G-cell Hyperplasia Research Articles

Vonoprazan as a Long-term Maintenance Treatment for Erosive Esophagitis: VISION, a 5-Year, Randomized, Open-label Study

Background & AimsAcid secretion inhibitors are associated with hypergastrinemia, which can lead to gastric mucosal changes. Potassium-competitive acid blockers, such as vonoprazan, are more potent than proton pump inhibitors, but long-term safety data are lacking. MethodsIn this phase 4, randomized trial, patients with erosive esophagitis (EE) received induction therapy (once-daily vonoprazan 20 mg or lansoprazole 30 mg; ≤8 weeks). Those with healed EE received maintenance therapy (once-daily vonoprazan 10 mg or lansoprazole 15 mg) for 260 weeks (2:1). The primary endpoint was the proportion of patients with malignant epithelial cell alterations, parietal cell hyperplasia, foveolar hyperplasia, enterochromaffin-like (ECL) cell hyperplasia, and G-cell hyperplasia. ResultsOverall, 202/208 patients (vonoprazan n=139; lansoprazole n=69) achieved healed EE and received maintenance therapy. No malignant alterations or gastric neuroendocrine tumors (NETs) were observed; there was one adenoma in each group. At week 260, more patients taking vonoprazan versus lansoprazole had parietal cell hyperplasia (97.1% vs 86.5%) and foveolar hyperplasia (14.7% vs 1.9%); proportions of patients with ECL cell hyperplasia (4.9% vs 7.7%) and G-cell hyperplasia (85.3% vs 76.9%) were similar. Median serum gastrin levels were higher with vonoprazan treatment versus lansoprazole (625 pg/mL vs 200 pg/mL). Incidences of adverse events were comparable for both treatments. ConclusionsThe exploratory VISION study assessed the safety profile of vonoprazan and lansoprazole over 5 years in Japanese patients with healed EE. While gastrin concentration, parietal cell hyperplasia and foveolar hyperplasia were higher in the vonoprazan group, there was no increased risk of malignant epithelial cell alterations and gastric NETs. (ClinicalTrials.gov, NCT02679508.)

Histologic features in an autoimmune gastritis patient with hypergastrinemia: Call for a grading system for G cell hyperplasia

Abstract Introduction/Objective Autoimmune gastritis (AG) is characterized by oxyntic glands destruction, metaplasia, enterochromaffin-like endocrine cell abnormality and G-cell hyperplasia with hypergastrinemia. The gastrin level can be extraordinarily high in certain cases to justify suspicion of Zollinger-Ellison syndrome. We herein report one such case and discuss clinical implication of a grading system for G-cell hyperplasia to correlate histology with gastrin levels. Methods/Case Report The patient was a symptomatic 65 year-old female with hypergastrinemia (2,068 pg/mL), negative abdomen/pelvis CT scan, positive anti-intrinsic factor and anti-parietal cell antibodies. Under esophagogastroduodenoscopy, biopsies were obtained from gastric cardia, fundus, corpus, incisura angularis, and antrum. Morphology and immunostains confirmed autoimmune gastritis. Diffuse linear pattern G-cell hyperplasia was evident in antrum and incisura angularis, counting up to 200 G-cells per linear millimeter. One study defined G-cell hyperplasia as >140 gastrin-positive cells per linear millimeter while another proposed a 2-tier stratification, i.e., simple hyperplasia (4-5 cells for each gland) and linear hyperplasia (continuous chain-like distribution of G-cells). Such scoring, however, was largely qualitative and fell short in delineating the extent of G-cell hyperplasia and correlation with gastrinemia. Results (if a Case Study enter NA) NA Conclusion Lack of G-cell grading system hindered our unequivocal determination of the G-cell hyperplasia as underlying or contributing cause of hypergastrenemia. The unique features of our case highlighted the necessity for installing a practical grading system that incorporates G-cell density, pattern (linear vs. nodular), extent of involved areas, other features of AG to correspond to gastrin level. With accumulation of clinical information, one such grading system is feasible and will improve our knowledge and patient care.

Neuroendocrine neoplasms of the esophagus and stomach

SummaryEsophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient’s clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis.

