The Interaction Between Subclinical Hypothyroidism And Dyslipidemia In Middle Aged And Elderly People

Background:Subclinical hypothyroidism (SCH), defined by elevated serum thyroid-stimulating hormone (TSH) and normal serum free thyroxine (FT4), is the most common thyroid dysfunction.SCH continues to progressively increase all over the world (the prevalence has increased from less than 5.0% in England in 1972-1974 to 9.0% in the United States in 1995 and 19.3% in India in 2012) and was regarded as an independent cardiovascular risk factor in a large number of studies. Therefore, it is considerably necessary to further investigate the etiology of SCH, which has not been fully elucidated. Several risk factors, i.e., autoimmunity, abnormal iodine intake and inflammation, have been associated with SCH. However, the presence of SCH could not be fully explained by the above-stated reasons in the following interesting phenomenon. Jankovic et al. observed that obese subjects with hypertriglyceridemia exhibited the increased serum TSH concentrations; interestingly, the TSH levels significantly decreased after the serum triglyceride (TG) levels decreased after bariatric surgery. Similarly, the decreased serum T3 and T4 concentrations, representing the impaired thyroid function, were also observed in animals fed a high-fat diet. These lines of evidence suggested that the presence of SCH might be associated with hypertriglyceridemia.High circulating TG levels lead to the increased importation of fatty acids into nonadipose tissues, contributing to ectopic intracellular lipid accumulation, also known as lipotoxicity. Lipotoxicity attracts great attention worldwide for its serious and extensive impact on human health. Apart from its important role in the pathogenesis of metabolic diseases (such as type 2 diabetes mellitus, obesity and nonalcoholic fatty liver disease), the effect of lipotoxicity in other diseases, such as heart failure, chronic kidney disease and endothelial cell dysfunction has also drawn intensive interest. However, so far, no research has explored whether thyroid is another organ affected by lipotoxicity.In the other hand, previous studies have demonstrated that SCH is an important risk factor for dyslipidemia. Among 25,862 participants in a statewide health fair in Colorado, fasting total cholesterol (TC) and low-density lipoprotein cholesterol (LDI-C) were gradually elevated with the increasing TSH levels. Whickham survey found that serum TC levels were significantly higher in SCH subjects than in euthyroid subjects. With L-thyroxine replacement therapy, TSH concentrations were decreased into the reference range and dyslipidemia was improved accordingly. Our previous study also illustrated the positive association between TSH and lipid after adjustment for thyroxine and other confounders in patients with coronary heart diseases or subjects with euthyroidism. It suggested that TSH might play a role in lipid metabolism independent of thyroid hormones.Age is the common risk factor for both SCH and dyslipidemia. According to the National Health and Nutrition Examination Survey III (NHANES III), TSH levels were increased by approximately 40% in adults aged 60-69 years compared with individuals aged 20-29 years. In addition, large-scale epidemiological survey in China showed that age was positively associated with serum lipid profile. However, few studies explored the interaction of age and SCH on lipid profiles.The present study investigated the association between thyroid dysfunction and dyslipidemia. First, we assessed the association between serum TG levels and risk for SCH. Second, we identified the association between serum TSH and lipid profiles. Furthermore, we compared the regression coefficients of TSH and lipid parameters in different age groups, as well as evaluated the serum lipid elevation associated with age in subjects with different thyroid status. Our study might be helpful in providing attractive and feasible approaches to resist SCH and dyslipidemia.Objectives:1. To assess the association between serum TG levels and risk for SCH.2. To identify the association between serum TSH levels and lipid frofile.3. To investigate the potential interaction of age and SCH on lipid parameters.Methods:1. Study ParticipantsThe present study was part of the community-based Risk Evaluation of cAncers in Chinese diabeTic Individuals:A 1ONgitudinal (REACTION) Study aiming to investigate the epidemiology of metabolic diseases that was conducted across China from April 1, 2011, through May 30,2012. We selected three communities from the east, west, and south of China with similar and stable iodine nutrition status. A total of 24,100 participants provided an overnight fasting blood sample and were asked to complete a self-reported questionnaire. In the Part I, after exclusion,5,033 cases were defined as those participants with diagnoses of SCH from