Ellison Syndrome Research Articles

Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines

Counselling of patients and closely related family members has to take a central place in management of hereditary diseases, like multiple endocrine neoplasia (MEN) syndromes including von Hippel-Lindau (VHL) disease. In the strategy of health care, preventive medicine such as periodic clinical examination of families at-risk needs a high priority, because in general it is assumed that continuity in attendance is cost-effective. Counselling has to be based on individual medical experience of the doctor, adjusted to common guidelines and the findings in the family. Information leaflets, appropriate outpatient departments and an extensive network of specialists will facilitate continuity in care. Flow diagrams involving practical guidelines for diagnosis, treatment and follow up need to be applicable and after adjustment, should be accepted generally. Specially trained paramedics for counselling are required as a network that will guarantee periodic clinical examination and secure optimal prevention. Such paramedics will coordinate nationwide multidisciplinary guidance, and organize preventive and emergency cure for these patients. They will be supervised by expert clinicians in the field, and collaborate with specialists for social and psychological issues, patient organizations and clinical genetic centres. All of these professionals are responsible together for providing patients with up to date clinical information (via newsletters, Internet, etc.). Recently, in the Netherlands, a project was initiated to guarantee continuity in care and study the delivery of care. In order to realize this plan, funding has to be provided in the current research programme. In a future system support has to be obtained on a continuous base, preferably by the government and health care insurers and supervised by the national institute for health care.

ZOLLINGER-ELLISON SYNDROME WITH NORMAL SERUM GASTRIN LEVEL

Introduction: Zollinger-Ellison syndrome is characterized by gastric acid hypersecretion leading to refractory/recurrent peptic ulceration due to non-beta islet cell tumor. Diagnosis of Zollinger-Ellison syndrome is made by elevated serum gastrin levels or secretin stimulation test in appropriate clinical setting. We describe a case of Zollinger-Ellison that had near normal serum gastrin levels. Diagnosis was made with endoscopic ultrasound and confirmed by octreotide receptor scintigraphy and histopathology. Case Report: 53-year-old white male with history of 40 lbs weight loss over four months and peptic stricture was referred for evaluation of abdominal pain, diarrhea and symptoms of gastroesophageal reflux despite being on omeprazole 40 mg twice daily. Abdominal exam did not show any evidence of fluid or masses. The patient underwent an esophageal gastroduodenoscopy, which showed diffuse ulceration of esophagus, erosions in the stomach, ulceration in the duodenal bulb and second part of the duodenum. Liver enzymes were elevated and a trans abdominal ultrasound showed dilated pancreatic duct. A CT scan obtained at the same time did not reveal any abnormalities. Serum gastrin level initially was 37 pg/ml and later rose to 161 pg/ml; normal (40–200 pg/ml). Patient refused secretin stimulation test because of fear of symptoms off proton pump inhibitors. An endoscopic ultrasound (EUS) was performed which showed a 25 mm × 30 mm mass in the head of the pancreas. Fine needle aspirate of that mass suggested endocrine tumor. Octerotide scan showed high uptake in the mid epigastric area consistent with gastrinoma. The patient underwent a Whipple procedure and resection of low grade neuroendocrine tumor of the pancreas which stained positive for chromogranin, synaptophysin and pancytokeratin consistent with gastrinoma. The patient was discharged home after one week stay in the hospital. Currently patient is doing well without any complaints of gastroesophageal reflux, one-month post surgery. Discussion: Our case illustrates the fact that normal serum gastrin levels do not rule out the diagnosis of Zollinger-Ellison syndrome. When clinical suspicion of Zollinger- Ellison syndrome is high additional testing i.e. secretin stimulation test (which shows a paradoxical rise in the gastrin levels) or EUS should be done to confirm or refute the diagnosis. A EUS can be very helpful in such situations by not only establishing the diagnosis but also localizing the tumor for surgery.

Images of interest. Gastrointestinal: multiple endocrine neoplasia type I and duodenal gastrinomas.

