1

ABSTRACT INTRODUCTION
Barrett's esophagus is a premalignant metaplastic process that typically involves the distal esophagus. Its presence is suspected by endoscopic evaluation of the esophagus, but the diagnosis is confirmed by histologic analysis of

endoscopically biopsied tissue.

OBJECTIVE To determine frequency of Barrets oesophagus in patients with symptoms of gastroesophageal reflux presenting to outpatient department of Military Hospital Rawalpindi

STUDY DESIGN
Descriptive Analytical study

DURATION
Study was conducted from 1st Jan 2005 to 19th May 2005

SETTING Department of Gastroenterology Military Hospital Rawalpindi.

2 SUBJECTS AND METHODS A total of 150 patients with symptoms of Gastroesophageal reflux were included in the study. After clinical examination, patients were instructed to fast for 12 hours on day of endoscopy. IV line was secured with 18G cannula & 5% dextrose saline. Local anaesthesia with 4% lignocaine spray & iv diazepam 5mg diluted in 10 cc water over 10 min were adminstered. Upper gastrointestinal endoscopy was performed with Pentax EG 2940. Three biopsies were taken and samples were dispatched in 10% formaline for histopathology.

RESULTS Out of 150 patients 112(74.7% ) were males and 38(25.3% ) were females. Male to Female ratio was 2.9:1. The age of patients with symptoms of Gastroesophageal reflux ranged from 18 to 86 years, mean age was 42+/_ 13.67. Out of 150 cases studied, 21(14%) were found to have Barretts esophagus on endoscopy. This was confirmed on microscopy. The remaining 129(86%) cases showed low and high grade inflammatory changes. Out of 21(14%) cases of Barrets Esophagus 19(90.5%) were Males and 2(9.5%) were Females. Male to female ratio was 9.5:1. Maximum no of cases were males 15( 78.9%) in the range of 18 to 38 years. In patients other than Barrets

esophagus various forms of gastritis like Pangastritis 22%, Antral gastritis 19.3%, Mild Antral gastritis 14%,Esophagitis 5% and normal cases 1.3% wer found (TableVI).

CONCLUSION Our study showed that Barretts esophagus is relatively more common & frequency of other diseases like ulcer, stricture, dysplasia and adenocarcinoma is less as compared to the studies from western countries. In view of the above it is recommended to perform an early endoscopy and biopsy in patients with symptoms of gastroesophageal reflux.

Key words: Barretts esophagus, Gastroesophegeal reflux, Endoscpy

INTRODUCTION
Gastroesophageal reflux disease is a condition commonly managed in the primary care setting. Patients with Gastroesophageal reflux disease may develop reflux esophagitis as the esophagus repeatedly is exposed to acidic gastric contents. Over time, untreated reflux esophagitis may lead to chronic complications such as esophageal stricture or the development of Barrett's esophagus. Barrett's esophagus is a premalignant metaplastic process that typically involves the distal esophagus. Its presence is suspected by endoscopic evaluation of the esophagus, but the diagnosis is confirmed by histologic analysis of endoscopically biopsied tissue. Risk factors for Barrett's esophagus include Gastroesophageal reflux disease, white or Hispanic race, male sex, advancing age, smoking, and obesity.
1

Barrett's esophagus is an acquired condition

characterized by a progressive columnar metaplasia of the distal esophagus caused by longstanding gastroesophageal reflux and reflux esophagitis. Barrett's esophagus is a premalignant condition associated with a significantly increased risk of developing esophageal adenocarcinoma Barrett's esophagus carries a risk of malignant change. Endoscopy and biopsy are generally advocated to make a definitive diagnosis.2 The esophageal complications of gastroesophageal reflux disease include peptic esophageal erosion and ulceration, peptic esophageal strictures, and Barrett's esophagus. Endoscopy is the diagnostic procedure of choice for the initial evaluation of lesions. Because Barrett's esophagus predisposes individuals to esophageal adenocarcinoma, these patients are advised to have regular

5 endoscopic surveillance to detect early curable disease 3 Gastroesophageal reflux disease is a common condition, characterised by symptoms or tissue damage due to reflux of gastric contents into the oesophagus. It is estimated that about 20% of adults experience weekly episodes of heartburn while 7-10% complain of daily symptoms. The severity varies from often ignored retrosternal burning to a severe chest pain which keeps the patient up all night. 4 Barrett's esophagus is usually discovered during endoscopic examinations of middle-aged and older adults whose mean age at the time of diagnosis is approximately 55 years. Although Barrett's esophagus can affect children, it rarely occurs before the age of five.
5

This observation supports the contention

that Barrett's esophagus is an acquired condition, not a congenital one. Barrett's esophagus appears to be uncommon in blacks and Asians. The prevalence in Hispanics is similar to Caucasians. 6 The sensitivity of endoscopy for detection of Barrett's is related to the length of involved mucosa, with detection being more likely in patients who have long segment Barrett's. 7 Barrett's esophagus develops through the process of metaplasia in which one kind of fully differentiated cell replaces another. Metaplasia occurs when tissue is exposed chronically to noxious factors (such as acid reflux) that injure mature cells while simultaneously promoting epithelial repair through the aberrant differentiation of immature, proliferating cells.The metaplastic columnar cells of Barrett's esophagus are in some ways a favorable adaptation to chronic reflux since they appear to be more resistant to reflux-induced injury than the native squamous cells. Unfortunately, esophageal columnar metaplasia predisposes to the development of

6 adenocarcinoma. The pattern of acid secretion may be an important determinant of Barrett's metaplasia. This heterogeneous response could contribute to the unpredictable progression in patients with Barrett's esophagus. Studies have demonstrated that patients with longstanding and severe reflux symptoms are at increased risk for adenocarcinoma of the esophagus. 8 Due to the broad spectrum of symptoms attributable to reflux, there is little agreement as to what constitutes typical reflux disease. In general terms, Gastroesophageal reflux disease is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. The distinction between normal and Gastroesophageal reflux disease is blurred because some degree of reflux is physiologic. Physiologic reflux episodes typically occur postprandial, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux is associated with symptoms, often including nocturnal episodes. Reflux esophagitis describes a subset of patients with symptoms of Gastroesophageal reflux disease who also have endoscopic or histopathologic evidence of esophageal inflammation. Epidemiologic estimates regarding the prevalence of Gastroesophageal reflux disease are based upon the assumption that heartburn is the indicator of the disease. Using this definition, one report assessed the prevalence of Gastroesophageal reflux disease in 335 hospital employees. Heartburn occurred at least daily in 7 percent and monthly in 15 percent.9 Similar findings were noted when a reliable self-report questionnaire

7 was sent to 2200 residents of Olmsted County, Minnesota. Heartburn and/or acid regurgitation occurred in approximately 60 percent of subjects and at least weekly in 19.8 percent. Many of these subjects took antacids, but only 5 percent reported a recent physician visit for these symptoms.
10

The impact of this study in future will help the need to predict people at high risk for developing Barrets esophagus at a stage when treatment might prevent or postpone it more successfully i.e. early detection and management.

REVIEW OF LITERATURE
The sensitivity of endoscopy for detection of Barrett's is related to the length of involved mucosa, with detection being more likely in patients who have long segment Barrett's.11-12 The overall reliability of endoscopy for detection of Barrett's esophagus is approximately 80 percent. This was illustrated in a study that included 116 patients who were involved in a Veterans Administration Cooperative Study that required two endoscopies six weeks apart. 13 Barrett's esophagus was found in only one of the two endoscopies in 20 percent of patients. GERD associated with Barrett's esophagus frequently is complicated by esophageal ulceration, stricture, and hemorrhage. Some studies have suggested that patients with a peptic stricture have a higher prevalence of Barrett's esophagus than those without strictures. This relationship is not surprising since both peptic stricture and Barrett's esophagus are associated with more severe GERD. However, this association has been challenged in study of patients referred for endoscopy for GERD in whom the prevalence of intestinal metaplasia was the same with or without strictures .13

CLINICAL FEATURES
The most common symptoms of GERD are heartburn (or pyrosis), regurgitation, and dysphagia. In addition, a variety of extraesophageal manifestations have been described including asthma, laryngitis, and chronic coughing. Heartburn is typically described as a retrosternal burning discomfort, radiating toward the neck, and most commonly experienced in the postcibal period.

9 Regurgitation is the effortless return of gastric or esophageal contents into the pharynx without nausea, retching, or abdominal contractions. Patients typically regurgitate acidic material mixed with small amounts of undigested food. Dysphagia is common in the setting of long-standing heartburn. Slowly progressive dysphagia for solids with episodic esophageal obstruction is suggestive of a peptic stricture. Other, more common, causes of dysphagia are esophageal inflammation and impaired peristalsis. The most dreaded cause of dysphagia is esophageal cancer, either adenocarcinoma arising from Barrett's metaplasia or squamous cell carcinoma. Other symptoms of GERD include chest pain, water brash, globus sensation, odynophagia, and nausea. GERD-related chest pain may mimic angina pectoris, and is typically described as squeezing or burning, located substernally and radiating to the back, neck, jaw, or arms, lasting anywhere from minutes to hours, and resolving either spontaneously or with antacids. It usually occurs after meals, awakens patients from sleep, and may be exacerbated by emotional stress. The preponderance of patients with reflux-induced chest pain also have typical reflux symptoms. Water brash or hypersalivation is a relatively unusual symptom in which patients can foam at the mouth, secreting as much as 10 mL of saliva per minute in response to reflux.9 Globus sensation is the almost constant perception of a lump in the throat (irrespective of swallowing), which has been related to GERD in some studies. However, the role of esophageal reflux in this disorder is uncertain. One study

10 suggested that globus was associated with a hypertensive upper esophageal sphincter rather than with reflux.14 Odynophagia is an unusual symptom of GERD but, when present, usually indicates an esophageal ulcer. Nausea is infrequently reported with GERD but may considered in patients with otherwise unexplained symptoms. In one report, nausea resolved after therapy for GERD in 10 patients who previously had intractable symptoms. 15 For patients who require diagnostic evaluation, potentially useful tests are endoscopy, and ambulatory pH monitoring, each of which provides distinct but related information.16

