Colorectal cancer (CRC) is the third most prevalent cancer and it is the leading cause of cancer-related death in the world. In addition, the incidence of CRC has increased by approximately 2 to 4 times in the past decades in many Asian countries, including China, Japan, South Korea, and Singapore.[2,3] Most CRCs develop through the adenoma–carcinoma sequence, and the prevalence of colorectal adenomas is increasing in Korea. Colorectal adenomatous polyps are considered precursors of CRCs, which allows for screening and prevention of CRC by using colonoscopy and polypectomy.[4,6] Screening for CRCs should be started at the age of 50 years in an asymptomatic individual in an average-risk population. However, in addition to age, factors like sex, smoking, family history, race, and obesity can affect the risk of CRC.[7,8]
So far, many epidemiological studies have shown an association between the risk of CRC and obesity measured by the body mass index (BMI), waist circumference (WC), and/or waist-to-hip ratio (WHR).[9,10] Previous studies have shown that visceral fat area (VFA) measured using computed tomography (CT) is a better predictor of colon neoplasms (CRNs) than BMI or WC,[11–14] in that VFA is directly associated with the risk of CRC. However, Asian adults generally have a lower central distribution of body weight and a smaller body size than Western adults. Thus, a more accurate measurement of abdominal fat distribution in obesity other than BMI and WC may be warranted. Furthermore, the relative ratio of visceral fat to subcutaneous fat may be necessary to indicate obesity more accurately because of individual differences in the absolute amount of visceral adipose tissue and abdominal fat distribution. Therefore, the relative ratio of visceral fat to subcutaneous fat may indicate obesity more accurately.
In the present study, we hypothesized that the ratio of VFA to subcutaneous fat area (SFA), measured using CT might significantly correlate with the risk of colorectal adenoma. Therefore, the aim of this study was to investigate the association between abdominal fat distribution measured by CT and the incidence of colorectal adenoma.
2 Materials and methods
2.1 Study population
We reviewed the medical records of subjects aged >40 years who participated in a routine checkup program at Chung-Ang University Hospital Health Care Center between January 2013 and December 2015. For this study, 336 participants who underwent colonoscopy and abdominal CT scan, physical examinations (height, body weight, WC, BMI, and blood pressure), and blood tests (white blood cell, hemoglobin, platelet, glucose, albumin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, triglyceride, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, C-reactive protein, and high-sensitivity C-reactive protein) were considered. The exclusion criteria were a history of colonic disease (CRC, polyps, or inflammatory bowel disease), colorectal surgery, or colonoscopy, within the previous 10 years, and a family history of CRC. To avoid the potential protective effect of aspirin and statins on colorectal adenomas, patients who had been taking aspirin or a statin for ≥1 year were also excluded.
Of the 336 participants, those who could not undergo total colonoscopy (n = 26) and those who could not undergo biopsy (n = 1) were excluded. The remaining 309 participants were enrolled in the study (Fig. 1). The institutional review board approved the study (C2014024(1220)), and all the participants provided written informed consent for the use of personal data for this research.
2.2 Measurement of anthropometric parameters
Weight and height measurements were automated (GL-150, G-Tech International Co., Uijungbu City, South Korea; Inbody720, Biospace Co., Chun-An City, South Korea), and BMI was calculated as body-weight divided by height squared (kg/m2). After fasting for 12 hours, a blood sample was taken, from which blood lipids and glucose levels were measured.
