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Objective: An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ., Design: Clinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised., Results: Twenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial ( Helicobacter pylori ) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett's oesophagus (BO)., Conclusions: This international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ., Competing Interests: Competing interests: KS serves as an advisor for Fujifilm Medical Co. and received a lecture fee from Fujifilm Medical Co. MF received lecture fee from Olympus Medical Systems Co. and Fujifilm Medical Co. He also received research grant from Olympus Medical Systems Co, Fujifilm Medical Co. and HOYA Pentax Co. HI serves as an advisor for Olympus Medical Systems Co. HM received a lecture fee from Fujifilm Medical Co. GT and HT received lecture fees from Olympus Medical Co. and Fujifilm Medical Co. Other authors have declared no competing interests regarding this manuscript, (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Chronic gastro-oesophageal reflux might lead to the development of Barrett's oesophagus (BO) or even oesophageal adenocarcinoma. There has been no definitive systematic review and meta-analysis of data to estimate global prevalence of BO or oesophageal adenocarcinoma in individuals with gastro-oesophageal reflux., Design: We searched MEDLINE, Embase and Embase Classic to identify cross-sectional surveys that reported prevalence of BO or oesophageal adenocarcinoma in adults with gastro-oesophageal reflux. We extracted prevalence for all studies, both for endoscopically suspected and histologically confirmed cases. We calculated pooled prevalence according to study location, symptom frequency and sex, as well as ORs with 95% CIs., Results: Of the 4963 citations evaluated, 44 reported prevalence of endoscopically suspected and/or histologically confirmed BO. Prevalence of BO among individuals with gastro-oesophageal reflux varied according to different geographical regions ranging from 3% to 14% for histologically confirmed BO with a pooled prevalence of 7.2% (95% CI 5.4% to 9.3%), whereas pooled prevalence for endoscopically suspected BO was 12.0% (95% CI 5.5% to 20.3%). There was heterogeneity in many of our analyses. Prevalence of BO was significantly higher in men, both for endoscopically suspected (OR=2.1; 95% CI 1.6 to 2.8) and histologically confirmed BO (OR=2.3; 95% CI 1.7 to 3.2). Dysplasia was present in 13.9% (95% CI 8.9% to 19.8%) of cases of histologically confirmed BO, 80.7% of which was low-grade., Conclusion: The prevalence of Barrett's oesophagus among individuals with gastro-oesophageal reflux varied strikingly among countries, broadly resembling the geographical distribution of gastro-oesophageal reflux itself. Prevalence of BO was significantly higher in men., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype., Design: Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation., Results: In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets., Conclusions: In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Abdominal obesity has been associated with increased risk of Barrett's oesophagus (BE) but the underlying mechanism is unclear. We examined the association between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and the risk of BE., Design: A case-control study among eligible patients scheduled for elective oesophagastroduodenoscopy (EGD) and in a sample of patients eligible for screening colonoscopy recruited at the primary care clinic. All cases with definitive BE and a random sample of controls without BE were invited to undergo standardised mid-abdomen non-contrast computerised axial tomography images, which were analysed by semiautomated image segmentation software. The effect of VAT and SAT surface areas and their ratio (VAT to SAT) on BE were analysed in logistic regression models., Results: A total of 173 BE cases, 343 colonoscopy controls and 172 endoscopy controls underwent study EGD and CT scan. Participants with BE were more than twice as likely to be in the highest tertile of VAT to SAT ratio (OR: 2.42 (1.51 to 3.88) and adjusted OR 1.47 (0.88 to 2.45)) than colonoscopy controls, especially for those long (≥3 cm) segment BE (3.42 (1.67 to 7.01) and adjusted OR 1.93 (0.92 to 4.09)) and for white men (adjusted OR 2.12 (1.15 to 3.90)). Adjustment for gastroesophageal reflux disease (GERD) symptoms and proton pump inhibitors (PPI) use attenuated this association, but there was a significant increase in BE risk even in the absence of GERD or PPI use., Conclusions: Large amount of visceral abdominal fat relative to subcutaneous fat is associated with a significant increase in the risk of BE. GERD may mediate some but not all of this association.

