Pharmacy Clinic
Gastroesophageal Reflux Disease
Natural History

Many patients with even severe reflux esophagitis may be symptomatic for months or even years before they seek medical help. In one large series
of 200 patients with severe disease, 18% had experienced significant symptoms for less than 1 year and 50% had been symptomatic for less than 3
years, but 24% had endured for more than 10 years.
The frequency of spontaneous remission in gastroesophageal reflux disease (GERD) remains unclear, however. Symptoms of the disease can
improve, even disappear, without treatment.
Furthermore, GERD symptoms may differ in intensity over time, not correlated with the severity of esophagitis.
Studies that look at pharmacologic reduction of gastric acid have demonstrated that the majority of patients with reflux esophagitis remain in
remission as long as therapy is continued. In most patients, however, both symptoms and esophagitis return after treatment is stopped.
Despite its prevalence, chronicity, and propensity for complications, GERD rarely causes death.
In the study of 200 patients with severe esophagitis, for example, those followed for up to 16 years had the same mortality rate as that expected for
a similarly aged group in the general population.


Pathophysiology
Healthy individuals experience, on the average, one to four episodes of gastroesophageal reflux per hour during the first 3 hours after a meal. This
normal physiologic reflux occurs as the lower esophageal sphincter (LES) relaxes in response to swallowing, occuring spontaneously at other times,
and lasts up to 30 seconds.
The development and severity of gastroesophageal reflux disease (GERD) is contingent on the presence of three conditions:
•        Increased frequency of reflux
•        Increased duration of reflux
•        Injurious effects of gastric contents on the esophageal mucosa.
These conditions are created, in turn, by a process in which a variety of factors increase esophageal exposure to injurious gastric contents. One or
more of several abnormalities may predominate in a given patient:
•        Compromised integrity of LES
•        Increased nocturnal reflux
•        Impaired esophageal clearance
•        Increased intra-abdominal pressure
•        Increased intragastric volume, acidity
•        Gastric distention
•        Duodenal-gastric reflux
•        Gastric hypersecretion
•        Injury to the esophageal tissue barrier
•        Hiatal hernia.
Of these many contributory factors, the first, a structurally or functionally compromised LES is responsible in some degree for the development of the
others. The majority of reflux episodes occur during so-called transient relaxations of the LES. With increasing severity of esophagitis, however,
absent basal LES pressure becomes a progressively more common mechanism, accounting for 23% of reflux episodes in patients with severe GERD.
The Role of the Lower Esophageal Sphincter
The LES is a unique band of smooth muscle fibers 2.5 cm to 4.0 cm in length, located partly in the abdomen and partly in the hiatal canal formed by
the right crus of the diaphragm.
The LES, crural diaphragm, and phrenoesophageal ligament, which anchors the distal esophagus to the diaphragm, are the anatomic structures that
comprise the gastroesophageal junction (GEJ), the anatomic barrier to reflux of gastric contents.

The LES normally maintains a resting pressure that is more than 12 mm Hg higher than the intragastric pressure, thus providing a barrier against the
reflux of gastric contents. It relaxes with the peristaltic wave initiated by a pharyngeal swallow before returning to its resting level. Gastric juice that
flows back through the open valve is rapidly cleared back into the stomach by a series of peristaltic contractions
Although gastroesophageal reflux may occur by any of several different mechanisms, the common denominator seems to be low sphincter tone,
accounted for by either persistently low LES resting pressure or a transient LES relaxation.

Transient Lower Esophageal Sphincter Relaxations
Transient LES relaxations (TLESRs), which may be spontaneous and not associated with any detectable motor activity, may follow immediately on
either a normal peristaltic sequence or synchronous contraction in the esophageal body. These apparently normal physiologic events are usually of
longer duration than those associated with normal peristaltic waves and appear to be unrelated to basal LES tone. Only about 35% of TLESRs were
associated with reflux in asymptomatic volunteers as compared to 65% in patients with GERD.
The factors that determine the occurrence of reflux during TLESRs are not completely understood. However, their abrupt onset and brief duration
suggest that they are neurally mediated.
Studies in healthy volunteers have established that TLESRs are a normal response to gastric distention, the probable mechanism underlying the
increase in both TLESRs and reflux episodes after meals. Although the neural pathways involved have yet to be defined, current evidence favors a
vagovagal reflex initiated by stimulation of mechanoreceptors in the gastric wall.

