The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

Deiodinases and Thyroid Hormone Metabolism

The main hormone produced by the thyroid, the prohormone T4, is converted to T3 in peripheral target tissue cells by deiodinases (Figure 3). Conversion of T4 to T3 is in fact responsible for most of the T3 in the body. Deiodinase activity varies from tissue to tissue. Type I deiodinase is found mainly in the liver and kidney, Type II deiodinase in brain astrocytes, and Type III deiodinase in brain neurons. Animal studies have shown that approximately 80% of the active T3 in the brain is produced locally[49] by Type II deiodinase, which catalyzes deiodination in the outer ring (Figure 3). In the brain, Type II deiodinases are found in astrocytes, where they convert T4 into T3.[50] T3 then interacts with the α and β thyroid receptors in oligodendrocytes and neurons. The role of deiodinases in the production of T3 has been studied in animal models.

Figure 3.

The metabolism of T3 and T4 into active and inactive intermediates involves the action of 3 types of deiodinases. The thyroid gland secretes approximately 100 μg of T4 and 6 μg of T3 daily.[87] An additional 24 μg of T3 is produced as a result of the deiodination of T4 in extrathyroidal tissues.[87] Thyroid hormone is activated when the prohormone T4 is converted to the active hormone (T3) through the removal of an iodine atom from its outer ring and deactivated when an iodine atom is removed from its inner ring (which converts thyroxine to the inactive rT3). Deiodination occurs mainly within the cells; thus, cell-specific deiodinases play an important role in determining the activity of thyroid hormone. Three deiodinases are found in humans: (1) Type 1 (found mainly in the liver and kidney), which can remove iodine both rings; (2) Type 2 (found mainly in skeletal muscle and in the heart, fat, thyroid, and central nervous system [including the brain]), which can induce deiodination in the outer ring, making it the main activating enzyme; and (3) Type 3 (found in fetal tissue and in the placenta), which induces deiodination in the inner ring only and, thus is the main inactivating enzyme. Approximately 20% of T3 is actually made in the thyroid gland. It has been observed that tissues in need of thyroid hormone convert T4 to T3 at different rates; therefore, the administration of T3 as well as T4 may be a better solution for hypothyroidism than T4 alone.[88]

A mouse model deficient in Type II deiodinases was recently created to determine the role of this enzyme in neuronal function.[51] Type II deiodinase knock-out mice exhibit normal circulating T3 levels but increased T4 and TSH levels, supporting that Type II deiodinase regulates the hypothalamic-pituitary-thyroid axis. In the brain, however, T4 levels were elevated, whereas T3 levels were substantially decreased (by 50%), indicating a reduction in T3 production. Despite low T3 levels in the brain, neural function—indicated by learning, memory, and locomotor skills—was unaffected in contrast to findings in animals with severe hypothyroidism.[52] Other studies have used mice devoid of any 5′-deiodinase activity to assess the role of these enzymes in brain function. Unexpectedly, Type I/Type II deiodinase double knock-out mice had normal serum T3 levels and only mild neurological impairments.[53] Type III deiodinase is also strongly expressed in neurons,[54] where it catalyzes deiodination in the inner ring, thereby inactivating local hormones and, thus, opposing Type III deiodinase activity. These studies identify the key roles for Type I and Type II deiodinases in the production of active T3 and suggest that other yet unknown deiodinases may play a role in the conversion of T4 to T3. Due to the need for peripheral conversion, deiodinase activity is particularly important in T4 monotherapy.

The importance of the deiodinases is further illustrated by the dynamic way in which they are regulated. Deiodinase activity follows circadian rhythms, varying with the season and body tissue (due to tissue-specific variations in expression). In this context, serum thyroid hormone levels may remain steady while intracellular its concentrations vary with deiodinase activity.[55] Based on the importance of deiodinases, it is plausible that patients with impaired neuronal deiodinase activity would psychologically benefit from T3/T4 combination therapy.