Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature.

We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and < 60% for BAO > 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of < 15% in patients with no prior acid-reducing surgery. The proposed criterion of BAO/MAO ratio > 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH < or = 1 was met by only 27% of patients, and pH < or = 0.96 by 21% of patients with previous acid-reducing surgery. For patients with MEN1 with no prior acid-reducing surgery, the sensitivities were lower compared with patients with the sporadic form of ZES. The mean gastric volume in patients without prior acid-reducing surgery was 314 +/- 10 mL/hr and 247 +/- 25 mL/hr in patients with prior acid-reducing surgery. A basal volume criteria of > 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.

Use of omeprazole in Zollinger-Ellison syndrome: a prospective nine-year study of efficacy and safety.

H+, K(+)-ATPase inhibitors such as omeprazole are the antisecretory agents of choice for the management of gastric acid hypersecretory states, including the Zollinger-Ellison syndrome. However, long-term follow-up data on the overall efficacy and safety of these agents in large numbers of patients are lacking. In the current study we examined the long-term efficacy and safety of omeprazole in 116 patients with Zollinger-Ellison syndrome treated with oral omeprazole at a single centre for up to 114 months (mean +/- S.E.M. = 38 +/- 3 months). The initial omeprazole maintenance dose was established according to the acute upward dose titration method in 89/116 patients (77%). Gastric acid output was effectively controlled using 60 mg of omeprazole once daily in 41/89 patients (46%) and 22/89 patients (25%) required twice daily omeprazole therapy. The mean ranitidine equivalent dose for patients who required 60 mg omeprazole once daily (2.5 +/- 0.2 g/day) was significantly lower than the mean ranitidine equivalent dose for patients who required more than 60 mg omeprazole once daily (4.3 +/- 0.3 g/day). Long-term omeprazole maintenance therapy was discontinued in 36/116 patients (31%) but in no cases was discontinuation due either to drug-induced side-effects or uncontrolled gastric acid output. Fasting serum gastrin levels were significantly elevated above pre-treatment levels at only one time point during follow-up and were likely due to tumour growth rather than a drug effect. The final long-term omeprazole maintenance doses were lower than the initial doses but correlated closely with the pre-omeprazole basal acid output (r = 0.41, P < 0.001) and ranitidine equivalent dose requirements (r = 0.49, P < 0.001). We conclude that omeprazole effectively and safely controls gastric acid hypersecretion in all patients with Zollinger-Ellison syndrome for up to nine years without evidence by tachyphylaxis.

Prospective study of the long-term efficacy and safety of lansoprazole in patients with the Zollinger-Ellison syndrome.

The long-term safety and efficacy of lansoprazole were studied in 21 patients with Zollinger-Ellison syndrome. The initial maintenance dose was determined by acid inhibition studies. In all patients lansoprazole controlled gastric acid hypersecretion and peptic symptoms in both the short and long term. Patients were treated for a mean of 31 months (range 1-43 months) with all but 4 patients followed for > 18 months. The mean initial dose was 60 mg/day, with 2 patients requiring a twice daily dose and the others a single daily dose. During long-term treatment 6 patients required an increased dosage, 5 within the first year. Long-term maintenance doses were reduced in 5 of the 6 patients in whom this was attempted. No changes in serum gastrin concentration, haematological parameters, liver function studies or other biochemical parameters occurred due to lansoprazole. No patient developed a gastric carcinoid tumour while being treated with lansoprazole. These results demonstrate that long-term treatment with lansoprazole is both safe and effective in patients with Zollinger-Ellison syndrome, and suggest that this drug will be useful in such patients. Furthermore, maintenance doses of lansoprazole, determined by the currently recommended method of acute acid titration studies in patients with Zollinger-Ellison syndrome, are too high.

Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high.

The efficacy of omeprazole increases during the first few days of administration, suggesting that long-term maintenance dose requirements in patients with Zollinger-Ellison syndrome may be lower than those initially established by upward titration. Long-term maintenance doses of omeprazole were prospectively reduced in 37 patients who had been taking omeprazole for 22 +/- 4 months. Successful reduction was defined as reduction to 20 mg once or twice daily with an absence of symptoms, endoscopy without evidence of active acid-peptic disease, and a gastric acid output of < 10 mEq/h. Sixty-eight percent of patients (25/37) were successfully reduced to 20 mg of omeprazole once (18/24) or twice daily (7/13). Ninety-five percent of patients (20/21) without multiple endocrine neoplasia type I, severe gastroesophageal reflux disease, or previous partial gastrectomy had safe reductions of doses. It is concluded that the currently used omeprazole maintenance doses in patients with Zollinger-Ellison syndrome are too high and advocated that the initial dose still be established by acute daily upward titration followed by gradual reduction once control of acid output has been achieved.