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대한갑상선학회 International Journal of Thyroidology International Journal of Thyroidology 제8권 제1호
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2015.1
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75 - 80 (6page)

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Introduction The incidence of thyroid cancer is increasing in many countries.1-3) The main risk factors for thyroid cancer are exposure to radiation, a history of benign thyroid disease, and a family history of thyroid cancer.4-6) A meta-analysis showed that obesity was associated with the development of many cancers, including those of the esophagus, colon, kidney, breast, skin, rectum and gallbladder.7) Recently, we reported a positive correlation between obesity and thyroid cancer prevalence in women, when evaluated in a routine health checkup setting.8) The underlying mechanism between obesity and cancer is unclear. We considered persistent organic pollutants (POPs) as a possible basis of the association between obesity and thyroid cancer. POPs (such as PCB153, oxychlordane, etc.) are persistent lipophilic xenobiotic that accumulate in adipose tissue after exposure to environmental pollution. The International Agency for Research on Cancer (IARC; www.iarc.fr/index.php) defines POPs as carcinogens. Lee et al.9) reported that serum gamma-glutamyl transferase (GGT) was linearly associated with concentration of POPs, and that GGT might be a biomarker reflecting exposure to environmental pollutants. Although serum GGT has traditionally been used as a marker of hepatobiliary disease or alcohol consumption,10,11) a recent prospective study demonstrated that it was independently associated with several types of cancers.12) To the best of our knowledge, no study evaluating the relationship between GGT and thyroid cancer has been reported. This study was conducted to evaluate the mechanism behind the association of obesity with thyroid cancer. We hypothesized that serum GGT may be a surrogate marker of exposure to POPs and examined this connection in a systematically screened population by ultrasonography. Materials and Methods Study Population This cross-sectional study initially enrolled 24,935 subjects who underwent a routine health checkup from January 2007 to December 2008 at a Health Screening and Promotion Center. Thyroid ultrasonography was included in each checkup. If a subject received two or more health checkups during the study periods, only the first one was included in the analysis. We selected 20,366 subjects who had normal liver enzyme levels (AST and ALT ＜40 IU/L). We excluded those with a prior history of thyroid disease (thyroid dysfunction, n=799; thyroid nodule, n=648; thyroid cancer, n=10; surgery on thyroid, n=154; medication for thyroid disease, n=466), a family history (first-degree relatives only) of thyroid cancer (n=1142), or a prior history of hepatobiliary disease (HBV carrier, n= 973; chronic hepatitis C, n=123; liver cyst, n=330; hepatocellular carcinoma, n=14; cholangiocarcinoma, n=3; surgery on gall bladder, n=387). The final analysis included 15,131 subjects (7662 men and 7469 women) for whom we had data on GGT level, alcohol consumption, blood pressure, fasting glucose, cholesterol, triglyceride and insulin levels, and smoking status. We reviewed the medical records and analyzed risk factors for thyroid cancer separately in men and women. The local ethics committee approved the study protocol. Biochemical and Anthropometric Measurements Venous blood was collected from 12-hour fasting subjects in the morning and analyzed for glucose, cholesterol, triglyceride, insulin, and GGT at a central laboratory. Glucose, cholesterol, triglyceride, and GGT levels were quantified with a TBA-200FR auto-analyzer (Toshiba Medical System Co., Ltd, Tokyo, Japan), and insulin was measured by radioimmunoassay (Insulin IRMA kit; Izotop, Budapest, Hungary). We divided serum GGT levels into four groups by quartiles (the cut-off points of serum GGT were the 25th, 50th, and 75th sex-specific percentiles). At the initial visit, height and weight were measured. