Abdominal Visceral Adipose Tissue Volume Is Associated With Increased Risk of Erosive Esophagitis in Men and Women

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1 GASTROENTEROLOGY 2010;139: Abdominal Visceral Adipose Tissue Volume Is Associated With Increased Risk of Erosive Esophagitis in Men and Women SU YOUN NAM,* IL JU CHOI, KUM HEI RYU,* BUM JOON PARK,* HYUN BUM KIM, and BYUNG HO NAM *Center for Cancer Prevention and Detection, Center for Gastric Cancer, Department of Radiology, and Center for Clinical Trials, National Cancer Center, Goyang, Korea See editorial on page BACKGROUND & AIMS: Data on the association between erosive esophagitis and obesity are inconsistent because of variations in study populations and methods used to determine obesity. METHODS: Participants in a prospective health-screening cohort underwent esophagogastroduodenoscopy and computed tomography. The association between erosive esophagitis and obesity (measured by body mass index [BMI], waist circumference, and abdominal visceral adipose tissue volume) was estimated with odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounding factors. We also analyzed the association between obesity and erosive esophagitis by sex. RESULTS: The prevalence of erosive esophagitis was 9.3% (495/5329). The OR for erosive esophagitis correlated with obesity measured by BMI, waist circumference, and abdominal visceral adipose tissue volume (P.001 for each factor). The multivariate OR for erosive esophagitis was 1.97 (95% CI: ) for a visceral adipose tissue volume of cm 3, 2.27 (95% CI: ) for cm 3, and 2.94 (95% CI: ) for 1500 cm 3, compared with participants who had visceral adipose tissue volumes less than 500 cm 3. When measures of obesity were analyzed simultaneously, abdominal visceral adipose tissue volume, but not BMI or waist circumference, was associated with erosive esophagitis. The 3 measures of obesity were significantly associated with erosive esophagitis in males, but only visceral adipose tissue volume was associated with erosive esophagitis in females (P.002). CONCLUSIONS: In contrast to BMI or waist circumference, abdominal visceral adipose tissue volume is associated with an increased risk of erosive esophagitis in males and females. Keywords: Gastroesophageal Reflux Disease; Reflux Esophagitis; Visceral Fat; Abdominal Obesity. Gastroesophageal reflux disease (GERD) is a major health problem in Western countries. 1 The prevalence of GERD is increasing in Asian countries, and the prevalence of obesity has also increased over the past few decades. 2 4 Population-based studies have identified a positive association between GERD symptoms and obesity. 5,6 Although many studies have suggested that the risk for developing GERD symptoms or erosive esophagitis increases with increasing body mass index (BMI), 4,7 10 the association between these 2 factors is inconsistent and varies with sex, ethnic origin, and other confounding factors A recent study using large cohorts reported that GERD symptoms were more closely associated with BMI than with waist-to-hip ratio in women. 14 However, GERD symptoms were positively associated with abdominal diameter in white males, independently of BMI. 15 Abdominal visceral adipose tissue not only has metabolic effects 16 but may also increase intra-abdominal pressure. In a previously published study, increase of BMIs had increased expiratory and inspiratory intragastric pressure. 17 Furthermore, visceral adipose tissue is a source of inflammatory cytokines and is associated with systemic inflammation in obese subjects. 18,19 Data from a recent study suggested that abdominal visceral adipose tissue may be a better predictor of GERD than BMI or waist circumference. 20 Abdominal adipose tissue distribution varies according to age, sex, and ethnicity. 21,22 The association between type of adipose tissue with BMI or waist circumference was strongest for total adipose tissue, intermediate for subcutaneous adipose tissue, and weakest for visceral adipose tissue. 23 In contrast to subcutaneous adipose tissue, which can be estimated from simple anthropometric measurements such as subscapular and paraumbilical skin fold measured by caliper, visceral adipose tissue can only be measured using magnetic resonance imaging (MRI) or computed tomography (CT). 24 To determine whether BMI, waist circumference, and visceral adipose tissue volume are strong predictors of erosive esophagitis, we compared the association between erosive esophagitis and abdominal visceral adipose tissue volume versus the association between erosive esophagitis and BMI or waist circumference in Korean males and females. Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; CT, computed tomography; GERD, gastroesophageal reflux disease; MRI, magnetic resonance imaging; OR, odds ratio by the AGA Institute /$36.00 doi: /j.gastro

