Diarrhea associated with pancreatic islet-cell tumors

Summary 1. Two cases of noninsulin-secreting pancreatic islet-cell tumors presenting as severe diarrhea are reported. The first patient had steatorrhea and marked gastric hypersecretion, but no ulcer. Removal of the tumor was followed by normalization of gastric secretion and disappearance of steatorrhea. The second patient had profuse, watery diarrhea with severe fluid and electrolyte depletion. He was achlorhydric. Resection of the tumor completely relieved the diarrhea, but the patient later succumbed to pancreatic necrosis.2. On the basis of this personal experience and of a review of 45 cases described in the literature, it appears (1) that pancreatic islet-cell tumors are often responsible for diarrhea; (2) that this effect is mediated via gastric hypersecretion in a majority of instances; and (3) that stimulation of intestinal secretions is a probable mechanism in the few patients with low gastric secretion or anacidity.     

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.     

Current concepts on physiological control of gastric acid secretion. Clinical applications.

Gastric acid secretion by the parietal cell is a single digestive process involving a continuous interplay between nervous and hormonal stimuli. Gastric acid hypersecretion and hypergastrinemia may represent pathologic disturbance of the normal "gastric phase" of acid secretion (excluded antrum syndrome) or abnormal gastrin secretion from a nongastric source as in the Zollinger-Ellison syndrome. Diagnosis of these two syndromes preoperatively is dependent on immunoassay for serum gastrin. A fall in serum gastrin level after the injection of secretin will distinguish the excluded antrum syndrome from the Zollinger-Ellison syndrome. Which hormone or hormones cause the acid hyposecretion of the watery diarrhea hypokalemia achlorhydria syndrome is still uncertain. Potential candidates include secretin, glucagon (alone or combined with gastrin), vasoactive intestinal peptide and gastric inhibitory polypeptide. Secretin has undergone trials as therapy in peptic ulcer whereas glucagon is under investigation for the treatment of acute pancreatitis because of its dual actions as (1) an enterogastrone and (2) an inhibitor of pancreatic secretion.     

A new cause of Zollinger-Ellison syndrome: non-small cell lung cancer

Numerous epidemiologic studies suggest a relationship between lung cancer and peptic ulcer disease. Furthermore, various lung cancers synthesize and release a number of peptides such as gastrin and gastrin-releasing peptide that could cause acid hypersecretion; however, Zollinger-Ellison syndrome (ZES), because of a lung tumor, has never been described. We report such a patient for the first time. A 60-year-old man with a non-small cell lung carcinoma (large cell type) presented with diarrhea, heartburn, abdominal pain, and duodenal ulcers. Evaluation showed ZES was present (fasting hypergastrinemia, hyperchlorhydria) and control of all symptoms by omeprazole. No abdominal or cardiac tumor, the other known locations of gastrinomas causing ZES, was found on detailed tumor imaging studies. Resection of the lung tumor resulted in a decrease in gastrin levels to normal values. Plasma radioimmunoassays showed elevated gastrin, chromogranin A and normal levels of gastrin-releasing peptide, and 9 other hormones. The tumor showed similar immunocytochemical results. The characteristics of this case are compared with 100 cases of sporadic abdominal gastrinomas, and the evidence reviewed suggests why ZES should be considered in patients with lung cancer with peptic symptoms.     

Clinical recovery owing to target parietal cell failure in a patient with Zollinger-Ellison syndrome.

A patient is presented with Zollinger-Ellison syndrome, in whom spontaneous disappearance of gastric hypersecretion and peptic ulcer disease occurred subsequent to an intercurrent illness causing acute nonspecific inflammation of the gastric mucosal lining. The dramatic clinical improvement after subsiding of the intercurrent illness was obviously linked to pronounced failure of the parietal cell mass for acid secretion and not to infarction of the gastrinoma because gastrin secretion by the tumor was unchanged.     

Effect of small bowel bypass on serum gastrin levels and gastric acid secretion in man.

In animals massive resection of the small intestine is followed by increased gastric acid secretion and an increase in serum gastrin levels. Whether hypersecretion occurs in man after intestinal resections or intestinal bypass is unclear, but an increase in fasting gastrin levels has been reported after intestinal resection. In this series a significant increase in basal gastric acid secretion and fasting serum gastrin levels has been demonstrated after intestinal bypass. However, none of the patients developed peptic ulcer or clinical symptoms of hypersecretion after the bypass operation. Whether the increase in basal secretion and the serum gastrin concentration are interrelated or of any clinical importance is uncertain.     

