Thyroid Disorders in Mental Patients

Robertas Bunevicius

Disclosures

Curr Opin Psychiatry. 2009;22(4):391-395. 

In This Article

Abstract and Introduction

Abstract

Purpose of Review: Thyroid hormones play important roles in brain development and function. Recent findings concerning thyroid hormones secretion, transport, and metabolism in the brain have provided a better understanding of the role of thyroid hormones in mental disorders.
Recent Findings: The intracellular actions of thyroid hormones in brain are determined by a complex of factors, including circulating concentrations of thyroid hormones, availability of free hormone, activity of thyroid hormone transporters and deiodinase enzymes, and activity of thyroid hormone receptors. Individual genetic variations and mutations of thyroid-axis-related proteins influence thyroid hormone activity in the brain and contribute to the presentation of mental disorders, as well as to response to psychiatric treatments.
Summary: Consideration of molecular mechanism related to genetic alterations in thyroid hormone transport into the neuron, intracellular thyroid hormone metabolism in the brain, as well as polymorphism in thyroid hormone receptors, opens new venues for better understanding of thyroid hormone effects in the brain as well as for finding genetic markers and new targets for the treatment of mental disorders.

Introduction

Thyroid hormones are critical for the proper development of several tissues, especially the development of the brain. Thyroid hormones also play an important role in the functioning of the mature brain. Mental symptoms, notably cognitive dysfunction and depression, are common expression of thyroid disorders. Moreover, abundant evidence suggests that abnormalities in the metabolism of thyroid hormones and in thyroid system immunity are important in mental disorders, especially in mood disorders. Thyroid-brain interactions and neuropsychiatric symptoms in thyroid disorders and in mood disorders have been discussed in detail in the review by Bauer et al..[1•]

Secretion of thyroid hormones is controlled by pituitary thyrotropin, which in turn is stimulated by hypothalamic thyrotropin-releasing hormone (TRH) and suppressed by negative feedback from serum thyroid hormones. In serum, more than 99% of thyroid hormones are bound to specific proteins; only free hormones are active. The thyroid gland secretes several hormones, including thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3). The main secretion of the thyroid gland is T4, and the thyroid gland is the only source of this hormone. In contrast, no more than 20% of the more biologically active hormone T3 is secreted by the thyroid gland. The remainder of T3 is produced in other tissues by removal of iodine from the T4 molecule by enzymes, called deiodinases, which exist in several forms and are located in cells.

Type-I deiodinase (D1) is located primarily in liver and kidney and is responsible for producing as much as 80% of T3. Type-II deiodinase (D2) is located mostly in brain glial cells and in muscles and is responsible for T3 tissue concentrations. Type-III deiodinase (D3) converts T4 to rT3, which is inactive, and also degrades T3. In brain, D3 is located in neurons. Gereben et al.[2] reviewed mechanisms involved in deiodinase regulation in a time-specific and tissue-specific fashion; they concluded that tissue activation and inactivation of thyroid hormones play a broader role than previously thought. Panicker et al.[3] have demonstrated that common genetic variation in D1, but not genetic variations in D2 or D3, alters deiodinase function, resulting in an alteration in the balance of circulating thyroid hormones. On the other hand, several earlier studies, reviewed by Peeters et al.,[4] have found that polymorphism in D2 gene (DIO2), as well as in D1 gene (DIO1), makes changes in thyroid hormone parameters.

Until recently, it was presumed that cellular entry by free thyroid hormones was mediated via passive diffusion because of their lipophylic nature. Now it is recognized that thyroid hormones enter target cells using an energy-dependent transport mechanism that is mediated by the monocarboxylate trasporter-8 (MCT8) and by other transporters such as the organic anion transporter 1c1 protein (OATP1c1). Molecular characterization of thyroid hormone transporters and their role in disease were reviewed by Visser et al..[5•] Particular attention in this review was given to the role of MCT8 mutation for the development of Allan-Herndon-Dudley syndrome (AHDS) (see below).

The genomic action of T3 is mediated via nuclear thyroid hormone receptors, which are members of the steroid/thyroid family and have two isoforms, thyroid hormone receptor-a and thyroid hormone receptor-ß. Thyroid hormone receptors bind T3 and as ligand-inducible transcription factors regulate expression of T3-responsive target genes. Sorensen et al.[6] hypothesized that thyroid hormone receptor gene polymorphism may affect thyroid function. They mapped thyroid hormone receptor-a and thyroid hormone receptor-ß for the occurrence and frequencies of single nucleotide polymorphisms and related the results to thyroid parameters. They found that only thyroid hormone receptor-ß polymorphism was associated with increased serum thyrotropin concentrations in a large population of Danish twins.

The neurophysiological mechanisms of thyroid hormone action in the developing and mature brain have been comprehensively reviewed by Williams.[7•] The main cellular site of T3 action is the neuron. The portion of T3 that is active in brain must cross the blood-brain barrier or the choroid-plexus-cerebrospinal fluid (CSF) barrier. OATP1c1 is a T4-specific transporter, whereas MCT8 may transport T3 as well as T4. In brain, T4 enters astrocytes, where it is converted to T3 by local D2. T3 generated in the astrocytes as well as T3 from the general circulation is transported into neurons via MCT8, where after completion of its action, it is degraded by D3. MCT8 and thyroid hormone receptors are widely distributed in brain, especially in phylogenetically younger brain regions such as cortex, amygdala, and hippocampus, which play an important role in cognitive functioning and mood disorders.

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