Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies.

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.

CagA-positive Helicobacter pylori strain containing three EPIYA C phosphorylation sites produces increase of G cell and decrease of D cell in experimentally infected gerbils (Meriones unguiculatus).

PURPOSE: Human infection by Helicobacter pylori is associated with an increase in the number of gastrin-producing G cells and a concomitant decrease of somatostatin-producing D cells. However, to our knowledge, changes in G and D cell numbers in response to infection with H. pylori CagA-positive strains containing different number of EPIYA-C phosphorylation sites have not been analyzed to date. Therefore, the aim of this study was to perform a quantitative analysis of the number of G and D cells in Mongolian gerbils challenged with H. pylori strains with different numbers of EPIYA-C motifs. MATERIALS AND METHODS: Mongolian gerbils were inoculated with isogenic H. pylori strains containing one to three phosphorylation sites. Mucosal fragments were evaluated by morphometry and immunohistochemistry using primary polyclonal rabbit anti-gastrin and anti-somatostatin antibodies. Positive cells were counted using an image analyzer. RESULTS: Forty-five days after infection, there was a decrease in the number of D cells and an increase in the G/D cell ratio in the group with three EPIYA-C. Six months after infection, there was a progressive and significant increase in the number of G cells and in the G/D cell ratio, with a concomitant decrease in the number of D cells, especially in the three EPIYA-C group. CONCLUSIONS: CagA-positive H. pylori strains containing a large number of EPIYA-C phosphorylation sites induce a decrease in D cell number and an increase in G cell number and G/D ratio, which were correlated with the number of inflammatory cells of the lamina propria.

Is there any association between Helicobacter Pylori infection and laryngeal carcinoma?

OBJECTIVE: To investigate the possible role of Helicobacter pylori as a cause of squamous cell carcinoma of larynx in a case-control study in an otolaryngology ward at an academic university. SUBJECTS AND METHODS: A total of 65 patients with laryngeal cancer and 65 matched cancer-free controls underwent esophagogastroduodenoscopy and biopsy of antral and body regions of the stomach for evaluation of Helicobacter pylori infection. RESULTS: The proportion of subjects with a positive rapid urease test for gastric infection was similar between the two groups (49.2 % in cases vs. 40% in controls). However, a positive rapid urease test for body was less frequently seen in patients with laryngeal cancer whereas a positive rapid urease test for antrum was significantly higher (P=0.04). CONCLUSION: Our study failed to show Helicobacter pylori as one of the etiologies of laryngeal cancer. However, it supported the hypothesis that colonization of Helicobacter pylori only in the gastric body might have a protective effect against laryngeal cancer with decreasing gastric acid while antral Helicobacter pylori, increasing gastric acid due to G cell hyperplasia, may be a predisposing factor for laryngeal cancer, with acid reflux as a possible underlying etiology.

[Gastric neuroendocrine tumors. Endoscopic and surgical treatment]. / Neuroendokrine Tumoren des Magens. Endoskopische und chirurgische Therapie.

Neuroendocrine tumors (NETs) of the stomach are the most frequent among all neuroendocrine neoplasms in the digestive tract. The diagnosis and classification are complicated by the fact that these tumors have to be categorized not only by common staging and grading but also according to their pathophysiological background (types). The types differ in their biological behaviour (aggressiveness) which influences therapeutic concepts. This article explains and summarizes the etiology and classification of gastric NETs and offers a precise concept for diagnosis and treatment to improve clinical outcome.

G cells and gastrin in chronic alcohol-treated rats.

Numerous reports have described gastric mucosal injury in rats treated with high ethanol concentrations. However, to the best of our knowledge, ultrastructural characteristics of G cells and antral gastrin levels have not been previously reported, either in rats that chronically consumed alcohol or in human alcoholics. The goal of this study was to examine the effect of ethanol consumption (8.5 g/kg) over a 4-month period, under controlled nutritional conditions, on antral and plasma levels of gastrin, ultrastructure of G cells, morphometric characteristics of G cells by stereological methods, and analysis of endocrine cells in the gastric mucosa by immunohistochemistry. The chronic alcohol consumption resulted in a nonsignificant decrease in gastrin plasma levels and unchanged antral gastrin concentrations. A slightly damaged glandular portion of the gastric mucosa and dilatation of small blood vessels detected by histological analysis, suggests that ethanol has a toxic effect on the mucosal surface. Chronic alcohol treatment significantly decreased the number of antral G cells per unit area, and increased their cellular, nuclear, and cytoplasmatic profile areas. In addition, the volume density and diameter of G-cell granules, predominantly the pale and lucent types, were increased, indicating inhibition of gastrin release. Ethanol treatment also decreased the number of gastric somatostatin-, serotonin-, and histamine-immunoreactive cells, except the somatostatin cells in the pyloric mucosa, as well as both G: D: enterochromaffin cells (EC) cell ratios in the antrum and D: ECL cell ratios in the fundus. These results indicate that the change of morphometric parameters in G cells may be related to cellular dysfunction. Our findings also suggest that regulation of G-cell secretion was not mediated by locally produced somatostatin in ethanol-consuming rats, but may involve gastric luminal content and/or neurotransmitters of gastric nerve fibers.

