S. Bonfils

Results of surgical management in 92 consecutive patients with Zollinger-Ellison syndrome.

Hospital records and follow-up information on 92 patients with surgically proven Zollinger-Ellison syndrome have been reviewed, and data relating to symptomatology, age and sex incidence, pathologic findings, and early and late results of surgical procedures have been summarized. The postoperative mortality rate was 15%, and was adversely affected by previous peptic ulcer surgery, by the necessity of urgent operation for complications of peptic ulcer, and by employment of a procedure that failed to control acid secretion. Thirteen patients were found to have primary gastrinomas of the duodenum and an additional 13 patients had islet cell hyperplasia without evidence of frank neoplasm; prognosis in these two groups appears to be particularly favorable. Despite the current availability of effective nonoperative measures for control of gastric hypersecretion, surgical exploration is warranted in all patients to determine location and extent of tumor and to attempt to control the ulcer diathesis by resection of tumor. Long-term therapy with H2 receptor antagonists is advised for patients whose hypersecretory state has not been alleviated by tumor resection or whose gastrinoma cannot be removed. Total gastrectomy is still indicated in patients whose tumors are not amenable to resection and who are resistant to, or cannot follow, a rigid medical regimen.

Clinical, Anatomical, and Evolutive Features of Patients with the Zollinger-ellison Syndrome Combined with Type I Multiple Endocrine Neoplasia

The clinical evolution of type I multiple endocrine neoplasia (MEN I) was studied in 45 patients among a consecutive series of 172 with Zollinger-Ellison syndrome (ZES). These 172 patients were seen in our hospital between 1959 and 1989. Diarrhea was half as frequent in ZES-MEN I as in sporadic ZES cases. At diagnosis, mean basal acid output and serum gastrin levels in MEN I patients (28.8 ± 6.6 mmoVh and 587 ± 487 pg/ml, respectively) were not different from those observed in the others with sporadic ZES. Laparotomy was performed in all 36 patients with no diffuse liver involvement to attempt the removal of gastrinomas. Twenty-nine patients had adenomas, located in the pancreas in 21, in the duodenal wall in 3, and in both in 5. Adenomas were multiple in 23 cases (78%). No tumor was found in seven patients. Twenty-nine of the 36 operated patients were tumor-free after surgery; 7 died in the postoperative period between 1959 and 1970. Median follow-up of the 38 other patients was 95 months (range 17–278 months). Among the 24 patients without residual tumor at discharge (group I), biological and or morphological evidence of a persistent or recurrent source of gastrin was obtained in 22. Among the 14 patients with residual tumor (group II), an increase in tumor size was seen in 5 after a median of 27 months (range 9–36 months), while no change occurred in 9 after 54 months (3-100 months). Actuarial survival curves were not different, either in group I versus group I1 patients (67 and 72% at 5-year follow-up, respectively) or in MEN I versus sporadic ZES patients. Apparently, complete resection of primary tumor did not reduce the incidence of subsequent liver metastases. In all, 21 of the 45 patients had malignant gastrinomas (47%), consisting of liver metastases in 14 (31%), metastatic lymph nodes in 11 (24%), and lung metastases in 2 (4%). Monitoring of fundic argyrophil cells disclosed hyperplasia in 13 of the 14 MEN I patients (92%), and 5 had invasive carcinoid tumors. Taken together, these results prompt us to recommend that in ZES-MEN I patients, surgery should be avoided and oxyntic mucosa regularly monitored.

Effect of somatostatin on diarrhea and on small intestinal water and electrolyte transport in a patient with pancreatic cholera

SummaryThe effects of somatostatin on diarrhea and on small intestinal flow of water and electrolytes (slow-maker perfusion technique) in a patient with pancreatic cholera are reported. Continuous intravenous infusion of somatostatin (8 μg/kg/hr) suppressed the diarrhea, but a rebound was observed after somatostatin. Infusion of somatostatin at the same dosage decreased the ileal fluid flow rate to within control values. This effect was mainly due to a sharp reduction in the rate fluid entered the jejunum, but was also due to a suppression of the abnormal water and electrolyte secretion in the proximal jejunum. Secretion in the rest of the small bowel remained unchanged. Somatostatin did not noticeably after the high preinfusion plasma level of prostaglandin E1, but decreased the initially high plasma concentration of vasoactive intestinal peptide to normal values. These results suggest that long-acting somatostatin analogs could be of value in the symptomatic treatment of diarrhea in pancreatic cholera.