Objective: Abdominal obesity has been associated with erosive oesophagitis (EO) and Barrett's oesophagus (BO). As gluteofemoral obesity protects against diabetes mellitus and cardiovascular disease, we hypothesised that gluteofemoral obesity would be inversely associated with EO and BO., Design: We conducted a cross-sectional study on 822 male colorectal cancer screenees who were recruited to also undergo upper endoscopy. An additional 80 patients with BO clinically detected by upper endoscopy referred for clinical indications were recruited shortly after their diagnoses of BO. Logistic regression was used to estimate the effects of abdominal obesity (waist circumference), gluteofemoral obesity (hip circumference) and waist-to-hip ratio (WHR) on EO and BO (vs neither condition)., Results: There were 225 cases of either BO or EO and 675 controls. After adjustment for potential confounders, a positive association was observed between waist circumference and BO and/or EO, which became stronger with further adjustment for hip circumference. In contrast, hip circumference was inversely associated with BO and/or EO. Compared with the lowest quartile of WHR, the adjusted ORs were 1.32 (95% CI 0.747 to 2.33) for the 2nd quartile, 1.54 (95% CI 0.898 to 2.63) for the 3rd quartile, and 2.68 (95% CI 1.57 to 4.55) for the highest quartile. Similar results were obtained for BO and EO treated as separate outcomes., Conclusions: In a population of older, mostly overweight men, the distribution of obesity is associated with the presence of EO and BO. Abdominal obesity appears to increase the risk of these outcomes, whereas gluteofemoral obesity may be protective.

Objective: Barrett's oesophagus is a precursor lesion of oesophageal adenocarcinoma, a cancer that, in the USA, has increased in incidence over 600% during the past 40 years. Barrett's oesophagus and oesophageal adenocarcinoma are much more common among men than among women; this finding is unexplained and most earlier studies lacked sufficient numbers of women to evaluate sex-specific risk factors. We leveraged the power of an international consortium to assess sex-specific relationships between body mass index (BMI), abdominal circumference and Barrett's oesophagus., Design: Four case-control studies provided a total of 1102 cases (316 women, 786 men) and 1400 population controls (436 women, 964 men) for analysis. Study-specific estimates, generated using individual participant data, were combined using random effects meta-analysis., Results: Waist circumference was significantly associated with Barrett's oesophagus, even after adjustment for BMI; persons in the highest versus the lowest quartiles of waist circumference had approximately 125% and 275% increases in the odds of Barrett's oesophagus among men and women, respectively (OR 2.24, 95% CI 1.08 to 4.65, I(2)=57; OR 3.75, 95% CI 1.47 to 9.56, I(2)=0). In contrast, there was no evidence of a significant association between BMI and the risk of Barrett's oesophagus, with or without adjustment for waist circumference., Conclusions: Waist circumference, independent of BMI, was found to be a risk factor for Barrett's oesophagus among both men and women. Future studies examining the biological mechanisms of this association will extend our knowledge regarding the pathogenesis of Barrett's oesophagus.

Background: It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett's oesophagus (BO) has not been well examined., Methods: Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n = 135), GORD (n = 135) and screening colonoscopy (n = 932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO., Results: Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79)., Conclusions: These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.

Objective: Barrett's oesophagus is associated with abdominal obesity. Adiponectin is a peptide that is secreted from adipocytes and circulates in three multimeric forms: low molecular weight (LMW), middle molecular weight (MMW), and high molecular weight (HMW). The anti-inflammatory effects of adiponectin are specific to individual multimers, with LMW being most anti-inflammatory. We postulated that circulating levels of adiponectin and its multimers would be associated with the risk of Barrett's oesophagus., Design: Cross-sectional study., Setting: Outpatient clinic in North Carolina, USA., Patients: Cases of Barrett's oesophagus and controls undergoing upper endoscopy for gastro-oesophageal reflux disease (GORD)., Main Outcome Measures: Adjusted odds ratios of plasma adiponectin levels and its multimers for Barrett's oesophagus., Results: There were 112 cases of Barrett's oesophagus and 199 GORD controls. Total adiponectin was not associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile adjusted odds ratio (aOR) = 0.88; 95% confidence interval (CI) = 0.44 to 1.78). High levels of LMW adiponectin were associated with a decreased risk of Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.33; 95% CI, 0.16 to 0.69), and a high LMW/total ratio appeared particularly inversely associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.27; 95% CI, 0.13 to 0.58)., Conclusions: High levels of LMW adiponectin are associated with a decreased risk of Barrett's oesophagus among patients with GORD. Further human studies are required to confirm these findings, and in vitro studies are needed to understand if there is a mechanism whereby adiponectin may affect Barrett's metaplasia.

