Iodothyronine deiodinases are important mediators of thyroid hormone (TH) action. They are present in tissues throughout the body where they catalyse 3,5,3′-triiodothyronine (T₃) production and degradation via, respectively, outer and inner ring deiodination. Three different types of iodothyronine deiodinases (D1, D2 and D3) have been identified in vertebrates from fish to mammals. They share several common characteristics, including a selenocysteine residue in their catalytic centre, but show also some type-specific differences. These specific characteristics seem very well conserved for D2 and D3, while D1 shows more evolutionary diversity related to itsKm, 6-n-propyl-2-thiouracil sensitivity and dependence on dithiothreitol as a cofactorin vitro. The three deiodinase types have an impact on systemic T₃levels and they all contribute directly or indirectly to intracellular T₃availability in different tissues. The relative contribution of each of them, however, varies amongst species, developmental stages and tissues. This is especially true for amphibians, where the impact of D1 may be minimal. D2 and D3 expression and activity respond to thyroid status in an opposite and conserved way, while the response of D1 is variable, especially in fish. Recently, a number of deiodinases have been cloned from lower chordates. Both urochordates and cephalochordates possess selenodeiodinases, although they cannot be classified in one of the three vertebrate types. In addition, the cephalochordate amphioxus also expresses a non-selenodeiodinase. Finally, deiodinase-like sequences have been identified in the genome of non-deuterostome organisms, suggesting that deiodination of externally derived THs may even be functionally relevant in a wide variety of invertebrates.

Introduction: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T₃) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T₃ availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T₃ syndrome in prolonged critical illness. Methods: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors α (TRα) and β (TRβ) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes. Results: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T₄) and low-normal T₃ concentrations, without a change at the thyroid hormone receptor level. Conclusions: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T₄ and T₃ content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.

Because the avian thyroid gland secretes almost exclusively thyroxine (T₄), the availability of receptor-active 3,3′,5-triiodothyronine (T₃) has to be regulated in the extrathyroidal tissues, essentially by deiodination. Like mammals and most other vertebrates, birds possess three types of iodothyronine deiodinases (D1, D2, and D3) that closely resemble their mammalian counterparts, as shown by biochemical characterization studies in several avian species and by cDNA cloning of the three enzymes in chicken. The tissue distribution of these deiodinases has been studied in detail in chicken at the level of activity and mRNA expression. More recently specific antibodies were used to study cellular localization at the protein level. The abundance and distribution of the different deiodinases shows substantial variation during embryonic development and postnatal life. Deiodination in birds is subject to regulation by hormones from several endocrine axes, including thyroid hormones, growth hormone and glucocorticoids. In addition, deiodination is also influenced by external parameters, such as nutrition, temperature, light and also a number of environmental pollutants. The balance between the outer and inner ring deiodination resulting from the impact of all these factors ultimately controls T₃ availability.