GERD: A New Understanding of Pathology, Pathophysiology, and Treatment

GERD

A New Understanding of Pathology, Pathophysiology, and Treatment

Parakrama T. Chandrasoma

Table of Contents

Cover image

Title page

Dedication

Copyright

Acknowledgments

Introduction: Discovery: A Path to a New Solution for Gastroesophageal Reflux Disease

Chapter 1. Definition of Gastroesophageal Reflux Disease: Past, Present, and Future

1. Potential Criteria to Define Gastroesophageal Reflux Disease

2. Past Definitions of Gastroesophageal Reflux Disease Based on Ulcers and Erosions

3. Present (Symptom-Based) Definitions of Gastroesophageal Reflux Disease

4. Problems With Present Symptom-Based Definition

5. A New Cellular Definition of Gastroesophageal Reflux Disease

6. A New Definition Based on Lower Esophageal Sphincter Damage

Chapter 2. Present Diagnosis and Management of Gastroesophageal Reflux Disease: The Good, Bad, and Ugly

1. Prevalence and Impact of Gastroesophageal Reflux Disease on People and the Economy

2. Present Diagnosis of Gastroesophageal Reflux Disease

3. Present Treatment Modalities of Gastroesophageal Reflux Disease

4. Effects of Acid-Suppressive Drug Therapy in Gastroesophageal Reflux Disease

5. What Does the Future Without Any Change Hold?

6. The Future With the New Method of Assessment of Lower Esophageal Sphincter Damage

Chapter 3. Fetal and Postnatal Development of the Esophagus and Proximal Stomach

1. Anatomic Development of the Fetal Esophagus and Stomach

2. Fetal Development of the Esophageal Epithelium

3. Fetal Development of the Stomach and Its Epithelium

4. Fetal Development of the Gastroesophageal Junctional Region

5. Summary of Fetal Epithelial Development in the Esophagus and Stomach

Chapter 4. Histologic Definition and Diagnosis of Epithelia in the Esophagus and Proximal Stomach

1. Present Value of Histology in Diagnosis of Gastroesophageal Reflux Disease

2. A Histologic Definition of the Gastroesophageal Junction

3. Diagnostic Criteria for Epithelia in the Esophagus and Stomach

4. Controversy Regarding the Epithelia of the Esophagus and Proximal Stomach

5. Proliferation Characteristics of These Epithelial Types

6. Problems in Pathologic Diagnosis

7. Expression of Other Markers in Metaplastic Columnar Epithelia

8. Pathologic Reporting of Biopsy Findings

9. Precision and Accuracy of Diagnosis of Columnar Epithelia

Chapter 5. Definition of the Normal State—A Yet Unfinished Saga

1. Normal Cardiac Epithelium: A Myth Resulting in a Presently Held False Dogma

2. Eradication of the Myth That Cardiac Epithelium Normally Lines the Proximal Stomach

3. Study of the Region Distal to the Endoscopic Gastroesophageal Junction in Resected Specimens

4. Endoscopic Biopsy in Asymptomatic Volunteers

5. Endoscopic Biopsy Studies in Clinical Patients

6. Multilevel Endoscopic Biopsies Distal to the Endoscopic Gastroesophageal Junction

7. What Is the Significance of Cardiac Epithelium Distal to the Endoscopic Gastroesophageal Junction?

8. Reviews of the Meaning of Cardiac Epithelium Distal to the Endoscopic Gastroesophageal Junction

9. Does Cardiac Epithelium Have Features of Columnar-Lined Esophagus or Gastric Epithelium?

10. Relationship of Cardiac Epithelium to Gastroesophageal Reflux Disease and Gastritis

11. Relationship of Cardiac Epithelium to Visible Columnar-Lined Esophagus

12. Conclusion

Chapter 6. Definition of the Gastroesophageal Junction

1. Anatomy of the Esophagus and Proximal Stomach

2. Criteria Available to Define the Gastroesophageal Junction

3. Historical Definitions of the Gastroesophageal Junction

4. Present Definition of the Gastroesophageal Junction

5. The Gastroesophageal Junctional Zone

6. Accurate Definition of the Gastroesophageal Junction

7. Definition of the True Gastroesophageal Junction

8. Corroboration of Proximal Margin of Gastric Oxyntic Epithelium as the True Gastroesophageal Junction

9. Endoscopic Localization of the True Gastroesophageal Junction

10. Conclusion

Chapter 7. The Normal Lower Esophageal Sphincter

1. Physiology of Deglutition (Swallowing)

2. The Normal Esophagus and Stomach Defined by Histology

3. The Meaning of Cardiac Epithelium

4. The Normal Lower Esophageal Sphincter

5. Manometric Assessment of the Lower Esophageal Sphincter

6. Mechanisms of Lower Esophageal Sphincter Relaxation in the Physiologic State

7. Mechanism of Maintaining Lower Esophageal Sphincter High Pressure

8. Pathological Lower Esophageal Sphincter Relaxation

Chapter 8. The Pathogenesis of Early GERD

1. Definition of the Squamooxyntic Gap

2. Definition of the Dilated Distal Esophagus

3. The Mechanism of Development of the Squamooxyntic Gap in the Dilated Distal Esophagus

4. A Human Experiment of the Pathogenesis

5. A New Histology-Based Definition of Gastroesophageal Reflux Disease: Reflux Carditis

6. The Diagnosis and Significance of Reflux Carditis

7. Relationship of Carditis to Helicobacter pylori

8. Summary and Conclusions

Chapter 9. Correlation of LES Damage and GERD

1. Lower Esophageal Sphincter Parameters That Define Lower Esophageal Sphincter Failure

2. Correlation Between Lower Esophageal Sphincter Damage and Gastroesophageal Reflux Disease

3. Lower Esophageal Sphincter Failure

4. Mechanism Underlying Lower Esophageal Sphincter Failure (Transient Lower Esophageal Sphincter Relaxation)

5. Onset and Progression of Abdominal Lower Esophageal Sphincter Damage

6. Relationship of Progression of Lower Esophageal Sphincter Damage to Time

7. Rate of Progression of Abdominal Lower Esophageal Sphincter Damage

Chapter 10. The Effect of Damage to the Abdominal Segment of the LES: The Dilated Distal Esophagus

1. Definition of the Dilated Distal Esophagus

2. Pathogenesis of the Dilated Distal Esophagus

3. Variation in Length of the Dilated Distal Esophagus

4. Mathematical Formulae to Define the Normal and Abnormal States

5. Anatomical Changes Associated With Abdominal Lower Esophageal Sphincter Damage

6. Clinical Syndromes Associated With the Dilated Distal Esophagus

7. Histologic Composition of the Dilated Distal Esophagus

8. Relationship Between the Dilated Distal Esophagus and Visible Columnar-Lined Esophagus

Chapter 11. Columnar-Lined Esophagus (Microscopic and Visible) and Barrett Esophagus

