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.     

Effect of parietal cell vagotomy on acid secretory responsiveness to circulating gastrin in humans. Relationship to postprandial serum gastrin concentration

To study the relationship between gastric acid secretion and serum gastrin concentration after vagotomy, gastric acid output and serum gastrin concentration were measured simultaneously during intravenous infusion of graded doses of human gastrin heptadecapeptide (G-17) in duodenal ulcer patients with parietal cell vagotomy and in unoperated patients with duodenal ulcer disease (controls). The curve relating serum gastrin concentration to gastric acid output was shifted downward and to the right after vagotomy; the peak acid output to G-17 was reduced by 50% (p less than 0.001). The serum gastrin concentration that produced half of peak acid output (EC50%) averaged 185.5 pg/ml after vagotomy and 74.1 pg/ml in controls (p less than 0.01). Mean basal and postprandial serum gastrin concentrations were twofold to threefold higher in vagotomy patients than in controls (p less than 0.005). However, when peak postprandial serum gastrin concentrations were used to predict acid secretion from curves relating serum gastrin to acid output, predicted acid secretion was only 12.6 mmol/h in vagotomy patients compared to 24.4 mmol/h in controls. Parietal cell vagotomy decreases "functional" parietal cell mass, as reflected by a 50% decrease in peak acid output, and also reduces the responsiveness of "functional" parietal cells to gastrin to such an extent that acid secretion is reduced after vagotomy despite basal and postprandial hypergastrinemia.     

Antral hypergastrinemia--a report of three cases

Three patients with juxtapyloric ulcers and hypergastrinemia are presented. Fasting and food-stimulated serum gastrin concentration (SGC) were measured in 1970, 1972 and 1973 before the primary ulcer operation (selective gastric vagotomy and Jaboulay gastroduodenostomy; SGV + GD). Fasting SGC were 105, 149 and 158 pg/ml and the postprandial concentrations were 400, greater than 800 and greater than 800 pg/ml, respectively. The pentagastrin-stimulated acid secretion was within the normal range. After SGV + GD, only a slight decrease in acid secretion was observed. The hypergastrinemia persisted unchanged or decreased slightly in 1 patient. A recurrent ulcer developed and a precise antrectomy was carried out. Postoperatively, the fasting SGC was markedly reduced and the postprandial gastrin response abolished. The resected specimens were subjected to immunocytochemical gastrin cell quantitation. The number of gastrin cells was elevated in all 3 patients and the gastrin cell topography was distorted, with cells being present both in the lower and upper thirds of the antropyloric glands.     

A nongastrin malignant ampullary tumor causing gastric acid and pepsin hypersecretion. A case report

We report a case of multiple duodenal ulcers with gastric hypersecretion due to a nongastrin secretagogue produced by a malignant tumor of the pancreas in a 78-year-old man. The case resembled a Zollinger-Ellison syndrome (ZES) with high acid output (basal acid output 27, sham meal-stimulated 37, maximum acid output 47 mEq/h), but with fasting gastrin 43 pg/ml, nonresponsive to secretin. As in ZES, pepsin output was comparatively low, and secretion was inhibitable by atropine (50% inhibited by 1 microM). The tumor removed at surgery contained less than 1 ng gastrin per gram, but was many times more potent than pentagastrin in stimulating acid from a lumen-perfused rat stomach. The tumor also contained cholecystokinin (CCK-8 and CCK-33), motilin, insulin, and somatostatin, which were also present in adjacent normal pancreas; in addition, the tumor contained pancreatic polypeptide and pancreatic cancer-associated antigen. This case represents a rare syndrome due to an as yet undefined peptide secreted by a (frequently malignant) pancreatic endocrine tumor and masquerading as ZES. This is the first report of studies of pepsin secretion and of the effect of atropine, suggesting that the physiologic effects of the secretagogue resemble that of gastrin.     

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.     

G cell population of the gastric antrum, plasma gastrin, and gastric acid secretion in patients with and without duodenal ulcer.