Objective: Excess body mass is associated with symptoms of gastro-oesophageal reflux disease, and cross-sectional studies suggest an association between body mass index (BMI) and Barrett's oesophagus. The present study sought prospectively to examine the influence of BMI and other anthropomorphic measures on the risk for Barrett's oesophagus among women., Methods: This was a prospective study of 15 861 women who participated in the Nurses' Health Study, without a history of cancer, who underwent upper gastrointestinal endoscopy for any reason between 1986 and 2004. The main outcome measures were 261 cases of pathologically confirmed specialised intestinal metaplasia within the oesophagus (Barrett's oesophagus). Self-reported data on weight were collected from biennial questionnaires. Self-reported height was collected in 1976, and self-reported waist and hip circumferences were collected in 1986., Results: Compared with women with a BMI of 20-24.9 kg/m(2), women with a BMI of 25-29.9 had a multivariate OR for Barrett's oesophagus of 0.92 (95% CI 0.66 to 1.27), women with a BMI > or =30 had a multivariate OR of 1.52 (95% CI 1.02 to 2.28) and women with a BMI <20 had a multivariate OR of 0.92 (95% CI 0.65 to 1.31). Results were similar when controlling for symptoms of gastro-oesophageal reflux, and among the entire Nurses' Health Study cohort (n = 93 609) regardless of a history of endoscopy. In contrast, waist-to-hip ratio, waist circumference and height did not appear to be associated with Barrett's oesophagus., Conclusions: Obese, but not overweight, women appear to be at increased risk for Barrett's oesophagus.

Background: Exposure to acid and duodeno-gastro-oesophageal reflux (DGOR) both increase with oesophageal lesions in gastro-oesophageal reflux disease (GORD). It is unknown whether DGOR exposure is an independent risk factor for oesophageal lesions. A multivariate analysis was performed on the relationship between oesophageal lesions and demographics and acid and DGOR exposure., Methods: In 422 patients with suspected GORD, upper endoscopy, oesophageal manometry, and pH and DGOR monitoring were performed. Stepwise logistic regression was used to identify factors associated with the presence of oesophagitis, severity of oesophagitis and the presence of Barrett's oesophagus. ORs and 95% CIs were computed at different cut-offs., Results: 54% of the patients had no oesophagitis, 36% had grade A-B oesophagitis, 3% had grade C-D oesophagitis and 7% had Barrett's oesophagus. In multivariate analysis, oesophagitis was associated with hiatal hernia (OR 3.621, 95% CI 2.263 to 5.794) and DGOR exposure (OR up to 2.236, 95% CI 1.356-3.685), while a low body mass index (BMI) seemed protective (OR for BMI >first quartile 2.245, 95% CI 1.371 to 3.677). Severity of oesophagitis was only associated with acid exposure (OR up to 5.038, 95% CI 1.452 to 17.480). The presence of Barrett's oesophagus was associated with male sex (OR 3.621, 95% CI 2.263 to 5.794), DGOR (OR up to 5.017, 95% CI 2.051 to 12.274) and acid exposure (OR up to 3.031, 95% CI 1.216 to 7.556)., Conclusions: Several independent factors are associated with oesophageal lesions in GORD. The risk of oesophagitis is associated with hiatal hernia, BMI and DGOR exposure; severity of oesophagitis depends on acid exposure; and Barrett's oesophagus is associated with male sex and exposure to both acid and DGOR.

Background: Obesity is associated with increased risks of Barrett's oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis; however, the relationship with Barrett's oesophagus remains unexplored., Methods: Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case-control study conducted in Brisbane, Australia. Cases were people aged 18-79 years with histologically confirmed Barrett's oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis., Results: In the pilot analysis (51 cases, 67 controls) risks of Barrett's oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett's oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett's oesophagus among women decreased with increasing serum leptin concentrations., Conclusions: High serum leptin is associated with an increased risk of Barrett's oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.

