An Association Between Varying Degrees of Hypothyroidism and Hypercholesterolemia in Women: The Thyroid‐Cholesterol Connection

Abstract

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...

Thyroid Dysfunction and Their Relation to Cardiovascular Risk Factors such as Lipid Profile, hsCRP, and Waist Hip Ratio in Korea

“…With thyroid hormone therapy, adverse effects can be controlled and total cholesterol and low-density lipoprotein cholesterol values can be decreased 26 ) . However, there is no clear evidence that subclinical hypothyroidism can cause cardiovascular disease, as results are contradictory 20 – 23 , 26 ) Recently, several studies have found than an increase in total cholesterol and low-density lipoprotein cholesterol levels are a primary cause of arteriosclerosis and cardiovascular diseases in subclinical hypothyroidism 19 , 27 , 28 ) . Various mechanisms are involved in the relationships between subclinical hypothyroidism arteriosclerosis and cardiovascular diseases.…”

A Population Based Study on the Association of Thyroid Status with Components of the Metabolic Syndrome

“…Overt hypothyroidism acts as a CVD risk factor through several mechanisms, as a result of which the incidence of heart attack can increase over two fold in hypothyroid subjects [7][8][9][10][11]. A positive association between overt hypothyroidism and hypercholesterolemia is well recognized [12]. In addition it is reported that thyroid hormones influence vascular smooth muscles, consequently reducing arterial resistance, and causing a decline in diastolic blood pressure [13].…”

Serum lipids in hypothyroid children: effect of disease and levothyroxine replacement therapy

“…TC and LDL-C concentrations obtained in the patients treated with L-T 4 correlated well with the corresponding TSH levels (Figure 2). Significant associations with TSH were reported for TC and LDL-C by other authors as well (3,15) and have been variously attributed to suboptimal therapy and/or an abnormal setting of the T4 negative feedback control of pituitary TSH secretion (16 '18). Further investigations are needed to explain which of the two mechanisms caused the persistence of elevated TSH values in some of the L-T 4 -treated children included in this study.…”

“…However, LDL-receptor gene is also one of the thyroid hormone target genes. Although cholesterol synthesis is impaired in hypothyroid state, this effect is overwhelmed by a markedly decreased fractional clearance of LDL particles because of a reduced number of LDL receptors in the liver (2,3). This leads to LDL accumulation and high serum TC and LDL-C concentrations.…”