Control of gastric acid hypersecretion in the management of patients with Zollinger-Ellison syndrome

Abstract

During the last 5 years important advances have occurred in the control of gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES). The increased availability of potent gastric acid antisecretory agents such as histamine H2-receptor antagonists and more recently the H+K(+)-ATPase inhibitors such as omeprazole and lansoprazole have made it possible to medically control acid secretion in all patients. Increased understanding of the variation in antisecretory drug dosage between individual patients has led to identification of criteria to ensure effective antisecretory control and to the recognition of subgroups of patients who require special monitoring. Effective regimens for parenteral antisecretory control during surgery have been established. The importance of parathyroidectomy in patients with multiple endocrine neoplasia type I with ZES and the possible usefulness of highly selective vagotomy have been investigated. We review here the new data that led to increased understanding in each of these areas from our studies and studies by others.

Fig. 1.

Determination of the intravenous (top) and oral (bottom) antisecretory doses of histamine H₂-receptor antagonist required in two patients with ZES. Top. Acid secretory data from a typical patient with ZES demonstrating the method for determining the minimum intravenous cimetidine infusion dose to reduce gastric acid output to less than 10 mEq/hr, the accepted level of control (dotted line). Basal acid output (54 mEq/hr) was determined off all antisecretory medication. In this patient, cimetidine 1 mg/kg/hr IV was insufficient to reduce gastric acid output to less than 10 mEq/hr. Increasing the infusion rate to 2 mg/kg/hr was also insufficient. The minimum dose required to control gastric acid output was 3 mg/kg/hr. Bottom. Determination of the minimum 6-hourly dose requirement for famotidine, ranitidine, and cimetidine in a typical patient with ZES. The numbers at the top of the vertical bars indicate the dose of drug in grams per 6 hours. Gastric acid output was measured during the 6th hour after each indicated dose of drug. The dotted line represents an output of 10 mEq/hr, the accepted level of control. In this patient the minimum 6-hourly oral dose required to control gastric acid output was 0.06 g of famotidine, 0.9 g of ranitidine, or 2.4 g of cimetidine. (Top: modified from ref. ; bottom modified from ref. .)

Fig. 2.

Effects of intravenous cimetidine (top) or omeprazole (bottom) on gastric acid secretion in patients with ZES. Top: Effect of continuous infusion of intravenous cimetidine on gastric acid secretion in 46 patients with ZES. Basal acid output was determined in all patients at a time when they were not taking any antisecretory medications. The minimum infusion dose to reduce acid output below 10 mEq/hr, the accepted level of control, in each patient is shown in parentheses. Bottom: Effect of an intravenous bolus dose of omeprazole on gastric acid secretion during the last hour before the next dose of drug in 20 patients with ZES. Basal acid output was determined on a previous occasion in all patients at a time when they were taking no antisecretory medications. The dotted line represents an acid output of 10 mEq/hr, the accepted level of control. (Top: modified from ref. ; bottom: modified from ref. .)

Fig. 3.

Duration of action of oral histamine H₂-receptor antagonists and omeprazole in patients with ZES. Top: Duration of action of equipotent doses of famotidine, ranitidine, and cimetidine in 5 patients with ZES. The minimum dose requirement for each drug to reduce gastric acid output to less than 10 mEq/hr during the 6th hour after administration was determined in each patient. Thereafter, gastric acid output was measured from the beginning of the 6th hour to the end of the 12th hour in each patient with each of the three equipotent doses for famotidine, ranitidine, and cimetidine. Bottom: Duration of action of omeprazole in 5 patients with ZES. The minimum dose requirement for omeprazole to reduce gastric acid output to less than 10 mEq/hr during the last hour before the next dose of drug was determined. Gastric acid output was measured every 8 hours after the last dose of omeprazole. The dotted line represents the mean BAO for the subjects being tested prior to receiving these drugs. Results given are means from five determinations. Vertical bars represent l SEM. (Top: modified from ref. ; bottom: modified from ref. .)

Fig. 4.

Effect of progressive reduction of acid output on gastroesophageal reflux disease (GERD) in 122 patients with ZES. Uncomplicated GERD is defined as symptoms of gastroesophageal reflux including dysphagia with or without endoscopic evidence of inflammation but without stricture formation. Complicated GERD is defined as the presence of esophageal stricture requiring dilation. Left. GERD was present in 74 patients (uncomplicated in 64 and complicated in 10) prior to reduction of acid to less than 10 mEq/hr. When acid output was reduced to less than 10 mEq/hr, GERD resolved completely in 54 patients (including 6 with complicated disease) but persisted in 20 patients (4 with complicated disease). Middle. When acid output was reduced further to less than 1 mEq/hr, in 13 of the 20 patients (including all 4 with complicated disease) who were uncontrolled with acid outputs of less than 10 mEq/hr, uncomplicated GERD resolved in all but 1 patient. Symptoms of GERD decreased in the four patients with strictures but the strictures remained. Right. Reduction of acid output to less than 1 mEq/hr in 4 patients with esophageal strictures reduced the required frequency of dilations from once every 2 to 4 weeks to once every 4 to 6 months. (Modified from ref. .) All strictures subsequently resolved with continued treatment.

Fig. 5.

Effects of curative gastrinoma resection on basal acid output and antisecretory drug requirement. Top. Basal acid output was measured before and up to 4 years after curative gastrinoma resection in 17 patients with ZES. Data for men (n = 9) and women (n = 8) are shown on the left and right, respectively. Data from 3 patients with previous partial gastrectomy are excluded. The dotted line represents the upper limit ofnormal for men (10 mEq/hr) [92] and women (5.6 mEq/hr) [92]. Bottom. Antisecretory dose requirements for control of gastric acid hypersecretion before and up to 4 years after curative gastrinoma resection. Control is defined as an acid output below 10 mEq/hr during the last hour before the next dose of drug [18, 36, 43] in patients without previous partial gastrectomy (n = 15) and below 5 mEq/hr during the last hour before the next dose of drug [44] in patients with previous partial gastrectomy (n = 3). The ranitidine equivalent dose is the amount of ranitidine or after converting from famotidine or cimetidine to ranitidine equivalent dose [20] for each patient. Two patients taking omeprazole preoperatively are excluded. The numbers in parentheses indicate the number of patients followed postoperatively for the indicated time. Each dot represents a patient who was able to discontinue antisecretory medication at the time specified. (Modified from ref. .)

Fig. 6.

Effect of parathyroidectomy on basal acid output (left panel), fasting serum gastrin determination (middle panel) and antisecretory drug requirements (right panel) in patients with multiple endocrine neoplasia type 1 (MEN-I), hyperparathyroidism, and ZES. Left. Basal acid output before and after parathyroidectomy in 10 patients. Except for patient 4, all patients were normocalcemic after surgery. Middle. Fasting serum gastrin concentrations before and after parathyroidectomy in 10 patients. Except for patient 4, all patients were normocalcemic after surgery. The dotted line represents the upper limit of normal for fasting serum gastrin. Right. Antisecretory drug requirements in 2 patients before and after parathyroidectomy. Acid output in patient 1 was suppressed for 7 hours but not for 8 hours after 150 mg ranitidine preoperatively. Postoperatively, the same dose of ranitidine caused improved suppression of acid output that persisted for at least 8 hours. Patient 2 required 160 mg of famotidine preoperatively to cause a inhibition of acid output similar to that caused by 120 mg of famotidine postoperatively at 5 hours after the last dose was administered. (Modified from ref. .)