer of the CDH1 promoter. In contrast, the pathogenesis of IGCA
pathogenesis appeared as clearly dissimilar in clinical and is less well-defined. However, it appears to follow a multistep
epidemiological entities. These are gastric adenocarcinomas progression that is usually initiated by H. pylori infection.
of diffuse (DGCA) and intestinal (IGCA) subtypes. However, Some tumors display areas of both intestinal and diffuse
in clinical practice, particularly as far as survival is concerned, phenotypes. In such cases, CDHI mutations and loss
all classification of gastric cancer is of limited significance of expression of E-cadherin are seen only in the diffuse
so far. The clinical stage of GCA, irrespective of cancer type component of the tumor, suggesting that E-cadherin loss is
is the most important single and independent factor that the likely basis for the divergence of a diffuse type clone from
determines survival. an intestinal type gastric cancer.
Gastric adenocarcinoma is one of the few malignant Intestinal type caners is most common in high-risk
neoplasms for which infectious agent have been recognized populations, more likely to be sporadic than inherited and
as having an important etiologic role. related to environmental factors, such as diet, cigarette
In 1994, based mostly upon epidemiologic evidence, the smoking and alcohol use. It is also the type that has
International Association for Research on Cancer, a World decreased most markedly over the past several decades. In
Health Organization (WHO) organ, recognized infection low-risk populations, the frequency of IGCA more closely
by H. Pylori as a primary cause of gastric adenocarcinoma. approximates the incidence of DGCA.
However H. pylori-associated preneoplastic lesions are a Intestinal type of gastric cancer are causally related to
feature of IGCA and the DGCA type. The DGCA is more likely H. pylori while the infection usually starts in infancy or
to have a primary genetic etiology and the involvement of H. early childhood, there is a long latency period, a prolonged
pylori is probably limited to a subset of sporadic cases. precancerous process takes place, represented by a cascade
Outcomes of H. pylori infection vary individually and only of events with the following well-characterized, sequential
a small minority of infected subjects develops gastric cancer histopathological stages: chronic active nonatrophic gastritis,
(estimated at approximately three cases per year for every multifocal atrophic gastritis, intestinal metaplasia, dysplasia
10,000 infected persons). It is thought that modulation of the and invasive cancer, while there is a steady progression from
effects of H. pylori by gastric susceptibility, environmental infection to invasive cancer, there may be temporary episodes
factors, and possibly bacterial strain differences influence its of regression to a less advanced stage. The manner in which
evolution into a neoplastic or nonneoplastic process. environmental risk factors contribute to or influence the
progression of H. pylori-induced gastric carcinogenesis is
unclear.
Intestinal versus Diffuse Types Nonatrophic gastritis is the first stage, predominates in the
As noted above, there are two distinct types of gastric gastric antrum, and is characterized by an interstitial infiltrate
adenocarcinoma, intestinal (well-differentiated), and of lymphocytes, macrophages, and plasma cells. The term
diffuse (undifferentiated), which have distinct morphologic activity has been coined to specify the presence of focal acute
appearance pathogenesis and genetic patterns. The inflammation-infiltration of polymorphonuclear neutrophils
morphological differences are attributable to intercellular in the stroma and epithelial layer in a background of chronic
adhesion molecules, which are well-preserved in intestinal gastritis.
type tumors and defective in diffuse carcinomas. In IGCA, Atrophic gastritis is characterized by multifocal loss of
the tumor cells adhere to each other and tend to arrange the original gastric glands. Nonatrophic antral gastritis is the
themselves in tubular or glandular formations. In contrast, predominant finding in H. pylori-associated duodenal peptic
a lack of adhesion molecules in DGCA allows the individual ulcer, not associated with cancer risk.
tumor cells to grow and invade neighboring structures Intestinal metaplasia is the appearance of glands having an
without the formation of tubules or glands. A molecular basis intestinal phenotype. The larger the atrophic and metaplastic
for this difference is now apparent. The main carcinogenic area, the greater the cancer risk.
46 Textbook of Hepato-gastroenterology

As atrophic and metaplastic glands replace original proximal stomach and gastroesophageal junction have
glands, the normal gastric secretions decrease leading to actually increased in frequency
hypochlorhydria and low levels of perinogen-I and gastrin 17. Cardia cancers are also biologically more aggressive, with
These markers can be used as an indicator of gastric atrophy a worse prognosis than distal cancers. Cardia cancers have
and cancer risk. a greater tendency toward deeper wall penetration, lymph
Dysplasia is the next step in the progression of the node metastases and lymphatic vessel invasion
precancerous process. Neoplastic phenotype is characterized It has been suggested that the genetic alterations seen in
by the large, hyperchromatic and disorganized nuclei, cardia cancers more closely resemble those of esophageal
confined to the glandular structures and do not penetrate rather than distal gastric adenocarcinomas
basement membrane. Dysplasia is classified as low grade or The relationship of proximal gastric cancers with H. pylori
high grade. Rates of progression to invasive carcinoma from infection and their association with preneoplastic atrophic
low-grade dysplasia are 023%, while the corresponding rates gastritis/intestinal metaplasia has been questioned.
for high-grade dysplasia are 6085%. These observations support the view that at least a subset
Majority of clinician recommend surgical or endoscopic of proximal cancers represents different subtype from distal
resection for patients with high grade dysplasia, because gastric cancers.
areas of microinvasion can be found in some high-grade
resection samples.
Grossly most IGCA are ulcerated masses, located in the HISTOLOGIC APPEARANCE
region of the incisura angularis and its neighboring antral and
corpus mucosa. Some have their epicenter in the antrum or The WHO classification assigns the terms tubular, papillary
the corpus. and mucinous to the histologic varieties of intestinal type
cancers. Regardless of the specific variant the depth of
invasion in to the stomach wall determines the primary
Diffuse Type Gastric Cancer tumor (T) stage.
Like intestinal type cancers, DGCA can be induced by H.
pylori infection; there are also prominent differences between
these two variants, H. pylori-associated invasive IGCA are
Association between H. pylori and
characterized by a defined series of preneoplastic stages Gastric Cancers
which are not seen with DGCA. Epidemiological studies and several meta-analyses
Diffuse types of gastric cancer are highly metastatic demonstrate a strong correlation between H. pylori
and characterized by rapid disease progression and a poor seropositivity and gastric cancer incidence. H. pylori can
prognosis. DGCA also have a greater tendency to invade be identified histologically in the uninvolved mucosa from
gastric wall, sometimes extending to the lower esophagus or stomachs harboring cancers or precancerous changes.
to the duodenum. Occasionally, a broad region of the gastric Regression of premalignant lesion has been demonstrated
wall or even the entire stomach is extensively infiltrated, with eradication of H. pylori, although whether progression to
resulting in a rigid thickened stomach, termed linitis plastica. invasive gastric cancer can be halted is still unclear. Only one
Histologically, individual tumor cells are seen to invade randomized trial was sufficiently powered to demonstrate that
the surrounding tissues, there is no gland formation. When invasive cancer can be prevented if anti-H. pylori treatment is
intracellular mucin is abundant, it pushes aside the nucleus undertaken before the development of gastric precancerous
of the individual cells, resulting in the so-called signet ring lesions, such as atrophy or intestinal metaplasia.
carcinoma. Signet ring histology is an independent predictor Several hypotheses have been proposed to explain the
of poor prognosis in gastric adenocarcinoma. role of H. pylori in gastric cancer initiation, although the
exact mechanism is incompletely understood. Initiation of
carcinogenesis process has been linked to oxidative stress
Proximal versus Distal Carcinomas brought about by inducible nitric oxide synthase (iNOS)
Proximal cancers that are located in the cardia differ in a that is produced by inflammatory cells responding to H.
number of ways from distal cancers: pylori infection. Nitric oxides are mutagenic and may induce
From an epidemiologic standpoint, although the incidence abnormalities in the DNA of epithelial cells. Furthermore,
of gastric cancer has decreased over the past decades, this support for the role of oxidative and nitrosative stress in
accounted for almost exclusively by distal; cancers of the gastric carcinogenesis is provided by the finding that H. pylori
Gastric Cancer 47

isolates from high cancer risk populations have the ability to infection with cag-A producing H. pylori strain, but not with
induce excessive expression of iNOS and spermine oxidase, the noncarcinogenic clinical isolate.
enzymes linked to DNA damage.
The subsequent molecular events, which promote
progression through the precancerous cascade and culminate Hereditary Diffuse Gastric Cancer
in the development of an invasive gastric cancer are largely Hereditary diffuse gastric cancer (HDGC) has an autosomal
unknown. It is proposed that well-defined histopathologic dominant pattern of inheritance, with early onset gastric
stages of gastric carcinogenesis are accompanied by a stepwise cancers in the majority of affected individuals. The lifetime
accumulation of genetic and/or epigenetic alterations. A cumulative risk for gastric cancer (penetrance) is 4067% in
comprehensive compilation of all the events in the molecular men and 6083% in women. These early gastric cancers are
pathogenesis of gastric cancer is beyond the scope of this multifocal and located beneath an intact mucosal surface.
chapter. The proposed abnormalities are observed in K-ras Because of the difficulty in early detection and the poor
oncogene mutations, p53 tumor suppressor gene alteration, prognosis of these tumors when locoregionally advanced
mutations in the adenomatous polyposis coli gene, loss are candidates for prophylactic gastrectomy. H. pylori seems
of trefoil factor family (TFF) proteins (protect mucous not to play any role in HDGC. Germline CDHI mutations are
epithelium), cyclin E overexpression (cell-cycle regulator) identified in families with an inherited propensity to diffuse
and aberrant gene promoter methylation as an epigenetic gastric cancer (HDGC).
event and all these are associated with H. pylori infection
and have high risk for gastric cancer. The orderly sequential
accumulation of genetic abnormalities as an explanation for CLINICAL FEATURES, DIAGNOSIS, AND
cancer development is being challenged.
It is increasingly recognized that tumor progression STAGING OF GASTRIC CANCER
for colorectal and other cancers is characterized by a
temporary loss of cellular differentiation at the leading edge Clinical Features
of invading tumor cells. Once established, the invading Most patients with gastric cancer are symptomatic and already
cells then redifferentiates from mesenchymal to epithelial have advanced incurable disease at the time of presentation.
phenotypes. This dynamic process of dedifferentiation, At diagnosis approximately 50% have disease that extends
invasion and redifferentiation cannot be explained solely beyond locoregional confines and only half of those who
by the accumulation of genetic alternations; it is regulated appear to have locoregional tumor involvement can undergo
by the tumor microenvironment. Beta-catenin is a critical a potentially curative resection. Surgically curable early
component that regulates morphogenesis during embryonic gastric cancers are usually asymptomatic and infrequently
development. In normal mucosa and well-differentiated detected outside the realm of a screening program.
tumor cells beta-catenin is normally bound to protein The common presenting symptoms are weight loss and
complexes in the cell membrane that are involved in normal persistent abdominal pain. Weight loss usually results from
intercellular adhesions. insufficient caloric intake rather than increased catabolism
Beta-catenin mutation is a frequent cause of activation and may be attributable to anorexia, nausea, abdominal
of gastric carcinogenesis. It has been proposed that gastric pain, early satiety and/or dysphagia. Abdominal pain tends
carcinogenesis involves an initial stage of dedifferentiation to be epigastric, vague and mild early in the disease but more
(gastric atrophy), followed by abnormal redifferentiation severe and constant as the disease progresses.
(intestinal metaplasia), and that this process is mediated by Dysphagia is a common presenting symptom in patients
the effect of H. pylori infection particularly cag-A containing with cancers arising in the proximal stomach or at the
strains on beta-catenin. H. pylori strains carrying virulence esophagogastric junction.
factors cag-A and vac-A s1 and m1 are associated with severe Patients may also present with nausea or early satiety from
gastritis, precancerous lesions, and gastric cancer. Cag-A the tumor mass or in cases of an aggressive form of diffuse type
expression disrupt E-cadherin dependent cell-to-cell contact gastric cancer called linitis plastica, from poor distensibility
and impairs the complex formation between E-cadherin and of the stomach. They may also present with gastric outlet
beta-catenin, causing cytoplasmic and nuclear accumulation obstruction from an advanced distal tumor.
of beta-catenin and constitutive activation of transcription Occult gastrointestinal bleeding with or without iron-
markers of intestinal differentiation. Nuclear localization of deficiency anemia is not uncommon, while overt bleeding
beta-catenin was observed in a human gastric cell line after (i.e. melena or hematemesis) is seen in less than 20% of
48 Textbook of Hepato-gastroenterology

cases. The presence of palpable abdominal mass is the most DIAGNOSIS


common physical finding and generally indicates long-
standing, advanced disease. Even though a delay in diagnosis has not been associated with
A pseudoachalasia syndrome may occur as the result of a poorer prognosis, a prompt diagnostic evaluation should be
involvement of Auerbachs plexus due to local extension or commenced when gastric cancer is suspected.
due to malignant obstruction near the gastroesophageal
junction.
Approximately 25% of patients have a history of gastric Endoscopy
ulcer. All gastric ulcers should be followed to complete Tissue diagnosis and anatomic localization of the primary
healing and those that do not heal should undergo resection. tumor are best obtained by upper gastrointestinal (upper
GI) endoscopy. This procedure is more specific and sensitive
for diagnostic modalities (such as barium studies). Since
Signs of Tumor Extension or Spread up to 5% of malignant ulcers appear benign grossly, it is
Propensity of gastric cancer spread by direct extension imperative that all such lesions be evaluated by biopsy and
through gastric wall, as an example, are feculent emesis or histologic assessment. A single biopsy has 70% sensitivity
passage of recently ingested material in the stool can be seen while performing multiple biopsies (up to seven) from the
with malignant gastrocolic fistula. Patients may present with ulcer margin and base increases the sensitivity to greater than
signs or symptoms of distant metastatic disease. The most 98% for diagnosing any suspicious appearing gastric ulcer
common metastatic distribution is to the liver, peritoneal harboring gastric cancer. It may be even more important to
surfaces and distant lymph nodes. Less commonly metastasis take numerous biopsies from smaller, benign-appearing
may be seen in ovaries, central nervous system, bone and gastric ulcers, since the diagnosis of early gastric cancer offers
lungs. the greatest opportunity for surgical cure and long-term
Physical examination may reveal a left supraclavicular survival. Combination of strip and bite biopsy techniques
adenopathy (a Virchows node) due to spread via lymphatics, should be used in cases of linitis plastica type cancer because
is the most common physical finding of metastatic disease. involvement is usually in the submucosa and muscularis
Periumbilical nodule (Sister Mary Josephs node) and left propria. Poor distensibility of the stomach at endoscopy
axillary node (Irish node) are the less common examination may suggest the presence of this type of lesion. If bleeding
findings. Patients may present with an enlarged ovarian mass with biopsy is of concern to the endoscopist, it is reasonable
(Krukenbergs tumor) or mass in the cul-de-sac on rectal to brush the ulcer base, since the risk of bleeding from this
examination (Blumers shelf ) can result from peritoneal technique is negligible.
spread. Follow-up endoscopy for gastric ulcers: In view of the
Presence of ascites, an indication of peritoneal metastasis sensitivity of multiple biopsy technique, the issue of follow-
and a palpable liver mass can indicate metastases. Jaundice up endoscopy for documented gastric ulcers is controversial.
or clinical evidence of liver failure is seen in the terminal Most of the literature supporting the need for endoscopic
stages of metastatic disease. follow-up of gastric ulcers to document healing is based upon
older surgical and radiologic, rather than endoscopic data.
More recent studies have called in question the common
Paraneoplastic Manifestations practice of repeat endoscopy to verify post-treatment gastric
The phenomena are rarely seen at initial presentation. ulcer healing. Studies have shown that in more than 98%
Dermatological findings may include the appearance of cases malignant lesions can be identified by their appearance
diffuse seborrheic keratoses or acanthosis nigricans, which and/or by histology on initial endoscopy. However, a large
is characterized by velvety and darkly pigmented patches on study found that early gastric cancer were likely to be missed
skin folds. Neither finding is specific for gastric cancer. Other by relying upon appearance and histology alone, and
paraneoplastic abnormalities that can occurr in gastric cancer that follow-up endoscopy with repeat biopsy of unhealed
include microangiopathic hemolytic anemia, membranous ulcers was essential for diagnosing early lesions. The issue
nephropathy and hypercoagulable states (Trousseaus of whether it is cost-effective to routinely perform repeat
syndrome). endoscopy for all gastric ulcers needs to be determined.
Gastric Cancer 49

Until such time, the American Society of Gastrointestinal Staging and Preoperative Evaluation
Endoscopy recommends follow-up endoscopy 812 weeks
after initial endoscopy and initiation of therapy to verify There are two major classification systems currently in use for
healing with repeat biopsies performed on any remaining gastric cancer. The most elaborate, the Japanese classification
ulcers. is based upon refined anatomic location, particularly of the
Barium studies can identify both malignant gastric ulcers lymph node stations. The other and more widely used staging
and some early gastric cancers; however, false-negative barium system, developed jointly by the American Joint Committee on
studies can occur in as many as 50% of cases. Thus, in most Cancer (AJCC) and the Union for International Cancer Control
settings, upper endoscopy is the preferred initial diagnostic (UICC), is the classification most often used in the Western
test for patients in whom gastric cancer is suspected. hemisphere and now commonly in Asian countries as well.
The barium study may be superior to upper endoscopy in Tumor, node, and metastasis (TNM) staging criteria, the
patients with linitis plastica. The characteristic stiff, leather- staging, schema of the AJCC/UICC is based upon tumor (T),
flask appearing stomach is more obvious on the radiography node (N) and metastasis (M) classifications and is outlined in
and the endoscopic appearance may be relatively normal. Table 1.

Table 1: TNM staging for gastric cancer

Primary tumor (T)


TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: Intraepithelial tumor without invasion of the lamina propria
T1 Tumor invades lamina propria, muscularis mucosae or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures.
Tumor invades serosa (visceral peritoneum) or adjacent structures.
T4 Tumor invades serosa (visceral peritoneum)
T4a Tumor invades adjacent structures.
T4b
Regional lymph nodes (N)
NX Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 12 regional lymph nodes
N2 Metastasis in 36 regional lymph nodes
N3 Metastasis in seven or more regional lymph nodes
N3a Metastasis in 715 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic stage/prognostic groups
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2 N0 M0
T1 N1 M0
Stage IIA T3 N0 M0
T2 N1 M0
T1 N2 M0
Stage IIB T4a N0 M0
T3 N1 M0
T2 N2 M0
T1 N3 M0

Contd...
50 Textbook of Hepato-gastroenterology

Contd...

Stage IIIA T4a N1 M0


T3 N2 M0
T2 N3 M0
Stage IIIB T4b N0 M0
T4b N1 M0
T4a N2 M0
T3 N3 M0
Stage IIIC T4b N2 M0
T4b N3 M0
T4a N3 M0
Stage IV Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the on their symptoms and functional status. The purpose of
pathologic classification. A tumor may penetrate the preoperative evaluation is to stratify patients into two clinical
muscularis propria with extension into the gastrocolic groups: those with locoregional (stage I to III) disease and
or gastrohepatic ligaments, or into the greater or lesser those with systemic (stage IV) involvement.
omentum, without perforation of the visceral peritoneum
covering these structures. In this case, the tumor is classified
T3. If there is perforation of the visceral peritoneum covering
Abdominal Computed Tomography Scan
the gastric ligaments or the omentum, the tumor should be It is best suited to evaluating widely metastatic disease,
classified T4. especially hepatic, adnexal metastases, ascites, or distant
The adjacent structures of the stomach include the spleen, nodal spread. CT defined visceral metastases need biopsy
transverse colon, liver, diaphragm, pancreas, abdominal wall, confirmation to avoid false-positive findings. Peritoneal
adrenal gland, kidney, small intestine, and retroperitoneum. metastases and hematogenous metastases smaller than
Intramural extension to the duodenum or esophagus is 5 mm are frequently missed by CT. Accuracy of CT in the T
classified by the depth of the greatest invasion in any of these stage assessment is about 5070% of cases. Sensitivity and
sites, including the stomach. specificity rates for detection of regional nodal metastases
A designation of pNO should be used if all examined range from 6597%. Furthermore, false-positive findings may
lymph nodes are negative, regardless of the total number
be attributed to inflammatory lymphadenopathy.
removed and examined. Used with the permission of the
AJCC, Chicago, Illinois. The original source for this material
is the AJCC Cancer Staging Manual, Seventh Edition (2010) Endoscopic Ultrasonography
published by springer, New York, Inc.
Endoscopic ultrasonography (EUS) is one of the reliable
T stage is dependent on the depth of tumor invasion and
methods available for evaluating the depth of invasion of
not size. Nodal stage is based upon the number of positive
primary gastric cancers, particularly for early (T1) lesions. The
nodes rather than proximity of the nodes to the primary
accuracy of EUS for differentiation of individual tumor stages
tumor.
(T1 to T4) ranges from 77 to 93%, with the experience of the
Regional nodes include those located along the greater
curvature (greater omental, gastroduodenal, gastroepiploic, operator markedly influencing these rates. In comparative
prepyloric and pancreaticoduodenal) lesser curvature (lesser studies, EUS generally provides a more accurate prediction
omental, left gastric, cardioesophageal, common hepatic, of T-stage than does CT, although three-dimensional
celiac and hepatoduodenal) and pancreatic and splenic multidetector row CT and MRI may achieve similar results in
area. Involvement of other intra-abdominal nodal groups term of diagnostic accuracy in T-staging. Accuracy for nodal
(i.e. hepatoduodenal, retropancreatic, portal, mesenteric staging is between 65% and 90%.
and para-aortic) is classified as distant metastases. Clinical Endoscopic ultrasonography-guided fine needle aspiration
staging/preoperative evaluation (Table 2, AJC stage group) of suspicious nodes and regional areas adds to the accuracy of
although staging is most accurately determined through nodal staging. However, overstaging can occur that is attributed
surgical pathology, clinical staging directs the initial approach to inflammation around the tumor or in lymph nodes. Risk of
to therapy. Patients who have locoregional disease after serious complications is negligible, most of which occurs in the
evaluation are potentially curable. Patients with systemic setting of obstructing esophageal tumors. Due to limited field
disease are usually referred for palliative therapy depending of vision with echoendoscope, the utility of EUS as a screen for
Gastric Cancer 51

metastatic disease is questionable. EUS findings alone rarely in serum pepsionogen II or decreases in the pepsinogen I to
affect decisions regarding the need for laparotomy, except when II ratio has been used in population screening programs to
considering patients for a neoadjuvant therapy. Clinical trials identify patients at increased risk for gastric cancer. However,
in individuals with T1 disease are generally excluded from such these markers are not sufficiently sensitive or specific for
studies. However, even patients with locoregionally advanced establishing a diagnosis in an individual patient.
tumors may still be candidates for surgery, particularly
if a palliative resection would be considered. EUS is not
recommended for pretreatment evaluation of gastric cancer in Staging Laparoscopy
guidelines from the National Comprehensive Cancer Network Laparoscopy, though more invasive than CT or EUS has the
(NCCN). EUS staging is of greatest utility for patients with early advantage of directly visualizing liver surface, the peritoneum
gastric cancer to assess accurate submucosal invasion and and local lymph nodes. Between 20% and 30% of patients
essential before considering the option of endoscopic mucosal laparoscopy detects peritoneal metastases despite having
resection (EMR). a negative CT scan. On the other hand, sensitivity of PET
scans is nearly 50% in the detection of peritoneal metastases.
Opportunity to perform peritoneal cytology without visible
Positron Emission Tomography Scan evidence of peritoneal spread is another important advantage
The role of positron emission tomography (PET) scan using of laparoscopy. Positive cytology is a poor prognostic sign,
8-fluorodeoxyglucose in the preoperative staging of gastric even in the absence of overt peritoneal dissemination and
adenocarcinoma is evolving. The integrated PET/CT imaging predicts for early peritoneal relapse. Patients found to have
is especially useful to confirm malignant involvement of CT- peritoneal disease on laparoscopy will never require a
detected lymphadenopathy. Furthermore, large tumors with laparotomy or resection. Positive peritoneal cytology in the
low metabolic activity and most DGCA maybe PET negative. absence of other evidence of intra-abdominal disease is an
The main benefit of PET is that it is more sensitive than CT for indication for neoadjuvant therapy. Therefore, it is routinely
the detection of distant metastases. advised to obtain peritoneal washings during laparoscopy in
The PET scan is not an adequate replacement for staging the absence of visible peritoneal disease.
laparoscopy due to its poor sensitivity in the detection of National Comprehensive Cancer Network guidelines
peritoneal metastasis. NCCN guidelines suggest integrated suggest that laparoscopy should be considered for patients
PET/CT for preoperative evaluation of gastric cancer. who appear to have locoregional disease after conventional
radiographic and EUS staging, especially the patients who
appears to have more than T1 lesion on EUS.
Chest Imaging
Sensitivity of chest X-ray for metastasis is limited. However,
chest CT scan is preferred particularly for patients with a Treatment
proximal gastric cancer in the detection of intrathoracic
disease, which would help the treatment plan. Surgery
Surgery in patients with advanced gastric cancer: Despite
the best efforts of clinicians, gastric cancer in most countries
Serologic Markers is usually diagnosed at a fairly advanced stage. Once the
Low rates of sensitivity and specificity prevent the use of disease has become invasive and spread into the submucosa,
serologic markers as diagnostic tests for gastric cancer. In the risk of dissemination to the lymphatic system increases
a minority of patients, an elevated level of CEA and/or CA- rapidly. Curative treatment for disease, which has entered the
125 may correlate with response to preoperative therapy submucosa is therefore generally centered around surgical
but clinical decisions are never made based upon tumor extirpation. Still surgery remains the mainstay of treatment
marker changes alone. Recommendations for preoperative with curative intent for established gastric cancer. Patient
evaluation of gastric cancer from the NCCN do not include selection is critical to achieving satisfactory outcomes and
assay of any tumor marker. involves careful assessment of both patient fitness and
Hepatoid adenocarcinoma of the stomach a subset of disease stage. Current best practice involves a combination
gastric cancer is associated with elevated level of alpha- of spiral CT scan, endoscopic ultrasound, PET scanning, and
fetoprotein (AFP) has histologic appearance similar to that laparoscopy. Only a minority of patients progress to potentially
of hepatocellular carcinoma. AFP producing gastric cancers curative surgery after staging and fitness assessment in
are aggressive and associated with poor prognosis. Increases Western centers. Prognosis has improved only marginally
52 Textbook of Hepato-gastroenterology

over the last 2 decades despite the declining incidence and options: a distal subtotal gastrectomy or a total gastrectomy.
significant advances in surgical therapy and postoperative These have multiplied in recent years, due to improvement in
care. The overall 5 years survival rate for all stages combined staging, multiplied in surgical technique, pathophysiological
was 27% between 1999 and 2005, compared to 16% between understanding of the disease and minimally invasive
1975 and 1977. The high mortality rate reflects the presentation instrumentation.
and relatively aggressive biology. Early lesions are usually
asymptomatic and infrequently detected outside the realm
of screening program. An additional contributing factor to Extent of Gastric Resection
persistently high mortality is the change in the distribution of Tumors in the pyloric canal, antrum or on the lesser curve
cancers from the body and antrum to the proximal stomach in the body of the stomach can be treated by subtotal
during the past 20 years. gastrectomy. This normally encompasses a four-fifths gastric
Surgery for gastric cancer is often challenging because resection, but this is not strictly necessary providing that an
of the extent of the operation and the frailty of the patient. adequate margin can be provided from the edge of gastric
The extent of the resection required has been the subject of tumor. A 5 cm margin in the operative specimen is generally
considerable debate. The mode of spread of gastric cancer adequate. Traditional teaching has been that a wider margin
differs substantially from that of colorectal cancer. Whilst is required for diffuse cancers than for well-differentiated
liver metastasis without evidence of other metastatic disease intestinal tumors and some have advanced the idea of total
is relatively common in colorectal disease, it is very rare in gastrectomy for these tumors, but the results of a large well-
gastric cancer, which conversely has a tendency to remain designed randomized trial comparing total versus subtotal
confined to the stomach and locoregional nodes until a very gastrectomy indicate that in practice this is not necessary.
late stage. This observation has been used by some as an An exception is generally made for linitis plastica, whose
argument for more radical surgical therapy. propensity for widespread infiltration mandates a total
Surgical procedures: The selection of the appropriate surgical gastrectomy even in cases where one portion of the stomach
techniques requires integration of the information from appears unaffected. There is considerable evidence of
staging and fitness assessment. The first decision for the additional mortality risk and a poorer nutritional result with
surgeon is whether the aim of the operation is complete a total gastrectomy and this should sway the surgeon toward
removal of all malignant tissue with a view to surgical cure preservation of a portion of the stomach where this can be
or palliation of symptoms. If aim is the former, then a further carried out safely. For relatively early tumors in the distal
decision needs to be made about the extent of surgical stomach, techniques have been described preserving the
resection required to remove all locoregional disease whilst vagus nerves and pylorus to improve gastric emptying and
minimizing the risks to the patient. There is considerable function.
evidence available about the outcomes of the various surgical For diseases in the proximal half of the stomach, the time-
options, but the selection of the correct procedure for the honored treatment is total gastrectomy. In most Western
individual patient remains a matter where experience and countries there has been a rapid rise in the incidence of
judgments are important. In particular, the attitude of the tumors at or close to be gastroesophageal junction (GEJ) over
patient is crucial in weighing up the balance of risks versus the last 2030 years. Where these are detected at an early stage,
benefits. the surgeon is often placed in the rather paradoxical position
A limited surgery for cure: where disease is confined to of resecting the entire stomach for a lesion that is only just
the mucosa or in the submucosa EMR may be a satisfactory within the stomach itself and may be extremely small. Another
treatment option. This has been fully dealt with in the early option for the surgeon is that a 2 cm difference in the location
gastric cancer section of the chapter. of the primary tumor, from just below the GEJ to just above
Decisions on the extent of surgery the surgeon is required it, changes the classically recommended procedure from a
to make four choices in designing the appropriate operation total gastrectomy to a total esophagectomy with resection of
for an individual. First, the proximal and distal extent of the cardia. There are two main reasons for this odd situation.
the resection of the stomach (with or without esophagus or First, neither esophagectomy nor total gastrectomy was
duodenum); second, the extent and site of the lymph node designed for the type of tumor that are currently seeing
dissection required to give the best chance of removing in large numbers in the West. Second, long experience
any locoregional disease; third, the least invasive option had taught surgeons that a limited resection of the upper
combining adequate resection of both the GI tube and the stomach and lower esophagus with esophagogastrostomy
lymph nodes; finally, what reconstruction technique should is a disastrous operation, inducing appalling bile reflux
be used. Traditional surgical teaching provided just two symptoms in majority of the patients, with consequently poor
Gastric Cancer 53

quality of life. Currently, the extent of gastric and esophageal Postmortem studies and observations from case series
resection for junctional tumors is dependent mainly on the pointed out that gastric cancer remained a macroscopically
surgeons preference and the normal practice of the treating locoregional disease at the time of death in a high percentage
unit. However, option for relatively small or early tumors is of cases, differing markedly in this respect from colorectal
a proximal gastrectomy with jejunal interposition. This was cancer and other tumors, such as breast cancer. Large
originally described by Merendino as a possible antireflux prospective Japanese studies also confirmed that the
procedure, but good outcome has been observed when it is progression of gastric cancer to local lymph nodes proceeded
used for early proximal cancer. in a highly predictable stepwise fashion. These factors led
surgeons from the US and Japan to propose radical enbloc
resection of the lymphatic tissue along the branches of the
Total versus Subtotal Gastrectomy celiac axis in association with gastrectomy in an attempt to
Gastrectomy is the most widely used approach for therapy remove all locoregional disease. The American experiments
of invasive gastric cancer, although superficial cancers can were attended by a high mortality and quickly abandoned but
sometimes be treated endoscopically. Total gastrectomy is the Japanese series produced impressive results and a much
usually performed for lesions in the proximal (upper-third) of better safety record. Therefore, it becomes one of the most
the stomach, while distal subtotal gastrectomy with resection controversial areas in the surgical management of gastric
of adjacent lymph nodes appears to be sufficient for lesions cancer regarding the optimal extent of lymph node dissection.
in the distal (lower two-thirds) of the stomach. However, The term extended lymphadenectomy variably refers to
patients with large mid gastric lesions or infiltrative disease either a D2 or a D3 lymph node dissection. The draining
(e.g. linitis plastica) may require total gastrectomy. In most lymph node basins for the stomach can be divided into 16
series, quality of life after subtotal gastrectomy is superior to stations: stations 16 are perigastric and the remaining 10 are
that after a total gastrectomy at least at short term. located adjacent to major vessels, behind the pancreas and
along the aorta.
A D1 lymphadenectomy refers to a limited dissection of
Linitis Plastica only the perigastric lymph nodes
In about 5% of primary gastric cancers, a broad region of A D2 lymphadenectomy is an extended lymph node
the gastric wall or even the entire stomach is extensively dissection, entailing removal of nodes along the hepatic,
infiltrated by malignancy, resulting in a rigid thickened left gastric, celiac and splenic arteries as well as those in
stomach, termed linitis plastica. The prevalence may be the splenic hilum (stations 111)
higher in younger individuals. Although most commonly A D3 dissection is a super extended lymphadenectomy.
due to poorly differentiated (diffuse type) infiltrating gastric The term has been used by some to describe a D2
cancers, this pattern can, in rare circumstances, represent lymphadenectomy plus the removal of nodes within the
metastatic spread from lobular cancer of the breast. Linitis porta hepatis and periaortic regions (stations 116), while
plastica has an extremely poor prognosis. other use the term to denote a D2 lymphadenectomy plus
It has been reported that one-half of all patients had periaortic nodal dissection alone. Most Western surgeons
metastatic disease (mainly within peritoneal cavities) at classify disease in these regions as distant metastases and
diagnosis: Nodal involvement frequent. Many surgeons do not routinely remove nodes in these areas during a
consider the presence of linitis plastica to be a contraindication potentially curative gastrectomy.
to potentially curative resection. The arguments in favor of extended lymphadenectomy
(i.e. D2 or D3 versus D1) are that removing a larger number
of nodes more accurately stages the disease extent and that
Nodal Dissection failure to remove these nodes leaves behind the disease in as
The appropriate extent of lymph node dissection in gastric many as one-third of patients, which would adversely affect
cancer surgery has been a major topic of surgical controversy survival. The influence of total lymph node count on stage-
for several decades. The survival results of limited surgery, specific survival was studied in a large series of patients
as reported in the Western literature prior to 1970, were undergoing gastrectomy for T1-3 No-1 stages. For every
extremely poor, whilst a number of features of gastric cancer stage subgroup (T1/2 No, T1N1, T2 N0, T3 N1), survival was
suggested that radical enbloc lymph node dissection might significantly better as more nodes were examined. However,
improve survival rates. Detailed lymphatic mapping studies there are two main arguments against the routine use of an
showed that there appeared to be centrifugal flow of lymph extended lymphadenectomy: the higher associated morbidity
from the stomach to a series of concentric rings of nodes in and mortality and the lack of survival benefit for extended
a stepwise fashion, which could be relatively well-predicted. lymphadenectomy in most large randomized trials.
54 Textbook of Hepato-gastroenterology

