Nitrite concentrations in fasting gastric juice are related inversely [30] to hydrogen ion concentrations; the nitrite concentration can

be increased up to 50-fold in the fasting gastric juice find more of subjects with pernicious anaemia [31]. Studies suggest that hypochlorhydria and achlorhydria favour bacterial overgrowth, including nitrate reducing strains, leading to the production of N-nitroso compounds [32] and progression from gastric atrophy to intestinal metaplasia, dysplasia and carcinoma. The role of pernicious anaemia as a risk factor for gastric carcinoma was determined by a meta-analysis of six studies, including 842 patients with pernicious anaemia followed for 7·8–15 years, which reported 58 cases of gastric cancer, equivalent to a fivefold increase in the risk of gastric cancer in these patients [33]. In a Swedish study, which followed 4517 patients with pernicious anaemia for a mean of 5·9 years, 102 (2·3%) patients developed gastric cancer, giving a standardized incidence ratio (SIR) of 2·9 (95% CI 2·4 −3·5). The risks of oesophageal carcinoma and gastric carcinoid were also increased [34]. A larger Swedish retrospective cohort study followed 21 265 patients hospitalized for pernicious anaemia for an average of 7·1 years. They found an increased risk of non-cardia gastric cancer in patients with pernicious anaemia, with a SIR of 2·4 (95% CI 2·1–2·7); they also found an increased risk of gastric carcinoid

and squamous cell carcinoma of the oesophagus [35]. It has been proposed that the same mechanism as that for Helicobacter may be involved [36,37]. An increased risk of gastric cancer BMN-673 in patients with CVIDs was recognized in 1985, when a prospective study of 220 patients with CVIDs followed for 11 years reported a 47-fold increased risk [36]. A multi-centre Tobramycin study using Scandinavian cancer and disease registries reported an SIR of 10·3 (95% CI 2·1–30·2) [10], but no increased risk in family members of patients with CVIDs. This suggests that

the increased risk of gastric cancer in CVIDs relates to the immunodeficiency rather than to genetic traits or H. pylori virulence shared with relatives [10]. There are some reports of gastric cancer presenting at a young age in patients with CVIDs [7,9]. Nevertheless, outcome studies of large CVID cohorts followed for medians of 11 and 7 years, respectively, found only four cases of gastric carcinoma in 472 patients [38,39], indicating that the absolute risk is low (about 1% per decade). A recent study from Australia [40] showed an even lower SIR of 6·1 (95% CI 1·26–17·84). While variability in prevalence from different locations is not surprising [5], the considerable differences, especially over time, suggest that environmental factors are important. The mechanisms underlying an increased frequency of gastric cancer in CVIDs are not understood. Specific antibodies have been shown to kill H.