16 Gastroesophageal Reflux Disease & Its
ComplicationsCurrent Diagnosis & Treatment in
Gastroenterology
Gastroesophageal Reflux Disease & Its Complications16
Stuart Jon Spechler, MDPathophysiology of Gastroesophageal
Reflux DiseaseGeneral ConsiderationsClinical
FindingsTreatmentComplications
Chapter ReferencesThe reflux of material from the stomach into
the esophagus does not invariably result in disease. Indeed, normal
individuals daily experience brief, asymptomatic episodes of
gastroesophageal reflux that cause no esophageal injury. When the
reflux of gastric material into the esophagus causes symptoms,
tissue damage, or both, the resulting condition is called
gastroesophageal reflux disease (GERD). Heartburn and regurgitation
are the symptoms most frequently associated with
GERD.Reflux-induced esophageal injury (reflux esophagitis) is
recognized endoscopically by the presence of erosions and
ulcerations in the squamous epithelium of the esophagus. Reflux
esophagitis can be complicated further by the development of
esophageal strictures and columnar epithelial metaplasia (Barrett's
esophagus). Furthermore, the complications of GERD are not limited
to the esophagus. In some patients, refluxed gastric material
reaches the oropharynx and causes sore throat, burning tongue, and
dental erosion. Aspiration of the refluxed material can cause
laryngitis and pulmonary problems, including cough, bronchitis, and
asthma. Thus, GERD can have protean clinical manifestations.The
development of GERD is a multifactorial process that involves
dysfunction of mechanisms that normally prevent excessive
gastroesophageal reflux and of mechanisms that normally clear the
esophagus rapidly of noxious material.Pathophysiology of
Gastroesophageal Reflux DiseaseA. ANTIREFLUX MECHANISMS
1. Lower esophageal sphincter (LES)Normally, there is a positive
pressure gradient between the abdomen and the thorax that tends to
promote the reflux of material from the stomach into the esophagus.
In the absence of effective antireflux mechanisms, this pressure
differential would result in virtually continuous gastroesophageal
reflux. One of the primary barriers to reflux is the LES, a 1.0- to
3.5-cm segment of specialized circular muscle in the wall of the
distal esophagus that prevents reflux by maintaining a resting
pressure some 1045 mm Hg higher than that of the stomach (Figure
161).
Figure 161. Lower esophageal sphincter anatomy. The esophagus
passes into the abdomen through the esophageal hiatus, an opening
in the right crus of the diaphragm. The distal few centimeters of
circular muscle in the esophagus comprise the lower esophageal
sphincter. (Reproduced, with permission, from the Clinical Teaching
Project of the American Gastroenterological Association.)
Although the muscle of the LES cannot be distinguished
morphologically from the muscle of the esophageal body, the LES
exhibits a number of distinctive functional characteristics. Unlike
muscle of the esophageal body, strips of LES muscle develop
spontaneous tension on stretching and relax with transmural
electrical stimulation. Gastroesophageal reflux can result from any
of several types of LES dysfunction, including intrinsic weakness
of the LES muscle that causes feeble resting LES pressure
(hypotonic LES), inadequate LES response to increased abdominal
pressure, and transient episodes of LES relaxation (Figure
162).
Figure 162. Schematic representation of three different lower
esophageal sphincter mechanisms for gastroesophageal reflux. Acid
reflux (a drop in esophageal pH below 4) is represented by vertical
lines. A: Acid reflux associated with a transient lower esophageal
sphincter relaxation. B: Acid reflux during an inadequate lower
esophageal sphincter response to increased intraabdominal pressure
(note that the rise in lower esophageal sphincter pressure is not
as great as the rise in gastric pressure). C: Acid reflux in a
patient with feeble resting lower esophageal sphincter pressure.
(Reproduced, with permission, from Dodds WJ et al: Mechanisms of
gastroesophageal reflux in patients with reflux esophagitis. N Engl
J Med 1982;307:1547.)