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m2). BMI was categorized as follows: ＜18.5, 18.5-22.9, 23.0-24.9, 25.0-29.9, ≥30 for underweight, normal weight, overweight, obesity, and severe obesity, respectively, following the WHO (World Health Organization) guidelines for Asians.13) We used questionnaires to collect information on alcohol consumption and smoking status. We estimated alcohol consumption by frequency of drinking per week, not quantity and type of drinking. Smokers included both ex-smokers and current smokers. Identification of Thyroid Cancer Patients with abnormal thyroid ultrasonography findings were referred to endocrinologists, regardless of nodule size or characteristics. Fine needle aspiration (FNA) cytology was performed for thyroid nodule(s) of larger than 1 cm, or of smaller than 1 cm when there were suspicious sonographic features such as micro-calcification, hypo-echogenicity, “taller than wide” shape, irregular margins, or neck lymph node enlargement.14) Of the study subjects, 260 were finally diagnosed with thyroid cancer by surgery. Statistical Analysis Categorical variables are presented as numbers and percentages. Continuous variables are expressed as means (standard deviations) or medians (inter-quartile range). Comparisons of continuous variables were performed by Student’s t-test. Trends across BMI categories were performed by the chi-square test. Quartiles of variables were calculated based on values of the sex-specific populations. R (version 2.12) and R libraries survival (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org) were used for statistical analysis. The associations between variables and thyroid cancer are presented as an odds ratio (OR) with a 95% confidence interval (CI) calculated by binominal logistic regression. p＜0.05 was considered statistically significant. Results Baseline Characteristics of Healthy Subjects and Those with Cancer A total of 15,131 subjects (7662 men and 7469 women) without any history of thyroid disease or hepatobiliary disease were included in this study. Thyroid cancer was diagnosed in 260 patients. A comparison of clinical characteristics between healthy subjects and those with cancer revealed significant differences in all variables between men and women Table 1. Comparison of the clinical characteristics of subjects without thyroid cancer and those with thyroid cancer 　 Male p value Female p value Non-cancer (n=7561) Cancer (n=101) Non-cancer (n=7310) Cancer (n=159) Age (years) 52.6±9.0 50.9±7.8 0.038 50.8±9.4 51.1±8.6 0.672 Smoking 6130 (81%) 80 (79%) 0.276 634 (9%) 6 (4%) 0.330 GGT (U/L)* 25 (17-40) 26 (20-36) 0.618 12 (10-17) 12 (10-15) 0.931 BMI (kg/m2) 0.070 0.090 ＜18.5 (Underweight) 84 (1%) 1 (1%) 302 (4%) 3 (2%) 18.5-22.9 (Normal weight) 1934 (26%) 20 (20%) 3824 (52%) 64 (40%) 23.0-24.9 (Overweight) 2315 (31%) 28 (28%) 1681 (23%) 48 (30%) 25.0-29.9 (Obesity) 3046 (40%) 46 (45%) 1376 (19%) 35 (22%) ≥30.0 (Severe obesity) 182 (2%) 6 (6%) 127 (2%) 9 (6%) Systolic BP (mmHg) 117.5±9.4 118.4±7.7 0.261 111.4±11.4 114.7±10.6 0.001 Glucose (mg/dL) 101 (94-110) 100 (95-108) 0.949 95.0 (89-102) 96.0 (90-105) 0.078 Insulin (mU/L) 6.3 (4.4-8.8) 6.5 (4.6-8.6) 0.967 5.7 (4.1-8.1) 6.5 (4.7-9.2) 0.083 Cholesterol (mg/dL) 191.2±33.1 189.8±29.9 0.631 193.0±35.3 192.4±37.3 0.842 HDL (mg/dL) 50 (43-59) 50 (42-61) 0.789 60 (51-71) 57 (50-65) 0.001 Alcohol consumption 0.067 0.272 1 time per week 3058 (40%) 39 (39%) 6378 (87%) 137 (86%) 2-3 times per week 2660 (35%) 39 (39%) 734 (10%) 17 (10%) 4-6 times per week 1221 (16%) 21 (20%) 137 (2%) 4 (3%) 7 times per week 622 (8.2%) 2 (2%) 　 61 (1%) 1 (1%) 　 BMI: body mass index, BP: blood pressure, GGT: gamma-glutamyl transferase, HDL: high density lipoprotein (Table 1). Therefore, the data were analyzed separately based on gender. Male subjects with thyroid cancer were significantly younger than subjects without cancer. Females with cancer had higher systolic blood pressure and lower high density lipoprotein levels than those without cancer. BMI of those with cancer was higher than non-cancer subjects in both male and female, but the differences were not significant. The percentage of obese subjects (BMI≥25) was greater