期刊论文详细信息
BMC Endocrine Disorders
Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment
João B. T. Rocha2  Marta M. M. F. Duarte3  Daiane F. Meinerz2  Diego L. Rovaris5  Alexandre A. Naujorks1  Luiz A. F. Pereira4  Roseane C. Marchiori4 
[1] Serviço de Metodos Graficos, Hospital Universitario de Santa Maria, Universidade Federal de Santa Maria, Av. Roraima n° 1000, Cidade Universitaria, Camobi, Santa Maria, RS, Brazil;Departamento de Bioquímica e Biologia Molecular, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Av. Roraima n° 1000, Cidade Universitaria, Camobi, Santa Maria, RS, Brazil;Ciencias da Saude, Universidade Luterana do Brasil (ULBRA), campus Santa Maria, BR 287, Km 252, Trevo Maneco Pedroso, Boca do Monte, Santa Maria Cx. Postal 21834RS, Brazil;Departamento de Clinica Médica, Centro de Ciencias da Saude, Universidade Federal de Santa Maria, Av. Roraima n° 1000, Cidade Universitaria, Camobi, Santa Maria, RS, Brazil;Departamento de Genetica, Instituto de Biociencias, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, Porto Alegre, 9500, Brazil
关键词: Atherosclerosis;    Levothyroxine;    Hashimoto’s thyroiditis;    Subclinical hypothyroidism;    Overt hypothyroidism;    Oxidative stress;    Inflammation;   
Others  :  1215934
DOI  :  10.1186/s12902-015-0032-3
 received in 2015-02-21, accepted in 2015-06-12,  发布年份 2015
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【 摘 要 】

Background

There are several specific inflammatory and oxidative correlates among patients with hypothyroidism, but most studies are cross-sectional and do not evaluate the change in parameters during the treatment. The aim of this study was to investigate the effect of levothyroxine replacement therapy on biomarkers of oxidative stress (OS) and systemic inflammation in patients with hypothyroidism.

Methods

In this prospective open-label study, 17 patients with recently diagnosed primary hypothyroidism due to Hashimoto’s thyroiditis who were not taking levothyroxine were included. The following parameters were measured before and at 6 and 12 months of levothyroxine treatment with an average dose of 1.5 to 1.7 μg/kg/day: thyroid-stimulating hormone (TSH), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP), interleukin 1 (IL-1), IL-6, IL-10, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), thiobarbituric acid-reactive substances (TBARS), activity of aminolevulinic acid dehydratase (δ-ALA-D), nonprotein and total thiol (NP-SH and T-SH) groups, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Generalized estimating equation (GEE) modeling was used to analyze the effects of LRT (at pre-treatment, 6 months and 12 months) on those variables. The hypothyroidism status (i.e., overt or subclinical hypothyroidism) was included as a confounder in all analyses. An additional GEE post hoc analysis was made to compare time points.

Results

There was a significant decrease in TSH over time (P < 0.0001), (initial levels were on average 32.4 μIU/mL and 10.5 μIU/mL at 12 months). There was a significant increase in FT4 (P < 0.0001) (initial levels were on average 0,8 ng/dL and 2.7 ng/dL at 12 months). There were significant changes in interleukin levels over time, with a significant increase in IL-10 (P < 0.0001) and significant decreases in IL-1 (P < 0.0001), IL-6 (P < 0.0001), INF-γ (P < 0.0001) and TNF-α (P < 0.0001). No significant difference in hs-CRP over time was observed (P < 0.284). There was a significant reduction in NP-SH (P < 0.0001).

Conclusions

This study observed significant changes in the inflammatory profile in hypothyroid patients under treatment, with reduction of pro-inflammatory cytokines and elevation of anti-inflammatory cytokine. In these patients, a decrease in low-grade chronic inflammation may have clinical relevance due to the known connection between chronic inflammation, atherosclerosis and cardiovascular events.

