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Notes: Background: The mechanism of hypergastrinaemia during omeprazole therapy is unclear, but is generally assumed to be entirely a consequence of acid suppression. However, direct stimulation of G cells by omeprazole could also be a factor. In order to further investigate the mechanism of omeprazole-induced hypergastrinaemia, we have studied the effects of the drug on plasma gastrin in patients with achlorhydria, in whom altered acid secretion cannot play a role. Methods: We estimated fasting and peptone meal stimulated plasma gastrin in nine patients (seven female) with pernicious anaemia and achlorhydria, before and on the final day of 4 weeks’dosing with omeprazole 40 mg daily. Results: Despite the high fasting gastrin concentrations, the peptone meal produced a further elevation in plasma gastrin concentrations, median gastrin concentrations rising from 1500 ng/L (range 225–10875 ng/L) to 3750 ng/L (range 585–15600 ng/L) post-prandially (P = 0.004). The median post-prandial rise in plasma gastrin at this initial visit was 44% (3–260%), and the median time interval until plasma gastrin concentrations returned to fasting levels was 120 min (range 10- 〉 150 min). There was a significant negative correlation between fasting plasma gastrin concentrations and the percentage increase in plasma gastrin levels in response to meal stimulation (Spearman correlation coefficient -0.79, P= 0.01). Fasting plasma gastrin concentrations were similar pre-omeprazole (median 1950 ng/L, range 240–16500 ng/L) and postomeprazole (median 1500 ng/L, range 315–7650 ng/L). Likewise, peak plasma gastrin concentrations were also similar pre-omeprazole (median 2700 ng/L, range 585–16500 ng/L) and post omeprazole (median 3420 ng/L, range 720–11250 ng/L). Conclusions: (i) The hyperplastic G cell mass in patients with pernicious anaemia can be further stimulated by a peptone meal, which causes a prolonged rise in plasma gastrin concentrations. (ii) There is a negative correlation between fasting plasma gastrin concentrations and the percentage increase in plasma gastrin levels in response to meal stimulation. (iii) Omeprazole has no effect on plasma gastrin in achlorhydric patients, which is consistent with its hypergastrinaemic effect being entirely secondary to acid inhibition.