Biochemical diagnosis of gastroenteropancreatic endocrine tumors.

Functioning gastroenteropancreatic endocrine tumors produce and secrete different substances that can be detected in the plasma and cause hormone-related syndromes. Symptoms such as diarrhea associated either with typical skin rash or peptic ulcer disease may be suggestive of the presence of intestinal carcinoid or gastrinoma. Other clinical manifestations such as severe hypoglycemia, diabetes, necrolytic erythema and gallbladder disease may also indicate an endocrine tumor. Sometimes, patients present no, or just vague, symptoms such as dyspepsia or abdominal pain and nonfunctioning endocrine tumors in these patients can be found incidentally during diagnostic imaging procedures or at operation. Usually, the diagnosis is established by the measurement of the specific tumor marker in the plasma and, sometimes, in the urine. In some cases, normal basal hormone levels are observed even in the presence of typical symptoms. Therefore, stimulatory tests such as the secretin test for gastrinomas are required to establish the diagnosis. General markers for the diagnosis of gastroenteropancreatic endocrine tumors are also available. Among these, chromogranin A has proved to be of great value for diagnosing nonfunctioning tumors and is considered the most sensitive general marker. The availability of both specific and general markers as well as stimulatory tests may enable the clinician to diagnose functioning gastroenteropancreatic endocrine tumors at an early stage and to recognize nonfunctioning tumors.

MEN1 gene mutations are a rare event in patients with sporadic neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the gastroenteropancreatic (GEP) tract are encountered either as a sporadic type or as part of multiple endocrine neoplasia type 1 (MEN-1) syndrome. Inactivating MEN1 gene mutations have been found to be responsible for this syndrome and have also been described in sporadic cases. The aim of the present study was to evaluate the presence of mutations in the MEN1 gene in a series of 10 well-differentiated neuroendocrine tumors: five of the foregut and five of the midgut tract. METHODS: Retrospective screening for MEN1 gene mutations was carried out in 10 archived, paraffin-embedded neuroendocrine tumors. Polymerase chain reaction amplification and automated sequence analysis of the DNA extracted from the tumors were performed. RESULTS: One mutation (359 del 4) in exon 2 of the MEN1 gene was identified in a neuroendocrine tumor of the foregut (VIPoma of the pancreas). No mutation was identified in midgut neuroendocrine tumors. CONCLUSIONS: Our data confirm that retrospective genetic analysis can be used to identify mutations in the MEN1 gene and indicate that somatic MEN1 gene mutations are a rare event in sporadic neuroendocrine GEP tumors. The frequency of these mutations was 10% in our series, which may differ from that in other studies, due to the small number of cases analyzed.

Pancreatic somatostatinoma presenting with chronic intestinal pseudo-obstruction syndrome.

A case of pancreatic somatostatinoma in a patient with long-standing symptoms of intestinal pseudo-obstruction is reported. Diagnosis was made incidentally following an exploratory laparotomy for an episode of acute intestinal obstruction. After surgical excision of the endocrine neoplastic tissue there was a decrease in plasma somatostatin levels, associated with a striking improvement of symptoms related to gut motility dysfunction. Delayed intestinal transit and gastric emptying and impaired gallbladder contraction persisted after surgery during a follow-up of 9 years in association with a positive calcium-pentagastrin test, suggestive of residual tumoral somatostatin secretion. This case report shows that a chronic intestinal pseudo-obstruction syndrome can be associated with a somatostatin-producing endocrine neoplasm and confirms the clinical heterogeneity of somatostatinoma patients.

Use of calcium provocative test in the diagnosis of gastroenteropancreatic endocrine tumors.

Calcium infusion has been advocated as a provocative test for the diagnosis of some endocrine tumors of the pancreas and gastrointestinal tract (gastrinoma, insulinoma, intestinal carcinoids). The release of gastrin from gastrinoma tissue is very sensitive to alterations in the serum calcium level, and the calcium infusion test is recommended in Zollinger-Ellison syndrome when the results of secretin stimulation are equivocal. The calcium provocative test in the detection of insulinoma and carcinoid tumors is less reliable than other safer and simpler procedures. Intravenous injection of calcium followed by pentagastrin stimulates the release of somatostatin in patients with somatostatinoma and offers a reliable means for establishing the diagnosis of this tumor. Calcium administration has not proven to be useful in the diagnosis of other endocrine tumors of the digestive system.

[Duodenal somatostatinoma associated with von Recklinghausen's neurofibromatosis]. / Somatostatinoma duodenale associato a neurofibromatosi di von Recklinghausen.