Mechanical Failure of the Lower Esophageal Sphincter
Mechanical dysfunction of the LES may be the result of abnormal pressure or, in a sphincter with normal pressure, of its inadequate length or
position.
Inadequate LES pressure, the most common reason for mechanical failure, is probably caused by defective myogenic function. The sphincter's
intrinsic tone is modulated by neural and hormonal mechanisms. Esophagus and sphincter are innervated by both excitatory and inhibitory fibers
from the vagus nerve, which seems to coordinate sphincter relaxation with esophageal contraction.
Sphincter pressure is increased by some hormones, peptides, and pharmacologic agents, including antacids, and decreased by others, such as
anticholinergics and theophylline. Peppermint, chocolate, coffee, ethanol, and fat are associated with reduced
LES pressure, which may explain esophageal symptoms after a rich meal.
Although a linear correlation between LES resting pressure and reflux has not been found, patients with severe disease often have extremely low LES
resting pressures (< 5 mm Hg).

Lower Esophageal Sphincter Length
A sphincter with normal pressure may also be compromised by either inadequate abdominal length or abnormally short overall resting length.
If the abdominal portion of the LES is too short, it may be unable to maintain resting tone during the increases in intra-abdominal pressure that
occur with daily activities or changes in body position. When the overall resting length is inadequate, increases in gastric pressure caused by
increased gastric volume or outlet obstruction may overwhelm the sphincter and cause reflux.
Persons with such short sphincters are also vulnerable to postprandial reflux since normal dilatation of the stomach secondary to eating further
shortens the already compromised LES.

Nocturnal Reflux
Although nocturnal reflux has been considered a significant factor in the pathogenesis of GERD, 24-hour pH studies have shown that the majority of
patients with either mild erosive esophagitis or no endoscopic abnormality experience most reflux during the daytime postprandial periods.
The progressively greater acid exposure associated with more severe esophagitis is predominantly due to an increase in nocturnal reflux. The
longest period of unbuffered basal gastric output occurs at night. This is due to both impaired clearance of acid from the esophagus and reduced
neutralization by salivary bicarbonate.
Sleep reduces both salivation and esophageal motility.

Esophageal Clearance
Effective clearance of refluxed gastric contents from the esophagus is a two-step process. Most of the refluxed gastric juice that gains entry through
physiologic TLESRs is cleared from the esophagus by a primary peristaltic wave initiated by a pharyngeal swallow. The small amount of residual acid
is neutralized by the bicarbonate in swallowed saliva.

Inadequate or delayed clearance, which results in prolonged esophageal exposure to gastric juice, is influenced by four major factors:
•        Defective esophageal motor activity
•        Reduced salivation
•        Absence of gravity's positive effects
•        Loss of distal esophagus' intra-abdominal anchorage (hiatal hernia).


Defective Esophageal Motor Activity
An estimated 48% of GERD patients with symptomatic esophagitis have esophageal peristaltic dysfunction. A long-standing question has been
whether this dysmotility precedes or is the result of reflux. Although there is no definitive answer, evidence indicates that acid perfusion can induce a
variety of esophageal motor abnormalities.
In a recent large study, for example, Crozier and colleagues found that in 90 of 275 patients (33%) with noncardiac chest pain and normal baseline
manometry, their chest pain could be reproduced along with motor abnormalities (increased amplitude, increased duration, and simultaneous or
spontaneous contractions) by acid perfusion.
On the other hand, a number of studies have found no evidence that healing of esophagitis improves defective LES or esophageal body function,
suggesting that the motor abnormalities precede the inflammation, or that the change is irreversible.

Reduced Salivation
Depression of salivation provides less buffer to neutralize the microdroplets of acid that remain in the esophagus after a normal peristaltic
contraction. Salivary gland output may be compromised by:
•        Smoking
•        Radiotherapy
•        Anticholinergic medications
•        Age
•        Sjögren's syndrome.
A drop in esophageal pH consequent to the reduction of salivary flow may initiate secondary peristaltic waves. However, ambulatory motility studies
indicate that these secondary waves have little effect on esophageal clearance. Their abnormal patterns actually reduce the efficiency of clearance
and encourage regurgitation of refluxed material into the pharynx, predisposing the patient to aspiration.
Saliva production may increase in response to acid in the lower esophagus, resulting in hypersalivation, or "water brash," in some patients with
severe reflux.
Effect of Gravity
During sleep, without gravity's benefit, clearance is delayed. Normal physiologic reflux may be further compromised by peristaltic dysfunction or
reduced salivary flow.

Loss of Intra-Abdominal Anchorage
The close anatomical relationship of the structures that comprise the GEJ suggests an active role for the diaphragm in LES pressure and, in turn,
prevention of reflux.
Some play in the intact phrenoesophageal ligament allows the distal esophagus to slide in and out of the diaphragmatic hiatus during esophageal
peristalsis and LES relaxation.
In the presence of a hiatal hernia that does not reduce between swallows, however, esophageal clearance may be impaired during dynamic stresses
such as swallowing and abrupt increases in abdominal pressure (see Hiatal Hernia, this section).

