Lipid abnormalities in thyroid disease

INTRODUCTION — A relationship among hypothyroidism, lipid disorders, and coronary artery disease was first suggested in the 1960s [1]. This was at a time when the diagnosis of hypothyroidism was based upon symptoms and signs, and sometimes serum cholesterol measurements, rather than measurements of serum thyroxine (T4) and thyroid-stimulating hormone (TSH). In some cases, a high serum cholesterol concentration was regarded as evidence for "premyxoedema" in the absence of symptoms of hypothyroidism [2]. How many of these patients in fact had hypothyroidism is not known. While there is no doubt that many hypothyroid patients have abnormal serum lipid concentrations, the increased risk of coronary artery disease seen in hypothyroid patients is likely multifactorial in etiology. (See "Cardiovascular effects of hypothyroidism".)

OVERT HYPOTHYROIDISM — Many hypothyroid patients have high serum concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol [3], and some have high serum concentrations of triglycerides [4], intermediate-density lipoproteins [5], apolipoprotein A1 [6], and apolipoprotein B [6-8]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

In one study of 295 hypothyroid patients, the following patterns of serum lipids were noted, using the Frederickson classification [9]:

●Type IIa (hypercholesterolemia) – 56 percent

●Type IIb (hypercholesterolemia and hypertriglyceridemia) – 34 percent

●Type IV (hypertriglyceridemia) – 1.5 percent

●No abnormality – 8.5 percent

With respect to serum high-density lipoprotein (HDL) cholesterol concentrations, high, normal, or low values have been reported in different series [10,11]. Among the subfractions of HDL cholesterol, it is the HDL2, not HDL3, fraction that may be high in hypothyroidism and normalize during T4 (levothyroxine) therapy [8,12]. In a study of 18 hypothyroid women after thyroidectomy, HDL cholesterol was higher, but the transfer of esterified and nonesterified cholesterol, triglycerides, and phospholipids was reduced [13].

The excess risk of coronary heart disease observed with hypothyroidism has been thought to be due, at least in part, to the characteristic lipid abnormalities (including high LDL). However, in a study using nuclear magnetic resonance (NMR) spectroscopy to assess lipid subparticle concentrations, hypothyroid women had a shift toward less atherogenic large LDL, small very low-density lipoprotein (VLDL), and large HDL subparticle sizes [14].

Overt hypothyroidism is associated with both hepatic and pancreatic steatosis [15,16].

Effect of T4 therapy — In a meta-analysis, treatment of hypothyroidism (and to a lesser extent subclinical hypothyroidism) resulted in a fall in total, LDL, and HDL cholesterol; triglycerides; apolipoprotein A and B; and lipoprotein(a) [17]. In individual studies, changes in serum lipoprotein(a) concentrations in hypothyroidism and during T4 (levothyroxine) therapy vary. In some patients, serum lipoprotein(a) concentrations are high and fall during T4 therapy [7,18,19], whereas others have normal values that do not change during therapy [6,8,20,21]. One study found that total cholesterol, triglycerides, LDL cholesterol, apolipoprotein B, and the ratio of apolipoprotein A-I to A-II were elevated in hypothyroid and fell with T4 therapy, while elevated levels of HDL cholesterol and apolipoprotein E did not respond to T4 administration [22].

An analysis of 19 published studies evaluated the effects of T4 therapy on the serum total cholesterol concentration in patients with overt hypothyroidism [23]. Patients with an initial value of 310 mg/dL (8.0 mmol/L) or less had a mean fall of 46 mg/dL (1.2 mmol/L) during T4 therapy; those with an initial value of more than 310 mg/dL (8.0 mmol/L) had a much greater mean fall of 131 mg/dL (3.4 mmol/L).

Remnant lipoprotein concentrations (intermediate-density lipoproteins), a predictor of coronary heart disease risk, may also be elevated in overt hypothyroidism with a lowering in response to T4 therapy [24]. The same investigators have reported similar findings in patients with subclinical hypothyroidism. (See 'Subclinical hypothyroidism' below.)

Non-HDL cholesterol (total cholesterol minus HDL cholesterol) was also lowered in both overt and subclinical hypothyroidism after T4 therapy [25].

Pathophysiology — The primary mechanism for hypercholesterolemia in hypothyroidism is accumulation of LDL cholesterol due to a reduction in the number of cell-surface receptors for LDL [26], resulting in decreased catabolism of LDL. A decrease in LDL receptor activity has also been described [27].

