Published 14 August 2009, doi:10.1136/bmj.b2788
Cite this as: BMJ 2009;339:b2788

Head to Head

Does Helicobacter pylori really cause duodenal ulcers? No

¹ University College London Medical School, London N20 8AS , ² Rotherham General Hospital, Rotherham, ³ Windeyer Institute for Medical Sciences, University College London

The link between duodenal ulcer and Helicobacter pylori has revolutionised treatment. Alexander Ford and Nicholas Talley (doi:10.1136/bmj.b2784) argue that the association is causal, but Michael Hobsley and colleagues believe acid secretion is the key

Helicobacter pylori and duodenal ulcer are linked. However, association does not prove causation. An association between A and B may mean that A causes B, B causes A, or both B and A are caused by another factor.

Without detracting from the Nobel prize winning investigation that first drew attention to the role of H pylori, we think that H pylori infection does not cause duodenal ulcer but prevents healing of an ulcer produced by hypersecretion of gastric acid. Acid diminishing treatment reduces the principal barrier against gastric H pylori infection and so the patient becomes infected.

No link with prevalence

If H pylori were the primary cause, we would not see regional variation in the prevalence of duodenal ulcer within areas of high prevalence, particularly developing countries.^{1 2 3 4 5} This does not refer to Holcombe’s "African enigma,"⁶ the alleged finding that duodenal ulcer was uncommon in Africa despite near ubiquity of the organism; that suggestion has been consigned to oblivion by Agha and Graham’s elegant systematic review showing that difficulties in reporting and in delivering medical care were responsible.⁷ However, in rural areas in developing countries, there are marked differences in prevalence of duodenal ulcer. These differences seem to be related to the staple diet and the local climate. For instance, in both India and China duodenal ulcer is commoner in the south than the north despite a lack of corresponding differences in H pylori infection.^{1 2 3 4} This regional effect is visible in Agha and Graham’s review: the percentages of endoscopic duodenal ulcer in areas of low rainfall are about one half of those in other areas, supporting earlier findings.⁵ Moreover, H pylori infection has been present for many centuries, but duodenal ulcer emerged only around 1900.¹

Can different virulent strains explain these discrepancies? Reports from 19 developing countries, where H pylori infection is almost ubiquitous (70-90%) and 77-88% of the strains carry the virulence factors cagA and vacA, show no relation between these factors and clinical outcome.⁸

In developed countries, duodenal ulcers occur in people without H pylori infection, even if we exclude factors such as non-steroidal anti-inflammatory drugs and Crohn’s disease. Ulcers are proportionately more common (up to 75% of all cases) in areas of low H pylori prevalence.¹ Duodenal ulceration can also recur after eradication without re-infection.⁹ Again, half of patients with acute perforations of a duodenal ulcer (that is, with only a brief period of previous indigestion) are H pylori negative.¹⁰ Three papers report patients with a short history of duodenal ulcer being H pylori negative and that infection rates increase with length of history. These results are more consistent with duodenal ulcer causing infection with H pylori than with the reverse.^{11 12 13}

Acid secretion

These arguments preclude H pylori infection as the primary cause, but there is no doubt that treatment of H pylori infection does lead to quicker and more stable healing of duodenal ulcer. How can this be explained? Before Warren’s epic paper in 1984 it was generally accepted that duodenal ulcer was due to high acid secretion. Effective measures to reduce acid output, surgical or medical, led to long term healing, despite (presumably) persistence of H pylori infection; ineffective measures did not. We conclude that a high acid output is the primary cause, and that H pylori infection is secondary, delaying healing and leading to chronicity. It delays healing by impairing angiogenesis,^{14 15} diminishing the local blood supply to the ulcer area, and by interfering with the healing of damaged duodenal epithelial cells.¹⁶ These effects explain how eradicating the organism converts a chronic relapsing disease into one that can be cured.

Our suggestions explain the fact that H pylori infection is more common in people with duodenal ulcer than those without ulcers. The ability of H pylori to colonise the stomach is pH dependent.^{17 18} At a low pH the patient is likely to be uninfected. Later, as a result of treatment suppressing acidity, H pylori infection occurs, starting initially in the antrum because of its higher pH.

The antral infection results in hypergastrinaemia, which causes an increased output of acid. Many think that this increase is sufficient to cause duodenal ulceration. However, duodenal ulcer occurs only in patients whose maximal acid output in response to continuous intravenous histamine stimulation exceeds a certain level; above that level ulcers increase with secretion rate, and above the upper 95% tolerance limit of the population they become inevitable.¹⁹ Accurate techniques²⁰ show that H pylori infection reduces maximal histamine stimulated acid output in people with and without duodenal ulcer.²¹ A bacterium that depresses maximally stimulated gastric secretion is unlikely to cause a condition associated with hypersecretion of maximally stimulated gastric acid.

Advocates of eliminating H pylori from a population to reduce gastric cancer incidence should be aware that they may be increasing the likelihood of duodenal ulcer by removing a brake on gastric acid secretion.

Cite this as: BMJ 2009;339:b2788

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Competing interests: KDB has received partial reimbursement from Nycomed, with whom he has worked for many years on oesophageal reflux, for attending two American Gastroenterological Association Meetings and an unconditional grant to fund a PhD programme in the history of medicine at Manchester University.

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