Estimates of the G cell population were made in 24 resected human pyloric antra from counts of cells in multiple samples and from measurements of antral size. Measurements had been made previously in 20 subjects of acid output (basal and after pentagastrin) and in 10 subjects of plasma gastrin (basal and after insulin + bicarbonate). G cells were most dense near the pylorus, but their circumferential distribution was even. The G cell populations ranged from 8 to 15 (mean 10) million in four control patients and from 3 to 43 (mean 18) million in 15 patients with duodenal ulcer. Those with recurrent ulcer after vagotomy had either a low G cell count and incomplete vagotomy, or a high G cell count and apparently complete denervation. Two patients with hypergastrinaemia and duodenal ulcer had moderate (29 X 10(6)) or marked (56 X 10(6)) excesses of G cells. 'G cell hyperplasia' may represent the extreme end of the normal range of G cell numbers in the antrum, and can be assessed by semi-quantitative grading of G cell hyperplasia in antral biopsies. There were significant direct correlations between antral area and G cell density, between peak acid output and G cell population, and between basal plasma gastrin and G cell density (but not population). We suggest that, in patients with duodenal ulcer, acid and gastrin secretion are interrelated and that both are related to the masses of parietal cells and of G cells.     

Gastric argyrophil (enterochromaffin-like), gastrin,and somatostatin cells after proximal selective vagotomy in man

The number, size, and volume density of endocrine cells was determined in biopsies obtained endoscopically in patients after proximal selective vagotomy (PSV;N=31), antrectomy (N=9), untreated duodenal ulcer (DU) disease (N=11), and in controls (N=15). Serum gastrin was significantly elevated after PSV (mean 60 pg/ml) compared to DU patients (29 pg/ml), controls (26 pg/ml), and after antrectomy (11 pg/ml). Volume density of fundic argyrophil (largely enterochromaffin-like) cells after PSV (0.74%) and in DU disease (0.63%) were significantly (P<0.001) higher when compared with controls (0.37%) but lower after antrectomy (0.24%;P<0.02). The density of argyrophil cells was not influenced by the interval following PSV or the magnitude of hypergastrinemia. Antral gastrin cells were increased after vagotomy, whereas the antral and fundic somatostatin cell numbers were reduced after PSV. It is concluded that: (1) a major role of the vagal nerve as a trophic factor for enterochromaffin-like cells could not be demonstrated after PSV, and (2) moderate hypergastrinemia after PSV did not induce proliferation of ECL cells.     

The detection and measurement of circulating gastrin-like activity by bioassay

A perfused rat stomach technique which can detect synthetic human gastrin I in amounts greater than 10 ng and measure by block assay amounts greater than 50 ng was used to study circulating gastrin-like activity in normal subjects, patients with peptic ulcer, and patients with the Zollinger-Ellison syndrome. No detectable activity was found in normal subjects or patients with gastric ulcer before or after meals. No activity was found in the fasting plasma of patients with duodenal ulcer but after meals activity could be detected in duplicate samples in seven of 20 patients. In nine proven cases of the Zollinger-Ellison syndrome, gastrin-like activity in the plasma ranged from 15 to 356 ng/ml. The gastrin-like content of two tumours was 6.4 and 29.1 mug/g of tissue. The significance of these findings in relation to immunoassay is described.     

Serum gastrin response to secretin after vagotomy

It is unknown whether the gastrin response to secretin (secretin test) can distinguish hypergastrinemia due to vagotomy from hypergastrinemia due to Zollinger-Ellison syndrome (ZES). Therefore, we measured serum gastrin concentrations basally and in response to intravenous secretin in 13 vagotomized duodenal ulcer patients without preoperative evidence of ZES and in 5 vagotomized patients with ZES. Following secretin, serum gastrin concentrations increased 40 pg/ml or less [mean (± SE) rise 23±3 pg/ml] in the vagotomized patients without ZES. On the other hand, in the patients with ZES serum gastrin increments after secretin ranged from 105 to 1224 pg/ml. Thus, a large (>100 pg/ml) rise in serum gastrin concentrations following secretin in a vagotomized patient should suggest Zollinger-Ellison syndrome and not be attributed to vagotomyper se.Supported by Research Grants AM16816, AM17328 (to the Center for Ulcer Research & Education), and AM17294 from the National Institutes of Arthritis, Metabolism, and Digestive Diseases and a grant from Southwestern Medical Foundation's Kinsler Williamson Brown Fund, Dallas, Texas.     

Progression of gastric enterochromaffin-like cells growth in Zollinger-Ellison syndrome and atrophic body gastritis patients