DIAGNOSTIC CRITERIA
There has been intense controversy regarding the diagnostic criteria for Barrett's esophagus. The deceptively simple, conceptual definition of the disorder is a condition in which columnar epithelium replaces squamous epithelium in the distal esophagus which does not translate easily into practical diagnostic criteria, primarily because there are no reproducible landmarks that clearly delimit the end of the esophagus. The esophagogastric junction has been defined differently by anatomists, radiologists, physiologists, and endoscopists, and the location of the junction identified by these different criteria may vary by several centimeters or more.17 Columnar epithelium, with its reddish color and velvet-like texture, can be distinguished readily from the pale, glossy squamous epithelium of the esophagus on endoscopic examination. It can appear as tongues extending from the squamocolumnar junction, continuous areas extending into the distal

11 esophagus, or discrete islands within normal appearing squamous mucosa. Heterotopic gastric mucosa with a similar appearance can be seen on occasion in the proximal 3 cm of the esophagus, frequently immediately below the upper esophageal sphincter (an "inlet patch"). The majority of such cases are clinically insignificant, although rare complications (tracheoesophageal fistula, an

increased risk of peptic esophagitis from biopsies obtained near the patch, adenocarcinoma arising from within the patch, and cervical webs and rings) have been described.18 Three different terms have been used to describe the presence of intestinal metaplasia in the esophagus: Long segment Barrett's esophagus Short segment Barrett's esophagus Junctional intestinal metaplasia These definitions are based upon two anatomic landmarks seen on endoscopy: the squamocolumnar junction, and the esophagogastric junction. The squamocolumnar junction is the border between the squamous lined epithelium of the esophagus and the columnar epithelium of the stomach (also referred to as the "Z line"). The esophagogastric junction is the border between the esophagus and the stomach. It is usually recognized during endoscopy by appreciation of where the proximal gastric folds end and the tubular esophagus begins. The Z line is normally located within 2 cm of the proximal edge of the gastric folds. The length of intestinal metaplasia between the esophagogastric junction and the

12 squamocolumnar junction represents the extent of Barrett's esophagus. However, recognition of these landmarks can be difficult, particularly in patients who have hiatal hernia, which is usually present in patients with Barrett's esophagus. Furthermore, intestinal metaplasia may not always be apparent on endoscopy. In one study, the positive predictive value of endoscopy for the presence of intestinal metaplasia was only 34 percent; correct diagnosis was more likely in patients with long segment Barrett's esophagus. 15

Long segment
Initial investigations of Barrett's esophagus established arbitrary criteria for the extent of esophageal columnar lining necessary to include patients in studies. Published diagnostic criteria varied substantially, ranging from as few as 2 cm to as many as 5 cm of columnar lined esophagus. 19 Many authorities have now settled on 3 cm as the cutoff for long segment Barrett's. These arbitrary criteria, designed specifically by investigators for use in clinical trials, were adopted into clinical practice. By adhering to these diagnostic criteria, clinicians limited the problem of false-positive diagnoses, but failed to recognize short segments of metaplastic epithelium in the distal esophagus.

Short segment
Diagnostic difficulties arise in patients who have short segments of columnar epithelium that appear to be confined to the distal esophagus. Without precise landmarks for the esophagogastric junction, it can be difficult to determine whether these short segments of columnar epithelium line the distal esophagus or whether they line a tubular segment of the gastric cardia that the endoscopist

13 has mistakenly identified as esophagus. Some authorities have proposed that the term "short-segment Barrett's esophagus" should be used in patients who have less than 2 to 3 cm of specialized intestinal metaplasia lining the distal esophagus.20

Junctional intestinal metaplasia

To further complicate matters, intestinal metaplasia can exist below the squamocolumnar conjunction. When the esophagogastric junction and the squamocolumnar junction are in the same location it is referred to as specialized intestinal metaplasia of the squamocolumnar junction or junctional specialized columnar epithelium.21 Specialized intestinal metaplasia of the squamocolumnar junction has been linked to adenocarcinoma of the gastric cardia and distal esophagus. However, its relationship to GERD is uncertain. To overcome these problems with definitions, some authorities have proposed that the diagnosis of Barrett's esophagus should be based solely upon the presence of specialized intestinal metaplasia, not upon any specific extent of esophageal columnar lining.22 Others have suggested that the term Barrett's esophagus should be eliminated altogether, and that the condition should be called simply "columnarlined esophagus".19 Unfortunately, even these approaches have not eliminated diagnostic difficulties. A major consideration with defining Barrett's esophagus solely by the presence of specialized intestinal metaplasia relates to the high frequency with which short segments can be found in the distal esophagus and its uncertain relationship to malignant transformation and reflux. In one report, for example, short, inconspicuous segments of intestinal-type epithelium were found

14 in the region of the esophagogastric junction in approximately 20 percent of patients in a general endoscopy unit who underwent protocol biopsies, many of whom had no signs or symptoms of GERD. 23 These observations have been confirmed by a number of subsequent reports. 24-25 Most studies on Barrett's esophagus have exclusively included patients with the endoscopically obvious condition in which the distal esophagus is lined extensively by metaplastic, intestinal-type epithelium. Until the debate is over and terminology resolved, the term Barrett's esophagus should be used to refer to such patients.

Differences between long and short segment Barrett's

As discussed above, the prevalence of short segment is much higher than long segment Barrett's esophagus. Both conditions are diagnosed most frequently in patients between the ages of 55 and 65 and are predominantly seen in male Caucasians. Patients with junctional intestinal metaplasia are a possible exception; an equal gender distribution has been reported in this group of patients.21 These observations were illustrated in a study that included 889 patients undergoing upper endoscopy who had protocol biopsies obtained at the esophagogastric junction.25 The overall prevalence of specialized intestinal metaplasia was 13.2 percent with the following distribution: Long-segment 1.6 percent Short segment 6.4 percent Intestinal metaplasia of the esophagogastric junction 5.6 percent. Patients with long and short segment Barrett's were predominantly male, white smokers. Patients with short segment Barrett's had a shorter history of heartburn.

15 In contrast, those with intestinal metaplasia of the esophagogastric junction had a similar gender distribution and were more likely to be infected by Helicobacter pylori. The degree and mechanism of acid exposure in patients with short and long segment Barrett's esophagus suggest that patients who develop long segments Barrett's were predisposed to more severe reflux. 26 Patients with long segment Barrett's tend to have upright and supine reflux in contrast to those with short segment Barrett's who have predominantly upright reflux. Proximal esophageal acid exposure is more common in patients with long segment Barrett's. Compared to patients with long segment Barrett's, those with short segments tend to have higher LES pressures and increased distal esophageal peristaltic amplitudes.

Dysplasia and adenocarcinoma in short segment Barrett's

The risk of dysplasia and adenocarcinoma in patients with short segment Barrett's esophagus is being clarified. It is reasonable to assume and data confirm that patients with short segment Barrett's have a lower incidence of dysplasia since less mucosa is involved (6 to 8 versus 15 to 24 percent in long segment Barrett's).25 Similarly, the risk of adenocarcinoma has been estimated to be 2 to 15 times higher in patients with long segment Barrett's. The following three studies illustrate the range of findings: In one study the prevalence and incidence of dysplasia and adenocarcinoma were compared between 78 patients with long segment and 74 patients with

16 short segment Barrett's esophagus. 27 At diagnosis, the prevalence of dysplasia was significantly higher in those with long segment (24 versus 8 percent). Adenocarcinoma was detected only in patients with long segment Barrett's. During follow-up ranging from 12 to 40 months, dysplasia developed significantly more often in patients with long segment Barrett's (8 versus 4 percent). No patients with short segment Barrett's developed high grade dysplasia or adenocarcinoma. In another report that included 94 patients with intestinal metaplasia discovered during endoscopy, dysplasia or cancer were significantly more common in those with long compared to short segment Barrett's, or intestinal metaplasia of the esophagogastric junction (31, 10, and 6.4 percent, respectively). 25 A third study included 309 patients with Barrett's esophagus who were followed for an average of 3.8 years.28 A nonsignificant trend toward an increased risk of adenocarcinoma was observed with longer lengths of Barrett's; a 5 cm difference in segment length was associated with a 1.7-fold increased cancer risk.

PATHOPHYSIOLOGY
An essential concept in the pathogenesis of gastroesophageal reflux disease (is that the extent of symptoms and of mucosal injury is proportional to the duration of mucosal acidification and the caustic potency of refluxed fluid. The integrity of the esophageal mucosa in normal individuals requires a balance between aggressive forces (acid reflux, potency of refluxate) and defensive forces (esophageal acid clearance, mucosal resistance). For one or more reasons, this balance becomes impaired in patients who develop reflux esophagitis.

17

MECHANISMS OF REFLUX
The primary event in the pathogenesis of GERD is movement of gastric juice from the stomach into the esophagus. The three dominant pathophysiologic mechanisms causing gastroesophageal junction incompetence are: Transient lower esophageal sphincter relaxations (tLESRs) A hypotensive lower esophageal sphincter (LES) Anatomic disruption of the gastroesophageal junction, probably associated with a hiatal hernia Although examples of each mechanism have been documented, their relative importance continues to be debated. The dominant mechanism may vary as a function of disease severity with tLESRs predominating with mild disease and mechanisms associated with a hiatus hernia and/or a weak sphincter predominating with more severe disease . The relatively recent availability of esophageal impedance testing, which can detect reflux irrespective of pH, discern reflux of gas from liquid, and determine the distribution and velocity of refluxate, will likely help determine the impact of these variables on the clinical features of GERD.29

TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS

Transient lower esophageal sphincter relaxations account for essentially all reflux events in individuals with a normal LES pressure at the time of reflux . There are several major differences between tLESRs and swallow-induced LES relaxation: tLESRs occur without an associated pharyngeal contraction, are unaccompanied by esophageal peristalsis, and persist for longer periods (>10 sec) than do

