Thyroid, Lipids, and Risk of Atherosclerosis

  • Gabriela Brenta
  • Laura Schreier


Lipoprotein metabolism is largely recognized as a target of thyroid hormone (TH) action which includes both synthesis and degradation of lipids. Furthermore, thyrotropin (TSH) through novel extrathyroidal effects can also increase cholesterol synthesis and lower hepatic excretion of bile acids.

Depending on the level of TH, balance will be tilted toward an excess in catabolism that occurs in thyrotoxicosis or lipid accumulation due to lower catabolism as in hypothyroidism.

Overt hypothyroidism is associated with atherosclerosis, and secondary dyslipidemia is in great part responsible for this. The consequences of subclinical hypothyroidism (ScH) as shown in different studies are milder and may reflect normal or mildly increased cholesterol levels.

Although elevated total and LDL cholesterol (C) levels describe the main lipoprotein alteration in hypothyroidism, VLDL accumulation and its atherogenic remnants, known as RLP, are also accumulated in circulation, both in overt and ScH.

Levothyroxine replacement can reverse the lipid alterations described in hypothyroid patients, but the degree of restoration to normal will depend upon the severity of the thyroid deficit.

In this chapter, the regulation by TH on the lipoprotein metabolism will be described together with the changes associated with both overt and ScH. Evidence from both the available observational and intervention studies will be described together with data on possible thyromimetics devoided of the undesired thyroid action in the heart.


Lipoproteins Hypercholesterolemia Triglycerides Hypothyroidism Hyperthyroidism 


  1. 1.
    Hussain MM. Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol. 2014;25(3):200–6.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 2014;1841(7):919–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Tiwari S, Siddiqi SA. Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol. 2012;32(5):1079–86.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292–333.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64(23):2525–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakajima K, Tanaka A. Atherogenic postprandial remnant lipoproteins; VLDL remnants as a causal factor in atherosclerosis. Clin Chim Acta. 2018;478:200–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Reiss AB, Shah N, Muhieddine D, Zhen J, Yudkevich J, Kasselman LJ, et al. PCSK9 in cholesterol metabolism: from bench to bedside. Clin Sci (Lond). 2018;132(11):1135–53.CrossRefGoogle Scholar
  11. 11.
    Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet. 2012;380(9841):572–80.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34(17):1279–91.Google Scholar
  15. 15.
    Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med. 2011;17(10):594–603.CrossRefGoogle Scholar
  16. 16.
    Rothblat GH, Phillips MC. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr Opin Lipidol. 2010;21(3):229–38.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008;263(3):256–73.PubMedCrossRefGoogle Scholar
  19. 19.
    Sviridov D, Mukhamedova N, Remaley AT, Chin-Dusting J, Nestel P. Antiatherogenic functionality of high density lipoprotein: how much versus how good. J Atheroscler Thromb. 2008;15(2):52–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Brenta G, Danzi S, Klein I. Potential therapeutic applications of thyroid hormone analogs. Nat Clin Pract Endocrinol Metab. 2007;3(9):632–40.PubMedCrossRefGoogle Scholar
  21. 21.