BACKGROUND: Enterochromaffin-like cell hyperplasia of the gastric body mucosa occurs in hypergastrinaemic conditions such as atrophic body gastritis and Zollinger-Ellison syndrome. However, the time course of change or factors involved are not known. AIMS: To compare the rate of change of enterochromaffin-like cell proliferation in patients with atrophic body gastritis and Zollinger-Ellison syndrome. PATIENTS: From a consecutive series of atrophic body gastritis and Zollinger-Ellison syndrome patients, studied at the time of first diagnosis, 10 atrophic body gastritis (4 with pernicious anaemia) and 14 Zollinger-Ellison syndrome (4 with multiple endocrine neoplasia type 1) patients were followed-up for a median time of 48 months. METHODS: At entry and during follow-up patients underwent: plasma gastrin determination, endoscopic sampling of body mucosa for qualitative assessment of enterochromaffin-like cell hyperplasia pattern and degree of glandular atrophy, qualitative and morphometric analyses of body mucosa endocrine cells. RESULTS: At time of diagnosis, enterochromaffin-like cell lesions were more severe in atrophic body gastritis than in Zollinger-Ellison syndrome. During follow-up, no significant variations were observed in gastrin values, enterochromaffin-like cell patterns and grade of body mucosa atrophy in atrophic body gastritis. In contrast, gastrin levels were significantly increased [median 1200 (235-2625) vs 1947 (225-5200) pg/ml; p<0.001)] as was total volume density of enterochromaffin-like cells [median 1.60 (0.53-4.06) vs 3.18 (1.35-21.13)% of mucosal epithelial component; (p<0.005)] in Zollinger-Ellison syndrome. Micronodular hyperplasia of enterochromaffin-like cells, present in only one patient at diagnosis, was observed in 8 Zollinger-Ellison syndrome patients at follow-up. CONCLUSIONS: These data suggest that the progression of enterochromaffin-like cell growth in human gastric mucosa requires an increase of and/or a prolonged exposure to severe hypergastrinaemia.     

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.     

Differences between peptic ulcer and control patients on the basis of the response to secretin

The secretin injection test is considered a useful adjunct to the diagnosis of gastrinoma, although it may lack specificity. This study determined whether the release of gastrin in response to secretin was different in duodenal ulcer and control patients. Tests were performed on 10 duodenal ulcer patients, 10 normal control subjects, 20 patients asymptomatic after ulcer surgery, of whom 13 had a vagotomy and drainage, 4 a highly selective vagotomy and 3 a vagotomy and antrectomy. The secretin test was also performed in 49 patients with endoscopically proven recurrent ulcers. The surgery performed in this latter had consisted of a vagotomy and drainage in 36, a highly selective vagotomy in 7 and a vagotomy and antrectomy in 6 patients. The basal plasma gastrin level was similar in normal controls, duodenal ulcer patients and patients with vagotomy and antrectomy, both with and without recurrent ulcers. The level was elevated in all the other groups of patients with vagotomy both with and without recurrent ulcer. The plasma gastrin did not change significantly after secretin injection in the normal control or asymptomatic ulcer surgery patients, but rose in the duodenal ulcer patients and all the groups of patients with recurrent ulcer. Most of these increases were validated statistically as were the differences in response between the ulcer and control patients. These results indicate that there are differences in the plasma gastrin response to intravenous secretin between active duodenal ulcer and control patients. This findings may aid our understanding of the pathophysiology of peptic ulcer disease and explains the lack of specificity of the secretin test.     

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.     

Therapy with gastrin antibody in the Zollinger-Ellison syndrome

The therapeutic effectiveness of parenterally administered rabbit antigastrin antibody was evaluated in a patient with the Zollinger-Ellison syndrome who had a fasting serum gastrin level of 3020 pg/ml and a basal gastric acid secretion of 48.9 mEq/hr. Control globulin reduced gastric secretion to 32 mEq/hr. Gastrin antibody reduced it further to 8.7 mEq/hr. Betazole hydrochloride which was given 75 min after administration of gastrin antibody stimulated acid secretion to 57.2 mEq/hr. One day later basal acid secretion was uninhibited although some antibody activity was present in the patient's serum. The results suggested that gastrin antibody acutely inhibited basal but not betazole-stimulated secretion.A portion of this paper was presented to the Gastroenterology session of the American Federation for Clinical Research, Southern Section, January 25, 1973.     

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.     

Case report: gastrocolic fistula mimicking Zollinger-Ellison syndrome.

Fasting serum gastrin levels greater than 1000 pg/ml are said to establish the diagnosis of gastrinoma in a patient with peptic ulcer disease. The authors observed a patient with recurrent peptic ulcer disease, diarrhea, and a fasting serum gastrin of 1044 pg/ml who had a gastrocolic fistula, not the Zollinger-Ellison syndrome. The provocative tests of gastrin secretion, including secretin infusion and standard meal test, were helpful in ruling out a gastrinoma. This is the first reported association of gastrocolic fistula and hypergastrinemia. The patient demonstrates that the differential diagnosis of markedly elevated serum gastrin should be expanded to include gastrocolic fistula.     

