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Textbook of

Hepato-gastroenterology

Textbook of

Hepato-gastroenterology

Editors

Mahmud Hasan

Chairman Bangladesh Medical Research Council Former Vice Chancellor Bangabandhu Sheikh Mujib Medical University Former Chairman Department of Gastroenterology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh

Sheikh Mohammad Fazle Akbar

Principal Investigator Department of Medical Sciences Toshiba General Hospital, Tokyo, Japan Adjunct Professor Faculty of Medical Sciences State University of Bangladesh Dhaka, Bangladesh

Mamun-Al-Mahtab

Associate Professor Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh

Sheikh Mujib Medical University Dhaka, Bangladesh Foreword Parveen J Kumar The Health Sciences Publishers New

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

Dedicated to Bangabandhu Sheikh Mujibur Rahman Father of the Nation of the People’s Republic of Bangladesh

Bangabandhu Sheikh Mujibur Rahman

Father of the Nation of the People’s Republic of Bangladesh None of us and nothing would have been here, had “HE” not been there!

CONTRIBUTORS
CONTRIBUTORS

CONTRIBUTORS

CONTRIBUTORS
CONTRIBUTORS
CONTRIBUTORS
CONTRIBUTORS

A Kadir Dokmeci Professor Department of Gastroenterology Ankara University School of Medicine Ankara, Turkey Professor Department of Gastroenterology Ankara University School of Medicine Ankara, Turkey

Abhijit Chowdhury Professor and Head Department of Hepatology School of Digestive and Liver Diseases Institute of Post Professor and Head Department of Hepatology School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata, West Bengal, India

Ajay Duseja Assistant Professor Department of Hepatology Post Graduate Institute of Medical Education and Research Chandigarh, India Assistant Professor Department of Hepatology Post Graduate Institute of Medical Education and Research Chandigarh, India

Ajesh Goyal Consultant Gastroenterology and Hepatology Tagore Hospital Jalandhar, Punjab, India Consultant Gastroenterology and Hepatology Tagore Hospital Jalandhar, Punjab, India

Amna Subhan Butt Assistant Professor Consultant Gastroenterologist Department of Medicine Aga Khan University Hospital Karachi, Pakistan Assistant Professor Consultant Gastroenterologist Department of Medicine Aga Khan University Hospital Karachi, Pakistan

Andrew Vaillant Vice President, Operations and Chief Scientific Officer, REPLICor Inc. Montreal, Canada Vice President, Operations and Chief Scientific Officer, REPLICor Inc. Montreal, Canada

Anil Arora Chairman Department of Gastroenterology and Hepatology Ganga Ram Institute for Postgraduate Medical Education and Research Chairman Department of Gastroenterology and Hepatology Ganga Ram Institute for Postgraduate Medical Education and Research Sir Ganga Ram Hospital New Delhi, India

Arun J Sanyal Professor and Chairman Division of Gastroenterology Hepatology and Nutrition Virginia Commonwealth University Medical Professor and Chairman Division of Gastroenterology Hepatology and Nutrition Virginia Commonwealth University Medical Center - MCV Campus West Hospital, Richmond, USA

Ashish Kumar Associate Professor and Consultant Hepatologist Department of Gastroenterology and Hepatology Ganga Ram Institute for Associate Professor and Consultant Hepatologist Department of Gastroenterology and Hepatology Ganga Ram Institute for Postgraduate Medical Education and Research Sir Ganga Ram Hospital, New Delhi, India

AS Soin Chairman and Chief Liver Transplant and Hepatobiliary Surgeon Medanta Institute of Liver Diseases and Transplantation Chairman and Chief Liver Transplant and Hepatobiliary Surgeon Medanta Institute of Liver Diseases and Transplantation Medanta- The Medicity Gurgaon, Haryana, India

Axel Hsu Resident Specialist Division of Gastroenterology and Hepatology Department of Medicine Queen Mary Hospital Hong Kong Resident Specialist Division of Gastroenterology and Hepatology Department of Medicine Queen Mary Hospital Hong Kong

Cassiano Ribeiro Pires Gastroenterologist Member of the Medical Staff in Endoscopy Unit of Azevedo, Lima State Hospital Rio Gastroenterologist Member of the Medical Staff in Endoscopy Unit of Azevedo, Lima State Hospital Rio de Janeiro, Brazil

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Textbook of Hepato-gastroenterology

Christopher A Wadsworth Senior Research Fellow St Mary’s Hospital Campus Imperial College of London London, UK Senior Research Fellow St Mary’s Hospital Campus Imperial College of London London, UK

Cihan Yurdaydin Chief, Hepatology Institute Professor of Gastroenterology Department of Gastroenterology University of Ankara Medical Chief, Hepatology Institute Professor of Gastroenterology Department of Gastroenterology University of Ankara Medical School Ankara, Turkey

Cristiane Alves Villela-Nogueira Associate Professor Department of the Internal Medicine Hepatology Division School of Medicine Federal University of Associate Professor Department of the Internal Medicine Hepatology Division School of Medicine Federal University of Rio de Janeiro Rio de Janeiro, Brazil

Debashis Misra Resident Medical Officer cum Clinical Tutor Division of Gastroenterology School of Digestive and Liver Diseases Resident Medical Officer cum Clinical Tutor Division of Gastroenterology School of Digestive and Liver Diseases Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India

Fazal Karim Associate and Head Department of Hepatology Sir Salimullah Medical College Mitford Hospital Dhaka, Bangladesh Associate and Head Department of Hepatology Sir Salimullah Medical College Mitford Hospital Dhaka, Bangladesh

Furqan Ahmed Consultant Gastroenterologist and Hepatologist South City Hospital Karachi, Pakistan Consultant Gastroenterologist and Hepatologist South City Hospital Karachi, Pakistan

GK Dhali Professor and Head School of Digestive and Liver Diseases Institute of Postgraduate Medical Education and Professor and Head School of Digestive and Liver Diseases Institute of Postgraduate Medical Education and Research Kolkata, West Bengal, India

Gourdas Choudhuri Director and Head Department of Gastroenterology and Hepato- Biliary Sciences Fortis Medical Research Institute Gurgaon, Director and Head Department of Gastroenterology and Hepato- Biliary Sciences Fortis Medical Research Institute Gurgaon, Haryana, India

Govind K Makharia Additional Professor Department of Gastroenterology and Human Nutrition All India institute of Medical Sciences New Additional Professor Department of Gastroenterology and Human Nutrition All India institute of Medical Sciences New Delhi, India

Hamama-tul-Bushra Khaar Professor Department of Medicine Rawalpindi Medical College Gastroenterologist and Hepatologist Holy Family Hospital Professor Department of Medicine Rawalpindi Medical College Gastroenterologist and Hepatologist Holy Family Hospital Rawalpindi, Pakistan

Hamizah Razlan Associate Professor Consultant Gastroenterologist Head of Gastroenterology Unit Medical Department Faculty of Medicine Associate Professor Consultant Gastroenterologist Head of Gastroenterology Unit Medical Department Faculty of Medicine University Kebangsaan Malaysia Kuala Lumpur, Malaysia

Izazul Haque Assistant Professor and Head Department of Hepatology Comilla Medical College Comilla, Bangladesh Assistant Professor and Head Department of Hepatology Comilla Medical College Comilla, Bangladesh

Javed Yakoob Assistant Professor Department of Medicine Aga Khan University Karachi, Pakistan Assistant Professor Department of Medicine Aga Khan University Karachi, Pakistan

Julio Cesar Aguilar Head of Clinical Trials Vaccine Division Department of Biomedical Research Center for Genetic Engineering and Head of Clinical Trials Vaccine Division Department of Biomedical Research Center for Genetic Engineering and Biotechnology Havana, Cuba

Contributors

ix
ix

Kaushal Kishor Prasad Additional Professor and Chief Division of GE Histopathology In-Charge, Division of GE Enzymology Department of Additional Professor and Chief Division of GE Histopathology In-Charge, Division of GE Enzymology Department of Superspeciality of Gastroenterology Postgraduate Institute of Medical Education and Research Chandigarh, India

Khin Maung Win Head Department of Hepatology Yangon GI and Liver Center Yangon, Myanmar Head Department of Hepatology Yangon GI and Liver Center Yangon, Myanmar

Kshaunish Das Associate Professor Division of Gastroenterology School of Digestive and Liver Diseases Institute of Postgraduate Medical Associate Professor Division of Gastroenterology School of Digestive and Liver Diseases Institute of Postgraduate Medical Education and Research Kolkata, West Bengal, India

Mahesh Gupta Consultant Gastroenterologist Kailash Group of Hospitals New Delhi, India Consultant Gastroenterologist Kailash Group of Hospitals New Delhi, India

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

Man-Fung Yuen Chairman, Gastroenterology and Hepatology and Li Shu Fan Medical Foundation in Medicine Assistant Dean, Faculty Chairman, Gastroenterology and Hepatology and Li Shu Fan Medical Foundation in Medicine Assistant Dean, Faculty of Medicine The University of Hong Kong Chief, Division of Gastroenterology and Hepatology Deputy Chief, Service and Honorary Consultant Department of Medicine, Queen Mary Hospital Hong Kong

Mandish K Dhanjal Consultant Obstetrician and Gynecologist Honorary Senior Lecturer Queen Charlotte’s and Chelsea

Mandish K Dhanjal Consultant Obstetrician and Gynecologist Honorary Senior Lecturer Queen Charlotte’s and Chelsea Hospital Imperial College Healthcare NHS Trust London, UK

Mazhar Haque Senior Lecturer, Department of Medicine University of Queensland Staff Specialist Gastroenterologist Mater

Mazhar Haque Senior Lecturer, Department of Medicine University of Queensland Staff Specialist Gastroenterologist Mater Adult Hospital Brisbane, Australia

Md Delwar Hossain

Md

Delwar Hossain

Head Department of Gastroenterology Combined Military Hospital Dhaka, Bangladesh

Md Rabiul Hossain

Md

Rabiul Hossain

Consultant Physician General Bangladesh Armed Forces Dhaka, Bangladesh

Mian Mashhud Ahmad Professor and Senior Consultant Department of Gastroenterology LabAid Specialized Hospital Dhaka,

Mian Mashhud Ahmad Professor and Senior Consultant Department of Gastroenterology LabAid Specialized Hospital Dhaka, Bangladesh.

Moisés Copelman Assistant Professor Department of Gastroenterology Postgraduate Course in the Medical and Rehabilitation

Moisés Copelman Assistant Professor Department of Gastroenterology Postgraduate Course in the Medical and Rehabilitation Brazilian Institute (IBMR) Member of the Medical Staff Gastroenterology and Endoscopy Unit State University of Rio de Janeiro (UERJ) Residency Supervisor Digestive Endoscopy Program Bonsucesso Federal Hospital Rio de Janeiro, Brazil

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Textbook of Hepato-gastroenterology

Monjur Ahmed Clinical Associate Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Clinical Associate Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Philadelphia, USA

Muhammad Umar Principal Rawalpindi Medical College Chief, Allied Hospitals, Rawalpindi Chief Gastroenterology and Hepatology Division Principal Rawalpindi Medical College Chief, Allied Hospitals, Rawalpindi Chief Gastroenterology and Hepatology Division Holy Family Hospital Rawalpindi, Pakistan

Murat Saruç Professor Department of Gastroenterology Acibadem University School of Medicine Istanbul, Turkey Professor Department of Gastroenterology Acibadem University School of Medicine Istanbul, Turkey

Mustafa Yakut Professor Department of Gastroenterology Ankara University School of Medicine Ankara, Turkey Professor Department of Gastroenterology Ankara University School of Medicine Ankara, Turkey

Narendra Choudhary Consultant Hepatologist Medanta Institute of Liver Transplantation and Regenerative Medicine Medanta- The Medicity Consultant Hepatologist Medanta Institute of Liver Transplantation and Regenerative Medicine Medanta- The Medicity Gurgaon, Haryana, India

Natalia Balbi Flores Gastroenterologist Member of the Medical Staff in Endoscopy Unit of Getulio Vargas State Hospital Rio Gastroenterologist Member of the Medical Staff in Endoscopy Unit of Getulio Vargas State Hospital Rio de Janeiro, Brazil

Nurdan TÖzün Prefessor Department of Gastroenterology Acibadem University Acibadem Kozyatagi Hospital Istanbul, Turkey Prefessor Department of Gastroenterology Acibadem University Acibadem Kozyatagi Hospital Istanbul, Turkey