Background: Gastro-oesophageal reflux disease complications may reflect imbalances between protective and injurious factors. Through its effects on cell growth, leptin may influence oesophageal mucosal homeostasis., Aims: To determine whether leptin receptors are present in the oesophagus, and whether serum or gastric leptin levels are associated with oesophageal inflammation and metaplasia., Methods: From patients referred for upper endoscopy, biopsies were obtained from the stomach and distal oesophagus, and serum samples were collected. Patients were classified as having normal, inflamed or Barrett's oesophagus. Quantitative immunohistochemistry was performed on representative sections, and leptin levels in plasma and gastric biopsy samples were determined by specific immunoassay., Results: Of 269 individuals enrolled, 105 were Helicobacter pylori-negative. Of the 88 patients with complete oesophageal biopsies, 44 were normal, 24 were inflamed and 20 were Barrett's oesophagus. Receptors for leptin were highly expressed on oesophageal epithelial cells, with similar density and staining pattern in all three conditions, and plasma and antral leptin levels did not differ significantly. Patients with Barrett's had significantly (p = 0.01) higher fundic leptin levels (median 202 (interquartile range 123-333) pg/mg) compared with normal (126 (78-221) pg/mg) or inflamed (114 (76-195) pg/mg) oesophagus. In multivariate analysis, for every twofold increase in fundic leptin, the odds of having Barrett's was 3.4 times (95% CI 1.5 to 7.6) higher compared with having a normal oesophagus., Conclusions: Leptin receptor expression on oesophageal epithelial cells provides a pathway for leptin-mediated signal transduction. Variation in gastric leptin production could contribute to differential oesophageal healing and metaplasia progression.

Objectives: Bile reflux contributes to oesophageal injury and neoplasia. COX-2 is involved in both inflammation and carcinogenesis; however, the precise mechanisms by which bile acids promote COX-2 expression in the oesophagus are largely unknown. We analysed the molecular mechanisms that govern bile acid-mediated expression of COX-2 in Barrett's oesophagus and oesophageal adenocarcinoma (OA)., Design: The effects of bile acids on COX-2 expression were analysed in immortalised Barrett's oesophagus and OA cells using immunoblotting and transient transfections. Pharmacological inhibitors, phospho-specific antibodies, dominant-negative mutants and siRNA techniques were used to identify relevant signalling pathways. Flow cytometry and reactive oxygen species (ROS) scavengers were used to examine ROS involvement. Immunohistochemistry was performed on oesophageal mucosa obtained from an established rat model of bile reflux., Results: Unconjugated bile acids potently stimulated COX-2 expression and induced AKT and ERK1/2 phosphorylation in concert with COX-2 induction. These findings were mimicked in the in vivo rat model. Dominant-negative (DN) AKT and LY294002 (PI3K inhibitor) or U0126 (MEK-1/2 inhibitor) blocked chenodeoxycholic acid (CD) and deoxycholic acid (DC) mediated COX-2 induction. CD and DC also induced CREB phosphorylation and AP-1 activity. CREB-specific siRNA and DN AP-1 blocked CD and DC-induced COX-2 induction. Finally, CD and DC increased intracellular ROS, while ROS scavengers blocked COX-2 induction and the signalling pathways involved., Conclusions: Unconjugated bile acids induce CREB and AP-1-dependent COX-2 expression in Barrett's oesophagus and OA through ROS-mediated activation of PI3K/AKT and ERK1/2. This study enhances our understanding of the molecular mechanisms by which bile acids promote the development of oesophageal adenocarcinoma.

Background and Aims: When saliva, with its high nitrite content derived from the enterosalivary recirculation of dietary nitrate, meets acidic gastric juice, the nitrite is converted to nitrous acid, nitrosative species, and nitric oxide. In healthy volunteers this potentially mutagenic chemistry is focused at the gastric cardia. We have studied the location of this luminal chemistry in Barrett's patients during acid reflux., Methods: Ten Barrett's patients were studied before and after administration of 2 mmol nitrate. Using microdialysis probes we measured nitrite, ascorbic acid, total vitamin C, and thiocyanate concentrations and pH simultaneously in the proximal oesophagus, Barrett's segment, hiatal sac, proximal stomach, and distal stomach. In a subgroup, real time nitric oxide concentrations were also measured., Results: During acid reflux, Barrett's segment was the anatomical site with maximal potential for acid catalysed nitrosation, with its median concentration of nitrite exceeding that of ascorbic acid in two of 10 subjects before nitrate and in four of nine after nitrate. Thiocyanate, which catalyses acid nitrosation, was abundant at all anatomical sites. On entering the acidic Barrett's segment, there was a substantial fall in nitrite and the lowest ascorbic acid to total vitamin C ratio, indicative of reduction of salivary nitrite to nitric oxide at this anatomical site. Episodes of acid reflux were observed to generate nitric oxide concentrations of up to 60 muM within the Barrett's segment., Conclusion: The interaction between acidic gastric refluxate and nitrite rich saliva activates potentially mutagenic luminal nitrosative chemistry within Barrett's oesophagus.

