Development of cimetidine resistance in the Zollinger-Ellison syndrome.

A patient with the Zollinger-Ellison syndrome was followed with multiple gastric secretion tests and serum gastrin analyses for six years. During this period cimetidine requirement increased to a daily dose of 8 g, but it reversed spontaneously after two years. The altered cimetidine effectiveness was not associated with reduced oral bioavailability and serum calcium was unchanged. Total serum gastrin was very high at all times, and fractionation of gastrins in serum by gel filtration showed varying proportion of big to small gastrins, but not in a mode which explained the parietal cell resistance to cimetidine.     

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.     

Effect of isopropamide on response to oral cimetidine in patients with Zollinger-Ellison syndrome

Patients with Zollinger-Ellison syndrome whose gastric acid secretion or symptoms were not controlled by cimetidine in conventional dosage were selected for studies of responsiveness of their acid secretion to increasing doses of cimetidine, used either alone or in combination with a long-acting anticholinergic agent, isopropamide iodide. Results indicate that in the group as a whole the suppression achieved with a 900-mg dose of cimetidine was not significantly better than that achieved with a 300-mg dose, although in individual cases this did not hold true. In individuals the combination of cimetidine and isopropamide was generally more effective in suppressing acid secretion than cimetidine alone, used either in the same dose as in the combination or in the next highest possible dosage. This was also true in the group as a whole, where combined therapy showed significant advantage over either drug alone in controlling acid secretion, in the third, fourth, and fifth hours following administration of the drugs. The data suggest that in the minority of patients not controlled by cimetidine 300–600 mg q6hper os, addition of isopropamide (20–40 mg/day) may be preferrable to further increasing the dose of cimetidine.This work was presented to the Annual Meeting of the American Gastroenterological Association, and has been published in abstract form: Gastroenterology 76(5):1198, 1979.     

Zollinger-Ellison syndrome

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

Zollinger-Ellison syndrome

Summary A 29-year-old female patient had severe peptic ulcer disease associated with Zollinger-Ellison syndrome caused by a large islet cell carcinoma of the pancreas. She was treated successfully for 44 months with large doses of anticholinergic drugs. After the removal of the pancreatic tumor, a 50% gastrectomy, and a vagotomy, there was marked reduction of gastric secretion, and the patient remained symptom-free for 44 months. She had two successful pregnancies, one prior to and one after the tumor had been removed. At her request, further pregnancies were prevented by an intrauterine contraceptive device.When peptic ulcer symptoms and gastric hypersecretion recurred, the patient was again explored. The pancreas appeared normal and no metastatic lesions could be found. At this time she had a total gastrectomy with colonic interposition. Serum gastrin levels, assayed on two occasions, approximately 2 years later, were elevated. Almost 3 years later the patient feels well, is working daily, and maintains her weight at 135 lb.The authors wish to express their appreciation to the staff of the Lilly Laboratory for Clinical Research—the surgical staff, particularly Dr. A. L. Gardner; the Pathology Department, particularly Dr. A. C. Michael; and the members of the Gastrointestinal Clinic, particularly Mrs. Juanita Oates—for their help and cooperation in this case, and to Dr. J. E. McGuigan for the serum gastrin assays.     

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 Zollinger-Ellison syndrome (ZES) is caused by a gastrin-producing tumor called a gastrinoma, which results in gastric acid hypersecretion. Gastrin stimulates the parietal cell to secrete acid directly and indirectly by releasing histamine from enterochromaffin-like (ECL) cells, and induces hyperplasia of parietal and ECL cells. ZES should be suspected in patients with severe erosive or ulcerative esophagitis, multiple peptic ulcers, peptic ulcers in unusual locations, refractory peptic ulcers, complicated peptic ulcers, peptic ulcers associated with diarrhea, and a family history of multiple endocrine neoplasia type 1 (MEN-1) or any of the endocrinopathies associated with MEN-1. The initial diagnostic test for ZES should be a fasting serum gastrin level when antisecretory medications are discontinued. If the gastrin level is elevated, gastric acidity should be assessed through pH or gastric analysis. It should be noted that hypochlorhydria causes feedback stimulation of antral gastrin secretion. In suspected cases of ZES with mild hypergastrinemia, the secretin stimulation test may be useful. Initial treatment for ZES should be oral high-dose proton pump inhibitors. If parenteral therapy is needed, intermittent bolus injection of pantoprazole is recommended. Total gastrectomy and antisecretory surgery is rarely required. Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice. Endoscopic ultrasound (EUS) may have a similar sensitivity for identifying primary tumors. A combination of SRS and EUS detects greater than 90% of gastrinomas. In patients without metastasis and without MEN-1, surgical cure is possible in 30%. It has been suggested that patients with gastrinomas larger than 2.5 cm, irrespective of whether they have MEN-1, should undergo surgical resection in an effort to decrease the risk for metastasis.     

