Extrathyroidal types 1 and 2 iodothyronine deiodinase as sources of plasma T₃

Maia AL et al. (2005) Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 115: 2524–2533

Peripheral conversion of T₄ to T₃ accounts for 80% of T₃ production in humans. Extrathyroidal types 1 and 2 iodothyronine deiodinases (D1 and D2) have been identified in the liver and in skeletal muscle, respectively, but their quantitative contribution to the production of serum T₃ from T₄ in normal individuals and those with thyroid disorders is unknown.

To establish the relative roles of the two enzymes, Maia and colleagues calculated the rate of conversion of T₄ to T₃ in transfected cells transiently expressing D1 or D2, at physiologically relevant concentrations of free T₄ (2 pM, 20 pM and 200 pM). Cells were then sonicated for assay of deiodinase activities. The ratio of T₃ production in cell sonicates was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2). Extrapolating the results from these in vitro studies, the authors conclude that D2 from extrathyroidal sites such as skeletal muscle is the major source of T₃ in euthyroid individuals. In hypothyroidism, D2-generated T₃ accounts for ∼71% of peripheral production; D1-generated T₃ makes up the majority (67%) in thyrotoxic patients. Furthermore, intracellular D2-generated T₃ has a twofold to threefold greater effect on T₃-dependent gene transcription than that from D1. Given the important role of D2 in euthyroid individuals, and its short half-life, the authors also argue that the rapid decrease in serum T₃ seen in patients with euthyroid sick syndrome is more likely to be due to impairment of D2-catalysed T₃ generation rather than to the smaller decrease seen in hepatic D1 activity.