Thyroid and Lipid Metabolism

Home , Lipid, Lipid metabolism, Metabolism, Thyroid hormones

E Pucci1, L Chiovato1 and A Pinchera1*

1Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del lavoro, Sezione di endocrinologia, Universita'di Pisa, Pisa, Italy

Thyroid hormones in¯uence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With speci®c regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is in¯uenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esteri®ed fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia. International Journal of Obesity (2000) 24, Suppl 2, S109±S112

Keywords: thyroid hormones; lipid metabolism; atherosclerosis; angina pectoris

Introduction of thyroid hormone de®ciency. The metabolism of different apolipoproteins is also affected.1 The main Thyroid hormones in¯uence nearly all major meta- and best-known effects of thyroid hormones on lipid bolic pathways. Their most obvious and well-known metabolism are discussed in the present review. action is the increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. They do not intervene in the minute-to- minute regulation of metabolism, but rather they Effects of thyroid hormones on lipid modulate the activities of metabolic pathways on a metabolism medium-or long-term basis, either by a direct action or by modifying the activity of other regulatory Lipolysis hormones such as insulin, glucagon and catechol- Thyroid hormones stimulate the utilization of lipid amines. The effect of thyroid hormones on protein substrates owing to an increased mobilization of metabolism is characterized by a profound stimulatory triglycerids stored in adipose tissue. Increased con- effect on the synthesis of numerous cytosolic and centrations and appearance rates of plasma non-ester- mitochondrial proteins as well as of secretory proteins i®ed fatty acids (NEFA) and glycerol re¯ect this such as albumin and hormones. Tracer studies in action. The mechanisms of thyroid hormone action humans have clearly shown that endogenous glucose on lipolysis remain unclear. No direct lipolytic effect production and utilization rates are increased by has been found in vitro. The increased lipolytic rate thyroid hormones. All aspects of lipid metabolism produced by thyroid hormones in vivo might be rela- including synthesis, mobilization and degradation ted to the increased subcutaneous blood-¯ow or to a are in¯uenced by thyroid hormones, but degradation modi®cation of the lipolytic action of catecholamines. is affected more than synthesis. Thyrotoxicosis is associated with a depletion in the stores of most lipids and with a decrease of their concentration in Hepatic fatty acid metabolism plasma. This is true for triglycerides, phospholipids There is a great deal of evidence that, in addition to and cholesterol. Opposite changes occur in conditions stimulating fatty acids oxidation through an increased NEFA availability, thyroid hormones induce lipogen- esis in the liver. The simultaneous stimulation of fatty acid oxidation and synthesis may represent a futile *Correspondence: A Pinchera, Dipartimento di Endocrinologia, Via Paradisa Italy. 2, 56124 Pisa, Italy. cycle of metabolites contributing to the increased E-mail: [email protected] energy expenditure. Hepatic synthesis and output of Thyroid and lipid metabolism E Pucci et al S110 triglycerides are decreased by thyroid hormones. The sometimes with hypertension, which may predispose synthesis and secretion of very-low density lipopro- patients to develop and=or may accelerate CAD. The teins (VLDL) are stimulated. precise mechanism responsible for hypertension in hypothyroidism has not been fully elucidated. Fatty acids utilization by extra-hepatic tissues Changes in circulating catecholamines, their receptors NEFA oxidation is increased by thyroid hormones, as and the renin ± angiotensin ± aldosterone system have well as plasma triglycerides clearance. Lipoprotein ± all been implicated.3 Despite a high prevalence of lipase activity is elevated in hypothyroid subjects. severe atherosclerosis found at autopsy, hypothyroid patients have a relatively low frequency of angina Lipoprotein metabolism pectoris and myocardial infarction during life. The Hypothyroidism is a well-known cause of hyperlipide- question of whether or not hypothyroidism predis- mia in both humans and animals. In hypothyroid patients poses to the development of ischemic heart disease is the most frequent lipid abnormality is hypercholester- a controversial one.4,5 Both