After bowel preparation, colonoscopy was performed by experienced endoscopists using a flexible colonoscope (CFH260AL, Olympus, Tokyo, Japan). The various drugs administered for bowel preparation were used as follows: we performed colonoscopies that reached the cecum, after bowel preparation with 4 L of CoLyte powder (Taejoon Pharm Co., Ltd, South Korea). The CoLyte powder was composed of polyethylene glycol (3350.29 g), anhydrous sodium sulfate (2.85 g), sodium hydrogen carbonate (0.84 g), sodium chloride (0.73 g), and potassium chloride (0.37 g). We examined colonoscopic features, including the size, location, number, and histological findings of polyps. Polyp size was assessed by using open colonoscope biopsy forceps (MTW-Endoskopie Manufaktur, Wesel, Germany). Adenoma size was classified into <10 and ≥10 mm, with the largest size used for multiple adenomas. The location of the colorectal adenomas was divided into 3 categories as follows: the proximal colon, including the cecum, ascending colon, and transverse colon; the distal colon, including the splenic flexure, descending colon, sigmoid colon, and rectum; and both sides of the colon. The number of adenomas was classified as either single or multiple (≥2). Histological findings were classified according to their premalignant potential as follows: Colorectal adenomas included tubular, villous, or serrated adenomas, and controls had normal colonoscopic findings and nonpolypoid, benign lesions, such as nonspecific colitis or histologically confirmed hyperplastic polyps. In addition, advanced adenomas were defined as ≥1 cm in estimated diameter, containing ≥25% villous features, and/or high-grade dysplasia.
2.4 Measurement of abdominal adipose tissue area by using CT
Abdominal adipose tissue area was quantified by using 64-multidetector CT (Brilliance, Philips Medical Systems, Cleveland, OH). The fat area was determined by measuring the mean value of the pixels within the range of −175 to −25 Hounsfield units. Total abdominal fat area (TFA), VFA, and SFA were measured using a 10-cm CT slice scan image between the third and fourth lumbar vertebrae that was obtained during suspended respiration.
Area (cm2) was calculated by using the Extended Brilliance Workspace version 1–4.5.2 software (Philips Healthcare, Best, the Netherlands). VFA was calculated by delineating the intra-abdominal cavity bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and paraspinal muscles. SFA was calculated by subtracting VFA from TFA.
2.5 Statistical analysis
The Pearson χ2 test or Fisher exact test for independent samples was used to assess the difference in risk factors between the subjects with and those without colorectal adenoma. For continuous variables, the data distribution was first evaluated for normality using the Shapiro–Wilk test. Normally distributed data were compared using Student's t test and nonnormally distributed data were analyzed using Mann–Whitney U test. To detect the dose–response relationship, we used cut points to categorize the patients into quartiles in terms of VFA, SFA, and the VFA to SFA ratio (VFA/SFA). The relationship between colorectal adenoma and obesity (obesity indexes: BMI, VFA, SFA, and VFA/SFA) was assessed based on odds ratios (ORs) with 95% confidence intervals (CIs) obtained by using the logistic regression model. The lowest quartiles of VFA, SFA, and VFA/SFA were selected as reference groups before the analysis. The significance of risk factors other than the obesity indices was examined by univariate and multivariate analyses. A P value of <.05 was considered statistically significant. The software package used for the statistical analysis was SPSS version 20.0 (SPSS Inc., Chicago, IL).
3.1 Baseline demographic characteristics of the subjects
For this study, 309 subjects (male-to-female ratio, 246:63) were included. The mean age was 48.8 ± 10.1 years. The mean BMI was 25.2 ± 3.24 kg/m2, and the mean WC was 87.7 ± 8.58 cm. The mean VFA and SFA measured by using CT scan were 139.9 ± 68.2 and 152.8 ± 64.2 cm2, respectively. The mean VFA/SFA was 0.98 ± 0.45. The baseline characteristics of the subjects are shown in Table 1.
