Published 14 August 2009, doi:10.1136/bmj.b2784
Cite this as: BMJ 2009;339:b2784

Head to Head

Does Helicobacter pylori really cause duodenal ulcers? Yes

Alexander C Ford, lecturer in medicine1, Nicholas J Talley, professor of medicine, visiting professor of medicine2,3

1 Department of Academic Medicine, St James’s University Hospital, Leeds LS9 7TF, 2 Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida, FL 32224, USA, 3 Department of Medicine, University of Sydney, Nepean Hospital, Sydney, Australia

Correspondence to: A C Ford alexf12399{at}yahoo.com

The link between duodenal ulcer and Helicobacter pylori has revolutionised treatment. Alexander Ford and Nicholas Talley argue that the association is causal, but Michael Hobsley and colleagues (doi:10.1136/bmj.b2788) believe acid secretion is the key

Helicobacter pylori infects the human stomach and is acquired predominantly in childhood.1 Infection is from person to person, and evidence points to transmission through the gastro-oral route.2 Gastric biopsy shows that all infected people have either antral or corpus predominant gastritis.3 Which of the two develops probably depends on the person’s parietal cell mass at the time of infection.

Evidence

Although causation can never be proved (hypotheses can only be dispelled), evidence for the causative role of H pylori in duodenal ulcer is remarkably compelling and fulfils the Bradford Hill criteria—for example, showing a strong, consistent, specific, and temporal association (box). The National Institutes of Health judged H pylori to be the main cause of the condition in 1994. A causal association between H pylori and chronic gastritis was proposed at the time of its discovery, and Koch’s postulates have since been fulfilled for this histological lesion.4


Bradford Hill criteria for causal link between H pylori and duodenal ulcer
Strength—Odds ratio for association strong (4-fold to 16-fold increased risk)6
Consistency—Relation between H pylori and duodenal ulcer observed worldwide12
Specificity—No other likely explanation for the association, eg, excessive gastric acid8 9 10
Temporality—H pylori infection predates occurrence of duodenal ulcer1 6
Biological gradient—Falling prevalence of H pylori is linked to lower incidence of duodenal ulcer10
Plausibility—Mechanism between cause and effect described3 8
Coherence—H pylori causes antral gastritis and excessive acid production. Mongolian gerbils develop duodenal ulcer after H pylori infection5
Experiment—Eradication of H pylori leads to duodenal ulcer healing and a large reduction in risk of recurrence7


It has been more difficult to confirm the same link in duodenal ulcer as in gastritis because it would be unethical to inoculate people with the bacterium to induce an ulcer. However, when Mongolian gerbils are injected with H pylori, they develop duodenitis, gastric metaplasia, and duodenal ulcer.5 In humans, pre-existing infection with H pylori is significantly associated with subsequent development of duodenal ulcer.6 This, together with the fact that most infection is acquired during childhood,1 suggests that presence of the bacterium predates and predisposes to ulcer formation, rather than that existing ulceration provides ideal conditions for H pylori to exploit.

In patients who go on to develop duodenal ulcer it is proposed that H pylori infection induces antral gastritis, which leads to hypergastrinaemia, and hypersecretion of acid by the corpus. Excess acid washing over the duodenal bulb causes gastric metaplasia in the duodenum, allowing colonisation by H pylori, induction of an inflammatory response, and focal ulceration. A meta-analysis of randomised controlled trials has shown that eradication of H pylori infection in people with duodenal ulcer confers significant benefits, in terms of both facilitation of ulcer healing and prevention of relapse, compared with a course of acid suppression therapy alone.7 Successful eradication of the organism also leads to normalisation of acid production by the stomach.8

Chicken and egg

Before the discovery of H pylori, duodenal ulcer was thought to arise as a result of excessive acid production. However, gastric acid secretion is proportional to lean body mass,9 which is increasing in the general population. If duodenal ulcer were predominantly acid related, its incidence should be increasing in the Western world, in line with that of other acid related disorders such as gastro-oesophageal reflux disease.10 Instead, the reverse is the case, with studies showing a fall.10 This is mirrored closely by trends in H pylori infection, with prevalence falling by increasing year of birth over the past 20 to 30 years.1 11 The advent of treatment to eradicate H pylori infection has greatly reduced the frequency with which duodenal ulcer is encountered at endoscopy.11 Taken together, these data provide further support for a causative role of H pylori in duodenal ulcer.

