In a large population-based study of older adults, we found that increasing TSH levels were associated with greater odds of prevalent metabolic syndrome. We also observed a significant association between continuous TSH and prevalent MetS among euthyroid participants. This suggests that even within the normal range, there may be a higher prevalence of metabolic abnormalities as TSH levels increase. In addition, we found a significant increase in the odds of prevalent MetS in participants with marked subclinical hypothyroidism (TSH 10–20 mIU/L). This is the same category of individuals who, in a recent meta-analysis by Rodondi et al, were found to have increased incidence of CHD events and mortality, suggesting that cardiometabolic risk may be determined in part by degree of TSH elevation.2
Although results for the association between continuous TSH and prevalent MetS were unchanged after excluding thyroid hormone users, the relationship between marked subclinical hypothyroidism and prevalent MetS was no longer statistically significant. This suggests that our power to detect an association within this group may have been decreased by excluding 11 of 34 participants (32%). Another possibility is that the observed association among this group was due to the inclusion of under-treated overt hypothyroid participants; therefore excluding these individuals attenuated the effect.
Previous cross-sectional studies have inconsistently found an association between MetS and higher TSH levels or subclinical hypothyroidism.10, 11
This may be due to differences in how thyroid function was categorized, the outcome assessed, and the age of participants under study. In a Mexican cohort of over 3000 participants, Garduño-Garcia et al. reported a relationship between FT4 and HDL, insulin and HOMA-IR levels, however there was no difference in the prevalence of the MetS between euthyroid and subclinical hypothyroid individuals.11
Of note, participants in this study with TSH values ≥10 mIU/L were classified as overt hypothyroid regardless of FT4 level. This may have obscured an association between subclinical hypothyroidism and MetS since we found a significant relationship only in those with a TSH >10 mIU/L. In a cohort of 2700 euthyroid participants, Roos et al. found an association between FT4 and 4 of the 5 MetS criteria, however this study did not use MetS as a composite endpoint.10
In both of these studies, the average age of participants (mean age 40’s) was much younger than the Health ABC, suggesting that age might play a role in modifying the effect of TSH on the MetS and its components.
Two recent cross-sectional studies showed a positive association between TSH levels and prevalent MetS. One study of a euthyroid German cohort (mean age 52) found that TSH in the upper normal range (2.5–4.5 mIU/L) was associated with a 1.7-fold increased risk of MetS compared with a low-normal TSH (0.3–2.5 mIU/L).12
Another study of nearly 1000 euthyroid post-menopausal women in Korea (mean age 59) reported an odds ratio for MetS of 1.9 in participants with the highest vs. lowest quartiles of TSH.13
In both studies only the triglyceride component of MetS was independently associated with TSH. These finding are consistent with our results, although we also found HDL levels to be weakly associated.
Current evidence suggests that many of the individual components of the metabolic syndrome may be more prominent as TSH levels increase. Both the HUNT and Tromsø studies reported a linear positive association between TSH levels and blood pressure among euthyroid individuals which may be mediated by increased arterial stiffness and impaired vascular smooth muscle relaxation.21–23
The HUNT study also found higher TSH to be associated with higher triglycerides and lower HDL; furthermore, the relationship was stronger among overweight individuals (BMI>25 kg/m2
Thyroid hormone may suppress liver triglycerides synthesis, and there is increasing evidence that thyroid hormone increases reverse cholesterol transport, thereby promoting HDL cholesterol activity.25
Increased insulin resistance has also been documented in both overt and subclinical hypothyroidism.26, 27
Insulin resistance is generally thought to be the underlying cause of the metabolic syndrome.9
However, we did not find an association between thyroid function and insulin resistance as measured by HOMA-IR or fasting glucose. The only individual components of the metabolic syndrome independently associated with thyroid function were triglycerides and HDL cholesterol. HDL cholesterol is an independent predictor of cardiovascular disease even in individuals who are adequately treated for elevated LDL cholesterol.28, 29
Therefore the association between thyroid function and HDL observed in our study might represent one of the mechanisms by which subclinical hypothyroidism increases cardiovascular risk in previous studies that adjusted for traditional CVD risk factors.
Several limitations of this study should be noted. First, TSH values were measured only once despite previous data reporting spontaneous normalization of abnormal TSH in a significant proportion of people.30, 31
This would likely result in non-differential misclassification and attenuate our observations. In addition, FT4 levels were only measured in participants with TSH values <0.1 or greater than 7.0 mIU/L which may have resulted in misclassification of individuals with overt hyper- or hypothyroidism as having subclinical disease, though studies of outpatient populations suggest that overt thyroid disease is rare with mild TSH abnormalities.32
Furthermore, given the overall low prevalence of overt hyper- or hypothyroidism in Health ABC participants with markedly high or low TSH values (<1% for each condition),17
it is likely that few individuals were misclassified due to a lack of complete FT4 measurements and a sensitivity analysis excluding these potentially misclassified participants yielded similar results. Secondly, because only a small proportion of the cohort had FT4 measurements (n=129), we were unable to evaluate the association between FT4 and MetS.
The lack of significant association among individuals with overt hypothyroidism represents an inconsistent finding of this study. Although the association between continuous TSH and prevalent MetS was found to be linear, the odds ratios for prevalent disease in individuals with overt hypothyroidism were not elevated. This may be due to the small number of participants with overt hypothyroidism (n=21) and consequent lack of power.
In addition, there is some evidence that obesity itself may be responsible for elevated TSH levels which are not indicative of thyroid dysfunction, but rather a consequence of greater fat mass.33, 34
In obese individuals, increased adipose tissue may secrete greater amounts of leptin, which in turn may stimulate the hypothalamic-pituitary-thyroid axis to secrete TSH. Because of this bidirectional relationship, it is possible that in some participants obesity and MetS preceded the measurement of elevated TSH. However, we observed no correlation between TSH and measures of obesity (BMI or waist circumference) and TSH values were not significantly different between obese and non-obese participants (p=0.62). Furthermore, results remained unchanged after adjustment for BMI, and analyses stratified by BMI≤ or >30 kg/m2
were not significantly different. These results are in contrast to those reported by Rotondi et al, who found significantly higher TSH values in euthyroid morbidly obese (BMI>40) and obese (BMI>30) individuals versus normo-weight controls.35
Finally, our results showed an association between thyroid function and prevalent, but not incident MetS, and causal relationships cannot be established from cross-sectional data. Although our results for incident disease were not statistically significant, the point estimates for the odds of incident MetS were similar to those for prevalent disease. However, we were underpowered in this analysis due to the very small number or participants with marked subclinical hypothyroidism (n=12).
In conclusion, we describe an association between higher TSH levels and increased prevalence of the metabolic syndrome not only in those with abnormal thyroid function but also within the euthyroid range. In addition, individuals with subclinical hypothyroidism and TSH >10mIU/L may be at greater risk for MetS and its associated complications. The relationship between thyroid function and MetS appears to be driven primarily by higher triglycerides and lower HDL. Further prospective studies are needed to determine whether treatment of elevated TSH can attenuate these metabolic abnormalities.