When the resting pressure in the LES remains at or near zero
(feeble resting LES pressure), the sphincter does not pose an
effective barrier to reflux (Figure 162C). Normal individuals
uncommonly exhibit such feeble resting LES pressures, and few
episodes of gastroesophageal reflux in normal subjects are
associated with this phenomenon. In patients who have severe GERD,
however, approximately 25% of all episodes of acid reflux are
associated with feeble resting LES pressure.LES pressure rises
rapidly with the sudden abdominal pressure elevations that occur
during coughing, sneezing, or straining. Some patients,
particularly those who exhibit feeble resting LES pressure, may
have an inadequate LES response to increased abdominal pressure. If
sudden increases in abdominal pressure are not accompanied by a
commensurate rise in LES pressure, gastric material can be
propelled into the esophagus (Figure 162B). The precise
contribution of this mechanism to GERD is disputed, as is the
contribution of the crural diaphragm to the observed increase in
LES pressure.Transient LES relaxation (TLESR) appears to be the
most important LES mechanism for reflux (Figure 162A). During
primary peristalsis (peristalsis induced by swallowing), the LES
normally relaxes for 310 seconds to allow the swallowed bolus to
enter the stomach. TLESRs, in contrast, are not preceded by a
normal peristaltic sequence and last for up to 45 seconds. When LES
pressure falls to zero during a TLESR, the sphincter does not
function as an antireflux barrier. This phenomenon explains how
patients with apparently normal resting LES pressures can
experience frequent episodes of reflux.The TLESR is part of the
normal belch reflex that is triggered by gaseous distention of the
stomach. In this situation, the TLESR allows gas to escape from the
gastric fundus. The nucleus tractus solitarius in the medulla is
involved in the reflex, both in integrating sensory information
from the stomach and in controlling the neural circuits that
trigger the TLESR. Medullary neurons with g-aminobutyric acid B
(GABAB) receptors appear to inhibit TLESRs. Cholinergic blockade
with atropine also inhibits TLESRs through a central mechanism. The
sphincter relaxation that characterizes a TLESR is mediated by the
activation of cholecystokinin-A receptors in LES muscle. Brief
episodes of gastroesophageal reflux occur daily in normal
individuals, and the vast majority of these episodes are the result
of TLESRs. In patients with severe GERD, approximately 70% of
reflux episodes are the result of TLESRs. TLESRs occur
approximately two to six times per hour in normal subjects and
three to eight times per hour in patients with GERD. Approximately
4050% of TLESRs in normal subjects are accompanied by acid reflux,
whereas acid reflux is observed in 6070% of TLESRs in patients with
GERD.2. Crural diaphragmThe esophagus passes from the thorax into
the abdomen through an opening in the right crus of the diaphragm
called the esophageal hiatus (see Figure 161). When the crural
diaphragm contracts, as occurs during inspiration, the crurae come
together and pinch the distal esophagus. This pinching effect
appears to function as an important barrier to reflux during
inspiration and during other activities that increase
intraabdominal pressure. In this fashion, the crural diaphragm
serves as an external esophageal sphincter that buttresses the
antireflux function of the LES. As evidence of the efficacy of this
external sphincter mechanism, studies in dogs have shown that
gastroesophageal reflux does not occur during transient LES
relaxation unless the relaxation is attended by inhibition of the
crural diaphragm. Furthermore, transient LES relaxation with
inhibition of the crural diaphragm in dogs often is associated with
contraction of the costal diaphragm that further promotes reflux. A
similar sequence of events is seen in humans during belching,
suggesting that gastroesophageal reflux during transient LES
relaxation may occur through a variant of the belch reflex.3.
