Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?

Abstract

The universal applicability of levothyroxine (LT4) monotherapy for the treatment of hypothyroidism has been questioned in recent years. Indeed, it is now clear that about 10–15% of LT4-treated hypothyroid patients are dissatisfied with their treatment. It is plausible that this subset of hypothyroid patients may need T3 + T4 combined therapy to restore peripheral euthyroidism. To address this issue, many clinical trials have investigated the effect of T3 + T4 combinations versus standard LT4-based therapy. However, to date, results have been inconclusive, mainly due to the lack of markers that identify candidates for combination therapy. A breakthrough in this field came with the recent finding that several single-nucleotide polymorphisms in the deiodinase genes are associated with the persistence of hypothyroid symptoms in biochemically euthyroid LT4-treated patients, and are thus markers of candidates for combination therapy. In addition, whole-genome association studies are expanding our knowledge of other genes of the thyroid hormone (TH) pathway that affect serum TH levels. To target the right population for the T3 + T4 combined therapy, the next step is to translate these new findings into prospective trials. Hopefully, this will pave the way to personalized therapy for each hypothyroid patient.

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References

  1. 1.

    J. Jonklaas, A.C. Bianco, A.J. Bauer, K.D. Burman, A.R. Cappola, F.S. Celi, D.S. Cooper, B.W. Kim, R.P. Peeters, M.S. Rosenthal, A.M. Sawka, Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 24, 1670–1751 (2014). https://doi.org/10.1089/thy.2014.0028

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    C. Luongo, M. Dentice, D. Salvatore, Deiodinases and their intricate role in thyroid hormone homeostasis. Nat. Rev. Endocrinol. 15, 479–488 (2019). https://doi.org/10.1038/s41574-019-0218-2

    Article  PubMed  Google Scholar 

  3. 3.

    S.J. Peterson, A.R. Cappola, M.R. Castro, C.M. Dayan, A.P. Farwell, J.V. Hennessey, P.A. Kopp, D.S. Ross, M.H. Samuels, A.M. Sawka, P.N. Taylor, J. Jonklaas, A.C. Bianco, An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. 28, 707–721 (2018). https://doi.org/10.1089/thy.2017.0681

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    P.N. Taylor, D. Albrecht, A. Scholz, G. Gutierrez-Buey, J.H. Lazarus, C.M. Dayan, O.E. Okosieme, Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018). https://doi.org/10.1038/nrendo.2018.18

    Article  PubMed  Google Scholar 

  5. 5.

    J. Jonklaas, B. Davidson, S. Bhagat, S.J. Soldin, Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 299, 769–777 (2008). https://doi.org/10.1001/jama.299.7.769

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    D. Gullo, A. Latina, F. Frasca, R. Le Moli, G. Pellegriti, R. Vigneri, Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE. 6, e22552 (2011). https://doi.org/10.1371/journal.pone.0022552

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    S.J. Peterson, E. McAninch, A.C. Bianco, Is a normal TSH synonymous with “Euthyroidism” in levothyroxine monotherapy? J. Clin. Endocrinol. Metab. 101, 4964–4973 (2016). https://doi.org/10.1210/jc.2016-2660

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    M. Ito, A. Miyauchi, M. Hisakado, W. Yoshioka, A. Ide, T. Kudo, E. Nishihara, M. Kihara, Y. Ito, K. Kobayashi, A. Miya, S. Fukata, M. Nishikawa, H. Nakamura, N. Amino, Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Thyroid. 27, 484–490 (2017). https://doi.org/10.1089/thy.2016.0426

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    E. McAninch, K.B. Rajan, C.H. Miller, A.C. Bianco, Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 103, 4533–4542 (2018). https://doi.org/10.1210/jc.2018-01361

    Article  PubMed Central  Google Scholar 

  10. 10.

