This paper reviews knowledge on the structure and function and evolution of the 
thyroid hormone binding protein transthyretin (TTR), with particular reference 
to factors affecting thyroid hormone distribution and delivery to the brain. The 
pool of thyroid hormones critical for the biological actions of the hormones is 
the pool of free thyroid hormone. The size of this pool is determined for short 
time periods by uptake/release of thyroid hormones into/from cell and 
binding/release of thyroid hormones by thyroid hormone-binding proteins. Both 
proportions and absolute concentrations of these proteins differ in blood plasma 
and cerebrospinal fluid (CSF). The most pronounced difference is found for TTR 
which is the only thyroid hormone-binding plasma protein synthesized in the 
brain. TTR is also distinct from the other two thyroid hormone-binding plasma 
proteins in humans by the absence of genetic deficiencies. TTR gene expression 
was initiated during evolution much earlier in the brain than in the liver. The 
structure of the domains of TTR involved in thyroxine (TR) T4 binding has been 
completely conserved for 350 million years. These observations point to a 
special functional significance of TTR in the brain. It is proposed that this is 
the determination of the level of free T4 in the extracellular compartment of 
the brain. T4 can then be converted in the brain to triiodothyronine T3 by 
specific deiodinases. This T3 can interact with receptors in the cell nuclei, 
regulating gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)