Can You See the Carcinoid Tumor? A Case of Autoimmune Metaplastic Atrophic Gastritis (AMAG) and Carcinoid Tumor

Atrophic gastritis is a known risk factor for the development of carcinoid tumor and gastric adenocarcinoma. In AMAG, there is destruction of parietal cells which leads to G-cell hyperplasia and elevated gastrin levels resulting in the proliferation of enterochrommaffin-like cells. These cells serve as precursors to carcinoid tumors, thus can be neoplastic in nature. A majority of carcinoid tumors appear on upper endoscopy (EGD) as polypoid lesions in the gastric body or fundus. We would like to present a unique case of carcinoid tumor in the context of AMAG, with grossly normal EGD. Our patient is a 25 year old female without significant past medical history with sole complaint of chronic dyspepsia and upper abdominal pain. She presented to clinic for a second opinion after a recent diagnosis of a neuroendocrine malignancy on EGD one month prior. The patient underwent repeat EGD with biopsies taken from the antrum, body, and fundus. An area of hypopigmented mucosa was identified in the antrum, prompting biopsies. The remainder of the stomach, duodenum, and esophagus were grossly normal. Pathology from the antrum and fundus all revealed chronic gastritis with mild enterochromaffin-like cell hyperplasia and severe reactive changes. The fundic biopsy showed chronic atrophic gastritis with antralized mucosa, suggestive of AMAG. The biopsies from the body of the stomach demonstrated well-differentiated neuroendocrine tumor (NET) grade 1, arising in the background of chronic atrophic gastritis. KI67 demonstrates proliferation index less than 2%. No lymphovascular invasion was seen. Her prior EGD showed well differentiated NET on antral biopsy. Patient underwent EGD/EUS with biopsies at a tertiary center, which was unremarkable, and biopsy showed atrophic gastritis. She was advised to repeat EGD every 6-12 months. This case raises concern for therapy modalities as minimal literature exists in regards to treatment of NET in the setting of AMAG with normal EGD. Given the lack of gross focality to the carcinoid lesion, does one resect or surveil? Although gastric carcinoid in the setting of atrophic gastritis is rarely malignant, one must ponder the malignancy potential given that we were unable to pinpoint the lesion despite multiple EGD's. Further cases must be studied to adequately manage such patients and better understand disease progression.3087_A Figure 1. EGD with normal appearing mucosa3087_B Figure 2. EGD with normal appearing mucosa and narrow band imaging

The morphological and immunohistochemical spectrum of gastric biopsies of patients with absorptive hypercalciuria

ObjectiveIdiopathic hypercalciuria is characterised by renal stone formation and vertebral osteoporosis. The syndrome displays high clinical variability with patients almost equally distributed between fasting or renal type (prevalent calcium loss)...

Histologic changes in type A chronic atrophic gastritis indicating increased risk of neuroendocrine tumor development: the predictive role of dysplastic and severely hyperplastic enterochromaffin-like cell lesions

The role of putative preneoplastic enterochromaffin-like cell lesions, either hyperplastic or dysplastic, in the genesis of type 1 enterochromaffin-like cell neuroendocrine tumors associated with type A chronic atrophic gastritis, their actual neoplastic risk, and their precise histogenetic mechanism deserve further clarification by specific histopathologic studies coupled with patient follow-up. A total of 100 patients with severe type A chronic atrophic gastritis, enterochromaffin-like cell hyperplasia, and antral G-cell hyperplasia were endoscopically and histologically followed up for a median of 90.1 months (total of 9118 person-months). Preneoplastic enterochromaffin-like cell lesions and newly developed neuroendocrine tumors were investigated histologically and histochemically, in parallel with enterochromaffin-like cell lesions found in nontumor mucosa of another 32 well-characterized and previously reported type 1 neuroendocrine tumors. Both neuroendocrine and nonneuroendocrine mucosa changes were analyzed and statistically evaluated. During follow-up, 7 of 100 patients developed neuroendocrine tumors: 5 were in a group of 20 cases with previous enterochromaffin-like cell dysplasia and 2 were among 80 cases showing only enterochromaffin-like cell hyperplasia throughout the study (hazard ratio, 20.7; P < .001). The severity of enterochromaffin-like cell hyperplasia at first biopsy, with special reference to linear hyperplasia with 6 chains or more per linear millimeter, also increased the risk of neuroendocrine tumor development during follow-up (hazard ratio, 13.0; P < .001). Enterochromaffin-like cell microinvasive dysplastic lesions arising at the epithelial renewal zone level, in connection with immature proliferating mucous-neck cells, were found to be linked to early intramucosal neuroendocrine tumor histogenesis. Both enterochromaffin-like cell dysplasia and severe hyperplasia indicate increased risk of neuroendocrine tumor development in type A chronic atrophic gastritis with hypergastrinemia/G-cell hyperplasia.