Om Parkash Senior Instructor Consultant Gastroenterologist Department of Medicine The Aga Khan University and Hospital Karachi, Senior Instructor Consultant Gastroenterologist Department of Medicine The Aga Khan University and Hospital Karachi, Pakistan

Paisarn Vejchapipat Associate Professor and Head Pediatric Surgery Unit Department of Surgery Chulalongkorn Hospital Bangkok, Thailand Associate Professor and Head Pediatric Surgery Unit Department of Surgery Chulalongkorn Hospital Bangkok, Thailand

Parimal Lawate Consultant Gastroenterologist Department of Gastroenterology and Endoscopy Jehangir Hospital Pune, Maharashtra, India Consultant Gastroenterologist Department of Gastroenterology and Endoscopy Jehangir Hospital Pune, Maharashtra, India

P Karayiannis Professor Department of Microbiology and Molecular Virology St George’s University of London Medical School at Professor Department of Microbiology and Molecular Virology St George’s University of London Medical School at University of Nicosia Nicosia, Cypsus

Premashis Kar Director and Professor of Medicine and Gastroenterologist Department of Medicine Maulana Azad Medical College University Director and Professor of Medicine and Gastroenterologist Department of Medicine Maulana Azad Medical College University of Delhi New Delhi, India

Punit Singla Associate Consultant Liver Transplant and Gastrointestinal Surgeon Medanta Institute of Liver Diseases and Transplantation Associate Consultant Liver Transplant and Gastrointestinal Surgeon Medanta Institute of Liver Diseases and Transplantation Medanta- The Medicity Gurgaon, Haryana, India

Rakesh Kochhar Professor Department of Superspeciality of Gastroenterology Postgraduate Institute of Medical Education and Research, Professor Department of Superspeciality of Gastroenterology Postgraduate Institute of Medical Education and Research, Chandigarh, India

Contributors

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xi

Ramazan Idilman Professor in Medicine Department of Gastroenterology Ankara University Faculty of Medicine Ankara, Turkey Professor in Medicine Department of Gastroenterology Ankara University Faculty of Medicine Ankara, Turkey

Ravi Mohanka Senior Consultant Hepatobiliary and Multiorgan Transplant Surgeon Medanta Institute of Liver Diseases and Transplantation Senior Consultant Hepatobiliary and Multiorgan Transplant Surgeon Medanta Institute of Liver Diseases and Transplantation Medanta- The Medicity Gurgaon, Haryana, India

Roger W Chapman Consultant Hepatologist John Radcliffe Hospital Oxford University Hospitals Oxford, UK Consultant Hepatologist John Radcliffe Hospital Oxford University Hospitals Oxford, UK

Rosmawati Mohamed Consultant Hepatologist Department of Medicine Faculty of Medicine University Malaya Kuala Lumpur, Malaysia Consultant Hepatologist Department of Medicine Faculty of Medicine University Malaya Kuala Lumpur, Malaysia

SM Wasim Jafri Ali Charan Professor of Medicine (Gastroenterology) Associate Dean Chairman, Department of Continuing Professional Ali Charan Professor of Medicine (Gastroenterology) Associate Dean Chairman, Department of Continuing Professional Education Aga Khan University Karachi, Pakistan

Sabyasachi Ray Consultant Gastroenterologist Peerless Hospital Kolkata, West Bengal, India Consultant Gastroenterologist Peerless Hospital Kolkata, West Bengal, India

Sachin Gupta Assistant Professor Department of Gastroenterology Laxmi Narayan Medical College and Hospital Bhopal, Madhya Pradesh, India Assistant Professor Department of Gastroenterology Laxmi Narayan Medical College and Hospital Bhopal, Madhya Pradesh, India

Saeed Hamid The Ibn-e-Sina Chair and Professor Consultant Gastroenterologist Department of Medicine The Aga Khan University and The Ibn-e-Sina Chair and Professor Consultant Gastroenterologist Department of Medicine The Aga Khan University and Hospital Karachi, Pakistan

Salimur Rahman Professor Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh Professor Department of Hepatology Bangabandhu Sheikh Mujib Medical University Dhaka, Bangladesh

Sanjay Govil Senior Consultant HPB Surgery and Liver Transplantation Global Health City Chennai, Tamil Nadu, India Senior Consultant HPB Surgery and Liver Transplantation Global Health City Chennai, Tamil Nadu, India

Saroj Kant Sinha Additional Professor Department of Superspeciality of Gastroenterology Postgraduate Institute of Medical Education and Additional Professor Department of Superspeciality of Gastroenterology Postgraduate Institute of Medical Education and Research Chandigarh, India

Shahab Abid Professor and Head Section of Gastroenterology Department of Medicine Aga Khan University Karachi, Pakistan Professor and Head Section of Gastroenterology Department of Medicine Aga Khan University Karachi, Pakistan

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Shahid A Khan Senior Lecturer in Hepatology and Consultant Physician St Mary’s Hospital Campus Imperial College of London Senior Lecturer in Hepatology and Consultant Physician St Mary’s Hospital Campus Imperial College of London London, UK

Sheikh Mohammad Fazle Akbar Principal Investigator Department of Medical Sciences Toshiba General Hospital, Tokyo, Japan Adjunct Professor Faculty of Principal Investigator Department of Medical Sciences Toshiba General Hospital, Tokyo, Japan Adjunct Professor Faculty of Medical Sciences State University of Bangladesh Dhaka, Bangladesh

Shelley Haynes Consultant Obstetrician and Gynecologist Southampon General Hospital Southampton, UK Consultant Obstetrician and Gynecologist Southampon General Hospital Southampton, UK

Shivaram Prasad Singh Head Department of Gastroenterology SCB Medical College Cuttack, Odisha, India Head Department of Gastroenterology SCB Medical College Cuttack, Odisha, India

Simon D Taylor-Robinson Professor of Translational Medicine Clinical Dean, Faculty of Medicine Department of Medicine St Mary’s Hospital Professor of Translational Medicine Clinical Dean, Faculty of Medicine Department of Medicine St Mary’s Hospital Campus Imperial College London London, UK

Sittisak Honsawek Professor Department of Biochemistry Faculty of Medicine Chulalongkorn Hospital Bangkok, Thailand Professor Department of Biochemistry Faculty of Medicine Chulalongkorn Hospital Bangkok, Thailand

Sony Sebastian Thazhath PhD Research Fellow Discipline of Medicine University of Adelaide Adelaide, Australia PhD Research Fellow Discipline of Medicine University of Adelaide Adelaide, Australia

Sujay Ray Associate Professor Division of Gastroenterology School of Digestive and Liver Disease Institute of Postgraduate Medical Associate Professor Division of Gastroenterology School of Digestive and Liver Disease Institute of Postgraduate Medical Education and Research and SSKM Hospital Kolkata, West Bengal, India

Taranjeet S Jolly Resident St Joseph Mercy Health System Livonia, USA Resident St Joseph Mercy Health System Livonia, USA

Uday C Ghoshal Professor Department of Gastroenterology Sanjay Gandhi Postgraduate Institute Lucknow, Uttar Pradesh, India Professor Department of Gastroenterology Sanjay Gandhi Postgraduate Institute Lucknow, Uttar Pradesh, India

Vikas Singla Senior Resident All India Institute of Medical Sciences New Delhi, India Senior Resident All India Institute of Medical Sciences New Delhi, India

Voranush Chongsrisawat Associate Professor Department of Pediatrics Faculty of Medicine, Chulalongkorn University Bangkok, Thailand Associate Professor Department of Pediatrics Faculty of Medicine, Chulalongkorn University Bangkok, Thailand

YK Chawla Director Postgraduate Institute of Medial Education and Research Chandigarh, India Director Postgraduate Institute of Medial Education and Research Chandigarh, India

Yong Poovorawan Professor Center of Excellence in Clinical Virology Faculty of Medicine, Chulalongkorn University Bangkok, Thailand Professor Center of Excellence in Clinical Virology Faculty of Medicine, Chulalongkorn University Bangkok, Thailand

Zaigham Abbas Head Department of Hepatogastroenterology Sindh Institute of Urology and Transplantation Karachi, Pakistan Head Department of Hepatogastroenterology Sindh Institute of Urology and Transplantation Karachi, Pakistan

Ziauddin Ahmed Professor of Medicine Drexel University College of Medicine Philadelphia, USA Professor of Medicine Drexel University College of Medicine Philadelphia, USA

F O R e w O R d
F O R e w O R d

F O R

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F O R e w O R d
F O R e w O R 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

and authoring a new textbook is not for the faint-hearted person. The idea has to be

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

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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

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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.

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Chapter 1:

Gastroesophageal Reflux Disease

1

Sujay Ray, Kshaunish Das, GK Dhali

Definition 1;

Epidemiology 1;

Pathogenesis 4;

Diagnosis 5;

Management 8

Chapter 2:

Carcinoma of Esophagus

17

Md Rabiul Hossain, Md Delwar Hossain

Epidemiology 17; Risk Factors 17; Biology and Genetics 18; Clinical Presentation 18; Complications 19; Prognostic Factors 19; Investigations 20; Treatment 21; Prognosis 23

Chapter 3:

Peptic Ulcer Disease

25

Javed Yakoob, SM Wasim Jafri

Clinical Features 25;

Etiology 26;

Risk Factors 27;

Differential Diagnosis 28;

 

Diagnosis 29; Treatment 29

Chapter 4:

Peptic Ulcer Disease in Asia–Pacific

31

Sony Sebastian Thazhath, Mazhar Haque

Prevalence 31;

Risk Factors 31;

Helicobacter pylori and Peptic Ulcer Disease in

 

Asia 32;

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; Functional Dyspepsia and Quality of Life 41

Management 38;

Chapter 6:

Gastric Cancer

43

Mian Mashhud Ahmad, Mamun-Al-Mahtab

Etiology 43;

Histologic Appearance 46;

staging of Gastric Cancer 47;

Further Research 57;

Pathology and Molecular Pathogenesis of Gastric Cancer 45;

Clinical Features, Diagnosis, and

Diagnosis 48;

Treatment 51;

Early Gastric Cancer 57

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Chapter 7:

Malabsorption Disorders

61

Axel Hsu, Man-Fung Yuen

Epidemiology 61; Pathophysiology 61; Clinical Features 62; 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 Features 71; Investigations 71; Differential Diagnosis 75; Management 75

 

Chapter 9:

Inflammatory Bowel Disease

77

Vikas Singla, Govind K Makharia

Epidemiology 77; Pathogenesis 77; 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

Pathophysiology 94; Diagnostic Testing 96;

Clinical Manifestations 95; Differential Diagnosis 97;

Physical Examination 96; Management 97

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 Diagnosis 112; Management 113; Treatment 115

Chapter 12:

Gastrointestinal Lymphomas

121

Moisés 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

Histogenesis 132;

Epidemiology 132;

Clinical Features 132;

Imaging 133;

Histology 133;

Immunohistochemistry 133;

Cytogenetics 133;

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Contents

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Gists and Their Associations 134;

Risk stratification 135;

Prognostic Value of Genetic Aberrations 134;

Treatment of Gastrointestinal stromal Tumors 135

Chapter 14:

Acute Diarrheal Diseases

 

138

Sabyasachi Ray

Definition 138;

Epidemiology 138;

Etiology 138;

Mechanisms 139;

 

Bacteria 140;

Virus 141;

Parasites 141;

Prevention 142;

Management 142

Chapter 15:

Liver Immunology

 

145

Julio César 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; Activation within the Liver 149;

Toll-like Receptors and Innate Immunity 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

 

Genotypes of Hepatitis B Virus 165;

Modes of Hepatitis B

Hepatitis B Virus 165; 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; Hepatitis B Virus Treatments 181

Implications for Current and Future

Chapter 20:

Hepatitis C

184

Amna Subhan Butt, SM Wasim Jafri

Discovery of Novel Hepatitis C Virus 184;

Incidence 186;

Global Burden of Hepatitis C 184;

Risk Factors for HCV Transmission 187;

Population at Higher

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Risk 188;

Viral Characteristics 188;

Disease 189;

Economic Burden of Hepatitis C 191;

Control Hepatitis C 195;

Genotypes: Distribution Across the World 188;

Pathogenesis and

Clinical Characteristics and Natural History of the

Who should be screened for Hepatitis C? 189;

Treatment 191;

Challenges 195

Diagnostic Workup 190;

strategies to Prevent and

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 C Virus 202

Hepatitis E Virus 200;

Hepatitis B Virus 201;

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 Disease 207; Diagnosis 207; Management 210