Background: Adequacy of acid suppression is a critical factor influencing healing in gastro-oesophageal reflux disease (GORD). The European prospective study ProGORD was set up to determine the endoscopic and symptomatic progression of GORD over five years under routine care, after initial acid suppression with esomeprazole. We report on factors influencing endoscopic healing and symptom resolution during the acute treatment phase., Methods: Patients with symptoms suggestive of GORD underwent endoscopy and biopsies were obtained from the oesophagus for diagnosis of abnormalities, including Barrett's oesophagus (BO). Data from 6215 patients were included in the "intention to treat" analysis, 3245 diagnosed as having erosive reflux disease (ERD) and 2970 non-erosive reflux disease (NERD). ERD patients were treated with esomeprazole 40 mg for 4-8 weeks for endoscopic healing while NERD patients received 20 mg for 2-4 weeks for resolution of heartburn symptoms., Results: Endoscopic healing occurred overall in 87.7% of ERD patients although healing was significantly lower in those with more severe oesophagitis (76.9%) and in those with BO (72.4%), particularly in Helicobacter pylori negative BO patients (70.1%). Age, sex, and body mass index appeared to have no significant impact on healing. Complete heartburn resolution was reported by 70.4% of ERD patients and by 64.8% of NERD patients at the last visit. Only H pylori infection had a significant influence on complete heartburn resolution in the NERD group (68.1% and 63.7% for H pylori positive and H pylori negative, respectively; p = 0.03)., Conclusion: The presence of Barrett's mucosa, as well as severe mucosal damage, exerts a negative impact on healing. H pylori infection had a positive influence on healing in ERD patients with coexistent BO but no influence on those without BO.

There has been no published indepth systematic evaluation of the best approaches to symptom evaluation in gastro-oesophageal reflux disease (GORD). A two day international multidisciplinary workshop was therefore held in Marrakech, Morocco, in September 2002 to address these issues. The aim of the workshop was to critically review the data regarding the reliability, processes, and priorities for symptom evaluation in GORD patients. The workshop was designed to give outputs that could be readily reported and to arrive at specific recommendations on best practice in symptom evaluation in reflux disease.

Background and Aim: It is known that bile acids can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis. A large body of genetic and biochemical evidence indicate that the biosynthetic pathway of prostaglandin E2 (PGE2) may play an important role in human and rodent tumours. Therefore, we examined the expression pattern of cyclooxygenase 1 (COX-1), COX-2, and microsomal prostaglandin E synthase 1 (mPGES-1), as well as EP receptor subtypes in rat oesophageal lesions induced by duodenal contents reflux., Methods: Oesophagoduodenal anastomosis was performed in rats to induce duodenal contents reflux. We examined histological changes and expression of COX-1, COX-2, mPGES-1, and EP receptor subtypes in the oesophagus by immunohistochemistry and reverse transcription-polymerase chain reaction., Results: Normal control oesophageal tissues showed COX-1 expression in subepithelial stromal cells, including endothelial cells and muscular cells, and did not reveal expression of COX-2 or mPGES-1. In the case of squamous cell lesions, immunoreactivity of COX-1 was similar to that of normal lesions, and COX-2 was maximally expressed around the vascular papillae of tissues showing dysplasia and surrounding epithelial layer and basal layer. mPGES-1 was highly expressed in stromal cells with COX-2 expression. In the case of Barrett's oesophagus, COX-2 and mPGES-1 were predominantly in subepithelial stromal cells. mRNA levels of COX-2, mPGES-1, EP2, EP3, and EP4 were higher in the experimental groups than in controls., Conclusions: We suggest that the biosynthetic pathway of PGE2 may play an important role in oesophageal squamous cell dysplasia and glandular metaplasia induced by duodenal contents reflux.