Commentary: netazepide for gastric acid suppression – another kid on the block?

Just when it seemed all over, the manuscript by Boyce et al.1 examining the pharmacokinetics and pharmacodynamics of single dose administration of netazepide, a peripheral CCK-B (gastrin) receptor antagonist, in normal volunteers will most certainly reinvigorate interest in gastric acid secretion and its pharmacological inhibition. Netazepide appears to be a potent inhibitor of gastric acid secretion with rapid onset and a prolonged duration of action.1 If it can be shown to be both safe and effective as maintenance therapy, it may well give proton pump inhibitors (PPIs) a real run for their money. The PPIs, which irreversibly block the final common path of gastric acid production,2 have been the dominant class of antisecretory drugs for over two decades and their continuing supremacy was all but assured with the demise of the potassium competitive acid blockers (PCABs) (although there may be a comeback for this class of agents too3). In addition, concerns have surfaced recently about potential adverse effects from prolonged PPI use4 which has opened the door to other novel compounds such as netazepide. Of course, much work remains to be done with this agent and there are, as yet, many unanswered questions (some of which the authors may well address in two upcoming manuscripts concerning repetitive dosing of netazepide). For example, will tachyphylaxis develop after repeated administration of this competitive receptor antagonist, a phenomenon that has been well described with histamine H2 receptor antagonists, which act one step further along the gastric acid secretory pathway?5 In addition, the endocrine, neurocrine and paracrine networks that control gastric acid secretion and its feedback are redundant.6 It remains to be seen whether upregulation of other pathways could occur leading to additional loss of efficacy (tolerance) with time. Alternatively, will the drug, which appears to have a long secondary half-life, accumulate after repeated dosing leading to unexpected side effects? Moreover, little is known about the metabolism of this agent which has only been administered to a small cadre of normal volunteers. Will the effect of this agent be predictable in patients or will alterations in metabolism lead to ‘slow’ and ‘fast’ metabolisers and unpredictable antisecretory effects? Finally, will potent ECL-cell inhibition by netazepide lead to G-cell hyperplasia and hypergastrinaemia, with the potential for rebound ECL-cell histamine release and excessive gastric acid production4 on withdrawal of the drug? This possibility is of some interest given current concerns regarding rebound gastric acid hypersecretion in double-blind randomised trials of PPI use vs. placebo in normal volunteers.7, 8 On the other hand, judicious use of netazepide in concert with PPIs may lead to more precise titration of individual antisecretory effects, thereby mitigating ECL-cell hyperplasia and parietal cell hypertrophy. This is an exciting and provocative first-in-human study of a novel compound with significant potential. I fully agree with the authors' conclusions that ‘studies of repeated doses of netazepide are justified’.1 Declaration of personal interests: David Metz has served as a consultant and advisory board member for Novartis, as a consultant for AstraZeneca and Takeda, and has received research funding from Fercica. Declaration of funding interests: None

Sporadic Duodenal Bulb Gastrin-cell Tumors: Association With Helicobacter pylori Gastritis and Long-term Use of Proton Pump Inhibitors

