Advertisement

Central Adiposity Is Associated With Increased Risk of Esophageal Inflammation, Metaplasia, and Adenocarcinoma: A Systematic Review and Meta-analysis

      Background & Aims

      Central adiposity has been implicated as a risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), possibly promoting the progression from inflammation to metaplasia and neoplasia. We performed a systematic review and meta-analysis of studies to evaluate the association between central adiposity and erosive esophagitis (EE), BE, and EAC, specifically exploring body mass index (BMI)–independent and gastroesophageal reflux (GERD)–independent effects of central adiposity on the risk of these outcomes.

      Methods

      We performed a systematic search of multiple databases through March 2013. Studies were included if they reported effect of central adiposity (visceral adipose tissue area, waist-hip ratio, and/or waist circumference) on the risk of EE, BE, and EAC. Summary adjusted odds ratio (aOR) estimates with 95% confidence intervals (CIs), comparing highest category of adiposity with the lowest category of adiposity, were calculated by using random-effects model.

      Results

      Forty relevant articles were identified. Compared with patients with normal body habitus, patients with central adiposity had a higher risk of EE (19 studies; aOR, 1.87; 95% CI, 1.51–2.31) and BE (17 studies; aOR, 1.98; 95% CI, 1.52–2.57). The association between central adiposity and BE persisted after adjusting for BMI (5 studies; aOR, 1.88; 95% CI, 1.20–2.95). Reflux-independent association of central adiposity and BE was observed in studies that used GERD patients as controls or adjusted for GERD symptoms (11 studies; aOR, 2.04; 95% CI, 1.44–2.90). In 6 studies, central adiposity was associated with higher risk of EAC (aOR, 2.51; 95% CI, 1.54–4.06), compared with normal body habitus.

      Conclusions

      On the basis of a meta-analysis, central adiposity, independent of BMI, is associated with esophageal inflammation (EE), metaplasia (BE), and neoplasia (EAC). Its effects are mediated by reflux-dependent and reflux-independent mechanisms.

      Keywords

      Abbreviations used in this paper:

      aOR (adjusted odds ratio), BE (Barrett's esophagus), BMI (body mass index), CI (confidence interval), CT (computed tomography), EAC (esophageal adenocarcinoma), EE (erosive esophagitis), GERD (gastroesophageal reflux disease), OR (odds ratio), RR (relative risk), WC (waist circumference), WHR (waist-hip ratio)
      Obesity has been implicated in a spectrum of reflux-related esophageal diseases ranging from esophageal inflammation (erosive esophagitis [EE]) to metaplasia (Barrett's esophagus [BE]) to neoplasia (esophageal adenocarcinoma [EAC]).
      • Cook M.B.
      • Greenwood D.C.
      • Hardie L.J.
      • et al.
      A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus.
      • Corley D.A.
      • Kubo A.
      Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.
      • Hampel H.
      • Abraham N.S.
      • El-Serag H.B.
      Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
      • Lagergren J.
      Influence of obesity on the risk of esophageal disorders.
      • Turati F.
      • Tramacere I.
      • La Vecchia C.
      • et al.
      A meta-analysis of body mass index and esophageal and gastric cardia adenocarcinoma.
      Obesity promotes gastroesophageal reflux disease (GERD) through disruption of the gastroesophageal junction anatomy and physiology, which can lead to EE.
      • Pandolfino J.E.
      • El-Serag H.B.
      • Zhang Q.
      • et al.
      Obesity: a challenge to esophagogastric junction integrity.
      • Friedenberg F.K.
      • Xanthopoulos M.
      • Foster G.D.
      • et al.
      The association between gastroesophageal reflux disease and obesity.
      This reflux-induced chronic esophageal inflammation predisposes to BE and a higher risk of progressing to EAC.
      • Lagergren J.
      Influence of obesity on the risk of esophageal disorders.
      In previous studies, increased body mass index (BMI) was found to be a risk factor for GERD but not for the development of BE in those with GERD.
      • Cook M.B.
      • Greenwood D.C.
      • Hardie L.J.
      • et al.
      A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus.
      • Corley D.A.
      • Kubo A.
      Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.
      • Hampel H.
      • Abraham N.S.
      • El-Serag H.B.
      Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
      This suggested that the effect of BMI on BE pathogenesis may be mediated predominantly by promoting reflux.
      • Moayyedi P.
      Barrett's esophagus and obesity: the missing part of the puzzle.
      Several recent preclinical and observational studies have demonstrated that the pattern of body fat distribution may be more important than overall adiposity in determining the risk of EE, BE, and EAC.
      • Lagergren J.
      Influence of obesity on the risk of esophageal disorders.
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      Although some studies have shown that central adiposity may have a BMI-independent effect on the risk of these adverse esophageal outcomes,
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      others have failed to demonstrate this association.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      In addition to promoting GERD, metabolically active visceral adipose tissue releases proinflammatory adipocytokines, which may contribute to development of metaplasia and neoplasia.
      • Friedenberg F.K.
      • Xanthopoulos M.
      • Foster G.D.
      • et al.
      The association between gastroesophageal reflux disease and obesity.
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      • Tilg H.
      • Moschen A.R.
      Visceral adipose tissue attacks beyond the liver: esophagogastric junction as a new target.
      Such a reflux-independent effect of central adiposity on BE and EAC, however, is not consistent among all studies.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Higgins J.P.T.
      Cochrane handbook for systematic reviews of interventions.
      Therefore, to better understand the relationship between central adiposity and esophageal inflammation, metaplasia and neoplasia, we conducted a systematic review and meta-analysis of all observational studies that investigated the association between central adiposity and risk of these outcomes. Through predetermined subgroup analyses, we sought to understand whether central adiposity has a BMI-independent association with these outcomes, and whether central adiposity has a reflux-independent effect on BE and EAC.

      Methods

      This systematic review was conducted following guidance provided by the Cochrane Handbook
      • Higgins J.P.T.
      Cochrane handbook for systematic reviews of interventions.
      and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The process followed a priori established protocol.

       Search Strategy

      First, a systematic literature search of PubMed (1966 through March 1, 2013), followed by Embase (1988–March 1, 2013) and Web of Science (1993–March 1, 2013) databases, was conducted to identify all relevant articles on the effect of central adiposity on the risk of EE, BE, and EAC. Medical subject heading (MeSH) terms used in the search included a combination of “Obesity”, “Waist Circumference”, “Waist-Hip Ratio”, “Body Fat Distribution”, “Adiposity”, “Abdominal Fat”, “Obesity, Abdominal” AND “Esophagitis”, “Barrett esophagus” OR “esophageal neoplasm”. The title and abstract of studies identified in the search were reviewed by 2 authors independently (S.S., A.N.S.) to exclude studies that did not answer the research question of interest, which was based on prespecified inclusion and exclusion criteria. The full text of the remaining articles was examined to determine whether it contained relevant information. The coefficient of agreement between the 2 reviewers for article selection (κ = 0.84; 95% confidence interval [CI], 0.72–0.94) was excellent. Next, the bibliographies of the selected articles and review articles on the topic were manually searched for additional articles. Third, a manual search of conference proceedings from major gastroenterology meetings (2005–2012) was performed for additional abstracts on the topic. These were not included in the primary analysis, but sensitivity analysis after including these abstracts was performed for each outcome.

       Selection Criteria

      Studies considered in this meta-analysis were observational studies that met the following inclusion criteria: (1) evaluated and defined a measure of central adiposity, visceral adipose tissue area (cm2) or volume (cm3) as measured using abdominal computed tomography (CT), waist-hip ratio (WHR), and/or waist circumference (WC); (2) reported its association with esophageal disease outcomes (EE defined on upper endoscopy, BE and/or EAC validated by pathology review); and (3) reported a measure of association, relative risk (RR) or odds ratio (OR), or provided data for their calculation. Inclusion was not otherwise restricted by study size, language, or publication type. Figure 1 summarizes the process of study identification, inclusion, and exclusion.
      Figure thumbnail gr1
      Figure 1Flowchart showing study identification and selection process.

       Data Abstraction

      Data on the following were independently abstracted onto a standardized form by 2 reviewers (S.S., A.N.S.): (1) study characteristics: study design, time period, country, source population, presence or absence of GERD symptoms; (2) exposure assessment: measure of central adiposity (visceral adipose tissue area, WHR, and/or WC), how it was defined, and whether it was reported as a continuous or categorical variable, along with categories (binary divided as median or normal and abnormal, tertiles, quartiles, and reference category), evaluation of dose-response relationship; (3) primary outcome reported: EE, BE, and/or EAC; and (4) analysis: OR and 95% CIs with and without adjustment for confounding factors, as well as ORs reported after adjustment for BMI and after adjustment for presence of GERD symptoms in each individual study. In addition, for each included study, if the relation between BMI (as a surrogate for overall obesity) and abdominal subcutaneous adipose tissue area (cm2) (measured on CT) and esophageal outcomes was reported as OR, these data were abstracted in the same fashion as above. Conflicts in data abstraction were resolved by consensus, referring back to the original article and in consultation with the principal investigator (P.G.I.). Data on the following confounding risk factors for relevant esophageal outcomes were also abstracted from each study: age, sex, race, BMI, smoking status, alcohol consumption, GERD symptoms, use of proton pump inhibitors or histamine receptor antagonists, presence of hiatal hernia, family history of EAC, caffeine intake, Helicobacter pylori infection, use of putative chemopreventive agents (aspirin, nonsteroidal anti-inflammatory drugs, statins), and for studies reporting EAC as outcome, presence, length, and histology of BE.

       Exposure and Outcome Assessment

      The primary analysis focused on assessing the relationship between central adiposity and each esophageal disease outcome: EE, BE, or EAC. When multiple measures of central adiposity were reported in the same study, preference was given to OR reported for central adiposity measured by using visceral adipose tissue area, followed by WHR (or waist-thigh ratio) and last to WC. When exposure was reported in tertiles or quartiles, the comparison was performed between the highest quartiles and the lowest quartiles (or referent category) for the primary analysis. When results were reported as mean and standard deviations in cases and controls, we transformed this into a binary OR (comparing values above the mean to the referent category that was below the mean) using the Chinn equation (details in Supplementary Material).
      • Chinn S.
      A simple method for converting an odds ratio to effect size for use in meta-analysis.
      The referent groups for all these outcomes were patients in the lowest category of body habitus (usually normal body habitus).
      In addition, to explore the presence of a BMI-independent effect of central adiposity on EE, BE, and EAC, we performed subgroup analysis of studies that provided OR after adjustment for BMI. Likewise, to explore a GERD-independent effect of central adiposity on BE and EAC, we performed subgroup analysis of studies that adjusted for GERD symptoms or studied only patients with GERD. Anticipating potential heterogeneity in the direction and magnitude of effect among the studies, we performed pre-planned subgroup analyses on study-related variables to explore sources of heterogeneity.

