ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 3.14 | DOI: 10.1530/ey.18.3.14

Thyroid. 2020;30:1732–1744. doi: 10.1089/thy.2019.0825.

This study is of importance, revealing a relevant clinical problem in patients under long-term levothyroxine (LT4) substitution and challenging the concept that all hypothyroid patients can be well controlled with LT4 monotherapy.

Lacámara et al. present a small but elegant clinical study describing a so far unrecognized resistance to exogenous thyroxine (RETH) in 18 paediatric and adult patients under LT4 substitution for congenital and acquired hypothyroidism. These patients presented with elevated TSH values despite increased FT4 values due to supraphysiological substitution with LT4, suggesting hypothalamic and pituitary non-responsiveness to the exogenous LT4. Such a phenotype has been described earlier in iodothyronine deiodinase type 2 (dio2) knockout mice [1]. Dio2 encodes D2, that mediates T4 to T3 deiodination, as D1, but with tissue specificity in the hypothalamus and pituitary gland.

To characterize the phenotype in affected patients more in detail, the authors combined detailed laboratory investigations to provide insight into the deiodination process in these patients by measuring not only TSH and FT4, but also T4, T3 and rT3 and their ratios under different doses of LT4. The results suggested reduced T4 to T3 deiodination and increased T4 to inactive rT3 conversion, resulting in decreased negative feed-back loop activation. Further, they excluded mutations in thyroid hormone receptor-beta (THRB), DIO2 and selenocysteine binding protein 2 (SECISBP2), all genes possibly explaining the biochemical phenotype if mutated. Finally, they showed in one patient, that a combination of T4 and T3 for substitution, with reduced T4 dose, normalized their elevated TSH levels with normal FT4 and FT3 levels.

Whether T4+T3 combination therapy is the key in this context remains open and needs to be analysed by randomized controlled trial, as suggested by a recent consensus statement from the American, British, and European Thyroid Associations (ATA/BTA/ETA) [2].

Reference: 1. Fonseca TL, Correa-Medina M, Campos MP, Wittmann G, Werneck-de-Castro JP, Arrojo e Drigo R, Mora-Garzon M, Ueta CB, Caicedo A, Fekete C, Gereben B, Lechan RM, Bianco AC. Coordination of hypothalamic and pituitary T3 production regulates TSH expression. J Clin Invest. 2013;123:1492–500. doi: 10.1172/JCI61231.2. Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, McAninch EA, Moeller LC, Nygaard B, Sawka AM, Watt T, Dayan CM. Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. Thyroid. 2021;31:156–182. doi: 10.1089/thy.2020.0720.

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