Zollinger-Ellison syndrome]

A survey of pathogenesis, pathobiochemistry, pathological anatomy, clinic, diagnostics and therapy of the Zollinger-Ellison-syndrome is given. The Zollinger-Ellison-syndrome is, it is true, relatively rare, but its limitation from the usual peptic ulcer has great practical consequences. The suspicion of a Zollinger-Ellison-syndrome is aroused by therapy-resistent ulcers, which in every third person are associated with a diarrhoea, by recidivations of ulcer after gastric operations and by a large basal secretion of acid. The decisive diagnostic means is the serum gastrin determination. The only promising therapy is, as a rule, the gastrectomy.     

Treatment of Zollinger-Ellison syndrome

In this article, we have reviewed the main therapeutic measures for the treatment of Zollinger-Ellison syndrome (ZES). Review of the literature was based on computer searches (Pub-Med, Index Medicus) and personal experiences. We have evaluated all the measures now available for treating patients with sporadic gastrinomas or gastrinomas associated with Multiple Endocrine Neoplasia Type 1, (MEN 1) including medical therapy such as antisecretory drugs and somatostatin analogs (SST), chemotherapy and chemoembolization, and surgical procedures. In ZES patients, the best therapeutic procedure is surgery which, if radical, can be curative. Medical treatment can be the best palliative therapy and should be used, when possible, in association with surgery, in a multimodal therapeutic approach.     

Metiamide in the Zollinger-Ellison syndrome

The histamine H₂-receptor antagonist metiamide is an inhibitor of endogenous and stimulated gastric-acid secretion. It appears to have therapeutic possibilities in duodenal-ulcer disease. Three patients exhibiting the Zollinger-Ellison syndrome have been treated with this drug for six months or more. Rapid symptomatic improvement occurred in each case, followed by ulcer healing. There were also reductions in gastric secretion and consistent changes in the fasting serum-gastrin concentration. One patient relapsed temporarily during therapy. There have been no side effects. It is concluded that, in the short term, metiamide is of benefit in the Zollinger-Ellison syndrome.     

Omeprazole in the Zollinger-Ellison syndrome

Treatment with omeprazole was evaluated in nine patients with the Zollinger-Ellison syndrome, in whom the effect of H2-receptor antagonists had become inadequate. Treatment with 20-80 mg omeprazole daily reduced basal acid secretion by 77-100%. The effect persisted during a continuous treatment of up to 2 years. In five patients the initial dose could be reduced after some time of treatment. In eight patients the treatment promptly relieved all symptoms, and in the last patient, who had disseminated metastatic disease and large anastomotic ulcers, the symptoms disappeared gradually over a period of 10 weeks. No adverse events were seen. We conclude that omeprazole is an effective inhibitor of the acid hypersecretion in Zollinger-Ellison patients, also when H2-receptor antagonists have failed.     

Failure of oral bromocriptine to affect hypergastrinemia in two patients with the Zollinger-Ellison syndrome.

Bromocriptine was administered to 2 subjects with gastrin-secreting tumors of the pancreas. The absorption of the drug was confirmed by a rise in growth hormone levels but no change in the elevated serum gastrin levels were observed. Bromocriptine does not appear to affect gastrin hypersecretion in the way that it influences the hypersecretion of pituitary hormones.     

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.     

Canine Zollinger-Ellison syndrome.

The unusual finding of peptic esophagitis and duodenal ulceration in a dog was associated with a malignant pancreatic islet cell tumor producing gastrin and ACTH. The finding of a gastrinoma in a non-human species introduces the potential for developing an animal model for the study of the protean genetic biochemical, physiologic and metabolic aspects of the Zollinger-Ellison syndrome.