Diagnosis and management of Zollinger-Ellison syndrome

With the recent widespread availability of gastrin radioimmunoassays, the development of increasingly effective medical therapy for gastric hypersecretion, and improved methods to localize gastrinomas in patients with Zollinger-Ellison syndrome, the diagnosis, treatment of the gastric acid hypersecretion, and approach to the tumor have changed significantly. Recent advances in each of these areas and the current management of a patient with Zollinger-Ellison syndrome are reviewed.     

Diagnosis of Zollinger-Ellison syndrome: Increasingly difficult

In the present paper the increasing difficulty of diagnosis of Zollinger-Ellison syndrome (ZES) due to issues raised in two recent papers is discussed. These issues involve the difficulty and need to withdraw patients suspected of ZES from treatment with Proton Pump Inhibitors (omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole) and the unreliability of many gastrin radioimmunoassays. The clinical context of each of these important issues is reviewed and the conclusions in these articles commented from the perspective of clinical management.     

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.

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

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.     

Diagnosis of Zollinger-Ellison syndrome. From symptoms to biological evidence

With insulinoma, Zollinger-Ellison syndrome is one of the most common functional islet-cell tumour. Since it is a life-threatening condition, needing appropriate management, the diagnosis must be accurately established. This paper reviews the clinical situations leading to suspect the diagnosis and the biological tests, mainly the secretin test, that confirm the diagnosis. The different ways of performing the secretin test and the respective results are presented. This review will also focus on some aspects of the diagnosis of multiple endocrine neoplasia type 1 in these patients.     

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.     

Helicobacter pylori and Zollinger-Ellison syndrome

Helicobacter pylori (previously Campylobacter pylori) is almost invariably associated with chronic duodenal ulcer disease. The relationship between H. pylori infection and duodenal ulcer in Zollinger-Ellison syndrome is unknown. We investigated the frequency of H. pylori infection in Zollinger-Ellison syndrome and also what effect H. pylori infection had on gastric function in patients with Zollinger-Ellison syndrome. H. pylori infection was diagnosed based on a specific serologic (ELISA) assay based on high-molecular-weight cell-associated proteins of H. pylori. We studied 20 patients with Zollinger-Ellison syndrome; 15 men and 5 women ranging in age from 24 to 71 years, median age 51. Six Zollinger-Ellison syndrome patients had H. pylori infection compared to 100 consecutive patients with chronic recurrent duodenal ulcer disease (P less than 0.05). Pretreatment basal acid output in Zollinger-Ellison syndrome patients ranged from 7.9 to 95.0 mmol/hr, median 35.2. Pentagastrin-stimulated maximal acid output ranged from 8.5 to 132 mmol/hr; median 52.7. Acid secretion was lower in the H. pylori-infected patients than the uninfected patients (BAO 24.5 +/- 6.5 vs 45.4 +/- 6.6, and MAO 44.3 +/- 11.8 vs 67.9 +/- 10.7, for H. pylori infected vs uninfected patients, respectively). The difference in BAO was statistically significant (P less than 0.05). The present results indicate that H. pylori is not a major contributing factor in duodenal ulcer associated with Zollinger-Ellison syndrome. The association of a reduced BAO with H. pylori suggests that these findings may be related.     

Nesidioblastosis and the Zollinger-Ellison syndrome

Summary The most common cause of the Zollinger-Ellison syndrome is the over-production of a gastrin-like hormone by a non-beta islet cell neoplasm of the pancreas. Hyperplasia and neoformation of islets alone and in combination with neoplasia have been reported in association with the syndrome, but there has been little effort to implicate these findings in the pathogenesis of the Zollinger-Ellison syndrome.Here was presented the findings of nesidioblastosis of islets, proliferation of centroacinar and intercalated duct cells, with discussion of the ultrastructural characteristics of the non-beta granules in the pancreas of a patient having the Zollinger-Ellison syndrome.The findings in this case, together with what is already known, suggest that an extrapancreatic agent is responsible for certain of the histologic changes of the pancreas, which, in turn, may lead to excessive gastrin-production and the Zollinger-Ellison syndrome.The authors wish to thank Miss Susan Dennison, Mr. Raymond Freeman, and Miss Elizabeth McKee for their technical assistance. We are indebted to Drs. L. E. Edwards and R. P. Hudson for advice.