The extent of upregulation of the LDL receptor by T4 therapy varies considerably in patients with different polymorphisms of the LDL receptor gene. In one study, patients homozygous for one specific genotype (-/-) had a fourfold greater reduction in serum cholesterol during T4 therapy than those who were homozygous for a different genotype (+/+) [28].

Other mechanisms also may affect the serum cholesterol concentration in hypothyroidism:

●LDL oxidation is significantly increased in hypothyroid patients, the degree of which is directly related to the serum LDL cholesterol concentration [29].

●Diminished secretion of cholesterol into bile has been demonstrated in hypothyroid rats [30].

●Reduced cholesteryl ester transfer (the net transfer of cholesterol from HDL to LDL and VLDL) in hypothyroidism may minimize the increase in serum LDL cholesterol concentrations [31].

A different mechanism, reduced lipoprotein lipase activity, is responsible for the development of hypertriglyceridemia in hypothyroidism [3,32]. The rate of synthesis of triglycerides was normal in one study [32], but increased in another [33].

Chylomicron remnants accumulate in hypothyroidism and are cleared more rapidly during T4 treatment [34].

Prevalence of hypothyroidism in patients with hyperlipidemia — A separate question is the frequency of hypothyroidism among patients with hypercholesterolemia. In a retrospective study of 8795 patients with a total serum cholesterol of ≥200 mg/dL or LDL cholesterol of at least 160 mg/dL, serum thyroid-stimulating hormone (TSH) was measured in 49 percent [35]. Of these 4349 patients, 3.5 percent (151) had a serum TSH of 5 to 10 mIU/L and 1.7 percent (74) had a TSH greater than 10 mIU/L. In another study of 248 patients referred to a lipid disorders clinic, 2.8 percent had overt hypothyroidism and 4.4 percent had subclinical hypothyroidism [36].

Thus, all patients with hypercholesterolemia (and hypertriglyceridemia) should be screened for hypothyroidism (and other secondary causes of hyperlipidemia) before being given specific lipid-lowering drug therapy (see "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Candidates for screening' and "Secondary causes of dyslipidemia"). If hypothyroidism is present, the patient should be treated for three to four months with T4. If the serum lipid concentrations are not then normal, specific lipid-lowering therapy may be indicated. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

Patients in the latter group presumably have hypothyroidism superimposed upon primary hyperlipidemia. The effect of hypothyroidism varies with the underlying lipid disorder: It can raise serum intermediate-density lipoprotein cholesterol concentrations in patients with "broad beta" disease [5], exacerbate hypercholesterolemia in patients with familial hypercholesterolemia (who have an underlying defect in the LDL receptor) [37], and exacerbate hypertriglyceridemia in patients with familial hypertriglyceridemia [38].

Hypothyroidism, autoimmunity, and coronary heart disease — Coronary heart disease is increased among patients with overt hypothyroidism; however, in addition to abnormal lipid concentrations, diastolic hypertension (often present in hypothyroidism), as well as abnormalities in endothelial function, C-reactive protein, and other parameters, may be contributing factors. (See "Cardiovascular effects of hypothyroidism".)

In one study, thyroid antibodies were a risk factor for coronary disease independent of serum cholesterol concentrations or the systemic blood pressure [39]. In another study, euthyroid, normocholesterolemic men and postmenopausal women with either antithyroglobulin or antithyroid peroxidase antibodies had high serum lipoprotein(a) concentrations, which may be a risk factor for coronary disease [40]. (See "Lipoprotein(a)".)

SUBCLINICAL HYPOTHYROIDISM — Most patients with subclinical hypothyroidism have normal serum lipid concentrations. However, some have slightly high serum total and low-density lipoprotein (LDL) cholesterol, triglycerides (due to an increase in both very small and very large triglyceride-rich particles), and lipoprotein(a) concentrations [6,23,41-45], whereas serum high-density lipoprotein (HDL) cholesterol concentrations may be low [41,46,47]. In one study, the effect of subclinical hypothyroidism on total and LDL cholesterol was greater in older (age 60 to 69) than younger (age 40 to 49) patients in one study [48].

Treatment with T4 (levothyroxine) improves total and LDL cholesterol [17,23,42,43,49]. In a meta-analysis of 12 studies (940 individuals), total cholesterol was reduced on average by 11.2 mg/dL (0.29 mmol/L) and LDL cholesterol by 8.5 mg/dL (0.22 mmol/L) with T4 treatment, but there was no change in HDL cholesterol or triglycerides [50]. The effect of T4 may be more pronounced in those with overt hypercholesterolemia; in one study, as an example, serum LDL cholesterol fell by 36 mg/dL (0.9 mmol/L, p<0.01) in such patients [51].

