As already mentioned, the thyroid releases mostly T4
and very small amounts of T3
, yet T3
has greater thyroid activity than T4
. The main source of circulating T3
is peripheral deiodination of T4
). Approximately 80% of T4
produced by the thyroid undergoes deiodination in the periphery. Approximately 40% of T4
is deiodinated at carbon 5 in the outer ring to yield the more active T3
, principally in liver and kidney. In approximately 33% of T4
, iodine is removed from carbon 5 in the inner ring to yield reverse T3 (rT3)
. Reverse T3
has little or no biologic activity, has a higher metabolic clearance rate than T3
, and has a lower serum concentration than T3
. Following conversion of T4
, these are converted to T2
, a biologically inactive hormone. Therefore, thyroid hormone peripheral metabolism is a sequential deiodination process, leading first to a more active form of thyroid hormone (T3
) and finally to complete inactivation of the hormone. Thus, loss of a single iodine from the outer ring of T4
produces the active hormone T3
, which may either exit the cell (in deiodinase type I–containing cells), enter the nucleus directly (in deiodinase type II–containing cells), or possibly even both (eg, in human skeletal muscle). Thyroid hormones can be excreted following hepatic sulfo- and glucuronide conjugation and biliary excretion.
This extrathyroidal progressive deiodination of thyroid hormones catalyzed by deiodinases plays a significant role in thyroid hormone metabolism and requires the trace element selenocysteine for optimal enzymatic activity. Three types of deiodinases have been identified, which differ in their tissue distribution, catalytic profiles, substrate specificities, physiologic functions, and regulation.
Type I deiodinase catalyzes outer- and inner-ring deiodination of T4 and rT3. It is found predominantly in the liver, kidney, and thyroid. It is considered the primary deiodinase responsible for T4 to T3 conversion in hyperthyroid patients in the periphery. This enzyme also converts T3 to T2. The activity of type I deiodinase expressed in the thyroid gland is increased by TSH-stimulated cAMP production and has a significant influence on the amount of T3 released by the thyroid. Propylthiouracil and iodinated x-ray contrast agents such as iopanoic acid inhibit the activity of this enzyme and consequently the thyroidal production of T3.
Type II deiodinase is expressed in the brain, pituitary gland, brown adipose tissue, thyroid, placenta, and skeletal and cardiac muscle. Type II deiodinase has only outer-ring activity and converts T4 to T3. This enzyme is thought to be the major source of T3 in the euthyroid state. This enzyme plays an important role in tissues that produce a relatively high proportion of the receptor-bound T3 themselves, rather than deriving T3 from plasma. In these tissues, type II deiodinases are an important source of intracellular T3 and provide more than 50% of the nuclear receptor-bound T3. The critical role of the type II deiodinases is underscored by the fact that T3 formed in the anterior pituitary is necessary for negative feedback inhibition of TSH secretion.
Type III deiodinase is expressed in the brain, placenta, and skin. Type III deiodinase has inner-ring activity and converts T4 to rT3, and T3 to T2, thus inactivating T4 and T3. This process is an important feature in placental protection of the fetus. The placental conversion of T4 to rT3 and of T3 to T2 reduces the flow of T3 (the most active thyroid hormone) from mother to fetus. Small amounts of maternal T4 are transferred to the fetus and converted to T3, which increases the T3 concentration in the fetal brain, preventing hypothyroidism. In the adult brain, the expression of type III deiodinases is enhanced by thyroid hormone excess, serving as a protective mechanism against high thyroid hormone concentrations.