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  • Review Article
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Deiodinases and their intricate role in thyroid hormone homeostasis

Nature Reviews Endocrinology volume 15, pages 479–488 (2019)Cite this article

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Abstract

The deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the deiodinases became implicated in tissue development and homeostasis, as well as in the pathogenesis of a wide range of human diseases. Three deiodinases have been identified, namely, types 1, 2 and 3 iodothyronine deiodinases, which differ in their catalytic properties and tissue distribution. Notably, the expression of these enzymes changes during the lifetime of an individual in relation to the different needs of each organ and to ageing. The systemic homeostatic role of deiodinases clearly emerges during changes in serum concentrations of thyroid hormone, as seen in patients with thyroid dysfunction. By contrast, the role of deiodinases at the tissue level allows thyroid hormone signalling to be finely tuned within a given cell in a precise time–space window without perturbing serum concentrations of thyroid hormone. This Review maps the overall functional role of the deiodinases and explores challenges and novel opportunities arising from the expanding knowledge of these ‘master’ components of the thyroid homeostatic system.

Key points

  • The coordinated action of the hypothalamic–pituitary–thyroid axis and deiodinases is critical to ensure a stable plasma concentration of T3 in euthyroid conditions and to counteract alterations in thyroid hormone levels under pathological conditions.

  • Deiodinases allow tissues to customize either enhancing or decreasing the intracellular concentration of thyroid hormone at the single-cell level and independently of plasma.

  • Deiodinase action is essential to ensure optimal intracellular concentrations of T3 at the single-cell level, in a temporal-dependent window.

  • The common DIO2 Thr92Ala polymorphism affects enzyme stability and activity, which, in turn, alters thyroid hormone metabolism, thereby exposing carriers to reduced conversion of T4 to T3 that could be critical in those who are athyreotic.

  • In levothyroxine-treated patients who are athyreotic, TSH levels within the reference range do not guarantee tissue euthyroidism; therefore, clinical or metabolic biomarkers of peripheral euthyroidism are required, particularly for patients who are symptomatic but biochemically euthyroid.

  • Studies are required to identify genetic or metabolic traits in patients with hypothyroidism in whom levothyroxine treatment alone does not suffice to restore tissue euthyroidism and clinical well-being.

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Fig. 1: Deiodinase thyroid hormone action.
Fig. 2: Thyroid hormone metabolism is dynamically regulated during linear progression of satellite cells.
Fig. 3: The interplay between thyroid hormone and oncogenic signalling pathways in cancer cells.
Fig. 4: The tumorigenesis of basal cell carcinoma is highly sensitive to thyroid hormone action.

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Acknowledgements

The authors acknowledge the support of grants from the European Research Council under the European Union’s Horizon 2020 Programme — EU FP7 contract Thyrage (grant number 666869) to D.S. and ERCStG2014 (STARS — 639548) to M.D. The authors thank J. A. Gilder (Scientific Communication srl., Naples, Italy) for assistance with language editing.

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  1. Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy

    Cristina Luongo & Monica Dentice

  2. Department of Public Health, University of Naples “Federico II”, Naples, Italy

    Domenico Salvatore

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  1. Cristina Luongo
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C.L. and M.D. researched data for the article, provided substantial contribution to discussion of the content, wrote the paper and reviewed and edited the manuscript before submission. D.S. wrote the paper and reviewed and edited the manuscript before submission.

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Correspondence to Domenico Salvatore.

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Luongo, C., Dentice, M. & Salvatore, D. 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

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