Age-related change in thyroid-stimulating hormone: a cross-sectional study in healthy euthyroid population

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1 Original doi: /endocrj.ej Age-related change in thyroid-stimulating hormone: a cross-sectional study in healthy euthyroid population Juan Chen 1), 2) *, Weihong Zhou 3) *, Fenghui Pan 1), Wenxia Cui 1), Man Li 1) 1), 4) and Yun Hu 1) Department of Geriatrics, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China 2) Department of Endocrinology, Huai an First People s Hospital, Nanjing Medical University, Huai an, China 3) Department of Medical Examination Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China 4) State Key Laboratory of Analytical Chemistry for Life Science Department of Chemistry Nanjing University, Nanjing, China Abstract. This cross-sectional study aimed to examine changes in thyroid-stimulating hormone (TSH) concentration over age in China and investigate relationship between TSH and risk factors for cardiovascular disease (CVD) among euthyroid subjects. TSH, free triiodothyronine (FT3), free thyroxine (FT4), blood lipid, and glucose were measured. 7,693 individuals were subdivided into different age groups. Associations between TSH and CVD risk factors [age, body mass index (BMI), systolic and diastolic blood pressure, total cholesterol (TC), triglycerides, low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C) and fasting plasma glucose (FPG)] were evaluated with Pearson correlation analysis. Results showed that 2.5th percentile for TSH was consistent across age groups, whereas 97.5th percentile increased in subjects older than 40 years with upper limit being 6.83 miu/l in subjects aged years and 8.07 miu/l in those older than 70 years. The age-specific upper limits reclassification rate was higher in all age bands as compared to the common cutoff value. TSH was positively associated with age, SBP, DBP, TC and LDL-C and negatively with FT3 and FT4. Serum TSH within new reference range had a linear correlation with SBP, TC and LDL-C in subjects aged <60 years. There were no significant differences in BMI, blood pressure, lipid profile or FPG among subjects and older than or equal to 70 years. Elevated TSH within new reference range is associated with risk factors for CVD in subjects aged <60 years. Thus, there might be age-related difference in the relationship between CVD risk factors and elevated serum TSH. Key words: Thyroid-stimulating hormone, Euthyroid individuals, Age, Cardiovascular disease THE SERUM thyroid stimulating hormone (TSH) is the most sensitive indicator in the evaluation of thyroid function. Subclinical hypothyroidism and subclinical hyperthyroidism are defined as abnormally increased or decreased serum TSH level with a normal serum free thyroxine (FT4) level. Serum TSH level is affected by age, genetics, gender, thyroid autoantibodies, iodine intake and thyroid disease [1-5]. Therefore, the National Academy of Clinical Biochemistry recommends that the Submitted Mar. 19, 2018; Accepted Jul. 3, 2018 as EJ Released online in J-STAGE as advance publication Aug. 1, 2018 Correspondence to: Yun Hu, Department of Geriatrics, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, State Key Laboratory of Analytical Chemistry for Life Science Department of Chemistry Nanjing University, 321 Zhongshan Road, Nangjing , China. huyundr@sina.com *Equal contributors serum TSH reference range should be established after rigorously screening euthyroid volunteers without evidence of thyroid disease [6]. The National Health and Nutrition Examinations Survey III (NHANES III) in the United States suggests that, in the absence of thyroid disease, serum TSH concentration in adults increases with age [7]. In 14,376 participants with no history of thyroid disease, free of overt hyperthyroidism or hypothyroidism and with negative tests for thyroid peroxidase and thyroglobulin antibodies in the NHANES III study, there was a progressive shift in the TSH curve towards higher values with age [8]. This has been confirmed by other studies [6, 9]. It has been suggested that the age-specific TSH reference range may minimize the under-diagnosis of subclinical hypothyroidism in young adults and prevent over-diagnosis in the elderly [5, 8]. However, questions remain about whether TSH level increases with age in Chinese. The Japan Endocrine Society

