INTRODUCTION — Helicobacter pylori (H. pylori) is an important risk factor for the development of peptic ulcer disease, gastric adenocarcinoma, and primary B cell lymphoma of the stomach. A possible role for H. pylori in the pathogenesis of gastroesophageal reflux disease (GERD) has also been suggested in a growing number of studies. However, the link between GERD and H. pylori is complex.
This topic review will summarize the available evidence suggesting a role for H. pylori in GERD. The pathophysiology of GERD and the treatment of H. pylori are discussed separately. (See "Pathophysiology of reflux esophagitis" and "Treatment regimens for Helicobacter pylori in adults".)
EPIDEMIOLOGY — Suspicion of an interaction between H. pylori and gastroesophageal reflux disease (GERD) stems from epidemiologic data showing that as the prevalence of H. pylori decreased in Western societies, the prevalence of GERD and adenocarcinoma of the esophagus increased [1]. This trend led several investigators to examine the prevalence of H. pylori in patients with GERD.
Several reports have suggested that H. pylori-positive patients were less likely to have GERD, and, when present, the severity of esophagitis was decreased compared with those who were H. pylori negative [2-4]. A lower prevalence of Barrett's metaplasia and esophageal adenocarcinoma has also been described in individuals who were H. pylori positive [5,6].
Some studies suggested that H. pylori strains positive for Cag A (strains strongly associated with the development of corpus gastritis) may be particularly protective against the development of esophageal adenocarcinoma [7-9]. Thus, the available data suggest that colonization with H. pylori, particularly Cag A strains, may be protective against the more severe forms of GERD. Unfortunately, Cag A positive strains have also been associated with gastric adenocarcinoma. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)
PATHOPHYSIOLOGY OF GERD AS IT RELATES TO H. PYLORI — Gastroesophageal reflux disease (GERD) is a clinical condition that results from the reflux of caustic fluid from the stomach into the esophagus. The pathophysiology of GERD is multifactorial with the disease ultimately related to the balance between factors tending to damage (or sensitize) the esophageal mucosa (excessive mucosal exposure time to caustic refluxate) and those tending to preserve it (a competent esophagogastric junction [EGJ] and normal esophageal acid clearance). GERD occurs when the balance is tipped in favor of the caustic factors. (See "Pathophysiology of reflux esophagitis".)
For H. pylori to exert a direct pathogenetic effect on GERD, it must have an impact on one of these primary disease determinants. However:
●H. pylori has no apparent effect on EGJ competence [3].
●There are no data suggesting that H. pylori decreases lower esophageal sphincter (LES) pressure or the frequency of transient LES relaxations.
●Esophageal peristaltic function and acid clearance are unlikely to be affected by H. pylori.
●There have been reports of H. pylori colonizing the esophageal mucosa. Whether such colonization affects mucosal sensitivity has not been determined.
The primary mechanism by which H. pylori might predispose to GERD is by modifying the gastric refluxate. However, the effects appear to be different in antral-dominant and corpus-dominant or pangastritis (figure 1).
Antrum-dominant gastritis — H. pylori infection has a major effect on somatostatin secreting D cells in the gastric antrum such that feedback inhibition by luminal acid on gastrin release is interrupted. As a result, gastrin levels are higher in H. pylori-infected individuals [10]. (See "Association between Helicobacter pylori infection and duodenal ulcer".)
Thus, lack of feedback inhibition may be responsible for the increased acid secretion found in patients with duodenal ulcers who are H. pylori positive and have antral-dominant gastritis. Another theory suggests that eradication of H. pylori restores gastric bicarbonate secretion to levels seen in patients without H. pylori infection without affecting gastric acid secretion [11]. The net effect is the same — increased acidity of gastric secretions.
Corpus-dominant and pangastritis — H. pylori infection associated with corpus (fundus)-dominant gastritis is also associated with increased gastrin levels, but acid secretion is reduced. It has been proposed that corpus-dominant gastritis decreases acid secretion via local inflammation and increased levels of cytokines, such as tumor necrosis factor alpha and interleukin-1-beta. These changes can eventually lead to hypochlorhydria and gastric atrophy.