We reviewed the clinicopathologic profile of a series of recently diagnosed sporadic duodenal gastrin-cell (G-cell) tumors. All cases were discovered incidentally and had a unique clinicopathologic profile: all 18 cases were gastrin-positive tumors located in the duodenal bulb, were small in size (mean size 5.4 mm), demonstrated an insular architectural pattern, and were localized to the lamina propria and submucosa. None of the patients had Zollinger-Ellison or carcinoid syndrome. The behavior was indolent and there was no evidence of metastasis at diagnosis or during follow-up. In our sampled population, the presence of Helicobacter pylori gastritis and the use of proton pump inhibitors (PPIs) were significantly associated with the presence of G-cell tumors. Both the presence of H. pylori gastritis and use of PPI remained significant in a logistic regression model adjusted for age, race/ethnicity, and sex with P values of 0.0016 (odds ratio=10.1, 95% confidence interval: 2.3 to 42.4) and 0.008 (odds ratio=8.9, 95% confidence interval: 1.76 to 45.4), respectively. Most patients with tumors showed G-cell hyperplasia in the nontumorous regions of the duodenum. The high incidence of sporadic duodenal G-cell tumors in patients with H. pylori gastritis and long-term PPI use suggests an association that needs to be further explored. Presence of G-cell hyperplasia in the nontumorous duodenal mucosa suggests that these may originate from a proliferative phase, similar to the hyperplasia-dysplasia-neoplasia sequence seen in other endocrine tumors.

Surgery for peptic ulceration associated with hypergastrinaemia.

Between 1971 and 1983, 31 males and 13 females were found to have peptic ulceration associated with hypergastrinaemia. An antral G-cell lesion was present in 11 (25 per cent) and a gastrinoma in 14 (32 per cent). There were 11 patients with multiple endocrine adenomatosis (MEA) (25 per cent) and 4 (9 per cent) with primary hyperparathyroidism. Four patients (9 per cent) were unclassified. Length of history and level of gastrin did not differentiate between the groups and an average of 2.5 operations was performed per patient, while the overall mortality was 27.3 per cent. The patients with G-cell lesions were significantly younger than all the other groups (P less than 0.01). Partial gastrectomy adequately treated G-cell hyperplasia. Total gastrectomy was required to treat pancreatic gastrinomata but additional pancreatic resection did not improve the outcome. In MEA, parathyroidectomy did not influence the treatment of a gastrinoma. This is the first recorded experience of surgery for hypergastrinaemia in the United Kingdom and the outcome of such a retrospective study may be a guide to the future management of these conditions.

Development of an inveterate gastroduodenal ulcer caused by antral G-cell hyperplasia of the stomach (pseudo-Zollinger-Ellison Syndrome): Report of a case

We describe herein the case of a 54-year-old Japanese woman in whom an inveterate peptic ulcer developed in association with pseudo-Zollinger-Ellison Syndrome (pseudo-ZES). The patient presented with weight loss and abdominal distension caused by antral and duodenal stenosis due to an inveterate peptic ulcer. Her serum gastrin level was very high; however, no evidence of a gastrinoma or carcinoid tumor was detected by preoperative examinations or surgery. A total gastrectomy and double-tract reconstruction was performed, and pathological examination revealed a gastric ulcer (UL-IV) with no histopathological evidence of a neoplasm. Immunohistochemical staining showed an obvious increase in the number of endocrine cells that were positive for chromogranin A, and marked G-cell hyperplasia was observed in the antral mucosa. Furthermore, the number of enterochromaffin-like cells was remarkably high. From the results of the immunohistochemical examination, the patient was diagnosed as having hypergastrinemia due to antral G-cell hyperplasia. Postoperatively, the patient's serum gastrin level fell rapidly to within the normal range, her nutritional status improved, and her weight increased by about 10 kg within 1 year.