2 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS 1903 Figure 1. Study flow. MDCT, multidetector computed tomography. Patients and Methods Study Population and Questionnaire A comprehensive health-screening program was launched at Korean National Cancer Center in May For the baseline examination, the screening program included physical examination, blood tests, lowdose chest CT, abdominal ultrasonography, esophagogastroduodenoscopy, colonoscopy, and questionnaires including lifestyle factor, medication, and chronic disease. Among the participants, a total of 5500 racially homogenous Korean participants underwent an additional abdominal CT between February 2008 and November 2008 (Figure 1). 26 We excluded patients who had undergone previous gastric surgery, those who did not receive a test for Helicobacter pylori, and current users of proton pump inhibitors. Two well-trained research nurses independently interviewed participants who completed the entire questionnaire, which included questions regarding age, sex, alcohol consumption, smoking status, personal medical history, medication history, GERD symptoms, job, and socioeconomic status prior to screening examination. Smoking and alcohol consumption status were classified as current (daily or occasionally) and noncurrent. Socioeconomic data included duration of education ( 12 years, 12 years) and income per month ( $4000, $4000). Each participant was examined for typical GERD symptoms, including heartburn and acid regurgitation, as well as extraesophageal symptoms, such as globus sensation, hoarseness, epigastric soreness, and chronic cough. The subjects reported the frequency of symptoms as one of the following: none in the past year, less than once a month, approximately 1 to 3 times per a month, approximately once a week, several times a week, or daily. Severity of symptom was reported as mild ( can be ignored if I don t think about it ), moderate ( cannot be ignored, but does not affect my lifestyle ) or severe ( affects my lifestyle or disturbs work or sleeping ). 4 The National Cancer Center Institutional Review Board approved the study (NCCNCS ), and all participants provided written informed consent for the use of personal data for research. Endoscopy Esophagogastroduodenoscopy was performed using a flexible endoscope (Q260; Olympus Optical, Tokyo, Japan) after overnight fasting. Pharyngeal anesthesia with 4% xylocaine spray and conscious sedation using midazolam (0.06 mg/kg) was provided routinely. We inspected the gastroesophageal junction before inflation of the stomach and acquired at least 3 photos of the Picture Archiving Communications System images (Infinitt Healthcare, Seoul, South Korea). The severity of erosive esophagitis was graded from A to D according to the Los Angeles (LA) classification system. 27 Minor changes, including distal esophageal erythema or hyperemia, granularity, and blurring in the squamocolumnar junction, were excluded to increase specificity. Four gastroenterologists with gastroenterology and endoscopy specialty board certification (S. Y. Nam, K. H. Ryu, B. J. Park, and K. W. Park) performed all endoscopic procedures while blinded to the questionnaire results. During each endoscopic examination, a biopsy specimen was obtained at the greater curvature of the body for H pylori evaluation using the rapid urease test (Pronto Dry; Medical Instruments, Solothurn, Switzerland). Hiatal hernia was recorded as present if the gastroesophageal junction extended at least 2 cm above the diaphragmatic hiatal impression during quiet respiration. Measurement of the hiatal hernia was performed at the start of the endoscopic examination before inflation of the stomach or at the end of the examination after deflation of the stomach. 28 For estimation of interobserver agreement, Picture Archiving Communications System images lasting approximately 30 seconds from 40 randomly selected cases were reviewed in a single conference room, and the 4 clinicians recorded their gastroesophageal findings. Measurement of Anthropometric Parameters Weight and height measurements were automated (X-SCAN PLUS II; Jawon Medical Co, Kyungsan City, Korea), and BMI was calculated as weight divided by height squared (kg/m 2 ). 29 Participants were categorized according to BMI ( 20.0, , , and 30.0). Waist circumference of each subject was measured by trained nurses at the midpoint between the lower borders of the rib cage and upper pole of iliac crest. Hip circumference was measured using the greatest circumference between the iliac crest and thighs. Waist-tohip ratio was calculated as the ratio of waist circumfer-

3 1904 NAM ET AL GASTROENTEROLOGY Vol. 139, No. 6 ence to hip circumference. Participants were categorized according to waist circumference ( 80.0 cm, cm, cm, and cm). After fasting for 12 hours, a blood sample was taken from which blood lipids and glucose were measured. Measurement of Abdominal Adipose Tissue Volume by CT Participants underwent CT in a supine position using a 64-multidetector CT (Brilliance-64; Philips, Best, The Netherlands). 