Two molecules of DIT combine within the thyroglobulin molecule to form l-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3. In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity. Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT are then deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Eighty percent of T3 circulating in the blood is derived from peripheral metabolism of thyroxine and the rest from direct thyroid secretion (see below, Figure 38–2).
Transport of Thyroid Hormones
Thyroxine and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form (as FT4 and FT3).
Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remain normal, reflecting feedback control.
Peripheral Metabolism of Thyroid Hormones
The primary pathway for the peripheral metabolism of thyroxine is deiodination by three 5′deiodinase enzymes (D1, D2, D3). Deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3′-triiodothyronine (T3), which is three to four times more potent than T4. The D1 enzyme is responsible for about 24% of the circulating T3 while 64% of peripheral T3 is generated by D2, which also regulates T3 levels in the brain and pituitary. D3 deiodination produces metabolically inactive 3,3′,5′-triiodothyronine (reverse T3 [rT3]), (Figure 38–2). The low serum levels of T3 and rT3 in normal individuals are due to the high metabolic clearances of these two compounds.
Drugs such as amiodarone, iodinated contrast media, β blockers, and corticosteroids, as well as severe illness or starvation, inhibit the 5′-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. A polymorphism in the D2 gene can reduce T3 activation and impair thyroid hormone response. The pharmacokinetics of thyroid hormones are listed in Table 38–1.
Evaluation of Thyroid Function
The tests used to evaluate thyroid function are listed in Table 38–2.
FIGURE 38–2 Peripheral metabolism of thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.)
A. Thyroid-Pituitary Relationships