Multiple endocrine neoplasia type I (MEN I) syndrome is an autosomal dominant disorder characterized by tumors in the pituitary gland, parathyroid glands and upper gastrointestinal tract. While almost all patients have pituitary and parathyroid tumors, only approximately 60% develop islet cells tumors that secrete gastrin (gastrinomas). The presence of gastrinomas causes the Zollinger–Ellison syndrome, a syndrome characterized by hypersecretion of gastric acid and aggressive peptic ulceration. However, only a minority of patients with the Zollinger–Ellison syndrome have MEN I; the majority (70%) have ‘sporadic’ tumors without MEN I. Most gastrinomas occur in the ‘gastrinoma triangle’ that includes the first, second and third parts of the duodenum and the head of the pancreas. However, tumors can occur elsewhere in the pancreas, in peripancreatic lymph nodes and, rarely, in distant sites such as the ovary. Whether tumors in peripancreatic lymph nodes are primary tumors or a site of local spread from a tiny focus in the pancreas remains unclear. Typical gastrinomas occur with similar frequency in the duodenum and pancreas. However, in contrast to ‘sporadic’ gastrinomas, gastrinomas associated with MEN I are more likely to be located in the duodenum, more likely to be small and multiple and more likely to be associated with gastric carcinoid tumors. In addition, gastrinomas associated with MEN I have a lower metastatic potential and a greater longer-term survival (90% at 20 years). Because of the multifocal nature of gastrinomas in MEN I, cure by surgery is less frequent and the majority of patients are managed medically with proton pump inhibitor drugs. Figures 1 and 2 show the endoscopic appearances of multiple polypoid gastrinomas in a patient with MEN I. The diagnosis was confirmed by endoscopic biopsies.

Les gastrinomes dans les néoplasies endocriniennes multiples de type 1. Une étude de cohorte de 127 cas du groupe des tumeurs endocrines (GTE)

On July 2000, 127 gastrinomas (31.1%) were studied by the Endocrine Tumour Group (GTE) using a 408-patient cohort of Multiple Endocrine Neoplasia Type 1 patients. The aim of this study was to assess clinical, biological, surgical data as well as their trends over three periods (<1980–1980/1989–>1990). A Zollinger–Ellison syndrome (SZE) was present in 96% of the cases. Mean age at the onset of the disease was 39.4 years. There were 55.9% of men. Synchronous liver metastasis was present in 7.1%. Taken independently, the positivity of the four main diagnosis tests decreased over the time. The diagnosis of oesophagitis increased (4.5–29.7%), as well as the size of the resected tumours (9.9–16.8 mm). There was an increase in the familial background diagnosis (73.1–80%), an increasing use of Octreoscan scintigraphy and transduodenal ultrasound with positive detection of metastasis and tumours in 81.3% and 92.3%, respectively after 1991. Patients were operated on less frequently (96–52.5%), less frequently from the pancreas (87.5–37.5%), and from the gastro-intestinal tract (70.8–30%). The relative percentage of major pancreatic resections increased (with at least removal of the duodenum and the pancreatic head) (10–26.7%). The operative mortality disappeared. Six out of the seven patients (85.7%) who benefited from major pancreatic resections normalized their gastrine level postoperatively versus 15% in less radical techniques. Overall 5 years survival was 90 ± 4.4%. Survival increased after 1985 (85 ± 4.8% versus 95 ± 3.6, P = 0.1). Conclusion. – SZE in NEM1 were diagnosed at an earlier stage and were less frequently operated on. Nevertheless, the incidence of synchronous metastasis did not change significantly. Patients were mainly operated on for gastric emergencies and pancreatic tumours in order to prevent metastasis without mortality after 1991.

Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1).

The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence.

Novel therapeutic strategies in acid-related disorders

Acid-related disorders of the upper gut encompass diseases of the oesophagus, stomach and duodenum, such as gastro-oesophageal reflux disease (GORD), gastric and duodenal (peptic) ulcers, Zollinger–Ellison syndrome and iatrogenic ulcers and gastrointestinal bleeding mostly induced by non-steroidal anti-inflammatory drugs (NSAIDs). Gastric acid and pepsin are largely involved in their pathophysiology, both factors acting with Helicobacter pylori (especially in peptic ulcers) or with either NSAIDs, stress or smoking. All these diseases can benefit from agents that neutralise gastric acid or inhibit its secretion. Neutralising acid with antacids or decreasing acid secretion with histamine H2-receptor antagonists (H2-RAs) was the standard of care before the introduction of proton pump inhibitors (PPIs), which have been one of the major advances in the field of gastrointestinal pharmacology. Their superior efficacy in acid-related disorders with respect to other acid reducing drugs is now widely recognised. PPIs are also used to control atypical GORD symptoms, such as laryngitis, asthma and cough associated with reflux. In spite of their clinical efficacy in a number of conditions, the emerging need for new therapeutic approaches, such as ‘on-demand’ treatment for GORD symptoms, requires some features (e.g., fast onset of action at day 1 with an acid suppressant effect throughout the day and night, to avoid the nocturnal acid breakthrough) that currently available PPIs only partially achieve. Moreover, a subset of patients with GORD still do not respond to the available therapeutic regimens. Novel agents (or novel formulations of available PPIs) have recently been patented to try to overcome these problems.