    A.C. Bianco, B.S. Kim, Pathophysiological relevance of deiodinase polymorphism. Curr. Opin. Endocrinol. Diabetes Obes. 25, 341–346 (2018). https://doi.org/10.1097/MED.0000000000000428

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    A.C. Bianco, D. Salvatore, B. Gereben, M.J. Berry, P.R. Larsen, Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr. Rev. 23, 38–89 (2002). https://doi.org/10.1210/edrv.23.1.0455

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    V. Panicker, C. Cluett, B. Shields, A. Murray, K.S. Parnell, J.R.B. Perry, M.N. Weedon, A. Singleton, D. Hernandez, J. Evans, C. Durant, L. Ferrucci, D. Melzer, P. Saravanan, T.J. Visser, G. Ceresini, A.T. Hattersley, B. Vaidya, C.M. Dayan, T.M. Frayling, A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J. Clin. Endocrinol. Metab. 93, 3075–3081 (2008). https://doi.org/10.1210/jc.2008-0397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    A. Bunevicius, E.R. Laws, A. Saudargiene, A. Tamasauskas, G. Iervasi, V. Deltuva, T.R. Smith, R. Bunevicius, Common genetic variations of deiodinase genes and prognosis of brain tumor patients. Endocrine. 66, 563–572 (2019). https://doi.org/10.1007/s12020-019-02016-6

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    R.P. Peeters, H. van Toor, W. Klootwijk, Y.B. de Rijke, G.G.J.M. Kuiper, A.G. Uitterlinden, T.J. Visser, Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J. Clin. Endocrinol. Metab. 88, 2880–2888 (2003). https://doi.org/10.1210/jc.2002-021592

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    F.J. de Jong, R.P. Peeters, T. den Heijer, W.M. van der Deure, A. Hofman, A.G. Uitterlinden, T.J. Visser, M.M.B. Breteler, The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. J. Clin. Endocrinol. Metab. 92, 636–640 (2007). https://doi.org/10.1210/jc.2006-1331

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    M. Medici, W.M. van der Deure, M. Verbiest, S.H. Vermeulen, P.S. Hansen, L.A. Kiemeney, A.R.M.M. Hermus, M.M. Breteler, A. Hofman, L. Hegedüs, K. Ohm Kyvik, M. den Heijer, A.G. Uitterlinden, T.J. Visser, R.P. Peeters, A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur. J. Endocrinol. 164, 781–788 (2011). https://doi.org/10.1530/EJE-10-1130

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    R.P. Peeters, A.W. van den Beld, H. Attalki, H. van Toor, Y.B. de Rijke, G.G.J.M. Kuiper, S.W.J. Lamberts, J.A.M.J.L. Janssen, A.G. Uitterlinden, T.J. Visser, A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am. J. Physiol. Endocrinol. Metab. 289, E75–E81 (2005). https://doi.org/10.1152/ajpendo.00571.2004

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    H.C. Hoftijzer, K.A. Heemstra, T.J. Visser, S. le Cessie, R.P. Peeters, E.P.M. Corssmit, J.W.A. Smit, The type 2 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. 96, E1527–E1533 (2011). https://doi.org/10.1210/jc.2011-0235

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    M.Y. Peltsverger, P.W. Butler, A.T. Alberobello, S. Smith, Y. Guevara, O.M. Dubaz, J.A. Luzon, J. Linderman, F.S. Celi, The K258A/G (SNP rs12885300) polymorphism of the human type 2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH. Eur. J. Endocrinol. 166, 839–845 (2012). https://doi.org/10.1530/EJE-11-1073

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    M.G. Castagna, M. Dentice, S. Cantara, R. Ambrosio, F. Maino, T. Porcelli, C. Marzocchi, C. Garbi, F. Pacini, D. Salvatore, DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient patients. J. Clin. Endocrinol. Metab. 102, 1623–1630 (2017). https://doi.org/10.1210/jc.2016-2587

    Article  PubMed  Google Scholar 

  21. 21.