2 2 Chen et al. Thyroid dysfunction is associated with the pathogenesis of cardiovascular disease (CVD) and coronary heart disease related death [10]. Dyslipidemia in hypothyroidism, also in some cases of subclinical hypothyroidism, is associated with an increased risk for CVD [10-12]. Available studies have shown that the elevated serum levels of total cholesterol (TC), low density lipoproteincholesterol (LDL-C) and triglycerides (TG) in individuals with overt hypothyroidism [13], is reversible after levothyroxine therapy [14]. Recently, the association between TSH and CVD has been investigated among euthyroid individuals. A prospective study shows that higher TSH and lower FT4 within the reference range are positively and linearly associated with CVD mortality in women [15]. Ruhla et al. [16] found that euthyroid subjects with TSH in the upper normal range have higher TG level and an increased incidence of metabolic syndrome. However, other studies fail to show the relationship between TSH and CVD risk factors in euthyroid individuals [17, 18]. Thus, it is necessary to investigate the age-specific reference intervals [19]. In this study, we investigated whether TSH level increased with age in Chinese population and examined the relationship between TSH and CVD risk factors. Materials and Methods Subjects A total of 7,900 Chinese who received routine physical examination in the Nanjing Drum Tower Hospital, were recruited between January 1, 2016 and December 31, To exclude the influence of thyroid disease and other confounders, following exclusion criteria were used in this study: self-reported thyroid disease or goiter; overt hypothyroidism (TSH >20 miu/l or TSH >4.2 miu/l and FT4 <12 pmol/l); overt hyperthyroidism (TSH <0.27 miu/l and FT4 >22 pmol/l); use of T4 or antithyroid drugs; abnormal thyroid ultrasound or positive thyroid antibodies in those subjects with enlarged thyroid at palpation; use of amiodarone, lithium carbonate, carbamazepine or phenytoin (because of the effects of these drugs on thyroid function or thyroid function tests); and discordant results suggestive of pituitary dysfunction or assay interference (e.g. increased TSH with increased FT4). In addition, pregnant or breast-feeding women were excluded. Finally, 7,693 individuals were recruited as the reference population. Anthropometric and biochemical measurements Height and weight were measured, and body mass index (BMI) was calculated as weight (kg) divided by square meters of height (m 2 ). Blood pressure (BP) was measured using an automated device (A & D Co., Japan) in a sitting position, after 10-min rest. Venous blood samples were taken in the morning after overnight fasting and processed for the detection of TC, TG, LDL-C, high density lipoprotein cholesterol (HDL- C), fasting plasma glucose (FPG), serum TSH, FT4 and free triiodothyronine (FT3). Serum levels of TC, TG, LDL-C, HDL-C and FPG were measured using enzymatic methods with Olympus reagents by automated spectrophotometry on the Olympus AU5400 system (Olympus Corporation, Tokyo, Japan). Serum TSH, FT4 and FT3 were measured by chemiluminescence immunoassay (ADVLA Centaure, Siemens, USA). The reference ranges were as follows: TSH, miu/l; FT4, pmol/l; FT3, pmol/l. Statistical analysis Normal distribution was assessed with the Kolmogorov-Smirnov test. Continuous variables with normal distribution are expressed as means ± standard deviation (SD). TSH concentration was log-transformed due to its abnormal distribution. Statistical methodologies from published guidelines were applied to define TSH reference interval between 2.5th percentile and 97.5th percentile. Comparisons of the median of TSH for different age groups were calculated by Kruskal-Wallis one-way ANOVA in a single gender. The correlation between TSH and clinical variables was evaluated using Pearson s correlation analysis. The association between TSH and CVD risk factors was assessed in different age groups (<60 years, years and 70 years). Subjects were divided into five groups according to serum TSH concentration in the new reference range, and then ANOVA was used to compare means among groups. Statistical analysis was performed using SPSS version 21.0 for Windows (USA). A value of p < 0.05 was considered statistically significant. Results Baseline characteristics of study population Of 7,693 subjects, there were 5,397 men and 2,296 women. The mean age was 51.8 ± 14.7 years (range, years) and the mean BMI was 24.5 ± 3.0 kg/m 2

