GASTROESOPHAGEAL REFLUX DISEASE
In the United States, gastroesophageal reflux disease (GERD) is common, and it is estimated that one in five adults has symptoms of heartburn or gastroesophageal regurgitation at least once a week. Although most cases follow a relatively benign course, GERD in some individuals can cause severe erosive esophagitis; serious sequelae include stricture formation and Barrett’s metaplasia (replacement of squamous by intestinal columnar epithelium), which, in turn, is associated with a small but significant risk of adenocarcinoma. Most of the symptoms of GERD reflect injurious effects of the refluxed acid-peptic content on the esophageal epithelium, providing the rationale for suppression of gastric acid.
The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. Proton pump inhibitors clearly are more effective than H2-receptor antagonists in achieving these goals. Healing rates after 4 weeks and 8 weeks of therapy with protein pump inhibitors are approximately 80% and 90%, respectively, while the corresponding healing rates with H2-receptor antagonists are 50% and 75%, respectively. Indeed, proton pump inhibitors are so effective that their empirical use is advocated as a therapeutic trial in patients in whom GERD is suspected to play a role in the pathogenesis of symptoms.
Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient. In general, the optimal dose for each patient is determined based upon symptom control, and routine measurement of esophageal pH to guide dosing is not recommended. Strictures associated with GERD also respond better to proton pump inhibitors than to H2-receptor antagonists; indeed, the use of proton pump inhibitors reduces the requirement for esophageal dilation. Unfortunately, one of the other complications of GERD, Barrett’s esophagus, appears to be more refractory to therapy, as neither acid suppression nor antireflux surgery has been shown convincingly to produce regression of metaplasia or to decrease the incidence of tumours.
Regimens for the treatment of GERD with proton pump inhibitors and histamine H2-receptor antagonists are listed. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2-receptor antagonists, twice-daily dosing usually is required. Antacids are recommended only for the patient with mild, infrequent episodes of heartburn. In general, prokinetic agents are not particularly useful for GERD, either alone or in combination with acid-suppressant medications.
The extremely high concentration of H+ in the gastric lumen requires robust defense mechanisms to protect the esophagus and the stomach. The primary esophageal defense is the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. The stomach protects itself from acid damage by a number of mechanisms that require adequate mucosal blood flow, perhaps because of the high metabolic activity and oxygen requirements of the gastric mucosa. One key defense is the secretion of a mucus layer that protects gastric epithelial cells.
Gastric mucus is soluble when secreted but quickly forms an insoluble gel that coats the mucosal surface of the stomach, slows ion diffusion, and prevents mucosal damage by macromolecules such as pepsin. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Thus, alcohol, aspirin, and other drugs that inhibit prostaglandin formation decrease mucus secretion and predispose to the development of acid-peptic disease. A second important part of the normal mucosal defense is the secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes the acid in the region of the mucosal cells, thereby raising pH and preventing acid-mediated damage.
GERD is a chronic disorder that requires long-term therapy. Some experts advocate “step-down” approaches that attempt to maintain symptomatic remission by either decreasing the dose of the proton pump inhibitor or switching to an H2-receptor antagonist. Other experts have advocated intermittent, “on-demand” therapy with proton pump inhibitors for symptomatic relief in patients who have responded initially but continue to have symptoms. However, many patients will maintain their requirement for proton pump inhibitors, and several studies suggest that these drugs are better than H2-receptor antagonists for maintaining remission in GERD.
In patients with severe symptoms or extra intestinal manifestations of GERD, twice-daily dosing with a proton pump inhibitor may be needed. However, it is difficult if not impossible to render patients achlorhydric¾even on twice-daily doses of proton pump inhibitors¾and two-thirds or more of subjects will continue to make acid, particularly at night. This phenomenon, called nocturnal acid breakthrough, has been invoked as a cause of refractory symptoms in some patients with GERD. However, decreases in gastric pH at night while on therapy generally are not associated with acid reflux into the esophagus, and the rationale for suppressing nocturnal acid secretion (even if feasible) remains to be established. Nevertheless, patients with continuing symptoms on twice-daily proton pump inhibitors are often treated by adding an H2-receptor antagonist at night. While this can further suppress acid production, the effect is short-lived, probably due to the development of tolerance.
With varying levels of evidence, acid reflux has been implicated in a variety of atypical symptoms, including noncardiac chest pain, asthma, laryngitis, chronic cough, and other ear, nose, and throat conditions. Proton pump inhibitors have been used with some success in certain patients with these disorders, generally in higher doses and for longer periods of time than those used for patients with more classic symptoms of GERD.
Heartburn is estimated to occur in 30% to 50% of pregnancies, with an incidence approaching 80% in some populations. In the vast majority of cases, GERD ends soon after delivery and thus does not represent an exacerbation of a pre-existing condition. Nevertheless, because of its high prevalence and the fact that it can contribute to the nausea of pregnancy, treatment often is required. Treatment choice in this setting is complicated by the paucity of data for the most commonly used drugs. In general, most drugs used to treat GERD fall in FDA Category B, with the exception of omeprazole (FDA Category C).
Mild cases of GERD during pregnancy should be treated conservatively; antacids or sucralfate are considered the first-line drugs.
If symptoms persist, H2-receptor antagonists can be used, with ranitidine having the most established track record in this setting. Proton pump inhibitors are reserved for women with intractable symptoms or complicated reflux disease. In these situations, lansoprazole is considered the preferred choice among the proton pump inhibitors, based on animal data and available experience in pregnant women. The success of acid-suppressing agents in a variety of conditions is critically dependent upon their ability to keep intragastric pH above a certain target, generally pH 3 to 5; this target varies to some extent with the disease being treated.
By: Ammarah Khan
