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Helicobacter pylori and the efficacy of omeprazole therapy for gastroesophageal reflux disease
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 4, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00037-4
ORIGINAL CONTRIBUTIONS
Helicobacter pylori and the Efficacy of Omeprazole Therapy for Gastroesophageal Reflux Disease B. E. Schenk, M.D., E. J. Kuipers, M.D., Ph.D., E. C. Klinkenberg-Knol, M.D., Ph.D., S. A. Eskes, M.D., and S. G. M. Meuwissen, M.D., Ph.D. The Department of Gastroenterology, Free University Hospital, Amsterdam, The Netherlands
OBJECTIVE: Helicobacter pylori infection may affect gastric acid output and intragastric pH. In patients with an insufficient lower esophageal sphincter, this effect may theoretically influence the severity of reflux disease, as well as the efficacy of acid suppressive therapy. To evaluate whether the H. pylori status of patients with gastroesophageal reflux disease (GERD) affects the severity of disease and the efficacy of omeprazole therapy to maintain disease remission, we conducted this study. METHODS: Patients with GERD were prospectively studied by upper gastrointestinal endoscopy with biopsy sampling for histology and H. pylori culture before start of treatment and at annual follow-up. At endoscopy, esophagitis was graded according to the criteria of Savary-Miller, and the presence of Barrett’s esophagus, hiatal herniation, or other abnormalities was recorded. Omeprazole was started at an initial dose of 20 mg daily; the dose was adjusted based on symptoms and the endoscopical findings. RESULTS: One hundred thirty-seven GERD patients were included and followed up for a mean 56.6 months; 49 (36%) of them were infected with H. pylori. H. pylori-infected and -uninfected patients did not differ with respect to age (60 6 13 vs 61 6 14 yr, p 5 0.65) or duration of follow-up (54 6 30 vs 58 6 31 months, p 5 0.12). H. pylori-negative patients tended to present with more severe esophagitis at baseline (median Savary-Miller score 3 vs 2, p 5 0.06) and had a higher prevalence of Barrett’s esophagus (39/88 vs 10/49, p 5 0.006). However, no difference was found with respect to the dose of omeprazole needed for maintained relief of symptoms and endoscopical signs of esophagitis (median 40 mg in both groups, p 5 0.35). CONCLUSIONS: H. pylori-negative GERD patients have a higher prevalence of Barrett’s esophagus, but do not need a higher dose of omeprazole to maintain symptomatic and endoscopical disease remission. (Am J Gastroenterol 1999; 94:884 – 887. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Helicobacter pylori (H. pylori) is the main pathogenetic factor in the development of gastritis and peptic ulcer disease. Bacterial colonization, gastric mucosal inflammation,
and host acid output interact closely. Two different patterns are generally recognized. First, in a situation of normal to elevated acid output, bacterial colonization and gastritis are confined predominantly to the antrum. This pattern is observed in most patients with duodenitis and duodenal ulcers. Second, in a situation of reduced acid output, H. pylori causes a pangastritis of both antrum and corpus. This pattern is observed in most patients with atrophic gastritis and its associated conditions, such as gastric ulcer disease and gastric cancer. In these cases, H. pylori-induced inflammation of the corpus mucosa causes a further reduction of the already impaired acid output. After H. pylori eradication in patients with atrophic gastritis, improvement of gastric inflammatory parameters has been observed to be associated with a partial restoration of acid output (1). By analogy, recent observations in healthy volunteers have shown that omeprazole treatment causes higher 24-h intragastric pH values in H. pylori-infected subjects than in H. pyloriuninfected subjects (2, 3). In the absence of omeprazole treatment this difference was not observed. Intragastric pH measurement before and after eradication in H. pylori-positive subjects treated with omeprazole or ranitidine showed a decrease in the median intragastric 24-h pH after eradication treatment (4 – 6). In the absence of omeprazole therapy, no changes were observed in intragastric pH after bacterial eradication (5). If patients without H. pylori have lower intragastric pH, they could be at higher risk for pathological esophageal acid exposure and the development of gastroesophageal reflux disease (GERD). In the presence of GERD, they might also require a higher dose of omeprazole for remission of reflux-related symptoms. We therefore tested the hypothesis that the severity of reflux-disease in GERD patients and the maintenance dose of omeprazole needed are related to H. pylori status.