3 Age-related change in TSH 3 Table 1 Baseline characteristics of 7,693 euthyroid subjects Characteristic Range Mean ± SD Male/Female 5,397/2,296 Age (years) ± 14.7 BMI (kg/m 2 ) ± 3.0 SBP (mmhg) ± 16.4 DBP (mmhg) ± 11.2 FPG (mmol/l) ± 1.1 TC (mmol/l) ± 0.9 TG (mmol/l) ± 1.0 LDL-C (mmol/l) ± 0.7 HDL-C (mmol/l) ± 0.3 TSH (miu/l) ± 1.5 FT3 (pmol/l) ± 0.7 FT4 (pmol/l) ± 2.3 Note: SD, standard deviation; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; LDL-C, lowdensity lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TSH, thyroid stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine. Data are presented as mean ± SD. (range, kg/m 2 ). The mean lipid profile was as follows: TC, 4.9 ± 0.9 mmol/l (range, mmol/l), TG, 1.6 ± 1.0 mmol/l (range, mmol/l), LDL- C, 2.6 ± 0.7 mmol/l (range, mmol/l), and HDL-C, 1.2 ± 0.3 mmol/l (range, mmol/l). The mean serum TSH, FT3 and FT4 were 2.6 ± 1.5 miu/l (range, miu/l), 4.8 ± 0.7 pmol/l (range, pmol/l) and 17.2 ± 2.3 pmol/l (range, pmol/l), respectively (Table 1). The possible association between serum TSH level and clinical variables was assessed using Pearson s correlation analysis. As shown in Table 2, there was positive correlation of TSH with age (r = 0.096, p = 0.000), SBP (r = 0.095, p = 0.000), DBP (r = 0.039, p = 0.001), TC (r = 0.035, p = 0.002) and LDL (r = 0.027, p = 0.017). In addition, serum TSH was negatively associated with FT3 and FT4 (p < 0.001). However, TSH had no relationships with BMI, FPG, TG and HDL-C (p > 0.05). There was negative correlation of FT4 with age (r = 0.115, p = 0.000), BMI (r = 0.033, p = 0.005), TC (r = 0.033, p = 0.004) and TG(r = 0.051, p = 0.000). In addition, serum FT4 was positively associated with DBP (r = 0.049, p = 0.000). However, FT4 had no relationship with FPG, SBP, LDL-C or HDL-C (p > 0.05) (Table 2). Table 2 Correlations between serum TSH, FT4 and clinical variables TSH FT4 r p value r p value Age BMI SBP DBP FBG TC TG LDL-C HDL-C Note: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TSH, thyroid stimulating hormone; FT4, free thyroxine. Change in serum TSH and FT4 level with age To determine the age-related serum TSH level, 7,693 participants were divided into six age groups with an interval of 10 years (20 29, 30 39, 40 49, 50 59, and 70 years). Table 3 shows the median, 2.5th and 97.5th percentiles for TSH in different age groups. The median TSH concentration was 2.25, 2.10, 2.15, 2.26, 2.35 and 2.39 miu/l in 20 29, 30 39, 40 49, 50 59, and 70 years groups, respectively. In addition, the serum TSH level increased with age and the highest median TSH was found in 70 years group. The 2.5th percentile for TSH was 0.77, 0.74, 0.82, 0.88, 0.81 and 0.78 miu/l in 20 29, 30 39, 40 49, 50 59, and 70 years groups, respectively, but and >70 years groups showed no change with an increasing age. The 97.5 percentile for TSH increased steadily with age, being 5.07 miu/l in years group, 5.22 miu/l in years group, 6.03 miu/l in years group, 6.26 miu/l in years group, 6.83 miu/l in years group and 8.07 miu/l in 70 years group. Furthermore, we analyzed the age-related serum TSH level in different age groups of women and men, respectively. The serum TSH level also increased with age (p < 0.001) and the highest median TSH was also found in 70 years group of women and men, respectively. The 2.5th percentile for TSH showed no change in different age groups of women and men, respectively. The 97.5th percentile for TSH in women and men increased steadily

