Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women

Paulo H. N. Harada; Julie E. Buring; Nancy R. Cook; Michael E. Cobble; Krishnaji R. Kulkarni; Samia Mora

Disclosures

J Endo Soc. 2017;1(2):113-123. 

In This Article

Discussion

In this population of apparently healthy middle-aged and older women, individuals with SCH and HT had differences in the lipid and lipoprotein subclass profile that indicated worsening insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol. Of the other biomarkers, only hs-CRP and HbA1c were associated with SCH and HT. For TSH quintiles mostly within the normal range, lipid and lipoprotein results for TSH quintiles were generally similar but null for other biomarkers. Hence, progressive thyroid hypofunction was associated with insulin-resistant and proatherogenic lipids and lipoproteins profile in a graded manner, with potential clinical consequences.

This study adds to the literature by describing the graded relationship of progressive thyroid hypofunction, even within the "normal" range of euthyroidism, as manifested by increasing lipoprotein insulin resistance. For inflammatory, coagulation, and glucose metabolism biomarkers, only hs-CRP and HbA1c were higher across the euthyroid to HT spectrum, but none of those biomarkers was higher along the TSH spectrum within euthyroid and SCH. Given that, the current classification of euthyroidism, SCH, and HT may be less sensitive to earlier thyroid disturbances within euthyroidism, in particular in relationship to insulin resistance–related dyslipidemia/dyslipoproteinemia.

We studied an apparently healthy population of women who were predominantly insulin sensitive (89% with HbA1c < 5.7%). Should the progressive insulin resistance–related dyslipidemia along thyroid hypofunction have any impact on clinical outcomes as incident T2D or CVD, even small relative risk may have a high population impact. This is due to the very broad generalizability of our findings, as euthyroid and SCT women comprise 97.3% of middle-aged women in the United States.[1] Previous studies have found strong associations for LPIR with incident T2D,[21,22] and also in the current Women's Health Study population.[23] The robust association between thyroid and LPIR may be a pathophysiological pathway of its hypofunction toward T2D. For CVD, despite neutral risk with increasing TSH levels within the euthyroid range,[24] the role of SCH is still open to debate.[25] In these contexts, our findings suggest that lipids and lipoproteins are potentially important mediators for therapeutic targeting beyond TSH replacement.

The literature regarding euthyroid and hypothyroid relationships with the panel of biomarkers that we examined is rather mixed. For standard lipids, the association of thyroid hypofunction with low HDL cholesterol and high triglycerides has been shown in a population study with >30,000 euthyroid people.[12] Alternatively, in the Framingham Offspring Study population, there was no association between TSH and either HDL cholesterol or triglycerides.[11] Additionally, in the 2 studies mentioned previously there was higher total and LDL cholesterol for increasing TSH. However, it is not possible to infer to which extent population profile and adjustment models explain the divergent results.

Regarding lipoprotein subclasses, Hernández-Mijares[26] found, similarly to the current study, an increasing proportion of LDL pattern B profile patients from euthyroid to SCH. However, they did not address LDL subclasses across the euthyroidism range. In contrast, Pearce et al.[11] found lipoprotein subclass profiles totally opposite to the present results, toward insulin sensitivity in analyses adjusted for age, BMI, systolic blood pressure, antihypertensive treatment, diabetes, smoking, HDL cholesterol, and triglycerides. Nevertheless, thyroid hypofunction seems to equally affect HDL cholesterol, triglyceride, and lipoprotein subclasses toward insulin resistance profile. After further adjusting our current models for HDL and triglycerides, lipoprotein subclass profiles on SCH and HT were null or compatible with insulin sensitiveness (data not shown), similar to the study by Pearce et al..[11] Thus, the collinear effect of thyroid hypofunction on HDL, triglyceride, and lipoprotein subclasses could justify those paradoxical results.

Regarding inflammation, in our study SCH and HT were associated with high hs-CRP, but not after adjustment for BMI. Lee et al.[27] also found no association of thyroid function with hs-CRP adjusted for BMI, which raises the hypothesis of BMI mediation between thyroid and inflammation. Also, Hueston et al.[28] did not find association of SCH with hs-CRP or homocysteine levels in a US adult population (National Health and Nutrition Examination Survey). However, the authors did not adjust for smoking, which is positively associated with inflammation[29] and inversely with HT.[30] This is corroborated by the fact that in our study there was no hs-CRP difference for euthyroid, SCH, and HT when smoking was not adjusted for (data not shown). Regarding homocysteine, Zhou et al.[13] also did not find an association with SCH, but they did find a positive association with HT. Nevertheless, in that meta-analysis, there was evidence for study heterogeneity and publication bias. Fibrinogen, a marker of hypercoagulation state, was similarly not associated with HT in other studies,[31,32] despite their limited adjustment for confounders. sICAM-1, associated with initiation and formation of atherosclerosis in animal models,[33] and GlycA, a novel composite marker of acute phase glycoproteins signaling chronic inflammation,[20] were both not associated with thyroid hypofunction in the present study. To the best of our knowledge, the association of euthyroidism, SCH, and HT with sICAM-1 and GlycA has not been reported previously. Finally, reverse causation for thyroid function and inflammation should be considered. The most common cause for thyroid hypofunction is Hashimoto disease,[34] which may confound the association by its inflammatory pathophysiology. We could not address this hypothesis due to unavailable thyroid peroxidase antibodies.

Underlying Mechanisms

Thyroid hormones act as modulators of cholesterol synthesis and degradation through key enzymes. One of the main mechanisms is the stimulus of thyroid hormones over sterol regulatory element–binding protein 2, which in turn induces LDL receptor gene expression.[35] However, it was shown that the association of HT and higher LDL cholesterol levels is present only in insulin-resistant subjects.[36] Indeed, the lack of LDL cholesterol differences could be explained by our insulin-sensitive study population (low HbA1c levels). HT has also been associated with lower catabolism of lipid-rich lipoproteins by lipoprotein lipase,[37] hepatic lipase,[38] and decreased activity of cholesterol ester transfer protein[39] that mediates exchanges of cholesteryl esters of HDL particles with triglyceride-rich LDL and VLDL particles. These mechanisms might explain the relationship of thyroid hypofunction with atherogenic and insulin-resistant lipid and lipoprotein abnormalities.

Finally, the milder differences noted in HbA1c compared with LPIR across thyroid categories may be explained by the earlier effects of insulin resistance on lipoprotein metabolism than on glucose metabolism.[40]

Strengths and Limitations

Our study has a relatively large sample of apparently healthy middle-aged and older women free of CVD, which may limit generalizability to men or higher risk woman. The study design is cross-sectional, which limits any causal inferences. Additionally, there is no information about duration of thyroid dysfunction as well as thyroid hormone replacement and/or thyroid-modulating drugs. In spite of that, these factors may have limited impact given that our sample is composed of apparently healthy women on enrollment. We had an unprecedented comprehensive set of biomarkers, which offered a broad perspective on pathways between thyroid hypofunction and cardiometabolic risk. Despite the large number of biomarkers examined, insulin resistance is the common biological mechanism that is likely underlying the overall findings. Therefore, it is improbable that our results were due to chance alone.

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