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The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

DOI: 10.1155/2012/302537

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Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo. 1. Introduction Graves' disease is a most common cause of hyperthyroidism in iodine sufficient areas [1]. It is characterized by diffuse goitre and hyperthyroidism. Graves' orbitopathy represents orbit involvement and is clinically relevant in about half of the patients with the Graves' disease. In 3 to 5% of the patients, orbitopathy is severe [2]. Graves' disease is an autoimmune disease characterized by the presence of the serum autoantibodies. TSH receptor antibody represents the major autoantibody in Graves' disease [3]. Autoimmune process induces an inflammatory reaction and reactive oxygen species (ROSs) are among its products. ROSs are formed as normal metabolic products and are important in normal cellular functioning, but their production can be increased under pathological conditions and cause damage [4, 5]. Therefore, a large number of antioxidant systems act as protective mechanism. Among them are superoxide dismutase which catalyses dismutation of superoxide to peroxide, catalase which catalyses the decomposition of hydrogen peroxide to water and oxygen, while glutathione peroxidise which reduces lipid hidroperoxides while simultaneously oxidizing glutathione [6]. Situation in which balance between oxidants and antioxidants is disturbed in favour of the oxidants is termed “oxidative stress” (OS) [4]. 2. Oxidative Stress and the Thyroid Gland Synthesis of thyroid hormones requires formation of the hydrogen peroxide, a highly reactive oxidant. Hydrogen peroxide and oxidized iodine are immediately


[1]  P. Laurberg, K. M. Pedersen, H. Vestergaard, and G. Sigurdsson, “High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland,” Journal of Internal Medicine, vol. 229, no. 5, pp. 415–420, 1991.
[2]  W. M. Wiersinga and L. Bartalena, “Epidemiology and prevention of Graves' ophthalmopathy,” Thyroid, vol. 12, no. 10, pp. 855–860, 2002.
[3]  T. J. Smith, “Pathogenesis of Graves' orbitopathy: a 2010 update,” Journal of Endocrinological Investigation, vol. 33, no. 6, pp. 414–421, 2010.
[4]  H. Sies, “Oxidative stress: oxidants and antioxidants,” Experimental Physiology, vol. 82, no. 2, pp. 291–295, 1997.
[5]  M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur, and J. Telser, “Free radicals and antioxidants in normal physiological functions and human disease,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 1, pp. 44–84, 2007.
[6]  J. M. Matés, C. Pérez-Gómez, and I. N. de Castro, “Antioxidant enzymes and human diseases,” Clinical Biochemistry, vol. 32, no. 8, pp. 595–603, 1999.
[7]  P. R. Larsen, T. F. Davies, M. Schlumberger, and I. D. Hay, “10,” in Williams Textbook of Endocrinology, H. M. Kronenberg, S. Melmed, K. S. Polonsky, and P. R. Larsen, Eds., pp. 299–332, Saunders Elsevier, 2008.
[8]  Y. Song, N. Driessens, M. Costa et al., “Roles of hydrogen peroxide in thyroid physiology and disease,” The Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 10, pp. 3764–3773, 2007.
[9]  A. C. Gérard, M. C. Many, C. Daumerie, B. Knoops, and I. M. Colin, “Peroxiredoxin 5 expression in the human thyroid gland,” Thyroid, vol. 15, no. 3, pp. 205–209, 2005.
[10]  T. Mono, R. Shinohara, K. Iwase et al., “Changes in free radical scavengers and lipid peroxide in thyroid glands of various thyroid disorders,” Hormone and Metabolic Research, vol. 29, no. 7, pp. 351–354, 1997.
[11]  S. Poncin, I. M. Colin, B. Decallonne et al., “N-acetylcysteine and 15 deoxy-Δ12,14-prostaglandin J2 exert a protective effect against autoimmune thyroid destruction in vivo but not against interleukin-1α/interferon γ-induced inhibitory effects in thyrocytes in vitro,” The American Journal of Pathology, vol. 177, no. 1, pp. 219–228, 2010.