among the males with cancer than among the males without cancer (51% vs. 42%) and also among the female (28% vs. 21%). Association between GGT and Thyroid Cancer Risk The prevalence of thyroid cancer, unadjusted for other factors, in the 1st, 2nd, 3rd, and 4th GGT quartiles was 1.7%, 0.8%, 1.6%, and 1.1%, respectively, in men, and 2.1%, 2.2%, 2.6%, and 1.6%, respectively, in women (Fig. 1). Fig. 1. The prevalence of thyroid cancer according to GGT quartiles. These prevalence estimates are not adjusted for other factors. Quartiles for GGT: 4.0-16.9, 17.0-24.9, 25.0-39.9, and 40.0-614.0 U/L in men; 4.0-9.9, 10.0-11.9, 12.0-16.9, and 17.0-309.0 U/L in women. GGT: gamma-glutamyl transferase. No continuous increase or decrease in thyroid cancer frequency was thus evident according to increasing serum GGT level. We examined the possible relationships between GGT and thyroid cancer according to 4 models involving adjustment for increasing numbers of factors. Before adjusting for other factors, high serum GGT level did not correlate with frequency of thyroid cancer in either men or women (Table 2: Model 1). Table 2. Unadjusted and adjusted odds ratios for presence of thyroid cancer according to GGT quartiles Baseline serum GGT (U/L) Q1 Q2 Q3 Q4 Odds ratio p value Odds ratio p value Odds ratio p value Male Cases/controls 34/1993 14/1653 32/1994 21/1918 Model 1 1 0.50 (0.26-0.91) 0.029 0.94 (0.58-1.53) 0.807 0.65 (0.37-1.10) 0.115 Model 2 1 0.52 (0.27-0.94) 0.037 0.93 (0.57-1.51) 0.763 0.60 (0.35-1.04) 0.071 Model 3 1 0.54 (0.28-0.99) 0.054 0.92 (0.56-1.50) 0.735 0.61 (0.34-1.09) 0.099 Model 4 1 0.52 (0.27-0.96) 0.043 0.95 (0.58-1.56) 0.847 0.65 (0.36-1.17) 0.156 Female Cases/controls 31/1426 38/1723 59/2188 31/1952 Model 1 1 1.01 (0.63-1.64) 0.954 1.23 (0.81-1.93) 0.343 0.73 (0.44-1.21) 0.225 Model 2 1 1.02 (0.63-1.65) 0.942 1.23 (0.80-1.93) 0.349 0.73 (0.44-1.20) 0.209 Model 3 1 1.06 (0.66-1.72) 0.780 1.18 (0.77-1.85) 0.46 0.63 (0.38-1.06) 0.080 Model 4 1 1.07 (0.67-1.74) 0.769 1.14 (0.74-1.79) 0.568 0.59 (0.35-0.99) 0.046 Model 1: unadjusted Model 2: adjusted for matching factors age Model 3: adjusted for matching factors age, BMI, smoking, and alcohol consumption Model 4: adjusted for matching factors age, BMI, smoking, alcohol consumption, systolic blood pressure, serum glucose, serum cholesterol, serum HDL, and serum insulin After adjusting for clinical variables, no association between serum GGT levels and frequency of thyroid cancer was observed in any models (Table 2). In model 3 (adjustment of age, smoking status, alcohol intake, BMI), compared with the lowest quartile, ORs (95% CI) were 0.54 (0.28- 0.99) for the 2nd quartile, 0.92 (0.56-1.50) for the 3rd quartile, and 0.61 (0.34-1.09) for the 4th quartile in men. In women, elevated serum GGT was also unrelated to the frequency of thyroid cancer. Adjusted ORs were 1.06 (0.66-1.72), 1.18 (0.77-1.85), 0.63 (0.38-1.06) for the 2nd quartile, 3rd quartile, and 4th quartile, respectively. In model 4 (adjustment of all variables), the risk of thyroid cancer was significantly lower in the 2nd quartile for men (OR 0.52, CI 0.27-0.96) and in the 4th quartile for women (OR 0.59, CI 0.35- 0.99), but these results do not follow any dose response relationship. Discussion We have found that obesity is associated with a higher prevalence of thyroid cancer, especially in women (OR 1.63, 95% CI 1.24-2.10, p＜0.001) when evaluated in a routine health checkup setting.8) The relationship between obesity and carcinogenesis is not yet well understood. This study was conducted to evaluate the mechanism behind the association of obesity with thyroid cancer. Hyperinsulinemia and/or increased levels of insulin like growth factors have been recognized as potential contributors, especially in colon, breast, endometrial, and pancreatic cancer.15-17) However, we found no association between serum insulin level and thyroid cancer risk in a previous study.8) This means that other mechanism(s) are responsible for the link between obesity and thyroid cancer. Measurement of serum GGT level is commonly used as an indicator of hepatobiliary disease and a biological marker of excessive alcohol