This case report describes a 27-year-old man with von Recklinghausen's neurofibromatosis, manifested as cutaneous cafè au lait spots and neurofibromas, associated with duodenal somatostatinoma. The patient presented with ultrasonographic evidence of dilatation of the biliary and pancreatic ducts, in absence of clinical symptoms. The reason for the performance of ultrasonography was to identify the cause of an increase of hepatic enzymes during the last two years. Diagnostic ERCP showed an ulcerated tumor in the papillary region and pathological findings were compatible with somatostatinoma. Endoscopic sphincterotomy with placement of endoprostheses was successful in achieving biliary and pancreatic drainage. Subsequently a curative resection of the tumor was performed by the Whipple procedure and provocative tests demonstrated normal plasma somatostatin concentrations.

Effect of hypothyroidism on vasoactive intestinal polypeptide-immunoreactive neurons in forebrain-neurohypophysial nuclei of the rat brain.

We have recently reported that hypothyroidism increases immunoreactive (IR)-vasoactive intestinal polypeptide (VIP) and VIP mRNA content in both parvocellular and magnocellular neurons of the rat, hypothalamic paraventricular nucleus (PVN). As VIP can stimulate vasopressin (AVP) secretion, we conducted an anatomical investigation to determine whether VIP-containing neurons in other regions of the brain that are involved with homeostatic mechanisms of water and salt conservation are also affected by hypothyroidism. The distribution and intensity of VIP immunostaining in neurons and fibers of the magnocellular-neurohypophysial system, including the hypothalamic PVN, supraoptic nucleus (SON) and accessory magnocellular cell groups, circumventricular subfornical organ (SFO), preoptic and anterior hypothalamus, midline thalamus, subthalamic zona incerta and posterior septal nuclei were studied using a highly sensitive immunocytochemical technique and unbiased neuronal counting methods, based on the optical dissector principle. Hypothyroidism increased the intensity of VIP immunostaining and/or the number/section, percentage and numerical density of IR-VIP neurons in the PVN, SON, nucleus circularis, periventricular preoptic nucleus of the hypothalamus and SFO. In addition, IR-VIP perikarya and/or fibers in the hypothalamic medial preoptic area and anterior periventricular nucleus, nucleus reuniens of the thalamus and dorsal fornix-triangular septal nucleus complex were also apparent in the hypothyroid animals while no immunostaining was seen in these areas in control animals. No quantitative and/or qualitative modifications in IR-VIP neurons and fibers were noted in the anterior hypothalamic area, suprachiasmatic nucleus, thalamic paraventricular nucles an subthalamic zona incerta between hypothyroid and control animals. These findings suggest an inverse relationship between thyroid hormone and VIP content and/or distribution of IR-VIP neurons in specific forebrain regions involved in the control of AVP release, extracellular fluid volume, thirst, blood pressure and anterior pituitary secretion. This raises the possibility that changes in fluid homeostasis and cardiovascular function occurring in hypothyroidism may be mediated, at least in part, by VIP-producing neurons in diverse regions of the brain.

Vasoactive intestinal polypeptide (VIP) secretion and refractory diarrhea in patients with AIDS or AIDS-related complex (ARC).

Elevated plasma levels of vasoactive intestinal polypeptide (VIP) (as assessed by a radio-immunoassay), were found in 7/11 patients with AIDS or AIDS-related Complex (ARC), evaluated because of prolonged intractable diarrhea with either an infectious (6 cases) or a non-infectious (5 cases) etiology. Six subjects have been treated with the somatostatin analogue octreotide, which gave both a favourable clinical response and a significant reduction in plasma VIP concentrations. Evaluation of plasma VIP levels may provide a pathophysiological basis for explaining the efficacy of octreotide therapy in HIV-infected patients suffering from both infectious and non-infectious refractory diarrhea.

Elevated plasma levels of vasoactive intestinal peptide in AIDS patients with refractory idiopathic diarrhoea. Effects of treatment with octreotide.

OBJECTIVE: To evaluate plasma levels of vasoactive intestinal peptide (VIP) in AIDS patients with refractory idiopathic diarrhoea, and to assess the role of treatment with octreotide. PATIENTS: Three AIDS patients were evaluated for severe watery diarrhoea of 2-6 months' duration, which was complicated by weight loss, weakness, and fluid and electrolyte abnormalities. They had not shown a significant response to several regimens of empirical antimicrobial chemotherapy, or symptomatic antidiarrhoeal treatment. METHODS: A complete diagnostic examination, including repeated microbiological evaluation and radiological, ultrasonographic, endoscopic and histological examination, was performed. Plasma levels of VIP were determined by radioimmunoassay and compared with concentrations in a group of healthy subjects. RESULTS: Since no clinically significant results were obtained from standard diagnostic evaluation and empirical therapeutical attempts, idiopathic refractory diarrhoea was diagnosed. Plasma concentrations of VIP were moderately elevated in all three subjects examined, with levels of 11.5, 17.5 and 9.5 pmol/l (values < 8.8 pmol/l in the control group). One patient received 50-100 micrograms octreotide three times daily subcutaneously for 6 months, resulting in complete resolution of diarrhoea and significant improvement in body weight and quality of life, together with a reduction in VIP concentration to within normal values. CONCLUSIONS: Although the somatostatin analogue octreotide has been used successfully in the management of both infectious and non-infectious AIDS-related diarrhoea, gastrointestinal neuroendocrine function and circulating humoral mediators of diarrhoea have not hitherto been investigated extensively in HIV-infected subjects. Our data on the association of idiopathic secretory diarrhoea and elevated plasma VIP levels provide a possible pathophysiological rationale for identifying AIDS patients whose refractory diarrhoea may be more responsive to octreotide treatment.