Sporadic versus hereditary gastrinomas of the duodenum and pancreas： Distinct clinico-pathological and epidemiological features

INTRODUCTION Gastrinomas are de?ned as gastrin-producing tumors that are associated with Zollinger-Ellison syndrome (ZES) due to inappropriate gastrin secretion. ZES is characterized by elevated fasting gastrin serum levels, positive gastrin secretin stim…     

Digestive hormones and gastric diseases. Facts and hypotheses (author's transl)]

Relationships between hormonal secretions from the GI tract and gastric functional and/or pathological abnormalities could be studied according to 2 main lines : 1) gastric secretory changes could be the main symptom of hormonal secretory tumors, i.e. acid hypersecretion in the Zollinger Ellison syndrome, acid hyposecretion in pancreatic cholera and in somatostatinoma. In these cases, hormonal hypersecretion is directly responsible for the functional disturbances and the related symptoms; 2) gastric pathological conditions are sometimes accompanied by changes in hormonal secretion, but the level of interdependence is variable : high blood gastrin is directly depending upon the atrophic gastritis in pernicious anemia; this mechanism was also suggested in case of gastric carcinoma. Concerning ulcer disease, numerous problems are unsolved in respect to blood gastrin (basal and stimulated) abnormalities, as well as somatostatin and GIP secretions.     

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.     

Reversible Basal Gastric Hypersecretion with Parathyroid Adenomas and Duodenal Ulcer

Summary: Profound hypersecretion of gastric acid, basally, was detected in a duodenal ulcer patient with familial primary hyperparathyroidism. Repeated fasting serum gastrin estimations were normal. Following surgical treatment of the hyperparathyroidism, there was a sustained fall in basal acid output from 34 to 4.5 mEq per hour. Two years later, an infusion of calcium intravenously re-produced dramatic gastric acid hyper-secretion, up to 64 mEq per hour, confirming the extreme hypersensitivity to mild hypercalcaemia. The infusion also provoked a rise in serum gastrin levels.
This study has demonstrated that pronounced basal acid hypersecretion with ulcer may occur in hyperparathyroidism in the absence of the Zollinger-Ellison syndrome. Thus, parathyroid adenomas do sometimes influence gastric secretion like a gastrin-producing tumour, or a retained excluded gastric antrum. This exaggerated response may be mediated by rises in serum gastrin, stimulated by calcium.     

Histamine and gastrin in plasma of patients with upper gastrointestinal diseases

The etiology of peptic ulcer disease is completely unknown. However, gastric acid secretion plays an important role in the pathogenesis of the disease. Acetylcholine, gastrin and histamine are recognized as the main stimulators of the acid secretion. Extensive studies on blood gastrin have not incriminated this hormone in the pathogenesis of the disease. The present study was done to evaluate the role of circulating histamine in peptic ulcer disease using a sensitive and specific radioimmunoassay method. Since gastrin at least in some species seems to exert its stimulatory effect by releasing histamine, serum gastrin was also determined. There was no significant difference in plasma histamine between patients with duodenal or gastric ulcer, nonulcer dyspepsia or ulcer patients after proximal gastric vagotomy. However, patients taking a histamine-2 blocker (cimetidine or ranitidine) had significantly higher plasma histamine than those not taking these drugs. This effect was not due to interference in the histamine assay. There was no correlation between plasma histamine and plasma gastrin. Plasma gastrin was significantly increased in patients having been operated on with a proximal gastric vagotomy. In conclusion, plasma histamine is similar in patients with different upper gastrointestinal disorders. However, histamine-2 blockers may increase plasma histamine.     

Basophilic leukemia and the hypersecretion of gastric acid and pepsin

A 48-yr-old man with chronic myelogenous leukemia and basophilia developed a duodenal ulcer and hemorrhage. Gastric analysis revealed basal hyper-secretion of acid (33.1 mEq/h) and pepsin (44.5 x 10(-4) peptic units/h). Blood, serum, and urine histamine was elevated and serum gastrin was normal. Although acid output was markedly suppressed with ranitidine (50 mg i.v.), pepsin secretion was only inhibited 63% and had returned to basal levels by the sixth hour. Maximal acid output does not suggest a trophic effect of histamine in this patient. The previously reported cases of basophilic leukemia and gastric hypersecretion or duodenal ulcer disease are reviewed.     

Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication

BACKGROUND: It remains controversial whether or not Helicobacter pylori infection causes altered gastric acid secretion. A novel test for evaluating gastric acid secretion (endoscopic gastrin test; EGT) has recently been developed. AIM: To investigate by EGT the effects of H pylori eradication on the state of gastric acid secretion in patients with peptic ulcer. METHODS: Twenty six patients with duodenal ulcer and 33 with gastric ulcer, for all of whom H pylori infection had been documented, were studied by EGT, histological examination of gastric mucosa, and measurement of plasma gastrin levels before and one and seven months after H pylori eradication. RESULTS: In patients with duodenal ulcer, the mean EGT value before H pylori eradication was higher than that in H pylori negative controls, but it had decreased significantly seven months after the treatment. In contrast, the mean EGT value of patients with gastric ulcer before H pylori eradication was lower than that in H pylori negative controls, but it had increased one month after the treatment; this was followed by a slight decrease at seven months. In both groups, mean EGT values seven months after the treatment were not significantly different from the mean control value. CONCLUSIONS: The reduced acid secretion in gastric ulcer patients and gastric acid hypersecretion in duodenal ulcer patients were both normalised after the clearance of H pylori.     

Gastric and extragastric gastrin release in normal subjects in duodenal ulcer patients, and in patients with partial gastrectomy (Billroth I).

In 10 normal subjects, in 32 patients with duodenal ulcer (DU), and in 11 patients with partial gastrectomy (Billroth I), serum gastrin rose significantly after an oral and intraduodenal test meal. The highest increases were observed in DU patients after the oral as well as after the intraduodenal test meal. After the intraduodenal test meal in 4 normal subjects and in 17 DU patients an increase of gastric acid secretion and serum gastrin was measured. In basal state, after an intraduodenal or an oral test meal, DU patients with normal gastric acid secretory capacity had higher serum gastrin concentrations than DU patients with gastric hypersecretion. There was a good correlation between peak serum gastrin levels after the oral and after the intraduodenal test meal. From these data it is concluded: (1) Intraduodenal application of a test meal results in release of gastrin from extragastric sites. (2) Extragastric gastrin is biologically active. (3) DU patients are able to release more antral and more extragastric gastrin in response to a test meal. Further studies, however, are necessary to show the significance of these findings in the pathogenesis of peptic ulcer disease.     

Effect of placebo on meal-stimulated gastric acid secretion and serum gastrin concentration

The effect of placebos on gastric acid secretion in humans is unknown, even though placebo therapy is relatively effective in ulcer patients. Therefore, we evaluated the effect of a placebo capsule on meal-stimulated gastric acid secretion and serum gastrin concentrations in 10 healthy subjects and also in 10 patients with chronic duodenal ulcer. Each subject and patient was studied twice and in random order, once with placebo therapy prior to the meal and once without placebo. In either healthy subjects or duodenal ulcer patients, meal-stimulated acid secretion and serum gastrin concentrations were not significantly different with or without placebo administration. These studies demonstrate that a placebo capsule, administered by a physician just prior to a meal, has little, if any, effect on acid secretion or gastrin release in response to the meal. Any beneficial effects of placebos in treating patients with peptic ulcer disease are probably unrelated to inhibition of meal-stimulated gastric acid secretion.     

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.     

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.     

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.     

Marked hypergastrinemia in gastric outlet obstruction

We report a 45-year-old woman with chronic peptic ulcer disease and multiple episodes of bowel obstruction, who was admitted with gastric outlet obstruction. Because of gastric hypersecretion, a diagnosis of Zollinger-Ellison syndrome was suspected and an initial serum gastrin of 1,251 pg/ml supported this diagnosis. Subsequent evaluation failed to reveal a gastrinoma. A repeat serum gastrin level after 14 days of continuous nasogastric decompression was 43 pg/ml, suggesting that the initial hypergastrinemia was due to antral distention. It is important to consider the possibility of gastric outlet obstruction as a stimulus for serum gastrins in the range previously considered diagnostic for the Zollinger-Ellison syndrome.     

Surgical treatment and prognosis of gastrinoma

Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.