Aliment. Pharmacol. Therap. (1990) 4, 131-138.
Serum gastrin levels during long-term omeprazole treatment
H. K O O P , M. KLEIN & R. A R N O L D Division of Gasfroenferologyand Mefabolism, Deparfmenf of Medicine, Philipps- University, Marburg, FR G Accepted for publication 8 October 1989
SUMMARY
Serum gastrin was determined in 33 patients during treatment with the proton pump inhibitor omeprazole. After 4 weeks of therapy, gastrin levels increased to a median of 55 pg/ml compared to 15 pg/ml prior to omeprazole (P < 0.001). There was a close correlation (r = 0.939; P < 0.001) between pre-treatment gastrin and levels at 4 weeks. Comparison of serum gastrin concentrations at 1month of omeprazole with levels at 6 (M = 21) and 12 months (n = 12) continuous therapy revealed a close correlation (r = 0.961 and r = 0.882, respectively; P < 0.001) despite dose adjustment. In marked hypochlorhydria documented by continuous pH monitoring, serum gastrin varied from normal up to profound hypergastrinaemia. These results demonstrate that the serum gastrin increase under powerful acid-inhibitory drug therapy depends upon a number of variables. (a) Only in patients with elevated gastrin levels, prior to omeprazole treatment, can moderate to marked hypergastrinaemia during omperazole be expected. (b) Gastrin increases reached during the initial period of omeprazole treatment remain constant during long-term therapy. (c) Acid inhibition itself is not necessarily associated with an increase in serum gastrin in every patient, which suggests that the individual sensitivity of the gastrin cell to acid Correspondence to : Dr Herbert Koop, Department of Medicine, Philipps-University, Baldingerstrasse, D-3550 Marburg, FRG. 131
132
H.KOOP et al. inhibition is more important for serum gastrin changes than the degree of acid inhibition itself.
INTRODUCTION The substituted benzimidazole, omeprazole, is a powerful antisecretory drug which is able to induce marked hypochlorhydria. Toxicology studies, have shown that life-long administration of very high omeprazole dosages induces gastric carcinoid tumours in rats.' These tumours develop from enterochromaffin-like (ECL) cells under the constant trophic effect of high circulating gastrin levels.' Shorter treatment periods with substituted benzimidazoles induce proliferation of gastrin cells within several weeks in the same specie^.^" In man, administration of omeprazole for 2-4 weeks leads to less pronounced increases in serum gastrin7-I4compared to rats. However, data on long-term effects of continuous omeprazole treatment are mandatory as prolonged omeprazole therapy is needed by many patients (for example, these with reflux oesophagitis). In the present study we report on changes in serum gastrin levels during healing and maintenance therapy with omeprazole. MATERIALS A N D M E T H O D S Thirty-three patients with peptic ulcers and reflux oesophagitis, unresponsive to H,-receptor antagonists, were included in the study. All had undergone extended periods of treatment (at least 3 months) with regular (for example 300 mg ranitidine daily) and higher doses of H,-blockers. The underlying disease was reflux oesophagitis in 27, gastric ulcer in one, and duodenal ulcer in five patients. During the healing period all patients received 40 mg omeprazole as a single morning dose prior to breakfast. After complete healing of peptic lesions proven by endoscopy, the omeprazole dose was reduced to 20 mg daily; in the case of a recurrence the dose was increased again to 40 mg. If healing could not be accomplished after 3 (in one case after 9) months at 40 mg omeprazole, a higher daily dose of 80 mg was administered. Thus, the number of patients on 20,40 and 80 mg omeprazole was 11,9,and I patient after 6-month of therapy and 4,6, and 2 patients after 12-months of treatment, respectively. A blood sample was obtained in the fasting state from each patient before omeprazole during H,-blocker treatment, during omeprazole