18 swallow-induced LES relaxations.However, not all tLESRs are accompanied by reflux. Different investigators have documented reflux during as many as 93 percent or as few as 9 to 15 percent of such events .It seems most likely that tLESRs are a physiologic response to gastric distension by food or gas and are the mechanism responsible for gas venting of the stomach; acid reflux is an inconstant, associated phenomenon. It has become increasingly clear that tLESRs play an important role in belching. The frequency of tLESRs is greatly increased by distension of the stomach by gas or by assuming an upright posture. Furthermore, tLESRs are integrated motor responses involving not only LES relaxation, but also crural diaphragmatic inhibition and contraction of the costal diaphragm. Animal and human experiments have demonstrated that tLESRs can be inhibited by gamma aminobutyric acid receptor type B agonists (such as baclofen), suggesting a potential new approach to the treatment of GERD.30

HYPOTENSIVE LOWER ESOPHAGEAL SPHINCTER

The LES is a 3 to 4 cm long segment of tonically contracted smooth muscle at the distal end of the esophagus. LES tonic contraction is a property of both the muscle itself and of its extrinsic innervation. Normal resting tone of the LES varies from 10 to 30 mmHg, being least in the post-cibal period and greatest at night .Only a minority of individuals with GERD have a grossly hypotensive LES (<10 mmHg) when determined during fasting measurements. There are, however, a host of factors that can reduce LES pressure: gastric distension, cholecystokinin, various foods (fat, chocolate, caffeine, alcohol), smoking, and

19 many drugs. Thus, many patients have periods of gross LES hypotension as a result of foods, drugs, or habits. Gastroesophageal reflux can occur with diminished LES pressure either by stress reflux or free reflux: Stress reflux occurs when a hypotensive LES is overcome and "blown open" by an abrupt increase of intraabdominal pressure. Manometric data suggest that stress reflux is a relatively unusual mechanism of reflux, primarily being seen when the LES pressure is less than 4 mmHg. 31 However, these studies were not controlled for the effect of the required instrumentation (recumbent subjects reading or watching television with a manometric assembly and a pH probe in their nose), or of a hiatal hernia (see below). During free reflux a fall in intraesophageal pH occurs without identifiable change in either intragastric or LES pressure. Free reflux is observed only when LES pressure is within 0 to 4 mmHg of intragastric pressure.

HIATAL HERNIA AND THE DIAPHRAGMATIC SPHINCTER

The diaphragm as well as the LES contributes to gastroesophageal sphincter competence. Recordings of LES pressure usually exhibit inspiratory increases as a result of contraction of the diaphragmatic crus that encircles the LES. Observations of the antireflux mechanism during maneuvers such as leg raising and abdominal compression suggest a "pinchcock" effect of crural contraction that augments the antireflux barrier. The crural diaphragmatic component of gastroesophageal junction pressure is most relevant in patients with hiatal hernia, in whom this component may be impaired. The susceptibility to reflux under circumstances of abrupt increases of intraabdominal pressure (eg, during

20 bending or coughing) depends upon both the instantaneous LES pressure and the diaphragmatic sphincter. Patients with hiatus hernia can have progressive disruption of the diaphragmatic sphincter depending upon the extent of axial herniation. Therefore, although neither condition (hiatus hernia or hypotensive LES) alone results in severe incompetence; the two conditions interact with each other in more than an additive fashion. The severity of esophagitis correlates with the size of the hiatal hernia. Two other factors also appear to be important in patients with reflux associated with a hiatus hernia. A hiatus hernia is associated with a reduced threshold for eliciting tLESRs in response to gastric distension. It is also associated with malfunction of the gastroesophageal barrier during periods of low LES pressure, during normal swallow-associated LES relaxation, and during deep inspiration or straining. 32

ESOPHAGOGASTRIC JUNCTION COMPLIANCE

Compliance of the esophagogastric junction may be important in regulating both the volume and content of reflux. One way in which compliance can be measured is by determining the cross-sectional area (CSA) of the relaxed

gastroesophageal junction in response to distension. This can be done by analyzing digitized fluoroscopic images of the gastroesophageal junction during low-pressure distension (using a modified barostat technique in which a contrastfilled bag is straddled across the esophagogastric junction). The lower the pressure needed to increase CSA, the greater the compliance. A study using this approach compared seven controls with nine patients with GERD without a hiatus hernia, and seven patients with GERD with a hiatus hernia. 33 The CSA at

21 each distension pressure was greater in patients with GERD with a hiatus hernia compared to those without a hiatus hernia (and both groups were greater than controls). The authors speculated that the increased compliance may permit increased volume of reflux. Furthermore, it may explain the diminished ability of GERD patients to selectively reflux gas as opposed to liquid during tLESRs.

ESOPHAGEAL ACID CLEARANCE

Following reflux, the period that the esophageal pH remains less than 4 is called the acid clearance time. Esophageal acid clearance begins with emptying the refluxed fluid from the esophagus by peristalsis and is completed by titration of the residual acid by swallowed saliva . Approximately 7 mL of saliva will neutralize 1 mL of 0.1 N HCl, with 50 percent of the neutralizing capacity being attributable to salivary bicarbonate. The normal rate of salivation is about 0.5 mL/min; maneuvers that increase salivation (eg, oral lozenges or gum chewing) will hasten acid clearance while circumstances of diminished salivation (eg, sleep) will delay it.Prolongation of esophageal acid clearance occurs in about one-half of patients with esophagitis. Abnormal acid clearance improves with an erect posture, suggesting that gravity compensates for impaired fluid emptying.

ESOPHAGEAL EMPTYING IN GERD

Two mechanisms of impaired esophageal emptying have been identified: Peristaltic dysfunction, resulting in either failed or hypotensive (<30 mmHg) peristaltic contractions. Peristaltic dysfunction becomes more common with increasing severity of esophagitis. Whether peristaltic dysfunction associated with peptic esophagitis is reversible is disputed. Most likely, acute dysfunction

22 associated with active esophagitis is partially reversible, while chronic dysfunction associated with stricturing or extensive fibrosis is not. Re-reflux" associated with hiatal hernias, which also impair esophageal emptying. Scintiscanning and pH recording concurrent with fluoroscopy demonstrate "re-reflux" from the hernia sac during swallowing. This occurs only with "non-reducing" hernias which are evident between swallows and during peristalsis-induced esophageal shortening. In one report, for example, retrograde flow or "re-reflux" was seen with almost 50 percent of test swallows in patients with non-reducing hernias, impairing both esophageal emptying and esophageal acid clearance.34

MECHANISMS OF DEFENSES AGAINST ESOPHAGEAL INJURY

The development of esophagitis in GERD on a cellular level is due to hydrogen ion diffusion into the mucosa, leading to cellular acidification and necrosis. As noted above, reflux, impaired esophageal emptying, and diminished salivary function contribute to increased exposure of the esophagus to hydrogen ions. In contrast, esophagitis is not caused by increased gastric acid secretion in GERD patients. Pepsin, bile acids, trypsin, and food hyperosmolality increase the susceptibility of the esophageal mucosa to acid injury. Pepsin and bile acids have been subjected to the most scrutiny. At pH 2, pepsin disrupts the histologic integrity of the mucosal barrier, increases hydrogen ion permeability, and causes hemorrhage. In contrast, an esophagus exposed to a pepsin perfusate at pH 7.5 followed by a solution at pH 2 without pepsin shows minimal mucosal disruption

23 or changes in permeability. Thus, pepsin's ability to cause mucosal injury is pH dependent, with maximal enzyme activity below pH 3. Bile acids have been implicated in the development of esophagitis primarily in patients with increased duodenogastric reflux following gastric surgery. 35 However, bile acids are not as important as acid and pepsin.

EPITHELIAL DEFENSE
The esophageal mucosa possesses several morphologic and physiologic defenses against cellular acidification. Conceptually, epithelial defenses can be subdivided into preepithelial, epithelial, and postepithelial factors. Preepithelial defenses (surface mucous and bicarbonate that maintain a significant pH gradient between lumen and cell surface) are poorly developed in the esophagus; as a result, the pH gradient in the mucus layer is minimal or nil . Although the esophageal epithelium contains a few submucosal glands that secrete bicarbonate into the submucosa, mucosa, and lumen, the main defense against acid injury is the epithelial barrier itself. The esophageal mucosa is a relatively "tight" epithelium, resistant to ionic movements at the intercellular as well as the cellular level because of the tight junctions and the lipid rich matrix in the intercellular space. This mucosa can retard hydrogen ion penetration in the face of ion gradients of greater than 5 pH units. The importance of tight junctions has been demonstrated by the luminal and serosal application of low molecular weight markers of paracellular permeability. When applied luminally, the paracellular movement of these markers was restricted to the first few layers of

24 the stratum corneum by tight junctions; when applied serosally, they permeated freely through the basal cell and stratum spinosum layers and were retarded only within seven to nine cell layers of the lumen. These observations illustrate the vulnerability of the esophageal mucosa to injury once the superficial cell layers have been lost. A histomorphometric correlate of increased paracellular permeability is the presence of dilated intercellular spaces, evident in transmission electron microscopy. Detailed analyses have shown this to be a sensitive and reversible marker for a reflux injured esophagus. 36 Further defense of the esophageal epithelium is provided by hydrogen ion extrusion. Two pH-activated acid extruding processes are located on esophageal membranes: a Na/H exchanger; and a sodium dependent Cl/HCO3 exchanger. Once extruded, the hydrogen ions are buffered by extracellular bicarbonate in equilibrium with the blood. Thus, blood flow is the main postepithelial defense, interacting with epithelial factors to protect against acid injury. In addition to providing nutrients for metabolic activity, blood flow increases in response to luminal acid, delivering more bicarbonate to the intracellular space. Finally, when the epithelial cells are no longer able to maintain intracellular pH, they lose the ability to volume regulate and cellular edema ensues. Esophageal acid injury also stimulates cell proliferation, which is observed in biopsy specimens as thickening of the basal cell layer of the epithelium.

ESOPHAGEAL HYPERSENSITIVITY
Despite careful evaluation, some patients who have typical reflux-like symptoms do not have pathologic reflux documented by endoscopy or 24-hour pH studies.