Anatomic featuresIn addition to the LES and the crural diaphragm,
certain other anatomic features of the distal esophagus may
contribute to the antireflux barrier (see Figure 161). For example,
the acute angle formed by the junction of esophagus and stomach
(the angle of His) may result in a one-way flap valve that prevents
reflux. Also, a segment of the distal esophagus ordinarily is
located within the abdomen where the segment is subject to external
pressure that tends to force the walls together, thereby preventing
reflux.4. Effects of hiatal hernia on the antireflux barrierMost
patients with severe GERD have a sliding hiatal hernia in which
both the esophagogastric junction and a portion of the gastric
fundus protrude through the hiatus in the crural diaphragm into the
chest. The susceptibility to gastroesophageal reflux induced by
abrupt elevations of intraabdominal pressure has been found to
correlate significantly with hiatal hernia size. It has been known
for decades that large hiatal hernias are associated with low LES
pressure, but only recently has the mechanism underlying this
association been elucidated. During a standard esophageal motility
study, esophageal pressures are measured by transducers that are
placed in the lumen of the esophagus. The LES pressure measured
during such a study reflects pressure on the transducer that is
generated by both the LES muscle (intrinsic sphincter) and the
crural diaphragm (extrinsic sphincter). A better term for this
value would be gastroesophageal junction pressure, but the term LES
pressure is conventional. With a large hiatal hernia, the LES
muscle is displaced up into the chest, dissociated from the crural
diaphragm. The intrinsic pressure generated by the sphincter muscle
of the esophagus may be normal, but when separated from the crural
diaphragm that ordinarily contributes to the pressure at the
gastroesophageal junction, the measured LES pressure value appears
to be low. With a large hiatal hernia that dissociates the internal
and external sphincters of the distal esophagus, reflux may occur
during the elevations in abdominal pressure caused by events such
as inspiration, coughing, and straining. In this situation, the
crurae can no longer buttress the LES by pinching the distal
esophagus. Rather, contraction of the crurae creates an
intrathoracic pouch of stomach whose contents are readily available
for reflux. Compared with normal individuals, furthermore, patients
with large hiatal hernias exhibit an increased frequency of TLESRs
induced by gastric distention.All of these mechanisms appear to
contribute to GERD in patients who have large hiatal hernias,
although it is difficult to quantitate that contribution.
Clinicians should appreciate that hiatal hernia is not always
associated with GERD, and vice versa. Finally, a study in opossums
has shown that esophageal acid perfusion causes the long axis of
the esophagus to shorten, an effect that could promote the
development of a sliding hiatal hernia. This observation raises the
possibility that hiatal hernia might be an effect rather than a
cause of reflux esophagitis in some cases.B. GASTRIC CONTENTS
Gastroesophageal reflux causes esophageal injury only when the
refluxed material is caustic to the esophageal mucosa. Potentially
caustic agents that can be found in the stomach include acid,
pepsin, bile, and pancreatic enzymes. The dramatic efficacy of
potent inhibitors of gastric acid secretion (eg, proton-pump
inhibitors) in the treatment of GERD emphasizes the importance of
acid and pepsin in the pathogenesis of reflux esophagitis in most
cases. However, refluxed bile or pancreatic secretions might
contribute to esophageal damage for some patients. Using sensitive
radionuclide tests, some investigators have found delayed gastric
emptying in more than 50% of patients with GERD. Delayed gastric
emptying causes gastric distention that can stimulate gastric acid
secretion and trigger transient relaxation of the LES. Both of
these effects can be harmful for patients with GERD.C. ESOPHAGEAL
CLEARANCE MECHANISMS
If caustic material is cleared quickly from the esophagus, no
damage may result. Normally, the esophagus is cleared of acid by
four important mechanisms: (1) gravity, (2) peristalsis, (3)
salivation, and (4) intrinsic esophageal bicarbonate production.
When a bolus of acid enters the esophagus, most of the material is
cleared by the combined effects of gravity and peristalsis. The
small quantity of residual acidic material that escapes clearance
by gravity and peristalsis might cause mucosal damage if it were
not neutralized by swallowed saliva, which is highly alkaline, and
by bicarbonate produced by the esophageal mucosa itself. GERD can
be associated with conditions that impair esophageal clearance. For
example, the severe reflux esophagitis that occurs in patients with
scleroderma often is associated with disordered peristalsis that
delays esophageal clearance. Reflux that occurs during sleep can be
particularly damaging to the esophagus for several reasons relating
to esophageal clearance. In recumbency during sleep, gravity
retards the clearance of refluxed material. Swallowing and
salivation virtually cease during sleep and, therefore, there is no
primary peristalsis and little saliva available to clear acid from
the esophagus. Cigarette smoking has been shown to increase
esophageal acid exposure by increasing the frequency of acid reflux
events and, perhaps, by decreasing salivary flow. Finally, hiatal
hernia has been shown to interfere with esophageal clearance.D.