Background: There is increasing evidence that reflux of bile plays a part in the pathogenesis of Barrett's oesophagus. Bile injury to the gastric mucosa results in a "chemical" gastritis in which oedema and intestinal metaplasia are prominent., Aim: To determine if patients with Barrett's oesophagus have more bile related changes in antral mucosa than patients with uncomplicated gastro-oesophageal reflux disease (GORD) or non-ulcer dyspepsia (NUD)., Patients and Methods: Patients were identified by a retrospective search of pathology records and those with a clinically confirmed diagnosis of either Barrett's oesophagus or reflux oesophagitis who had oesophageal and gastric biopsies taken at the same endoscopy and had no evidence of Helicobacter pylori infection entered the study. Control biopsies were taken from H pylori negative NUD patients. Antral biopsies were examined "blind" to clinical group and graded for a series of histological features from which the "reflux gastritis score" (RGS) and "bile reflux index" (BRI) could be calculated. The reproducibility of these histological scores was tested by a second pathologist., Results: There were 100 patients with Barrett's, 61 with GORD, and 50 with NUD. The RGSs did not differ between groups. BRI values in the Barrett's group were significantly higher than those in GORD subjects (p=0.014) which in turn were higher than those in NUD patients (p=0.037). Similarly, the frequency of high BRI values (>14) was significantly greater in the Barrett's group (29/100; 29%) than in the GORD (9/61; 14.8%) or NUD (4/50; 8%) group. However, agreement on BRI values was "poor", indicating limited applicability of this approach., Conclusion: Patients with Barrett's oesophagus have more evidence of bile related gastritis than subjects with uncomplicated GORD or NUD. The presence of bile in the refluxate could be a factor in both the development of "specialised" intestinal metaplasia and malignancy in the oesophagus.

The previous paradigm that Barrett's is an irreversible premalignant lesion has recently been challenged by a proliferation of reports documenting elimination of Barrett's by a variety of endoscopic techniques. Whether Barrett's is entirely eliminated is unknown as endoscopic biopsy samples the surface of the epithelium only. Numerous reports document underlying specialised columnar epithelium in many of these trials. Until now there have been no reports of pathological examination of the entire oesophagus as a specimen. This case documents complete elimination of intestinal metaplasia from the oesophagus and supports the biological plausibility of these research techniques.

Background: Gastro-oesophageal reflux disease (GORD) plays a major role in the development of Barrett's oesophagus. However, it has yet to be elucidated what factors determine the length of Barrett's mucosa in each individual patient., Aims: To determine if there is a correlation between oesophageal acid exposure and the length of Barrett's mucosa. We also compared the extent of oesophageal acid exposure between patients with short segment (SSBE) and long segment (LSBE) Barrett's oesophagus., Methods: Twenty seven patients with Barrett's oesophagus were recruited prospectively into the study from the outpatient gastroenterology clinic at the Southern Arizona VA Health Care System. Diagnosis of Barrett's oesophagus and its anatomical characteristics were determined during upper endoscopy. Ambulatory 24 hour oesophageal pH monitoring assessed the extent of oesophageal acid exposure., Results: There was a significant correlation between per cent total time pH less than 4 and length of Barrett's mucosa (r=0.6234, p=0.0005). In addition, there was a significant correlation between per cent upright and supine time pH less than 4 and length of Barrett's mucosa (r=0.5847, p=0.0014 and r=0.6265 p=0.0006, respectively). Patients with SSBE had significantly less oesophageal acid exposure than patients with LSBE, in terms of both per cent total time and per cent supine time pH less than 4 (p<0.05)., Conclusions: The length of Barrett's mucosa correlated with the duration of oesophageal acid exposure. Patients with LSBE experienced significantly more oesophageal acid exposure than patients with SSBE. Duration of oesophageal acid exposure appears to be an important contributing factor in determining the length of Barrett's mucosa.

Background: Barrett's oesophagus, columnar metaplasia of the epithelium, is a premalignant condition with a 50-100-fold increased risk of cancer. The condition is caused by chronic gastro-oesophageal reflux. Regression of metaplasia may decrease the cancer risk., Aims: To determine whether elimination of acid gastro-oesophageal reflux induces a regression of metaplastic epithelium., Methods: Sixty eight patients with acid reflux and proven Barrett's oesophagus were included in a prospective, randomised, double blind study with parallel groups, and were treated with profound acid secretion suppression with omeprazole 40 mg twice daily, or with mild acid secretion suppression with ranitidine 150 mg twice daily, for 24 months. Endoscopy was performed at 0, 3, 9, 15, and 24 months with measurement of length and surface area of Barrett's oesophagus; pH-metry was performed at 0 and 3 months. Per protocol analysis was performed on 26 patients treated with omeprazole, and 27 patients treated with ranitidine., Results: Omeprazole reduced reflux to 0.1%, ranitidine to 9.4% per 24 hours. Symptoms were ameliorated in both groups. There was a small, but statistically significant regression of Barrett's oesophagus in the omeprazole group, both in length and in area. No change was observed in the ranitidine group. The difference between the regression in the omeprazole and ranitidine group was statistically significant for the area of Barrett's oesophagus (p=0. 02), and showed a trend in the same direction for the length of Barrett's oesophagus (p=0.06)., Conclusions: Profound suppression of acid secretion, leading to elimination of acid reflux, induces partial regression of Barrett's oesophagus.

