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  • Review Article
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Scope and limitations of iodothyronine deiodinases in hypothyroidism

Nature Reviews Endocrinology volume 11, pages 642–652 (2015)Cite this article

Subjects

Key Points

  • Levothyroxine monotherapy at doses that normalize serum levels of TSH does not universally restore parameters of thyroid hormone levels for patients with hypothyroidism

  • The iodothyronine deiodinases provide a cell-specific, prereceptor mechanism that controls thyroid-hormone signalling

  • Localized thyroid-hormone signalling has a critical role in different areas of the brain, as mediated by thyroid hormone transporters and the iodothyronine deiodinases

  • DIO2 ubiquitination induced by tetraiodothyronine (T4) normally decreases tri-iodothyronine (T3) production, but not in the hypothalamus

  • The levothyroxine dose that normalizes serum levels of TSH in an animal model is lower than the dose that normalizes serum levels of T3, which explains the increased serum T4 to T3 ratio observed in patients treated with levothyroxine

  • If patients carrying the Thr92AlaD2 polymorphism derive benefit from combination therapy with levothyroxine and liothyronine, then genotyping for this single nucleotide polymorphism might become a component of the management of hypothyroidism

Abstract

The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition.

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Figure 1: Iodothyronine deiodinases modulate thyroid-hormone signalling in T3 target cells.
Figure 2: T4-induced DIO2 ubiquitination in thyroid hormone homeostasis.

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Acknowledgements

B.G. is supported by the Hungarian Brain Research Program and Hungarian Scientific Research Fund (OTKA 109415). M.O.R. is supported by CAPES and FAPESP. A.C.B. is supported by the NIDDK.

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Authors and Affiliations

  1. Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony Street 43, Budapest, H-1083, Hungary

    Balázs Gereben

  2. Division of Endocrinology and Metabolism, Rush University Medical Center, 212 Cohn Building, 1735 West Harrison Street, Chicago, 60612, IL, USA

    Elizabeth A. McAninch & Antonio C. Bianco

  3. Developmental Disorders Program, Center for Biological and Health Science, Mackenzie Presbyterian University, Rua da Consolação 930, Building 16, São Paulo, 01302, SP, Brazil

    Miriam O. Ribeiro

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  1. Balázs Gereben
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  2. Elizabeth A. McAninch
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Contributions

All authors contributed to researching the data for the article and the writing the article. B.G., E.A.M. and A.C.B. provided a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission. B.G. and E.A.M. contributed equally to this Review.

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Correspondence to Antonio C. Bianco.

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Gereben, B., McAninch, E., Ribeiro, M. et al. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11, 642–652 (2015). https://doi.org/10.1038/nrendo.2015.155

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