       Statistical Analysis

      We used the random-effects model described by DerSimonian and Laird
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      to calculate meta-analytic OR and 95% CI for each outcome. Adjusted ORs (aORs) (for case-control and cross-sectional studies) or RRs (for cohort studies) reported in studies were used for analyses to account for confounding variables. We assessed heterogeneity between study-specific estimates by using 2 methods.
      • Kanwal F.
      • White D.
      Systematic reviews and meta-analyses in Clinical Gastroenterology and Hepatology.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • et al.
      Measuring inconsistency in meta-analyses.
      First, the Cochran Q test, which tests the null hypothesis that all studies in a meta-analysis have the same underlying magnitude of effect, was measured. Because this test is underpowered to detect moderate degrees of heterogeneity,
      • Thompson S.G.
      • Pocock S.J.
      Can meta-analyses be trusted?.
      a P value <.10 was considered suggestive of significant heterogeneity. Second, to estimate the proportion of total variation across studies related to heterogeneity rather than chance, the I2 statistic was calculated. In this, values of <30%, 30%–60%, 60%–75%, and >75% were suggestive of low, moderate, substantial, and considerable heterogeneity, respectively.
      • Kanwal F.
      • White D.
      Systematic reviews and meta-analyses in Clinical Gastroenterology and Hepatology.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 7—rating the quality of evidence: inconsistency.
      Between-study sources of heterogeneity were investigated by using subgroup analyses by stratifying original estimates according to study characteristics, with P < .05 for differences between subgroups (Pinteraction) being considered statistically significant. Publication bias was assessed quantitatively by using Egger regression test (publication bias considered present if P ≤ .10)
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • et al.
      Bias in meta-analysis detected by a simple, graphical test.
      and qualitatively by visual inspection of funnel plots.
      • Easterbrook P.J.
      • Berlin J.A.
      • Gopalan R.
      • et al.
      Publication bias in clinical research.
      All P values were two-tailed. For all tests (except for heterogeneity and publication bias), a probability level <.05 was considered statistically significant. All calculations and graphs were performed using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ).

      Results

      From a total of 260 unique studies identified using our search strategy, 40 relevant studies (37 independent populations) were identified. Of these, 19 studies (18 independent populations) reported the association between central adiposity and EE,
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      • Chua C.S.
      • Lin Y.M.
      • Yu F.C.
      • et al.
      Metabolic risk factors associated with erosive esophagitis.
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      • Gunji T.
      • Sato H.
      • Iijima K.
      • et al.
      Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      • Hsu C.S.
      • Wang P.C.
      • Chen J.H.
      • et al.
      Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.
      • Koo J.S.
      • Lee S.W.
      • Park S.M.
      • et al.
      Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      • Mulholland H.G.
      • Cantwell M.M.
      • Anderson L.A.
      • et al.
      Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      • Park J.H.
      • Park D.I.
      • Kim H.J.
      • et al.
      Metabolic syndrome is associated with erosive esophagitis.
      • Tai C.M.
      • Lee Y.C.
      • Tu H.P.
      • et al.
      The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
      • Wu P.
      • Ma L.
      • Dai G.X.
      • et al.
      The association of metabolic syndrome with reflux esophagitis: a case-control study.
      • Kang M.S.
      • Park D.I.
      • Oh S.Y.
      • et al.
      Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
      • Kato M.
      • Watabe K.
      • Hamasaki T.
      • et al.
      Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.
      • Lee S.J.
      • Jung M.K.
      • Kim S.K.
      • et al.
      [Clinical characteristics of gastroesophageal reflux disease with esophageal injury in Korean: focusing on risk factors].
      17 studies (15 independent populations) reported the association between central adiposity and BE,
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      • Akiyama T.
      • Yoneda M.
      • Inamori M.
      • et al.
      Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease.
      • Edelstein Z.R.
      • Bronner M.P.
      • Rosen S.N.
      • et al.
      Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
      • El-Serag H.B.
      • Kvapil P.
      • Hacken-Bitar J.
      • et al.
      Abdominal obesity and the risk of Barrett's esophagus.
      • Healy L.A.
      • Ryan A.M.
      • Pidgeon G.
      • et al.
      Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
      • Jacobson B.C.
      • Chan A.T.
      • Giovannucci E.L.
      • et al.
      Body mass index and Barrett's oesophagus in women.
      • Kendall B.J.
      • Macdonald G.A.
      • Hayward N.K.
      • et al.
      The risk of Barrett's esophagus associated with abdominal obesity in males and females.
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      • Kramer J.R.
      • Fischbach L.A.
      • Richardson P.
      • et al.
      Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
      and 6 studies reported the association between central adiposity and EAC.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Beddy P.
      • Howard J.
      • McMahon C.
      • et al.
      Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
      • Corley D.A.
      • Kubo A.
      • Zhao W.
      Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
      • MacInnis R.J.
      • English D.R.
      • Hopper J.L.
      • et al.
      Body size and composition and the risk of gastric and oesophageal adenocarcinoma.
      • O'Doherty M.G.
      • Freedman N.D.
      • Hollenbeck A.R.
      • et al.
      A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
      • Steffen A.
      • Schulze M.B.
      • Pischon T.
      • et al.
      Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition.
      Lee et al
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      reported the relationship between central adiposity and EE by using both WHR and CT-measured visceral adipose tissue area (in a subset of patients). Likewise, for one independent population, relation between CT assessment of central adiposity and BE was performed in a subset of patients who underwent anthropometry and was reported in separate studies.
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      • Kramer J.R.
      • Fischbach L.A.
      • Richardson P.
      • et al.
      Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
      One group reported the association between central adiposity and EE and BE in a single study.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      Corley et al
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Corley D.A.
      • Kubo A.
      • Zhao W.
      Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
      used 2 separate Kaiser Permanente health checkup cohorts to study the association between central adiposity and BE and EAC. Likewise, the FINBAR study group reported the association between central adiposity and EE, BE, and EAC in 2 separate articles.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Mulholland H.G.
      • Cantwell M.M.
      • Anderson L.A.
      • et al.
      Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      Two sets of studies from western Washington
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Thompson O.M.
      • Beresford S.A.
      • Kirk E.A.
      • et al.
      Serum leptin and adiponectin levels and risk of Barrett's esophagus and intestinal metaplasia of the gastroesophageal junction.
      and Kaiser Permanente population
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Kubo A.
      • Levin T.R.
      • Block G.
      • et al.
      Cigarette smoking and the risk of Barrett's esophagus.
      were from overlapping populations, and hence only one from each of these was included.
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.

       Characteristics and Quality Assessment of Included Studies

      Of the 40 studies, 18 were performed in the Asian population (including 17 studies on risk of EE)
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      • Chua C.S.
      • Lin Y.M.
      • Yu F.C.
      • et al.
      Metabolic risk factors associated with erosive esophagitis.
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      • Gunji T.
      • Sato H.
      • Iijima K.
      • et al.
      Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      • Hsu C.S.
      • Wang P.C.
      • Chen J.H.
      • et al.
      Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.
      • Koo J.S.
      • Lee S.W.
      • Park S.M.
      • et al.
      Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      • Park J.H.
      • Park D.I.
      • Kim H.J.
      • et al.
      Metabolic syndrome is associated with erosive esophagitis.
      • Tai C.M.
      • Lee Y.C.
      • Tu H.P.
      • et al.
      The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
      • Wu P.
      • Ma L.
      • Dai G.X.
      • et al.
      The association of metabolic syndrome with reflux esophagitis: a case-control study.
      • Kang M.S.
      • Park D.I.
      • Oh S.Y.
      • et al.
      Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
      • Kato M.
      • Watabe K.
      • Hamasaki T.
      • et al.
      Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.
      • Lee S.J.
      • Jung M.K.
      • Kim S.K.
      • et al.
      [Clinical characteristics of gastroesophageal reflux disease with esophageal injury in Korean: focusing on risk factors].
      and the remainder in the Western population. Eight studies used visceral adipose tissue area as measure of central adiposity (4 each in patients with EE
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      • Gunji T.
      • Sato H.
      • Iijima K.
      • et al.
      Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      and BE
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Akiyama T.
      • Yoneda M.
      • Inamori M.
      • et al.
      Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease.
      • El-Serag H.B.
      • Kvapil P.
      • Hacken-Bitar J.
      • et al.
      Abdominal obesity and the risk of Barrett's esophagus.
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      ), 23 studies used WHR (7 studies on EE,
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      • Mulholland H.G.
      • Cantwell M.M.
      • Anderson L.A.
      • et al.
      Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      • Tai C.M.
      • Lee Y.C.
      • Tu H.P.
      • et al.
      The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
      • Wu P.
      • Ma L.
      • Dai G.X.
      • et al.
      The association of metabolic syndrome with reflux esophagitis: a case-control study.
      11 studies on BE,
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      • Jacobson B.C.
      • Chan A.T.
      • Giovannucci E.L.
      • et al.
      Body mass index and Barrett's oesophagus in women.
      • Kendall B.J.
      • Macdonald G.A.
      • Hayward N.K.
      • et al.
      The risk of Barrett's esophagus associated with abdominal obesity in males and females.
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      • Kramer J.R.
      • Fischbach L.A.
      • Richardson P.
      • et al.
      Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
      and 5 studies on EAC
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Corley D.A.
      • Kubo A.
      • Zhao W.
      Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
      • MacInnis R.J.
      • English D.R.
      • Hopper J.L.
      • et al.
      Body size and composition and the risk of gastric and oesophageal adenocarcinoma.
      • O'Doherty M.G.
      • Freedman N.D.
      • Hollenbeck A.R.
      • et al.
      A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
      • Steffen A.
      • Schulze M.B.
      • Pischon T.
      • et al.
      Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition.
      ). The characteristics of the included studies for each outcome are shown in Table 1, Table 2, Table 3. The overall quality of the included studies was moderate. Supplementary Tables 1, 2, and 3 report details of the quality assessment of included studies.
      Table 1Characteristics of Included Studies Assessing the Association Between Central Adiposity and EE
      StudyDesignLocationStudy settingTime periodAscertainment of adiposityEE casesControls
      MeasureCategories, highest vs lowest (referent)DefinitionN
      Gunji
      • Gunji T.
      • Sato H.
      • Iijima K.
      • et al.
      Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
      Cross-sectionalTokyo, JapanVoluntary health check-up, hospital-based2007–2010CT; WC (cm); BMI (kg/m2)Continuous