26 Contiguous 5-mm slices (120 kvp; 150 ma; gantry rotation time, 750 ms) were acquired, and adipose tissue volume was measured using 20 slices measuring 50 mm above to 50 mm below the umbilicus, with a total of 100 mm being covered. Dose-length product of the CT scan was mgy*cm, and the radiation dose was msv. Abdominal fat compartments were manually traced on each image, segmentation of the 20 slices was automatically reconstructed, and volume (cm 3 ) was calculated using Extended Brilliance Workspace version 3.5 software (Philips). By setting attenuation values for a region of interest within a range of 25 to 175 Hounsfield units (window center, 100 Hounsfield units; window width, 150 Hounsfield units), this software automatically calculates the area of abdominal fat. Observers drew outline of the skin and total adipose tissue volume excluding vertebral fat. Visceral adipose tissue volume was defined as intra-abdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and paraspinal muscles. The subcutaneous adipose tissue volume was obtained by subtracting visceral adipose tissue volume from total adipose tissue volume. Validation of Adipose Tissue Volume and Cutoff Values We evaluated reproducibility by analyzing data from 100 subjects (age range, years; 47% females) randomly selected from the 5500 participants in the comprehensive screening program who underwent 64- multidetector CT. To assess interobserver reproducibility, 2 experienced readers measured subcutaneous and visceral adipose tissue volumes. To assess intraobserver reproducibility, 1 reader repeated the measurements at 2 time points, 1 week apart. We then evaluated the association among BMI, waist circumference, and abdominal adipose tissue volume and estimated the difference in obesity indexes by sex. Participants were categorized according to visceral adipose tissue volume ( 500 cm 3, cm 3, cm 3, and 1500 cm 3 ) and according to subcutaneous adipose tissue volume ( 1000 cm 3, cm 3, cm 3, and 2000 cm 3 ). Statistical Analyses We assessed interobserver agreement for esophageal lesions using statistics. Interobserver and intraobserver reproducibility for measuring abdominal adipose tissue volume using CT were assessed using the intraclass correlation coefficient. 30 An intraclass correlation coefficient value close to 1 indicates excellent agreement between the 2 readings. The correlation between abdominal adipose tissue volume and anthropometric measurements was determined by calculating the Pearson correlation coefficient. Differences in the distribution of obesity indexes based on gender were assessed by the t test. P values for trends between obesity indexes and age by sex were calculated using linear regression with continuous variables. The Pearson 2 test or Student t test for independent samples was used to assess the difference in risk factors between subjects with and without erosive esophagitis. The effects of obesity, as measured by BMI, waist circumference, and visceral adipose tissue volume, on erosive esophagitis were estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analysis. Risk factors that were determined as significant by univariate analysis were then subjected to multivariate analysis. We also assessed the association between erosive esophagitis and obesity based on sex. All statistical analyses were performed using STATA software (version 10; College Station, TX). All statistical tests were 2-sided, and P.05 was considered statistically significant. Results Characteristics of Participants A total of 5329 participants met the study inclusion criteria and were enrolled in the study from February 2008 to November 2008 (Figure 1). There was no statistically significant difference between excluded persons and included persons in terms of BMI ( in excluded vs in included persons, P.11) or waist circumference ( cm in excluded vs cm in included persons, P.08). The prevalence of erosive esophagitis, minor changes, and GERD symptoms was 9.3%, 19.8%, and 9.0%, respectively (Figure 1). Whereas BMI, abdominal visceral adipose tissue volume, waist circumference, waist-to-hip ratio, and triglyceride levels were higher in participants with erosive esophagitis, subcutaneous adipose tissue volume was not associated with erosive esophagitis (Table 1). Erosive esophagitis was associated with hypertension, being a current smoker, current alcohol consumption, hiatal hernia, absence of H pylori, absence of atrophic gastritis, and education duration 12 years (Table 1). Most subjects with erosive esophagitis had mild esophagitis, with 75.4% having LA-A (n 373), 23.2% having LA-B (n 115), and 1.4% having LA-C (n 7) esophagitis. The values for erosive esophagitis for the 4 endoscopists were 0.70 for minor changes, 0.86 for grade A, 0.93 for grade B, and 0.91 for grade C. The prevalence of Barrett s esophagus

4 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS 1905 Table 1. Characteristics of 4274 Participants Normal (n 3779) Erosive esophagitis a (n 495) P value Males, number of persons (%) 2042 (54.0) 432 (87.3).001 Age, y, mean standard deviation Measures of obesity, mean standard deviation BMI, kg/m Waist circumference, cm Waist-to-hip ratio Visceral adipose tissue volume, cm Subcutaneous adipose tissue volume, cm Total adipose tissue volume, cm Ratio of visceral/total adipose tissue volume Lipid and glucose profile, mean standard deviation Triglyceride, mmol/l High-density lipoprotein, mmol/l Glucose, mmol/l Known chronic disease and medication, number of persons (%) Hypertension 705 (18.7) 121 (24.4).002 Asthma 126 (3.3) 17 (3.4).91 Diabetes 225 (6.0) 43 (8.7).03 Use of lipid lowering drugs 160 (4.2) 23 (4.6).67 Use of NSAIDs 60 (1.6) 9 (1.8).70 Use of aspirin 373 (9.9) 55 (11.1).31 Lifestyle factors, number of persons (%) Current smoking 1016 (26.9) 248 (50.1).001 Current alcohol consumption 2264 (59.9) 380 (76.8).001 Concomitant endoscopic findings, number of persons (%) Presence of H pylori 2154 (57.0) 135 (27.3).001 Hiatal hernia 33 (0.9) 51 (10.3).001 Presence of atrophic gastritis 1174 (31.1) 90 (18.2).001 Presence of duodenal ulcer or scar 427 (11.3) 65 (13.1).87 Presence of gastric ulcer or scar 102 (2.7) 14 (2.8).23 Socioeconomic status, number of persons (%) Education duration 12 y 2114 (55.9) 309 (62.4).02 Income per month $ (67.3) 346 (69.9).24 BMI, body mass index; H pylori, Helicobacter pylori; NSAIDs, nonsteroidal anti-inflammatory drugs. a Erosive esophagitis refers to reflux esophagitis, Los Angeles classification of grades A to D. was 0.7% (36/5329). The prevalence of other endoscopic findings was 28% (n 1482) for chronic atrophic gastritis, 2.6% (n 138) for benign gastric ulcer or scar, and 11.9% (n 633) for duodenal ulcer or scar. GERD symptoms that occurred weekly had no association with visceral adipose tissue volume, BMI, waist-to-hip ratio, or waist circumference (Supplementary Table 1). Validation of Adipose Tissue Volume Measurements and Distribution of Adipose Tissue by Gender Intraobserver and interobserver measurements were highly reproducible with respect to visceral and subcutaneous adipose tissue volume determination (each intraclass correlation coefficient 0.999). Visceral adipose tissue volume was positively correlated with anthropometric measures, which are widely used obesity indexes (Supplementary Table 2). BMI or waist circumference, however, was most positively correlated for total and subcutaneous adipose tissue volume and least correlated for visceral adipose tissue volume in both sexes (Supplementary Table 2). Males have higher visceral adipose tissue volume and lower subcutaneous adipose tissue volume than females (Table 2). Visceral adipose tissue volume and waist-to-hip ratio increased with advancing age in both sexes (P.001); however, subcutaneous adipose tissue volume and BMI increased with age in females but decreased with age in males (P.001, Table 2). Association of Obesity With Erosive Esophagitis Erosive esophagitis was positively correlated with BMI, abdominal visceral adipose tissue volume, waist-tohip ratio, and waist circumference, but not with subcutaneous adipose tissue volume, as determined by univariate analysis (Table 3). When BMI, waist circumference, and visceral adipose tissue volume were considered separately, the multivariate ORs for erosive esophagitis increased with increasing values for each obesity index (P value for each trend.001, Table 4). When BMI, waist circumference, and visceral adipose tissue volume were considered simultaneously by multivariate analysis, erosive esophagitis had no association with BMI, waist circumference, or waist-to-

5 1906 NAM ET AL GASTROENTEROLOGY Vol. 139, No. 6 Table 2. Distribution of Abdominal Adipose Tissue Volume by Age and Sex Obesity indexes Sex Mean SD P value a Correlation coefficient b P value c VAV d Males Females SAV d Males Females TAV d Males Females BMI Males Females WC Males Females WHR Males Females BMI, body mass index; SAV, subcutaneous adipose tissue volume; SD, standard deviation; TAV, total abdominal adipose tissue volume; VAV, visceral adipose tissue volume; WC, waist circumference; WHR, waist-to-hip ratio. a P values for differences between the sexes were calculated using the Student t test. b Correlation coefficient denotes coefficient and refers to an increase of the variables (obesity indexes) with an increase in age of 1 year. c P value from the simple linear regression analysis. d Adipose tissue volumes were calculated based on multidetector computed tomography scans. hip ratio (P for trend.08,.91, and.88, respectively) but remained strongly associated with visceral adipose tissue volume (P for trend.02, Table 4). In multivariate analysis including visceral adipose tissue volume as an obesity index, strong risk factors for erosive esophagitis included current smoker (OR, 1.60; 95% CI: ; P.001), male sex (OR, 4.17; 95% CI: ; P.001), and presence of hiatal hernia (OR, 10.45; 95% CI: ; P.001). Presence of H pylori (OR, 0.25; 95% CI: ; P.001) and atrophic gastritis (OR, 0.61; 95% CI: ; P.001) were both negatively associated with erosive esophagitis. Table 3. Effect of Obesity on Erosive Esophagitis by Univariate Analysis Obesity measure Number of persons (%) Normal (n 3779) Erosive esophagitis (n 495) OR (95% CI) P value Body mass index, kg/m (9.7) 18 (3.6) (58.6) 236 (47.7) 2.17 ( ) (29.3) 217 (43.8) 3.98 ( ) (2.4) 24 (4.9) 5.48 ( ).001 Waist circumference, cm (25.0) 58 (11.7) (46.2) 219 (44.2) 2.06 ( ) (24.9) 186 (37.6) 3.29 ( ) (3.9) 32 (6.5) 3.54 ( ).001 Waist-to-hip ratio (12.8) 17 (3.4) (40.5) 109 (22.1) 2.02 ( ) (41.3) 307 (62.0) 5.57 ( ) (5.4) 62 (12.5) 8.62 ( ).001 Visceral adipose tissue volume, cm (22.2) 37 (7.5) (41.7) 190 (38.4) 2.74 ( ) (26.3) 176 (35.5) 4.02 ( ) (9.8) 92 (18.6) 5.66 ( ).001 Subcutaneous adipose tissue volume, cm (7.1) 31 (6.3) (31.6) 154 (31.1) 1.11 ( ) (35.8) 189 (38.2) 1.20 ( ) (25.5) 121 (24.4) 1.08 ( ).71 CI, confidence interval; OR, odds ratio.