Background: Bile acid toxicity has been shown in the gastric, colonic, and hepatic tissues; the effect on oesophageal mucosa is less well known., Aims: To determine the spectrum of bile acids refluxing in patients with gastro-oesophageal reflux disease and its relation to oesophageal pH using a new technique of combined oesophageal aspiration and pH monitoring., Methods: Ten asymptomatic subjects and 30 patients with symptoms of gastro-oesophageal reflux disease (minimal mucosal injury, erosive oesophagitis (grade 2 or 3 Savary-Miller), Barrett's oesophagus/stricture; n=10 in each group) underwent 15 hour continuous oesophageal aspiration with simultaneous pH monitoring. Bile acid assay of the oesophageal samples was performed using modified high performance liquid chromatography., Results: The peak bile acid concentration and DeMeester acid scores were significantly higher in the patients with oesophagitis (median bile acid concentration 124 micromol/l; acid score 20.2) and Barrett's oesophagus/stricture (181 micromol/l; 43. 3) than patients with minimal injury (14 micromol/l; 12.5) or controls (0 micromol/l; 11.1). The predominant bile acids detected were cholic, taurocholic, and glycocholic acids but there was a significantly greater proportion of secondary bile acids, deoxycholic and taurodeoxycholic acids, in patients with erosive oesophagitis and Barrett's oesophagus/stricture. Although bile acid reflux episodes occurred at variable pH, a temporal relation existed between reflux of taurine conjugates and oesophageal acid exposure (r=0.58, p=0.009)., Conclusion: Toxic secondary bile acid fractions have been detected in patients with extensive mucosal damage. Mixed reflux is more harmful than acid reflux alone with possible toxic synergism existing between the taurine conjugates and acid.

Background: Prevalence of short segment Barrett's (SSB) oesophagus, defined as the absence of macroscopic Barrett's but histologically identifiable intestinal metaplasia, has been reported to be 18% based on haematoxylin and eosin (H&E) staining., Aims: To define the prevalence of SSB oesophagus using H&E and alcian blue staining and to determine whether SSB oesophagus is associated with inflammation at the gastro-oesophageal junction (GOJ)., Subjects: Consecutive patients (n = 158) presenting for endoscopy completed a structured interview., Methods: Two biopsy specimens taken from the GOJ were stained with H&E, alcian blue and Giemsa. A third specimen was obtained from the distal oesophagus. Intestinal metaplasia was diagnosed if goblet cells were definitely identified by two independent observers., Results: SSB oesophagus was present in 46 (prevalence 36%, 95% confidence interval (CI) 28.5-43.5) using alcian blue staining. If H&E had been the sole staining method used, 50% cases of intestinal metaplasia would have been overlooked. There were no cases of intestinal metaplasia identified by H&E but missed by alcian blue staining. Logistic regression analysis identified age (odds ratio (OR) per decade 1.03, 95% CI 1.01-1.06), histological oesophagitis (OR 3.2, 95% CI 1.4-7.2) and inflammation at the gastrooesophageal junction (OR 5.9, 95% CI 2.2-15.6) as independent risk factors for SSB oesophagus., Conclusion: Unrecognised SSB oesophagus is highly prevalent in patients presenting for diagnostic upper endoscopy if alcian blue staining is applied.

Background: Although oesophagitis is the most common diagnosis made at upper gastrointestinal endoscopy, data on the longterm outcome of affected patients are sparse., Aims: This study assessed the level of reflux symptoms, quality of life, drug consumption, and complications in patients at least 10 years after diagnosis of oesophagitis at one centre., Patients: One hundred and fifty two patients with typical reflux symptoms and a first time diagnosis by endoscopy of grade I-III oesophagitis between 1981 and 1984, were followed up using a postal questionnaire and telephone interview., Results: Eighteen of 152 patients had died, 33 failed to respond, and 101 replied (mean follow up 11 years, range 121-160 months). Over 70% of patients still had heartburn at least daily (32%) or weekly (19%) or required daily acid suppression treatment (20%). Two patients (2%) had developed oesophageal strictures and one had Barrett's oesophagus. Two of eight quality of life scores (physical function and social function) measured by the Short Form-36 were significantly lower than Northern Ireland population scores., Conclusion: Nearly three quarters of patients previously diagnosed as having oesophagitis still had significant morbidity related to gastro-oesophageal reflux disease more than 10 years after diagnosis. Some quality of life scores were significantly lower than those of the general population.

