Use of omeprazole in patients with Zollinger-Ellison syndrome

Omeprazole, a substituted benzimidazole, has been shown to be a potent inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome (ZES). We review our experience, as well as the published data on 210 patients with ZES who have required omeprazole for control of gastric acid hypersecretion over the past seven years. The dose of omeprazole required in individual patients ranged from 10 to 180 mg/24 hr with 20-60% requiring a split dosage regimen. Omeprazole was effective in approximately 99% of the patients over a period ranging from 0.5 to 54 months. Twenty-four percent of patients required an increase in omeprazole dose, while 26% required a decrease in dose. Adverse effects attributable to omeprazole were reported in 2% of patients, and in all cases, they were mild (ie, rash, constipation, headache). There was no effect of omeprazole on serum gastrin concentration or on gastric endocrine cells in three studies. Although one patient with multiple endocrine neoplasia, type-I syndrome (MEN-I) in this series developed a gastric carcinoid while taking omeprazole, evidence is presented that suggests the presence of MEN-I per se may be important in determining the development of gastric carcinoid in patients with ZES. It is concluded that omeprazole is safe and effective in patients with ZES, and in these patients, it is the drug of choice for the management of gastric acid hypersecretion. However, yearly assessment is indicated to clearly evaluate the long-term risk of gastric carcinoid as well as therapy directed at the gastrinoma itself.     

Long-term efficacy and tolerability of omeprazole in 20 patients with severe Zollinger-Ellison syndrome

Omeprazole efficacy and tolerance were evaluated in 20 patients with longstanding Zollinger-Ellison syndrome (ZES) committed to long-term antisecretory therapy. The study included 13 men and 7 women, aged 53 (30-74) years (median and range). Nineteen patients presented with epigastric pain, 14 with vomiting, and 9 with diarrhea. All patients had gastroduodenal ulcerations, associated with esophagitis in 9 cases. Median and extreme values for basal acid output (BAO) and serum gastrin (SG) levels before omeprazole treatment were 41 (3.7-80) mmol H+/h and 413 (111-11,490) pg/ml, respectively. In 18 patients, omeprazole treatment was initiated because of resistance to H2-antagonists, and in 2 patients because of carbothioamide RP 40749 discontinuation. Initial doses of omeprazole were 60 mg per day in 10 patients and ranged from 80 to 160 mg per day in the others. Esophagogastrectomy was performed in one patient at day 15 because of esophageal stenosis. In the remaining 19 patients, median duration of treatment was 16 (7-54) months and median doses of omeprazole were 70 (20-160) mg per day during the survey. Omeprazole therapy was highly effective in inducing rapid disappearance of clinical abnormalities in 18 of 19 patients. Twenty-two days after initiation of treatment, median BAO was 4 (0-14) mmol/h and ulcerations had healed in 17 of 19 patients. Median BAO was less than 5 mmol/h during follow-up. However, asymptomatic ulcer recurrence was noted in 4 patients, but disappeared quickly after omeprazole doses were increased. Median basal gastrin level was 700 (116-36.625) pg/ml at the least determination and was statistically higher than pretreatment values (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

BACKGROUND & AIMS: Parenteral control of gastric acid hypersecretion in conditions such as Zollinger-Ellison syndrome (ZES) or idiopathic gastric acid hypersecretion is necessary perioperatively or when oral medications cannot be taken for other reasons (e.g., during chemotherapy, acute upper gastrointestinal bleeding, or in intensive care unit settings). METHODS: We evaluated the efficacy and safety of 15-minute infusions of the proton pump inhibitor pantoprazole (80-120 mg every 8-12 hours) in controlling acid output for up to 7 days. Effective control was defined as acid output >10 milliequivalents per hour (mEq/h) (<5 mEq/h in patients with prior acid-reducing surgery) for 24 hours. RESULTS: The 21 patients enrolled had a mean age of 51.9 years (range, 29-75) and a mean disease duration of 8.1 years (range, <0.5-21); 13 were male, 7 had multiple endocrine neoplasia syndrome type I, 4 had undergone acid-reducing surgery, 2 had received chemotherapy, and 13 had undergone gastrinoma resections without cure. Basal acid output (mean +/- SD) was 40.2 +/- 27.9 mEq/h (range, 11.2-117.9). In all patients, acid output was controlled within the first hour (mean onset of effective control, 41 minutes) after an initial 80-mg intravenous pantoprazole dose. Pantoprazole, 80 mg every 12 hours, was effective in 17 of 21 patients (81%) for up to 7 days. Four patients required upward dose titration, 2 required 120 mg pantoprazole every 12 hours, and 2 required 80 mg every 8 hours. At study end, acid output remained controlled for 6 hours beyond the next expected dose in 71% of patients (n = 15); mean acid output increased to 4.0 mEq/h (range, 0-9.7). No serious or unexpected adverse events were observed. CONCLUSIONS: Intravenous pantoprazole, 160-240 mg/day administered in divided doses by 15-minute infusion, rapidly and effectively controlled acid output within 1 hour and maintained control for up to 7 days in all ZES patients.     

Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study

To determine the long-term efficacy, safety, and toxicity of omeprazole, we studied 40 patients with Zollinger-Ellison syndrome given omeprazole for 6-51 mo (median 29). The mean daily dose of omeprazole required to control gastric acid secretion was 82 +/- 31 mg. Thirty-one patients required omeprazole once per day. In 9 patients acid output was not controlled by 120 mg once per day, but was controlled by 60 mg every 12 h. The daily dose of omeprazole correlated with the previous dose of histamine H2-receptor antagonist (r = 0.89, p less than 0.001), basal acid output (r = 0.43, p less than 0.01), and maximal acid output (r = 0.39, p less than 0.02) but not with serum concentration of gastrin (r = -0.32). Increases in the dose of omeprazole were required in 9 patients. Twenty-nine patients had mild peptic symptoms with acid outputs less than 10 mEq/h while taking histamine H2-receptor antagonists. Symptoms resolved completely in 23 patients and partially in 3 when taking omeprazole. Omeprazole prevented mucosal disease in all patients including 17 in whom histamine H2-receptor antagonists had produced only partial resolution despite acid output being less than 10 mEq/h and in those with symptoms during omeprazole therapy. Omeprazole therapy was not associated with any significant side effects, nor with any evidence of hematologic or biochemical toxicity. Serum concentrations of gastrin did not change significantly during therapy. In 6 patients treated with omeprazole for 1 yr there was no change in basal or maximal acid output. In all patients, gastric morphology and histopathology demonstrated no evidence of gastric carcinoid formation. These results demonstrate that with long-term treatment of up to 4 yr, omeprazole is safe, with no evidence of hematologic, biochemical, or gastric toxicity. Furthermore, omeprazole remained effective, with only 23% of patients requiring an increase in dose, and continued to control symptoms in patients who had not been entirely symptom-free despite high doses of histamine H2-receptor antagonists. Omeprazole is now the drug of choice in patients with Zollinger-Ellison syndrome.     

Effectiveness of omeprazole in seven patients with Zollinger-Ellison syndrome resistant to histamine H2-receptor antagonists

The inhibitory effect of omeprazole, a benzimidazole derivative, on gastric acid secretion was investigated in seven patients with Zollinger-Ellison syndrome resistant to treatment with large doses of histamine H₂-receptor antagonists administered alone or in combination with pirenzepine. In two patients with an acute form of the syndrome, rapid control of acid overproduction was achieved with 180-mg intravenous and 120-mg oral daily doses, respectively. The other five patients, who were free of complication, initially received a standard regimen of omeprazole 60 mg orally once a day; dosage was subsequently adjusted until the basal acid output, measured 1 hr before the next dose of the drug, was less than 10 mmol/hr. The initial daily dose proved to be adequate in three patients and had to be increased to 80 mg and 60 mg bid, respectively in the remaining two patients. In all patients omeprazole therapy resulted in clinical recovery and rapid healing of mucosal lesions. The seven patients have now been followed up for 4–24 months (average 15 months). The adequacy of the daily dosage was periodically reassessed by measuring basal acid output in the hour preceding the morning dose. In one patient initially treated with 180 mg/day, dosage could be reduced to 60 mg/day. In three others, who were initially controlled with 60 mg/day, dosage had to be increased during follow-up. Despite adequate control of gastric acid secretion, one patient underwent total gastrectomy and tumor resection and another died of extensive liver metastases. The five patients still receiving omeprazole remain free of symptoms and mucosal lesions. No side effects or laboratory abnormalities ascribable to the drug were observed. It is concluded that omeprazole therapy is a good alternative in patients with Zollinger-Ellison resistant to currently available antisecretory drugs. Its safety and effectiveness in long-term therapy remain to be evaluated.     

Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome

Although most patients with Zollinger-Ellison syndrome can be effectively treated with histamine H2-receptor antagonists, many patients require large doses of drug to inhibit gastric acid secretion adequately. The purpose of the present study was to compare the pharmacokinetics of a 1200-mg oral dose of cimetidine in 9 patients with Zollinger-Ellison syndrome requiring more than 2.4 g/day of cimetidine with 5 age-matched normal volunteers receiving intravenous pentagastrin infusions. Poor responsiveness to cimetidine in patients with Zollinger-Ellison syndrome has several different causes. The concentration of cimetidine in the blood required to inhibit gastric acid secretion by 50% was markedly increased in 3 of the patients with Zollinger-Ellison syndrome, suggesting parietal cell resistance. One patient showed a substantial decrease in cimetidine absorption and 4 patients had delayed cimetidine absorption. Thus 7 of the 9 patients with Zollinger-Ellison syndrome who required more than 2.4 g/day of cimetidine to inhibit gastric acid secretion had abnormal cimetidine pharmacokinetics.     

Reflux esophagitis in patients with Zollinger-Ellison syndrome

The incidence of ulcers of the stomach and duodenum and their response to medical therapy, in patients with Zollinger-Ellison syndrome is well described. However, reflux esophagitis is less well recognized. In this study we determined the frequency of reflux esophagitis in 122 patients with Zollinger-Ellison syndrome and examined their response to medical therapy. Esophageal symptoms, endoscopic abnormalities, or both were present in 61% of patients. Forty-five percent of patients had esophageal symptoms consisting of heartburn, dysphagia, or both. Forty-three percent of patients had endoscopic abnormalities of the esophagus, and 23% demonstrated moderate or severe disease. When sufficient antisecretory medication was administered to lower gastric acid secretion to less than 10 mEq/h in the last hour before the next dose of drug, 67% of the patients with reflux esophagitis responded with complete disappearance of symptoms and normalization of the endoscopic abnormalities. The other 33% of patients required an increase in medication to lower acid output to less than 5 mEq/h in 7% and less than 1 mEq/h in the other 26% to resolve symptoms and signs completely. We conclude that reflux esophagitis occurs in the majority of patients with Zollinger-Ellison syndrome and responds well to medical therapy, although one third of patients require intensive antisecretory medication.     

Development of sustained achlorhydria in a patient with the Zollinger-Ellison syndrome treated with omeprazole.

Spontaneous remission of gastric acid hypersecretion in the Zollinger-Ellison syndrome occurs rarely. This study shows the development of gastric secretory mucosal atrophy resulting in achlorhydria and loss of pepsin secretion in a 63-year-old woman with the Zollinger-Ellison syndrome. Reduced secretion began soon after starting treatment with omeprazole, and achlorhydria became complete 6 months later. The patient remains well with normal endoscopy results and is achlorhydric 4 years after the start of treatment and 34 months after stopping omeprazole. She was not colonized with Helicobacter pylori until 36 months after developing achlorhydria. Serum gastrin has increased from 1000 to between 5000 and 12,500 ng/L (pg/mL), was not suppressible by gastric acidification, and was not associated with G-cell hyperplasia. She also has a normal Schilling test and normal immunoglobulins, and lacks antibodies to parietal cells or H+, K(+)-ATPase. Moderate enterochromaffinlike cell hyperplasia is apparent for the first time on the latest biopsy sample.     

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.     

Parenteral antisecretory drug therapy in patients with Zollinger-Ellison syndrome

Forty-six patients with Zollinger-Ellison syndrome were studied prospectively to determine a safe and effective method and criterion for controlling gastric acid hypersecretion during periods when oral antisecretory agents could not be used. In each patient it was possible to reduce acid secretion to less than or equal to 10 mEq/h after an i.v. bolus of 150 or 300 mg of cimetidine and a stepwise titration of cimetidine given by continuous infusion. The mean dose given by i.v. infusion was 2.9 mg/kg body wt.h but there was a wide range (0.5-7.0 mg/kg body wt.h) and the minimal dose had to be determined individually for each patient. The minimal i.v. cimetidine dose did not correlate with basal or maximal acid output or fasting gastrin concentration, but correlated closely with either the previous oral dose of cimetidine (r = 0.96, p less than 0.001) or the previous oral dose of ranitidine or famotidine (r = 0.95, p less than 0.001). To study the efficacy and safety of an i.v. infusion of cimetidine, 34 patients undergoing surgery were maintained on i.v. cimetidine for a mean of 12 days (range 1-83 days). One-half of the patients did not require dose adjustment, whereas the remainder required an average of 2 adjustments, usually in the first 3 postoperative days. No patient developed complications attributable to gastric acid hypersecretion in the postoperative period, and there was no detectable neurologic, hematologic, or hepatic toxicity. This study demonstrates that a continuous i.v. infusion of cimetidine adequately inhibits gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. However, high doses were frequently required, the dose had to be determined in a stepwise fashion individually for each patient, and the i.v. dose correlated with the previous oral dose. Reducing acid secretion to less than or equal to 10 mEq/h was a safe criterion during surgery and continuous i.v. cimetidine was safe and effective in achieving this degree of control for up to 83 days.     

