Evidence of an association between subclinical hypothyroidism and cardiovascular disease is mounting. The impact of thyroid hormone on lipid levels is primarily mediated through triiodothyronine (T 3 )-bound thyroid protein binding and activation of the promoter regions of the low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A-reductase genes, leading to a reduction in serum cholesterol levels. Thus, the decreased T 3 seen in hypothyroidism may result in increased serum cholesterol. Although a clear correlation exists between overt hypothyroidism and clinically significant hypercholesterolemia, there is a logarithmic relationship between thyroid-stimulating hormone and cholesterol, and the effects of subclinical hypothyroidism on cardiovascular disease are under debate. However, current data suggest that normalizing even modest thyroid-stimulating hormone elevations may result in improvement in the lipid profile. ( T he thyroid gland is responsible for synthesizing and secreting the two thyroid hormones, thyroxine (T 4 ) and triiodothyronine (T 3 ), in response to stimulation by thyroid-stimulating hormone (TSH). Standing in contrast to the economy of this system are the myriad organic functions regulated by T 3 and T 4 . As essential elements of DNA-binding proteins that regulate transcription, thyroid hormones influence the utilization of essentially all substrates, vitamins, and hormones. The signs and symptoms frequently associated with the most common form of thyroid disease, chronic thyroiditis, (Hashimoto's disease, autoimmune thyroiditis) 1 are known to most physicians, and include fatigue, depression, and unexplained moderate weight gain. Often overlooked is the effect of thyroid disease on cholesterol levels. Although the connection between clinical hypothyroidism and elevated cholesterol has been known for some time, recent studies have suggested that even mild thyroid disease can affect the metabolism of cholesterol, and in certain population groups, such as elderly women, may have adverse clinical consequences.
REDUCTION IN CHOLESTEROL CLEARANCEIn the hypothyroid patient, there is reduced expression of the low-density lipoprotein (LDL) receptor gene, resulting in a decreased removal of LDL particles from circulation. 2 T 3 and T 4 , which is converted into T 3 , bind to thyroid-binding protein in the nucleus, which then binds to promoter regions on specific genes, including the LDL receptor gene. In hypothyroidism, when circulating thyroid hormone is lowered and expression of the LDL receptor gene is reduced, decreased removal of cholesterol from the serum leads to elevation in serum LDL cholesterol. 3 Expression of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene is also reduced in hypothyroid patients. 4 This liver enzyme catalyzes the rate-limiting step in cholesterol biosynthesis and is the target of the statin class of cholesterol-lowering agents. Thus, in hypothyroidism, there is a paradoxic decrease in LDL production in the liver in the face of dim...
