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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

The aim of this study was to investigate whether there was a relationship between colorectal adenoma and metabolically obese but normal weight (MONW) among Korean men and women. The MONW phenotype is defined as a BMI <25, but fulfilling the metabolic syndrome (MS) criteria with a modified waist circumference (≥90 cm for men and ≥85 cm for women) appropriate for Korean. A total of 3,430 subjects (2,263 men and 1,167 women; 23–75 years old) were included in the study. Colorectal adenomas were diagnosed in 775 men and 199 women. The rate of advanced adenomas in males was 24.3% and in females 21.1%. A significant association between MONW and advanced colorectal adenoma was found in men (age-adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.06–3.47) but not in women (age-adjusted OR = 1.80, 95% CI: 0.50–6.45). The findings suggest that men with MONW may have an increased risk of developing advanced colorectal adenoma whereas this does not seem true for females.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

According to the Korean National Cancer Registry, colorectal cancer is the second most common cancer in 2007, and the incidence rate has been increasing rapidly over the past three decades in Korea (1). The age-standardized incidence rates of total colorectal cancer increased by 7.3% and 5.5% for men and women, respectively, between 1999 and 2005, while the incidence rates of the most prevalent cancers in Korea, such as stomach, liver, and cervical cancers, have decreased between 1983 and 2008. The age-standardized mortality rates were increased from 3.0 to 14.5 in 100,000 for men and from 2.3 to 7.9 in 100,000 for women during the same period (2).

It has been well documented that most colorectal cancers arise from colorectal adenomas (3). Thus, the identification of risk factors of colorectal adenoma will be helpful in the prevention of colorectal cancer. Several reports indicate positive associations between metabolic syndrome (MS) or its individual components and risks of colorectal adenomas (4,5,6,7,8).

Although the MS is more prevalent in obese people, many obese people do not have the condition. Certain human sub-populations are metabolically obese but normal weight (MONW (9)). Indeed, MONW individuals are frequently undetected and undiagnosed because of their normal BMI. Based on the data from the 3rd Korean National Health and Nutrition Examination Survey (KHANES III), the prevalence of MONW was 8.7% (10.1% among men, 7.6% among women (10)). To date, there has not been any report on the incidence of colorectal adenomas in MONW populations. The aim of this study is to investigate the relationship between colorectal adenomas and MONW phenotype in Korean adults.

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Study population

A total of 3,430 subjects enrolled in this study had undergone laboratory tests and colonoscopic examination on the same day during a routine health checkup at the Health Promotion Center of Ulsan University Hospital, Korea, between January 2007 and December 2009.

Exclusion criteria were (i) underweight as BMI <18.5; (ii) incomplete study due to poor bowel preparation; (iii) failure to carry out cecal intubation, and (iv) symptomatic patients.

The ethical committee of Ulsan University Hospital approved this study and written informed consent was obtained from all the participants.

Questionnaire information

Using a structured self-administered questionnaire, subjects were asked about their smoking and drinking habits, physical activity, medical history, and socioeconomic status. Smoking habit was categorized as never, ex-smoker, and current smoker. Anyone reporting smoking in the last 30 days was classified as a current smoker. An ex-smoker was defined as an individual who had smoked at least one pack-year and was distinguished from someone who had never smoked. Drinking habit was classified as drinker and nondrinker. Drinker was defined as an individual who had consumed alcohol more than once per week over a period of at least 1 year or longer. Physical activity was classified as regular, irregular, and none based on the regularity reported regardless of exercise type or intensity level. An individual who reported exercising regularly within the past year was classified as regular exercise group. An individual who exercised irregularly was distinguished from someone who had never exercised in past 1 year.

Anthropometric and laboratory measurements

Anthropometric height and weight were measured by trained examiners to the nearest 0.1 cm and 0.1 kg, respectively using Inbody 2.0 (Biospace, Seoul, Korea). BMI value was calculated by dividing weight in kilograms by height in meters squared. Waist circumference (WC) was measured to the nearest 0.1 cm, at the narrowest point between the lower border of the lowest rib and the iliac crest. Blood pressure was measured by trained nurses using a mercury sphygmomanometer after at least 10 min of rest with subjects in sitting position.

