Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric carcinoma is thought to develop via the actions of inducers and promoters of carcinogenesis. Tryptophan in charred fish or animal meat, ultraviolet rays, and irradiation, which damage genes of normal cells, have long been regarded as inducers of carcinoma, and agents such as alcohol, tobacco, aflatoxin, and nitrosoamine as promoters, with tobacco having both activities. The interaction between these environmental factors, principally diet, and Helicobacter pylori (Hp) is important in the genesis of gastric carcinoma. In this report, the histopathological feature of the Hp gastritis-carcinoma sequence is outlined, and the pathological characteristics of gastroesophageal reflux disease (GERD) and endoscopically negative reflux disease (ENRD) and the risk factors for lower esophageal carcinoma after Hp eradicated status in particular are discussed regarding aspects of cell cycle-associated factors. We conclude that (1) Infection with Hp increases the risk of gastric cancer in two histological phenotypes (i.e., diffuse undifferentiated type and intestinal differentiated type). Excessive cell replication and interrupting the mucus secretion mechanism may result in a large proportion of cells with genetic abnormalities. (2) Genetic alterations in gastric carcinogenesis may differ from those in colonic carcinogenesis. (3) The degree of GERD in Japanese patients is milder than that in patients from Western countries, although the incidence of GERD increases the status after successful eradication of Hp. It is also possible that accumulation of genetic abnormalities increases the number of cardiac and lower esophageal cancers. Investigation of cell cycle factors in GERD including ENRD can be expected to reveal the risk of carcinogenesis.
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PMID:Pathological issues of gastric and lower esophageal cancer: helicobacter pylori infection and its eradication. 1210 62

Helicobacter pylori infection is recognized to be a pathogen of various gastroduodenal disease. Eradication therapy of H. pylori reduces the recurrence of gastro-duodenal ulcer, improves histological gastritis, and is suggested to act a certain role in protection against gastric carcinogenesis. Although, several studies show uncomfortable results arise after H. pylori infection was cured. These studies suggest that gastro-esophageal reflux disease (GERD) and gastro-duodenal erosion may increase after successful eradication of H. pylori. Recently, adenocarcinoma of the gastric cardia and esophagus increase in incidence. Reflux esophagitis and Barrett's esophagus are recognized as precancerous lesion of esophageal adenocarcinoma. It is uncertain the association of newly occurrence of GERD after H. pylori eradication and increase of esophageal adenocarcinoma. GERD may cause adenocarcinoma development, though long term observations is necessary after H. pylori eradication.
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PMID:[Occurrence of upper gastrointestinal tract disease after Helicobacter pylori eradication]. 1218 64

The literature for the proliferative effect of bile acids on the GI tract has been reviewed and three hypotheses developed regarding their carcinogenicity. Considered as a unit, the GI tract is protected from this carcinogenicity in different ways in the esophagus, stomach, small bowel and colon. Uncharged BAs can enter the esophageal epithelial cells by reflux of gastroduodenal juices in humans, and in animals by surgical alteration of the GI tract or by adding bile concentrate to the diets, and this can initiate GERD and eventually cancer. Acid suppressant therapy used to treat GERD patients, converts stomach pH to >4. This will remove the charges on conjugated bile acids allowing them entry into the epithelium thus casting doubt on the efficacy of acid suppression. From these observations, we postulate that (a) uncharged BA in daily contact with the esophagus can cause GERD and eventually cancer. This might explain the cancers obtained by Fein et al. (b) Clinical trials designed to test the effectiveness of acid suppressants will be meaningless since up to approximately 87% of these patients (in one study) have bile in their refluxate, and this, combined with acid suppressants, will initiate carcinogenesis. (c) Bile reaching a colon made sterile by antibiotics or other means, will not be deconjugated and so, with pKa's of 2 and 4, will be uncharged and therefore can easily enter the colonic cells where the pH is >6. This should be of some concern, especially on a high-fat diet when more bile enters the colon. A group of physicians noted that approximately 47% of patients with esophageal cancers also had some form of colon cancer and postulated that an etiological factor in the environment was responsible. Could this factor be bile? Reactions of certain bile salts with epithelial cells suggest a useful role for them in chemotherapy. Experiments to test hypotheses a, b and c are presented in the addendum.
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PMID:Three hypotheses linking bile to carcinogenesis in the gastrointestinal tract: certain bile salts have properties that may be used to complement chemotherapy. 1220 78

Gastroesophageal reflux (GER) has been strongly associated with carcinogenesis of the lower esophagus and development of several otolaryngologic disorders. Epidemiologic studies support concept that the malignant transformation of laryngeal mucosal surfaces is due to GER-initiated chronic laryngeal inflammation. However, large clinical studies with matched control groups and further experimental investigations are necessary to ascertain the relationship between reflux and laryngeal carcinoma. This review stresses that early diagnosis of GER disease, based on clinical suspicion, ambulatory 24-hour double-probe pH monitoring, and endoscopic examination, as well as effective treatment of reflux, are considered the keys for relief of symptomatology and preventing the chronic irritation of the laryngeal mucosa that may contribute to the development of laryngeal carcinoma.
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PMID:The role of gastroesophageal reflux in the pathogenesis of laryngeal carcinoma. 1243 Jan 27

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and alpha-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.
Carcinogenesis 2002 Dec
PMID:Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylornithine on tumorigenesis in a rat surgical model. 1250 33

