Increased Serum Gastrin Levels Research Articles

Usefulness of computed tomography during arteriography in a selective arterial calcium agent injection test for pancreatic gastrinoma: a case description.

Pancreatic gastrinoma is a rare pancreatic neuroendocrine tumor with an incidence of about 0.5–21.5 cases per million people worldwide. The most common sites are the duodenum (75%), pancreas (20%), and other organs (5%). Gastrinomas are malignant in about 60–90% of cases (1-5). Malignant gastrinomas originating beneath the duodenal mucosa often metastasize to the liver, even if the tumor diameter is ≤1 cm. Therefore, in patients with gastrinoma and Zollinger–Ellison syndrome, it is important to determine the number and site(s) of gastrinoma(s), as well as the presence or absence of liver metastases. However, the detection sensitivity of computed tomography (CT) and magnetic resonance imaging is about 10–50%, that of angiography is 20–50%, and that of somatostatin receptor scintigraphy is 30–70%. Tumor size is strongly correlated with the detection sensitivity of any examination modality, and tumors of <1 cm in diameter are often difficult to detect (1,2). Therefore, the selective arterial calcium agent injection (SACI) test was developed as an effective method to detect small gastrinomas (2,6,7). In the SACI test, calcium gluconate is injected via a microcatheter into selected arterial branches to stimulate gastrin secretion from the gastrinoma located in the corresponding arterial territory. Generally, calcium gluconate is selectively injected into the gastroduodenal artery (GDA), superior mesenteric artery (SMA), distal or proximal portion of the splenic artery (distal SpA, proximal SpA), and the proper hepatic artery (PHA). The subsequent increase in the serum gastrin level is monitored using blood samples taken from the hepatic vein before and at 30, 60, 90, and 120 s after the injection. The location of the gastrinoma is determined based on a significant increase in serum gastrin levels in response to calcium gluconate (maximum serum gastrin level after calcium injection/serum gastrin level before calcium agent injection; with a median change of about 4.21 times baseline) (8). However, there are two limitations of the SACI test. First, the distribution of calcium varies between individual patients due to anatomical differences in the pancreatic arterial branches and the arterial territories. Second, there are many false positives following the injection of calcium gluconate into the GDA (median change of 4.15 times the baseline value) because calcium gluconate may stimulate normal gastrin-secreting cells in the gastric prepylorus and duodenal bulbus (8,9). It is possible to visualize the distribution of calcium following its injection by performing CT during arteriography (CTA). Here, we report a case in which the SACI test was combined with CTA for the diagnosis of a gastrinoma located in the pancreatic head and to exclude the presence of liver metastases.

Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia.

Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75mg alone, vonoprazan 10mg alone, and vonoprazan 10mg plus pirenzepine 75mg administered in a randomized crossover fashion. Median pH 4 holding time ratios (range) achieved with pirenzepine 75mg, vonoprazan 10mg, and vonoprazan 10mg plus pirenzepine 75mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200pg/ml) induced by vonoprazan 10mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180pg/ml (P = 0.028). Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.

Endoscopic Characteristics of Rugal Hyperplasia and Related Acid Condition in Helicobacter pylori-Infected Stomach

Background/AimsRugal hyperplastic gastritis (RHG) is associated with Lauren’s diffuse-type gastric cancer (GC) and the accompanying active inflammation is linked to gastric hypoacidity. We tried to establish the steps for identifying high-risk GC patients. MethodsWe included 196 patients with confirmed Helicobacter pylori infection by rapid urease test during screening endoscopy for health check-up from January 2016 to September 2016; all patients underwent blood tests for pepsinogen I and II and fasting serum gastrin. We compared RHG findings with various other endoscopic mucosal images. We also evaluated the relationships between RHG and other mucosal aspects for a given acid status based on serological markers. ResultsHypoacid and ultra-low-acid (67%) statuses were dominant, with only 18% hyperacid patients. RHG with high acid was related to a less atrophic body type (p=0.001), and RHG with ultra-low acid was associated with body xanthoma (p=0.029) and increased serum gastrin level (p=0.038). However, RHG’s influence on gastric acidity was only seen in closed-type endoscopic atrophic border (EAB), not in open type (p=0.001). ConclusionsThe majority of RHG patients had hypoacid status. RHG frequency showed no difference between closed and opentype EAB, but gastric acidity was influenced by RHG only in closed-type EAB.