25 The clinical manifestations of these hypersensitive patients are similar to those with GERD. This was illustrated in a study that compared 70 patients whose initial pH study demonstrated normal acid exposure but had symptoms of GERD with 58 patients found to have excess reflux on 24-hour pH studies. 37 During follow-up of 4.4 to 6.5 years, a similar proportion of patients continued to have symptoms in both groups (87 versus 79 percent, respectively). Furthermore, approximately 60 percent of patients in both groups regularly continued take medications for GERD.The cause of heartburn in these patients is uncertain but may be related to heightened esophageal sensitivity (also called visceral hyperalgesia). This hypothesis was evaluated in a study of 152 patients with chronic heartburn who underwent endoscopy, esophageal manometry, 24-hour pH monitoring, intraesophageal balloon distension, and Bernstein testing (infusion of 0.1N HCl or saline in the esophagus in a blinded fashion). 38 Normal acid contact time (less than 6 percent) was observed in 43 percent of patients. Of these patients, 64 percent had normal lower esophageal sphincter pressure, and 79 percent had a normal endoscopy. However, 89 percent developed heartburn during Bernstein testing, and 52 percent had lower pain thresholds for esophageal balloon distension than normal values in healthy volunteers. These results indicate that heartburn may be due to esophageal hypersensitivity to normal acid exposure or other stimuli in some patients. This is analogous to the visceral hyperalgesia described in a variety of other disorders including noncardiac chest pain, functional dyspepsia, and irritable bowel syndrome.

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PATHOLOGY
Barrett's esophagus develops through the process of metaplasia in which one kind of fully differentiated cell replaces another. Metaplasia occurs when tissue is exposed chronically to noxious factors (such as acid reflux) that injure mature cells while simultaneously promoting epithelial repair through the aberrant differentiation of immature, proliferating cells. The metaplastic columnar cells of Barrett's esophagus are in some ways a favorable adaptation to chronic reflux since they appear to be more resistant to reflux-induced injury than the native squamous cells. Unfortunately, esophageal columnar metaplasia predisposes to the development of adenocarcinoma. The pattern of acid secretion may be an important determinant of Barrett's metaplasia. This heterogeneous response could contribute to the unpredictable progression in patients with Barrett's esophagus. Another report found that the length of Barrett's esophagus correlated with the percent of supine reflux and percent of time that esophageal pH was <4. 39 Other studies have demonstrated that patients with longstanding and severe reflux symptoms are at increased risk for adenocarcinoma of the esophagus. 40 Several physiologic abnormalities contribute to the severity of GERD in patients with Barrett's esophagus. As a result, patients who have Barrett's esophagus are predisposed to reflux highly caustic gastric contents (often without warning symptoms) into an esophagus whose ability to protect itself is compromised by defective clearance mechanisms and diminished secretion of growth factors. Given the propensity for severe GERD in patients with Barrett's esophagus, it was initially assumed that the

27 metaplasia progressed in extent over the years as columnar epithelium replaced more and more reflux-damaged squamous epithelium. However, for reasons that are unclear, such progression is observed only infrequently. In most cases, Barrett's esophagus appears to develop to its full extent over a short period of time (ie, <1 year), with little or no subsequent progression. Why this occurs is not well understood.

TYPES OF EPITHELIUM IN BARRETS ESOPHAGUS

Three types of columnar epithelia have been described in Barrett's esophagus.

JUNCTIONAL-TYPE EPITHELIUM (also called cardiac epithelium) which has a foveolar (pitted) surface and glands
that are lined almost exclusively by mucus-secreting cells; these cells resemble those in the gastric cardia.

GASTRIC FUNDIC-TYPE EPITHELIUM

Which has a foveolar surface lined by mucus-secreting cells, and a deeper glandular layer that contains chief and parietal cells; these cells resemble those in the gastric fundus.

SPECIALIZED INTESTINAL METAPLASIA

(Also called specialized columnar epithelium), which has intestinal-type crypts lined by mucus-secreting columnar cells and goblet cells. Specialized intestinal metaplasia has intestinal features such as goblet cells and villi that readily distinguish it from normal gastric and esophageal mucosae. It is the most common histologic type and the only one that has a clear malignant potential. Thus, it is preferable to use the term "specialized intestinal metaplasia" when

28 referring to the increased cancer risk in Barrett's esophagus. Specialized intestinal metaplasia. The two main epithelial components of Barrett's esophagus are the surface epithelium and the underlying glands. Reduplication of the muscularis mucosae with interposed lamina propria may be present. The mucosa is usually flat but may become villiform, particularly if dysplasia or inflammation is present. The metaplastic cells of specialized columnar epithelium contain a number of intestinal-type cells including goblet cells, gastric, small intestinal and colonic-like columnar cells, endocrine, and Paneth cells with intermediate features. Pancreatic acinar-type cells are present in approximately 10 percent of patients. Specialized intestinal metaplasia is indistinguishable histologically from intestinal metaplasia type II or III of the stomach.The presence of goblet cells is the most useful feature for distinguishing specialized intestinal metaplasia from gastric cardiac or fundic-type mucosa. The goblet cells of specialized intestinal metaplasia contain acidic mucins (sialomucins and sulfomucins) that can be demonstrated by staining with Alcian blue. They may also contain colonic-like mucins that can be demonstrated with diamine staining.

DYSPLASIA
Specialized intestinal metaplasia may become dysplastic. Dysplasia is often unifocal and is characterized by a number of architectural and cytologic abnormalities. Architectural abnormalities in dysplasia include budding, and branching of the glandular epithelium with cellular crowding, irregular shapes, and papilliform extensions. The dysplastic epithelium occasionally appears as a mass, in which case it is called an adenoma. Cytologic changes in dysplasia

29 often include mucus depletion and prominent basophilia of the cytoplasm. Two patterns have been recognized.41 A pattern resembling adenomatous changes elsewhere in the gastrointestinal tract. Cytologic features include enlarged, crowded, elongated hyperchromatic nuclei and increased numbers of mitoses. This pattern of dysplasia is associated with "intestinal types" of invasive cancer. A pattern associated with incomplete intestinal metaplasia with gastric-type mucin production. Cytologic features include vesiculated nuclei that are enlarged, pleomorphic, contain dense chromatin, and have lost their polarity. This pattern of dysplasia is associated with poorly differentiated adenocarcinoma. Dysplasia is graded as low or high grade or indefinite. The classification into these categories is based upon the architectural and cytologic features discussed above. In low grade dysplasia, the architectural changes are mild. There may be some degree of crypt branching but with little glandular distortion. The cytologic changes are also mild compared to high grade dysplasia. The nuclear polarity is relatively well preserved, and the nuclei are smaller and less hyperchromic. High grade dysplasia is characterized by marked branching of the glands with complex patterns, which may take on a villiform appearance that resembles a villous adenoma of the colon. Cytologic abnormalities include marked

pseudostratification and loss of basal polarity; the nuclei and nucleoli are enlarged and vary in size and shape. High grade dysplasia may be difficult to be distinguished from well-differentiated adenocarcinoma. Changes that are too severe to be labeled nondysplastic but have insufficient characteristics are to be

30 called as dysplasia indefinite for dysplasia. Reactive changes are often present due to inflammation, erosion, and regeneration, which make diagnosis of definite dysplasia difficult.

ADENOCARCINOMA ARISING FROM BARRETT'S

Barrett's esophagus is thought to be the precursor of adenocarcinoma of the esophagus and of the esophagogastric junction. Adenocarcinomas that straddle the esophagogastric junction are approximately twice as common as adenocarcinomas that clearly arise from the esophagus. With straddling tumors, it can be difficult to determine whether the neoplasm arose from the columnar epithelium in the distal esophagus or in the proximal stomach (the gastric cardia). These tumors cannot be distinguished from one another morphologically, and they share a number of epidemiologic features including an association with GERD, a strong predilection for white males, and a rapidly rising incidence in Western countries. Biochemical studies are also consistent with the hypothesis that Barrett's esophagus is the precursor for esophagogastric junction tumors. In one series, for example, similar profiles of intestinal-type proteins were detected by immunofluorescence microscopy in Barrett's esophagus and in 26 cases of adenocarcinoma with or without obvious Barrett's in tumors from both esophagus and cardia.42 These profiles were not seen in normal stomach or esophageal mucosa or in peptic esophagitis or squamous cell carcinoma. However, the pattern of cytokeratin staining is different in Barrett's mucosa and metaplastic mucosa of the gastric cardia, suggesting different pathobiology. Barrett's mucosa stains predominantly for cytokeratin 7 in contrast to metaplastic

31 mucosa of the gastric cardia, which stains predominantly for cytokeratin. 43 The utility of cytokeratin staining as a clinical tool remains unclear. 44 Also supporting a distinct pathobiology are differences in the genetic alterations in

adenocarcinomas arising from Barrett's esophagus compared to those arising from gastric mucosa.45

MECHANISMS OF MALIGNANT TRANSFORMATION

Carcinogenesis in metaplastic cells begins with genetic alterations that either activate protooncogenes, disable tumor suppressor genes, or both. 46 Neoplastic progression observed in patients with Barrett's esophagus include alterations in the tumor suppressor genes p53 (also known as TP53) and p16 (also known as CDKN2A), and non-random losses of heterozygosity (LOH) In addition to these changes, aneuploid or tetraploid populations are observed in more than 90 percent of adenocarcinomas and predict progression in Barrett's epithelium prior to malignant transformation. These DNA abnormalities endow the cells with certain growth advantages permitting them to hyperproliferate. During

hyperproliferation, the cells acquire more genetic changes that eventuate in autonomous cell growth (neoplasia). When enough DNA abnormalities accumulate, a clone of malignant cells emerges that has the ability to invade adjacent tissues and to proliferate in unnatural locations. The evolution of genetic changes leading from Barrett's esophagus to adenocarcinoma is incompletely understood. It appears that diploid progenitor cells first develop abnormalities in p53 and p16, which permit clonal expansion. 47-48 These abnormal cells are

capable of spreading within large regions of the esophageal mucosa.