Following an overnight fasting, blood samples were collected and analyzed on a Hitachi Modular DPE system (Roche Diagnostics, Penzberg, Germany). Fasting plasma glucose levels were measured using a hexokinase UV method. Triglycerides and high-density lipoprotein cholesterol levels were measured by enzymatic colorimetric method.

Hemoglobin A1c was measured by the high-performance liquid chromatography method with a Bio-Rad Variant II system (Bio-Rad Laboratories, Hercules, CA).

Definition of MONW

In this study MS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria with a modified WC appropriate for Koreans. The cutoff points of WC for abdominal obesity in Koreans are 90 cm for men and 85 cm for women, respectively (11).

For the diagnosis of MONW, the Asia-Pacific criteria for obesity based on the BMI guidelines were used (12). Thus, the MONW phenotype was defined as an individual with a BMI <25, but fulfilling the MS criteria requiring three or more of the following clinical features: (i) central obesity with WC ≥90 cm for men or 85 cm for women; (ii) triglycerides ≥150 mg/dl or specific treatment for this lipid abnormality; (iii) high-density lipoprotein cholesterol <40 mg/dl for men or 50 mg/dl for women; (iv) elevated blood pressure ≥130/85 mm Hg or use of antihypertensive medications; and (v) fasting plasma glucose ≥100 mg/dl or hemoglobin A1c ≥6.4%, or use of diabetes medications.

Study subjects were assigned to one of four groups based on BMI scores and MS status as follows: (i) MONW (BMI <25); (ii) MHNW: metabolically healthy and normal weight (BMI <25); (iii) MHOB: metabolically healthy but obese by BMI (BMI ≥25); and (iv) MOOB: metabolically obese and obese by BMI (BMI ≥25).

Diagnosis of colorectal adenoma

Colonoscopies were performed by experienced colonoscopists unaware of the clinical features of the subjects. Bowel preparations were carried out using 4 l of colonlyte solution. Most subjects were consciously sedated with midazolam and pethidine. The locations, sizes, numbers, and types of all polyps were recorded. Locations of colorectal adenoma were categorized as proximal colon (including the cecum, ascending colon, and transverse colon) and distal colon (including the splenic flexure, descending colon, sigmoid colon, and rectum). The size of each polyp was estimated by the use of an 8-mm-diameter open-biopsy forceps.

Histological assessment of the polyps was performed by a single pathologist who was unaware of each subject's status. In this study, the adenomas were classified as tubular, serrated, villo-tubular, high-grade dysplasia, and adenocarcinoma types according to the World Health Organization classification (13). Hyperplastic polyps were included in adenoma-free group. Advanced adenoma was defined as a polyp size of ≥10 mm in diameter, villous type (containing > 25% villous features), high-grade dysplasia, or invasive cancer.

Statistical analysis

Continuous variables are expressed as means ± s.d. For intergroup comparisons, continuous variables were analyzed using the Student's t-test and categorical variables using the χ2-test. Logistic regression analysis was used to estimate the odds ratio (OR) of colorectal adenoma by MHOB, MONW, and MOOB. Data analyses were performed using SPSS version 17.0 (SPSS, Chicago, IL). All tests were two-tailed and P values of <0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Characteristics of study participants are presented in Table 1. Among the 3,430 study subjects 974 (28.4%) had adenomatous polyps and 2,456 (71.6%) were adenoma-free at colonoscopy. Subjects with adenoma were statistically significantly older and more obese, compared to those without adenoma in both male and female groups. There was no significant difference in reported mean cigarette smoking, alcohol consumption, or exercise among the male subjects with and without adenomas.

Table 1.  Descriptive characteristics of study subjects
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The colonoscopic findings of adenomas according to MS and obesity were summarized in Table 2. Tubular adenoma is the most common histological types of colorectal adenoma.