3.2 Clinical characteristics of the subjects with and those without colorectal adenoma
The characteristics of the subjects with and those without colorectal adenoma are compared in Table 2. Among the 309 subjects, 119 (38.5%) had colorectal adenoma. The mean age was significantly higher in the patients with colorectal adenoma than in those without it (52.0 ± 9.3 vs 46.7 ± 10.2, P < .001). The male-to-female ratio did not differ between the patients with and those without colorectal adenoma (101:18 vs. 145:35, P = .082). Of the anthropometric measurements of obesity, BMI, and WC did not differ between the groups. The mean VFA (153.3 ± 67.9 cm2 vs 131.4 ± 44.9 cm2, P = .006) and VFA/SFA (1.07 ± 0.51 vs 0.92 ± 0.41, P = .006) were significantly higher in the patients with colorectal adenoma that in those without colorectal adenoma, whereas the amounts of SFA did not differ between the groups. Of the various metabolic markers assayed, fasting plasma glucose concentration was higher in the patients with colorectal adenoma (108.6 ± 25.1 mg/dL vs 102.7 ± 21.3 mg/dL, P = .027), but albumin was lower in patients with colorectal adenoma than in those without it (4.61 ± 0.27 g/dL vs 4.55 ± 0.29 g/dL, P = .042).
3.3 Characteristics of colorectal adenoma according to abdominal fat distribution
In the subjects with colorectal adenoma, the mean VFA, SFA, and VFA/SFA were not associated with tumor location, number, and advancement of colorectal adenoma. The size of colorectal adenoma was not significantly associated with VFA and VFA/SFA, but significantly correlated with the number of colorectal adenoma (r = 0.365, P < .001). The characteristics of colorectal adenoma, including endoscopic and pathological features according to abdominal distribution, are summarized in Table 3.
3.4 Abdominal fat distribution according to sex-related differences
The males had higher VFA and VFA/SFA but lower SFA than the females (Table 4). In addition, their mean VFA and VFA/SFA were significantly increased with age. Positive correlations were found between the following obesity indexes: BMI and VFA (r = 0.678, P < .001), BMI and SFA (r = 0.724, P < .001), and VFA and SFA (r = 0.452, P < .001).
3.5 Association between abdominal fat distribution and risk of colorectal adenoma
We categorized subjects into quartile according to VFA, SFA, and VFA/SFA as abdominal fat distribution. As a result, the incidence of colorectal adenoma showed increasing tendency with increasing quartiles of VFA, SFA, and VFA/SFA (P for trends were .001, .501, and .002, respectively, Fig. 2).
In the univariate analysis, colorectal adenoma was not associated with SFA but was associated with VFA (P for trend .001) and VFA/SFA for both categorical data and trend (P for trend .002; Table 5). In the multivariate analysis, colorectal adenoma was significantly associated with VFA rather than VFA/SFA (Table 5). The highest quartile of VFA was associated with a 2.8-fold risk of colorectal adenoma when compared with the lowest quartile.
3.6 Association between abdominal fat distribution and risk of colorectal adenoma according to sex-related differences
Data were analyzed according to sex because significant correlations were found between sex and VFA (P < .001), SFA (P < .001), and VFA/SFA (P < .001). In the univariate analysis, colorectal adenoma was significantly associated with VFA (P for trend .006) and VFA/SFA (P for trend .024) for both categorical data and trend in the men, but not in the women. SFA was not associated with colorectal adenoma in both the men and women. In the multivariate analysis, colorectal adenoma was significantly associated with VFA rather than VFA/SFA in the men (Table 6). Especially the highest quartile of VFA was associated with a 2.9-fold risk of colorectal adenoma when compared with the lowest quartile. However, VFA, SFA, and VFA/SFA were not associated with colorectal adenoma in the women.
This study investigated the association between abdominal fat distribution and the incidence of colorectal adenoma. Based on our results, we demonstrated that the presence of colorectal adenoma was positively associated with VFA rather than VFA/SFA. Furthermore, the presence of colorectal adenoma was significantly associated with VFA only in men. This demonstrated that abdominal visceral fat might contribute to the growth and progression of colorectal adenoma.
