Effects of L-thyroxine Replacement Therapy on Carotid Intima-media Thickness in Patients with Primary Hypothyroidism

Abstract

Background: In hypothyroid patients, the risk for cardiovascular disease is higher and ultrasonography (US) demonstrates that the carotid intima-media thickness (CIMT) is significantly increased. We hypothesized that L-thyroxine replacement therapy might be able to reverse the process associated with increase in CIMT in patients with primary hypothyroidism.

Patients: In this study, a total of 43 females with primary hypothyroidism and 21 euthyroid females as control group were included. In hypothyroid patients, CIMT was measured using US and the measurement was repeated 6 months after euthyroidism was achieved with L-thyroxine replacement therapy. Biochemically, lipid profile, high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitory-1 (PAI-1) and fibrinogen levels were measured.

Results: It was found that in hypothyroid patients the value of CIMT was significantly higher than those in control group (0.534±0.08 mm vs. 0.443±0.05 mm, respectively; p<0.001). However, the value of CIMT decreased significantly in all but two patients after euthyroidism was achieved with L-thyroxine replacement therapy (0.534±0.08 mm and 0.465±0.06 mm, respectively; p<0.001). Moreover, there was a positive correlation between the CIMT value and all other parameters except patient age, including total cholesterol (r=0.437, p=0.003), low density lipoprotein (LDL) cholesterol (r=0.415, p=0.006), total cholesterol/high density lipoprotein (HDL) cholesterol ratio (r=0.391, p=0.01) basal levels.

Conclusion: This report demonstrates that in patients with primary hypothyroidism, in addition to values of total cholesterol, LDL cholesterol, and total cholesterol/HDL cholesterol ratio, the CIMT value was higher compared to healthy controls. Importantly, the value of CIMT, as well as the levels of lipid parameters, decreased to normal level after L-thyroxine replacement therapy. Furthermore, significant correlations were detected between the changes of CIMT and the changes of total cholesterol and LDL cholesterol respectively. Thus, it is suggested that an increased CIMT value may be an objective sign of accelerated atherosclerosis in patients with primary hypothroidism.