Table 2.  Histological findings of adenomas in the four phenotypes
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The proportions of men and women with abdominal obesity were 3.9% and 4.2% in MHNW, 47.6% and 60.3% in MHOB, 31.0% and 44.7% in MONW, and 87.3% and 95.2% in MOOB, respectively. Therefore, the proportion of abdominal obesity was highest in the MOOB phenotype, followed by MHOB, MONW, and MHNW phenotypes in both sex groups. But the proportion of advanced adenomas was higher in the MONW than the MOOB phenotypes.

Logistic regression was used to calculate ORs and 95% CIs assessing the risk of colorectal adenomas in nonadvanced adenoma and advanced adenoma by MHOB, MONW, and MOOB. Confounding variables included age, exercise, smoking status, alcohol drinking. But there are no significant differences of ORs with and without these variables except age. Finally age-adjusted model were used to evaluate association between four phenotypes and risk of nonadvanced adenoma and advanced adenoma. Age-adjusted ORs of adenoma by gender are shown in Table 3, comparing the four obesity phenotypes. Among men, MONW (OR = 1.92, 95% CI: 1.06–3.47) and MOOB (OR = 1.84, 95% CI: 1.17–2.89) phenotypes had significantly higher OR of advanced adenoma than the MHNW phenotype (OR = 1). However, among women, MHOB phenotype (OR = 1.76, 95% CI: 1.14–2.71) had significantly higher OR of nonadvanced adenoma than the MHNW phenotype (OR = 1).

Table 3.  Age-adjusted odds ratios (ORs) with 95% confidence interval (CI) for the adenoma by gender
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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

The concept of the MONW individual was first proposed in 1981 by Ruderman et al. (9). Since then several studies have shown that the MONW phenotype is associated with major chronic diseases such as type 2 diabetes and cardiovascular disease (14,15,16,17,18).

In this study, there was a significant association between MONW phenotype and advanced colorectal adenoma. The proportion of abdominal obesity and the mean of WC were higher in MHOB subjects than in MONW subjects. But males with MONW phenotype had increased risk for advanced colorectal adenoma (age-adjusted OR = 1.92, 95% CI: 1.06–3.47), but those with MHOB phenotype were not (age-adjusted OR = 1.25, 95% CI: 0.85–1.85). However, no significant association were observed between MONW phenotype and advanced colorectal adenoma (age-adjusted OR = 1.80, 95% CI: 0.50–6.45) among females. These findings suggest that clusters of individual components of MS, regardless of obesity based on BMI, have a key role in the development of advanced colorectal adenoma in males. To our knowledge, this is the first report indicating that MONW individuals have significantly higher risk for advanced colorectal adenomas compared to those with MHNW in Korean men but not in women.

Our results are in broad agreement with the previous studies in Asian countries. In 2005, Morita et al. first reported the association of MS and colorectal adenoma among Japanese (4). Similar results were shown recently in two Chinese studies by different research groups which found that high BMI and central obesity were significantly associated with colorectal adenoma (5,6). Kim et al. showed that MS was associated with colorectal adenoma and that the abdominal obesity of the individual components of MS was significantly associated with age, gender, smoking, alcohol, and other covariate factors adjusted OR for colorectal adenoma (OR = 1.39, 95% CI: 1.15–1.68) in Korean (7). Recently Kang et al. also showed that the visceral obesity was associated with an increased prevalence of colorectal adenoma in apparently healthy general population and that the elevated visceral adipose tissue area increases the risk of multiple adenomas and advanced adenomas in Korean (8). However, to date, there are no reports on the relationship between MONW phenotype and advanced colorectal adenoma yet.

The pathology of MS is considered to be primarily attributable to insulin resistance (19). The chief role of insulin is to regulate the glucose level in the blood. When people are insulin resistant, their bodies need more insulin to help glucose enter cells to be used for energy. Excess glucose builds up in the bloodstream, increases the chance of developing type 2 diabetes. Several epidemiological studies indicate that hyperinsulinemia is associated with increased risks of colorectal cancer or adenoma (20,21,22). Hyperinsulinemia is thought to promote weight gain and the development of MS (19). In this study, the risk of advanced adenoma increased in the metabolically obese group. At the same time neither MONW nor MOOB was associated with nonadvanced adenomas. This phenomenon may be due to the presence of different developmental pathways for advanced and nonadvanced adenomas. A similar finding was well discussed in the article by Boman and Huang on colon cancer stem cells (23).

