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    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.

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    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

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    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

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    endoscopic surveillance to detect early curable disease3 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

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    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.8Due 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

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    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.

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    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.

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    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

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    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

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    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

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    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

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    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 "columnar-

    lined 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

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    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.

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    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

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    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.

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    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

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    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

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    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

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    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 contrast-

    filled 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

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    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 (

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    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

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    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

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    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.

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    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

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    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

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    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

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    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

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    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

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    mucosa of the gastric cardia, which stains predominantly for cytokeratin.43 The

    utility of cytokeratin staining as a clinical tool remains unclear. 44Also 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.

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    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 excessivegastroesophageal 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

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    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.

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    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

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    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

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    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 meta-

    analysis 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

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    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

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    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

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    metronidazole), and HIV protease inhibitors, which inhibit the cytochrome P-

    4503A4 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

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    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

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    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

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    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 long-

    term treatment with PPIs.68

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    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 acid-

    suppressive 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

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    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 step-

    down 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

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    medical therapy should undergo endoscopy to rule out Barrett's esophagus.

    Antireflux surgery is also an option62 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

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    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 sex-

    matched 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

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    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 cost-

    effectiveness 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

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    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

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    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

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    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.

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    ENDOSCOPIC TECHNIQUES TO DETECT DYSPLASIA

    Several endoscopic techniques that could augment the ability to detect dysplasia

    have been evaluated. These include Chromoendoscopy, magnification

    endoscopy, endoscopic ultrasound, optical coherence tomography, and

    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

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    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 short-

    segment Barrett's esophagus.102 The administration of exogenous fluorophores

    (such as 5-aminolevulinic acid) to augment this approach is also under

    investigation.103

    BIOMARKERS

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    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

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    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

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    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.

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    MATERIAL