32 Subsequently, a number of additional genetic alterations develop involving LOH at chromosome 5q, 13q, and 18q in no discernible order relative to one another. Before the cells acquire enough DNA damage to become frankly malignant, the earlier genetic alterations often cause morphologic changes that can be recognized on histologic examination as dysplasia. As discussed above, the dysplastic changes are graded as low-grade or high-grade depending upon the degree of alterations in nuclear morphology and glandular architecture. Whether acid suppression influences the genetic evolution of Barrett's epithelium is uncertain. However, effective acid suppression with a proton pump inhibitor has been associated with increased epithelial cell differentiation and decreased proliferation, suggesting that it has a favorable effect on dysplasia progression. 49 The selective COX-2 inhibitors may also hinder cell proliferation in vitro, suggesting a possible role in chemoprevention. 50

Helicobacter pylori infection

The observation that Helicobacter pylori can colonize Barrett's epithelium suggested a potential role for this organism in the pathogenesis of esophageal adenocarcinoma. However, several studies have demonstrated that H. pylori is not more common and does not have a different distribution in patients with Barrett's esophagus than in controls. 51 In contrast, H. pylori may be a significant factor for cancers arising from the gastric cardia. Such cases may be difficult to distinguish from cancers arising in the distal esophagus, particularly when the disease is advanced. H. pylori eradication has also been implicated in the development of GERD. However, the relationship between H. pylori and GERD is

33 complex and may depend upon the distribution of H. pylori in the stomach, whether or not patients are predisposed to GERD, and may be related to specific strains of H. pylori.52

MANAGEMENT
The management of patients with Barrett's esophagus involves three major components: Treatment of the associated gastroesophageal reflux Endoscopic surveillance to detect dysplasia Treatment of dysplasia

TREATMENT OF REFLUX
The management of GERD for patients with Barrett's esophagus involves similar principles to the treatment of patients who have reflux without Barrett's esophagus. Reflux esophagitis results from the combination of excessive gastroesophageal reflux of gastric juice and impaired esophageal clearance of the refluxate. Although the relationship is imprecise, the likelihood of developing reflux symptoms or esophageal epithelial injury is a function of the quantitative abnormality of esophageal acid exposure. Thus, for therapy to be effective, it must be titrated to disease severity.

LIFESTYLE MODIFICATIONS
Minimal, but sensible, therapy for GERD patients is comprised of lifestyle modification, dietary modification, as needed antacid use, and over-the-counter H2 receptor antagonists. These lifestyle modifications are aimed at enhancing

34 esophageal acid clearance, minimizing the incidence of reflux events, or both as with cessation of smoking and avoidance of late meals.

HEAD OF BED ELEVATION,

It can be achieved either by putting 6- to 8-inch blocks under the legs at the head of the bed or a Styrofoam wedge under the mattress. Head of bed elevation is important for individuals with nocturnal or laryngeal symptoms

DIETARY MODIFICATION
May be helpful but prohibition of many enjoyable foods virtually ensures noncompliance. It is more practical to suggest avoidance of a core group of reflux-inducing foods (fatty foods, chocolate, peppermint, and excessive alcohol, which may reduce lower esophageal sphincter pressure) and then to suggest that the patient selectively avoid foods known to cause symptoms. As an example, a number of beverages have a very acidic pH and can exacerbate symptoms. These include colas, red wine, and orange juice (pH 2.5 to 3.5).

SUPINE POSITION
Refraining from assuming a supine position after meals and avoidance of meals before bedtime, both of which will minimize reflux.

TIGHT FITTING GARMENTS

Avoidance of tight fitting garments, which reduces reflux by decreasing the stress on a weak sphincter.

35

OBESITY
Although obesity is a risk factor for GERD improvement in symptoms following weight loss is not uniform. Nevertheless, because of a possible benefit, and because of its other salutary effects, weight loss should be recommended.

PROMOTION OF SALIVATION
Promotion of salivation by either chewing gum or use of oral lozenges may also be helpful in mild heartburn. Salivation neutralizes refluxed acid, thereby increasing the rate of esophageal acid clearance.

ALCOHOL
Restriction of alcohol use and elimination of smoking; smoking is deleterious in part because it diminishes salivation.

ACID-SUPPRESSIVE MEDICATIONS
The most common and effective treatment of peptic esophagitis or symptomatic gastroesophageal reflux disease (GERD) is to reduce gastric acid secretion with either an H2 blocker or a proton pump inhibitor. The medication dose is titrated to the severity of disease for each patient, with the goal being to raise the intragastric pH above 4 during the periods of the day that reflux is likely to occur.53 The greater the degree of esophageal acid exposure, the greater the degree of acid suppression that is required. These therapies do not prevent reflux, they remove the caustic elements of the refluxate. Many trials have established the efficacy of the various proton pump inhibitors and H2 antagonists in the treatment of esophagitis. However, ascertaining the relative efficacy of these drugs is complicated by the fact that esophagitis exists

36 along a continuum of severity and unless the medications are compared head to head, comparability of study populations among trials cannot be assumed. One way of indexing the severity of esophagitis studied among trials is by the placebo healing rate. The placebo healing rate is very low with severe esophagitis and relatively high in mild esophagitis. The H2 receptor antagonists offer a therapeutic gain of 10 to 24 percent relative to the placebo for healing esophagitis. However, the gain is nearly constant regardless of the placebo healing rate, indicating that these drugs are ineffective for severe esophagitis. The different H2 receptor antagonists have equivalent efficacy if drug dose is adjusted for potency. An increased dose or continued use of an H2 antagonists is unlikely to produce relief for patients who continue to have heartburn after six weeks of treatment with a standard dose of an H2 antagonists. The proton pump inhibitors are more effective in healing esophagitis than the H2 receptor antagonists, with a therapeutic gain of 57 to 74 percent relative to placebo. In addition, proton pump inhibitors lead to more rapid healing and symptom relief than H2 receptor antagonists. In a meta-analysis, complete relief from heartburn occurred at a rate of 11.5 percent per week with a proton pump inhibitor compared to 6.4 percent per week with an H2 receptor antagonist . 54

NONEROSIVE GASTROESOPHAGEAL REFLUX DISEASE

The majority of patients with typical symptoms of GERD do not have esophagitis; such patients have been referred to as having nonerosive gastroesophageal reflux disease or nonerosive reflux disease (NERD). 55 Some of these patients have symptoms despite having normal levels of esophageal acid exposure as

37 assessed by a 24-hour pH study; such patients may have esophageal hypersensitivity to physiologic degrees of acid reflux; others have abnormal acid exposure but have not developed overt mucosal injury. Both groups of patients respond to antisecretory therapy. At least three controlled trials and a metaanalysis suggest that proton pump inhibitors were associated with more effective symptom relief than placebo or H2 antagonists. 56

PROTON PUMP INHIBITORS IN H2 RECEPTOR ANTAGONIST RESISTANT DISEASE

A major trial from the Netherlands specifically evaluated the efficacy of proton pump inhibitors in 91 patients with severe esophagitis that was resistant to therapy with H2 receptor antagonists.57 Thirty-two patients had Barrett's ulcer, 25 had failed antireflux surgery, and 28 had recurrent strictures. All patients treated with omeprazole in a dose of 40 mg/day or 60 mg/day (one patient) were healed. However, a substantial number of these patients had recurrent esophagitis when the dose was reduced to 20 mg/day. Thus, the efficacy of the proton pump inhibitors, as with the H2 receptor antagonists, is dose-dependent. Furthermore, the likelihood of healing erosive esophagitis with a particular pharmacologic regimen is proportional to the fraction of the day that the intragastric pH is above 4. One report found the following pattern of acid control (defined as the portion of the day during which the intragastric pH was > or =4) when omeprazole (20 mg/day) was given to 52 patients with duodenal ulcer.58 18 to 24 hours 55 percent

38 12 to 18 hours 10 percent 6 to 12 hours 14 percent 0 to 6 hours 21 percent Assuming that 12 hours of gastric pH control is necessary for moderate to severe esophagitis, it would be anticipated that 65 percent of these patients would respond to a 20 mg once daily dose of omeprazole, 14 percent would probably require 20 mg twice daily, and 21 percent would probably require either 40 mg or more, once or twice daily. The last category of patients requiring high-dose therapy is generally underrecognized. These individuals do not respond to a 20 mg dose and are equally unlikely to respond to multiple 20 mg doses (the half-life of omeprazole is approximately two hours). The effectiveness of a single higher dose of omeprazole compared to a 20 mg twice daily dose was confirmed in a small group of "omeprazole resistant" patients with GERD utilizing intragastric pH monitoring.59

DIFFERENCES IN PROTON PUMP INHIBITORS

Most studies have demonstrated that the different proton pump inhibitors have similar efficacy when given in equivalent doses. Although the drugs differ in their bioavailability and antisecretory potency upon initial dosing, these differences are probably not clinically significant in the usual setting in which patients are treated with repeated dosing. As an example, one study suggested that rabeprazole was associated with significantly decreased 24-hour intragastric acidity compared to omeprazole during the first 24 hours of administration in healthy male volunteers.60 However, after eight days of dosing, the difference was not

39 statistically significant. On the other hand, controlled trials suggested that esomeprazole (an optical isomer of omeprazole) may have clinical benefits compared to other PPIs.

PROKINETIC DRUGS
Prokinetic drugs (bethanechol, metoclopramide, and cisapride) have the potential to be useful in GERD by counteracting some physiologic abnormalities that are present. These drugs can increase lower esophageal sphincter pressure, enhance gastric emptying, and improve peristalsis. Bethanechol and metoclopramide have a number of side effects that limit their use in GERD. Cisapride is available only on a severely restricted basis in the United States because of concerns related to cardiac arrhythmias.

BETHANECHOL
It has generalized cholinergic effects of increasing gastric acid secretion, bronchoconstriction, and bladder contraction.

METOCLOPRAMIDE
It has a 20 to 50 percent incidence of fatigue, restlessness, tremor, Parkinsonism, or tardive dyskinesia .

CISAPRIDE
Although cisapride has generally had an excellent safety profile, its recent widespread use in the United States has been associated with cardiac arrhythmias. Cardiac toxicity is most likely to occur when cisapride is taken in combination with macrolide antibiotics (erythromycin and clarithromycin) or drugs in the imidazole class (ketoconazole, fluconazole, itraconazole, or

40 metronidazole), and HIV protease inhibitors, which inhibit the cytochrome P4503A4 enzyme and increase cisapride levels. European trials comparing cisapride (10 mg four times daily) to H2 receptor antagonists (ranitidine 150 mg twice daily or cimetidine 400 mg twice daily) have demonstrated similar efficacy in relieving GERD symptoms and in healing mild esophagitis. 61 Neither regimen demonstrated good therapeutic results with higher grades of esophagitis. Another study demonstrated improved healing of mild to moderate esophagitis with cisapride and cimetidine in combination compared to cimetidine alone (70 versus 46 percent healed after 6 to 12 weeks) . Cisapride is not as effective as omeprazole for relieving heartburn. Thus, cisapride has similar efficacy to H2 receptor antagonists in the treatment of mild esophagitis when used as the primary agent and some facilitating effect when used in conjunction with these drugs.