Effect of chronic hypergastrinemia on human enterochromaffin-like cells: Insights from patients with sporadic gastrinomas

Background & Aims: The effect of chronic hypergastrinemia alone on gastric enterochromaffin-like (ECL) cells in humans is largely unknown because in the common chronic hypergastrinemic states (atrophic gastritis, chronic proton pump inhibitor use), it is not possible to separate the effect of hypergastrinemia and other factors, such as gastritis or atrophy. Studies of patients with sporadic Zollinger–Ellison syndrome (ZES) allow this separation. Methods: In 106 patients with ZES, gastric biopsies were taken, and the qualitative ECL cell pattern/grade and the α-subunit of human chorionic gonadotropin (α-hCG) expression were determined. Results: In patients with active disease, 99% had ECL hyperplasia and abnormal α-hCG staining. Fifty percent had advanced changes in both of these, with 7% having dysplasia and 0% having carcinoids. Advanced ECL cell and α-hCG changes were most affected by the level of hypergastrinemia. For ECL cell changes, even mild hypergastrinemia had an effect. Advanced ECL change was also affected by the duration of drug treatment, cure status, and presence of atrophic gastritis, but not by sex or previous vagotomy. The α-hCG expression independently predicted dysplasia. Conclusions: In humans, chronic hypergastrinemia alone causes advanced ECL cell change and abnormal expression of mucosal α-hCG. No threshold for this effect was detected, as reported by some, and in contrast to animal studies, sex and vagal tone did not play a major role. The long-term risk of developing gastric carcinoids with chronic hypergastrinemia is low in patients with sporadic gastrinomas (at least 100 times less than in patients with multiple endocrine neoplasia type 1 with ZES) for at least 15–20 years.GASTROENTEROLOGY 2002;123:68-85

Experimental and calculated 1H, 13C, 15N NMR spectra of famotidine

Famotidine, 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]- N-(aminosulfonyl), is a histamine H 2-receptor blocker that has been used mainly for the treatment of peptic ulcers and the Zollinger–Ellison syndrome. Its NMR spectra in different solvents were reported earlier; however, detailed interpretation has not been done thus far. In this work, experimental 1H, 13C and 15N NMR spectra of famotidine dissolved in DMSO-d 6 are shown. The assignment of observed chemical shifts is based on quantum chemical calculation at the Hartree–Fock/6-31G ∗ level. The geometry optimization of the famotidine molecule with two internal hydrogen bonds, i.e. [N(3)–H(23)⋯N(9) and N(3)⋯H(34)–N(20)], is done by using the B3LYP method with the 6-31G ∗ basis set.

Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole.

Helicobacter pylori is said to cause atrophy of the gastric corpus and enterochromaffin-like cell proliferation in gastro-oesophageal reflux disease (GERD) patients treated long-term with a proton pump inhibitor. To determine the effect of H. pylori infection on gastritis, enterochromaffin-like cell density and hyperplasia, mucosal atrophy and serum gastrin in patients with gastric hypersecretion (basal acid output gt; 15 mmol/h) with either hypergastrinemia (Zollinger-Ellison syndrome) or normal gastrin (non-Zollinger-Ellison syndrome) before and during long-term treatment with lansoprazole. Lansoprazole was individually titrated to reduce basal acid output to < 5 mmol/h (< 1 mmol/h in post-surgical Zollinger-Ellison syndrome). Gastric corpus biopsies were obtained every 6 months before treatment and up to 8 years later. H. pylori was present in corpus biopsies in approximately 50%, causing active gastritis which resolved rapidly in 15 subjects after elimination of H. pylori. Patchy mild/moderate corpus atrophy was present at entry in two and at the end in four out of 60 patients, one being H. pylori-positive. Intestinal metaplasia (< 10%) was seen in six isolated biopsies (1% of total). H. pylori did not affect serum gastrin, enterochromaffin-like cell density or hyperplasia. Enterochromaffin-like cell density was twice as high in Zollinger-Ellison syndrome as in non-Zollinger-Ellison syndrome patients (241 vs. 126 cells/mm2, P < 0.001). Enterochromaffin-like cells remained normal in the non-Zollinger-Ellison syndrome hypersecretors regardless of H. pylori status. Corpus enterochromaffin-like cell increases were related to serum gastrin elevation, but neither H. pylori nor long-term treatment with lansoprazole alone or together had any effect on enterochromaffin-like cell density or hyperplasia. Corpus acute gastritis resulted from H. pylori infection, but did not result in mucosal atrophy despite long-term proton pump inhibitor treatment and promptly resolved with loss of H. pylori.

Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger–Ellison syndrome

Background & Aims: Parenteral control of gastric acid hypersecretion in conditions such as Zollinger–Ellison syndrome (ZES) or idiopathic gastric acid hypersecretion is necessary perioperatively or when oral medications cannot be taken for other reasons (e.g., during chemotherapy, acute upper gastrointestinal bleeding, or in intensive care unit settings). Methods: We evaluated the efficacy and safety of 15-minute infusions of the proton pump inhibitor pantoprazole (80–120 mg every 8–12 hours) in controlling acid output for up to 7 days. Effective control was defined as acid output >10 milliequivalents per hour (mEq/h) (<5 mEq/h in patients with prior acid-reducing surgery) for 24 hours. Results: The 21 patients enrolled had a mean age of 51.9 years (range, 29–75) and a mean disease duration of 8.1 years (range, <0.5–21); 13 were male, 7 had multiple endocrine neoplasia syndrome type I, 4 had undergone acid-reducing surgery, 2 had received chemotherapy, and 13 had undergone gastrinoma resections without cure. Basal acid output (mean ± SD) was 40.2 ± 27.9 mEq/h (range, 11.2–117.9). In all patients, acid output was controlled within the first hour (mean onset of effective control, 41 minutes) after an initial 80-mg intravenous pantoprazole dose. Pantoprazole, 80 mg every 12 hours, was effective in 17 of 21 patients (81%) for up to 7 days. Four patients required upward dose titration, 2 required 120 mg pantoprazole every 12 hours, and 2 required 80 mg every 8 hours. At study end, acid output remained controlled for 6 hours beyond the next expected dose in 71% of patients (n = 15); mean acid output increased to 4.0 mEq/h (range, 0–9.7). No serious or unexpected adverse events were observed. Conclusions: Intravenous pantoprazole, 160–240 mg/day administered in divided doses by 15-minute infusion, rapidly and effectively controlled acid output within 1 hour and maintained control for up to 7 days in all ZES patients. GASTROENTEROLOGY 2000;118:696-704

FT-IR and FT-Raman spectra of cimetidine and its metallocomplexes

We present vibrational spectra of three stable, well-reproducible, polymorphic forms of cimetidine (cim), a drug which is a powerful histamine H2-receptor antagonist used in the treatment of peptic ulcer and the Zollinger–Ellison syndrome. Assignments of Raman and IR bands are made using semiempirical methods: MNDO, AM1 and PM3. We also describe the synthesis of Me(cim)2(ClO4)2, where Me=Cu(II), Cd(II), Co(II) and Ni(II), and present their vibrational data. We show that the obtained complexes are isostructural, however a metal ion that occupies a center of octahedral unit introduces some distortions that can be seen in the spectra. We also make tentative assignment of metal–ligand stretching modes observed in low frequency range.

