Peripheral Metabolism of Thyroid Hormones: A Review

Alternative Medicine Review, August, 2000 by Greg Kelly

Abstract

Peripheral metabolism of thyroid hormones is a critical component of the impact these hormones have on intracellular function. Thyroid hormones can be metabolized in peripheral tissue by deiodination, conjugation, deamination, and decarboxylation enzyme reactions. Therefore, alterations in these metabolic pathways might significantly impact the quantity of specific thyroid hormone metabolites influencing function at the cellular level. Available evidence also suggests that, under some circumstances, the activity of hepatic antioxidant enzyme systems and lipid peroxidation might influence the peripheral metabolism of thyroid hormones. Several syndromes, such as "euthyroid sick syndrome" and "low T3 syndrome," have been classified within the medical literature. The common feature of these disorders is a low level of circulating T3, with generally normal to slightly elevated blood T4 levels and either normal or slightly suppressed TSH levels. This pattern of altered thyroid hormone levels is generally agreed to be a result of impairment in extra-thyroidal peripheral metabolism. Hepatic and renal pathology, as well as catabolic states such as those induced subsequent to severe injury, illness, or trauma result in consistent shifts in the thyroid hormone profile, secondary to their impact on peripheral enzyme pathways. Lifestyle factors, such as stress, caloric restriction, and exercise, influence peripheral metabolism of thyroid hormones. Exposure to toxic metals, chemical poisons, and several drugs can also influence the peripheral fate of thyroid hormones. While the role of vitamins, minerals, and botanical extracts in thyroid hormone metabolism requires further elucidation, current evidence supports a role for selenium in the hepatic 5'-deiodination enzyme.

(Altern Med Rev 2000;5(4):306-333)

Introduction

Peripheral metabolism of thyroid hormones is a critical component of the impact these hormones have on intracellular function. Primary hypothyroidism, which manifests as elevated thyroid stimulating hormone (TSH) and low T4 levels, and secondary hypothyroidism, manifesting as a combination of low T4 levels and low TSH secondary to pituitary dysfunction, are both well defined. However, perturbations in thyroid hormone levels secondary to alterations in peripheral metabolism have received far less clinical attention. Several syndromes, such as "euthyroid sick syndrome" (ESS) and "low T3 syndrome," have been classified within the medical literature. The common feature of these disorders is a low level of circulating T3, with generally normal to slightly elevated blood T4 levels, and either normal or slightly suppressed TSH levels. This pattern of altered thyroid hormones is now generally agreed to be a result of impairment in extra-thyroidal peripheral metabolism.

The liver, and to a lesser degree the kidneys, play a dominant, although often under-discussed role in the metabolism of thyroid hormones. The majority of the most metabolically active thyroid hormone, 3,5,3'-triiodothyronine (T3) (Figure 1), is generated in peripheral tissue. Similarly, the preponderance of its competitive inhibitor, 3,3',5'-triiodothy-ronine (rT3; reverse T3) (Figure 1) is generated outside the thyroid gland. Further transformations to T2 and TI isomers also occur almost exclusively in peripheral tissue. These transformations are all catalyzed by deiodination enzymes which remove iodine atoms from the inner tyrosyl or outer phenolic benzene rings. This stepwise deiodination is the major route of thyroid hormone metabolism and results in both active and inactive metabolites.[1]

[Figure 1 ILLUSTRATION OMITTED]

A second pathway of thyroid hormone metabolism involves the conjugation of the phenolic hydroxyl group of the outer phenolic ring with sulfate or glucuronic acid. These conjugation reactions occur primarily in the liver, and to a lesser degree in the kidney, and result in biotransformation of T4 and T3. The resultant metabolites are primed for elimination and are considered relatively inactive.1 It is thought that partially deiodinated thyroid hormone metabolites are preferred substrates for these conjugation reactions.[2,3]

Thyroid hormones can also undergo deamination and decarboxylase reactions in the liver, resulting in the formation of so-called acetic acid analogues. These reactions occur at the alanine side-chain of the inner tyrosyl ring. Although these analogues are thought to be metabolically active, little is known about the quantifies produced or their contribution to hormone activity in animals or humans.[1]

The role of lipid peroxidation and other antioxidant enzyme systems has also received some attention with respect to thyroid hormone metabolism. Currently, the contribution of these metabolic pathways to thyroid hormone metabolism is not clear in humans; however, the current associations in animal models will be discussed.

Review of Thyroid Hormones

The thyroid gland, in response to stimulation by TSH, produces 3,5,3', 5'-tetratiodothyronine (T4) (Figure 1), T3, and rT3. The synthesis of these hormones requires the amino acid tyrosine and the trace mineral iodine. Within the cells of the thyroid gland, iodide is oxidized to iodine by hydrogen peroxide, a reaction termed the "organification" of iodide. Iodine then binds to the number 3 position in the tyrosyl ring in a reaction catalyzed by thyroid peroxidase enzyme, a reaction yielding 3-monoiodotyrosine (MIT). A subsequent addition of another iodine to the number 5 position of the tyrosyl residue on MIT creates 3,5-diiodotyrosine (DIT). T4 is created by the condensation or coupling of two DIT molecules. Within the thyroid, smaller amounts of DIT can also condense with MIT to form either T3 or rT3.