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      The Effect of Abdominal Visceral Fat, Circulating Inflammatory Cytokines, and Leptin Levels on Reflux Esophagitis

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          Abstract

          Background/Aims

          Although adipocytes secrete inflammatory cytokines and adipokines, their role in reflux esophagitis is controversial. We investigated the association between visceral fat and inflammatory cytokines or adipokines in reflux esophagitis.

          Methods

          Abdominal visceral fat and cytokines were measured in 66 individuals with reflux esophagitis and 66 age- and sex-matched controls. The mean values for visceral fat and cytokines were compared in cases and controls. Second, correlations between visceral fat and inflammatory cytokines were measured. Finally, multiple logistic regression models for odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the effects of visceral fat and cytokines on reflux esophagitis.

          Results

          Visceral fat, leptin, interleukin (IL)-6, and IL-1β were higher in reflux esophagitis compared to controls. Visceral fat showed a strong positive correlation with IL-6 ( r = 0.523, P < 0.001), IL-8 ( r = 0.395, P < 0.001), and IL-1β ( r = 0.557, P < 0.001), and a negative correlation with adiponectin ( r = −0.466, P < 0.001). With adjusted analysis, visceral fat/100 (OR, 4.32; 95% CI, 2.18–8.58; P < 0.001) and leptin (OR, 1.36; 95% CI, 1.10–1.69; P = 0.005) independently increased the risk of reflux esophagitis, but the effects of other cytokines were abolished.

          Conclusions

          Visceral fat may increase the risk of reflux esophagitis by increasing the levels of inflammatory cytokines. Leptin showed a positive association with reflux esophagitis that was independent of visceral fat.

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          Most cited references27

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          Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.

          Reflux esophagitis is believed to be caused by the caustic effects of refluxed gastric acid on esophageal epithelial cells. However, caustic chemical injuries develop rapidly whereas esophagitis might not appear until weeks after the induction of reflux in animal models. We studied early histologic events in the development of reflux esophagitis in a rat model and performed in vitro experiments to determine whether exposure to acidified bile salts causes esophageal epithelial cells to secrete chemokines that might contribute to inflammation. At various time points after esophagoduodenostomy, the rat esophagus was removed and inflammatory changes were analyzed by histologic analyses. Human esophageal squamous cell lines were exposed to acidified bile salts to evaluate their effects on cytokine production and immune-cell migration. Reflux esophagitis started at postoperative day 3 with lymphocytic infiltration of the submucosa that progressed to the epithelial surface-these findings contradicted those expected from a caustic chemical injury. Basal cell and papillary hyperplasia preceded the development of surface erosions. Exposure of squamous cells to acidified bile salts significantly increased the secretion of interleukin-8 and interleukin-1beta; conditioned media from these cells caused significant increases in the migration rates of T cells and neutrophils. These findings support, but do not prove, an alternative concept for the development of reflux esophagitis in which refluxed gastric juice does not directly damage the esophagus, but rather stimulates esophageal epithelial cells to secrete chemokines that mediate damage of esophageal tissue.
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            Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis.

            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. 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. 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. 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. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Metabolic syndrome and visceral obesity as risk factors for reflux oesophagitis: a cross-sectional case-control study of 7078 Koreans undergoing health check-ups.

              Obesity has been associated with reflux oesophagitis. However, the relationship between metabolic syndrome characterised by visceral obesity and reflux oesophagitis is unclear. To investigate whether metabolic syndrome or visceral obesity is a risk factor for reflux oesophagitis. A cross-sectional study of 7078 subjects undergoing upper endoscopy during health check-ups was conducted (3539 patients with reflux oesophagitis vs age- and sex-matched controls). We further analysed according to categories of visceral adipose tissue and subcutaneous adipose tissue area with 750 cases and age-, sex- and waist circumference-matched controls who underwent abdominal CT scan. The prevalence of metabolic syndrome was higher in cases than controls (26.9% vs 18.5%, p<0.001). Multivariate analysis demonstrated that metabolic syndrome is associated with reflux oesophagitis (odds ratio (OR) = 1.42; 95% confidence interval (CI), 1.26 to 1.60). Among the individual components of metabolic syndrome, waist circumference (OR = 1.47; 95% CI, 1.30 to 1.65) and triglyceride (OR = 1.20; 95% CI, 1.05 to 1.36) independently increased the risk for reflux oesophagitis. On sub-analysis, cases showed higher mean visceral adipose tissue area (cm(2)) (136.1 (SD 57.8) vs 124.0 (SD 54.7), p<0.001) and subcutaneous adipose tissue area (cm(2)) (145.9 (SD 56.8) vs 133.5 (SD 50.7), p<0.001). However, only visceral adipose tissue area was an independent risk factor for reflux oesophagitis after adjusting for multiple confounders including smoking, alcohol, body mass index (BMI) and subcutaneous adipose tissue area (OR = 1.60; 95% CI, 1.03 to 2.48, lowest quartile vs highest quartile). Metabolic syndrome was associated with reflux oesophagitis. Abdominal obesity, especially visceral obesity, was an important risk factor for reflux oesophagitis.
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                Author and article information

                Journal
                J Neurogastroenterol Motil
                J Neurogastroenterol Motil
                Journal of Neurogastroenterology and Motility
                Korean Society of Neurogastroenterology and Motility
                2093-0879
                2093-0887
                April 2015
                : 21
                : 2
                : 247-254
                Affiliations
                [1 ]Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Gyeonggi-do, Korea
                [2 ]Center for Gastric Cancer, Kyungpook National University Hospital, Daegu, Korea
                [3 ]Center for Gastric Cancer, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do, Korea
                [4 ]Department of Radiology, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do, Korea
                [5 ]Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do, Korea
                Author notes
                [* ]Correspondence: Su Youn Nam, MD, PhD, Center for Gastric Cancer, Kyungpook National University Hospital, 807, Hoguk-ro, Buk-gu 702-911, Daegu, Korea, Tel: +82-53-200-1620, E-mail: mascha@ 123456medimail.co.kr
                Il Ju Choi, MD, PhD, Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsan dong-gu, Goyang, Gyeonggi-do 411-769, Korea, Tel: +82-31-920-2282, Fax: +82-31-920-1127, E-mail: cij1224@ 123456ncc.re.kr
                Article
                jnm-21-247
                10.5056/jnm14114
                4398239
                25843077
                4e2942bc-77e1-42cd-86af-4624f366bd4d
                © 2015 The Korean Society of Neurogastroenterology and Motility

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 October 2014
                : 15 December 2014
                : 26 December 2014
                Categories
                Original Article

                Neurology
                adipokines,cytokines,esophagitis
                Neurology
                adipokines, cytokines, esophagitis

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