S2948 Long-Term Proton Pump Inhibitor-Induced Gastric Microcystic Glandular Changes Leading to Gastric Wall Thickening

INTRODUCTION: Long term (LT) proton pump inhibitor (PPI) induced gastric microcystic glandular mucosal changes could lead to significant gastric wall thickening which must be further evaluated to exclude underlying neoplastic process. CASE DESCRIPTION/METHODS: An 81-year-old male with GERD and Barrett’s esophagus (BE) on chronic omeprazole 40mg BID was evaluated by endoscopic ultrasound (EUS) for 1cm gastroesophageal junction (GEJ) sub epithelial lesion (SEL) seen on EGD and thickened gastric mucosa (2.6 cm) normalizing just proximal to GEJ identified on an otherwise negative CT abdomen done to evaluate for epigastric pain. EGD showed irregular carpet-like thickened gastric folds with cobble stoning sparing the gastric antrum. EUS showed a small cystic SEL at GEJ and marked diffuse thickening of gastric body mucosa (16 mm) with intact muscularis propria and absence of regional lymphadenopathy. Endoscopic biopsies revealed no H. pylori but gastric mucosa with microcystic glandular changes consistent with gastric mucosal trophic changes secondary to chronic PPI use. Due to BE however, patient was continued on PPI. DISCUSSION: PPIs remain the cornerstone for GERD treatment. Adverse effects from inappropriate PPI use are more clinically manifested in the elderly population. These include drug-drug interactions and increased risk of LT PPI adverse effects on digestive and extra-digestive organs (such as dementia, decreased bone density, and community acquired pneumonia). LT PPI use can lead to fundic gland polyp formation, small intestinal bacterial overgrowth, and collagenous colitis. Gastric trophic changes were found to occur secondary to LT PPI use in the form of parietal cell protrusion into the gastric lumen and fundic gland polyp formation resulting from increased serum gastrin level. Hypertrophic changes due to LT PPI induce gastric mucosal changes that can be appreciated endoscopically as gastric cobblestone-like lesions (GCLL). Sparing of the antrum in our patient of such changes can be explained by parietal cells being anatomically present in gastric fundic glands located primarily in the gastric fundus and body. Histopathology of gastric biopsies in these cases show fundic microcystic glandular change, parietal cell hyperplasia, and cytoplasmic vacuolation. A gastroenterologist should be familiar with such changes due to LT PPI use and, yet, must biopsy the gastric mucosa to exclude any underlying gastric infiltrative and neoplastic process.Figure 1.: Endoscopic view of gastric corpus showing thickened folds, carpet like polypoid lesions.Figure 2.: Radial EUS showing markedly thickened gastric mucosa and intact muscularis propria.Figure 3.: Histopathology of gastric corpus biopsies showing microcystic glandular conformation.

Diagnostic accuracy of selective arterial calcium injection test for localization of gastrinoma.

The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.

Increased serum gastrin in patients with different clinical forms of Chagas disease coinfected with Helicobacter pylori.

