gastrins and Barrett-Esophagus

Despite being an overall safe drug, several long-term adverse effects are associated with proton pump inhibitors (PPIs). The link between PPI use and gastric neuroendocrine tumors (NETs), gastric adenocarcinomas and Barrett's esophagus progression gastric cancers has been investigated due to PPI-induced hypergastrinemia.. The pathophysiological mechanisms underlying PPI exposure and gastric NETs, gastric adenocarcinomas and Barrett's esophagus progression are discussed. The quality of randomized control studies, cohort studies and case reports investigating the link between gastric cancers and PPIs are examined. Recommendations for clinicians are provided.. PPIs cause a hypergastrinemic state, increasing enterochromaffin-like cell dysplasia and risk of gastric NET development, increasing gastritis severity in the context of Helicobacter pylori infection, and progression of carcinogenesis in a certain predisposed subset of Barrett's esophagus patients. There are case reports of PPI-induced gastric NETs and adenocarcinomas as consequences of these effects. In pernicious anemia and chronic gastritis, clinicians should be aware of potential increased risk of gastric NET development with chronic PPI use in these patients. Eradication status of H. pylori prior to commencing long-term PPI therapy should be established to reduce the risk of severe atrophic gastritis and development of gastric dysplasia.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Disease Progression; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Neuroendocrine Tumors; Proton Pump Inhibitors; Stomach Neoplasms

Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren't biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.

Topics: Adenocarcinoma; Animals; Apoptosis; Barrett Esophagus; Biopsy; Cell Proliferation; Colorectal Neoplasms; Esophageal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Mice

Oesophageal adenocarcinoma (OA) remains one of the more deadly forms of gastro-intestinal cancer with a mortality rate exceeding 90%. The incidence of OA remains unabated and has a reported fivefold increase since 1970 [Pera M, Cameron AJ, Trastek VF, Carpenter HA & Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993; 104(2): 510-513]. Gastro-oesophageal reflux disease and its sequelae, Barrett's oesophagus, is one of the principle risk factors in the development of OA, with a 30-fold increased risk in Barrett's patients compared with the general population [Tytgat GNJ. Does endoscopic surveillance in esophageal columnar metaplasia (Barrett's-Esophagus) have any real value. Endoscopy 1995; 27(1): 19-26]. OA is thought to be a microcosm of evolution, developing sequentially along the metaplasia-dysplasia-adenocarcinoma sequence. Progression is attributed to a series of genetic and epigenetic events that ultimately allow for clonal selection of Barrett's cells via subversion of intrinsic control mechanisms regulating cellular proliferation and/or apoptosis. This review will describe the current suppositions of the mechanisms behind the selection and subsequent expansion of Barrett's clones, and focus on some of the principle hallmarks associated with this transition.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Bile Acids and Salts; Cell Transformation, Neoplastic; Disease Progression; Esophageal Neoplasms; Esophagogastric Junction; Gastrins; Gastroesophageal Reflux; Humans; Inflammation Mediators; Metaplasia; Prevalence

The pathogenesis of cancer in Barrett's esophagus is multifactorial. Gastroesophageal reflux seems to be important in the initiation of Barrett's esophagus, but its role in promoting carcinogenesis has yet to be established. Diet, lifestyle and carcinogens, especially the nitrates, may be important in the development of carcinogenesis, and require further investigation. Inhibition of reflux-stimulated inflammatory changes, for example by inhibiting cyclooxygenase, holds promise for decreasing cancer progression. Similarly, dietary and lifestyle modification used in the management of reflux may also help to prevent the development of esophageal cancer. The molecular changes that are associated with the development of cancer in Barrett's esophagus offer several potential areas of intervention to prevent and manage esophageal cancer. Limiting cell growth, increasing apoptosis of damaged cells, limiting cell invasion and angiogenesis factors could be useful to accomplish this goal. Having a greater understanding of the pathogenesis of this condition can only help to develop more management options in the future.

Topics: Barrett Esophagus; Gastrins; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans

Several case reports have emphasized that esophageal carcinoid tumors are associated with a poor prognosis. To expand our knowledge about the pathology and biologic behavior of these rare tumors, we reviewed the clinicopathologic and immunohistochemical findings of four cases of primary esophageal carcinoid. The age of the patients ranged from 48 to 82 years (mean 63 years; median 61 years). The lower segment of the esophagus was involved in two cases and the mid segment was involved in one case. The sizes of the tumors ranged from 0.3 cm to 3.5 cm. Two tumors were confined to the lamina propria and two invaded into the muscular wall. Two tumors appeared polypoid, whereas the remaining two were incidental findings and associated with adenocarcinoma arising in a background of Barrett esophagus. The adenocarcinoma was superficially invasive in one case, whereas it penetrated the muscular wall in the other. All four carcinoid tumors were immunoreactive with chromogranin and synaptophysin. There was focal expression of serotonin in two cases, glucagon in one case, and pancreatic polypeptide in one case. Endocrine cell hyperplasia was noted in both the Barrett esophagus and the invasive adenocarcinoma. One patient died secondary to postoperative pneumonia. Three patients are alive and disease free at 1, 6, and 23 years status post therapy. None of the patients had metastatic disease. These findings show that esophageal carcinoids are associated with a favorable prognosis. They arise in two settings: (1) a single large polypoid tumor or (2) an incidental finding and in association with adenocarcinoma arising in the background of Barrett esophagus. The presence of endocrine cell hyperplasia in the Barrett mucosa and the adenocarcinoma supports the hypothesis that these lesions arise from a common stem cell.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Barrett Esophagus; Carcinoid Tumor; Chromogranins; Esophageal Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Pancreatic Polypeptide; Polyps; Prognosis; Synaptophysin

