Calcium and secretin as provocative stimuli in the Zollinger-Ellison syndrome

The effects of calcium and secretin were studied in 8 patients with the Zollinger-Ellison syndrome and 18 patients with duodenal ulcer disease. Intravenous infusion of calcium gluconate produced marked increases in serum gastrin levels in the patients with Zollinger-Ellison syndrome (4,350 +/- 1,625 pg/mg) and very slight increases in the patients with duodenal ulcer disease (140 +/- 49 pg/ml). Secretin given as a single intravenous injection also induced marked elevations in serum gastrin in the group with the Zollinger-Ellison syndrome (4,063 +/- 1,990 pg/ml). By contrast, intravenous secretin resulted in a progressive fall in serum gastrin levels in the duodenal ulcer group (from 119 to 97 pg/mg). These results suggest that both stimuli are very useful dagnostic tools in discriminating between Zollinger-Ellison and non-Zollinger-Ellison patients. The secretin challenge test is felt to be superior to the calcium infusions because it is simpler, safer and very rarely produces false-negative or-positive results.     

Serum gastrin in duodenal ulcer: Part I Basal levels and effect of food and atropine

Fasting serum gastrin has been measured by radioimmunoassay in 72 patients with duodenal ulcer and compared with that in normals, patients with gastric ulcer, and with the Zollinger-Ellison syndrome. The mean (+/- SEM) gastrin levels were 15.7 +/- 1.5 pg/ml in the duodenal ulcer group, 32.1 +/- 4.3 pg/ml in normals, 118 +/- 18.1 pg/ml in gastric ulcer, and between 450 and 2,000 pg/ml in the Zollinger-Ellison syndrome. There were no difficulties in distinguishing simple ulcer from the Zollinger-Ellison syndrome as the presence of hyperchlorhydria in combination with hypergastrinaemia led to a confident diagnosis of the latter disease.The effect of protein, glucose, and cream feeding with and without atropine was also assessed in a group of these patients with duodenal ulcer. As in normals, there was no stimulation of gastrin release by either atropine alone, distilled water, glucose, or cream. However, protein alone produced a greater rise in serum gastrin levels compared with that in normals and prior atropinization augmented this response greatly in duodenal ulcer. This indicates an increased amount of releasable gastrin in the latter disease, the release of which, under basal conditions, is suppressed by the high acidity in the antrum.     

Zollinger-Ellison syndrome in a patient with normal screening gastrin level

A 59-year-old female presented with multifocal peptic ulcer disease and diarrhea. A fasting serum gastrin level obtained while the patient was receiving no antacid therapy was normal. A secretin stimulation test was positive. A small gastrinoma was found in the anterior duodenal wall at exploratory laparotomy. Normal fasting gastrin levels do occur in patients with overt Zollinger-Ellison syndrome and should not deter further investigation if clinical suspicion of this syndrome is high.     

Diagnostic value of serum pepsinogen C in patients with raised serum concentrations of pepsinogen A.

Hypopepsinogenaemia A is often found in patients with gastric atrophy and gastric surgery. In these conditions serum pepsinogen C provides additional diagnostic information, especially when expressed as pepsinogen A:C ratio. Hyperpepsinogenaemia A has been shown in patients with duodenal ulcer disease, Zollinger-Ellison syndrome, hypertrophic gastropathy, chronic renal failure, and during omeprazole treatment. As patients with hyperpepsinogenaemia A often overlap in symptoms, endoscopical findings, and serum gastrin values, this study has evaluated whether measurement of serum pepsinogen C in subjects with hyperpepsinogenaemia A can help in differentiating clinical conditions. Serum concentrations of pepsinogen A and C were measured in serologically Helicobacter pylori negative blood transfusion donors (127) as reference population, and in patients with Zollinger-Ellison syndrome (24), duodenal ulcer (50), hypertrophic gastropathy (5), and chronic renal failure (50), and also in reflux oesophagitis patients on longterm omeprazole treatment (28). A low pepsinogen A:C ratio was found in all patients with hypertrophic gastropathy. A pepsinogen A:C ratio above the critical value of 4.7 was found in 14 (70.0%) of the Zollinger-Ellison patients, two (9.5%) of the duodenal ulcer patients, 11 (25.6%) of the patients with chronic renal failure, and in one (7.1%) of the patients receiving longterm omeprazole treatment. In fact, all but three hyperpepsinogenaemia A patients with a pepsinogen A:C ratio greater than 4.7 and normal renal function had the Zollinger-Ellison syndrome. In patients with hyperpepsinogenaemia A, a low pepsinogen A:C ratio may point to hypertrophic gastropathy, while a pepsinogen A:C ratio greater than 4.7 is suggestive for the Zollinger-Ellison syndrome.     