ESOPHAGEAL EPITHELIAL RESISTANCE
Epithelial protective factors enable the esophagus to resist
peptic injury (Figure 163). Ambulatory esophageal pH monitoring
studies have shown that normal individuals experience brief
episodes of acid reflux daily. Apparently, the normal epithelial
defenses are sufficient to prevent these brief episodes from
causing esophagitis. Most patients with reflux esophagitis have an
abnormally prolonged duration of esophageal acid exposure that
overwhelms the normal epithelial defenses (Figure 164). However,
some patients have reflux esophagitis even though 24-hour pH
monitoring studies demonstrate a normal daily duration of acid
reflux. These patients may have yet uncharacterized defects in
their epithelial protective factors.
Figure 163. Preepithelial defenses. The esophageal preepithelial
defenses against acid include the surface layer of mucus, unstirred
water layer, and bicarbonate ions. [Reproduced, with permission,
from Orlando RC: Esophageal epithelial defense against acid injury.
J Clin Gastroenterol 1991;13(Suppl 2):S1.]
Figure 164. Epithelial defenses. The epithelial cell membranes,
the intercellular junction complexes, and lipids and mucins (L/M)
in the intercellular spaces all limit the penetration of H+ ions.
Once within the cell, H+ ions are buffered by intracellular
proteins and bicarbonate. The H+ ions also can be extruded by a
Na+/H+ exchange mechanism. [Reproduced, with permission, from
Orlando RC: Gastroesophageal Reflux Disease: Pathogenesis,
Diagnosis, Therapy. Castell DO, Wu WC, Ott DJ (editors). Futura
Publishing, 1985.]
E. NSAIDS AND GERD
Epidemiologic studies suggest that the ingestion of aspirin and
other nonsteroidal antiinflammatory drugs (NSAIDs) can contribute
to GERD. Patients with esophageal strictures appear to be
especially susceptible to NSAID-induced esophageal injury. Many
NSAID preparations are caustic to the mucosa, and severe local
injury can result when a stricture impedes passage of the NSAID
tablet into the stomach. Esophageal strictures themselves may be
the result of NSAID-induced injury. For patients without
strictures, the mechanisms whereby NSAIDs contribute to GERD are
not clear. F. HELICOBACTER PYLORI AND GERD
Helicobacter pylori are microaerophilic, gram-negative bacteria
that are uniquely adapted for survival in the human stomach. More
than 50% of the world's population is infected with H pylori. The
infection causes a chronic gastritis that is associated with the
development of intestinal metaplasia and cancer in the stomach. H
pylori does not infect the esophagus. However, recent data suggest
that gastric H pylori infection may protect the esophagus from GERD
and its complications, perhaps by decreasing gastric acidity. There
are reports of GERD developing after the eradication of H pylori.
It has even been proposed that the declining frequency of H pylori
infection in Western countries may underlie the rising frequency of
adenocarcinoma in Barrett's esophagus (see below). Presently, the
role of H pylori infection in the pathogenesis of GERD and its
complications is controversial.
ESSENTIALS OF DIAGNOSIS
Heartburn and/or regurgitation.Esophagitis (eg, erosions,
ulcerations).
General ConsiderationsGERD can be defined as any symptomatic
condition or anatomic alteration caused by the reflux of noxious
material from the stomach into the esophagus. It is important to
appreciate that by this definition, patients with GERD can have
symptoms without objective evidence of esophagitis. The finding of
reflux esophagitis on endoscopic examination confirms the diagnosis
of GERD, but a normal esophagoscopy does not rule out GERD as a
cause of symptoms.Clinical FindingsA. SYMPTOMS AND SIGNS
Heartburn, the cardinal symptom of GERD, is an uncomfortable,
hot or burning sensation located beneath the sternum. The sensation
frequently originates in the epigastrium and radiates up the chest,
sometimes into the throat or back. When describing heartburn,
patients often wave their open hand vertically over the sternum, in
contrast to patients with angina pectoris due to cardiac ischemia
who typically hold their clenched fist stationary over the chest
while describing their pain. If refluxed gastric material reaches
the oropharynx, the patient may experience the symptom of
regurgitation wherein sour or bitter-tasting material appears in
the mouth. Patients who have peptic strictures of the esophagus
often complain of dysphagia. Even in the absence of a fixed
stricture, however, dysphagia may be associated with the
esophagitis and motility abnormalities that can accompany GERD.