    Shin DJ, Osborne TF. Thyroid hormone regulation and cholesterol metabolism are connected through sterol regulatory element-binding protein-2 (SREBP-2). J Biol Chem. 2003;278(36):34114–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Bakker O, Hudig F, Meijssen S, Wiersinga WM. Effects of triiodothyronine and amiodarone on the promoter of the human LDL receptor gene. Biochem Biophys Res Commun. 1998;249(2):517–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Moon JH, Kim HJ, Kim HM, Choi SH, Lim S, Park YJ, et al. Decreased expression of hepatic low-density lipoprotein receptor-related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism. Thyroid. 2013;23(9):1057–65.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Bonde Y, Breuer O, Lutjohann D, Sjoberg S, Angelin B, Rudling M. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans. J Lipid Res. 2014;55(11):2408–15.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Damiano F, Rochira A, Gnoni A, Siculella L. Action of thyroid hormones, T3 and T2, on hepatic fatty acids: differences in metabolic effects and molecular mechanisms. Int J Mol Sci. 2017;18(4).PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Boone LR, Lagor WR, Moya Mde L, Niesen MI, Rothblat GH, Ness GC. Thyroid hormone enhances the ability of serum to accept cellular cholesterol via the ABCA1 transporter. Atherosclerosis. 2011;218(1):77–82.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Johansson L, Rudling M, Scanlan TS, Lundasen T, Webb P, Baxter J, et al. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci U S A. 2005;102(29):10297–302.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ness GC, Pendleton LC, Li YC, Chiang JY. Effect of thyroid hormone on hepatic cholesterol 7 alpha hydroxylase, LDL receptor, HMG-CoA reductase, farnesyl pyrophosphate synthetase and apolipoprotein A-I mRNA levels in hypophysectomized rats. Biochem Biophys Res Commun. 1990;172(3):1150–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Berkenstam A, Kristensen J, Mellstrom K, Carlsson B, Malm J, Rehnmark S, et al. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A. 2008;105(2):663–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Galman C, Bonde Y, Matasconi M, Angelin B, Rudling M. Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone. Gastroenterology. 2008;134(4):1127–36.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Kuusi T, Taskinen MR, Nikkila EA. Lipoproteins, lipolytic enzymes, and hormonal status in hypothyroid women at different levels of substitution. J Clin Endocrinol Metab. 1988;66(1):51–6.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Valdemarsson S, Nilsson-Ehle P. Hepatic lipase and the clearing reaction: studies in euthyroid and hypothyroid subjects. Horm Metab Res. 1987;19(1):28–30.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Tan KC, Shiu SW, Kung AW. Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. J Clin Endocrinol Metab. 1998;83(8):2921–4.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Klieverik LP, Coomans CP, Endert E, Sauerwein HP, Havekes LM, Voshol PJ, et al. Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo. Endocrinology. 2009;150(12):5639–48.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Prieur X, Huby T, Coste H, Schaap FG, Chapman MJ, Rodriguez JC. Thyroid hormone regulates the hypotriglyceridemic gene APOA5. J Biol Chem. 2005;280(30):27533–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Fugier C, Tousaint JJ, Prieur X, Plateroti M, Samarut J, Delerive P. The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone. J Biol Chem. 2006;281(17):11553–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Song Y, Xu C, Shao S, Liu J, Xing W, Xu J, et al. Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4alpha/CYP7A1 axis. J Hepatol. 2015;62(5):1171–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Zhou L, Wu K, Zhang L, Gao L, Chen S. Liver-specific deletion of TSHR inhibits hepatic lipid accumulation in mice. Biochem Biophys Res Commun. 2018;497(1):39–45.PubMedCrossRefGoogle Scholar
  39. 39.
    Beukhof CM, Massolt ET, Visser TJ, Korevaar TIM, Medici M, de Herder WW, et al. Effects of thyrotropin on peripheral thyroid hormone metabolism and serum lipids. Thyroid. 2018;28(2):168–74.PubMedCrossRefGoogle Scholar
  40. 40.
    Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995;155(14):1490–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Tagami T, Kimura H, Ohtani S, Tanaka T, Hata S, Saito M, et al. Multi-center study on the prevalence of hypothyroidism in patients with hypercholesterolemia. Endocr J. 2011;58(6):449–57.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Willard DL, Leung AM, Pearce EN. Thyroid function testing in patients with newly diagnosed hyperlipidemia. JAMA Intern Med. 2014;174(2):287–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Brenta G, Vaisman M, Sgarbi JA, Bergoglio LM, Andrada NC, Bravo PP, et al. Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metabol. 2013;57(4):265–91.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988–1028.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Brenta G, Fretes O. Dyslipidemias and hypothyroidism. Pediatr Endocrinol Rev. 2014;11(4):390–9.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Duntas LH, Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Med Clin North Am. 2012;96(2):269–81.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    O’Brien T, Dinneen SF, O'Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc. 1993;68(9):860–6.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Sigal GA, Tavoni T, Silva B, Kalil Filho R, Brandao LG, Maranhao RC. Effects of short term hypothyroidism on the lipid transfer to HDL and other parameters related to lipoprotein metabolism in patients submitted to thyroidectomy for thyroid cancer. Thyroid. 2019;29(1):53–8.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Zambon A, Deeb SS, Bensadoun A, Foster KE, Brunzell JD. In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity. J Lipid Res. 2000;41(12):2094–9.PubMedGoogle Scholar
  51. 51.