      WC: >85.8 vs <85.8

      BMI: >23.8 vs <23.8
      1831Healthy; non-GERD8009
      Ha
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      Cross-sectionalSeoul, South KoreaVoluntary health check-up, hospital-based2004–2006WHR; BMIBinary

      WHR: >0.9 vs ≤0.9

      BMI: >25 vs ≤25
      292Patients; GERD500
      Hsu
      • Hsu C.S.
      • Wang P.C.
      • Chen J.H.
      • et al.
      Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.
      Cross-sectionalHualein, TaiwanVoluntary health check-up, hospital-based2007WC; BMIBinary

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: >23.6 vs <23.6
      131Healthy; non-GERD612
      Kang
      • Kang M.S.
      • Park D.I.
      • Oh S.Y.
      • et al.
      Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
      Cross-sectionalSeoul, South KoreaVoluntary health check-up, hospital-based2004–2005WC; BMIBinary

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: >30 vs <25
      161Healthy; non-GERD2281
      Kato
      • Kato M.
      • Watabe K.
      • Hamasaki T.
      • et al.
      Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.
      Cross-sectionalOsaka, JapanVoluntary health check-up, hospital-based2007–2008WC; BMIContinuous

      WC: >82.9 vs <82.9

      BMI: >22.7 vs <22.7
      235Healthy; non-GERD2170
      Lee
      • Lee S.J.
      • Jung M.K.
      • Kim S.K.
      • et al.
      [Clinical characteristics of gastroesophageal reflux disease with esophageal injury in Korean: focusing on risk factors].
      Cross-sectionalDaegu, South KoreaHospital-based2008–2010WC; BMIContinuous

      WC: >84.0 vs <84.0

      BMI: >23.6 vs <23.6
      278Patients; non-GERD172
      Nam
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      Cross-sectionalGoyang, South KoreaVoluntary health check-up, hospital-based2001–2006WC; BMIQuartiles

      WC: ≥100.0 vs <80.0

      BMI: ≥30.0 vs <20.0
      552Healthy; non-GERD8019
      Nam
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      Cross-sectionalGoyang, South KoreaVoluntary health check-up, hospital-based2008WC, WHR, BMI, CT fat volumeQuartiles

      WHR: ≥1.0 vs <0.8

      WC: ≥100.0 vs <80.0

      BMI: ≥30.0 vs <20.0
      495Healthy; non-GERD3779
      Chua
      • Chua C.S.
      • Lin Y.M.
      • Yu F.C.
      • et al.
      Metabolic risk factors associated with erosive esophagitis.
      C-CTaipei, TaiwanVoluntary health check-up, hospital-based2004–2006WC; BMIBinary

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: ≥25.0 vs <25.0
      427Healthy; non-GERD427
      Chung
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      C-CSeoul, South KoreaVoluntary health check-up, hospital-based2004–2007CT; WC; BMIQuartiles (for CT); binary (for WC)

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: ≥25.0 vs <23.0
      3539Healthy; non-GERD3539
      Lee
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      C-CSeoul, South KoreaVoluntary health check-up, hospital-based2003–2005CT; WHR; BMITertiles

      WHR: >1.0 vs <0.8

      BMI: >30.0 vs <20.0
      292Healthy; non-GERD2896
      Mokrowiecka
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      C-CLodz, PolandHospital-based2009–2011WHR; WC; BMIContinuous

      WHR: >0.65 vs <0.65

      WC: >83 vs <83

      BMI: >25 vs <25
      30Patients; non-GERD30
      Mulholland
      • Mulholland H.G.
      • Cantwell M.M.
      • Anderson L.A.
      • et al.
      Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      C-CBelfast, IrelandPopulation-based2002–2004WHR; BMITertiles

      WHR: Tertiles, NR

      BMI: >29.0 vs <25.8
      219Healthy; non-GERD260
      Park
      • Park J.H.
      • Park D.I.
      • Kim H.J.
      • et al.
      Metabolic syndrome is associated with erosive esophagitis.
      C-CSeoul, South KoreaVoluntary health check-up, hospital-based2006WC; BMIBinary

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: >24.0 vs <24.0
      1679Healthy; non-GERD3358
      Wu
      • Wu P.
      • Ma L.
      • Dai G.X.
      • et al.
      The association of metabolic syndrome with reflux esophagitis: a case-control study.
      C-CShanghai, ChinaVoluntary health check-up, hospital-based2010WC; WHR; BMIBinary

      WHR: >0.9 (for men), >0.8 (for women) vs ≤0.9 or ≤0.8

      WC: ≥90 (for men), ≥80 (for women) vs <90 or <80

      BMI: ≥28.0 vs <28.0
      182Healthy; non-GERD190
      Koo
      • Koo J.S.
      • Lee S.W.
      • Park S.M.
      • et al.
      Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
      CohortSeoul, South KoreaVoluntary health check-up, hospital-based2003–2006WC; BMITertiles

      WC: ≥90 vs <80

      BMI: ≥25.0 vs <23.0
      42Healthy; non-GERD987
      Sogabe
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      CohortKagawa, JapanHospital-based2008–2009WC; BMIBinary

      WC: ≥90 vs <90

      BMI: ≥25.0 vs <25.0
      55Men with metabolic syndrome; non-GERD210
      Tai
      • Tai C.M.
      • Lee Y.C.
      • Tu H.P.
      • et al.
      The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
      CohortKaohsiung, TaiwanHospital-based2007–2009WC; WHR; BMIContinuous

      WHR: >0.93 vs <0.93

      WC: >120 vs <120

      BMI: >42 vs <42
      84Bariatric clinic; non-GERD176
      C-C, case-control.
      Table 2Characteristics of Included Studies Assessing the Association Between Central Adiposity and BE
      StudyDesignLocationStudy settingTime periodAscertainment of adiposityBE casesControls
      MeasureCategories, highest vs lowest (referent)DefinitionN
      Rubenstein
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      Cross-sectionalMichiganHospital-based2008–2011WHR; WC; BMITertiles

      WHR: >1.024 vs <0.979

      WC: >108 vs ≤108

      BMI: ≥30.0 vs ≤20.0–25.0
      70Colorectal cancer screenees; non-GERD751
      Anderson
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      C-CBelfast, IrelandPopulation-based2002–2004WHR; BMITertiles

      WHR: Tertiles, NR

      BMI: >29.0 vs <25.8
      224Healthy; non-GERD260
      Corley
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      C-CCaliforniaPopulation-based
      From Kaiser-Permanente Northern California population.
      2002–2005WTR; WC; BMIDeciles/binary

      WTR: >1.7 vs <1.7

      WC: ≥130.0 vs <80.0

      BMI: >35.0 vs <25.0
      329
      • Population; non-GERD
      • GERD
      317

      316
      Edelstein
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Edelstein Z.R.
      • Bronner M.P.
      • Rosen S.N.
      • et al.
      Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
      C-CWashingtonPopulation-based
      Community gastroenterology clinics.
      1997–2000WHR; WTR; WC; BMITertiles

      WHR: ≥0.9 (for men) or ≥0.85 (for women) vs <0.9 or <0.85

      WC: ≥102 (for men) or ≥88 (for women) vs <94 or <79

      BMI: ≥30 vs 25
      97
      193 patients with squamous intestinal metaplasia, but only 97 with both endoscopic and histologic diagnosis.
      • Population; non-GERD
      • GERD
      211

      419
      El-Serag
      • El-Serag H.B.
      • Kvapil P.
      • Hacken-Bitar J.
      • et al.
      Abdominal obesity and the risk of Barrett's esophagus.
      C-CTexasHospital-based2000–2003CT; BMIContinuous

      BMI: >30 vs <25
      36Hospitalized patients
      Able to do separate subgroup analysis comparing patients with BE and patients with GERD leading to EE.
      ; mixed GERD/non-GERD
      93
      Greer
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      C-COhioHospital-based2005–2009WHR; BMIContinuous

      WHR: >0.98 vs <0.98

      BMI: >30 vs <30
      135
      • Colonoscopy; non-GERD
      • GERD
      182

      135
      Healy
      • Healy L.A.
      • Ryan A.M.
      • Pidgeon G.
      • et al.
      Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
      C-CDublin, IrelandHospital-basedNRWC; BMIBinary

      WC: >94 (for men) or >80 (for women) vs ≤94 or ≤80

      BMI: >28.2 vs <28.2
      118Patients; GERD113
      Kendall
      • Kendall B.J.
      • Macdonald G.A.
      • Hayward N.K.
      • et al.
      The risk of Barrett's esophagus associated with abdominal obesity in males and females.
      C-CBrisbane, AustraliaPopulation-based2003–2009WHR; WC; BMITertiles

      WHR and WC: tertiles, NR

      BMI: ≥30.0 vs 20.0–25.0
      237Healthy; non-GERD247
      Kramer
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      • Kramer J.R.
      • Fischbach L.A.
      • Richardson P.
      • et al.
      Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
      C-CTexasHospital-based2008–2011CT; WHR; WC; BMIBinary
      CT assessment of visceral adipose tissue surface area reported as both binary (for GERD + stratified analysis) and tertiles (for GERD-nonadjusted, used in assessing dose-response relationship).
      ;tertiles

      WHR: ≥0.9 (for men) or ≥0.85 (for women) vs <0.9 or <0.85

      WC: ≥117.6 vs <99.5

      BMI: ≥30.0 vs <25.0
      237Patients; “Endoscopy” and “Colonoscopy” controls1500
      Mokrowiecka
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      C-CLodz, PolandHospital-based2009–2011WHR; WC; BMIContinuous