1. The Past: Historical Evolution of Columnar-Lined Esophagus

2. The Present State of the Art

3. The Future: The Complete Understanding of Columnar-Lined Esophagus

4. Prevalence of Columnar-Lined Esophagus

5. Clinical Manifestations of Columnar-Lined Esophagus

6. Histology of Columnar-Lined Esophagus

7. The Detection of Intestinal Metaplasia in Columnar-Lined Esophagus by Endoscopic Biopsy

8. The Distribution of Epithelial Types in Visible Columnar-Lined Esophagus

9. Difference in the Prevalence of Intestinal Metaplasia With Different Length of Visible Columnar-Lined Esophagus

10. (Future) Definitions Based on the New Concepts

11. Relationship of Columnar-Lined Esophagus to Adenocarcinoma

Chapter 12. Esophageal Adenocarcinoma

1. Does Present Medical Therapy Promote Esophageal Adenocarcinoma?

2. Should Adenocarcinoma Be Included in the Definition of Gastroesophageal Reflux Disease?

3. The Changing Definition of Esophageal Adenocarcinoma

4. Epidemiology of Esophageal Adenocarcinoma

5. Proposed New Terminology for Esophageal Adenocarcinoma

6. The Window of Opportunity for Preventing Esophageal Adenocarcinoma

7. Target Epithelium for Carcinogenesis: Intestinal Metaplasia

8. Increased Risk for Carcinogenesis: Decision for Surveillance

9. Risk Indicators for Esophageal Adenocarcinoma

Chapter 13. Progression of GERD at the Clinical Level

1. Categorization of Gastroesophageal Reflux Disease

2. Is Gastroesophageal Reflux Disease a Categorical or Progressive Disease?

3. Gastroesophageal Reflux Disease is Always a Progressive Disease From the Perspective of Lower Esophageal Sphincter Damage

4. Impact of Overwhelming Numbers in Gastroesophageal Reflux Disease

5. Who Develops Esophageal Adenocarcinoma?

6. Cost of Treating Gastroesophageal Reflux Disease With the Present Management Algorithm

7. Clinical Prediction of Future Disease Progression

8. Gastroesophageal Reflux Disease is a Progressive Disease

9. Definition of Irreversibility of Gastroesophageal Reflux Disease

10. Prevention of the Irreversible State

Chapter 14. Progression of GERD at a Pathological Level

1. Histologic Definition of Gastroesophageal Reflux Disease

2. Vertical and Horizontal Pathologic Progression of Gastroesophageal Reflux Disease

3. Factors Causing Vertical and Horizontal Progression

4. Vertical Pathological Progression of Gastroesophageal Reflux Disease

5. Horizontal Pathologic Progression of Gastroesophageal Reflux Disease

6. Esophageal Carcinogenesis

7. Present Concept of Pathologic Progression: A Stark Contrast

Chapter 15. Molecular Evolution of Esophageal Epithelial Metaplasia

1. Fetal Development in the Esophagus and Stomach (See Chapter 3)

2. Dynamic Structure of Adult Esophageal and Gastric Epithelia

3. Molecular Signaling in the Fetal Esophagus and Stomach

4. Molecular Signaling in the Adult Esophagus and Stomach

5. Structure and Molecular Signaling in the Fetal and Adult Intestine

6. Summary of Molecular Signaling in the Gastrointestinal Tract

7. Transdifferentiation and Transcommitment

8. Histologic Pathways of Evolution of Cardiac Epithelium

9. Squamous Epithelium→Metaplasia to Cardiac Epithelium→Intestinal Metaplasia

10. Molecular Basis of Squamous Epithelium→Cardiac Epithelium

11. Molecular Basis of Intestinal Metaplasia in Cardiac Epithelium

12. Summary of the Squamous→Cardiac→Intestinal Metaplastic Process

13. Cardiac Epithelium to Oxyntocardiac Epithelium

14. Explanation of Distribution of Epithelia in Columnar-Lined Esophagus

15. Practical Value of Understanding Molecular Pathways

Chapter 16. Progression of GERD From the Perspective of LES Damage

1. The Normal State (Zero Lower Esophageal Sphincter Damage)

2. Phase of Compensated Lower Esophageal Sphincter Damage (>0–15mm Lower Esophageal Sphincter Damage)

3. Clinical Gastroesophageal Reflux Disease (>15–35mm Lower Esophageal Sphincter Damage)

4. Comparison Between Assessment of Gastroesophageal Reflux Disease Progression by Clinical, Pathological Molecular Criteria and Lower Esophageal Sphincter Damage

Chapter 17. New Pathologic Test of LES Damage

1. Feasibility of the New Test for Lower Esophageal Sphincter Damage

2. Assessment of Lower Esophageal Sphincter Damage With Present Technology

3. Pathologic Measurement of the Dilated Distal Esophagus

4. A Multilevel Biopsy Protocol to Measure the Dilated Distal Esophagus

5. The Need for a New Biopsy Device

Chapter 18. New Method of Functional Assessment of the LES

1. Present Assessment of Reflux

2. Correlation of Abdominal Lower Esophageal Sphincter Damage and Reflux

3. Residual (Functional) Abdominal Lower Esophageal Sphincter Length and Reflux

4. Combined Manometric and pH Testing for Gastroesophageal Reflux Disease

Chapter 19. Prediction of Future Progression of LES Damage

1. The Point of Onset of Lower Esophageal Sphincter Damage From Initial Length

2. Point of Lower Esophageal Sphincter Damage That Results in Lower Esophageal Sphincter Failure

3. Impact of Factors Other Than Lower Esophageal Sphincter Damage in Gastroesophageal Reflux Disease

4. Progression of Lower Esophageal Sphincter Damage With Increasing Age

5. Type of Progression of Lower Esophageal Sphincter Damage: Linear or Not?

6. Assessing the Rate of Progression of Lower Esophageal Sphincter Damage

7. My Vision for the Future of Management of Gastroesophageal Reflux Disease

Chapter 20. Proof of Concept of the New Diagnostic Method

1. The Need for Proof of Concept

2. Cardiac Epithelium

3. The Definition of the True Gastroesophageal Junction

4. Relationship Between Lower Esophageal Sphincter Damage and Cardiac Metaplasia

5. The New Pathologic Assessment of Lower Esophageal Sphincter Damage

6. Procurement of Tissue to Measure the Length of Cardiac Epithelium

7. Correlation Between Lower Esophageal Sphincter Damage and Reflux

8. Prediction of Future Lower Esophageal Sphincter Damage

9. A Personal Lower Esophageal Sphincter Damage Assessment

10. Research and Development of Technology in Support of New Method

11. Methods to Control Progression of Lower Esophageal Sphincter Damage

Chapter 21. Application of the New Method to Present and Future Management of GERD