4 4 Chen et al. Table 3 Age (years) Females The 2.5th and 97.5th percentiles for TSH analyzed by age bands and by gender (n = 7,693) n MedianTSH (miu/l) 2.5th percentile 97.5th percentile All 2, Males , , , All 5, Total , , , All 7, with age, which was consistent with the total population (Table 3). According to the age-related upper TSH level, subjects would be reclassified from abnormal to normal, being 6.9% in years group, 3.7% in years group, 7.0% in years group, 8.0% in years group and 9.7% in years group. The highest reclassification rate was observed in the older participants, being 13.5% in those aged over 70 years. The median FT4 concentration was significantly decreased with age (p < 0.001) and the lowest median FT4 was found in 70 years group in total or in a single gender. In the total population, the 2.5 percentile and 97.5 percentile for FT4 decreased steadily after years group. However, the 2.5th percentile and 97.5 percentile for FT4 in a single gender did not change significantly with age (Supplementary Table 1). Association between TSH and CVD risk factors in different age groups To explore the influence of age on the relationship between TSH and CVD risk factors (<60, and 70 years). The subjects were divided into five subgroups based on the quintiles of TSH within age-related reference range. In <60 years group, years group and 70 years group, the reference range was miu/l, miu/l and miu/l, repectively. In <60 years group, subjects were further subdivided into five groups according to the TSH quintiles: Q1, miu/l; Q2, miu/l; Q3, miu/l; Q4, miu/l; Q5, miu/l. As shown in Table 4, there were significant increases in SBP, TC and LDL-C with the elevation of serum TSH (all p < 0.05), while serum BMI, DBP, FPG, TG, and HDL-C were comparable among five subgroups (all p > 0.05). Especially, compared with Q1 group (the lowest TSH quintile), subjects in Q5 group (the highest TSH quintile) had significantly higher SBP, TC and LDL-C. Subjects aged years were also subdivided into five groups according to serum TSH concentration (Q1, miu/l; Q2, miu/l; Q3, miu/l; Q4, miu/l; Q5, miu/l). Serum TSH quintile had no significant relationship with age, BMI, SBP, DBP, FPG and lipid profiles (Table 5). As shown in Table 6, participants aged 70 years were also subdivided into 5 groups according to the quintiles of serum TSH (Q1, miu/l; Q2, miu/l; Q3, miu/l; Q4, miu/l; Q5, miu/l). Age, BMI, SBP, DBP, FPG and lipid profiles had no relationship with the quintiles of TSH. Discussion The present study showed that the upper limit of serum TSH level increased with age in euthyroid subjects. This confirms the routine use of age-specific TSH reference range which may improve the diagnostic accuracy. The findings on the association between age and TSH in our study were consistent with previously reported [4, 7, 8, 20, 21]. In the US NHANES III study, the distribution of TSH and peak frequency were shifted towards higher TSH level with age, and the 97.5th percentile for TSH increased from 3.56 miu/l in years group to 7.49 miu/l in 80 years group [8]. A more recent study

5 Age-related change in TSH 5 Table 4 CVD risk factors in different TSH quintile groups among subjects aged <60 years Q1 ( ) Q2 ( ) Q3 ( ) Q4 ( ) Q5 ( ) p n 913 1,022 1,030 1, Age (years) ± ± ± ± ± BMI (kg/m 2 ) ± ± ± ± ± SBP (mmhg) ± ± ± ± ± DBP (mmhg) ± ± ± ± ± FPG (mmol/l) 5.14 ± ± ± ± ± TC (mmol/l) 4.80 ± ± ± ± ± TG (mmol/l) 1.52 ± ± ± ± ± LDL-C (mmol/l) 2.57 ± ± ± ± ± HDL-C (mmol/l) 1.27 ± ± ± ± ± Note: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Table 5 CVD risk factors in different TSH quintile groups among subjects aged years Q1 ( ) Q2 ( ) Q3 ( ) Q4 ( ) Q5 ( ) p n Age (years) ± ± ± ± ± BMI (kg/m 2 ) ± ± ± ± ± SBP (mmhg) ± ± ± ± ± DBP (mmhg) ± ± ± ± ± FPG (mmol/l) 5.54 ± ± ± ± ± TC (mmol/l) 4.87 ± ± ± ± ± TG (mmol/l) 1.61 ± ± ± ± ± LDL-C (mmol/l) 2.60 ± ± ± ± ± HDL-C (mmol/l) 1.28 ± ± ± ± ± Note: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Table 6 CVD risk factors in different TSH quintile groups among subjects older than 70 years Q1 ( ) Q2 ( ) Q3 ( ) Q4 ( ) Q5 ( ) p n Age (years) ± ± ± ± ± BMI (kg/m 2 ) ± ± ± ± ± SBP (mmhg) ± ± ± ± ± DBP (mmhg) ± ± ± ± ± FPG (mmol/l) 5.54 ± ± ± ± ± TC (mmol/l) 4.57 ± ± ± ± ± TG (mmol/l) 1.55 ± ± ± ± ± LDL-C (mmol/l) 2.41 ± ± ± ± ± HDL-C (mmol/l) 1.23 ± ± ± ± ± Note: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