      WHR: >0.65 vs <0.65

      WC: >83 vs <83

      BMI: >25 vs <25
      47Patients; non-GERD30
      Nelsen
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      C-CMinnesotaHospital-based2009CT; WC; BMIBinary

      WC: ≥97.8 vs <97.8

      BMI: ≥30.0 vs <30.0
      50Patients; non-GERD50
      Rubenstein
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      C-CMichiganHospital-basedNRWHR; WC; BMIContinuous

      NR
      60Patients; mixed GERD and non-GERD60
      Rubenstein
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      C-CNorth CarolinaHospital-based2002–2007WHR; WC; BMIContinuous

      WHR: >0.90 vs <0.90

      WC: >93.0 vs <93.0

      BMI: >28.5 vs <28.5
      112Patients; GERD199
      Akiyama
      • Akiyama T.
      • Yoneda M.
      • Inamori M.
      • et al.
      Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease.
      CohortYokohama, JapanHospital-based2003–2009CT; BMIContinuous

      BMI: >25.0 vs <25.0
      69NAFLD patients; non-GERD94
      Jacobson
      • Jacobson B.C.
      • Chan A.T.
      • Giovannucci E.L.
      • et al.
      Body mass index and Barrett's oesophagus in women.
      CohortUSAPopulation-based
      Prospective Nurses' Health Study.
      1986–2004WHR; WC; BMIQuartiles

      WHR: ≥0.82 vs ≤0.73

      WC: ≥86.4 vs ≤68.6

      BMI: >30.0 vs <25.0
      261Healthy women; non-GERD15,600
      C-C case-control; NAFLD, nonalcoholic fatty liver disease; WTR, waist-thigh ratio.
      a From Kaiser-Permanente Northern California population.
      b Community gastroenterology clinics.
      c 193 patients with squamous intestinal metaplasia, but only 97 with both endoscopic and histologic diagnosis.
      d Able to do separate subgroup analysis comparing patients with BE and patients with GERD leading to EE.
      e Prospective Nurses' Health Study.
      f CT assessment of visceral adipose tissue surface area reported as both binary (for GERD + stratified analysis) and tertiles (for GERD-nonadjusted, used in assessing dose-response relationship).
      Table 3Characteristics of Included Studies Assessing the Association Between Central Adiposity and EAC
      StudyDesignLocationStudy settingTime periodAscertainment of adiposityEAC casesControls
      MeasureCategories, highest vs lowest (referent)DefinitionN
      Anderson
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      C-CBelfast, IrelandPopulation-based2002–2004WHR; BMITertiles

      WHR: tertiles, NR

      BMI: >29.0 vs <25.8
      227Population, non-GERD260
      Beddy
      • Beddy P.
      • Howard J.
      • McMahon C.
      • et al.
      Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
      C-CDublin, IrelandHospital-based2005–2008CTContinuous

      WC, WHR, BMI: not applicable
      110Patients, non-GERD90
      Corley
      • Corley D.A.
      • Kubo A.
      • Zhao W.
      Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
      C-CCaliforniaPopulation-based
      From Kaiser-Permanente Northern California population.
      1964–2006WC; BMIQuartiles

      WC: ≥25.0 vs <20.0

      BMI: ≥30.0 vs <18.0
      101Population, non-GERD2800
      MacInnis
      • MacInnis R.J.
      • English D.R.
      • Hopper J.L.
      • et al.
      Body size and composition and the risk of gastric and oesophageal adenocarcinoma.
      CohortMelbourne, AustraliaPopulation-based1990–2004WHR; WC; BMITertiles

      WHR: ≥0.95 (for men) or ≥0.80 (for women) vs <0.9 or <0.75

      WC: ≥102 (for men) or ≥88 (for women) vs <94 or <80

      BMI: ≥30.0 vs <25.0
      62
      Includes 19 cases of gastric cardia cancers.
      Population, non-GERD55
      O'Doherty
      • O'Doherty M.G.
      • Freedman N.D.
      • Hollenbeck A.R.
      • et al.
      A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
      Cohort6 states, USAPopulation-based1995–2006WHR; WC; BMIQuartiles

      WHR: ≥1.02 (for men) or ≥0.9 (for women) vs <0.88 or <0.73

      WC: >110.5 (for men) or >99 (for women) vs <86.4 or <70.6

      BMI: ≥35.0 vs 18.5–24.9
      253Population, non-GERD218,601
      Steffen
      • Steffen A.
      • Schulze M.B.
      • Pischon T.
      • et al.
      Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition.
      CohortEurope
      Prospective cohort of European Prospective Investigation into Cancer & Nutrition (EPIC).
      Population-based1992–2007WHR; WC; BMIQuintiles

      WHR: ≥1.01 (for men) or ≥0.88 (for women) vs <0.86 or <0.71

      WC: >107.5 (for men) or >96.0 (for women) vs <82.4 or <67.0

      BMI: ≥29.2 (for men) or ≥28.8 (for women) vs <23.4 or <21.7
      88Population, non-GERD346,466
      C-C, case-control.
      a From Kaiser-Permanente Northern California population.
      b Includes 19 cases of gastric cardia cancers.
      c Prospective cohort of European Prospective Investigation into Cancer & Nutrition (EPIC).

       Erosive Esophagitis

      Meta-analysis of 18 independent studies revealed a significantly higher risk of EE with increased central adiposity (highest category of central adiposity) (aOR, 1.87; 95% CI, 1.51–2.31) and with highest category of BMI (aOR, 1.59; 95% CI, 1.33–1.89), compared with lowest category of body habitus and BMI, respectively (Figure 2A). In an analysis restricted to 8 studies that adjusted for overall obesity (BMI),
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      • Chua C.S.
      • Lin Y.M.
      • Yu F.C.
      • et al.
      Metabolic risk factors associated with erosive esophagitis.
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      • Koo J.S.
      • Lee S.W.
      • Park S.M.
      • et al.
      Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      • Kang M.S.
      • Park D.I.
      • Oh S.Y.
      • et al.
      Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
      the effect of central adiposity on increased risk of EE persisted (aOR, 1.93; 95% CI, 1.38–2.71). In subgroup analyses, results were stable across study designs, location, and population type, as well as across different measures of central adiposity (Table 4). Each individual measure of central adiposity had an independent significant effect on risk of EE; the association was not significant for subcutaneous adipose tissue area (n = 4 studies; aOR, 1.25; 95% CI, 0.94–1.67). Significant heterogeneity was observed in the overall analysis (Cochran Q, P < .01, I2 = 89%), which was primarily seen in the magnitude of effect and not in the direction of effect and was partly explained by study setting (hospital-based studies reporting higher estimates than population-based studies; P value for difference between groups < .01) (Table 4).
      Figure thumbnail gr2
      Figure 2Central adiposity, overall obesity (BMI), and risk of (A) EE, (B) BE, and (C) EAC. This represents the overall pooled OR by combining categorical OR (for highest category, compared with lowest referent category) with estimated OR from continuous variables.
      Table 4Subgroup Analysis and Dose-Response Relationship: Central Adiposity and Risk of EE
      SubgroupsCategoriesNo. of studiesAdjusted OR95% CIP value between groups
      Study-related variables
       Study locationAsian161.941.59–2.36.97
      Western21.850.20–17.6
       Study designCross-sectional81.901.54–2.35.95
      C-C71.861.15–3.01
      Cohort32.161.01–4.60
       Study settingHospital-based172.001.64–2.44<.01
      Statistically significant difference between sub-groups.
      Population-based10.610.44–0.85
       Population typeHealthy volunteers131.841.43–2.37.84
      Patients51.921.38–2.68
      Central adiposity-related variables
       Adjusted for BMIYes91.931.38–2.71.74
      No91.801.38–2.34
       Reporting adiposity
      Comparison of studies that reported data as categories with studies that reported means and standard deviations of adiposity in cases with EE and controls without EE (unadjusted) and transformed into a binary OR by using a statistical equation.
      Categorical131.761.28–2.41.38
      Continuous52.171.54–3.05
       Different measures of central adiposityVisceral adipose tissue area42.081.28–3.39.63
      WHR72.041.13–3.67
      WC141.661.43–1.92
      Dose-response relationship
       Central adiposity (reported as tertiles/quartiles)Q2 (vs Q1)51.630.96–2.77.16
      Q3/Q4 (vs Q1)52.131.49–3.04
      C-C, case-control; Q, quartile.
      a Statistically significant difference between sub-groups.
      b Comparison of studies that reported data as categories with studies that reported means and standard deviations of adiposity in cases with EE and controls without EE (unadjusted) and transformed into a binary OR by using a statistical equation.
      A trend toward dose-response relationship was observed, with higher levels of central adiposity associated with higher risk of EE (Table 4). Further subgroup analysis that was based on presence or absence of GERD symptoms and gender-specific impact of central adiposity on risk of EE was not possible on the basis of available information. To assess whether any one study had a dominant effect on the meta-analytic OR for risk of EE, each study was excluded, and its effect on the main summary estimate was evaluated. No study dominantly affected the summary estimate or P value for heterogeneity. Inclusion of 2 additional studies published only in the abstract form did not significantly alter the association between central adiposity and EE (aOR, 1.88; 95% CI, 1.54–2.31).
      • Leggett C.
      • Dunagan K.T.
      • Katzka D.A.
      • et al.
      Influence of central obesity on esophageal injury: a population based study.
      • Rubenstein J.H.
      • Chey W.D.
      • Murray J.A.
      • et al.
      Acid reflux, erosive esophagitis, and Barrett's esophagus are associated with different measures of abdominal obesity in men.