The effects of T4 treatment on serum lipoprotein(a) concentrations is variable; in two studies, they declined by as much as 23 percent [52,53], but did not change in another study [19]. Remnant lipoprotein concentrations (intermediate-density lipoproteins), a predictor of coronary heart disease risk, may also be elevated in both overt and subclinical hypothyroidism with a lowering in response to T4 therapy [54]. In one study, the reductions in remnant-like lipoproteins in patients with subclinical hypothyroidism who were treated with T4 were associated with an increase in hepatic lipoprotein lipase, suggesting a possible mechanism for the reduction [55].

Subclinical hypothyroidism is associated with both hepatic and pancreatic steatosis [15,16]. In addition, coronary heart disease may be increased among patients with subclinical hypothyroidism who have thyroid-stimulating hormone (TSH) values greater than 7 to 10 mIU/L. (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Cardiovascular disease'.)

Conversely, there is evidence that hypertriglyceridemia (and obesity) per se may cause an elevation in TSH via a "lipotoxic" effect on the thyroid [56].

Whether TSH has a direct role in lipid metabolism is currently under investigation. For example, one study supports the hypothesis that TSH may increase PCSK9, which would result in higher LDL cholesterol by increasing LDL receptor degradation [57].

HYPERTHYROIDISM — Patients with hyperthyroidism have changes in lipid metabolism generally opposite to those described above for hypothyroidism. Serum total, low-density lipoprotein (LDL), very small triglyceride-rich particles, and high-density lipoprotein (HDL) cholesterol concentrations tend to be low [45,58], as do serum apolipoprotein B concentrations [7]. Fatty acid clearance is increased, but lipolysis is increased even more, resulting in high serum fatty acid concentrations [4]. Serum lipoprotein(a) concentrations were low in one study, but did not increase during antithyroid drug therapy [58]. In a meta-analysis, treatment of overt, but not subclinical, hyperthyroidism increased total, LDL, and HDL cholesterol; apolipoprotein A and B; and lipoprotein(a) [17]. In an individual study, radioiodine treatment of grade 2 subclinical hyperthyroidism (TSH <0.2 mIU/L) increased total and LDL cholesterol [59].

SUMMARY

●Overt hypothyroidism and serum lipids – Hypothyroid patients have increased serum total and low-density lipoprotein (LDL) cholesterol levels. Many also have high serum triglycerides, intermediate-density lipoproteins, apolipoprotein A1, and apolipoprotein B concentrations. T4 (levothyroxine) therapy may reduce total and LDL cholesterol, lipoprotein A and B, and intermediate-density lipoprotein concentrations, especially in patients with significant elevations prior to treatment. (See 'Overt hypothyroidism' above.)

●Subclinical hypothyroidism and serum lipids – Similar findings are noted in patients with subclinical hypothyroidism whose thyroid-stimulating hormone (TSH) concentrations are >10 mIU/L. (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Cardiovascular disease'.)

●Prevalence of hypothyroidism in patients with hyperlipidemia – Among patients with hyperlipidemia, overt and subclinical hypothyroidism are common. Thus, patients with hypercholesterolemia (and hypertriglyceridemia) should be screened for hypothyroidism (and other secondary causes of hyperlipidemia) before being given specific lipid-lowering drug therapy. (See 'Prevalence of hypothyroidism in patients with hyperlipidemia' above and "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Candidates for screening'.)

●Hypothyroidism and coronary heart disease – The increased risk of coronary artery disease seen in overtly hypothyroid patients is likely multifactorial due to elevated lipids, diastolic hypertension, elevated C-reactive protein, endothelial dysfunction, and other factors. Coronary heart disease may be increased among patients with subclinical hypothyroidism who have thyroid-stimulating hormone (TSH) values greater than 7 to 10 mIU/L. (See 'Hypothyroidism, autoimmunity, and coronary heart disease' above and "Cardiovascular effects of hypothyroidism" and "Subclinical hypothyroidism in nonpregnant adults", section on 'Cardiovascular disease'.)

●Hyperthyroidism and serum lipids – Hyperthyroidism is associated with lower levels of total, LDL, and high-density lipoprotein (HDL) cholesterol. (See 'Hyperthyroidism' above.)