MATERIALS AND METHODS Patients referred to our outpatient clinic with symptoms suggestive of GERD, in particular heartburn, regurgitation, or dysphagia, underwent flexible endoscopy of the upper gastrointestinal tract, following standard procedures and using Olympus Q10/20, GIF 100, and IT 100 endoscopes. Presence and grade of esophagitis, diaphragmal herniation, Barrett’s esophagus, or any other abnormality were re-
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H. pylori and Omeprazole Therapy in GERD
corded. Patients were eligible to enter the study if endoscopical esophagitis grade 1 or more was present, according to the criteria of Savary-Miller (7). Exclusion criteria were use of proton pump inhibitors, H2-receptor antagonists in a dose exceeding the equivalent of 300 mg ranitidine daily, or prokinetic drugs in the month before study entry, as well as previous major upper gastrointestinal surgery, known or suspected Zollinger Ellison syndrome, or hypochlorhydria due to (autoimmune) atrophic gastritis. Each patient was questioned about past medical history and drug use, and was subject to physical examination. After endoscopy, omeprazole was initiated at a dose of 20 mg once daily. Follow-Up Patients were seen at the outpatient clinic semiannually. A control endoscopy was performed every year. The dose of omeprazole was adjusted if the patient complained of recurrent, poorly controlled reflux symptoms, or if endoscopy revealed recurrent signs of esophagitis. This dose adjustment was done by steps of 20 mg. Omeprazole was given as a single morning dose, unless more than 40 mg was needed. In such a case, twice-daily dosing was prescribed. If such a prescription required two unequal doses, the highest dose was usually prescribed in the morning unless nightly symptoms clearly prevailed. Biopsies At each endoscopy a total of eight biopsy specimens was obtained. For histopathological examination, two antrum and four corpus biopsies were fixated in buffered formalin. After both hematoxylin and eosin and modified Giemsa staining, they were graded by one pathologist according to the updated Sydney System for both active and chronic gastritis, atrophy, and presence of H. pylori (8). The pathologist was blinded for clinical and endoscopical data. One antrum and one corpus biopsy specimen were used for culture of H. pylori. A patient was considered H. pylori infected if culture or histopathology was positive. Statistical Analysis For statistical analysis the Student’s t, Mann-Whitney, or Wilcoxon rank-sum tests were used when applicable. A two-sided p value , 0.05 was considered significant.
RESULTS Of a total of 165 patients referred for upper gastrointestinal endoscopy with suspicion of GERD, 152 patients met the
885
Table 1. Demographics of Patients Included Into Final Analysis, Stratified for H. pylori Status
n (%) Age (SD) (yr) Follow-up (SD) (months)
H. pylori Positive
H. pylori Negative
p Value*
49 (36%) 60 6 13 54 6 30
88 (64%) 61 6 14 58 6 31
0.65 0.12
* Mann-Whitney test.
inclusion criteria and entered the study. However, 15 patients were lost to follow-up. The data of the remaining 137 patients were used for final analysis. Twelve of them participated previously in a multicenter study with emphasis on H. pylori and atrophic gastritis (9); the other patients did not participate in any previous study. A demographic description of the patients included is given in Table 1. Forty-nine (36%) patients were H. pylori positive. At baseline, 41 of them had both positive culture and histology, five patients had positive histology only, and three had positive cultures but negative histology. During follow-up, all patients remained H. pylori positive at all occasions studied, with minor variations with respect to individual test results for antrum and corpus by means of histology and culture. No differences were found between H. pylori-positive and -negative patients with respect to mean age (SD) (60 6 13 vs 61 6 14 yr at baseline, respectively; p 5 0.65, Student’s t test) or duration of follow-up (SD) (54 6 30 vs 58 6 31 months, respectively; p 5 0.12, Student’s t test). None of the H. pylori-infected patients received eradication treatment during follow-up. H. pylori-infected GERD patients tended to present at baseline with less severe disease, as judged by endoscopical scoring (median Savary-Miller score 2 vs 3; p 5 0.056, Mann-Whitney test). Barrett’s esophagus was present more often among H. pylori-negative than among H. pylori-positive patients (39/88 [44%] vs 10/49 [20%]; p 5 0.006, Fisher exact test). Hiatal herniation was observed with equal prevalence in both patient groups (in 31/49 [63%] H. pyloripositive and 61/88 [69%] H. pylori-negative GERD patients; p 5 0.57, Fisher exact test) (Table 2). All patients were treated initially with 20 mg omeprazole once daily, which was sufficient to maintain remission throughout follow-up in 42 (31%) of the 137 patients. Upon long-term follow-up, an increase of the omeprazole dose to either 40 (n 5 74, 54%), 60 (n 5 5, 4%), 80 (n 5 14, 10%), or 120 (n 5 2, 2%) mg was required for symptomatic or
Table 2. Relation Between H. pylori Status, Presence of Barrett’s Esophagus, Hiatus Hernia, and Dose (Range) Required for Remission of GERD Median Savary-Miller score (1–4) Barrett’s esophagus, n (%) Hiatus hernia, n (%) Median omeprazole maintenance dose (mg) * Mann-Whitney test; † Fisher exact test.