1. The New Histologic Test of Abdominal Lower Esophageal Sphincter Damage

2. Drawing a Line in the Sand: Visible Columnar-Lined Esophagus

3. Correlation Between Abdominal Lower Esophageal Sphincter Damage and Visible Columnar-Lined Esophagus

4. Temporal Progression of Abdominal Lower Esophageal Sphincter Damage

5. Potential Impact of the New Diagnostic Method

6. Use of the New Diagnostic Method in the Present Management Algorithm of Gastroesophageal Reflux Disease

7. New Management of Different Patient Groups Defined by the New Test

8. Differences in Management Between the Present and New Method

9. Future Directions in Management of Gastroesophageal Reflux Disease

10. Cost Comparison Between New and Present Methods of Management of Gastroesophageal Reflux Disease

11. The Large Window of Opportunity for Preventing Esophageal Adenocarcinoma

Author Index

Subject Index

Dedication

This book is dedicated to:

Cherine,

Who was born before esophageal adenocarcinoma was reported;

My children,

Who saw a seven-fold increase in its incidence;

And my grandchildren,

Who I hope will see the day it is eradicated.

With

Gratitude, Respect, and Love.

Copyright

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Acknowledgments

This book represents a new pathologic perspective of GERD that is based on the examination of the unique material produced over a period of 25  years by the Department of Foregut Surgery at the Keck School of Medicine, University of Southern California, Los Angeles.

The vision, dedication, and commitment to the academic pursuit of esophageal diseases in that unit are almost entirely those of Dr. Tom DeMeester. His pioneering work in pH testing, manometry, Nissen fundoplication, en-bloc esophagectomy, and LINX established much of the objectivity in the practice of esophageal disease. Many ideas expressed in this book are inextricably linked to his exceptional mind.

I express my deep gratitude to Tom for innumerable hours of discussion and unfettered debate about the most arcane elements of the lower esophageal sphincter and for his and Carol’s wonderful friendship.

I also owe my thanks to the exceptional surgeons who were part of his team. The most important of them were the permanent faculty: the incomparable Dr. Cedric Bremner, Dr. Jeffrey Peters, Dr. Steven DeMeester, and Dr. Jeffrey Hagen. Additionally, they include an international cast of fellows that are too numerous to mention individually. These surgeons are now the leaders of the practice of esophageal surgery in all corners of the world. They follow the vision of Dr. DeMeester and are responsible for many of the new advances in the field. Their work represents a significant amount of the evidence that is cited in this book.

Introduction: Discovery: A Path to a New Solution for Gastroesophageal Reflux Disease

This book is aimed at changing the way gastroesophageal reflux disease (GERD) is managed. Its basis is a new understanding of the cellular changes defined by histologic examination. Its primary goal is to develop a method of managing GERD with a view to preventing esophageal adenocarcinoma. Secondary goals are to preventing people from progressing to treatment failure and the misery of GERD where symptoms cannot be controlled. In the process of developing this new understanding, it has become apparent that the goal can be expanded to actually eradicating GERD as a disease.

These are lofty goals emanating from a pathologist. However, the goals and methods are developed from the unique and novel perspective of trying to explain the entire pathogenesis of GERD from the normal state to adenocarcinoma at a cellular level. This must inevitably involve the way the lower esophageal sphincter (LES), which is the mechanism designed to prevent reflux, undergoes damage. It must involve the development of a new ability to measure LES damage by pathology. This it does. This book is about one person’s attempt at taking a new diagnostic test for GERD, accurate histopathologic measurement of LES damage, and taking its potential application into the future.

1. Statement of Conflict of Interests

I have an unusual background. After medical school (a bachelor’s degree, MBBS, from Sri Lanka) and internship, I entered a neurosurgery residency. I changed course after the first year to become a lecturer in pathology at my medical school. In the 6  years I practiced medicine in Sri Lanka before immigrating to the United States, I was immersed in an unusual combination of pathology and internal medicine. My study during this time culminated in the highest postgraduate qualification in internal medicine in Sri Lanka (MD in general medicine) and the membership of the Royal College of Physicians in the United Kingdom. This strong clinical background in both surgery and medicine is unusual for any pathologist in the United States.

This introduction is designed to outline the scope of the book and provide information regarding the expertise that allows me to write this book and any conflicts of interest that may induce bias.

It is also designed to show the limitations of my ability to understand GERD from aspects with which I have no direct experience. I do not talk to, evaluate, treat, and follow patients; I do neither endoscopy nor surgery; I never look at radiologic images or interpret pH, impedance, and manometric tests. I have obtained all my information and knowledge on these areas secondhand, largely from a relatively small number of people who I talk to and trust on matters of GERD. I believe they have taught me well and they have my gratitude.

Conflict of interest plagues medicine. Government funding sources are the lifeblood that drives research of many experts in the field who largely hold positions in academic institutions. This research funding is valuable and largely unfettered but requires these experts to produce data to justify and maintain government funding and their position and promotion in the university. Many experts also receive support from private commercial sources, which makes bias difficult to avoid. In general, disclosure of these funding sources is required for physicians presenting at meetings and submitted papers for publication.

The presence of conflict does not (appropriately) disqualify the conflicted expert from a presentation or publication. It is left to the listener and reader to evaluate the conflict that is disclosed and eliminate the possibility of bias. Whether physicians listening to a lecture at a meeting or reading a paper effectively evaluates bias is unknown.

I have never applied for, let alone received, any grant funding. I have never developed any association with a commercial venture of any kind. I own no stock in a pharmaceutical or medical device company except through the mutual funds of my retirement plans and my futile efforts at playing the stock market! I have no, and have never had any, conflicts of interest.

2. Period up to 1990: No Interest in Discovery

I am, and always have been, a general surgical pathologist. Ever since I was hired as a surgical pathologist at the University of Sri Lanka Medical School in 1973, my primary life goals have been to provide the highest level of pathologic diagnosis to patients and to provide education to pathology trainees. I immigrated to the United States in 1978. At the end of my residency, I was hired into the Department of Pathology, University of Southern California (USC), as the Chief of Surgical Pathology at the Los Angeles County  +  University of Southern California Medical Center. I have worked in this capacity since 1982 and continue to provide high-level general surgical pathology expertise to the largely indigent patients in this hospital. I am not subspecialized in gastrointestinal or esophageal pathology in my daily function as a surgical pathologist.

I run a successful private consultation service that provides expert opinion on difficult problems in all areas of surgical pathology to community pathologists. I also direct the surgical pathology fellowship program at my institution and participate on a daily basis in teaching residents and fellows. I believe I have achieved and continue to further my life’s primary goals.