In-111 DTPA octreotide scintigraphy in gastric G-cell hyperplasia

In-111 DTPA octreotide scintigraphy in gastric G-cell hyperplasia

4758 Gastrin is expressed in jejunum biopsies of postgastrectomy patients.

The antrum is the richest source of gastrin. G-cell hyperplasia is found among hypochlorydric patients with atrophic gastritis. Only a slightly decreased fasting serum gastrin level is found in postgastrectomy patients, despite of having their antrum removed. Aim:To investigate gastrin immunoexpression in postgastrectomy mucosa and proximal jejunum. Methods: 176 endoscopic biopsies from eight sites of 22 postgastrectomy patients for benign disease with Billroth II reconstruction, 15-47 (mean=28.3) years following partial gastrectomy were evaluated. Immunohistochemical analysis of gastrin was performed on formalin fixed, paraffin embedded tissue using the avidin-biotin-peroxidade complex method. Results: In the controls, all cells positive for gastrin stained vividly, whereas stump biopsies specimens demonstrated cells with brown cytoplasmic staining scarcely distributed in the glands. Gastrin immunoexpression was observed in 17/154 (11.03%) of the gastric biopsies and in 9/22 (40.9%) of the patients. All jejunum biopsies (n= 22) revealed a strong reactivity, preferentially at the basal layer of the epithelia. There was no association between gastrin expression and the presence of Helicobacter pylori , cystic dilation, atrophy, intestinal metaplasia and dysplasia in the gastric stump. Conclusion: Immunoexpression of gastrin in the proximal jejunum and in the gastric stump may explain the serum gastrin level in postgastrectomy patients.

Antral G-cell hyperplasia: a vanishing disease?

The diagnosis and management of antral gastrin-(G-) cell hyperplasia was a major topic of interest in the 1970s. Following the discovery of Helicobacter pylori in the 1980s, little attention was paid to this condition until it was shown that H. pylori infection was associated with hypergastrinaemia and that eradication of the organism returned the gastrin level to normal. Recent reports have examined the relationship between H. pylori and antral G-cell hyperplasia. H. pylori infection is present in about 50% of cases of antral G-cell hyperplasia and, importantly, eradication of the organism normalizes not only the gastrin level but also the antral G-cell count. Eradication treatment should be the therapy of choice. It is also of interest that H. pylori-negative antral G-cell hyperplasia or hyperfunction does exist. The historical aspects, the relationship between antral G-cell hyperplasia and H. pylori and recent case reports are reviewed.

Alteration in gastric nerve fibers containing gastrin-releasing peptide in relation to the gastrin-producing cell population after truncal vagotomy in a rat model

The fine structural alteration in the gastric nerve fibers containing gastrin-releasing peptide (GRP) was studied in relation to the dynamics of gastrin-producing cells (G-cells) after truncal vagotomy in a rat model. The circulating gastrin levels were markedly elevated from the 1st day after vagotomy and the number of G-cells with positive immunoreaction for G17 and G34(1-15) was significantly increased in the vagotomized group. On the 3rd day after vagotomy, the G-cells showed conspicuous ultrastructural changes characterized by hypertrophy of the Golgi complexes and increased numbers of secretory granules. The GRP-positive nerve fibers formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa close to the blood vessels and showing varicosities composed of either small clear or GRP-positive large vesicles containing an electron-dense core. In the oxyntic mucosa of the vagotomized rats, axonal swelling of the nerves occurred on the 3rd day, and a depletion of GRP immunoreactivity was evidenced by a markedly decreased number of large-cored vesicles on the 7th day, when the serum GRP levels were also found to be markedly elevated. These findings indicate that the alteration in gastric nerve fibers containing GRP after truncal vagotomy may be related to hypergastrinemia and antral G-cell hyperplasia in the rat gastric mucosa.

Gastrointestinal neuroendocrine cell proliferations

The gastrointestinal neuroendocrine cell proliferations are comprised of a few hyperplasias and various neoplasias. The better characterized hyperplasias include G-cell hyperplasia, either primary or secondary, enterochromaffin-like (ECL)-cell hyperplasias, generally secondary to hypergastrinemia, and EC-cell hyperplasias. The neoplasias include carcinoid tumors, demonstrating low malignancy and divided into foregut, midgut, and hindgut varieties, poorly differentiated neuroendocrine carcinomas resembling their pulmonary counterparts the “oat cell” carcinomas both in histological pattern and in their highly malignant behavior mixed endo-exocrine tumors, which in turn can be divided into composite tumors formed by a population of endocrine cells and a population of exocrine cells, and amphicrine tumors formed by a uniform population of cells with a mixture of endocrine and exocrine phenotypic traits. Although some of these mixed tumors show a degree of malignancy intermediate between the classical carcinoid and an adenocarcinoma, more information must be gathered to establish firm prognostic parameters for these relatively new entities.