TREATMENT OF HELICOBACTER PYLORI INFECTION

A possible role for H. pylori in the pathogenesis of gastroesophageal reflux disease has been suggested in a number of studies. However, the link between GERD and H. pylori is complex and remains poorly defined.

MAINTENANCE THERAPY
Given the propensity of esophagitis to relapse, maintenance acid suppressive therapy is often necessary. Reducing the dose of the medication or attempting maintenance with a less potent agent than that used for healing often results in a high recurrence rate. This can be illustrated by the findings in two randomized controlled trials. One trial evaluated 175 patients with reflux esophagitis who had

41 confirmed healing after four to eight weeks of therapy with omeprazole, 40 mg/day.62 The patients were then randomized to one of five different regimens and the continued remission rate noted by repeat endoscopy at 12 months: Ranitidine, 150 mg twice daily 49 percent Cisapride, 10 mg three times daily 54 percent Cisapride plus ranitidine 60 percent Omeprazole, 20 mg once daily 80 percent Cisapride plus omeprazole 89 percent Omeprazole was significantly more effective as monotherapy than the other drugs, and ranitidine plus cisapride was significantly more effective than either agent alone. The second trial consisted of 175 patients with documented healing who were randomized to placebo or one of two doses of lansoprazole, 15 or 30 mg once daily.63 The persistent healing rates at 12 months were: 24 percent with placebo 79 percent with 15 mg of lansoprazole 90 percent with 30 mg of lansoprazole Long-term follow-up data in patients treated with omeprazole have demonstrated that the low rate of relapse is maintained in the majority of patients. This was illustrated in a study involving 230 patients in which only 158 relapses occurred during 1490 years of treatment (ie, one per 9.4 years). 57

INTERMITTENT THERAPY
The optimal approach for prescribing intermittent therapy has not been well established. One trial included 677 patients with mild to moderate heartburn and

42 a normal endoscopy or only mild erosive changes were randomly assigned to omeprazole (10 or 20 mg/day) or ranitidine (150 mg twice daily). 64 After two weeks, asymptomatic patients were given no further therapy unless symptoms returned upon which they were treated for two to four weeks with the drug that initially caused remission. At the end of one year, approximately 50 percent of patients in all three treatment groups had not required medication for at least six months.

SAFETY
With maintenance antisecretory therapy being the rule rather than the exception, drug safety becomes an important issue.

HYPERGASTRINEMIA
A major safety issue with omeprazole has been the induction of hypergastrinemia and gastric carcinoid tumors in rats, changes also demonstrated with chronic ranitidine exposure or subtotal resection of the gastric fundus. However, these observations have not generalized to species with gastrin physiology more analogous to humans. Furthermore, although patients treated with omeprazole for up to 11 years have shown some corpus gastritis and argyrophil cell hyperplasia, no dysplasia or neoplastic changes have been observed. 65 The hypergastrinemia induced by omeprazole may partially depend upon whether or not patients are infected with H. pylori. In one study, patients with symptomatic GERD who were infected with H. pylori were randomized to treatment to eradicate infection or simply to control symptoms. 66 One month later, all received a four-week course of omeprazole (40 mg/day) followed by 20 mg/day for six

43 months. Eradication of infection was associated with significantly lower fasting serum gastrin concentrations during omeprazole therapy.

ATROPHIC GASTRITIS
Although the risk of Omeprazole related atrophic gastritis in this remains unclear, it could theoretically lead to an increased incidence of gastric cancer.. However, since the omeprazole-treated patients developed atrophy only in the presence of a concomitant Helicobacter pylori infection, the most significant risk factor is the H. pylori infection.Thus, an argument can be made for the detection and eradication of H. pylori in patients who will be given maintenance therapy with a proton pump inhibitor. Although some physicians have adopted this practice, an FDA panel reviewing these data in November 1996 concluded that at that time there was insufficient evidence to warrant this approach. This recommendation was supported by a subsequent controlled trial involving 155 patients who were randomly assigned to anti reflux surgery or omeprazole. 67 After three years, no significant differences were observed in the development of gastric glandular atrophy or the occurrence of intestinal metaplasia, irrespective of H. pylori status.

VITAMIN B12 MALABSORPTION

Long-term therapy with omeprazole has been associated with vitamin B12 malabsorption. Iron absorption does not appear to be affected. Thus, it is reasonable to assess vitamin B12 levels periodically in patients who are on longterm treatment with PPIs.68

44

PREGNANCY
The smooth muscle relaxation that occurs during pregnancy predisposes to gastroesophageal reflux. Lifestyle modifications, antacids, or sucralfate should be first-line therapy in symptomatic women. However, some patients are not controlled by these measures.The greatest experience with pharmacologic acidsuppressive therapy in pregnant women has been with the H2 receptor antagonists ranitidine and cimetidine, which appear to be safe during pregnancy. There is less experience using proton pump inhibitors during pregnancy. However, they are probably safe. In one study, 113 pregnant women exposed to omeprazole during pregnancy were compared with controls exposed to known non teratogens and with women who took H2 blockers during pregnancy. 69 Birth weight, gestational age at delivery, preterm deliveries, and neonatal

complications were comparable among the three groups. A population-based case-control study involving 3236 births found that first trimester exposure to cimetidine, omeprazole, or ranitidine was not associated with an increased risk of congenital malformations, preterm delivery, or growth retardation. 70 Currently, omeprazole is rated pregnancy category C; lansoprazole, pantoprazole and rabeprazole are rated pregnancy category B.

PROPOSED MODE OF MANAGEMENT

Recommendations for the management of GERD have been proposed by a number of authorities and organizations including an international workshop and the American College of Gastroenterology.71 The optimal acute therapy is

estimated and initiated based upon the patient's history. Endoscopy is initially

45 warranted if there is significant doubt regarding the diagnosis of GERD or if the patient relays alarm symptoms suggesting more ominous diagnoses (eg, dysphagia, bleeding, weight loss, odynophagia). Depending upon the initial therapy rendered, the medical regimen is then adjusted in a step-up or stepdown fashion to ascertain the least potent effective regimen according to the scale of potency in. Patient comfort is optimized using a step-down approach, with incremental changes in therapy being made at two- to four-week intervals. 72 Once identified, the optimal acute therapy should be maintained for at least eight weeks. Further evaluation should be undertaken if the most potent medical therapy still results in a poor response.67 If, on the other hand, acute medical therapy alleviates symptoms, the patient should be given a trial off medication. The need for maintenance medical therapy is determined by the rapidity of recurrence. Recurrent symptoms in less than three months suggest disease best managed with continuous therapy, while remissions in excess of three months can be adequately managed by repeated courses of acute therapy as necessary. The three-month figure is derived from observations of patients randomized to placebo in maintenance trials of proton pump inhibitors. If recurrence were going to occur within one year, it invariably occurred within the first three months. In one of the trials described above, for example, 76%of patients treated with placebo were recurrent at one year; 55 percent (72 % of the recurrences) developed within the first month.63 Patients on effective maintenance therapy may opt to have elective antireflux surgery after a thorough discussion of the associated risks and benefits. Any patient who requires continuous maintenance

46 medical therapy should undergo endoscopy to rule out Barrett's esophagus. Antireflux surgery is also an option 62 although it does not appear to be more effective at preventing death from cancer than medical therapy. 73- 74Supporting this recommendation are the observations that the elimination of symptoms does not guarantee the normalization of acid reflux in patients with Barrett's esophagus.75 These patients may have an increased threshold for the sensation of esophageal acid exposure, and it has been suggested that adequate acid suppression may impede the progression of Barrett's epithelium to dysplasia or lead to its partial regression.76-78 As a result of these considerations, some authorities have recommended that patients with Barrett's esophagus should undergo 24-hour pH monitoring while on therapy to assure the adequacy of acid suppression; however, the cost-effectiveness of this approach is uncertain. At the present time, the American College of Gastroenterology recommends that the goal of therapy should be to relieve symptoms and maintain a healed mucosa. 79

ENDOSCOPIC SURVEILLANCE
Survival benefit in patients undergoing surveillance has not been demonstrated in randomized prospective trials, which would be prohibitively large and costly to perform and whose study design would raise practical and ethical problems 80.

INFLUENCE OF BARRETT'S ESOPHAGUS ON MORTALITY

Estimates of the annual cancer incidence in patients with Barrett's esophagus have ranged from 0.2 to 2.0 percent. 81-82 Data from six prospective studies on cancer development in Barrett's esophagus suggest that the mean annual incidence of esophageal cancer in this condition is approximately 1 percent. 83

47 However, this estimate may be influenced by publication bias among studies reporting the incidence of cancer in Barrett's esophagus. 84 An annual incidence of approximately 0.5 percent may be more accurate after adjusting for this effect. The risk of developing esophageal cancer is increased at least 30-fold above that of the general population. Despite the increased incidence, esophageal cancer appears to be an uncommon cause of death in patients with Barrett's esophagus.85 Two groups of investigators have found that the actuarial survival of patients with endoscopically obvious Barrett's esophagus (whose mean ages were greater than 55 years) did not differ significantly from that of age- and sexmatched control subjects in the general population. Many of these older patients succumbed to other diseases before developing adenocarcinoma in their Barrett's esophagus. However, these studies did not account for the more likely adverse effect on survival in younger patients with Barrett's esophagus. Furthermore, the context of surveillance should be considered in light of the unexplained dramatic rise in the incidence of esophageal adenocarcinoma during the past two decades. The issue of surveillance is further complicated by the many variables that are involved in deciding upon a benefit. Examples include the incidence of dysplasia or esophageal carcinoma in Barrett's esophagus (which has varied from 0.2 to 2 percent in different reports), the decrement in quality of life and risk of the procedure in patients who are subjected to the worry and bother of endoscopic surveillance, the risk of surgery, and the quality of life after surgery. These and many other variables were analyzed in a decision analysis that found the benefit of surveillance for high-grade dysplasia depended

48 most upon the incidence of esophageal adenocarcinoma in the population under evaluation.80

Evidence supporting surveillance

Observational studies and computer models suggest that in patients with Barrett's esophagus who are undergoing surveillance, cancer is detected at earlier stages and there may be increased survival. 86-87 Improved quality-adjusted life expectancy with surveillance occurs in patients in whom the risk of cancer exceeds 0.2 percent.80 In one observational study, the clinical characteristics of 19 patients with adenocarcinoma of the esophagus who had undergone endoscopic surveillance were compared to the characteristics in 58 patients with adenocarcinoma in whom the diagnosis was based upon clinical features of the disease.88 Patients who had undergone surveillance were more likely to have stage 0 or I disease (58 versus 17 percent), less likely to have stage III disease (21 versus 47 percent), and had a higher five-year actuarial survival (62 versus 20 percent). In a subsequent report, the investigators concluded that the costeffectiveness of endoscopic surveillance in Barrett's esophagus was comparable to mammography.86 These studies are not definitive, however, because they suffer from a number of biases that might inflate the value of surveillance programs such as healthy volunteer bias, lead-time bias, and length-time bias.