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;

Management of Complications 223;

Diagnosis 222;

Medical Treatment 225;

Prognosis 225; Hepatic Transplantation 225; secondary sclerosing Cholangitis 225

 

Chapter 25:

Primary Biliary Cirrhosis

229

Nurdan Tözün, Murat Saruç

Epidemiology 229;

Etiology and Pathophysiology 230;

Diseases Associated with Primary Biliary Cirrhosis 232;

Clinical Manifestations 231; special Cases 232;

 

Diagnosis 233;

Patient Management and Treatment 234

Chapter 26:

Autoimmune Hepatitis

239

Khin Maung Win

Epidemiology 239; Classification 239; Immunopathogenesis 240;

 

Clinical Features 242;

Differential Diagnosis 243;

Diagnosis 243;

Treatment 243

Chapter 27:

Amebic Liver Abscess

248

Premashis Kar

Pathology 248; Clinical Presentation 248; Diagnosis 249; Medical Therapy 249; Aspiration or Drainage of Abscess 250; surgical Intervention 250; Long-term Follow-up 250; Prognostic Marker 250

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Chapter 28:

Pyogenic Liver Abscess

251

Furqan Ahmed

Epidemiology 251;

Pathogenesis 251;

Clinical Manifestations 252;

Microbiology 252;

Diagnosis 253;

Differential Diagnosis 253;

Treatment 253;

Complications 255;

Mortality 255

Chapter 29:

Hydatid Cyst of Liver

257

Fazal Karim, Salimur Rahman

Epidemiology 257;

Transmission 258;

Clinical Features 258;

Complications 258;

Diagnosis 258;

Treatment 259;

Prevention 261

Chapter 30:

Leptospirosis

262

Izazul Haque, Fazal Karim

Epidemiology 262; Risk Factors 262; Microbiology 262; Pathogenesis 263; Clinical Manifestations 263; Differential Diagnosis 264; Laboratory Diagnosis 264; Treatment 265; Prognosis 265; Prevention 265

 

Chapter 31:

Cirrhosis of Liver

267

Anil Arora, Ashish Kumar

Pathogenesis of Cirrhosis 268;

Clinical Presentation 269;

Diagnosis 269;

Complications of Cirrhosis and its Management 273

 

Treatment of Cirrhosis 272;

Chapter 32:

Ascites

280

Gourdas Choudhuri, Ajesh Goyal

Etiology 280; Pathogenesis 280; Evaluation and Diagnosis 282; Physical Examination 282; Definitions of some Commonly used Terms 285; Complications 285; Treatment of Ascites 288; Refractory Ascites 293; Prognosis 295

 

Chapter 33:

Hepatic Encephalopathy

297

Cihan Yurdaydin, Ramazan Idilman

Clinical signs and Clinical Importance of Hepatic Encephalopathy 297; Diagnosis 298;

Minimal Hepatic Encephalopathy 298;

Pathogenesis 299;

Treatment 300

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; Treatment 307; Prevention 310

 

Chapter 35:

Portal Hypertension: Pathophysiology and Management

313

Debashis Misra, Abhijit Chowdhury

Portal Vein and Portal Hypertension 313;

Etiology 314;

Pathophysiology of

Portal Hypertension in Cirrhosis 316;

Clinical sequelae of Portal Hypertension 317;

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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 Presentation 330; Incidence 331; Precipitants 331; Diagnosis 331; Differential Diagnosis 331; Treatment 332; surgical Procedures 332; Prevention 333; Prognosis 333

 

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; Treatment 343; Prevention 344

Management and

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; Transplantation for Acute Liver Failure 358

Liver

Chapter 39:

Biliary Atresia

359

Voranush Chongsrisawat, Sittisak Honsawek, Paisarn Vejchapipat, Yong Poovorawan

Pathogenesis 360; Diagnosis 361; screening for Biliary Atresia 361; Clinical Manifestations 361; Investigations 361; Management 364

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, selection, and Prioritization for Organ

Allocation 381;

Indications for Liver Transplantation 380;

Contraindications for Liver Transplantation 383;

Recipient

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Evaluation and Preparation 383;

surgical Technique 386;

Postoperative Management, Complications, and Outcomes 392

Donor Evaluation and Preparation 385;

Innovative strategies in Liver Transplantation 391;

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; Treatment 420; Published Guidelines 423

 

Chapter 44:

Acute Pancreatitis

426

Mahesh Gupta, Uday C Ghoshal

 

Definitions 426; Etiology 426; Pathophysiology 430; Factors Determining the

 

severity of Pancreatitis 431; severity Assessment 432;

Complications of

Acute Pancreatitis 434; Management 436; Diagnosis 436; Treatment 438

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

Pathogenesis 466;

Tumor Markers 468;

Imaging/staging 468;

Treatment 469

Index

473

cHAPTER

1

Gastroesophageal Reflux Disease

DeFInItIon

Gastroesophageal reflux disease (GERD) is a disorder in which gastric contents reflux recurrently into esophagus, causing troublesome symptoms and/or complications This statement is similar to the Montreal definition. 1 The term ‘troublesome’connotes impairment of quality of life .

epIDemIology

Gastroesophageal reflux disease is a major clinical problem in Western countries. Several recent studies have suggested that the overall prevalence of reflux esophagitis (RE) in Western countries was around 10–20%. 2 In contrast, GERD has traditionally been considered to be less common in Asian countries. 3 But more recent studies suggest that the prevalence of GERD in Asia is increasing in Japan, and the overall prevalence of RE among the adult population is around 16%. 4 While in Taiwan, the prevalence of RE in patients evaluated for upper gastrointestinal tract sympoms is 15%. 5 These results are similar to the findinngs reported in the West. RE has been considered quite rare among Koreans. However, recent studies have revealed that the incidence is increasing in the Korean population. RE prevalence in subjects undergoing a routine check-up was reported to 2.36% in 1993 3 and 3.4% in 1997. 6 In 1999, the prevalence of RE was found to be 5.3% in subjects with gastrointestinal symptoms. However in a recent study from Korea in 2009 the prevalence of RE in male was 14.6% and the in female was only 4.7%. 7 According to univariate analysis, male sex, smoking history, total cholesterol >250 mg/dL, LDL cholesterol ≥160 mg/dL, triglyceride ≥150 mg/dL, high BP, and fasting glucose ≥110 mg/ dL, were significant risk factors of RE. 7 The prevalence rate of GERD in Qashgai migrating Nomads in sourthern Iran, defined as reflux occurring at least one time per week in the preceding year, was 33%. 8 In a study from urban and rural population of southern Iran, the prevalence of refux symptoms occurring

Sujay Ray, Kshaunish Das, GK Dhali

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 et al. 10 demonstrated that only 4.8% of Chinese population had GERD. On the other hand, Wong et al. 11 in a study by telephone contact,reported a prevalence of 29.8%.Thus Geographic differences in GERD prevalence are difficult to interpret, due to 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 between lower educational status and the prevalence of GERD probably reflects the interaction of certain unhealthy lifestyle habits or poor ability to modify such habits. Meucci et al. 13 found that patients with reflux-like and ulcer-like dyspepsia, the prevalence of migraine headache did not differ from that in controls, whereas a higher prevalence of migraine was noted in patients with dysmotility-like dyspepsia and in patients with nausea and vomiting alone. In the study by Aamodt et al. 14 higher prevalence of headache was found in individuals with reflux, diarrhea, constipation, and nausea. They suggested that headache sufferers commonly are predisposed to gastrointestinal complaints. In a recent multicentric study from India study showed that 8% of Indians reported symptoms of GER frequent or severe enough to be diagnosed as GERD. The low prevalence could be attributed to genetic factors as Asians have a smaller parietal cell mass and a lower acid output compared with Caucasians.The lower prevalence of hiatus hernia and smaller body mass index in the Asian population might also have accounted for the lower prevalence of GERD similar to that reported from the rest of south Asian countries. H. pylori infection, common in Indian population, might also reduce the frequency of GERD by causing gastritis and reduced acid secretion. Subjects with GERD were older, more often female, frequently consulted doctors, and often had overlapping functional lower GI symptoms. Frequency of intake meat, fried food, fruit and spices was higher amongst subjects with GERD; also, meat, fried food, spice, aerated drink, tea, coffee, and smoking were often associated with induction of symptoms among subjects with GERD. On multivariate analysis, induction of symptoms of GERD following smoking

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and nonvegetarian foods was independently associated with GERD. Frequency of GERD was comparable in northern and southern Indian population. (ISG Task Force Report -In Press). Assessment of health-related quality of life (HRQL) through the use of validated patient-completed questionnaires is likely to provide a good indication of how troublesome gastroesophageal reflux symptoms are. There are few studies assessing the relationship between HRQL and symptoms of GERD in the general population using validated questionnaires. 15 A population-based study in Malmö, Sweden showed that even mild reflux symptoms on a weekly basis were associated with a clinically meaningful reduction in well-being, 16 while another large survey of the Swedish population (the Kalixanda study) found that daily or weekly symptoms of heartburn and/or regurgitation substantially disrupted subjects’ everyday lives. 17 Similar results were 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 few data on the impact of GERD on HRQL in Asia generally. One epidemiological study of GERD in Sanghai, East China, evaluated HRQL impairment in GERD subjects using a Chinese version of the SF-36 20 (Figs 1 and 2).

Symptoms

Typical symptoms of reflux are heartburn (retrosternal burning sensation) and acid regurgitation. Heartburn, although an english term that has no equivalent in any of the Asian languages, is now thought to be increasingly understood by Asian patients. 21,22 Doctors may still have to describe in

words in the local language what heartburn means, i.e. ‘a burning discomfort arising from the epigastrium and rising retrosternally’to clarify the term. Asian patients more easily understand acid regurgitation, meaning the experience of sour or acidic fluid in the mouth. Other symptomatic presentations are chest pain, belching, nausea, dysphagia, early satiety, and epigastric pain, with or without typical reflux symptoms. There was much discussion that Asian patients may not complain of the cardinal symptoms of heartburn and acid regurgitation, but instead complain of other upper gastrointestinal symptoms which may be more prominent. Noncardiac chest pain, is a common condition among Asian patients. 23,24 and may be a presenting feature of GERD. GERD symptoms among Asian patients are more protean, and atypical symptoms may occur in the absence of heartburn and acid regurgitation (Table 1).

Spectrum

Symptomatic GERD is endoscopically manifested in three spectrum—nonerosive reflux disease (NERD), consisting of majority of around 60%, erosive esophagitis of around 35%, and complicated GERD of 5%.Compliations of GERD are peptic stricture, bleeding ulcer, Barrett’s esophagus, and esophageal adenocarcinoma. NERD is defined as troublesome reflux symptoms in the absence of esophageal mucosal damage on endoscopy. Barrett’s esophagus is the presence of columnar lined epithelium suspected at endoscopy and proven by histology which requires the presence of intestinal metaplasia. The term Barrett’s esophagus has been loosely used, giving rise to undue alarm and concern among doctors and patients.

rise to undue alarm and concern among doctors and patients. Fig. 1: Health-related quality of life

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 reflux disease; QOLRAD, Quality of Life in Reflux 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

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Gastroesophageal Reflux Disease 3 Fig. 2: Health status and well-being in subjects with and without GERD.