    Ito M, Arishima T, Kudo T, Nishihara E, Ohye H, Kubota S, et al. Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients. J Clin Endocrinol Metab. 2007;92(2):608–11.PubMedCrossRefGoogle Scholar
  52. 52.
    Ito M, Takamatsu J, Matsuo T, Kameoka K, Kubota S, Fukata S, et al. Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement. Clin Endocrinol. 2003;58(5):621–6.CrossRefGoogle Scholar
  53. 53.
    Nikkila EA, Kekki M. Plasma triglyceride metabolism in thyroid disease. J Clin Invest. 1972;51(8):2103–14.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gjedde S, Gormsen LC, Rungby J, Nielsen S, Jorgensen JO, Pedersen SB, et al. Decreased lipid intermediate levels and lipid oxidation rates despite normal lipolysis in patients with hypothyroidism. Thyroid. 2010;20(8):843–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther. 2014;141(3):358–67.PubMedCrossRefGoogle Scholar
  56. 56.
    Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag. 2016;12:171–83.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Nordestgaard BG, Zilversmit DB. Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res. 1988;29(11):1491–500.PubMedGoogle Scholar
  58. 58.
    Tzotzas T, Krassas GE, Konstantinidis T, Bougoulia M. Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment. Thyroid. 2000;10(9):803–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Grover GJ, Egan DM, Sleph PG, Beehler BC, Chiellini G, Nguyen NH, et al. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3′-triiodo-L-thyronine. Endocrinology. 2004;145(4):1656–61.PubMedCrossRefGoogle Scholar
  60. 60.
    Angelin B, Kristensen JD, Eriksson M, Carlsson B, Klein I, Olsson AG, et al. Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome. J Intern Med. 2015;277(3):331–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. 1997;82(10):3421–4.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Diekman T, Demacker PN, Kastelein JJ, Stalenhoef AF, Wiersinga WM. Increased oxidizability of low-density lipoproteins in hypothyroidism. J Clin Endocrinol Metab. 1998;83(5):1752–5.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Benvenga S, Cahnmann HJ, Robbins J. Localization of the thyroxine binding sites in apolipoprotein B-100 of human low density lipoproteins. Endocrinology. 1990;127(5):2241–6.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Hanna AN, Feller DR, Witiak DT, Newman HA. Inhibition of low density lipoprotein oxidation by thyronines and probucol. Biochem Pharmacol. 1993;45(3):753–62.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Benvenga S, Robbins J. Altered thyroid hormone binding to plasma lipoproteins in hypothyroidism. Thyroid. 1996;6(6):595–600.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Pearce EN. Update in lipid alterations in subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97(2):326–33.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–28.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol. 1999;50(2):217–20.CrossRefGoogle Scholar
  69. 69.
    Leclere J, Cousty C, Schlienger JL, Wemeau JL. [Subclinical hypothyroidism and quality of life of women aged 50 or more with hypercholesterolemia: results of the HYOGA study]. Presse Med. 2008;37(11):1538–46.Google Scholar
  70. 70.
    Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526–34.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Vierhapper H, Nardi A, Grosser P, Raber W, Gessl A. Low-density lipoprotein cholesterol in subclinical hypothyroidism. Thyroid. 2000;10(11):981–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Hueston WJ, Pearson WS. Subclinical hypothyroidism and the risk of hypercholesterolemia. Ann Fam Med. 2004;2(4):351–5.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sgarbi JA, Matsumura LK, Kasamatsu TS, Ferreira SR, Maciel RM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: the Japanese-Brazilian thyroid study. Eur J Endocrinol. 2010;162(3):569–77.PubMedCrossRefGoogle Scholar
  74. 74.
    Walsh JP, Bremner AP, Bulsara MK, O’Leary P, Leedman PJ, Feddema P, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005;165(21):2467–72.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Boekholdt SM, Titan SM, Wiersinga WM, Chatterjee K, Basart DC, Luben R, et al. Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin Endocrinol. 2010;72(3):404–10.CrossRefGoogle Scholar
  76. 76.
