It is generally accepted that overt hypothyroidism accelerates the progression of CHD by increasing levels of TC and LDL-C. Whereas controversy still exists as to whether there is an association between SCH and an adverse lipid profile. Moreover, the issue of the association between SCH and CHD remains complex [16
]. Because there is a consensus that most of the CHD patients should take statins, which might change the lipid profiles, we chose to investigate those with newly diagnosed asymptomatic CHD to avoid the confounding effects of statins on lipid levels. Furthermore, to exclude the possible confounding effects of smoking and to better understand the role of TSH in CHD, we mainly focused on euthyroid non-smokers in this study. We found that even within the normal range, TSH was positively and linearly correlated with lipid profiles in non-smokers with newly diagnosed asymptomatic CHD.
Thyroid hormones play essential roles in a variety of metabolic and developmental processes, and abnormal thyroid hormone metabolism is one of the important causes of coronary artery sclerosis [18
]. Besides the direct effects of FT3 and FT4, the relationship between serum TSH concentration and metabolic effects has been the focus of recent studies, which have yielded conflicting results. One study in Japan found that compared with the normal control subjects, CHD patients had a relatively high level of TSH [19
]. In a prospective population-based study with a mean follow-up of 10.6 years [20
], researchers demonstrated that within the normal range, the TSH level was associated with TC, LDL-C, and HDL-C more strongly than FT4 among both men and women. In the present study, we also found a significant positive linear correlation between serum TSH levels within the normal range and the levels of TC and non-HDL-C. Similarly, a recent large cohort study of Indian women with normal thyroid function [21
] also suggested that TSH in the upper limits of the reference range (above 2.5 mIU/L) was associated with higher TC.
In addition, our study showed that TSH was positively correlated with TG, which was also observed in healthy men in Spain [22
]. Moreover, a previous study [23
] revealed that euthyroid subjects with a TSH level in the high-normal range (2.5-4.5 mIU/L) had higher TG levels than those with TSH levels in the low-normal range (0.3-2.5 mIU/L) (1.583 ± 0.082 vs. 1.422 ± 0.024 mmol/L, P
= 0.023). We speculated that this association could not be explained by the levels of FBG alone, because the FBG in those with high normal TSH were significantly lower than that in those with TSH in the lower limits of the normal range. The positive association between FT3 and log-transformed values of HDL-C in our study was in accordance with the observations of Ness et al. [24
], who found that triiodothyronine could raise HDL-C in rat.
Furthermore, we found that the TSH level was significantly higher in the hypercholesterolemic and hypertriglyceridemic subjects than in patients with normal levels of TC and TG. Similar results have been obtained by Lai et al. [25
], who demonstrated that the TSH level in the hypertriglyceridemia group was much higher than in the normal control group. In case of lipid profiles, the concentrations of TC, TG and non-HDL-C were significantly higher in patients whose TSH level were in the upper limits than those whose TSH levels were in the lower limits of the normal range. This phenomenon was supported by the HUNT study [7
], which suggested that within the clinically normal TSH range, the increasing level of TSH was associated with less favorable lipid concentrations.
Concerning the risk of dyslipidemia, our data showed that the subjects with relatively high TSH levels within the reference range were more likely to have hypercholesterolemia and hypertriglyceridemia, with the ORs of approximately 1.640 and 1.349. Therefore, according to these results, even within the normal range, subjects with relatively high TSH levels might be prone to dyslipidemia. More attention should be paid to lipid profiles of those patients who had relatively higher serum TSH levels, even within the normal range.
The detailed mechanisms responsible for the effects of TSH on the lipid profile remained unclear. Traditionally, the main function of TSH is to stimulate the synthesis and release of thyroid hormones in the thyroid gland via the specific cell membrane receptor-TSHR. It is now recognized that TSHR is expressed widely in a variety of extra-thyroidal organs including kidney, bone marrow and adipose tissue [26
], and act as a physiological regulator in the growth and development of adipocytes [27
]. More importantly, emerging evidence suggests that TSH not only acts on the thyroid gland, but also targets on several other organs and tissues. The mechanisms for the regulation of cholesterol homeostasis include effects on biosynthesis, uptake, and metabolism; and the liver is vital for both endogenous cholesterol synthesis and elimination [28
]. Previously, our laboratory [29
] demonstrated that TSHR is functionally present in both human and rat hepatocytes. A late study [13
] revealed that TSH promoted the expression of HMGCR, the rate-limiting enzyme in cholesterol synthesis in liver cells. Based on these findings, we assumed that TSH, even within the normal range, might act through TSHR expressed on hepatocytes to up-regulate the expression of HMGCR resulting in increased TC levels in CHD patients. Moreover, we also speculated that there might be other mechanisms involved in the regulation of lipid profiles by TSH.
To date, the pathophysiological role of TSH per se
on the cardiovascular system remains unclear. The administration of recombinant human TSH has been reported to be associated with the acute impairment of endothelial function in patients without evidence of functional thyroid tissue [30
]. Considering the elevated levels of TC, TG and non-HDL-C and the increased prevalence of hypercholesterolemia among patients whose TSH levels were in the upper limits, we hypothesized that high-normal TSH might have harmful effects on cardiovascular health. Meanwhile, we should also note that all current associations between TSH and lipid profiles have been weak to modest, and thus the detailed mechanism and clinical implications about the effects of TSH on the lipid profile and CHD remains to be elucidated.
The main limitation of this study is its small size. Furthermore, the thyroid status was classified in all patients based on one blood test. Thus, some individuals with transient TSH elevations might have been misclassified. Further studies should involve repeated TSH testing. In addition, with a retrospective study that did not include follow-up, we were unable to determine whether differences in TSH represent an actual risk factor for CHD. In the statistical analysis, the relatively simple multivariate regression models we used explained only a limited amount of variations in the serum lipid profiles. In the future, large-scale studies with longer follow-up peroids will be needed to estimate the real impact of this association and its clinical significance.
In summary, we found that the TSH level was positively and linearly correlated with the TC, non-HDL-C and TG levels, and the prevalence of hypercholesterolemia and hypertriglyceridemia in non-smokers in a Chinese population with newly diagnosed asymptomatic CHD. Our study indicated that even within the normal range, TSH in the upper limits might exert adverse effects on the lipid profile and thus might represent a risk factor for hypercholesterolemia and hypertriglyceridemia in these patients. In the treatment of CHD and dyslipidemia, thyroid function (especially the serum TSH level) should be monitored and maintained in the relatively low-normal range. Further large prospective studies are needed to clarify the above relationship and to confirm its clinical implications.