Gastroesophageal reflux (GER) occurs in 2 distinct forms that differ in pathophysiology, clinical presentation, natural history, and therapy: mild GER (with no or minimal esophagitis) and classic, severe reflux (at risk for erosive esophagitis). A minority of subjects (< 20%) have the classic, potentially severe pattern of GER caused by reduced lower esophageal sphincter (LES) pressure and prolonged acid reflux, particularly at night, but also during the day. Evaluation and management must be catered to patients with this pattern of reflux. In contrast, symptoms in mild reflux (the majority) often occur during the day after meals in an upright posture (upright reflux); resting LES pressure is usually normal (reflux episodes are related to transient relaxation of the LES) and little reflux occurs at night. Acid reflux, which occurs mostly during the day, overlaps with the normal range and esophagitis is rare; however, symptoms can be distressing. Optimal management is controversial because no outcome trials have been conducted to address management in primary care settings. However, clinical clues can help differentiate mild and severe reflux and guide management decisions. This article provides a detailed approach to current management of GER syndromes.

Topics: Anti-Ulcer Agents; Barrett Esophagus; Cisapride; Endoscopy, Gastrointestinal; Gastrins; Gastroesophageal Reflux; Hernia, Hiatal; Humans; Omeprazole; Predictive Value of Tests; Proton Pump Inhibitors; Risk Factors

Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.. We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.. Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.. While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.

Topics: Adult; Aged; Barrett Esophagus; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Esophagus; Female; Gastric Mucosa; Gastrins; Gene Expression; Humans; Male; Middle Aged; Precancerous Conditions; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

To determine the results of a new surgical procedure for patients with Barrett's esophagus.. In addition to pathologic acid reflux into the esophagus in patients with severe gastroesophageal reflux and Barrett's esophagus, increased duodenoesophegeal reflux has been implicated. The purpose of this study was to establish the effect of a new bile diversion procedure in these patients.. Sixty-five patients with Barrett's esophagus were included in this study. A complete clinical, radiologic, endoscopic, and bioptic evaluation was performed before and after surgery. Besides esophageal manometry, 24-hour pH studies and a Bilitec test were performed. After surgery, gastric emptying of solids, gastric acid secretion, and serum gastrin were determined. All patients underwent highly selective vagotomy, antireflux procedure (posterior gastropexy with cardial calibration or fundoplication), and duodenal switch procedure, with a Roux-en-Y anastomosis 60 cm in length.. No deaths occurred. Morbidity occurred in 14% of the patients. A significant improvement in symptoms, endoscopic findings, and radiologic evaluation was achieved. Lower esophageal sphincter pressure increased significantly (p < 0.0001), as did abdominal length and total length of the sphincter (p < 0.0001). The presence of an incompetent sphincter decreased from 87.3% to 20.9% (p < 0.0001). Three of seven patients with dysplasia showed disappearance of this dysplasia. Serum gastrin and gastric emptying of solids after surgery remained normal. Basal and peak acid output values were low. Twenty-four hour pH studies showed a mean value of 24.8% before surgery, which decreased to 4.8% after surgery (p < 0.0001). The determination of the percentage time with bilirubin in the esophagus was 23% before surgery; this decreased to 0.7% after surgery (p < 0.0001). Late results showed Visick I and II gradation in 90% of the patients and grade III and IV in 10% of the patients.. This physiologic approach to the surgical treatment of patients with Barrett's esophagus produces a permanent decrease of acid secretion (and avoids anastomotic ulcer), decreases significantly acid reflux into the esophagus, and abolishes duodenoesophageal reflux permanently. Significant clinical improvement occurs, and dysplastic changes at Barrett's epithelium disappear in almost 50% of the patients.

Topics: Adult; Aged; Barrett Esophagus; Bile Reflux; Duodenum; Female; Follow-Up Studies; Fundoplication; Gastric Acid; Gastric Emptying; Gastrins; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Postoperative Complications; Prospective Studies; Vagotomy

Barrett's esophagus is a metaplastic condition resulting from gastroesophageal reflux disease. Previous medical and surgical therapies have failed to predictably eradicate Barrett's. The objective of this study was to assess the impact of long-term, high-dose lansoprazole, a proton pump inhibitor, on Barrett's esophagus.. Patients with Barrett's esophagus at least 3 cm long and with specialized columnar epithelium were treated with 60 mg of lansoprazole each morning. Every 6 months, patients had standardized symptomatic, laboratory, and endoscopic assessment. The length of Barrett's esophagus was measured, photo-documented, and biopsied.. Twenty-seven patients with Barrett's esophagus have been treated an average of 2.9 yr. Symptoms improved (70%, 19 patients), and erosive esophagitis healed (100%, 13 patients), but there was no significant reduction in the length of Barrett's epithelium (mean length at baseline 5.7 cm, final visit 5.3 cm). However, by the final visit, 20 of 26 patients (77%) had squamous islands: two unchanged in size, six with increased surface area, and 12 newly developed on therapy. Initially, mean fasting gastrin levels rose significantly but then plateaued after 1 month of therapy. Of 10 patients with gastrin levels for 18 months or longer, only one had a level > or = 400 pg/ml.. Lansoprazole 60 mg for up to 3 yr was safe and effective in controlling symptoms and esophagitis. The impact on the extent of Barrett's esophagus over this time interval was manifested by the extension and development of squamous islands.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Epithelium; Esophagus; Female; Gastrins; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors

The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice.. L2-IL-1β mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug.. Hypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia.. Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.