conditions are relatively olemia, mainly due to an increased concentration of low common among 40 ± 60 y-old adults in industrialized density lipoproteins (LDL). Elevation of very low nations. Epidemiological studies estimate at 0.5 ± 10% density lipoproteins (VLDL) and high density lipopro- the prevalence of hypothyroidism in the general teins (HDL cholesterol) have also been reported. Plasma adult ± elderly population screened on the basis of triglycerides are increased because of an enhanced elevated serum TSH. Thus, the coexistence of esteri®cation of fatty acids at hepatic level. Plasma hypothyroidism and ischemic heart disease might be concentrations of lipoprotein (a) increase in hypothyr- due only to a statistical coincidence,6 and a real oidism. Lp(a) has been shown to have a thrombogenic cause ± effect relationship between the two conditions and an atherogenic effect. Epidemiological studies indi- might not exist. If this assumption is true, why is it cate that a greater cardiovascular risk is related to that the atherosclerotic lesions observed at autopsy in increased plasma concentrations of Lp(a). This lipopro- hypothyroid patients do not result in clinical CAD? tein favors the deposition of cholesterol in endothelial This discrepancy is most likely explained by the lesions, thus resulting in an increased atherogenic risk. decreased oxygen demand placed on myocardium in While thyrotoxicosis has a profound in¯uence on hypothyroid patients. lipid metabolism, these changes do not produce long- A more direct association between hypothyroidism term sequelae. More relevant from the clinical point of and CAD has been postulated in other studies.7 Inter- view are lipid changes associated with hypothy- estingly, angina pectoris and myocardial infarction roidism. As previously discussed, hyperlipidemia display a rather atypical course in hypothyroid occurs in patients with overt hypothyroidism and patients. This might be explained by the hypometa- might be responsible for an increased risk of coronary bolic state associated with hypothyroidism which is artery disease (CAD). Plasma levels of total cholesterol probably bene®cial to the ischemic myocardium by and LDL cholesterol are increased in patients with lowering energy demands and requirements. Indeed, hypothyroidism. However, it is not usually appreciated hypothyroidism is not associated with an unfavorable that hypothyroid patients also have increased plasma course of acute myocardial infarction. On the other levels of HDL cholesterol. In some studies, both the hand, hypothyroid patients appear to have an total=HDL cholesterol ratio and the HDL=LDL choles- increased incidence of residual ischemia after an terol ratio have been reported to predict the progression acute myocardial infarction, which may be explained of CAD. In other studies only the total=HDL cholesterol by the occurrence of a more severe and diffuse CAD ratio was found to be predictive of CAD. Since both total in hypothyroidism.8 cholesterol and HDL cholesterol levels are increased in patients with hypothyroidism, there is no obvious reason for increased cardiovascular risk. It is interesting to Angina and overt hypothyroidism underline that, as compared with primary hypothy- Despite a large body of data from clinical, epidemio- roidism, the lipid pro®le is more atherogenic in second- logical and autopsy studies linking overt hypothyroid- ary hypothyroidism, because the plasma levels of HDL ism to the development of atherosclerotic heart cholesterol are lower in the latter condition. Further- disease, the precise relationship between the two more, secondary hypothyroidism may coexist with conditions and the pathogenetic mechanisms involved adrenal cortical insuf®ciency, and the latter condition are complex and still poorly understood. Lipid may produce additional negative effects on the cardio- abnormalities associated with myxedema undoubtedly vascular system.2 play an important role, but other factors are involved as well. Hypothyroidism, mostly when reaching the severity of myxedema, can profoundly affect the Coronary artery disease (CAD) and circulation system, resulting in the clinical picture of overt hypothyroidism `myxedema heart'. The term myxedema, often used as synonym of severe hypothyroidism, refers to the Overt hypothyroidism is associated with a number of brawny, nonpitting soft-tissue swelling caused by the well-known abnormalities of lipid metabolism and accumulation of a proteinaceous extracellular ¯uid