ABSTRACT Trypanosoma cruzi and Helicobacter pylori (HP) are pathogens that cause chronic diseases and have been associated with hypergastrinemia. The aim of this study was to evaluate the fasting gastrin levels in patients with different clinical forms of Chagas disease (CD), coinfected or not by HP. The enrolled individuals were outpatients attending at the university hospital. HP infection was assessed by serology and 13 C-urea breath test. Fasting serum gastrin concentration was measured by chemiluminescence assay. Gastric endoscopic and histological features were also evaluated. Associations between CD and serum gastrin level were evaluated in a logistical model, adjusting for age, gender and HP status. A total of 113 patients were evaluated (45 with Chagas disease and 68 controls). In the multivariate analysis, increasing serum gastrin levels (OR= 1.02; 95% CI= 1.01-1.12), increasing age (OR= 1.05; 95% CI= 1.02 - 1.09) and HP-positive status (OR = 2.88; 95% CI = 1.10 - 7.51) remained independently associated with CD. The serum gastrin levels were significantly higher in the group of patients with the cardiodigestive form ( P = 0.03) as well as with digestive form ( P = <0.001) of Chagas disease than in the controls. In conclusion, patients with cardiodigestive and digestive clinical forms of CD have increased basal serum gastrin levels in comparison with controls. Moreover, we also demonstrated that H. pylori coinfection contributes to the hypergastrinemia shown in CD.

The Effect of Salt Intake and Potassium Supplementation on Serum Gastrin Levels in Chinese Adults: A Randomized Trial.

Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects against cardiovascular disorders. Gastrin, which is produced by the G-cells of the stomach and duodenum, can increase renal sodium excretion and regulate blood pressure by acting on the cholecystokinin B receptor. The aim of our study was to assess the effects of altered salt and potassium supplementation on serum gastrin levels in humans. A total of 44 subjects (38–65 years old) were selected from a rural community in northern China. All subjects were sequentially maintained on a relatively low-salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for 7 days (18.0 g/day of NaCl), and then a high-salt diet supplemented with potassium for another 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). The high-salt intake significantly increased serum gastrin levels (15.3 ± 0.3 vs. 17.6 ± 0.3 pmol/L). This phenomenon was alleviated through potassium supplementation (17.6 ± 0.3 vs. 16.5 ± 0.4 pmol/L). Further analyses revealed that serum gastrin was positively correlated with 24 h urinary sodium excretion (r = 0.476, p < 0.001). By contrast, gastrin level was negatively correlated with blood pressure in all dietary interventions (r = −0.188, p = 0.031). The present study indicated that variations in dietary salt and potassium supplementation affected the serum gastrin concentrations in the Chinese subjects.

Effect of combined Metformin and Esomeprazole therapy on plasma gastrin and blood glucose in elderly patients with type 2 diabetes mellitus

Objective To investigate the effect of combined Metformin and esomeprazole therapy on plasma levels of gastrin, blood glucose, glycosylated hemoglobin(HbA1c)and insulin in elderly patients with type 2 diabetes. Methods A randomized, double-blind, placebo-controlled study of 41 elderly patients with type 2 diabetes was conducted.Patients were randomly assigned into treatment group(combination therapy with Metformin 0.5 g, bid or tid and Esomeprazole 20 mg, qd, for 12 weeks)and placebo group(Metformin monotherapy 0.5 g, bid or tid, for 12 weeks). Fasting blood samples were taken from vein before and after treatment.Fasting serum levels of gastrin, glucose, HbA1c, insulin, lipids, liver and renal functions were compared between the two groups.The homeostasis model of assessment for insulin resistance index(HOMA-IR)and insulin secretion index(HOMA-β)were calculated, and complications were recorded. Results There were no significant differences in body mass index and waist circumference between the two groups.Serum gastrin level was slightly increased in the treatment group 12 weeks after treatment, but without statistically significance 〔(127.20±9.21)ng/L vs.(131.53±7.84)ng/L, P>0.05〕, and serum gastrin level had no significant differences in the placebo group before and after treatment 〔(128.42±4.58)ng/L vs.(127.51±3.47)ng/L, P>0.05〕. However, there were no significant differences in the changes of blood glucose, HbA1c, insulin, HOMA-β and HOMA-IR before versus after therapy, and between the two group(all P>0.05). Conclusions Combined Metformin and insulin therapy cannot increase serum gastrin and insulin levels and has no significant effect on reducing blood glucose and HbA1c levels in elderly patients with type 2 diabetes. Key words: Diabetes mellitus, type 2; Proton pump inhibitor; Metformin; Gastrins; Blood glucose

Serum gastrin levels in different stages of distal gastric carcinogenesis: is there a role for serum gastrin in tumor growth?