Although the majority of colorectal cancers arise from adenomas, most adenomas do not progress to cancer (24). Advanced colorectal adenomas are more likely to transition to colorectal cancer (25,26). Apart from the natural history of colorectal adenomas, several studies reported on the relationship between males and the development of lesions. Martinez et al. reported that males were more likely to be at an increased risk for metachronous advanced colorectal neoplasia (OR = 1.40, 95% CI: 1.19–1.65 (27)). Jacobs et al. reported that BMI was significantly related to most histologic characteristics of metachronous colorectal adenomas among men but not among women (28). Terry et al. reported that increased physical activity was more strongly associated with reduced risk for advanced colorectal adenomas (OR = 0.4, 95% CI: 0.2–1.0) than with reduced risk for nonadvanced adenomas (OR = 0.8, 95% CI: 0.5–1.2) among men (29). In this study, we also found that the association between the MONW phenotype and advanced colorectal adenoma was significant in men but not in women. Therefore, colorectal adenomas seem to be associated with male gender.

In addition, we could not find a significant association between MONW phenotype and advanced colorectal adenoma in Korean women. The similar finding was reported by Lee et al. (30). However, in Western studies, women with high BMI had an increased risk for advanced neoplasia but the data is not as strong for men (31,32,33). The populations of these studies had higher BMI than those in this study. BMI is essential to the monitoring and comparing obesity trends. Since the early 1990s, the World Health Organization defines obesity as a BMI equal to or >30 kg/m2. However, BMI may not correspond to the same degree of fatness in different populations due to different body proportions. Some Asian populations have higher amounts of body fat for a given BMI and have health risks at lower BMI than Western populations; thus lower BMI cut point of 25 is recommended to define obesity (12). In 2005, the Ministry of Health and Welfare of Korea also has accepted the BMI 25 for obesity (10).

Several prospective studies reported that BMI was associated positively with colon cancer risk for Asian males, whereas the pattern for women was not clear (34,35,36,37,38). It is possible that the protective effect of estrogen may be masking the true effect of metabolically obese on colorectal neoplasms in women. However, it could not be confirmed whether estrogen or progesterone had a protective effect on the development of colorectal adenoma. Since the number of female subjects in this study was fairly small, lack of significance could be due to a limited statistical power. Further studies will be required to clarify this phenomenon.

One limitation of this study is that information on cigarette smoking, alcohol consumption, and physical activity was self-reported, which allows for recalling bias. Another limitation of this study is that the study population may not be representative of the general population because they were not randomly selected. In this study, of the 3,430 participants, the proportion of the MONW was 5.6% among men, and 3.3% among women. These results were slightly lower than those of KHANES III (10). This may be underestimated because this study was conducted on participants who visited a health exam center for a checkup. Also, heterogeneity may exist in the measurements in terms of fasting status and time of day that blood was collected, and inevitably, some degree of measurement error occurs in laboratory assays.

One advantage of this study is that actual measurement of height and weight were made by trained staff. This is preferred over self-reported data, which have been used frequently in a number of well-known large-scale cohort studies, because heavier individuals tend to under report their weight. Furthermore, strength of this study was the inclusion of simultaneously measures anthropometrics, fasting blood sugar, triglycerides, high-density lipoprotein cholesterol levels, blood pressure, and adenoma incidence in a population of individuals with average risk for adenoma.

Identification of risk factors that influence the development of adenomas may also provide useful information to improve the tailoring screening intervals. In the recent American College of Gastroenterology guidelines, BMI is introduced as a possible risk factor but the recommendation was tempered due to the need for more data (39). However, to further minimize the risk of colorectal cancer, subjects with MONW must be considered when clinicians are determining appropriate follow-up screening intervals.

In conclusion, regardless of weight status, metabolically obese men have significantly high prevalence and increased risk of advanced colorectal adenomas. This finding suggests that further investigation for risk factors associated with colorectal cancer may be warranted in normal weight subject with MS.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES
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