H. pylori Positive
H. pylori Negative
p Value
2 10/49 (20%) 31/49 (63%) 40 (20–80)
3 39/88 (44%) 61/88 (69%) 40 (20–120)
0.06* 0.0055† 0.57† 0.35*
886
Schenk et al.
Figure 1. Maintenance dose of omeprazole in mg required for disease remission for H. pylori-positive (20 mg: 33%, 40 mg: 59%, 80 mg: 8% of patients) and -negative GERD patients (20 mg: 30%, 40 mg: 51%, 60 mg: 6%, 80 mg: 11%, 120 mg: 2% of patients). No difference in median dose (40 mg daily) for either patient group was observed.
endoscopical signs of GERD relapse. Decisions for dose adjustment were made by the treating gastroenterologist, without consideration of the H. pylori status. The dose of omeprazole required to keep patients in both symptomatic and endoscopical remission did not differ between the two groups (median: 40 mg vs 40 mg, respectively; p 5 0.35 Mann-Whitney U test). The distribution of the prescribed doses for both groups is given in Figure 1.
DISCUSSION H. pylori gastritis and gastric acid production influence each other closely. Starting with the effect of acid on H. pylori gastritis, various researchers have shown that alterations in acid production lead to changes in the pattern of H. pylori gastritis (10 –12). High acid production is associated with an antral-predominant gastritis pattern; low acid production is associated with corpus-predominant pangastritis. This effect is related to the optimum pH for H. pylori growth (13, 14). Contrariwise, H. pylori gastritis also influences acid production. This is a distinct phenomenon, which is most obvious at a relatively high intragastric pH, given the negative pH log scale. This is illustrated by the decrease of fasting intragastric pH after H. pylori eradication and resolution of gastritis in patients with corpus mucosal atrophy (1) and by similar effects of H. pylori status on the intragastric pH during acid-suppressive therapy (2– 6). The mechanism underlying this phenomenon remains to be elucidated. Possible explanations include bacterial production of ammonia-buffering gastric acid, and the direct effects of bacterial products, such as the vacuolating cytotoxin A and the acidinhibitory protein of H. pylori, on parietal cell function. In our opinion, however, the most likely explanation is that it is related to the effect of acid suppression on the distribution of H. pylori gastritis. Abnormal acid exposure of the esophagus is considered essential in the mechanism responsible for the symptoms and mucosal damage of reflux disease. The inhibitory effect of H. pylori gastritis on acid production may thus play a
AJG – Vol. 94, No. 4, 1999
protective role against development of GERD. The evidence in favor of this hypothesis comes from various authors. Two studies reported that GERD patients have a lower H. pylori prevalence than control subjects (15, 16). Furthermore, H. pylori eradication in duodenal ulcer patients may lead to subsequent clinical symptoms of GERD (17, 18). Finally, recent decades have shown opposing time trends of H. pylori prevalence versus incidence of esophagitis and cancer of the cardia and distal esophagus (19). In agreement with this theory, H. pylori infection, in particular of the cagApositive type, is negatively associated with cardia carcinoma (20). Our first hypothesis therefore was that the H. pylori status affects the severity of disease in patients diagnosed with pathological gastroesophageal reflux. Our data support this hypothesis, as the H. pylori-negative GERD patients tended to present with more severe reflux disease. Although the difference in reflux score between H. pylori-positive and -negative patients did not reach statistical significance (p 5 0.06), this trend was supported by the observation that the prevalence of Barrett’s esophagus was significantly higher in the uninfected patient group then among infected patients. Severe pathological gastroesophageal acid reflux is considered to be the inciting and ongoing factor for the development of Barrett’s esophagus (21). This higher prevalence of Barrett’s esophagus among H. pylori-negative GERD patients is in accordance with other studies, reporting a very low H. pylori prevalence among Barrett’s patients (15), and in particular a low prevalence of cagA-positive strains (22). The latter H. pylori type is associated particularly with more severe gastric mucosal inflammation (23) and may thus have a more