Enterochromaffin-like Cells Research Articles

A Strong Stomach for Somatostatin.

Evolution of life from single cell to complex multicellular organisms necessitated sophistication in communication between a myriad of specialized cell types. This communication is enabled by a network of neurocrine, endocrine, paracrine, and juxtracrine (contact-dependent) arrangements. The first 3 forms involve release of chemical messengers that activate receptors expressed on the surface or within the target cell to affect a response. Such an array of communication modes enables rapid (eg, neurocrine) and selective (eg, paracrine) communication, while also ensuring a broader reach of chemical substances to all cells within the system (eg, endocrine). One unique chemical within the organism that functions and is regulated by all of the aforementioned modes is somatostatin. Originally isolated from hypothalamic extracts as an inhibitory signal to GH release from the pituitary gland (1, 2), somatostatin was later found to be synthesized by an extensive network of distinct endocrine cells in the gastrointestinal (GI) tract and pancreas (3). Somatostatin subsequently was discovered to function broadly throughout the body as an inhibitor of multiple secretory processes, including insulin and glucagon from the pancreas, gastrin, secretin, cholecystokinin (CCK), vasoactive intestinal peptide, glucagon-like peptide 1, gastric inhibitory peptide, ghrelin, pepsin, and gastric acid from the digestive tract, T3, T4, and calcitonin from the thyroid gland, aldosterone from the adrenal gland, and monoamines from the brain (4, 5). Clinical therapeutics has taken advantage of some of these functions, resulting in the development of various somatostatin analogues for diagnosis, staging and treatment of certain neuroendocrine tumors and for treatment of acromegaly; they also hold promise to treat inflammatory conditions as well as obesity and diabetic complications (4, 6–8). Further studies on somatostatinsecreting cells, and in particular, the mechanisms regulating somatostatin release, hold similar promise. Gastric D cells serve as a major source for circulating somatostatin and are of particular interest because of their relatively large numbers as compared with other sources and due to their distinctive ability to secrete somatostatin in response to a plethora of neurotransmitters, hormones as well as nutrients. These somatostatin-secreting cells are similar to other gastric endocrine cells, which include ghrelin cells, serotonin-secreting enterochromaffin cells, histamine-secreting enterochromaffin-like cells and gastrin-secreting G cells, in that they are sparsely distributed within the mucosa. Nestled among neighboring endocrine and exocrine cells, the D cells exert inhibitory input onto their neighbors’ secretory capacities via release of somatostatin from characteristic basal cytoplasmic peduncles. Gastric D cells are also major contributors to the picomolar concentrations of somatostatin found in circulation, even though most of the somatostatin produced in the stomach acts locally and is rapidly degraded by proteases. Somatostatin therefore lacks selectivity and precision in its role as a “hormone,” in terms of both site of origin and its target organs (9). The speckled distribution of D cells within the gastric mucosa has hindered the derivation of homogenous populations of D cells thus slowing research on their physiology. Also, lack of selective antibodies to membrane-bound G protein-coupled receptors (GPCRs) and other receptor classes has largely prevented immunohistochemical characterization of the signaling systems that directly regulate somatostatin secretion and other aspects of D-cell function. Instead, insights into somatostatin secretion from D cells so far have been obtained mostly

Functional anatomy and physiology of gastric secretion

This review summarizes the past year's literature regarding the neuroendocrine and intracellular regulation of gastric acid secretion, discussing both basic and clinical aspects. Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High acidity kills ingested microorganisms and limits bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. The main stimulants of acid secretion are gastrin, released from antral gastrin cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Ghrelin and coffee also stimulate acid secretion whereas somatostatin, cholecystokinin, glucagon-like peptide-1, and atrial natriuretic peptide inhibit acid secretion. Although 95% of parietal cells are contained within the oxyntic mucosa (fundus and body), 50% of human antral glands contain parietal cells. Proton pump inhibitors are considered well tolerated drugs, but concerns have been raised regarding dysbiosis, atrophic gastritis, hypergastrinemia, hypomagnesemia, and enteritis/colitis. Our understanding of the functional anatomy and physiology of gastric secretion continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders, prevention and management of neoplasia, and the development of novel medications.