therapy at 4-week intervals until healing, and thereafter at least at %monthly intervals. Patients were asked to take the final omeprazole capsule(s) on the day preceding the visit. Blood was therefore obtained approximately 24 h after the final dose. Gastrin was determined using a previously described radioimmunoassay. l5 The antibody recognizes both G-17 and G-34 but does not crossreact with the Cterminus of the gastrin/CCK molecule. The lower limit of detection was 6 pg/ml. In a large population of healthy volunteers the upper limit of normal was 60 pg/ml. Twenty-four-hour pH recordings were performed in 13 patients during
LONG-TERM OMEPRAZOLE A N D SERUM GASTRIN
133
omeprazole therapy (20 or 40 mg daily in two and 11 cases, respectively). The technique has been described in detail earlier.17''' Briefly, a bipolar glass electrode (440M4; Ingold, Urdorf, Switzerland) was passed into the stomach and placed 5 cm below the gastro-oesophageal junction. The intragastric pH was monitored every 5 s by a solid-state recorder (Digitrapper MK 11; Synectics, Bromma, Sweden). During the pH monitoring the patients were on a strict protocol with meals at 8.00, 12.00, and 18.00 hours and additional snacks at 16.00 and 22.00 hours.19 Evaluation of the pH profile (median pH, pH readings below 2.5) was carried out using commercial software (Gastrosoft, Synectics). Data are presented as either mean or median, with interquartile ranges as indicated below. Statistical analysis employed the non-parametric Wilcoxon ranked sum test.16In addition, linear regression analysis has been performed. RESULTS Prior to omeprazole treatment (that is, during therapy with H,-blockers), gastrin levels were elevated in five out of 33 patients, one of whom had undergone selective proximal vagotomy. Four weeks after the start of omeprazole administration, serum gastrin levels had increased from a median of 15-55 pg/ml ( P < 0.001). There was a close correlation between gastrin levels prior to omeprazole and after 1-month treatment (Figure I): high circulating gastrin levels during H,-blocker therapy were associated with marked hypergastrinaemia during omeprazole administration
/
n :33
r :0.939 P
Serum gastrin levels during long-term omeprazole treatment
H. K O O P , M. KLEIN & R. A R N O L D Division of Gasfroenferologyand Mefabolism, Deparfmenf of Medicine, Philipps- University, Marburg, FR G Accepted for publication 8 October 1989
SUMMARY
Serum gastrin was determined in 33 patients during treatment with the proton pump inhibitor omeprazole. After 4 weeks of therapy, gastrin levels increased to a median of 55 pg/ml compared to 15 pg/ml prior to omeprazole (P < 0.001). There was a close correlation (r = 0.939; P < 0.001) between pre-treatment gastrin and levels at 4 weeks. Comparison of serum gastrin concentrations at 1month of omeprazole with levels at 6 (M = 21) and 12 months (n = 12) continuous therapy revealed a close correlation (r = 0.961 and r = 0.882, respectively; P < 0.001) despite dose adjustment. In marked hypochlorhydria documented by continuous pH monitoring, serum gastrin varied from normal up to profound hypergastrinaemia. These results demonstrate that the serum gastrin increase under powerful acid-inhibitory drug therapy depends upon a number of variables. (a) Only in patients with elevated gastrin levels, prior to omeprazole treatment, can moderate to marked hypergastrinaemia during omperazole be expected. (b) Gastrin increases reached during the initial period of omeprazole treatment remain constant during long-term therapy. (c) Acid inhibition itself is not necessarily associated with an increase in serum gastrin in every patient, which suggests that the individual sensitivity of the gastrin cell to acid Correspondence to : Dr Herbert Koop, Department of Medicine, Philipps-University, Baldingerstrasse, D-3550 Marburg, FRG. 131
132
H.KOOP et al. inhibition is more important for serum gastrin changes than the degree of acid inhibition itself.
