Hyperthyroidism in Patients with Graves’ Ophthalmopathy, and Thyroidal, Skeletal and Eye Muscle Specific Type 2 Deiodinase Enzyme Activities

Abstract

Graves’ ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T₃ levels than T₄ due to deiodinase enzymes.

The effect of Graves’ patient’s sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with ¹²⁵I-T₄ substrate, while thyroid hormone and antibody levels with immunoassays.

In Graves’ ophthalmopathy, sera with elevated FT₄ or FT₃ levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, P<0.006). Effect of sera with increased FT₃ levels demonstrated also reduced DII activities in patients with Graves’ ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, P<0.006 for thyroidal fraction, 4.07±2.72 vs 29.22±15.46 pmol/mg/min, P<0.004 for skeletal muscle, 5.3±3.47 vs 37.87±18.82 pmol/mg/min, P<0.003 for eye muscle). Hyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves’ ophthalmopathy.

In summary, the actions of hyperthyroid sera derived from patients with Graves’ disease were tested on tissue-specific DII activities. Elevated FT₄ level-induced DII inactivation is present in Graves’ ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves’ ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT₄ levels.

Key words

type 2 5’-deiodinase - Graves’ ophthalmopathy - hyperthyroidism - TSH receptor antibodies - thyroid peroxidase antibodies.