Microscopic Carcinoid: An Unusual Presentation of Gastric Carcnioid

51 year old Caucasian male with history of hyperlipidemia presented with complain of melena. Patient had noticed one episode of bright red blood per rectum. On questioning patient also complained of feeling tired lately with generalized body aches. He also had some numbness and tingling in both lower extremities which had been gradually worsening. Neurological exam showed decreased sensation, vibration and position sensation in both lower extremities. Digital rectal exam was positive for frank blood in rectal vault. Initial laboratory work up showed hemoglobin of 8.5 with MCV of 110. Patient underwent upper endoscopy which showed non-bleeding gastric ulcer. Also there were few scattered small focal areas of erythematous lesions in gastric cardia and proximal body with significant loss of the gastric folds. Biopsy of the lesions showed increase in fibrous tissue with moderate active inflammation of lamina propria and Chronic atrophic gastritis while rapid urease test was negative. Interestingly, carcinoid changes with chronic intestinal metaplasia were found on biopsy suspicious for carcinoid tumor. Given the finding on biopsy, fasting serum Gastrin Chromogranin A levels, Parietal cell antibodies, Intrinsic Factor antibodies, 24 hour urine for 5-HIAA, Computerized tomography (CT) scan of the abdomen and pelvis, and Octreotide scan were ordered to look for primary location of carcinoid tumor. Fasting serum Gastrin Chromogranin A levels, Parietal cell antibodies, Intrinsic Factor antibodies were found to be elevated the diagnosis of Carcinoid Tumor but there were no mass lesions but only scattered cells in the stomach. Patient subsequently underwent frequent endoscopies with biopsies which reconfirmed well differentiated carcinoid tumor cells scattered in the stomach but no mass lesion. Meanwhile patient underwent extensive work up for peripheral neuropathy and was found to have vitamin B12 deficiencies in setting of atrophic gastritis leading towards diagnosis of pernicious anemia which was likely cause of the underlying carcinoid changes. Patient is currently treated with vitamin B12 with marked improvement in his symptoms and is undergoing Surveillance endoscopies of carcinoid changes. Discussion: Carcinoid tumors Originate from Enterochromaffin-like (ECL) cells, found in gastric wall. There are three types of gastric carcinoid tumors. Type 1 are smaller and less than 1 cm, multiple, polypoid lesions with central ulceration associated with chronic atrophic gastritis and pernicious anemia. Type 2 occurs in association with gastrinomas (Zollinger-Ellison syndrome), often in setting of MEN type 1 and are mostly indolent in nature. While type 3 are Sporadic as they occur in the absence of atrophic gastritis or the Zollinger-Ellison /MEN1 syndromes and are very aggressive in nature. They are characterized by normal gastrin level. Diagnosis for carcinoid tumors include biochemical testing including urinary excretion of 5-HIAA, Chromogranin level, Blood serotonin concentration, Gastrin level and Anti parietal cell antibodies. Tumor localization is done by CT, Magnetic resonance Imaging, Octreotide scan. Type 1 and 2 are treated with endoscopic resections and survelliant endoscopies. Treatment for type 3 gastric carcinoid tumors is partial or total gatstrectomy considering the aggressive nature. Conclusions: Carcinoid tumors usually appear as discrete masses but microscopic carcinoid tumor in stomach is a very rare.

Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology.

Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy. To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology. A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology. A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found. Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Pediatric non-Helicobacter pylori atrophic gastritis: a case series.

Although autoimmune atrophic gastritis is classically a disease of elderly adults, recent studies have described the disease in younger adults, particularly in those with other autoimmune diseases and iron-deficiency anemia. Atrophic gastritis in pediatrics is a rare and possibly underdiagnosed entity that has been primarily reported as single-case reports. This retrospective study of atrophic gastritis not associated with Helicobacter pylori infection was performed to further expand the knowledge of clinical presentation, pathologic findings, and natural history of this disease in the pediatric population. Twelve patients with a histologic diagnosis of atrophic gastritis were identified, with an age range of 8 months to 18 years. Seven had other autoimmune diseases and/or immunodeficiency. Atrophy was confined to the oxyntic mucosa in 10 patients, with intramucosal inflammation in a diffuse or basal-predominant pattern. Active inflammation was present in 7 patients. Pseudopyloric, intestinal, or squamous/mucinous metaplasia was seen at initial biopsy or on follow-up in 8 patients, and enterochromaffin-like cell hyperplasia was seen in 5. One patient developed an adenocarcinoma during the follow-up period of 10 years. Two false-negative diagnoses were retrospectively identified. In the majority of cases, the possibility of atrophic gastritis was not raised by the submitting physician, and the endoscopic findings were not specific. Therefore, accurate diagnosis requires a high degree of suspicion on the part of the pathologist, and the diagnosis should be considered particularly in patients with a clinical history of other autoimmune diseases or iron-deficiency anemia.