Other Etiologic Factors
Intra-Abdominal Pressure
Stress-induced reflux occurs when intra-abdominal pressure overwhelms LES resting tone. Squatting, stooping, and straining maneuvers are among
the relatively common activities associated with transient physiologic reflux in healthy persons. In patients with GERD, these common reflux triggers
may exacerbate symptoms.

Gastric Volume
Increased gastric volume caused by overeating or slow gastric emptying may overcome the LES resting tone to increase the occurrence of physiologic
TLESRs.

Gastric Distention
Gastric distention (with concomitant shortening of LES length) in patients with GERD may be the result of slow gastric emptying or of aerophagia, an
increase in pharyngeal swallowing in an unconscious effort to improve esophageal clearance.


Gastroduodenal Reflux
Gastroduodenal reflux, caused perhaps by an incompetent pyloric sphincter, may allow excess amounts of proteolytic enzymes and bile acids into the
stomach and eventually into the esophagus. Several investigators have examined the role of refluxed duodenal contents in esophageal injury.
In addition to confirming the well known contribution of acid to esophagitis, Fiorucci and colleagues also demonstrated that mixed acid/alkaline reflux
occurred commonly in severe disease.
Stein and associates found the complications of GERD to be particularly frequent and severe in patients with both a defective sphincter and increased
acid/alkaline exposure. Lin and associates have shown that the presence and severity of reflux complications are related to both a mechanically
defective sphincter and increased esophageal exposure to excessive reflux of duodenal and gastric juice.
However, Gotley and associates found no relationship between severity of esophagitis and the concentration of bile acids in aspirated refluxate and
concluded that bile acids (and trypsin) are probably unimportant compared to acid and pepsin. The issue remains unresolved.

Gastric Hypersecretion
Gastric hypersecretion can increase esophageal exposure to gastric juice by the physiologic reflux of concentrated acid. In one study of patients with
increased esophageal exposure to gastric juice, as measured by 24-hour pH monitoring, 28% were found to secrete excessive amounts of gastric
acid. However, a mechanically defective sphincter was more important than gastric hypersecretion in the development of complications of GERD.

The Esophageal Tissue Barrier
The esophageal tissue barrier, an integrated complex of anatomic and physiologic components, acts to maintain the integrity of the esophageal
mucosa. Minor damage to the squamous epithelial cell surface wrought by brief exposure to even highly concentrated gastric acid is rapidly repaired
(< 1 hour) by viable epithelial cells, which migrate in amoeba-like fashion over the areas of bared basement membranes.
In GERD, however, the barrier is breached by repeated, prolonged exposure to gastric acid and pepsin and perhaps by refluxed bile salts, and
pancreatic enzymes. Surface cells are sloughed and new epithelial cells are produced in the regenerative (basal) zone. With continued exposure to
unmodified acid, the surface layer thins and the basal zone widens, with extension of the papillae to the cell surface.

Hiatal Hernia
The pathogenic relationship between a hiatal hernia and GERD is somewhat confusing. According to one study, although most patients with moderate
to severe esophagitis do have hiatal hernias, the converse is not true: the majority of patients with sliding hiatal hernias do not have esophagitis.
A later trial, which correlated hiatal hernia and symptomatic esophagitis, found the deciding factor to be the LES pressure.
Patients with pressures greater than 12 mm Hg were asymptomatic regardless of whether they had hiatal hernias. Those with lower LES pressures,
with or without hernias, had symptoms.
However, according to a study by Sloan and associates, in the presence of low LES pressure, hiatal hernia does contribute to reflux. The study was
designed to examine the recently generated "two sphincter hypothesis" of GEJ incompetence, that is, both the smooth muscle LES and the right
diaphragmatic crus encircling the LES serve sphincteric functions. In particular, the diaphragm augments the LES during inspiration, coughing or a
Mueller maneuver (inspiration against a closed glottis).
What then, asked the investigators, would be the effect of a hiatal hernia on GEJ competence in patients challenged by abrupt increases in intra-
abdominal pressure, specifically Valsalva and Mueller maneuvers, leg lifts, and gradual inflation of an abdominal cuff placed below the ribs? The
major finding was that susceptibility to gastroesophageal reflux induced by abrupt increases in intra-abdominal pressure was strongly related to both
the size of the hiatal hernia and LES pressure. In other words, hiatal hernia increases the vulnerability to reflux during periods of concomitant low LES
pressure. Therefore, medicines, foods, and habits that reduce LES pressure are more likely to result in reflux in patients with hernias than in those
without.