Topics: Animals; Barrett Esophagus; Biomarkers; Disease Models, Animal; Disease Progression; Gastrins; Gene Expression Regulation; Hyperglycemia; Immunohistochemistry; Metaplasia; Mice; Mice, Transgenic; Myoblasts, Cardiac; Phenotype; Receptor, Cholecystokinin B

Topics: Barrett Esophagus; Carcinoma, Neuroendocrine; Colonic Polyps; Diagnosis, Differential; Diarrhea; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Recurrence; Vomiting; Weight Loss; Zollinger-Ellison Syndrome

An algorithm (GastroPanel) for the non-invasive diagnosis of atrophic gastritis has been previously proposed, based on serum pepsinogen-I, gastrin-17, and Helicobacter pylori (H. pylori) antibodies. The aim of the present study was to evaluate whether serum markers correlate with and predict gastric atrophy in gastroesophageal reflux disease (GERD) patients.. The baseline data of the prospective ProGERD study, a study on the long-term course of GERD (n=6215 patients), served to select patients with atrophic gastritis diagnosed in biopsies from gastric antrum and corpus, and control cases without atrophy. A total of 208 pairs were matched for age, sex, GERD status (erosive vs non-erosive), presence of Barrett's esophagus, and histological H. pylori status were retrieved. Serum pepsinogen-I, gastrin-17, and H. pylori antibodies were determined using specific enzyme immunoassays.. A significant negative correlation was found between the degree of corpus atrophy and the level of serum pepsinogen-I. A previously-reported negative correlation between the degree of antral atrophy and serum gastrin-17 could not be confirmed. The low sensitivity (0.32) and specificity (0.70) of the GastroPanel algorithm were mainly due to over diagnosis and under diagnosis of advanced atrophy in the antrum.. The diagnostic validity of the GastroPanel algorithm to diagnose gastric atrophy non-invasively is not sufficient for general use in GERD patients.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Barrett Esophagus; Biomarkers; Biopsy; Case-Control Studies; Endoscopy, Gastrointestinal; Europe; Female; Gastrins; Gastritis, Atrophic; Gastroesophageal Reflux; Helicobacter pylori; Humans; Immunoenzyme Techniques; Male; Matched-Pair Analysis; Middle Aged; Pepsinogen A; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index; Young Adult

Barrett's esophageal cancer is usually included in gastroesophageal (GE) junction adenocarcinoma in Japanese people. No study on the pathogenesis of Barrett's esophageal cancer in comparison with GE junction adenocarcinoma other than Barrett's esophageal cancer has been reported in Japan. The aim of this study was to evaluate the clinical and pathological characteristics and gastric acid secretion of Barrett's esophageal cancer and GE junction adenocarcinoma other than Barrett's esophageal cancer in Japanese subjects.. Twenty-three patients with Barrett's esophageal cancer and 23 patients with GE junction adenocarcinoma other than Barrett's esophageal cancer were enrolled in this study. We evaluated and compared them by assessing the Helicobactor pylori (HP) infection status and gastric acid secretion using the endoscopic gastrin test (EGT).. In the patients with Barrett's esophageal cancer, no significant difference was found in the mean EGT value between HP-positive and -negative patients, but in the patients with GE junction adenocarcinoma other than Barrett's esophageal cancer, the mean EGT value in HP-positive patients was significantly lower than that in HP-negative patients.. Two distinct types of cancer of different origin may be mixed in GE junction adenocarcinomas. One is Barrett's esophageal cancer associated with high gastric acid secretion and reflux of gastric acid into the esophagus, the other is cancer resembling distal gastric cancer associated with gastric atrophy and low gastric acid secretion.

Topics: Adenocarcinoma; Aged; Barrett Esophagus; Case-Control Studies; Endoscopy, Digestive System; Esophageal Neoplasms; Esophagogastric Junction; Female; Gastric Acid; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Male; Middle Aged; Prevalence; Severity of Illness Index

Proton pump inhibitors (PPIs) are frequently prescribed to patients with Barrett's esophagus (BE), but in a subset, they can induce significant hypergastrinemia. Elevated levels of gastrin have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the association between serum gastrin levels and dysplasia in BE.. We performed a cross-sectional study and enrolled patients with BE without dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (AC), as well as gastroesophageal reflux disease controls, all chronically taking PPIs. Fasting serum gastrin was measured, and data were collected on patient characteristics, medication use, and the highest degree of BE neoplasia.. A total of 95 patients were enrolled. The mean age was 64.7 (+/-10.0) years, and 70.5% were male. The median serum gastrin level was 40 pM. There was no significant difference in gastrin levels with increased degrees of BE neoplasia (overall P=0.68). In multivariable analysis, the highest quartile of gastrin was associated with significantly increased odds of advanced neoplasia (HGD or AC) (odds ratio (OR): 5.46, 95% confidence interval (CI): 1.20-24.8).. In BE patients taking PPIs, an elevated serum gastrin is associated with a history of HGD or AC. Prospective studies are needed to determine whether patients with nondysplastic BE and elevated serum gastrin are at increased risk for neoplastic progression.

Topics: Adenocarcinoma; Aged; Barrett Esophagus; Biomarkers, Tumor; Biopsy, Needle; Cell Transformation, Neoplastic; Confidence Intervals; Cross-Sectional Studies; Esophageal Neoplasms; Esophagoscopy; Female; Gastrins; Gastroesophageal Reflux; Humans; Immunohistochemistry; Incidence; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Precancerous Conditions; Probability; Prognosis; Proton Pump Inhibitors; Regression Analysis; Risk Assessment

Topics: Barrett Esophagus; Esophageal Neoplasms; Gastrins; Humans; Proton Pump Inhibitors

Topics: Barrett Esophagus; Gastric Mucosa; Gastrins; Humans; Proton Pump Inhibitors; Receptor, Cholecystokinin B

Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) are regarded as complications of gastro-oesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for OAC cells. We have examined the effects of glycine-extended gastrin (G-Gly), an alternative product of progastrin processing on apoptosis in the QhERT Barrett's oesophageal cell line and OE33 and BIC-1 OAC cells. G-Gly inhibited serum-starvation and camptothecin-induced apoptosis in all three cell lines, G-17 was only effective in OE33 cells. By contrast to the effects of G-17, the anti-apoptotic effect of G-Gly was independent of both the CCK(2) receptor and cyclo-oxygenase-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependent STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL2L1 but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL2L1 in OE33 cells. We conclude that G-Gly inhibits apoptosis in BO and OAC via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in BO.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Line, Tumor; Cyclooxygenase Inhibitors; Enzyme Activation; Esophageal Neoplasms; Gastrins; Humans; Janus Kinase 2; Receptors, Cholecystokinin; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor

It has been reported that patients with Barrett's esophagus (BE) may have gastric acid hypersecretion. Serological markers such as serum pepsinogen or gastrin have been used to estimate the gastric secretory function. The aim of this study was to compare the serum pepsinogen and gastrin concentrations in view of Helicobacter pylori infection status between BE patients and the controls.. Thirty-six patients with long-segment BE were enrolled in this study. Three age- and sex-matched controls were assigned to each patient. Serum pepsinogen and gastrin concentrations were measured by radioimmunoassay and H. pylori infection was determined by histology and serum IgG antibodies.. Helicobacter pylori infection was present in 4 of 36 patients (11%) with BE and in 80 of 108 controls (74%), being less prevalent in BE patients than in the controls (P < 0.0001). When examined in the H. pylori-negative subjects, both the serum pepsinogen I and pepsinogen II concentrations in BE patients were significantly higher than those in the controls (mean pepsinogen I:BE 51.0 +/- 14.0 ng/mL vs control 38.9 +/- 13.5 ng/mL, P = 0.0012; mean pepsinogen II:BE 10.8 +/- 4.0 ng/mL vs control 7.9 +/- 2.0 ng/mL, P = 0.0097). There was no significant difference in the serum gastrin levels between BE patients and the controls irrespective of the H. pylori infection status.. Most of the Japanese BE patients are characterized by the absence of H. pylori infection and high levels of serum pepsinogen. Determination of the serum pepsinogen level in combination with the H. pylori infection status could be a useful serological marker for BE screening.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Asian People; Barrett Esophagus; Biomarkers; Case-Control Studies; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Japan; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Predictive Value of Tests; Prevalence; Up-Regulation

The aim of this study was to determine the contribution of preoperative gastric secretory and hormonal response, to the appearance of Barrett's esophagus in the esophageal stump following subtotal esophagectomy.. Thirty-eight end-stage chagasic achalasia patients submitted to esophagectomy and cervical gastric pull-up were followed prospectively for a mean of 13.6 +/- 9.2 years. Gastric acid secretion, pepsinogen, and gastrin were measured preoperatively in 14 patients who have developed Barrett's esophagus (Group I), and the results were compared to 24 patients who did not develop Barrett's esophagus (Group II).. In the group (I), the mean basal and stimulated preoperative gastric acid secretion was significantly higher than in the group II (basal: 1.52 vs. 1.01, p = 0.04; stimulated: 20.83 vs. 12.60, p = 0.01). Basal and stimulated preoperative pepsinogen were also increased at the Group I compared to Group II (Basal = 139.3 vs. 101.7, p = 0.02; stimulated = 186.0 vs. 156.5, p = 0.07. There was no difference in preoperative gastrin between the two groups. Gastritis was present during endoscopy in 57.1% of the Group I, while it was detected in 16.6% of the Group II, p = 0.014.. Barrett's esophagus in the esophageal stump was associated to high preoperative levels of gastric acid secretion, serum pepsinogen, and also gastritis in the transposed stomach.

Topics: Adult; Barrett Esophagus; Chagas Disease; Epithelium; Esophageal Achalasia; Esophagectomy; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Pepsinogen A; Preoperative Period; Risk Assessment; Young Adult

Glycine-extended gastrin (G-Gly) is a mitogen for several gastrointestinal tissues although the mechanisms responsible are ill-defined and it is unknown if G-Gly can influence signalling in Barrett's oesophagus. G-Gly stimulated proliferation in OE19 and OE33 cells in a dose-dependant manner. This was unaffected by a CCK2 receptor antagonist but abolished by COX-2 inhibitors. G-Gly induced proliferation, COX-2 mRNA abundance, and PGE2 secretion, were all abolished by inhibition of JAK2, PI3-kinase, Akt or NF-kappaB. G-Gly stimulated phosphorylation of JAK2 and increased PI3-kinase activity in JAK2 immunoprecipitates. G-Gly increased Akt phosphorylation and kinase activity and NF-kappaB reporter activity in a JAK2-, PI3-kinase- and Akt-sensitive manner. G-Gly increased COX-2 promoter transcription in an Akt and NF-kappaB-dependent manner and also reduced COX-2 mRNA degradation in an Akt-insensitive manner. We conclude that G-Gly induced signalling involves a JAK2/PI3-kinase/Akt/NF-kappaB sequence leading to COX-2 transcription. G-Gly also seems to stabilise COX-2 mRNA via a separate pathway.