Long-term histologic consequences of suppression/eradication of Helicobacter pylori in antral mucosa

Purpose To assess histological and local immunological consequences of Helicobacter pylori suppression/eradication. Design Thirty-four patients with non-healing or recurrent duodenal ulcer were treated with omeprazole followed by triple therapy. At least two gastric mucosal samples from the antral portion of the stomach and from the duodenum were collected prior to, and immediately after omeprazole therapy, 4 weeks after completion of triple therapy, and subsequently at monthly intervals up to 2 years. Twenty antral biopsies collected from 10 patients uninfected with H. pylori served as controls. Methods Samples were fixed in buffered formaldehyde and examined histologically and histochemically for inflammation, mucin secretion, atrophy, intestinal metaplasia, density of H. pylori colonization, and immunohistochemically for the density of gastrin-secreting cells, immunoglobulins (IgA, IgG, IgM), T lymphocytes and complement C3c. Results At the initial examination, all 34 patients had endoscopically and histologically confirmed active duodenal ulcer. All had histologically diagnosed H. pylori infection and antral gastritis of varying degrees of severity. Eradication was noted in 68% of patients when tested 1 month following triple therapy. Gastric mucosa after eradication of H. pylori showed improvement in epithelial cells, disappearance of inflammatory infiltrate and normal secretion of previously reduced mucin content. One patient showed recurrence of infection within 2 years of follow-up. G-cell hyperplasia observed after cessation of omeprazole and triple therapy was not present in the sequential biopsies. Glandular atrophy and intestinal metaplasia present before therapy in nine out of the 34 patients failed to resolve during the follow-up period. Atrophy and intestinal metaplasia developed during the 2-year follow-up period in four out of 23 patients in whom H. pylori was eradicated, and in two out of 11 with persistent H. pylori infection. Conclusion Atrophic/metaplastic mucosal lesions are resistant for eradication of H. pylori, when present initially or when they occur after therapy. Local cellular and immune response by antral mucosa is not responsible for the pathogenesis of these lesions.

Gastrin

Gastrin represents a direct pathogenic factor only in rare subgroups of ulcer patients, such as in the Zollinger-Ellison syndrome, the antral G-cell hyperplasia syndrome, and in patients in whom the gastric antrum was erroneously retained following partial gastrectomy. Gastrin may play a contributory role in the pathogenesis of uncomplicated peptic ulcer disease, as an exaggerated, but reversible gastrin release appears to be associated with Helicobacter pylori colonization. The known trophic effects of gastrin could account for the overall increase in the parietal cell mass of patients suffering from duodenal ulcer disease. Circumstantial evidence suggests that the abnormal gastrin release could also explain the upregulation of the parietal cell to the acid stimulatory effect and the consequent increase in gastrin sensitivity in patients suffering from duodenal ulcer disease. Conversely, the trophic effects of gastrin have also been linked to ulcer healing, especially since potent acid inhibitors induce a substantial hypergastrinemia. The evidence for such an association, however, is only circumstantial and potent and selective gastrin receptor antagonists are necessary to fully clarify the role gastrin exerts in ulcer healing.

Development of sustained achlorhydria in a patient with the Zollinger-Ellison syndrome treated with omeprazole

Spontaneous remission of gastric acid hypersecretion in the Zollinger-Ellison syndrome occurs rarely. This study shows the development of gastric secretory mucosal atrophy resulting in achlorhydria and loss of pepsin secretion in a 63-year-old woman with the Zollinger-Ellison syndrome. Reduced secretion began soon after starting treatment with omeprazole, and achlorhydria became complete 6 months later. The patient remains well with normal endoscopy results and is achlorhydric 4 years after the start of treatment and 34 months after stopping omeprazole. She was not colonized with Helicobacter pylori until 36 months after developing achlorhydria. Serum gastrin has increased from 1000 to between 5000 and 12,500 ng/L (pg/mL), was not suppressible by gastric acidification, and was not associated with G-cell hyperplasia. She also has a normal Schilling test and normal immunoglobulins, and lacks antibodies to parietal cells or H+,K+-ATPase. Moderate enterochromaffinlike cell hyperplasia is apparent for the first time on the latest biopsy sample.

