Thyroid Disease and Mental Disorders: Cause and Effect or Only comorbidity?

Robertas Bunevičius; Arthur J. Prange Jr

Disclosures

Curr Opin Psychiatry. 2010;23(4):363-368. 

In This Article

Thyroid Hormone Metabolism in the Brain

The thyroid gland produces two major hormones: thyroxine (T4), which is usually considered a pro-hormone, and triiodothyronine (T3), which is more active and is responsible for most metabolic effects. The thyroid gland secretes mainly T4, and T4 has no other source. Only 20% of T3 is produced by the thyroid gland. The remainder is produced in other tissues by removal of iodine from the T4 molecule by type-I deiodinase (D1), which accounts for most T3 in the general circulation, and by type-II deiodinase (D2), which accounts for T3 in tissues, including brain. Type-III deiodinase (D3) converts T4 to reverse T3 (rT3), which is inactive, and also degrades T3. In the brain, D2 is located in glial cells, including astrocytes; D3 is located in neurons. To enter the brain, thyroid hormones must cross the blood–brain barrier via energy-dependent transport mechanisms. Organic anion transporter protein 1c1 (OATP1c1) is a T4-specific transporter, whereas monocarboxylate transporter 8 (MCT8) may transport T3 as well as T4. T3 produced in the brain as well as T3 from the general circulation is transported to neurons by MCT8.[2]

The genomic action of T3 is mediated via nuclear thyroid hormone receptors. Human thyroid hormone receptors have α and β isoforms. Thyroid hormone receptors bind T3, and, as ligand-inducible transcription factors, regulate expression of T3-responsive genes. Thyroid hormone receptor α-1, β-1, and β-2 isoforms can be occupied by T3, whereas the thyroid hormone receptor α-2 isoform cannot be occupied by T3. Thyroid hormone receptors, whether or not occupied by T3, bind to the DNA response elements, producing different effects on gene expression. Binding of T3-occupied thyroid hormone receptors leads to activation; binding of T3-unoccupied thyroid hormone receptors leads to suppression of responsive genes. In the brain, thyroid hormone receptors are widely distributed in regions that regulate cognition and mood.[3]

Regulation of thyroid hormone homeostasis in specific regions of the brain is achieved by temporal and spatial regulation of the deiodinase and transporters system as well as by expression of thyroid hormone receptors. For example, D3 in early gestation suppresses thyroid hormone activity in fetal tissues, thus maintaining proliferation and inhibiting differentiation. Later, expression of D2 activity initiates T3 production and tissue differentiation. Deiodinase activity also tends toward brain–thyroid hormone homeostasis in hyperthyroidism by increasing expression of D3 and suppressing expression of D2, and in hypothyroidsim by increasing expression of D2.[2]

A comprehensive review of thyroid hormone roles in various physiological processes including brain functioning from the perspective of common genetic variation is presented by Dayan and Panicker.[4••] Single nucleotide polymorphisms, in contrast to mutations, which are relatively rare, are common genetic variations causing minor alterations in the activity of target proteins. Polymorphism in the D1 gene (DIO1) is associated with T4/T3 balance in the circulation but does not affect thyrotropin concentrations. Polymorphisms in the D2 gene (DIO2) and in the D3 gene (DIO3) may result in alterations of T3 concentrations in the brain without changes in serum concentrations. Polymorphisms in thyroid transporters may affect both balance of circulating thyroid hormone concentrations and intracellular thyroid hormone concentrations, including intraneuronal thyroid hormone activity. For example, mutations in the MCT8 gene blockT3 transport into neurons, causing isolated neuronal hypothyroidism.[2,5]

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