Advertisement

Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves’ disease influencing the therapeutic efficacy

  • Ildikó MolnárEmail author
  • József A. Szentmiklósi
  • Rudolf Gesztelyi
  • Éva Somogyiné-Vári
Original Article

Abstract

Graves’ disease is an organ-specific autoimmune disease with hyperthyroidism, diffuse goiter and autoantibodies against TSH receptor, thyroid peroxidase (TPO) and/or thyroglobulin (Tg). Graves’ hyperthyroidism is characterized by T3 dominance due to the conversion of T4 into T3 through type 1 and 2 deiodinase enzymes (DIO1, DIO2). Methimazole (MMI) and propylthiouracil (PTU) therapies inhibit thyroid hormone synthesis blocking the activity of deiodinase and TPO enzymes. The study investigated the occurrence of autoantibodies against DIO2 peptides (cys- and hom-peptides) with the effect of antithyroid drugs on their frequencies in 78 patients with Graves’ disease and 30 controls. In hyperthyroidism, the presence of DIO2 peptide antibodies was as follows: 20 and 11 cases out of 51 for cys- and hom-peptide antibodies, respectively, of whom 8 cases possessed antibodies against both peptides. Antithyroid drugs differently influenced their frequencies, which were greater in PTU than in MMI (3/6 vs 13/45 cases, P < 0.016 for cys- and 0/6 vs 2/45 cases for hom-peptide antibodies). Antibodies against both peptides demonstrated more reduced levels of anti-TPO (P < 0.003) and anti-Tg antibodies (P < 0.002) compared with those without peptide antibodies. PTU compared with MMI increased the levels of TSH receptor antibodies (32.5 UI/l vs 2.68 IU/l, P < 0.009). MMI treatment led to more reduced FT3 levels and FT3/FT4 ratios in hyperthyroid Graves’ ophthalmopathy (P < 0.028 for FT3, P < 0.007 for FT3/FT4 ratio). In conclusion, the presence of DIO2 peptide antibodies is connected to Graves’ hyperthyroidism influencing the levels of antibodies against TPO, Tg and TSH receptor, as well as the therapeutic efficacy of antithyroid drugs.

Keywords

Antithyroid drugs Hyperthyroidism Graves’ disease Antithyroid antibodies Type 2 deiodinase 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standard of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study, formal consent was not required.

