Gastroesophageal Reflux Disease Newsletter___________Series 1, Issue 2, 2007

THE ROLE OF HELICOBACTER PYLORI INFECTION IN THE PATHOGENESIS OF GERD

Michael AJ Sawyer, MD, FACS
Comanche County Memorial Hospital

MAJ Elizabeth M Sawyer, MD
Reynolds Army Community Hospital

The elucidation of a cause and effect relationship between Helicobacter pylori infection and peptic ulcer disease¹ revolutionized understanding of the pathogenesis of peptic ulcers and created new paradigms for their therapy and prevention. As frequently happens with such momentous discoveries, more questions were raised than answered. In addition to the role of active H pylori infection, questions were raised about associations with other medical conditions in the pathogenesis of gastroesophageal reflux disease (GERD) and the significance of the eradication of the infection in the medical management of GERD. These other medical conditions include the development of gastric lymphoma and adenocarcinoma of the body and antrum of the stomach and other extragastric conditions, such as iron deficiency anemia and rheumatological conditions.

H pylori infection and GERD are both common in the general population. H pylori infection coexists in approximately 38% of patients with GERD.² This statistic in itself, however, does not imply a cause and effect relationship. In fact, the relationship between the presence and eradication of H pylori infection and the pathogenesis of GERD remains a complex and incompletely understood issue. A possible explanation may be the heterogeneity of the gastric locus of H pylori infection and the variable effect of such heterogeneity on gastric acid secretion.³ Antrum-predominant gastritis causes hypergastrinemia and acid hypersecretion and is not associated with gastric atrophy, while corpus-predominant gastritis is associated with gastric atrophy and decreased acid production. Most patients infected with H pylori demonstrate a mixed gastritis pattern with no increase in acid secretion due to involvement of the corpus. The evidence linking H pylori infection and subsequent eradication to GERD is sparse. Trials sufficiently powered to address these issues have almost unanimously shown no relationship between H pylori status and the development or prevalence of GERD or heartburn.^4-6 Just as importantly, successful eradication of H pylori infection does not negatively impact the efficacy of antisecretory drug therapy for GERD.⁷ Furthermore, the results of several studies based on objective metrics such as endoscopy with biopsies, esophageal manometry, and 24-hour pH level testing support these conclusions.^8-10

The Bristol Helicobacter project⁴ enrolled participants (N = 10,537) with or without H pylori infection. At baseline, heartburn (odds ratio [OR] = 1.14) but not GERD (OR = 1.05) was more prevalent in those with H pylori infection. Eradication therapy did not affect the prevalence of heartburn (OR = 0.99) or GERD (OR = 1.04); it was also not efficacious in improving preexisting heartburn or GERD. The authors concluded that H pylori infection was associated with a modest increase in the prevalence of heartburn but not GERD and that eradication of H pylori infection did not benefit patients in terms of those conditions.

The HUNT study⁵ randomly enrolled 472 persons with reflux symptoms and 472 persons without reflux symptoms as control subjects from 65,363 persons in a single county in Norway. H pylori infection and presence of the H pylori virulence factor CagA were determined by immunoblot assay. The prevalence of gastric mucosal atrophy was determined by serum pepsinogen I measurements. The risk of gastric mucosal atrophy was increased (OR = 8.9) in participants infected with H pylori, and gastric atrophy was associated with a decreased (OR = 0.2) risk of reflux symptoms. The authors concluded that gastric atrophy induced by H pylori was associated with decreased reflux symptoms. However, H pylori infection did not affect overall risk of reflux symptoms (OR = 1.1); that is, the prevalence of reflux symptoms in the study population was unchanged because of the relative infrequency of gastric atrophy in the population.

The effect of H pylori infection on response rate and time to response for treatment of GERD symptoms with rabeprazole has been studied in 1548 patients, 25.5% of whom were infected with H pylori.⁶ The mean time to onset of adequate symptom control was approximately 4 days with no significant difference observed between the 2 cohorts (ie, those patients with H pylori infection and those not infected). Complete symptom relief was achieved in more than 70% of participants. The authors concluded that H pylori status did not impact the rate or degree of symptom relief in patients with GERD who were treated with rabeprazole and that no dose adjustment was necessary based on H pylori status.