International Journal of Obesity Thyroid and lipid metabolism E Pucci et al S111 due to thyroid hormone de®ciency. Although periph- administration.10 Mild abnormalities of lipid metabo- eral water retention is common in myxedema, the lism have also been reported in subclinical hypothy- actual blood volume is low. Body weight is modestly roidism.10 Fowler and Swale in 197011 described a increased even in severe myxedema. An important family in which hypercholesterolemia preceded by feature of the `myxedema heart' is the pericardial many years any evidence of hypothyroidism. This effusion that occurs in up to one-third of patients with stage of autoimmune thyroiditis characterized by long-standing severe hypothyroidism. hypercholesterolemia alone was called `premyxe- The above described cardiac abnormalities are dema'. Following this ®rst report, Bastenie et al12 mostly `silent'8 in hypothyroid patients, since they found a signi®cant association between thyroid anti- do not produce clinical symptoms for a more pro- bodies and the occurrence of obesity, hypertension, longed period than in euthyroid individuals. This diabetes mellitus and CAD. In this study a signi®- subclinical course may be related to the tendency of cantly higher proportion of patients with CAD not hypothyroid patients to pursue a quiet and inactive associated with obesity, hypertension and diabetes had life, even appearing sluggish. As a consequence, the thyroid antibodies as compared with a normal popula- heart is insuf®ciently stressed to cause noticeable tion. At variance with these early investigations indi- angina pectoris. In later stages, progression of cor- cating a slight increase of CAD in subjects with onary atherosclerosis, together with other complicat- positive thyroid antibodies, with or without subclini- ing factors such as the anemia of hypothyroidism, cal hypothyroidism, the Whickham study reported no cause angina pectoris in 5 ± 10% of hypothyroid association between autoimmune thyroiditis, as patients.9 de®ned by hypothyroidism, raised serum TSH, or positive thyroid antibodies, and CAD.13 Studies from Tanis et al,14 Pare et al,15 Miura et al16 and Dickman et al,17 even if con®rming mild alterations Coronary artery disease and of lipid metabolism in patients with subclinical subclinical hypothyroidism hypothyroidism, failed to demonstrate a clear-cut association between subclinical hypothyroidism and The combination of raised serum TSH levels and increased incidence of CAD. normal serum concentrations of thyroid hormones in apparently asymptomatic patients is known as `subclinical hypothyroidism'. This disorder is the mildest form of a spectrum of thyroid failures and commonly occurs in the natural history of autoimmune thyroi- Thyroid hormone therapy in ditis. Thyroid antibodies are often the sole ®nding of hypothyroid patients with cardiac autoimmune thyroiditis associated with subclinical disease hypothyroidism. Whether tissues other than the ante- rior pituitary recognize that thyroid hormones levels Patients presenting both untreated hypothyroidism and are suboptimal, although highly possible, remains angina pose challenging management problems for dif®cult to prove. the clinician. The physician treating hypothyroid This state of latent thyroid failure, which should be patients with angina will note unusual, exaggerated more properly de®ned as mild hypothyroidism, may responses to most medications, such as nitrates, digi- persist for years or may evolve to myxedema. In the talis, diuretics and beta-adrenergic blocking agents.9 Whickham survey the annual risk of developing overt As a consequence, it is necessary to start medical hypothyroidism was 4% in women with both raised treatment with particularly low-dosage regimens. The serum TSH and positive thyroid antibody, 3% if only endocrinologist, while bringing the patients toward TSH was raised, and 2% if only thyroid antibodies the euthyroid state by increasing doses of thyroid were positive.10 Progression rates ranging from 7% to replacement, must consider that angina can appear 18% per year were reported in other studies.10 or worsen. A myocardial infarction may possibly It is worth emphasizing that the hormonal thyroid ensue. However, in most cases angina is ameliorated secretion should be normal or mildly reduced, but still and sometimes disappears during L-thyroxine treat- in the normal range. As a consequence, most meta- ment.18 This paradox has been accredited to a rever- bolic pathways and organ systems in¯uenced by sible endocrine cardiomyopathy indistinguishable, in thyroid hormones should be unaffected. In spite of the beginning, from the idiopathic form. However, these assumptions, mild complaints consistent with there is little recent clinical research addressing this thyroid hormone de®ciency, subtle alterations in myo- issue. Among 55 hypothyroid patients with CAD, cardial contractility (mainly during exercise), cogni- administration of thyroid hormones exacerbated tive dysfunction and depression have been reported in heart disease in only nine, while the remainder were patients with subclinical hypothyroidism. 9,10 Restora- unchanged or improved.19 Generally, for patients tion of normal cardiac contractility, improved psycho- having extensive coronary artery disease the potential metric tests and reduced hypothyroid symptom rating for exacerbation of angina by replacement of thyroid were observed in some patients after L-thyroxine hormone is greater. In elderly hypothyroid patients