Another major goal in my early career was teaching medical students. In my second year of residency, I was commissioned to write, with Dr. Clive Taylor as a coauthor, what ultimately became the Lange series textbook of Pathology, Concise Pathology.¹

This experience changed me. I interacted with Jack Lange’s chief medical editor, Jim Ransom, who over a period of 3  years of the most compulsive and critical review tried to teach me the art of medical writing. Whatever clarity exists in my writing I owe to Jim Ransom.

I never had any ambition toward new discovery. I had no interest and made no effort toward basic research. I have always funded my own clinical research. I became a tenured professor at the University of Southern California in 1996. My job is largely in clinical service and teaching. I am under little of no pressure to publish. If not for my discovery, I would have had a relatively short publication list of papers resulting from collaboration with other researchers. I write only what I believe to be new information that is true and important for others to know.

In 1982, I became involved in a new technology to perform needle biopsies of brain lesions. Dr. Michael Apuzzo, a neurosurgeon at USC, had procured one of the prototypic stereotactic biopsy instruments. Over the next decade, I helped him develop a method of pathologic interpretation of the small biopsies he obtained from targeted points within the lesion.²,³ Without any specialized neuropathology expertise, I found myself being considered a neuropathologist. This reputation persists; I am still a popular neuropathology consultant for pathologists in Los Angeles.

3. The Discovery: 1990 to the Present

My academic interest turned sharply from brain to esophageal pathology in 1990 when Dr. Tom DeMeester took the position of Chairman of Surgery at the University of Southern California. He was recruited to develop a clinical program in foregut surgery at the newly built USC University Hospital. He came with his team of surgeons and staff, including nurses and technicians, who ran his physiology laboratory. His pathologist at Creighton University did not accompany his team to USC, and I was assigned to do his work.

This was an exciting new task for me. My interest in gastrointestinal pathology at that time was only as part of my routine surgical pathology work at the County Hospital. In preparation for doing the pathology for Dr. DeMeester’s patients, I read every available textbook and paper on the subject. I thought I was totally prepared by the time I received my first biopsy.

3.1. The Material on Which Expertise Was Developed

Dr. DeMeester brought with him over two decades of experience and research in esophageal diseases. He had pioneered pH testing and manometry and made fundamental changes in the technique of performing Nissen fundoplication. The results of the pH test are expressed as the DeMeester score. He was a giant in his field.

Incredibly, he had developed a unique biopsy protocol (Fig. 1) that he used for every patient who underwent endoscopy, irrespective of the presence of symptoms or endoscopic findings.

In the endoscopically normal patient (Fig. 1A), this included multiple biopsies from three specimens locations: (1) biopsies across the squamocolumnar junction, (2) retroflex biopsies of the area within 1  cm distal to the squamocolumnar junction, and (3) random biopsies of gastric body and antrum. In patients with a visible columnar-lined esophagus (CLE) (Fig. 1B), additional biopsies were taken at 1–2  cm intervals within the entire columnar-lined segment.

Figure 1  (A) Routine DeMeester biopsy protocol for endoscopically normal patients. Biopsy sets (2–4 biopsies at each level) are taken straddling the squamocolumnar junction, within 1   cm distal to the first biopsy on retroflex view, and from the distal body and antrum. (B) Biopsy protocol for patients with a 5-cm segment of endoscopically visible columnar-lined esophagus (yellow). In addition to the biopsy sets in (A), samples are taken at 1-cm intervals distal to the biopsy straddling the squamocolumnar junction to the endoscopic GEJ. All biopsies taken in antegrade view are designated as the distance from the incisor teeth. CLE , columnar-lined esophagus; GEJ , gastroesophageal junction.

By the time I was assigned to read his biopsies, he and his team were generating biopsies that were done according to this protocol from 2 to 8 patients every day. The pathologic findings were correlated at a weekly meeting with clinical, endoscopic, radiologic (most patients had a video-esophagogram), and physiologic testing (many patients had 24  h pH testing and manometry).

Over the next two decades, Dr. DeMeester’s group generated these biopsies continuously at the rate of 800 patients per year for a total of over 15,000 patients. I just happened to be the recipient of this unique pathologic material from the esophagus and stomach. The only reason for my discovery was that it was so obvious in the material that I could not help it; the discovery simply fell into my lap.

Evaluating the biopsies at the endoscopic gastroesophageal junction (GEJ) and a retroflex biopsy from what was called the cardia in all people including those with normal endoscopy resulted in the almost immediate realization that the entire literature relating to normal histology in this region was flawed.

The reason why the flaw was not previously recognized is that no one had taken biopsies of normal people in this way. The reason why it is difficult for me to convince people of the discovery is that no one takes biopsies of normal people in this way even today. The American Gastroenterological Association expressly recommends that biopsies should not be taken in patients with GERD who do not have an endoscopic abnormality.⁴

I am waging a battle against an unproved dogma that cardiac mucosa is a normal epithelium in this region. Most people arguing on the other side are so steeped in the belief of this false dogma that they refuse to even test the alternative evidence-based truth that cardiac mucosa is an abnormal metaplastic epithelium in the esophagus, not a normal epithelium in the stomach. Whenever anyone has tested this concept, the data have largely supported this concept.

This book is ultimately about that new discovery, its evolution over two decades, the research it has stimulated throughout the world, the present state of its acceptance by the medical community, and its yet unrealized potential value in the future management of GERD.

3.2. Cardiac Epithelium Does Not Exist Normally

The discovery was simple. What was called cardiac mucosa/epithelium and believed to normally line the most proximal part of the stomach, which was called the gastric cardia, was, in fact, neither normal nor gastric. It was always an abnormal epithelium that resulted when the squamous epithelium of the esophagus was exposed to gastric acid.

In this book I will use the term cardiac epithelium rather than the more commonly used cardiac mucosa. The reason for this was a question by Tom DeMeester: Para, why do you use the term cardiac mucosa? Does the mucosa not include the lamina propria and muscularis mucosae? Is it not more accurate to use the term cardiac epithelium? Yes, Tom, it is.

Unfortunately, like many changes that make sense, this will cause dismay. The short forms for the three epithelial types in CLE will change from CM with intestinal metaplasia, CM, and OCM (oxyntocardiac mucosa) to CE with intestinal metaplasia, CE, and OCE. I will not use these abbreviations in the book. One pleasant side effect of this change is that nonintestinalized cardiac epithelium which did not have an abbreviation can now be called NICE. I will not apologize for this change. Accuracy in terminology is worth the minor confusion it may cause.

I will limit the use of abbreviations in the text of this book to the following: GERD for gastroesophageal reflux disease; CLE for columnar-lined esophagus; LES for lower esophageal sphincter; GEJ for gastroesophageal junction; and SCJ for squamocolumnar junction.

