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