Although retrospective reports suggest that extended may be possible laparoscopically in first elderly patients
lymphadenectomy improves survival, multiple prospective who would not be candidates for a laparotomy. As ye,t there
randomized trials both in Asian and Western populations are insufficient data to allow definite conclusions about the
have failed to show a survival benefit with D2 versus D1 or place of laparoscopic gastrectomy, but it seems likely that it
with D3 compared D2 lymphadenectomy. Any statement will become an option in most specialist centers in the near
about lymph node dissection in gastric cancer surgery is liable future, probably for small bulk disease and in poorer risk
to prove controversial, but a reasonable summary based on patients.
the evidence would be as follows:
Gastric cancer frequently spreads to local and regional
lymph nodes once the submucosa is invaded and Palliative Surgery
consideration should therefore be given to resection of Palliative surgery for cancer should by definition concentrate
lymph nodes which are liable to be involved with cancer on relieving symptoms. The role of surgery in palliating
The extent of nodal invasion can be predicted with symptoms of gastric cancer has declined in recent years,
reasonable accuracy from the characteristics of the because of the improving results of nonsurgical options.
primary tumor. Modern staging investigations provide The principal symptoms, which need treatment in patients
further information with advanced gastric cancer are pain, vomiting, bleeding
The main argument against radical lymph node dissection and anorexia. Gastrectomy has no role to play in correcting
in gastrectomy is its association with increased morbidity anorexia but can effectively deal with the other three
and mortality. This type of surgery should therefore only symptoms in particular circumstances. Intractable pain from
be carried out in units, which can demonstrate satisfactory gastric cancer is relatively rare and is often associated with
results in a properly conducted audit very widespread disease. Operation for pain should therefore
In patients where there is clear evidence of locoregional only be undertaken when there is good evidence from CT or
node involvement curative surgery must of necessity other modalities that a resection is feasible and nonsurgical
involve the resection of these nodes. There will therefore measures have failed to relieve the pain. Chronic hemorrhage
be a subset of patients for whom the surgical choices are from gastric cancer commonly leads to anemia but this
palliative resection and radical lymph node dissection can very often be dealt with by repeated transfusions on a
Both the randomized trials and case series, indicate very fortnightly basis.
clearly that splenectomy and distal pancreatectomy Occasional patients present with large life-threatening
are strongly associated with increased morbidity and hemorrhages, surgery is usually effective in arresting this
mortality. They should not therefore be carried out unless type of hemorrhage although resection of the tumor is often
this is strictly necessary to ensure clearance of all tumor not possible. Ligation of the left gastric artery together with
tissue gastrostomy and oversewing of particular bleeding points is
Finally, very extensive (D3) resection should not be often adequate palliation and less likely to put the patient life
regarded as a suitable treatment option in centers without at immediate risk than an attempted emergency palliative
extensive experience of this and other radical cancer resection. If the patient can be successfully resuscitated, it
operations. may be preferable to attempt embolization of the left gastric
In patients with poor level of fitness, a commonly selected artery or other vessel feeding the tumor, thereby, avoiding
option is the D1 + 7 operation, involving removal of the surgery altogether.
stomach and perigastric nodes together with the whole left Intractable vomiting from gastric cancer commonly
gastric artery and associated lymph nodes. arises either from pyloric obstruction, complete paralysis of
the gastric tube due to widespread infiltration or multiple
peritoneal and retroperitoneal metastases causing effective
Minimally Invasive Surgery paralysis of the entire GI tract. Clearly the infiltrative lesion
Laparoscopic distal gastrectomy was first performed in 1992 has no surgical solution, however, patients with linitis
and total gastrectomy in 1996. Technical advances together plastica can occasionally be benefited from a palliative total
with increasing experience laparoscopic resection appear gastrectomy and experience an improved quality of life for a
safe associated with a lower mortality rate in comparison to limited period of time. Pyloric obstruction on the other hand is
open operation in the same type of patient. now being dealt with successfully by duodenal stenting in the
Randomized comparisons have shown that average majority of cases and this should undoubtedly be preferred to
hospital stay and return to normal activities were shorter surgical bypass if it is technically possible. Although there is
than for open operation. Nevertheless, safe gastrectomy as yet no randomized trial evidence, the symptoms relief and
Gastric Cancer 55

survival rates from stenting are impressive, as is the relatively attributed to suture line and dissected lymphatic trunks
minor disruption to the patients quality of life. This should leakage.
be contrasted with higher mortality from gastrojejunostomy
in the debilitated patient with advanced cancer, which
approaches 30% in many series. Where stenting cannot be Clinical Practice Points
achieved, gastrojejunostomy may still have a role to play and Patient selection for gastric cancer surgery should involve
should be carried out laparoscopically to minimize the effects careful assessment of both fitness and disease stage, as
of surgery on the patient. well as the attitude of the patient
Staging should include a high quality CT scan, together
with the laparoscopy, PET scan and endoscopic ultrasound
Efficacy and Side Effects of Surgery as clinical indications and local resources dictate
The main outcome measure for the efficacy of surgery for There is a case for radical node dissection in selected cases
established gastric cancer is long-term patient survival. but only in units which can demonstrably perform this
Figures for this vary greatly depending on the stage of the without additional morbidity and mortality
tumor at the time of operation. The majority of cancer Splenectomy, distal pancreatectomy and total gastrectomy
recurrence in gastrectomy occurs during the first 2 years after should be avoided unless oncologically necessary
the operation. The most common areas of recurrence are the Gastric function may be preserved by constructing
peritoneal cavity, followed by locoregional disease originating substitute reservoirs, avoiding resection of the pylorus or
from regional lymph nodes or the resection margin. Overall 5 vagi or proximal gastrectomy with jejunal interposition
years survival figures of 3040% are now frequently reported Minimally invasive gastrectomy is feasible but requires
for apparently curative resection from major Western centers. further study.
Stage-specific survival has been confounded by the problem
of stage migration, because the removal of more lymph nodes
lead to the discovery of more positive lymph nodes. These
Role of Chemotherapy in Patients with
patients are therefore classified as having more advanced Established Gastric Cancer
stage. Chemotherapy significantly improves survival in comparison
to best supportive care (BSC) in patients with metastasized
Mortality gastric cancer.
Chemotherapy for metastasized gastric cancer (TNM
Gastrectomy is traditionally seen as a major procedure with T1-4, NXM1, AJCC stage IV) the use of chemotherapy is
a high mortality risk. Publications from high volume expert internationally accepted as standard of care. However, the use
centers in countries with well-developed health systems of single agent or combination chemotherapy and the best
currently report mortality rates between 3% and 5%. Total combination chemotherapy regimens are matters of ongoing
gastrectomy is consistently at least twice as dangerous as debate. A recently published Cochrane review addressed the
distal gastrectomy, although there are some exceptions to following comparisons:
this rule. There is a reasonable amount of evidence about
Adjuvant therapy: Gastric cancer frequently manifests
the factors which are associated with high and low mortality
with local and systemic recurrence after curative surgical
from gastrectomy. Apart from selection of procedure
resection. Hence, postoperative therapy with chemoradiation
the factor with the strongest association with increased
was explored. Chemoradiation has shown some encouraging
mortality is comorbid pathology and strong correlations
results but has not translated into an overall survival (OS)
between decreasing fitness and operative risk are found in
benefit in some of small studies. The benefit of postoperative
a number of studies. Age is certainly a risk factor although adjuvant combined modality therapy using contemporary
not an independent one in the effect of fitness. Sex is a factor radiotherapy techniques and leucovorin-modulated
in some series, female patients doing better than males. 5-fluorouracil was undertaken by United States Intergroup
In common with other forms of major cancers surgery, Study (INT-0116), showed a significantly better 3 years OS
gastrectomy morbidity is associated with uncorrected and disease-free survival receiving chemoradiotherapy (52%
preoperative malnutrition. versus 41% and 49% versus 32%, respectively).
Causes of mortality: The principal causes of death after However, interpretation of the benefit of chemoradiotherapy
gastrectomy are respiratory infections and failure, cardiac is complicated by the inadequacy of surgical treatment.
failure and liver failure in cirrhotic patient and anastomotic Nevertheless, patients undergoing potentially curative
leaks and their consequences. Intra-abdominal abscesses resection of gastric cancer should be offered postoperative
56 Textbook of Hepato-gastroenterology

combined modality therapy. Postoperative chemoradiation MAGIC and French trials have led to the adoption of the
with 5 FU/LV remains the standard care in the United perioperative chemotherapy approach to treatment of gastric
States. Updated analysis demonstrated that adjuvant cancer in much of Europe and other parts of the World.
chemoradiation for gastric cancer was not associated with Preoperative chemoradiation: Preoperative therapy has
late toxic events. However, the most predominant reported certain potential advantages over postoperative therapy.
hematologic and gastrointestinal toxicities are leucopenia Preoperative therapy may downstage the tumor and
and nausea, emesis and diarrhea, respectively. Mortality was potentially increases the rate of respectability. Preoperative
uncommon. The results of adjuvant chemotherapy in gastric therapy may sterilize the operative field and thereby reduce
cancer have been disappointing. A number of randomized the risk of tumor seeding. Furthermore early administration
studies conducted over the last 3 decades have failed to of systemic chemotherapy in the preoperative setting may
show a consistent survival benefit. Recently, meta-analysis eliminate micrometastasis without delay. Preoperative
of adjuvant gastric cancer trials has shown marginal benefit chemoradiation also allows better radiation field design.
of adjuvant chemotherapy with some showing a relative risk Clinically, preoperative chemoradiation is better tolerated.
reduction of 2028%. Most recently, the GASTRIC (Global Number of prospective studies have assessed the efficacy
Advance/Adjuvant Stomach Tumour Research International of preoperative chemoradiation in gastric cancer. The
Collaboration) Group-I published a large scale of meta- pathologic complete response rates (RR) were between 16%
analysis that included recently published studies using newer and 27% of patients and R0 resection rate was up to 77%.
agents, such as epirubicin. The studies showed that adjuvant The 3 years OS rate was higher in the chemoradiation
chemotherapy is associated with a statistically significant group (47%) compared with the chemomonotherapy group
benefit OS (hazard ratio 0.82, 95% CI 0.750.9, P < 0.001). (28%) in a recent randomized trial from Germany. The results
Neoadjuvant chemotherapy and chemoradiotherapy: The of these prospective studies of preoperative chemoradiation
goals of preoperative therapy are to increase the respectability appeared promising. However, randomized trials are needed
rate, reduce the rate of local and distant recurrences and to validate the benefit of preoperative chemoradiation.
ultimately improve survival.

Therapy for Metastatic Disease


Preoperative/Perioperative Chemotherapy Both single-agent and combination chemotherapy have
The benefit of perioperative chemotherapy has been been used in advanced gastric cancer. Active agents include
demonstrated in metastatic colon cancer and squamous cell 5-FU, cisplatin, mitomycin C, doxorubicin, epirubicin, and
carcinoma of the esophagus. The most compelling evidence etoposide with RRs varying from 10 to 20%. Meta-analysis
for perioperative is the phase III UK Magic trial. The largest from randomized trials showed that chemotherapy is better
and most influential trial is the United Kingdom Medical than BSC, combination chemotherapy with doublet is
Research Council MAGIC Trial, in which patients with superior than single agent and the best survival is achieved
potentially resectable gastric, distal esophageal or GE junction with three agents at the cost of more toxicities.
adenocarcinomas were randomly assigned to surgery alone Commonly used single, doublet and triplet agents are
or surgery plus perioperative chemotherapy [epirubicin, 5-FU, 5-FU plus adriamycin, 5-FU plus cisplatin and S-1
cisplatin, and 5 fluorouracil (ECF)]. A higher proportion of plus cisplatin; etoposide, cisplatin and 5-FU (ECF) and
the perioperative chemotherapy ECF treated patients had a docetaxel-cisplatin 5-FU (DCF), etc., respectively. Three-
potentially curative procedure and had a significantly better drug combinations have almost similar RRs but associated
OS, 5 years survival rate and progression free survival. The with increasing hematological toxicities. Therefore, palliative
trial was criticized for its nonstandardized surgery, resulting chemotherapy in patients with metastatic gastric cancer
in a relatively poor outcome in the surgery alone group. should be individualized. For those with good performance
Clearly, the MAGIC trial demonstrated survival advantage of status, DCF and ECF are reasonable first-line therapies.
perioperative chemotherapy, similar benefit for preoperative Integration of targeted agents has been extensively
chemotherapy was noted in a French multicenter trial. investigated over past couple of years. Agents have been
Patients undergoing neoadjuvant chemotherapy were evaluated included bevacizumab, cetuximab and trastuzumab.
significantly more likely to undergo curative resection (R0). Randomized trial in patients with Her 2/Neu positive metastatic
With median 5.7 years follow-up, neoadjuvant chemotherapy gastric cancer who receives either chemotherapy plus
was associated with a significant (35%) reduction in the risk trastuzumab/bevacizumab or chemotherapy alone. Overall
of disease recurrence and a significant (31%) lower risk of RR was up to 47%, the medium OS was up to 13.5 months with
death. addition of targeted agent with chemotherapy.
Gastric Cancer 57

Intraperitoneal Chemotherapy FURTHER RESEARCH


The observation that resected gastric cancer tends to recur The balance between relief of tumor-associated symptoms
within the peritoneum has provided the rationale for the and treatment-associated toxicity needs to be evaluated from
evaluation of adjuvant intraperitoneal (IP) chemotherapy. the patients perspective to determine the palliative value of
Meta-analysis of a number of trials has shown a significant any novel therapy for metastasized disease.
survival benefit for hyperthermic IP chemotherapy, but these
investigators were unable to detect a significant survival
benefit from normothermic intraoperative IP chemotherapy.
However, there is insufficient evidence from randomized
SUMMARY
trials to recommend intraperitoneal chemotherapy. The poor long-term survival rates after surgery alone in patients
with gastric cancer have led to the exploration of a variety of
Postoperative Cancer Surveillance adjuvant and neoadjuvant treatment strategies incorporating
chemotherapy and radiation therapy. In patients with
There are no randomized trials to guide the postoperative metastasized gastric cancer, chemotherapy significantly
surveillance strategy. Consensus-based guidelines from the improves survival in comparison to BSC. Best survival results
NCCN suggest the following: are achieved with regimens containing 5-FU, an anthracycline
History and physical examination every 36 months for 13 and cisplatin, such as ECF or epirubicin, oxaliplatin, and
years, then every 6 months for years 4 and 5, then annually. capecitabine. Adjuvant 5-FU-based chemoradiation is
Complete blood count and chemistry profile, as clinically accepted as a therapeutic standard in the United States,
indicated but not in Europe because of considerable toxicity and the
Radiologic imaging or endoscopy, as clinically indicated type of surgery with minimal lymphadenectomy used in the
Monitor for vitamin B12 deficiency in surgically treated relevant trial. According to the results from the UK MAGIC
patients and treat as indicated. trial, perioperative treatment with ECF (3 cycles prior to and
post-surgery) results in a significantly reduced risk of death
for patients with resectable gastric cancer as compared to
Practice Points surgery alone. Neoadjuvant chemotherapy has the ability to
In patients with metastatic disease and without relevant down size gastric tumors and appears to improve curative
comorbidities, chemotherapy with ECF (as continuous (R0) resection rates. Since its potential to improve OS is still
infusion) should be regarded as standard of care. However, questionable, it should be performed within clinical trials.
results for ECF have been challenged by EOX (epirubicin,
oxaliplatin and capecitabine) in the recently presented
REAL-2 trial EARLY GASTRIC CANCER
For patients with metastasized disease, in whom a three
drug regimen is not considered as the treatment of Gastric cancer is one of the most common causes of cancer
choice, either combinations of 5-FU/cisplatin or 5-FU and mortality worldwide. Although there has been a decline in
anthracycline or single-agent chemotherapy with 5-FU gastric cancer incidence in developed countries over the last
should be administered several decades, gastric cancer still accounts for over 10% of
5-Fluorouracil should be given as a continuous infusion annual cancer deaths, second only to lung cancer.
when used in combination of chemotherapy Because of the high incidence of gastric cancer in regions,
Docetaxel+cisplatin-5-FU and IFF [irinotecan, 5-FU such as Eastern Asia and Western South America, nationwide
(folinic acid)] are new, alternative treatment options for screening programs to detect gastric cancer have been
patients with metastasized disease implemented in countries such as Japan, Chile and Venezuela
Perioperative therapy with ECF should be considered in and have led to some improvements in mortality associated
patients with stages II and III gastric cancer with gastric cancer. In the United States where the incidence
Adjuvant chemoradiation is not accepted as international is much lower, screening does not appear warranted and is
standard of care not recommended.
Some patients with locally advanced disease may benefit One of the benefits of large-scale screening programs
from preoperative chemotherapy but no optimal regimen in high-risk areas has been the identification of early
has been defined. gastric cancer (EGC). As proposed by Japanese Society of
58 Textbook of Hepato-gastroenterology

Gastroenterological Endoscopy in 1962, early gastric cancer for progression between these stages. Estimated median
is defined as adenocarcinoma that is limited to the gastric duration of EGC before becoming advanced was 37 months,
mucosa or submucosa regardless of whether regional lymph reported in a Japanese follow-up without surgery. EGC has
nodes are involved or not. EGC represents a subset of gastric been reported to have a higher frequency of synchronous
cancers that has a favorable prognosis compared to invasive cancers and longer symptom duration compared to advanced
gastric cancers that extend beyond the submucosa. disease. These observations suggest that EGC undergoes
Survival rates of 85 to over 90% 5 years after surgical a period of slow growth before becoming advanced. From
resection of EGCs have been reported in Japan and the different series it has been observed that antisecretory therapy
West. In one series from Europe reported a similar survival could mask the symptoms associated with gastric cancer,
for EGC and benign gastric ulcer and no EGC patient died perhaps due in part to the ability of antisecretory therapy to
of disseminated disease. On the other hand, 5-year survival mask the disease by permitting mucosal healing.
without surgery was only 65% in a series from Japan due This is an important cause why most patients with gastric
to progression to invasive disease. These survival rates are cancer tend to present with advanced disease despite the
still better than the 1544% 5 year survival that is reported availability of endoscopy.
after surgery for more advanced (T3/4 or node positive) but The average size of EGC ranges from 1.7 to 3.0 cm.
nonmetastatic invasive gastric cancers, indicating that EGC However, with improved techniques for detection, there is a
may be an earlier stage of disease with a long latent period. trend toward increased reporting of small diameter lesions.
Since EGC usually progresses to invasive disease, the The depth of invasion generally parallels the macroscopic
pathogenesis of the two disorders (at least for the most appearance of the tumor, as ulcerated lesions tend to have
common intestinal type variety) is thought to be similar, deeper penetration than flat lesions; lymph-node invasion is
following a sequence of superficial gastritis, atrophic gastritis, present in 1020% of cases and is more common in tumors
intestinal metaplasia, dysplasia, cancer. that invaded submucosa. Distant metastases in EGC are
infrequent.

Epidemiology
The reported incidence of EGC is higher in Japan, being present
Classification
in 40% of surgically resected specimens. On the other hand, According to Lauren classification the tumors are subdivided
reports from Western centers indicate that EGC is detected into intestinal and diffuse types:
in 1020% of all resections for gastric carcinoma. There do The intestinal type (expanding) is characterized by the
not appear to be significant differences in the epidemiologic presence of distinct glands that are comprised of well-
features of EGC between Japan and the West. The sex and age differentiated columnar epithelial cells with a well-developed
distribution of EGC are similar in Japan, Europe and America. brush border. The morphologic appearance is similar to that
The average age at diagnosis is approximately 60 years and of intestinal carcinomas; hence, the term intestinal type. The
men are more commonly affected. intestinal type is seen in 5070% of patients with EGC.
The diffuse (infiltrative) type is characterized by the
Histological Interpretation absence of intercellular adhesions poorly organized clusters
or solitary mucin-rich (signet ring) cells that lack distinct
Regional histological interpretation explains variation in glandular formations and a diffusely infiltrating growth
the EGC incidence between parts of the World. The main pattern.
differences in interpretation were due to the requirement
of the Western pathologists for invasion into the lamina
propria before diagnosing a cancer, while nuclear features Endoscopic Appearances
and glandular structures were more important for Japanese Type I lesions found in the human as a polypoid lesion
pathologists. with a short, broadband stalk, occasionally multiple but
remain localized
Early Gastric Cancer versus Invasive Disease Type II lesions are superficial, flat, either slightly elevated
or without distinct elevations or depressions. Some of the
Patients with EGC tend to be younger than those with type II lesions have localized area of depression of less than
advanced disease, presumably reflecting the time required 1.5 cm in area without penetration of muscularis mucosa.
Gastric Cancer 59

Clinical Features Endoscopic Ultrasonography


Because mass screening is designed to detect asymptomatic Endoscopic ultrasonography has become a useful method for
lesions, there is little recent information on the symptoms staging EGC, can identify the degree of gastric wall invasion
of EGC in Japan. In reports from the West, symptoms were and regional lymph nodes. In addition, EUS permits fine
present from 6 to 12 months prior to the diagnosis of EGC needle biopsies and aspiration cytology.
and occurred in 9095% of patients. Ulcerated lesions have a
longer prodrome of symptoms than protuberant lesions. Most
of the symptoms, however, are fairly vague and nonspecific, Treatment
such as mild epigastric pain or dyspeptic symptoms and Worldwide, gastrectomy remains the most widely used
some patients are asymptomatic. Incidence of symptoms in approach for the treatment of EGC, but endoscopic therapy is
European patients with EGC: gaining popularity in countries with a high incidence of EGC.
Epigastric pain and/or dyspepsia, similar to peptic ulcer Either subtotal or total gastrectomy is used, depending upon
disease 6590% the tumor location. A total gastrectomy is usually performed
Nausea and/or vomiting 640% for lesions in the upper third of the stomach, and subtotal
Anorexia 1240%. gastrectomy for lesions in the lower two-thirds.
Warning or alarm signs or symptoms suggestive of invasive The role of adjuvant therapy, either with systemic
disease, such as anemia or weight loss, occur less frequently chemotherapy, or RT, is not clearly established for EGC
(515% and 440% respectively). In comparison weight loss especially for patients with node-negative disease.
occurs in more than 60% of those with invasive gastric cancer.
However, consensus recommendations are that endoscopy
be performed for dyspepsia in patients over age 45 or with Endoscopic Mucosal Resection/Endoscopic
alarm symptoms suggestive of invasive disease. Submucosal Dissection
On endoscopy, EGC may appear as a subtle polypoid
protrusion, superficial plaque, mucosal discoloration, Endoscopic mucosal resection is an alternative to surgery,
depression or ulcer. Detection of small lesions can be difficult generally involves intramucosal injection of saline to raise
and may be missed even by experienced endoscopists. The the lesion and electrocautery for resection. EMR has been
optional number of biopsies to obtain an accurate diagnosis increasingly used for selected cases, such as, elevated lesions
is uncertain. The finding of intestinal metaplasia or dysplasia less than 2 cm in size, depressed lesions less than 1 cm in size
in the region of subtle mucosal abnormality should further without ulceration and absence of lymph node metastasis.
heighten vigilance, since these changes are precursors to Recent series confirmed the excellent long-term prognosis
adenocarcinoma and may be seen in the vicinity of a cancer. following EMR for small EGCs.
Improved detection of abnormal lesions may be possible with
chromoendoscopy and magnification endoscopy. A novel Endoscopic Submucosal Dissection
endoscopic technology that is rapidly gaining widespread
acceptance is narrow band imaging (NBI). NBI uses green, Endoscopic submucosal dissection (ESD) has been
red and blue filters with narrow wavelength ranges to introduced to resect large tumors and obtain more reliable
visualize the superficial microvascular network with excellent pathologic specimens. Various types of endoscopic
resolution. The potential benefit of NBI is the targeting of electrosurgical knives are used to incise and remove large
endoscopic biopsies to areas of alterations the superficial neoplastic lesions enbloc.
mucosal patterns for the detection of dysplasia and neoplasia. A needle knife is used to incise mucosa surrounding the
The role of follow-up endoscopy for gastric ulcer is uncertain. tumor. The mucosa is subsequently dissected away from the
In one series, follow-up endoscopy with repeat biopsy of underlying submucosa and the entire tumor is removed in
unhealed ulcers detected a small number of additional early one piece.
cancers. The issue of whether it is cost-effective to routinely Although this technique permits larger EGCs to be
perform repeat endoscopy for all gastric ulcers needs to be removed endoscopically than can be excised with EMR,
determined. Therefore, it is still recommended that follow-up lesions with lymphovascular or deep submucosal infiltration
endoscopy of gastric ulcers 812 weeks after initial endoscopy should still not be considered for ESD because of low chance
and initiation of therapy to verify healing, with repeat biopsies of cure, as these findings indicate a significant risk of lymph
performed on remaining ulcers. node metastasis.
60 Textbook of Hepato-gastroenterology

Other endoscopic modalities are photodynamic therapy, ulcers within the EGC develop secondary to the EGC and
Nd: YAG laser treatment and argon plasma coagulation. These favor cancer extension and metastasis.
therapies are considered tissue destroying therapies whereas
EMR and ESD are tissue retrieving therapies. Tissue retrieving
therapies allow tissue to be acquired en bloc for a detailed Post-treatment Surveillance
pathological examination of the tumor and assessment of the There is no randomized trial to guide surveillance strategy
tumors depth of penetration, in contrast to tissue destroying following remission. NCCN suggests the following:
which do not. History and physical examination on the following
schedule: up to 3 years: every 36 months
Years 4 and 5: then every 6 months
Anti-Helicobacter pylori Therapy Thereafter: annually
A meta-analysis found that there is a strong association of H. Complete blood count (CBC) and blood chemistries
pylori infection with EGC, when compared both to controls (electrolytes, renal and liver function studies glucose)
and to patients with advanced gastric cancer. Furthermore, Radiologic imaging or endoscopy
eradication of H. pylori following endoscopic resection of EGC Vitamin B12 levels in surgically treated patients
reduced metachronous recurrence rates in a randomized Recurrence rates after gastrectomy were 44, 67 and 86%
controlled trial. Because of association of H. pylori with within 2, 3 and 5 years respectively. Computed tomography
metachronous gastric cancer, eradication is appropriate for (CT) detected 81% of recurrences. It has been suggested that
patients with EGC and H. pylori. patients be followed by CT scan for at least 5 years following
Late recurrences or metachronous lesions occur in the surgical gastrectomy.
gastric remnant in approximately 28% of cases of EGC. Local recurrence rates for either EMR or ESD range from 2
Two major risk factors for recurrence are multifocal areas of to 39%. Close endoscopic surveillance is warranted to monitor
malignancy and lymph node involvement. Late recurrences recurrence who have undergone endoscopic management
are frequently found around the stoma and suture line. for EGC. Most authorities perform surveillance endoscopy on
a quarterly basis during the first year and once to twice yearly
thereafter.
Molecular Markers
Improved understanding of the genetic alterations associated
with gastric cancer has revealed a number of markers that are BIBLIOGRAPHY
associated with disease progression and recurrence. Genetic
pathways differ between intestinal types and diffuse type 1. Farman D, Burley VJ. Gastric cancer: global pattern of the disease
tumors, markers are: and an overview of environmental risk factors. Best Pract Res Clin
Gastroenterol. 2006;20(4):633-49.
Individual with atrophic gastritis who had baseline
2. Correa P. Pathology and molecular pathogenesis of gastric
mutations in K-ras were three times more likely than those
cancer. Official reprint from up-to-date (www.uptodate.com)
without mutations to progress to more advanced lesions 2011.
The expression of P53 (a tumor suppressor gene) and DNA 3. Mansfield PF. Clinical features, diagnosis and staging of gastric
ploidy were associated with tumor invasiveness cancer. Official reprint from up-to-date (www.uptodate.com)
Microsatellite instability and/or loss of heterozygosity 2011.
predicted the development of cancer of the gastric cardia 4. McCulloch P. The role of surgery in patients with advanced gastric
in patients younger than age 40 cancer. Best Pract Res Clin Gastroenterol. 2006;20(4):767-87.
Reduced expression of alpha catenin and overexpression 5. Wagner AD, Schneider PM, Fleig WE. The role of chemotherapy
of P53 predicted lymph node metastasis. in patients with established gastric cancer. Best Pract Res Clin
Gastroenterol. 2006;20(4):789-99.
6. Earle C, Mamon H. Adjuvant and neo-adjuvant treatment of
Coexisting Peptic Ulcer Disease gastric cancer (www.uptodate.com) 2011.
7. Bendell J. Local palliation for advanced gastric cancer (www.
The presence of coexisting peptic ulcer disease may influence uptodate.com) 2011.
the natural history of EGC. Coexisting ulcers located outside 8. Madanick RD, Shaheen NJ. Early gastric cancer (www.uptodate.
of EGC are associated with the intestinal type of EGC whereas com) 2011.
7
cHAPTER

Malabsorption Disorders

Axel Hsu, Man-Fung Yuen

INTRODUCTION expression causes a primary lactase deficiency resulting in


failed lactose absorption that persists to adulthood. Besides
Malabsorption is defined as the inability to adequately pediatric conditions that include inborn errors of metabolism
absorb nutrients, vitamins, or minerals. It is a common or congenital enzyme defects, many if not most malabsorptive
problem frequently encountered by physicians and conditions occur in the adult population. The rest of this
gastroenterologists. Malabsorption is an important problem chapter focuses primarily on adult causes of malabsorption.
with significant morbidity. It ranges from malabsorption of
a particular type of nutrient to total intestinal failure from
severe small bowel pathologies. As malabsorptive syndrome PATHOPHYSIOLOGY
encompasses a broad scope of gastrointestinal diseases,
this chapter focuses on various types of malabsorption that Malabsorption is a clinical entity related to the inability for
we frequently encounter and the clinical consequences. A the absorption of macronutrients delivered to the small
rational diagnostic approach with comprehensive blood tests, intestines. There are three main stages of absorption. The
imaging, and dedicated tests related to malabsorption have first phase is digestion, commonly known as the luminal
been presented. Finally, a brief management plan related to phase. It is during this phase that the ingested foodstuff
malabsorption in general with a focus on some of the more becomes chemically broken down and hydrolyzed by
common malabsorption syndromes or diseases have been enzymatic activity secreted by the upper gastrointestinal
elaborated. The reader is advised to refer to other chapters tract and pancreas. Polysaccharides are broken down to
of this textbook for a more thorough discussion on the larger monosaccharides. Triglycerides are broken down to fatty
malabsorption-related topics. acids. Proteins are broken down to amino acids. The inability
to digest enzymatically these macronutrients will lead to
specific nutrient deficiencies. Therefore, maldigestion of any
EPIDEMIOLOGY macronutrient will lead to malabsorption. The second phase
is absorption itself. This phase is often known as the mucosal
Malabsorption is a global worldwide problem and occurs phase where chemically broken down proteins, carbohydrates
across all ethnic groups and social economic backgrounds. It is and fats are absorbed through the intact mucosa. Mucosal
important to remember that in patients with failure to absorb absorption can occur by active or passive transport or by
an adequate oral intake is assumed; therefore, malabsorption diffusion. The transport phase is the last postabsorptive
should not be confused with malnourishment, which remains phase where the absorbed nutrients are delivered to the
to be a significant problem in many developing countries. liver via portal system for further processing. This last phase
In more severe malabsorptive disorders, the end result is also relies on an intact vascular and lymphatic circulation,
failure to thrive in pediatric populations, and weight loss and and disease processes here can hinder systemic delivery
anemia in adults resulting in overt malnutrition. A common of absorbed nutrients. A problem at any one of the three
cause of malabsorption worldwide is celiac disease, which phases of absorption results in malabsorption. The problem
is a gluten sensitive enteropathy affecting mainly the young could be a failure of chemical breakdown due to digestive
adult population. Other common causes that affect many problems or a failed enzymatic pathway. Any breach of the
populations, in particular the Asians, are lactose intolerance absorptive ability of the intestinal mucosa and brush border
and lactose malabsorption. During postweaning period, a could also hinder on absorption. Although the three phases
genetically programmed downregulation of intestinal lactase of absorption are simple to understand from a physiological
62 Textbook of Hepato-gastroenterology

framework, clinical malabsorption is often more complex CLINICAL FEATURES


and may be interrelated through various phases that affect
each other in causing malabsorption. Besides the intestinal Clinical features of malabsorption most often include
tract, the completion of absorption also relies on the exocrine diarrhea that persists beyond the 4th week when acute
function of the pancreas in aiding digestion of primarily fats infectious etiologies are less likely. In fact, a clinician should
and proteins. Furthermore, solubilization is required for the be alerted to possible malabsorption, if unexplained diarrhea
absorption of nutrients, such as fat or calcium. It cannot be or steatorrhea persists. On the other hand, some patients
overemphasized that the liver, biliary tract, and stomach have more constitutional symptoms that are more vague or
also play a crucial role in digestion and absorption, and insidious in onset. Subtle manifestations, in particular those
significant pathologies in these organs will lead to a certain with extraintestinal manifestations, such as anemia in celiac
degree of malabsorption. In systemic disorders that affect disease, may be more difficult to detect and should not be
gastrointestinal motilitydiabetic autonomic neuropathy, overlooked. For the more common presentation, classical
systemic sclerosis, or hyperthyroidism to name just a few, too symptoms often include malodorous bulky diarrhea, in
quick or too slow intestinal transit can alter the gut flora or particular steatorrhea, significant unintended weight loss and
impair absorption. associated symptoms, which may be related to the underlying
Although the three phases of absorption is a simple etiology. Steatorrhea is often described as foul smelling, oily
concept, in practice, the clinical presentation is often related and bulky stool that floats and is difficult to flush away. Besides
to the malabsorbed substrate. Fat digestion requires adequate steatorrhea, nonspecific abdominal pain, and distension often
mixing of fat with intestinal secretions, adequate bile acid accompanied by bloated sensation is a common coexisting
and micelle formation, and exocrine pancreatic lipase and symptom. Initially, a combination of these symptoms may
colipase secretion. Therefore, diseases with predominant suggest a functional disorder like irritable bowel syndrome.
fat malabsorption include celiac disease, pancreatic Appetite is often preserved, although patients tend to eat less
insufficiency, gut resection and biliary pathologies. Protein or avoid foods that particularly worsen their symptoms. A
malabsorption arises when there are intraluminal defects typical history in a lactose intolerant patient is gastrointestinal
in proteolysis, such as gastric resection, and can also occur symptoms of diarrhea, abdominal pain and bloating that often
in patients with congenital defects of amino acid transport occur within 90 minutes of ingestion of lactose-containing
within the enterocyte. Hartnups disease is a typical congenital foods. Isolated deficiencies may occur and represent the only
disorder in which several neutral amino acids, including presenting feature, and iron deficiency in celiac disease is a
tryptophan are not being absorbed, which ultimately leads typical example. Anemia is often encountered in clinically
to neuropsychiatric features of niacinamide deficiency in significant malabsorption and symptoms of fatigue, malaise,
susceptible pediatric patients. Carbohydrate is an important exertional chest pain, or dyspnea should not be overlooked.
substrate and failure to hydrolyze complex carbohydrates A patient with established chronic liver disease with features
can be due to severe pancreatic insufficiency, extensive small of cholestasis may complain of diarrhea, which reflects bile
bowel disorders with defective mucosa, such as Crohns acid malabsorption. It is important to distinguish whether
disease, and is also commonly seen in postenteritis states. the predominant symptom is diarrhea or steatorrhea as the
Lactose intolerance is common and invariably leads to bile acid malabsorption may be compensated (diarrhea)
diarrhea when lactose-containing foods are taken. Vitamin or decompensated (steatorrhea), and the treatment is
malabsorption, particularly the fat-soluble vitamin K, can different for each. Another symptom is easy bruising and
lead to clinically significant coagulopathy. Vitamin B12 ecchymosis on examination point to acquired vitamin K
(cobalamin) is an important water-soluble vitamin and deficiency as a result of malabsorption. As malabsorption
its deficiency can arise from diseases in the stomach and is a syndrome with many causes, it is important to elicit a
terminal ileum. A search for the cause (see section on vitamin detailed and comprehensive history with an emphasis on
B12 malabsorption) is important as untreated vitamin B12 past health, history of gastrointestinal surgical operations
deficiency can lead to irreversible neurological damage. (with operation records if available), dietary and drinking
Folate deficiency is commonly related to poor oral intake habits, and family history. Fat and protein malabsorption is
and is also often seen in chronic alcoholics. Malabsorption of common in postgastrectomy patients. Concomitant iron or
specific minerals and trace elements can result from extensive vitamin B12 deficiency should be sought. Roux-en-Y bypass
mucosal disease and reduced absorptive mucosal surfaces. In surgery in bariatric patients may lead to clinically significant
short gut syndrome, for example, multiple mineral and trace fat malabsorption and other metabolic disturbances, such
elements are deficient and require exogenous replacement by as hyperoxaluria. Although travel history is more relevant in
dietary supplementation. the context of acute diarrheal illnesses, a recent travel to the
Malabsorption Disorders 63

tropical countries (30 north and south of the equator) and Table 1: Diseases where malabsorption is commonly seen in clinical
subsequent chronic diarrhea should prompt one to think practice
about tropical sprue. Tropical sprue is an infection-triggered
Gastric diseases
autoimmune disease that has clinical and endoscopic features
Atrophic gastritis
somewhat similar to celiac disease. Finally, drugs that can
Pernicious anemia
cause malabsorption include acarbose, olestra, and laxatives Gastric resection or bypass surgery
to name a few. It cannot be overemphasized that a detailed
Intestinal diseases
and comprehensive history is paramount in narrowing down
Amyloidosis
many possible causes of malabsorption.
Celiac disease
Graft-versus-host disease
Immunodeficiencies (selective IgA deficiency)
DIFFERENTIAL DIAGNOSES Infections (HIV and AIDS, cryptosporidiosis, giardiasis, Mycobacterium
avium-complex, tuberculosis, helminth and viral infections, Whipples
disease)
Differential diagnoses related to the classical malabsorption
Intestinal ischemia
syndrome are myriad and extensive. Table 1 illustrates Intestinal resection or bypass
some of the more commonly encountered conditions where Intestinal lymphoma
malabsorption is an important or predominant feature. For Radiation enteritis
clarity and simplification, rare conditions are omitted and the Sarcoidosis
Small bowel intestinal overgrowth
reader is reminded that this list is by no means exhaustive.
Sprue (tropical, collagenous)
Hepatobiliary diseases

DIAGNOSTIC WORKUP Biliary tract obstruction


Biliary tract tumors
Cirrhosis and portal hypertensive states
Approach Inborn errors of bile acid metabolism or transport
Sclerosing or recurrent cholangitis
The diagnostic workup of malabsorption includes tests that Pancreatic diseases
confirm the diagnosis and those that address the related
Congenital pancreatic enzyme deficiency
complications or sequalae as a result of malabsorption. It is Chronic pancreatitis
important to remember that many of the diagnostic tests are Cystic fibrosis
laborious if not tedious and are often only available at tertiary Pancreatic tumors
centers with the necessary equipment and expertise available. Lymphatic diseases
Not all patients will require a stringent workup or battery of Primary intestinal lymphangiectasia
tests. To illustrate, in a patient with suspected small bowel Secondary intestinal lymphangiectasia (lymphoma, tumors, thoracic
intestinal overgrowth, we commonly prescribe an empirical duct pathology)
course of antibiotic therapy. A dramatic improvement in Systemic and metabolic diseases
symptoms often correlates with the suspected diagnosis and Abetalipoproteinemia
is both rewarding for the physician and the patient alike. It is Diabetes
Hyperthyroidism
important to remember that diagnostic workup and choice of
Systemic sclerosis
tests depend on the underlying clinical suspicion, physician Systemic lupus erythematosus
and patient preference and the availability of specialized tests.
Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired
immunodeficiency syndrome