Serum disappearance rate of gastrin-17 after vagotomy

Six duodenal ulcer patients were investigated before and after truncal vagotomy and pyloroplasty. Four doses of gastrin-17 were injected intravenously (15.625, 31.25, 62.5, and 125 micrograms/kg body weight); the gastric secretory response and the disappearance rate of gastrin were measured. After vagotomy the basal level of gastrin increased from 64 pg/ml to 106 pg/ml. When corrected for the basal levels of gastrin, the peak levels and disappearance rate of gastrin-17 were observed to be the same after vagotomy as before (half-life before vagotomy, 5.6 min; after, 5.8 min). This indicates that vagus does not influence the metabolism of exogenous gastrin-17. The gastric secretion of acid was reduced to 30% after vagotomy, which shows that there is a synergism between vagus and gastrin-17.     

Impact of Stress on Serum Gastrin in Zollinger-Ellison Syndrome

We report an impressive case with Zollinger-Ellison syndrome (ZES), in which stress-induced sympathetic discharge influenced serum gastrin. Our patient was a 35-yr-old female who complained of frequent and massive vomiting (more than 4000 ml of gastric juice) which was aggravated especially by psychosocial stress. Basal hypergastrinemia (1900 pg/ml) was found after the admission. The most striking finding was that laboratory stress dramatically increased serum gastrin (from 1900 to 5400 pg/ml) and plasma noradrenaline (from 180 to 1130 pg/ml). Mental arithmetic stress further enhanced hypergastrinemia (5800 pg/ml) with a concomitant increase in plasma noradrenaline (1240 pg/ ml). Neostigmine (10 μg/kg im) also increased serum gastrin up to 6100 pg/ml but propranolol (40 μg/kg iv) reduced these elevations (noradrenaline: 990 pg/ml, gastrin: 5000 pg/ml). In this case, the effect of stress on serum gastrin mimicked the effect of catecholamine infusion in ZES. These findings suggest that psychological stress induces serum gastrin secretion via β-adrenoceptor with exacerbation of symptoms in some cases with ZES.     

Pseudo-Zollinger--Ellison syndrome in a child presenting with anemia

Pseudo-Zollinger--Ellison syndrome appears to very rarely afflict young children. Hypergastrinemia, regardless of the etiology, presents with signs and symptoms of nonhealing or multiple gastric or duodenal ulcers, or both. We present a 7-yr-old boy with fasting hypergastrinemia (serum gastrin 200-500 pg/ml) who had mild to moderate iron deficiency anemia, but was asymptomatic. Stool guaiac was positive and gastric acid secretion was almost 40-fold above normal. Endoscopy showed multiple small gastric fundal ulcerations and severe gastritis. Workup for Zollinger--Ellison syndrome was negative. Changes in serum gastrin levels after secretin injection and after ingestion of a protein meal were compatible with those noted in adults with pseudo-Zollinger--Ellison syndrome. This child may be the first case of pseudo-Zollinger--Ellison syndrome under the age of 17 yr.     

Bombesin and G-17 dose responses in duodenal ulcer and controls

Gastric acid and pepsin secretion and serum gastrin concentrations were measured in nine patients with uncomplicated duodenal ulcer (DU) and 10 normal controls in the fasting state and in response to graded doses of bombesin, a tetradecapeptide gastrin releaser, and, for reference, synthetic gastrin G-17. Serum gastrin with bombesin stimulation was significantly greater in duodenal ulcer (maximum 467 pg/ml) than in controls (153 pg/ml), while in seven of the DU group tested gastrin levels after a meal were not different from that seen in five of the normal controls. Gastric acid concentrations and outputs were greater in duodenal ulcer with both stimuli. Secretory responses were then related to serum gastrin levels; despite increasing gastrin levels with bombesin stimulation, peak outputs achieved with bombesin were only 50% of G-17 maximum in normals and up to 90% of maximum in duodenal ulcer. Up to the point of peak response to bombesin, acid and pepsin outputs were the same with exogenous and endogenous gastrin, ie, bombesin acted only via G-17. Furthermore, in direct comparison of duodenal ulcer and normals with G-17 infusion, acid and pepsin outputs related to serum gastrin were congruent up to 75% of duodenal ulcer maximum, at which point normals reached their maximum level. These data have shown that duodenal ulcer patients are not more sensitive to either exogenous or endogenous gastrin; we have also shown regulatory defects in duodenal ulcer patients not previously described: (1) an exaggerated release of gastrin with bombesin stimulation, and (2) a defective inhibition of acid and pepsin secretion with higher doses of bombesin.Presented at AGA, Washington, D.C., 1983.