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 reflux 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

Typical symptoms

Alarm symptoms

Heartburn (pyrosis)

Dysphagia

Acid regurgitation

Gastrointestinal hemorrhage

 

Iron deficiency anemia

 

Nausea and/or vomiting

 

Weight loss

 

Family history of cancer

Histological confirmation of columnar lined epithelium with intestinal metaplasia in the definition of Barrett’s esophagus, in addition to endoscopic diagnosis is important (Fig. 3). Community-based studies identified older age and male sex as risk factors for GERD symptoms. 25,26 Endoscopy-based studies have also revealed age and male sex as risk factors for ERD. 27,28 Alcohol , smoking , BMI more than 25 and hiatus hernia are important risk factors. 29 Three reports from South- east Asia identified Indian race as being a risk factor for GERD. 28,30

Asia identified Indian race as being a risk factor for GERD. 2 8 , 3 0

Fig 3: Spectrum of gastroesophageal disease

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The prevalence and incidence of GERD is increasing in asian countries as revealed in many studies. 31,32 Time trend studies have shown both an increase in symptoms of GERD 33 in the community, as well as an increase in the prevalence of esophagitis. 34-40 The prevalence of Barrett’s esophagus and adenocarcinoma of the esophagus, although lower than in the Western populations, is also increasing in Asia. The prevalence of Barrett’s esophagus is generally low in Asian patients and ranges from 0.9 to 2%. 13,35 An isolated study, however, showed prevalence rates of up to 6% of patients endoscoped, which was different from other studies from the same region. A study based at the Singapore Cancer Registry has shown a significant decrease in squamous cell carcinoma of the esophagus over 34 years and a numerical, but not statistically significant, increase in adenocarcinoma of the esophagus. 41

pathogenesIs

Pathophysiology Esophageal Dysmotility and hiatus hernia

The GERD results from imbalance between aggressive and protective factors which interact at lower esophageal mucosa (Fig. 4). The protectve factors being lower esophageal sphincter 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

are the acid peptic secretion of stomach and bile which Fig. 4: Pathogenesis of gastroesophageal disease

Fig. 4: Pathogenesis of gastroesophageal disease

comes into contact of lower esophageal mucosa during reflux episodes.The pathophysiological mechanisms of GERD in Asian patients are similar to those in Western populations. Among the various motor dysfunction abnormalities of esophagus, transient lower esophageal sphincter relaxation (TLESR) with excessive acid reflux is the single most important mechanism. 42 In patients with more severe GERD, hiatus hernia, impaired esophageal peristalsis and weak lower esophageal sphincter (LES) pressure play a more important role in the pathogenesis. 4244 However, it is intriguing to note that rates of TLESR tend to be lower in both Asian GERD patients and healthy volunteers compared to their Western counterparts. 42 Furthermore, the reported prevalence of hiatus hernia in Asian populations is substantially lower than those reported in Western populations. 45 Chang et al. reported that the prevalence of hiatus hernia was only 2.2% in the Taiwanese 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 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 reported as being lower in Asian GERD patients, ranging from 7 to 20% in NERD, and 20 to 30% in esophagitis. 47,48 Further studies are required to elucidate whether there are clear ethnic differences in TLESR dysfunction and hiatus hernia, but the apparent lower prevalence of these conditions could contribute to the lower prevalence of GERD and its complications in Asia.

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

Gastroesophageal Reflux Disease

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5

obesity-related GERD is/are unclear. It has been reported that the prevalence of hiatus hernia increases with BMI, suggesting that hiatus hernia may play a role in the development of GERD- associated obesity. 57 It has also been reported that BMI and waist circumference are significantly correlated with TLESR and gastroesophageal pressure gradient in both asymptomatic and GERD patients. This finding indicates that postprandial LES dysfunction plays an important role in the pathogenesis of obesity related GERD. 58 The rising problem of obesity may be one of the major contributing factors for the increasing prevalence of GERD in Asia.

Role of h. pylori

The role of H. pylori in GERD has been a controversial subject and a major area of substantial discrepancies between Asian and Western studies. Most case-control and population-based studies tend to suggest a negative association between H. pylori infection and GERD in Asia. The prevalence of H. pylori infection in GERD patients ranges from 25 to 35%, which is 25–40% lower than that of the ‘non-reflux’ population in Asia. 59,60 The negative association is more prominent in the elderly, 61 however, is only confined to patients with severe GERD in Western countries, especially for those infected by more virulent cytotoxin-associated gene A (CagA+) strains. 62-64 The prevalence of H. pylori is also inversely related to the severity of GERD. The prevalence of H. pylori in patients ranges from 20 to 33% for esophagitis 65, 66 and 0 to 37% for Barrett’s esophagus. 67 Furthermore, patients with reflux esophagitis have lower rates of virulence for H. pylori infection compared to non-reflux controls. 67, 68 Compared to cross-sectional prevalence studies, however, the results are less consistent in H. pylori eradication studies for peptic ulcer patients. 69, 70 These conflicting observations may be attributed to different dominant patterns of H. pylori gastritis and acid secretion between peptic ulcer patients and nonulcer patients in the general population. Changes in patients with duodenal ulcer and nonulcer dyspepsia are characterized by antrum- predominant gastritis, hypergastrinemia, and relatively- preserved acid-secreting corpus mucosa. As a result, gastric acid hypersecretion is a common feature. 71,72 However, patients with gastric ulcer and gastric cancer are characterized by corpus-predominant gastritis or pangastritis, which is associated with profound destruction or even atrophy of acid- secreting mucosa. These patients are characterized by gastric acid hyposecretion, while eradication of H. pylori is followed by rebound gastric acid hypersecretion. It has been reported that recovery of gastric acid secretion and the emergence of reflux esophagitis occurs after H. pylori eradication in patients with corpus gastritis and atrophic gastritis. 73,74

DIagnosIs

Heartburn and regurgitation (or both) that occurs after meals are symptoms highly suggestive for GERD. Although the Montreal Consensus reported a high level of agreement on this issue, but the definition of heartburn and the specificity of the term for GERD had been studied mostly in Caucasian populations, whereas the term ‘heartburn’ carries different meanings to different parts in Asia. 1 There is lack of published data on the specificity and sensitivity of heartburn as a predictor of GERD in the Asia- Pacific region so the term heartburn must be clealy described and tested in different regions. GERD symptoms do not predict the severity of esophagitis. However, there is some correlation between the severity of symptoms and the presence and grade of esophagitis. 21,75 Longer duration of symptoms, with increased frequency and presence of symptoms at night, as well as in the daytime, are features that are more likely to be associated with erosive esophagitis (Figs 5 and 6). This correlation has been established in Caucasian GERD patients; about 30–40% of patients are found to have ERD, with the remainder having NERD. In Asian populations, the ratio of ERD to NERD is much lower and the correlation of symptoms with erosive disease in this population has not been tested sufficiently. Endoscopy should be done in patients with alarm symptoms. But the sensitivity and specificity of alarm symptoms (like dysphagia, weight loss, and anemia) varies on the definitions, duration of symptoms, and the population studied. Clinical diagnosis made by a physician on the basis of alarm symptoms is very specific (range, 97–98%), but it lacks sensitivity. 76 Urgent endoscopy in patients with alarm symptoms results in a significant yield of cancer (approximately 4% in one series) and of serious benign disease, such as peptic ulcer, stricture, and severe esophagitis (13%). 77 There are no published regional data on the correlation between alarm symptoms and peptic stricture and esophagitis mainly because of the rarity of these in the Asia-Pacific region. In this region, patients with alarm features more likely to have gastric rather than esophageal pathology due to the higher prevalence of peptic ulcer disease and gastric cancer in the region. Nevertheless, alarm features suggest advanced malignancy. 78 In clinical practice, expectation and anxiety of the patient is a major driver because any delay in the diagnosis of any pathologic condition will lead to patient dissatisfaction. Patients with GERD symptoms for 5 years but no alarm features should also undergo endoscopy to exclude Barrett’s esophagus. But the statement is irrelevant to Asia as there is a very low prevalence of Barrett’s esophagus and adenocarcinoma of the esophagus at present in this region. Due to the overlap of upper gastrointestinal symptoms and the greater prevalence

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A
A
B
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
A
B
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

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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 Barrett’s esophagus. The highest risk factor for development of Barrett’s esophagus is in white men with chronic symptoms of GERD. 79 However, the criteria to select patients for screening of Barrett’s are not yet well defined and it is recognized that persons with Barrett’s esophagus may be asymptomatc. Even within the Western population, this a strategy of screening for Barrett’s esophagus is not uniformly accepted. 80 Such a strategy is irrelevant to Asia at this time because of it’s low prevalence. 31,32 A recent direct comparative study also found a lower prevalence of esophagitis (6% vs 27%) and columnar-lined esophagus (1% vs 4%) in Asians compared to Western patients. 81 In this region, the major reason for endoscopy is to diagnose or exclude gastric cancer or peptic ulcer. There is considerable debate regarding performance of endoscopy at least once in patients with chronic upper gut symptoms, recognizing the difficulty of clinical diagnosis between GERD and peptic ulcer and the ability of endoscopy to provide or exclude a diagnosis and aid in tailoring therapy. In one study, 18% of patients suffering from H. pylori-related peptic ulcers were misdiagnosed as GERD based on symptoms alone. 82 As fear of gastric cancer is a major concern, endoscopy should be performed early rather than later. Empiric use of

proton pump inhibitors (PPIs) is common prior to endoscopy resulted increased risk of a false-negative H. pylori biopsy test, so there is requirement to cease PPI prior to testing. Widespread availability of endoscopy in many parts of the region favored endoscopic approaches over a noninvasive test. Symptomatic response to a trial of PPI is sufficient for

a presumptive diagnosis of GERD in a patient with typical symptoms, in the absence of alarm symptoms. Although a symptomatic response to a trial of PPI therapy has been used to support a diagnosis of GERD in patients with typical symptoms,

a meta-analysis revealed that the combined sensitivity and

specificity of this is only modest. 83 As there is overlap of GERD

with the symptoms of peptic ulcer and the response of ulcer symptoms to PPI therapy, and the higher prevalence of ulcer in the region, such a strategy needs to be validated locally. However, there is support for an empirical trial of PPI in those with typical symptoms, particularly in the primary care setting. Histopathology also plays an important role in diagnosis of GERD and its complication. Barrett’s esophagus is defined as presence of specialized intestinal metaplasia on histological examination of biopsies taken from suspected areas (if present) above gastroesophageal junction. Biopsies are taken from all four quadrants of distal 5 cm of the esophagus for histopathologic diagnosis of GERD which require presence of any of the following findings: (i) an increase in thickness

A B C
A
B
C

Fig. 7: Endoscopic biopsy: (A) Normal mucosa; (B) Reflux esophagitis; (C) Eosinophilic esophagitis

of basal cell layer to more than 15% of the thickness of the epithelium, (ii)an increase in height of the papilla to greater than two third of thickness, (iii) presence of blood lakes at the top of papilla, (iv) presence balloon cells, or (v) presence of inflammatory cells in epithelium or lamina propia (Fig. 7). A negative ambulatory pH study off therapy helps exclude GERD, if a PPI test fails. The test is considered positive if the total time for which pH is <4 is >4.5% (Fig. 8). However ambulatory pH testing is not widely available in Asia and is rarely done outside of major centers. Furthermore, there are few data on the test characteristics in Asian populations. For diagnostic purposes, the need to have patients off PPIs when performing pH studies was stressed. The likelihood of a positive test while on PPIs is low; the main role of the test with the patient on PPIs is for the assessment of the adequacy of acid suppression in patients with GERD who are not responding to therapy. Other diagnostic modalities are barium swallow and fluoroscopy and radionuclide scintigraphy, which are not commonly used tests. In a recent study from Delhi, when all the individual tests were compared against the gold standard of three or more positive tests, then as a single test, 24-hour pH monitoring had the best combination of sensitivity and specificity. 84 There is currently no established role for the use of narrow band imaging (NBI), capsule endoscopy, and wireless pH monitoring in the routine management of GERD in the Asia- Pacific region. However, these newer diagnostic modalities require validation as research tools and for clinical practice. It is recognized that they are not appropriate for routine clinical use in the region at present as the impact on diagnosis and management and the cost effectiveness of these new tests are yet to be determined. Nevertheless, NBI is considered a potentially valuable tool in diagnosing GERD, in particular in patients with Barrett’s esophagus. Wireless pH monitoring has been shown to increase the diagnostic yield of GERD by 20%, 85 in Caucasian population. Diagnostic strategies in the Asia-Pacific region must take consideration regarding the coexistence of GERD with other

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8 Textbook of Hepato-Gastroenterology Fig. 8: Common pattern of24 hours esophageal pH monitoring. Upper panel showing

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 cancer still accounts for nearly one million deaths worldwide annually, with much of this occurring in the region. There is immense difficulty in designing the management strategies in a large diverse region, where the prevalence and spectrum 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 functional dyspepsia frequently overlap, causing difficulty in differentiating these conditions clinically. H. pylori testing should be considered in patients presenting with GERD symptoms in regions with a high prevalence of gastric cancer or peptic ulcer disease. Symptoms were an imprecise way of distinguishing between upper gastrointestinal conditions in Asia and that GERD may coexist. Peptic ulcer and gastric cancer have greater impact than GERD on morbidity and mortality. There is evidence that benefits are gained by testing and treating H. pylori infection in the context of reducing symptoms, curing ulcer disease, and reducing the risk of gastric cancer. 86 H. pylori does not cause or prevent reflux disease and that eradication of this organism does not appreciably increase the risk of GERD occurring. 87 Long-term PPI therapy for GERD increases the risk of progression of gastric atrophy and intestinal metaplasia in those

infected with H. pylori. It is accepted to offer eradication therapy prior to long-term PPI therapy in this setting. 88 The decision to test for and treat H. pylori infection in the context of reflux must be individualized based on patient factors including comorbidity, age, gastric histology, family history, and informed choice.