    Nakajima Y, Yamada M, Akuzawa M, Ishii S, Masamura Y, Satoh T, et al. Subclinical hypothyroidism and indices for metabolic syndrome in Japanese women: one-year follow-up study. J Clin Endocrinol Metab. 2013;98(8):3280–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Kanaya AM, Harris F, Volpato S, Perez-Stable EJ, Harris T, Bauer DC. Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study. Arch Intern Med. 2002;162(7):773–9.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Oh HS, Kwon H, Ahn J, Song E, Park S, Kim M, et al. Association between thyroid dysfunction and lipid profiles differs according to age and sex: results from the Korean National Health and Nutrition Examination Survey. Thyroid. 2018;28(7):849–56.PubMedCrossRefGoogle Scholar
  79. 79.
    Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur J Endocrinol. 2007;156(2):181–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Tognini S, Polini A, Pasqualetti G, Ursino S, Caraccio N, Ferdeghini M, et al. Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study. Thyroid. 2012;22(11):1096–103.PubMedCrossRefGoogle Scholar
  81. 81.
    Gobal FA, Mehta JL. Management of dyslipidemia in the elderly population. Ther Adv Cardiovasc Dis. 2010;4(6):375–83.PubMedCrossRefGoogle Scholar
  82. 82.
    Zhao M, Yang T, Chen L, Tang X, Guan Q, Zhang B, et al. Subclinical hypothyroidism might worsen the effects of aging on serum lipid profiles: a population-based case-control study. Thyroid. 2015;25(5):485–93.PubMedCrossRefGoogle Scholar
  83. 83.
    Ruhla S, Weickert MO, Arafat AM, Osterhoff M, Isken F, Spranger J, et al. A high normal TSH is associated with the metabolic syndrome. Clin Endocrinol. 2010;72(5):696–701.CrossRefGoogle Scholar
  84. 84.
    Park SB, Choi HC, Joo NS. The relation of thyroid function to components of the metabolic syndrome in Korean men and women. J Korean Med Sci. 2011;26(4):540–5.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lai Y, Wang J, Jiang F, Wang B, Chen Y, Li M, et al. The relationship between serum thyrotropin and components of metabolic syndrome. Endocr J. 2011;58(1):23–30.PubMedCrossRefGoogle Scholar
  86. 86.
    Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007;92(2):491–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298(3):299–308.PubMedCrossRefGoogle Scholar
  88. 88.
    Tanaci N, Ertugrul DT, Sahin M, Yucel M, Olcay I, Demirag NG, et al. Postprandial lipemia as a risk factor for cardiovascular disease in patients with hypothyroidism. Endocrine. 2006;29(3):451–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Arikan S, Bahceci M, Tuzcu A, Celik F, Gokalp D. Postprandial hyperlipidemia in overt and subclinical hypothyroidism. Eur J Intern Med. 2012;23(6):e141–5.PubMedCrossRefGoogle Scholar
  90. 90.
    McGowan A, Widdowson WM, O’Regan A, Young IS, Boran G, McEneny J, et al. Postprandial studies uncover differing effects on HDL particles of overt and subclinical hypothyroidism. Thyroid. 2016;26(3):356–64.PubMedCrossRefGoogle Scholar
  91. 91.
    Pedersen SB, Varbo A, Langsted A, Nordestgaard BG. Chylomicronemia risk factors ranked by importance for the individual and community in 108 711 women and men. J Intern Med. 2018;283(4):392–404.PubMedCrossRefGoogle Scholar
  92. 92.
    Zhao M, Tang X, Yang T, Zhang B, Guan Q, Shao S, et al. Lipotoxicity, a potential risk factor for the increasing prevalence of subclinical hypothyroidism? J Clin Endocrinol Metab. 2015;100(5):1887–94.PubMedCrossRefGoogle Scholar
  93. 93.
    Sigal GA, Medeiros-Neto G, Vinagre JC, Diament J, Maranhao RC. Lipid metabolism in subclinical hypothyroidism: plasma kinetics of triglyceride-rich lipoproteins and lipid transfers to high-density lipoprotein before and after levothyroxine treatment. Thyroid. 2011;21(4):347–53.PubMedCrossRefGoogle Scholar
  94. 94.
