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The mechanism of the positive association between atrophic gastritis and oesophageal squamous cell carcinoma
Helicobacter pylori infection is now widely accepted to be an important risk factor for a number of gastric and duodenal disorders. It is the major aetiological factor for gastric and duodenal ulcers unrelated to NSAID or aspirin-usage. In addition, it plays an essential role in the aetiology of most cases of non-cardia gastric cancer as well as low-grade gastric MALTomas. Such is the importance of H pylori infection in disorders of the stomach and duodenum that pathology distal to the gastro-oesophageal junction is rarely encountered when endoscoping H pylori naive subjects.
Over the past few years, interest in H pylori has extended from its role in the aetiology of diseases of the stomach and duodenum to its possible role in the aetiology of diseases of the oesophagus. This has focused largely on the possibility that H pylori infection may protect against the development of gastro-oesophageal reflux disease and its complications of Barrett’s oesophagus and oesophageal adenocarcinoma.
Most epidemiological studies have demonstrated a negative association between H pylori infection and gastro-oesophageal reflux disease or its complications. The prevalence of H pylori infection is lower in reflux patients than in controls.1–,3 There is also some evidence that reflux disease in H. pylori-negative patients tends to be more severe than in H. pylori-positive patients.4 In addition, more virulent, cytotoxin-associated gene A (cag A)-positive strains of H pylori are associated with less severe reflux disease.5,6 Numerous studies have now reported a strong negative association between H pylori infection and risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction.7,8,9,10,11 The strength of the negative association between H pylori infection and reflux disease or its complications appears to be related to the countries in which the association has been studied, being more marked in the East than the West.12
The negative association observed in epidemiological studies raises the possibility of a protective effect of the infection on reflux disease but does not establish it. Such association could be explained by confounding factors, which are influencing both the prevalence of infection and prevalence of oesophageal disease. Interventional studies examining the effect of treating the infection on oesophageal disease have examined the nature of the association. Such studies have produced conflicting results, showing that treating the infection may increase, decrease or have no effect on reflux disease.13,14 Just as an East-West divide is apparent with respect to the epidemiological relationship between H pylori and reflux disease, a similar East-West divide is apparent with respect to the effect of treating the infection on reflux disease. In the East, treating H pylori aggravates GERD, but not in the West.15–,18
Is there a biological explanation for the complex association between H pylori and reflux disease and the variations in the association between different regions of the world? A plausible explanation lies in the complex effects which H pylori infection exerts on gastric acid secretion, which is the most damaging factor in the development of reflux disease and its complications. H pylori infection may increase, decrease or have no overall effect on acid secretion, and its effect depends upon the pattern of gastritis induced by the infection.19 In some patients, the infection produces an antral-predominant, non-atrophic gastritis and this increases the level of gastric acid secretion. This pattern of gastritis is seen in subjects who develop duodenal ulceration. In other patients, the infection produces an atrophic gastritis involving the entire stomach and causing a marked reduction, or complete absence, of acid secretion. This pattern of gastritis is associated with an increased risk of non-cardia gastric cancer. In patients with gastric ulcers, the pattern of gastritis is between these two extremes or more towards the atrophic gastritis end of the spectrum.20–,25 Eradicating H pylori infection returns the levels of acid secretion towards normal, though full restoration of normal secretion is not achieved when there is severe atrophy.26 It can therefore be seen that H pylori infection should not be regarded as a single entity with respect to its effects on acid secretion, and thus also with regard to effects on oesophageal reflux disease and its complications.27
The paper by Bahmanyar et al27 in this issue of Gut (see page 464) investigates indirectly the influence of the pattern of gastritis induced by H pylori infection on the association between the infection and oesophageal adenocarcinoma. This has been done by examining the incidence of oesophageal adenocarcinoma developing in patients with a history of duodenal ulceration, gastric ulceration and controls. The duodenal ulcer patients represent a group with H pylori antral-predominant, non-atrophic gastritis and high acid secretion, and the gastric ulcer patients, a group with more atrophic gastritis and normal or low acid secretion.20–,25 They found that the H. pylori-infected duodenal ulcer subjects had an increased risk of oesophageal adenocarcinoma, whereas there was no association between gastric ulcer and oesophgeal adenocarcinoma.
This observation supports the hypothesis that it is not H pylori itself which may influence reflux disease and its complications but the effects of the infection on acid secretion. Consequently, H pylori infection may be associated with an increased risk of oesophageal adenocarcinoma in patients in whom it causes high acid secretion secondary to an antral-predominant, non-atrophic gastritis.
The pattern of gastritis induced by H pylori infection being the determinant of the effects of the infection on reflux disease fits comfortably with the different findings in the East versus West. In the East, H pylori infection tends to be associated with a high incidence of atrophic gastritis and low acid secretion, which is likely to protect against reflux disease.28 In contrast, in the West, the infection is more often associated with antral-predominant, non-atrophic gastritis, which may aggravate reflux disease.
The history of H pylori infection is that as soon as the mechanism of its association with one disease becomes clarified, its association with yet another disease becomes apparent. When the role of H pylori infection in gastric and duodenal disorders became established, its negative association with oesophageal reflux disease and oesophageal adenocarcinoma became apparent. No sooner has the mechanism of its role in these latter diseases become clear, than its association with oesophageal squamous cell carcinoma has become apparent.
Ye et al first reported that oesophageal squamous cell carcinoma was positively associated with both serological evidence of atrophic gastritis and with H pylori CagA-positive infection in the Swedish population.10 A similar association has recently been observed in Japan.29 The current paper by Bahmanyar in this issue of Gut provides further evidence of an association between H pylori atrophic pattern of gastritis and oesophageal squamous carcinoma by finding that gastric ulcer patients have an 80% increased risk of the cancer.
The new challenge facing us is to clarify the mechanism of the positive association between atrophic gastritis and oesophageal squamous cell carcinoma. Is it due to confounding factors that predispose to both oesophageal squamous cell carcinoma and gastric atrophy? The study by Ye et al largely excludes confounding due to smoking or alcohol.10 Is there an underlying genetic predisposition to both diseases? Or is there a mechanism by which atrophy increases the risk of oesophageal squamous carcinoma, such as bacterial overgrowth leading to N-nitroso compound generation or a nutritional effect? Each of these possible mechanisms now need to be investigated.
The extent and complexity of the association between H pylori and upper GI disease is now quite staggering. It is an important risk factor for ulcers of the stomach and duodenum, for gastric cancer and also for low-grade MALToma. It is associated with a reduced risk of oesophageal adenocarcinoma when it induces gastric atrophy but an increased risk when it induces a non-atrophic antral-predominant gastritis. It is now also associated with squamous cell carcinoma when it induces atrophic gastritis.
One concern about eradicating H pylori in the general population has been the possible adverse effects this might have on the incidence of reflux disease and oesophageal adenocarcinoma. However, the observation that H. pylori-positive subjects with an antral-predominant, non-atrophic gastritis have an increased risk of oesophageal adenocarcinoma and that H pylori atrophic gastritis is associated with an increased risk of oesophageal squamous cell carcinoma indicate that H pylori is not always protective with respect to serious oesophageal disease.
Competing interests: None declared.
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