Elevated levels of serum gastrin (SG) have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the relationship between SG and gastric epithelial lesions. A total of 90 patients with gastric epithelial lesions (hyperplastic polyp, 12; adenoma, 41; early gastric cancer, 29; advanced gastric cancer, 8) were enrolled as the case group and 79 patients without epithelial lesions were enrolled as the control group. Serum gastrin levels were significantly different between the case and control groups (p<0.001). A high SG level (>80 pg/mL), intestinal metaplasia, and a pepsinogen I/II ratio <3 were independently associated with an increased risk of epithelial lesions (odds ratio: 14.6, 9.4, and 4.1, respectively, p<0.05). SG levels in case subjects showed a unimodal distribution pattern as the disease progressed. The mean SG level was highest in those with hyperplastic polyps and then decreased significantly to the control level in the gastric cancer group. Higher SG levels in each disease category were not associated with increased tumor size, synchronicity, invasiveness, presence of lymph node metastasis, or a higher cellular proliferation index (p>0.05). An increased SG level was an independent and potent risk factor for gastric epithelial lesions. However, it does not seem to relate with distal gastric tumor growth. Serial decreases in SG levels should be considered a warning sign in index hypergastrinemic patients with no prior Helicobacter pylori eradication.

Helicobacter pylori but not gastrin is associated with the development of colonic neoplasms

Recent studies have suggested that Helicobacter pylori (H. pylori) constitutes a risk for the development of colonic neoplasia. Hypergastrinemia can be induced by H. pylori infection, and gastrin can act as putative promoter of colorectal carcinogenesis. Aim of our study was to assess whether H. pylori infection and/or increased serum gastrin levels are associated with the occurrence of colonic neoplasms. For this, we reviewed prospectively collected data of 377 patients with a minimum age of 50 years who underwent colonoscopy. H. pylori and CagA status were determined by serology. Serum gastrin levels were measured in fasting state by commercially available assay. In H. pylori infected patients (n = 138; 36.6%), the overall prevalence of colonic neoplasms was more frequent compared to H. pylori negative patients (n = 239; 63.4%) (OR = 2.73, 95% CI: 1.76-4.24). H. pylori infection occurred more frequently in patients with hyperplastic polyps (OR = 2.66, 95% CI: 1.23-5.74) and adenomas presenting with low grade intraepithelial neoplasia (IEN) (OR = 1.85, 95% CI: 1.14-2.99). Attributable risk for adenomas with high grade IEN and colorectal adenocarcinoma (n = 14) was not assessed due to the low number of cases. The expression of CagA was also associated with an increased risk for colonic neoplasms (OR = 2.25, 95% CI: 1.29-3.94). Hypergastrinemia did not increase the risk for any colonic neoplasms and there was no difference in basal serum gastrin levels between H. pylori positive and negative patients. In conclusion, H. pylori infection, including CagA expression is associated with an increased risk for the development of colonic neoplasm.

No Evidence of Cancer Risk from Long-Term PPI Therapy

Prolonged use of proton-pump inhibitors (PPIs) has been associated with an increase in serum gastrin levels, which could drive proliferation of

Proton pump inhibitors as a treatment method for type II diabetes

Recent reports have hypothesized a role for exogenously administered gastrin in regulating beta cell function or activity. We surmised that a class of agents, proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, rabeprazole, lansoprazole), known to increase serum gastrin levels could have such an effect, and that data might be available in our database which could address such an effect. We examined our electronic database to obtain glycohemoglobin (HgbA1c) levels measured in the past two years from all type II diabetics and extracted from those diabetics who were concurrently taking a proton pump inhibitor. A comparison of these groups showed an average HgbA1c of 7.6% for type II diabetics not taking a proton pump inhibitor (n=282) and an average HgbA1c of 7.0% for type II diabetics concurrently taking a proton pump inhibitor (n=65), T=-3.61, p=0.002. These data support the hypothesis that proton pump inhibitors can be used to treat type II diabetes.