pronounced acid-reducing effect in patients with corpus gastritis. Given the effect of H. pylori on intragastric pH during omeprazole therapy, our second hypothesis was that the H. pylori status also would affect the efficacy of omeprazole for maintenance treatment of GERD. Several studies have previously reported considerable individual differences with respect to doses of omeprazole required to maintain remission (varying between 20 and 120 mg daily), which variation did not correlate with the initial severity of reflux (24, 25). Although our H. pylori-negative GERD patients presented with more severe reflux disease, the mean dose of omeprazole needed for maintained remission of GERD symptoms did not depend on H. pylori status. This study therefore suggests that during proton pump inhibitor therapy, the slightly higher intragastric pH observed during infection with H. pylori is of little clinical significance for the maintenance treatment of GERD. This is in agreement with the hypothesis that the effect of H. pylori on acid output is limited and therefore only obvious at a higher pH. It is expected that in the near future more patients will receive eradication therapy for H. pylori, as indications for such therapy are broadening. Several studies have now consistently reported an accelerated progression to atrophic gastritis in H. pylori-infected GERD patients treated with pro-
AJG – April, 1999
found acid-suppressive maintenance therapy (9, 26, 27). Another recent study reported no such association between H. pylori-induced atrophic gastritis and profound acid suppression (28). In this study, 112 H. pylori-positive GERD patients were randomized to treatment with omeprazole or fundoplication. Eight of 62 of the patients receiving omeprazole developed atrophy, compared with five of 60 patients treated with a fundoplication; the difference was not significant. However, this study was hampered by a number of serious flaws. All patients, including those allocated to surgery, were first treated with omeprazole for up to 8 months. In addition, about half of the operated patients were treated not only with a fundoplication, but also with either a vagotomy or with omeprazole postoperatively. As a result, the relatively high incidence of atrophic gastritis among patients in the fundoplication group and the lack of statistical difference is likely to have been due to the inadequate control group and the limited number of patient-years of follow-up. The data presented in this study suggest that GERD patients will not require a higher dose of profound acidsuppressive therapy after H. pylori eradication. Further prospective studies are needed on this issue. We did not focus specifically on potential differences between H. pylori-positive and -negative GERD patients during the initial healing phase, nor did we randomize H. pylori-positive GERD patients to eradication or placebo, to compare the short- and long-term effects on the efficacy of acid-suppressive therapy. In conclusion, H. pylori infection affects the severity of disease in GERD patients, but the dose of omeprazole required for maintaining reflux disease in remission did not differ between H. pylori-negative and -positive GERD patients. Reprint requests and correspondence: B. E. Schenk, M.D., Department of Gastroenterology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Received Apr. 15, 1998; accepted Oct. 5, 1998.
REFERENCES 1. Ruiz B, Correa P, Fontham ETH, et al. Antral atrophy, Helicobacter pylori colonization and gastric pH. Am J Clin Pathol 1996;105:96 –101. 2. Verdu´ EF, Armstrong D, Idstro¨m J-P, et al. Intragastric pH during treatment with omeprazole: Role of Helicobacter pylori and H. pylori-associated gastritis. Scand J Gastroenterol 1996; 31:1151– 6. 3. Verdu´ EF, Armstrong D, Fraser R, et al. Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut 1995;36:539 – 43. 4. Verdu´ EF, Armstrong D, Idstro¨m J-P, et al. Effect of curing Helicobacter pylori on intragastric pH during treatment with omeprazole. Gut 1995;37:743– 8. 5. Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the pH raising effect of omeprazole in duodenal ulcer patients. Gastroenterology 1995;110:725–32. 6. Labenz J, Tillenberg B, Peitz U, et al. Effect of curing H. pylori infection on intragastric acidity during treatment with ranitidine in patients with duodenal ulcer. Gut 1997;41:33– 6.