Effect of Somatostatin on Normal and Gastric-Stimulated Cell Proliferation in the Gastric and Intestinal Mucosae of the Rat

The effects of an 8-hour infusion of somatostatin, saline, gastrin or a mixture of gastrin + somatostatin on DNA synthesis and mitotic activity of gastrointestinal progenitor cells were explored in conscious rats, using in vivo labeling with 3H-thymidine and radioautography. Infusion of somatostatin (day or night) was shown to transiently reduce nuclear uptake of 3H-thymidine and cell division in both fundic and antral progenitor cells. Cell DNA synthesis in the gastrin + somatostatin-stimulated stomach was lower than in the gastrin-stimulated stomach. In the intestine, nocturnal infusion of somatostatin decrease DNA synthesis whereas diurnal infusion decreased cell division but no effect was observed on gastrin stimulation. Evidently, somatostatin may inhibit, perhaps indirectly, the cell proliferation in digestive mucosae and antagonize the trophic activity of gastrin but only in fundic and antral mucosae.

Chromogranin a and Pancreastatin-Like Immunoreactivity in Serum of Gastrinoma Patients

Gastrin and pancreastatin-like immunoreactivity were determined by radioimmunoassay methods and chromogranin A was determined by enzyme-linked immunoassay in sera from 18 patients with gastrinomas (Zollinger-Ellison syndrome) and in 20 age and sex matched controls. Gastrin serum levels in the gastrinoma patients were in the range 26-80,000 pmol/l, and in the controls 5-31 pmol/l. Chromogranin A serum levels in the gastrinoma group were in the range 6-2,700 ng/ml (mean +/- SEM: 400 +/- 147 ng/ml). The mean value of chromogranin A was significantly higher than in the control group (8 +/- 2 ng/ml, p = 0.008). The serum levels of pancreastatin-like immunoreactivity in the gastrinoma patients were in the range 23-1,994 pg/ml (597 +/- 123 pg/ml). The mean value of pancreastatin-like immunoreactivity in the gastrinoma group was significantly higher than in the control group (104 +/- 25 pg/ml, p = 0.0002). The levels of chromogranin A and pancreastatin-like immunoreactivity were significantly higher in patients with verified metastatic disease (p = 0.04, p = 0.01 respectively). There was a significantly positive correlation between levels of gastrin and pancreastatin-like immunoreactivity (r = 0.7, p = 0.002), while no correlation was found between gastrin and chromogranin A levels or between levels of chromogranin A and pancreastatin-like immunoreactivity. The study demonstrates an elevation of both chromogranin A and pancreastatin-like immunoreactivity in serum of gastrinoma patients. The lack of correlation between gastrin and chromogranin A, however, gives an indication that the gastrinoma cells are not the main source of serum chromogranin A elevation.

Development of gastric argyrophil carcinoid tumors in a case of Zollinger-Ellison syndrome with primary hyperparathyroidism during long term antisecretory treatment

Fundic argyrophil carcinoid tumors developed in the course of a 5‐year continuous treatment with high dosages of H2‐antagonists in a well‐documented case of Zollinger‐Ellison syndrome with primary hyperparathyroidism, high basal acid output, and serum gastrin. Approximately 100 small polyps were disseminated throughout the gastric fundus exclusively, leading to total gastrectomy. Metastatic carcinoid in a lymph node and pancreatic gastrinomas also were found at surgery. Gastric endocrine cell proliferation varied from simple argyrophil cell hyperplasia to carcinoid tumors eroding the surface and infiltrating the submucosa. Ultrastructural studies showed that the tumoral proliferation was heterogeneous, and included tumors composed of enterochromaffin (EC) and typical enterochromaffin‐like (EC‐L) cells, and tumors in which a majority of cells exhibited dense round granules resembling those of A‐like or D1/P endocrine cell types. The risk of developing gastric fundic carcinoid tumors in ZES patients submitted to long‐term antisecretory treatment should be given increased attention.

Gastric HCO3−-stimulated ATPase: Evidence against its microsomal localization in rat fundus mucosa

