This large-scale, nationwide, population-based, cohort study of 4,658,473 persons aged 40–70 years demonstrated that the risk of developing thyroid cancer was significantly associated with the presence of MS and its components. This study also revealed a considerable role for sex in the risk and prevalence of thyroid cancer. In women, all five MS components were significantly linked to the risk of thyroid cancer, whereas only abdominal obesity, low HDL-cholesterol, and elevated blood pressure increased the risk of thyroid cancer in men. Moreover, the incidence of thyroid cancer per 10,000 person-years in subjects with MS or significant MS components was substantially higher in women than in men. Another key outcome of this study was that the risk of thyroid cancer increased significantly with the number of MS components. Indeed, the RR and incidence of thyroid cancer were significantly higher in subjects with just one or two MS components who did not meet the full definition of MS than in those without any MS components. Altogether, this study establishes an important association between MS and its components with the risk of thyroid cancer, which has important clinical implications for thyroid cancer surveillance in individuals with even one MS component.
Most previous studies have investigated the association between BMI or IR and the development of thyroid cancer. One systemic review of 42 articles revealed that patients with IR (RR, 1.59 [CI, 1.12–2.27]; p = 0.01), dysglycaemia (RR, 1.40 [CI, 1.15–1.70]; p < 0.001), BMI > 25 kg/m2 (RR, 1.35 [CI, 1.23–1.48]; p < 0.001), and hypertension (RR, 1.34 [CI, 1.22–1.47]; p < 0.001) showed an increased risk for thyroid cancer, whereas those with dyslipidaemia did not. (12) In the same review, the authors assigned quality levels to the evidence provided for each factor, ranging from ‘very low’ to ‘very high’. Importantly, the evidence quality levels were ‘low’ or ‘very low’ for every metabolic parameter except IR and BMI, which were graded ‘moderate’. (12) Thus, these results are not sufficient to establish an association between metabolic status and the risk of thyroid cancer. Similarly, there was limited evidence regarding the impact of MS on the risk of developing thyroid cancer. To our knowledge, only one other study (15) has comprehensively evaluated the association between MS or its components and the risk of developing thyroid cancer in a large-scale patient cohort. In that study, 9,890,917 South Korean adults without thyroid cancer were grouped according to obesity status and assessed. (15) The study demonstrated that thyroid cancer risk was higher in the MS group (Hazard ratio [HR], 1.15 [CI, 1.13–1.17]) than in the non-MS group, and the association between MS and thyroid cancer risk was significant in the obese group (defined as BMI > 25 kg/m2) (HR, 1.10 [CI, 1.07–1.13]) but not in the non-obese group (HR, 1.00 [CI, 0.98–1.03]). (15) The study also emphasized the combined effect of obesity and MS on the risk of developing thyroid cancer, revealing that obese men with MS had the highest risk of thyroid cancer, but obese women with MS did not. (15) Additionally, they showed that the risk of thyroid cancer significantly increased with an increase in the number of MS components in the obese group, but not in the non-obese group. (15) Although the study supports an association between MS and thyroid cancer, it suffers from an analytical perspective. The authors analysed the HRs of MS and its components for thyroid cancer development according to obesity status to obtain their results. However, BMI, which was used to define obesity status, is a continuous variable. To evaluate the association between a continuous variable and a target outcome, continuous data, like BMI, are dichotomized, split into several categories, or handled as a continuous variable with an imposed linear relationship between the variable and the outcome. (16) These commonly used modelling approaches carry relatively stringent statistical assumptions and can lead to loss of information, which may either weaken the predictive ability of the model or yield a poor fit between the continuous variable and the target outcome. (16) Thus, these approaches are not recommended in fields of medicine with variables and outcomes that show a non-linear continuous association. (17) The present study addresses this concern by adjusting for age and BMI prior to evaluation of risk.
Unlike earlier studies, the present study enrolled only subjects aged 40–70 years. This range was selected because thyroid cancer and MS are more prevalent at this age, and atypical events tend to occur in extremely young or old individuals. Although the study discussed above compared baseline characteristics between MS and non-MS groups, our study compared thyroid cancer and non-thyroid cancer groups, because thyroid cancer development was the target outcome in our study. All RRs and incidences of thyroid cancer were calculated after adjusting for age and BMI to avoid any statistical inappropriateness and to enhance the applicability of our results. Interestingly, the RRs and incidences of thyroid cancer gradually increased with the number of MS components in both men and women as well as in individuals with only one or two MS components who did not meet the definition for MS. Altogether, these results further support the association between MS and the risk of thyroid cancer.
Several pathophysiological mechanisms have been proposed to explain how thyroid carcinogenesis is associated with MS or its components. For example, thyroid carcinogenesis may be driven by increased proliferation, angiogenesis, cellular mobility, and DNA damage due to IR and hyperglycaemia. IR may also overstimulate insulin-like growth factor-1, -2, and insulin receptors, which contribute to thyroid carcinogenesis. Additionally, obesity is associated with the release of cytokines, bioactive molecules, and oestrogen from visceral fat, immune cells, and adipocytes, which are also factors in thyroid cancer development. (18–23) These proposed mechanisms all revolve around IR and obesity, which do not fully encompass MS. Although IR and obesity are key factors in the pathophysiology of MS, the impact of other MS components on thyroid carcinogenesis remains unclear. Based on our results, abdominal obesity, low HDL-cholesterol, and elevated blood pressure impose greater RRs for developing thyroid cancer than hyperglycaemia and hypertriglyceridemia, which were not significant in men. Nevertheless, the exact pathophysiological mechanisms remain unclear. As correlation does not equal causation, it is important to identify whether the association of MS or its components and the development of thyroid cancer is due to the incidental overlapping of two prevalent disorders or due to connected pathophysiological mechanisms. To make this distinction, additional large-scale, multicentre-based studies are needed. If these two disorders are indeed mechanistically connected, then MS and its components would not only serve as important risk factors for thyroid cancer development but would also provide a clinically actionable prevention strategy via modification of lifestyle behaviours, such as physical exercise and diet.
In this study, we selected patients aged 40–70 years and excluded data that were not mathematizable or subjective, such as smoking status, alcohol consumption status, and physical activity, from the analyses. We focused instead on concise analyses of basic demographics (age and sex), anthropometric and laboratory measurements, and the resultant statuses of MS and its components. Of note, these decisions may have introduced a selection bias in the study population due to the non-obligatory nature of the health examinations provided by the NHIS. We also acknowledge a lack of clinicopathological data specific to thyroid cancer, including histologic subtype, primary tumour size, extrathyroidal extension, and lymph node or distant metastasis, which reflect the biological aggressiveness of the cancer. Furthermore, our study could not include the duration of MS or its components in the analyses.
Based on the results of the present study, MS and its components, especially abdominal obesity, low HDL-cholesterol, and elevated blood pressure, are likely to contribute to the development of thyroid cancer, with a higher incidence in women than in men. Although the exact mechanisms that connect the two disorders remain unclear, MS and its components are predictive of thyroid cancer risk and may be useful in screening efforts to diagnose thyroid cancer at early stages. Therefore, MS patients and patients with even a single MS component should be routinely screened for thyroid cancer.