Reverse T₃ or perverse T₃? Still puzzling after 40 years

Four decades after reverse T₃ (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 T₃ and want to be tested for it, and some even bring in test results from independent laboratories.  

HOW THYROID HORMONES WERE DISCOVERED

The 20th century saw important advances in knowledge of the biochemistry of thyroid hormones (Figure 1),^1–18 such as the isolation of thyroxine (T₄) by Kendall¹ in 1915 and its synthesis by Harington and Barger³ in 1927. Another milestone was the isolation and synthesis of triiodothyronine (T₃) by Gross and Pitt-Rivers⁵ in 1953. In 1955, Pitt-Rivers et al⁶ suggested that T₃ is formed in vivo from conversion of T₄, but this theory remained unproven in humans at that time.

In 1970, Braverman et al⁹ showed that T₄ is converted to T₃ in athyreotic humans, and Sterling et al¹⁰ demonstrated the same in healthy humans. During that decade, techniques for measuring T₄ were refined,¹¹ and a specific radioimmunoassay for reverse T₃ allowed a glimpse of its physiologic role.¹² In 1975, Chopra et al¹³ noted reciprocal changes in the levels of T₃ and reverse T₃ in systemic illnesses—ie, when people are sick, their T₃ levels go down and their reverse T₃ levels go up.

In 1977, Burman et al¹⁷ developed a radioimmunoassay for reverse T₃ that confirmed its presence in the serum of normal humans. Further, they showed that serum reverse T₃ levels were low in hypothyroid patients and in athyreotic patients receiving low daily doses of levothyroxine. Conversely, reverse T₃ 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 T₄ metabolites, including the development of a radioimmunoassay for 3,3´-diiodothyronine (3-3´ T₂).¹⁸

The observed reciprocal changes in serum levels of T₃ and reverse T₃ suggested that T₄ degradation is regulated into activating (T₃) or inactivating (reverse T₃) 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 T₄ and some T₃

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 T₃ by fusing 1 DIT and 1 MIT molecule, but this process accounts for no more than 20% of the circulating T₃ in humans. The rest of T₃, and 95% to 98% of all reverse T₃, is derived from peripheral conversion of T₄ through deiodination.

T₄ is converted to T₃ or reverse T₃

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

The number 4 in T₄ means it has 4 iodine atoms. It can lose 1 of them, yielding either T₃ or reverse T₃, depending on which iodine atom it loses (Figure 3). Loss of iodine from the five-prime (5´) position on its outer ring yields T₃, the most potent thyroid hormone, produced at a rate of 30 to 40 µg per day.²¹ On the other hand, when T₄ loses an iodine atom from the five (5) position on its inner ring it yields reverse T₃, produced at a rate slightly less than that of T₃, 28 to 40 µg per day.²¹ Reverse T₃ is inactive.

Both T₃ and reverse T₃ can shed more iodine atoms, forming in turn various isomers of T₂, T₁, and ultimately T₀. Other pathways for thyroid hormone metabolism include glucuronidation, sulfation, oxidative deamination, and ether bond cleavage.^20–22

D1 and D2 catalyze T₃, D3 catalyzes reverse T₃

Three types of enzymes that mediate deiodination have been identified and designated D1, D2, and D3. In humans they are expressed in variable amounts throughout the body:

• D1 mainly in the liver, kidneys, thyroid, and pituitary, but notably absent in the central nervous system
• D2 in the central nervous system, pituitary, brown adipose tissue, thyroid, placenta, skeletal muscle, and heart
• D3 in the central nervous system, skin, hemangiomas, fetal liver, placenta, and fetal tissues.²³

D1 and D2 are responsible for converting T₄ to T₃, and D3 is responsible for converting T₄ to reverse T₃.

Plasma concentrations of free T₄ and free T₃ are relatively constant; however, tissue concentrations of free T₃ vary in different tissues according to the amount of hormone transported and the activity of local deiodinases.²³ Most thyroid hormone actions are initiated after T₃ binds to its nuclear receptor. In this setting, deiodinases play a critical role in maintaining tissue and cellular thyroid hormone levels, so that thyroid hormone signaling can change irrespective of serum hormonal concentrations.^22–24 For example, in the central nervous system, production of T₃ by local D2 is significantly relevant for T₃ homeostasis.^22,23

Deiodinases also modulate the tissue-specific concentrations of T₃ in response to iodine deficiency and to changes in thyroid state.²³ During iodine deficiency and hypothyroidism, tissues that express D2, especially brain tissues, increase the activity of this enzyme in order to increase local conversion of T₄ to T₃. In hyperthyroidism, D1 overexpression contributes to the relative excess of T₃ production, while D3 up-regulation in the brain protects the central nervous system from excessive amounts of thyroid hormone.²³