Regulation of Thyroid Hormone Bioactivity in Health and Disease

TThyroid hormone plays an essential role in a variety of metabolic processes in the human body. Examples are the effects of thyroid hormone on metabolism and on the heart. The production of thyroid hormone by the thyroid is regulated by thyroid stimulating hormone (TSH) via the TSH receptor. The thyroid produces T4, which is not biologically active. Therefore, T4 has to be converted to the active hormone T3, a process that is regulated by three enzymes, the deiodinases (D1-D3). D1 and D2 are thyroid hormone activating enzymes that catalyze the conversion of T4 to T3. D3 is an inactivating enzyme that converts T4 to the inactive metabolite rT3 and breaks down T3 to 3,3’-T2. In the General Introduction, a more detailed overview of the regulation of thyroid hormone production, as well as the regulation of thyroid hormone bioactivity, is presented. Furthermore, the rationale behind the performed studies and an outline of the thesis are presented. This PhD project has focused on the regulation of thyroid hormone bioactivity, and consists of two major parts. In Part A of the thesis, we have analyzed the importance of subtle genetic variations in thyroid hormone pathway genes. Current estimates are that ~65% of inter-individual variation in serum thyroid hormone levels is due to genetic factors. Already minor changes in thyroid hormone levels can have important effects on metabolism and heart rate. We therefore investigated genes encoding key proteins in thyroid hormone metabolism for the occurrence of genetic variations (polymorphisms). Since these polymorphisms may have subtle effects on thyroid hormone bioactivity throughout life, we also analyzed if they were associated with thyroid hormone-related clinical endpoints.

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