Odynophagia in patients with GERD suggests the presence of
esophageal ulceration. Some patients describe the symptom of water
brash, in which the mouth suddenly fills with saliva as a result of
reflex salivary secretion stimulated by acid in the
esophagus.Heartburn associated with GERD can be aggravated by the
ingestion of foods that predispose to reflux by decreasing pressure
in the LES. These include chocolate, onions, peppermint, coffee,
and foods that have a high content of fat and sugar. Certain foods
have no affect on the LES but can cause the sensation of heartburn
in patients with GERD by irritating the esophageal mucosa directly.
These include spicy foods, citrus products, and tomato products.
Certain practices that predispose to reflux by increasing
intraabdominal pressure also can precipitate heartburn in
susceptible patients. For example, many patients experience
heartburn when they bend over, lift a heavy object, strain to
defecate, or run.Characteristically, heartburn caused by
gastroesophageal reflux is relieved, if only temporarily, by
antacids. For most patients with GERD, the symptom of heartburn can
be eliminated by the administration of potent acid-suppressing
agents.B. DIAGNOSTIC TESTS
Table 161 lists the diagnostic tests that are commonly used to
evaluate patients with GERD and the clinical questions for which
these tests can supply answers. Note that the barium swallow,
endoscopic examination, and histologic examination of esophageal
biopsy specimens are performed primarily to seek the anatomic
alterations of reflux esophagitis. As previously noted, GERD is any
symptomatic condition or anatomic alteration caused by the reflux
of noxious material from the stomach into the esophagus. Based on
this definition, patients can have GERD without anatomic
alterations. For patients who have a characteristic history, for
example, patients who complain of typical heartburn and
regurgitation that respond readily to treatment with
acid-suppression therapy, diagnostic tests are not necessary merely
to establish the diagnosis of GERD. An endoscopic examination might
be performed in such patients to seek evidence of esophagitis that
could require more aggressive therapy or to look for complications,
such as Barrett's esophagus, that cannot be diagnosed on the basis
of history alone. However, a normal esophagoscopy would not
eliminate acid reflux as the cause of symptoms.
Table 161. Clinical questions and diagnostic tests for
GERD.1
Diagnostic tests may be required for patients with atypical
signs or symptoms or for patients with typical signs and symptoms
that do not respond well to acid suppression. A barium swallow can
reveal signs of esophagitis including thickening of the esophageal
folds, erosions, ulcerations, and strictures; it can also
demonstrate the gastroesophageal reflux of barium. Radiography is
considerably less sensitive than endoscopy for demonstrating
esophagitis, however, and endoscopic examination has the added
advantage that biopsy specimens can be obtained from any abnormal
areas.How often do patients with typical heartburn have endoscopic
evidence of reflux esophagitis? Several studies suggest that
esophagitis is present endoscopically in approximately 5070% of
patients with typical, frequent heartburn. Histologic changes of
esophagitis are found more frequently, with over 90% of patients
exhibiting histologic changes characteristic of GERD. The
histologic changes of reflux esophagitis include lengthening of the
papillae so that they occupy more than two-thirds of the thickness
of the squamous mucosa, hyperplasia of cells in the basal zone so
that this zone occupies more than 15% of the mucosal thickness, and
infiltration of the epithelium with eosinophils and
polymorphonuclear cells. The importance of the histologic changes
of GERD are disputed, however, and most authorities hold that the
endoscopic findings have more clinical relevance.Several studies
suggest that severity of heartburn is not a reliable index of
esophagitis. There appears to be no significant correlation between
the severity of heartburn reported by the patient and the severity
of reflux esophagitis on endoscopic examination. In fact, patients
can have severe esophagitis with no heartburn. The precise
frequency of this situation is not clear, as asymptomatic patients
seldom have endoscopic examinations, but a number of reports have
described patients who had severe ulcerative esophagitis with no
complaints of heartburn. It appears that less than two-thirds of
patients with esophagitis complain of frequent heartburn.Diagnostic
tests may be needed for patients who have atypical chest pains with
features that are suggestive, but not entirely characteristic, of
reflux-induced heartburn. For example, occasionally patients are