The aim of this study was to assess clinical and radiological findings of gastro-oesophageal reflux in adults who were diagnosed as having a hiatal hernia in infancy or early childhood. One hundred and eighteen patients with a minimum age of 20 who were diagnosed as having a hiatal hernia in childhood were interviewed; barium meal examination was performed in 96 of these cases. Ninety four patients had not required surgery for their hernia. The hiatal hernia persisted in 53% of these patients and 46% experienced heartburn at least monthly but in only three was this severe. Heartburn was significantly more common in patients in whom reflux was seen on barium meal. The consumption of antacids was significantly lower (20% v 46%) in patients who responded well to treatment as children. Eighteen of 24 patients who underwent surgery as children experienced heart-burn monthly but in only one patient was this severe. Two patients underwent endoscopy at their request because of symptoms during this follow up. Both had Barrett's oesophagus. In conclusion, despite the persistence of the hiatal hernia in half of the non-surgically treated patients, few complained of significant symptoms. Effective treatment in childhood was associated with a significant reduction in antacid consumption for heartburn as adults. The finding of Barrett's oesophagus in two patients high-lights a possible role for endoscopic screening in this patient group.

Of 46 patients who had Nissen fundoplication for proved gastro-oesophageal reflux, 25 were available for follow up after a median of 20 years, 15 had died of unrelated causes, and six could not be traced. All 25 patients in the follow up study were personally interviewed: 21 consented to an endoscopy, 14 to 24 hour recording of oesophageal pH and manometry, and 15 to radionuclide transit test. Repeat fundoplication for recurrent reflux was performed in two cases during the study. Heartburn and regurgitation were significantly lessened (p < 0.005), but the incidence of dysphagia was slightly increased. Endoscopy showed six of 21 fundic wraps to be defective. Erosive oesophagitis was seen in two patients, and Barrett's oesophagus (histologically confirmed) in one of them and six other patients. Total reflux time was abnormal in four of 14 patients. No patient with an intact fundic wrap seen on endoscopy, only two of seven with Barrett's oesophagus, and one of four with abnormal reflux had oesophagitis. Fundoplication in itself did not affect oesophageal motility or transit, provided that the wrap was intact. It is concluded that Nissen fundoplication gave a reasonably good longterm effect in chronic reflux disease, with the stage of the fundic wrap as the main determinant of outcome.

A manometric study to determine the role of gastro-oesophageal reflux in Barrett's oesophagus was performed on 20 patients with Barrett's oesophagus and 53 patients with reflux oesophagitis without Barrett's oesophagus (25 with mild oesophagitis and 28 with severe oesophagitis). For the same reason, the 20 patients with Barrett's oesophagus also underwent 24 hour continuous oesophageal pH monitoring, and the results obtained were compared with those of 20 oesophagitis patients without Barrett's oesophagus (10 with mild oesophagitis and 10 with severe oesophagitis). The manometric results show that the motor changes found in the Barrett's group are specific but similar to the motor dysfunction associated with reflux oesophagitis. Motor anomalies are probably related more to the inflammatory process in the oesophageal wall than to the metaplastic changes themselves. The pH monitoring results show that while reflux in the Barrett's oesophagus patients was greater overall than in the oesophagitis group without Barrett's oesophagus, the changes are similar when the results are compared with the severe oesophagitis group. In conclusion there are other factors besides gastro-oesophageal reflux involved in the pathogenesis of Barrett's oesophagus.

Oesophageal manometry and 24 hour ambulatory pH recordings from the distal oesophagus were carried out in 25 patients with complications of oesophagitis (stricture, Barrett's oesophagus or oesophageal ulcer) and compared with 25 patients with uncomplicated oesophagitis. Acid reflux was more severe in the complicated group with 26.2% of time below pH 4 compared with 11.3% in uncomplicated patients (p less than 0.01). This difference was most marked at night, when complicated patients had long periods of acid reflux with 35.6% time less than pH 4 compared with 5.2% uncomplicated (p less than 0.001). The mean duration of nocturnal acid reflux was 15.4 minutes (2.1 minutes uncomplicated, p less than 0.001). Oesophageal motility was markedly abnormal in all groups, but with no demonstrable differences in lower oesophageal sphincter pressure or peristalsis between the groups. Patients with complications of oesophagitis have different patterns of acid reflux from uncomplicated patients, with prolonged nocturnal bathing of the oesophageal mucosa, which may be the cause of stricture formation, metaplasia, or ulceration.