H. pylori and Omeprazole Therapy in GERD
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7. Savary M, Miller G. The esophagus. Switzerland: Solothurn, 1977. 8. Price AB. The Sydney System: Histological division. J Gastroenterol Hepatol 1991;6:209 –22. 9. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 96;334:1018 –22. 10. Kuipers EJ, Uyterlinde AM, Pen˜a AS, et al. Increase of Helicobacter pylori associated corpus gastritis during acid suppressive therapy: Implications for long-term safety. Am J Gastroenterol 1995;90:1401– 6. 11. Logan RPH, Walker MM, Misiewicz JJ, et al. Changes in the intragastric distribution of Helicobacter pylori during treatment with omeprazole. Gut 1995;36:12– 6. 12. Solcia E, Villani L, Fiocca R, et al. Effects of eradication of Helicobacter pylori on gastritis in duodenal ulcer patients. Scand J Gastroenterol 1994;29(suppl 201):28 –34. 13. McGowan CC, Cover TL, Blaser MJ. H. pylori and gastric acid: biological and therapeutic implications. Gastroenterology 1996;110:926 –38. 14. Sachs G. Gastritis H. pylori and proton pump inhibitors. Gastroenterology 1997;112:1033– 6. 15. Werdmuller BFM, Loffeld RJLF. Helicobacter pylori has no role in the pathogenesis of reflux oesophagitis. Dig Dis Sci 1997;42:103–5. 16. Mihara M, Haruma K, Kamada K, et al. Low prevalence of H. pylori infection in patients with reflux oesophagitis. Gut 1996; 39(suppl 2):A94. 17. Sacca N, De medici A, Rodino S, et al. Reflux oesophagitis: A complication of Helicobacter pylori eradication therapy? Gut 1996;39(suppl 2):A91. 18. Labenz J, Tillenburg B, Peitz U, et al. Long-term consequences of Helicobacter pylori eradication: Clinical aspects. Scand J Gastroenterol 1996;31(suppl 215):111–5. 19. El Seraq HB, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gastroenterology 1997;112:A113. 20. Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA1 strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res 1998;58:588 –90. 21. Hassall E. Barrett’s esophagus: Congenital or acquired? Am J Gastroenterol 1993;88:819 –24. 22. Schnell JW, Vicari JJ, Perez-Perez GI, et al. H. pylori cagAnegative strains predominate in gastroesophageal reflux disease, Barrett’s esophagus, and esophageal dysplasia/adenocarcinoma. Gastroenterology 1997;112:A283. 23. Kuipers EJ, Pe´rez-Pe´rez GI, Meuwissen SGM, et al. Helicobacter pylori and atrophic gastritis; importance of the cagA status. J Natl Cancer Inst 1995;87:1777– 80. 24. Klinkenberg-Knol EC, Festen HPM, Jansen JBMJ, et al. Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Int Med 1994;121:161–7. 25. Koop H, Arnold R. Long-term maintenance treatment of reflux esophagitis with omeprazole. Prospective study in patients with H2-blocker-resistant esophagitis. Dig Dis Sci 1991;36:552–7. 26. Solcia E, Fiocca R, Havu N, et al. Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment. Digestion 1992;51(suppl 1):82–92. 27. Eissele R, Brunner G, Simon B, et al. Gastric mucosa during treatment with lansoprazole: Helicobacter pylori is a risk factor for argyrophil-cell hyperplasia. Gastroenterology 1997; 112:707–17. 28. Lundell L, Havu N, Andersson A, et al. Gastritis development and acid suppression therapy revisited: Results of a randomized clinical study with long-term follow-up. Gastroenterology 1997;112:A128.
Vol. 94, No. 4, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00037-4
ORIGINAL CONTRIBUTIONS
Helicobacter pylori and the Efficacy of Omeprazole Therapy for Gastroesophageal Reflux Disease B. E. Schenk, M.D., E. J. Kuipers, M.D., Ph.D., E. C. Klinkenberg-Knol, M.D., Ph.D., S. A. Eskes, M.D., and S. G. M. Meuwissen, M.D., Ph.D. The Department of Gastroenterology, Free University Hospital, Amsterdam, The Netherlands
OBJECTIVE: Helicobacter pylori infection may affect gastric acid output and intragastric pH. In patients with an insufficient lower esophageal sphincter, this effect may theoretically influence the severity of reflux disease, as well as the efficacy of acid suppressive therapy. To evaluate whether the H. pylori status of patients with gastroesophageal reflux disease (GERD) affects the severity of disease and the efficacy of omeprazole therapy to maintain disease remission, we conducted this study. METHODS: Patients with GERD were prospectively studied by upper gastrointestinal endoscopy with biopsy sampling for histology and H. pylori culture before start of treatment and at annual follow-up. At endoscopy, esophagitis was graded according to the criteria of Savary-Miller, and the presence of Barrett’s esophagus, hiatal herniation, or other abnormalities was recorded. Omeprazole was started at an initial dose of 20 mg daily; the dose was adjusted based on symptoms and the endoscopical findings. RESULTS: One hundred thirty-seven GERD patients were included and followed up for a mean 56.6 months; 49 (36%) of them were infected with H. pylori. H. pylori-infected and -uninfected patients did not differ with respect to age (60 6 13 vs 61 6 14 yr, p 5 0.65) or duration of follow-up (54 6 30 vs 58 6 31 months, p 5 0.12). H. pylori-negative patients tended to present with more severe esophagitis at baseline (median Savary-Miller score 3 vs 2, p 5 0.06) and had a higher prevalence of Barrett’s esophagus (39/88 vs 10/49, p 5 0.006). However, no difference was found with respect to the dose of omeprazole needed for maintained relief of symptoms and endoscopical signs of esophagitis (median 40 mg in both groups, p 5 0.35). CONCLUSIONS: H. pylori-negative GERD patients have a higher prevalence of Barrett’s esophagus, but do not need a higher dose of omeprazole to maintain symptomatic and endoscopical disease remission. (Am J Gastroenterol 1999; 94:884 – 887. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Helicobacter pylori (H. pylori) is the main pathogenetic factor in the development of gastritis and peptic ulcer disease. Bacterial colonization, gastric mucosal inflammation,