Blood Tests
As the clinical features of malabsorption syndrome may C-reactive protein, electrolytes including calcium and
overlap with functional disorders, a good initial approach is phosphate levels, and liver function tests. Thyroid function
to perform simple screening blood tests to look for common should also be checked as symptoms of thyrotoxicosis may
features of malabsorption, such as iron deficiency anemia, often include persistent diarrhea and significant weight loss.
hepatitis, hypoalbuminemia, and vitamin deficiencies. In the presence of microcytic anemia, an iron profile should
A simple blood panel for malabsorption would include be ordered to look for iron deficiency. Macrocytic anemia
complete blood picture, erythrocyte sedimentation rate, is often related to vitamin B12 or folate deficiency. Anemia
64 Textbook of Hepato-gastroenterology

of chronic illness pattern may superimpose on etiologies produced by the pancreas) are also tested in suspected
where inflammation is long-standing. A raised erythrocyte pancreatic insufficiency. Furthermore, stool testing can often
sedimentation rate or C-reactive protein or hypoalbuminemia culture Giardia or other ova, cysts and parasites, which are
also suggest organic pathology. A prolonged prothrombin the common intestinal infections related to malabsorption.
time may be due to vitamin K deficiency, a clue to fat-soluble
vitamin malabsorption. Although laboratory investigation
abnormalities are not usually pathognomonic, such results Tests for Carbohydrate Malabsorption
often point to a possible underlying disease process. For Tests for carbohydrate malabsorption rely upon fermentation
example, a patient with extensive ileal resection (of more of undigested carbohydrates by intestinal bacteria, or
than 60 cm resected) who has confirmed vitamin B12 by direct measurement of the absorbed nutrient after
deficiency is most certainly related to surgical operation. administration of a test dose. The hydrogen breath test is a
Therefore, it is important to correlate the laboratory findings simple but important tool in carbohydrate malabsorption.
to the appropriate clinical setting. Patients suspected to have It can be used to diagnose lactose, fructose or sucrose
celiac disease should have blood serology for antiendomysial malabsorption. Normally, the colonic bacteria ferment
antibodies. The more recently accepted test for celiac disease the nonabsorbed carbohydrate substrate, and hydrogen is
is antitransglutaminase antibody, which has a 98% sensitivity released and exhaled. When lactose or fructose intolerance
and specificity. Once an underlying pathological disease is suspected, an ingestion of a small amount of the substrate
process is suspected, further specific tests for malabsorption (e.g. 2050 grams of lactose) will lead to an excessive amount
should be requested based on the malabsorbed substrate. of hydrogen, which is then detected by the breath test. The
acceptable cutoff often is expressed as greater than 20 ppm
compared with baseline. Furthermore, the hydrogen breath
Tests for Fat Malabsorption test is also useful in documenting patients with suspected
Since the workup of malabsorption entails many different small intestinal bacterial overgrowth. Patients with history of
and often sophisticated tests, it is prudent to confirm the gastric bypass surgery (with blind loops), altered small bowel
presence of steatorrhea if the history is in doubt to avoid transit (systemic sclerosis, diabetes, etc.) and diverticulosis
further unnecessary tests. On the other hand, screening stool are at risk of small bowel bacterial overgrowth. It is important
tests may be unnecessary if the history and macroscopic stool to remember when administrating the hydrogen breath test
appearance are typical and obvious. There are several tests that concurrent or recent antibiotic treatment often alters
performed for fat malabsorption. A good screening test is to the results. In subjects who are nonhydrogen producers (up
collect a stool specimen and to apply acetic acid and Sudan to 18% nonhydrogen producers in the general population),
III stain to look for fat globules under microscopy. Normally, a false negative result may also occur. In these subjects, the
up to 100 globules less than 4 mm diameter per high-power lactose tolerance test could be used instead in which glucose
field is considered normal. Once fat globules are detected, levels are measured at 30 minutes after a test dose of lactose.
a quantitative 72-hour stool collection while taking a 100 Normally, in postlactose ingestion, the serum glucose level
grams fat/day diet is often a good (but not always needed) increases more than 20 mg/dL (or 1.11 mmol/L). In lactose
confirmatory test. An individual normally absorbs about 93% intolerance, the increase is less than 20 mg/dL. These breath
of ingested fat. Therefore, a 72-hour fecal fat excretion greater tests are often limited by the lack of high sensitivity but are
than 7 grams per day is clinically significant steatorrhea commonly performed as they are readily available and
and this finding requires further workup. Up to 14 grams of relatively cheap.
stool output is allowed in patients with diarrhea to account D-xylose breath test is another similar test to determine
for the volume effect of the diarrhea. It is also important to whether malabsorption is due to intestinal cause or
remember that olestra consumption, a fat substitute added pancreatic cause. Normally, xylose is absorbed via intact
to food products, can increase fecal fat excretion leading to proximal intestines by both active transport and passive
a falsely higher excretion value. Besides these limitations, diffusion, and is metabolically excreted unchanged in 50% by
the 3-day fecal fat collection is not always reliable, requires the urine. After an overnight fast, a 25 gram dose of D-xylose is
hospitalization and is cumbersome to perform. Other less ingested and urine collected for next 5 hours. A venous blood
often used tests include the acid steatocrit (a gravimetric assay sample of xylose is also collected at 1 hour. Normal excretion
in which stool mixed with HClO4 is centrifuged and the fatty of D-xylose is 6.0 +/- 1.5 gram in urine and greater than 20 mg/
and solid layers are calculated as a percentage) and the near dL in serum (at 1 hour). In intestinal causes, the level of urine
infrared reflectance analysis but these tests are not widely excretion is reduced and the serum level is low, whereas in
available. Fecal elastase and chymotrypsin (two proteases pancreatic malabsorption, the urine and serum levels remain
Malabsorption Disorders 65

normal. It is important to remember that false-negative test acute infectious gastroenteritis was found to have triggered
results occur in impaired renal function and false positive test chronic diarrhea with confirmed bile acid malabsorption. In
results may occur in those with impaired gastric emptying. patients in whom response to Crohns therapy or empirical
As mentioned previously, small bowel bacterial overgrowth bile acid binding therapy, e.g. cholestyramine is suboptimal,
is an important cause of malabsorption, and therapeutic trial objective testing is performed by the selenium homocholic
with antibiotic therapy is often attempted without the tedious acid taurine (75SeHCAT) test. In this test, selenium-75-
testing. With the wide availability of the breath tests, traditional labeled synthetic bile acid (sele-homotaurocholic acid) is
quantitative method of endoscopic intubation to collect small orally ingested followed by measurement of the bile acid by
intestinal aspirate and bacterial counts is becoming obsolete. whole body gamma-scintigraphic scanning on the 7th day
This procedure is both technically demanding and requires to detect the amount of bile acid retention. The test result is
meticulous attention to avoid contamination from nasal and abnormal when the body has less than 5% uptake at day 7.
oral sources. It has been found that in about one-third of irritable bowel
syndrome subjects where diarrhea was the predominant
symptom, the 75SeHCAT test was abnormal and a majority
Vitamin B12 Malabsorption responded well to bile acid chelator therapy.
Vitamin B12 (cobalamin) malabsorption has previously
been mentioned and results in megaloblastic anemia with
possible neurological complications. The Schilling test is
Exocrine Pancreatic Insufficiency
performed to determine whether the malabsorption is at Pancreatic insufficiency can arise from sequalae of chronic
the gastric or at the ileal level. Normally, food cobalamin is pancreatitis and pancreatic tumors with obstruction or cystic
bound to intrinsic factor produced by gastric parietal cells fibrosis. Exocrine function of the pancreas is compromised
and absorbed in the terminal ileum. In the Schilling test, an only when at least 90% of the acinar tissue is destroyed.
oral dose of radiolabeled (57cobalt or 58cobalt) vitamin B12 Simple tests to look for pancreatic insufficiency include fecal
is ingested and intramuscular dose of non-radiolabeled elastase and chymotrypsin, both of which are pancreatic
vitamin B12 is soon given afterwards. The intramuscular dose enzymes. Low levels suggest pancreatic insufficiency.
of vitamin B12 temporarily saturates vitamin B12 carriers Studies have shown that elastase in particular is the preferred
in the liver, hence the excess B12, if absorbed properly, will enzyme of choice and is better at discriminating diarrhea
be excreted in the urine. If less than 710% of administered due to pancreatic from nonpancreatic causes. In suspected
dose is detected in the urine over a 24-hour period, vitamin cases where fecal enzyme assays are inconclusive or
B12 malabsorption is confirmed. In a subsequent part of the equivocal, invasive tests such as pancreatic function tests are
test, oral intrinsic factor is given and if normalization of test available. Although not widely performed, these tests require
result occurs, the cause of malabsorption is gastric in origin duodenal intubation and collection of duodenal aspirates
with pernicious anemia being the likely cause. If oral intrinsic for pancreatic juice volume, bicarbonate and enzyme levels.
factor fails to correct the test result, then ileal pathology is the Venous injection of secretin and cholecystokinin to stimulate
cause of vitamin B12 malabsorption. Although confirmatory, pancreatic enzyme secretion allows for documentation of
the traditional Schilling test is no longer widely performed pancreatic insufficiency. These invasive and uncomfortable
due to (i) lack of production of the cobalt-labeled isotopes, tests with technical limitations are no longer commonplace
(ii) simple and cheap administration of vitamin B12 injection, in standard gastroenterological practice.
which is given regardless of the cause, and (iii) availability
of anti-intrinsic factor and antigastric parietal cell antibody
assays in diagnosing pernicious anemia. Tests for Protein Malabsorption
Protein malabsorption is not routinely investigated
in the clinical setting. It is seldom to see patients with
Bile Acid Malabsorption isolated protein (without concomitant carbohydrate or fat
It is important to consider tests that differentiate bile acid malabsorption) malabsorption. Rather, intestinal protein loss
malabsorption from fat malabsorption as their treatment is more often encountered and is investigated by the stool
differs. The common causes of bile acid malabsorption include alpha-1-antitrypsin clearance. Once protein loss is confirmed
diseases of the terminal ileum, such as Crohns disease with by a raised alpha-1-antitrypsin clearance, further tests are
small bowel involvement or ileal resection greater than 100 performed to target the cause of the hypoalbuminemia.
cm. Human immunodeficiency virus infection and primary 99m-Technetium-labeled albumin injection can localize
bile acid disorders are other causes to consider. Recently, post- the suspected small bowel pathology. This test and other
66 Textbook of Hepato-gastroenterology

nuclear scintigraphy tests are often only available at tertiary Crohns disease and lymphangiectasia. Random and targeted
referral centers. Another test not commonly performed is biopsies (aim to have at least 46 well-labeled specimens) are
plasma citrulline and arginine concentrations. The level of recommended during endoscopic examination. Although
these two alpha-amino acids is highly correlated to small rare, it is important to remember that Whipples disease is
bowel length. Therefore, in patients suffering from short gut only diagnostically supported by duodenal biopsy specimens
syndrome, postabsorptive plasma citrulline levels correlate that stain positive for the organism Tropheryma whipplei.
with an estimated functional absorptive bowel length and Endoscopic examination of the stomach and duodenum
help determine the likelihood of intestinal failure. is also necessary for assessment and diagnosis of atrophic
and autoimmune gastritis. Crohns disease with stomach
or duodenal involvement can be detected by biopsies and
Radiological Tests histological assessment. Deep duodenal aspirates can be
A commonly used test is radiographic examination of the examined microscopically in cases of bacterial overgrowth,
small bowel using barium contrast. The meal and follow- and bacterial organisms are quantified and studied. However,
through contrast examination allows a gross depiction of this technically demanding procedure is now infrequently
the intestinal mucosal surface and for structural assessment done as simpler breath tests yield similar information.
especially when extensive ulceration, stricture formation or Colonoscopy with terminal ileum examination is often
fistulous communication is suspected. The transit time of the required when ileal pathology is present or suspected. This is
contrast can also reveal abnormalities pointing toward local the diagnostic standard for Crohns disease with large or small
pathology or a more global motility problem. Small bowel bowel involvement. Other potentially significant findings
enteroclysis via a nasojejunal catheter can improve mucosal during endoscopic examination include strictures and
fold detail by better luminal distension. Often this procedure ulcerations for which biopsies are important for histological
is less well tolerated than the traditional small bowel meal diagnosis. Recently, the wireless capsule endoscopy has
and follow-through. Although not diagnostic and nonspecific, revolutionized the study of small bowel. Although ideal
barium small bowel studies can complement further detailed for detecting small bowel bleeding source and organic
imaging, such as computed tomography (CT) abdominal pathologies, its use in malabsorption syndromes remains
imaging, magnetic resonance enteroscopy or direct relatively new and most studies are on Crohns disease or
examination using (single or double) balloon enteroscopy. celiac disease. It is important to remember that in suspected
Computed tomography imaging of the pancreas can often small bowel obstruction, e.g. Crohns stricture, capsule
delineate the long-standing features of chronic pancreatitis or endoscopy may result in capsule retention. In these cases,
other pancreatic pathology. The reader is advised to refer to barium contrast and CT studies may be the preferred imaging
other parts of this textbook for radiological features of specific of choice. As previously mentioned, investigations dedicated
disease entities. to the pancreas have changed from laborious pancreatic
function tests to more simple tests, such as fecal elastase and
endoscopic retrograde cholangiopancreatography, which
Endoscopic Assessment remain the gold standard for diagnosing chronic pancreatitis.
Endoscopic examination of the whole gastrointestinal tract Endoscopic ultrasound examination of the pancreas in
is now possible with the recent advances in small bowel tertiary centers allows for endoscopic assessment with its
enteroscopy and capsule endoscopy. An upper endoscopy favorable advantage of contrast and radiation-free exposure.
with deep duodenal intubation (beyond the ampulla of
Vater) is often required if celiac disease is suspected, and
the characteristic reduced duodenal folds and scalloping of MANAGEMENT PLAN
mucosa may sometimes be seen which correlate with villous
atrophy on histological studies. While a diagnosis of celiac The general management plan in patients with
disease can often be supported by compatible endoscopic or malabsorption should focus on (i) symptom control, (ii)
histological findings, serological tests are now frequently used replacement of the malabsorbed nutrient, and (iii) monitor
including the antiendomysial and tissue transglutaminase for complications as a result of the malabsorptive disorder.
antibodies that serve as screening and confirmatory Equally important is the treatment of the underlying
purposes. The details on the diagnostic workup for celiac cause of malabsorption. Dietary restriction or avoidance,
disease are discussed elsewhere. One caveat to remember and subsequent adherence are of crucial importance.
during endoscopic small bowel examination is to note that Patients who have bloating and diarrhea from malabsorbed
some intestinal conditions are more focal and patchy, such as carbohydrates should avoid poorly absorbable sugars
Malabsorption Disorders 67

such as fructose, sorbitol or fermentable dietary fibers. CONCLUSION


Replacement by supplementation of deficient electrolytes,
minerals and vitamins is often simple and effective. Malabsorption is an important problem commonly
Adequate calcium intake or supplementation is important encountered in medical and surgical practice. It is important
in preventing metabolic bone disease. Iron, vitamin B12 to recognize that presenting symptoms may be insidious
or folate supplementation can improve anemia with in onset and symptoms may seem to suggest functional
normalization of hemoglobin levels. In order to tackle the bowel disorders. The diagnostic workup includes a battery
more specific diseases related to the underlying disorder, of investigations that include blood tests, stool analysis,
a gastroenterologist with experience in the particular area endoscopy, imaging and dedicated tests for malabsorbed
is recommended. Empirical courses of antibiotics are substrates. Celiac disease remains an important disease
important in small intestinal bacterial overgrowth and have and serves as a good model for studying malabsorption.
both diagnostic and therapeutic roles. Frequently, a dietitian The approach and management to malabsorptive disorders
referral is necessary as nutritional counseling and dietary requires a good knowledge of the basic underlying
adjustments are required in patients with celiac disease pathophysiologic mechanisms and to utilize the approach
or carbohydrate intolerance. Medium chain triglyceride tests in arriving at the diagnosis. The workup and investigations
(MCT) diets are beneficial in patients with troublesome are often specialized and challenging. It is important that
steatorrhea since MCT absorption does not require micelle physicians and gastroenterologists alike be familiar with the
formation (for fat solubilization and absorption), which workup of malabsorption. Management principles target
is often required in dietary fat intake. Strict adherence to underlying disorder and symptomatic treatment aims at
an MCT diet can benefit patients with primary intestinal improving quality of life. The reader is encouraged to refer to
lymphangiectasia, short gut syndrome and pancreatic other parts of this textbook for more detailed information on
insufficiency. Furthermore, the MCT diet is recommended specific disease entities related to malabsorption.
for patients with intestinal lymphangiectasia due to the
portal route of absorption rather than the lymphatic route.
Pancreatic protease and lipase preparations are available BIBLIOGRAPHY
commercially and are often effective in clinically significant
pancreatic insufficiency, i.e. steatorrhea with greater than 1. Duerksen DR, Fallows G, Bernstein CN. Vitamin B12 malabsorption
15 g/day fat excreted. Commercially available pancreatic in patients with limited ileal resection. Nutrition. 2006;22:1210-3.
2. Fernandez-Banares F, Rosinach M, Esteve M, et al. Sugar
lipase preparations should start at 40,00050,000 United
malabsorption in functional abdominal bloating: a pilot study on
States Pharmacopeia (USP) units of lipase per meal given
the long-term effect of dietary treatment. Clin Nutr. 2006;25:824-31.
with meal thrice daily. This dose can be titrated until there 3. Masoero G, Zaffino C, Laudi C, et al. Fecal pancreatic elastase 1
is normalization of stool consistency and appearance. If in the work up of patients with chronic diarrhea. Int J Pancreatol.
higher doses do not show marked improvement, empirical 2000;28:175-9.
addition of a proton-pump inhibitor to lower the intestinal 4. Menon S, Jones BJ. Postinfective bile acid malabsorption: is this a
pH can improve drug bioavailability to the proximal long-term condition? Eur J Gastroenterol Hepatol. 2011;23:308-10.
intestine. In patients with malabsorptive disorders, proper 5. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac
treatment coupled with good patient dietary and drug disease and lymphocytic enteropathy by parallel serology and
compliance will often ensure a good clinical outcome. For histopathology in a population-based study. Gastroenterology.
those with chronic medical problems such as inflammatory 2010;139:112-9.
6. Wedlake L, AHern R, Russell D, et al. Systematic review: the
bowel disease or celiac disease, life-long therapy with
prevalence of idiopathic bile acid malabsorption as diagnosed by
medications and dietary discretion is required. Often those
SeHCAT scanning in patients with diarrhea-predominant irritable
with more complex conditions such as short gut syndrome bowel syndrome. Aliment Pharmacol Ther. 2009;30:707-17.
are jointly managed by gastroenterologists, surgeons and 7. Yadav P, Das P, Mirdha BR, et al. Current spectrum of malabsorption
dietitians with a multidisciplinary approach. syndrome in adults in India. Indian J Gastroenterol. 2011;30:22-8.
8
cHAPTER

Abdominal Tuberculosis

Zaigham Abbas

INTRODUCTION PATHOGENESIS
Tuberculosis (TB) is still common in the developing countries.
Gastrointestinal Tract
The disease has now made a comeback even in the Western
countries with the epidemic of acquired immunodeficiency Tuberculosis is a chronic granulomatous inflammatory
syndrome (AIDS). It is still a killer disease affecting more the disease. The bacteria reach the gastrointestinal tract via
lower socioeconomic classes in the developing countries. hematogenous spread from a primary lung focus and
Abdominal TB denotes involvement of the gastrointestinal infection occurs following reactivation of latent tuberculous
tract, peritoneum, lymph nodes, and solid viscera, e.g. liver, foci in the peritoneum. Gastrointestinal tract may also be
spleen, and pancreas. Tuberculosis of the gastrointestinal involved by ingestion of infected sputum, or direct spread
tract is the sixth most frequent form of extrapulmonary site from infected contiguous lymph nodes and fallopian tubes.
after lymphatic, genitourinary, bone and joint, miliary, and The intestinal lesions may be ulcerative (60%), hypertrophic
meningeal TB. Mycobacterium tuberculosis is the pathogen in (10%), and ulcerohypertrophic (30%). Hypertrophic form is
most cases. Mycobacterium bovis causes disease in some parts characterized by scarring, fibrosis, and pseudotumor lesions.
of the world where pasteurization of milk is not practiced. Ulcerohypertrophic form is more common in the ileocecal
region.
The affinity of M. tuberculosis for ileocecal region may
RISK FACTORS be due to its relative stasis and abundant lymphoid tissue.
The organism penetrates the mucosa and localizes in the
Tuberculosis flourishes wherever there is poverty and submucosal lymphoid tissue and Peyers patches, where
crowding. Vulnerability increases when body defenses are it initiates an inflammatory reaction with tuberculous
weakened, such as chronic debilitating diseases, diabetes granuloma formation, lymphangitis, endarteritis, caseation
mellitus, Hodgkins disease, chronic lung disease, particularly necrosis, mucosal ulceration, and scarring. Then the
silicosis, malnutrition, underlying malignancy, cirrhosis, inflammatory process in the submucosa reaches to the serosa
alcoholism, and immunosuppression, especially AIDS, via lymphatics. The lymphatic obstruction of mesentery
corticosteroid therapy and following treatment with anti- and bowel causes a thick fixed mass. Spread may occur
tumor necrosis factor (TNF) agents, patients undergoing to the glands in the mesenteric root to the para-aortic
continuous ambulatory peritoneal dialysis and in elderly. The glands and on to the cisterna chyli and then to the thoracic
emergence of multidrug resistant bacilli and AIDS has posed duct resulting in miliary dissemination. Caseous glands
newer threats. may invade the peritoneum or form a localized abscess.
Sometimes, intestinal obstruction may result from pressure
of glands or kinking through adhesions and their healing by
SITES OF INVOLVEMENT fibrosis or calcification leading to napkin ring strictures.
Hypertrophic cecal TB may also lead to obstruction.
Tuberculosis can involve any part of the gastrointestinal tract Perforation may occur proximal to a stricture. Malabsorbtion
from mouth to anus (49%), the peritoneum (42%), mesenteric occurs secondary to bacterial overgrowth in stagnant loops,
lymph nodes (4%), and the solid viscera, including liver and bile salt deconjugation, diminished absorptive surface due to
pancreatobiliary system (5%). The most common site of ulceration, and involvement of lymphatics, and lymph nodes.
involvement in intestinal TB is the ileocecal region followed Granulomas associated with TB tend to be large and
by the colon and jejunum. confluent often with caseation necrosis in contrast to those
Abdominal Tuberculosis 69

loops and lymph nodes felt as typical doughy abdomen, or


(iii) encysted (loculated) type with a localized abdominal
swelling, or (iv) a combination of above. Tuberculous
peritonitis has a female predominance. The peritoneum
is studded with multiple yellow-white tubercles (Fig. 3).
It is thick and hyperemic with a loss of its shiny luster.
The peritoneal tubercles are large and loops of intestine
are inflamed and swollen. Ascites develops secondary to
exudation of proteinaceous fluid from the tubercles, similar
to the mechanism leading to ascites in patients with peritoneal
carcinomatosis. Widespread adhesions and fibrosis may lead
to adhesive intestinal obstruction.

Fig. 1: Colonic tuberculosis: inflammation, ulceration, and granuloma


formation in the submucosa (HE x100)

in Crohns disease. Granulomas are often seen just beneath


the ulcer bed, mainly in the submucosal layer (Fig. 1).
Tubercular ulcers are relatively superficial and usually do
not penetrate beyond the muscularis. They may be single or
multiple, and the intervening mucosa is usually uninvolved.
These ulcers are usually transversely oriented in contrast
to Crohns disease where the ulcers are longitudinal or
serpiginous. Cicatricial healing of the circumferential girdle Fig. 2: Thickening of cecal wall in hypertrophic form of ileocecal
ulcers results in strictures. Occlusive arterial changes may tuberculosis
produce ischemia and contribute to the development of
strictures. Patients with strictures have occlusion of the vasa
recta, while ulcerated lesions have hypervascularity. Small
bowel lesions are usually ulcers or strictures while colonic
and ileocecal lesions are ulcerohypertrophic (Fig. 2). The
disease may involve both sides of the ileocecal valve leading
to incompetence of the valve, another point of distinction
from Crohns disease. Isolated involvement of colon without
ileocecal region has also been reported with skip lesions and
multifocal involvement in some cases. In such cases, Crohns
disease is again an important differential.

Peritoneum
Peritoneal involvement may occur by hematogenous
spread or by direct extension from caseating and breaking,
down lymph nodes. It may either be (i) ascitic type with
abdominal distension, or (ii) adhesive (plastic) type resulting Fig. 3: Laparoscopic findings of peritoneal involvement of tuberculosis:
in mesenteric and omental thickening, with matted bowel tubercles and adhesions
70 Textbook of Hepato-gastroenterology

Abdominal Lymph Nodes


Lymphadenopathy may present without any other evidence
of abdominal involvement. Mesenteric lymph nodes may
get enlarged and matted, and may caseate. Characteristic
granulomas may be seen in these lymph nodes. There is relative
lack of retroperitoneal lymphadenopathy in patients with TB,
in spite of extensive mesenteric and peritoneal abnormalities.
This can be explained by the fact that mesenteric lymph nodes
drain directly into the thoracic duct (via the cisterna chyli).
This observation can help differentiate abdominal TB from
other systemic diseases, such as lymphomas.

Pancreas
Pancreas is biologically protected from being infected by M. Fig. 4: Well formed hepatic granuloma in a patient with abdominal
tuberculosis, probably because of the presence of pancreatic tuberculosis (HE x400)
enzymes that interfere with the seeding of M. tuberculosis.
Tuberculosis of pancreas is rare and may pose a diagnostic
challenge, specially differentiating it from carcinoma of the
pancreas. Its indolent course and vague symptomatology along
with nonspecific laboratory and radiological findings call for
greater vigilance. Infection is said to involve the pancreas by
direct extension, lymphatic or hematogenous dissemination
or following reactivation of previous abdominal TB.

Liver
Tuberculosis of the liver in isolation is rare. Liver is involved in
association with foci of infection in lungs or intra-abdominal
organs, such as the peritoneum, mesentery, mesenteric
lymph glands, biliary tract, and the gallbladder. The disease
commonly involves the hepatic parenchyma and sometimes
the biliary tree. The most common type of presentation is
diffuse miliary liver involvement via hepatic artery associated
with pulmonary TB. The second form is diffuse hepatic
infiltration without evidence of TB elsewhere. The third form Fig. 5: Hepatic granuloma with Langhans giant cells (HE x400)
presents as a focal or nodular lesion in liver as tuberculoma or
abscess and the portal of entry is the portal vein. The patients
with liver involvement may or may not have jaundice. may coalesce to form a large tumor like tuberculoma. A
Jaundice is usually cholestatic but sometimes obstructive tuberculoma, which has undergone extensive caseation and
either due to porta hepatis nodes causing biliary compression liquefaction necrosis, forms a tubercular abscess.
or pericholangitis or rupture of a tuberculous granuloma into
the bile ducts.
Tuberculosis is an important cause of granulomatous liver
Gallbladder
disease (Figs 4 and 5). Hepatic epitheloid cell granulomas Gallbladder may get involved by hematogenous or lymphatic
may occur in other diseases as well. Only 25% of patients spread from the primary site or secondary to hepatic TB from
with tuberculous granulomas show characteristic caseation excreted bacteria into the biliary tree or by direct spread
in the biopsy specimen. The granulomas are most frequently from liver or periportal lymph nodes. Patients may present
found in the periportal areas (zone 1 of Rappaport) but may with cholecystitis, obstructive jaundice or rarely only with
occasionally occur in zone 3. In focal TB, various granulomas gallbladder wall thickening on sonography.
Abdominal Tuberculosis 71

CLINICAL FEATURES
Abdominal TB is predominantly a disease of young adults.
Majority of the patients are in their twenties and thirties
at the time of presentation, and the sex incidence is equal.
Patients with abdominal TB present with fever, abdominal
pain aggravated by meals, vomiting, weight loss, night sweats,
diarrhea alone or alternating with constipation, abdominal
distension, mass in the right lower abdomen and occasionally
hematochezia. Pain can either be colicky due to luminal
compromise, or dull and continuous when the mesenteric
lymph nodes are involved. Symptoms are usually of moderate
intensity and usually present for more than 3 months when
the patient seeks the medical advice. Presence of coexistent Fig. 6: Esophageal biopsy showing mucosal ulceration and large well
pulmonary TB significantly increases the frequency of fever formed epitheloid granuloma in mucosa (HE x100)
and night sweats, weight loss and pulmonary symptoms.
On examination, pallor, ascites or doughy abdomen and
generalized abdominal tenderness, especially in the right
iliac fossa may be present. Patient may have hepatomegaly.
Abdominal masses due to enlarged lymph nodes, adherent
bowel loops or a cold abscess may be noted.
Patients of ileocecal and small bowel TB present with
colicky abdominal pain, borborygmi, and may have a
palpable lump in the right lower quadrant. These patients
may present with one of the complications like intestinal
obstruction, perforation, or malabsorption, especially in the
presence of stricture. Tuberculosis may also present as an
enterocutaneous fistula after bowel surgery, an umbilical
abscess, a discharging sinus or as nonhealing surgical wound.
Rare clinical presentations of gastrointestinal TB include
dysphagia, odynophagia, and a midesophageal ulcer due to
esophageal TB (Fig. 6); dyspepsia, hematemesis, melena, or
gastric outlet obstruction due to gastroduodenal TB (Fig. 7);
Fig. 7: Well formed epitheloid granuloma with Langhans giant cell in
lower abdominal pain and hematochezia due to colonic TB; gastric antral mucosa. Gastric tuberculosis (HE x200)
and annular rectal stricture and multiple perianal fistulae due
to rectal and anal involvement.
The clinical presentation of hepatic TB is usually insidious mass or hypodense lymph nodes in the peripancreatic region,
and often nonspecific. The patient may present with a particularly if the patient presents with fever and is young, not
protracted illness frequently associated with fever, malaise, jaundiced, lives in an area of endemicity, or was exposed to
weight loss, jaundice, abdominal pain and hepatomegaly. TB in the past.
The liver is usually not tender on percussion or palpation.
Splenomegaly may be present in some cases. These patients
are usually anemic. Mild jaundice may be present. Obstructive INVESTIGATIONS
jaundice may develop if enlarged hilar glands of the liver
compress common hepatic ducts. Diagnosis is based on history, physical examination, and
Pancreatic TB is more common in females. The patients investigations. Laboratory investigations may show anemia,
present with epigastric pain, fever and weight loss; jaundice leukopenia, leukocytosis with left shift, thrombocytopenia,
may or may not be present. Other clinical presentations thrombocytosis, elevated ESR, hyponatremia, elevated
include acute or chronic pancreatitis and gastrointestinal alkaline phosphatase and gamma-glutamyl transferase
bleeding secondary to splenic or portal vein thrombosis. It (GGT), mild elevation of transaminases, hyperbilirubinemia,
should be suspected in young patients having a pancreatic hypoxemia, and sterile pyuria. Anemia, which may be
72 Textbook of Hepato-gastroenterology

present in about 60% of patients, is usually a normochromic diagnosing pancreatic TB is approximately 5060%. Culture
normocytic anemia of chronic infection. Leukocytosis is results are positive in only 7075% of all pancreatic TB
more common than leukopenia. Cholestatic jaundice is also cases. Finding of liver granulomas histologically, even in the
well documented in miliary TB. Amylase and lipase levels absence of caseation necrosis or AFB is accepted as evidence
would become elevated in cases of pancreatitis associated of tubercular etiology in most instances unless proven
with miliary TB. otherwise (Figs 4 and 5).
The diagnosis of abdominal TB is confirmed by
demonstration of bacilli from tissues by smear, culture
or polymerase chain reaction (PCR) and demonstrating Tuberculin Skin Test
caseating granulomata at histopathology. Unfortunately, in Tuberculin testing with purified protein derivative (PPD) is
most of our patients such confirmation is not possible. The positive in approximately 70% of patients; however, a negative
treatment for abdominal TB is often instituted on the basis result is of no help in excluding the disease. Intradermal
of a high index of clinical suspicion and ancillary supportive injection of 0.1 mL of PPD should produce a 610 mm wheal
evidences without actually recovering the bacilli. when read at 4872 hours. If first test is negative, retesting
may be done in 13 weeks. Patients with a weakened immune
response may be anergic at the time of PPD reading.
Microbiology
Mycobacteria are aerobic, acid-fast bacilli (AFB). They are
poorly stained with Gram staining, and M. tuberculosis
Interferon-gamma Release Assays
grows slowly with a doubling time of 18 hours compared to They measure T cell release of interferon-gamma (IFN-
most other bacteria having doubling time of less than 1 hour. gamma) following stimulation by antigens unique to M.
Due to this, slow growth cultures of clinical specimens must tuberculosis and have the specificity greater than 90% for
be held for 68 weeks before recording the result. Broth- the diagnosis of latent TB. These tests would take the place
based culture systems to improve the speed and sensitivity of tuberculin skin tests. They are not affected by Bacille
of detection have been developed. The BACTEC system can Calmette-Gurin (BCG) vaccination status. However, they
detect M. tuberculosis in approximately 2 weeks and is more cannot distinguish between latent infection and active TB
sensitive in recovery of mycobacteria than the conventional disease. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay
LowensteinJensen medium and smear microscopy. is an enzyme-linked immunosorbent assay (ELISA) based
Examination of an acid fast stained smear of ascitic fluid test, while T-SPOT is an enzyme-linked immunosorbent spot
has a disappointingly low yield of 06% and the frequency assay (ELISPOT). The reported sensitivity and specificity of
of a positive ascites culture is less than 20%. Demonstration ELISPOT in the diagnosis of extrapulmonary TB is 94% and
of AFB is more common in tubercular abscess verses solid 88% respectively. The assay may be performed on peripheral
tuberculomas because AFB are abundant in liquefied blood or ascitic fluid.
caseous material. Endoscopic biopsies are culture positive in
40% cases. Polymerase chain reaction assays, which amplify
mycobacterial 16S ribosomal RNA, show promise of rapid Plain X-ray
detection of mycobacteria and are highly sensitive. X-ray of the chest is done to rule out any concomitant
pulmonary TB or any evidence of past infection. Active
pulmonary disease is present in less than one-fifth of patients.
Histopathology A normal chest radiograph does not rule out the diagnosis of
Endoscopic biopsies have low yield for granulomas as the abdominal TB. Plain X-ray of the abdomen may show features
disease is mainly submucosal (Figs 1, 6 and 7). Granulomas of obstruction, perforation or intussusception and evidence
may be seen in 848% of the cases and with caseation in about of ascites. In addition, there may be calcified lymph nodes,
one-third of positive cases. Percutaneous image-guided fine calcified granulomas and hepatosplenomegaly.
needle aspiration (FNA) of suspicious peritoneal, omental
or nodal lesions might suggest the diagnosis of TB, thereby
obviating the need for a diagnostic laparoscopy or explorative
Barium Studies
laparotomy. In case of pancreatic lesion, FNA may be obtained Barium studies are not diagnostic as similar lesions may
by computed tomography (CT) or ultrasound guidance be found in other diseases especially inflammatory bowel
or during endosonography. The success rate of image- disease. Small bowel studies may show features like
guided percutaneous fine needle aspiration for cytology in accelerated intestinal transit, hypersegmentation of the
Abdominal Tuberculosis 73

is seen in healing lesions. Both caseation and calcification


are highly suggestive of a tubercular etiology. Ascites may
be detected. Interloop ascites appears as localized fluid
between radially oriented bowel loops due to local exudation
from the inflamed bowel (the club-sandwich or sliced-bread
sign). The intestinal loops may be dilated or matted. Bowel
wall thickening is best appreciated in the ileocecal region
and is uniform and concentric as opposed to the eccentric
thickening at the mesenteric border found in Crohns disease
and the variegated appearance of malignancy.
A tuberculoma in the liver may be seen as a hypoechoic
lesion without a distinct wall resulting from the conglomeration
of numerous small tubercles or as a low density lesion with
a hyperechoic rim relating to a tuberculous abscess. In both
cases, calcification may be observed.

Fig. 8: Conical cecum, shrunken in size and pulled out of the iliac Computed Tomography
fossa Scan of Abdomen
Computed tomography (CT) scan and CT enteroclysis are
barium column, precipitation, flocculation and dilution of important investigational tools for abdominal TB. Bowel
barium, stiffened and thickened folds, luminal stenosis with wall thickening, adherent loops, mesenteric thickening and
smooth but stiff contours (hour-glass stenosis). Multiple lymphadenopathy are picked up by the scan (Figs 9 and 10).
strictures with segmental dilatation of bowel loops may also Caseating lymph nodes are seen as having hypodense centers
be found as well as fixity and matting of bowel loops. and peripheral rim enhancement. This is in contrast to non-

Early involvement of the ileocecal region on barium Hodgkin lymphoma where homogeneously enhanced lymph
enema manifests as spasm and edema of the ileocecal valve. nodes are seen in the body and root of small bowel mesentery.
There may be thickening of the lips of the ileocecal valve Mesenteric involvement of TB is seen on CT scan as a patchy
or wide gaping of the valve with narrowing of the terminal or diffuse increase in density, strands within the mesentery
ileum. Terminal ileal TB may present with thickening of folds, and a stellate appearance. CT scan can also pick up ulceration
contour irregularity and focal or diffuse aphthous ulcers, or nodularity within the terminal ileum or circumferential
which tend to be linear or stellate, following the orientation wall thickening, narrowing of the lumen and ulceration.
of lymphoid follicles (longitudinal in the terminal ileum). Complications of the disease like perforation, abscess, and
Cecal involvement may end up in conical cecum, shrunken obstruction may also be seen.
in size and pulled out of the iliac fossa due to contraction
and fibrosis of the mesocolon (Fig. 8). Terminal ileum may
become dilated in such cases. When acute inflammation
is superimposed on a chronically involved segment, there
is lack of barium retention in the inflamed segments of the
ileum, cecum and a variable length of the ascending colon.
Persistent narrowing of terminal ileum indicates stenosis.
Crohns disease is an important differential in the setting of
above findings.

Sonography
Findings in patients with abdominal TB include an echogenic
thickened mesentery (15 mm) or omentum. Mesenteric
lymphadenopathy may be discrete or matted with mixed
echotexture. Small discrete anechoic areas representing Fig. 9: Marked thickening of small bowel wall in patient with
zones of caseation may be seen within the nodes. Calcification tuberculosis (D/D lymphoma)
74 Textbook of Hepato-gastroenterology

while colonoscopy is an excellent tool to diagnose colonic


and terminal ileal involvement. Colonoscopic findings of
ileocecal TB include ulcers, strictures, nodules, pseudopolyps,
fibrous bands, fistulae and deformed ileocecal valves (Figs
11 and 12). Tuberculous ulcers in colon are circumferential
or transversely located and are usually surrounded by
inflamed mucosa or nodules; while in Crohns disease, there
are aphthous ulcers with normal surrounding mucosa or
longitudinal or serpiginous ulcers and cobblestoning. The
ileocecal valve may be patulous with surrounding heaped

Fig. 10: Extensive omental caking and thickening adjacent to anterior


abdominal wall (D/D malignancy)

Computed tomography findings of hepatic TB may


reveal hypodense mass with or without a hyperdense rim
after enhancement study or a multiseptate liver abscess.
Sometimes, a lesion may have heterogenous density with
central necrosis or central calcification. In cases of pancreatic
involvement, contrast enhanced CT scans may demonstrate a
focal hypodense mass or diffuse enlargement of the pancreas.
Ring enhancement or low-density areas within enlarged
peripancreatic lymph nodes should make one suspect
tuberculous lymph nodes.
Fig. 11: Involvement of ileocecal valve in a patient with tuberculosis

Laparoscopy
Blind peritoneal biopsies have a low success rate in cases of
tuberculous peritonitis. The biopsies from peritoneum, liver
and lymph glands taken under direct vision by laparoscopy
or minilaparotomy have a high diagnostic yield. Laparoscopic
findings consist of multiple yellowish white 45 mm
peritoneal tubercles or scattered erythematous patches (Fig.
3). Thickening of peritoneum with thick adhesions may be
seen in fibroadhesive variety. Histology of peritoneal biopsy
specimens shows granulomas with caseation in majority of
patients, with or without presence of AFB.