    Fabbrini E, Magkos F, Patterson BW, Mittendorfer B, Klein S. Subclinical hypothyroidism and hyperthyroidism have opposite effects on hepatic very-low-density lipoprotein-triglyceride kinetics. J Clin Endocrinol Metab. 2012;97(3):E414–8.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Brenta G, Berg G, Miksztowicz V, Lopez G, Lucero D, Faingold C, et al. Atherogenic lipoproteins in subclinical hypothyroidism and their relationship with hepatic lipase activity: response to replacement treatment with levothyroxine. Thyroid. 2016;26(3):365–72.PubMedCrossRefGoogle Scholar
  96. 96.
    Abbas JM, Chakraborty J, Akanji AO, Doi SA. Hypothyroidism results in small dense LDL independent of IRS traits and hypertriglyceridemia. Endocr J. 2008;55(2):381–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Pearce EN, Wilson PW, Yang Q, Vasan RS, Braverman LE. Thyroid function and lipid subparticle sizes in patients with short-term hypothyroidism and a population-based cohort. J Clin Endocrinol Metab. 2008;93(3):888–94.PubMedCrossRefGoogle Scholar
  98. 98.
    Ozcan O, Cakir E, Yaman H, Akgul EO, Erturk K, Beyhan Z, et al. The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism. Clin Endocrinol. 2005;63(2):203–6.CrossRefGoogle Scholar
  99. 99.
    Roscini AR, Lupattelli G, Siepi D, Pagliaricci S, Pirro M, Mannarino E. Low-density lipoprotein size in primary hypothyroidism. Effects of hormone replacement therapy. Ann Nutr Metab. 1999;43(6):374–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Kim CS, Kang JG, Lee SJ, Ihm SH, Yoo HJ, Nam JS, et al. Relationship of low-density lipoprotein (LDL) particle size to thyroid function status in Koreans. Clin Endocrinol. 2009;71(1):130–6.CrossRefGoogle Scholar
  101. 101.
    Liu XL, He S, Zhang SF, Wang J, Sun XF, Gong CM, et al. Alteration of lipid profile in subclinical hypothyroidism: a meta-analysis. Med Sci Monit. 2014;20:1432–41.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Duntas LH, Mantzou E, Koutras DA. Circulating levels of oxidized low-density lipoprotein in overt and mild hypothyroidism. Thyroid. 2002;12(11):1003–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Ittermann T, Baumeister SE, Volzke H, Wasner C, Schminke U, Wallaschofski H, et al. Are serum TSH levels associated with oxidized low-density lipoprotein? Results from the Study of Health in Pomerania. Clin Endocrinol. 2012;76(4):526–32.CrossRefGoogle Scholar
  104. 104.
    Brenta G, Berg G, Arias P, Zago V, Schnitman M, Muzzio ML, et al. Lipoprotein alterations, hepatic lipase activity, and insulin sensitivity in subclinical hypothyroidism: response to L-T(4) treatment. Thyroid. 2007;17(5):453–60.PubMedCrossRefGoogle Scholar
  105. 105.
    Brenta G, Berg G, Zago V, Muzzio ML, Schnitman M, Sinay I, et al. Proatherogenic mechanisms in subclinical hypothyroidism: hepatic lipase activity in relation to the VLDL remnant IDL. Thyroid. 2008;18(11):1233–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Boren J, Williams KJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol. 2016;27(5):473–83.PubMedCrossRefGoogle Scholar
  107. 107.
    Ito M, Takamatsu J, Sasaki I, Hiraiwa T, Fukao A, Murakami Y, et al. Disturbed metabolism of remnant lipoproteins in patients with subclinical hypothyroidism. Am J Med. 2004;117(9):696–9.PubMedCrossRefGoogle Scholar
  108. 108.
    du Souich P, Roederer G, Dufour R. Myotoxicity of statins: mechanism of action. Pharmacol Ther. 2017;175:1–16.PubMedCrossRefGoogle Scholar
  109. 109.
    Gronich N, Deftereos SN, Lavi I, Persidis AS, Abernethy DR, Rennert G. Hypothyroidism is a risk factor for new-onset diabetes: a cohort study. Diabetes Care. 2015;38(9):1657–64.PubMedCrossRefGoogle Scholar
  110. 110.
    Krysiak R, Gilowski W, Okopien B. Different effects of atorvastatin on metabolic and cardiovascular risk factors in hypercholesterolemic women with normal thyroid function and subclinical hypothyroidism. Exp Clin Endocrinol Diabetes. 2015;123(3):182–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Duntas LH, Brenta G. Thyroid hormones: a potential ally to LDL-cholesterol-lowering agents. Hormones (Athens). 2016;15(4):500–10.CrossRefGoogle Scholar
  112. 112.
    Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85(9):2993–3001.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001;86(10):4860–6.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J Clin Endocrinol Metab. 2002;87(4):1533–8.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Monzani F, Caraccio N, Kozakowa M, Dardano A, Vittone F, Virdis A, et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004;89(5):2099–106.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):CD003419.Google Scholar
  117. 117.
    Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007;92(5):1715–23.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromso Study. J Intern Med. 2006;260(1):53–61.PubMedCrossRefGoogle Scholar
  119. 119.
    Mikhail GS, Alshammari SM, Alenezi MY, Mansour M, Khalil NA. Increased atherogenic low-density lipoprotein cholesterol in untreated subclinical hypothyroidism. Endocr Pract. 2008;14(5):570–5.PubMedCrossRefGoogle Scholar
  120. 120.
    Teixeira Pde F, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Buescu A, et al. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res. 2008;151(4):224–31.PubMedCrossRefGoogle Scholar
  121. 121.
    Zhao M, Liu L, Wang F, Yuan Z, Zhang X, Xu C, et al. A worthy finding: decrease in total cholesterol and low-density lipoprotein cholesterol in treated mild subclinical hypothyroidism. Thyroid. 2016;26(8):1019–29.CrossRefGoogle Scholar
  122. 122.
    Li X, Wang Y, Guan Q, Zhao J, Gao L. The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: a systematic review and meta-analysis of randomized controlled trials. Clin Endocrinol. 2017;87(1):1–9.CrossRefGoogle Scholar
  123. 123.
    Asvold BO, Bjoro T, Vatten LJ. Associations of TSH levels within the reference range with future blood pressure and lipid concentrations: 11-year follow-up of the HUNT study. Eur J Endocrinol. 2013;169(1):73–82.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Santos-Palacios S, Brugos-Larumbe A, Guillen-Grima F, Galofre JC. A cross-sectional study of the association between circulating TSH level and lipid profile in a large Spanish population. Clin Endocrinol. 2013;79(6):874–81.CrossRefGoogle Scholar
  125. 125.
    Jain RB. Associations between the levels of thyroid hormones and lipid/lipoprotein levels: data from National Health and Nutrition Examination Survey 2007-2012. Environ Toxicol Pharmacol. 2017;53:133–44.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Alberiche M, Boronat M, Saavedra P, Perez N, Marrero D, Lopez-Plasencia Y, et al. Thyrotropin levels and their relationship with cardiovascular risk factors in the island of Gran Canaria, Spain. Implications of lowering the upper reference limit of thyrotropin stimulating hormone. J Endocrinol Investig. 2009;32(2):102–6.CrossRefGoogle Scholar
  127. 127.
    van Tienhoven-Wind L, Dullaart RP. Low normal thyroid function as a determinant of increased large very low density lipoprotein particles. Clin Biochem. 2015;48(7–8):489–94.PubMedCrossRefGoogle Scholar
  128. 128.
    Triolo M, Kwakernaak AJ, Perton FG, de Vries R, Dallinga-Thie GM, Dullaart RP. Low normal thyroid function enhances plasma cholesteryl ester transfer in Type 2 diabetes mellitus. Atherosclerosis. 2013;228(2):466–71.PubMedCrossRefGoogle Scholar
  129. 129.
    Deetman PE, Kwakernaak AJ, Bakker SJ, Dullaart RP. Low-normal free thyroxine confers decreased serum bilirubin in type 2 diabetes mellitus. Thyroid. 2013;23(11):1367–73.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    van Tienhoven-Wind LJN, Gruppen EG, James RW, Bakker SJL, Gans ROB, Dullaart RPF. Serum paraoxonase-1 activity is inversely related to free thyroxine in euthyroid subjects: the PREVEND Cohort Study. Eur J Clin Investig. 2018;48(1).Google Scholar
  131. 131.