6 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS 1907 Table 4. Effect of Obesity on Erosive Esophagitis by Multivariate Analysis Multivariate analysis a Multivariate analysis b Obesity measure OR (95% CI) P value OR (95% CI) P value Body mass index, kg/m ( ) ( ) ( ) ( ) ( ) ( ).07 P for trend Waist circumference, cm ( ) ( ) ( ) ( ) ( ) ( ).44 P for trend Waist-to-hip ratio ( ) ( ) ( ) ( ) ( ) ( ).60 P for trend Visceral adipose tissue volume, cm ( ) ( ) ( ) ( ) ( ) ( ).006 P for trend CI, confidence interval; OR, odds ratio. a Adjusted for age, sex, smoking, alcohol, hiatal hernia, atrophic gastritis, diabetes, antihypertensive drug, education, and presence of Helicobacter pylori. b Adjusted for age, sex, education, smoking status, alcohol use; presence of hiatal hernia, atrophic gastritis, Helicobacter pylori, and diabetes; use of antihypertensive drugs; and body mass index, visceral adipose tissue volume, and waist circumference. Effect of Obesity on Erosive Esophagitis by Sex A BMI 30 (the highest BMI category) was the only BMI category positively associated with erosive esophagitis in males and females (Table 5). By analyzing continuous variables for trends, we determined that erosive esophagitis was associated with BMI, waist-to-hip ratio, waist circumference, and subcutaneous adipose tissue volume in males (P value for each trend.001) but not in females. However, visceral adipose tissue volume was strongly associated with erosive esophagitis in both sexes (males, P.001; females, P.002). Using multivariate analysis mutually adjusted for visceral adipose tissue volume and subcutaneous adipose tissue volume, erosive esophagitis increased according to visceral adipose tissue volume in men (P.01) and women (P.05). However, erosive esophagitis had no association with subcutaneous adipose tissue volume in either males (P.28) or females (P.90). Effect of Visceral Adipose Tissue Volume on Esophagitis Severity The severity of reflux esophagitis was positively correlated with visceral adipose tissue volume (P value for trend.001, Table 6). The risk of reflux esophagitis, LA-A, LA-B, and LA-C in persons who have visceral adipose tissue volume 1000 cm 3 increased 1.96-, 2.47-, and 4.43-fold, respectively. Discussion In a large health-screening cohort, we identified a positive correlation between erosive esophagitis and each of the obesity indexes, including BMI (a marker of body fat percentage), waist circumference (a marker of central obesity), waist-to-hip ratio, and abdominal visceral adipose tissue volume when these variables were considered individually. However, when these parameters were considered simultaneously, our data show that only abdominal visceral adipose tissue volume was associated with erosive esophagitis. Several hypotheses have been offered to explain how obesity can cause GERD. Abdominal adipose tissue may cause reflux through an increase in intra-abdominal pressure and subsequent esophageal acid exposure. 31,32 Obesity as measured by BMI is also associated with increased transient lower esophageal sphincter relaxation. 33 Waist circumference and BMI are significantly associated with intragastric pressure, gastroesophageal pressure gradient, and separation of the gastroesophageal junction pressure components. 17,34 However, data indicating an association

7 1908 NAM ET AL GASTROENTEROLOGY Vol. 139, No. 6 Table 5. Effect of Obesity on Erosive Esophagitis by Sex With Multivariate Analysis Males Females Number of persons (%) Number of persons (%) Obesity measure Normal (n 2042) Erosive esophagitis (n 432) Adjusted OR (95% CI) a P value a Normal (n 1737) Erosive esophagitis (n 63) Adjusted OR (95% CI) a P value a Body mass index, kg/m (3.4) 10 (2.3) (17.1) 8 (12.7) (54.6) 197 (45.6) 1.27 ( ) (63.3) 39 (61.9) 1.17 ( ) (39.0) 204 (47.2) 1.88 ( ) (18.0) 13 (20.6) 1.34 ( ) (3.0) 21 (4.9) 2.74 ( ) (1.6) 3 (4.8) 4.55 ( ).04 P for trend Waist circumference, cm (12.4) 37 (8.6) (39.6) 21 (33.3) (49.2) 197 (45.6) 1.52 ( ) (42.8) 22 (34.9) 0.84 ( ) (33.3) 167 (38.6) 1.91 ( ) (15.1) 19 (30.2) 2.21 ( ) (5.1) 31 (7.2) 2.02 ( ) (2.5) 1 (1.6) 0.78 ( ).82 P for trend Waist-to-hip ratio (0.3) 2 (0.5) (26.8) 15 (23.8) (15.7) 64 (14.8) 1.43 ( ) (69.6) 45 (71.4) 0.71 ( ) (73.6) 304 (70.4) 1.79 ( ) (3.4) 3 (4.8) 1.14 ( ) (9.8) 62 (14.3) 2.78 ( ).20 3 (0.2) 0 (0) None P for trend Visceral adipose tissue volume, cm (9.6) 23 (5.3) (37.1) 14 (22.2) (37.3) 158 (36.6) 1.93 ( ) (46.8) 32 (50.8) 1.68 ( ) (37.8) 162 (37.5) 2.06 ( ) (12.8) 14 (22.2) 3.17 ( ) (15.3) 89 (20.6) 2.88 ( ) (3.3) 3 (4.8) 3.42 ( ).08 P for trend Subcutaneous adipose tissue volume, cm (10.2) 30 (6.9) 1 58 (3.3) 1 (1.6) (40.5) 147 (34.0) 1.52 ( ) (21.1) 7 (11.1) 0.90 ( ) (34.6) 164 (38.0) 1.89 ( ) (37.4) 25 (39.4) 1.48 ( ) (14.7) 91 (21.1) 2.31 ( ) (38.2) 30 (47.6) 1.72 ( ).61 P for trend CI, confidence interval; OR, odds ratio. a Adjusted for age, smoking, alcohol use, hiatal hernia, atrophic gastritis, diabetes, antihypertensive