Commentary

Reverse T3 or perverse T3? Still puzzling after 40 years

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Four decades after reverse T 3 (3,3´5´-triiodothyronine) was discovered, its physiologic and clinical relevance remains unclear and is still being studied. But scientific uncertainty has not stopped writers in the consumer press and on the Internet from making unsubstantiated claims about this hormone. Many patients believe their hypothyroid symptoms are due to high levels of reverse T 3 and want to be tested for it, and some even bring in test results from independent laboratories.

HOW THYROID HORMONES WERE DISCOVERED

Thyroid hormones: A timeline
Figure 1.
The 20th century saw important advances in knowledge of the biochemistry of thyroid hormones ( Figure 1 ),1–18 such as the isolation of thyroxine (T 4) by Kendall 1 in 1915 and its synthesis by Harington and Barger 3 in 1927. Another milestone was the isolation and synthesis of triiodothyronine (T 3) by Gross and Pitt-Rivers 5 in 1953. In 1955, Pitt-Rivers et al 6 suggested that T 3 is formed in vivo from conversion of T 4, but this theory remained unproven in humans at that time.

In 1970, Braverman et al 9 showed that T 4 is converted to T 3 in athyreotic humans, and Sterling et al 10 demonstrated the same in healthy humans. During that decade, techniques for measuring T 4 were refined, 11 and a specific radioimmunoassay for reverse T 3 allowed a glimpse of its physiologic role. 12 In 1975, Chopra et al 13 noted reciprocal changes in the levels of T 3 and reverse T 3 in systemic illnesses—ie, when people are sick, their T 3 levels go down and their reverse T 3 levels go up.

Individual values of serum reverse T3 levels
Figure 2. Individual values of serum reverse T 3 levels in normal, hypothyroid, and hyperthyroid people and in athyreotic patients who had been given 50 µg of levothyroxine (LT 4) and 400 µg of LT 4 daily.
In 1977, Burman et al 17 developed a radioimmunoassay for reverse T 3 that confirmed its presence in the serum of normal humans. Further, they showed that serum reverse T 3 levels were low in hypothyroid patients and in athyreotic patients receiving low daily doses of levothyroxine. Conversely, reverse T 3 levels were high in hyperthyroid patients and in athyreotic patients receiving high doses of levothyroxine ( Figure 2 ).17

The end of the 70s was marked by a surge of interest in T 4 metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T 2).18

The observed reciprocal changes in serum levels of T 3 and reverse T 3 suggested that T 4 degradation is regulated into activating (T 3) or inactivating (reverse T 3) pathways, and that these changes are a presumed homeostatic process of energy conservation. 19

HOW THYROID HORMONES ARE METABOLIZED

In the thyroid gland, for thyroid hormones to be synthesized, iodide must be oxidized and incorporated into the precursors 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT). This process is mediated by the enzyme thyroid peroxidase in the presence of hydrogen peroxide. 20

The thyroid can make T 4 and some T 3

T4 is the main iodothyronine produced by the thyroid gland, at a rate of 80 to 100 µg per day. 21 It is synthesized from the fusion of 2 DIT molecules.

The thyroid can also make T 3 by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T 3 in humans. The rest of T 3, and 95% to 98% of all reverse T 3, is derived from peripheral conversion of T 4 through deiodination.

T4 is converted to T 3 or reverse T 3

The metabolic transformation of thyroid hormones in peripheral tissues determines their biologic potency and regulates their biologic effects.

Thyroxine (T4)
Figure 3. Thyroxine (T 4) can shed 1 iodine atom to become the active thyroid hormone 3,5,3’-triiodothyronine (T 3) in a reaction catalyzed by D1 and D2, or its inactive isomer 3,3’5’-triiodothyronine (reverse T 3) in a reaction catalyzed by D3. In further reactions (not shown) both molecules successively lose more iodine atoms, eventually becoming T 0.

The number 4 in T 4 means it has 4 iodine atoms. It can lose 1 of them, yielding either T 3 or reverse T 3, depending on which iodine atom it loses ( Figure 3 ). Loss of iodine from the five-prime (5´) position on its outer ring yields T 3, the most potent thyroid hormone, produced at a rate

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