Topics: Adenocarcinoma; Barrett Esophagus; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Dinoprostone; Esophageal Neoplasms; Gastrins; Humans; Janus Kinase 2; NF-kappa B; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Receptor, Cholecystokinin B; RNA Stability; Signal Transduction

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; bcl-Associated Death Protein; Cyclooxygenase 2; Disease Progression; Esophageal Neoplasms; Gastrins; Gastroesophageal Reflux; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Models, Biological; Neoplasm Proteins; NF-kappa B; Prevalence; Survivin

We have previously reported that Helicobacter pylori infection prevents reflux esophagitis (RE) and Barrett's esophagus (BE) by decreasing gastric acid secretion. Gastroesophageal (GE) junction adenocarcinoma, including Barrett's adenocarcinoma, has been thought to be a complication of gastroesophageal reflux disease (GERD). However, the relationship between H. pylori infection, gastric acid secretion, and GE junction adenocarcinoma has not yet been investigated in Japan. The aim of this study was to evaluate this relationship in the Japanese population.. A total of 168 Japanese patients (RE alone: 80, short-segment BE (SSBE): 16, long-segment BE (LSBE): 20, GE junction adenocarcinoma: 12, distal early gastric cancer (EGC): 40; male/female = 106/62; mean age 61.5 yr) and 80 Japanese control subjects who had no localized lesions in the upper gastrointestinal tract (male/female = 43/37, mean age 58.1 yr) were enrolled for this study. The prevalence of H. pylori infection was determined by biopsy, the rapid urease test, and measurement of the serum H. pylori IgG antibody. Gastric acid secretion was assessed by the endoscopic gastrin test (EGT). RE was diagnosed according to the Los Angeles classification.. The prevalence of H. pylori infection in the patients with RE alone (30%) was significantly lower than that in control subjects (71.2%). There was also a tendency for the prevalence of H. pylori infection to be lower in patients with BE (SSBE, 18.7%; LSBE, 0%) when compared to that in patients with RE alone. On the other hand, while the prevalence of H. pylori infection in patients with GE junction adenocarcinoma (58.3%) was significantly lower than that in patients with EGC (87.5%), it tended to be higher than that in patients with RE alone or BE. The mean EGT value in patients with RE alone (3.74 mEq/10 min) was significantly higher than that in control subjects (1.83). The mean EGT value in patients with BE (SSBE, 4.74; LSBE, 4.76) tended to be even higher than that in patients with RE alone. The mean EGT value in patients with GE junction adenocarcinoma (3.94) was significantly higher than that in control subjects and patients with EGC (0.67), but it was comparable to that independent of the H. pylori infection status in patients with RE alone or BE.. Preservation of gastric acid secretion may be important for the development of GE junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status.

Topics: Adenocarcinoma; Barrett Esophagus; Esophageal Neoplasms; Esophagitis, Peptic; Esophagogastric Junction; Female; Gastric Acid; Gastric Acidity Determination; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Prevalence; Stomach Neoplasms

Long-term administration of PPI causes hyperplastic changes of the gastric parietal cells; however, the detailed mechanism remains to be clarified. We administered high-dose omeprazole to patients with Barrett's esophagus for 2 years, and investigated changes in gastric ECL (Enterochromaffin-like) cells using endoscopic biopsy specimens to clarify the etiology of hyperplasia of the parietal cells.. The subjects were 69 patients who were diagnosed as having Barrett's esophagus (39 males, 30 females). We established two groups, an omeprazole-treated group and a ranitidine-treated group. Upper digestive tract endoscopy was performed before administration, and 12 and 24 months after the start of administration. Biopsy was performed in the greater curvature of the gastric body. The ECL/parietal cell counts and the grade of hyperplasia of the gastric mucosa were determined under a microscope. In addition, the fasting serum gastrin level was measured, and statistical analysis was performed.. In the omeprazole-treated group, the ECL cell count was markedly increased 12 months after the start of administration, but was lower than the pretreatment value 24 months after the start of administration. The parietal and ECL cell counts significantly increased. Furthermore, there were no changes in mucosa thickness. The fasting serum gastrin level significantly increased. In the ranitidine-treated group, there was no increase in the ECL cell count, and the parietal cell count was decreased. There was no significant increase in mucosa thickness. The fasting serum gastrin level increased, although the rate of increase was markedly smaller than that in the omeprazole-treated group.. Not the direct pharmacological actions of PPI but hypergastrinemia-associated secondary changes may be etiologically involved in hyperplasia of the parietal cells related to long-term administration of PPI.

Topics: Anti-Ulcer Agents; Barrett Esophagus; Cell Count; Dose-Response Relationship, Drug; Enterochromaffin Cells; Female; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Omeprazole; Parietal Cells, Gastric; Proton Pump Inhibitors; Time Factors

To examine whether the fasting levels of serum gastrin-17 (G-17) are lower in Barrett's esophagus (BE) patients than in non-Barrett controls.. Nineteen patients with BE (presenting with a tubular segment > or =2 cm long in lower esophagus and intestinal metaplasia of incomplete type ("pecialized columnar epithelium") in endoscopic biopsies from the tubular segment below the squamocolumnar junction were collected prospectively from outpatients referred to diagnostic gastroscopy. The controls comprised 199 prospectively collected dyspeptic outpatients without BE or any endoscopically visible lesions in the upper GI tract. Fasting levels of serum G-17 (G-17fast) were assayed with an EIA test using a mAb highly specific to amidated G-17. None of the patients and controls received therapy with PPIs or other antisecretory agents.. The mean and median levels of G-17fast in serum were significantly lower (P = 0.001) in BE patients than in controls. The positive likelihood ratios (LR+) of low G-17fast to predict BE in the whole study population at G-17fast levels <0.5, <1, or <1.5 pmol/L were 3.5, 3.0, and 2.8, respectively. Among patients and controls with healthy stomach mucosa, the LR+ were 5.6, 3.8, and 2.6, respectively. In the whole study population, serum G-17 was below 2 pmol/L in 15 of 19 BE patients (79%). The corresponding prevalence was 66 of 199 (33%) in controls (P<0.001). The G-17fast was 5 pmol/L or more in only one of the 19 BE patients (5%). In controls, 76 of the 199 patients (38%) had such high serum G-17fast levels (P<0.01).. Serum levels of G-17fast tend to be lower in native patients with BE than in healthy controls.