COST-EFFECTIVENESS
Several cost-effectiveness analyses regarding surveillance in Barrett's esophagus have been published.88-90 However, it is important to emphasize the limitations of these estimates, which have been based upon computer models

49 that incorporate multiple layers of uncertain estimates and questionable assumptions. Nevertheless, considered together they suggest that the cost of surveillance is in the same range as other surveillance and screening interventions that society has considered to be cost-effective (eg, screening mammography). The variable results from these reports can be illustrated by the following examples: A study from the United Kingdom estimated that the cost of detecting one case of cancer in Barrett's esophagus with endoscopic surveillance was much higher among women than men ($65,000 versus $23,000)]. A similar study from the United States estimated the cost to be $38,000, an amount lower than the cost of surveillance mammography ($55,000 for each cancer detected). 86 A decision-analysis examining screening in patients with reflux concluded that one-time screening for Barrett's was cost-effective (considering a 50-year-old man as the base case).91

DYSPLASIA AS A MARKER OF RISK

There is general agreement that the development of adenocarcinoma in patients with Barrett's esophagus is preceded by low- and then high-grade dysplasia. However, two factors remain less clear: The risk of developing high-grade dysplasia, particularly in patients who are being treated with acid suppression or who have undergone acid reflux surgery The risk and the rate at which high-grade dysplasia will develop into adenocarcinoma

50 These uncertainties have direct bearing on the benefit of endoscopic surveillance programs. Further complicating matters is the variable diagnostic accuracy of endoscopic biopsies for dysplasia. The grading of dysplastic changes is subjective and, therefore, vulnerable to considerable disagreement even among experienced pathologists. In addition, sampling variability can lead to false negative results in terms of both dysplasia and cancer, particularly in patients who have a large area of Barrett's mucosa. 82

Natural history of high-grade dysplasia

Endoscopic surveillance programs have the goal of detecting high-grade dysplasia without invasive adenocarcinoma. Esophageal resection is a reasonable option for patients with high-grade dysplasia because of the high risk of concurrent or subsequent cancer. In one study, for example, 7 of 29 patients (24 percent) with high-grade dysplasia progressed to invasive cancer during a follow-up of 2 to 46 months. 92 In another report from a surgical series that included 30 patients with only high-grade dysplasia detected by endoscopy,(43 %) had adenocarcinoma detected on resection specimens. Even endoscopy protocols involving systematic jumbo biopsies may miss concurrent cancers. 93 However, high-grade dysplasia can persist for many years without the development of cancer, and regression of high-grade dysplasia to lesser grades has been observed. One of the largest experiences was reported in a study that focused on 79 veterans with high-grade dysplasia who were followed with an intensive endoscopic surveillance program for a mean of 7.3 years. 94 Four patients developed adenocarcinoma within the first year. Of the remaining 75

51 patients, 12 (16 %) subsequently developed cancer of whom 11 were cured with surgery or ablation therapy. Only one patient died of esophageal cancer 10 years after the initial diagnosis of high-grade dysplasia. A problem with this study is that only one pathologist reviewed the biopsy specimens. 95 As a result, it is possible that the dysplastic changes were "over-read," a hypothesis supported by the extremely high rate of dysplasia detected in the cohort Barrett's patients from which the original 79 patients were drawn. Approximately 80 percent of the 1099 patients that the investigators evaluated developed some degree of dysplasia during the study, a number much higher than in several other series. Thus, the above results need to be confirmed by others. In addition, the results may not apply to younger patients in whom high-grade dysplasia may have a more aggressive course and in whom life-long intensive surveillance may not be desirable. The risk of cancer may also depend upon the extent of the dysplastic changes. In a study of 100 patients, for example, the cumulative cancer incidence at three years was much higher in patients with diffuse compared to focal-high-grade dysplasia (56 versus 14 %). 96 Furthermore, the effectiveness of the intensive surveillance program conducted by these investigators may not be possible in other clinical settings. Thus, the debate concerning optimal management of patients with high-grade dysplasia is unsettled.

ALTERNATIVE SURVEILLANCE APPROACHES

Because of the difficulties involved in surveillance programs using endoscopic biopsies for dysplasia discussed above, several new biologic markers and techniques for detecting dysplasia continue to be evaluated.

52

ENDOSCOPIC TECHNIQUES TO DETECT DYSPLASIA

Several endoscopic techniques that could augment the ability to detect dysplasia have been evaluated. endoscopic These include Chromoendoscopy, coherence magnification and

endoscopy,

ultrasound,

optical

tomography,

fluorescence detection techniques.

CHROMOENDOSCOPY
Chromoendoscopy involves the application of vital dyes that enhance the visibility of dysplastic mucosa. Vital dyes that have been studied include those that preferentially stain normal squamous mucosa (such as Lugol's iodine), those that preferentially stain intestinal metaplasia (such as toluidine blue and methylene blue) and those that highlight mucosal features (such as indigo carmine). The value of staining with methylene blue was questioned in one report in which it prolonged endoscopy, increased patient discomfort, and did not appear to be highly sensitive or specific for intestinal metaplasia. 97 The benefit of methylene blue staining for the diagnosis of short segment Barrett's esophagus is controversial.98

MAGNIFICATION ENDOSCOPY
Endoscopy using a magnifying endoscope combined with tissue staining has been used to identify the villous appearance of intestinal metaplasia.

ENDOSCOPIC ULTRASOUND
The application of an endoscopic ultrasound (EUS) transducer directly to the wall of the esophagus produces detailed images of the wall of the esophagus. Dysplastic areas may produce an area of thickening. However, pilot studies

53 evaluating this approach have been disappointing. On the other hand, EUS may be useful for determining treatment options in patients with confirmed high-grade dysplasia or intramucosal carcinoma.99

OPTICAL COHERENCE TOMOGRAPHY

Optical coherence tomography is a radiographic technique that produces high resolution, cross-sectional images of the esophageal mucosa. Its resolution is approximately 10 times better than endoscopic ultrasound,but its role in the evaluation of patients with Barrett's esophagus has yet to be determined. 100

FLUORESCENCE ENDOSCOPY
Fluorescence endoscopy takes advantage of the variable amounts of endogenous fluorophores (such as NADPH and porphyrins) that can absorb laser light and emit fluorescent light that have wavelengths detectable by fluorescence spectroscopy. A pilot study evaluating this technique in 36 patients with Barrett's esophagus found good correlation between fluorescence findings and high-grade dysplasia but not low-grade dysplasia on histologic

examination.101 Another study suggested that fluoresence endoscopy may provide an increased detection rate of high-grade dysplasia in patients with shortsegment Barrett's esophagus.102 The administration of exogenous fluorophores (such as 5-aminolevulinic acid) to augment this approach is also under investigation.103

BIOMARKERS

54 Several biomarkers for stratifying the risk of malignancy in Barrett's esophagus have been studied.104 None has been shown to provide sufficient additional information to justify their routine application in clinical practice.

p53 ABNORMALITIES
Deletion or mutation of the tumor suppressor gene p53 (located on chromosome 17p) has been associated with a number of human malignancies including the majority of cancers associated with Barrett's esophagus. 104,105 In addition, p53 abnormalities correlate with the histologic severity of dysplasia in patients with Barrett's esophagus without adenocarcinoma.106 Serum antibodies against p53 can be found in patients with Barrett's esophagus or esophageal carcinoma, potentially providing a biomarker that can be obtained without endoscopy; however, the sensitivity of this finding is quite low. 107

DNA ABNORMALITIES
An abnormal number of chromosomes (such as aneuploidy or tetraploidy) is present in many types of human cancers. These abnormalities can be detected by flow cytometry. Flow cytometry involves the treatment of cell nuclei with a fluorescent dye, which can be detected by a flow cytometer after laser irradiation. Abnormalities in flow cytometry are a marker of histologic progression in Barrett's esophagus. In one study, for example, abnormal flow cytometry was detected in 13 of 62 (21 percent) patients with Barrett's esophagus, of whom nine developed high-grade dysplasia during a mean follow-up of 34 months. 108

55

OBJECTIVE OF STUDY
The objective of the study is: To determine frequency of Barrets oesophagus in patients with symptoms of gastroesophageal reflux presenting to outpatient department of Military Hospital Rawalpindi

56

OPERATIONAL DEFINITION

ADULT

All patients equal or more than 18 years of age.

GERD
Due to the broad spectrum of symptoms attributable to reflux, there is little agreement as to what constitutes typical reflux disease. In general terms, GERD is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. The distinction between normal and GERD is blurred because some degree of reflux is physiologic.

BARRETS ESOPHAGUS
Barrett's esophagus is an acquired condition characterized by a progressive columnar metaplasia of the distal esophagus in response to continued change in environment (acid pepsin) caused by longstanding gastroesophageal reflux and reflux esophagitis.