encountered who complain of a burning sensation in the lower chest
that does not radiate, that is unaffected by activities, and that
is only partially or unreliably relieved by antacids and
antisecretory drugs. This is not typical heartburn, and it is not
clear that the symptom is triggered by acid reflux even if
endoscopic examination demonstrates esophagitis.The acid perfusion
(Bernstein) test has been used in this situation to support acid
reflux as the cause of symptoms. During this test, the esophagus is
perfused with 0.1 N hydrochloric acid. Reproduction of the
patient's chest pain with acid perfusion implicates GERD as a cause
of the chest pain and suggests a role for antireflux therapy. This
test has limited sensitivity and specificity, however, and has
largely been replaced by ambulatory esophageal pH
monitoring.Ambulatory monitoring of esophageal pH can be used to
document the pattern, frequency, and duration of acid reflux, and
to seek a correlation between reflux episodes and symptoms. In most
ambulatory systems, an episode of acid reflux is defined (somewhat
arbitrarily) as a drop in esophageal pH below 4. Standard 24-hour
pH monitoring records a number of different variables, such as the
total number of reflux episodes, the number of episodes longer than
5 minutes in duration, and the duration of the longest episode.The
single most clinically applicable variable appears to be the total
percentage of the monitoring period that esophageal pH remains
below 4. In normal individuals, esophageal pH remains below 4 for
less than 4.5% of the 24-hour monitoring period. Most patients who
have both endoscopic signs and symptoms of GERD also have abnormal
24-hour esophageal pH monitoring studies, whereas subjects with no
such signs and symptoms usually have normal studies. It is
difficult to determine the precise sensitivity and specificity of
the test, however, because there is no universally accepted gold
standard for the diagnosis of GERD.In theory, protracted esophageal
pH monitoring should be very useful in establishing that acid
reflux is the cause of heartburn in individual patients. In
practice, however, the correlation between discrete episodes of
acid reflux and heartburn is poor. For example, although normal
individuals often experience brief episodes of acid reflux during
the day (particularly after meals), these episodes usually are not
associated with heartburn. Even in patients with heartburn who have
endoscopic evidence of reflux esophagitis, 24-hour esophageal
monitoring reveals that fewer than 20% of episodes of acid reflux
(defined as a drop in pH of less than 4) are accompanied by
heartburn. These observations indicate that most episodes of acid
reflux do not trigger the sensation of heartburn.It is not clear
why only a minority of episodes of acid reflux cause heartburn. It
appears, however, from experimental studies that provocation of
pain is dependent on the pH of the refluxate and the length of time
of acid exposure. The duration of acid perfusion required to
produce pain is a function of the pH of the perfusion solution, ie,
the lower the pH, the shorter the duration of acid perfusion
necessary to produce heartburn. The frequency with which acid
perfusion induces pain also is related to the pH. In one study all
patients experienced heartburn during perfusion with solutions of
pH 1, whereas only 50% of patients experienced pain during
esophageal perfusion with solutions of pH 2.56. Once a subject had
experienced pain with an acid solution, subsequent perfusions of
the same solution caused pain more rapidly than the first
perfusion. During 24-hour pH monitoring, reflux episodes associated
with pain were significantly longer than those without pain, and
often were preceded by another episode of heartburn. These findings
suggest that the reflux of strongly acidic material is more likely
to cause heartburn than weakly acidic material. Furthermore, once
an episode of reflux has caused pain, the esophagus may become
sensitized so that subsequent reflux episodes are more likely to be
painful.TreatmentWhen planning a management strategy for patients
with GERD, it is important to appreciate that the efficacy of any
antireflux therapy is inversely related to the severity of the
underlying reflux esophagitis, ie, the worse the esophagitis, the
poorer the healing rate. A treatment that is highly effective for
patients with mild esophagitis may be virtually useless for
patients with severe disease. This section outlines a stepwise
approach to the therapy of GERD. For patients who are found to have
severe, ulcerative, reflux esophagitis, it may be appropriate to
begin therapy immediately with potent acid suppression (eg, by
administering a proton-pump inhibitor) rather than proceeding
stepwise through trials of agents less likely to effect healing.