At the time I began to read the biopsies of Dr. DeMeester’s patients in 1990, it was believed that cardiac epithelium normally lined the distal 2  cm of the esophagus and the proximal 3  cm of the stomach. As I began seeing specimens from the squamocolumnar junction and within 1  cm distal to it, it became immediately clear that many people had less than 1  cm of cardiac epithelium. Some had no cardiac epithelium at all in the biopsies.

In the correlative weekly conferences, it became clear that the presence of cardiac epithelium in the biopsies was greatest in extent and amount of inflammation in patients with GERD and least in those without GERD. It was therefore obvious to me from the outset that cardiac epithelium was an abnormal epithelium associated with GERD.

The hypothesis that cardiac mucosa at the GEJ was an abnormal epithelium caused by exposure of esophageal squamous epithelium to gastric contents rather than a normal epithelium lining the proximal stomach was first published from our group as an abstract at Digestive Diseases Week by Clark et al. in 1994.⁵

A review of a large series of our patients in 1997 confirmed my observation that the presence of cardiac epithelium in a biopsy of an endoscopically normal patient correlated with the presence of abnormal reflux by a 24-h pH test and associated with abnormalities in the LES.⁶

Publication of the new hypothesis created a considerable amount of interest in the medical community, largely among surgeons. I was invited to a panel discussion on Barrett esophagus at the Digestive Diseases Week and to give the keynote address at the SSAT in 1998. Both these invitations resulted because the faculty of the USC Department of Surgery (Dr. Tom DeMeester and Dr. Jeffrey Peters) had influence regarding the selection of the speaker.

The reaction of the audience to the new information was interest mixed with skepticism and confusion. Histology is not a subject that is quickly assimilated by nonpathology audiences. The keynote SSAT presentation required me to write a review that outlined the new hypothesis.⁷

3.3. Autopsy Studies of the Region

A review of the literature showed that there had never been any previous autopsy study of the GEJ in people without clinical GERD. All the information regarding the normal histology of the region was derived from studies in patients with GERD.

In 1996, I undertook an autopsy study that essentially showed that cardiac mucosa was either absent (Fig. 2) or very limited in length (Fig. 3) in the majority of non-GERD people.⁸ This confirmed the hypothesis, at least in my mind. Surely, I thought, a normal epithelium cannot be absent in some people. I knew I had an important new piece of information that needed to be advertised to the world.

Incredibly, our paper reporting the detailed histology of the GEJ region in the first autopsy study ever done was rejected by every medical, gastroenterology, and pathology journal, to which it was submitted from 1996 to 2000⁸

Publication of the paper followed a presentation at the International Academy of Pathology in San Francisco where I was invited to present my autopsy findings. At the end of the conference, the then editor of the American Journal of Surgical Pathology came up to me and expressed his interest in the paper and asked me to send it to him. I did not have the heart to tell him that the paper had been summarily rejected previously by the journal he edited.

Although scientific papers are supposed to be evaluated entirely on their content, a paper is much more likely to be accepted when the author has a reputation. This is appropriate because establishing credibility of the data presented in a paper is important and difficult to assess in the review process when the author is unknown. Networking is a critical part of getting known and I had not done that at all. It was largely my fault that the critical information was rejected; it was too radical to be believed when the source was unknown.

3.4. The Normal Histologic State of the Esophagus and Stomach: The Zero Squamooxyntic Gap

If cardiac mucosa was always an abnormal metaplastic epithelium in the esophagus, it must follow that the entire normal esophagus was lined by squamous epithelium and the entire normal proximal stomach (including the area adjacent to the junction with esophageal squamous epithelium, fundus, and body) was lined by gastric oxyntic epithelium.

Figure 2  Section taken at the squamocolumnar junction at autopsy in a young child who died of a road traffic accident. The esophageal squamous epithelium transitions to gastric oxyntic epithelium characterized by straight tubular glands containing parietal cells. No cardiac epithelium is present. This is a zero squamooxyntic gap.

Figure 3  Section taken at the squamocolumnar junction at autopsy in a 15-year-old male who died of a drug overdose. The esophageal squamous epithelium transitions to cardiac and oxyntocardiac epithelium. Cardiac epithelium has only mucous cells. Oxyntocardiac epithelium has small round parietal cells with central nuclei in addition to the mucous cells. No gastric oxyntic epithelium is seen in this section. This represents the proximal part of the squamooxyntic gap. CM, cardiac mucosa; OCM, oxyntocardiac mucosa.

If accurate, this would greatly simplify the understanding of GERD. Of the two epithelia normally present in this region, esophageal squamous epithelium was the only one that was damaged by exposure to gastric juice. Gastric oxyntic epithelium was obviously resistant.

This observation resulted in the development of the concept of the squamooxyntic gap.⁹ If squamous epithelium lined the entire esophagus and gastric oxyntic epithelium lined the entire proximal stomach, it meant that the normal GEJ was the junction between the squamous epithelium and gastric oxyntic epithelium. There was no gap between squamous and gastric oxyntic epithelium (Fig. 4A). The normal state was a zero squamooxyntic gap. If cardiac epithelium resulted from the metaplasia of squamous epithelium, it must cause a cephalad migration of the squamous epithelium, separating it from gastric oxyntic epithelium by the intervening metaplastic cardiac epithelium, thereby creating a squamooxyntic gap (Figs. 4B and 5).⁹

3.5. A Cellular Definition of Gastroesophageal Reflux Disease

The squamooxyntic gap composed of cardiac mucosa identifies with absolute accuracy people whose esophageal squamous epithelium has been damaged by exposure to gastric juice. I suggested this as a cellular definition for GERD in 2005 in a review that I was invited to write for Histopathology, the British journal for the specialty of surgical pathology.¹⁰

The gastroenterology community has largely ignored this definition. In many large consensus meetings that were convened to evaluate a definition for GERD, a cellular definition has never even been considered.¹¹,¹² The American College of Gastroenterology’s position statement on GERD recommends that the diagnosis of GERD should be made by its symptoms and the empiric proton pump inhibitor (PPI) test, without the use of barium radiographs, upper endoscopy, biopsies, manometry, and pH monitoring.¹³

Figure 4  (A) Diagrammatic representation of the normal state. The entire esophagus is lined by squamous epithelium (gray), which transitions at the gastroesophageal junction (GEJ) to gastric oxyntic epithelium that lines the entire stomach (blue). The entire LES (red in wall) is intact. The rugal folds reach the GEJ. There is no cardiac mucosa between squamous and gastric oxyntic epithelium, i.e., the squamooxyntic gap is zero. (B) Diagrammatic representation of the majority of people in the world with no visible columnar-lined esophagus at endoscopy. The distal part of the lower esophageal sphincter (LES) has been damaged (white replacing red in the wall) and the squamous epithelium has been replaced by metaplastic columnar epithelium (yellow, green, and purple). This part of the esophagus has dilated to assume the contour of the saccular stomach. The tubular esophagus has shortened and the angle of His has become more obtuse. Rugal folds extend above the true GEJ (marked by the proximal limit of gastric oxyntic epithelium). Note the concordance between the shortening of the LES, dilatation of the distal esophagus, and length of metaplastic columnar epithelium.