A comparison of nizatidine and ranitidine in the maintenance treatment of duodenal ulcer. A randomized, double blind, multicentre, 2-year study.

UNLABELLED: One hundred and eight patients with an endoscopically documented healed duodenal ulcer (DU) participated to a multicentre, randomized, double-blind, long-term study. The study was planned with the aim to compare the efficacy of nizatidine 150 mg with ranitidine 150 mg in preventing relapse during the 2 years following the DU healing. Fifty four patients were assigned to each treatment. Endoscopic examinations were scheduled at 6, 12 and 24 months. Clinical evaluations were performed every two months. Routine laboratory tests were investigated at the beginning of the study and at each of the scheduled endoscopies. STATISTICS: chi-squared test with Yate's correction, Student's t test for unpaired data, Wilcoxon Rank Sum test and Logrank test. Twenty five patients dropped-out: 15 in the nizatidine and 10 in the ranitidine group. The cumulative relapse rate was 18% for nizatidine and 21% for ranitidine treatment (p:ns). Both drugs resulted safe, as only minor side effects were registered. IN CONCLUSION: nizatidine is as effective and safe as ranitidine in the long-term (2 year) treatment of DU.

Comparison of 150 mg nizatidine BID or 300 mg at bedtime, and 150 mg ranitidine BID in the treatment of gastric ulcer--an 8-week randomized, double-blind multicentre study.

One hundred and one active gastric ulcer patients concluded an 8-week, randomized, double-blind multicentre study, planned with the aim to compare the effectiveness of a new H2 blocker, nizatidine, with ranitidine. Thirty-three patients received 300 mg nizatidine at bedtime, 34,150 mg nizatidine b.i.d. and 34,150 mg ranitidine b.i.d. The three groups were well matched for the common clinical parameters. After 4 weeks, healing rates were 51.5% (confidence intervals 95%: 34.1-68.9%), 61.8% (41.2-82.4%), 76.5% (51-102%), respectively. At this check point ranitidine showed a significantly better outcome than did 300 mg nizatidine at bedtime (p less than 0.05). After 8 weeks, healing rates were 81.8% (54.1-109.5%), 88.2% (58.7-117.7%) and 88.2% (58.7-117.7%); these differences were not statistically significant. Age, sex, ulcer symptoms, alcohol and cigarette consumption, concomitant treatments, ulcer size and site and length of ulcer history were all found not to influence ulcer healing. Pain relief and antacid consumption were comparable in the three treatment groups. No clinically significant unwanted effects were recorded throughout the study. Nizatidine can, in our opinion, be successfully used in the treatment of active gastric ulcer.

Treatment of chronic erosive gastritis: a double-blind trial of pirenzepine and cimetidine.

In a double-blind study, 59 patients with chronic erosive gastritis received 50 mg of pirenzepine twice daily and 55 patients received 400 mg of cimetidine twice daily for six weeks. In both groups, days of pain, of heartburn, and of nausea per week were significantly reduced during treatment (P less than 0.01). After six weeks, 64% of the pirenzepine group and 62% of the cimetidine group were free of symptoms and endoscopy revealed healing of lesions in 78% and 80%, respectively. Differences between groups were not significant.

Clinical anatomy of the suprarenal arteries: a quantitative approach by aortography.

The angiographic visualization, arterial origin and mean diameter per age group (20-40, 41-60 years) of the suprarenal arterial vessels have been quantitatively investigated by aortography in 100 patients without suprarenal disease. Visualization of the various arteries was achieved in a percentage substantially comparable to the anatomic data of the literature, though with lower detection of the superior suprarenal vessels. A variable site of origin was present particularly for the superior and middle suprarenal vessels compared to the inferior suprarenal arteries and possible embryological reasons and clinical implications are discussed. Statistically significant differences were found in the mean diameter of each arterial vessel in all the subjects examined, thus substantiating the concept of differential arterial supply to various portions of the gland. Age-related changes were demonstrated in the right middle suprarenal artery, suggesting a predominant role of this vessel in the physiological adaptation of the blood supply to the gland with increasing age.