       Barrett's Esophagus

      Meta-analysis of 15 independent studies revealed a significantly higher risk of BE with increasing central adiposity (aOR, 1.98; 95% CI, 1.52–2.57), as compared with lowest category of central adiposity. BMI was associated with a borderline significant risk of BE (aOR, 1.24; 95% CI, 1.02–1.52) (Figure 2B). Restricting analysis to studies that adjusted for BMI, the independent effect of central adiposity on increased risk of BE persisted (n = 5 studies; aOR, 1.88; 95% CI, 1.20–2.95).
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Edelstein Z.R.
      • Bronner M.P.
      • Rosen S.N.
      • et al.
      Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      The results were stable across different measures of central adiposity (visceral adipose tissue area vs WHR vs WC) (Table 5); on the other hand, the association between subcutaneous adipose tissue area and BE was not significant (n = 4 studies; aOR, 1.38; 95% CI, 0.96–1.99). A trend toward dose-response relationship was apparent. The relation between central adiposity was stronger for long-segment BE as compared with short-segment BE, which was based on pooled analysis of 5 studies.
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Healy L.A.
      • Ryan A.M.
      • Pidgeon G.
      • et al.
      Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      Significant heterogeneity was observed in the overall analysis (Cochran Q, P < .01, I2 = 66%), which was primarily seen in the magnitude of effect and not in the direction of effect. This was explained by differences in study design (case-control vs cohort, aOR: 2.22 vs 1.27; P value for difference between groups = .05) and method of exposure ascertainment (measured vs self-reported, aOR: 2.08 vs 1.20; P value for difference between groups = .03) (Table 5). No single study markedly affected the overall summary estimate or P value for heterogeneity. There was insufficient information to perform a pooled analysis of effect of central adiposity and risk of dysplasia in patients with BE.
      Table 5Subgroup Analysis and Dose-Response Relationship: Central Adiposity and Risk of BE
      SubgroupsCategoriesNo. of studiesAdjusted OR95% CIP value between groups (Pinteraction)
      Study-related variables
       Study locationAsian11.450.82–2.55.31
      Western142.011.49–2.72
       Study designCross-sectional11.650.82–3.33.05
      Statistical significance.
      C-C122.221.61–3.06
      Cohort21.270.93–1.73
       Study settingHospital-based102.301.59–3.31.10
      Population-based51.541.12–2.11
       Method of ascertainmentMeasured142.081.58–2.74.02
      Statistical significance.
      Self-reported11.200.83–1.74
      Central adiposity–related variables
       Adjusted for BMIYes51.881.20–2.95.79
      No102.031.45–2.84
       Reporting adiposity
      Comparison of studies that reported data as categories with studies that reported means and standard deviations of adiposity in cases with BE and controls without BE (unadjusted) and transformed into a binary OR by using a statistical equation.
      Categorical91.561.25–1.96.06
      Continuous62.771.61–4.75
       Different measures of central adiposityVisceral adipose tissue area41.781.19–2.67.43
      WHR/WTR112.041.49–2.81
      WC111.581.25–1.99
      Length of BE
      Long-segment51.961.39–2.75.14
      Short-segment51.340.93–1.94
      Dose-response relationship
       Central adiposity (reported as tertiles/quartiles)Q2 (vs Q1)81.651.11–2.44.53
      Q3/Q4 (vs Q1)81.921.47–2.50
      C-C, case-control; Q, quartile; WTR, waist-thigh ratio.
      a Statistical significance.
      b Comparison of studies that reported data as categories with studies that reported means and standard deviations of adiposity in cases with BE and controls without BE (unadjusted) and transformed into a binary OR by using a statistical equation.

       Reflux-independent Effect of Central Adiposity on Barrett's Esophagus

      When we restricted analysis to studies that used patients with GERD as controls
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      • Edelstein Z.R.
      • Bronner M.P.
      • Rosen S.N.
      • et al.
      Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
      • El-Serag H.B.
      • Kvapil P.
      • Hacken-Bitar J.
      • et al.
      Abdominal obesity and the risk of Barrett's esophagus.
      • Healy L.A.
      • Ryan A.M.
      • Pidgeon G.
      • et al.
      Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      or that adjusted for GERD symptoms,
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      the effect of central adiposity on risk of BE persisted (11 studies; aOR, 2.04; 95% CI, 1.44–2.90), whereas no relation was seen between overall obesity and risk of BE (10 studies; aOR, 1.15; 95% CI, 0.89–1.47). Similarly, restricting analysis to studies that compared central adiposity in patients with BE with those with GERD (symptoms and/or endoscopic evidence of EE) but without BE showed that central adiposity was associated with increased risk of BE (7 studies; aOR, 2.51; 95% CI, 1.48–4.25); this effect was again not significant for BMI (7 studies; aOR, 1.23; 95% CI, 0.90–1.66). These results suggest that central adiposity, rather than overall obesity, may have a GERD symptom-independent effect on development of esophageal metaplasia.

       Esophageal Adenocarcinoma

      Of the 6 studies that reported the association between central adiposity and EAC, in 2 studies,
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      • Beddy P.
      • Howard J.
      • McMahon C.
      • et al.
      Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
      central adiposity was measured at time of EAC diagnosis, whereas in the other 4 studies, it was measured at least 5 years preceding the diagnosis of EAC. In 1 of the 2 studies,
      • Beddy P.
      • Howard J.
      • McMahon C.
      • et al.
      Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
      the average weight loss since EAC diagnosis was only 1.4%; hence, adiposity assessment was believed to closely reflect pre-diagnosis adiposity; such information on post-diagnosis weight loss was not available for the other study, and it was excluded from further analysis.
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      Meta-analysis of these studies revealed a significantly higher risk of EAC with central adiposity (aOR, 2.51; 95% CI, 1.56–4.04) than lowest category of central adiposity (normal body habitus), with substantial heterogeneity (Cochran Q test, P = .03, I2 = 62%) (Figure 2C). This relationship was also observed for high BMI and risk of EAC (n = 5 studies; aOR, 2.45; 95% CI, 1.84–3.28). Including one study published only in the abstract form did not alter the relationship between central adiposity and EAC risk (aOR, 2.14; 95% CI, 1.34–3.42).
      • Cooper S.C.
      • Podmore L.K.
      • Nightingale P.
      • et al.
      The effect of smoking, body mass index, and waist circumference on the development of oesophageal adenocarcinoma: results from MOSES (Midlands Oesophageal Adenocarcinoma Epidemiology Study).
      Because of the small number of studies, subgroup analysis to understand BMI-independent and GERD-independent effect was not conducted. Data were insufficient to evaluate a dose-response relationship between central adiposity and risk of EAC.

       Publication Bias

      There was no evidence of significant publication bias observed in the analysis on risk of EE or EAC, both qualitatively by visual inspection of the funnel plot or quantitatively by using the Egger regression test (P value for EE = .72 and for EAC = .67). However, on analysis of the risk of BE with central adiposity, a significant publication bias was observed on visual inspection of the funnel plot (Supplementary Figure 1), as well as with the Egger test (P = .02). Therefore, we performed a sensitivity analysis by using the trim-and-fill method, which conservatively imputes hypothetical negative unpublished studies to mirror the positive studies that cause funnel plot asymmetry.
      • Duval S.
      • Tweedie R.
      Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
      The pooled analysis incorporating the hypothetical studies continued to show a statistically significant association between central adiposity and risk of BE (aOR, 1.64; 95% CI, 1.22–2.21).