GERD IN BREIF

Gastroesophageal reflux, retrograde movement of gastric contents into the lower esophagus, is a transient, usually postprandial event that occurs
undetected and without symptoms several times a day in healthy individuals.
How these benign incursion‏ evolve into gastroesophageal reflux disease (GERD) was, until recently, believed to be related to the presence of a hiatal
hernia and, like other so-called acid-peptic disorders, to too much gastric acid.
Now we know the mechanism is more complex, having to do primarily with the failure of the lower esophageal sphincter (LES) as an antireflux barrier.
Furthermore, the essential cause of both symptoms and esophageal damage in GERD, unlike the other acid peptic disorders, is the displacement
rather than the hypersecretion of acid.
Gastroesophageal reflux disease, which accounts for 75% of esophageal pathology, is characterized by a broad spectrum of clinical presentations,
from simple heartburn to ulcerative esophagitis, esophageal stricture ‏, and Barrett's metaplasia with its tendency to become malignant.
Cross-sectional surveys of the adult US population have found that 7% to 10% have heartburn daily and 15% to 40% have heartburn monthly.
Approximately one-third of the patients with heartburn who seek medical care have endoscopic evidence of esophagitis and about 10% to 20% have
severe complications of esophagitis.
The progression from transient reflux to heartburn to esophageal injury is dependent on a number of anatomic and physiologic factors associated
with the structural and functional integrity of the LES. This progression, as well as recent trends in epidemiology, pathogenesis, and management.

Symptoms
The symptoms of gastroesophageal reflux disease (GERD) are diverse and often suggestive of a number of other, sometimes more serious,
diseases (Table 3.1).
The typical manifestations are:
•        Heartburn
•        Acid regurgitation
•        Hypersalivation
•        Nonobstructive dysphagia.
Heartburn
Heartburn, a burning, substernal pain traveling up the esophagus toward the pharynx, is the most common symptom of GERD. It most often occurs:
•        30 to 60 minutes after meals
•        On reclining after food intake
•        With certain body positions.
Approximately one-tenth of the U.S. population experiences heartburn daily; a third, once a month; and a quarter of women have it throughout
pregnancy.

Acid Regurgitation
Regurgitation of digestive juice to the throat often accompanies heartburn. An occasional patient may refer to regurgitation as vomiting; a differential
clue is that it occurs without effort and is often precipitated by a postural change.

Hypersalivation
Hypersalivation, or water brash, another common symptom, may be a protective response to refluxed acid. Odynophagia and esophageal sensitivity
to hot liquids or alcohol also suggests GERD.
Nonobstructive Dysphagia

Nonobstructive dysphagia is reported in up to 45% of reflux patients. Ambulatory manometric studies of 27 GERD patients revealed more meal-
related swallows followed by inadequate peristaltic waves in the 16 patients (59%) with dysphagia. Thus a peristaltic abnormality may be responsible
for this relatively common symptom in patients with reflux. However, dysphagia warrants careful diagnosis since it often indicates esophageal
stricture or Barrett's esophagus (Figure

Atypical‏)Symptoms
The major atypical symptoms of GERD are:
•        Chest pain
•        Respiratory symptoms
•        Hoarseness.
•        
Chest Pain
According to an early study by Bennett and Atkinson, 23% of patients admitted as emergencies with clinically suspected myocardial infarction were
eventually found to have alimentary tract disease, mostly esophagitis.
More recently, Anggiansah and colleagues found GERD to be associated with noncardiac chest pain in 38% of patients referred from the department
of cardiology in one hospital and originally thought to have angina.

Respiratory Symptoms
Respiratory symptoms are increasingly seen in reflux disease. Microaspiration of refluxate that reaches the hypopharynx appears to be the principal
mechanism. The resulting symptoms of cough, choking (خانق‏), and even recurrent pneumonia often evade initial association with GERD. Repair of
respiratory epithelium lost secondary to aspiration can take as long as seven days, during which the acid-induced irritation gives rise to a chronic
cough.
Thus studies during that period of repair may find no relationship between the cough and reflux episodes. The cause of aspiration seems to lie
primarily in abnormal lower esophageal sphincter (LES) function and esophageal clearance, which are more common in GERD patients who have
pulmonary complications.
Pulmonary symptoms are particularly common in older patients, in whom radiographic changes on chest x-rays (parenchymal scarring and pleural
thickening) may be the only indicators of GERD.
Whether chronic bronchitis can be a consequence of GERD is unclear. It has been suggested that reflux can induce bronchial constriction either by
aspiration or by stimulation of vagal efferent fibers to the lung. In patients with adult-onset non allergic asthma, particularly those with nocturnal
wheezing, reflux should be considered.

Hoarseness
Occasionally, hoarseness may be a major manifestation. How the physiologic factors in GERD contribute to this laryngeal manifestation is unknown.
Prolonged pH monitoring in patients with hoarseness or laryngeal cancer has demonstrated abnormal acid refluxate in the distal esophagus, but not
consistently in the pharyngeal region.
Associated complaints include:
•        Sore throat
•        Bad breath
•        A full sensation in the neck (globus).

Treatment Options