[12]  L. C. Cardoso, D. C. L. Martins, M. D. L. Figueiredo et al., “Ca2+/nicotinamide adenine dinucleotide phosphate-dependent H2O2 generation is inhibited by iodide in human thyroids,” The Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 9, pp. 4339–4343, 2001.
[13]  N. Knudsen, I. Bülow, P. Laurberg, L. Ovesen, H. Perrild, and T. J?rgensen, “Association of tobacco smoking with goiter in a low-iodine-intake area,” Archives of Internal Medicine, vol. 162, no. 4, pp. 439–443, 2002.
[14]  C. Steinmaus, M. D. Miller, and R. Howd, “Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 National Health and Nutrition Examination Survey,” Environmental Health Perspectives, vol. 115, no. 9, pp. 1333–1338, 2007.
[15]  S. Poncin, A. C. Gérard, M. Boucquey et al., “Oxidative stress in the thyroid gland: from harmlessness to hazard depending on the iodine content,” Endocrinology, vol. 149, no. 1, pp. 424–433, 2008.
[16]  M. Abalovich, S. Llesuy, S. Gutierrez, and M. Repetto, “Peripheral parameters of oxidative stress in Graves' disease: the effects of methimazole and 131 iodine treatments,” Clinical Endocrinology, vol. 59, no. 3, pp. 321–327, 2003.
[17]  E. Ademo?lu, N. ?zbey, Y. Erbil et al., “Determination of oxidative stress in thyroid tissue and plasma of patients with Graves' disease,” European Journal of Internal Medicine, vol. 17, no. 8, pp. 545–550, 2006.
[18]  P. Venditti and S. Di Meo, “Thyroid hormone-induced oxidative stress,” Cellular and Molecular Life Sciences, vol. 63, no. 4, pp. 414–434, 2006.
[19]  A. Cetinkaya, E. B. Kurutas, M. A. Buyukbese, B. Kantarceken, and E. Bulbuloglu, “Levels of malondialdehyde and superoxide dismutase in subclinical hyperthyroidism,” Mediators of Inflammation, vol. 2005, no. 1, pp. 57–59, 2005.
[20]  D. N. Nandakumar, B. C. Koner, R. Vinayagamoorthi et al., “Activation of NF-κB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: possible role of oxidative stress,” Immunobiology, vol. 213, no. 5, pp. 409–415, 2008.
[21]  B. Makay, O. Makay, C. Yenisey et al., “The interaction of oxidative stress response with cytokines in the thyrotoxic ratpIs there a link?” Mediators of Inflammation, vol. 2009, Article ID 391682, 7 pages, 2009.
[22]  V. B. Vrca, F. Skreb, I. Cepelak, Z. Romic, and L. Mayer, “Supplementation with antioxidants in the treatment of Graves' disease; the effect on glutathione peroxidase activity and concentration of selenium,” Clinica Chimica Acta, vol. 341, no. 1-2, pp. 55–63, 2004.
[23]  J. Bednarek, H. Wysocki, and J. Sowiński, “Oxidative stress peripheral parameters in Graves' disease: the effect of methimazole treatment in patients with and without infiltrative ophthalmopathy,” Clinical Biochemistry, vol. 38, no. 1, pp. 13–18, 2005.
[24]  M. Messarah, A. Boumendjel, A. Chouabia et al., “Influence of thyroid dysfunction on liver lipid peroxidation and antioxidant status in experimental rats,” Experimental and Toxicologic Pathology, vol. 62, no. 3, pp. 301–310, 2010.
[25]  S. Chattopadhyay, D. K. Sahoo, A. Roy, L. Samanta, and G. B. N. Chainy, “Thiol redox status critically influences mitochondrial response to thyroid hormone-induced hepatic oxidative injury: a temporal analysis,” Cell Biochemistry and Function, vol. 28, no. 2, pp. 126–134, 2010.