Conversely, it may not be appropriate to begin the treatment of
very mild GERD with a proton-pump inhibitor. The official
indications, dosage, and duration of treatment for commonly
prescribed antireflux medications are listed in Table 162.
Table 162. Official indications, dosage, and duration of
treatment for commonly prescribed antireflux medications.1
A. LIFE-STYLE MODIFICATIONS
The management of GERD traditionally begins with life-style
modifications (Table 163) aimed at reducing acid reflux and
minimizing the duration of contact between refluxed material and
the esophageal mucosa. The head of the bed is elevated on 4- to
6-inch blocks to exploit the effect of gravity in clearing the
esophagus of noxious material.
Table 163. Life-style modifications for GERD.
Obese patients are advised to lose weight, with the rationale
that obesity may contribute to reflux by increasing abdominal
pressure; dieting also helps patients avoid fatty foods that
promote reflux. Bedtime snacks can stimulate gastric acid
production and trigger transient LES relaxation. Both of these
effects promote the reflux of gastric acid during sleep, a time
when swallowing and salivation decrease dramatically. With no
swallowing to initiate peristalsis and no saliva to buffer retained
acid, reflux during sleep can be especially damaging.Tobacco and
alcohol consumption should be avoided because these agents may
decrease LES pressure and because cigarette smoking also decreases
salivation. Fatty foods, chocolate, and carminatives (spearmint,
peppermint) contribute to GERD by decreasing LES pressure and by
delaying gastric emptying. Drugs that have anticholinergic effects
(eg, phenothiazines, tricyclic antidepressants), theophylline
preparations, and calcium channel blocking agents can decrease LES
pressure and delay gastric emptying; these medications should be
avoided if possible. NSAIDs can be caustic to the esophageal
mucosa, and these agents also should be avoided.B. H2-RECEPTOR
BLOCKING AGENTS
In some patients who have mild GERD, life-style modifications
alone can be very effective therapy and medications may not be
necessary. For these patients, antacids with or without alginic
acid can be used as necessary for occasional episodes of heartburn.
For patients who remain symptomatic despite the implementation of
life-style modifications, a histamine H2-receptor blocking agent
(cimetidine, famotidine, nizatidine, or ranitidine) often is the
next step. When administered in conventional doses, H2 blockers
relieve symptoms of GERD and heal esophagitis within 12 weeks in
approximately one-half to two-thirds of patients. If relief is not
complete, the dose of the agent can be increased, although many
physicians will proceed to a proton-pump inhibitor if
conventional-dose histamine H2-receptor blocker therapy fails. C.
PROKINETIC AGENTS
Prokinetic agents can decrease gastroesophageal reflux by
increasing LES pressure, and by enhancing gastric and esophageal
emptying. Presently, the only prokinetic agent available for use in
the United States for GERD is metoclopramide, a dopamine antagonist
that can be effective in treating patients who have relatively mild
disease. Metoclopramide increases pressure in the LES, and enhances
gastric emptying by coordinating motor activity in the stomach,
pylorus, and duodenum. The use of this agent often is limited by
its frequent side effects, including agitation, restlessness,
somnolence, and extrapyramidal symptoms, that occur in up to 30% of
patients. D. SUCRALFATE
Sucralfate is an exceptionally safe medication that has been
found to be effective in the treatment of mild reflux esophagitis.