International Journal of Obesity Thyroid and lipid metabolism E Pucci et al S112 with coexistent or suspected cardiac disease, L-thy- oxine therapy is indicated even in patients with a high roxine therapy should be initiated with 12.5 ± risk of angina pectoris. Subclinical hypothyroidism 25 mg=day, followed by careful increments of 12.5 ± could also affect cardiac function and increase the risk 25 mg=day every 4 ± 8 weeks, to reach the full replace- of atherosclerotic cardiovascular disease, mainly ment dose in several months. As previously discussed, when associated with other underlying cardiac or L-thyroxine substitution may precipitate angina or metabolic disorders. Even in these cases thyroid myocardial infarction in the elderly with CAD. On hormones, through their metabolic effects, can be the other hand, L-thyroxine substitution ameliorates useful to protect the cardiovascular system against reversible coronary dysfunction inherent with atherosclerosis. hypothyroidism and produces bene®cial effects on hypothyroid hyperlypidemia. In hypothyroid patients with CAD, euthyroidism can be achieved with L- References thyroxine, although some compromise may be 1 Nikitin VN, Babenko NA. Thyroid hormones and lipid meta- needed in the management of the two conditions. bolism. Fiziol. Zh. 1989, 35: 91 ± 98. Coronary by-pass or angioplasty can be safely per- 2 O'Brien T, Dinneenn SF, O'Brien P, Palumbo PJ. Hyperlip- formed before starting L-thyroxine administration. demia in patients with primary and secondary hypothyroidism. Propranolol may not be effective in reducing the Mayo Clin Proc 1993; 68: 860 ± 866. 3 Fletcher AK, Weetman AP. Hypertension and hypothyroid- cardiac effects of L-thyroxine replacement therapy in ism. J Hypertens 1998; 12: 79 ± 82. CAD patients. Dihydropyridine calcium channels 4 De Groot LJ. Thyroid and the heart disease. Mayo Clin Proc blockers may be more suitable to control angina in 1972; 47. hypothyroid patients given L-thyroxine. Some experts 5 Bennet JM, Stein AF. The heart and hypothyroidism. S Afr advise cardiac catheterization for any hypothyroid Med J 1983; 63: 564 ± 572. 6 Ragozzino MW, Melton LJ. Disease associations: need for patient with pre-existing angina before initiation of increased scrutiny of the literature. Mayo Clin Proc 1984; 59: thyroid replacement. 719 ± 721. The effect of subclinical hypothyroidism and its 7 Comtois R, Lamay C, LaliberteÂ A. Coexistence of hypothy- treatment upon circulating lipids is also controversial. roidism and myocardial infarction. Can J Cardiol 1994; 11: A meta-analysis of the literature14 showed that sub- 37 ± 42. 8 Bernstein R, Muller K, Midtbo K, Smith G, Haug E, Herzem- clinical hypothyroidism is two to three times more berger L. Silent myocardial ischemia in hypothyroidism. Thy- frequent in people with elevated plasma total choles- roid 1995; 5: 443 ± 447. terol, and that plasma total cholesterol is slightly 9 Baxley WA. Medical management of the patient with angina elevated in patients with subclinical hypothyroidism. and hypothyroidism. Prac Cardiol 1982; 8: 120 ± 128. Restoration of normal TSH levels with L-thyroxine 10 Chiovato L, Mariotti S, Pinchera A. Thyroid diseases in the decreased total cholesterol by 0.4 mmol=l, producing elderly. Bailliere's Clin Endocr Metab 1997; 11: 251 ± 270. 11 Fowler PBS, Swale J. Hypercholesterolemia in borderline an average 6% reduction in total cholesterol levels hypothyroidism. Lancet 1970; 2:5±6. that in hypercholesterolemic patients might contribute 12 Bastenie PA, Vanhalest L, Bonnyns M, Neve P. Preclinical to reducing ischemic heart disease.14 In a recent study, hypothyroidism: a risk factor for coronary heart-disease. coronary artery disease progression could be pre- Lancet 1971; 1: 203 ± 204. vented by adequate L-thyroxine replacement in 13 Vanderpump MPJ, Tunbridge WMJ, French JM, Appleton D, 19 Bates D, Clark F, Grimley Evans J, Rodgers H, Tunbridge F, hypothyroidism. Thus, thyroid hormones can be Young ET. The development of ischemic heart disease in protective against atherosclerosis, presumably due to relation to autoimmune thyroid disease in a 20-year follow-up their metabolic effects on lipid metabolism and even- study of an English community. Thyroid 1996; 6: 155 ± 160. tually on plaque progression. 14 Tanis B, Rudi G, Smelt HM. Effect of thyroid substitution on hypercholesterolemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocr 1996; 44: 643 ± 649. 15 Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Conclusions Circulating lipids and minor abnormalities of thyroid function. Clin Endocr 1992; 37: 411 ± 414. The understanding of the impact of thyroid hormones 16 Miura S, Itaka M, Yoshimura H, Kitahama S, Fukasawa N, on lipid metabolism has been considerably improved. Kawakami Y, Sakurai S, Urabe M, Sakatsume Y, Ito K, Ishii J. Intern Med 1994; 33: 413 ± 417. Nevertheless, some questions remain to be elucidated. 17 Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Pre- Thyroid hormone de®ciency represents a well-known valence and correction of hypothyroidism in a large cohort of cause of hyperlipidemia both in overt and subclinical patients referred for dyslipidemia. Arch Intern Med 1995; 155: hypothyroid patients. The reported frequencies of 1490 ± 1495. dyslipidemia vary considerably due to differences in 18 Klemperer JD, Ojamaa K, Klein I. Thyroid hormone therapy in cardiovascular disease. Prog Cardiovasc Dis 1996; 38: patients' selection, sex and age distribution, and 329 ± 336. degree of hypothyroidism. Nevertheless, current evi- 19 Kahaly GJ. The thyroid and the heart. Thyroid Int 1998; 4:1± dence suggests that in overt hypothyroidism L-thyr- 20.

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