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Endocrine Abstracts (2014) 34 PL4 | DOI: 10.1530/endoabs.34.PL4

Erasmus University Medical Center, Rotterdam, The Netherlands.

Thyroid hormone (TH) is essential for the development of tissues, in particular the brain, and for their metabolic function throughout life. The thyroid secretes mostly the prohormone T4 and a small amount of the active hormone T3. Most T3 is generated by outer ring deiodination of T4 in peripheral tissues, and both T4 and T3 are degraded by inner ring deiodination to inactive metabolites. This involves three different deiodinases (D1–3).

Most actions of TH are initiated by binding of T3 to nuclear receptors (TRs), which results in a change in the expression of TH responsive genes. TRs are encoded by two genes; THRA is located on human chr 17 and THRB on chr 3. Both genes give rise to different proteins of which TRα1, TRβ1 and TRβ2 represent bonafide T3-binding receptors.

The active sites of the deiodinases and the receptors are located inside the cell. Both metabolism and action of TH therefore require the transport of the hormone across the plasma membrane mediated by specific TH transporters. Multiple transporters have been identified but only three of them are specific for TH, namely MCT8, MCT10 and OATP1C1.

The syndrome of thyroid hormone resistance β (RTHβ) has been known for a long time. RTHβ is characterized by a combination of elevated FT4 and non-suppressed TSH levels. The clinical phenotype is usually mild but may comprise among others tachycardia and atrial fibrillation. RTH is caused by a heterozygous mutation in the T3-binding domain of TRβ1/2, resulting in an impaired negative feedback of TH on TSH secretion mediated by TRβ2.

Only very recently patients have been identified with heterozygous mutations in TRα1 resulting in RTHα. These patients show a strongly delayed bone development and mildly delayed mental and motor development. This is explained by the important expression of TRα in bone and brain. These patients have low FT4 and high T3 but normal TSH levels.

TH resistance may also be caused by an impaired cellular transport of the hormone. This has been demonstrated in patients with mutations in MCT8, which gene is located on the X chromosome. Males with hemizygous mutations in MCT8 suffer from severe psychomotor retardation. They also have low FT4 and high T3 but usually normal TSH levels.

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