Controversies in Management: Helicobacter pylori is not the causative agentBMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6968.1571 (Published 10 December 1994) Cite this as: BMJ 1994;309:1571
- C O Record, consultant physician in gastroenterologya
A pathogenic role for helicobacter in the stomach has been proposed for the past 10 years, but despite about a thousand publications a year on this subject, treatment to eradicate helicobacter remains controversial. Several questions need to be considered.
Does Helicobacter pylori cause peptic ulcers?
In the 19th century there was much controversy concerning the role of micro-organisms and the causation of disease. These discussions resulted in the formulation of Koch's postulates. The first is that the infectious agent occurs in every case of the disease and under circumstances that can account for the pathological changes and clinical course of the disease.
About 95% of patients with symptomatic duodenal ulcer are colonised with H pylori, 50% of those with perforated duodenal, and 17% of those with bleeding duodenal ulcers.1 2 3 About 77% of patients with gastric ulcer are colonised.4 Thus not all patients are infected while those with the severest disease resulting in complications exhibit a lower colonisation rate than patients presenting with uncomplicated dyspepsia.
By extension of this first postulate the organism should not occur in other disease as a fortuitous and non-pathogenic parasite. Epidemiological studies in Europe have shown about 33% of normal adults are colonised with H pylori.5 In developing countries 67% of asymptomatic adults and 40% of children under 10 years old are colonised in the absence of peptic ulcer disease.5 Thus in most patients H pylori must be considered as a fortuitous and non-pathogenic agent.
Koch also stated that after being isolated and grown in pure culture the organism should be able to induce the disease. There are two studies which need to be considered. In the first one by Marshall et al inoculation resulted in dyspepsia on day 7 and biopsy proved gastritis in the presence of H pylori at day 10.6 Gastric biopsies on day 14 showed a decrease in gastritis, and organisms could no longer be recovered. Morris and Nicholson also found dyspepsia at day 3, biopsy proved gastritis at day 5, and gastritis associated with H pylori colonisation at day 11.7 However, between days 11 and 19 there was hypochlorhydria (intragastric pH 7.6 to 7.9). Duodenal ulcers are known to develop in patients with high acid production, and achlorhydria is generally regarded as protective. Not surprisingly in these studies there was no endoscopic evidence of peptic ulceration. Other studies have also commented on epidemic hypochlorhydria that has developed after measuring 24 hour intragastric pH. The hypochlorhydria has been attributed to coincidental infection from a contaminated pH electrode, probably with H pylori.8
Can H pylori be eradicated?
Many studies have shown that eradicating H pylori is difficult. Traditional remedies for peptic ulcer disease, including H2 receptor antagonists, proton pump inhibitors, and sucralfate do not affect antihelicobacter activity. But bismuth chelates have minimum concentrations to achieve 90% inhibition of 16-25 mg/l.9 A large range of antibiotics have high activity against H pylori, with minimum inhibitory concentrations ranging from 0.03 mg/l for ampicillin to 1 mg/l for rifampicin.9 However, when used singly antibiotics are largely ineffective for eradicating H pylori. Thus amoxycillin 375 mg eight hourly for 28 days resulted in only a 30% elimination rate, while 500 mg 12 hourly of tetracycline failed to eradicate any organisms.10 In a meta-analysis amoxycillin on its own eradicated 23% of cases, bismuth 19.6%, and miscellaneous other agents 8.2%.11 The efficacy could be greatly improved by combining three antibiotics, and the combination of bismuth, metronidazole, and amoxycillin for between 10 days and one month led to a 73% eradication rate. A regimen of tetracycline, metronidazole, and bismuth for up to four weeks eradicated 94%, the overall efficacy of all triple drug treatment being 82%.11
The main problem with prolonged treatment is compliance. For triple treatment up to 350 tablets have to be taken over four weeks, and when there is an appreciable departure from the treatment schedule, much lower eradication rates are observed. Furthermore about 30% of patients experience complications of drug therapy. Compliance with five day regimens is low, so the prospects of compliance for two to four week courses are remote.
Does eradication cure the disease?
The combination of H2 receptor antagonist with antibiotics for the acute treatment of duodenal ulcer leads to only a small gain in healing rate compared with the H2 receptor antagonist alone.12 In one study 48% of patients remaining free of colonisation four weeks after completing the course of eradication developed an ulcer within six months of healing.13
Is eradication cost effective?
H pylori has been associated with peptic ulcer, gastritis, and gastric cancer. More than 20 million people are infected with the organism in the United Kingdom, and treatment of all of these will be required to significantly alter the burden of upper gastrointestinal disease in the community. Assuming 100% efficacy and no reinfection, a four week triple therapy course including tetracycline would cost more than pounds sterling 500 million.
Perhaps we should consider another common gastrointestinal condition—namely, diverticulosis. This is more common in the population than peptic ulcer. Like H pylori it is progressively acquired through life. All patients with diverticulosis have bacteroides in their colon. Exacerbations of diverticulitis are usually treated with courses of antibiotics, but does bacteroides cause colonic diverticula? Very few people would draw such a conclusion. Until more effective antibiotics are available eradication of H pylori should not be pivotal in the management of peptic ulceration, but it would seem prudent to attempt elimination when ulcers recur after other treatment.
Commentary: eradication worth while if colonisation is established
It is clear that Helicobacter pylori does not cause all cases of duodenal and gastric ulceration. On the other hand, it is associated with a sizeable proportion of these conditions and, more im-portantly, eradicating H pylori by means of antibiotics leads to healing of the ulcer. Routine eradication of H pylori in all people with peptic ulceration seems inappropriate since many people will be treated unnecessarily for a problem they haven't got. But if a person with peptic ulcer disease is shown to have H pylori then eradication is indicated.—PETER C RUBIN, professor of therapeutics, University of Nottingham
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