Endoscopy
Upper gastrointestinal endoscopy is used to detect
esophageal, stomach, and duodenal TB. Capsule endoscopy Fig. 12: Colonoscopy showing circumferential cecal involvement in
and enteroscopy are used to visualize the small intestine, tuberculosis
Abdominal Tuberculosis 75

up folds or destroyed with fish-mouth opening. Looking into rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA)
terminal ileum, there may be thickening of folds, contour given for 2 months followed by INH and RIF. Ethambutol is
irregularity and focal or diffuse ulcers, which tend to be linear continued in cases of recurrent disease, drug resistance or
or stellate. Endoscopic biopsy is often diagnostic. Multiple serious illness. The utility of corticosteroid for the first 23
biopsies should be taken from the edge of the ulcers. Deep months to decrease fibrosis associated with healing lesions
endoscopic biopsies should be taken from the ulcer margins has not been proven, and evidence-based guidelines do not
and bed since TB granulomas are often submucosal in recommend it. Nearly 80% of patients respond very well to
comparison to the mucosal location of Crohns disease chemotherapy. Supportive measures like good nutrition
granulomas. The material should be sent for histology and and multivitamins help correct deficiencies, which are often
culture and PCR for Mycobacterium. present. Concomitant administration of pyridoxine (vitamin
B6) reduces the chances of INH neurotoxicity.
Isoniazid, RIF, and PZA can cause hepatitis. In general,
Ascitic Fluid Analysis treatment of TB should be discontinued, if a patients
Ascitic fluid in TB is straw colored with protein greater than transaminase level exceeds three times the upper limit of
3 g/dL in more than 90% cases, serum ascites albumin normal when associated with symptoms, or five times the
gradient less than 1.1 g/dL and a total cell count of 1504,000/ upper limit of normal, if the patient is asymptomatic. The risk
L, consisting predominantly of lymphocytes (>70%). Serum is more in patients with pre-existing liver disease. However,
adenosine deaminase (ADA) level above 54 U/L, ascitic fluid because of the effectiveness of these drugs, these should
ADA level above 36 U/L and a ascitic fluid to serum ADA ratio be used if at all possible, even in such patients. If serum
greater than 0.985 may be suggestive of TB. However, the transaminases are elevated more than three times the upper
sensitivity is substantially lower in patients with cirrhosis. limit of normal before the initiation of treatment and the
abnormalities are not thought to be caused by TB, one option
is to treat with RIF, EMB and PZA for 9 months, avoiding
DIFFERENTIAL DIAGNOSIS INH. A second option is to treat with INH, RIF and EMB for 2
months followed by INH and RIF avoiding PZA. For patients
The differential diagnosis of TB includes Crohns disease, with severe liver disease, a regimen with only one hepatotoxic
non-Hodgkin lymphoma, ulcerative colitis, amebic colitis, agent, generally RIF plus EMB could be given for 12 months,
disseminated carcinoma, chronic liver disease, sarcoidoisis, preferably with another agent, such as a streptomycin or
peritoneal mesothelioma and appendicitis. Isolated fluoroquinolone (levofloxacin, moxifloxacin) for the first 2
lymphadenopathy may be easily confused with lymphomas months.
involving abdominal lymph nodes. The differential diagnosis The recommended surgical procedures today are
of ileocecal TB includes Crohns disease, colon cancer, and conservative, and a period of preoperative drug therapy is
less commonly, infection due to Yersinia enterocolitica controversial. Conservative therapy is advocated initially for
and Y. pseudotuberculosis, mucoceles, typhlitis, amebiasis, patients presenting with intestinal obstruction. Obstruction
actinomycosis, carcinoid, appendicular mass and lesions due may become exacerbated during antituberculous therapy
to nonsteroidal anti-inflammatory drugs. Hepatic epitheloid due to healing by cicatrization. Surgical procedures include
cell granuloma alone can occur in primary biliary cirrhosis, resection, anastomosis, adhesiolysis, omentectomy and
sarcoidosis, Crohns disease, chronic active hepatitis, drug stricturoplasty, primary repair of perforation, ileostomy
hypersensitivity, and extrahepatic biliary obstruction. and exteriorization of gut. Right quarter colectomy and
anastomosis (limited ileocecal resection) is the most
common surgical procedure done. Diseased segments of
MANAGEMENT bowel with adequate free margins are removed, avoiding
extensive resection. Extensive adhesiolysis should be avoided
If the clinical, radiographic, and endoscopic data are in patients with advanced plastered intestine as it may end
consistent with the diagnosis of abdominal TB and are up with fistulae formation. If ascites is present, it is evacuated
adequate to rule out other common diseases, e.g. cancer, and the abdomen is closed without leaving drains. In all
nonspecific inflammatory bowel disease, and other cases, histopathological examination of resected specimen
specific infections, it is considered appropriate to give or mesenteric lymph nodes should be performed. Recurrent
a trial of antitubercular chemotherapy. Management is fistula in ano and abscesses are common in tropical countries
with conventional antitubercular therapy for 69 months. and respond to antitubercular treatment. Colonoscopic
Antitubercular therapy regimen includes isoniazid (INH), balloon dilation can be used to manage readily accessible,
76 Textbook of Hepato-gastroenterology

short and fibrous tuberculous ileal strictures causing subacute 2. Malik AM, Shah M, Pathan R, et al. Pattern of acute intestinal
obstructive symptoms and may obviate the need for surgery. obstruction: is there a change in the underlying etiology? Saudi
J Gastroenterol. 2010;16(4):272-4.
3. Chong VH, Lim KS. Hepatobiliary tuberculosis. Singapore Med J.
2010;51(9):744-51.
SUMMARY 4. Desai CS, Josh AG, Abraham P, et al. Hepatic tuberculosis in
absence of disseminated abdominal tuberculosis. Ann Hepatol.
Abdominal TB can involve any part of the gastrointestinal
2006;5(1):41-3
tract, the peritoneum, mesenteric lymph nodes, and the 5. Dong P, Wang B, Sun QY, Cui H. Tuberculosis versus non-
solid viscera including liver and pancreatobiliary system. The Hodgkins lymphomas involving small bowel mesentery:
affinity of M. tuberculosis for ileocecal region may be due to evaluation with contrast-enhanced computed tomography.
its relative stasis and abundant lymphoid tissue. Tuberculous World J Gastroenterol. 2008;14(24):3914-8.
granulomas tend to be large and confluent often with 6. Jakubowski A, Elwood RK, Enarson DA. Clinical features of
caseation necrosis. The intestinal lesions may be ulcerative, abdominal tuberculosis. J Infect Dis. 1988;158(4):687-92.
hypertrophic and ulcerohypertrophic. Peritoneal involvement 7. Khan IA, Khattak IU, Asif S, et al. Abdominal tuberculosis an
may be ascitic type, adhesive (plastic) type or encysted experience at Ayub Teaching Hospital Abbottabad. J Ayub Med
(loculated) type. Mesenteric lymph nodes in TB get enlarged Coll Abbottabad. 2008;20(4):115-8.
8. Lai CC, Lee TC, Hsiao CH, et al. Differential diagnosis of
and matted, and may caseate. Liver may get involved in miliary
Crohns disease and intestinal tuberculous by enzyme-linked
TB or there may be isolated granulomatous liver disease.
immunospot assay for interferon-gamma. Am J Gastroenterol.
Focal tuberculomas or abscesses in liver may also occur. 2009;104(8):2121-2.
Patients with abdominal TB present with fever, abdominal 9. Makharia GK, Srivastava S, Das P, et al. Clinical, endoscopic,
pain, vomiting, weight loss, night sweats, and diarrhea alone and histological differentiations between Crohns disease and
or alternating with constipation, abdominal distension intestinal tuberculosis. Am J Gastroenterol. 2010;105(3):642-51.
and mass in the right lower abdomen. These patients may Epub 2010 Jan 19.
also present with one of the complications like intestinal 10. Manohar A, Simjee AE, Haffejee AA, et al. Symptoms and
investigative findings in 145 patients with tuberculous peritonitis
obstruction, perforation or malabsorption especially in the
diagnosed by peritoneoscopy and biopsy over a five year period.
presence of strictures. Diagnosis of abdominal TB is based
Gut. 1990;31(10):1130-2.
on history, physical examination and investigations, which 11. Muneef MA, Memish Z, Mahmoud SA, et al. Tuberculosis in the
include routine tests, endoscopies, barium studies, CT scan belly: a review of forty-six cases involving the gastrointestinal
and biopsy results. Interferon-gamma release assays would tract and peritoneum. Scand J Gastroenterol. 2001;36(5):528-32.
take the place of tuberculin skin tests to rule out exposure 12. Purl AS, Nayyar AK, Vij JC. Hepatic tuberculosis. Ind J Tub.
to TB. The treatment for abdominal TB is often instituted on 1994;41:131-4.
the basis of a high index of clinical suspicion and ancillary 13. Safarpor F, Aghajanzade M, Kohsari MR, et al. Role of laparoscopy
supportive evidences without actually recovering the bacilli. in the diagnosis of abdominal tuberculosis. Saudi J Gastroenterol.
Management is with conventional antitubercular therapy for 2007;13(3):133-5.
69 months. There is no role for steroids. 14. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J Med Res.
2004 Oct;120(4):305-15.
15. Centers for Disease Control and Prevention. (2010). Updated
guidelines for using interferon gamma release assays to detect
BIBLIOGRAPHY Mycobacterium tuberculosis infectionUnited States, 2010.
1. Afzal S, Qayum I, Ahmad I, et al. Clinical diagnostic criteria for Morbidity and Mortality Weekly Report. [online]. Available from
suspected ileocaecal tuberculosis. J Ayub Med Coll Abbottabad. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm
2006;18(4):42-6. [Accessed January, 2013].
9
cHAPTER

Inflammatory Bowel Disease

Vikas Singla, Govind K Makharia

INTRODUCTION countries suggest that the incidence and prevalence rates


of IBD in AsiaPacific region are low compared with Europe
Inflammatory bowel disease (IBD) is a group of idiopathic, and North America. They are however, increasing rapidly.
chronic, inflammatory diseases of intestine, and they occur In the AsiaPacific region, where the prevalence of IBD is
because of interaction between genetic, environmental, and generally low; the incidence and prevalence of UC is more
immunological factors. IBD consists of two main categories common than CD in most Asian countries. The prevalence
of the diseases, namely ulcerative colitis (UC) and Crohns rates of UC in Asian countries range from 630 per 1,00,000
disease (CD). In UC, the disease is limited to the colon, and the population, which is lower compared to 37.5229 and 21.4
involvement is generally limited to mucosa and submucosa. 243 per 1,00,000 population in North America, and Europe,
Whereas any part of the gastrointestinal (GI) tract from respectively. Similarly, the incidence of UC in Asian countries
mouth to anus can be involved in CD and the inflammation ranges from 0.42.1 per 1,00,000 population, which is lower
in the intestine may be transmural. While the involvement than that in incidence rates of 615.6 and 1020.3 per 1,00,000
of the colon is symmetrical and continuous in patients with in North America and Europe, respectively.
UC, skip lesions and discontinuous lesions are characteristic While IBD in the west is characteristically associated
of CD (Table 1). About 10% of patients while have features of with a bimodal age distribution pattern with a peak at the
IBD; they however, cannot be categorized either into UC or ages of 2039 and a second smaller peak at the age of 6079
CD. They are called IBD unclassified. In their natural course years; such bimodal distribution of age has however not
of evolution, IBD unclassified may ultimately evolve into been consistently observed in Asian studies. The onset of
either UC or CD. the disease may be delayed, and some patient might present
at age more than 60 years also. In the European and North
American studies, the distribution of UC is equal in both
EPIDEMIOLOGY men and women at all ages or in some studies there tends
to be a slight male preponderance while studies of CD have
Inflammatory bowel disease is a disorder of modern society,
consistently revealed a greater incidence in women than in
and its frequency in developed countries has been increasing
men. A male predominance has been reported in patients
since the mid-20th century. In countries where the overall
with UC from a few Asian studies.
IBD prevalence is low, UC appears to be more common than
CD. In countries where the prevalence of IBD is high, CD
tends to be the dominant subtype. Generally, it is thought
that in high-prevalence areas, the incidence of both diseases PATHOGENESIS
may have stabilized but in low-prevalence areas, an initial
increase in UC incidence is followed by an increase in CD Inflammatory bowel disease is a result of complex interplay
incidence years later. of genetic, environment, and immune factors. IBD represents
The AsiaPacific region has been marked as an area with a a state of excessive immune response, which may be targeted
low incidence of IBD, although confusion exists as to whether against an innocuous or pathogenic microorganism. Studies
this low incidence is a result of low diagnostic awareness, a on animal models of IBD suggest that in genetically susceptible
high incidence of infective diarrhea and its diagnostic overlap host, commensal bacteria can induce an inappropriate state
or a true low incidence. As epidemiological studies from Asian of inflammation akin to IBD.
78 Textbook of Hepato-gastroenterology

Table 1: Differences between ulcerative colitis and Crohns disease

Features Ulcerative colitis Crohns disease


Clinical
Bloody diarrhea Almost always 50%
Abdominal pain Less severe Very common, more severe
Intestinal obstruction Very uncommon Common
Perianal disease None 2030%
Fever Occasional More common
Growth retardation in children Less marked More marked
Nutritional deficiency Less common More common
Site of the disease
Colon Always In two-thirds
Terminal Ileum 510% In two-thirds
Small intestine Never In two-thirds
Upper gastrointestinal tract Never Occasional
Rectum involvement Almost always In 50% patients
Endoscopic/radiological features
Involvement Diffuse, continuous Skip lesions, discontinuous
Type of ulcer Superficial Deep
Longitudinal ulcer Never Characteristic, present in 30%
Aphthous ulcers
Cobblestoning lesions Never Characteristic, present in 30%
Stricture None Yes
Fistula Never Yes
Pathological features
Type of involvement Mucosa and submucosa Transmural
Granuloma None/rare Noncaseating granuloma
Fibrosis None Yes
Mesenteric thickening None Yes
Fibrofatty proliferation None Yes

Genetic Factors inheritance patterns are not seen in them, and IBD cannot be
credited to a single gene locus. Furthermore, the genetic risk
Variability of prevalence of IBD amongst various ethnic ratio is higher for CD compared to that with UC. Twin studies
groups, and the increased risk amongst the family members are important way to determine a genetic contribution
of patients with IBD suggest an important role of genetic for a disease. If a disease is entirely due to genetics, the
factor in the pathogenesis of IBD. While IBD is more common concordance rates in monozygotic/identical twins will be
in Jewish population and whites; Africans and Asians have higher (and should be approaching 100%) than dizygotic/
low prevalence of IBD. The prevalence of IBD is higher in nonidentical twins (which should be approaching 50%). If
family members of IBD. The risk of IBD increases 213-folds the disease is dependent only on environmental or acquired
in offspring of patients with IBD as compared with the general factors, the concordance rates will be similar among both
population. This predisposition in the offsprings can be types of twins. The concordance rate of CD in monozygotic
attributed to either the shared environment or genetic factors. twins is 2050% and less than 10% in dizygotic twins,
Numerous studies have demonstrated that genetics plays a emphasizing a definite genetic component. The concordance
role in the manifestation of IBD. However, classic Mendelian rates for UC in monozygotic twins is 16% and for dizygotic
Inflammatory Bowel Disease 79

twins is 4%. Recently, genome-wide association studies have Environmental Factors


provided information regarding various genetic loci and
the overall disease pathogenesis. Analyses of these genes Clinical and experimental observations suggest involvement
and genetic loci suggest important role for several pathways of intestinal bacterial microbiota in the pathogenesis of
which are crucial for intestinal homeostasis, including IBD. CD and UC preferentially involve the areas of intestine
barrier function, epithelial restitution, microbial defense, that contains the highest concentration of the bacteria, i.e.
innate immune regulation, reactive oxygen species (ROS) terminal ileum and colon. Diverting fecal stream in CD have
generation, autophagy, regulation of adaptive immunity, been found to help in healing of lesions of CD. In the animal
endoplasmic reticulum (ER) stress and metabolic pathways models for IBD, germ free mice do not develop inflammation,
associated with cellular homeostasis. Approximately 30% of but after bacterial introduction, intestinal inflammation
genetic loci are shared between UC and CD, indicating that rapidly develops. All these evidences, highlight the role of
these diseases may involve common pathways. Till date more bacterial flora in the development of IBD and the dynamic
than 90 nonoverlapping genetic risk loci, including 28 that are balance between microbes, particularly commensal flora,
shared between CD and UC. and host defensive responses at the mucosal frontier has a
Thus far, three pathways in pathogenesis of CD have been pivotal role in the initiation and maintenance of inflammation
highlighted by the genetic studies. The first susceptibility in chronic IBD.
locus for CD was identified in 2001 as (nucleotide-binding The defect in innate immunity or hyper-responsive
oligomerization domain 2 (NOD2) gene, also known as immune response against nonpathogenic bacteria may be
caspase recruitment domain 15 (CARD15). Missense responsible for the chronic low-grade inflammation. On
mutation and frame-shift mutation of NOD2/CARD15 gene the other hand, there may be alteration in gut flora in IBD,
are found to be associated with CD. Both heterozygosity and the loss of protective bacteria may lead to overgrowth
and homozygosity for this mutation are associated with the of pathogenic bacteria. The exact pathogenesis is still to be
increased risk for CDs. In patients with CD with associated defined, but more than one mechanism(s) may be acting in
mutated NOD2, there is decreased activation of NF-B in an individual patient.
mononuclear cells, and expression of NF-B is increased in Smoking is other environmental factor, which may be
inflamed tissues. Moreover, the production of defensin by contributing to the etiology of IBD. UC is more common
the paneth cells is defective in these patients. About 2030% among nonsmokers. After cessation of smoking, within first
of Caucasian patients with CD harbor abnormal variants of two years, risk of developing UC is higher. On the other hand,
NOD2/CARD15. Surprisingly, NOD2/CARD15 gene mutation CD is more common in current smokers. CD is more common
is not seen in CD in the Japanese, Korean, Chinese and Indian in higher socioeconomic group. Past appendectomy is
population. protective against UC.
Genome-wide association studies have suggested the role
of autophagy-related genes in pathogenesis of CD. Minor
Role of Mucosal Barrier and
allele of autophagy-related 16-like 1 (ATG16L1) is found to be
protective against CD. Rare variant of interleukin-23 (IL-23) Immune System
gene is strongly protective against CD, while more common The intestinal mucosa exists in a functional equilibrium with
variant are associated with increased risk for CD. Some the complex luminal bacterial flora. Loss of this functional
variants of IL-12B have also been found to be associated with equilibrium contributes to the pathophysiology of many GI
increased risk of CD. disorders, including IBD. In addition to nutrient absorption,
Similarly, certain genetic variations are found to be intestinal epithelial cells perform both barrier and signal-
associated with risk and protection against UC. Linkage transduction functions, with the capacity to sense luminal
studies have suggested the susceptibility genes on contents through surface receptors and, in return, secrete
chromosomes 1, 2, 3, 5, 6, 7, 10, 12, and 17. IBD2 locus on regulatory products that can coordinate an appropriate
chromosome 12 appears to have strong linkage with UC. response in the underlying lamina propria. Abnormal
Similarly, certain polymorphism of multidrug resistance gene intestinal permeability has been observed in IBD patients
1 (MDR1) gene, which codes for P-glycoprotein, a protein that and in some of their first-degree relatives.
serves an important barrier function, is associated with UC. Normal epithelium, with its highly evolved tight junctions
Similarly, certain alleles of IL-23R, IL-12 are associated with and products of goblet-cell populations, most notably trefoil
risk of UC. peptides and mucin glycoproteins, provides an effective
80 Textbook of Hepato-gastroenterology

barrier against luminal agents. The integrity of the barrier Table 2: Extent of the disease (ulcerative colitis) according to the
may be compromised by genetic variations in key molecular Montreal classification
determinants, a diminished reparative response to injury, or
E1 Proctitis
exogenous agents, such as nonsteroidal anti-inflammatory
E2 Left-sided extending up to splenic flexure
drugs (NSAIDs). Chronic, recurrent intestinal inflammation
appears to result from stimulation of the mucosal immune E3 More extensive disease
system by products of commensal bacteria in the lumen.
Antigens from dietary sources may also contribute.
in the setting of UC is due to several mechanisms, including
Stimulation may occur as a result of the penetration of
rectal irritability, failure to absorption of salt and water,
bacterial products through the mucosal barrier, leading
increase in mucosal permeability, and increased colonic
to their direct interaction with immune cells, especially
motility. A few patients, especially those with proctitis, may
dendritic cells and lymphocyte populations, to promote a
complain of constipation.
classic adaptive immune response. Alternatively, bacterial
Abdominal pain in patients with UC occurs generally
products may stimulate the surface epithelium, possibly
during the active phase of the disease. Abdominal pain in
through receptors that are components of the innate immune
them is usually localized to infraumbilical region and left
response. The epithelium can, in turn, produce cytokines
iliac fossa. Persistent pain and worsening in the severity of
and chemokines that recruit and activate mucosal immune
pain in a patient with active UC should suggest an impending
cells. Activation of classic antigen-presenting cells, such
complication, such as toxic megacolon or perforation.
as dendritic cells, or direct stimulation through pattern-
Anemia and pedal edema are seen in patients with severe and
recognition receptors promotes the differentiation of type 1
continuous disease and are due to blood and albumin loss
helper T cells (Th1) in patients with CD type 2 helper T cells in
through the inflamed colon. Patient with UC may lose weight
patients with UC. The stereotypical products of Th1 promote
because of a catabolic state during active phase of the disease
a self-sustaining cycle of activation with macrophages. In
and poor nutritional intake.
addition to producing the key cytokines that stimulate Th1
Physical signs depend upon the severity of the disease.
(IL-12, IL-18, and macrophage migration inhibitor factor),
macrophages produce a mix of inflammatory cytokines, Patients with severe disease can have tachycardia, fever,
including IL-1, IL-6, and most notably tumor necrosis factor anemia, signs of weight loss and malnutrition. Abdomen may
(TNF), which target a broad variety of other types of cells. The be tender in these patients, and the bowel sounds are usually
latter includes endothelial cells, which then facilitates the normal or increased. Patients with severe disease should be
recruitment of leukocytes to the mucosa from the vascular observed for peritoneal signs, which may suggest onset of
space, as well as fibroblasts and epithelium, modulating their perforation and toxic megacolon. Patients with mild clinical
functional properties. As discussed above, these functions disease, may appear normal, exhibiting few clinical signs.
may be altered either by genetically determined variants, such
as NOD2, the product of the IBD1 locus, or by environmental
factors.
Crohns Disease
Symptoms of CD are more heterogeneous, and depend upon
the location and the behavior of the disease. Characteristically,
CLINICAL MANIFESTATIONS (TABLE 1) any part of GI tract can be involved in patients with CD and
there may be multifocal involvement of the intestine. The
Ulcerative Colitis location of the disease is classified as terminal ileal disease,
The extent of the disease is classified according to Montreal isolated colonic disease, ileocolonic disease and upper
classification (Table 2). The cardinal symptoms of UC are GI tract disease. The behavior of the CD is of three types:
bloody diarrhea, urgency, tenesmus, passage of mucus, inflammatory, stricturing and penetrating (fistulizing).
and lower abdominal pain. Almost 95% of patients present (Table 3) The symptoms secondary to inflammatory nature
with episodes of bloody diarrhea. Most patients at the time of the disease include diarrhea and bleeding. The stricturing
of presentation recall presence of these symptoms in the disease will present predominantly with intestinal colic and
past; though few patients can present with acute onset of intestinal obstructive features (bloating, heaviness, gurgling,
severe bloody diarrhea. Urgency and tenesmus (feeling of feeling of movement of ball of wind and/or obstipation).
incomplete evacuation) are due to rectal inflammation and Penetrating disease will present with fistula formation such
loss of rectal capacitance, which leads to desire for defecation, as internal fistula (jejunoileal, jejunocolonic, colocolic) or
even with the small amount of stool in the rectum. Diarrhea perianal fistula. Any or a combination of the three kinds of
Inflammatory Bowel Disease 81

Table 3: Phenotype of Crohns disease according to the Montreal loops of the intestine through inflamed serosa. Uncontrolled
classification inflammation in such situation can lead to microperforation
and fistula formation between two adjacent intestinal loops.
Age of onset Location Behavior
Depending upon location of such severe inflammation,
L1: <16 years L1: Terminal ileal disease B1: Non-tricturing, the intestinal loops may communicate with the skin
nonpenetrating
(enterocutaneous fistula), the urinary bladder (enterovesical
L2: 1740 years L2: Colonic B2: Stricturing fistula), and genitalia (rectovaginal fistula) or to an abscess
L3: >40 years L3: Ileocolonic B3: Penetrating cavity in the mesentery. Enterocutaneous fistulas follow
L4: Isolated upper
tissue planes of least resistance, usually draining through
gastrointestinal involvement abdominal surgical scars. Enterovesical fistulas typically
present as dysuria or recurrent bladder infections or less
Note: Disease modifiers: perianal disease, p if perianal disease
commonly as pneumaturia or fecaluria. Enterovaginal fistulas
are rare and present as dyspareunia or as a feculent or foul-
smelling, often painful vaginal discharge.
symptoms can be present in a given patient with CD. Systemic Approximately 20% of all patients with CD develop
symptoms, such as malaise, anorexia, weight loss, and fever symptoms during childhood, and 5% are diagnosed before
are more common in patients with CD. 10 years of age. Typical complications of CD in the pediatric
The ileocolonic disease and terminal ileal disease are the population include delayed puberty, linear growth failure and
most common types of disease in CD. These patients present osteopenia. Active or relapsing disease may slow or even arrest
with recurrent episodes of right lower quadrant pain and the progression of puberty once it has begun. Unlike with
diarrhea. Sometimes the initial presentation mimics acute healthy children, delayed or shortened puberty in children
appendicitis with pronounced right lower quadrant pain, a with CD may result in permanent growth impairment. Thus,
palpable mass, fever, and leukocytosis. Intestinal obstruction inducing disease remission before the onset of puberty
may take several forms. In the early stages of disease, bowel and maintenance of remission during the pubertal years
wall edema and spasm produce intermittent obstructive is crucial. This is required to prevent or even minimize the
manifestations and increasing symptoms of postprandial pain. consequences of a missed pubertal growth spurt, abnormal
Over several months and years, persistent and progressive bone mineralization, and the maintenance of prepubertal
inflammation gradually produces fibro-stenotic narrowing levels of sex hormones. Osteopenia is another important
in the intestine. Acute episodes of intestinal obstruction can potential complication of pediatric IBD because more than
occur as well, precipitated by bowel inflammation and spasm 90% of peak bone mass is attained during childhood and
or sometimes by impaction of undigested food or medication. adolescence. A failure to attain peak bone mass during this
Extensive inflammatory disease involving small intestine stage in development increases future fracture potential.
can lead to loss of surface area for absorption and thus leads to
malabsorption. There could be loss of protein (both albumin
and globulin) from the ulcerated area, a condition called EXTRAINTESTINAL MANIFESTATIONS
protein losing enteropathy. Nutritional deficiencies can also
result from poor intake and enteric losses of protein and other About 1550% of patients with IBD can have extraintestinal
nutrients. Intestinal malabsorption along with protein losing manifestations. Some of these symptoms can be quiet
enteropathy can lead to malnutrition, hypoalbuminemia, distressing. The extraintestinal manifestations of IBD are
hypocalcemia, and hyperoxaluria with nephrolithiasis. described in Table 4.
Vertebral fractures are caused by a combination of vitamin D
deficiency, hypocalcemia, and prolonged glucocorticoid use.
Diarrhea in patients with CD is multifactorial, including DIAGNOSTIC CRITERIA
colonic inflammation, malabsorption, bacterial overgrowth
in obstructive segment, internal fistulization (jejunoileal, There is no single gold standard test for the diagnosis of
jejunocolonic, colocolic) bile-acid malabsorption due to either UC or CD. The diagnosis of both UC and CD is based
diseased or resected terminal ileum. on a combination of clinical, endoscopic, histological, and
Severe and transmural nature of inflammation in a few radiological features. An infectious cause of the colonic
patients with CD can lead to adhesions between adjacent inflammation should be ruled out.
82 Textbook of Hepato-gastroenterology

Table 4: Extraintestinal manifestation of inflammatory bowel disease should prompt a thought toward a possibility of associated
primary sclerosing cholangitis and osteomalacia.
Joints Peripheral arthritis
Fecal calprotectin may be used to differentiate IBD from
Ankylosing spondylitis functional diarrhea. Microbiological testing for Clostridium
Sacroiliitis difficile toxin should be done during acute exacerbation.
Skin, mucous membrane Erythema nodosum Reactivation of cytomegalovirus (CMV) is common in patients
Pyoderma gangrenosum with IBD on immunosuppression, therefore a possibility of
Aphthous ulcers
CMV infection should be considered and excluded specially
in those patients with IBD who respond poorly to steroid.
Hepatobiliary Fatty liver
Antineutrophil cytoplasmic antibody (ANCA) and
Pericholangitis anti-Saccharomyces cerevisiae antibody (ASCA) are useful
Primary sclerosing cholangitis adjunctive tests to distinguish between UC and CD in
Gallstones patients with known IBD. ANCA is associated with UC and
Autoimmune hepatitis ASCA is associated with CD. There is insufficient information
Cholangiocarcinoma
at present to recommend the use of these serologic tests to
screen patients with undiagnosed GI symptoms for IBD in
Ocular Conjunctivitis
general population. Patients with undifferentiated colitis who
Episcleritis is ANCA-negative and ASCA-positive is likely to progress to
Uveitis CD, whereas those with ANCA-positive and ASCA-negative
Hematological Agranulocytosis are likely to develop UC.
Hemolytic anemia
Renal Oxalate stone
Amyloidosis INVESTIGATIONS FOR THE DIAGNOSIS
AND EXTENT OF THE DISEASE
The best investigation for diagnosis and evaluation of the
extent of UC is colonoscopy. Through colonoscope, one
EVALUATION OF PATIENTS can examine the nature of the lesion, activity of the lesion
and extent of the disease. Colonoscopy should be avoided
A detailed history should be taken from each patient, including or carefully performed by experienced endoscopist, during
duration of symptoms, severity of symptoms, remissions and episode of acute severe disease, because of high risk of
relapses, and medication history (including antibiotics and perforation. Changes of UC are typically seen in the rectum,
NSAIDs). Particular attention should be paid to factors, which and progress proximally in a symmetrical and circumferential
can have bearing on IBD, such as established risk factors pattern to the variable extent. Endoscopic findings of UC
including smoking, family history, previous appendicectomy vary from edema, loss of vascularity, granularity, friability
and recent episodes of infectious gastroenteritis. A complete of the mucosa, spontaneous bleeding and ulcerations.
physical examination, including perineal and perianal Depending upon the mucosal appearance, the severity of UC
examination should be done. can be classified as mild (loss of vascular pattern, erythema,
Laboratory investigations should include full blood count, granularity, mild friability), moderate (erosions and moderate
liver function tests and erythrocyte sedimentation rate or and friability) and severe (ulcerations and spontaneous bleeding)
C-reactive protein. Patients with active disease, particularly (Figs 1A to F). For the diagnosis of UC, even a sigmoidoscopic
pancolitis, usually have anemia, which is microcytic and examination is sufficient; however, every patient with IBD
hypochromic. Anemia can also be due to bone marrow should have a complete evaluation of the whole colon in
suppression secondary to anemia of chronic disease or order to know the extent of the disease and for differentiation
medications including antimetabolites. Leukocytosis and from CD.
thrombocytosis suggest presence of active disease. Active Colonoscopy helps to differentiate UC from CD, which
disease is also associated with raised levels of markers of is typically characterized by rectal sparing, aphthous
inflammation, such as C-reactive protein, and erythrocyte ulcers, skip lesions (areas of inflammation alternating with
sedimentation rate. These markers do not have diagnostic normal mucosa), a cobblestone pattern, and longitudinal,
value, but can be useful for the assessing the activity of the irregular ulcers (Figs 1A to F). In patients with repeated
disease. A persistently raised serum alkaline phosphatase cycles of inflammation and healing and in those with
Inflammatory Bowel Disease 83

lesions are generally superficial in UC and deep in CD (Table


1). Transmural nature of CD leads to intestinal fibrostenotic
lesions, while fibrostenotic lesions do not occur in those with
UC. The histological characteristic, especially the density
of inflammatory cells, differ during the active phase of the
disease and during the phase of remission. Typical histological
A B C
features of UC include basal plasmacytosis (presence of plasma
cells around or beneath the level of the crypts), a diffuse and
transmucosal increase in chronic inflammatory infiltrates
in the lamina propria and crypt architectural abnormalities
(branching, irregularity in crypt size, shape, orientation and
spacing, and decreased crypt density). Neutrophils are not
D E F normally present in normal colonic mucosa. The presence
Figs 1A to F: (A) Colonoscopy pictures showing a normal colonic and infiltration of neutrophils into the lamina propria, crypt
mucosa with normal vascular pattern in a normal individual. In epithelium (cryptitis) and crypt lumen (crypt abscesses) are
patients with ulcerative colitis, (B) there is a loss of vascular pattern the signs of the active disease. Features of acute colitis (such
and erythema, and (C) superficial ulcers. (D) In Crohns disease, as cryptitis or crypt abscesses also present in infectious colitis
patients can have discrete ulcers. (E) Longitudinal and deep ulcers and other colitides and is not pathognomonic of UC (Figs 2A
and (F) cobblestoning of mucosa although seen in one third of to D). The severity of inflammation on histologic examination
patients with Crohns disease, but they are characteristic lesions of and the severity of disease on endoscopic examination may
Crohns disease not always coincide; for instance, histologic findings may
indicate severe disease even in a patient having mild disease
and vice versa. The biopsies should be evaluated for epithelial
chronic, unremitting inflammation, colonoscopy may reveal dysplasia and colonic mitosis especially if the duration of UC
pseudopolyps or mucosal bridging (Table 1). is longer.
Radiology has the limited role in the management of
patients with UC; however, it is quiet useful in knowing the
extent of the involvement in patients with CD (discussed
below). Abdominal plain X-ray should be done in patients
with acute severe colitis to rule out toxic megacolon or
intestinal perforation. The use of barium enema in the
diagnosis of IBD has generally declined; it however has a role
in certain situations. In patients with colonic narrowing due
to stricture or malignancy, where proximal examination may
be difficult, barium enema may provide essential information
regarding the length, location and diameter of the stricture. A B
Moreover, involvement of mucosa proximal to the stricture
can also be evaluated. Earliest sign of UC on barium enema
is fine mucosal granularity. With increasing severity, mucosal
lining become thickened and irregular and superficial and
deep ulcers can appear. The colonic haustral folds may be lost
in long standing disease, but may be normal or thickened in
C D
patients with shorter duration of the disease.
Figs 2A to D: (A) Photomicrographs of histology of the colon from
a patient with ulcerative colitis showing crypt disarray and an
Histologic Evaluation inflammatory infiltrate predominately restricted above muscularis
mucosae (H&E X100) and (B) loss of crypts and crypt branching
Adequate biopsies from different regions of the colon
(arrow) are seen, along with dense mixed inflammatory infiltrate at
(including rectum) and distal ileum should be obtained
lamina propria (H&E X100). (C) Biopsies from patient with ulcerative
for a reliable diagnosis of IBD. In UC, the inflammation is colitis show crypt abscess (arrow) with dense mixed inflammatory
characteristically restricted to the mucosa and submucosa infiltrate in lamina propria (H&E X100). (D) A biopsy from a case of
of the colon; while in CD, the inflammation may involve all Crohns disease shows pericryptal non-necrotizing microgranuloma
the four layers (transmural) of the intestine. Therefore, the (arrow) (H&E X40)
84 Textbook of Hepato-gastroenterology

The earliest microscopic lesions in patients with CD are value and body weight. A CDAI score of 150 or less indicates
aphthoid ulcerations and focal crypt abscesses with loose remission, a score of greater than 150 and up to 220 indicates
aggregations of macrophages, which later form noncaseating mild disease activity, a score of greater than 220 and less
granulomas. Granulomas can be seen in lymph nodes, than 450 indicates moderate disease activity, and a score of
mesentery, peritoneum, liver and pancreas. Although CD 450 or greater indicates severe disease activity. The Harvey-
is a granulomatous disease, granulomas are seen in 2040% Bradshaw Index is a simplified version of a clinical disease
of endoscopic mucosal biopsies (Figs 2A to D). Therefore, it activity index often used in long-term open-label studies.
may consider a possibility of CD even if granulomas are not Endoscopic severity could be assessed using CD endoscopic
seen in the endoscopic mucosal biopsies. Surgical resections
reveal granulomas in about half of the patients with CD. Other
histologic features of CD include submucosal or subserosal Table 6: Ulcerative Colitis Disease Activity Index (UCDAI)
lymphoid aggregates, particularly away from areas of
ulcerations, gross and microscopic skip areas, and transmural Variables Frequency Scores
inflammation that is accompanied by fissures that penetrate No. of stools Normal 0
deeply into the bowel wall and sometimes form fistulous >12 than normal 1
tracts or local abscesses. >34 than normal 2
>4 than normal 3
Rectal bleeding No bleeding 0
ASSESSMENT OF THE ACTIVITY OF
Mild 1
THE DISEASE Moderate 2

The natural history of IBD is that of remission and relapses Severe 3


of the disease. The severity of IBD is generally assessed Mucosal friability No friability 0
using clinical parameters, systemic manifestations, mucosal Mild friability 1
appearance and global impact of the disease on the Moderate friability 2
individuals quality of life. The most commonly used clinical
Exudation and spontaneous bleeding 3
disease activity assessment criteria for UC are Truelove and
Physician global Normal 0
Witts criteria and Ulcerative Colitis Disease Activity Index
assessment
(Tables 5 and 6). For CD, although there are many indices Mild 1
for assessment of severity, such as Harvey-Bradshaw index, Moderate 2
van Hees or Dutch Index, St Marks Index; CD Activity Index Severe 3
(CDAI) has been used mostly especially in the clinical trial
Note: UCDAI score: Normal, <2; Mild, >2<4; Moderate, >4<8; Severe, >8
(Table 7). In the CDAI, eight independent variables, including
number of liquid stools, severity of abdominal pain, general
well-being, need for antidiarrheal drugs, presence of
Table 7: Crohns disease activity index (CDAI)
abdominal mass, extraintestinal manifestations, hematocrit
Item (day) Weight
No. liquid or very soft stools (each day for 7 days) 2
Table 5: Truelove and Witts criteria for of severity of ulcerative colitis Abdominal pain, sum of 7 days rating 5
(0 = none, 1 = mild, 2 = moderate, 3 = severe)
Variables Mild Severe Fulminant
General well-being (14) 7
Stools (Number/day) <4 >6 >10
Extraintestinal manifestations (1 per finding) 20
Blood in the stool Intermittent Frequent Continuous arthritis/arthralgia, mucocutaneous lesion, iritis/uveitis
Temperature (oC) Normal >37.5 >37.5 anal disease (fissure, fistula), external fistula