Effects of Melatonin in Mild diabetics with Dyslipidaemia

Diabetes is spreading at an exponential rate in Indian sub-continent. Existing infrastructure of health in India is poor, particularly in its rural sectors. Of all verities of diabetes, Type 2 diabetes is commoner and is about 80%. Different drugs, herbal medicines and neutraceuticals are used to control diabetes. Melatonin, the hormone of pineal gland is being considered as a neutraceutical by FDA. Many workers thought melatonin might have a role in diabetes control through central mechanisms. The studies lead to many controversies and counterclaims. Present study is intended to observe the effects of melatonin at a higher dosage per day. The effects in rural Indian diabetic population at that melatonin dosage in different blood parameters were observed and also change in endocrine secretions observed. Melatonin caused reduction in Serum Insulin, Serum Cortisol, Serum ACTH and Serum TSH levels while increase in Serum Gastrin level. Of the biochemical parameters, melatonin caused reductions in TLC, LDLC and FBS while increase in HDLC. It also caused reduction in neutrophil and increase in lymphocyte count in a diabetic with increase in faecal fat excretion.

Proton Pump Inhibitors and the Risk of Colorectal Cancer

Proton pump inhibitor (PPI) use is associated with increased serum gastrin levels and bacterial overgrowth, resulting in more toxic bile salt formation. Concern has risen that these factors may increase the risk of developing colorectal neoplasia. To investigate the association between the use of PPIs and the risk of colorectal cancer. A population-based case-control study was conducted within the Dutch Primary Care Information (IPCI) database over the period 1996-2005. Cases with colorectal cancer were matched with up to 20 controls on age, gender, calendar time, and duration of follow-up prior to diagnosis. Cumulative exposure to PPIs was assessed in the 5 yr prior to diagnosis with a 1-yr lag time analysis. We calculated adjusted odds ratios (OR) with 95% confidence intervals (95% CI) using multivariate, conditional logistic regression analysis. Within the source population of 457,024 persons, we identified 595 colorectal cancer cases. The odds of colorectal cancer were not increased among patients ever using PPIs compared with patients who never used PPIs (OR 0.85, 95% CI 0.63-1.16). Also, the use of PPIs for >365 days was not associated with a greater risk of colorectal cancer (OR 0.79, 95% CI 0.44-1.41) compared with nonusers. The odds of colorectal cancer in neither the right nor the left hemicolon were significantly increased in patients using PPIs. The present study indicates no association between PPI use and the risk of colorectal cancer. Larger numbers of long-term PPI users are needed to confirm the absence of a risk-increasing effect of long-term PPI exposure.

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

Validation of a New Endoscopic Technique to Assess Acid Output in Zollinger–Ellison Syndrome

To safely manage the hypersecretory state in patients with Zollinger-Ellison syndrome, both upper endoscopy and gastric analysis are required to titrate optimal medical therapy. Conventional gastric analysis requires more than 1 hour to perform and results in significant patient dissatisfaction. In this study, we have validated endoscopic gastric analysis as a novel technique that can effectively replace conventional gastric analysis. In a prospective, cross-over study, 12 patients with Zollinger-Ellison syndrome underwent gastric analysis, first by the conventional method and then by an endoscopic technique performed on the same day. Acid concentration was determined by titration, volume output was recorded, and acid output was calculated using standard methodologies and formulas. Agreement was assessed following the Bland-Altman method. To assess repeatability, both techniques were repeated on the same day in a subset of patients. Excellent agreement was reported between acid output (95% limits of agreement, -1.27 to 1.61 mEq/h) and acid concentration (95% limits of agreement, -0.01 to 0.01 mEq/mL), although poor agreement was observed between volume output measured. Endoscopic gastric analysis showed greater reproducibility regarding acid and volume output measured. We introduce a new, rapid, reproducible, and accurate endoscopic technique to measure acid output in patients with Zollinger-Ellison syndrome who require both annual endoscopy and gastric analysis. The data presented here suggest that endoscopic gastric analysis would be equally effective in determining acid output in other hypersecretory states. Additional analysis of cost effectiveness is needed to evaluate its use as a screening tool in select populations.