Gisbert and colleagues⁸ studied H pylori status with endoscopic evaluation and 24-hour pH level measurements in 100 consecutive patients with GERD symptoms. Abnormal Johnson-DeMeester scores (a highly sensitive and specific calculated score used to diagnose GERD in 24-hour pH level monitoring) were reported in 54% of patients with H pylori infection and in 59% of patients without H pylori infection. Furthermore, H pylori infection was detected in 57% of patients with an elevated score and in 52% of patients with a score in the reference range. No results were statistically significantly different. H pylori infection did not correlate with abnormal 24-hour pH level scores (OR = 0.8). Similar rates of hiatal hernia (41% vs 41%), Savary-Miller endoscopic esophagitis (54% vs 46%), and Barrett metaplasia (15% vs 11%) were noted in the study populations. Lower esophageal sphincter (LES) pressures (12 + 8 mm Hg vs 14 + 12 mm Hg) were also similar. The authors concluded that H pylori infection has no association with GERD as determined by standard objective measurements.

Verma and coworkers⁹ described GERD prevalence in patients during H pylori infection and following eradication. Participants infected with H pylori underwent manometry and 24-hour pH level testing followed by eradication, which was confirmed by urea breath test. Manometry and 24-hour pH level testing were repeated 1 year later. GERD was detected in 45% of patients infected with H pylori at baseline, and this percentage was unchanged following eradication therapy. The percentage of time during the 24-hour pH level monitoring when the pH level was less than 4 (4.69 + 3 vs 4.79 + 3) and the total Johnson-DeMeester scores (16.8 + 7.5 vs 26.8 + 18) were also noted to be similar in patients before and after eradication of the H pylori infection. Overall, the authors concluded that eradication of H pylori infection had no impact on key measures of the prevalence of GERD.

Vakil and associates studied the effect of H pylori eradication on the prevalence of GERD symptoms and erosive esophagitis in a randomized placebo-controlled trial with 693 participants.¹⁰ Heartburn and regurgitation scores were significantly improved in patients with antrum-predominant gastritis 1 year following eradication therapy. Additionally, erosive esophagitis developed in 2% of control subjects and in 7% of the treatment group, though esophagitis rates were not different when adjusted for esophagitis that had been present prior to treatment. The authors concluded that symptoms improved in both treatment and placebo groups and that the development of esophagitis following H pylori eradication therapy is uncommon.

Currently available evidence suggests that clinicians should test for H pylori infection when suspicion exists, and, if active infection is documented, eradication therapy should be administered to address associations of H pylori infection with peptic ulcer disease, with the development of gastric lymphoma and adenocarcinoma of the body and antrum of the stomach, and with other extragastric conditions, such as iron deficiency anemia and rheumatological conditions, regardless of concern for preexisting GERD or its potential development. Separately, proton pump inhibitor (PPI) therapy is indicated to treat patients with GERD regardless of H pylori status. The reader should note specifically that, based on the studies cited, the efficacy of PPI therapy for GERD is not decreased following H pylori eradication and no dose adjustment is necessary based on H pylori status.

1. Warren JR, Marshall BJ. Unidentified curved bacilli in the stomachs of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-5.

2. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ. 2003;326(7392):737-9.

3. Labenz J, Malfertheiner P. Helicobacter pylori in gastro-oesophageal reflux disease: causal agent, independent or protective factor? Gut. 1997;41(3):277-80.

4. Harvey RF, Lane JA, Murray LJ, et al, for the Bristol Helicobacter Project. Randomised controlled trial of effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux: Bristol helicobacter project. BMJ. 2004;328(7453):1417.

5. Nordenstedt H, Nilsson M, Johnsen R, et al. Helicobacter pylori infection and gastroesophageal reflux in a population-based study (The HUNT Study). Helicobacter. 2007;12(1):16-22.

6. de Boer W, de Wit N, Geldof H, et al. Does Helicobacter pylori infection influence response rate or speed of symptom control in patients with gastroesophageal reflux disease treated with rabeprazole? Scand J Gastroenterol. 2006;41(10):1147-54.

7. Liu Y, Akiyama J, Graham DY. Current understandings of Helicobacter pylori, peptic ulcer and gastroesophageal reflux disease. Minerva Gastroenterol Dietol. 2006;52(3):235-48.

8. Gisbert JP, de Pedro A, Losa C, et al. Helicobacter pylori and gastroesophageal reflux disease: lack of influence of infection on twenty-four-hour esophageal pH monitoring and endoscopic findings. J Clin Gastroenterol. 2001;32(3):210-4.

9. Verma S, Jackson W, Floum S, Giaffer MH. Gastroesophageal reflux before and after Helicobacter pylori eradication. A prospective study using ambulatory 24-h esophageal pH monitoring. Dis Esophagus. 2003;16(4):273-8.

10. Vakil N, Talley NJ, Stolte M, et al. Patterns of gastritis and the effect of eradicating Helicobacter pylori on gastro-oesophageal reflux disease in Western patients with non-ulcer dyspepsia. Aliment Pharmacol Ther. 2006;24(1):55-63.