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied with multiple endocrine neoplasia type 1

A case of Zollinger-Ellison syndrome produced by gastrinoma in the duodenum accompanied by multiple endocrine neoplasia type-1 (MEN-1) is reported. A 46 year-old female underwent distal gastrectomy due to gastric ulcer 5 years ago. As ulceration of the residual stomach recurred, further examination was performed. Hyperprolactinemia, hypergastrinemia, primary hyperparathyroidism, pancreatic tumor, and duodenal carcinoid were evident, and the diagnoses of Zollinger-Ellison syndrome and MEN-1 were established. The origin of the gastrin secretion was suspected to be from the pancreatic tumor, so sampling of the portal blood was performed. As lesion on the gastrinoma in the pancreas could not be identified, total parathyroidectomy was performed for primary hyperparathyroidism. The level of the gastrin secretion, however, remained high. Partial resection of the duodenum for the duodenal carcinoid and a distal pancreatectomy were carried out concurrently. Immunohistochemical study of the anti-gastrin antibody revealed duodenal tumor cells. Initially, the gastrinoma was thought to be in the pancreas, however, the lesion accompanied with MEN-1 and the Zollinger-Ellison syndrome had occurred in the duodenum.     

Value of Serum Gastrin in the Diagnosis of the Zollinger-Ellison Syndrome

Summary: Serum gastrin has been measured by radioimmunoassay in 300 consecutive patients with known or suspected Zollinger-Ellison syndrome. Thirty of these patients had an elevated serum gastrin between 320 pg/ml and 200 ng/ml; the remainder had levels below 250 pg/ml. Of the 30 patients, 14 had histologically proven Zollinger-Ellison syndrome, eight had suspected Zollinger-Ellison syndrome but without histological proof, seven had histologically proven Zollinger-Ellison tumours with either hyperparathyroidism (4) or insulinoma (3) and one patient had a retained excluded antrum. These results illustrate the relative rarity of the Zollinger-Ellison syndrome but also highlight the importance of serum gastrin estimation in the correct diagnosis of the syndrome. The high mortality from inadequate surgery makes this diagnosis mandatory.     

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).     

Two types of Zollinger-Ellison syndrome: immunofluorescent, cytochemical and ultrastructural studies of the antral and pancreatic gastrin cells in different clinical states

In this survey the antral, pancreatic and, where present, the neoplastic gastrin cells, were studied in eight cases of the Zollinger-Ellison syndrome. The antral G cells alone were studied in one case of Z-E syndrome, seven cases of simple duodenal ulcer, and five cases of pernicious anaemia.The Z-E cases were divided into two numerically equal groups. The first group had ;short' histories, high serum gastrin levels, and profound antral G cell hyperplasia. The second group had ;long' histories, relatively lower serum gastrin levels, normal antral G cells, and either pancreatic D cell hyperplasia or gastrinoma.Antral G cell hyperplasia, with maximal gastrin storage and normal serum gastrin levels, was found in the duodenal ulcer cases. Antral G cell hyperplasia with minimal storage and high serum gastrin levels was observed in the cases of pernicious anaemia.On the basis of our findings we propose that there exist at least two distinct types (or perhaps stages) of the Z-E syndrome. Suggestions for their pathogenesis are offered.     

Misdiagnosis of the Zollinger-Ellison syndrome due to hyperlipidemia

Most authorities feel that diagnosis of the Zollinger-Ellison syndrome is established when the serum gastrin level is greater than 1000 pg/mL (1000 ng/L) in a patient with gastric acid hypersecretion and clinical manifestations consistent with the diagnosis. A patient with recurrent peptic ulcer disease is reported who was thought to have had the Zollinger-Ellison syndrome based on two serum gastrin level measurements greater than 1000 pg/mL (1000 ng/L). Subsequent evaluation revealed the gastrin elevation to be spurious because the sample was hyperlipidemic. Lipemic serum samples may yield falsely elevated serum gastrin determinations as determined by radioimmunoassay.     

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.     

An enucleated duodenal gastrinoma with multiple type 1 endocrine neoplasia located by selective arterial calcium injection

We report a duodenal gastrinoma in a 50-year-old man who was admitted to our hospital with tarry stools. Esophagogastroduodenoscopy revealed multiple ulcers in the duodenal bulb and a submucosal tumor in the descending duodenum. His serum gastrin level was 1400pg/ml. We suspected Zollinger-Ellison syndrome and performed selective arterial calcium injection to locate the gastrinoma. Increase in the hepatic venous gastrin level was seen only in the gastroduodenal artery area. We diagnosed a gastrinoma located in the pancreaticoduodenal area. Genetic examination showed a single-base deletion in the MEN-1 gene. At operation, the tumor was found in the submucosal layer of the descending duodenum and was extirpated. He is alive without recurrence 3 years after surgery.     