Figure 5  Histologic section of a 2-mm squamooxyntic gap in a young child without gastroesophageal reflux disease. The distal limit of squamous epithelium (SCJ) is separated from the proximal limit of gastric oxyntic epithelium (GEJ) by a 2-mm segment of metaplastic cardiac and oxyntocardiac epithelium. Note the disorganized, thin metaplastic cardiac epithelium with chronic inflammation (=reflux carditis) compared with the uninflamed, thicker gastric oxyntic epithelium.

However, interest in the concept remains. In a recent review that I was invited to write by Dr. Stuart Spechler, the highly influential gastroenterologist, I was encouraged to reiterate the concept and the definition.¹⁴ The mere duration of survival of interest in the hypothesis and the fact that it still has forward momentum suggest it has merit.

3.6. Location of Cardiac Mucosa: Definition of the True Gastroesophageal Junction and the Definition of the Dilated Distal Esophagus

I struggled for many years with an obvious contradiction. Cardiac epithelium that resulted from reflux was found distal to the endoscopic GEJ, i.e., in the proximal stomach (Fig. 4B). This was impossible; GERD could not produce damage in the stomach. Something was awry.

In 2007, I undertook a study on esophagectomy specimens that provided the answer (Fig. 6).¹⁵ The reason for the contradiction was that the universally used definition of the GEJ (the proximal limit of rugal folds as defined by endoscopy and gross examination of specimens) was incorrect. The study showed that the true GEJ was distal to the endoscopic GEJ by 0.36–2.05  cm in the 10 cases in the study.¹⁵ This led to a new definition of the GEJ as the proximal limit of gastric oxyntic epithelium.¹⁵ Endoscopy was not capable of defining the true GEJ because it cannot differentiate cardiac and gastric oxyntic epithelia. This can be done only by histology.

This made logical sense. As the distal squamous epithelium underwent columnar metaplasia by exposure to gastric juice, the squamocolumnar junction would move cephalad. The proximal limit of gastric oxyntic epithelium would remain at the same location, marking the original true GEJ. There would be a gap between the endoscopic GEJ and the true GEJ; in the person without visible CLE, this is the squamooxyntic gap (Fig. 5). The gap is easily identified by the presence of cardiac epithelium (with and without parietal and/or goblet cells) (Fig. 7) between the residual esophageal squamous epithelium and gastric oxyntic epithelium (Fig. 4B).

A finding in this study of esophagectomy specimens that took me by surprise was the anatomic appearance of the damaged distal esophagus that was lined by metaplastic cardiac epithelium. It was no longer tubular. It was dilated and had taken the contour of the stomach. Its mucosal surface had rugal folds (Fig. 6A and B).¹⁵

The damaged abdominal segment of the esophagus had an appearance that confused physicians throughout history and continues to do so. It exactly resembled everyone’s concept of the proximal stomach. It was part of the dilated sac distal to the presently accepted endoscopic GEJ (proximal limit of rugal folds) and the distal end of the tubular esophagus.

Figure 6  (A) Esophagogastrectomy specimen in a patient with an adenocarcinoma arising in a long segment of Barrett esophagus. The specimen shows rugal folds extending to the point where the tubular esophagus flares into what most people think is stomach. (B) Histologic study shows cardiac epithelium with intestinal metaplasia extending from the squamocolumnar junction ( red line ) to the yellow line . Cardiac epithelium without intestinal metaplasia extends to the black line , which is 2.05   cm distal to the proximal limit of rugal folds and the end of the tubular esophagus. The fact that this 2.05   cm between the presently defined gastroesophageal junction and the proximal limit of gastric oxyntic epithelium ( black line ) is esophagus is proved by the presence of esophageal submucosal glands ( black dots ) up to the black line .

Figure 7  A retroflex biopsy taken immediately distal to the squamocolumnar junction in a person with no visible CLE at endoscopy. The biopsy shows oxyntocardiac epithelium (OCM; with parietal cells), cardiac epithelium (CM; mucous cells only), and cardiac epithelium with intestinal metaplasia (IM; with goblet cells). Note the presence of squamous-lined ducts of esophageal submucosal glands. This proves that this biopsy from distal to the endoscopic GEJ is esophageal. CLE, columnar-lined esophagus; CM, cardiac mucosa; GEJ, gastroesophageal junction; IM, intestinal metaplasia; OCM, oxyntocardiac mucosa.

After trying out many terms for this new entity, I named it the dilated distal esophagus. Credit for this term belongs to Dr. George Triadofilopoulos. Sitting on a balcony in a hotel in Dubrovnik, overlooking the Adriatic Sea, discussing the subject, George complained about the term I had previously used—dilated end-stage esophagus. He said it confused him because his mind immediately went to the esophagus of achalasia of the cardia. After a few more drinks, the term dilated distal esophagus was suggested by George and endorsed by everyone.

The paper that provided an evidence-based definition of the GEJ and clarified the decades-old error wherein the GERD-damaged distal esophagus was deemed to be the proximal stomach was also rejected by multiple gastroenterology journals before being accepted in a pathology journal.¹⁵

This highlights an important issue about the medical literature. There is no evidence whatsoever to support the present belief among gastroenterologists that the proximal limit of rugal folds is the true GEJ. The proximal limit of rugal folds is simply an endoscopic landmark.¹⁶ The basis for the definition is the opinion of experts.¹⁷ In a world where all experts pronounce that they practice evidence-based medicine, the same experts have no trouble rejecting evidence that contradicts their opinion that is baseless in evidence. It is notoriously difficult to overturn strongly held dogma by evidence.

3.7. Correlation Between the Dilated Distal Esophagus and Damage to the Lower Esophageal Sphincter

Approximately 3  years ago, at a presentation of the hypothesis to a small meeting of community gastroenterologists in San Diego, I was asked a critically important question: Dr. Chandrasoma, let us assume that you are correct and cardiac epithelium is esophageal and not gastric. What practical value does that information have for me when I treat my patients?

I tried to tell that gastroenterologist that there surely was scientific value in being able to differentiate between esophagus and stomach when treating a patient with GERD. This was a shallow reply; this new concept would have little value if it did not impact the management of patients with GERD. What did it matter to that gastroenterologist if he was mistaking the GERD-damaged distal esophagus for the proximal stomach if it did not change the way he treated his GERD patient? He would still use PPIs the same way he would have done without that information. The purity of knowledge without a practical value held no attraction to him.