Effect of mica monomer powder on chief and parietal cells as well as G and D cells in gastric mucosa of chronic atrophic gastritis in rats.

OBJECTIVE: To study the regulative action of mica monomer powder preparation on the chief and parietal cells as well as G and D cells in the gastric mucosa of the experimental atrophic gastritis (CAG) rats. METHODS: Intervention therapy was given to the experimental CAG rats at three different doses of mica monomer powder preparation to evaluate the changes of chief and parietal cells as well as G and D cells in the gastric mucosa and the histopathological changes of gastric mucosa. RESULTS: Mica monomer powder preparation at three different doses could increase the amount of chief and parietal cells as well as G and D cells in gastric mucosa of the experimental CAG rats and alleviate and control the inflammation of gastric mucosa and the atrophy of gastric mucosa glands. Especially, better effects were shown in the mid and high dose groups. CONCLUSION: Mica has the pharmacological action of protecting the gastric mucosa, enhancing blood flow of the gastric mucosa, and consequently improving the inflammatory responses of the gastric mucosa. One of the mechanisms is associated with promoting the secretion of gastric acid and gastric pepsin and regulating the neuroendocrine mechanism including gut hormone secretion (gastrin and somatostatin) by increasing the number of chief and parietal cells as well as G and D cells.

Serum gastrin concentration and changes in G and D cell densities in gastric antrum in children with chronic gastritis.

BACKGROUND: Elevated gastrin concentration leading to gastritis is explained as the effect of change in the density of D and G cells. The aim of the study was to determine and compare fasting serum gastrin concentrations, G and D cell densities in gastric antrum mucosa in children with chronic gastritis and in children with no gastritis or Helicobacter pylori infection. MATERIAL AND METHODS: A total of 184 patients aged 6-18 years, with chronic abdominal pain underwent endoscopic examination. We created three groups: I--patients with chronic gastritis and H. pylori infection; II--patients with chronic gastritis but no H. pylori infection; III--patients with neither gastric mucosal abnormalities nor H. pylori infection. G and D cell densities were determined in the biopsy specimens (using Rbalpha H Gastrin & Somatostatin antibodies). Fasting serum gastrin concentrations were measured using a Beckmann gamma-counter and a GASK-PR kit. RESULTS: The mean serum gastrin concentration in group I was higher when compared with group II (p = 0.04) and group III (p = 0.019). No statistically significant differences were found between groups II and III (p = 0.91). There were no statistically significant differences in G and D cell densities between groups. CONCLUSION: The mean G/D cell ratios in groups I and III were almost identical. The mean fasting serum gastrin concentration was higher in children with both chronic gastritis and H. pylori infection compared with patients without infection or without antral inflammation. No difference in the G cell density or D cell density in children was found, regardless of the presence or absence of gastritis or H. pylori infection.

Gastrinoma--morphological aspects.

Gastrinomas are defined as gastrin producing tumors that are associated with an elevated fasting gastrin serum level, a positive gastrin secretin stimulation test and certain clinical symptoms, e.g. recurrent peptic ulcer disease and occasionally diarrhea, the so-called Zollinger-Ellison syndrome. Most gastrinomas occur in the duodenum (approx. 70%) and not in the pancreas. The duodenal gastrinomas are small, and when they occur in association with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1), they are multicentric and originate from precursor lesions. The prognosis of duodenal gastrinomas is better than that of pancreatic gastrinomas, since despite early lymph node metastasis they progress slowly to liver metastasis.

An immunohistochemical study of endocrine cells in the stomach of hypertensive rats.