【 授权许可】

   
2015 Marchiori et al.

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【 参考文献 】
  • [1]Garber JR, Cobin RH, Guarib H, Hennessey JV, Klein I, Mechanik 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; 18:989-1028.
  • [2]Ganesh BB, Bhattacharya P, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and supression of thyroid autoimmunity. J Interferon Citokine Res. 2011; 31:721-31.
  • [3]Canaris GJ, Manowitz NR, Mayor G, Ridgway C. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160:526-34.
  • [4]Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypothyroidism is an independent risk fator for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000; 132:270-8.
  • [5]Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J. Subclinical hypothyroidism is associated with a low grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin Endocrinol (Oxf). 2004; 61:232-8.
  • [6]Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007; 116:1725-35.
  • [7]Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003; 88:2438-44.
  • [8]Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012; 32:2045-51.
  • [9]Welsh P, Packard CJ, Sattar N. Novel antecedent plasma biomarkers of cardiovascular disease: improved evaluation methods and comparator benchmarks raise the bar. Curr Opin Lipidol. 2008; 19:563-71.
  • [10]Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk fator for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Forces. Ann Intern Med. 2009; 151:483-95.
  • [11]Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB et al.. Long-term interleukin-6 levels and subsequente risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 2008; 5:e78.
  • [12]The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012; 379:1214-24.
  • [13]Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J et al.. Effects of Interleukin-1 Beta inhibition with Canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen. A phase IIb randomized, placebo-controlled trial. Circulation. 2012; 126:2739-48.
  • [14]Pedersen ER, Midttun O, Ueland PM, Schartum-Hansen H, Seifert R, Igland J et al.. Systemic markers of Interferon-gamma-mediated imune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2011; 31:698-704.
  • [15]Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of Tumor Necrosis Factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101:2149-53.
  • [16]Kaptoge S, Seshasai SRK, Gao P, Freitag DF, Butterworth AS, Borglykke A et al.. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J. 2014; 35:587-9.
  • [17]Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endotelial apoptosis and tissue fator expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol. 2004; 24:1309-14.
  • [18]Baskol G, Atmaca H, Tanriverdi F, Baskol M, Kocer D, Bayram F. Oxidative stress and enzymatic antioxidant status in patient with hypothyroidism before and after treatment. Exp Clin Endocrinol Diabetes. 2007; 115:522-6.
  • [19]Kebapcilar L, Akinci B, Bayraktar F, Comlekci A, Solak A, Demir T et al.. Plasma thiobarbituric acid-reactive substance levels in subclinical hypothyroidism. Med Princ Pract. 2007; 16:432-6.
  • [20]Mehmetçik G, Becer E, Akbey A. Serum total antioxidant status, lipid profile, malondialdehyde and erythrocyte superoxide dismutase levels in Hashimoto thyroiditis patients treated with levothyroxine. Turkiye Kinikleri J Med Sci. 2012; 32:1241-6.
  • [21]Bhimte B, Agrawal BK, Sharma VK, Chauhan SS. Oxidative stress status in hypothyroid patients. Biomed Res. 2012; 23:286-8.
  • [22]Gerenova J, Gadjeva V. Oxidative stress and antioxidant enzyme activities in patients with Hashimoto’s thyroiditis. Comp Clin Pathol. 2007; 16:259-64.
  • [23]Erdamar H, Demirci H, Yaman H, Erbil MK, Yakar T, Sancak B et al.. The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin Chem Lab Med. 2008; 46:1004-10.
  • [24]Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L et al.. Low-grade systemic inflammation causes endotelial dysfunction in patients with Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2006; 91:5076-82.
  • [25]Türemen EE, Çetinarslan B, Sahin T, Cantürk Z, Tarkun I. Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr J. 2011; 58:349-54.
  • [26]Marfella R, Ferraraccio F, Rizzo MR, Portoghese M, Barbieri M, Basilio C et al.. Innate immune activity in plaque of patients with untreated and L-thyroxine-treated subclinical hypothyroidism. J Clin Endocrinol Metab. 2011; 96:1015-20.
  • [27]Christ-Crain M, Meier C, Guglielmetti M, Huber PR, Riesen W, Staub JJ, Müller B. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis. 2003; 166:379-86.
  • [28]Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L et al.. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003; 88:3731-7.
  • [29]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 (Oxf). 2005; 63:203-6.