    J.M. Dora, W.E. Machado, J. Rheinheimer, D. Crispim, A.L. Maia, Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis. Eur. J. Endocrinol. 163, 427–434 (2010). https://doi.org/10.1530/EJE-10-0419

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    N. Grarup, M.K. Andersen, C.H. Andreasen, A. Albrechtsen, K. Borch-Johnsen, T. Jørgensen, J. Auwerx, O. Schmitz, T. Hansen, O. Pedersen, Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects. J. Clin. Endocrinol. Metab. 92, 363–366 (2007). https://doi.org/10.1210/jc.2006-1958

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    H. Verloop, O.M. Dekkers, R.P. Peeters, J.W. Schoones, J.W.A. Smit, Genetic variation in deiodinases: a systematic review of potential clinical effects in humans. Eur. J. Endocrinol. 171, R123–R135 (2014). https://doi.org/10.1530/EJE-14-0302

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    M. Torlontano, C. Durante, I. Torrente, U. Crocetti, G. Augello, G. Ronga, T. Montesano, L. Travascio, A. Verrienti, R. Bruno, S. Santini, P. D’Arcangelo, B. Dallapiccola, S. Filetti, V. Trischitta, Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients. J. Clin. Endocrinol. Metab. 93, 910–913 (2008). https://doi.org/10.1210/jc.2007-1067

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    S. Jo, T.L. Fonseca, B.M.L.C. Bocco, G.W. Fernandes, E.A. McAninch, A.P. Bolin, R.R. Da Conceição, J.P. Werneck-de-Castro, D.L. Ignacio, P. Egri, D. Németh, C. Fekete, M.M. Bernardi, V.D. Leitch, N.S. Mannan, K.F. Curry, N.C. Butterfield, J.H.D. Bassett, G.R. Williams, B. Gereben, M.O. Ribeiro, A.C. Bianco, Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain. J. Clin. Investig. 129, 230–245 (2019). https://doi.org/10.1172/JCI123176

    Article  PubMed  Google Scholar 

  26. 26.

    E. Porcu, M. Medici, G. Pistis, C.B. Volpato, S.G. Wilson, A.R. Cappola, et al., A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLOS Genet. 9, e1003266 (2013). https://doi.org/10.1371/journal.pgen.1003266

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    A. Teumer, L. Chaker, S. Groeneweg, Y. Li, C. Di Munno, C. Barbieri et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat. Comm. 9, 4455 (2018). https://doi.org/10.1038/s41467-018-06356-1

    CAS  Article  Google Scholar 

  28. 28.

    G.L. Roef, E.R. Rietzschel, T. De Meyer, S. Bekaert, M.L. De Buyzere, C. Van Daele, K. Toye, J.M. Kaufman, Y.E. Taes, Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones. Clin. Chim. Acta. 425, 227–232 (2013). https://doi.org/10.1016/j.cca.2013.08.017

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    E. Park, J. Jung, O. Araki, K. Tsunekawa, S.Y. Park, J. Kim, M. Murakami, S.Y. Jeong, S. Lee, Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism. Sci. Rep. 8, 10090 (2018). https://doi.org/10.1038/s41598-018-28480-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    S. Cantara, C. Ricci, F. Maino, C. Marzocchi, F. Pacini, M.G. Castagna, Variants in MCT10 protein do not affect FT3 levels in athyreotic patients. Endocrine. 66, 551–556 (2019). https://doi.org/10.1007/s12020-019-02001-z

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    A. Carlé, J. Faber, R. Steffensen, P. Laurberg, B. Nygaard, Hypothyroid patients encoding combined MCT10 and DIO2 gene polymorphisms may prefer L-T3 + L-T4 combination treatment—data using a blind, randomized, clinical study. Eur. Thyroid J. 6, 143–151 (2017). https://doi.org/10.1159/000469709

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Jean Ann Gilder (Scientific Communication srl., Naples, Italy) for writing assistance.

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TP wrote the paper and DS wrote and reviewed the paper.

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Correspondence to Tommaso Porcelli.

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Porcelli, T., Salvatore, D. Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?. Endocrine (2020). https://doi.org/10.1007/s12020-020-02391-5

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Keywords

  • Hypothyroidism
  • Personalized therapy
  • SNPs
  • Deiodinases
  • TH pathway