Reply

We appreciate Dr. Waldum's interest in our study1Rindi G. Azzoni C. La Rosa S. et al.ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis.Gastroenterology. 1999; 116: 532-542Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar on gastric ECL cell tumors and poorly differentiated endocrine carcinomas; we would like to point out the following in reply to the questions and comments raised. First, the 258 tumors were diagnosed in 4 different pathology departments that operate as reference centers for gut endocrine tumors. All morphological means presently known to be relevant for such diagnoses, from histopathology to immunohistochemical tests for various hormones and endocrine markers, and electron microscopy in many cases, have been used as specified in the present and previous articles.2Solcia E. Capella C. Fiocca R. et al.Gastric argyrophil carcinoidosis in patients with Zollinger–Ellison syndrome due to type 1 multiple endocrine neoplasia. A newly recognized association.Am J Surg Pathol. 1990; 14: 503-513Crossref PubMed Scopus (204) Google Scholar, 5Rindi G. Bordi C. Rappel S. et al.Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology and behavior.World J Surg. 1996; 20: 168-172Crossref PubMed Scopus (375) Google Scholar, 3Bordi C. Yu J.Y. Baggi M.T. et al.Gastric carcinoids and their precursor lesions. A histological and immunohistochemical study of 23 cases.Cancer. 1991; 67: 663-672Crossref PubMed Scopus (166) Google Scholar, 4Rindi G. Luinetti O. Cornaggia M. et al.Three subtypes of gastric argyrophil carcinoids and the gastric neuroendocrine carcinoma: a clinicopathological study.Gastroenterology. 1993; 104: 994-1006PubMed Google Scholar Pertinent diagnostic criteria, including differential diagnosis between well-differentiated and poorly differentiated endocrine tumors as well as between endocrine and nonendocrine gastric tumors, were also detailed in these articles. In particular, the diagnosis of poorly differentiated endocrine carcinoma was based on diffuse to poorly defined solid structure; severe cellular atypia; poor, scanty, or absent reactivity for hormonal products and endocrine granule markers, such as chromogranins or silver stains; reactivity for cytosolic or small clear vesicles neuroendocrine markers, such as synaptophysin, in a substantial proportion of tumor cells; lack of reactivity for exocrine differentiation markers, such as mucins and pepsinogens; and ultrastructural evidence of a few secretory granules of unquestionable endocrine nature (exocrine secretory granules must be ruled out). Recently, such criteria were accepted by the international WHO group for the histological typing of endocrine tumors.6Solcia E. Klöppel G. Sobin L.H. Histological typing of endocrine tumours. WHO International Histologic Classification of Tumours. Springer, Berlin2004Google Scholar Mixed exocrine-endocrine tumors showing evidence of substantial differentiation in both exocrine and endocrine directions inside the same tumor were excluded from the study. Second, our investigation dealt with the 102 tumors that, after extensive review of all available material by at least 2 of us, were found to fulfill all requirements for careful clinicopathologic evaluation, including prolonged follow-up information and extensive tumor and nontumor tissue sampling. Third, concerning poorly differentiated endocrine carcinoma, Dr. Waldum's concern that iatrogenic hypergastrinemia is a major risk factor for gastric malignancy remains to be substantiated by facts. Available evidence suggests that endogenous hypergastrinemia is a risk factor for the well-differentiated ECL cells carcinoids arising in a background of severe type A chronic atrophic gastritis or combined multiple endocrine neoplasia Zollinger–Ellison syndrome, very few of which proved malignant.1Rindi G. Azzoni C. La Rosa S. et al.ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis.Gastroenterology. 1999; 116: 532-542Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 3Bordi C. Yu J.Y. Baggi M.T. et al.Gastric carcinoids and their precursor lesions. A histological and immunohistochemical study of 23 cases.Cancer. 1991; 67: 663-672Crossref PubMed Scopus (166) Google Scholar Presently, no established evidence supports a role for hypergastrinemia, either endogenous or iatrogenic, in the genesis of the frequently malignant sporadic ECL cell carcinoid, most highly malignant poorly differentiated endocrine carcinomas, or common nonendocrine gastric cancers, an issue beyond the scope of our study.

Prospective study of the value of serum chromogranin A or serum gastrin levels in the assessment of the presence, extent, or growth of gastrinomas

BACKGROUND Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas. METHODS In 112 consecutive patients with the Zollinger–Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors. RESULTS Serum CgA levels drawn on 2 consecutive days correlated closely (P < 0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P < 0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P < 0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results. CONCLUSIONS The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia. Cancer 1999;85:1470–83. © 1999 American Cancer Society.