Abstract Rat gastric mucosa was shown to contain a Mg 2+ -dependent ATPase which is stimulated by HCO 3 − at pH 8–9. Triton X-100 solubilizes this HCO 3 − -stimulated, Mg 2+ -dependent ATPase (ATP phosphohydrolase, EC 3.6.1.3). The gastric mucosa was resolved into five subcellular fractions by differential centrifugation. A large granule fraction (Fraction M), 28 000 g · min, was characterized by cytochrome c oxidase (marker enzyme for mitochondria). A microsomal fraction (Fraction P), 2 760 000 g · min, was characterized by 5′-nucleotidase(5′-ribonucleotide phosphohydrolase, EC 3.1.3.5) (plasma membrane). The Mg 2+ -dependent ATPase was demonstrated to have a bimodal mitochondrial membranous localization: 24% of its activity is associated with cytochrome c oxidase, and 75% with 5′-nucleotidase(5′-ribonucleotide phosphohydrolase, EC 3.1.3.5) at pH 8. The HCO 3 − addition resulted in two opposite effects: (1) a strong stimulation (84%) in Fraction M; (2) a slight inhibition (12%) in Fraction P. Fraction M was subfractionated by equilibration on a sucrose gradient. It gave rise to a homogeneous mitochondrial ( d , 1.17–1.21) Mg 2+ -dependent ATPase, closely associated with cytochrome c oxidase. This ATPase is strongly stimulated ( ×2 ) by HCO 3 − . The subfractionation of Fraction P gave rise to two distinct ATPases: (1) the major one is associated with membranous ( d , 1.10–1.15) material marked by 5′-nucleotidase and is slightly inhibited by HCO 3 − ; (2) the other is associated with denser ( d , 1.17–1.21) material and is stimulated by HCO 3 − . The bicarbonate-stimulated fraction of the Mg 2+ -dependent ATPase activity found in the gastric microsomal fraction is assumed to arise from mitochondrial cross-contamination. Further support comes from the optimal HCO 3 − concentration. In addition, SCN − is shown to specifically inhibit the ATPase of Fraction M. From these results it appears that the implication of HCO 3 − -stimulated ATPase in the gastric secretion of H + is not as clear as had been suggested. However, in the view of an ATPase-supported model for H + secretion, attention can be directed towards the Mg 2+ -dependent ATPase found to be associated with microsomes.

Comparative Effects of Antrocolic Transposition and Antrectomy on Fundic Mucosa and Acid Secretion of the Rat

Three groups of male Wistar rats were surgically prepared with chronic gastric fistulae in the rumen: 15 had a transposition of the whole antrum of the colon, 11 had an antrectomy, and 11 with intact stomachs served as controls. From the 15th to the 45th day after the operation, acid secretory tests were made twice weekly. On the 45th day the fundus was prepared for cellular count estimation. The average acid output was not significantly different in controls and antrectomies (112 ± 18 μEq per 2 hr and 96 ± 18 μEq per 2 hr, respectively) but significantly increased in antrocolic transpositions (384 ± 24 μEq per 2 hr). After a postoperative period of 6 weeks there was no. significant difference between cell count data for controls and antrectomies. Only the height of the fundic mucosa in the latter decreased significantly. However, antrocolic transposition caused a hyperplasia of parietal (P

Long‐term treatment with octreotide in patients with the Zollinger‐ElIison syndrome

Abstract. This study reports the effects of 4 and 5‐year treatment with octreotide (200 μg sc bid) in the Zollinger‐Ellison syndrome (ZES). No symptoms related to acid hypersecretion were observed in the four patients throughout the study, and upper GI endoscopy was normal. Basal acid output (BAO) measured 12 h after injection, was below 10 mmol h‐1 in three to four patients and previous ranitidine treatment was discontinued. In the fourth case (pre‐treatment BAO value: 115 mmol h‐1), BAO progressively decreased to 42 mmol h‐1 after 5 years of octreotide treatment. At the end of the study, serum gastrin levels were 58.5% (30–68) of the pretreatment values and two patients had normal gastrin levels. Peak acid output (PAO) decreased markedly after 2, 4 and 5 years, by 68% (35–89) suggesting that octreotide had exerted an antitrophic effect on parietal cell mass. Diffuse hyperplasia of fundic argyrophil cells present in two patients before octreotide, decreased during the treatment. Mean argyrophil cell density for all patients was not significantly modified. Antral gastrin‐cell density was in the normal range. No long‐term side effect of octreotide treatment was observed. Although octreotide may not be considered as a substitute for benzimidazoles in the treatment of ZES, its specific properties may be of therapeutic benefit in some ZES patients.

Evaluation of antisecretory drug therapy of Zollinger-Ellison syndrome (ZES) using 24-hour pH monitoring.

Clinical and endoscopic findings were compared with 24-hr pH profiles in 8 patients with Zollinger-Ellison syndrome (ZES), who were being treated, during consecutive periods, with doses of cimetidine or ranitidine. There was a positive correlation between the effect on gastric pH and the outcome of treatment, with ranitidine proving to be more effective. The reduction of gastric acidity was correlated with ranitidine plasma levels. In the medical management of ZES patients, the 24-hr pH profile appears to be a measurement which is of value in the choice of appropriate drug regimes and which promises to increase our understanding of treatment failure.