Essential hypertension is a complex disease with both genetic and environmental determinants. The effect of spontaneous hypertension on the distribution and occurrence of somatostatin-, gastrin- and serotonin-immunoreactive cells in the fundus and pylorus of the rat stomach was examined by immunohistochemistry. The animals were killed by decapitation at 4 and 16 weeks of age (5 control rats and 5 hypertensive rats). Endocrine cells generally increase in number in hypertensive rats as compared to control rats. However, the detailed responses of endocrine cells to hypertension depend on the cell type, region of gastric mucosa and age of animals. The present results suggest that hypertension has an influence on the intrinsic regulatory system by endocrine cells control in the rat stomach.

[Study on histogenesis of enterochromaffin-like carcinoid in autoimmune atrophic gastritis associated with pernicious anemia].

BACKGROUND/AIM: Autoimmune atrophic fundic gastritis induces the pernicious anemia (PA), as well as the changes in both epithelium and endocrine cells of gastric mucosa. The most important complications are: achlorhydria, hypergastrinemia, gastric cancer and enterochromaffin-like (ECL) carcinoid. The aim of this study was to examine ECL carcinoid histogenesis in A-gastritis associated with PA. METHODS: During the period from 2000-2006, 65 patients with PA and 30 patients of the control group were examined. Histopathological examination was done in endoscopical biopsies of gastric mucosa fixed in 10% formaldehyde. Paraffin sections were stained with classic hematoxylin-eosin (HE); histochemical AB-PAS (pH 2.5), cytochemical argyrophilic Servier-Munger's and immunocytochemical PAP methods for G cell identification and chromogranin A antibodies - specific marker for neuroendocrine ECL cells. Both G and ECL cells were counted per 20 fields, of surface 0.0245312 mm2 by a field. Basal gastrin serum levels were also examined by using radioimmunoassay (RIA) method. The obtained results were statisticaly calculated by using Student's t test. RESULTS: Marked antral G cell hyperplasia associated with corporal ECL hyperplasia was found. ECL cell hyperplasia was of simplex, linear, adenomatoid type to the pattern of intramucous ECL cell carcinoid. An average number of G cells was statistically significant in the patients with PA as compared to the control group (p < 0.05) as well as an average number of ECL cells. CONCLUSION: We concluded that antral G cell hyperplasia accompanied by gastrinemia induces ECL hyperplasia and ECL corporal carcinoid in A-gastritis and that their histogenesis develops trough simple, linear and adenomatoide hyperplasia.

Adaptive changes of the enterochromaffin and gastrin cells in the rat gastrointestinal tract following subtotal colectomy.

OBJECTIVE: Colectomized patients often have diarrhoea and increased gastric acid secretion. Although serotonin influences gastrointestinal (GI) motility and secretion, GI serotonin-producing enterochromaffin (EC) cells have not been investigated after colectomy, nor have the antral gastrin cells. The aim of this experimental study was to investigate the GI tract in rats 8 weeks after subtotal colectomy, with particular emphasis on the frequency and distribution of EC and gastrin cells. MATERIAL AND METHODS: Immunohistochemical techniques were used to identify the two endocrine cell types. RESULTS: The colectomized animals had diarrhoea. Body-weight was lower and the small intestine shorter in the colectomized animals compared with sham-operated and untreated controls. In the two surgically treated groups, the antral mucosa was thinner and the small intestinal mucosa was thicker compared with that of the untreated rats, whereas the thickness of the rectum of the colectomized rats was increased compared with that of the control groups. In the colectomized animals, the number of EC cells was increased in the small intestine and rectum, whereas the numbers of both EC and gastrin cells were decreased in the antrum. CONCLUSIONS: The results indicate that colectomy exerts a significant influence on the GI mucosa and on the endocrine cell systems studied. An increased number of EC cells can result in alterations in motility and secretion, which may be important in the pathogenesis of the diarrhoea that often occurs after colectomy.

Gastrin (G) cells and somatostatin (D) cells in patients with dyspeptic symptoms: Helicobacter pylori associated and non-associated gastritis.