Pulse (per minute) Normal 90100 >100 Fever >36.8

Hemoglobin Normal <75% of normal Transfusion Antidiarrheal use 30


requirement Abdominal mass (none = 0, equivocal =2, definite = 5) 10
ESR (mm/hour) <30 >30 >30 Hematocrit (males, 47) (Females, 42) 6
Serum albumin (g/dL) Normal <3.0 <3.0 Body weight (1body weight/standard weight) 100 1
Note: Moderate disease includes features of both mild and severe disease Total CDAI score
Inflammatory Bowel Disease 85

index of severity (CDEIS), which includes lesions, such as basal lymphoid aggregates should point toward a possibility
pseudopolyps, healed ulcerations, erythema, mucosal edema, of UC. Yersinia infections can lead to small intestinal and
aphthoid ulcerations, superficial and deep ulcerations and colonic involvement and the clinical presentation may mimic
stenoses. The index is refined by incorporating the percentage with that of IBD. Stool culture and antibody titer should be
of involvement of all the endoscopic segments (ileum, done for differentiation. Pseudomembranous enterocolitis
ascending colon, transverse colon, descending and sigmoid should be suspected in patients, who had received antibiotics
colon, rectum). in recent time. Moreover, this infection can cause relapse
in the patients, who had otherwise silent UC. Sexually
transmitted disease, such as gonorrhea, Chlamydia and
ASSESSMENT FOR THE EXTENT OF lymphogranuloma venereum may cause proctitis, which may
resemble IBD. History of high-risk behavior, and copious pus
THE DISEASE discharge should raise the suspicion, and the appropriate
tests should be ordered.
The extent of the UC is limited to only rectum (proctitis) in
Intestinal tuberculosis is an important disease in Asian
1020%, rectum, left sided colitis in 3040%, and 3040% of
countries. The clinical, morphological and histological
patients have pancolitis or extensive colitis. In patients with
features of intestinal tuberculosis and CD are so similar that it
CD, about two-thirds of patients have involvement of both
becomes difficult to differentiate between these two entities.
small intestine and large intestine, and one-third each have
In geographical regions like Asia where both CD and intestinal
isolated either small or large intestinal involvement. About
tuberculosis are prevalent, differential diagnosis between
2030% of patients have perianal disease (hemorrhoids,
the two may be challenging. In Asia, intestinal tuberculosis
anal fissure, perianal abscess or perianal fistula). About
is common, but CD is also being increasingly reported from
510% patients have involvement of the upper GI tract all over Asia. Natural history of CD is quite different from
concomitantly. Unlike UC, which almost always involves the that of intestinal tuberculosis. While intestinal tuberculosis
rectum, the rectum is not involved in half of patients with CD. gets cured by appropriate antitubercular treatment, CD has
All patients should undergo evaluation for the extent of a remitting/relapsing or persistent course and usually stays
the disease. Large intestinal involvement can be assessed lifelong. Because of similarity in the clinical presentation and
using colonoscopy and retrograde ileoscopy. Small intestinal morphology of these two entities, at times such patients are
evaluation can be done using CT/MR enteroclysis, or capsule treated empirically with antituberculous drugs. The clinical,
endoscopy/double balloon enteroscopy depending upon endoscopic and histological features which can differentiate
individual centers expertise. Upper GI endoscopy, especially these two diseases are summarized in Table 8. From the Table
in pediatric patients, should also be done to complete the 8, it is obvious that almost all the features are seen in these two
evaluation. All patients with UC should have evaluation of the conditions and, in isolation, they are not diagnostic. However,
colon only; while patients with CD require evaluation of both with a use of combination of these features, one is able to
small and large intestine. make a diagnosis of either tuberculosis or CD in almost half
of patients. Wherever differentiation is not possible, one can
try a course of antituberculous treatment in such situation.
DIFFERENTIAL DIAGNOSIS One should re-evaluate patient not only for resolution of
symptoms but also for healing of the mucosal lesions using
Infections are important differential diagnosis in the ileocolonoscopy and/or enteroscopy. There are instances
first episode of IBD. Moreover, infections can complicate where patients are treated with antituberculous drugs time
underlying IBD, so infections should be ruled out in every and again for non-resolution of symptoms or reappearance
flare of IBD. The most common organisms causing infectious of symptoms, such a strategy is not good. One should revise
colitis, such as Entamoeba histolytica, Salmonella, Shigella the diagnosis and consider CD in such situations. It will be
and Escherichia coli present with short history of fever, pain appropriate to refer such patients at a higher center or to a
abdomen and bloody diarrhea. Initially most such patients gastroenterologist for complete evaluation.
are treated with IV antibiotics, nonresponse to the adequate Noninfectious disease mimicking IBD include diseases
antibiotics course should raise the clinical suspicion of UC, like colonic malignancies, colonic diverticulitis, radiation
and sigmoidoscopy should be done. Sigmoidoscopy picture colitis, diversion colitis, and ischemic colitis, microscopic
may be similar in two conditions; however, biopsy may resolve and drug induced colitis. Colonic malignancies especially
the issue. The presence of chronic inflammatory infiltrate, rectal malignancies may mimic the IBD, and a colonoscopic
architectural disturbance like crypt atrophy, crypt disarray, examination should sort out the issue.
86 Textbook of Hepato-gastroenterology

Table 8: Clinical, endoscopic and histological differentiation between year, one can predict that the disease may remain in the stage
intestinal tuberculosis and Crohns disease of remission in the coming year. There may be extension of
the involvement with time in some patients with UC. Overall,
Variables Intestinal Crohns disease
tuberculosis (%) (%) patients with UC have a normal life expectancy.
Symptoms
Chronic diarrhea 2040 6080 Crohns Disease
Blood in the stools 1020 5070
About 1320% of patients with CD have a chronic active
Abdominal pain 90 6080 course of disease activity, 6773% have a chronic intermittent
Constipation 50 1030 course and only 1013% remain in remission for several years.
Partial intestinal obstruction 5060 2030 After 20 years, most patients with CD will require surgery.
Perianal disease 5 3080 Although the anatomical location of CD remains fairly stable,
behavior of the disease varies substantially during its course.
Fever 4070 30
Almost 5060% of patients with CD develop stricture and or
Loss of appetite 4080 4060
fistula over 20 years follow-up. The life expectancy of patients
Weight loss 6090 5060 with CD is slightly reduced.
Extraintestinal manifestations 10 2050
Involvement of the intestine
Anal canal <5 1550 MANAGEMENT
Rectum 1020 4060
Sigmoid colon 510 1050 Drugs Used in
Descending colon 510 1050 Inflammatory Bowel Disease
Ascending colon 4060 5070
Ileocecal area 7090 60
5-Aminosalicylates
Ileum 1020 2040 Sulfasalazine and the newer 5-aminosalicylates (5-ASA)
Endoscopic features are first-line therapy for the treatment of UC. Sulfasalazine
contains a 5-ASA moiety that is linked to sulfapyridine by an
Aphthous ulcers 510 3050
azo bond and is delivered intact to the colon. On entering
Linear ulcers 5 2030
the colon, the azo bond is cleaved by bacterial enzyme
Deep ulcers 5070 3040 azo-reductase, and releases sulfapyridine and 5-ASA. The
Nodularity 50 20 sulfapyridine is absorbed systematically and accounts for
Cobblestoning of the mucosa None 1520 most of the drugs toxicity and intolerance. The 5-ASA is
Histological features the active anti-inflammatory compound and ultimately is
excreted in the feces. As 5-ASA is the active compound, but
Granuloma 3060 30
when administered by mouth, it is rapidly absorbed into
Necrosis in the granuloma 1030 None
the jejunum and consequently does not get into the colon.
Therefore, various delivery systems have been used to obtain
high concentrations of the drug in the colonic lumen. The
NATURAL HISTORY first method is to coat 5-ASA with a resin or a semipermeable
membrane that is pH-sensitive and the second is to link
Ulcerative Colitis 5-ASA with another molecule by an azo bond. Mesalamines
(Mesacol, Tidocol) are coated with Eudragit S, which
Half the patients with UC remain in the state of clinical dissolve at pH 7.0 or higher, whereas salofalk or claversal
remission at any given time, and half have some degree of are coated with Eudragit L. Pentasa is mesalamines within a
activity of the disease. In the first 37 years after diagnosis, 25% semipermeable membrane that releases the drug at luminal
of patients are in remission, 18% has activity every year, and pH values of more than 6.0 in time release manner.
57% has intermittent relapses. The most important predictor Sulfasalazine and 5-ASA are anti-inflammatory agents
of relapse or remission is the disease activity in the preceding that interfere with the production of arachidonic acid by
year. If the disease remained in the remission phase in the last affecting the thromboxane and lipoxygenase synthesis
Inflammatory Bowel Disease 87

pathways. Although the precise mechanism of action of due to suppression of T-cell function and natural killer cell
the medications in the treatment of IBD is not known, activity. The usual doses are 2.02.5 mg/kg/day for AZA and
sulfasalazine and the 5-ASA also may have an immune- 1.01.5 mg/kg/day for 6-MP. Idiosyncratic or allergic type
modulatory effect. reactions to AZA include pancreatitis, fever, rash, arthralgia,
Sulfasalazine and the newer 5-ASA preparations are diarrhea and nausea. Non-allergic type reactions include
effective treatment for mild-to-moderate UC. Sulfasalazine bone marrow suppression, infection and hepatitis. AZA or
controls disease activity and induces remission in 6-MP induced pancreatitis usually occurs within the first
approximately 70% of patients. There is a dose response for few weeks of treatment and resolves on discontinuation of
sulfasalazine, and although the maximal recommended the drug. Profound leukopenia can develop suddenly and
dose is 4 g/day, there are data showing increased efficacy unpredictably. It is recommended that each patient on AZA
at 6 g/day. The newer 5-ASA agents have similar efficacy should be monitored. Full blood count and liver function
to sulfasalazine and improve disease in 5075% of treated tests should be done every 24 weeks initially for 2 months
patients. Sulfasalazine and the 5-ASA formulations are and then every 48 weeks.
effective for maintenance of remission of UC. When the active
disease is controlled, the dose required to maintain remission
is the same as that used to induce remission. Generally, 24 Cyclosporine
g/day of sulfasalazine and 2.44.8 g/day of the newer 5-ASA Cyclosporine is a lipophilic peptide that inhibits the
agents are necessary to maintain remission. proliferation and activation of T helper cells by interfering
with IL-2 production. It also decreases recruitment of
Corticosteroids cytotoxic T cells and inhibits production of IL-3, IL-4, TNF-,
and interferon-. In contrast to 6-MP and AZA, intravenous
Corticosteroids were the first medications to be evaluated cyclosporine has an onset of action within days. Compiled
systematically in patients with IBD. In addition to their results from 20 uncontrolled trials showed a benefit of
nonspecific effects on cellular and humoral immune cyclosporine for patients with severe UC failing to respond to
functions, corticosteroids inhibit the production of IV steroids. Of the 185 patients treated with cyclosporine, 68%
cytokines and inflammatory mediators, enhance sodium
initially avoided colectomy, but only 42% had a sustained
and water re-absorption and improve the sense of well-
response after discontinuing therapy. In a randomized,
being. Systemic corticosteroids are effective treatment
placebo-controlled trial, 20 patients with severe UC failing
for moderate-to-severe UC and for controlling acute
intravenous steroids were randomized to either intravenous
exacerbations. Topical corticosteroids are delivered
cyclosporine (4 mg/kg/day) or placebo. Nine of the 11 (82%)
rectally and are effective treatment for distal colitis. Several
modifications of the glucocorticoid backbone have been patients treated with cyclosporine achieved a response by
developed to maximize the mucosal delivery and enteric day 7 compared with none of the patients in the placebo
anti-inflammatory effects while minimizing systemic side group. At the 6 month follow-up, only 59% maintained
effects. Budesonide, a corticosteroid with extensive first- a response on oral cyclosporine and approximately 30%
pass hepatic metabolism and targeted delivery to the required colectomy.
ileum and right colon via a formulation that is pH and The oral microemulsion form of cyclosporine (Neoral)
time dependent, markedly reduces side effects of systemic has similar bioavailability compared with intravenous
corticosteroids. cyclosporine and is more effective than the standard low-
dose oral formulations. Monitoring cyclosporine blood levels
is required to reduce the chance of toxicity. Potential toxicity
Immunosuppressants: Azathioprine and limits the use of cyclosporine and common side effects include
6-Mercaptopurine paresthesias, hypertrichosis, tremor hypertension, nausea,
gingival hyperplasia, vomiting, headaches, nephrotoxicity,
Azathioprine (AZA) and 6-mercaptopurine (6-MP) are
immunomodulators that are effective for the treatment and seizures.
of steroid dependent UC. After absorption, AZA is non-
enzymatically converted to 6-MP, which then is metabolized
to the active end product, 6-thioguanine nucleotide. The
Biological Agents
6-thioguanine nucleotides inhibit ribonucleotide synthesis As understanding of the initiating and amplifying components
and exhibit antiproliferative effects on activated lymphocytes. of the immuno-inflammatory response contributing to
These agents have a direct anti-inflammatory effect that is the syndromes of UC or CD is developing further, novel
88 Textbook of Hepato-gastroenterology

therapeutic approaches are also evolving. We now have the Management of Ulcerative Colitis
ability to interrupt both proximal (e.g. lymphocyte or cytokine
mediated) and distal (e.g. arachidonic acid derivatives The goals of management of UC are to induce remission,
leukotrienes, platelet activating factor, oxygen free radicals, maintain remission, prevent complications and improve
nitric oxide) mediators. As is anticipated from the experience quality of life. The treatment of UC depends upon the activity
with steroids and cyclosporine, the more proximal the of the disease (active phase, remission phase), extent of
inhibition, more potential for systemic immune compromise. the disease (proctitis, left sided colitis and pancolitis), and
dependency on steroid, and needs to be individualized for
Thus the present therapy which is evolving is more target
each patient.
specific neutralization of an inflammatory cytokines (anti-
TNF-), and inhibition of specific lymphocytic population.
TNF is a key inflammatory cytokine and mediator of Induction of Remission
intestinal inflammation. Three antiTNF agents are used
in the treatment of IBD. Infliximab is a murinehuman Mild-to-moderate proctitis and left-sided colitis: Delivery of
chimeric monoclonal antibody, adalimumab is a humanized the anti-inflammatory drugs directly to the inflamed segment
monoclonal antibody, and certolizumab pegol is a PEGylated is UC is the best option. The topical route of administration
monoclonal antigen binding fragment (Fab) to TNF|. Other while it delivers a higher dose of the drug directly to the
antiTNF biological agents currently in clinical trial include involved mucosa, the systemic drug absorption is minimized
golimumab, and this may offer an additional therapeutic and has less systemic adverse effects. Therefore, a disease
option. distal to the splenic flexure is treated best by delivering
the drug topically with suppositories, enemas, foams and
The alternative Th17 pathway involves IL23, liberating
gel. The choice of preparation depends on the extent of the
IL17A, IL17F, IL22, and TNF. Cell adhesion molecules
colitis (for example, suppositories are suitable for proctitis
are cell surface proteins involved in cellular binding of
and enemas can reach up to the splenic flexure). Patient
homing leukocytes to each other, to endothelial cells or to
preference regarding route of drug delivery should also be
tissue. Selective adhesion molecules of intestinal endothelial
considered. 5-ASA enemas and suppositories are effective
cells are therefore therapeutic targets for blocking leukocyte first-line therapies for patients with left sided colitis and
trafficking and activation in IBD, particularly because they do ulcerative proctitis. If topical therapy is used, suppositories
not induce systemic immune suppression. Natalizumab is a are most appropriate for proctitis, whereas more extensive
humanized monoclonal antibody directed against the cellular disease affecting the sigmoid colon or greater parts of the left
adhesion molecule 4integrin. This agent blocks leukocyte colon need the addition of enemas or foams. Patients with left
adhesion to the endothelium in the intestinal tract, but also sided colitis can also be treated by oral 5-ASA, but they are
to the brain. The latter property led to its use in patients with less effective than topical 5-ASA compounds.
multiple sclerosis. However, the development of progressive
Mild-to-moderately active extensive colitis: Mild-to-
multifocal leukoencephalopathy (PML), a devastating and moderately active extensive colitis is initially managed with
often fatal cerebral infection caused by the John Cunningham oral 5-ASA compounds in the doses up to 3.24.8 g/day. Once-
virus (JCV), has limited its use in IBD. daily dose of 5-ASA or newer, controlled-release formulations,
such as multi-matrix 5-ASA (1.2 g tablets) are reported to be
Probiotics in Ulcerative Colitis as effective and to promote adherence to treatment. For those
patients who do not respond to only oral 5-ASA, a combined
Intestinal microflora may play an important role in the oral and topical 5-ASA is superior to oral mesalamine alone.
pathogenesis of UC. Several studies have reported an Clinical (and endoscopic) remission can occur in up to 64
unusually high number of pathogenic E. coli strains in patients 70% within 2 weeks.
with UC. Probiotics have been used in induction of remission Severely active ulcerative colitis: Patients with mild-to-
of active disease and maintenance of remission; however, moderately active UC that is refractory to topical therapy
evidences are not sufficient to recommend probiotics for or oral therapy and those with moderate to severe disease
routine use. Probiotic VSL#3 (3,600 billion colony-forming should be treated with oral glucocorticoids. Patients who
units per day for 8 weeks) in conjunction with 5-ASA can have failed to respond to maximal oral treatment with a
help induce remission in mild-to-moderate UC. Probiotics combination of 5-ASA and/or steroids those who present
especially VSL#3 has been found to be very effective in both with severe/fulminant disease should be admitted for
inducing remission in active pouchitis and maintenance of intensive intravenous corticosteroids (hydrocortisone 400
remission in pouchitis. mg/day or methylprednisolone 60 mg/day) therapy. The
Inflammatory Bowel Disease 89

patient should be monitored for number and consistency for maintenance of remission of UC are 1,6002,400 mg of
of stool, amount of blood in the stool, vital signs and mesalazine, and 2,000 mg of sulfasalazine.
abdominal signs (fullness, abdominal tenderness, rebound Patients who relapse while on oral 5-ASA, those who are
tenderness, and bowel sound). Therefore a constant vigil on steroid-dependent, and those with severe UC who need
the overall condition of the patient is mandatory. Hemogram, induction therapy with cyclosporine or tacrolimus are
erythrocyte sedimentation rate (ESR), C-reactive protein, candidates for immunosuppressive therapy, such as AZA, or
serum electrolytes and serum protein should be repeated 6-MP. AZA is dosed at 23 mg/kg/day and 6-MP at 1.01.5 mg/
at every 23 days. If on an initial abdominal radiography, kg/day. Infliximab is effective for maintenance of remission
the diameter of transverse colon is found to be dilated (>5.5 and is steroid-sparing in patients who are unable to maintain
cm), then abdominal skiagram should be repeated every remission while on AZA or 6-MP. Most patients will require
day. Anticholinergic, antidiarrheal agents and opioid drugs maintenance treatment for lifelong.
are best avoided, as they can precipitate colonic dilatation.
NSAID can worsen disease activity. Most patients are
generally on mesalamines; mesalamines may be continued Surgery for Ulcerative Colitis
once oral intake resumes. Patients requiring surgery for IBD are best managed under
Patients who do not improve significantly after 57 days the joint care of a surgeon and a gastroenterologist. Surgery
of maximal medical management are unlikely to benefit remains an important component in the treatment algorithm
from prolongation of this form of management and should of UC and early surgical consultation is recommended
either be referred for surgery or offered treatment with an especially for acute severe UC that requires hospitalization.
intravenous cyclosporine or anti-TNF therapy. Although About 520% of patients with UC require colectomy. The
cyclosporine can be effective, it generally delays rather than decision to operate is best taken by the gastroenterologist
prevents subsequent colectomy. Furthermore, infliximab is
and colorectal surgeon in conjunction with the patient.
increasingly used as an alternative treatment for patients with
The type of surgery is dependent on the acuteness of the
refractory disease, given its effectiveness and better short-
indication and the patients condition. The indications may
term safety profile as compared with other therapies.
be classified as emergency (exsanguinating hemorrhage,
Immediate surgical referral is necessary if there is evidence
intestinal perforation and severe colitis unresponsive to
of toxic megacolon (transverse colon diameter >5.5 cm, or
intensive medical treatment) and elective (steroid dependent
cecum >9 cm). The urgency with which surgery is undertaken
after recognition of colonic dilatation depends on the disease, steroid refractory disease, intolerable side effects of
condition of the patient: the greater the dilatation and the drugs and unaffordability of medical treatment or strongly
greater the degree of systemic toxicity, the sooner surgery suspected/confirmed carcinoma). When indicated, the gold
should be undertaken, but signs may be masked by steroid standard elective surgery for UC is proctocolectomy with ileal
therapy. In select patients with mild colonic dilatation, an pouch anal anastomosis (IPAA) and this should be performed
expectant conservative management can be continued, and in a specialized center. Acute complications of IPAA include
clinical, laboratory, or radiological deterioration mandates anastomotic leak, sepsis, and injury to local structures,
immediate colectomy. Those with toxic megacolon, colonic including pelvic nerves.
decompression can be augmented by frequent change in Pouchitis, the most common and the most clinically
posture to knee elbow position. important long-term complication of IPAA, is a nonspecific
inflammation probably caused by an immune response to the
newly established microbiota in the ileal pouch (dysbiosis).
Maintenance of Remission The incidence of pouchitis can be as high as 40%; in 1020%
After remission has been achieved, the goal is to maintain of cases, pouchitis becomes chronic. Symptoms of pouchitis
the symptom-free status, which can be accomplished with include increased stool frequency, urgency, incontinence,
various medications, with the exception of glucocorticoids, seepage, abdominal and perianal discomfort. Treatment of
which have no place in maintenance therapy, given the pouchitis consists primarily of antibiotics (metronidazole,
marked side effects associated with their long-term use. First- ciprofloxacin, or rifaximin). Pouch failure, a condition
line therapy for the maintenance of remission is oral or topical requiring pouch excision or permanent diversion, occurs
mesalamines. Both oral and rectal 5-ASA have greater efficacy in 810% of patients. Probiotics especially VSL#3 has been
than placebo for maintenance of remission in patients with found to be very effective in both inducing remission in active
distal disease. The appropriate dose of 5-ASA compounds pouchitis and maintenance of remission in pouchitis.
90 Textbook of Hepato-gastroenterology

Management of Crohns Disease Box 1: Treatment guidelines for Crohns disease

Crohns disease is a dynamic and progressive disease. Since Sulfasalazine can be used for mild CD limited to the colon. There
is no evidence of efficacy of mesalamines in them. Moderately
there is no definite cure for most patients with CD, the
severe or severe colonic disease should be treated with conventional
main objectives of treatment therefore include induction corticosteroids
of remission and maintenance of remission, minimization
Mild-to-moderately active CD involving terminal ileum or localized
of complications of the disease, such as strictures, fistulae, ileocecal disease should be treated with budesonide. Conventional
osteoporosis, short- and long-term toxicities of the drugs, steroids should be used if budesonide is unavailable or fails to respond.
improvement in quality of life, decrease in number of For severe disease, conventional corticosteroid is the initial treatment of
hospitalizations and surgeries, and maintenance of linear choice. Surgical resection and anti-TNF are alternatives
growth in pediatric patients. For extensive small intestinal disease, patients should be treated with
At present, control of symptoms is considered to be an conventional corticosteroids. Alternatives for extensive small intestinal
disease include anti-TNF agent and surgery
end point; however, over the past years, mucosal healing
has emerged as a major therapeutic goal in clinical trials Patients with ileocolonic disease should be treated with conventional
corticosteroids. Alternative include anti-TNF agent and surgery
in patients with CD and UC. Available evidences indicate
that mucosal healing may change the natural course of the Patients with moderate-to-severe disease despite treatment with
sulfasalazine, mesalamine, budesonide, and conventional corticosteroids
disease by decreasing the need for surgery and reducing
can be treated with infliximab. Infliximab is given at a dose of 5 mg/kg at
hospitalization rates in both CD and UC. Mucosal healing 0, 2, and 6 weeks. An alternative to infliximab is a fully human anti-TNF
may also prevent the development of long-term disease antibody, adalimumab, given subcutaneously with a loading dose of 160
complications, such as strictures and fistulae. mg at week 0 and 80 mg at week 2. In the near future, a PEGylated anti-
The treatment of CD depends upon the activity (active TNF antibody FAb fragment certolizumab pegol will become available
that is given subcutaneously at a dose of 400 mg at weeks 0, 2, and 4
phase, remission phase), location, extent and behavior
(inflammatory, stricturing, fistulizing) of the disease. The Active Crohns disease with a concomitant abdominal abscess should
be treated with antibiotics, percutaneous or surgical drainage followed
treatment needs to be tailored for each patient. The predictors
by delayed resection if necessary, in addition to specific medical
of poor outcome in patients with CD include young age of management of CD
onset, presence of extensive disease, stricturing disease and
positive smoking history.

Induction of Remission (Box 1) remission, relapse rates among patients receiving placebo
range from 30 to 60% at one year, and from 40 to 70% at two
Mesalamine has not consistently proved efficacious in years. Patients in remission for at least one year have a risk
patients with CD. Two trials of mesalamine at doses of 3,200 of relapse lower than those with a flare during the previous
4,000 mg/day showed efficacy whereas two other trials with year. About 7080% of patients with active disease during
4,000 mg/day of mesalazine that were never fully reported one year of follow up had active disease in the following
failed to show efficacy. A meta-analysis, which included year; conversely, 80% of patients in remission had no flare
the three largest trials, did not show a clinically important in the following year. The majority of patients treated with
treatment effect. Sulfasalazine at doses of 3,0004,500 mg/day steroids will not be in remission after 1 year and will therefore
is effective for induction of remission in mild-to-moderately require maintenance therapy. All patients should be advised
active disease limited to the colon. Moderately severe or to quit smoking, which is an important factor in maintaining
severe colonic disease should be treated with conventional remission and reducing the risk of relapse in CD. The choice
corticosteroids. of medication for maintenance of remission depends upon
An alternative explanation for symptoms other than active the course of the disease (initial presentation, frequency,
disease should be considered (such as infection, abscess and severity of flares); the extent of disease (localized or
formation, bacterial overgrowth, bile salt malabsorption, extensive) and the effectiveness and tolerance of treatments
dysmotility, gallstones) and disease activity confirmed before previously used for induction of remission or maintenance.
initiating new therapies. Other factors, such as financial resources and tolerance to
drugs should be considered in making treatment choices.
Sulphasalazine, 5-ASA compounds, prednisolone and
Maintenance of Remission budesonide are not effective in long-term maintenance
The natural course of CD is marked by remissions and of in patients with CD. The first line of treatment of
relapses. In clinical trials designed for the maintenance of maintenance of remission in patients with CD is thiopurines
Inflammatory Bowel Disease 91

or methotrexate. The dose of AZA should be optimized. Other than clinical examination and endoscopic activity
For those who relapse once immunosuppressants are of the disease, additional diagnostic tests to delineate fistula
stopped, current evidence suggests that AZA/6-MP can be anatomy, extent, and relationship of the tracks to the sphincter
safely restarted. In patients with active CD, the likelihood muscles include pelvic magnetic resonance imaging,
of response to AZA or 6-MP is increased after 17 weeks and anorectal endoscopic ultrasonography, and examination
the clinical response to methotrexate does not occur for 68 under an anesthesia.
weeks, indicating that because of the slow onset of action, While asymptomatic simple perianal fistula may be
these drugs should mainly be considered as maintenance observed, symptomatic fistula requires treatment. Bacterial
rather than induction drugs. AZA is dosed at 23 mg/kg/day infection is thought to play a role in the appearance and
and mercaptopurine at 1.01.5 mg/kg/day. Methotrexate is persistence of perianal fistulous disease. Thus, antibiotics are
given parenterally at doses of 25 mg/week for maintenance used as first-line therapy for fistula healing in simple perianal
therapy. fistula. Overall, antibiotics remain a mainstay of treatment for
Infliximab is effective for maintenance of remission, steroid- simple perianal fistula in patients with CD despite the lack of
sparing, and mucosal healing in patients who are unable to controlled trial evidence. Either metronidazole (7501,500
maintain remission or who remain steroid dependent despite mg/day) or ciprofloxacin (5001000 mg/day) can be used.
treatment with AZA, 6-MP, or methotrexate. For maintenance The antibiotic is generally required to be continued for 34
therapy, infliximab is given at a dose of 5 mg/kg every 8 weeks. months. The adverse events, such as neuropathy especially
Episodic dosing is associated with immunogenicity (loss of with metronidazole can appear with prolonged use.
efficacy and infusion reactions). Alternatives to infliximab are All patients should receive treatment for active intestinal
adalimumab given subcutaneously for maintenance therapy disease. Optimization of medical therapy for control of
as 40 mg subcutaneously every other week. Certolizumab disease elsewhere and in the colon and rectum is important
pegol will be available in the near future, which is given and may help in healing of fistula. Those who have active
subcutaneously for maintenance therapy as 400 mg every 4 perianal abscess, use of corticosteroids should be avoided in
weeks. them.
Azathioprine and 6-MP are effective in healing of fistula
due to CD. Anti-TNF drugs are quiet effective in healing of
Perianal Crohns Disease perianal fistula. Infliximab is given as 5 mg/kg at 0, 2, and 6
The transmural inflammatory nature of CD predisposes weeks for induction and then every 8 weeks for maintenance.
these patients to develop fistula and abscesses. Because An alternative to infliximab is adalimumab, which is given
of local pain and perianal discharge, perianal disease has subcutaneously as 160 mg at week 0 and 80 mg at week 2, and
a very negative impact on the quality of life of the affected then 40 mg every other week beginning at week 4. Surgery
patients. The perianal fistula occurs more often when there is should be used in conjunction with best medical therapy.
involvement of the colon and the rectum. Seton drainage can be a useful technique to provide symptom
The treatment of perianal fistula depends upon the control and can be used as a prelude to medical treatment.
location of fistula, nature of fistula, such as simple or Other surgical approaches, such as advancement flaps, and
complex, presence of abscess and severity of intestinal fistula plugs may be appropriate for persistent or complex
disease. A good examination of perianal area is of immense fistulae in combination with medical treatment.
importance and helps in classification of fistula type. Fistulas
can be classified as either simple or complex. A simple
fistula is low (superficial or low intersphincteric or low trans- FERTILITY AND PREGNANCY
sphincteric origin of the fistula tract), has single external
opening, has no pain or fluctuation to suggest perianal Although fertility in inactive IBD is unaffected, active
abscess, has no evidence of a rectovaginal fistula, and has no disease diminishes the fertility. The reasons for decrease
evidence of anorectal stricture. A complex fistula is high (high fertility in IBD include inflammatory changes in the female
intersphincteric or high trans-sphincteric or extrasphincteric reproductive system during active phase of the disease, local
or suprasphincteric origin of the fistula tract), may have sepsis, pelvic surgery, prior surgery and reversible decrease
multiple external openings, may be associated with the in sperm motility by sulphasalazine. The frequency of
presence of pain or fluctuation to suggest a perianal abscess, abortions, preterm deliveries, cesarean sections, congenital
may be associated with the presence of a rectovaginal abnormalities, and birth weight is no different in patients with
fistula, may be associated with the presence of an anorectal IBD compared with non-IBD controls, as seen in a prospective
stricture, and may be associated with the presence of active study including 332 pregnant women with IBD (145 with CD
rectal disease at endoscopy. and 187 with UC) from 12 European countries. Women who
92 Textbook of Hepato-gastroenterology

have IBD are more likely to have a cesarean section, especially B12 deficiency occur. Drug-induced anemia secondary
those with CD. to AZA, 6-MP or sulfasalazine also occurs. Patients with
If pregnancy is planned, patient should be counseled IBD should have at least annual hemoglobin check. The
to conceive during remission and advised to continue their nutritional status of these patients should be assessed and
maintenance medication. Prior to conception patients should optimum nutritional therapy should be provided to them.
be well nourished and should take folate supplements. Osteoporosis is quiet common in patients with IBD.
Maintaining adequate disease control during pregnancy is Systemic inflammation secondary to active colitis and
essential for both maternal and fetal health. Pregnant women recurrent or chronic use of high dose corticosteroids are
with IBD should be managed jointly by a gastroenterologist risk factors for osteoporosis. Optimal nutrition, calcium
and obstetrician. Patients with acute severe disease or other and vitamin D intake, weight-bearing exercise, cessation
life-threatening complications of disease should be managed of smoking, moderation of alcohol consumption, and
minimization of the use of corticosteroids are recommended.
as for the nonpregnant patient. Optimal management of
Because glucocorticoids are mainstay of treatment of
maternal IBD is the key to the best fetal outcome. The mode of
patients with CD, it is important to recognize the effects
delivery should be carefully considered. The mode of delivery
they have on bone remodeling. Corticosteroids have been
is best guided by the obstetric indications rather that of the
shown to impair osteoblast function, induce osteoblast
IBD. Patients with perianal CD or ileoanal pouch formation
apoptosis, reduce intestinal calcium absorption, and increase
may best have a cesarean section to avoid the risk of damage renal excretion of calcium. Patients on glucocorticoids are
to the anal sphincter. Absolute indications for surgery are at increased risk for fracture, with the greatest bone loss
unaltered by pregnancy and surgery should only be delayed occurring in the initial months of treatment. Patients at risk
where aggressive medical therapy may allow critical fetal for or with osteoporosis should receive calcium and vitamin
maturation. D supplementation. The recommendation for younger men
Active flares during pregnancy need to be treated and premenopausal women is daily intake of elemental
aggressively using drugs established to be safe in pregnancy. calcium of 1,000 mg, either from diet or supplementation.
Corticosteroids tend to be safe in pregnancy as placental Men and women over 50 years of age require 1,500 mg of
11-hydroxygenase converts steroids to less active metabolites. calcium. Vitamin D intake of 400800 IU/day should be
Drugs that absolutely need to be avoided during pregnancy adequate for relatively healthy individuals, but patients with
are methotrexate and thalidomide. intestinal malabsorption or housebound patients may need
an increased amount.