drug, education, and presence of Helicobacter pylori. between BMI and GERD vary with sex, ethnic origin, and other confounding factors The plausible mechanisms of acid reflux suggest that intra-abdominal and subsequent intragastric pressure play a significant role in GERD. Thus, abdominal visceral adipose tissue volume, which may be related to increased intra-abdominal pressure, might be a good predictor for GERD than other obesity parameters. Factors other than intra-abdominal pressure, such as hormones, may be responsible for the association be- Table 6. Association Between Visceral Adipose Tissue and Severity of Reflux Esophagitis Visceral fat volume (cm 3 ) Normal (n 3779) Minor change (n 1055) LA-A (n 373) LA-B (n 115) LA-C (n 7) Mean (SD) 878 (455) 906 (448) 1083 (474) 1183 (494) 1179 (308) Group, No of persons (%) (63.9) 658 (62.4) 177 (47.5) 48 (41.7) 2 (28.6) (36.1) 397 (37.6) 196 (52.5) 67 (58.3) 5 (71.4) OR (95% CI) ( ) 1.96 ( ) 2.47 ( ) 4.43 ( ) P value P for trend.001 CI, confidence interval; OR, odds ratio; SD, standard deviation; LA, Los Angeles classification system.

8 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS 1909 tween visceral fat and esophagitis, because data by others show that esophagitis is associated with subclinical inflammation elsewhere in the body. 18,19 Furthermore, visceral fat has been shown to be a significant predictor of inflammatory markers such as interleukin-6, C-reactive protein, and tumor necrosis factor, regardless of race or sex. 18,19 Further studies are needed to elucidate the main underlying mechanism of the association between visceral fat volume as measured by CT and inflammatory factors, intragastric pressure, or intra-abdominal pressure. The prevalence of GERD symptoms as determined in a study investigating a cohort form North America did not differ between males and females. 35 In contrast, erosive esophagitis is more common in males than females from Asia. 4,36 Furthermore, data from several studies have indicated a different effect of obesity on GERD by sex. 5,11 In this study, waist circumference was associated with erosive esophagitis in males but not in females. However, abdominal visceral adipose tissue volume was strongly associated with erosive esophagitis in both sexes. The fact that obesity as determined by different anthropometric measurements is differentially associated with esophagitis may be due to varying abdominal adipose tissue distribution by age and sex. Our data show that subcutaneous adipose tissue volume was positively associated with erosive esophagitis in males but not in females in separate multivariate analysis models. However, when subcutaneous and visceral adipose tissue volumes were considered together, there was no association between subcutaneous adipose tissue volume and erosive esophagitis in subjects of either sex. We speculate that the metabolic effect by visceral fat is the main mechanism that causes erosive esophagitis in females. In males, even if both the metabolic effects caused by visceral fat and the intra-abdominal pressure caused by subcutaneous fat are important mechanisms causing erosive esophagitis, the metabolic effects might be the more critical factor in the development of esophagitis. Our study showed that males had higher visceral and lower subcutaneous adipose tissue volumes than females, consistent with results from a previous study. 37 Our study also showed that both BMI and waist circumference were more strongly associated with total adipose tissue volume than visceral adipose tissue volume. Furthermore, BMI increased with age in females and but decreased with age in males. Total, visceral, and subcutaneous adipose tissue volumes for a given waist circumference also differed by age and sex. 37 Therefore, the effect of BMI or waist circumference on GERD may vary and be inconsistent by both age and sex as shown in previous studies. 14,15 BMI and waist circumference are easily obtainable but imprecise measures of abdominal adiposity. 38 Although quantitative assessment of abdominal adipose tissue volume using CT or MRI allows for separate analysis of subcutaneous and visceral adipose tissue, 39,40 the feasibility of MRI is limited because of long acquisition time and high cost. We acquired CT images in an additional 1 to 2 minutes when participants underwent low-dose chest CT. A previous study showed that low-dose CT provided accurate and reproducible measurements of abdominal adipose tissue volume compared with MRI. 41 Although area-based assessment of adipose tissue using CT was highly reproducible, 42 volume-based assessment had even better reproducibility. 37 For abdominal subcutaneous adipose tissue, volume was well associated with area. However, regarding visceral adipose tissue, volume was less well associated with area. 43 Therefore, we used a volumebased rather than an area-based method for assessing abdominal adipose tissue. Data from this study show that erosive esophagitis was strongly positively correlated with being a current smoker, male sex, and presence of hiatus hernia. In contrast, erosive esophagitis was negatively correlated with presence of H pylori and atrophic gastritis. Our results were consistent with previous studies. 