management

Goals of Therapy

Resolution of symptoms (symptoms no longer bothersome) Healing of esophagitis or ulcer, if present. Prevent long-term, etc. complications (ulcer, bleeding, Barrett’s esophagus, stricture, etc.). Weight loss and elevation of head of bed could improve symptoms in GERD patient. There is insufficient data to support other lifestyle modification recommendations. Lifestyle modifications are commonly used as first line of therapy in patients presenting with GERD-related symptoms. They include weight loss, smoking cessation, avoidance of postprandial recumbency for a period of at least 3 hours, elevation of the head of the bed, avoidance of tight-fitting garments, and avoidance of large heavy meals as well as food

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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 modifications 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 modifications 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 profiles 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 PPIs are the most effective medical intervention for GERD. Studies have shown repeatedly and consistently that PPIs are superior to histamine 2 receptor antagonists (H2RAs) in healing the esophageal mucosa and relieving GERD-related symptoms of patients with ERD. 9294 In a meta-analysis, the investigators demonstrated that after 12 weeks of treatment, healing rates were 83.6% with PPIs, 51.9% with H2RAs, 39.2% with sucralfate, and 28.2% with placebo. 95 In addition, treatment with PPIs resulted in healing rates of esophageal inflammation and relief of GERD symptoms that were twofold higher than what was observed in patients receiving H2RAs. Similarly, PPIs demonstrate superiority in relieving heartburn symptoms in patients with NERD when compared to H2RAs. 96-98 The superiority of PPIs over H2RAs in ERD is not limited to acute therapy but has also been demonstrated in maintenance studies over as long as 11 years. 99 The symptoms response rate to once daily PPI in randomized controlled trials has been shown to be significantly higher in patients

has been shown to be significantly higher in patients Fig. 9: Healing rates following up to

Fig. 9: Healing rates following up to 4 weeks of treatment with esomeprazole 40 mg (n = 1562) or pantoprazole 40 mg (n = 1589) by baseline Los Angeles (LA) grade of erosive esophagitis severity. Aliment Pharmacol Ther. 2005;21:739-46

with ERD, as compared to those with NERD. In one meta- analysis, response rates at 4 weeks were significantly higher for patients with ERD as compared to those with NERD (56% vs 37%, P < 0.0001). 98 All PPIs are equally efficacious. In GERD/NERD/esophagitis 6 good quality systematic reviews—no clinically important differences in standard doses PPIs. Comparisons showing some degree of difference involved non-equivalent comparisons (e.g. high dose vs. standard dose). However with higher grades of esophagitis esomeprazole is more effective (Fig. 9). High or double-dose PPI, as initial therapy, is no better than standard daily dose therapy in the management of erosive esophagitis (Fig. 10). Double-dose PPIs: step-up therapy for nonresponders to standard dose PPI can be used.

therapy for nonresponders to standard dose PPI can be used. Fig. 10: Result of studies showing

Fig. 10: Result of studies showing comparison between Standard vs double dose PPI—no difference in healing of esophagitis or symptom relief

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H2RAs and antacids are useful in treating episodic heartburn. H2RAs and antacids are commonly used for episodic heartburn, primarily for postprandial heartburn. The perception of heartburn serves as a trigger for medication use, and the expectation is an immediate symptom relief that PPIs are unlikely to provide. The onset of action of antacids on esophageal acid concentration is 30 min after dosing and inhibition persists for 1 hour. 100 However, studies reported that effective heartburn relief can be achieved 19 min after consumption. 101 In contrast, H2RAs have been shown to provide symptom relief within 30 min of dosing that can last up to 12 hours. 102 When consumed 30 min prior to a meal, H2RAs are effective in completely or partially preventing postprandial heartburn. 103 There is some evidence to suggest that simultaneous consumption of both an H2RA and an antacid provides better control of heartburn symptoms, when compared to the clinical effect of each one of these products alone. 100 On-demand treatment with H2RAs has been shown to be safe and effective in GERD patients. In one study, ranitidine 75 mg daily was consumed on demand (up to three times daily) as compared to placebo in patients with uninvestigated GERD. 104 The study revealed that 38–41% of those receiving H2RAs reported relief of at least 75% of heartburn episodes during the study period as compared to 28% on placebo. The use of prokinetic agents either as monotherapy or adjunctive therapy to PPIs may have a role in the treatment of GERD in Asia. Several recent studies have demonstrated the value of prokinetic agents in GERD management. Itopride, a dopamine D2 antagonist with antiacetylcholinesterase effect, has been recently evaluated in patients with an abnormal pH test and mild ERD. After 30 days of treatment in an open label study design, itopride significantly reduced the extent of esophageal acid exposure and improved GERD-related symptoms as compared to baseline values. 105 Mosapride, a newly developed 5-HT4 agonist, has been shown to increase the rate of complete esophageal bolus transit and enhances esophageal bolus transit in normal controls. 106 In one study from India, 68 patients suffering from heartburn twice a week were randomized to either pantoprazole 40 mg twice daily or pantoprazole 40 mg twice daily plus mosapride 5 mg thrice daily for a period of 8 weeks. 107 The investigators found that the PPI + mosapride regimen provided significantly better symptom control in patients with ERD as compared to the PPI alone. However, there was no difference between the two therapeutic arms in ERD healing rates or symptomatic response of subjects with NERD. Further studies using the new prokinetic agents are needed, but those that are currently available demonstrate little efficacy as sole therapy or in combination with a PPI in subsets of patients with GERD. NERD patients will require a minimum of 4 weeks of initial continuous therapy with a PPI. Almost all therapeutic trials

in NERD patients have lasted only 4 weeks. The studies were designed with the assumption that 4 weeks are sufficient to assess symptom improvement as opposed to esophageal mucosal healing, which requires more than 4 weeks of PPI therapy. This arbitrary time frame is unlikely to provide the full symptomatic response rate of patients with NERD undergoing PPI treatment. A systematic review of the literature, revealed a trend in increased therapeutic gain for NERD patients throughout the 4 weeks, suggesting that

a 4-week follow-up evaluation alone may be insufficient to

show the full therapeutic gain in this patient population. 98

ERD patients will require a minimum of 4–8 weeks of initial continuous therapy with a PPI. Therapeutic studies in patients with ERD have almost always lasted 8 weeks. Healing rates in those receiving PPI once daily for 8 weeks ranged from 85–96%, regardless of the PPI that was used and the underlying severity or ERD. 108-111 However, patients with severe grades of ERD demonstrated higher PPI failure rates as compared to those with mild-to- moderate disease after 8 weeks of treatment. 107 In one study, patients were randomized to either omeprazole 20 mg once daily versus esomeprazole 40 mg

once daily. 112 The failure rate in those with Los Angeles grade

A was 9.6% and 6.6%; grade B, 28.7% and 10.6%; grade C,

29.6% and 12.8%; and grade D 26.2% and 20%, respectively. Patients with lower grades of ERD are likely to heal earlier, and thus 4 weeks of treatment could be sufficient. This is particularly important in the Asian context where generally patients are less likely to develop severe ERD, specifically Los Angeles grades C and D, as compared to their Western

counterparts. 32 The rate of symptom resolution in patients with ERD is commonly 5–15% lower when compared to esophageal mucosal healing rate after 8 weeks of

treatment. 108-112 This clearly suggests that a small portion of the patients with ERD will continue to report GERD-related symptoms despite complete esophageal mucosal healing. In

a meta-analysis of 43 therapeutic trials in ERD, the authors

reported an overall 65% healing rate of esophageal mucosa after 4 weeks, 80% after 8 weeks, and 84% after 12 weeks of treatment with PPI once daily. PPIs provided a healing rate of 11.7% per week and complete heartburn relief at a rate of 11.5% per week. The meta-analysis demonstrated that 12 weeks of treatment with PPI once a day provided only a modest increase in the healing rate as compared to 8 weeks of treatment in patients with ERD. On-demand therapy is an appropriate ongoing management strategy in NERD patients. Several alternative therapeutic strategies have been proposed for patients with NERD. The one that has been studied the most is on-demand therapy defined as PPI consumption (up to once daily) when needed and for the duration desired. This patient-driven therapeutic strategy has been shown

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to be clinically efficacious and cost effective. On-demand therapy is attractive to patients because it provides their input into their own management, addresses concerns about chronic ingestion of PPIs, and offers personal cost savings. Studies have also demonstrated that patients are commonly consuming PPIs in an on-demand fashion despite instructions to take their medications on a daily basis. 113 Many studies have assessed the value of on-demand PPI therapy as a maintenance strategy in patients with NERD. 114-120 These 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 of 6 months. Commonly used clinical endpoints included GERD symptom–load, days and nights without heartburn, discontinuation due to insufficient control of heartburn, and daily antacids consumption. All studies have shown that on- demand PPI therapy was superior to placebo in controlling GERD-related symptoms, antacids consumption, and patients’ satisfaction with therapy. Several cost effectiveness analyses have demonstrated that on-demand treatment with a PPI is cost effective compared with other therapeutic strategies for GERD (e.g. lifestyle therapy and antacids, H2RA therapy, step-up, step-down, as well as others). 121,122 It must be clarified that although the term ‘on-demand’ is used, it does not mean that patients take PPI whenever they like. The pharmacology of PPIs is such that to maximize gastric acid suppression, PPI should be taken 30–60 min before the first meal of the day and continued for 5–14 days on a daily basis when restarted.

Role of Surgery

For GERD patients who want to discontinue maintenance treatment, fundoplication could be offered when an experienced surgeon is available. Antireflux surgery is an effective therapeutic strategy for a subset of patients with GERD. 123,124 Long-term maintenance studies comparing medical therapy for GERD with antireflux surgery have demonstrated either similar clinical efficacy or significantly better control of symptoms post surgery. 125-127 Patients’ satisfaction with antireflux surgery has been reported to be exceptionally high. 128,129 Long-term follow-up of patients who underwent antireflux surgery (up to 13 years post-surgery) demonstrated a high rate of symptoms relapse requiring continuing antireflux medications. 122-124 This phenomenon can be seen soon after surgery and appears to increase in prevalence over the years, affecting up to 62% of patients more than 10 years post- surgery. 128-130 This is also compounded by a postoperative mortality of up to 0.8% and a variety of complications after antireflux surgery, such as dysphagia, postvagotomy symptoms, gas-bloat syndrome and others. 131-133 Furthermore, a surgeon’s experience in performing

antireflux surgery is highly predictive of clinical success. 132 In addition, several cost-effectiveness analyses have revealed that medical therapy is significantly less costly than antireflux surgery. 134 Thus, only in GERD patients who wish to discontinue maintenance of medical treatment, surgery by a fully trained and highly experienced surgeon is recommended. Endoscopic treatment of GERD should not be offered outside well-designed clinical trials

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59. Wu JC, Sung JJ, Ng EK et al. Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: a study from the East. Am. J. Gastroenterol. 1999;94:1790-4.

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61. Haruma K, Hamada H, Mihara M et al. Negative association between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter. 2000;5:

24-9.

62. Weston AP, Badr AS, Topalovski M, Cherian R, Dixon A, Hassanein RS. Prospective evaluation of the prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett’s esophagus, Barrett’s dysplasia, and Barrett’s adenocarcinoma. Am. J. Gastroenterol.

2000;95:387-94.

63. Lord RV, Frommer DJ, Inder S, Tran D, Ward RL. Prevalence of Helicobacter pylori infection in 160 patients with Barrett’s oesophagus or Barrett’s adenocarcinoma. Aust. N Z. J. Surg.

2000;70:26-33.

64. Vicari JJ, Peek RM, Falk GW et al. The seroprevalence of cagA- positive Helicobacter pylori strains in the spectrum of gastro- esophageal reflux disease. Gastroenterology. 1998;115:50-7.

65. Koike T, Ohara S, Sekine H et al. Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. Am. J. Gastroenterol. 1999;94:3468-72.

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67. Rajendra S, Ackroyd R, Robertson IK, Ho JJ, Karim N, Kutty KM. Helicobacter pylori, ethnicity, and the gastroesophageal reflux disease spectrum: a study from the East. Helicobacter. 2007;12:

177-83.