Gastric endocrine cell evolution in patients with Zollinger-Ellison syndrome

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r=0.68,P=0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM).     

Is surgery useful for Zollinger-Ellison syndrome?

Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 1999;341:635–44.     

Frequency of endocrine disorders in patients with the Zollinger-Ellison syndrome

To evaluate the frequency of associated endocrine disorders, 26 patients with the Zollinger-Ellison syndrome were restudied in a uniform screening programme. The examinations were directed primarily against disorders in the pituitary, parathyroid, thyroid, adrenal cortex, and endocrine pancreas. Fourteen endocrine disorders were found in 10 patients (38%). Ten of these were newly diagnosed. Five patients had hyperparathyroidism, and in two of these a pituitary adenoma was also suspected. Two had pituitary adenomas, one was suspected of having a pituitary adenoma and one of having adrenocortical hypofunction, and one showed multiple hormone production with hypoglycaemia and flushing. It is concluded that most cases of associated endocrinopathies are not diagnosed until specifically looked for. In the Danish population of patients with the Zollinger-Ellison syndrome the prevalence is about 38%.     

Zollinger-Ellison syndrome with pneumopericardium

Summary A 55-year-old white male was found to have the Zollinger-Ellison syndrome in 1971. Supposed total gastrectomy was performed at that time. When an esophageal ulcer was found, six years later, esophagoscopic biopsy revealed residual gastric mucosa. The patient was given cimetidine 300 mg qid because it was felt he could not tolerate further surgery. After eight months of cimetidine therapy, the patient was admitted to the hospital because of retrosternal pain. Pneumopericardium was discovered, and at autopsy a large penetrating gastrojejunal ulcer was demonstrated.Supported by the Medical Research Service of the Veterans Administration.     

Basis for failure of cimetidine in patients with Zollinger-Ellison syndrome

When and why does the medical management of the gastric secretory activity of patients with the Zollinger-Ellison syndrome fail? (Editor's note). In the November issue of Digestive Diseases and Sciences, a paper by Ziemniak and associates discussed the reasons for failure of cimetidine in the treatment of Zollinger-Ellison syndrome. The editors have invited Dr. R.T. Jensen of the Intramural Program in Digestive Diseases at the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases to comment on this important problem.     

Zollinger-Ellison syndrome

SinceHelicobacter pylori infects the gastric mucosa in most patients with chronic duodenal ulcer, infection with this organism has been implicated in the pathogenesis of this common disease. We postulated that ifH. pylori is pathogenic in the usual type of duodenal ulcer, it should be less common when duodenal ulcer has another, specific etiology, such as Zollinger-Ellison syndrome. Gastric mucosa was compared from 18 patients with proven Zollinger-Ellison syndrome (17 of whom had had duodenal ulcer disease) and 18 controls with chronic duodenal ulcer without such a diagnosis. All subjects, who were matched for age and sex, had undergone elective gastric resections. Gastric tissues were stained by hematoxylin-eosin and Giemsa and were reviewed by an experienced pathologist who was unaware of the diagnosis. The frequency ofH. pylori in patients with Zollinger-Ellison syndrome (8/18) was lower than in controls with duodenal ulcer (16/18;P<0.02). Moreover, chronic antral gastritis scores were higher in patients with duodenal ulcer (P<0.01). In Zollinger-Ellison syndrome, peak acid output was lower in patients positive (median 22 meq/30 min) compared to those negative forH. pylori (median 32 meq/30 min;P<0.02) but serum gastrin was correspondingly lower in patients positive forH. pylori (P<0.05).H. pylori infection appears to be more frequent when duodenal ulceration is not associated with another etiology, such as acid hypersecretion in Zollinger-Ellison syndrome.H. pylori infection in Zollinger-Ellison syndrome may also be associated with decreased gastric acid secretion.Supported in part by grant DK34988 from the National Institutes of Health, U.S. Public Health Service.This work was presented in part at the American College of Gastroenterology Annual Meeting, New Orleans, October 1989, and published in abstract form in theAmerican Journal of Gastroenterology (84:1159, 1989).     

Zollinger-Ellison syndrome

Opinion statement  The first goal of therapy is the control of gastric acid hypersecretion using PPIs or high-dose H2R antagonists.