Some researchers argue that H pylori is a bystander in duodenal ulcer, and cite a high prevalence of infection with the bacterium in the developing world, coupled with a low prevalence of duodenal ulcer, as evidence against causality. This has been termed the African enigma. A systematic review that examined this issue identified 40 studies reporting prevalence of endoscopic findings in 17 African nations, with duodenal ulcers occurring in 20% of individuals.12 It concluded that the frequency of complications of H pylori infection in Africa are similar to those seen in Western countries, with no dissociation between prevalence of H pylori infection and H pylori related diseases.

Arguments for eradication

Even if H pylori is not the causative agent in duodenal ulcer, eradication of the organism leads to ulcer healing and significantly reduces the likelihood of ulcer relapse, unless infection recurs (in contrast to acid suppression therapy where disease usually recurs after discontinuation). It is also cost effective, dominating all other management strategies in Markov modelling.7

H pylori has been linked definitively to the development of distal gastric cancer,13 and the World Health Organization classifies it as a human carcinogen. Searching for and eradicating the bacterium in high risk populations reduces incidence of gastric cancer.14 Critics argue against adopting this approach as gastric cancer is becoming rare in western countries. However, population screening and treatment programmes conducted in Europe have shown significant reductions in the prevalence of dyspepsia in the community. This strategy is therefore likely to be cost neutral to the health service in the long term.15

When we encounter a duodenal ulcer at upper gastrointestinal endoscopy, we call in our registrars because it is now a rare occurrence. The explanation that by far best fits all of the known facts is simple: H pylori causes peptic ulcer disease directly. We know of no compelling argument disproving this link.

Cite this as: BMJ 2009;339:b2784

Competing interests: None declared.

References

  1. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis 1993;168:219-21.[Web of Science][Medline]
  2. Leung WK, Siu KLK, Kwok CKL, Chan SY, Sung R, Sung JJY. Isolation of Helicobacter pylori from vomitus in children and its implication in gastro-oral transmission. Am J Gastroenterol 1999;94:2881-4.[CrossRef][Web of Science][Medline]
  3. Schultze V, Hackelsberger A, Gunther T, Miehlke S, Roessner A, Malfertheiner P. Differing patterns of Helicobacter pylori gastritis in patients with duodenal, prepyloric, and gastric ulcer disease. Scand J Gastroenterol 1998;33:137-42.[CrossRef][Web of Science][Medline]
  4. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch’s postulates for pyloric Campylobacter. Med J Aust 1985;142:436-9.[Web of Science][Medline]
  5. Ohkusa T, Okayasu I, Miwa H, Ohtaka K, Endo S, Sato N. Helicobacter pylori infection induces duodenitis and superficial duodenal ulcer in Mongolian gerbils. Gut 2003;52:797-803.[Abstract/Free Full Text]
  6. Rosenstock S, Jorgensen T, Bonnevie O, Andersen L. Risk factors for peptic ulcer disease: A population based prospective cohort study comprising 2416 Danish adults. Gut 2003;52:186-93.[Abstract/Free Full Text]
  7. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: Systematic review and economic analysis. Am J Gastroenterol 2004;99:1833-55.[CrossRef][Web of Science][Medline]
  8. Iijima K, Ohara S, Sekine H, Koike T, Kato K, Asaki S, et al. Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication. Gut 2000;46:20-6.[Abstract/Free Full Text]
  9. Baron JH. Lean body mass, gastric acid and peptic ulcer. Gut 1969;10:637-42.[Abstract/Free Full Text]
  10. El-Serag H, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gut 1998;43:327-33.[Abstract/Free Full Text]
  11. Harvey RF, Spence RW, Lane JA, Nair P, Murray LJ, Harvey IM, et al. Relationship between the birth cohort pattern of Helicobacter pylori infection and the epidemiology of duodenal ulcer. QJM 2002;95:519-25.[Abstract/Free Full Text]
  12. Agha A, Graham DY. Evidence-based examination of the African enigma in relation to Helicobacter pylori infection. Scand J Gastroenterol 2005;40:523-9.[CrossRef][Web of Science][Medline]
  13. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347-53.[Abstract/Free Full Text]
  14. Moayyedi P, Hunt RH, Ford AC, Talley NJ, Forman D. Helicobacter pylori eradication reduces the incidence of gastric cancer: results of a systematic review of randomized controlled trials. Gastroenterology 2008;134(suppl 1):A631-2.
  15. Ford AC, Forman D, Bailey AG, Axon ATR, Moayyedi P. A community screening program for Helicobacter pylori saves money: ten-year follow-up of a randomised controlled trial. Gastroenterology 2005;129:1910-7.[CrossRef][Web of Science][Medline]

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