the eligible subjects, and the controls were matched one to one with the cases by age, gender and region from subjects without either SCH or overt hypothyroidism. In the Part II,17,046 participants were included for the cross-sectional analysis.2. Data CollectionBlood samples were collected from all participants between 8:00 AM and 10:00 AM after a minimum 10-hour fasting. Chemiluminescent methods (Cobas E601; Roche) were used to quantitate thyroid function based FT3, FT4, and TSH levels. The serum lipid profile was determined using the ARCHITECT ci16200 Integrated System (Abbott). The intraassay and interassay coefficients of variation were always below 5% for all of the above parameters.3. Study OutcomesThe laboratory reference ranges were 3.1-6.8 pmol/L (2.01-4.42 pg/mL) for FT3, 12-22 pmol/L (0.94-1.72 ng/dL) for FT4, and 0.27-4.2 mIU/L for TSH. SCH was defined as a combination of high TSH and normal FT4. Based on the serum TSH level, SCH was further divided into mild SCH (TSH:4.2-10.0 mIU/L) and severe SCH (TSH> 10.0 mIU/L).According to the National Cholesterol Education Pro gram Adult Treatment Panel Ⅲ, high TC, high TG, high LDL-C and low HDL-C were defined as TC> 6.20 mmol/L, TG> 1.69 mmol/L, LDL-C> 4.13 mmol/L, HDL< 1.04 mmol/L (Male)/< 1.30 mmol/L (Female).4. Statistical AnalysesStatistical tests were performed using SPSS version 18.0 for Windows (SPSS Inc). The conditional logistic regression was used to estimate the risk for SCH. The linear regression model was used to estimate the association between TSH and lipid parameters. The linear-by-linear association chi-square test was used to analyze the association between age and the prevalence of dyslipidemia. The relationships between TSH and serum lipid parameters were evaluated using partial correlation analysis. We generated a general linear model to estimate the marginal mean of lipid or thyroid functions.Results:1-1 The risk for SCH was higher in subjects with hypertriglyceridemiaAfter adjustment for confounders, hypertriglyceridemia was associated with a 32.7% (OR= 1.327,95%CI= 1.003-1.756, P= 0.047) increased risk for SCH in men and a 39.2% (OR= 1.392,95%CI= 1.212-1.598,P<0.001) increased risk in women.1-2 The risk for SCH was progressively increased following higher TG/HDL-C ratioThe population was stratified according to the quartiles of TG/HDL-C ratio. In male, compared with Quartile 1, the ORs for Quartile 2, Quartile 3 and Quartile 4 were 1.865, 1.978 and 2.376, respectively. In female, the ORs were 1.052,1.270 and 1.476, respectively.1-3 Positive correlation between serum TG levels and TSH concentrationsThe population was stratified according to the quartiles of TG levels. The log-transformed serum TSH levels showed a significantly positive association with the TG levels, whereas the FT4 and FT3 levels were not correlated significantly.2 The positive relationship between TSH and TC, LDL-C and TGAfter adjustment for thyroid hormones and other confounders, TSH was positively related to TC (r= 0.0102, P< 0.0001), LDL-C (r= 0.0070, P< 0.0001) and logTG (r= 0.0017, P= 0.0001), but not related to HDL-C (r=-0.0001, P= 0.8820).3-1 The linear association between age and the prevalence of dyslipidemiaFollowing the increasing age, the prevalence of high TC (Linear trend coefficient= 0.070,P< 0.001), high TG (Linear trend coefficient= 0.017, P= 0.024) and high LDL-C (Linear trend coefficient= 0.059, P< 0.001) was linearly elevated, whereas the prevalence of low HDL-C was decreased (Linear trend coefficient=-0.022, P= 0.003).3-2 With the increasing age, regression coefficients of TSH and TC or LDL-C were elevatedAfter adjustment for thyroid hormones and other confounders, each 1 mlU/L increase in TSH was estimated to elevate the TC level by 0.0147 mmol/L,0.0395 mmol/L, and 0.0551 mmol/L,0.0521 mmol/L, respectively, in individuals aged 40-49 years,50-59 years,60-69 years and≥70 years. The relationship was similar for LDL-C: each 1 mIU/L increase in TSH was estimated to elevate the LDL-C level by 0.0098 mmol/L,0.0290 mmol/L, and 0.0343 mmol/L,0.0332 mmol/L, respectively, in individuals aged 40-49 years,50-59 years,60-69 years and≥70 years.3-3 Compared with euthyroidism, the effect of age on TC or LDL-C was greater in SCHIn euthyroidism, compared with subjects aged 40-49 years, TC levels in subjects aged 60-69 years was increased by 7.39%. In mild and severe SCH, TC levels in subjects aged 60-69 years was increased by 7.52% and 9.88%, respectively. The effect on LDL-C was similar:in euthyroidism, mild SCH and severe SCH, LDL-C levels in subjects aged 60-69 years was increased by 9.06%,10.76% and 14.83%, respectively compared to subjects aged 40-49 years.Conclusion:1. Hypertriglyceridemia was positively associated with the risk for SCH.2. Serum TSH levels were positively related to TC, LDL-C and TG concentrations.3. The interaction of age and TSH on TC and LDL-C was identified in the population.