Effect of netazepide, a gastrin/CCK2 receptor antagonist, on gastric acid secretion and rabeprazole-induced hypergastrinaemia in healthy subjects.

To compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. Thirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. All treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. Netazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.

Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.

Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.

Gastric neuroendocrine tumors: prevalence in Europe, USA, and Japan, and rationale for treatment with a gastrin/CCK2 receptor antagonist

Objective. Gastric carcinoids (neuroendocrine tumors) arise from enterochromaffin-like cells in the gastric mucosa. Most are caused by hypergastrinemia. The objectives were to determine if their prevalence in Europe, USA and Japan meets the criteria for an orphan disease and to justify treatment with a gastrin/CCK2 receptor antagonist. Methods. We obtained data from European and USA cancer registries, and searched PubMed. Results. Prevalence per 10,000 population obtained from cancer registries was: median 0.32 (range 0.09–0.92) for Europe; and 0.17 for the USA, equivalent to 4812 for the whole population. A PubMed search for gastric carcinoids yielded prevalence for Japan only, which was 0.05 per 10,000 population, equivalent to 665 for the entire population. A further search for gastric carcinoids in patients with pernicious anemia (PA) or autoimmune chronic atrophic gastritis (CAG), two presentations of about 80% of gastric carcinoids, produced prevalence rates of 5.2–11%. Prevalence of PA itself was 0.12–1.9%. Data on CAG epidemiology were sparse. Conclusion. Prevalence of gastric carcinoids varied widely. All sources probably underestimate prevalence. However, prevalence was below the limits required for recognition by drug regulatory authorities as an orphan disease: 5 per 10,000 population of Europe; 200,000 for the whole population of the USA; and 50,000 for the whole population of Japan. Because gastric carcinoids are an orphan disease, and nonclinical and healthy volunteer studies support treatment with netazepide, a gastrin/CCK2 antagonist, netazepide has been designated an orphan medicinal product in Europe and the USA for development as targeted treatment for gastric carcinoids.

Adenosine A1 receptor activation inhibits histamine release in gastric enterochromaffin-like cells

Adenosine acts as a gastroprotective factor decreasing inflammation and reducing gastric acid secretion. Quantitative RT-PCR was used to determine the expression of the adenosine receptor genes (A1AR, A2AAR, A2BAR and A3AR) and that of the gastrin receptor B gene (CCKBR) in isolated, short-term cultured enterochromaffin-like (ECL) cells. Both the A1AR and the CCKBR genes were expressed at a level higher than the other genes. Also, the effect of 2-chloroadenosine, a stable agonist of A1 and A2A receptors, was explored on ECL cells, with a resulting inhibition of both basal and gastrin-stimulated histamine release. Also, dipropylcyclopentylxanthine (DPCPX), a selective A1 antagonist, prevented the inhibitory effects of 2-chloroadenosine, suggesting the effect of 2-chloroadenosine is mediated by A1 receptors. It is concluded that isolated, short-term cultured ECL cells are a suitable model for studies relating gene expression and function, and that the gastroprotective actions of adenosine are at least partly mediated through A1 receptors.

Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours.

To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite. Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients. In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms. Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

Endoscopic diagnosis and management of type I neuroendocrine tumors

Type I gastric neuroendocrine tumors (TI-GNETs) are related to chronic atrophic gastritis with hypergastrinemia and enterochromaffin-like cell hyperplasia. The incidence of TI-GNETs has significantly increased, with the great majority being TI-GNETs. TI-GNETs present as small (< 10 mm) and multiple lesions endoscopically and are generally limited to the mucosa or submucosa. Narrow band imaging and high resolution magnification endoscopy may be helpful for the endoscopic diagnosis of TI-GNETs. TI-GNETs are usually histologically classified by World Health Organization criteria as G1 tumors. Therefore, TI-GNETs tend to display nearly benign behavior with a low risk of progression or metastasis. Several treatment options are currently available for these tumors, including surgical resection, endoscopic resection, and endoscopic surveillance. However, debate persists about the best management technique for TI-GNETs.

Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach.

Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp.

Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions.