thyroxine - primary hypothyroidism - carotid artery - ultrasonography

References

• 1 Becerra A, Bellido D, Luengo A. et al . Lipoprotein (a) and other lipoproteins in hypothyroid patients before and after thyroid replacement therapy.  Clin Nutr. 1999;  18 319-322
• 2 Binder BR, Christ G, Gruber F. et al . Plasminogen activator inhibitor-1: physiological and pathophysiological roles.  News Physiol Sci. 2002;  17 56-61
• 3 Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease.  Endocrine. 2004;  24 1-13
• 4 Cakal B, Cakal E, Demirbaş B. et al . Homocysteine and fibrinogen changes with L-thyroxine in subclinical hypothyroid patients.  J Korean Med Sci. 2007;  22 431-435
• 5 Cantürk Z, Çetinarslan B, Tarkun İ. et al . Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism.  Thyroid. 2003;  13 971-977
• 6 Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis.  J Clin Endocrinol Metab. 2003;  88 2438-2444
• 7 Chadarevian R, Bruckert E, Leenhardt L. et al . Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism.  J Clin Endocrinol Metab. 2001;  86 732-737
• 8 Chait A, Bierman EL, Albers JJ. Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts.  J Clin Endocrinol Metab. 1979;  48 887-889
• 9 Christ-Crain M, Meier C, Guglielmetti M. et al . Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial.  Atherosclerosis. 2003;  166 379-386
• 10 Danesh J, Whincup P, Walker M. et al . Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.  BMJ. 2000;  321 199-204
• 11 Duman D, Demirtunc R, Sahin S. et al . The effects of simvastatin and levothyroxine on intima-media thickness of the carotid artery in female normolipemic patients with subclinical hypothyroidism: a prospective, randomized-controlled study.  J Cardiovasc Med. 2007;  8 1007-1011
• 12 Epstein FH, Kohler HP, Grant PJ. Plasminogen-activator inhibitor type-1 and coronary artery disease.  N Eng J Med. 2000;  342 1792-1801
• 13 Erem C, Kavgaci H, Ersöz HO. et al . Blood coagulation and fibrinolytic activity in hypothyroidism.  Int J Clin Pract. 2003;  57 78-81
• 14 Folsom AR. Atherosclerosis risk in communities. Prospective study of hemostatic factors and incidence of coronary heart disease.  Circulation. 1997;  96 1102-1108
• 15 Frishman WH. Biologic markers as predictors of cardiovascular disease.  Am J Med. 1998;  104 18S-27S
• 16 Grobbee DE, Bots ML. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis.  J Intern Med. 1994;  236 567-573
• 17 Hak AE, Pols HA, Visser TJ. et al . Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: Rotterdam Study.  Ann Intern Med. 2000;  132 270-278
• 18 Klein I, Ojamaa K. The cardiovascular system in hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's The Thyroid. 8th edn. Lippincott: Williams & Wilkins 2000: 777-782
• 19 Knoflach M, Kiechl S, Kind M. et al . Cardiovascular risk factors and atherosclerosis in young males: ARMY study (Atherosclerosis Risk-Factors in Male Youngsters).  Circulation. 2003;  108 1064-1069
• 20 Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk?.  Arch Intern Med. 2002;  162 867-869
• 21 Lam KS, Chan MK, Yeung RT. High-density lipoprotein cholesterol, hepatic lipase and lipoprotein lipase activities in thyroid dysfunction-effects of treatment.  Q J Med. 1986;  59 513-521
• 22 Lekakis JP, Papamichael CM, Cimponeriu AT. et al . Atherosclerotic changes of extracoronary arteries are associated with the extent of coronary atherosclerosis.  Am J Cardiol. 2000;  85 949-952
• 23 Makita S, Nakamura M, Hiramori K. The association of C-reactive protein levels with carotid intima-media complex thickness and plaque formation in the general population.  Stroke. 2005;  36 2138-2142
• 24 Monzani F, Caraccio N, Kozakowa M. 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 2099-2106
• 25 Muller B, Tsakiris DA, Roth CB. et al . Hemostatic profile in hypothyroidism as potential risk factor for vascular or trombotic disease.  Eur J Clin Invest. 2001;  31 131-137
• 26 Nagasaki T, Inaba M, Henmi Y. et al . Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function.  Clin Endocrinol (Oxf). 2003;  59 607-612
• 27 Pignoli P, Tremoli E, Poli A. et al . Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.  Circulation. 1986;  74 1399-1406
• 28 Poli A, Tremoli E, Colombo A. et al . Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients: a new model for the quantification and follow up of preclinical atherosclerosis in living human subjects.  Atherosclerosis. 1988;  70 253-261
• 29 Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease.  Arterioscler Thromb. 1991;  11 1245-1249
• 30 Sengül E, Cetinarslan B, Tarkun I. et al . Homocysteine concentrations in subclinical hypothyroidism.  Endocr Research. 2004;  30 351-359
• 31 Serter R, Demirbas B, Korukluoglu B. et al . The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism.  J Endocrinol Invest. 2004;  27 897-903
• 32 Simons PC, Algra A, Bots ML. et al . Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of ARTerial disease).  Circulation. 1999;  100 951-957
• 33 Tan KC, Shiu SW, Kung AW. Plasma cholesteryl ester transfer protein activity in hyper- and hypo thyroidism.  J Clin Endocrinol Metab. 1998;  83 140-143
• 34 Thompson GR, Soutar AK, Spengel FA. et al . Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo.  Proc Natl Acad Sci USA. 1981;  78 2591-2595
• 35 Weintraub M, Grosskopf I, Trostanesky Y. et al . Thyroxine replacement therapy enhances clearance of chylomicron remnants in patients with hypothyroidism.  J Clin Endocrinol Metab. 1999;  84 2532-2536
• 36 Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor.  Circulation. 2004;  109 ((Suppl II)) II2-10

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