BACKGROUND: Gastrin G cells and somatostatin D cells are important regulators of gastric acid secretion and alterations in their relative numbers may play a key role in gastroduodenal disease. AIM: To investigate the effect of Helicobacter pylori infection on the density of immunoreactive G and D cells in gastric antral and corpus biopsies from patients with dyspeptic complaints. METHODS: One hundred and twenty two patients with dyspeptic complaints had two antrum and two corpus biopsies taken during upper endoscopy. The severity of inflammation and the density of H pylori were evaluated semiquantitatively. In addition, the density and distribution of neuroendocrine cells, especially G and D cells, were examined using immunohistochemistry. Patients were divided into three groups, those with H pylori positive gastritis, H pylori negative gastritis, and histologically normal gastric mucosa. RESULTS: The number of immunoreactive G cells was significantly higher and the number of immunoreactive D cells lower in patients with H pylori positive gastritis compared with H pylori negative gastritis or histological normal gastric mucosa. The percentage of G cells as a percentage of mucosal endocrine cells was also raised and that of D cells was decreased. CONCLUSIONS: Helicobacter pylori infection produces alterations in the number of endocrine cells responsible for regulating acid secretion in relation to intragastric pH and feeding. The alterations correlate best with the severity of inflammation and not with H pylori density.

Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas.

BACKGROUND & AIMS: The identification of precursor lesions has a great impact on the understanding of tumorigenesis. Precursor lesions of endocrine tumors are known to occur in the setting of the MEN1 syndrome. The aim of this study was to test the hypothesis that MEN1-associated duodenal gastrinomas originate from diffuse preneoplastic gastrin cell changes. Precursor lesions may precede the development of duodenal gastrinomas because, in contrast to sporadic gastrinomas, these tumors are usually multiple. METHODS: The distribution of endocrine cells in the nontumorous duodenal tissue was analyzed qualitatively and quantitatively for 25 patients operated on for a duodenal gastrinoma. MEN1 status was assessed clinically and by polymerase chain reaction-based mutational analysis. RESULTS: Fourteen of 25 patients with gastrinoma had proliferative, hyperplastic lesions consisting of gastrin cells in the nontumorous duodenal mucosa, similar to the gastric enterochromaffin-like cell lesions observed in chronic atrophic gastritis. All patients with Zollinger-Ellison syndrome with proven MEN1 had such proliferative gastrin cell lesions, and all patients with Zollinger-Ellison syndrome without precursor lesions were MEN1 negative. CONCLUSIONS: Duodenal gastrinomas in MEN1, but not sporadic duodenal gastrinomas, are associated with proliferative gastrin cell changes within the nontumorous mucosa. It is likely that these lesions precede the development of MEN1-associated duodenal gastrinomas.

Effects of duodenogastric reflux on gastrin cells, somatostatin cells and serotonin cells in human antral gastric mucosa.

Duodenogastric reflux (DGR) has been found to give rise to a hypochlorhydria secondary to alkaline reflux. We investigated whether there is a link between DGR and the gastrin, somatostatin, and serotonin cell numbers and the granular content of gastrin, somatostatin, and serotonin in endocrine cells in human antral mucosa. We investigated 38 selected Helicobacter pylori-negative patients with visual primary excessive DGR in upper endoscopy and symptoms of epigastric pain and bile vomiting. Ten control patients were included in this study. None of the patients had peptic ulcer or had received any medication. Antrum (10 biopsies from five different zones: the lesser and major curvature, the anterior and posterior wall, and the pylorus) and corpus (two biopsies from major curvature about 10 cm below the cardia) biopsy specimens were collected for routine histology, as well as for light and electron immunohistochemistry. In patients without atrophy or intestinal metaplasia and in patients with mild atrophy or mild intestinal metaplasia, the number of gastrin and somatostatin cells was not different from that in controls. In moderate atrophy or moderate intestinal metaplasia, however, the number of gastrin and somatostatin cells decreased. Serotonin cell number was significantly higher in all patients with DGR as compared with controls. The mean somatostatin granular content was increased (3.6+/-0.2 vs. 3.2+/-0.1). In addition, lysosomes with engulfed somatostatin granules were found. The mean serotonin granular content was decreased (2.3+/-0.3 vs. 2.9+/-0.3), while the mean gastrin granular content remained unchanged (2.5+/-0.3 vs. 2.4+/-0.2). Ultrastructurally, the granules in serotonin-positive cells corresponded to the gastric variant or to the intestinal variant of serotonin cells. The endocrine cells were found to have few granules positive for serotonin. It is concluded that DGR inhibits somatostatin granular release, but stimulates both serotonin granular release and serotonin cell growth.

Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia.