Proton pump inhibitors (PPIs) are the most effective drugs to reduce gastric acid secretion. PPIs are one of the most commonly prescribed classes of medications worldwide. Apart from short-term application, maintenance therapy with PPIs is recommended and increasingly used in certain diseases, such as Zollinger-Ellison syndrome and gastro-oesophageal reflux disease, especially for people with erosive oesophagitis or Barrett's oesophagus. Although PPIs are generally safe, their efficacy and safety of long-term use remains unclear. The question of whether the long-term use of PPIs could promote the development of gastric pre-malignant lesions has been widely investigated, but results are inconsistent. Limited insight on this problem leads to a dilemma in decision making for long-term PPI prescription. To compare the development or progression of gastric pre-malignant lesions, such as atrophic gastritis, intestinal metaplasia, enterochromaffin-like (ECL) cell hyperplasia, and dysplasia, in people taking long-term (six months or greater) PPI maintenance therapy. We searched the following databases (from inception to 6 August 2013): the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL. In addition, we searched the reference lists of included trials and contacted experts in the field. We searched for randomised controlled trials (RCTs) in adults (aged 18 years or greater) concerning the effects of long-term (six months or greater) PPI use on gastric mucosa changes, confirmed by endoscopy or biopsy sampling (or both). Two review authors independently performed selection of eligible trials, assessment of trial quality, and data extraction. We calculated odds ratios (OR) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CI). We included seven trials (1789 participants). Four studies had high risk of bias and the risk of bias in the other three trials was unclear. In addition, it was difficult to assess possible reporting bias. We pooled 1070 participants from four RCTs to evaluate corporal atrophy development revealing an insignificantly increased OR of 1.50 (95% CI 0.59 to 3.80; P value = 0.39; low-quality evidence) for long-term PPI users relative to non-PPI users. In five eligible trials, corporal intestinal metaplasia was assessed among 1408 participants, also with uncertain results (OR 1.46; 95% CI 0.43 to 5.03; P value = 0.55; low-quality evidence). However, by pooling data of 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment were more likely to experience either diffuse (simple) (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) or linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence) than controls. No participant showed any dysplastic or neoplastic change in any included studies. There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.

Histopathological and Immunohistochemical Characterization of Methyl Eugenol-induced Nonneoplastic and Neoplastic Neuroendocrine Cell Lesions in Glandular Stomach of Rats.

Methyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap. Archived slides and paraffin blocks were retrieved from the National Toxicology Program Archives. NE hyperplasias and tumors were stained with chromogranin A, synaptophysin, amylase, gastrin, H(+)/K(+) adenosine triphosphatase (ATPase), pepsinogen, somatostatin, and cytokeratin 18 (CK18) antibodies. Many of the rats had gastric mucosal atrophy, due to loss of chief and parietal cells. The hyperplasias and tumors were confined to fundic stomach, and females were more affected than the males. Hyperplasia of NE cells was not observed in the pyloric region. Approximately one-third of the females with malignant NE tumors had areas of pancreatic acinar differentiation. The rate of metastasis was 21%, with liver being the most common site of metastasis. Immunohistochemically, the hyperplasias and tumors stained consistently with chromogranin A and synaptophysin. Neoplastic cells were also positive for amylase and CK18 and negative for gastrin, somatostatin, H(+)/K(+) ATPase, and pepsinogen. Metastatic neoplasms histologically similar to the primary neoplasm stained positively for chromogranin A and synaptophysin. Based on the histopathological and IHC features, the neoplasms appear to arise from enterochromaffin-like cells.