and host acid output interact closely. Two different patterns are generally recognized. First, in a situation of normal to elevated acid output, bacterial colonization and gastritis are confined predominantly to the antrum. This pattern is observed in most patients with duodenitis and duodenal ulcers. Second, in a situation of reduced acid output, H. pylori causes a pangastritis of both antrum and corpus. This pattern is observed in most patients with atrophic gastritis and its associated conditions, such as gastric ulcer disease and gastric cancer. In these cases, H. pylori-induced inflammation of the corpus mucosa causes a further reduction of the already impaired acid output. After H. pylori eradication in patients with atrophic gastritis, improvement of gastric inflammatory parameters has been observed to be associated with a partial restoration of acid output (1). By analogy, recent observations in healthy volunteers have shown that omeprazole treatment causes higher 24-h intragastric pH values in H. pylori-infected subjects than in H. pyloriuninfected subjects (2, 3). In the absence of omeprazole treatment this difference was not observed. Intragastric pH measurement before and after eradication in H. pylori-positive subjects treated with omeprazole or ranitidine showed a decrease in the median intragastric 24-h pH after eradication treatment (4 – 6). In the absence of omeprazole therapy, no changes were observed in intragastric pH after bacterial eradication (5). If patients without H. pylori have lower intragastric pH, they could be at higher risk for pathological esophageal acid exposure and the development of gastroesophageal reflux disease (GERD). In the presence of GERD, they might also require a higher dose of omeprazole for remission of reflux-related symptoms. We therefore tested the hypothesis that the severity of reflux-disease in GERD patients and the maintenance dose of omeprazole needed are related to H. pylori status.
MATERIALS AND METHODS Patients referred to our outpatient clinic with symptoms suggestive of GERD, in particular heartburn, regurgitation, or dysphagia, underwent flexible endoscopy of the upper gastrointestinal tract, following standard procedures and using Olympus Q10/20, GIF 100, and IT 100 endoscopes. Presence and grade of esophagitis, diaphragmal herniation, Barrett’s esophagus, or any other abnormality were re-
AJG – April, 1999
H. pylori and Omeprazole Therapy in GERD
corded. Patients were eligible to enter the study if endoscopical esophagitis grade 1 or more was present, according to the criteria of Savary-Miller (7). Exclusion criteria were use of proton pump inhibitors, H2-receptor antagonists in a dose exceeding the equivalent of 300 mg ranitidine daily, or prokinetic drugs in the month before study entry, as well as previous major upper gastrointestinal surgery, known or suspected Zollinger Ellison syndrome, or hypochlorhydria due to (autoimmune) atrophic gastritis. Each patient was questioned about past medical history and drug use, and was subject to physical examination. After endoscopy, omeprazole was initiated at a dose of 20 mg once daily. Follow-Up Patients were seen at the outpatient clinic semiannually. A control endoscopy was performed every year. The dose of omeprazole was adjusted if the patient complained of recurrent, poorly controlled reflux symptoms, or if endoscopy revealed recurrent signs of esophagitis. This dose adjustment was done by steps of 20 mg. Omeprazole was given as a single morning dose, unless more than 40 mg was needed. In such a case, twice-daily dosing was prescribed. If such a prescription required two unequal doses, the highest dose was usually prescribed in the morning unless nightly symptoms clearly prevailed. Biopsies At each endoscopy a total of eight biopsy specimens was obtained. For histopathological examination, two antrum and four corpus biopsies were fixated in buffered formalin. After both hematoxylin and eosin and modified Giemsa staining, they were graded by one pathologist according to the updated Sydney System for both active and chronic gastritis, atrophy, and presence of H. pylori (8). The pathologist was blinded for clinical and endoscopical data. One antrum and one corpus biopsy specimen were used for culture of H. pylori. A patient was considered H. pylori infected if culture or histopathology was positive. Statistical Analysis For statistical analysis the Student’s t, Mann-Whitney, or Wilcoxon rank-sum tests were used when applicable. A two-sided p value , 0.05 was considered significant.