4,9,44 Although we did not use the Hill grading method for assessing the severity of the hiatus hernia, our data did show that the presence of a hiatus hernia was strongly associated with erosive esophagitis. The positive correlation between GERD severity and BMI or metabolic syndrome has been demonstrated in previous studies 14,20,45 This present study, however, is the first to show the strong positive correlation between visceral adipose tissue volume and severity of reflux esophagitis. In contrast to erosive esophagitis, data from our study showed that typical GERD symptoms had no association with BMI, waist circumference, waist-to-hip ratio, or visceral adipose tissue volume. In studies from Western countries using large cohorts, the association between GERD symptoms and obesity was inconsistent among both sexes and multiple ethnicities. 14,15 In these studies, subjects with GERD symptoms included both patients with reflux esophagitis having reflux symptoms and patients with nonerosive reflux disease. Mechanisms inducing acid reflux include increased number of transient lower esophageal sphincter relaxation, 33 increased gastroesophageal pressure gradients, hiatus hernia, 46 and estrogen. 5 In nonerosive reflux disease patients, however, visceral hypersensitivity and psychologic stress are also important contributing factors. 47,48 Therefore, the evaluation of GERD symptoms should be performed in conjunction with assessing visceral hypersensitivity and psychosocial stress, as well as acid regurgitation. Importantly, the finding that there is no association between visceral fat volume and GERD symptoms indicates that the underlying mechanism causing erosive esophagitis favors a hormonal effect rather than the mechanical effect of visceral fat causing an increase in intra-abdominal pressure. Further investigation is needed to elucidate the mechanisms by which visceral fat may

9 1910 NAM ET AL GASTROENTEROLOGY Vol. 139, No. 6 induce erosive esophagitis by measuring intragastric pressure or inflammatory cytokine levels as surrogate markers. Our study has several strengths. First, the methods used in this study allowed for the acquisition of highquality data. Erosive esophagitis was objectively evaluated with esophagogastroduodenoscopy and categorized by LA classification, and we excluded minor changes to increase specificity. The values for erosive esophagitis for the 4 gastroenterologists were very high. Anthropometric parameters were measured directly instead of by questionnaire. A second strength is that abdominal visceral adipose tissue volume was measured using a 64- multidetector CT, which has been shown to have a high degree of validity and reproducibility in estimating abdominal adipose tissue. 37 The third strength is the large size of the study cohort, which allowed us to evaluate subpopulations and their interactions by sex, after adjusting for confounding factors. Last, most participants (87%) in the overall health-screening program were enrolled, and we consider this group to be representative of the general population. Our study also had several limitations. First, the population was a self-motivated screening cohort. Therefore, there may be selection bias. Because a population-based study using esophagogastroduodenoscopy may not be realistic, our study using a screening cohort without serious underlying disease may be a very useful alternative. Second, although the radiation dose was much lower than with conventional CT, use of a CT protocol for measuring abdominal adipose tissue volume may be limited because of the risk of radiation exposure. The third limitation is that we did not evaluate the participants diet. Last, there is no clear consensus for defining optimal cutoff values for normal versus abnormal with regard to anthropometric and abdominal adipose tissue volume measurements. Disease-specific cutoff values by age, sex, and ethnicity should be evaluated in future studies. In conclusion, abdominal visceral adipose tissue volume is positively associated with erosive esophagitis and, therefore, is an excellent predictor for risk of the disease. In addition, severity of erosive esophagitis was positively correlated with visceral adipose tissue volume. The association between erosive esophagitis and abdominal visceral adipose tissue volume was consistent among males and females, unlike the association between erosive esophagitis and BMI or waist circumference. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. El-Serag HB, Petersen NJ, Carter J, et al. Gastroesophageal reflux among different racial groups in the United States. Gastroenterology 2004;126: Cho YS, Choi MG, Jeong JJ, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol 2005;100: Wong WM, Lai KC, Lam KF, et al. Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Aliment Pharmacol Ther 2003;18: Kim N, Lee SW, Cho SI, et al. 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10 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS Carroll JF, Chiapa AL, Rodriquez M, et al. Visceral fat, waist circumference, and BMI: impact of race/ethnicity. Obesity (Silver Spring) 2008;16: Oka R, Miura K, Sakurai M, et al. Comparison of waist circumference with body mass index for predicting abdominal adipose tissue. Diabetes Res Clin Pract 2009;83: Bonora E, Micciolo R, Ghiatas AA, et al. Is it possible to derive a reliable estimate of human visceral and subcutaneous abdominal adipose tissue from simple anthropometric measurements? Metabolism 1995;44: Nam SY, Choi IJ, Nam BH, et al. Obesity and weight gain as risk factors for erosive oesophagitis in men. Aliment Pharmacol Ther 2009;29: Nam SY, Kim BC, Han KS, et al. Abdominal visceral adipose tissue predicts risk of colorectal adenoma in both sexes. Clin Gastroenterol Hepatol 2010;8: Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. 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Visceral adiposity and its anatomical distribution as predictors of the metabolic syndrome and cardiometabolic risk factor levels. Am J Clin Nutr 2008;88: Yoon DY, Moon JH, Kim HK, et al. Comparison of low-dose CT and MR for measurement of intra-abdominal adipose tissue: a phantom and human study. Acad Radiol 2008;15: Thaete FL, Colberg SR, Burke T, et al. Reproducibility of computed tomography measurement of visceral adipose tissue area. Int J Obes Relat Metab Disord 1995;19: Kobayashi J, Tadokoro N, Watanabe M, et al. A novel method of measuring intra-abdominal fat volume using helical computed tomography. Int J Obes Relat Metab Disord 2002;26: Anderson LA, Murphy SJ, Johnston BT, et al. Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case-control study. Gut 2008;57: Nocon M, Labenz J, Jaspersen D, et al. Association of body mass index with heartburn, regurgitation and esophagitis: results of the Progression of Gastroesophageal Reflux Disease study. J Gastroenterol Hepatol 2007;22: Wilson LJ, Ma W, Hirschowitz BI. Association of obesity with hiatal hernia and esophagitis. Am J Gastroenterol 1999;94: Knowles CH, Aziz Q. Visceral hypersensitivity in non-erosive reflux disease. Gut 2008;57: Jansson C, Nordenstedt H, Wallander MA, et al. Severe gastrooesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study. Aliment Pharmacol Ther 2007;26: Received January 30, Accepted August 12, Reprint requests Address requests for reprints to: Il Ju Choi, MD, PhD, Research Institute and Hospital, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang, Gyeonggi, , Korea. cij1224@ncc.re.kr; fax: (82) Acknowledgments The authors thank Dr K. W. Park for performing esophagogastroduodenoscopies, research nurses S. H. Yoon and Y. J. Park for interviewing participants, and J. O. Kim for assistance with abdominal adipose tissue volume measurements. The funding source had no role in the design or conduct of the study; management, analysis, or interpretation of the data; or the preparation, review, or approval of manuscript. Conflicts of interest The authors disclose no conflicts. Funding Supported by a grant (NCC ) from the National Cancer Center, Korea, which had a role in the collection of the questionnaires and was financially responsible for the abdominal multidetector computed tomography.

11 1911.e1 NAM ET AL GASTROENTEROLOGY Vol. 139, No. 6 Supplementary Table 1. Association Between Weekly GERD Symptom and Obesity Indexes No of persons (%) Absence of GERD symptom Presence of GERD symptom (n 4848) a (n 481) a Body mass index, kg/m (8.8) 43 (8.9) (57.7) 270 (56.1) (30.8) 158 (32.8) (2.6) 10 (2.1) Waist circumference, cm (23.1) 113 (23.5) (46.0) 228 (47.4) (26.7) 116 (24.1) (4.2) 24 (5.0) Waist-to-hip ratio (11.7) 55 (11.4) (38.1) 193 (40.1) (44.0) 209 (43.5) (6.2) 24 (5.0) Visceral adipose tissue volume, cm (20.0) 93 (19.3) (41.7) 214 (44.5) (27.6) 126 (26.2) (10.6) 48 (10.0) Subcutaneous adipose tissue volume, cm (7.0) 32 (6.7) (31.3) 152 (31.6) (36.5) 162 (33.7) (25.2) 135 (28.0) GERD, gastroesophageal reflux disease. a GERD symptom means presence of at least weekly heartburn or acid regurgitation. b P values were derived from 2 test. P value b

12 December 2010 VISCERAL ADIPOSE TISSUE AND ESOPHAGITIS 1911.e2 Supplementary Table 2. Correlation Coefficients Among Waist Circumference, Body Mass Index, and Abdominal Adipose Tissue Volume Men (n 2474) Women (n 1800) VAV, cm 3 SAV, cm 3 TAV, cm 3 VAV, cm 3 SAV, cm 3 TAV, cm 3 BMI, kg/m WC, cm Waist-to-hip ratio NOTE. Correlation coefficients were calculated by Pearson correlation coefficient. Each P value was.001. BMI, body mass index; SAV, subcutaneous adipose tissue volume; TAV, total abdominal adipose tissue volume; VAV, visceral adipose tissue volume; WC, waist circumference.