Carcinoid Tumor Development in Crohn’s Disease

Introduction: A 2007 study at Vanderbilt University indicated that carcinoid tumors are 15 times more common in patients with Crohn’s disease (CD). There has previously been debate in the literature about the exact pathophysiological link. It takes approximately 10 years for enterochromaffin-like cell (ECL) hyperplasia to develop into a carcinoid. A 1998 study by Szabo showed that carcinoid tumors are found more frequently in an inflamed appendix (0.24%) compared to an appendix from autopsy (0.03%). Several inflammatory cytokines involved with CD, such as interleukin 12, tumor necrosis factor alpha, and interferon gamma contribute to carcinoid tumor formation. This case report adds to the growing body of literature illustrating a possible link between the inflammatory environment of CD and the development of a gastrointestinal carcinoid tumor. A 37-year-old female first diagnosed with CD via colonoscopy in 2001 was initially treated with azathioprine and mesalamine. Her symptoms were never completely controlled on this regimen. In 2008, the patient stopped all medications and follow-up. In 2013, she was admitted for a Crohn’s flare, and a high-grade small bowel obstruction was noted on CT and MR enterography. She was loaded with certolizumab and she restarted azathioprine. One month later, her symptoms persisted, and she underwent an 18-cm jejunal resection. An esophagogastroduodenoscopy and a colonoscopy were scheduled 2 months later to evaluate the extent of her disease and to work up severe weight loss. EGD was normal, but a 4-mm rectal polyploid-appearing lesion with yellow hue was found during colonoscopy and biopsied in a bite-on-bite fashion. Pathology revealed a carcinoid tumor strongly positive for synaptophysin (SP11) and negative for chromogranin (LK2H10). Researchers have hypothesized that the inflammation and hyperplasia caused by CD predisposes patients to develop carcinoid tumors. The incidence of carcinoid among CD patients appears to be higher than would be expected, possibly as a consequence of distant inflammatory cytokine effects. Radiographically, carcinoid tumors may appear like Crohn’s disease. Histologically, carcinoid tumors also appear similar to CD with fibrosis and wall thickening. Due to these similarities, the incidence of carcinoid among CD patients may actually be higher than the less than 50 case reports that exist in the literature. This case adds to the growing body of evidence illustrating the development of carcinoid tumor among CD patients.

Clinical features and management of type I gastric carcinoids.

Type I gastric carcinoids (TIGCs) are related to chronic atrophic gastritis and are characterized by hypergastrinemia and hyperplasia of enterochromaffin-like cells. TIGCs are the most frequently diagnosed of all gastric carcinoids, accounting for about 70-80 %. Endoscopically, TIGCs are present as small (<10 mm), polypoid lesions or, more frequently, as smooth, rounded submucosal lesions. Histologically, TIGCs arise in the deep mucosa, with some invading the submucosa. Most TIGCs are well-differentiated tumors, with metastasis being rare. Therefore, patients with TIGCs generally have an excellent prognosis. Among the currently available treatment options are total gastrectomy, partial resection, antrectomy, endoscopic resection, and endoscopic surveillance, although no consensus has been reached on their optimal management. Further studies are needed to develop better management options for patients with TIGC.

The gastric mucosa 25 years after proximal gastric vagotomy

Objective. Vagotomy causes inhibition of basal and post-prandial acid secretion in humans, but the knowledge about the trophic effect of the vagal nerves is limited. Vagotomy is known to induce hypergastrinemia and we aimed to study the long-term effects of proximal gastric vagotomy (PGV) on the oxyntic mucosa and the enterochromaffin-like (ECL) cell density in particular. Material and methods. Eleven patients operated with PGV because of duodenal ulcer and age- and sex-matched controls were examined 26 to 29 years postoperatively by gastroscopy with biopsies from the antrum and oxyntic mucosa. Neuroendocrine cell volume densities were calculated after immunohistochemical labeling of gastrin, the general neuroendocrine cell marker chromogranin A (CgA) and the ECL cell marker vesicular monoamine transporter 2 (VMAT2). Gastritis was graded and Helicobacter pylori (H. pylori) status was determined by polymerase chain reaction of gastric biopsies. Fasting serum gastrin and CgA were measured. Results. Serum gastrin was higher in the PGV group compared to controls (median 21.0 [interquartile range (IQR) = 22.0] pmol/L vs 13.0 [IQR = 4.0] pmol/L, p = 0.04). However, there was neither a significant difference in serum CgA or in CgA (neuroendocrine) nor VMAT2 (ECL cell) immunoreactive cell volume density in the oxyntic mucosa. There was significantly more inflammation and atrophy in H. pylori-positive patients, but PGV did not influence the grade of gastritis. Conclusion. Despite higher serum gastrin concentrations, patients operated with PGV did not have higher ECL cell mass or serum CgA. Vagotomy may prevent the development of ECL cell hyperplasia caused by a moderate hypergastrinemia.

Gastrin

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors

The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1+2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.

Sa1813 The Efficacy of REIC/DKK-3 Gene Therapy for Pancreatic Cancer

cells displayed cytoprotection through crinophagy. The longer gastrin stimulation (months), the more accumulation of lipofuscin bodies, leading to an impaired function and eventually, cell death. The poorly differentiated cells within the ECL cell tumor are probably derived directly or indirectly via runaway autophagy which is associated with anti-apoptotic pathways. We suggest that autophagy-targeted therapy should focus on this runaway pathway in gastrin-driven neoplasia.