Topics: Aged; Barrett Esophagus; Case-Control Studies; Esophagoscopy; Female; Gastrins; Humans; Male; Middle Aged; Prospective Studies

Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Benzodiazepines; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagus; Gastrins; Hormone Antagonists; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Tumor Cells, Cultured

Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett's esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK(2)) receptor.. COX-2 and prostaglandin E(2) expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett's esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK(2) receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK(2) (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.. COX-2 expression is significantly increased in Barrett's esophagus before dysplasia development. Expression is highly variable within Barrett's dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett's esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E(2), and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398.. COX-2 is up-regulated early in the Barrett's metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK(2) receptor.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Benzodiazepines; Blotting, Western; Case-Control Studies; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Gastrins; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Longitudinal Studies; Male; Membrane Proteins; Middle Aged; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Cells, Cultured

The molecular mechanisms responsible for the progression of malignant transformation in Barrett's esophagus (BE) are still poorly understood. This study was undertaken (1) to investigate the gene and protein expression of cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor-gamma (PPARgamma), interleukin-8 (IL-8), hepatocyte growth factor (HGF), gastrin, and its receptor (CCK-2) in the Barrett's epithelium; (2) to analyze the activity of NFkappaB in Barrett's esophagus with low-grade dysplasia; and (3) to assess the effects of PPARgamma ligand (ciglitazone) and gastrin on cell proliferation in the cell line derived from esophageal adenocarcinoma (OE-33). COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expression levels relative to the control gene encoding GAPDH were analyzed by RT-PCR and Western blot in specimens of BE with low-grade dysplasia (n = 20) and compared with that in the normal squamous esophageal mucosa from the middle portion of the esophagus (n = 20). In vitro experiments included the incubation of cell line OE-33 with ciglitazone (1-15 microM) and gastrin (100 nM). NFkappaB activity in biopsies specimens was measured by highly sensitive ELISA. COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expressions were significantly increased in BE compared with normal squamous esophageal mucosa. NFkappaB activity was significantly upregulated in BE. Ciglitazone inhibited cell proliferation of OE-33 cells as assessed by BrdU and this effect was attenuated partly by gastrin. (1) COX-2, PPARgamma, HGF, gastrin, and its receptor are significantly upregulated in BE, suggesting a possible role for these factors in Barrett's carcinogenesis; (2) the increased NFkappaB activity is probably linked to increased IL-8 and COX-2 expression; and (3) PPARgamma ligands might be useful as a new therapeutic option in the prevention and treatment of Barrett's carcinoma.

Topics: Aged; Aged, 80 and over; Barrett Esophagus; Blotting, Western; Cyclooxygenase Inhibitors; Disease Progression; Esophageal Neoplasms; Female; Gastrins; Hepatocyte Growth Factor; Humans; Hypoglycemic Agents; Interleukin-8; Male; Middle Aged; Mucous Membrane; NF-kappa B; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Thiazolidinediones; Transcription Factors

Factors associated with the development and malignant progression of Barrett's esophagus are poorly understood. Gastrin is a mitogen capable of inducing growth in normal and malignant gastrointestinal mucosa. It is unknown whether gastrin can influence cellular events in the esophagus in Barrett's.. Reverse-transcription polymerase chain reaction (RT-PCR) and northern analysis for the cholecystokinin (CCK(2)) receptor were performed on normal, inflamed, metaplastic, and malignant esophageal mucosa. Real-time PCR quantified expression of the receptor. [(125)I]-G17-autoradiography localized the CCK(2) receptor in mucosal sections. [(3)H]-thymidine and bromodeoxyuridine (BrdU) incorporation determined proliferation in response to G17 in biopsy specimens incubated ex vivo. Proliferation and signaling studies were performed on OE33(E) cells transfected with the CCK(2) receptor.. RT-PCR identified receptor expression in 3 of 9 controls, 5 of 7 patients with esophagitis, 10 of 10 patients with Barrett's metaplasia, and 7 of 12 esophageal adenocarcinomas. Real-time PCR quantified expression in 10 patients with Barrett's showing a level of expression 2 orders of magnitude higher than in 12 control patients. [(125)I]-G17 bound to epithelia within glandular regions of Barrett's mucosa. Ten nmol/L G17 induced a 2-fold (n = 7, P = 0.0257, t test) increase in [(3)H]-thymidine incorporation in mucosal biopsy specimens, abolished by the addition of the CCK(2) receptor antagonist L-740, 093. One nmol/L G17 induced a 1.94- +/- 0.13-fold (n = 6, t test, P = 0.001) increase in [(3)H]-thymidine incorporation in OE33(E)(GR) cells, abolished by L-740, 093.. Gastrin induces proliferation via the CCK(2) receptor in Barrett's mucosa. This may have implications for the management of patients with Barrett's esophagus in whom gastrin is elevated by acid-suppression therapy.

Topics: Adult; Aged; Aged, 80 and over; Autoradiography; Barrett Esophagus; Binding, Competitive; Blotting, Northern; Cell Division; Computer Systems; Female; Gastric Mucosa; Gastrins; Humans; Iodine Radioisotopes; Male; Metaplasia; Middle Aged; Radioimmunoassay; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; Thymidine; Tumor Cells, Cultured

Topics: Barrett Esophagus; Esophageal Neoplasms; Gastrins; Gastroesophageal Reflux; Humans

Topics: Barrett Esophagus; Cell Division; Enzyme Inhibitors; Esophageal Neoplasms; Gastrins; Humans; Proton Pump Inhibitors; Receptor, Cholecystokinin B

Topics: Barrett Esophagus; Cell Division; Gastrins; Humans; Metaplasia; Receptor, Cholecystokinin B