All of the different types of stomach epithelial cells are known to be derived from a single progenitor cell in each gland. Similarly, cancers develop from single cells, based on data from clonality analysis in C3H/HeN<-->BALB/c chimeric mice. Using gastric and intestinal epithelial cell markers, intestinal metaplasia (IM) can be divided into two major types: a gastric and intestinal (GI) mixed type, and a solely intestinal (I) type. Ectopic expression of Cdx genes and down-regulation of Sox2 in isolated single GI mixed IM glands suggests abnormal differentiation of stem cells that can produce both gastric (G) and I type cells. Similarly, phenotypic expression of gastric cancer cells of each histological type can be clearly classified into G and I type epithelial cells. The heterogeneity of phenotypic expression of gastric cancer cells in individual cancers is assumed to reflect this intrinsic potential for differentiation in two directions. Gastric cancers at early stages, independent of the histological type, mainly consist of G type cells, and phenotypic shift from G to I type expression is clearly observed with progression. The data thus suggest IM may not be a preneoplastic change in gastric carcinoma, but rather that cells of the I type may appear independently in the gastric mucosa in IM and in gastric cancers. Intestinalization of gastric mucosa and cancer cells may represent a kind of homeotic transformation. Whether disturbance of the regulation of Sox2 and Cdx genes may be of importance to the biological behavior of gastric cancers should therefore be clarified in future studies.

Gastrinaemia, tissue gastrin concentration and G cell density in the antral mucosa of swine with and without gastric ulcer of the pars oesophagea.

Gastric ulcer of the pars oesophagea (GUPO) of the stomach, which occurs spontaneously in swine, is of unknown aetiology. Because gastrin is a potent secretagogue linked to acid secretion, this study was designed to investigate, in pigs with or without GUPO, (1) basal and food-stimulated serum gastrin concentrations, (2) the concentration of tissue gastrin, and (3) gastrin-producing (G) cell density in the antral mucosa. Sixty-four pigs (32 with, and 32 without ulceration) were studied. Antral mucosa was obtained immediately after slaughter for assessment of G-cell number and tissue gastrin concentration. The presence or absence of GUPO was not significantly associated with either of the parameters measured.

Topical application of benzalkonium chloride to the stomach serosa increases gastric emptying time, acid secretion, serum gastrin and size of the mucosa.

AIM: In the present study we evaluated the effects of gastric myenteric denervation using benzalkonium chloride (BAC) on the time for gastric emptying, as well as gastric secretion, and mucosal epithelial cell size and population in rats. METHODS AND RESULTS: Wistar rats were treated with topical serosal application of BAC to the stomach. Control animals received saline. Ninety days after surgery, gastric emptying time, gastric acid secretion and serum gastrin levels were studied. Next, the animals were sacrificed and the stomachs were removed, fixed in formalin and histologically processed for histomorphometry of the height, area and volume of the glandular portion, and volume and population of mucous, chief, parietal, G- and labelled cells. BAC animals showed a significant delay in gastric emptying and an increase in gastric acid secretion and serum gastrin levels. These animals also presented a significant reduction of myenteric neuron number, hypertrophy of parietal and chief cells, hyperplasia of G cells and an increase in the gastric mucosa area. CONCLUSION: The absence of the myenteric plexus seems to protect the stomach from the hyperplastic effects of hypergastrinemia. Gastric food stasis may act as a factor triggering morphological and functional alterations of the gastric epithelium. Although gastric food stasis is a common finding in medical practice, its physiopathological consequences are poorly understood and have not been frequently discussed in the literature.

Collagenous gastritis: a long-term follow-up with the development of endocrine cell hyperplasia, intestinal metaplasia, and epithelial changes indeterminate for dysplasia.

This report reviews the literature pertaining to collagenous gastritis and describes the clinicopathologic evolution of this disease in a patient during a 12-year period. We examined 109 biopsy specimens of gastric mucosa from 19 different endoscopic procedures for the severity and distribution of collagenous gastritis in a single patient. Assessments were undertaken for the presence of endocrine and gastrin cell hyperplasias and dysplastic epithelial changes. Relative to biopsy specimens from age- and sex-matched control subjects, the patient's biopsy specimens showed a significantly lower number of antral gastrin cells, along with a significant corpus endocrine cell hyperplasia, suggesting an increased risk of endocrine neoplasia. Gastric corpus biopsy specimens revealed an active, chronic gastritis, subepithelial collagen deposition, smooth muscle hyperplasia, and mild to moderate glandular atrophy. Additional findings of intestinal metaplasia and reactive epithelial changes indeterminate for dysplasia raise concerns about the potential for adenocarcinoma.