Secretin-Induced Gastrin Response in the Zollinger-Ellison Syndrome and Chronic Duodenal Ulcer Patients before and after Cimetidine Treatment

A secretin provocative test was performed in 16 patients with chronic duodenal ulcer and in five patients with the Zollinger-Ellison syndrome. In four chronic duodenal ulcer patients a second secretin test was done during acute iv cimetidine administration. There were only slight variations of gastrin compared with the first test. A third test was done on the same four chronic duodenal ulcer patients after 1 month's po cimetidine treatment (1 g/day); gastrin at 0 time was significantly higher than in the previous two tests (p < 0.01). Integrated gastrin response after secretin was significantly lower in the third test than in the first (p < 0.05). In two Zollinger-Ellison syndrome patients treated with 1.0 and 1.4 g/day cimetidine for 3 months, gastrin at 0 time was not markedly increased, whereas compared with the first test gastrin levels were higher at each time after secretin. These data suggest that previous cimetidine treatment does not alter, and may even increase, the diagnostic sensitivity of the secretin test.     

The Zollinger-Ellison syndrome with acute bleeding pancreatitis

A 44-year-old Japanese man was diagnosed to have Zollinger-Ellison syndrome. His main complaint was anemia due to gastrointestinal bleeding. After performing gastrointestinal endoscopy, duodenal ulcers were found located in the posterior wall of the duodenal bulbus. Three months before presentation, he had undergone surgery at our hospital due to acute bleeding pancreatitis. A case of Zollinger-Ellison syndrome with acute bleeding pancreatitis is rare, and there have so far been few reports of such cases in the English medical literature.     

Zollinger-Ellison syndrome type 1: clinical and pathological correlations in a case

Some patients with the Zollinger-Ellison syndrome appear to have hypergastrinaemia and hyperplasia of the antral G cells but no tumour. This subgroup has been classified as Zollinger-Ellison syndrome type 1. We have treated such a patient by vagotomy and antrectomy, the fasting plasma gastrin and acid secretion subsequently returning to normal.A 17-year-old male had a four-year history of duodenal ulcer. Gastric secretion tests showed acid hypersecretion. Fasting plasma gastrin was 8350 pg/ml (normal 50-170 pg/ml). At laparotomy duodenal ulceration was confirmed but no pancreatic or other tumours were found. Truncal vagotomy and antrectomy was performed with distal pancreatectomy. Immunofluorescent staining showed hyperplasia of G cells in the resected antrum but a normal pancreas and duodenum.Six months after operation he was symptom free and acid secretion was reduced by 92%. The fasting plasma gastrin at two months was <50 pg/ml.These findings suggest that type 1 Zollinger-Ellison syndrome may be a clinical entity.     

A Case of Groove Pancreatitis with Duodenal Stenosis

A 58‐year‐old man presented with a 2‐month history of nausea and vomiting. Blood levels of hepatic enzymes and pancreatitis markers were slightly elevated. Hypotonic duodenographic and endoscopic examinations revealed stenosis encircling the descending duodenum. A computed tomography (CT) scan showed inflammatory changes in the head of the pancreas and thickening of the duodenal wall. Magnetic resonance cholangiography demonstrated stenosis of the intrapancreatic segment of the common bile duct and diffuse dilatation of the main pancreatic duct, without irregularity. At laparotomy, microscopic examination of a needle biopsy specimen of the head of pancreas revealed no evidence of malignancy. Distal gastrectomy with Billroth II anastomosis was performed. Microscopically, fibrous thickening of the duodenal wall, serositis and hyperplasia of Brunner's glands were found. The presence of duodenal stenosis due to segmental pancreatitis, referred to as groove pancreatitis, was confirmed. The elevated blood levels of pancreatitis markers returned to the normal range 8 months after the operation. Ultrasonic echography and abdominal CT also revealed a marked reduction in dilatation of the extrahepatic bile duct and the main pancreatic duct. In patients suspected of having pancreatic carcinoma or regional pancreatitis, groove pancreatitis should be included in the differential diagnosis.     

Pathophysiological responses to meals in the Zollinger-Ellison syndrome: I. Paradoxical postprandial inhibition of gastric secretion.

The gastric acid, pepsin, and secretory volume output in response to a mixed meal were measured in six patients with Zollinger-Ellison syndrome caused by a gastrin-producing tumour proved subsequently at surgery. The patients were all normocalcaemic, and none had previous abdominal surgery. In four of the six patients, ingestion of the meal markedly inhibited the gastric secretory output, which decreased to below fasting levels, returning later to basal values. In two other patients, whose fasting acid output was considerably lower, the secretory output increased after the meal, but some inhibiton of gastric secretion was also apparent for variable intervals of time. The serum gastrin concentration in all patients remained essentially unchanged or increased after the meal. Two patients were restudied after successful removal of the duodenal gastrin-producing tumour, and in each the normal gastric secretory and gastrin-releasing responses were completely restored. Our studies suggest that, in patients with the Zollinger-Ellison syndrome caused by a gastrinoma, physiological regulatory mechanisms triggered by food reduce the continuous stimulation of gastric secretion caused by their tumoural hypergastrinaemia.     