      Discussion

      Multiple previous observational studies as well as meta-analyses have noted a strong association between obesity and GERD, BE, and EAC.
      • Cook M.B.
      • Greenwood D.C.
      • Hardie L.J.
      • et al.
      A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus.
      • Corley D.A.
      • Kubo A.
      Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.
      • Hampel H.
      • Abraham N.S.
      • El-Serag H.B.
      Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
      • Lagergren J.
      Influence of obesity on the risk of esophageal disorders.
      • Turati F.
      • Tramacere I.
      • La Vecchia C.
      • et al.
      A meta-analysis of body mass index and esophageal and gastric cardia adenocarcinoma.
      In this meta-analysis, we make several key observations. First, we reaffirmed the importance of central adiposity as a key factor in the pathogenesis of EE, BE, and EAC, with consistent results across multiple studies by using multiple different measures of central adiposity (CT assessment of visceral fat [but not subcutaneous fat], measured WHR and WC) and after adjustment for multiple confounders. Second, we observed that central adiposity may have a BMI-independent effect on the risk of EE and BE, further validating the importance of visceral abdominal fat in the pathogenesis of esophageal inflammation and metaplasia. Third, we observed that central adiposity, and not overall obesity, has a GERD-independent effect on the risk of BE. There was insufficient information to assess BMI-independent and GERD-independent effect of central adiposity on EAC. We also observed a trend toward a dose-response relationship between the degree of central adiposity and the risk of EE and BE, further strengthening the possibility of a causative association.
      Body fat distribution is thought to play a key role in the pathogenesis of EE, BE, and EAC. Increasing abdominal girth, which is a surrogate for abdominal or visceral fat distribution, can mechanically disrupt the integrity of the gastroesophageal junction barrier and lead to increased esophageal reflux.
      • Pandolfino J.E.
      • El-Serag H.B.
      • Zhang Q.
      • et al.
      Obesity: a challenge to esophagogastric junction integrity.
      • El-Serag H.B.
      • Ergun G.A.
      • Pandolfino J.
      • et al.
      Obesity increases oesophageal acid exposure.
      Besides direct reflux-induced chronic esophagitis and metaplasia, metabolically active visceral fat may exert systemic as well as paracrine, proinflammatory effects that promote, independently or synergistically, esophageal metaplasia and carcinogenesis.
      • Coussens L.M.
      • Werb Z.
      Inflammation and cancer.
      These effects may be mediated through proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6,
      • Ryan A.M.
      • Duong M.
      • Healy L.
      • et al.
      Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets.
      and adipokines such as adiponectin
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      and leptin
      • Kendall B.J.
      • Macdonald G.A.
      • Hayward N.K.
      • et al.
      Leptin and the risk of Barrett's oesophagus.
      • Francois F.
      • Roper J.
      • Goodman A.J.
      • et al.
      The association of gastric leptin with oesophageal inflammation and metaplasia.
      released by visceral fat. An adipocytokine-mediated carcinogenic effect of increased visceral fat is also seen with other gastrointestinal malignancies (colon
      • Larsson S.C.
      • Wolk A.
      Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies.
      and pancreas
      • Aune D.
      • Greenwood D.C.
      • Chan D.S.
      • et al.
      Body mass index, abdominal fatness and pancreatic cancer risk: a systematic review and non-linear dose-response meta-analysis of prospective studies.
      ). A potential paracrine effect of visceral fat is evident by increased gastroesophageal junction fat area in patients with BE with associated esophagitis and dysplasia, independent of BMI.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      In addition to chronic systemic inflammation, visceral fat also is associated with insulin resistance, and recent studies support the role of the insulin–insulin growth factor-1 axis in promoting esophageal neoplasia.
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      • Doyle S.L.
      • Donohoe C.L.
      • Finn S.P.
      • et al.
      IGF-1 and its receptor in esophageal cancer: association with adenocarcinoma and visceral obesity.
      • McElholm A.R.
      • McKnight A.J.
      • Patterson C.C.
      • et al.
      A population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequence.
      Recent studies have also suggested a higher risk of progression of dysplasia in patients with BE with higher level of central adiposity.
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      • Hardikar S.
      • Onstad L.
      • Blount P.L.
      • et al.
      The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett's esophagus.
      Differential effect of body fat distribution on risk of EAC may also explain the significant sex difference observed in incidence of EAC.
      • Lagergren J.
      Influence of obesity on the risk of esophageal disorders.
      • Ryan A.M.
      • Duong M.
      • Healy L.
      • et al.
      Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets.
      The abdominal fat-predominant apple-shaped body habitus in men versus the predominantly hip and thigh, pear-shaped distribution of fat seen in women may explain the male predominance in the risk of esophageal metaplasia and neoplasia. This gender effect of body fat distribution on risk of EAC could unfortunately not be studied independently in this meta-analysis.
      Our review suggests that central adiposity may be associated with BE, independent of GERD. On analysis restricted to studies that accounted for GERD, we observed that the association of central adiposity with BE risk persisted (11 studies; aOR, 2.04; 95% CI, 1.44–2.90), whereas no relation was seen between overall obesity and risk of BE (10 studies; aOR, 1.15; 95% CI, 0.89–1.47). However, the included studies were based on reflux symptoms. It is possible that reflux may still be present in the absence of classical symptoms. Reflux symptoms may be underestimated in patients with EE and particularly BE; we could not be sure the level of reflux injury was similar in these groups. Studies that quantify acid and nonacid reflux are required to further examine the mechanism of obesity-related BE.
      The strengths of this analysis include (1) assessment of the association between central adiposity along the spectrum of esophageal inflammation, metaplasia and neoplasia; (2) incorporating the effect of multiple different measures of central adiposity, both collectively and independently, and assessment of a dose-response relationship between central adiposity and esophageal outcomes; (3) subgroup analyses that allowed assessment of BMI-independent and GERD-independent effects of central adiposity; (4) inclusion of all available studies and not restricting analysis on the basis of study design, publication type, or language, and hence being at low risk for selection or publication bias; (5) performance of analyses of maximally adjusted risk estimates reported in the studies to account for the effect of potential confounders; and (6) multiple subgroup analyses to ensure stability of the association and identify potential factors responsible for heterogeneity. Our results are similar to those observed in a recent pooled analysis of 4 studies that showed that WC, and not BMI, was associated with increased risk of BE in both men and women, with a dose-response relationship.
      • Kubo A.
      • Cook M.B.
      • Shaheen N.J.
      • et al.
      Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium.
      There were several limitations in our analysis that merit further discussion. First, significant heterogeneity was observed in the overall analysis. However, this heterogeneity was seen primarily in the strength of the association between central adiposity and esophageal outcomes and not in the direction of association. The heterogeneity could be explained by differences in study design, setting, method of exposure ascertainment, and/or differences in reporting central adiposity, as demonstrated through subgroup analyses. Such significant heterogeneity has also been observed in previous meta-analyses assessing the risk of obesity and adverse esophageal diseases.
      • Corley D.A.
      • Kubo A.
      Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.
      • Hampel H.
      • Abraham N.S.
      • El-Serag H.B.
      Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
      Second, there was variable adjustment for confounding variables in these studies, especially the effect of BMI and/or GERD. By using prespecified subgroup analysis, however, we were able to estimate the effects of central adiposity after accounting for these key variables. We could not exclude confounding by unmeasured exposures or incomplete control of confounding from measured factors such as diet. Sufficient information was not available to perform subgroup analysis that was based on race. In addition, there was limited information to perform subgroup analysis for EAC. Third, case-control and cross-sectional study designs cannot establish cause and effect. In particular, a temporal association between exposure (central adiposity) and outcome (EE and BE) is not possible to establish, because in most studies, adiposity was assessed at the time of outcome assessment. This is most relevant when studying EAC because cancer can induce weight loss and modify the relation between obesity and cancer through reverse causality. In our analysis, most studies on EAC were cohort studies, and for the one study in which central adiposity was assessed at time of outcome, the extent of cancer-induced weight loss was minimal. Last, a statistically significant publication bias was observed in analysis of central adiposity and risk of BE. However, because of the strong evidence in favor of biological plausibility, the strength of association observed with a potential dose-response relationship, by using multiple different measures of central adiposity, the clinical significance of this publication bias is probably low.
      In conclusion, central adiposity has a strong and consistent association with development of esophageal inflammation, metaplasia and neoplasia, independent of BMI. In addition, central adiposity may be more highly associated with a reflux-independent effect on the development of BE and perhaps explains the predominance of EAC in this population. Future studies aimed at understanding the mechanistic effect of obesity on esophageal inflammation and neoplasia should focus on visceral fat rather than overall obesity. The effect of interventions aimed at favorably modifying body fat distribution on the risk of BE and EAC should be studied.

      Supplementary Material

       Estimation of Odds Ratio From Mean and Standard Deviations

      Although most studies reported OR as a categorical variable (binary, tertiles, quartiles), some others reported the mean and standard deviation of cases and controls along with an OR for each unit change in exposure (or adiposity) (eg, for each 1-cm/5-cm increase in WC, for each 1-cm2 increase in visceral adipose tissue surface area, or for each decimal unit (0.1) increase in WHR). For studies in which OR was not reported as a categorical variable, we estimated the OR from mean, standard deviation, and sample size of the cases and controls. This was performed by using the equation below, which has been validated for use in meta-analysis when combining results from studies that report ORs and mean differences in continuous outcomes
      • Chinn S.
      A simple method for converting an odds ratio to effect size for use in meta-analysis.
      :
      lnOR=π3×SMD


      where lnOR is the logarithm of OR, and SMD is the standardized mean difference in cases and controls.
      Figure thumbnail fx1
      Supplementary Figure 1Funnel plot asymmetry seen in studies on patients with BE.
      Supplementary Table 1Newcastle-Ottawa Scale for Assessment of Quality of Included Studies: Case-control Studies
      Quality assessment criteriaAcceptable(*)Anderson
      • Anderson L.A.
      • Watson R.G.
      • Murphy S.J.
      • et al.
      Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
      Beddy
      • Beddy P.
      • Howard J.
      • McMahon C.
      • et al.
      Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
      Chua
      • Chua C.S.
      • Lin Y.M.
      • Yu F.C.
      • et al.
      Metabolic risk factors associated with erosive esophagitis.
      Chung
      • Chung S.J.
      • Kim D.
      • Park M.J.
      • et al.
      Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
      Corley
      • Corley D.A.
      • Kubo A.
      • Levin T.R.
      • et al.
      Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
      Corley
      • Corley D.A.
      • Kubo A.
      • Zhao W.
      Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
      Edelstein
      • Edelstein Z.R.
      • Farrow D.C.
      • Bronner M.P.
      • et al.
      Central adiposity and risk of Barrett's esophagus.
      • Edelstein Z.R.
      • Bronner M.P.
      • Rosen S.N.
      • et al.
      Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
      El-Serag
      • El-Serag H.B.
      • Kvapil P.
      • Hacken-Bitar J.
      • et al.
      Abdominal obesity and the risk of Barrett's esophagus.
      Greer
      • Greer K.B.
      • Thompson C.L.
      • Brenner L.
      • et al.
      Association of insulin and insulin-like growth factors with Barrett's oesophagus.
      Healy
      • Healy L.A.
      • Ryan A.M.
      • Pidgeon G.
      • et al.
      Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
      Kendall
      • Kendall B.J.
      • Macdonald G.A.
      • Hayward N.K.
      • et al.
      The risk of Barrett's esophagus associated with abdominal obesity in males and females.
      Kramer
      • El-Serag H.B.
      • Hashmi A.
      • Garcia J.
      • et al.
      Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
      • Kramer J.R.
      • Fischbach L.A.
      • Richardson P.
      • et al.
      Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
      Lee
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between GERD-related erosive esophagitis and obesity.
      • Lee H.L.
      • Eun C.S.
      • Lee O.Y.
      • et al.
      Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
      Mokrowiecka
      • Mokrowiecka A.
      • Daniel P.
      • Jasinska A.
      • et al.
      Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
      Mulholland
      • Mulholland H.G.
      • Cantwell M.M.
      • Anderson L.A.
      • et al.
      Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
      Nelsen
      • Nelsen E.M.
      • Kirihara Y.
      • Takahashi N.
      • et al.
      Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
      Park
      • Park J.H.
      • Park D.I.
      • Kim H.J.
      • et al.
      Metabolic syndrome is associated with erosive esophagitis.
      Rubenstein
      • Rubenstein J.H.
      • Dahlkemper A.
      • Kao J.Y.
      • et al.
      A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
      Rubenstein
      • Rubenstein J.H.
      • Kao J.Y.
      • Madanick R.D.
      • et al.
      Association of adiponectin multimers with Barrett's oesophagus.
      Wu
      • Wu P.
      • Ma L.
      • Dai G.X.
      • et al.
      The association of metabolic syndrome with reflux esophagitis: a case-control study.
      Selection
       Is the case definition adequate?Yes, with independent validation******************
       Representativeness of cases?Consecutive or obviously representative series of cases*****************
       Selection of controls?Community controls********
       Definition of controls?No history of EE/BE/EAC******************
      Comparability
       Study controls for age/sexYes******************
       Study controls for at least 3 additional factorsRace, BMI, smoking, alcohol, GERD or reflux symptoms, PPI use, hiatal hernia, family history of outcome, caffeine intake, Helicobacter pylori infection

      For studies on BE: medication use (aspirin/NSAIDs/PPIs/statins)

