The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

Thyroid Hormone Transporters

Prior to conversion of T4 to T3 by deiodinases in astrocytes, T4 must move across the blood-brain barrier and into cells. Although the transporter responsible for this is unknown, a possible candidate is Oatp1c1. Oatp1c1 is a member of the organic anion transporting polypeptide family for which T4, and inactive rT3, are substrates.[56,57] In parallel, T3 produced in astrocytes is transported to neurons and oligodendrocytes, where it is taken up by the monocarboxylate transporter 8 (MCT8).[58] Monocarboxylate transporter 8 is a membrane protein specific for T3 transport that is highly expressed in the liver and brain. However, T3 transport is only mildly affected in MCT8−/− mice,[59] suggesting that uptake into neural tissue is mediated by other transporters. Prospective candidates include members of the L-type amino acid transporter family and the MCT10 transporter (Figure 4).[60,61] Thyroxine transport into the astrocytes may also be important in T4 monotherapy. Any impairment in T4 uptake by the astrocyte could reduce the amount of T3 delivered to the neurons. This would be a local effect in the form of small changes in T3 levels that would not be detected in peripheral circulation. It is possible that T4/T3 combination therapy may improve clinical outcomes when T4 uptake is impaired; this hypothesis has not been tested in humans.

Figure 4.

Thyroid hormone action and metabolism in the cells. The transport of T3 into target cells occurs by thyroid hormone transporters and subsequent binding of thyroid receptor/retinoic acid (RXR) dimmers, which stimulate transcription of target genes. Thyroxine preferentially binds αVβ3 integrins to stimulate MAPK signaling pathways; T4 and rT3 stimulate actin polymerization. Triiodothyronine has also been shown to affect several mitochondrial functions and NO production via PI3K activation. All of these functions rely on deiodinase (D) activities (denoted as D1–D3). Adapted from Horn and Heuer, 2009.[48]