    Michalopoulou G, Alevizaki M, Piperingos G, Mitsibounas D, Mantzos E, Adamopoulos P, et al. High serum cholesterol levels in persons with ‘high-normal’ TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol. 1998;138(2):141–5.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Raziel A, Rosenzweig B, Botvinic V, Beigel I, Landau B, Blum I. The influence of thyroid function on serum lipid profile. Atherosclerosis. 1982;41(2–3):321–6.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Heimberg M, Olubadewo JO, Wilcox HG. Plasma lipoproteins and regulation of hepatic metabolism of fatty acids in altered thyroid states. Endocr Rev. 1985;6(4):590–607.PubMedCrossRefGoogle Scholar
  134. 134.
    Sjouke B, Elbers LPB, van Zaane B, Kastelein JJP, Hovingh GK, Gerdes VEA. Effects of supra-physiological levothyroxine dosages on liver parameters, lipids and lipoproteins in healthy volunteers: a randomized controlled crossover study. Sci Rep. 2017;7(1):14174.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    The coronary drug project. JAMA. 1972;221(8):918.CrossRefGoogle Scholar
  136. 136.
    Diekman MJ, Anghelescu N, Endert E, Bakker O, Wiersinga WM. Changes in plasma low-density lipoprotein (LDL)- and high-density lipoprotein cholesterol in hypo- and hyperthyroid patients are related to changes in free thyroxine, not to polymorphisms in LDL receptor or cholesterol ester transfer protein genes. J Clin Endocrinol Metab. 2000;85(5):1857–62.PubMedCrossRefGoogle Scholar
  137. 137.
    Oge A, Sozmen E, Karaoglu AO. Effect of thyroid function on LDL oxidation in hypothyroidism and hyperthyroidism. Endocr Res. 2004;30(3):481–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Yavuz DG, Yuksel M, Deyneli O, Ozen Y, Aydin H, Akalin S. Association of serum paraoxonase activity with insulin sensitivity and oxidative stress in hyperthyroid and TSH-suppressed nodular goitre patients. Clin Endocrinol. 2004;61(4):515–21.CrossRefGoogle Scholar
  139. 139.
    Beylot M, Martin C, Laville M, Riou JP, Cohen R, Mornex R. Lipolytic and ketogenic fluxes in human hyperthyroidism. J Clin Endocrinol Metab. 1991;73(1):42–9.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Cachefo A, Boucher P, Vidon C, Dusserre E, Diraison F, Beylot M. Hepatic lipogenesis and cholesterol synthesis in hyperthyroid patients. J Clin Endocrinol Metab. 2001;86(11):5353–7.PubMedCrossRefGoogle Scholar
  141. 141.
    Byeon SK, Park SH, Lee JC, Hwang S, Ku CR, Shin DY, et al. Lipidomic differentiation of Graves’ ophthalmopathy in plasma and urine from Graves’ disease patients. Anal Bioanal Chem. 2018;410(27):7121–33.PubMedCrossRefGoogle Scholar
  142. 142.
    Stein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, et al. Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol. 2015;133(3):290–6.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Sabini E, Mazzi B, Profilo MA, Mautone T, Casini G, Rocchi R, et al. High serum cholesterol is a novel risk factor for Graves’ orbitopathy: results of a cross-sectional study. Thyroid. 2018;28(3):386–94.PubMedCrossRefGoogle Scholar
  144. 144.
    Lammel Lindemann J, Webb P. Sobetirome: the past, present and questions about the future. Expert Opin Ther Targets. 2016;20(2):145–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Sjouke B, Langslet G, Ceska R, Nicholls SJ, Nissen SE, Ohlander M, et al. Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol. 2014;2(6):455–63.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Kelly MJ, Pietranico-Cole S, Larigan JD, Haynes NE, Reynolds CH, Scott N, et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dio xo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor beta agonist in clinical trials for the treatment of dyslipidemia. J Med Chem. 2014;57(10):3912–23.PubMedCrossRefGoogle Scholar
  147. 147.
    Senese R, de Lange P, Petito G, Moreno M, Goglia F, Lanni A. 3,5-Diiodothyronine: a novel thyroid hormone metabolite and potent modulator of energy metabolism. Front Endocrinol (Lausanne). 2018;9:427.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Gabriela Brenta
    • 1
  • Laura Schreier
    • 2
  1. 1.Unidad Asistencial Dr. César Milstein/PAMI-INSSJPBuenos AiresArgentina
  2. 2.Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Laboratorio de Lípidos y AterosclerosisUniversidad de Buenos AiresBuenos AiresArgentina

Personalised recommendations