Reversal of H. pylori-induced corpus-dominant gastritis (and associated hypochlorhydria) has the potential to increase gastric acid secretion, which could render caustic what was previously asymptomatic reflux [11]. Return of acid secretion shortly after successful eradication of H. pylori has been associated with increased expression of H/K ATPase mRNA, not increased parietal cell number [12]. Whether return of parietal cell numbers increases acid secretion in the long-term is unclear.
H. PYLORI ERADICATION AND GASTROESOPHAGEAL REFLUX DISEASE — Studies on the effect of H. pylori eradication and gastroesophageal reflux disease (GERD) have been conflicting. The disparities can be explained by an understanding of the variable effects of H. pylori on gastric acid secretion discussed above. Most of the initial studies failed to differentiate patients on the basis of gastritis severity or distribution. In addition, the period of observation in these studies may have been too short (approximately six months) to allow for physiological equilibration to occur. Bearing these limitations in mind, the following sections will summarize available data on the effect of H. pylori eradication on GERD in specific patient groups: duodenal ulcer, corpus-dominant gastritis, and GERD. (See "Treatment regimens for Helicobacter pylori in adults".)
Patients with duodenal ulcers — Chronic H. pylori infection is the most important risk factor predisposing to duodenal ulcer disease. The lifetime prevalence of peptic ulcer disease in H. pylori-infected patients is approximately 5 to 10 percent. (See "Association between Helicobacter pylori infection and duodenal ulcer".)
Because antrum-dominant H. pylori gastritis is associated with increased gastric acid secretion, such patients should be at increased risk for developing GERD and duodenal ulcer disease, and both conditions should improve with H. pylori eradication. Several studies addressing this issue have produced variable results, which may in part be explained in differences in study populations and endpoints measured [13-18]. Considered together, they suggest a modest benefit of H. pylori eradication on GERD-symptoms in patients with duodenal ulcer disease and preexisting GERD. (See 'Antrum-dominant gastritis' above.)
The following illustrates the range of findings in the largest studies:
●An analysis of eight double-blind prospective trials of H. pylori therapy in a total of 1165 patients with duodenal ulcer disease (940 active, 225 past history) found that eradication of H. pylori did not lead to the development of erosive esophagitis or new symptomatic GERD, but may improve symptoms (heartburn, regurgitation) in patients with preexisting GERD [17].
●Similar conclusions were reached in a systematic review of 27 studies, which found no evidence that H. pylori eradication in patients with duodenal ulcer disease provoked reflux esophagitis or worsened heartburn [18].
Patients with corpus-dominant or pangastritis — Significant corpus gastritis can be associated with decreased acid secretion. In such patients, H. pylori eradication may result in increased acid secretion, which could be clinically relevant in patients predisposed to GERD. Several investigators have observed that GERD was less common in patients with severe corpus gastritis [13,19,20], while others have demonstrated that improvement of gastritis in these patients has been associated with an increased risk for the development of GERD [21,22].
It is important to emphasize again that H. pylori eradication does not cause GERD, it only unmasks it. Patients with impaired defense mechanisms, such as impaired esophageal acid clearance, hiatal hernia, and a hypotensive LES, are predisposed to GERD but may be protected by the decreased acid secretion induced by the inflammation and atrophy caused by H. pylori gastritis. This was demonstrated by a study evaluating risk factors for incident esophagitis after H. pylori eradication [21]; after eradication, the cumulative prevalence of esophagitis was significantly higher among those with a hiatus hernia (26 versus 8 percent), a known risk factor for GERD.
Patients with GERD — Studying the effects of H. pylori eradication in patients with GERD is difficult because these patients necessarily have preserved acid secretion and EGJ compromise. Because they have preserved acid secretion, it is likely that these patients have either antral-dominant gastritis or only mild corpus gastritis. Regardless, eradication should not significantly worsen acid reflux in patients with preexisting GERD and should improve reflux in patients with antral-dominant gastritis. At least three studies support this hypothesis [23-25].
Effect of H. pylori on PPI therapy — H. pylori infection affects gastric acid secretion in patients treated with proton pump inhibitors (PPIs). For example, inhibition of gastric acid secretion with a PPI is greater in patients with H. pylori infection compared to H. pylori-negative subjects [26,27]. Studies of patients with duodenal ulcers have also demonstrated that the acid suppressing ability of PPIs is augmented in patients who are infected with H. pylori [26,28].