Response of the antral mucosa of the rat stomach to 2,3,7,8-tetrachlorodibenzo- p-dioxin

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) produces a striking hypergastrinemia in rats that is thought to mediate the antiatrophy effect of TCDD on the oxyntic gland mucosa of the stomach. However, effects of TCDD on the antral mucosa, which is the origin of most physiologically released gastrin and is not a target for the trophic action of gastrin, has yet to be thoroughly investigated. Also gastrin release from gastrin-containing cells (i.e., G-cells) in the antral mucosa is inhibited by the paracrine secretion of somatostatin from D-cells in the antrum. Our purpose was to determine if the antral mucosa is affected by the trophic influence of TCDD and if alterations in antral mucosa levels of gastrin or somatostatin cause the hyper-gastrinemia. TCDD (100 μg/kg, Day 14 post-treatment) had a trophic effect on the antral mucosa. This was demonstrated histologically and by significant increases in antral wet weight and antral mucosa height. In contrast, pair-fed control rats that lost the same amount of body weight developed antral mucosa atrophy. With respect to serum and antral levels of gastrointestinal hormones, TCDD produced a 7- to 10-fold increase in serum gastrin concentrations that was not detected until Day 14 post-treatment. In contrast, serum gastrin concentrations in pair-fed control rats were comparable to those of control rats. The number of G-cells in the antral mucosa was not affected by either TCDD treatment or paired-feed restriction. These findings demonstrate that hypergastrinemia in TCDD-treated rats is not caused by reduced feed intake or antral G-cell hyperplasia. A major finding was that antral mucosa levels of both gastrin and somatostatin were decreased significantly in TCDD-treated rats. However, the temporal development and dose-decreased of these TCDD effects on antral hormone levels were quite different than those for hypergastrinemia. TCDD-induced decreases in antral levels of gastrin and somatostatin were detected 1 week earlier than hypergastrinemia. Also, the ED50 of TCDD on Day 14 post-treatment for the decrease in antral mucosa content and concentration of gastrin (29 and 22 μg/kg, respectively) and somatostatin (24 and 19 μg/kg, respectively) was less than that for hypergastrinemia (46 μg/kg). These time- and dose-dependent differences demonstrate that hypergastrinemia in TCDD-treated rats is not a consequence of reduced antral levels of gastrin or somatostatin. We conclude that the antral mucosa, an epithelial tissue not responsive to the proliferative effect of gastrin, is nevertheless a target for the trophic influence and gastrointestinal hormone-altering effects of TCDD.

Dynamics of Gastrin‐producing Cells in the Rat after Truncal Vagotomy Evaluation by Double lmmunostaining for Bromodeoxyuridine and Little Gastrin

The mechanism of hyperplasia of gastrin-producing cells (G-cells) in the rat antral mucosa after truncal vagotomy was studied using double immunostaining for bromodeoxyuridine (BrdU) and little gastrin (G17). With single labeling of BrdU, a few G-cells (less than 1%) showed positive immunostaining for BrdU in the nucleus throughout the experimental period in both vagotomized rats and those given a sham operation. The labeled cells in both groups demonstrated a linear increase of BrdU labeling in an identical number of cells for each experimental time-point. The labeling index of the G-cells increased rapidly from day 2 to day 6 and attained a maximum level of 44.0% on day 10 in the vagotomized group after cumulative labeling. Even in this group, however, many G-cells showed no BrdU immunoreactivity throughout the experimental period. These cells did not replicate during the experimental period, but showed an intense reaction product for G17 in their cytoplasm after vagotomy. The present study indicates that the most important factor involved in G-cell hyperplasia observed after truncal vagotomy is the activation of pre-existing G-cells to synthesize and release hormone, together with the rapid maturation of progenitor cells to mature G-cells.