The Effect of Levothyroxine on Expression of Inflammation-Related Genes in Healthy Subjects: A Controlled Randomized Crossover Study

Abstract

An excess of thyroid hormone leads to a prothrombotic state; however, the underlying pathophysiological mechanisms remain unknown. As evidence points towards an extensive “cross-talk” between the inflammatory and coagulation cascade, inflammation has been claimed as a possible mechanism through which different risk factors trigger venous thrombus formation. We aimed to study changes in expression of inflammation-related genes of the leukocyte RNA expression profile in healthy subjects in response to supraphysiological doses of levothyroxine. In a randomized single-blinded crossover design, 12 healthy volunteers (aged 18–40 years) received levothyroxine and no medication, both for 14 days with a wash-out period of at least 28 days between the periods. Blood was sampled at baseline and day 14 of each study period. MRNA was isolated from whole blood and used for multiplex ligation-dependent probe amplification to study the expression of inflammation-related genes. Compared to the control situation no significant changes were found in the expression of proinflammatory cytokines and mediators after the intake of levothyroxine. The results of this study show that high thyroid hormone levels do not lead to an altered inflammatory profile. This provides evidence against a major role of the inflammatory system as mediator in the effect of thyroid hormone on the coagulation system. The mechanisms by which thyroid hormone may influence coagulation proteins remain to be elucidated.

Key words

hyperthyroidism - inflammation - coagulation - venous thrombosis

• References

• 1 Doyle JB. Obstruction of the longitudinal sinus. Arch Neurol Psychiatry 1927; 18: 374-382
• 2 Stuijver DJ, van Zaane B, Squizzato A, Meijers JC, Otten HM. The effects of an extremely high dose of levothyroxine on coagulation and fibrinolysis. J Thromb Haemost 2010; 8: 1427-1428
• 3 Squizzato A, Romualdi E, Buller HR, Gerdes VE. Clinical review: Thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab 2007; 92: 2415-2420
• 4 van Zaane B, Squizzato A, Huijgen R, van Zanten AP, Fliers E, Cannegieter SC, Büller HR, Gerdes VE, Brandjes DP. Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case-control study. Blood 2010; 115: 4344-4349
• 5 Franchini M, Lippi G, Manzato F, Vescovi PP. Thyroid-associated autoimmune coagulation disorders. J Thromb Thrombolysis 2010; 29: 87-91
• 6 Liu L, Wang X, Lin Z, Wu H. Elevated plasma levels of VWF:Ag in hyperthyroidism are mediated through beta-adrenergic receptors. Endocr Res 1993; 19: 123-133
• 7 Niessen RW, Pfaffendorf BA, Sturk A, Lamping RJ, Schaap MC, Hack CE, Peters M. The influence of insulin, beta-estradiol, dexamethasone and thyroid hormone on the secretion of coagulant and anticoagulant proteins by HepG2 cells. Thromb Haemost 1995; 74: 686-692
• 8 Takamura N, Akilzhanova A, Hayashida N, Kadota K, Yamasaki H, Usa T, Nakazato M, Maeda T, Ozono Y, Aoyagi K. Thyroid function is associated with carotid intima-media thickness in euthyroid subjects. Atherosclerosis 2009; 204: 77-81
• 9 Baumgartner-Parzer SM, Wagner L, Reining G, Sexl V, Nowotny P, Müller M, Brunner M, Waldhäusl W. Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells. J Endocrinol 1997; 154: 231-239
• 10 Shih CH, Chen SL, Yen CC, Huang YH, Chen CD, Lee YS, Lin KH. Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins. Endocrinology 2004; 145: 2804-2814
• 11 Conde I, Lopez JA. Classification of venous thromboembolism (VTE). Role of acute inflammatory stress in venous thromboembolism. J Thromb Haemost 2005; 3: 2573-2575
• 12 Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol 2007; 26: 306-311
• 13 Lubrano V, Pingitore A, Carpi A, Iervasi G. Relationship between triiodothyronine and proinflammatory cytokines in chronic heart failure. Biomed Pharmacother 2010; 64: 165-169
• 14 Salvi M, Pedrazzoni M, Girasole G, Giuliani N, Minelli R, Wall JR, Roti E. Serum concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. Eur J Endocrinol 2000; 143: 197-202
• 15 Siddiqi A, Monson JP, Wood DF, Besser GM, Burrin JM. Serum cytokines in thyrotoxicosis. J Clin Endocrinol Metab 1999; 84: 435-439
• 16 van Zaane B, Squizzato A, Debeij J, Dekkers OM, Meijers JC, Van Zanten AP, Büller HR, Gerdes VE, Cannegieter SC, Brandjes DP. Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study. J Thromb Haemost 2011; 9: 1816-1824
• 17 Lok CA, Boing AN, Reitsma PH, van der Post JA, van Bavel E, Boer K, Sturk A, Nieuwland R. Expression of inflammation-related genes in endothelial cells is not directly affected by microparticles from preeclamptic patients. J Lab Clin Med 2006; 147: 310-320
• 18 Spek CA, Verbon A, Aberson H, Pribble JP, McElgunn CJ, Turner T, Axtelle T, Schouten J, Van Der Poll T, Reitsma PH. Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo. J Clin Immunol 2003; 23: 132-140
• 19 Wiersinga WJ, Dessing MC, Kager PA, Cheng AC, Limmathurotsakul D, Day NP, Dondorp AM, van der Poll T, Peacock SJ. High-throughput mRNA profiling characterizes the expression of inflammatory molecules in sepsis caused by Burkholderia pseudomallei. Infect Immun 2007; 75: 3074-3079
• 20 Enia G, Panuccio V, Cutrupi S, Pizzini P, Tripepi G, Mallamaci F, Zoccali C. Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2007; 22: 538-544
• 21 van Aken BE, den Heijer M, Bos GM, van Deventer SJ, Reitsma PH. Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 2000; 83: 536-539
• 22 van Aken BE, Reitsma PH, Rosendaal FR. Interleukin 8 and venous thrombosis: evidence for a role of inflammation in thrombosis. Br J Haematol 2002; 116: 173-177
• 23 Christiansen SC, Naess IA, Cannegieter SC, Hammerstrom J, Rosendaal FR, Reitsma PH. Inflammatory cytokines as risk factors for a first venous thrombosis: a prospective population-based study. PLoS Med 2006; 3: 1414-1419