6 6 Chen et al. of Sriphrapradang et al. [4] reported that the upper normal limit of TSH tended to increase with age in Thais, particularly in those aged 80 years. Vadiveloo et al. [21] also reported that there was a significant increase in median serum TSH level (1.58 miu/l at years to 1.86 miu/l at >90 years) and 97.5th percentile for TSH (3.98 to 5.94 miu/l) with age in subjects from the reference population. Another study investigated serum TSH reported that, although the median TSH and 97.5th percentile for TSH increased steadily with age, the use of age-specific reference range for TSH had minor effect on the thyroid status, except in the very old population [20]. A close association between TSH and age was observed in our subjects with the upper limit increasing from 6.03 miu/l at years to 8.07 miu/l at 70 years. Our finding was inconsistent with that in a study conducted in Zhengzhou city of China in which no significant difference was observed in TSH among different age groups [22]. This difference might be ascribed to the sample size because the sample size was 211 in the study conducted in Zhengzhou city and 7,693 in the present study [22]. We also examined whether the trend with age for TSH differed in a single gender and found that the trend was consistent with the total population. However, our results showed that the upper reference range for TSH was higher than in Western countries [7, 21]. One possible explanation may be the ethnic difference. Several changes in thyroid physiology may contribute to the increased serum TSH level with age, such as reduced sensitivity of thyrotropin to negative feedback of thyroid hormone [23], age-related reduction in TSH bioactivity [24, 25], genetic influence [5, 26] and decreased iodine uptake [1, 27]. Further studies are required to clarify the underlying mechanism. While applying the age-specific upper reference limit, we found some subjects would be reclassified from abnormal to normal, being 7% at years, 8% at years, 9.5% at years and 13.5% at 70 years. Although Kalani et al. [20] found that the use of agespecific upper limit reclassified only 1% of subjects in most age groups, the reclassification rate was high ( %) in 85 years group. Our result suggests that the use of age-specific TSH reference range may improve the diagnostic accuracy. Thyroid dysfunction has been a significant public health problem. Overt thyroid disorder and subclinical hypothyroidism are progressively associated with increased risk for cardiovascular events and poorer outcomes [10, 12]. It is clear that thyroid dysfunction is a risk for CVD. Meta-analyses of risks of coronary heart disease [28] and stroke [29] among subjects with the reference range of TSH were reported. One cross-sectional study showed that people with serum TSH in upper normal range had higher TG, with 1.7-fold increase in the prevalence of metabolic syndrome [16]. Our study revealed that serum TSH was associated with serum TC and LDL-C. Similarly, positive correlation was also found between TSH and lipid profiles in euthyroid Chinese [30], Spanish [31] and Korean [32]. Our results, in agreement with the findings from the study of Chon et al. [33], showed that serum TSH had no relationship with FPG and BMI. Other studies also investigate the relationship between serum TSH and BP in euthyroid population. One study indicates that people with higher serum TSH level within normal range had elevated BP than those with lower serum TSH level in normal range [32]. However, another study from 4,985 euthyroid individuals reveals that there is no association in between serum TSH and BP [34]. In our study, results showed serum TSH had positive relationship with SBP and DBP. Above findings indicate that TSH has an association with CVD risk factors, such as age, SBP, DBP, TC and LDL- C. The impact of age on CVD risk in people with subclinical hypothyroidism has been reported by some studies. Cappola AR et al. reported that high prevalence of CVD was not associated with subclinical hypothyroidism in elderly patients [35]. Hyland KA et al. revealed that risk of CVD, heart failure, and cardiovascular death did not increase in older adults with persistent subclinical hypothyroidism [36]. However, some studies showed that the association between subclinical hypothyroidism and CVD was strong [37] or only existed [38] among individuals 65 yeas old. Treatment of subclinical hypothyroidism with levothyroxine provided no apparent benefits in older adults [39]. Higher levels of TSH may have different effects for younger and older people [40]. Thus, we speculate that there may be age-related difference in the relationship between CVD risk factors and elevated serum TSH. However, the effect of age on this relationship was neglected and less of them performed an age-stratified analysis. We then examined whether the relationship of TSH with CVD risk factors is influenced by age. Our results showed that higher TSH level within new reference range was associated with SBP, TC and LDL-C only in subjects aged <60 years. There were no significant differences in the BMI, BP, lipid profile and FPG among subjects with different serum TSH levels