      For studies on EAC: presence of BE, length of BE segment, histology of BE
      **************
      Exposure
       Ascertainment of exposure?Secure record, structured interview by healthcare practitioner, blinded to case/control status********
       Same method of ascertainment of cases/controls?Yes*******************
       Non-response rate?Same for both groups*******
      Overall study quality (maximum = 9)76568865649663785778
      NOTE. Each asterisk represents if individual criterion within the subsection was fulfilled.
      NSAIDs, nonsteroidal anti-inflammatory drugs; PPIs, proton pump inhibitors.
      Supplementary Table 2Newcastle-Ottawa Scale for Assessment of Quality of Included Studies: Cohort and Cross-sectional Studies
      Quality assessment criteriaAcceptable(*)Akiyama
      • Akiyama T.
      • Yoneda M.
      • Inamori M.
      • et al.
      Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease.
      Gunji
      • Gunji T.
      • Sato H.
      • Iijima K.
      • et al.
      Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
      Ha
      • Ha N.R.
      • Lee H.L.
      • Lee O.Y.
      • et al.
      Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
      Hsu
      • Hsu C.S.
      • Wang P.C.
      • Chen J.H.
      • et al.
      Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.
      Jacobson
      • Jacobson B.C.
      • Chan A.T.
      • Giovannucci E.L.
      • et al.
      Body mass index and Barrett's oesophagus in women.
      Kang
      • Kang M.S.
      • Park D.I.
      • Oh S.Y.
      • et al.
      Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
      Kato
      • Kato M.
      • Watabe K.
      • Hamasaki T.
      • et al.
      Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.
      Koo
      • Koo J.S.
      • Lee S.W.
      • Park S.M.
      • et al.
      Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
      Lee
      • Lee S.J.
      • Jung M.K.
      • Kim S.K.
      • et al.
      [Clinical characteristics of gastroesophageal reflux disease with esophageal injury in Korean: focusing on risk factors].
      MacInnis
      • MacInnis R.J.
      • English D.R.
      • Hopper J.L.
      • et al.
      Body size and composition and the risk of gastric and oesophageal adenocarcinoma.
      Nam
      • Nam S.Y.
      • Choi I.J.
      • Nam B.H.
      • et al.
      Obesity and weight gain as risk factors for erosive oesophagitis in men.
      Nam
      • Nam S.Y.
      • Choi I.J.
      • Ryu K.H.
      • et al.
      Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
      O'Dpherty
      • O'Doherty M.G.
      • Freedman N.D.
      • Hollenbeck A.R.
      • et al.
      A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
      Rubenstein
      • Rubenstein J.H.
      • Morgenstern H.
      • Appelman H.
      • et al.
      Prediction of Barrett's esophagus among men.
      Sogabe
      • Sogabe M.
      • Okahisa T.
      • Kimura Y.
      • et al.
      Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
      Steffen
      • Steffen A.
      • Schulze M.B.
      • Pischon T.
      • et al.
      Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition.
      Tai
      • Tai C.M.
      • Lee Y.C.
      • Tu H.P.
      • et al.
      The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
      Selection
       Representativeness of exposed cohort?Representative of average adult in community (age/sex/being at risk of disease)****
       Selection of the nonexposed cohort?Drawn from same community as exposed cohort*****************
       Ascertainment of exposure?Secured records, structured interview****************
       Demonstration that outcome of interest was not present at start of study?Only incident cases of outcome*****
      Comparability
       Study controls for age/sex?Yes***************
       Study controls for at least 3 additional risk factors?Race, BMI, smoking, alcohol, GERD or reflux symptoms, PPI use, hiatal hernia, family history of outcome, caffeine intake, Helicobacter pylori infection

      For studies on BE: Medication use (aspirin/NSAIDs/PPIs/statins)

      For studies on EAC: presence of BE, length of BE segment, histology of BE
      *************
      Outcome
       Assessment of outcome?Independent blinded assessment, record linkage**************
       Was follow-up long enough for outcome to occur?Follow-up >3 y*****
       Adequacy of follow-up of cohorts?Complete follow-up, or subjects lost to follow-up unlikely to introduce bias***
      Overall quality of studies (maximum = 9)45556546385585585
      NOTE. Each asterisk represents if individual criterion within the subsection was fulfilled. Note that cross-sectional studies were treated as cohort studies for quality assessment.
      NSAIDs, nonsteroidal anti-inflammatory drugs; PPIs, proton pump inhibitors.
      Supplementary Table 3Sensitivity Analysis of Studies That Reported ORs per Unit Change in Exposure
      No. of studiesUnitOR95% CI
      EE
       Visceral adipose tissue area1Per 1-cm2 increase1.0011.000–1.002
       Subcutaneous adipose tissue area1Per 1-cm2 increase0.9990.997–1.001
       WC3Per 1-cm increase1.0211.007–1.035
       BMI2Per 1-kg/m2 increase1.0621.029–1.095
      BE
       Visceral adipose tissue area2Per 1-cm2 increase (1 study);

      per 10-cm2 increase (1 study)
      1.007

      1.077
      1.000–1.015

      1.070–1.151
       BMI2Per 1-kg/m2 increase1.0150.935–1.103
      EAC
       WC2Per 1-cm increase (1 study);

      per 10-cm increase (1 study)
      1.100

      1.460
      1.032–1.172

      1.047–2.035
       WHR1Per 0.1-unit increase1.5900.935–2.704
       BMI1Per 1-kg/m2 increase1.0900.981–1.211