57

MATERIAL AND METHODS

a) SETTING
Department of Gastroenterology Military Hospital, Rawalpindi.

b) DURATION
Study was conducted from 1st Jan 2005 to 19th May 2005

C) SAMPLE SIZE
A total of 150 patients with symptoms of Gastroesophageal study. reflux were included in the

d) SAMPLING TECHNIQUE
Non-probability convenience sampling.

e) SAMPLE SELECTION INCLUSION CRITERIA

Patients with symptoms of Heart burn Retrosternal burning Water brash

58 Globus sensation Chest pain Regurgitation Adults>18(both males and females). All patients with symptoms of GERD more than three months duration

EXCLUSION CRITERIA
Diagnosed cases of peptic ulcer disease Patients who have used Helicobacter pylori eradication therapy HbsAg and Anti-HCV positive cases Patients on long term NSAID therapy patients of hiatus hernia patients of esophageal stricture

g)

STUDY DESIGN
Descriptive analytical study.

h)

DATA COLLECTION PROCEDURE

The data was collected from adult patients of all ages with symptoms of Gastroesophageal reflux like that of heart burn, retrosternal burning, water

59 brash, globus sensation, chest pain, regurgitation. Adults>18 years. All patients with symptoms of Gastroesophageal reflux more than three months. Following patients were excluded who were Diagnosed cases of peptic ulcer disease,

patients who have used Helicobacter Pylori eradication therapy, HBsAg and Anti HCV

positive cases, patients on long term therapy, patients of hiatus hernia and patients of

esophageal stricture

presenting to out patient

department of Military Hospital Rawalpindi and all information was recorded. Necessary clinical examination was performed on all patients. Upper gastrointestinal endoscopy was performed on all patients with Pentax EG 2940. Patients were instructed to fast for 12 hours on day of endoscopy. IV line secured with 18G cannula & 5% dextrose saline .Local anaesthesia with 4% lignocaine spray & iv diazepam 5mg diluted in 10 cc water over 10 min. Three biopsies were taken and samples were be dispatched in 10% formaline for histopathology. Sections were

stained with H&E and special mucin stains.

60 Patients were disposed off as per clinical condition. There was no further follow up.

i)

DATA ANALYSIS
The data was entered into SPSS version 10.0. Descriptive statistics including frequencies and proportion were computed for qualitative variables like gender, age group, endoscopic findings, histopathological findings. Means+/_ standard

deviation will be computed for quantitative variable like age.

RESULTS Out of 150 patients 112(74.7% ) were males and 38(25.3% ) were females. Male to Female ratio was 2.9:1(Table II). All the patients tolerated the procedure well and there were no complications. The age of patients with symptoms of

Gastroesophageal reflux ranged from 18 to 86 years, mean age was 42+/_ 13.67(Fig I).

61 Out of 150 cases studied, 21(14%) were found to have Barretts esophagus on endoscopy. This was confirmed on microscopy. The remaining 129(86%) cases showed low and high grade inflammatory changes(Table I). Out of 21(14%) cases of Barrets Esophagus 19(90.5%) were Males and 2(9.5%) were Females. Male to female ratio was 9.5:1(Table IV). Maximum no of cases were males 15( 78.9%) in the range of 18 to 38 years (Table V). In patients other than Barrets esophagus various forms of gastritis like Pangastritis 22%, Antral gastritis 19.3%, Mild Antral gastritis 14%, Esophagitis 5% and normal cases 1.3% were found. 9(42.9%) out of 21 cases of Barretts esophagus had symptoms of gastroesophageal reflux in the range of 1-5 years and similar number were observed in the range of 6-10 years.14.3% had symptoms for more than 10 years.

62

63

TABLE I FREQUENCY OF ENDOSCOPIC FINDINGS AMONG STUDY POPULATION (n=150)

Endoscopy Findings Negative Positive

Frequency 129 21

Percent (%) 86.0 14.0

Positive = Barrets Esophagus Negative= Other findings

64

TABLE II MALE AND FEMALE FREQUENCY AMONG STUDY POPULATION (n=150)

Gender male female

Frequency 112 38

Percent (%) 74.7 25.3

TABLE III

65

STATISTICS OF AGE(YEARS)

Mean Median Mode Std. Deviation

41.58 36.00 32 13.67

FIG -I

66

40 37

30

31

No. Of Patients

20 19

10

12 10 8 5 5 25 30 35 40 45 50 55 60 9 6 4 65 70 2 75 80 85 Std. Dev = 13.67 Mean = 42 N = 150.00

0 20

Age in Years

AGE DISTRIBUTION OF THE STUDY POPULATION n=150

TABLE IV

GENDER DISTRIBUTION OF PATIENTS WITH BARRETS ESOPHAGUS

67

Endoscopic Findings Negative

GENDER Male 93 72.1% 19 90.5% Female 36 27.9% 2 9.5%

TOTAL

129

Positive

21

Positive = Barrets Esophagus Negative= Other findings

TABLE V

ENDOSCOPIC FINDINGS WITH AGE AND GENDERS

GENDER

AGE_INT

Endoscopic Findings Negative Positive 15 78.9%

Male

18 - 38

48 51.6%

68 30 32.3% 14 15.1% 1 1.1% 17 47.2% 15 41.7% 4 11.1% 1 5.3% 3 15.8% 1 50.0% 1 50.0% -

39 - 59 60 - 80 > 80 18 - 38 Female 39 - 59 60 - 80

Positive = Barrets Esophagus Negative= Other findings

TABLE VI

DURATION OF SYMPTOMS OF GASTROESOPHAGEAL REFLUX IN PATIENTS WITH BARRETS ESOPHAGUS

Duration of symptoms in years

Endoscopic Findings Negative Positive 9 42.9%

"<1 "

80 62.0% 49 38.0%

"1 - 5 "

69 Total 129 9 42.9% 3 14.3% 21

"6 - 10" " > 10"

Positive = Barrets Esophagus Negative= Other findings

DISCUSSION
Barretts Esophagus is pathologic condition in which the normal squamous epithelium of the distal esophagus is replaced by columnar epithelium.1 It is believed by most investigators to be an acquired condition secondary to chronic Gastroesophageal reflux. In a study done in Pakistan in Oct 2003 at Jinnah Postgraduate Medical Center Karachi the observed frequency rate of Barretts esophagus was 32 % which is higher than reported in other studies (0.45 % to 12.4 %). The mean age of patients with barretts esophagus in the study was 41.3 years. Male to female ratio was 5.4:1 In patients with barretts esophagus which is in accordance with other studies. 109 As compared to above mentioned study observed frequency rate of barretts esophagus in our study was 14 % slightly higher than other studies.6 The reason could be intake of spicy meals in our population resulting in gastroesophageal reflux as indicated in above mentioned

70 study. Mean age of patients is 42 which is in accordance with study done in Pakistan.109 Male to Female ratio is 9.5:1 which is higher as compared with other studies.1 Patients with Gastroesophageal reflux may develop reflux esophagitis as the esophagus repeatedly is exposed to acidic gastric contents. Over time, untreated reflux esophagitis may lead to chronic complications such as esophageal stricture or the development of Barrett's esophagus. 9(42.9%) out of 21 cases of Barretts esophagus had symptoms of gastroesophageal reflux in the range of 1-5 years and similar number were observed in the range of 6-10 years.14.3% had symptoms for more than 10 years, which is almost in accordance with above mentioned study done in Pakistan showing 37.5% symptoms in the range of 5-10 years. 109 Patients having chronic

history of symptoms of gastroesophageal reflux are prone to develop Barrets esophagus as the studies have already shown. This could be related to the dietary habits of our population. Our population takes high amount of fats and spicy food resulting in gastroesophagel reflux. The lower frequency of Barretts in western developed countries may be the frequent use of diagnostic upper GI endoscopy in patients with symptoms of reflux, thus patients with esophagitis are screened out and treated. In our country diagnostic upper GI endoscopy is not routinely used. It is only performed when the symptoms are of severe

71 intensity and are refractory to treatment. Thus patients when undergo endoscopy Barrett;s esophagus has already developed. In the present study adenocarcinoma was not seen in any case with barretts esophagus. The frequency of adenocarcinoma in barretts esophagus reported in literature ranges from 0-37.5%. 42 The reliability of endoscopy for detection of Barrett's esophagus is approximately 80 percent. This was illustrated in a study that included 116 patients who were involved in a Veterans Administration Cooperative Study that required two endoscopies six weeks apart. 13 Barrett's esophagus was found in only one of the two endoscopies in 20 percent of patients. Gastroesophageal reflux disease associated with Barrett's esophagus frequently is complicated by esophageal ulceration, stricture, and hemorrhage. Some studies have suggested that patients with a peptic stricture have a higher prevalence of Barrett's esophagus than those without strictures. This relationship is not surprising since both peptic stricture and Barrett's esophagus are associated with more severe gastroesophageal reflux disease. However, this association has been challenged in study of patients referred for endoscopy for

gastroesophageal reflux

in whom the prevalence of intestinal

metaplasia was the same with or without strictures . 13

72 In our study Barrets Esophagus is common as compared to western countries but complications of Barrets Esophagus like esophageal ulceration, stricture, and hemorrhage are not common.

CONCLUSION

73 From our study we conclude that Barrets oesophagus is slightly more common in our population as compared to western countries. Frequency of complications like stricture, dysplasia, ulcer, and adenocarcinoma are less. It is recommended that routine endoscopy and biopsy be done in patients with chronic symptoms of GERD. Periodic endoscopic examination & biopsy should be done in patients with Barrets esophagus for early detection of any complications. Further studies are recommended in our population to know aetiological factors and malignant outcome of Barrets Esophagus.

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PROFORMA

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FREQUENCY OF BARRETS OESOPHAGUS IN PATIENTS WITH SYMPTOMPS OF GASTROESOPHAGEAL REFLUX PRESENTING TO OUTPATIENT DEPARTMENT OF MH RAWALPINDI,

I.D._________________

Date________________

Name__________________ Age____________________ Sex___________________ Presenting complaints Pain And Discomfort Bloating Fullness Nausea Anorexia Heartburn Regurgitation Belching

Upper GI endoscopy findings Histopathology findings