RESULTS Of a total of 165 patients referred for upper gastrointestinal endoscopy with suspicion of GERD, 152 patients met the
885
Table 1. Demographics of Patients Included Into Final Analysis, Stratified for H. pylori Status
n (%) Age (SD) (yr) Follow-up (SD) (months)
H. pylori Positive
H. pylori Negative
p Value*
49 (36%) 60 6 13 54 6 30
88 (64%) 61 6 14 58 6 31
0.65 0.12
* Mann-Whitney test.
inclusion criteria and entered the study. However, 15 patients were lost to follow-up. The data of the remaining 137 patients were used for final analysis. Twelve of them participated previously in a multicenter study with emphasis on H. pylori and atrophic gastritis (9); the other patients did not participate in any previous study. A demographic description of the patients included is given in Table 1. Forty-nine (36%) patients were H. pylori positive. At baseline, 41 of them had both positive culture and histology, five patients had positive histology only, and three had positive cultures but negative histology. During follow-up, all patients remained H. pylori positive at all occasions studied, with minor variations with respect to individual test results for antrum and corpus by means of histology and culture. No differences were found between H. pylori-positive and -negative patients with respect to mean age (SD) (60 6 13 vs 61 6 14 yr at baseline, respectively; p 5 0.65, Student’s t test) or duration of follow-up (SD) (54 6 30 vs 58 6 31 months, respectively; p 5 0.12, Student’s t test). None of the H. pylori-infected patients received eradication treatment during follow-up. H. pylori-infected GERD patients tended to present at baseline with less severe disease, as judged by endoscopical scoring (median Savary-Miller score 2 vs 3; p 5 0.056, Mann-Whitney test). Barrett’s esophagus was present more often among H. pylori-negative than among H. pylori-positive patients (39/88 [44%] vs 10/49 [20%]; p 5 0.006, Fisher exact test). Hiatal herniation was observed with equal prevalence in both patient groups (in 31/49 [63%] H. pyloripositive and 61/88 [69%] H. pylori-negative GERD patients; p 5 0.57, Fisher exact test) (Table 2). All patients were treated initially with 20 mg omeprazole once daily, which was sufficient to maintain remission throughout follow-up in 42 (31%) of the 137 patients. Upon long-term follow-up, an increase of the omeprazole dose to either 40 (n 5 74, 54%), 60 (n 5 5, 4%), 80 (n 5 14, 10%), or 120 (n 5 2, 2%) mg was required for symptomatic or
Table 2. Relation Between H. pylori Status, Presence of Barrett’s Esophagus, Hiatus Hernia, and Dose (Range) Required for Remission of GERD Median Savary-Miller score (1–4) Barrett’s esophagus, n (%) Hiatus hernia, n (%) Median omeprazole maintenance dose (mg) * Mann-Whitney test; † Fisher exact test.
H. pylori Positive
H. pylori Negative
p Value
2 10/49 (20%) 31/49 (63%) 40 (20–80)
3 39/88 (44%) 61/88 (69%) 40 (20–120)
0.06* 0.0055† 0.57† 0.35*
886
Schenk et al.
Figure 1. Maintenance dose of omeprazole in mg required for disease remission for H. pylori-positive (20 mg: 33%, 40 mg: 59%, 80 mg: 8% of patients) and -negative GERD patients (20 mg: 30%, 40 mg: 51%, 60 mg: 6%, 80 mg: 11%, 120 mg: 2% of patients). No difference in median dose (40 mg daily) for either patient group was observed.
endoscopical signs of GERD relapse. Decisions for dose adjustment were made by the treating gastroenterologist, without consideration of the H. pylori status. The dose of omeprazole required to keep patients in both symptomatic and endoscopical remission did not differ between the two groups (median: 40 mg vs 40 mg, respectively; p 5 0.35 Mann-Whitney U test). The distribution of the prescribed doses for both groups is given in Figure 1.