Whether or not the demonstrated effect of H. pylori on acid suppression with PPIs is clinically important has yet to be determined. In one study, PPIs appeared to be more effective in preventing and curing ulcers in patients who are H. pylori positive with or without NSAID use [29]. However, in a controlled trial comparing the efficacy of esomeprazole with lansoprazole, healing rates with PPIs were not influenced by H. pylori status [30]. In combined analysis of three large controlled trials of short- and long-term treatment in patients with reflux disease, H. pylori was a weak independent protective factor against relapse [31]. In another open-label study that included 971 patients with symptomatic reflux and esophagitis treated with pantoprazole, relief from heartburn and regurgitation and the likelihood of endoscopic healing after four weeks of therapy was significantly greater in H. pylori-positive patients compared with H. pylori-negative patients (87 versus 76 percent) [32]. Long-term studies evaluating maintenance therapy for GERD found no difference in the PPI dose required for H. pylori-negative and positive patients [33,34]. Thus, it appears that although H. pylori increases the acid suppressive effect of PPIs, there is no evidence suggesting a need to titrate the dose according to the presence of H. pylori.
Another issue that may be of clinical relevance is acid rebound after discontinuation of PPIs. Studies suggest that it may be more difficult to withdraw PPI therapy in H. pylori negative patients (see "Physiology of gastric acid secretion"). The potential significance of this effect was illustrated in a study in which basal acid output increased by 82 percent in H. pylori-negative patients and decreased by 32 percent in H. pylori-positive patients at day 15 after omeprazole therapy was discontinued [35]. The authors speculated that this phenomenon was the result of persistence of corpus gastritis in H. pylori-positive patients.
Theoretical risk of long-term PPI therapy — A major concern regarding long-term PPI therapy has been the suggestion that patients infected by H. pylori are at increased risk for the development of atrophic gastritis during long-term therapy with PPIs [36]. A US Food and Drug Administration panel reviewing the data supporting this contention concluded that the findings were flawed and inconclusive. (See "Medical management of gastroesophageal reflux disease in adults".)
However, at least two controlled trials have demonstrated that eradication of H. pylori in patients with reflux esophagitis receiving long-term acid suppression therapy decreases inflammation and reverses corpus gastritis [37,38]. As a result, European consensus guidelines suggest that H. pylori testing be performed in patients receiving long-term acid suppression with PPIs [39].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Acid reflux and gastroesophageal reflux disease in adults (The Basics)" and "Patient education: H. pylori infection (The Basics)")
●Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)" and "Patient education: Helicobacter pylori infection and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Eradication of H. pylori is associated with mild worsening of gastroesophageal reflux disease (GERD) in patients with corpus-dominant or pangastritis and improvement in those with antral-dominant gastritis. These effects must be balanced against the risks of continued infection (figure 1). (See 'Pathophysiology of GERD as it relates to H. pylori' above.)
●For H. pylori diagnosed in the context of peptic ulcer disease, eradication is the standard of care. Failure to eradicate H. pylori in the context of peptic ulcer disease is associated with a 60 to 100 percent annual ulcer recurrence rate compared with 10 percent after eradication. (See 'Patients with duodenal ulcers' above.)
●For H. pylori diagnosed outside the context of peptic ulcer disease, most authorities would advocate eradication based upon a 10 percent lifetime risk of developing peptic ulcer disease and a two to three times higher incidence of gastric adenocarcinoma. The mild increase in reflux associated with eliminating corpus gastritis does not outweigh these risks. Similarly, the overall impact that H. pylori may have on the risk of esophageal adenocarcinoma is insignificant. (See 'Corpus-dominant and pangastritis' above and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)
●For H. pylori diagnosed in the context of GERD, the available data do not demonstrate worsening disease with H. pylori eradication; in fact, GERD may be improved in individuals with antral-dominant gastritis. In addition, although H. pylori improves the ability of proton pump inhibitors to suppress acid, the dose required to maintain remission of esophagitis is not affected. (See 'Patients with GERD' above and 'Effect of H. pylori on PPI therapy' above.)