7 Age-related change in TSH 7 within new reference range in those aged over 60 years. Thus, though the age-related reference range may affect the association of TSH with cardiovascular risk in younger individuals, the slightly elevated TSH in the elderly may be acceptable, without the need of thyoxine treatment. A limitation of this study is that thyroid disease was excluded by clinical and laboratory evaluations, and not every subject had thyroid ultrasound and thyroid antibodies tests. Iodine status was not assessed in our study. In addition, whether our results are applicable in other ethnicities with different lifestyles is required to be further studied. In conclusion, our study reveals that the median TSH and 97.5th percentile for TSH increase over age. Elevated TSH in new reference range is associated with CVD risk factors only in subjects aged <60 years. Thus, in order to avoid misclassification and over-replacement, age-specific serum TSH range is recommended in the clinical practice. Acknowledgements The study was partially supported by the Natural Science Foundation of Jiangsu Province, China (BK ), and the Foundation of Jiangsu Province Health Bureau (BJ15005). The study was partially supported by Novo Nordisk young scientific talent funding. Disclosure statement None of the authors have any potential conflicts of interest associated with this research. References 1. Cho NH, Choi HS, Kim KW, Kim HL, Lee SY, et al. (2010) Interaction between cigarette smoking and iodine intake and their impact on thyroid function. Clin Endocrinol (Oxf) 73: Jeon MJ, Kim WG, Kwon H, Kim M, Park S, et al. (2017) Excessive iodine intake and thyrotropin reference interval: data from the Korean National Health and Nutrition Examination Survey. Thyroid 27: Rawal R, Teumer A, Volzke H, Wallaschofski H, Ittermann T, et al. (2012) Meta-analysis of two genomewide association studies identifies four genetic loci associated with thyroid function. Hum Mol Genet 21: Sriphrapradang C, Pavarangkoon S, Jongjaroenprasert W, Chailurkit LO, Ongphiphadhanakul B, et al. (2014) Reference ranges of serum TSH, FT4 and thyroid autoantibodies in the Thai population: the national health examination survey. Clin Endocrinol (Oxf) 80: Surks MI, Boucai L (2010) Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab 95: Bremner AP, Feddema P, Leedman PJ, Brown SJ, Beilby JP, et al. (2012) Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab 97: Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, et al. (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87: Surks MI, Hollowell JG (2007) Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 92: Yeap BB, Manning L, Chubb SA, Hankey GJ, Golledge J, et al. (2017) Reference ranges for thyroid-stimulating hormone and free thyroxine in older men: results from the Health in Men Study. J Gerontol A Biol Sci Med Sci 72: Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, et al. (2012) Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 172: Biondi B (2007) Cardiovascular effects of mild hypothyroidism. Thyroid 17: Martin SS, Daya N, Lutsey PL, Matsushita K, Fretz A, et al. (2017) Thyroid function, cardiovascular risk factors, and incident atherosclerotic cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) Study. J Clin Endocrinol Metab 102: Duntas LH, Brenta G (2012) The effect of thyroid disorders on lipid levels and metabolism. Med Clin North Am 96: Pearce EN (2012) Update in lipid alterations in subclinical hypothyroidism. J Clin Endocrinol Metab 97: Asvold BO, Bjoro T, Nilsen TI, Gunnell D, Vatten LJ (2008) Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med 168: Ruhla S, Weickert MO, Arafat AM, Osterhoff M, Isken F, et al. (2010) A high normal TSH is associated with the

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