DISCUSSION H. pylori gastritis and gastric acid production influence each other closely. Starting with the effect of acid on H. pylori gastritis, various researchers have shown that alterations in acid production lead to changes in the pattern of H. pylori gastritis (10 –12). High acid production is associated with an antral-predominant gastritis pattern; low acid production is associated with corpus-predominant pangastritis. This effect is related to the optimum pH for H. pylori growth (13, 14). Contrariwise, H. pylori gastritis also influences acid production. This is a distinct phenomenon, which is most obvious at a relatively high intragastric pH, given the negative pH log scale. This is illustrated by the decrease of fasting intragastric pH after H. pylori eradication and resolution of gastritis in patients with corpus mucosal atrophy (1) and by similar effects of H. pylori status on the intragastric pH during acid-suppressive therapy (2– 6). The mechanism underlying this phenomenon remains to be elucidated. Possible explanations include bacterial production of ammonia-buffering gastric acid, and the direct effects of bacterial products, such as the vacuolating cytotoxin A and the acidinhibitory protein of H. pylori, on parietal cell function. In our opinion, however, the most likely explanation is that it is related to the effect of acid suppression on the distribution of H. pylori gastritis. Abnormal acid exposure of the esophagus is considered essential in the mechanism responsible for the symptoms and mucosal damage of reflux disease. The inhibitory effect of H. pylori gastritis on acid production may thus play a
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protective role against development of GERD. The evidence in favor of this hypothesis comes from various authors. Two studies reported that GERD patients have a lower H. pylori prevalence than control subjects (15, 16). Furthermore, H. pylori eradication in duodenal ulcer patients may lead to subsequent clinical symptoms of GERD (17, 18). Finally, recent decades have shown opposing time trends of H. pylori prevalence versus incidence of esophagitis and cancer of the cardia and distal esophagus (19). In agreement with this theory, H. pylori infection, in particular of the cagApositive type, is negatively associated with cardia carcinoma (20). Our first hypothesis therefore was that the H. pylori status affects the severity of disease in patients diagnosed with pathological gastroesophageal reflux. Our data support this hypothesis, as the H. pylori-negative GERD patients tended to present with more severe reflux disease. Although the difference in reflux score between H. pylori-positive and -negative patients did not reach statistical significance (p 5 0.06), this trend was supported by the observation that the prevalence of Barrett’s esophagus was significantly higher in the uninfected patient group then among infected patients. Severe pathological gastroesophageal acid reflux is considered to be the inciting and ongoing factor for the development of Barrett’s esophagus (21). This higher prevalence of Barrett’s esophagus among H. pylori-negative GERD patients is in accordance with other studies, reporting a very low H. pylori prevalence among Barrett’s patients (15), and in particular a low prevalence of cagA-positive strains (22). The latter H. pylori type is associated particularly with more severe gastric mucosal inflammation (23) and may thus have a more pronounced acid-reducing effect in patients with corpus gastritis. Given the effect of H. pylori on intragastric pH during omeprazole therapy, our second hypothesis was that the H. pylori status also would affect the efficacy of omeprazole for maintenance treatment of GERD. Several studies have previously reported considerable individual differences with respect to doses of omeprazole required to maintain remission (varying between 20 and 120 mg daily), which variation did not correlate with the initial severity of reflux (24, 25). Although our H. pylori-negative GERD patients presented with more severe reflux disease, the mean dose of omeprazole needed for maintained remission of GERD symptoms did not depend on H. pylori status. This study therefore suggests that during proton pump inhibitor therapy, the slightly higher intragastric pH observed during infection with H. pylori is of little clinical significance for the maintenance treatment of GERD. This is in agreement with the hypothesis that the effect of H. pylori on acid output is limited and therefore only obvious at a higher pH. It is expected that in the near future more patients will receive eradication therapy for H. pylori, as indications for such therapy are broadening. Several studies have now consistently reported an accelerated progression to atrophic gastritis in H. pylori-infected GERD patients treated with pro-
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found acid-suppressive maintenance therapy (9, 26, 27). Another recent study reported no such association between H. pylori-induced atrophic gastritis and profound acid suppression (28). In this study, 112 H. pylori-positive GERD patients were randomized to treatment with omeprazole or fundoplication. Eight of 62 of the patients receiving omeprazole developed atrophy, compared with five of 60 patients treated with a fundoplication; the difference was not significant. However, this study was hampered by a number of serious flaws. All patients, including those allocated to surgery, were first treated with omeprazole for up to 8 months. In addition, about half of the operated patients were treated not only with a fundoplication, but also with either a vagotomy or with omeprazole postoperatively. As a result, the relatively high incidence of atrophic gastritis among patients in the fundoplication group and the lack of statistical difference is likely to have been due to the inadequate control group and the limited number of patient-years of follow-up. The data presented in this study suggest that GERD patients will not require a higher dose of profound acidsuppressive therapy after H. pylori eradication. Further prospective studies are needed on this issue. We did not focus specifically on potential differences between H. pylori-positive and -negative GERD patients during the initial healing phase, nor did we randomize H. pylori-positive GERD patients to eradication or placebo, to compare the short- and long-term effects on the efficacy of acid-suppressive therapy. In conclusion, H. pylori infection affects the severity of disease in GERD patients, but the dose of omeprazole required for maintaining reflux disease in remission did not differ between H. pylori-negative and -positive GERD patients. Reprint requests and correspondence: B. E. Schenk, M.D., Department of Gastroenterology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Received Apr. 15, 1998; accepted Oct. 5, 1998.
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