[26]  D. K. Sahoo, A. Roy, S. Bhanja, and G. B. N. Chainy, “Experimental hyperthyroidism-induced oxidative stress and impairment of antioxidant defence system in rat testis,” Indian Journal of Experimental Biology, vol. 43, no. 11, pp. 1058–1067, 2005.
[27]  A. Zamoner, K. P. Barreto, D. W. Filho et al., “Hyperthyroidism in the developing rat testis is associated with oxidative stress and hyperphosphorylated vimentin accumulation,” Molecular and Cellular Endocrinology, vol. 267, no. 1-2, pp. 116–126, 2007.
[28]  R. Mogulkoc, A. K. Baltaci, E. Oztekin, A. Ozturk, and A. Sivrikaya, “Short-term thyroxine administration leads to lipid peroxidation in renal and testicular tissues of rats with hypothyroidism,” Acta Biologica Hungarica, vol. 56, no. 3-4, pp. 225–232, 2005.
[29]  K. G. Moulakakis, M. V. Poulakou, K. I. Paraskevas et al., “Hyperthyroidism is associated with increased aortic oxidative DNA damage in a rat model,” In Vivo, vol. 21, no. 6, pp. 1021–1026, 2007.
[30]  A. S. R. Araujo, M. F. M. Ribeiro, A. Enzveiler et al., “Myocardial antioxidant enzyme activities and concentration and glutathione metabolism in experimental hyperthyroidism,” Molecular and Cellular Endocrinology, vol. 249, no. 1-2, pp. 133–139, 2006.
[31]  A. S. R. Araujo, P. Schenkel, A. T. Enzveiler et al., “The role of redox signaling in cardiac hypertrophy induced by experimental hyperthyroidism,” Journal of Molecular Endocrinology, vol. 41, no. 6, pp. 423–430, 2008.
[32]  A. S. Araujo, T. Fernandes, M. F. Ribeiro, N. Khaper, and A. Belló-Klein, “Redox regulation of myocardial Erk 1/2 phosphorylation in experimental hyperthyroidism: role of thioredoxin-peroxiredoxin system,” Journal of Cardiovascular Pharmacology, vol. 56, no. 5, pp. 513–517, 2010.
[33]  C. Pantos, V. Malliopoulou, I. Mourouzis et al., “Hyperthyroid hearts display a phenotype of cardioprotection against ischemic stress: a possible involvement of heat shock protein 70,” Hormone and Metabolic Research, vol. 38, no. 5, pp. 308–313, 2006.
[34]  T. Yamada, T. Mishima, M. Sakamoto, M. Sugiyama, S. Matsunaga, and M. Wada, “Oxidation of myosin heavy chain and reduction in force production in hyperthyroid rat soleus,” Journal of Applied Physiology, vol. 100, no. 5, pp. 1520–1526, 2006.
[35]  A. K. Eckstein, K. T. Johnson, M. Thanos, J. Esser, and M. Ludgate, “Current insights into the pathogenesis of Graves' orbitopathy,” Hormone and Metabolic Research, vol. 41, no. 6, pp. 456–464, 2009.
[36]  H. B. Burch, S. Lahiri, R. S. Bahn, and S. Barnes, “Superoxide radical production stimulates retroocular fibroblast proliferation in Graves' ophthalmopathy,” Experimental Eye Research, vol. 65, no. 2, pp. 311–316, 1997.
[37]  Y. Hiromatsu, D. Yang, I. Miyake et al., “Nicotinamide decreases cytokine-induced activation of orbital fibroblasts from patients with thyroid-associated ophthalmopathy,” The Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 1, pp. 121–124, 1998.
[38]  A. Hondur, O. Konuk, A. S. Dincel, A. Bilgihan, M. Unal, and B. Hasanreisoglu, “Oxidative stress and antioxidant activity in orbital fibroadipose tissue in Graves' ophthalmopathy,” Current Eye Research, vol. 33, no. 5-6, pp. 421–427, 2008.