Quantitative clinical anatomy of the pancreatic arteries studied by selective celiac angiography.

The angiographic visualization of the pancreatic arteries, their numerical variations, origins, course and anastomoses, as well as their mean diameter by age-group (20-40, 41-60, greater than 60 years) have been quantitatively investigated by selective celiac angiography in 72 patients without pancreatic disease. Visualization of the various arteries was achieved in a high percentage of cases except for the inferior pancreaticoduodenal arches, due to undervaluation of this vessel by celiac angiography. Confirmation of the great variability of the origin and anastomoses of the dorsal and transverse pancreatic arteries was obtained and possible embryologic reasons and clinical implications of this fact are discussed. Furthermore, a high percentage of multiple (quadruple or more) pancreatica magna and caudae pancreatis arteries has been observed and a functional role of this peculiar arrangement is suggested. Finally, no statistically significant differences were found in the diameter of any artery due to increasing age, probably reflecting maintained neural perivascular control of the pancreatic vessels in the elderly. Satisfactory sensitivity of the angiographic method has been found with respect to the evaluation of visualization and anastomoses of the pancreatic arteries in vivo.

Influence of gastric acid secretion on interdigestive gastric motor activity and serum motilin in the elderly.

The purpose of this study is to investigate the influence of gastric secretion on the interdigestive gastric motor activity and related serum motilin variations in elderly subjects. The study was carried out on two groups of elderly subjects: one with achlorhydria or marked hypochlorhydria due to chronic atrophic gastritis and the other with normal acid secretion. A group of nonelderly subjects with normal acid secretion was also examined as control. Gastric motility was studied manometrically and serum motilin was measured by radioimmunoassay on blood samples taken every 15 min during the entire motor recording period of 200-300 min. Both groups of elderly subjects showed (1) alterations in interdigestive gastric motility and (2) serum motilin which was steadily high without the normal cyclic fluctuations. These studies suggest that the alterations in gastric motor activity and serum motilin in aged subjects are not related to the acid secretory capacity of the stomach. Other factors, such as alterations in the neurohormonal control system of gut motility, should be considered in the genesis of these age-related disorders.

Interdigestive plasma motilin concentrations in aged adults.

The interdigestive plasma motilin concentrations were evaluated in 13 over-65 healthy adults with no evidence of significant disease and in 19 younger individuals. Plasma motilin levels were determined every 15 min during a 3-hr fasting period, using a radioimmunological method. The individual median values of plasma motilin concentrations during the entire study period were significantly higher in aged than younger adults. The individual median coefficients of variation of motilin concentrations and the percentage increases of plasma motilin above baseline at each peak were significantly lower in the aged than in the young group. The results of this study indicate that during the interdigestive period aged individuals have markedly elevated circulating motilin levels, with less pronounced fluctuations than younger persons. This particular hormone pattern could be involved in motor disturbances of the stomach in elderly adults.

Interdigestive gastroduodenal motility and serum motilin levels in patients with idiopathic delay in gastric emptying.

The interdigestive gastroduodenal motor activity and serum motilin levels were studied in 22 dyspeptic patients with markedly delayed gastric emptying not due to diseases known to impair gastroduodenal motility and in 7 control subjects with normal gastric emptying. Motor activity was recorded using a manometric probe positioned in the gastric antrum and in the proximal duodenum, and blood samples for radioimmunoassay of motilin were taken every 15 min during the recording period. The control subjects showed gastroduodenal activity fronts of the migrating motor complex associated with motilin peaks. Almost all patients with delayed gastric emptying showed no activity fronts in the stomach, and only half of them showed activity fronts starting in the duodenum. In these patients a significant reduction in the number of motilin peaks and in the integrated motilin output during the identified peaks was also observed. The results of this study indicate that most dyspeptic patients with idiopathic delay in gastric emptying may also have an alteration in interdigestive gastroduodenal motility, mainly characterized by a lack of gastric activity fronts, associated with an impaired motilin release.

Effect and tolerability of omeprazole in the treatment of duodenal ulcer disease.

In an open clinical trial, 16 hospital outpatients with endoscopically proven duodenal ulcer were given 30 mg omeprazole once daily for four weeks. After two weeks' treatment 14 of the 16 patients had healed and after four weeks all patients were healed. Reduction of pain was rapid and occurred during the first part of the trial. No serious adverse events or clinically significant deviations from normal laboratory values were reported. Serum gastrin levels significantly increased during treatment but returned to normal levels after the treatment was discontinued.