BREASTFEEDING
BIBLIOGRAPHY
5-aminosalicylates and corticosteroids are safe during
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clinical aspects and established and evolving therapies. Lancet.
babies exclusively breastfed by mother receiving thiopurines.
2007;369:1641-57.
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4. Chowers Y, Sturm A, Sans M, et al. Report of the ECCO workshop
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Inflammatory Bowel Disease 93

7. Makharia GK, Srivastava S, Das P, et al. Clinical, endoscopic, 13. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated
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10
cHAPTER

Irritable Bowel Syndrome

Monjur Ahmed

INTRODUCTION the pathogenesis of IBS. Small bowel manometry may show


prominent clustered contractions during phase 2 activity.
Irritable bowel syndrome (IBS) is a clinical diagnosis This may also occur in healthy individuals. But more patients
characterized by chronic or recurrent abdominal pain or with IBS with these contractions will be symptomatic than
discomfort associated with alteration of bowel habits. The healthy individuals with these contractions. In irritable bowel
symptoms cannot be explained by any structural lesion, syndrome with diarrhea (IBS-D), transit time through the
metabolic changes or infection of the gut. It is a functional small bowel is short whereas in irritable bowel syndrome with
disorder due to changes in motility, perception and sensation constipation (IBS-C), small bowel transit time is prolonged.
of the gut. No specific colonic dysmotility is found in IBS. High
There are several functional gastrointestinal disorders amplitude peristaltic contractions are more frequent after
described in Rome III classification, IBS being the most taking meals and before bowel movements. In IBS-D, colon
common (28% of outpatient gastroenterology practice and transit is rapid, and in IBS-C, colon transit is slow.
12% of primary care practice). It affects 820% of the adult
population in the western world with similar prevalence
reported in other parts of the world. The prevalence of
Visceral Hypersensitivity
IBS is higher among women although any socioeconomic Most of the patients with IBS have decreased pain threshold
group can be affected. Two-third of IBS patients do not seek in the gastrointestinal tract. How visceral hypersensitivity
healthcare although it varies from culture to culture. In Indian occurs in IBS is not exactly known. Painful and non-painful
subcontinent, self reporting of IBS symptoms is much less stimuli are transmitted from the gut to the brain via afferent
common than in the western world. Irritable bowel syndrome nerves. Many factors involve both peripheral and central
not only causes significant negative impact on the quality of neurons. The neurons in the myenteric plexus of the gut
life of the patients for years and years but also creates a huge may get exposed to a variety of inflammatory mediators and
economic impact on our society through direct healthcare cytokines (serotonin, prostaglandin, leukotrienes, histamine,
costs and negative productivity through workers absenteeism. reactive metabolites) during tissue injury. They act on the
nociceptor terminals and activate intracellular signaling
pathways, which upregulate the sensitivity of the gut. A
PATHOPHYSIOLOGY small percentage of patients with IBS give history of onset
of symptoms since an attack of gastroenteritis, as they have
The pathophysiology of IBS is not fully understood. The current developed hypersensitivity of the gut. Functional magnetic
thinking is that abnormal braingut control leads to visceral resonance imaging (MRI) studies suggested greater activation
hypersensitivity, and altered colonic and small bowel motility of middle and posterior dorsal cingulate gyri (responsible
and secretion. Multiple pathophysiologic mechanisms have for pain sensation) and less activity of supragenual anterior
been associated with IBS, and it seems reasonable that several cingulate cortex (responsible for pain inhibition) in response
mechanisms need to be present to manifest the disease. to rectal distention in IBS patients. This may implicate that
pain modulation may be altered in IBS patients.
Dysmotility of the Gut
Previously IBS was thought to be a purely motility disorder. Stress
But the motility disturbances seen in patients with IBS do Stress plays an important role in the pathogenesis and clinical
not always correlate with the symptoms and do not explain manifestations of IBS. Normal individuals may develop
Irritable Bowel Syndrome 95

abdominal cramps, diarrhea or constipation in response to CLINICAL MANIFESTATIONS


stress. This response is much more exaggerated in patients
with IBS. Stress is an acute threat (physical or psychological) Irritable bowel syndrome is commonly present in the younger
to the homeostasis of an individual. The response to stress is population as majority of the patients present below the age
mediated through hypothalamicpituitaryadrenal axis and of 45. The prevalence generally decreases with age. Females
the sympathetic nervous system. In IBS patients, this circuit are five to six times more frequently affected than males.
could be improperly functioning. Altered sympathetic activity Females are significantly more symptomatic, primarily with
or inadequate cortisol secretion may lead to persistence of less satisfied bowel movements and bloating. In one study,
gut inflammation despite eradication of infection leading to whites and African Americans had similar prevalence of IBS.
postinfectious IBS. Different stressful life events like accidents, Abdominal discomfort or pain is the main symptom of
death in the family, divorce, unemployment and financial IBS. Patients generally feel lower abdominal pain, but it
crisis may predispose and perpetuate the manifestations can be anywhere in the abdomen. The pain can be mild to
of IBS. Stress hormone like corticotrophin releasing factor severe, and is not well characterized, sometimes described
has been found to cause more colonic contractions and as crampy, sometimes gas-like, sometimes sharp, sometimes
more abdominal pain in patients with IBS than in normal dull and sometimes aching in nature. Onset of abdominal
individuals. pain is associated with change in bowel frequency or
consistency of stool. The pain is intermittent, aggravated by
taking food and generally relieved by defecation. Stressful life
Psychological Factors events precipitate the abdominal pain and change in bowel
Anxiety, depression, hypochondriasis, phobia, somatization habit. We generally follow Rome III diagnostic criteria, as they
and post-traumatic stress disorder are common in patients have high specificity for diagnosing IBS.
with IBS. In one study, 53% of women with IBS had a history of
abuse occurred during their childhood. These psychological
factors have been associated with increased visceral
Rome III Diagnostic Criteria for
perception leading to negative impact on the quality of life, Irritable Bowel Syndrome
increased doctors office visit and healthcare utilization,
Recurrent abdominal pain or discomfort at least 3 days per
ineffective coping skills and poor clinical outcome.
month in the last 3 months associated with two or more of the
following:
Enteric Infection and Gut Microbes Improvement with defecation
Onset associated with a change in the frequency of stool
Postinfective IBS can occur following bacterial infection Onset associated with a change in the form (appearance)
of the gut, the relative risk being 12%. Young female with a of stool
history of prolonged diarrhea but absence of vomiting as The symptoms should be present for at least 6 months
well as persons with anxiety, somatization and stressful life prior to diagnosis.
events before or during infection are at increased risk of Some of the symptoms we frequently find in patients with
developing IBS. Random colon mucosal biopsies may show IBS are not mentioned in Rome III criteria. These include
increased number of lymphocytes and enterochromaffin morning rush, i.e. repeated bowel movements in the morning
cells throughout the colon, and these changes may last for when stool form changes from solid to liquid, passage of
more than 3 months. Enterochromaffin cells can release mucus per rectum, abdominal bloating and gas sensation,
5-hydroxytryptamine (5-HT) in the postprandial period. visible abdominal distention and feeling of incomplete
Recently, it has been found that there is significant alteration evacuation of stool.
of fecal microflora in IBS patients. Those microflora may Irritable bowel syndrome is subtyped depending on
release proinflammatory cytokines. Increased prevalence the consistency of the stool. Subtyping is important for
(54%) of small intestinal bacterial overgrowth (SIBO) based therapeutic purposes as the treatment is directed toward
on lactulose or glucose breath test has been found in IBS symptoms. The Bristol Stool Form Scale (Fig. 1) is very helpful
patients. In another study, low concentration of bacteria in this situation. The stool form depends on colon transit
(>5,000 coliforms/mL) in jejunal culture was more frequently time, i.e. the more time stool remains in the colon, it becomes
found in IBS patients than in healthy controls (43% vs 12%). harder. Irritable bowel syndrome has four subtypes:
The significance of SIBO in the pathogenesis of IBS remains 1. IBS-C: Hard stools for more than 25% of the time and loose
uncertain. stools for less than 25% of the time.
96 Textbook of Hepato-gastroenterology

post-traumatic stress disorder. Many IBS patients cannot


manage well their stressful life events and they become
more symptomatic during these stress situations
Extracolonic symptoms: Many patients with IBS complain
of nausea and dyspepsia. A significant numbers of IBS
patients seek medical attention for headache, backache,
insomnia and genitourinary symptoms like impotence,
dyspareunia, dysmenorrhea, increased frequency and
urgency of micturition, sensation of incomplete bladder
emptying and nocturia.
Comorbidities: Irritable bowel syndrome is significantly
found in certain disorders like fibromyalgia, chronic
fatigue syndrome, temporomandibular joint disorder, and
chronic pelvic pain.
A thorough history taking is pertinent to find out red
flags that may indicate presence of an organic disorder.

Red Flags
Age greater than 50 years, particularly in patients with new
onset of symptoms or change in symptoms
Male sex
Rectal bleeding
Fig. 1: the bristol stool form scale Anemia
Source: Reproduced by kind permission of Dr KW Heaton, Reader in Fever
Medicine at the University of Bristol. Documented weight loss
2000 produced by Norgine Pharmaceutical Limited, manufacturer Nocturnal symptoms with wake up from sleep
of MOVICOL Family history of colon cancer or inflammatory bowel
disease

2. IBS-D: Loose stools for more that 25% of the time and hard
stools for less than 25% of the time. PHYSICAL EXAMINATION
3. IBS-mixed (IBS-M): Hard stools for more than 25% of the
time and loose stools for more than 25% of the time. This Physical findings are generally normal. Sometimes, we
subtype constitutes 3050% of all cases of IBS. find left lower quadrant abdominal tenderness and intense
4. Unsubtyped IBS (IBS-U): Neither hard nor loose stools for discomfort on rectal examination. The patient may look
more than 25% of the time. This constitutes 4% of all cases anxious or depressed.
of IBS.
Sometimes we use the term alternators to those IBS
patients whose symptoms change from one subtype to DIAGNOSTIC TESTING
another over a period of time.

Although Rome III criteria and Bristol Stool Form Scale Extensive workup is generally not needed to establish the
help us diagnosing and subtyping IBS, few important points diagnosis of IBS in the absence of red flags as mentioned
should be considered in its clinical spectrum: above. Complete blood count, erythrocyte sedimentation
Psychological aspects: Anxiety and depression are rate (ESR) and thyroid stimulating hormone (TSH) are
commonly found in patients with IBS. Many IBS patients generally done routinely. Abnormalities in these tests may
are hypochondriac. There are significant numbers of suggest systemic disease. Serum tissue transglutaminase
patients who have history of physical and sexual abuse antibody should also be done in patients with IBS-D and
during their childhood and they are more symptomatic IBS-M as few studies have suggested increased chance of
with pain, disability and psychological distress. Irritable having celiac disease in suspected IBS. In patients with IBS-D,
bowel disease has been found to be associated with three loose stool samples should be collected on separate
Irritable Bowel Syndrome 97

days for ova, parasites and Giardia antigen (ELISA). Flexible MANAGEMENT
sigmoidoscopy should be considered in suspected IBS
patients to evaluate any colitis in diarrhea and distal colonic
obstruction in constipation.
General Approach
Colonoscopy is generally indicated for patients with age 50 After establishing the diagnosis of IBS, a strong physician
and above, family history of colon cancer, positive fecal occult patient relationship should be established. Patients under-
blood test or rectal bleeding, and refractory diarrhea. standing and concern about the illness should be determined
Additional diagnostic testing may be necessary if the and adequate explanation should be given. The severity of
patients clinical course does not improve or deteriorate after symptoms and the impact on the quality of life should be
about a month of symptomatic treatment. evaluated. The physician should ask how much improvement
Further tests are performed depending on the patients of symptoms patients expect and the physician should answer
predominant symptoms. If the patient has predominant diar- realistically with consistent limits.
rhea, bacterial overgrowth, lactose intolerance, microscopic Detailed dietary history should be taken as most of the
colitis, secretory or osmotic diarrhea and malabsorption patients with IBS relate their symptoms to intake of certain
food. Fat is known to aggravate visceral sensation and
should be excluded. To evaluate these conditions, further in-
gastrocolic reflex, and consequently abdominal cramping
vestigations would include lactulose or glucose breath test,
and diarrhea. Excessive coffee, alcohol, lactose, fructose and
lactose breath test, colonoscopy with random biopsies from
sorbitol can aggravate IBS symptoms. Therefore, in certain
both left and right colon, stool osmolarity, stool for sodium
IBS patients, they should be avoided.
and potassium to calculate the fecal osmotic gap: 300 2
(Na + K), and 3-day stool collection for quantitative fat assay.
If the patient has predominant constipation, then colon Pharmacological Approach
inertia and anorectal dyssynergia should be excluded.
Medications are generally given to treat the patients
Additional tests would include colon transit study (Sitzmarks),
predominant symptoms.
anorectal manometry and defecography.
If the patient has predominant pain, then pancreatitis,
hepatitis and any intra-abdominal pathology should be Constipation
excluded. Further tests to be done are liver function test,
Patients should be advised to take plenty fibers in the diet with
serum amylase and lipase, and CT or MRI of abdomen and
plenty of water. High fiber diet may include fruits, vegetables,
pelvis.
whole grains, nuts, and seeds. The fiber ingestion should be
gradually increased over few weeks to about 2025 gm/day.
If dietary fiber does not improve constipation, next step is
DIFFERENTIAL DIAGNOSIS to add fiber supplements to regularize bowel movements.
Commercially available fiber supplements include psyllium
Celiac disease (Metamucil, Konsyl), methylcellulose (Citrocel) and
Inflammatory bowel disease: Crohns disease, ulcerative polycarbophil (Fibercon, Equalactone). The main side effect
colitis of fiber therapy is gas formation. In that case, patients should
Microscopic colitis be advised to reduce their fiber intake including gas-forming
Infectious diarrhea: Giardia, Entamoeba, Campylobacter, foods, which include certain vegetables like cabbage and
Yersinia beans, and certain fruits like apples and grapes. Fiber therapy
Small intestinal bacterial overgrowth does not reduce patients abdominal pain.
Food intolerance: Lactose, sorbitol, monosodium gluta- If fiber therapy fails, osmotic laxatives should be given
mate, fructose first before trying stimulant laxatives. Osmotic laxatives
Endocrine: Hyperthyroidism, carcinoid syndrome, cause influx of water into the small bowel and colon and thus
ZollingerEllison syndrome, mastocytosis forms bulky stool. Commonly used osmotic laxatives include
Tumors: Colon cancer, villous adenoma lactulose, polyethylene glycol (Miralax), magnesium citrate
Medications: Laxatives, magnesium containing antacids and magnesium hydroxide. Stimulant laxatives increase
Malabsorption: Pancreatic insufficiency, tropical sprue, colonic contraction by stimulating the myenteric plexus.
Whipples disease They should be used with caution, as they may damage the
98 Textbook of Hepato-gastroenterology

myenteric plexus permanently leading to cathartic bowel and Abdominal Pain and Global Symptoms
also for the potential for abuse. Commonly used stimulant
laxatives include bisacodyl, senna, and cascara. Antispasmodics are commonly used for the treatment of
If constipation still persists, chloride channel activator abdominal pain in IBS. Dicyclomine and hyoscyamine are
lubiprostone can be given. It causes active chloride secretion usually prescribed. They can be used regularly three to four
from the colon mucosa with obligatory secretion of sodium times a day about half an hour before meals or as necessary
and water making the stool hydrated. It improves constipation basis. They can improve abdominal pain as well as global
and global symptoms of IBS-C. The main side effect of symptoms of IBS. They can cause anticholinergic side effects
lubiprostone is nausea, which can be reduced if the pill is like dry mouth and constipation.
taken with food. Low-dose tricyclic antidepressants (TCA) have been found
The role of probiotics in IBS-C is not known. Limited data to be beneficial in improving the global symptoms of IBS. They
supports that Bifidobacterium animalis shortens colon transit reduce abdominal pain by acting on the central and periph-
and improves bowel movements. eral nervous system. They also reduce gut motility and so, they
Tegaserod (partial 5-HT4 receptor agonist) was efficacious are effective in patients with IBS-D. The medication should be
in relieving constipation as well as improving global started at a low dose and gradually increased over few weeks.
symptoms of IBS in women. But it was suspended from the It may take several weeks to get the effect of the tricyclics. Pa-
US market in 2007 because of its small but significant risk of tients may develop drowsiness and anticholinergic side effects.
ischemic cardiovascular events. Selective serotonin reuptake inhibitors (SSRIs) like
Recently, linactolide, a guanylate cyclase-C agonist has paroxetine, fluoxetine, and citalopram may improve global
been approved for IBC-C patients. It works by increasing symptoms of IBS, but they are not as good as tricyclics in
intestinal fluid secretion. It improves constipation and relieving abdominal pain.
reduces pain by decreasing visceral hypersensitivity. Another Serotonin-norepinephrine reuptake inhibitors (SNRIs)
5-HT4 receptor agonist, prucalopride, is under investigation. can be helpful in alleviating abdominal pain in IBS without
It has 150 times greater affinity on 5HT4 receptors than any anticholinergic side effects.
other 5HT receptors and, as a result, does not seem to have Few antibiotics have been investigated in the management
adverse cardiovascular events. Although it increases bowel of IBS as they can alter intestinal microflora. Neomycin was
movements in constipation, its role in IBS-C has not been found to improve global symptoms of IBS-C. But its side effects
formally evaluated. like neuromuscular blockade, ototoxicity and nephrotoxicity
limit us to use it very cautiously in IBS patients.
Diarrhea Rifaximin 550 mg three times a day for 2 weeks in
nonconstipated IBS patients was found to improve global
The common antidiarrheal agents used are loperamide and symptoms of IBS and bloating. The improvement was
lomotil (combination of diphenoxylate and atropine). Both maintained in 3-month follow-up.
loperamide and diphenoxylate are synthetic opoids, bind Probiotics are frequently used by IBS patients, although
to receptors on the myenteric plexus and thus reduce the there are only few studies. Bifidobacterium infantis 35624
gut motility. Cholestyramine (bile acid binder) has also been (Align) was found to improve abdominal pain, diarrhea,
used in IBS-D. As it works by binding bile acid in the colon, it bloating and global symptoms of IBS.
is more effective in IBS patients with rapid small bowel transit
or cholecystectomy.
Alosetron (5-HT3 antagonist) slows gastrointestinal Psychological Treatment
transit, reduces chloride and water secretion in the gut and
Patients with IBS can have other psychiatric comorbidities
diminishes visceral hypersensitivity. Alosetron has been
like anxiety, depression, panic attacks and substance abuse.
found to be helpful in reducing abdominal pain, diarrhea and
These patients need help from the psychiatrists. Besides
global symptoms in women with IBS-D. Alosetron 1 mg orally
these, if the patients symptoms are disabling, they should
twice a day in women with IBS-D was approved in USA in 2000
be referred for psychological assessment and treatment.
but in the same year it was taken off from the market because
Psychotherapy is commonly used to reduce symptoms.
it was infrequently associated with severe constipation and
ischemic colitis. Alosetron was reintroduced in the US market
in 2002 through a restricted access program0.5 mg twice Alternative Medicine
a day in women with IBS-D unresponsive to conventional
medical treatment. The chance of developing ischemic colitis A significant number of patients suffering from IBS also use
is rare, about 23 per 1,000 case over 6 months. alternative medicines, which include different vitamins,
Irritable Bowel Syndrome 99

Ayurvedic herbal medicine, homeopathic medicine, Chinese 6. Dickhaus B, Mayer EA, Firooz N, et al. Irritable bowel syndrome
herbal medicine and acupuncture. There are not many patients show enhanced modulation of visceral perception by
randomized placebo controlled trials with these alternative auditory stress. Am J Gastroenterol. 2003;98:135-43.
medicine therapies. The effectiveness of these therapies is 7. Drossman DA. Treatment of bacterial overgrowth in the irritable
unknown and safety is also a great concern as many herbal bowel syndrome. Ann Intern Med. 2006;145:626-8.
8. Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review
medicines can cause drug-induced hepatitis. One randomized
on irritable bowel syndrome. Gastroenterology. 2002;123:
controlled trial showed better result with standard medical
2108-31.
therapy than Ayurvedic herbal medicine. 9. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial:
lubiprostone in patients with constipation-associated irritable
bowel syndromeresults of two randomized placebo-
CONCLUSION controlled studies. Aliment Pharmacol Ther. 2009;29:329-41.
10. Drossman DA, Thompson WG. The irritable bowel syndrome:
Irritable bowel syndrome is a common clinical problem review and a graduated multicomponent treatment approach.
in our day-to-day medical practice. It is a chronic disorder Ann Intern Med. 1992;116:1009-16.
with recurrent symptoms. Although it does not cause excess 11. Ford AC, brandt LJ, Young C, et al. Efficacy of 5-HT3 antagonists and
mortality, it has a huge impact on our society considering 5-HT4 agonists in irritable bowel syndrome: systematic review and
meta-analysis. Am J Gastroenterol. 2009;104:1831-43.
the patients sufferings and the economic burden. In the last
12. Ford AC, Chey WD, Talley NJ, et al. Yield of diagnostic tests for
few decades, extensive research has explored the potential
celiac disease in individuals with symptoms suggestive of
mechanisms responsible for the symptomatology of IBS and irritable bowel syndrome: systematic review and meta-analysis.
new medical therapies have been developed. The disorder Arch Intern Med. 2009;169(7):651-8.
cannot be cured completely, but the symptoms can be 13. Hammerle CW, Surawicz CM. Updates on the treatment of irritable
alleviated by different therapies. In mild cases, symptoms can bowel syndrome. World J Gastroenterol. 2008;14(17):2639-49.
be improved by dietary and lifestyle modifications and taking 14. Johnson JF, Wald A, Tougas G, et al. Effect of tegeserod in chronic
over-the-counter medications. Moderate-to-severe cases will constipation: a randomized double-blind, controlled trial. Clin
require prescription medications. But a good doctorpatient Gastroenterol Hepatol. 2004;2:796-805.
relationship will be essential to keep the symptoms under 15. Lind CD. Motility disorders in the irritable bowel syndrome.
control for longer period of time. Patients with refractory Gastroenterol Clin North Am. 1991;20(2):279-95.
16. Low K, Hwang L, Hua J, et al. A combination of rifaximin
symptoms should be considered for psychotherapy. Our
and neomycin is most effective in treating irritable bowel
current knowledge does not suggest the routine use of
syndrome patients with methane on lactulose breath test. J Clin
alternative medicine as the remedy for IBS. As the research Gastroenterol. 2010;44(8):547-50.
is continuing, large numbers of medications are in the 17. Marshall JK, Thabane M, Borgaonkar MR, et al. Postinfectious
developmental phase for the treatment of IBS. irritable bowel syndrome after a food-borne outbreak of acute
gastroenteritis attributed to a viral pathogen. Clin Gastroenterol
Hepatol. 2007;5:457-60.
BIBLIOGRAPHY 18. Matheis A, Martens U, Kruse J, et al. Irritable bowel syndrome and
chronic pelvic pain: a singular or two different clinical syndrome?
1. Agnihotri MS. Ayurved (ancient Indian system of medicine) World J Gastroenterol. 2007;13(25):3446-55.
and modern molecular medicine. J Assoc Physicians India. 19. Mearin F, Balboa A, Badia X, et al. Irritable bowel syndrome
2000;48:366-7. subtypes according to bowel habit: revisiting the alternating
2. American College of Gastroenterology Task Force on Irritable subtype. Eur J Gastroenterol Hepatol. 2003;15(2):165-72.
Bowel Syndrome, Brandt LJ, Chey WD, et al. An evidence-based 20. Morgan V, Pickens D, Gautam S, et al. Amitriptyline reduces
position statement on the management of irritable bowel rectal pain related activation of the anterior cingulate cortex in
syndrome. Am J Gastroenterol. 2009;104(Suppl 1):S1-35. patients with irritable bowel syndrome. Gut. 2005;54:601-7.
3. Brenner DM, Moeller MJ, Chey WD, et al. The utility of probiotics 21. Pimentel M, Lembo A, Chey WD, et al. Rifaximin treatment for
in the treatment of irritable bowel syndrome: a systematic 2 weeks provide acute and sustained relief over 12 weeks of
review. Am J Gastroenterol. 2009;104:1033-49. IBS symptoms in non-constipated irritable syndrome: results
4. Cash BD, Schoenfield PS, Chey WD. Diagnostic tests in irritable from 2 North American Phase 3 trials (Target 1 and Target 2).
syndrome patients: a systematic review. Am J Gastroenterol. Gastroenterology. 2010;138(suppl 1):S64-5.
2002;97:2812-9. 22. Rhee PL. Definition and epidemiology of irritable bowel
5. Chey WD, Chey WY, Heath AT, et al. Long-term safety and efficacy syndrome. Korean J Gastroenterol. 2006;47(2):94-100.
of Alosetron in women with severe diarrhea predominant 23. Ringel Y, Drossman DA, Leserman JL, et al. Effect of abuse history on
irritable bowel syndrome. Am J Gastroenterol. 2004;99:2195- pain reports and brain responses to aversive visceral stimulation:
203. an FMRI study. Gastroenterology. 2008;134:396-404.
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24. Sperber AD, Shvartzman P, Friger M, et al. A comparative incidence of irritable bowel syndrome in children. Am J
reappraisal of the Rome II and Rome III diagnostic criteria: are Gastroenterol. 2010;105(4):933-9.
we getting closer to the true prevalence of irritable bowel 27. Thoua NM, Murray CD, Winchester WJ, et al. Amitriptyline
syndrome? Eur J Gastroenterol Hepatol. 2007;19(6):441-7. modifies the visceral hypersensitivity response to acute stress
25. Talley NJ, Fett SL, Zinsmeister AR, et al. Gastrointestinal tract in the irritable bowel syndrome. Aliment Pharmacol Ther.
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Gastroenterology. 1994;107:1040-9. 28. Whitehead WE, Palsson OS, Feld AD, et al. Utility of red flag
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11
cHAPTER

Colorectal Carcinoma

Kaushal Kishor Prasad, Saroj Kant Sinha, Rakesh Kochhar

INTRODUCTION tumor-associated antigens have opened new horizon for the


immunotherapy of advanced CRC.
Colorectal carcinoma (CRC) is the third most commonly
diagnosed tumors in the Western countries, and recently
its incidence is increasing rapidly in Asia. These increased EPIDEMIOLOGICAL TRENDS IN ASIA
rates are the result of increase in the risk factors that are
associated with westernization of Asian populations. Colorectal carcinoma has become one of the leading causes
Epidemiologically, alcoholism, cigarette smoking, diabetes of death in many Asian countries. Epidemiologic studies have
mellitus, consumption of red and processed meat, physical demonstrated geographical variations in the incidence of
inactivity and obesity are associated with CRC. The changes CRC across ethnic groups and socioeconomic groups. There
in dietary pattern and lifestyle are linked to increase in CRC is an increasing trend in CRC, which is considered as typical
incidence in Asian populations; however, the interaction of economically developed countries. CRC incidences differ
between these factors and genetic makeups might also play a considerably between Western and non-Western countries.
pivotal role. At present the incidence, anatomical distribution In past few decades, a steep rise in CRC incidence has been
and mortality of CRC among Asian populations are not reported in several Asian countries. The rising trend in the
different compared with Western countries. The mortality incidence and mortality from CRC is much more in affluent
related to CRC is also rising in Asia, except in Japan and than in poorer societies and differs to a great extent in different
Singapore. For the prevention and early intervention various ethnic groups. In South-East Asia, CRC is now the third most
screening options for CRC are available. In Japan, Korea and common neoplastic disease in both sexes. Although there
Taiwan CRC screening by fecal occult blood tests (FOBT) is at are evidences of increasing incidence in North-Western and
present national policy. Full length colonoscopy is the most Central Asia, CRCs are still very infrequent.
commonly used modality for the diagnosis of CRC. Surgery
is the only way to potentially cure the disease and may be
accomplished in 7080% of newly diagnosed cases. However, INCIDENCE OF COLORECTAL
about half of patients who underwent surgery alone ultimately CARCINOMA IN ASIA
relapse and dies due to widespread metastasis. Surgery with
additional adjuvant therapy utilizing chemotherapy and/or Colorectal carcinoma has a global annual incidence of
radiotherapy improves the final outcome for high-risk CRC 1 million cases and an annual mortality of more than 500,000
patients. After surgical treatment surveillance programs are cases. The overall estimated new cases of CRC in USA in
widely accepted as an integral part of the treatment plan 2013 are 142,820. CRC comprises 9% of the overall cancer
provided to CRC patients. burden and is most frequent in North America, Australia,
The importance of the molecular biology and its New Zealand, and Europe. CRC is considered as a disease
methodology has been growing for both detection of the of the Western lifestyle. In past few decades, China, Japan,
CRC and the selection of the best treatment for the individual South Korea, and Singapore have experienced an increase
patient during the last decade. The genetic and epigenetic of two to four times in the incidence of CRC. The most
characteristics of CRC help predict the prognosis of the striking increase in CRC incidence has been observed in
disease and also select the best treatment, which extends Japan, a developed nation with a strong economy. In the
the disease-free and overall survival of the patient. The last 4 decades, two of three registries recorded an increased
cloning techniques utilizing to identify genes and peptides of incidence of CRC of more than 90%. During this period,
102 Textbook of Hepato-gastroenterology

there has been a westernization of the Japanese diet with an the difference in the incidence of CRC amongst Asians of the
increased intake of dairy products, fat, and meat. It has been same racial origin (e.g. Indian) migrating to Southeast Asia
speculated that westernization may account for the major and to the North America. In Singapore and Malaysia the
shift in CRC incidence. The increase in incidence might be incidence of CRC is significantly lower among the Indian and
also due to actual increase in risk of CRC; however, it could be Malay populations than among the Chinese population. In
also due to increasing population or relative increase in the both these countries, the three major ethnic groups live in
high-risk groups, increased awareness, or availability of better the same environment. The lower incidence among Indians
diagnostic tools. The age-standardized rates (ASR) of CRC per and the higher incidence among Chinese living in South
100,000 men are 49.3 in Japan, 35.1 in Singapore, and 24.7 in east Asia reflect the incidence rates in the countries of origin
South Korea as compared to 44.4 in North America and 42.9 although both racial groups migrated few generations ago.
in Western Europe. Although overall ASR has increased in These evidences on racial differences indicate that the genetic
majority of Asian countries in the past few decades, there has makeup of a population is an important etiological factor in
been recent decrease in ASR in some countries, particularly in colorectal carcinogenesis.
those having younger population. In Singapore, CRC became
second most common carcinoma in both sexes, and similar
pattern has been observed in Hong Kong. The noticeable rises DISTRIBUTION ACCORDING TO AGE
in incidence of CRC have also been observed in China and AND SEX
Taiwan, but the reported data are not available from countries
like India, Indonesia, and Philippines. The observed overall The risk for onset of CRC increases with aging. In developed
incidence of advanced CRC in asymptomatic Asians is countries, 90% of CRC cases are 50 years or above. In the UK,
comparable with that of other developed countries. Figure 1 the peak age of onset is 70 years, while 510% of cases are 80
shows estimated ASR for CRC worldwide. years. The peak onset age in the USA is 75 years, while less
In many different ethnic groups in Asia, there are substantial than 6% of cases are under the age of 40 years. In Thailand,
differences in the incidence of CRC. The Japanese, Korean and the average age for patients of CRC is 61.2 years and 83.9% of
Chinese are found to have a higher risk of advanced colonic patients are above 50 years. In Philippines, the average onset
carcinoma than in the Indians, Thais and Filipinos. The age in patients of CRC is 55.3 years, while 17% of patients
genetic predisposition interacts with environmental factors are below 40 years. In Korea, the average onset age of colon
or lifestyle modification is substantiated by the evidence that carcinoma is 57.4 years and rectal carcinoma is 55.6 years. In

Fig. 1: Estimated age-standardized rates and mortality rates for colorectal carcinoma
Colorectal Carcinoma 103

Turkey genetic factors are thought to be playing an important CRC in many Asian countries. In Northwestern and Central
role as CRCs appear in younger age group more commonly Asia, there is a slight predominance of colon carcinoma over
than in Western populations. A similar pattern has been rectal carcinoma in both sexes and men have slightly higher
observed in Iran, where about 50% of CRC cases are also less incidence rates. Substantial increases of CRCs are observed
than 50 years of age and there is a family history in about 35% in Shiraz with no alteration in the ratio of right to left-sided
of cases. The apparent higher proportions of younger cases carcinomas, whereas in Tabriz a left shift of both colorectal
may also be due to relatively younger population in these adenomas and carcinomas are observed. In Turkey, colon
countries. carcinomas slightly outnumber those of the rectal carcinomas
Globally, CRC is the third most common carcinoma in men but the situation in Iran is unclear. Synchronous colonic and
and the second most common in women. More than 50% of rectal lesions may not be rare.
cases occur in developed countries and developed regions
of developing countries. The incidence rates vary between
10-folds in men and women, the highest rates estimated to be MORTALITY RATE FOR COLORECTAL
in Australia, New Zealand, and Western Europe, intermediate
in Latin America and the lowest in Africa (except Southern CANCER IN ASIA
Africa) and SouthCentral Asia. The incidence rates are higher
Deaths from CRC account for 8% of all cancer deaths, making it
in men than in women with overall sex ratio of the ASRs 1.4:1.
the fourth most common cause of death from cancer. Figure 1
The highest CRC incidence rates among men are observed
shows estimated mortality rates for CRC worldwide. The
in Europe, North America, and Oceania. In Asia, high rates
overall estimated deaths in USA from CRC in 2013 are 50,830.
are observed in Japan, Singapore, and Israel. Higher CRC
Similar to incidence, mortality rates are lower in women
incidence rates observed in these three countries recently and
than in men, except in the Caribbean. Globally there is less
are thought might be due to lifestyle or environmental factors.
variability in mortality rates, which are around sixfold in men
A slow rising trend in men has also been noted in Hong Kong.
and fivefold in women. The highest mortality rates in men
The highest CRC incidence rates among women are observed
and women observed in Central and Eastern Europe with
in New Zealand, Australia, and Israel. High CRC rates among
20.3 per 100,000 for men and 12.1 per 100,000 for women, and
women are also observed in Japan and Singapore; however,
rates for women are noticeably lower than those for men in the lowest rates in Middle Africa with 3.5 per 100,000 for men
these countries. The ASR of CRC among women in Hong Kong and 2.7 per 100,000 for women. A recent decreasing trends in
and Singapore had reached a plateau by 1995 and since then CRC in both sexes observed in USA, Australia, New Zealand,
it has downward trend, which has different trend from men. and the majority of Western Europe, including Germany,
The lower rates observed among women compared with men France, Austria, Ireland, and the UK. Increasing trends in CRC
may be associated with different lifestyle patterns in men and mortality rates recently observed in both sexes in Mexico,
women. Among both sex, the lowest CRC incidence rates Brazil, Chile, Ecuador, Romania, and Russia.
are observed in India, Oman, Egypt, Algeria, and Pakistan. The incidence of CRC in Asia has been increasing rapidly
In these developing countries, low CRC incidence rates may in recent decades, and mortality has also increased except
mirror a low prevalence of known CRC risk factors. in Japan and Singapore. The largest observed increase in
CRC deaths happened in Korean women, in past decades,
although mortality rates still remained relatively low (7.5 per
RIGHT SHIFT IN THE POSITION OF 100,000) in recent year. CRC mortality rates among Korean
men stabilized during recent time after increasing in past
COLORECTAL CANCER LESIONS decades. In Japan, death rates decreased in past decades in
both sexes; however, more marked in women.
A trend of relatively higher proportion of carcinomas in
ascending colon and cecum versus descending colon, sigmoid
colon and rectum (right shifting) has been observed in South
east Asia, including Japan, South Korea, and Hong Kong, COLORECTAL POLYPOID AND
which is not accountable by indications for colonoscopic NONPOLYPOID ADENOMA
examination or difference in age. The wider availability of
colonoscopy, aging populations and increasing trend of Colorectal polyps have conventionally been classified into two
right-sided CRC is accompanied by a continuous declining main types: neoplastic polyp, or adenoma, and hyperplastic
trend of rectal carcinoma in both sexes in all age groups polyp (HPP). Colorectal adenomas are precancerous
might explain in part the apparent increase in right-sided lesions for the CRCs; they have been classified into three
104 Textbook of Hepato-gastroenterology

histologic types, with increasing malignant potential: are more likely to be missed on colonoscopic examination
tubular, tubulovillous and villous adenoma. The different than conventional adenomas, and the progression of SAs to
biological and metabolic processes have been implicated carcinoma may be at rapid pace. Therefore, it is of paramount
to adenoma pathogenesis. The adenomatous polyps are importance for both gastroenterologists and gastrointestinal
benign tumors that may undergo malignant transformation (GI) histopathologists to recognize SAs, and affected patients
and this transformation of adenoma to carcinoma occurs in must undergo surveillance and lesions must be identified and
only about 5% of cases. Early detection and removal of all resected.
adenomas decreases CRC incidence and mortality rates. The The majority of CRC progresses slowly through polypoid
pathological features are unable to accurately discriminate growth, the nonpolypoid (flat and depressed) colorectal
which adenomas will progresses to carcinomas from those neoplasms (NP-CRN) also contribute to the progression
which will not. Large size of adenoma, villous pathology of CRC. The NP-CRN lesions appear to be slightly elevated,
and the degree of dysplasia within the adenomas are highly completely flat or slightly depressed with respect to the
correlated with the potential to transform into carcinoma. surrounding normal mucosa. Large, flat and depressed
Understanding the pathobiology of carcinoma progression lesions are more likely to be severely dysplastic. The NP-CRN
will help better characterize high-risk adenomas, and further lesions, initially thought to primarily exist in Japan, recently
help in establishing triage tests which will allow to safely it have been observed globally. The NP-CRN seems to be
reserving colonoscopic examination only for cases at high more prevalent in Asian populations. Since NP-CRN is small
probability of having truly high-risk lesions. The screening lesions and there are no adenomatous lesions in their close
tests based on changes at molecular levels that affect relevant vicinity, they are termed de novo carcinomas as they appear
biological and metabolic processes hold promising future. not to originate from any precursor lesion. The NP-CRN is
Overall in Asian continent, 57% of polyps are distal, 30% are unlikely to have K-ras mutations compared to CRCs arising
proximal and 13% are synchronous. In the Western world, 49% from the adenoma-carcinoma sequence. The colorectal
of polyps are distal, 49% are proximal and 2% are synchronous.
NP-CRN have tendency to reach deeper layers of the bowel
However, the advanced neoplastic lesion distributions are not
wall early in the course of disease and having a higher grade
significantly different between the Eastern and the Western
of dysplasia and for this reasons they are more invasive
world. There is a trend toward the right-shift of colonic
compared to the polypoid adenomas. In Japan up to a third of
polyps in Asia. A right-shift of adenoma is also apparent in
CRCs identified to be arisen de novo. The aging populations
Korea. In Japan, a large cohort study consisted of consecutive
have highest incidence rate of these carcinomas. In Taiwan
asymptomatic subjects indicated that the phenomenon of
at least 30% of CRCs might be arising de novo. The absence
right-shifting is resulting from aging, and hence full-length
of polypoid growth preceding carcinoma poses difficulties
colonoscopies are of importance in aging population.
Although a typical small and distal HPP without associated in screening for early CRCs by radiological imaging or even
dysplasia has little malignant potential, but individual with by different endoscopic techniques. Recent significant
hyperplastic polyposis syndrome (HPS) has an increased advances in endoscopic resolution and the development of
potential for progression to CRC. The HPS presents with improved diagnostic techniques and modalities might play
extensive phenotypic heterogeneity not only with respect an important role in the early management of such lesions.
to the number and size of polyps, but also with regard to
presence of CRC, polyp histology, sex ratios, age of onset,
and the presence of a family history of CRC. Hyperplastic PATHOPHYSIOLOGY OF
polyps are only part of the spectrum of polyps known as COLORECTAL CARCINOMA
serrated adenomas (SAs). SAs are a heterogeneous group
of lesions having distinct morphologic, histologic and Colorectal carcinoma is caused by interplay between the
molecular genetic characteristics that can potentially environmental factors and host with accumulation of
undergo malignant transformation to CRC through the gene alterations (acquired or inherited), such as activation
serrated polyp pathway. Sessile SAs usually presents as of oncogenes and inactivation of suppressor genes, and
a large usually greater than 1 cm sessile polyp that lacks generally involves an adenomacarcinoma sequence.
conventional dysplasia. Traditional serrated adenoma (TSA) Carcinogenesis progresses with multifactor, multi-hit and
is a rare type of colorectal polyp that has the cytologic features multistage mechanisms. In addition to nutritional aspects,
of an adenoma and the architectural features that of a HPP. other environmental factors include physical exercise,
The serrated polyp pathway may contribute to metachronous energy intake, obesity and parity. Environmental factors
or missed carcinomas for the reason being serrated lesions are modifiable risk factors that are thought to contribute
Colorectal Carcinoma 105