This study revealed an association between abdominal visceral fat and colorectal adenoma, providing the evidence of the role of visceral obesity in the development of CRN. Although many studies showed a positive association between obesity measured by using BMI and CRC,[16,17] recent studies suggested that WC and WHR, both surrogate markers of intra-abdominal fat or visceral adipose tissue, show a greater association with development of CRN than BMI.[18,19] Although the exact mechanism is not completely established, several possible mechanisms of visceral fat in colorectal carcinogenesis have been proposed. First, insulin resistance and subsequent hyperinsulinemia are involved in visceral adiposity. This may increase cell proliferation and reduces cell death, which can eventually lead to carcinogenesis.[10,21] Another mechanism has been linked to elevated serum levels of visceral fat, including interleukin 6, tumor necrosis factor alpha and adiponectin, and pro-inflammatory adipokines, which may be associated with the development of colorectal adenoma. Thus, measuring visceral fat directly using CT can better predict insulin resistance than WC or BMI. In general, routine use of CT is not cost-effective and has a risk of radiation exposure. However, it is important for Asian adults to measure visceral fat using CT because Asian adults generally have a smaller physique compared with Western adults, with a less central distribution of body weight.
In our present study, colorectal adenoma was not associated with the location, size, number, and advancement of adenoma. However, previous studies have shown a positive correlation between the presence of visceral fat and the presence of adenomas on both sides of the colon, large adenomas, and multiple adenomas.[11,23]
Furthermore, a recent study by Nagata et al showed that advanced adenomas were positively associated with higher VFA, but not with SFA. Taken together, abdominal visceral fat may influence the growth and progression of colorectal adenoma.
Among the various measurements of obesity in our present study, VFA and VFA/SFA were significantly associated with colorectal adenoma, but only VFA was independently associated with colorectal adenoma after adjusted analysis. Why VFA was the only significant factor among the obesity indexes is unclear. A previous study demonstrated that an absolute amount of visceral fat over a certain threshold is more important than the relative proportion of visceral fat in transitioning a patient into the phase of insulin resistance may be another probable mechanism. However, Nagata et al showed that VFA/SFA was independently associated with colorectal adenoma, but this result was observed only in men. Furthermore, abdominal subcutaneous and visceral fats have distinctly different functions with regard to insulin. Further studies are needed to investigate such importance of visceral fat proportion.
In this study, only VFA was associated with colorectal adenoma in men, but not in women. Obesity is a relatively higher risk for CRC in men than in women.[10,16,27] and women generally tend to accumulate less VFA even when they gain weight more than men. The difference between men and women is known to be related to estrogen levels in postmenopausal women and may be influenced by menopausal status and estrogen hormone use. Our result indicated that the distribution of abdominal adipose tissue differed according to sex (higher VAT volume and lower SAT volume in the men than in the women) may explain the sex-related difference in the effects of VFA on colorectal adenoma. However, 2 large-scale studies demonstrated that VFA was independently associated with colorectal adenoma in both sexes.[11,24] Further studies are needed to investigate such risk according to sex.
Our study has several strengths. First, the data were of high quality. Colonoscopies were performed by well-trained endoscopists. Second, the volume of abdominal adipose tissue was measured using 64-multidetector CT and the result showed high validity and reproducibility. Third, we assessed a healthy population to represent the general population. Accordingly, our results are applicable to clinical situations and could be used for future screening strategies.
Our study has some limitations. First, we did not assess the direct relationship between insulin resistance and the presence of colorectal adenomas despite obesity is considered a key mechanism in the development of colorectal adenoma.[10,20,21] Second, we did not evaluate the individuals’ diet or lifestyles such as smoking, which could be associated with colorectal adenoma.
In conclusion, VFA rather than VFA/SFA measured by using a CT scan was positively associated with the presence of colorectal adenoma, especially in men. Furthermore, average risk men with large visceral fat volume should be examined carefully in screening colonoscopy. Further large-scale studies are needed to clarify the underlying mechanism and causal relationship between abdominal visceral fat and CRN.
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