Abstract
Thyroid dysfunction, manifesting as either overt or subclinical hypothyroidism, negatively affects lipid metabolism: this leads to hypercholesterolemia which progressively increases the risk for cardiovascular disease and, potentially, mortality. Hypercholesterolemia in hypothyroidism is mainly due to a reduction in low-density lipoprotein (LDL) receptor activity, this accompanied by concomitant diminishing control by triiodothyronine (T3) of sterol regulatory element-binding protein 2 (SREBP-2), which modulates cholesterol biosynthesis by regulating rate-limit degrading enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity. Recently, 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, was found to repress the transcription factor carbohydrate-response element-binding protein (ChREBP) and also to be involved in lipid catabolism and lipogenesis, though via a different pathway than that of T3. While thyroid hormone could therapeutically reverse the dyslipidemic profile commonly occurring in hypothyroidism, it should be borne in mind that the potency of the effects may be age-and sex-dependent. Thyroid hormone administration possibly also sustains and enhances the efficacy of hypolipidemic drugs, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9), in patients with dyslipidemia and hypothyroidism.
Highlights
The link between thyroid diseases and serum cholesterol was firmly established following the classic article by Mason et al on Christmas Day of 1930, shedding light on the significance of thyroid function in cholesterol metabolism [1]
Hypothyroidism has been associated with obesity and hypercholesterolemia, the extent of the latter usually being greater in primary than in secondary hypothyroidism due to the more severe condition of the primary form [4, 5]
The development of powerful hypolipidemic drugs, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), which may be optimally combined with L-thyroxine (L-T4) to treat severe forms of familial hypercholesterolemia and hypothyroidism has opened up a new field of research investigating the underlying mechanisms connecting thyroid function to lipids [13]
Summary
The link between thyroid diseases and serum cholesterol was firmly established following the classic article by Mason et al on Christmas Day of 1930, shedding light on the significance of thyroid function in cholesterol metabolism [1]. Lipid levels increase in a graded fashion as thyroid function declines, while patients with TSH values between 5.1 and 10 mIU/L have significantly higher mean total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels as compared to euthyroid subjects. The dyslipidemia is mainly caused by a shift to increased synthesis over degradation rate, with the elevated levels of TC, LDL-C, providing the substrate for lipid peroxidation by reactive oxygen species (ROS), this resulting in oxidative stress [9]. The development of powerful hypolipidemic drugs, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), which may be optimally combined with L-thyroxine (L-T4) to treat severe forms of familial hypercholesterolemia and hypothyroidism has opened up a new field of research investigating the underlying mechanisms connecting thyroid function to lipids [13]. The aim of this review is to examine the knowledge acquired mainly over the past decade concerning the intriguing connections between thyroid hormone and lipid metabolism at the molecular level and to present a clinical assessment
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