The natural history of metaplasia and dysplasia in Barrett esophagus is not well defined. Publication bias, the selective reporting of studies that have positive or extreme results, has exaggerated the risk of esophageal adenocarcinoma in this condition. Recent data suggest that patients with Barrett esophagus develop these tumors at the rate of 0.5% per year, a cancer incidence considerably lower than was appreciated just a few years ago. Indirect evidence suggests that aggressive treatment of gastroesophageal reflux might decrease the risk of carcinogenesis, but no therapy yet has been proved to decrease the incidence of cancer in Barrett esophagus. Dysplasia in the metaplastic epithelium clearly is a worrisome finding, but the progression from dysplasia to cancer may take years and may not be inevitable.
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PMID:The natural history of dysplasia and cancer in esophagitis and Barrett esophagus. 1270 59

Barrett's esophagus (BE), a premalignant lesion to esophageal adenocarcinoma is associated with long-standing, gastroesophageal reflux disease (GERD). BE is a multi-phase process: during the initiation phase, genetically predisposed individuals (mostly white men) suffering from clinical or occult reflux damage their distal esophagus and form a new cell phenotype (incomplete intestinal metaplasia). During the formation phase, this phenotype occupies an area of variable surface (short or long-segment BE). During the progression phase, the metaplastic epithelium either remains dormant or progresses to dysplasia and adenocarcinoma. We review the recent clinical and basic research literature that explores the interaction of the refluxate (acid, bile, etc.) with BE. Acid and bile reflux variably affect BE and may cause dysplasia or adenocarcinoma. Regardless of the underlying biology, a patient with BE may suffer from GERD symptoms or may remain asymptomatic. Acid may be synergistic to bile or it could be antagonistic and protective. Acid suppressive therapy, if profound and continuous enough to abolish symptoms and esophageal acid exposure, may decrease proliferation, increase differentiation and reduce BE surface. Overexpression of cyclooxygenase-2 (COX-2), not entirely independent of acid/bile reflux, may increase proliferation and increase the invasiveness and metastatic potential of Barrett's metaplasia and neoplasia. Clinically, both acid and bile reflux need to be inhibited, either with potent acid-suppressing drugs or anti-reflux surgery. Cyclooxygenase inhibition using aspirin, NSAIDs or the safer COX-2 inhibitors added to these anti-reflux therapies may enhance the therapeutic benefit. Many questions remain unanswered. We still do not know why only a fraction of patients with GERD develop BE, what factors of the refluxate (acid, bile, etc.) initiate metaplasia and/or promote carcinogenesis, which patients are at risk for malignancy, and what is the best chemopreventive strategy. Ablation therapies and endoscopic mucosal resection are still under study.
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PMID:Management of Barrett's esophagus with and without dysplasia. 1279 81

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H(2) blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.
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PMID:Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections. 1290 57

From a clinical and biological point of view, the term "adenocarcinoma of the esophagogastric junction" (AEG) encompasses several distinct tumor entities. The topographic anatomic classification into adenocarcinoma of the distal esophagus (AEG I), true carcinoma of the cardia (AEG II), and subcardiac gastric cancer (AEG III) also reflects differences regarding the pathogenesis of these tumors and is increasingly accepted worldwide. Associated Barrett's esophagus, which usually develops as a consequence of chronic gastroesophageal reflux, can be documented in practically all patients with AEG I tumors and constitutes the most important precancerous lesion. A metaplasia-dysplasia-carcinoma sequence has been confirmed for these tumors. Barrett's esophagus is thus considered a model for studies on carcinogenesis and the prevention of esophageal adenocarcinoma. Its pathogenetic role in AEG II and III tumors must, however, be discussed differently. Our own experience shows that pathogenetic mechanisms similar to those in AEG I tumors may be present in up to 30% of tumors classified as AEG II. The majority of AEG II tumors, however, show morphologic, biologic and pathogenetic similarities with AEG III tumors and proximal gastric cancer.
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PMID:[Carcinoma of the oesophagogastric junction and Barrett's esophagus: an almost clear oncologic model?]. 1292 90

Abnormal gastro-oesophageal reflux and bile acids have been linked to the presence of Barrett's oesophageal premalignant lesion associated with an increase in mucin-producing goblet cells and MUC4 mucin gene overexpression. However, the molecular mechanisms underlying the regulation of MUC4 by bile acids are unknown. Since total bile is a complex mixture, we undertook to identify which bile acids are responsible for MUC4 up-regulation by using a wide panel of bile acids and their conjugates. MUC4 apomucin expression was studied by immunohistochemistry both in patient biopsies and OE33 oesophageal cancer cell line. MUC4 mRNA levels and promoter regulation were studied by reverse transcriptase-PCR and transient transfection assays respectively. We show that among the bile acids tested, taurocholic, taurodeoxycholic, taurochenodeoxycholic and glycocholic acids and sodium glycocholate are strong activators of MUC4 expression and that this regulation occurs at the transcriptional level. By using specific pharmacological inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase A and protein kinase C, we demonstrate that bile acid-mediated up-regulation of MUC4 is promoter-specific and mainly involves activation of phosphatidylinositol 3-kinase. This new mechanism of regulation of MUC4 mucin gene points out an important role for bile acids as key molecules in targeting MUC4 overexpression in early stages of oesophageal carcinogenesis.
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PMID:Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway. 1458 90


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