INTRODUCTION The substituted benzimidazole, omeprazole, is a powerful antisecretory drug which is able to induce marked hypochlorhydria. Toxicology studies, have shown that life-long administration of very high omeprazole dosages induces gastric carcinoid tumours in rats.' These tumours develop from enterochromaffin-like (ECL) cells under the constant trophic effect of high circulating gastrin levels.' Shorter treatment periods with substituted benzimidazoles induce proliferation of gastrin cells within several weeks in the same specie^.^" In man, administration of omeprazole for 2-4 weeks leads to less pronounced increases in serum gastrin7-I4compared to rats. However, data on long-term effects of continuous omeprazole treatment are mandatory as prolonged omeprazole therapy is needed by many patients (for example, these with reflux oesophagitis). In the present study we report on changes in serum gastrin levels during healing and maintenance therapy with omeprazole. MATERIALS A N D M E T H O D S Thirty-three patients with peptic ulcers and reflux oesophagitis, unresponsive to H,-receptor antagonists, were included in the study. All had undergone extended periods of treatment (at least 3 months) with regular (for example 300 mg ranitidine daily) and higher doses of H,-blockers. The underlying disease was reflux oesophagitis in 27, gastric ulcer in one, and duodenal ulcer in five patients. During the healing period all patients received 40 mg omeprazole as a single morning dose prior to breakfast. After complete healing of peptic lesions proven by endoscopy, the omeprazole dose was reduced to 20 mg daily; in the case of a recurrence the dose was increased again to 40 mg. If healing could not be accomplished after 3 (in one case after 9) months at 40 mg omeprazole, a higher daily dose of 80 mg was administered. Thus, the number of patients on 20,40 and 80 mg omeprazole was 11,9,and I patient after 6-month of therapy and 4,6, and 2 patients after 12-months of treatment, respectively. A blood sample was obtained in the fasting state from each patient before omeprazole during H,-blocker treatment, during omeprazole therapy at 4-week intervals until healing, and thereafter at least at %monthly intervals. Patients were asked to take the final omeprazole capsule(s) on the day preceding the visit. Blood was therefore obtained approximately 24 h after the final dose. Gastrin was determined using a previously described radioimmunoassay. l5 The antibody recognizes both G-17 and G-34 but does not crossreact with the Cterminus of the gastrin/CCK molecule. The lower limit of detection was 6 pg/ml. In a large population of healthy volunteers the upper limit of normal was 60 pg/ml. Twenty-four-hour pH recordings were performed in 13 patients during
LONG-TERM OMEPRAZOLE A N D SERUM GASTRIN
133
omeprazole therapy (20 or 40 mg daily in two and 11 cases, respectively). The technique has been described in detail earlier.17''' Briefly, a bipolar glass electrode (440M4; Ingold, Urdorf, Switzerland) was passed into the stomach and placed 5 cm below the gastro-oesophageal junction. The intragastric pH was monitored every 5 s by a solid-state recorder (Digitrapper MK 11; Synectics, Bromma, Sweden). During the pH monitoring the patients were on a strict protocol with meals at 8.00, 12.00, and 18.00 hours and additional snacks at 16.00 and 22.00 hours.19 Evaluation of the pH profile (median pH, pH readings below 2.5) was carried out using commercial software (Gastrosoft, Synectics). Data are presented as either mean or median, with interquartile ranges as indicated below. Statistical analysis employed the non-parametric Wilcoxon ranked sum test.16In addition, linear regression analysis has been performed. RESULTS Prior to omeprazole treatment (that is, during therapy with H,-blockers), gastrin levels were elevated in five out of 33 patients, one of whom had undergone selective proximal vagotomy. Four weeks after the start of omeprazole administration, serum gastrin levels had increased from a median of 15-55 pg/ml ( P < 0.001). There was a close correlation between gastrin levels prior to omeprazole and after 1-month treatment (Figure I): high circulating gastrin levels during H,-blocker therapy were associated with marked hypergastrinaemia during omeprazole administration
/
n :33
r :0.939 P