Inefficient Chronic Activation of Parietal Cells in Ae2a,b−/− Mice

In parietal cells, basolateral Ae2 Cl(-)/HCO(3)(-) exchanger (Slc4a2) appears to compensate for luminal H(+) pumping while providing Cl(-) for apical secretion. In mouse and rat, mRNA variants Ae2a, Ae2b1, Ae2b2, and Ae2c2 are all found in most tissues (although the latter at very low levels), whereas Ae2c1 is restricted to the stomach. We studied the acid secretory function of gastric mucosa in mice with targeted disruption of Ae2a, Ae2b1, and Ae2b2 (but not Ae2c) isoforms. In the oxyntic mucosa of Ae2(a,b)(-/-) mice, total Ae2 protein was nearly undetectable, indicating low gastric expression of the Ae2c isoforms. In Ae2(a,b)(-/-) mice basal acid secretion was normal, whereas carbachol/histamine-stimulated acid secretion was impaired by 70%. These animals showed increased serum gastrin levels and hyperplasia of G cells. Immunohistochemistry and electron microscopy revealed baseline activation of parietal cells with fusion of intracellular H(+)/K(+)-ATPase-containing vesicles with the apical membrane and degenerative changes (but not substantial apoptosis) in a subpopulation of these cells. Increased expression of proliferating cell nuclear antigen in the oxyntic glands suggested enhanced Ae2(a,b)(-/-) parietal cell turnover. These data reveal a critical role of Ae2a-Ae2b1-Ae2b2 isoforms in stimulated gastric acid secretion whereas residual Ae2c isoforms could account to a limited extent for basal acid secretion.

Acceleration of Gastric Ulcer Healing by Omeprazole in Portal Hypertensive Rats

Background: Gastric ulcer healing is delayed in patients with portal hypertension (PHT) and often responds poorly to histamine H₂ blockers. Although proton pump inhibitors are more effective anti-ulcer agents, there is little information regarding their efficacy for gastric ulcer in cases of PHT. Therefore, we investigated the effects of a proton pump inhibitor, omeprazole, on the healing of acetic-acid-induced gastric ulcer in PHT rats. Methods: Animals studied were 80 male Sprague-Dawley rats aged 7 weeks, of which half underwent two-staged portal vein ligation (PHT rats) and half underwent a sham operation (SO rats). Gastric ulcers were induced by acetic acid. Starting from day 4 after ulcer induction, rats received omeprazole or vehicle orally (50 mg/kg) for 5 or 10 days. Ulcer area, proliferating cell nuclear antigen labelling index (PCNA LI), and serum gastrin levels were recorded. Results: PHT significantly inhibited epithelial cell proliferation and delayed gastric ulcer healing as indicated by a decreased PCNA LI at the ulcer margin and almost 2-fold larger ulcer area in PHT versus SO rats 14 days after ulcer induction. Ten-day treatment with omeprazole (vs. vehicle) significantly accelerated ulcer healing to a similar extent in both PHT and SO rats. Serum gastrin levels were significantly higher in PHT rats than in SO rats following treatment with omeprazole. Omeprazole (vs. vehicle) restored the decreased PCNA LI at the ulcer margin in PHT rats to that noted in SO rats. Conclusions: In PHT rats, omeprazole accelerates gastric ulcer healing, stimulates epithelial cell proliferation at the ulcer margin, and increases serum gastrin levels. Since gastrin is a potent stimulator of gastric epithelial cell proliferation, increased serum gastrin levels may be an important factor in omeprazole-induced stimulation of epithelial cell proliferation and acceleration of gastric ulcer healing in conditions of PHT.

Discussion 2

Discussion 2

Regulatory mechanism of gastric acid secretion and mucosal integrity--an analysis with various gene deficient mice

Mechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K(+)-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-alpha were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.