  • [30]Aksoy DY, Cinar N, Harmanci A, Karakaya J, Yildiz BO, Usman A, Bayraktar M. Serum resistin and high sensitive CRP levels in patients with subclinical hypothyroidism before and after L-thyroxine therapy. Med Sci Monit. 2013; 19:210-5.
  • [31]Anagnostis P, Efstathiadou ZA, Slavakis A, Selalmatzidou D, Poulasouchidou M, Katergari S, et al. The effect of L-tiroxine substitution on lipid profile, glucose homeostasis, inflammation and coagulation in patients with subclinical hypothyroidism. Int J Clin Pract. 2014. doi:10.1111:1–7.
  • [32]Bachorik PS, Albers JJ. Precipitation methods for quantification of lipoproteins. Methods Enzymol. 1986; 129:78-100.
  • [33]Friedewald WT, Levy RI, Fredrickson DS. Estimation of the low-density lipoprotein cholesterol in plasma without the use of preparative ultracentrifuge. Clin Chem. 1972; 18:499-502.
  • [34]Ohkawa H, Ohishi H, Yagi K. Assay for lipid peroxide in animal tissues by thiobarbithuric acid reaction. Anal Biochem. 1979; 95:351-8.
  • [35]Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959; 82:70-7.
  • [36]Sassa S. Delta-aminolevulinic acid dehydratase assay. Enzyme. 1982; 28:133-45.
  • [37]Nagasaki T, Inaba M, Shirakawa K, Hiura Y, Tahara H, Humeda Y et al.. Increased levels of C-reactive protein in hypothyroid patients and its correlation with arterial stiffness in the common carotid artery. Biomed Pharmacother. 2007; 61:167-72.
  • [38]Poyrazoglu OK, Ozkan Y, Ozden M, Colak R, Ozalp G, Dönder E. L-thyroxine treatment of patients with subclinical hypothyroidism reduce inflammation. Open Endocrinol J. 2009; 3:34-7.
  • [39]Bilgir O, Bilgir F, Calam M, Calam OG, Yuksel A. Comparison of pre- and post-levothyroxine high-sensitivity c-reactive protein and fetuin-a levels in subclinical hypothyroidism. Clinics. 2015; 70:97-101.
  • [40]Luboshitzky R, Herer P. Cardiovascular risk factors in middle-aged women with subclinical hypothyroidism. Neuroendocrinol Lett. 2004; 25:262-6.
  • [41]Peleg RK, Efrati S, Benbassat C, Fygenzo M, Golik A. The effect of levothyroxine on arterial stiffness and lipid profile in patients with subclinical hypothyroidism. Thyroid. 2008; 18:825-30.
  • [42]Drugarin D, Negru S, Korech A, Zosin I, Cristea C. The pattern of a Th1 cytokine in autoimune thyroiditis. Immunol Lett. 2000; 71:73-7.
  • [43]Figueroa-Vega N, Alfonso-Pérez M, Benedicto I, Sánchez-Madrid F, González-Amaro R, Marazuela M. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2010; 95:953-62.
  • [44]Díez JJ, Hernanz A, Medina S, Bayon C, Iglesias P. Serum concentrations of tumor necrosis fator-alpha and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after treatment. Clin Endocrinol (Oxf). 2002; 57:515-21.
  • [45]Papanas N, Papazoglou D, Papatheodorou K, Antonoglou C, Kotsiou S, Maltezos E. Thyroxine replacement dose in patients with Hashimoto disease: a potencial role for interleukin-6. Cytokine. 2006; 35:166-70.
  • [46]Karanikas G, John P, Wahl K, Schuetz M, Dudczak R, Wilheim M. T-Lymphocyte cytokine production patterns in nonimmune severe hypothyroid state and after thyroid hormone replacement therapy. Thyroid. 2004; 14:488-92.
  • [47]Guclu F, Ozmen B, Kirmaz C, Kafesciler SO, Degirmenci PB, Taneli F, Hekimsoy Z. Down-regulation of the auto-aggressive processes in patients with hypothyroidism Hashimoto’s thyroiditis following substitutive treatment with L-thyroxine. Eur Cytokine Netw. 2009; 20:27-32.
  • [48]Tanis BC, Westendorp RGJ, Smelt AHM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol (Oxf). 1996; 44:643-9.
  • [49]Teixeira PF, 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; 151:224-31.
  • [50]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; 260:53-61.
  • [51]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; 92:1715-23.
  • [52]Danese MD, Ladenson PW, Meinert CL, Powe NR. Effect of thyroxine therapy on serum lipoproteins in patiens with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000; 85:2993-3001.
  • [53]Ineck BA, Ng TMH. Effect of subclinical hypothyroidism and its treatment on serum lipids. Ann Pharmacoter. 2003; 37:725-30.
  • [54]Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007; 18:CD003419.
  • [55]Bilgir F, Bilgir O, Calan M, Calan O, Isikyakar T. Subclinical hypothyroidism: comparison of adhesion molecule levels before and after levothyroxine therapy. J Intern Med Res. 2014; 42:806-14.
  • [56]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; 89:2099-106.
  • [57]Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP et al.. Subclinical thyroid dysfunction, cardiac function ant the risk of heart failure: the cardiovascular health study. J Am Coll Cardiol. 2008; 52:1152-9.
  • [58]Razvi S, Weaver JU, Vanderpump MP, Pearce SHS. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Wickham Survey Cohort. J Clin Endocrinol Metab. 2010; 95:1734-40.
  • [59]Razvi S, Weaver JU, Butler TJ, Pearce SHS. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012; 172:811-7.
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