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FAP: another indication to treat H pylori
  1. B Leggett
  1. Department of Gastroenterology, Royal Brisbane Hospital, Herston 4029, Brisbane, Australia; barbara-leggett{at}health.qld.gov.au

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Does infection of familial adenomatous polyposis (FAP) patients with Helicobacter pylori lead to chronic atrophic gastritis and an increased risk of gastric adenoma?

The report in this issue of Gut on the impact of Helicobacter pylori infection and mucosal atrophy on gastric lesions in patients with familial adenomatous polyposis (FAP)1 highlights the complex interplay between genetic and environmental factors in the genesis of malignancy and has therapeutic implications for the management of these patients [see page485]. A similar interplay has been observed in hereditary non-polyposis colorectal cancer where gastric cancer was quite common in earlier generations but has become less common recently, a change paralleling that seen in the general Western population.2

In Western patients with FAP the incidence of gastric adenoma is of the order of 2–6%. The incidence of gastric cancer is little if at all elevated above the general population3 and the major concern with these patients is the high risk of duodenal and periampullary cancer. However, in Japan the risk of gastric cancer in these patients is significantly elevated and a high incidence of gastric adenomas has been recognised for some time.4 The incidence of 39% reported in the present study is slightly less than the 50% reported by Iida and colleagues.4

The spectrum of APC gene mutations which cause FAP is not different between Japanese and Western populations so it seems that the observed differences in prevalence of gastric neoplasia are most likely related to the same factors which make sporadic gastric cancer much more common in Japan. One of these factors is the high prevalence of Helicobacter pylori which has been linked to sporadic gastric adenomas in addition to carcinoma.5 The relative risk of gastric cancer conferred by Helicobacter infection is greatest at a young age and is mainly confined to the distal stomach,6 the same location that gastric adenomas occur in FAP patients. Evidence suggests that Helicobacter predisposes to cancer by causing chronic atrophic gastritis and intestinal metaplasia.

These observations lead naturally to the hypothesis that infection of FAP patients with Helicobacter leads to chronic atrophic gastritis and an increased risk of gastric adenoma. The present study tests this hypothesis in one of the few practical ways: the occurrence of gastric adenomas in FAP patients is correlated with the presence of Helicobacter infection and gastric mucosal atrophy in a Japanese population where substantial numbers of patients have gastric adenomas and Helicobacter. The results support the hypothesis, as subjects with gastric adenomas alone had the highest incidence of Helicobacter and mucosal atrophy, subjects with fundic gland polyps alone had no Helicobacter, and subjects with mixed lesions or no lesions were intermediate. Previous studies have already shown that fundic gland polyps, which are common in Western FAP patients but have little malignant potential, rarely occur in patients infected with Helicobacter and this is also true for patients with sporadic fundic gland polyps.

Another way of testing the hypothesis is to use a mouse model and indeed the results of this study were published by Fox et al in 1997.7 Transgenic mice with a mutation in the APC at codon 1638 developed gastric tumours in old age. These were mainly adenomas in the pyloric region and fundic gland polyps did not occur. Infection of these mice with Helicobacter felis caused gastritis and metaplasia but did not increase the incidence of gastric adenoma. Furthermore, and quite unexpectedly, the APC 1638 mice demonstrated a decreased immune and inflammatory response to Helicobacter compared with control mice. However, the results must be interpreted with caution as there may be subtle phenotypic differences in the effect of genetic mutations on mice and humans and the time course of infection is limited by the mouse life span and death from colonic carcinoma.

In addition to the effect of Helicobacter, the present study suggests that gastric adenomas are more common in patients with easily detectable truncating APC mutations in the central portion of the gene. Germline mutations in this region have previously been associated with severe gastroduodenal disease.8 Further support for this association comes from the demonstration that somatic mutations in the remaining normal APC allele preferentially occur in the distal central portion of the gene between codons 1450 and 1556 in duodenal and gastric adenomas.9 This suggests that subtle differences in the function of mutant APC proteins may selectively promote tumorigenesis in the upper gastrointestinal tract. Interestingly, few somatic mutations have been observed in fundic gland polyps suggesting that they seldom lose APC function entirely and this may explain their low malignant potential. The few somatic mutations which have been observed may relate to foci of microadenoma within the fundic gland polyps.10

A unifying hypothesis which would explain the results of the present study is that all patients with FAP are predisposed to fundic gland polyps, perhaps related to increased proliferation and/or decreased apoptosis within the gastric mucosa. Acquisition of Helicobacter infection protects against the development of fundic gland polyps. Some patients with mutations in the central portion of APC are particularly predisposed to the development of gastric adenoma and carcinoma as well as duodenal neoplasia. However, this requires an environmental trigger. In the case of the duodenum this is bile which is always present. In the stomach this is Helicobacter which is now more common in Japanese than Western populations. How these environmental agents trigger carcinogenesis more efficiently in mucosa bearing a germline APC mutation is unknown but may relate to failure of apoptosis, the normal mucosal response following environmental damage. Such apoptosis deletes damaged cells possibly bearing additional genetic mutations.

Whatever the explanation, the present observations have therapeutic implications. There is some evidence that eradication of Helicobacter reduces the risk of sporadic gastric cancer and it certainly reduces the incidence of gastric atrophy and intestinal metaplasia. Therefore, it seems logical to suggest that Helicobacter infection should be sought and treated in patients with FAP, especially in communities where it is common. However, it is not at all certain that treatment stops an established adenoma from progressing to cancer11 and indeed in cases where there is advanced gastric atrophy due to Helicobacter, the organism can spontaneously die out but the cancer still progresses. Therefore, it would seem prudent to recommend that patients with FAP be screened early in life for Helicobacter if maximum benefit is to be gained from this strategy.

Does infection of familial adenomatous polyposis (FAP) patients with Helicobacter pylori lead to chronic atrophic gastritis and an increased risk of gastric adenoma?

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