fina dissertation barret oesophagus.doc
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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
percent of time that esophageal pH was
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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
time (ie,
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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