68. Lai CH, Poon SK, Chen YC, Chang CS, Wang WC. Lower prevalence of Helicobacter pylori infection with vacAs1a, cagA-positive, and babA2-positive genotype in erosive reflux esophagitis disease. Helicobacter. 2005;10:577-85.

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71. El Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology.

1995;109:681-91.

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74. Koike T, Ohara S, Sekine H et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut. 2001;49:330-4.

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76. Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy:

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79. Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am. J.Gastroenterol. 2002;97:1888-95.

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82. Wu JC, Chan FK, Ching JY et al. Empirical treatment based on ‘typical’reflux symptoms is appropriate in a population with a high prevalence of Helicobacter pylori infection. Gastrointest. Endosc.

83. Numans ME, Lau J, de Wit NJ, Bonis PA. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: a meta-analysis of diagnostic test characteristics. Ann. Intern. Med. 2004;140:518-27.

84. Kausal madan, Vineet Ahuja et al. Impact of 24-h esophageal pH monitoring on the diagnosis of gastroesophageal reflux disease; journal of Gastroenterology and hepatology. (2005)20,30-7

85. Prakash C, Clouse RE. Wireless pH monitoring in patients with non-cardiac chest pain. Am. J. Gastroenterol. 2006;101:446-52.

86. Wong BCY, Lam SK, Wong WM et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China. JAMA.

2004;291:187-94.

87. Katelaris PH. Gastro-oesophageal reflux disease and Helicobacter pylori. Minerva Gastroenterol. Dietol. 2003; 49:235-41.

88. Malfertheiner P, Megraud F, O’Morain C et al. Current concepts in the management of Helicobacter pylori infection – the Maastricht III Consensus Report. Aliment. Pharmacol. Ther. 2002;

16:167-80.

89. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am. J. Gastroenterol.

2005;100:190-200.

90. Kaltenbach T, Crockett S, Gerson L. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence- based approach. Arch. Intern. Med. 2006;166:965-71.

91. Fraser-Moodie C, Norton B, Gornall C et al. Weight loss has an independent beneficial effect on symptoms of gastro- oesophageal reflux in patients who are overweight. Scand. J. Gastroenterol. 1999;34:337-40.

92. Caro J, Salas M, Ward A. Healing and relapse rates in gastroesophageal reflux disease treated with the newer proton- pump inhibitors lansoprazole, rabeprazole and pantoprzole compared with omeprazole, ranitidine, and placebo: evidence from randomized clinical trials. Clin. Ther. 2001;23:998-1017.

93. Dekel R, Morse C, Fass R. The role of proton pump inhibitors in gastro-oesophageal reflux disease. Drugs. 2004;64:277-95.

94. Vigneri S, Termini R, Leandro G et al. A Comparison of five maintenance therapies for reflux esophagitis. N. Engl. J. Med.

1995;333:1106-10.

95. Chiba N, De Gara C, Wilkinson J, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease:

a meta-analysis. Gastroenterology. 1997;112:1798-810.

96. Richter J, Campbell D, Kahrilas P, Huang B, Fludas C. Lansoprazole compared with ranitidine for the treatment ofnonerosive gastroesophageal reflux disease. Arch. Intern. Med. 2000;160:

1803-9.

97. Fujiwara Y, Higuchi K, Nebik H et al. Famotidine vs. omeprazole: a prospective randomized multicentre trial to determine efficacy in non-erosive gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 2005;21:10-18.

98. Dean B, Gano A Jr, Knight K, Ofman J, Fass R. Effectiveness of proton pump inhibitors in non-erosive reflux disease. Clin. Gastroenterol. Hepatol. 2004;2:654-64.

99. Klinkenberg-Knol E, Nelis F, Dent J et al. Long-term omeprazole treatment in resistent gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology.

2000;118:661-9.

100. Robinson M, Rodriguez-Stanley S, Ciociola A et al. Synergy between low-dose ranitidine and antacid in decreasing gastric and oesophageal acidity and relieving meal-induced heartburn. Aliment. Pharmacol. Ther. 2001;15:1365-74.

101. Faaij R, Van Gerven J, Jolivet-Landreau I et al. Onset of action during on-demand treatment with Maalox suspension or low- dose ranitidine for heartburn. Aliment. Pharmacol. Ther. 1999;13:

1605-10.

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102. Pappa K, Gooch W, Buaron K et al. Low-dose ranitidine for the relief of heartburn. Aliment. Pharmacol. Ther. 1999;13:459-65.

103. Pappa K, Williams B, Payne J, Buaron K, Mussari K, Ciociola A.

A double-blind, placebo-controlled study on the efficacy and

safety of non-prescription ranitidine 75 mg in the prevention

of meal-induced heartburn. Aliment. Pharmacol. Ther. 1999;13:

467-73.

104. Galmiche J, Shi G, Simon B, Casset-Semanaz F, Slama A. On- demand treatment of gastro-oesophageal reflux symptoms:

a comparison of ranitidine 75 mg with cimetidine 200 mg or

placebo. Aliment. Pharmacol. Ther. 1998;12:909-17.

105. Kim Y, Kim T, Choi C et al. Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study. World. J. Gastroenterol.

2005;11:4210-4.

106. Cho Y, Choi M, Han H et al. The effect of mosapride on esophageal motility and bolus transit in asymptomatic volunteers. J. Clin. Gastroenterol. 2006;40:286-92.

107. Madan K, Ahuja V, Kashyap P, Sharma M. Comparison of efficacy of pantoprazole alone versus pantoprazole plus mosapride in therapy of gastroesophageal reflux disease: a randomized trial. Dis. Esophagus. 2004;17:274-8.

108. Adachi K, Hashimoto T, Hamamoto N et al. Symptom relief in patients with reflux esophagitis: comparative study of omeprazole, lansoprazole and rabeprazole. J. Gastroenterol. Hepatol.

2003;18:1392-8.

109. Richter J, Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial. Am. J. Gastroenterol.

2000;95:3071-80.

110. Bardhan K, Hawkey C, Long R et al. Lansoprazole versus ranitidine for the treatment of reflux oesophagitis. UK Lansoprazole Clinical Research Group. Aliment. Pharmacol. Ther. 1995;9:145-51.

111. Castell D, Richter J, Robinson M et al. Efficacy and safety of lansoprazole in the treatment of erosive reflux esophagitis. The Lansoprazole Group. Am. J. Gastroenterol. 1996;91:1749-57.

112. Richter J, Kahrilas P, Johanson J et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am. J.Gastroenterol. 2001;96:656-65.

113. Hungin A, Rubin G, O’Flanagan H. Factors influencing compliance

in long-term proton pump inhibitor therapy in general practice.

Br. J. Gen. Pract. 1999;49:463-4.

114. Pace F, Pallotta S, Bianchi Porro G. On-demand proton pump inhibitor therapy in patients with gastro-oesophageal reflux disease. Dig. Liver. Dis. 2002;34:870-7.

115. Scholten T, Dekkers C, Schütze K, Körner T, Bohuschke M, Gatz G. On-demand therapy with pantoprazole 20 mg as effective long- term management of reflux disease in patients with mild GERD:

the ORION trial. Digestion. 2005;72:76-85.

116. Zacny J, Zamakhshary M, Sketris I, Veldhuyzen Van Zanten S. Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump

inhibitors for gastro-oesophageal reflux disease patients. Aliment. Pharmacol. Ther. 2005;21:1299-312.

117. Lind T, Havelund T, Lundell L et al. On demand therapy with omeprazole for the long-term management of patients with heartburn without oesophagitis – a placebo-controlled randomized trial. Aliment. Pharmacol. Ther. 1999;13:907-14.

118. Talley N, Lauritsen K, Tunturi-Hihnala H et al. Esomeprazole 20 mg maintains symptom control in endoscopy-negative gastro- oesophageal reflux disease: a controlled trial of ‘on demand’ therapy for 6 months. Aliment. Pharmacol. Ther. 2001;15:347-54.

119. Tsai H, Chapman R, Shepherd A et al. Esomeprazole 20 mg on-demand is more acceptable to patients than continuous lansoprazole 15 mg in the long-term maintenance of endoscopy- negative gastro-oesophageal reflux patients: the COMMAND Study. Aliment. Pharmacol. Ther. 2004;20:657-65.

120. Ponce J, Arguello L, Bastida G, Ponce M, Ortiz V, Garrigues V. On- demand therapy with rabeprazole in nonerosive and erosive gastroesophageal reflux disease in clinical practice: effectiveness, health-related quality of life, and patient satisfaction. Dig. Dis. Sci.

2004;49:931-6.

121. Hughes D, Bodger K, Bytzer P, de Herdt D, Dubois D. Economic analysis of on-demand maintenance therapy with proton pump inhibitors in patients with non-erosive reflux disease. Pharmaeconomics. 2005;23:1031-41.

122. Wahlqvist P, Junghard O, Higgins A, Green J. Cost effectiveness of proton pump inhibitors in gastro-oesophageal reflux disease without oesophagitis. Pharmaeconomics. 2002;20:267-77.

123. Frantzides C, Richards C. A study of 362 consecutive laparoscopic Nissen fundoplications. Surgery. 1998;124:651-5.

124. Lundell L, Miettinen P, Myrvold H et al. Long-term management of gastro-oesophageal reflux disease with omeprazole or open antireflux surgery: results of a prospective, randomized clinical trial. Eur. J. Gastroenterol. Hepatol. 2000;12:879-87.

125. Lafullarde T, Watson D, Jamieson G, Myers J, Game P, Devitt P. Laparoscopic Nissen fundoplication. Arch. Surg. 2001;136:

180-4.

126. Lundell L, Miettinen P, Myrvold H et al. Continued (5-year) follow- up of a randomized clinical study comparing anti-reflux surgery and omeprazole in gastroesophageal reflux disease. J. Am. Coll. Surg. 2001;192:172-81.

127. Spechler S, Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. N. Engl. J. Med. 1992;326:786-92.

128. Madan A, Minocha A. Despite high satisfaction, majority of gastro- oesophageal reflux disease patients continue to use proton pump inhibitors after anti-reflux surgery. Aliment. Pharmacol. Ther.

2006;23:601-5.

129. Klapow J, Wilcox C, Mallinger A et al. Characterization of long- term outcomes after Toupet Fundoplication. J. Clin. Gastroenterol.

2002;34:509-15.

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130. Spechler S, Lee E, Ahnen D et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease. JAMA.

2001;285:2331-8.

131. Galmiche J, Zerbib F. Laparoscopic fundoplication is the treatment of choice for gastro-oesophageal reflux disease. Gut. 2002;51:472-4.

132. Soot S, Eshraghi N, Farahmand M et al. Transition from open to laparoscopic fundoplication: the learning curve. Arch. Surg.

1999;134:278-81.

133. Kozarek R, Low D, Raltz S. Complications associated with laparoscopic anti-reflux surgery: one multispecialty clinic’s experience. Gastrointest. Endosc. 1997; 46:527-31. 134. Arguedas M, Heudebert G, Klapow J et al. Re-examination of the cost-effectiveness of surgical versus medical therapy in patients with gastroesophageal reflux disease: the value of long-term data collection. Am. J. Gastroenterol. 2004;99:

1023-8.

cHAPTER

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Carcinoma of Esophagus

INTRODUCTION

Worldwide, esophageal cancer is the sixth leading cause of death from cancer. There were 7,966 people diagnosed with esophageal cancer in the UK in 2007, with twice as many cases occurring in men as in women. Squamous cell carcinoma (SCC) is the most common esophageal carcinoma worldwide. Adenocarcinoma is less common (<15%) esophageal cancer. Small cell carcinoma of esophagus is very rare. Approximately 15% of esophageal cancers arise in the upper one-third, 50% in the middle-third and 35% in the lower-third, and gastroesophageal junction.

EPIDEMIOLOGY

The incidence of carcinoma differs significantly by geographic regions, race, sex, and also types. The rates can vary between regions in a given country due to environmental and possibly nutritional factors. The disease predominantly affects older age groups with the peak incidence between 60 and 70 years of age. In 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, the highest risk populations (incidence rate >100 cases per 100,000 inhabitants/year) are found in north central China, northeastern Iran and the intervening central Asian countries sometimes collectively called “the Central Asian esophageal cancer belt”. Intermediate-risk populations with incidence rates approximately 20–50 cases per 100,000 inhabitants per year are found in eastern and southern Africa, southern Brazil, Uruguay, northern Argentina, and northwest France. Most of the world is considered low risk with the incidence rates less than 10 cases per 100,000 inhabitants per year. By far, SCC is the most common esophageal cancer worldwide and adenocarcinoma accounts for less than 15% of all esophageal cancers. Over the last two decades, the incidence of adenocarcinoma has risen sharply particularly among white males, although SCC remains the predominant cell type among African Americans.