The efficacy and safety of long-term acid suppression remains a subject for debate. We report data from patients with refractory reflux esophagitis who were undergoing maintenance therapy with >/=20 mg omeprazole daily for a mean period of 6.5 years (range, 1.4-11.2 years).. Patients with severe reflux esophagitis resistant to long-term therapy with H(2)-receptor antagonists and who were not eligible for surgery were evaluated at least annually for endoscopic relapse and histological changes in the gastric corpus.. In 230 patients (mean age, 63 years at entry; 36% were >/=70 years), there were 158 relapses of esophagitis during 1490 treatment years (1 per 9.4 years), with no significant difference in relapse rates between Helicobacter pylori-positive and -negative patients. All patients rehealed during continued therapy with omeprazole at the same or higher dose. The annual incidence of gastric corpus mucosal atrophy was 4.7% and 0.7% in H. pylori-positive and -negative patients, respectively, which was mainly observed in elderly patients who had moderate/severe gastritis at entry. In patients with baseline moderate/severe gastritis, the incidences were similar: 7.9% and 8.4%, respectively. Corpus intestinal metaplasia was rare, and no dysplasia or neoplasms were observed. The adverse event profile was as might be expected from this elderly group of patients.. Long-term omeprazole therapy (up to 11 years) is highly effective and safe for control of reflux esophagitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Barrett Esophagus; Child; Drug Resistance; Esophagitis; Female; Gastric Mucosa; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Humans; Hyperplasia; Male; Middle Aged; Omeprazole; Time Factors; Treatment Outcome

Topics: Anti-Ulcer Agents; Barrett Esophagus; Drug Administration Schedule; Esophageal Neoplasms; Esophagitis, Peptic; Fundoplication; Gastric Mucosa; Gastrins; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Humans; Omeprazole; Proton Pump Inhibitors; Time

Manifestations of esophageal disease are present in up to 60% of patients with Zollinger-Ellison syndrome (ZES), although esophageal function has been studied in only a few patients and the prevalence of Barrett's mucosa is unknown in these patients. It is unclear whether the high prevalence of esophageal disease is related to gastric acid hypersecretion alone or to abnormalities of esophageal motility or lower esophageal sphincter (LES) function in addition. To address these issues in the present study esophageal function was evaluated prospectively in 92 consecutive patients with ZES (66 with active disease, 26 disease-free after curative resection) seen during a 1-year period after controlling acid hypersecretion. In the patients with active disease the mean basal acid output (BAO) was 33 +/- 3.0 mEq/h, the maximal acid output (MAO) was 56 +/- 4.0 mEg/h, fasting serum gastrin was 8,736 +/- 4,813 pg/ml and duration of disease prior to study was 12.5 +/- 2.0 years. At the time of manometry, gastric acid secretion was controlled in all patients and no patient had evidence of gastroesophageal reflux disease at upper gastrointestinal endoscopy. Esophageal manometry revealed normal motility in 85% of patients. Eleven percent had low LES pressures, and only 1% of patients had an elevated LES pressure. The frequency of Barrett's mucosa (3%) was similar to that found in the general population but much less than that reported in patients with idiopathic GERD. No correlation was noted between LES pressures or manometric abnormalities and the fasting serum gastrin, BAO, MAO or the presence or absence of multiple endocrine neoplasia type I or previous vagotomy. Esophageal manometric results and LES pressure were similar in disease-free patients and those with active ZES. In conclusion, these results suggest that hypergastrinemia or other disease-specific abnormalities are not contributing to the high incidence of esophageal disease in patients with ZES because esophageal function in patients with ZES is similar to normals. Specifically, motility disorders in patients with ZES occur in similar frequency to normals, and LES pressure is normal in most patients. Despite the high levels of acid secretion and prominence of symptoms, the occurrence of Barrett's mucosa was uncommon (3%) raising the possibility of additional protective mechanisms in patients with ZES.

Topics: Adult; Aged; Barrett Esophagus; Biopsy; Endoscopy, Digestive System; Female; Follow-Up Studies; Gastric Acid; Gastrins; Humans; Male; Manometry; Middle Aged; Prospective Studies; Zollinger-Ellison Syndrome

To evaluate the long-term efficacy and safety of omeprazole in patients with gastroesophageal reflux disease resistant to treatment with histamine-2 (H2)-receptor antagonists.. Cohort analytic study with a mean follow-up of 48 months (range, 36 to 64 months).. Patients receiving ambulatory care from referral centers.. 91 patients with gastroesophageal reflux disease resistant to treatment with an H2-receptor antagonist but subsequently responsive to 40 mg of omeprazole daily.. Open maintenance therapy consisting of 20 mg of omeprazole daily in 86 patients and 40 mg daily in 5 patients.. Endoscopy to assess healing; side effects, laboratory values, fasting serum gastrin level, and gastric corpus biopsies to assess safety.. Esophagitis recurred in 47% of the patients receiving 20 mg of omeprazole daily, but all rehealed after the dose was doubled. Seven of 40 patients (18%) had a second relapse after a mean follow-up time of 24 months (range, 9 to 36 months) that was successfully treated with a further 20-mg dose increment for a mean period of 36 months (range, 6 to 39 months). Median gastrin levels increased initially from 60 ng/L before study entry to 162 ng/L (P < 0.01) with treatment and reached a plateau during maintenance treatment. Very high gastrin levels (> 500 ng/L) were observed in a subgroup (11%) of patients. The incidence of micronodular hyperplasia increased from 2.5% of the patients at first biopsy to 20% at the last biopsy (P = 0.001), with a corresponding progression of gastritis to subatrophic or atrophic gastritis from less than 1% to 25% (P < 0.001), which was more pronounced in patients with very high serum gastrin levels.. Maintenance therapy with omeprazole was effective for at least 5 years in patients with gastroesophageal reflux disease resistant to treatment with H2-receptor antagonists. Treatment was accompanied by a persistent increase in serum gastrin levels and an increase of micronodular argyrophil cell hyperplasia and subatrophic or atrophic gastritis.