intake. However, several epidemiologic studies have reported that elevated GGT is an independent predictor of death from causes other than liver disease, such as cardiovascular disease, chronic kidney disease, and type 2 diabetes.18-22) Interestingly, a recent prospective study showed that elevated GGT significantly increased overall cancer risk and was associated with several site-specific cancers, such as those of the digestive organs, respiratory system, intra-thoracic organs, and urinary organs.12) It is unclear what mechanisms are involved in the relationship between serum GGT and cancer. Lee et al.9) demonstrated that GGT may be a biomarker of exposure to cancer causing xenobiotic, including POPs. There is evidence from several experimental models that cellular GGT in involved in antioxidant/antitoxic defense mechanism via glutathione metabolism.23,24) After exposure to POPs, detoxification reactions occur to lower toxicity and increase the water solubility of POPs. Thus, serum GGT may increase in such situation when there is a need for conjugation to glutathione.25,26) The aforementioned finding led us to hypothesize that the role of POPs, as carcinogenic xenobiotic accounts for the association between obesity and thyroid cancer. Obese people have a lot of adipose tissue. As adipose tissue is a reservoir of POPs, the organs of individuals with higher amounts of adipose tissue are more likely to be exposed to accumulated POPs. We considered that serum GGT levels might reflect the extent of exposure to POPs in terms of carcinogenesis. Unfortunately, we did not find any relationship between serum GGT and thyroid cancer in either gender. Future studies on the possible mechanisms for this association are essential. The present study had some limitations. First, the study population was limited to individuals attending for a voluntary health checkup, and was not representative of the general population. Second, we did not measure metabolic variables repeatedly. A single value might be insufficient for cancer risk analysis. Third, there was no information on potential confounding factors, such as physical activity, diet, genetic and psychosocial variables. Fourth, we used GGT level as a surrogate for accumulation of POPs, instead of measuring serum POPs. Hence it would be wrong to infer that there is no association between POPs and thyroid cancer from our results with serum GGT. Despite of these limitations, this study had several strengths. First, all 15,131 subjects underwent thyroid ultrasonography, regardless of subjective symptoms. For this reason, almost all thyroid cancer cases were detected at very early stages, and this might represent the true prevalence of the disease. Second, this is the first study investigating the association of GGT and thyroid cancer within a single cohort. Third, thyroid ultrasonography and biochemical data were available from a single time point. Fourth, we applied same diagnostic and follow-up strategies for thyroid nodules to avoid selection bias. In conclusion, elevated GGT levels being regarded as a measure of exposure to POPs were not associated with a higher frequency of thyroid cancer in either gender when evaluated in a routine health checkup setting. Acknowledgments This study was supported by Korean Thyroid Association-Hanmi Pharmaceutical Company Research Award of year 2012.
#Gamma-glutamyl transferase #Persistent organic pollutant #Thyroid cancer #Obesity

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Blomberg M / 2012 / Thyroid cancer in Denmark 1943-2008, before and after iodine supplementation / Int J Cancer 131 (10) : 2360 ~ 2366 google schola Chen AY / 2009 / Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005 / Cancer 115 (16) : 3801 ~ 3807 google schola Cooper DS / 2006 / Management guidelines for patients with thyroid nodules and differentiated thyroid cancer / Thyroid 16 (2) : 109 ~ 142 google schola Davies L / 2006 / Increasing incidence of thyroid cancer in the United States, 1973-2002 / JAMA 295 (18) : 2164 ~ 2167 google schola Franzini M / 2006 / Modulation of cell growth and google schola

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