References

  1. 1.
    Fröhlich E, Wahl R. Thyroid autoimmunity: role of anti-thyroid antibodies in thyroid and extra-thyroidal disease. Front Immunol. 2017;8:1–15.CrossRefGoogle Scholar
  2. 2.
    Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. IOVS. 2014;55:1735–48.Google Scholar
  3. 3.
    Ikhan FA, Al-Jameil N, Khan MF, Al-Rashid M, Tabassum F. Thyroid dysfunction: an autoimmune aspect. Int J Clin Exp Med. 2015;8:6677–81.Google Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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;92:2149–56.CrossRefGoogle Scholar
  6. 6.
    Salvatore D, Bartha T, Harney JW, Larsen PR. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology. 1996;137:3308–15.CrossRefGoogle Scholar
  7. 7.
    Roy G, Mugesh G. Bioinorganic chemistry in thyroid gland: effect of antithyroid drugs on peroxidase-catalyzed oxidation and iodination reactions. Bioinorg Chem Appl. 2006.  https://doi.org/10.1155/BCA/2006/23214.Google Scholar
  8. 8.
    Ishi R, Imaizumi M, Ide A, et al. A long-term follow-up of serum myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves’ disease treated with propylthiouracil. Endocr J. 2010;57:73–9.CrossRefGoogle Scholar
  9. 9.
    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;44:203–4.CrossRefGoogle Scholar
  10. 10.
    Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1997;47:9–14.CrossRefGoogle Scholar
  11. 11.
    Molnár I, Szombathy Z, Kovács I, Szentmiklósi AJ. Immunohistochemical studies using immunized guinea pig sera with features of anti-human thyroid, eye and skeletal antibody and Graves’ sera. J Clin Immunol. 2007;27:172–80.CrossRefGoogle Scholar
  12. 12.
    Chrousos GP. The stress response and immune function: clinical implications. The 1999 Novera H. Spector lecture. Ann NY Acad Sci. 2000;917:38–67.CrossRefGoogle Scholar
  13. 13.
    Manna D, Roy G, Mugesh G. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action. Acc Chem Res. 2013;46:2705–15.CrossRefGoogle Scholar
  14. 14.
    Roy G, Mugesh G. Anti-thyroid drugs and thyroid hormone synthesis: effect of methimazole derivatives on peroxidase-catalyzed reactions. J Am Chem Soc. 2005;127:15207–17.CrossRefGoogle Scholar
  15. 15.
    Taurog A, Dorris ML, Hu WX, Guziec FS. The selenium analog of 6-propylthiouracil. Measurement of its inhibitory effect on type I iodothyronine deiodinase and of its antithyroid activity. Biochem Pharmacol. 1995;49:701–9.CrossRefGoogle Scholar
  16. 16.
    Nagasaka A, Hidaka H. Effect of antithyroid agents 6-propyl-2-thiouracil and 1-methyl-2-mercaptoimidazole on human thyroid iodine peroxidase. J Clin Endocrinol Metab. 1976;43:152–8.CrossRefGoogle Scholar
  17. 17.
    Lian G, Ding L, Chen M, Liu Z, Zhao D, Ni J. Preparation and properties of a selenium-containing catalytic antibody as type 1 deiodinase mimic. J Biol Chem. 2001;276:28037–41.CrossRefGoogle Scholar
  18. 18.
    Ferreira ACF, Cardoso LC, Rosenthal D, Carvalho DP. Thyroid Ca2+/NADPH-dependent H2O2 generation is partially inhibited by propylthiouracil and methimazole. Eur J Biochem. 2003;270:2363–8.CrossRefGoogle Scholar
  19. 19.
    Hosoi Y, Murakami M, Mizuma H, Ogiwara T, Imamura M, Masatomo M. Expression and regulation of type II iodothyronine deiodinase in cultured human skeletal muscle cells. J Clin Endocrinol Metab. 1999;84:3293–300.Google Scholar
  20. 20.
    Kashiwai T, Hidaka Y, Takano T, et al. Practical treatment with minimum maintenance dose of antithyroid drugs for prediction of remission in Graves’ disease. Endocr J. 2003;50:45–9.CrossRefGoogle Scholar
  21. 21.
    Lantz M, Planck T, Asman P, Hallengren B. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Exp Clin Endocrinol Diabetes. 2014;122:113–7.CrossRefGoogle Scholar
  22. 22.
    Molnár I, Balazs C, Szegedi G, Sipka S. Inhibition of type 2,5′-deiodinase by tumor necrosis factor alpha, interleukin-6 and interferon gamma in human thyroid tissue. Immunol Lett. 2002;80:3–7.CrossRefGoogle Scholar
  23. 23.
    Molnár I, Balázs C. High circulating IL-6 in Graves’ ophthalmopathy. Autoimmunity. 1997;25:91–6.CrossRefGoogle Scholar
  24. 24.
    Nakahar R, Tsunekawa K, Yabe S, et al. Association of antipituitary antibody and type 2 iodothyronine deiodinase antibody in patients with autoimmune thyroid disease. Endocr J. 2005;52:691–9.CrossRefGoogle Scholar
  25. 25.
    Guo TW, Zhang FC, Yang MS, et al. Positive association of DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China. J Med Genet. 2004;41:585–90.CrossRefGoogle Scholar
  26. 26.
    Grarup N, Andersen MK, Andreasen CH, et al. Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 danish white subjects. J Clin Endocrinol Metab. 2007;92:363–6.CrossRefGoogle Scholar
  27. 27.
    Hoftijzer HC, Heemstra KA, Visser TJ, et al. The type deiodinase ORFa-Gly3Asp polymorphism (rs12885300) influences the set point of the hypothalamus–pituitary–thyroid axis in patients treated for differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2011;96:E1527–33.CrossRefGoogle Scholar
  28. 28.
    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002;23:38–89.CrossRefGoogle Scholar
  29. 29.
    Abuid J, Larsen PR. Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Clin Investig. 1974;54:201–8.CrossRefGoogle Scholar
  30. 30.
    Schweizer U, Steegborn C. New insights into the structure and mechanism of iodothyronine deiodinases. J Mol Endocrinol. 2015;55:R37–52.CrossRefGoogle Scholar
  31. 31.
    Rijntjes E, Scholz PM, Mugesh G, Köhrle J. Se- and S-based thiouracil and methimazole analogues exert different inhibitory mechanisms on type 1 and type 2 deiodinases. Eur Thyroid J. 2013;2:252–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.ImmunoendocrinologyEndoMedDebrecenHungary
  2. 2.Department of Pharmacology and PharmacotherapyUniversity of DebrecenDebrecenHungary

Personalised recommendations