      References

        • Cook M.B.
        • Greenwood D.C.
        • Hardie L.J.
        • et al.
        A systematic review and meta-analysis of the risk of increasing adiposity on Barrett's esophagus.
        Am J Gastroenterol. 2008; 103: 292-300
        • Corley D.A.
        • Kubo A.
        Body mass index and gastroesophageal reflux disease: a systematic review and meta-analysis.
        Am J Gastroenterol. 2006; 101: 2619-2628
        • Hampel H.
        • Abraham N.S.
        • El-Serag H.B.
        Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.
        Ann Intern Med. 2005; 143: 199-211
        • Lagergren J.
        Influence of obesity on the risk of esophageal disorders.
        Nat Rev Gastroenterol Hepatol. 2011; 8: 340-347
        • Turati F.
        • Tramacere I.
        • La Vecchia C.
        • et al.
        A meta-analysis of body mass index and esophageal and gastric cardia adenocarcinoma.
        Ann Oncol. 2013; 24: 609-617
        • Pandolfino J.E.
        • El-Serag H.B.
        • Zhang Q.
        • et al.
        Obesity: a challenge to esophagogastric junction integrity.
        Gastroenterology. 2006; 130: 639-649
        • Friedenberg F.K.
        • Xanthopoulos M.
        • Foster G.D.
        • et al.
        The association between gastroesophageal reflux disease and obesity.
        Am J Gastroenterol. 2008; 103: 2111-2122
        • Moayyedi P.
        Barrett's esophagus and obesity: the missing part of the puzzle.
        Am J Gastroenterol. 2008; 103: 301-303
        • Corley D.A.
        • Kubo A.
        • Levin T.R.
        • et al.
        Abdominal obesity and body mass index as risk factors for Barrett's esophagus.
        Gastroenterology. 2007; 133 (quiz 311): 34-41
        • Edelstein Z.R.
        • Farrow D.C.
        • Bronner M.P.
        • et al.
        Central adiposity and risk of Barrett's esophagus.
        Gastroenterology. 2007; 133: 403-411
        • Rubenstein J.H.
        • Kao J.Y.
        • Madanick R.D.
        • et al.
        Association of adiponectin multimers with Barrett's oesophagus.
        Gut. 2009; 58: 1583-1589
        • Nam S.Y.
        • Choi I.J.
        • Ryu K.H.
        • et al.
        Abdominal visceral adipose tissue volume is associated with increased risk of erosive esophagitis in men and women.
        Gastroenterology. 2010; 139: 1902-1911
        • Anderson L.A.
        • Watson R.G.
        • Murphy S.J.
        • et al.
        Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma: results from the FINBAR study.
        World J Gastroenterol. 2007; 13: 1585-1594
        • Sogabe M.
        • Okahisa T.
        • Kimura Y.
        • et al.
        Visceral fat predominance is associated with erosive esophagitis in Japanese men with metabolic syndrome.
        Eur J Gastroenterol Hepatol. 2012; 24: 910-916
        • Tilg H.
        • Moschen A.R.
        Visceral adipose tissue attacks beyond the liver: esophagogastric junction as a new target.
        Gastroenterology. 2010; 139: 1823-1826
        • Nelsen E.M.
        • Kirihara Y.
        • Takahashi N.
        • et al.
        Distribution of body fat and its influence on esophageal inflammation and dysplasia in patients with Barrett's esophagus.
        Clin Gastroenterol Hepatol. 2012; 10 (quiz e61–e62): 728-734
        • Higgins J.P.T.
        Cochrane handbook for systematic reviews of interventions.
        ([updated March 2011]) The Cochrane Collaboration, Oxford, UK2011
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        Ann Intern Med. 2009; 151 (W64): 264-269
        • Chinn S.
        A simple method for converting an odds ratio to effect size for use in meta-analysis.
        Stat Med. 2000; 19: 3127-3131
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Kanwal F.
        • White D.
        Systematic reviews and meta-analyses in Clinical Gastroenterology and Hepatology.
        Clin Gastroenterol Hepatol. 2012; 10: 1184-1186
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Thompson S.G.
        • Pocock S.J.
        Can meta-analyses be trusted?.
        Lancet. 1991; 338: 1127-1130
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • et al.
        GRADE guidelines: 7—rating the quality of evidence: inconsistency.
        J Clin Epidemiol. 2011; 64: 1294-1302
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • et al.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Easterbrook P.J.
        • Berlin J.A.
        • Gopalan R.
        • et al.
        Publication bias in clinical research.
        Lancet. 1991; 337: 867-872
        • Chua C.S.
        • Lin Y.M.
        • Yu F.C.
        • et al.
        Metabolic risk factors associated with erosive esophagitis.
        J Gastroenterol Hepatol. 2009; 24: 1375-1379
        • Chung S.J.
        • Kim D.
        • Park M.J.
        • et al.
        Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.
        Gut. 2008; 57: 1360-1365
        • Gunji T.
        • Sato H.
        • Iijima K.
        • et al.
        Risk factors for erosive esophagitis: a cross-sectional study of a large number of Japanese males.
        J Gastroenterol. 2011; 46: 448-455
        • Ha N.R.
        • Lee H.L.
        • Lee O.Y.
        • et al.
        Differences in clinical characteristics between patients with non-erosive reflux disease and erosive esophagitis in Korea.
        J Korean Med Sci. 2010; 25: 1318-1322
        • Hsu C.S.
        • Wang P.C.
        • Chen J.H.
        • et al.
        Increasing insulin resistance is associated with increased severity and prevalence of gastro-oesophageal reflux disease.
        Aliment Pharmacol Ther. 2011; 34: 994-1004
        • Koo J.S.
        • Lee S.W.
        • Park S.M.
        • et al.
        Abdominal obesity as a risk factor for the development of erosive esophagitis in subjects with a normal esophago-gastric junction.
        Gut Liver. 2009; 3: 276-284
        • Lee H.L.
        • Eun C.S.
        • Lee O.Y.
        • et al.
        Association between GERD-related erosive esophagitis and obesity.
        J Clin Gastroenterol. 2008; 42: 672-675
        • Lee H.L.
        • Eun C.S.
        • Lee O.Y.
        • et al.
        Association between erosive esophagitis and visceral fat accumulation quantified by abdominal CT scan.
        J Clin Gastroenterol. 2009; 43: 240-243
        • Mokrowiecka A.
        • Daniel P.
        • Jasinska A.
        • et al.
        Serum adiponectin, resistin, leptin concentration and central adiposity parameters in Barrett's esophagus patients with and without intestinal metaplasia in comparison to healthy controls and patients with GERD.
        Hepatogastroenterology. 2012; 59: 2395-2399
        • Mulholland H.G.
        • Cantwell M.M.
        • Anderson L.A.
        • et al.
        Glycemic index, carbohydrate and fiber intakes and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.
        Cancer Causes Control. 2009; 20: 279-288
        • Nam S.Y.
        • Choi I.J.
        • Nam B.H.
        • et al.
        Obesity and weight gain as risk factors for erosive oesophagitis in men.
        Aliment Pharmacol Ther. 2009; 29: 1042-1052
        • Park J.H.
        • Park D.I.
        • Kim H.J.
        • et al.
        Metabolic syndrome is associated with erosive esophagitis.
        World J Gastroenterol. 2008; 14: 5442-5447
        • Tai C.M.
        • Lee Y.C.
        • Tu H.P.
        • et al.
        The relationship between visceral adiposity and the risk of erosive esophagitis in severely obese Chinese patients.
        Obesity (Silver Spring). 2010; 18: 2165-2169
        • Wu P.
        • Ma L.
        • Dai G.X.
        • et al.
        The association of metabolic syndrome with reflux esophagitis: a case-control study.
        Neurogastroenterol Motil. 2011; 23: 989-994
        • Kang M.S.
        • Park D.I.
        • Oh S.Y.
        • et al.
        Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population.
        J Gastroenterol Hepatol. 2007; 22: 1656-1661
        • Kato M.
        • Watabe K.
        • Hamasaki T.
        • et al.
        Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.
        J Gastroenterol. 2011; 46: 1361-1367
        • Lee S.J.
        • Jung M.K.
        • Kim S.K.
        • et al.
        [Clinical characteristics of gastroesophageal reflux disease with esophageal injury in Korean: focusing on risk factors].
        Korean J Gastroenterol. 2011; 57: 281-287
        • Akiyama T.
        • Yoneda M.
        • Inamori M.
        • et al.
        Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non-alcoholic fatty liver disease.
        BMC Gastroenterol. 2009; 9: 56
        • Edelstein Z.R.
        • Bronner M.P.
        • Rosen S.N.
        • et al.
        Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study.
        Am J Gastroenterol. 2009; 104: 834-842
        • El-Serag H.B.
        • Kvapil P.
        • Hacken-Bitar J.
        • et al.
        Abdominal obesity and the risk of Barrett's esophagus.
        Am J Gastroenterol. 2005; 100: 2151-2156
        • Healy L.A.
        • Ryan A.M.
        • Pidgeon G.
        • et al.
        Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.
        Dis Esophagus. 2010; 23: 386-391
        • Jacobson B.C.
        • Chan A.T.
        • Giovannucci E.L.
        • et al.
        Body mass index and Barrett's oesophagus in women.
        Gut. 2009; 58: 1460-1466
        • Kendall B.J.
        • Macdonald G.A.
        • Hayward N.K.
        • et al.
        The risk of Barrett's esophagus associated with abdominal obesity in males and females.
        Int J Cancer. 2013; 132: 2192-2199
        • Rubenstein J.H.
        • Dahlkemper A.
        • Kao J.Y.
        • et al.
        A pilot study of the association of low plasma adiponectin and Barrett's esophagus.
        Am J Gastroenterol. 2008; 103: 1358-1364
        • Greer K.B.
        • Thompson C.L.
        • Brenner L.
        • et al.
        Association of insulin and insulin-like growth factors with Barrett's oesophagus.
        Gut. 2012; 61: 665-672
        • Rubenstein J.H.
        • Morgenstern H.
        • Appelman H.
        • et al.
        Prediction of Barrett's esophagus among men.
        Am J Gastroenterol. 2013; 108: 353-362
        • El-Serag H.B.
        • Hashmi A.
        • Garcia J.
        • et al.
        Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: a case-control study.
        Gut. 2013; (Feb 13. Epub ahead of print.)
        • Kramer J.R.
        • Fischbach L.A.
        • Richardson P.
        • et al.
        Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett's esophagus in white men.
        Clin Gastroenterol Hepatol. 2013; 11: 373-381
        • Beddy P.
        • Howard J.
        • McMahon C.
        • et al.
        Association of visceral adiposity with oesophageal and junctional adenocarcinomas.
        Br J Surg. 2010; 97: 1028-1034
        • Corley D.A.
        • Kubo A.
        • Zhao W.
        Abdominal obesity and the risk of esophageal and gastric cardia carcinomas.
        Cancer Epidemiol Biomarkers Prev. 2008; 17: 352-358
        • MacInnis R.J.
        • English D.R.
        • Hopper J.L.
        • et al.
        Body size and composition and the risk of gastric and oesophageal adenocarcinoma.
        Int J Cancer. 2006; 118: 2628-2631
        • O'Doherty M.G.
        • Freedman N.D.
        • Hollenbeck A.R.
        • et al.
        A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
        Gut. 2012; 61: 1261-1268
        • Steffen A.
        • Schulze M.B.
        • Pischon T.
        • et al.
        Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 2079-2089
        • Thompson O.M.
        • Beresford S.A.
        • Kirk E.A.
        • et al.
        Serum leptin and adiponectin levels and risk of Barrett's esophagus and intestinal metaplasia of the gastroesophageal junction.
        Obesity (Silver Spring). 2010; 18: 2204-2211
        • Kubo A.
        • Levin T.R.
        • Block G.
        • et al.
        Cigarette smoking and the risk of Barrett's esophagus.
        Cancer Causes Control. 2009; 20: 303-311
        • Leggett C.
        • Dunagan K.T.
        • Katzka D.A.
        • et al.
        Influence of central obesity on esophageal injury: a population based study.
        Gastroenterology. 2012; 142 (S-759)
        • Rubenstein J.H.
        • Chey W.D.
        • Murray J.A.
        • et al.
        Acid reflux, erosive esophagitis, and Barrett's esophagus are associated with different measures of abdominal obesity in men.
        Gastroenterology. 2012; 142 (S-754)
        • Cooper S.C.
        • Podmore L.K.
        • Nightingale P.
        • et al.
        The effect of smoking, body mass index, and waist circumference on the development of oesophageal adenocarcinoma: results from MOSES (Midlands Oesophageal Adenocarcinoma Epidemiology Study).
        Gastroenterology. 2009; 136: A456
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • El-Serag H.B.
        • Ergun G.A.
        • Pandolfino J.
        • et al.
        Obesity increases oesophageal acid exposure.
        Gut. 2007; 56: 749-755
        • Coussens L.M.
        • Werb Z.
        Inflammation and cancer.
        Nature. 2002; 420: 860-867
        • Ryan A.M.
        • Duong M.
        • Healy L.
        • et al.
        Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets.
        Cancer Epidemiol. 2011; 35: 309-319
        • Kendall B.J.
        • Macdonald G.A.
        • Hayward N.K.
        • et al.
        Leptin and the risk of Barrett's oesophagus.
        Gut. 2008; 57: 448-454
        • Francois F.
        • Roper J.
        • Goodman A.J.
        • et al.
        The association of gastric leptin with oesophageal inflammation and metaplasia.
        Gut. 2008; 57: 16-24
        • Larsson S.C.
        • Wolk A.
        Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies.
        Am J Clin Nutr. 2007; 86: 556-565
        • Aune D.
        • Greenwood D.C.
        • Chan D.S.
        • et al.
        Body mass index, abdominal fatness and pancreatic cancer risk: a systematic review and non-linear dose-response meta-analysis of prospective studies.
        Ann Oncol. 2012; 23: 843-852
        • Doyle S.L.
        • Donohoe C.L.
        • Finn S.P.
        • et al.
        IGF-1 and its receptor in esophageal cancer: association with adenocarcinoma and visceral obesity.
        Am J Gastroenterol. 2012; 107: 196-204
        • McElholm A.R.
        • McKnight A.J.
        • Patterson C.C.
        • et al.
        A population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequence.
        Gastroenterology. 2010; 139: 204-212
        • Hardikar S.
        • Onstad L.
        • Blount P.L.
        • et al.
        The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett's esophagus.
        PLoS One. 2013; 8: e52192
        • Kubo A.
        • Cook M.B.
        • Shaheen N.J.
        • et al.
        Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium.
        Gut. 2013; (Jan 26. Epub ahead of print.)

      Linked Article

      • Weight Change and Weight Cycling Are Not Associated With Risk of Barrett’s Esophagus
        Clinical Gastroenterology and HepatologyVol. 14Issue 12
        • Preview
          We read with interest studies published in Clinical Gastroenterology and Hepatology demonstrating a strong association between obesity and esophageal inflammation, metaplasia, and neoplasia1 and the possible importance of weight loss in the treatment of patients with gastroesophageal reflux disease.2 Because of the continuing rise in incidence of esophageal adenocarcinoma,3,4 these studies highlight the potential number of cases of cancer (as well as Barrett’s esophagus [BE]) that could be prevented through maintaining a normal body weight.
        • Full-Text
        • PDF