In several studies performed outside of the United States, the
efficacy of sucralfate in relieving symptoms and healing
esophagitis appeared to be similar to that of the H2-receptor
blockers. Sucralfate can be administered either in tablet form or
as a suspension. E. PROTON-PUMP INHIBITORS
The proton-pump inhibitors (PPIs) omeprazole, lansoprazole,
rabeprazole, pantoprazole, and esomeprazole are the most effective
of the available agents for the treatment of GERD. In patients with
mild to moderately severe reflux esophagitis treated with PPIs in
conventional dosages, healing rates of 80100% can be expected
within 812 weeks. Very severe (grade 4) reflux esophagitis may
persist despite conventional-dose PPI therapy in up to 40% of
cases, however. In most such resistant cases, the esophagitis
usually can be healed by increasing the dose of the PPI. Recent
studies also have shown that aggressive acid suppression with PPIs
improves dysphagia and decreases the need for esophageal dilation
in patients who have peptic esophageal strictures. For patients
with severe GERD who respond to PPIs, GERD returns shortly after
stopping the drug in the majority of cases, and maintenance therapy
is required. For most patients, the dose of PPI necessary to
maintain remission is at least the dose required to heal the acute
esophagitis. For patients with severe GERD, furthermore, the PPI
maintenance dose requirement often increases with time. One
long-term study of patients who had severe GERD treated with a
maintenance dose of omeprazole (20 mg/d) found that relapses
occurred frequently (at the rate of 1 per 9.4 treatment-years), and
that patients often required increasing doses of omeprazole (up to
120 mg/d) to maintain GERD in remission.The profound acid
suppression that can be achieved with the use of PPIs has raised
theoretical concerns regarding their long-term safety. Protracted
acid suppression can elevate the serum level of gastrin, a hormone
that has trophic effects on the stomach and colon, and might result
in colonization of the stomach with bacteria that can convert
dietary nitrates to carcinogenic nitrosamines. These effects
conceivably might contribute to the development of gastric and
colonic neoplasms. Furthermore, some data suggest that sustained
acid suppression with PPIs might hasten the development of gastric
atrophy in patients who are infected with H pylori, and that
chronic PPI therapy might interfere with vitamin B12 absorption.
Despite these theoretical concerns, there are no reports of tumors
or nutritional deficiencies clearly attributable to the use of PPIs
after more than a decade of extensive clinical experience with
these agents.F. COMBINATION THERAPY
Most patients treated with PPIs in conventional dosages do not
exhibit complete suppression of gastric acid secretion.
Approximately 70% of individuals who take a PPI twice a day
experience nocturnal gastric acid breakthrough (defined as a
gastric pH 3 cm) above the esophagogastric junction. Although many
gastroenterologists have adopted those investigative criteria into
their clinical practices, diagnostic standards for Barrett's
esophagus that are based on a specified extent of columnar lining
clearly are arbitrary. For example, if 3 cm is selected as the
diagnostic criterion for Barrett's esophagus, then patients who
have 2.5 cm of metaplastic columnar lining (with potential for
neoplastic change) will be ignored. Furthermore, criteria based on
the extent of esophageal columnar lining are subject to the
considerable imprecision of endoscopic measurement.In an attempt to
avoid the diagnostic difficulties described, some investigators
have chosen to define Barrett's esophagus by the presence of
specialized intestinal metaplasia anywhere in the esophagus,
regardless of extent. Even this approach does not eliminate
diagnostic problems. Intestinal metaplasia in the stomach can be
histologically indistinguishable from esophageal intestinal
metaplasia, and inadvertent biopsy of an intestinalized gastric
cardia could result in a false-positive diagnosis of Barrett's
esophagus. Although intestinal metaplasia in the gastric cardia,
like its counterpart in the esophagus, may well predispose to
cancer of the esophagogastric junction, there is an obvious
conceptual problem inherent in calling intestinal metaplasia of the
stomach Barrett's esophagus.Perhaps the major problem in defining
Barrett's esophagus solely by the presence of specialized
intestinal metaplasia relates to the frequency with which short
segments of this epithelium can be found in the region of the
esophagogastric junction. In one recent study, all patients
scheduled for elective endoscopic examinations in a general
endoscopy unit, regardless of the indication for the procedure, had
biopsy specimens obtained at the squamocolumnar junction (the
Z-line) in the distal esophagus irrespective of its appearance and
location. Among 142 patients who had columnar epithelium
involving