• References

• 1 Drigo RA, Fonseca TL, Werneck-de-Castro JPS. et al. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 2013; 1830: 3956-3964
• 2 St Germain DL. GaltonVA Hernandez A. Minireview: Defining the roles of the iodothyronine deiodinases: Current concepts and challenges. Endocrinology 2009; 150: 1097-1107
• 3 Williams GR, Bassett JHD. Deiodinases: The balance of thyroid hormones. Local control of thyroid hormone action: Role of type 2 deiodinase. J Endocrinol 2011; 209: 261-272
• 4 Baqui MM, Gereben B, Harney JW. et al. Distinct subcellular localization of transiently expressed types 1 and 2 iodothyronine deiodinases as determined by immunofluorescence confocal microscopy. Endocrinol 2000; 141: 4309-4312
• 5 Curcio-Morelli C, Gereben B, Zavacki AM. et al. In vivo dimerization of types 1, 2, and 3 iodothyronine selenodeiodinases. Endocrinol 2003; 144: 937-946
• 6 Dentice M, Salvatore D. Deiodinases: the balance of thyroid hormone. Local impact of thyroid hormone inactivation. J Endocrinol 2011; 209: 273-282
• 7 Laurberg P, Vestergaard H, Nielsen S. et al. Sources of circulating 3,5,3’-triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J Clin Endocrinol Metab 2007; 92: 2149-2156
• 8 Maia AL, Goemann IM, Meyer ELS. et al. Deiodinases: The balance of thyroid hormone. Type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol 2011; 209: 282-297
• 9 Gereben B, Goncalves C, Harney JW. et al. Selective proteolysis of human type 2 deiodinase: A novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol 2000; 14: 1697-1708
• 10 Steinsapir J, Bianco AC, Buettner C. et al. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center. Endocrinology 2000; 141: 1127-1135
• 11 Williams GR, Bassett JHD. Deiodinases: The balance of thyroid hormone. Local control of thyroid hormone action: Role of type 2 deiodinase. J Endocrinol 2011; 209: 261-272
• 12 Ogiwara T, Araki O, Morimura T. et al. A novel mechanism fot the inhibition of type 2 iodothyronine deiodinase by tumor necrosis factor α: Involvement of proteasomal degradation. Endocrine J 2013; 60: 1035-1045
• 13 Hiroi Y, Kim HH, Ying H. et al. Rapid nongenomic actions of thyroid hormone. PNAS 2006; 103: 14104-14109
• 14 Aoki T, Tsunekawa K, Araki O. et al. Type 2 iodothyronine deiodinase activity is required for rapid stimulation of PI3K by thyroxine in human umbilical vein endothelial cells. Endocrinology 2015; 156: 4312-4324
• 15 Werner SC. Modification of classification of eye changes of Graves’ disease: Recommendations of the Ad Hoc Committee of American Thyroid Association. J Clin Endocrinol Metab 1977; 44: 2034
• 16 Mourits MP, Prummel MF, Wiersinga WM. et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf) 1997; 47: 9-14
• 17 Lowry OH, Rosenbrough NJ, Farr AL. et al. Protein measurement with the polyphenol reagent. J Biol Chem 1951; 193: 265-275
• 18 Molnár I, Czirják L. Euthyroid sick syndrome and inhibitory effect of sera on the activity of thyroid 5’-deiodinase in systemic sclerosis. Clin Exp Rheumatol 2000; 18: 719-724
• 19 Taurog A, Lothrop ML, Estabrook RW. Improvements in the isolation procedure for thyroid peroxidase: Nature of the heme prosthetic group. Arch Biochem Biophys 1970; 12: 221-224
• 20 Hamada N, Grimm C, Mori H. et al. Identification of a thyroid microsomal antigen by Western blot and immunoprecipitation. J Clin Endocrinol Metab 1985; 61: 120-128
• 21 Kaczur V, Vereb G, Molnár I. et al. Effect of anti-thyroid peroxidase (TPO) antibodies on TPO activity measured by chemiluminescence assay. Clin Chemistry 1997; 43: 1392-1396
• 22 Ito M, Toyoda N, Nomura E. et al. Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3’-triiodothyronine-predominant Graves’ disease. Eur J Endocrinol 2011; 164: 95-100
• 23 Abuid J, Larsen PR. Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Clin Invest 1974; 54: 201-208
• 24 Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. J Clin Invest 1975; 55: 224-229
• 25 Lum SMC, Nicoloff JT, Spencer CA. et al. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984; 73: 570-575
• 26 Hosoi Y, Murakami M, Mizuma H. et al. Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells. J Clin Endocrinol Metab 1999; 84: 3293-3300
• 27 Maia AL, Kim BW, Huang SA. et al. Type 2 iodothyronine deiodinase is the major source of plasma T₃ in euthyroid humans. J Clin Invest 2005; 115: 2524-2533
• 28 Molnár I, Szombathy Z, Kovács I. et al. Immunohistochemical studies using immunized guinea pig sera with features of anti-human thyroid, eye and skeletal antibody and Graves’sera. J Clin Immunol 2007; 27: 172-180
• 29 Drigo RA, Bianco AC. Type 2 deiodinase at the crossroads of thyroid hormone action. Int J Biochem Cell Biol 2011; 43: 1432-1441
• 30 Mizuma H, Murakami M, Mori M. Thyroid hormone activation in human vascular smooth muscle cells. Expression of type II iodothyronine deiodinase. Circ Res 2001; 88: 313-318
• 31 Murakami M, Araki O, Hosoi Y. et al. Expression and regulation of type II iodothyronine deiodinase in human thyroid gland. Endocrinology 2001; 142: 2961-2967
• 32 de Castro JPW, Fonseca TL, Ueta CB. et al. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 2015; 125: 769-781
• 33 Cettour-Rose P, Visser TJ, Burger AG. et al. Inhibition of pituitary type 2 deiodinase by reserve triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats. Eur J Endocrinol 2005; 153: 429-434
• 34 Fekete C, Lechan RM. Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons; role of neuronal afferents and type 2 deiodinase. Front Neuroendocrinol 2007; 28: 97-114
• 35 Schneider MJ, Fiering SN, Pallud SE. et al. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T₄ . Mol Endocrinol 2001; 15: 2137-2148
• 36 Rosene ML, Wittman G, Drigo RA. et al. Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. Endocrinology 2010; 151: 5961-5970
• 37 Fonseca TL, Correa-Medina M, Campos MPO. et al. Coordination of hypothalamic and pituitary T3 production regulates TSH expression. J Clin Invest 2013; 123: 1492-1500
• 38 Luongo C, Martin C, Vella K. et al. The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism. Endocrinology 2015; 156: 745-754
• 39 Weetman AP, Shepherdley CA, Mansell P. et al. Thyroid over-expression of type 1 and 2 deiodinase may account for the syndrome of low thyroxine and increasing triiodothyronine during propylthiouracil treatment. Eur J Endocrinol 2003; 149: 443-447
• 40 Wassen FWJS, Klootwlik W, Kaptein E. et al. Charateristics and thyroid state-dependent regulation of iodothyronine deiodinases in pigs. Endocrinology 2004; 145: 4251-4263
• 41 Toyoda N, Nishikawa M, Horimoto M. et al. Synergistic effetc of thyroid hormone and thyrotropin on iodothyronine 5’-deiodinase in FRTL-5 rat thyroid cells. Endocrinology 1990; 127: 1199-1205