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GastroenterologyHelicobacter pylori

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Reinhold Stockbrugger Get rid of H. pylori before you start a PPI.
Reinhold Stockbrugger, 15 July 2000

Gastric infection with Helicobacter pylori is now accepted as one possible cause of gastric cancer. Although eradication of this bacterium has been widely advocated for in the treatment and prevention of duodenal and (less often) gastric ulcer, global eradication for prevention of gastric cancer is still under discussion.

The carcinogenicity of H. pylori is thought to be conducted via its capacity to induce chronic atrophic gastritis with formation of intestinal metaplasia, both accepted as precancerous lesions. Specific properties of host and bacterium seem to condition the final outcome of gastric carcinoma.

In 1996 Kuipers et al. (N Engl J Med 1996; 304: 1018-22.) alarmed the medical public with a report indicating that H. pylori positive patients subjected to long-term gastric acid inhibition by proton pump inhibitors (PPIs) were at an elevated risk of developing atrophic gastritis.

The study was retrospective, as was the study published by Lundell et al. (Gastroenterology 1999; 117: 319-26.) comparing H. pylori-positive reflux patients treated by either PPI or anti-reflux surgery, and rejecting the conclusions of the Kuipers study.

About this controversy a heated discussion has been going on in many congress auditoria and in the medical press (Gastroenterology 2000; 118: 238-42.), without any final solution so far. However, recently some short-term prospective evidence has been published supporting the hypothesis that eradication of H. pylori before the start of long-term treatment with PPIs may prevent the accelerated development of chronic gastritis (Schenk et al. Gut 2000; 46: 615-21.).

Everything in this discussion would be much easier if a prospective, well-controlled, randomized long-term intervention study were available. Alternatively, at least a hypothesis could be formulated about the pathophysiology behind the potential acceleration of the chronic atrophic gastritis in PPI-treated H. pylori positive patients, which could be tested by proxy parameters.

The following lines will be used to present such hypothesis, claiming that double-infection of the stomach with H. pylori and non-H. pylori intragastric bacteria could be the cause of rapidly developing chronic atrophic gastritis during PPI treatment.

Let us recall what happens when H. pylori positive subjects - for whatever reason - are subjected to profound acid inhibition, either by sufficient doses of histamine 2 receptor antagonists (H2RAs) or by PPIs. The 24-hour intragastric pH will become considerably elevated, serum gastrin increases and also serum chromogranin A - possibly as a consequence of ECL cell hyperfunction or hyperplasia. The H. pylori is displaced from the gastric antrum to the corpus and fundus. Furthermore - and this was easily forgotten in the above mentioned discussion - the gastric lumen becomes colonized by aerobic and, to a minor degree, anaerobic gram-positive and gram-negative bacteria (Stockbrugger et al. Gut 1982; 23: 1048-54.). This bacterial overgrowth is similar to that found in spontaneous achlorhydria due to autoimmune atrophic gastritis or in the post-gastrectomy situation. Could the intragastric bacterial overgrowth be of any importance in the present discussion?

So far intragastric bacterial overgrowth has been seen as an innocent contamination, theoretically reversible when each occasional "shot" of gastric acid is supposed to clear the gastric lumen. This assumption is probably based on wishful thinking and on the lack of hard scientific data. One has to remember that the acceptance of the H. pylori as a gastric pathogen initially suffered from the unproven idea that it is just a saprophyte.

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In the past, to our knowledge, only one study has compared the type and concentration of non-H. pylori intragastric flora in gastric juice and gastric mucosa (Dolby et al. Scand J Gastroenterol 1984; 19: 105-10.). Recently we have developed a combined staining method that allows differentiation in the same gastric biopsy specimen between H. pylori and non-H. pylori flora. This has led to the discovery that the latter flora in patients with gastric cancer can be found in similar positions as H. pylori on the gastric surface and in the gastric crypts (Jonkers et al. Eur J Clin 1997; 27: 885-92.). It is plausible that the same could happen in long-term gastric acid inhibition, where the median 24-hour pH can reach values above 5.0 and where the lowest pH might remain well above the bactericidal pH of 3.0 throughout 24 hours.

What if it could be proven that intragastric growth of non-H. pylori bacterial flora, as a consequence of profound acid inhibition, was not just a contamination but a real superinfection of the gastric mucosa? Furthermore, what if the combined infection with both types of microbial flora (Helicobacter and non-Helicobacter) leads to development of atrophic gastritis more rapidly than the infection with either type of flora alone? In that case the Koch criteria for an infection could also be applied to the non-H. pylori flora developing during profound acid inhibition in H. pylori positive subjects.

A hypothesis like this could easily be tested in well-performed retrospective cohort studies (comparable to those by Parsonnet et al. suggesting the cancerogenecity of H. pylori (N Engl J Med 1991; 325: 1127-31.). Also, the hypothesis of the "double-infection" of the gastric mucosa as a cause of rapidly developing chronic atrophic gastritis could probably confirmed more easily by prospective studies than the carcinogenicity of H. pylori, as atrophic gastritis precedes the development of cancer by many years.

If the hypothesis of the gastric "double-infection" could be proven, would it be useful to get rid of H. pylori before launching a long-term treatment with PPIs or effective H2RAs in the individual patient? Our answer is: "Most probably, yes!" on the basis that the single infection with non-H. pylori bacteria does not seem to damage the gastric mucosa to a major degree (Stockbruegger et al. Scand J Gastroenterol 1984; 19: 355-64.). Eradicating the H. pylori would then at least prevent the slow progression of atrophic gastritis, that must be attributed to this microbe in any case, and would certainly interrupt the rapid development of chronic atrophic gastritis produced by the super-additive effect produced by the hypothesized intragastric "double-infection" with H. pylori and non-H. pylori bacterial flora.

It has to be mentioned that the hypothesis presented above is not only inspired by our extensive research in the field of non-H. pylori infection of the upper gastrointestinal tract, but is supported by a body of findings presently being submitted by this group to peer review in major journals and conventions.

Reinhold W. Stockbrugger, with Silvia Sanduleanu, Daisy Jonkers, Adriaan de Bruine*, Wim Hameeteman.

Depts of Gastroenterology/Hepatology and Pathology*, University Hospital Maastricht, The Netherlands.

This article originally appeared on 15 July 2000.

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