substantially to the variation in incidence. Improved success The MSI is usually associated with absence of expression of
in the management of CRC requires a better understanding one or more of the MMR proteins like MSH2, MLH1, MSH6
of its development and biological behavior. The key for this is and PMS2. About 15% of CRCs are characterized by genomic
molecular genetics, which is explored in more detail below. MSI arising as a consequence of loss of MMR activity. The MSI
cancers are characterized by the changes in repeating units of
DNA that normally occur throughout the genome known as
MOLECULAR BIOLOGY: IS IT DIFFERENT DNA microsatellites. Nearly 80% of carcinomas harboring MSI
are sporadic with hypermethylation of the promoter region of
IN ASIANS? the MMR gene MLH1. The remainder occurs as part of the
Our level of understanding of the molecular events underlying HNPCC. Tumors with MSI tend to arise in the proximal colon
CRC is far greater than for other common solid tumors. CRC and have a slightly better prognosis than tumors without MSI.
is used as a model for investigating the molecular genetics In carcinogenesis epigenetic silencing of genes is
of carcinoma development and progression; this is in part considered as an important mechanism for inactivation of
due to the stepwise progression of mutations facilitates the tumor suppressor genes. In CRC epigenetic changes comprise
histological transition from normal mucosa to adenoma chromatin modifications, aberrant DNA methylation and
to carcinoma. It arises as a consequence of genomic expression of noncoding RNAs, especially microRNA (miRs).
instability with an accumulation of genetic errors resulting DNA methylation and histone modification are involved in the
in dysregulation of molecular pathways controlling cell maintenance of gene silencing that cause carcinogenesis. The
migration, differentiation, apoptosis and proliferation. CRCs DNA methylation of cancer-related gene promoters usually
result from a variable combination of inactivation of the starts early in the process of carcinogenesis that affect various
tumor suppressor genes adenomatous polyposis coli (APC), types of CRC to differing degrees. Histone modifications play
p53, transforming growth factor beta (TGF-), activation of a pivotal role in the process of gene silencing in CRC as it
oncogene pathways including K-ras, and activation of the, impinges on chromatin structure and gene expression. The
cyclooxygenase (COX)-2, epidermal growth factor receptor DNA hypermethylation also leads to inappropriate expression
and vascular endothelial growth factor (VEGF) pathways. and down-regulation of certain miRs which act like tumor
These changes are similar whether they occur in inherited suppressor genes. MicroRNAs are a class of noncoding small
disorders like APC and hereditary nonpolyposis colorectal RNAs with critical regulatory functions as post-transcriptional
cancer (HNPCC) or acquired cancer in the elderly. In regulators. The miRs regulate tumor progression and invasion
addition to chromosomal instability (CIN) and microsatellite via direct interaction with target messenger RNAs (mRNAs).
instability (MSI), a third pathway, epigenetic instability has Colorectal carcinoma is associated with the under expression
been implicated in progression to CRC. of miR143. Expression of miRs in CRC cells had different
Chromosomal instability is the most common pathway effects and the miRs interact with different mRNAs. miR28-
by which CRC develops and is present in 6570% of cancers. 5p and miR28-3p are transcribed from the same RNA hairpin
Main genomic alterations in CIN cancers include alterations and are downregulated in CRC cells. Overexpression of each
in chromosome number (aneuploidy), loss of portions of has different effects on CRC cell proliferation and migration.
chromosome 5q, 18q and 17p, and mutation of the K-ras Recently, the p53 tumor suppressor and K-ras has identified
oncogene. The losses are associated with instability at as targets of miRs. Both proteins are known targets for at least
the molecular and chromosomal level. The commonly two miRs species (p53: miR125a/b and K-ras: miRlet7a/143).
involved genes in chromosome losses are APC (5q), DCC/ Many tumor suppressor genes contain CpG islands in
MADH2/MADH4 (18q) and TP53 (17p), and chromosome. their promoters. CpG island DNA methylation and aberrant
Inactivation of the tumor suppressor gene, APC is an early methylation of genes drive the initiation and progression
initiating event. Activating mutations in of the K-ras oncogene of CRC. CpG island methylator phenotype (CIMP) refers
follow. Additional mutations including mutations in TGF- to a subset of CRC that occur through the epigenetic
and p53 drive subsequent malignant transformation. The instability pathway and that are characterized by widespread
temporal acquisition of these genetic changes is matched by hypermethylation of promoter CpG island loci, resulting in
the progression from normal colonic epithelium to adenoma the inactivation of several tumor suppressor genes or tumor-
formation and subsequently CRC. related genes. Among the common targets for aberrant DNA
The MSI cancers occur as a result of defects in the DNA methylation is the p16 gene. The p16 is a gene, which seems
mismatch repair (MMR) system and having mostly intact to play a major role in colorectal carcinogenesis. It is a tumor
chromosome component. This phenomenon may occur due suppressor gene, which is also known as MTS1, INK4a or
to germline or somatic mutations or epigenetic alterations. CDKN2A. Inactivation of the p16 gene is recognized as the
106 Textbook of Hepato-gastroenterology

second most common molecular defect in human carcinoma metastasis-associated miRs like miR21, 135a, 335, 206 and
preferentially through de novo methylation of its 5-promoter- let7a expression levels in primary CRCs significantly correlates
associated CpG islands. The percentage of hypermethylation with the presence of metastatic disease. The circulating miRs
of the p16 gene ranged from 29 to 42% in Asian population. have potential as novel noninvasive biomarkers for carcinoma
Colorectal carcinomas can be classified by global genomic and other disease processes. Serum miR29a hold substantial
or epigenomic aberrations including CIN, MSI, and CIMP. potential as a novel noninvasive biomarker for early detection
Classification based on CIN has many problems because the of CRC with liver metastases.
methods or markers and criteria currently used for analysis of The identification of important CRC-related genes may
CIN are not uniform. The MSI and CIMP are relatively well- help facilitate the early diagnosis, prevention, and treatment
defined when compared with CIN; CRCs are usually classified of CRC. Genetic and epigenetic characteristics of the tumors
into four molecular subtypes on the basis of both CIMP and help to predict the prognosis of the disease and also select the
MSI statuses: CIMP+/MSI+, CIMP+/MSI, CIMP/MSI+ and best treatment, which extends the disease-free and overall
CIMP/MSI. There are differences between Western (United survival of the patient.
States and European Union) and Eastern (Korea and China)
populations in the number of CRC that are MSI+, and in the
number of MSI+ CRC that are CIMP+. The four molecular INHERITED SUSCEPTIBILITY TO
subtypes of CRC that are defined by their CIMP and MSI statuses
COLORECTAL CARCINOMA
are characterized by their own distinct clinicopathologic and
molecular features and precursor lesions. In particular, the About one-fourth of CRC cases are associated with a
clinicopathologic features of MSI+ CRC differ depending on family history of carcinoma. Up to 10% of CRC cases have
the CIMP status. Further understanding of the heterogeneity a true inherited susceptibility to CRC and these cases are
in CRC molecular pathways may help explain the diverse subdivided according to the presence or absence of colonic
morphologic features of CRC. The prevalence of MSI+ in polyps as a major disease manifestation. Those diseases
CRCs in Western populations is approximately 15% but tends having polyposis include familial adenomatous polyposis
to be lower in Korean populations. For CRCs in Western (FAP), MutY-homolog (MYH)-associated polyposis (MAP)
populations, approximately two-thirds of sporadic MSI+ CRCs and the hamartomatous polyposis syndromes including
are CIMP+. In contrast, approximately one-third of MSI+ CRCs Peutz-Jeghers syndrome and juvenile polyposis syndrome
are CIMP+ in CRCs in Korean populations. Environmental or (JPS). These conditions are all associated with a high risk of
ethnic differences between Eastern and Western populations developing CRC. Familial adenomatous polyposis and HNPCC
may account for this discrepancy. are dominantly inherited conditions with 100% and 80% life-
Colorectal cancer metastasis occurs in various organs, time risk of developing colorectal cancer, respectively. These
most frequently in liver. The liver metastases from many hereditary syndromes that predispose to CRC genesis have
cases of CRCs acquire genetic aberrations that are not present significantly contributed to our understanding of the genetic
in primary CRCs. These genetic alterations acquired by mechanisms underlying CRC formation. Occurrences of
metastatic tumors may be associated with either metastatic CRCs at younger age are one of the major clinical hallmarks of
process and/or adaption of metastatic cells to the liver this inherited susceptibility. The hereditary syndromes add a
microenvironment. The acquisition of metastatic aberrations wide range of risk, modes of inheritance, age at presentation,
predominantly consist of an increased frequency of genetic extracolonic manifestations, endoscopic appearances, and
alterations of chromosomes which are associated with histological findings. Inherited susceptibility should be
metastatic CRCs, including 1p, 7p, 8q, 13q, 17p, 18q and 20q suspected when CRCs occur in younger age, cases presenting
and acquisition of new chromosomal abnormalities like loss with synchronous or metachronous CRCs or adenomatous
of chromosomes 4 and 10q and gain of chromosomes 5p and polyps, or with a strong family history of CRC. The mutations
6p. In Taiwanese CRC patients UDP-glucuronosyltransferase in DNA MMR genes are most common and well-known
1A1 (UGT1A1): carriage of the variant-211 UGT1A1 allele, and predisposing factor for CRC that cause HNPCC or Lynch
also UGT1A7*3 allele represent a risk factor for development syndrome. The mutations in the base-excision repair (BER)
of metastases and also the determinant for metastases. gene MYH, and FAP which are due to mutations in the APC
The miRs are potential clinically useful prognostic tool as gene predispose to CRC in other hereditary syndromes.
Colorectal Carcinoma 107

Familial Adenomatous Polyposis: AFAP-related gene and encodes an enzyme DNA glycosylase,
MYH glycosylase, involved in oxidative DNA damage BER.
Classic and Attenuated The MYH gene is located on the chromosome 1p. Mutations
Familial adenomatous polyposis is one of the well- in this gene result in heritable predisposition to colon and
established and clearly understood of the all inherited stomach carcinoma. The MYH mutations are seen in 1020%
colon cancer syndromes. Majority of FAP cases are due to of classical FAP cases without an APC mutation and in 30% of
germline mutations of the APC gene on chromosome 5q21. AFAP cases. Polyps due to mutated MYH do not appear until
FAP is characterized by more than 100 adenomatous polyps adulthood and are less numerous than those found in patients
in the colorectum that usually appear during adolescence with APC gene mutations. MAP has broad range of clinical
or the third decade of life. It is associated with extracolonic presentations as the MYH genes has the ability to cause
manifestations in 70% of the cases that include congenital disease in its homozygous or compound heterozygous forms.
hypertrophy of the retinal pigment epithelium (CHRPE), The incidence of extracolonic cancers is significantly increased
which includes ovary, bladder, skin and breast cancers.
upper GI tumors, desmoid tumors, papillary carcinoma of
the thyroid, medulloblastoma, hepatoblastoma and soft
tissue tumors. This syndrome inevitably leads to CRC when Hamartomatous Polyposis Syndromes
left untreated and it is estimated that 1% of all CRC cases
are due to it. The risk of cancer is generally related to polyp PeutzJeghers syndrome is an autosomal dominant disorder
number. The risk of CRC development can be significantly characterized by the presence of hamartomatous polyps in
reduced when patients enter a screening-treatment program. the small intestine, together with dark-blue or dark-brown
freckling, especially around the mouth and on the lips, fingers,
Annual colonoscopy is indicated in individuals at risk of
or toes. Freckles generally appear in childhood and may fade
FAP from adolescence, followed by prophylactic colectomy
with age. There is a significantly higher risk of carcinoma
or proctocolectomy to eliminate the risk of subsequent
progression from the small intestinal polyps as well as breast
development of CRC only in those proven to have FAP.
cancer, CRC, and other types of cancer. The syndrome is
Attenuated FAP (AFAP) is a less severe phenotypic variant of
caused by germline mutations in the STK11 (LKB1) and
FAP characterized by an average 69% lifetime risk of CRC and
possibly other genes.
the presence of less than 100 polyps and a later onset of CRC.
Juvenile polyposis syndrome is another autosomal
AFAP is caused by autosomal-dominant inherited mutations
dominant disorder in which affected individuals are
in the APC gene which controls turnover of -catenin in the
predisposed to hamartomatous polyps occurring most
Wnt pathway. New or de novo APC mutations are responsible
commonly in stomach and colorectum. While the majority of
for approximately 25% of FAP cases. In 85% of classical
the polyps found in JPS are non-neoplastic, hamartomatous,
FAP families and in 2030% of AFAP cases, a germline APC self-limiting and benign, there is an increased risk of
mutation identified. The dense carpeting of colonic polyps adenocarcinoma progression to GI carcinoma occurs in
in classic FAP is associated with APC mutations that occur variable numbers (968%) of juvenile polyposis cases. Cases
between codons 169 and 1393. The sparse polyps are features with JPS are at an increased risk for developing specific types
of AFAP cases with mutations occur at the extreme ends of of cancer, including CRC, gastric, esophageal and pancreatic
the APC gene or in exon 9. APC mutations occurring between carcinoma. Germline mutations responsible for JPS have
codons 1445 and 1578 in Gardner syndrome characterized by been identified in the SMAD4 (DPC4), BMPR1A and PTEN
FAP with epidermoid cysts, osteomas, dental anomalies, and/ genes. There is a condition related to JPS that is also caused
or desmoid tumors. by alterations in the SMAD4 gene. This condition is known
as combined juvenile polyposis/hereditary hemorrhagic
telangiectasia syndrome (combined JPS/HHT syndrome). It
MutY-homolog-associated Polyposis is estimated that 1522% of people with a genetic alteration in
MutY-homolog-associated polyposis is an autosomal SMAD4 may have combined JPS/HHT syndrome. Mutations
recessive inherited polyposis syndrome. The MYH gene was in PTEN also account for Cowdens syndrome, which carries
first identified in 2002 in three siblings with multiple colonic an increased risk of early-onset breast cancer, thyroid cancer,
adenomas and CRC but no APC mutation. It is the second ovarian cancer and hamartomatous lesions of the skin.
108 Textbook of Hepato-gastroenterology

Hereditary Nonpolyposis Colorectal MOLECULAR GENETICS OF SPORADIC


Carcinoma/Lynch Syndrome COLORECTAL CARCINOMA
Hereditary nonpolyposis colorectal carcinoma is an Among the various causes of CRC, approximately 75% can be
autosomal-dominant disease with a 6882% lifetime risk attributed to sporadic disease, in which there is no apparent
of CRC caused by germline to MSI, also known as MSI-H, family history. The multicentric genome-wide association
which is a hallmark of this condition. It accounts for 5% of studies (GWAS) identified the complex genetic architecture
all cases of CRC and it is characterized by younger age of of the sporadic CRC cases. High penetrance mutations in a
onset, excess synchronous and metachronous CRCs, right- small group of genes have been identified as the causal agent
sided predominance and extracolonic cancers, including of CRC in high risk families. APC-I1307K, HRAS1-VNTR and
endometrium, ovary, pancreas, stomach, small intestine, MTHFR variants represent the low penetrance susceptibility
hepatobiliary tract, upper urinary tract, brain and skin. alleles. Implies that they have considerable impact on CRC
HNPCC can be divided into Lynch syndrome I (familial incidence even though genotypic risks are modest. The
colon cancer) and Lynch syndrome II (HNPCC associated GWAS of CRC have identified rs6983267 and trs10505477
with other cancers of the GI tract or reproductive system. polymorphisms as key loci in the 8q24 region to be associated
The variations in the MMR genes, including MLH1, MSH2, with CRC. The rs6983267 G more than T polymorphism is a
MSH6, and PMS2 genes on chromosome 2 increase the risk of risk factor for CRC in Asians, Europeans and Americans with
developing HNPCC. Mutations of the EPCAM gene that result European ancestry. The NOD1/CARD4 and NOD2/CARD15
in hypermethylation and silencing of MSH2 is also seen in gene polymorphisms are also associated with altered risk of
HNPCC cases. The Amsterdam criteria and revised Bethesda CRC. NOD1/CARD4 and NOD2/CARD15 are members of
guidelines are used in clinical practice to identify individuals nod-like receptor family and located in cytosol that binds
at risk for HNPCC who require further evaluation. bacterial and viral ligands.
MuirTorre syndrome (MTS), a rare variant of HNPCC The somatic mutations spectrum that contributes to the
in which the features of HNPCC are present along with CRC pathogenesis is far more extensive. Each tumor has a
multiple cutaneous tumors including sebaceous adenomas, distinct mutational gene signature. A tumor can accumulate
sebaceous carcinomas and keratoacanthomas. The clinical an average of approximately 90 mutant genes. Sixty-nine
variability is common; however, skin lesions and CRC define genes are considered to be relevant to the CRC pathogenesis,
the phenotype. Like HNPCC, cases with MTS linked to and each CRC can harbor an average of nine mutant genes
mutations in either MSH2 or MLH1 gene. per tumor. Mutations in APC are seen in 7080% of sporadic
tumors, and often occur early in the development of CRC.
Familial Colorectal Carcinoma Other tumor suppressor genes involved in CRC include p53,
which is mutated in 75% of sporadic tumors and deleted in
Familial CRC is an autosomal dominant disease which colorectal cancer (DCC), which is mutated in 70% of CRCs.
accounts for up to 25% of cases. Affected patients have a The K-ras oncogene is mutated in 50% of all sporadic CRCs. In
family history of CRC, but the pattern is not consistent with around 15% of sporadic CRCs, MMR genes are inactivated. In
one of the inherited syndromes described above. Individuals most cases of the CRCs mutations occur in the Wnt/-catenin
from these families are at increased risk of developing pathway and these mutations lead to increased nuclear
CRC, although the risk is not as high as with the inherited accumulation of the transcriptional coactivator, -catenin
syndromes. About 710% of cases have a first-degree relative and it associates with T-cell factor/lymphoid enhancer
with CRC and about twice that many have either a first- factor (TCF/LEF) sequence-specific transcription factors in
degree or a second-degree relative with CRC. It increases the nucleus to activate target gene expression by recruiting
the risk of developing CRC 1.7-fold over that of the general multiprotein complexes that remodel or modify chromatin
population. The genetic abnormalities underlying familial into a transcriptionally permissive state. The -catenin/TCF4
CRC remain incompletely understood. A subset of families complexes directly associate with the Yes-associated protein
with MSI-negative familial colorectal tumor found to link (YAP) gene locus and that -catenin is required for YAP
to chromosome 9q22.2-31.2. Other three potential loci in expression in CRC cells. The Hippo pathway also contributes
familial CRC families linked to chromosomes 11, 14 and 22. to colorectal carcinogenesis. This pathway restricts cellular
Colorectal Carcinoma 109

growth by preventing nuclear accumulation of the YAP Table 1: List of risk factors for colorectal carcinoma in Asia
transcriptional coactivator. YAP expression is elevated in
Lifestyle
CRCs similar to Wnt/-catenin signaling. The Wnt/-catenin
and Hippo/YAP signaling pathways converge to promote Alcohol and smoking
CRC. Physical inactivity
The genetic pathway of colorectal carcinogenesis parallels Obesity
with histological transition from adenoma to carcinoma. Dietary factors
Although most of the CRCs develop through the adenoma- High fatty diet
carcinoma sequence with APC, K-ras, DCC and p53 mutations,
Low dietary fiber and starch
an admixed HPP or serrated adenoma have been linked to a
distinct serrated polyp pathway of colorectal carcinogenesis Red and processed meat
which is characterized by MSI and deficiency in DNA MMR. Low intake of vegetables and fruits
HPPs associated with alterations in the components of the Low intake of micronutrients
mitogen-activated protein kinase signaling pathway, notably Soy and phytoestrogens
the oncogenes K-ras and BRAF. The HPPs associated CRC Reproductive factor
are also linked to MLH1 protein, MSI and MLH1 promoter
Late age at first child birth
methylation. A high proportion of SAs and TSAs have BRAF
mutations and DNA methylation. Early menarche
In the case of CRC that results after radiation exposure Late menopause
may influence MSI status through MSI-related epigenetic Menstrual regularity
and genetic changes, which may occur in the early stage of Number of abortion(s)
colorectal carcinogenesis. Infectious disease
The mechanism whereby lifestyle and other factors may
Schistosomiasis
interact with the expression of the above molecular pathways
Helicobacter pylori
is explored in detail below.
Other specific diseases
Inflammatory bowel disease
RISK FACTORS Ulcerative colitis
Crohns disease
The risk of developing CRC is influenced by both our lifestyle
Diabetes mellitus
and the environment where we live in apart from our genetic
makeup. The GI tract is influenced by diets, alcohol and GI
microecology. The microbiome forms an integral part of the alcoholic beverages are causally related to CRC. The inactive
human organism. External force that impacts human health form of aldehyde dehydrogenase-2 (ALDH2), encoded by
and diseases. Other external factors, including sedentary life the gene ALDH2*1/2*2, which is prevalent in Asians, exposes
and tobacco consumption have also impact on the diseases of them to higher levels of acetaldehyde after drinking and
GI tract. The list of risk factors for CRC in Asia is summarized is an important risk factor for CRC. Alcohol consumption
in Table 1. combined with a diet low in methionine and folate has strong
impact on colorectal carcinogenesis through antagonism of
Lifestyle methyl group metabolism.
Smoking is a well-known cause of lung carcinoma, but
With rapid modernization, lifestyle changes have been some of the carcinoma-causing substances are swallowed
blamed for an increased incidence of CRC. Physical inactivity, and can cause CRC. Long-term smokers are more likely than
smoking and alcohol intake have been associated with nonsmokers to develop CRC. An increased risk of CRC among
development of CRC. smokers related to the number of cigarette consumption and
age at the starting of smoking. Both men and women are
equally affected. Current smokers have a higher risk than
Alcohol and Smoking ex-smokers. In comparison to the nonsmokers, smokers
Alcohol itself is not carcinogenic. However, its first metabolite have 1.52.5 times increased risk of CRCs. Smoking interacts
(acetaldehyde) has been shown to be a potent carcinogen in with alcohol consumption in an additive fashion in affecting
humans. High alcohol consumption increased the risk of CRC the risk of CRC. Approximately 50% of the CRC cases can be
by up to 60%. Epidemiological study has demonstrated that prevented by tobacco and alcohol control.
110 Textbook of Hepato-gastroenterology

Physical Inactivity advanced colorectal adenoma. An elevated body mass index


(BMI) has been associated with both the development of
There is an inverse relationship between physical activity colonic adenomas and CRC in Japan, Korea, and China.
and risk of CRC. When those in the highest and lowest Visceral adiposity is a stronger risk factor for development of
categories of physical activity are compared, a reduction in CRC compared with BMI alone with an elevated risk of CRC in
the risk of CRC of up to 60% has been observed. High levels patients with higher waist-to-hip ratios. It is unclear whether
of physical activity have been associated with a lower risk of interventions to reduce weight could have an impact on the
colon carcinoma, but not rectal carcinoma in Western world development of CRC.
as well as in some Asian countries. A number of potential
mechanisms whereby physical activity could reduce the risk
of CRC have been described. Increase in GI transit time (with Dietary Factors
increased exposure of colorectal mucosa to fecal carcinogens), It is widely believed that environmental factors, particularly
altered immune function, increased prostaglandin levels dietary patterns, account for most of this marked variation in
and alterations in GI and pancreatic hormone profiles have
incidence rate of CRC. Differences in dietary habits have been
all been proposed to play a role. High levels of insulin and
implicated in the risk of developing CRC. Dietary factors are
insulin-like growth factor-1 (IGF-1) are associated with low
clearly linked to the development of CRC, and the increase
exercise levels. High levels of IGF-1 increase the risk of CRC.
in mortality from CRC over the last few decades in Asia has
Conversely, elevated levels of IGF-binding protein-3, which
been attributed to westernization of the diet. Diet influences
is associated with reduced levels of IGF-1, are associated
colonic microecology. High fruit and low meat containing
with a lower risk of CRC. It is interesting to note that genetic
diets have a protective effect by modulating the composition
mutations associated with development of CRC have been
of the normal nonpathogenic commensal microbiota,
linked to levels of physical activity. Mutations in both K-ras
thereby reducing the incidence of colorectal adenomas and
and p53 have been associated with reduced levels of physical
ultimately CRC.
activity. Colonic adenomas that develop in patients with
low levels of physical activity are also more likely to harbor
mutations in K-ras compared with individuals with higher High Fatty Diet
levels of physical activity.
Diet high in fat content leads to an excess of bile acid secretion
into the GI tract and is associated with CRC. The incidence
Obesity of CRC is related to the concentration of deoxycholic (DOC)
Obesity is one of the known strongest risk factors of CRC. The acid and secondary bile acids in the intestine. Bile acid
metabolic burden induced by excess adiposity accelerates can be transformed into carcinogenic compound known
uncontrolled cell growth and survival leading to increased as methylcholanthrene by enzyme. Bile acid promotes
risk of CRC genesis. Obesity raises the risk of CRC in both men synthesis of pentane in feces through bacteria. Toxic bile
and women, but the link seems to be stronger in men. Obesity acids accumulation induces oxidative damage and colorectal
causes metabolic stresses, including excessive reactive carcinogenesis, thereby some dietary antioxidants may
oxygen species production, increased gut permeability, ameliorate this carcinogenicity. High levels of serum high-
hyperinsulinemia and the elevated adipokine secretion. density lipoproteins are associated with a low risk of CRC.
The effect of hyperinsulinemia may be mediated by the IGF Long-chain -3 polyunsaturated fatty acids (PUFAs) and
system. Hyperinsulinemia is associated with elevated levels conjugated linoleic acid (CLA) have potential protective role
of IGF-1 which has itself been associated with an increased against CRC, whereas -6 PUFAs may promote carcinogenesis
risk of CRC. Obesity is associated with increased serum mediated in part through prostaglandin E2 (PGE2) production.
leptin levels and inversely associated with adiponectin
levels. Alterations in levels of these adipocytokines have
effects on cell proliferation, angiogenesis and promotion of
Red and Processed Meat
tumorigenesis in in vitro studies that could contribute to the A diet high in red and processed meats can increase risk
development of colorectal neoplasia in obese individuals. of CRC. Cooking meat at very high temperatures creates
A substantial increase in obesity among Asian populations chemicals that might increase cancer risk. The processed
has been associated with an increase in metabolic syndrome meat is associated with an increased risk of distal colon
and various GI carcinomas. In Korean patients with metabolic cancer. On the other hand, the intake of fish/-3 PUFAs
syndrome has an increased risk for proximal, multiple, and has long been considered as a factor decreasing the risk of
Colorectal Carcinoma 111

CRC. The heme content of red meat increases fecal levels of important molecular event leading to CRC. Supplementation
N-nitroso compounds. N-nitroso compounds are potentially of folate, methionine, riboflavin and vitamin B6 may prevent
carcinogenic and processed meat has also been found to aberrant DNA methylation, thereby prevent CRC.
contain N-nitroso compounds. Some classes of N-nitroso
compounds have alkylating agent properties and have been
demonstrated to induce GC to AT transitions at the second Soy and Phytoestrogens
base of codon 12 or 13 in K-ras gene. Red meats and haem Certain phytochemicals found in plant foods are known to
supplementation have also been associated with increased exert anticarcinogenic effects. Phytoestrogens, including
levels of DNA adducts within colonocytes. DNA adducts are isoflavones and lignin are associated with a significant
highly reactive agents that react with nucleophilic centers in reduction in colorectal adenoma and CRC. Phytoestrogens
DNA bases and have been recognized as playing a central role have molecular similarities to endogenous estrogens, which
in carcinogenesis. interact with estrogen receptors ER and ER. Both genomic
and nongenomic influences play role in anticarcinogenic
Low Dietary Fibers and Resistant Starch properties of phytoestrogens, including induction of apoptosis
and inhibition of tyrosine kinases and DNA topoisomerases.
The resistant starch (RS), non-starch polysaccharides (NSP) Far Eastern countries have lower incidence of CRC which in
and carotenoids are thought to be important protective part is attributable to high intake of soy products in their diet.
factors with a strong inverse relationship between RS
consumption and CRC incidence. RS and NSP reduces the
adverse effect of dietary fats and fecal bile acids by their Reproductive Factors
marked effect on composition and metabolic activity of large
Certain reproductive factors like early menarche, late age at
intestinal microflora, which affect gene expression and DNA
first childbirth, short duration of lifetime lactation and late
repair through excessive butyrate production. RS increases
menopause are associated with breast carcinoma and CRC.
fecal bulk as well as physically dilutes fecal contents by water
The exogenous female hormones use [i.e. oral contraceptive
absorption, reduces transit time thereby decreases exposure
and postmenopausal hormone (PMH)] reduces the mortality
of the colonic mucosa to carcinogens, reduces colonic pH
rates of CRC in women in many developed countries. Estrogen
which decreases conversion of primary bile salts to secondary
have protective effect against MSI carcinomas through
bile salts, increases short-chain fatty acids including butyrate,
acetate and propionate, decreases protein fermentation its effect on selected molecular targets. Postmenopausal
products like phenolic compounds, amines, ammonia, hormone therapy may reduce CRC risk through mechanisms
N-nitroso compounds and indoles; and reduces bile salts in beyond K-ras mutation status, but might provide greater
feces by binding bile acids and bile salts. benefits for K-ras mutation-negative than mutation-positive
tumors, at least in the distal colorectum.

Low Intake of Fruits and Vegetables


Drugs
Diets high in vegetables, fruits, and whole grains have been
associated with a reduced risk of CRC. Increased intake of The nonsteroidal anti-inflammatory drugs (NSAIDs), and
dry fruits, fruit juice and green leafy vegetables have been calcium have been associated with a lower risk of colorectal
associated with reduced risk of colonic adenoma and CRC adenomas and CRC. The NSAIDs act by inhibiting COX activity,
risk by altering the composition of colonic microflora. Both prostaglandin synthesis and the cascade of arachidonic acid
raw and green vegetables contain vitamins, dietary fibers and metabolites which are involved in cell transformation, tumor
phytochemicals which may exert anticancer effects. growth and metastasis. The NSAIDs like sulindac and the
selective COX-2 inhibitor, celecoxib significantly regresses
existing adenomas, whereas aspirin decreases CRCs that
Low Intake of Micronutrients overexpress COX-2 but not those with weak or absent COX-
Supplementation of micronutrients like calcium, vitamin 2 expression. The use of NSAIDs doubled during the past 2
D, folates, flavonoids, antioxidant vitamins (A, C and E) and decades in the USA and a similar trend occurring in many
selenium might have protective effect, whereas iron may Asian countries, which reduces risk of CRC in younger
potentiate risk of CRC. Aberrant DNA methylation is an populations.
112 Textbook of Hepato-gastroenterology

Other Specific Diseases the risk of CRC in the younger population is decreasing, while
the prevalence of rhinitis, rhinoconjunctivitis and eczema
Chronic inflammation plays a role in the progression to increased significantly among school children.
cancer. The risk of CRC is increased in inflammatory bowel
diseases (IBDs) ulcerative colitis (UC) and Crohns disease
(CD). However, much more is known about the risk in UC. Environmental Carcinogens
The risk of CRC in UC depends upon the duration and extent Industrial workers who are in contact for many years with
of disease. The risk of CRC for cases with IBD increases by inorganic dust coming from plastic substances and fuel oil
0.51% yearly approximately 810 years after diagnosis. While could have a greater risk of developing CRC. Sometimes, a
cases with UC lesions extending to the hepatic flexure or seafood product (e.g. shellfish) accumulates diarrheic shellfish
more proximally (pancolitis) have the greatest risk of CRC, poisoning toxins (i.e. okadaic acid and its derivatives), which
whereas the disease limited only to rectum have lowest risk. are tumor promoters that could increase CRC risk.
The UC-associated colorectal carcinomas (UCACRCs) are
the most common in the rectum and sigmoid colon and the
CRC associated with CD is evenly distributed between the Infectious Disease
right colon and rectosigmoid. The carcinogenesis pathway in
Schistosomiasis is associated with bladder cancer and CRC.
colitis-associated colorectal cancer is less clearly understood
Schistosoma japonicum is particularly associated with CRC.
than its sporadic counterpart. The flat dysplasia-associated
The schistosomal colitis is commonly associated with earlier
lesion or mass (DALM) is considered to be the precursor
onset of CRC that presents at an advanced stage. Helicobacter
lesion for UCACRCs. Therefore, it is of utmost importance
pylori infection is also associated with modest increase in the
to identify DALM and NP-CRN to reduce the morbidity and
risk of colorectal adenoma and CRC.
mortality from UCACRCs. Genetically, UCACRCs appear
to be characterized by early TP53 mutations, together with
much lower frequencies of APC and K-ras mutations than in Gut Microbiota and Colorectal Cancer
sporadic CRCs. Epigenetic changes, such as DNA methylation
and histone modification are thought to play an increasingly One of the important factors associated with CRC is the
important role in the development of CARCs. Clonal expansion human gut microbiota. The composition of the luminal
of procarcinogenic mutations can lead to large fields of microbiota and mucosa-adherent microbiota are different in
mutant tissue from which CARCs can arise, this phenomenon CRC cases. The luminal microflora potentially influences CRC
is called field concretization. In contrast to Western countries, risk through cometabolism or metabolic exchange with their
the incidence of CRC among cases with UC is low in Asian host. However, mucosa-associated microbiota potentially
countries. However, the prevalence of UC has been increasing affects CRC risk primarily through direct interaction
in Japan in the last few decades, although it is still lower than with the host. Microbial dysbiosis leads to induced-
Western countries. The incidences in Japan, Korea, Taiwan as procarcinogenic pathways by converting procarcinogenic
well as other Asian countries are increasing. Recently, KASID dietary substances to carcinogens. Increase of opportunistic
study revealed that the cumulative incidence of UCACRCs in pathogens and reduction of butyrate producers constitute
Korea is comparable to that of Western countries. CRC in IBD a major compositional imbalance of gut microbiota in CRC
patients is frequently diagnosed at an advanced stage, a factor cases. Such variations may allow for future utilization of the
that contributes to poor prognosis. The risk of UCACRCs fecal flora as markers for screening and diagnosis of CRC.
has decreased over time which might be due to intensive Probiotics are of potential importance in CRC prevention as
chemoprevention and surveillance colonoscopy. the microbial metabolic activities might have effects on the
Increasing evidence suggests that a history of type 2 CRC prevention by scavenging toxic substances or preventing
diabetes mellitus (T2DM) is an independent risk factor for their generation in vivo.
CRC in both women and men, and insulin therapy for diabetes
may increase this risk. Women with T2DM had higher rates
of colorectal adenomas. This finding adds to the evidence CLINICAL FEATURES AND DIAGNOSIS
that T2DM is an important factor in the progression of
adenoma-carcinoma sequence. Cigarette smoking appeared Colorectal carcinoma can present in a variety of ways and
to positively modify DM-associated CRC risk. with any of several symptoms. The alarm features like
Allergic disorders, including asthma, hay fever and eczema rectal bleeding, altered bowel habits, microcytic anemia,
is inversely associated with incidental CRC. In Hong Kong, or palpable right-sided abdominal mass or rectal mass are
Colorectal Carcinoma 113

usually considered important for CRC diagnosis and are to ensure optimal control of disease during an attempt to
used to prioritize access to urgent investigation. The rectal minimize their toxicity. Majority of CRC cases ultimately
bleeding and altered bowel habit toward increased softness die of their disease in spite of the significant advances in
or increased stool frequency are considered as major therapeutic approaches to CRC.
single predictors of cancer. Some cases manifest as surgical
emergencies like bowel obstruction or perforation. On the
other hand asymptomatic CRCs cases are usually detected by Preventive Measures
a screening procedure and they have a better Dukes staging. In last few decades two to four times increase in the incidence
Colorectal carcinomas occur with different frequencies at of CRC have been observed in many Asian countries like
different sites because of developmental and physiological China, Japan, South Korea and Singapore. This rising trend
differences that exist between anatomic segments of the of CRC incidence and mortality is significantly more in
colorectum. The differences in presentation of colonic and affluent societies and differs among different ethnic groups.
rectal carcinomas affect their outcome. Colonic cancer Prevention is and will remain a major goal of medicine
presents later than rectal cancer. The proximal, distal and and gastroenterology, which are based on identifying a
synchronous CRCs are 35%, 59% and 6% in USA and 29%, 52% preneoplastic lesions and altering their outcome by the
and 19% in Asian population. introduction of early intervention. Colorectal screening with
Colorectal carcinoma is mainly a disease of adulthood but FOBT is at present a national policy in Asian countries like
children are not spared. It accounts for 2% of all malignancies Taiwan, Japan, and Korea. Sigmoidoscopy and colonoscopy
in children. Childhood CRCs are usually diagnosed at an are potentially effective screening modalities for diagnosing
advanced stage, with mucinous histology and tend to have a CRCs and neoplasms. The incidence and mortality of CRC in
poorer outcome. Asian populations have been rising due to alterations in their
The CRCs are diagnosed at any stage, from a surgical lifestyle and therefore acceptable and efficient screening
emergency, symptomatic carcinoma or to an asymptomatic programs is an important issue in the prevention of this widely
carcinoma detected by screening. Colonoscopy is the most prevalent neoplastic disease. The implementation of primary
effective in the diagnosis of CRC. A colonoscopy database and secondary prevention, chemoprevention and screening
review of 10,603 Chinese patients revealed that 181 of Chinese programs are of paramount importance for reduction of CRC
patients with CRC presented without features indicative of incidence and mortality. Surveillance programs as tertiary
tumor formation. The overall prevalence of CRC was 3%. The prevention are widely accepted as an integral part of the
phenomenon of its diagnostic delay often occurs. However, treatment plan provided to patients after surgical treatment
the delay is not a major cause for its advanced stage and a of CRC. The number of CRC cases in men and women are
poor outcome. Its inherent biological characteristics may be increasing and probably it will surpass that of lung carcinoma
more important. Fluorine-18 (F) fluorodeoxyglucose (FDG) in future. There is need to prioritize primary and secondary
positron emission tomography/computed tomography prevention to control CRC in Asian populations.
(PET/CT) is a safe imaging method that can be used in the
determination of CRC recurrence in patients with elevated
carcinoembryonic antigen (CEA) levels. There is a compelling Screening
need for the identification of a panel of novel biomarkers Screening is an important armamentarium in modern day
for early diagnosis of CRC. An integrated proteomics and preventive medicine. The modalities of CRC screenings
metabolomics approach will promote the translation of varies worldwide and are influenced by the cost and
biomarkers with clinical value into routine clinical practice. diagnostic resources availability in that country. Screening
tests for CRC can be broadly divided according to two
distinctly different aims: cancer prevention versus early
MANAGEMENT detection of cancer. Screening methods for cancer
prevention target the precancerous stage before it becomes
In the era of personalized cancer therapy and prevention, malignant through detection and removal of precursor
adopting a multidisciplinary approach should be considered lesions. The preventive CRC screening success depends on
in order to broaden our knowledge of the complex compliance of the population of that region, minimal or low
etiopathogenesis of CRC, and to improve individualized adverse events and skill in detecting the lesions. Screening
preventive and therapeutic approaches. In regard to the tests for CRC fall under two categories: fecal-based tests
advancement in chemotherapeutic and chemopreventive including guaiac-based (gFOBT), immunochemical tests
agents, molecular and phenotyping of CRC is important (iFOBT) and stool DNA panel (sDNA); and endoscopic and
114 Textbook of Hepato-gastroenterology

radiologic tests including flexible sigmoidoscopy, flexible accurate identification of family members likely to have the
colonoscopy, optical colonoscopy, double-contrast barium faulty gene, enabling the targeting of screening and preventive
enema (DCBE) and computed tomography colonography surgery only to those at risk. Clinicians should discuss about
(CTC, also called virtual colonoscopy). The recommended prenatal testing with patients in childbearing age for either
CRC screening methods are flexible sigmoidoscopy and opting conventional prenatal diagnosis like amniocentesis
colonoscopy, and FOBTs including gFOBT and iFOBT. or chorionic villous sampling, or for preimplantation genetic
DCBE and CTC are not a commonly used screening method. diagnosis. Identification of individuals with Lynch syndrome
Colonoscopy is considered to be the gold standard for allows for increased surveillance of the affected individual
CRC screening; however, it requires skilled and dedicated and of potentially affected family members. A high index
personnel, involves high cost and is inconvenient to the of suspicion is required to detect cases and families who
patient. Colonoscopy is less protective for right-sided potentially have Lynch syndrome. Preliminary screening
tumors, which are more likely to be flat or depressed and tests can identify individuals unlikely to be affected by Lynch
are more affected by an inadequate bowel preparation. syndrome, thereby, reducing the need for full gene analysis.
Imaging technologies, such as chromoendoscopy and The familial clustering of CRC is usually seen in younger
narrow band imaging have been developed to improve probands and carcinomas are located in the proximal colon.
delineation of suspicious lesions during colonoscopy. The Every attempt should be taken to promote public awareness
iFOBT and sDNA tests may offer less invasive screening and screening strategies in those families with a member
options for patients who decline colonoscopy. Confocal affected by CRC, especially those at younger age or with
laser endomicroscopy (CLE) provides real-time, high- proximal colonic involvement. To diminish the incidence
resolution imaging at a micron level through endoscopes. of CRC, screening colonoscopy to the spouses of CRC
CLE and related technologies are termed virtual biopsy patients might be advised as married couples share home
as their images simulate to that are seen in conventional environments and lifestyle for years. The risk of developing
histology. Immediate potential applications of CLE are to neoplasia leading to CRC is significantly increased in UC and
guide biopsy sampling in CRC surveillance and evaluation most likely in CD. Patients with UC should not be denied the
of colorectal polyps. In underdeveloped resource poor benefits of a cancer surveillance program. The risk of colonic
countries, FOBT is the first choice for CRC screening. cancer is higher in patients with total colitis type and when
CRC screening should be initiated at the age of 50 years. has had the disease for more than 10 years. The cumulative
The smaller polyps measuring 59 mm in size should be incidence rates over 10 years and 20 years are 5.1% and 17.5%,
removed endoscopically and in case of follow-up negative respectively. Most of them are flat type poorly-differentiated
colonoscopic examination, a repeat colonoscopy should be adenocarcinomas. Therefore, patients with total colitis
performed every 10 years. type for more than 10 years should undergo colonoscopic
The carcinoma associated antigen in blood or feces, DNA surveillance.
MSI for family members at-risk, molecular techniques for fecal In North America, Europe, and Australia as well as New
oncogene or antioncogene, telomerase activity and exfoliative Zealand, there is a CRC screening guidelines but these
cytology for tumor marker are utilized but none of them are in guidelines are lacking in most Asian countries except Japan,
use for mass screening. Although hypermethylated genes in Korea, Singapore, Hong Kong, and Taiwan. Healthcare is
fecal samples have been used as biomarkers for the CRC or self-financed in most of the Asian countries (e.g. Brunei,
adenomas detection, the hypermethylated gene panels are China, India, Indonesia, Malaysia, Philippines, Thailand
not accurate enough to be used as a single test for colorectal and Vietnam) and national healthcare systems and health
neoplasia screening. Altered miRs expression is found in CRC insurance cover only minority of the Asian population.
and their expression patterns may serve as useful cancer In addition healthcare facilities access is limited in rural
biomarkers. areas and for the people of low socioeconomic status. Asian
In affected persons and family members at-risk initially continent has very heterogeneous population; therefore, it
requires early recognition of hereditary colon cancer is desirable to calculate risk stratification for people at the
syndromes followed by integration of genetic testing and highest CRC risk by considering age, gender, race and family
clinical examinations for effective cancer prevention. FAP history for prioritizing a screening program. Risk stratification
is a potentially preventable cause of CRC; clinicians should strategy using colonoscopy and CT colonography is utilized
have an adequate knowledge of it to identify the disease and in the Western world and this might be very useful in best
to manage the patient and family. After the identification utilization of limited resources in many Asian countries. A
of an index patient, genetic testing in combination with two-tier approach may reduce the colonoscopy work load
the detection of extracolonic manifestations allows more without jeopardizing the efficacy of screening program.
Colorectal Carcinoma 115