That gastroenterologist was correct. He had given me the reason why there was so much resistance to these new concepts. It was not necessarily that anyone believed I was wrong. It was because they did not find it necessary to change because it made no change in the way GERD was treated.

That question made me delve deeper into what I was seeing. It forced me to find that practical value. In this book, I will present that value in great detail. Ultimately, the power of what I was seeing will lead to a new diagnostic test for GERD based on measuring LES damage histologically. This, in turn, will permit prediction of future LES damage in the patient. The two combined will provide a method of preventing esophageal adenocarcinoma and, if followed aggressively with new technology, allow the complete eradication of GERD as a human disease.

The dilated distal esophagus, which is the area of the GERD-damaged esophagus between the endoscopic GEJ and the true GEJ (the proximal limit of histologically defined gastric oxyntic epithelium), varies in length from 0 to a maximum published length to date of 28  mm and a theoretical length of 35  mm. I will show that the dilated distal esophagus results from damage to the distal esophageal squamous epithelium when it is exposed to gastric contents as a result of gastric overdistension. Such damage ultimately causes cardiac metaplasia, which is associated with loss of tone in the LES.

The length of the metaplastic columnar epithelium in the dilated distal esophagus is equal to the shortening of the abdominal segment of the LES. Measurement of the squamooxyntic gap in the dilated distal esophagus therefore provides a pathological method of assessing the severity of damage of the abdominal segment of the LES.

This has proof. Examination of full thickness sections of the dilated distal esophagus shows the presence of submucosal glands under cardiac epithelium.¹⁵,¹⁸ Submucosal glands are limited to the esophagus. They are never found under gastric oxyntic epithelium.

I will show in this book how this assessment of LES damage is achieved practically by biopsy if an appropriate sample can be obtained. This will likely require the development of a new biopsy device that can remove a 20–25  mm vertical piece of mucosa from the region of the dilated distal esophagus.

This has the potential to change the way GERD is defined, assessed, prognosticated, and managed from its present symptom-based method to one that is based on severity of LES damage, the cause of GERD (Table 1). That one question in a small nonacademic meeting had a tremendous impact. I now have an answer to that gastroenterologist whose name I do not know.

The new test will provide an accurate and precise measurement of abdominal LES damage at any point in a person’s life, irrespective of whether that person has symptoms or not. Even more important, using an innovative algorithm, a prediction can be made as to future progression of LES damage to the end of the person’s expected natural life.

By this, the test will identify which patients will progress in the future to higher stages of abdominal LES damage that are associated with failure of PPIs to control symptoms, Barrett esophagus, and adenocarcinoma. All of these are associated with the severity of reflux into the esophagus, which in turn is dependent on the severity of LES damage. In effect, this book is a root cause analysis of GERD.

This ability to predict future LES damage will allow identification of the minority of patients who will progress to the category of severe GERD with sufficiently abnormal reflux to place the patient at high risk of treatment failure and visible CLE. This will permit early intervention in this minority to prevent this progression of LES damage. Theoretically, this attack of the primary cause of GERD, LES damage, will simultaneously reduce the incidence of adenocarcinoma and treatment failure.

4. Acceptance of the New Concepts

The discovery that cardiac mucosa is a GERD-induced metaplastic columnar epithelium in the esophagus rather than a normal proximal gastric epithelium is not yet accepted, although more and more people are beginning to believe that it has substance.

The trend toward acceptance is excellent. When I read the literature in 1990 in preparation for Dr. DeMeester, it was believed that cardiac mucosa normally lined the distal 2  cm of the esophagus and proximal 3  cm of the stomach. Largely because of the data generated in our unit, there is universal agreement that most normal (non-GERD) people have less than 0.4  cm of cardiac epithelium in this region.¹⁹ Many persons without GERD have no cardiac epithelium; some have no epithelia other than esophageal squamous and gastric oxyntic in at least a part of the circumference of the squamocolumnar junction.⁸

4.1. The Value of Clinical Research

The concept of medical research has changed. In an effort to prove that medicine is a science rather than an art, physicians have established a hierarchy that defines the value of research. Basic research is now the king; clinical research has been relegated into the background and, in many circles of elite medical scientists, regarded as inferior.

Physician scientists doing basic research in a laboratory have the luxury of developing a hypothesis, planning a scientific experiment, establishing appropriate tests and controls, and then performing a highly specific single test with sophisticated technology in a perfectly reproducible manner. The results are unquestionably true as long as the design and methodology are precise and the researchers are honest and interpret the results accurately and without bias. No defects exist in a well-planned experiment.

Such basic research is beautiful. Truths resulting from experiments come into the mainstream quickly after independent duplication. Funding for basic research is relatively easy to obtain. It is the lifeblood of scientific advancement.

Table 1

Stages of GERD Progression From the Point of Damage (Shortening) of the Abdominal Segment of the Lower Esophageal Sphincter (LES)

AbdLES, abdominal segment of the LES; CLE, columnar-lined esophagus; DDE, dilated distal esophagus; GERD, gastroesophageal reflux disease; NERD, nonerosive reflux disease.

The problem with such beautifully controlled basic research is that they usually address very small questions. Experiments are developed to test something that has been conceptualized. Their truths are often divorced from the patient and generated in animals or cell lines. The progress they produce is in small and logical steps, and many such small steps are required to develop a larger truth. However, such a cumulative change is inevitable, orderly, and predictable, albeit slow, and is the way science progresses.

I am not a basic scientist; my research is clinical. I am a busy, practicing academic physician who spends most of my time in patient care and teaching. I do not have the luxury of working entirely in a sterile laboratory that is the domain of the basic scientist. My salary is not supported by a grant. I encounter patients with the disease in which I am interested mixed with thousands of patients with many other diseases. My work can never have that knifelike focus and control of the laboratory experiment.

Clinical researchers have a completely different value to science than basic researchers. We see a problem as a whole in the context of a human population. We encounter a reality that is much broader and deeper. The reality is often precipitated by an unexpected observation, not directed by a prior body of research. We are emotionally affected by seeing patients suffer as a result of their disease and our impotence or failure. We desire to make things better quickly and solve entire problems, not in little steps but in one fell swoop. This is incredibly difficult and therefore rare. But, when it happens, the results are miraculous.

The rising incidence of esophageal adenocarcinoma is the most dramatic change in a disease that I have encountered in my lifetime. When I started looking at pathology slides in 1978 in Los Angeles, almost all esophageal cancers were squamous. I must have seen one adenocarcinoma for every 10 squamous carcinomas. Over the next 35  years, the numbers reversed.