Md Rabiul Hossain, Md Delwar Hossain

RISK FACTORS

Many factors are responsible for the development of esophageal cancer (Table 1). It varies with the types of carcinoma. Cigarette smoking and alcohol consumption are the most important predisposing factors for esophageal cancer in developed countries, particularly for SCC. The carcinogenic effects are more pronounced for SCC. The mechanism of carcinogenesis is obscure. It is postulated that many tobacco- derived chemicals, such as nitrosamines may initiate the

Table 1: Risk factors for esophageal carcinoma

Squamous cell carcinoma

•  Chronic tobacco use

•  Heavy alcohol consumption

•  History of radiation therapy

•  Chronic esophagitis (most common in Asia and Africa)

•  Chronic stricture

•  Tylosis

•  Plummer-Vinson syndrome

•  Achalasia

•   Dietary deficiency of carotene, vitamins C, E and riboflavin, selenium and zinc

•  Low intake of fruits and vegetables

•  High intake of red meat and nitrate-containing foods

•  Consumption of hot beverages

Adenocarcinoma

•  Barrett’s esophagus and gastroesophageal reflux disease

•  Obesity

•  Cigarette smoking

•  Alcohol consumption

•  Scleroderma

•  History of colon cancer

•  Medications: theophylline and β-agonists (long-term use >5 years)

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18 Textbook of Hepato-gastroenterology Fig. 1: Barrett’s esophagus—risk for esophageal carcinoma esophageal

Fig. 1: Barrett’s esophagus—risk for esophageal carcinoma

esophageal carcinoma or act as promotional agents. Barrett’s esophagus is the most important risk factor for esophageal adenocarcinoma (Fig. 1). It is a premalignant lesion that results from gastroesophageal reflux disease (GERD) in which the squamous epithelium of the distal esophagus is replaced by intestinal type columnar epithelium. The lifetime risk of esophageal carcinoma in Barrett’s esophagus is estimated to be 5%. In addition to this, GERD is an independent risk factor for esophageal adenocarcinoma.

Decreased Risk for Esophageal Carcinoma

The risk appears to be less in patients using aspirin or related drugs (NSAIDs). The role of Helicobacter pylori in progression to esophageal adenocarcinoma is still uncertain, but on the basis of population data, it may carry a protective effect. It is postulated that H. pylori induces chronic gastritis, which is a risk factor for reflux, which in turn is a risk factor for esophageal adenocarcinoma. According to the National Cancer Institute, diets high in cruciferous (cabbage, broccoli/broccolini, cauliflower, brussel sprouts), and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer. Moderate coffee consumption is associated with a decreased risk. According to one Italian study of “diet surveys completed by 5,500 Italians”—a study which has raised debates questioning its claims among cancer researchers cited in news reports about it, eating pizza more than once a week appears to be a

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 that may induce proliferation. Abnormal variants of interleukin-1 gene are associated with an increased risk of development of cancer of gastric cardia. So, these genes may make possible screening of individuals with intestinal metaplasia of the esophagus. Furthermore, anti-inflammatory drugs, such as cyclooxygenase inhibitors may provide a means of medical intervention.

CLINICAL PRESENTATION (TABLE 2)

Dysphagia

Progressive dysphagia (90%) is the most common presentation of esophageal cancer leading to its diagnosis. A patient may not manifest dysphagia until the lumen is more than 50–60% obstructed by the tumor mass by stretching the smooth muscle due to lack of serosal layer. Initially, there is dysphagia to solid and later on for both solid and liquid.

Table 2: Signs and symptoms of esophageal carcinoma

•  Dysphagia (most common)—solids then liquids

•  Odynophagia

•  Back pain and chest pain

•  Anorexia

•  Weight loss

•  Regurgitation

•  Hoarseness/voice change

•  Aspiration/cough/recurrent pneumonia

•  Anemia

•  Hematemesis

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Odynophagia

Odynophagia (50%) is the second most common presenting symptom of esophageal cancer. It may be due to an ulcerated area in the tumor or mediastinal involvement. But constant pain in the mid back or mid chest is the typical presentation of mediastinal invasion.

Anorexia and Weight Loss

Up to 75% of patients have experienced anorexia and weight loss when they seek medical attention.

Gastrointestinal Bleeding and Anemia

Overt gastrointestinal bleeding as manifested by hematemesis or melena rarely occur. But anemia is more common due to subclinical bleeding. Hoarseness of voice, severe cough and recurrent pneumonia may present.

COMPLICATIONS

Pulmonary complications: Dyspnea, chronic cough, aspiration and postobstructive pneumonia, lung abscess, esophagoairway fistula, pleural effusion, and halitosis Cardiovascular complications: Hemorrhage from the aorta, arrhythmias, conduction abnormalities, and pericardial effusion

PROGNOSTIC FACTORS

Radiographic Endoscopic

Tumors measuring less than 5 cm are often confined to the esophageal wall, whereas only 10% of those measuring greater than 5 cm are localized. The presence of metastases is a poor prognostic sign and is a contraindication to surgery. The presence of transmural invasion into adjacent organs, such as pericardium or trachea is associated with poor prognosis. Evidence of lymph node involvement is also associated with a poor overall 5-year survival (5%).

Pathologic

The prognosis of any malignancy depends on the histologic type and grade, and clinical stage. The vast majority of esophageal cancer are either SCC or adenocarcinoma. The overall prognosis of a poorly differentiated tumor is worse than that of a well-differentiated tumor.

Clinical Stage

The new system recognizes five major prognostic stages from stage 0 to stage IV of tumor extent and tumor stage based on local invasion, nodal involvement and presence of metastases (Table 3). The 5-year survival rates associated with the tumor invasion (T1 to T4) are approximately 80%, 45%, 25% and less than 20%, respectively.

Table 3: American Joint Committee on Cancer (AJCC) TNM staging system for esophageal cancers (1997 revision)

Primary tumor infiltration (T)

 

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

 

T1

Tumor limited to mucosa/submucosa

T2

Tumor involving muscularis propria

T3

Involvement of adventitia, no extraesophageal involvement

Regional lymph nodes (N)

 

NX

Regional lymph nodes cannot be assessed

N0

No nodal involvement

 

N1

Regional nodes involved

 

Distant metastasis (M)

 

MX

Distant metastases cannot be assessed

M0

No distant metastases

 
 

M1 Distant metastases for tumors of the lower thoracic esophagus M1a Metastases in celiac nodes M1b Other distant metastases Tumors of the mid-thoracic esophagus M1a Not applicable M1b Nonregional lymph nodes and/or other distant metastasis Tumors of the upper thoracic esophagus M1a Metastases in cervical nodes M1b Other distant metastases

AJCC stage groupings

 

Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage IIA

T2–3

N0

M0

Stage IIB

T1–2

N1

M0

Stage III

T3

N1

M0

 

T4

Any N

M0

Stage IV

Any T

Any N

M1

Stage IVA

Any T

Any N

M1a

Stage IVB

Any T

Any N

M1b

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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).

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 tumor’s 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.

Brush cytology may be used as a complementary technique. Fig. 2: Barium swallow of the esophagus

Fig. 2: Barium swallow of the esophagus showing irregular filling defects suggestive of esophageal carcinoma

irregular filling defects suggestive of esophageal carcinoma Fig. 3: CT with contrast axial image revealing esophageal

Fig. 3: CT with contrast axial image revealing esophageal carcinoma

CT with contrast axial image revealing esophageal carcinoma Fig. 4: Endoscopic view of esophageal carcinoma

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 5–10 mm (Fig. 3). For metastases detection by CT scan, the accuracy is 60–90% 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 that compared PET with CT and endoscopic ultrasonography (EUS) for local lymph node (LN) disease, the sensitivity of PET

Carcinoma of Esophagus

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A
A
B
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 may have been higher (87% vs 67%).

Endoscopic Ultrasonography

It is the most accurate in identifying T3 or T4 stage. Overall EUS nodal staging is less accurate. Endoscope ultrasound- guided fine-needle aspiration has significantly improved the diagnosis of malignant adenopathy (Figs 5A and B).

TREATMENT

Esophageal carcinoma is a treatable disease, but it is rarely curable. Whether the patient is a candidate for major curative surgery is to be determined first before going to start treatment. Unfortunately, over 60% patients with esophageal carcinoma are not candidates for surgery at the time of presentation due to advanced stage of the disease or significant comorbidity. Primary treatment modalities include:

Surgery alone

Chemotherapy with radiation therapy

Combined modality therapy (chemotherapy + surgery, chemotherapy and radiation therapy + surgery) is under clinical evaluation

Endoscopicmucosalresection(EMR)andorphotodynamic therapy in selected patients with superficial carcinoma is also under evaluation.

Primary Therapy Surgery

General considerations: Patients in the subgroup with limited local spread (T1–T2) and no regional lymph node involvement are potentially curable by surgery. Resectable tumors are characterized by the absence of extension into mediastinal structures and the absence of nodal or organ 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 40% is an ominous finding.

Surgical approach: The surgical options available for esophageal tumor resection include:

Transhiatal: It is currently the preferred surgical approach.

Combined right thoracic and abdominal (Ivor Lewis)

Left thoracoabdominal

En bloc, either two field- or three field-resection remains the definitive surgical cure for esophageal cancer (field one—celiac and splenic nodes, field two—infracarinal posterior mediastinal nodes, field three—upper mediastinal and cervical nodes).

Combination Therapy

It is alternative to surgery. Definitive radiation therapy in combination with chemotherapy (fluorouracil and mytomycin) is used for treatment.

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Treatment of Superficial Esophageal Cancer Endoscopically

EMR

Laser therapy

Argon plasma coagulation (APC)

Photodynamic therapy.

Palliation Therapy

Palliative therapy remains the mainstay of treatment options for incurable esophageal carcinoma with what the majority of patients present. The following palliative therapy options are available.

Radiation Therapy

External beam radiation therapy alone provides reasonable palliation for esophageal cancer. Radiotherapy achieves palliation of dysphagia in 70–90% of patients. Combination of external beam radiation with intraluminal irradiation using cobalt-60, cesium-137 or iridium-192 is possible to increase the dose of radiation to the tumor, and it is promising both in median and 5-year survival.

Contraindication to radiotherapy:

Tracheal or bronchial involvement

Cervical esophageal location of the tumor

Stenosis.

Chemotherapy

Single agents: The clinical response rates (5–10%) and duration response (2–4 months) of any single agent of any class of chemotherapy are poor.

Combination chemotherapy: It is superior to single agent chemotherapy in the management of esophageal cancer. In general, the cisplatin-based combination chemotherapy (commonly used) has yielded a response rate of 25–35%. To date, there is no role of single agent or combination chemotherapy as an adjuvant to surgery.

Endoscopic Therapy

Dilation: Esophageal dilation is commonly done by expandable balloons through-the-scope or wire-guided polyvinyl bougies under fluoroscopy.

Ablation: The available options for tumor ablation are as follows:

Chemical sclerosant injection: Absolute alcohol is the most widely used sclerosant chemical agent

Photodynamic therapy (PDT): It has been successful in

reducing tumor bulk and in opening the lumen in patients with complete obstruction. It also acts as a salvage therapy in patient with stents failure due to tumor ingrowth 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 red light at a wave length of 630 nm to tumor resulting in necrosis of the tumor

Monopolar and bipolar electrocautery: It is rarely used now a days

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 dysphagia in advanced esophageal cancer

Neodymium:yttrium-aluminium-garnet (Nd:YAG):

Nd:YAG laser relieves dysphagia by coagulating and vaporizing the malignant tissue under endoscopic control. Multiple laser sessions are required to improve dysphagia. The requirement for the laser therapy are as follows:

– Growth should be exophytic or polypoid

– Preferably, it will be located in the straight segment of esophagus

– Mass shorter than 5 cm.

Endoscopic mucosal resection: EMR or mucosectomy is used to treat superficial flat and polypoid neoplasm of the mucosa of gastrointestinal tract. Long-term studies show that EMR outcomes are similar to those of surgery to the treatment,

particularly in early gastrointestinal cancers. Different EMR techniques are as follows:

Injection and snare cautery

Injection with precut

EMR with cap

EMR with band ligation.