Chemoprevention the dietary guidelines have shown no protective effect on


overall carcinoma risk. However, good dietary adherence is
Efforts to prevent CRC have targeted early detection through associated with a reduced cancer-specific mortality.
screening and chemoprevention. Chemoprevention is
an intentional chemical interference with the process of
carcinogenesis by protecting against initiation or by arresting Health Education
or reversing later stages of carcinogenesis at various steps In most Asian countries population-based CRC screening
in the processes of promotion and progression. Primary program compliance rates are still far from the desirable rates
prevention is achieved by using chemopreventive agents to because of poor public knowledge about CRC, including
prevent carcinoma in apparently healthy individuals. Aspirin people above 50 years of age who may benefit from CRC
and other NSAIDs and calcium have shown significant screening. Compliance for CRC screening program requires
reductions of CRC risk. Traditional NSAIDs, as well as the considerable effort on the part of the individuals. The factors
new COX-2 selective inhibitors, such as rofecoxib and influencing population participation is crucial prior to
celecoxib, have a role in the setting of primary and secondary designing and launching a population-based CRC screening
prevention, and adjuvant therapy of both sporadic CRC as high levels of screening uptake are necessary for the
and FAP. Chemoprevention is possible through inhibition success of screening program. These influencing factors can
inducible nitric oxide synthase (iNOS/NOS-2), as it plays be classified as modifiable factors like knowledge about CRC
an important role as mediator of inflammation involved and its screening, attitudes of patient and healthcare providers
in early carcinogenesis. Indole-3-carbinol is a constituent or structural barriers for screening; and non-modifiable
of cruciferous vegetables like cabbages, cauliflowers and factors like demographic factors, education, health insurance
broccoli, which might be a chemopreventive agent for or income. Modifiable factors are of great importance as they
colorectal carcinogenesis. are plausible targets for health educational interventions to
The use of probiotics, prebiotics or synbiotics has potential increase the general populations knowledge about CRC and
to impact significantly on the development, progression its screening before implementation of population-based
and treatment of CRC. Probiotics and prebiotics alter the CRC preventive programs. To improve participation in CRC
intestinal microecology by reducing the levels of pathogenic screening, appropriate strategies must be directed toward
microorganisms and increasing concentrations of beneficial vulnerable populations, such as those with low socioeconomic
bacteria such as Lactobacillus and Bifidobacterium, which status and those above 50 years of age. Education and training
induces reduction in intestinal inflammation, enhancing for healthcare providers, including family doctors could also
immune function and antitumorigenic activity, binding to be an effective strategy to promote CRC screening.
potential food toxins, and a decrease in bacterial enzymes
including -glucuronidase which hydrolyze precarcinogenic
compounds. TREATMENT
It is beyond the scope of this chapter to discuss most forms
Vaccine of treatment modalities of CRC. The readers are referred
Cancer vaccine is a promising tool to achieve therapeutic reference works in the field for more complete information.
responses in patients by inducing antitumor immunity. Early stage of CRC detection and treatment with newer
Immunotherapy of patients with advanced carcinomas could effective agents would likely improve survival of high-risk
be possible by utilizing cloning techniques to identify genes CRC patients as most of CRC patients are in advanced stages
and peptides of tumor-associated antigens. Several cancer with poor prognosis. The important prognostic factors are
vaccine, including CEA, dendritic cells, human leukocyte stage of tumor, distant metastasis, grade of tumor and tumor
antigen-restricted peptides and epitope-encoding vectors size. A distinction between resectable, potentially resectable
have been tried for advanced CRC. Since their clinical impacts and unresectable CRCs should be made for establishing an
are still limited, extensive studies are underway in order to adequate therapeutic strategy. Complete surgical resection
identify more effective antigens. The cancer vaccines could with aggressive lymph node dissection is mainstay of
be a promising therapeutic option for CRC in future. treatment. The healthcare delivery systems difference affects
the treatment choices for unresectable CRC. Neoadjuvant
chemoradiation therapy is used for rendering unresectable
Dietary Guidelines tumors resectable. Active chemotherapeutic agents for CRC
Association between dietary guideline adherences and include fluorouracil, folinic acid (leucovorin), oxaliplatin,
overall cancer risk is inconclusive as good adherences to irinotecan, bevacizumab and cetuximab. Chemotherapy given
116 Textbook of Hepato-gastroenterology

concomitantly to radiotherapy and combined before or after secondary CRC prevention. Newer molecular techniques
radiation significantly reduces the risk of local recurrence. The will help to understand the underlying mechanisms of CRC
sterilization of the tumor (complete pathological response) carcinogenesis and identify sensitive biomarkers for early
by chemotherapy is a favorable prognostic factor. diagnosis and advancement in therapeutic modalities.
Growing subsets of patients with metastatic CRC are
being considered for treatment with curative intent.
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12
cHAPTER

Gastrointestinal Lymphomas

Moiss Copelman, Natalia Balbi Flores, Cassiano Ribeiro Pires

INTRODUCTION have heterogeneous aspects with the presence of small


lymphocytes (often centrocytic looking) or lymphocytes with
Gastrointestinal (GI) tract represents 3040% of extranodal a monocytoid appearance. A variable number of large cells
lymphomas and forms 420% of all non-Hodgkins lymphomas (immunoblasts and centroblasts) are usually present.
(NHL) cases. The stomach is the most common extranodal An increased number of large cells in a MALT lymphoma
site of lymphoma and accounts for 6875% of GI lymphomas can, at times, create problems from a diagnostic point of view,
followed by the small and the large bowel. Involvement of the suggesting a histological transformation into a DLBCLa
esophagus is quite rare. The real increase of NHL incidence in transformation that is usually defined by the presence of
the GI tract cannot exclude a correlation with improvements in compact aggregates or a sheet-like proliferation of large cells.
diagnostic procedures over the last years. Several autoimmune High-grade primary gastric lymphomas are nearly always
disorders like rheumatoid arthritis, Sjgrens syndrome, of the B-phenotype and are characterized by an aggressive
Wegeners granulomatosis, systemic lupus erythematosus, clinicopathological presentation.
and acquired immunodeficiency syndrome (AIDS) have an Whether all diffuse large B-cell gastric lymphomas are
increased risk of GI-associated lymphoma. derived from previous low-grade MALT lymphomas is still an
open question that is not yet resolved unequivocally.
It should be remembered, however, that the cytogenetic
GASTRIC LYMPHOMAS alterations common in gastric MALT lymphomas are different
from those typical of large-cell primary lymphomas of the
Primary gastric lymphoma accounts for approximately 3% stomach (Figs 1A to D).
of gastric neoplasms and shows an apparently increasing
incidence worldwide.
The disease reaches its peak incidence between the ages Clinical Features
of 50 years and 60 years with a slight male predominance.
Two histological types are particularly frequent in primary
Signs and Symptoms
extranodal lymphoma: (i) a preponderance of diffuse large The initial symptomatology of a gastric lymphoma is often
B-cell lymphomas (DLBCLs) and (ii) the marginal zone quite unspecific and more evocative of gastritis or an
B-cell lymphomas of the mucosa-associated lymphoid tissue ulcerous condition rather than a neoplasm; for this reason,
(MALT) type (therefore extranodal by definition), which is an its diagnosis is often delayed. The most common presenting
indolent lymphoma that frequently presents with localized, symptoms are epigastric pain or discomfort, anorexia, weight
early stage disease. loss, nausea and/or vomiting, occult GI bleeding and early
satiety. Systemic B symptoms (fever and night sweats) are
extremely rare. Hematemesis or melena occurs at the outset
Histology in 2030% of patients, while gastric occlusion and perforation
In 1983, Isaacson and Spencer proposed, for the first time, are quite uncommon. The duration of symptoms preceding
the concept of a MALT-type lymphoma. These lymphomas the diagnosis is quite variable ranging from a few days to 6
represent the most frequent histotype in low-grade years.
malignant primary gastric lymphomas. This extranodal The physical examination is often normal but may reveal
lymphoma develops from B lymphocytes of the marginal a palpable mass and/or peripheral lymphadenopathy
zone and is characterized by a cellular population that can when the disease is advanced, especially in cases where the
122 Textbook of Hepato-gastroenterology

A B

C D
Figs 1A to D: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma. (A) Small lymphocytes infiltrating the mucosa. Immuno
histochemical study shows (B) lymphoepithelial lesion CD20+; (C) low Ki-67 proliferation index; (D) cyclin D1-negative
Courtesy: Nilcimar Miranda, Rio de Janeiro, Brazil

histology is aggressive. Laboratory studies also tend to be is important in the diagnosis of illnesses that are unresponsive
normal at presentation. Anemia or an elevated erythrocyte to antibiotics, and this can be carried out by fluorescent in
sedimentation rate may be present in selected cases. situ hybridization on fixed material.
An endoscopic ultrasound (EUS) should determine the
depth of invasion and the presence of perigastric nodes. The
Diagnostic Evaluation pattern seen on EUS may correlate with the type of lymphoma
Diagnosis of gastric lymphoma is usually established during that is present.
upper endoscopy with biopsy. While it can be suggested
by findings on imaging, biopsy is required for a definitive
diagnosis.
Pathology
The most frequent sites of gastric lymphomas are at the The diagnosis of gastric lymphoma may be suggested by
pyloric antrum, corpus, and cardia. The extension of a lesion endoscopic and imaging findings, but must be confirmed
across the pylorus into the duodenum is highly suggestive, by biopsy. Both suspicious appearing lesions and normal
but again not pathognomonic of lymphoma; for this reason, appearing mucosa should be biopsied since gastric
verification through biopsy is always deemed necessary. lymphoma can occasionally present as multifocal disease
The findings on upper endoscopy are diverse and may with involvement of tissue that appears to be unaffected on
include any of the following: mucosal erythema, mass or initial visualization.
polypoid lesion with or without ulceration, benign-appearing Endoscopists should aim to attain the largest biopsy
gastric ulcer, nodularity, thickened, cerebroid gastric folds specimen possible. Conventional pinch biopsies may miss
(Figs 2A and B). Any of these findings should heighten the diagnosis, since gastric lymphoma can infiltrate the
suspicion of gastric lymphoma, but none is diagnostic. submucosa without affecting the mucosa; this problem is
Multiple biopsies should be obtained from the stomach, most likely to occur when no obvious mass is present. Jumbo
duodenum, gastroesophageal junction, and from abnormal biopsies, snare biopsies, biopsies within biopsies (well
appearing lesions. Identification of the t(11;18) translocation technique), and needle aspiration can all serve to increase
Gastrointestinal Lymphomas 123

A B
Figs 2A and B: Gastric lymphoma with ulcerations and erythema in corpus and antrum

the yield in such cases. Endoscopic ultrasound-guided fine Unilateral bone marrow biopsy and aspirate should be
needle aspiration biopsy (FNAB) or endoscopic submucosal performed in all patients with the possible exception of
resection may provide even greater diagnostic capability. those with localized gastric extranodal marginal zone
B-cell lymphoma
Additional studies [e.g. magnetic resonance imaging
Pretreatment Evaluation (MRI) of the orbit] should be reserved for selected patients
After a diagnosis of GI lymphoma is confirmed, a pretreatment who have findings on history and/or physical examination
evaluation determines the extent of disease. In addition to a concerning for involvement of additional sites.
history and physical examination, it is our practice to perform Men and women with childbearing potential should
the following pretreatment studies: receive counseling about the potential effect of treatment
Laboratory studies include a complete blood count on their fertility and options for fertility-preserving
with differential, human immunodeficiency virus (HIV) measures.
serology, chemistries with liver and renal function,
electrolytes and lactate dehydrogenase (LDH). Patients
should undergo serologic testing for hepatitis B and
Staging
hepatitis C The most widely accepted staging system is the Lugano that
A contrast-enhanced computed tomography (CT) scan of was developed to incorporate measures of distant nodal
the chest, abdomen, and pelvis should be performed to involvement. Early (stage I/II) disease includes a single
evaluate for distant disease. The use of positron emission primary lesion or multiple, noncontiguous lesions confined
tomography (PET) is controversial except in cases of to the GI tract that may have nodal involvement. There
DLBCL is no stage III in the Lugano system. Advanced (stage IV)
An endoscopic evaluation is performed based upon the disease displays disseminated extranodal involvement or
site of disease. Patients with gastric lymphoma should concomitant supradiaphragmatic nodal involvement.
undergo an esophagogastroduodenoscopy with EUS
to determine the depth of invasion and involvement of
perigastric lymph nodes Treatment
Patients with gastric lymphoma should be tested for Historically, therapeutic strategies in gastric lymphomas have
Helicobacter pylori (H. pylori), which can be detected by been, for a very long while, based on surgery, followed by
histologic specimen, biopsy urease test, urea breath test, radiotherapy or postoperative chemotherapy. This approach
stool antigen test or serology in the vast majority of gastric began to be questioned at the end of the 1980s when
MALT lymphomas (90%). In addition, fluorescence in situ several retrospective studies showed that surgery should
hybridization (FISH), or polymerase chain reaction (PCR) not necessarily be considered obligatory in all patients. At
testing for t(11;18) should be performed the same time, the demonstration of the effectiveness of
124 Textbook of Hepato-gastroenterology

antibiotics in localized MALT lymphomas gave a further push H. pylori at the time of diagnosis. These patients should be
toward abandoning front-line surgery, even for lymphomas treated with radiation therapy (RT) administered with curative
with a low-grade malignancy histology, where surgery (with intent. Radiation therapy is also appropriate for patients
or without adjuvant radiotherapy or chemotherapy) was with tumors that demonstrate the t(11;18) translocation that
considered the gold standard. is typically unresponsive to H. pylori eradication therapy.
Other treatments, including immunotherapy, single agent
chemotherapy and multiagent chemotherapy, are reserved
Gastric MALT Lymphoma for patients failing or recurring after RT and those with
Gastric MALT lymphomas represent 78% of all B-cell advanced stage disease (i.e. Lugano stage IV).
lymphomas and approximately 50% of primary gastric The treatment of patients with advanced stage (Lugano
lymphomas. They originate from the lymphatic tissue in the IV) disease is not clearly defined. These patients are typically
stomach that, in association with the mucous membrane, treated with H. pylori eradication therapy, if they are H. pylori-
usually develops following chronic H. pylori infection (Figs positive, and then generally observed until the development
1A to D). of symptoms at which time they undergo treatment with
Although H. pylori infects over 50% of the worlds immunotherapy or chemotherapy (similar fashion to those
population, most patients with H. pylori do not develop with advanced stage follicular lymphoma).
lymphomas; therefore, it is commonly believed that additional While successful treatment with radiation usually results
environmental, microbial, or hostgenetic factors may play in the disappearance of B-cell clonality, treatment with H.
a role in gastric lymphomagenesis. Infection with H. pylori pylori eradication therapy often demonstrates persistent
strains that carry the cytotoxin-associated antigen A (cagA) B-cell clonality on molecular studies. The ultimate clinical
is linked to gastric carcinoma, and it has been suggested that significance of persistent clonality in these treatment settings
cagA-positive strains may also be associated with lymphoma is unclear.
development, but available data remain controversial. Gastric resection is reserved for patients with complications
Gastric MALT lymphomas have an indolent clinical- such as perforation or obstruction.
biological behavior pattern, with a tendency to remain After initial therapy, patients must be monitored with
localized at the onset site in 7080% of cases. At present, the serial endoscopies to evaluate for disease response and
most widely accepted initial therapy for localized disease recurrence. Treatment failures should be treated with local
is aimed at the eradication of H. pylori using regimens RT administered with curative intent.
combining antibiotics and proton-pump inhibitors. One of
the most commonly used regimens combines omeprazole
with clarithromycin and amoxicillin; nonetheless, the choice
Response Evaluation
of a treatment regime must take into account the local Patients with early stage H. pylori positive, initially treated
epidemiology of the infection and the possible resistance with H. pylori eradication therapy need to be evaluated after
to certain antibiotics. This therapeutic approach is the one the completion of treatment to determine whether the H.
that is mostly investigated and successfully verified in a large pylori was successfully eradicated and whether there has
number of clinical studies. been a tumor response.
Four-to-eight weeks after the completion of H. pylori
eradication therapy, urea breath test should be performed
Treatment to confirm eradication of infection. Up to 20% of patients
The treatment of gastric MALT lymphoma is dictated will require a second H. pylori eradication regimen to fully
primarily by the presence or absence of a concomitant H. eliminate the infection. After successful eradication of H.
pylori infection. pylori, patients should undergo periodic upper endoscopy
The majority of patients with gastric lymphoma present with multiple biopsies to evaluate for tumor response and
with early stage (Lugano I/II) H. pylori-positive disease. monitor for relapse.
Therapy aimed at the eradication of H. pylori is the favored Endoscopic examination with multiple biopsies should be
initial treatment for patients, because of its low side effect done every 6 months for the first 2 years and then yearly to
profile and demonstrated efficacy. With this approach, monitor histological remission.
5080% of patients with localized gastric MALT achieve a
histologic complete remission (CR), which will be maintained
long-term for the majority of patients.
Conclusion
A minority of patients with early stage (Lugano I/II) The general consensus is nowadays limited to using an
gastric MALT lymphoma will not demonstrate infection with antibiotic therapy for the initial treatment of MALT type, H.
Gastrointestinal Lymphomas 125

pylori-positive lymphomas. In all other situations, the choice


between local therapy options (radiotherapy or surgery) and
systemic ones (chemotherapy and immunotherapy) must
be based on the characteristics of each individual patient
(histological type, stage, age, comorbidities and willingness
to undergo a rigorous endoscopic follow-up).

Diffuse Large B-cell Lymphoma


A B
Gastrointestinal DLBCL includes lesions previously called
high-grade MALT lymphoma. It can occur anywhere along
the GI tract and is the most common histology for primary
gastric lymphoma, representing approximately 50% of cases.
Compared with patients with low-grade lymphoma, these
patients tend to have more systemic symptoms, a more
advanced stage at diagnosis, and a worse prognosis.
Treatment options that have been evaluated in GI
DLBCL include surgery, RT, chemoimmunotherapy, H. C D
pylori eradication therapy, and combinations of the above.
Figs 3A to D: Gastric mantle cell lymphoma. (A) Mucosal infiltration
In general, most patients are treated with combination
with small lymphocytes. Immunohistochemistry shows (B)
chemoimmunotherapy regimens used for non-GI DLBCL.
lymphocytes CD20+; (C) moderated cell proliferation ndex/Ki-67; (D)
A few patients may be candidates for a trial of H. pylori positive D1 cyclin
eradication therapy. Surgery is reserved for patients with
Courtesy: Nilcimar Miranda, Rio de Janeiro, Brazil
complications, such as perforation, obstruction, or intractable
bleeding. This applies to both early stage and advanced
disease. nonspecific abdominal symptoms, which will depend on the
affected site, as well as tumor size and disease duration. The
most common is a subclinical form with an indolent course,
but if symptomatic, it can have a presentation from abdominal
SMALL INTESTINAL LYMPHOMAS pain to GI bleeding.
Histology and immunohistochemistry are similar to gastric
Mantle Zone Cell Lymphoma mantle cell lymphoma as seen in Figures 3A to D. The constant
Mantle zone cell lymphoma (MZL) is a rare disease of the GI and typical phenotypic features of the small cleaved tumor
tract recently identified, and it is estimated that its frequency cells are characterized as CD20+, CD5+, CD23-, CD43+ with
is between 4% and 9% of all GI B-cell NHL. It was originally a t(11;14) (q13;q32), and cyclin D1 overexpression of the bcl-1
called multiple lymphomatous polyposis (MLP) due to its gene on immunohistochemistry. The CD5 and CD43 markers
particular presentation, which looked to be of multiple are called aberrant, as they are products of T lymphocytes.
lymphomatous polyps involving the digestive tract, and in The treatment of this condition will depend on the stage of
some cases, more advanced extraintestinal dissemination the disease. Response to intensive chemotherapy is variable
was observed. and usually results in regression of gross and microscopic
Mantle cell lymphoma has been reported to involve the GI lesions. Surgery is indicated in some cases, especially
tract in 1530% of patients. Although any part can be affected, those who develop advanced disease with stenosis and
the most common site is in the ileocecal region, and in about consequently clinical obstruction. Even with good initial
90% of all patients who have GI involvement, it is through response to chemotherapy, it may not subsequently become
both distal small bowel and colon. responsive, with short remissions and median survival from 3
The disease usually arises from the sixth decade of life to 4 years.
with a slight predominance of male gender (2:1). Extranodal
involvement is relatively common, and in this situation, the
investigation of the spleen and bone marrow has become
Gastrointestinal Follicular Lymphoma
crucial. Most cases are usually present with generalized Gastrointestinal follicular lymphoma (GIFL) is a relatively
lymphadenopathy. Some patients may experience rare disease, representing only 13% of all GI tract B-cell NHL.
126 Textbook of Hepato-gastroenterology

The most common sites of involvement are the duodenum malabsorption syndrome, and should be investigated at the
and terminal ileum, and it is quite common for patients to time of diagnosis of celiac disease, or when this is already a
have obstructive symptoms as an overt presentation that known condition, and the patient develops worsening of
often requires surgical management. It is usually an indolent symptoms, even with a free gluten diet.
lymphoma that responds well to chemotherapy. While The estimated prevalence of celiac disease is of up to
multiple treatments show good response rates, most patients 12% in developed countries, being much more common in
relapse. It is a low-grade lymphoma that usually develops Caucasian individuals. Detection of a T-cell type lymphoma
very slowly. Primary extranodal FL without peripheral more often leads to clinical suspicion of possible adult celiac
lymphadenopathy is uncommon. disease, but both B-cell and T-cell type lymphomas have
As in MZL, several markers that make it possible to been described in single individuals with celiac disease. The
differentiate from other strains of B-cell lymphoma are occurrence of this lymphoma is not very common, which is
expressed from B cells. The CD19, CD20 and CD22 are usually responsible for only 5% of all GI lymphomas. The diagnosis is
identified, while surface immunoglobulins like CD10, CD5, around 50 years old and males are affected slightly more than
CD43, and especially the cyclin D1 marker are usually not, females by a ratio of 2:1. When biopsies from proximal small
which becomes a useful tool in differentiating with the FL.
bowel were obtained in adults with celiac disease, the overall
In up to 85% of cases, there is a translocation that results in
lymphoma risk was about 810%.
rearrangement and overexpression of the bcl-2 gene. The
The EATL can be divided into two groups based on genetic,
B-cell bcl-2 protein expression is useful in discriminating
morphological, and immunohistochemical features: (1)
GIFL from florid follicular hyperplasia, in which it is not
Type I is a large cell lymphoma, which is highly associated
expressed.
with celiac disease, and this was the most commonly found.
The diagnosis of this condition can be a real challenge for
(2) Type II has no known association with celiac disease
many physicians and certainly diagnostic resources should
be widely used. In this context, some recent researches have and unlike type 1, with the predominant symptoms of
shown the role of double-balloon enteroscopy and the use malabsorption, may occur in more severe cases, including
of magnification. The endoscopic study of GIFL in the small small bowel obstruction.
bowel using the virtual chromoscopy was clarified as a coiled Chronic ulcerative jejunitis (CUJ) is another etiology of
or elongated vascular pattern by narrow band imaging (NBI), malabsorption syndrome, and it is important in the differential
and small or whitish nodules by Fuji intelligent chromo diagnosis with EATL. Differentiating these two conditions
endoscopy (FICE). becomes quite difficult in clinical practice, because they both
If the diagnosis set in a medical challenge, the decision have the same histological features like crypt hyperplasia,
to treat is also the same thing. Some authors advocate if the villous atrophy, and inflammatory cell infiltrate by T cell; not
patient has no symptoms, immediate treatment may not to mention, the CUJ can be transformed into lymphoma after
be necessary. So far, there are no reports in the literature of several years.
a standard treatment. Then, both the use of chemotherapy, The EATL can affect any part of the small bowel; however,
radiation and biological agents are the choices currently the most often reported site is the jejunum. The symptoms
available and their combinations will be individualized in are quite variable and are directly related to the extent of
each case according to the stage. involvement of the GI tract, as well as any atypical sites, such
Yamamoto S et al. recently published the results of a few as liver, brain and nasal sinus. Abdominal pain is considered
series on the long-term outcomes of patients with GIFL the most common symptom. Perforation and obstruction
treated with conventional therapy. In the group of patients have been described with much less frequency in cases of
undergoing treatment, the median free time of relapses type II EATL.
ranged from 31 to 45 months, while those who were only Currently, several resources are available to make the
observed, the mean time was very similar, almost 38 diagnosis of this condition, including endoscopy with or without
months. virtual chromoendoscopy, double-balloon enteroscopy, video
capsule enteroscopy, CT, 18F-fluorodeoxyglucose PET scan, and
Enteropathy-type Intestinal T-cell magnetic resonance enteroclysis. Regardless of the resources
available, in some situations, this is a difficult condition to
Lymphoma diagnose, mainly in those patients in which the enteropathy is
Enteropathy-type intestinal T-cell lymphoma (EATL) a condition not yet even known.
has a close relationship with celiac disease. It is part Immunophenotypic markers have been identified in this
of the investigative algorithm when a patient develops disease. Some T lymphocytes markers help identify the EATL.
Gastrointestinal Lymphomas 127

The CD103 is seen quite often, while CD8 only in a minority of show thickening of folds with multiple small superficial
cases. ulceration, submucosal infiltration, diffuse dilation of
The therapy of EATL is not yet well defined, and duodenum and extensive nodularity involving antrum,
unfortunately, the prognosis is still poor with a 5-year survival duodenum and jejunum at upper GI endoscopy. Biopsy
rate of 820%. Often the patients nutritional status is a limit for findings include blunting or flattening of villi, dense mucosal
the proposed therapy, mainly because of the malabsorptive and submucosal cellular infiltrate with increase in lamina
syndrome experienced with hypoalbuminemia often present. propria lymphocytes.
The proposed treatment is in accordance with the stage of As noted above, there are several evidences that relate
disease and performance status of the patient, with a mix this particular form of lymphoma with infectious agents,
of chemotherapy (CHOP) and surgery. New therapies are primarily because of its high prevalence in regions where
developing and a monoclonal antibody, alemtuzumab, the number of cases of parasitic and bacterial infections
constitutes a relevant option in refractory celiac disease. are very high. Also, a satisfactory response when the use of
Through it all, the rates of complete remission for the disease antimicrobial agent is employed, and in this context, the
is around 58%, and less than 50% of patients completed Campylobacter jejuni is closely related to this condition. The
their planned chemotherapy courses, largely because of use of specific antibiotics for the eradication of C. jejuni like
complications of treatment. tetracycline (250 mg four times daily; 6 months to 2 years)
alone, especially in the early stages of disease, can achieve
remission rates of nearly 70%. Several studies have shown the
Immunoproliferative Small Intestinal presence of C. jejuni through PCR or other techniques as FISH
Disease assay. The FISH use an oligonucleotide probe directed at C.
jejuni 16S rRNA. In studies with mice, the C. jejuni has been
Immunoproliferative small intestinal disease (IPSID) is a
shown to persist in Peyers patches and mesenteric lymph
MALT lymphoma, with a strong geographic feature. This
nodes. So, this pathogen can stimulate IgA mucosal response
entity is well recognized in some underdeveloped regions,
and the chronic infection leads to sustained stimulation of
especially Mediterranean, Middle East, and African countries.
the mucosal immune system leading to IPSID.
It corresponds to about one-third of GI lymphomas in the
The staging for IPSID has not been uniformly defined,
Middle East, being the main site of extranodal lymphoma. Due
although the most commonly used system consists of early
to this regional landmark, it is also known as Mediterranean
benign (stage A), late benign (stage B), and lymphomatous
lymphoma and occurs rarely in western countries.
categories (stage C). Once malignancy develops, IPSID
This rare disease affects people with low socioeconomic
lymphoma can be divided into four stages of involvement: (i)
status and might have some relation with infectious agents. As
the intestine or the mesenteric lymph nodes, (ii) the intestine
is well documented in the literature regarding the association
and the mesenteric lymph nodes, (iii) retroperitoneal extra-
between H. pylori infection and gastric MALT lymphoma, the
abdominal lymph nodes, and (iv) noncontiguous non-
role of C. jejuni and IPSID appears to be very similar but, yet
lymphatic structures.
requires further analysis.
The main feature of this condition is an infiltrating plasma The identification of an association between C. jejuni and
cell population that secretes a monotypic immunoglobulin IPSID may lead to improvements in the management mainly
heavy chain (IgA), mainly observed in the early stages from patients in early stages (stages A and B) of the disease,
of the disease. This protein can be identified through the which can be eligible for treatment with antimicrobial
immunoassay in the serum of up to 70% of patients and also regimens, while for stage C patients, standard CHOP
can be isolated in the biopsy tissue. While IgA is directly chemotherapy was administered.
involved in the pathophysiological process, its serum levels
are very low. IgG and IgM can be found in high titers. The
disease usually affects younger people around the third
Others Types of Small Bowel Lymphoma
decade of life without gender preference. Less common types of lymphoma but with well-defined
The most affected region of the GI tract is the duodenum, clinical importance deserve a brief comment. Among these are
being reported in up to 62% of cases. The patients may the Malt lymphoma of B-cell type (MLB), Burkitt lymphoma
experience a wide variety of symptoms, but abdominal pain (BL), and natural killer of T-cell type (NKT) lymphoma.
is the most common. Similar to EATL, IPSID may present The MLB is a rare type of lymphoma with an approximately
with malabsorptive syndrome with significant diarrhea, 70% 5-year survival rate when an early diagnosis is achieved.
and progress with advanced signs and symptoms of poor As Malt lymphoma of the stomach, this lymphoma bears
nutrition. Fever may sometimes occur. Imaging studies can some similar histologic features. Like other lymphomas,
128 Textbook of Hepato-gastroenterology

it can affect any part of the GI tract, and the most common will dictate the therapy. Resection is the standard therapy,
presentation is a solitary lesion. Surgical treatment is the best with adjuvant chemotherapy only for patients with aggressive
option, when it is feasible. histology.
Burkitts, lymphoma is one of the most aggressive
forms of lymphoma. Depending on the subtype, it is very
common in children, and despite the aggressiveness of the Biliary Tract
disease, it usually responds well to chemotherapy. Three Biliary lymphomas account for less than 1% of lymphomas.
forms are reported: (i) the endemic, (ii) an association with Extrahepatic biliary tree can be occasionally involved and
immunodeficiency, and (iii) the sporadic. Children are most often are mistaken for cholangiocarcinoma.
affected, and males have a twofold increased risk than women.
All subtypes have a predilection for the ileocecal region,
but any area can be affected. Therefore, the initial presentation Appendix
with intestinal obstruction is relatively common. Abdominal Appendiceal lymphoma accounts for approximately 2% of all
pain is also the main clinical symptom. Some viruses have a GI lymphomas. Patients usually present with an appendiceal
close relationship with some subtypes of BL. Infection with diameter of more than 2.5 cm and acute appendicitis.
Epstein-barr virus (EBV) is present in most sporadic BL and Appendectomy is the treatment of choice. If there is extension
immunodeficiency associated, while the HIV is related only of tumor onto the mesentery or cecum, right hemicolectomy
to the latter. As previously mentioned, although the nature is advised.
of tumor is malignant, response to chemotherapy is usually
good, with rates of remission of up to 90% at initial stages.
Natural killer of T-cell type is very rare. Unlike the T-cell Pancreas
lymphoma related to celiac disease, this condition does
The pancreas is an uncommon site of lymphoma, representing
not have any relation with gluten. There is no consensus
less than 12% of all pancreatic malignancies and less than
on standard treatment and the approach is individualized
1% of extranodal NHL. The diagnosis should be regarded
according to the stage and to the affected site. whenever a large mass is identified in the pancreas without
biliary obstruction, pain or weight loss. An elevated level
of serum LDH supports a diagnosis of lymphoma. Patients
OTHERS SITES may have a clinical presentation similar to that of pancreatic
adenocarcinoma with abdominal pain and obstructive
Less commonly, NHL can affect the oral pharynx, esophagus, jaundice. High accuracy in diagnosis is obtained in FNA
liver, pancreas, biliary tree, retroperitoneum, colon, and with flow cytometry. Histology shows usually diffuse large
rectum. Some of these sites have been explored below. B-cell lymphoma. The diagnosis of pancreatic lymphoma
is important because prognosis is much better than for
Retroperitoneum pancreatic adenocarcinoma and treatment is primarily
nonsurgical, although a few patients with small tumors
The most common neoplasms are lymphomas or lympho thought to represent carcinomas, have been treated with
sarcomas. surgery alone and have had excellent survival. Treatment
usually consists of a combination of chemotherapy and RT.
Patients with biliary obstruction may require a drainage
Colon procedure before chemotherapy to avoid excessive
Colorectal lymphoma is rare, occurring in about 14% of all chemotherapy-related toxicity. Cure rates near 30% are
GI lymphomas, and representing approximately 1% of all reported in the literature.
colon cancers. The cecum is the most common site (75%),
followed by the rectum.
Weight loss and abdominal pain are the most common
Hepatosplenic T-cell Lymphoma
presenting complaints, and approximately 50% of patients This extremely rare form of NHL predominantly affects
have an abdominal palpable mass. Burkitts lymphoma and young males, although its incidence is unknown. It is a nearly
DLBCL are the most common histological subtypes (4060%). universally fatal form and has been described in patients with
It is important a colonic evaluation in patients with mantle Crohns disease in the setting of combination therapy with anti-
cell lymphoma because of the association of this subtype, tumor necrosis factor (TNF) agents and immunomodulators,
with 88% rate of colonic involvement. Histology and stage and less frequently, with immunomodulators alone.
Gastrointestinal Lymphomas 129

Liver Lymphoma Histology usually shows high-grade B-cell lymphoma,


most of them are of extranodal origin.
Primary hepatic lymphoma is an unusual site with diffuse Chemotherapy, surgery, radiotherapy, or combined
large cell lymphomas of B-cell origin being more frequently therapy have not substantially improved the survival of HIV
than T-cell or non-B, non-T-cell lymphomas. Patients with patients with GI lymphoma. On the other hand, highly active
primary lymphoma usually have evidence of mass lesions on antiretroviral therapy seems to have a protective effect against
imaging procedures that may mimic primary or metastatic the onset of NHL associated with HIV.
carcinoma. On the other hand, secondary lymphomatous
involvement of the liver is often only detected by histologic
evaluation.
Numerous reports of primary hepatic lymphoma of B-cell
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