This was partly because of my association with Dr. DeMeester, but a quick search of the literature showed that the increased incidence of esophageal adenocarcinoma was very real and much greater than any other cancer type (Fig. 8).²⁰ As a pathologist, any research goal that I would direct my efforts toward would have something to do with trying to impact the incidence of esophageal adenocarcinoma. I have no interest in taking baby steps toward that goal.

Figure 8  The sixfold increase in incidence of esophageal adenocarcinoma from 1973 to 2000 ( red line ) compared with the incidence of breast cancer ( purple line ) and colorectal cancer ( black line ) during the same period.

Everyone recognizes the difficulties associated with clinical research. The only clinical research that is considered truly scientific is the double-blinded randomized prospective clinical trial. The resources to conduct randomized trials are not available to most physicians like me. They require significant funding, large numbers of patients, which generally means a multicenter trial, a relatively narrow hypothesis, and accurate collection and analysis of critical data. Like basic research, randomized clinical trials usually answer small specific questions. Again, the little steps advance knowledge slowly but in an invaluable way because the results are irrefutable.

The studies done by clinical researchers like me tend to be messy and compare poorly with basic research and randomized clinical trials. The test base often has arbitrary selection criteria and the controls are imperfect based more on availability than design. The study methods frequently lack uniformity. When the data are presented, defects are common. Interpretation is subjective and almost always open to criticism. For these reasons, clinical researchers find it impossible to get published in the best scientific journals. Clinical research dwells in the pages of relatively low-impact clinical journals. All my papers are in pathology journals that are probably never read by gastroenterologists. The data and ideas are hidden in the massive volume of literature that emerges on a monthly basis.

Because of all these limitations, it is easy for my findings and truths to be relegated into obscurity. The scientific community does not need to even refute my findings. They can be simply ignored on the basis that they represent poor science or that they are in low-impact journals. Many physician scientists regard clinical research to be of little value in the new evidence-based world.

This is scientific elitism at its worst. Unlike scientists in laboratories, clinicians are on the front line. They are the only people who can make direct observations about what happens to real people. When clinical research stumbles upon a truth, that truth is often unattainable by any other type of research; not hundreds of basic science experiments and clinical trials. The reason for this is that the truth is such a deviation from accepted dogma that it is rarely a hypothesis for a planned experiment; it must dawn out of nowhere by a clinical observation. Such a truth has the power to suddenly cause new significant direction and change.

Clinicians who keep their eyes and minds open see things that never reach the brains of scientists in isolated ivory towers. Their observations have unique value: Jenner with cow pox, Marshall and Warren with Helicobacter pylori, and Semmelweiss with simple handwashing that he observed to decrease the incidence of puerperal sepsis were all clinical researchers. Their observations produce results and change that span centuries. Their research, based on one simple clinical observation, resulted not in small, incremental change but in revolution. These examples have not taught elitist scientists to be careful about belittling clinical research.

Despite the fact that I have found it extremely difficult to get other physicians to agree with me, I am absolutely convinced of my new truths about the pathophysiology of GERD. I also believe that these truths will potentially change the way GERD is fundamentally understood and that it will revolutionize research, treatment, and outcomes.

My published papers have been read, possibly with skepticism but largely without dissent. My lectures have been heard, again largely without dissent. But acceptance of these new truths has been painfully slow.

I used to feel frustrated at the pace of change but now recognize that this is the result of the nature of my research. I expect pathologists to give up their firm dogmas and accept a new truth that they do not encounter because the biopsies they are given do not have the thoroughness of our biopsy protocol. I expect physicians who never look at microscopic slides to understand histologic findings. This is unreasonable.

This is not a new phenomenon. Dr. Barry Marshall, a clinical microbiologist, and Robin Warren, a pathologist, in Australia, who in 1979 discovered the truth of Helicobacter pylori, encourage me. The fact that Marshall was led by his frustration at the disbelief of the world of his new truth to swallow a culture of the bacteria to prove his point is discouraging. But his end point of total acceptance is positive. The entry in Wikipedia of what they achieved: "Marshall and Robin Warren showed that the bacterium Helicobacter pylori (H. pylori) is the cause of most peptic ulcers, reversing decades of medical doctrine holding that ulcers were caused by stress, spicy foods, and too much acid. This discovery has allowed for a breakthrough in understanding a causative link between Helicobacter pylori infection and stomach cancer." Two relatively obscure clinical researchers succeeded in overcoming massive establishment resistance to change the world.

Like Dr. Marshall, who swallowed a culture of Helicobacter pylori to prove his case, I have had an endoscopic assessment of my LES according to my new protocol. I will describe the process and results in a later chapter. At this time, I will disclose that I know for certain that I am at zero risk for GERD and esophageal adenocarcinoma in my lifetime as a result of my test. Can anyone reading this make this statement with certainty?

4.2. Impossible Contradictions

The acceptance that there is only a very small amount of cardiac mucosa distal to the endoscopic GEJ has created numerous contradictory viewpoints. These contradictions are simply ignored. This is not acceptable. In science, contradictions in viewpoint must either be explained or rejected.

There is strong evidence that the presence of a very small amount of cardiac epithelium at the GEJ is associated with GERD. Oberg et al.⁶ showed that people who had cardiac mucosa at the GEJ were more likely to have an abnormal 24-h pH test and LES abnormalities than those without. It has been shown by Glickman et al.²¹ that children with >0.1  cm of cardiac epithelium at the GEJ have more reflux esophagitis than those with <0.1  cm. This contradicts the view that 0.4  cm of cardiac mucosa represents normal gastric epithelium. The truth that any cardiac mucosa distal to the squamocolumnar junction is a manifestation of GERD is the only rational explanation for this contradiction.

It is known that cardiac epithelium is frequently present in amounts that are much greater than the 0.4  cm that is considered normal. After all, it was accepted that the proximal 3  cm of the stomach was normally lined by cardiac epithelium. It is true that up to 3  cm of the region distal to the endoscopic GEJ can be lined by cardiac mucosa. What is also true is that this 3  cm is not normal and it is not stomach as is believed. The longest metaplastic epithelium reported is 2.8  cm.¹⁸

If normal cardiac epithelium in the proximal stomach is <0.4  cm, what is the disease process in the stomach that is defined by cardiac epithelial length from 0.4 to 2.8  cm? There is none. The presence of cardiac epithelium greater than 0.4  cm in length is still regarded as normal or simply ignored.

The only reasonable explanation for this is that the length of the dilated distal esophagus is equal to GERD-induced damage of the LES. In fact, dilatation of the abdominal esophagus only occurs when the protection of the high pressure zone of the LES is lost. It is not a coincidence that the abdominal segment of the LES has a normal length of approximately 3.5  cm.

Adenocarcinoma arising in the region distal to the endoscopic GEJ is called adenocarcinoma of the gastric cardia. For decades, this has been classified