Prognostic factors in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1

Background & Aims: Risk factors of metachronous liver metastases and death are not well known in patients with the Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. These factors were retrospectively determined in 77 patients. Methods: Data chart review was performed. Results: Median follow-up was 102 months (range, 12–366). Surgery was performed on 48 patients, including 9 of the 10 patients with large pancreatic tumors (≥3 cm). Liver metastases developed in 4 patients (40%) with large pancreatic tumors, in 3 (4.8%) without, and in 1 of the 4 patients with pancreatic tumors of unknown size; all had previously undergone surgery. The only independent factor associated with development of liver metastases identified by multivariate analysis was large pancreatic tumors (risk ratio, 29.0; 95% confidence interval [CI], 3.2–260.7). Surgery was not selected. The probability of being free of liver metastases in the 63 patients without large pancreatic tumors was 96% (95% CI, 88–100) at 10 and 15 years. Thirteen (16.9%) patients died. The only independent factors of death selected by multivariate analysis were Zollinger–Ellison syndrome diagnosis before 1980 (risk ratio, 8.2; 95% CI, 1.7–40.6) and age at diagnosis (risk ratio/year, 1.08; 95% CI, 1.03–1.14). Conclusions: Large pancreatic tumors are predictive of the development of metachronous liver metastases, and surgery does not seem to prevent them. GASTROENTEROLOGY 1999;116:286-293

Biological activity of carboxy-terminal gastrin analogs

Amidated forms of gastrin are derived by post-translational processing of a large precursor peptide and stimulate gastric acid secretion via the gastrin/CCK B receptor. Non-amidated biosynthetic intermediates may exert biological effects through other mechanisms, but their effect on gastric acid secretion is unclear. Amidated gastrins stimulate acid secretion mainly by releasing histamine from mucosal enterochromaffin-like cells. This study examines the effects on histamine release from the vascularly perfused rat stomach of amidated gastrin-17, COOH-terminal glycine-extended gastrin-17, gastrin-17 extended at the COOH-terminal including the remaining progastrin sequence, and carboxy-terminal progastrin fragments (SAEDEN and GRRSAEDEN). Carboxy-terminal extended gastrins induced histamine release which was inhibited by the gastrin/CCK B antagonist L-740,093, but had to be given in concentrations 100-fold higher than amidated gastrin-17 to produce comparable effects. These progastrin-derived peptides are found in high concentrations in some patients with the Zollinger–Ellison syndrome and may contribute to acid hypersecretion and other gastrin/CCK B receptor mediated responses.

Relationship between fundic endocrine cells and gastric acid secretion in hypersecretory duodenal ulcer diseases.

Acid hypersecretion is associated with duodenal ulcer disease in the following conditions: Zollinger-Ellison syndrome (ZES) and antral gastrin cell hyperfunction (AGCH) due to hypergastrinaemia, or hypersecretory duodenal ulcer (HDU) without hypergastrinaemia. To evaluate whether quantitative changes in fundic ECL and D cells may be involved in acid hypersecretion. Seven ZES, six AGCH and six HDU Helicobacter pylori-positive patients were compared. Basal (BAO) and pentagastrin-stimulated gastric acid secretions (PAO), and morphometry of fundic ECL and D cells were performed. The six AGCH and six HDU patients were investigated again using the same tests 1 year after H. pylori eradication. Median PAO values were no different in all the hypersecretory conditions studied. The median volume density of ECL cells in ZES was significantly higher than in controls (2.75, range 1.74-5.8 vs. 0.73, 0.52-1.11: P < 0.05), whereas it was in the control range in AGCH and HDU patients (0.77, range 0.20-1.39 and 0.99, range 0.42-1.51; respectively). The count of fundic D cells was significantly lower in AGCH patients than in all other investigated groups (median 0.16, range 0.1-0.52; P < 0.05). Cure of infection in AGCH and HDU patients did not modify the ECL cell volume density, whereas a significant increase in the count of fundic D cells was observed in AGCH patients. Thus, the ECL/D cell index was significantly affected in AGCH patients (P < 0.05), being higher during H. pylori infection (median 6, range 0.7-9.25) than after the cure (median 2.12, range 1.10-3.5). BAO and PAO were not affected by H. pylori eradication in either group. The study provides evidence, for the first time, that quantitative alterations in the fundic endocrine cells are not involved in acid hypersecretion of patients with hypersecretory states, and that eradication of H. pylori does not restore normal acid secretion values.

Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1

Zollinger-Ellison syndrome (ZES) is the most common symptomatic pancreatic endocrine tumour in patients with MEN-1. Besides the treatment of the usual endocrinopathies seen in patients with MEN-1, the treatment of the ZES requires attention be paid to controlling the gastric acid hypersecretion, to dealing with the gastrinomas per se which are malignant in 18-60% of cases, and to the diagnosis and treatment of gastric carcinoid tumours, that are increasingly seen in these patients. In this article the current management of each of the areas is reviewed and what is known or uncertain discussed, based on our studies at the NIH and data from others. Data from 231 patients including 45 with MEN-1 and 186 without MEN-1 is contrasted in this report. Gastric acid hypersecretion has been controlled in all patients medically with MEN-1 and ZES at the NIH for up to 22 years. The current drugs of choice are H+-K+ ATPase inhibitors and twice a day dosing is recommended. Periods of parenteral drug therapy (surgery, etc.) and pregnancy require important modifications. The appropriate surgical therapy of the gastrinoma is controversial. Eighty per cent of patients have a duodenal gastrinoma and 20-30% have a pancreatic tumour. Recent studies suggest gastrinoma enucleation combined with duodenotomy rarely results in cure. Aggressive surgery (Whipple resection) can result in cure of gastrinoma but effect on survival is unclear. There are important differences in gastrinoma location, extent, and percentage with aggressive disease in patients with or without MEN-1, which are discussed. Confusion has occurred because of lack of information on the natural history of the gastrinoma compared to the other pancreatic endocrine tumours that occur in MEN-1 and survival data from patients with and without MEN-1 is contrasted. The occurrence of gastric carcinoids in patients with and without MEN-1 with ZES is contrasted and the areas of certainty and disagreement reviewed.

Association of serum antibodies against p53 protein with poor survival in patients with Zollinger–Ellison syndrome

Background & Aims: Long-term survival of patients with Zollinger–Ellison syndrome (ZES) is largely determined by the presence or absence of liver metastases. However, because of the lack of precision of these criteria, development of further indicators is still required. Recent evidence showing that autoantibodies directed against the p53 protein could predict poor survival for some types of cancers prompted us to investigate the presence of such antibodies in sera from patients with ZES and their potential value as survival indicator. Methods: Anti-p53 antibodies were detected in the sera of 44 consecutive patients with ZES using both an enzyme-linked immunosorbent assay (ELISA) and Western blotting. The mean follow-up of these patients was 92 months. Results: Anti-p53 antibodies were detected in 7 of the patients with ZES (16%) by both ELISA and Western blotting. Univariate and multivariate analyses showed that the presence of anti-p53 antibodies ( P = 0.0009 and P = 0.017, respectively) and liver metastases ( P = 0.0009 and P = 0.012, respectively) was independently associated with shorter survival. Conclusions: These results suggest that anti-p53 antibodies are an indicator of survival and could be used in combination with staging to determine which patients with ZES have poor prognoses and therefore require reinforced therapy. GASTROENTEROLOGY 1998;114:37-43

Studies on the interrelation between Zollinger-Ellison syndrome, Helicobacter pylori, and proton pump inhibitor therapy

BACKGROUND & AIMS: The interrelation between Helicobacter pylori infection and proton pump inhibitor therapy in patients with Zollinger- Ellison syndrome is unknown. The aim of this study was to evaluate the influence of these factors on parameters of Zollinger-Ellison syndrome. METHODS: Prevalence of H. pylori was determined by biopsy and antibody testing in 84 patients. The influence of H. pylori status on clinical and laboratory parameters of Zollinger-Ellison syndrome was evaluated. Seroconversion after surgery was assessed retrospectively in infected patients. RESULTS: The prevalence of H. pylori exposure was 23% (10% with active infection). Acid output was higher in H. pylori-negative patients, but other clinical and biochemical parameters did not differ. Parameters were also similar for patients determined to be H. pylori positive by histology or antibody testing alone. Seroconversion rates did not differ between those rendered or not rendered disease free despite a significant reduction in acid output. CONCLUSIONS: H. pylori infection is not a risk factor for peptic ulceration in patients with Zollinger-Ellison syndrome. The prevalence is lower than in the general population and much lower than for patients with idiopathic peptic ulcer disease. Long-term omeprazole therapy in H. pylori-positive patients with Zollinger-Ellison syndrome may-lead to a reduction in parietal cell mass. (Gastroenterology 1997 Jan;112(1):84-91)

Diagnosis and treatment of zollinger - ellison syndrome /ZES/ in Slovakia

Diagnosis and treatment of zollinger - ellison syndrome /ZES/ in Slovakia