Serum gastrin in health and disease

Summary Recent developments have led to a further appreciation of the various species of circulating gastrin and to provocative tests for the presence of the Zollinger-Ellison syndrome. Studies of serum gastrin levels, together with other studies of physiologic response, have suggested some possible roles of gastrin in the complex gastric acid hypersecretory state that frequently accompanies duodenal ulcer. Finally, investigations of exogenous and endogenous serum gastrin have provided a mechanism to examine the possible physiologic effects of this hormone.Supported in part by research grants (AM 13711 and CA 15332) from the National Institutes of Health, and a grant (DT-17) from the American Cancer Society.     

The Zollinger-Ellison syndrome in a child

The Zollinger-Ellison syndrome was encountered in a boy aged 11 years who presented with a bulbar duodenal ulcer causing intractable pain and bleeding. The diagnosis was made by finding an overnight fasting gastric secretion of 1,300 ml containing 134 m-equiv/HCl, and little change of secretion after maximal histamine stimulus. A circumscribed non-beta islet cell pancreatic tumour was excised, with antrectomy. Postoperative acid secretion was normal and the boy was well after being followed up for 15 months. The diagnosis and management are discussed, as the view that total gastrectomy must be performed in all cases of the Zollinger-Ellison syndrome is questioned.     

Idiopathic gastric acid hypersecretion

Many patients with acid-peptic disease have idiopathic gastric acid hypersecretion defined as a basal acid output >10.0 meq/hr; however, a significant proportion have basal acid outputs >15.0 meq/hr, which is within the range found in Zollinger-Ellison syndrome. Although idiopathic gastric acid hypersecretion is more common than Zollinger-Ellison syndrome, it is important that these two disorders be differentiated because of differences in treatment and natural history. In the present study, we compared 124 patients with idiopathic gastric acid hypersecretion and 137 patients with Zollinger-Ellison syndrome. There were no significant differences with regard to age at diagnosis, history of upper gastrointestinal hemorrhage, nausea, vomiting, and family history of duodenal ulcer and other acid-peptic disease. However, significant differences were observed between patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome with regard to percentage of males: 77% compared to 64% (P=0.008), mean serum gastrin: 60 pg/ml compared to 3679 pg/ml (normal <100 pg/ml) (P<0.001), mean basal acid output: 15.4 meq/hr compared to 47.0 meq/hr (P<0.001), mean age at onset of symptoms: 33 years compared to 41 years (P<0.001), mean duration of symptoms before diagnosis: 11 years compared to five years (P<0.001), percentage with abdominal pain: 67% compared to 82% (P=0.00004), percentage with diarrhea: 12% compared to 75% (P<0.000001), percentage with pyrosis: 58% compared to 40% (P=0.003), percentage with duodenal ulcer: 53% compared to 74% (P<0.000001), and percentage with esophagitis: 31% compared to 42% (P=0.0004). The differences in clinical features could be attributed to difference in mean basal acid output, and/or differences in levels of basal acid output used for diagnosis of idiopathic gastric acid hypersecretion (basal acid output >10.0 meq/hr) and Zollinger-Ellison syndrome (basal acid output >15.0 meq/hr). When 45 patients with idiopathic gastric acid hypersecretion and 39 patients with Zollinger-Ellison syndrome with basal acid outputs 15.1–30.0 meq/hr were compared, the main significant differences were with regard to mean serum gastrin: 69 pg/ml compared to 655 pg/ml (P<0.001), percentage of male gender: 82% compared to 62% (P=0.03), and percentage with diarrhea: 16% compared to 64% (P=0.000005). These results indicate that in general patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome often have similar clinical features that can be difficult to distinguish. However, the increased frequency of diarrhea and female gender should lead to a strong suspicion of Zollinger-Ellison syndrome, which can be distinguished in almost every case by measurement of serum gastrin.     

Zollinger-Ellison Syndrome Unresponsive to Cimetidine

A patient with Zollinger-Ellison syndrome appeared initially to respond to cimetidine with a reduction in gastric acid secretion. Symptoms immediately improved but after three days recurred with increasing severity. Intravenous cimetidine had only a short-lived and partial inhibitory effect on the rate of acid production and because of continuing pain and progressive bleeding from his duodenal ulcer, total gastrectomy was performed. Evidence of the effect of atropine and of oral and intravenous cimetidine is presented. Despite recent optimism, cimetidine is not always adequate treatment for Zollinger-Ellison syndrome.