Topics: Barrett Esophagus; Drug Resistance; Esophagitis, Peptic; Female; Gastrins; Gastroscopy; Humans; Life Tables; Male; Omeprazole; Time Factors; Treatment Outcome

Seventy-six patients with Barrett's esophagus were cared for during a 10-year period. Fifty-six patients (74%) presented with complications of the disease. There were 20 strictures, 7 giant ulcers, 11 cases of dysplasia, and 29 patients with carcinoma. In patients with benign disease, 93% had mechanically defective sphincters and 83% had peristaltic failure of the lower esophageal body. Esophageal pH monitoring showed excessive esophageal exposure to pH less than 4 in 93% and excessive exposure to pH more than 7 in 34% of the patients tested. Ninety-three per cent of patients with excessive alkaline exposure had complications, compared to only 44% with normal alkaline exposure (p less than 0.01). Gastric pH monitoring, serum gastrin levels, and gastric acid analysis supported a duodenal source for the alkaline exposure. Antireflux surgery was performed using Nissen fundoplication in 30, Belsey partial fundoplication in 3, and Collis-Belsey gastroplasty in 2. Six required resection with colon interposition. Good symptomatic control was achieved in 77% after antireflux surgery. Four patients had symptoms and signs of duodenogastric reflux; three required a bile diversion procedure. Fifteen patients had an en bloc curative resection with colon interposition. One patient with high-grade dysplasia on biopsy was found to have intramucosal carcinoma after simple esophagectomy. Five tumors were intramucosal, seven were intramural, and four were transmural. Lymph node involvement occurred only in the latter two. Actuarial survival 5 years after curative resection was 53%. Median survival time for patients after palliative resection or no resection was 12 months. Study of en bloc specimens indicated that extent of resection should be adapted to extent of disease: esophagectomy for intramucosal disease, en bloc esophagectomy with splenic preservation for intramural and transmural disease. Serum CEA was useful in detecting recurrent disease after surgery when the primary tumor stained positively for CEA.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Carcinoembryonic Antigen; Esophageal Neoplasms; Female; Gastric Acid; Gastric Emptying; Gastrins; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Monitoring, Physiologic; Survival Rate

Gastric acid secretion in response to a protein meal and to exogenously administered synthetic human gastrin 17-I was measured in patients with Barrett's esophagus, patients with uncomplicated gastroesophageal reflux, and normal age- and sex-matched controls. Acid secretion, both basally and in response to gastrin 17-I, was significantly greater in patients with Barrett's esophagus compared to normal individuals without reflux. Basal gastrin levels and meal-stimulated levels of the hormone were similar among all three groups. Sensitivity to gastrin, expressed as the concentration causing half-maximal acid secretion, was also similar among the study groups. It is speculated that elevated basal acid production in Barrett's esophagus may contribute to the pathogenesis of the disorder.

Topics: Barrett Esophagus; Chronic Disease; Cimetidine; Female; Gastric Acid; Gastric Acidity Determination; Gastrins; Gastroesophageal Reflux; Humans; Male; Middle Aged; Monitoring, Physiologic; N-Methylscopolamine; Parasympatholytics; Scopolamine Derivatives

Barrett's epithelium refers to the presence of ectopic mucosal types in the squamous-lined oesophagus. Previous studies have documented argentaffin and argyrophil-positive cells as well as gastrin-like immunoreactivity in oesophageal tissue extracts from patients with Barrett's mucosa. In the present study, 125 oesophageal biopsies obtained under direct vision at endoscopy from 22 patients with Barrett's oesophagus were systematically studied using fluorescence and peroxidase antiperoxidase single and double-staining immunocytochemical methods employing highly specific antibodies to localize the following peptide-containing cell types in Barrett's mucosa: gastrin, somatostatin, gastric inhibitory polypeptide, motilin, neurotensin and pancreatic glucagon. In addition, EC cells were localized using a cytochemical silver staining method. The results of this study indicate that EC cells and gastrin- and somatostatin-containing endocrine cells are detectable in Barrett's epithelium.

Topics: Adolescent; Adult; Aged; Barrett Esophagus; Enterochromaffin Cells; Esophageal Diseases; Esophagus; Female; Gastric Inhibitory Polypeptide; Gastrins; Glucagon; Humans; Immunoenzyme Techniques; Male; Middle Aged; Motilin; Neurotensin; Peptides; Somatostatin

We present the patterns for the diagnosis, checking the clinical, radiological, endoscopical and histological data of 35 patients suffering from Barrett's Esophagus (BE) (columnar metaplasia lining the lower esophagus). The clinical characteristics are those of a severe esophagitis of long evolution, although metaplasia itself is asymptomatic, and its features depend on the inflammation degree. Radiology can bring out some data as GE reflux, hiatal hernia, ulcers or stricture, and perhaps double contrast may show any sign by means of which endobrachyesophagus (EBE) can be suspected. Endoscopy provides us with accurate data about EBE, ulcers, stricture and inflammation. Histology reveals the type of columnar metaplasia (junctional or cardial, gastric fundic, intestinal or specialized, or composite). Acquired or congenital etiology can be clarified by an immunohistochemical method, Peroxidase anti-Peroxidase (PAP), showing the presence of gastrin secretory cells (G cells) in the congenital cases.

Topics: Adult; Aged; Barrett Esophagus; Chromaffin System; Enterochromaffin Cells; Esophageal Diseases; Esophagoscopy; Esophagus; Female; Gastrins; Humans; Male; Middle Aged; Radiography