It is indicated:

When the lesion is superficial lesion

No evidence of lymph node metastasis Bleeding, perforation and necrosis are the major complications. The commonly employed modalities of EMR include strip biopsy, double-snare polypectomy, resection with combined use of highly concentrated saline and epinephrine, and resection using a cap.

Esophageal prostheses: The prostheses (stents) are inserted endoscopically under fluoroscopic guidance and provide relief of dysphagia effectively. At present, self-expanding metallic stents (SEMS) covered/uncovered are widely used

Carcinoma of Esophagus

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Carcinoma of Esophagus 23 Fig. 6: Self-expanding metallic stents used for the palliation of esophageal carcinoma

Fig. 6: Self-expanding metallic stents used for the palliation of esophageal carcinoma

(Fig. 6). Covering the stent with a polymer sheet effectively reduces tumor ingrowth and provides for treatment of tracheoesophageal fistulas. Commercially available SEMS are as follows:

The Wallstent II (Microvasive, Boston Scientific, Inc, Natick, Mass)

The Flamingo, Wallstent

The Ultraflex stent (Microvasive, Boston Scientific, Inc, Natick, Mass)

The “Z” stent (Cook medical, Inc, Winston-Salem, NC). Other than the SEMS, the Polyflex (Boston Scientific, Inc, Natick, Mass) is a completely covered self-expanding non- metallic (plastic) stent recently introduced. It is approved by the Food and Drug Administration (FDA) for palliation of malignant dysphagia. Major complications of SEMS placement include tumor ingrowth or tumor overgrowth (5–20%), which can be treated effectively with laser or thermal contact therapy, stent migration (10%) and chest pain. Other complications are food impaction, bleeding, and reflux esophagitis.

Enteral Nutrition

Enteral nutrition support may be indicated in an attempt to improve functional status before and after surgery, during

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 10–15%. 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 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%.

BIBLIOGRAPHY

1. Bollschweiler E, Wolfgarten E, Gutschow C, et al. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer. 2001;92(3):549-55.

2. Cancer research UK. Oesophageal cancer incidence statistics. [online]. Available from http://www.cancerresearchuk.org/

cancer-info/cancerstats/types/oesophagus/incidence/uk-

oesophageal-cancer-incidence-statistics. [Accessed January,

2013].

3. Corley DA, Kerlikowske K, Verma R, et al. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology. 2003;124:47-56.

4. EII C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s oesophagus. Gastroenterogy. 2000;118:670-7.

5. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med.

2003;349:2241-52.

6. Heath EI, Limburg PJ, Hawk ET, et al. Adenocarcinoma of the esophagus: risk factors and prevention. Oncology (Williston Park). 2000;14(4):507-14.

7. Koshy M, Esiashvilli N, Landry JC, et al. Multiple management modalities in esophageal cancer: epidemiology, presentation and progression, work-up and surgical approaches. Oncologist.

2004;9(2):137-46.

8. Ku GY, Ilson DH. Preoperative therapy for esophageal cancer. Gastroenterol Clin North Am. 2009;38(1):135-52.

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9. Lagergren J, Bergström R, Lindgren A, et al. Symptomatic

gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340(11):825-31.

10. Lepage C, Rachet B, Jooste V, et al. Continuing rapid increase in esophageal adenocarcinoma in England and Wales. Am J Gastroenterol. 2008;103(11):2694-9.

11. Narahara H, Lishi H, Tatsuta M, et al. Effectiveness of endoscopic mucosal resection with submucosal saline injection technique for superficial squamous carcinomas of the esophagus. Gastrointest Endosc. 2000;52:730-4.

12. NICE Interventional Procedural Guideline. (2007). Palliative photodynamic therapy for advanced oesophageal cancer.

[online]. Available from http://guidance.nice.org.uk/IPG206 [Accessed January, 2013].

13. Pisani P, Parkin DM, Bray F, et al. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999;83:

18-29.

14. Radu A, Wagnières G, van den Bergh H, et al. Phtodynamic therapy of early squamous cell cancers of the esophagus. Gastrointest Endosc Clin N Am. 2000;10(3):439-60.

15. Systemic review of the staging performance of 18F-fluorod- eoxyglucose position emission tomography in esophageal cancer. J Clin Oncol. 2004;22:3805-12.

cHAPTER

3

Peptic Ulcer Disease

INTRODUCTION

Peptic ulcers (PUs) are mucosal breaks in the gastric or small intestinal mucosa that extend through the muscularis mucosa. In contrast to erosions, which are small and superficial mucosal lesions, PU varies in size from 5 mm to several centimeters. The term “PU” is used to group together chronic duodenal ulcer (DU) and chronic benign gastric ulcer (GU). A precise diagnosis of either DU or GU is required to manage them clinically as separate though related diseases. PU is an important cause of morbidity and increased healthcare costs. They can progress to complete resolution without treatment or complications, such as bleeding and perforation with considerable morbidity and mortality. Those experiencing ulcer complications are at risk of further complications. Those with history of delayed ulcer healing are likely to experience early recurrence. These recurrences are usually associated with active Helicobacter pylori (H. pylori) infection, intake of nonsteroidal anti-inflammatory drugs (NSAIDs), etc. Eradication of H. pylori infection alters the incidence of ulcer relapse. A meta-analysis of 14 studies demonstrated recurrence of DUs followed in less than 10% who had documented H. pylori eradication compared to 65– 90% in those who did not have H. pylori eradicated.

CLINICAL FEATURES

Symptoms

The symptoms vary from nausea, vomiting, epigastric pain, postprandial belching, bloating, anorexia and early satiety. Clinical assessment has poor predictive value for the specific diagnosis found upon endoscopy. The “classic” symptoms of DU occur when acid is in excess. Symptoms also occur late at night when the circadian acid secretion is maximal. Symptoms relieved by food, antacids, and acid-reducing

Javed Yakoob, SM Wasim Jafri

drugs suggest the role of acid in this process. GU is associated with severe abdominal pain associated with meals that is infrequently relieved by food or antacids. Epigastric discomfort described as a vague or cramping is experienced in two-thirds of the patients that may localize in the upper quadrants or the hypochondrium. It may also be associated with burning pain that may radiate to the back. Symptomatic periods lasting weeks are associated with similar to longer duration symptom-free periods is characteristic of DUs. The reliance on symptoms alone may result in overdiagnosis of nonulcer dyspepsia (NUD) and will miss PUs in patients. The classic symptoms of acid dyspepsia relieved with food occur in only about 50% of patients with DU. An increase in appetite or weight gain, indigestion associated with particular dietary food resulting in anorexia, weight loss and fatty food intolerance is reported in approximately 20%. In 20–60%, DU pain may be described as heartburn or irritable bowel syndrome like crampy abdominal pain associated with altered bowel habit. Silent asymptomatic PU was detected on screening endoscopy in 11% of 6,457 subjects. 1 Also, 20–50% of complicated asymptomatic ulcers are presented in elderly patients and individuals on NSAIDs. 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 in DU patients are similar to that of asymptomatic patients and in controls. Often there is no correlation between the presence of an active ulcer and symptoms. Symptoms may persist in 40% of patients with endoscopically healed ulcers, while 15–44% with an ulcer crater may be symptom-free. Absence of symptoms does not guarantee ulcer healing is complete, nor does the persistence of symptoms predict the presence of an ulcer crater. In some cases, this sensitization to acid is related to an ulcer crater or secretion of an excess acid, but it may also occur in grossly normal mucosa with physiologic levels of acid secretion.

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Clinical Signs

The physical examination is often normal and unreliable. Some patients may exhibit epigastric tenderness to deep palpation. Hematemesis or occult blood may be detected in the setting of bleeding ulcers. Tachycardia and orthostatic hypotension may be found in patients with significant 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 noted in patients with an ulcer-associated outlet obstruction. The majority of DUs develop in the bulb or pyloric channel. Patients with DUs tend to have a younger age of onset, often between 30 years and 55 years. In the stomach, most benign ulcers are found in the antrum and lesser curvature of the stomach at the junction of the body and antrum. GUs often occur among patients between the ages of 55 years and 70 years with a peak incidence in the sixth decade.

ETIOLOGY

Multiple factors are involved in the pathophysiology of most PUs. Primary malfunction of gastric secretory, defense or repair mechanisms are uncommon causes of ulcer. Most ulcers are associated with H. pylori infection and NSAIDs intake.

Helicobacter pylori

H. pylori affects gastric acid secretion, gastric metaplasia, immune responses and mucosal defense mechanisms. Two virulence markers of H. pylori strains that include the cytotoxin-associated gene A (cagA) and the vacuolating cytotoxin (vacA) have been found to be associated with distinct gastroduodenal disorders. Various studies demonstrated an association between the presences of cagA antibodies and PU and gastric carcinoma. The gene encoding vacA is present in all H. pylori strains; however, the activity of this cytotoxin is dependent on its allelic type is positive in only 40–60% of 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), DU in 23 (72%) (p = 0.003) and GC in 29 (73%) (p = 0.001) compared to NUD in 51 (42%). The vacA allele s1am1 was associated with GU in 23 (72%) (p = 0.001), DU in 17 (53%)

(p < 0.001) and GC in 23 (58%) (p = 0.003) compared to NUD

in 38 (32%), while vacA s1bm1 was associated with GU in 9

(28%) (p = 0.001), DU in 12 (37%) (p < 0.001) and GC 11 (28%)

(p < 0.001) compared to NUD in 13 (11%), respectively. 2

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs act by inhibiting prostaglandin synthesis that affect the amount of gastric acid generated, integrity of the mucosal barrier, amount of bicarbonate and glutathione generated and rate of mucosal blood flow.

Gastric Acid Hypersecretion

Although only a small proportion of DU patients have acid hypersecretion, high normal or modestly elevated values appear to be associated with DU. Among H. pylori-positive subjects with DU, the drive for acid secretion that includes H. pylori-dependent hypergastrinemia reverses following cure of the infection. 3 Relative hypergastrinemia is seen in H. pylori-infected subjects are due to suppression of 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

in DU is related to impaired control of inhibitory mechanisms and can be seen in people without DU. The abnormalities in gastrin, somatostatin and acid secretion normalizes within 1 year of H. pylori eradication. A higher basal and pentagastrin-stimulated acid secretion was described in patients with recurrent ulcers following successful H. pylori eradication compared to patients without recurrent ulcers. Among H. pylori-negative subjects, a subset has acid hypersecretion without hypergastrinemia. Another study with non-H. pylori, non-NSAID DU found increased gastrin response to a meal and increased peak gastric acid secretion. Some subjects with non-H. pylori, non-NSAID hypersecretion may have a component of muscarinic-

dependent, vagal hyperactivity. In the absence of H. pylori or gastrinoma, fasting hypergastrinemia is only rarely found in hypersecretory DU patients, sometimes linked to antral G-cell hyperfunction. Increased acid secretion is an important factor in some patients with ulcer recurrences following successful

H. pylori eradication and in some patients with non-H. pylori,

non-NSAID DU.

Duodenum

The majority of DU patients have impaired duodenal

bicarbonate secretion, which is H. pylori-dependent, since cure of the infection reverses the defect. The increased gastric acid secretion with reduced duodenal bicarbonate lowers duodenal pH and promotes development of gastric metaplasia in the duodenum. Areas of gastric metaplasia infected by

H. pylori results in duodenitis and enhances the susceptibility

Peptic Ulcer Disease

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to acid injury and DU. In patients with endoscopy-negative, NUD has described duodenal colonization by H. pylori as a highly significant predictor of the subsequent development of DU. In gastrinoma patients, there is an excess gastric acid secretion, which is associated with prominent gastric metaplasia in the duodenum.

Gastric Ulcer

A GU occurring in the stomach proximal to the distal antrum and prepyloric region is usually associated with low-normal acid secretion associated with a low-normal parietal cell 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, patients with ulcers in the distal antrum or GU associated with concurrent DU have normal or even increased levels of acid secretion.

RISK FACTORS

Familial Aggregation

Studies have recognized a polygenic inheritance pattern in families with history of PU disease (PUD). First-degree relatives of patients with GU have a threefold increase in the prevalence of GU but not DU, while patients with DU have a threefold increase in the prevalence of DU but not GU.

Genetic Factors

Host factors appear to be important in predisposing to H. pylori infection and to disease outcomes, such as DU and gastric cancer. Genetic polymorphism related to synergy between host [tumor necrosis factor (TNF)-α promoter] and bacterial (induced by contact with epithelium, or the iceA1 gene) factors have been related to DU in children. 5 Host polymorphisms involving the cytokine interleukin (IL)-1-β