[39]  R. Lu, P. Wang, L. Wartofsky et al., “Oxygen free radicals in interleukin-1β-induced glycosaminoglycan production by retro-ocular fibroblasts from normal subjects and Graves' ophthalmopathy patients,” Thyroid, vol. 9, no. 3, pp. 297–303, 1999.
[40]  M. F. Tsan and B. Gao, “Heat shock proteins and immune system,” Journal of Leukocyte Biology, vol. 85, no. 6, pp. 905–910, 2009.
[41]  J. H. H. Williams and H. E. Ireland, “Sensing danger—hsp72 and hmgb1 as candidate signals,” Journal of Leukocyte Biology, vol. 83, no. 3, pp. 489–492, 2008.
[42]  A. E. Heufelder, B. E. Wenzel, and R. S. Bahn, “Methimazole and propylthiouracil inhibit the oxygen free radical-induced expression of a 72 kilodalton heat shock protein in Graves' retroocular fibroblasts,” The Journal of Clinical Endocrinology and Metabolism, vol. 74, no. 4, pp. 737–742, 1992.
[43]  C. C. Tsai, S. B. Wu, C. Y. Cheng et al., “Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves ophthalmopathy: evidence that oxidative stress has a role in this disorder,” Eye, vol. 24, no. 9, pp. 1520–1525, 2010.
[44]  C. C. Tsai, C. Y. Cheng, C. Y. Liu et al., “Oxidative stress in patients with Graves' ophthalmopathy: relationship between oxidative DNA damage and clinical evolution,” Eye, vol. 23, no. 8, pp. 1725–1730, 2009.
[45]  J. Thornton, S. P. Kelly, R. A. Harrison, and R. Edwards, “Cigarette smoking and thyroid eye disease: a systematic review,” Eye, vol. 21, no. 9, pp. 1135–1145, 2007.
[46]  S. Tanrikulu, S. Do?ru-Abbaso?lu, A. ?zderya et al., “The 8-oxoguanine DNA N-glycosylase 1 (hOGG1) Ser326Cys variant affects the susceptibility to Graves' disease,” Cell Biochemistry and Function, vol. 29, no. 3, pp. 244–248, 2011.
[47]  C. C. Tsai, S. C. Kao, C. Y. Cheng et al., “Oxidative stress change by systemic corticosteroid treatment among patients having active graves ophthalmopathy,” Archives of Ophthalmology, vol. 125, no. 12, pp. 1652–1656, 2007.
[48]  E. Akarsu, H. Buyukhatipoglu, ?. Aktaran, and N. Kurtul, “Effects of pulse methylprednisolone and oral methylprednisolone treatments on serum levels of oxidative stress markers in Graves' ophthalmopathy,” Clinical Endocrinology, vol. 74, no. 1, pp. 118–124, 2011.
[49]  E. A. Bouzas, P. Karadimas, G. Mastorakos, and D. A. Koutras, “Antioxidant agents in the treatment of Graves' ophthalmopathy,” American Journal of Ophthalmology, vol. 129, no. 5, pp. 618–622, 2000.
[50]  M. P. Rayman, “The importance of selenium to human health,” The Lancet, vol. 356, no. 9225, pp. 233–241, 2000.
[51]  L. H. Duntas, “Selenium and the thyroid: a close-knit connection,” The Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 12, pp. 5180–5188, 2010.
[52]  C. Marcocci, G. J. Kahaly, G. E. Krassas et al., “Selenium and the course of mild Graves' orbitopathy,” The New England Journal of Medicine, vol. 364, no. 20, pp. 1920–1931, 2011.
[53]  L. Bartalena, M. L. Tanda, E. Piantanida, and A. Lai, “Oxidative stress and Graves' ophthalmopathy: in vitro studies and therapeutic implications,” BioFactors, vol. 19, no. 3-4, pp. 155–163, 2003.


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