It is now known that a large majority of benign gastric and duodenal ulceration is due to H. pylori infection (following Marshall and Warren’s Nobel prize-winning experiments ¹^,²); most of the remainder can be attributed to NSAID use. Colonisation of the stomach with H. pylori is seen in virtually all patients with a duodenal ulcer and in 70–80% of those with gastric ulcers. H. pylori appears to stimulate increased acid secretion. All patients colonised with H. pylori develop gastritis, but only about 20% have ulcers or other lesions. As yet incompletely understood host factors and differences in strain of the organism are likely to explain this discrepancy.

H. pylori infection is carcinogenic and is the leading cause of gastric carcinoma. It is also highly associated with gastric MALT lymphoma. Eradication of the organism can lead to regression and even resolution of this latter malignancy.

Somewhat counterintuitively, H. pylori infection is not a cause of acid reflux disease, and in fact its eradication may precipitate or exacerbate acid reflux. Indeed, the recent surge in oeosphageal adenocarcinoma incidence in the West has been blamed by many on the now commonplace practice of searching for and eradicating H. pylori, although this has conversely resulted in a fall in the incidence of gastric cancer.

NSAIDs: enemies of the gut

Some 500 million prescriptions for NSAIDs are written each year in the UK, and 10–15% of patients develop dyspepsia while taking these drugs. Gastric erosions develop in up to 80%, but these are usually self-limiting. Gastric or duodenal ulcers occur in 1–5%. The incidence increases sharply with age in those over 60 years, and the risk of ulcers and their complications is doubled in patients aged more than 75 years and those with cardiac failure or a history of peptic ulceration or bleeding. All NSAIDs are ulcerogenic, but ibuprofen is less prone to cause these problems than other non-selective NSAIDs.

NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their non-ionic diffusion into gastric mucosal cells. Here the neutral intracellular pH causes the drugs to become ionised and trapped in the mucosa because they cannot diffuse out in this form.

Aspirin and the other NSAIDs inhibit cyclo-oxygenase (COX) (see Ch. 16). In the stomach, the constitutively expressed COX-1 isoform is responsible for the production of the gastroprotective prostaglandins E2 and I2 (see above). Inhibition of the inducible COX-2 isoform (which is normally up-regulated in activated inflammatory cells) is responsible for NSAIDs’ anti-inflammatory properties. Most NSAIDs inhibit both isoforms unselectively, so the beneficial anti-inflammatory effect is offset by the potential for mucosal injury by depletion of protective prostaglandins. Aspirin is particularly potent in this respect, perhaps because it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent.

Selective COX-2 inhibitors represent an attempt to provide beneficial anti-inflammatory effects without promoting ulceration. Unfortunately, there is evidence that unopposed COX-2 inhibition results in an increased risk of thrombotic events (including myocardial infarction and stroke); the UK Committee on Safety of Medicines therefore counsels against their use in preference to non-selective NSAIDs in the absence of a compelling indication, and cardiovascular risk should be assessed.