What is reverse T3 (reverse triiodothyronine)?

What is Reverse T3?

Reverse T3 (rT3) is a biologically inactive metabolite of thyroxine (T4) produced when the thyroid hormone T4 is converted by removing an iodine atom from its inner ring rather than its outer ring, creating 3',5'-triiodothyronine instead of the active hormone T3. 1, 2

Biochemical Formation and Metabolism

• rT3 is formed through peripheral 5-deiodination of T4 by type 1 and type 3 deiodinase enzymes (D1 and D3) in tissues throughout the body 2
• Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination, and during this same process, equal amounts of T3 and reverse T3 (rT3) are produced 1
• The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring in the kidney and other tissues 1
• Both T3 and rT3 are further deiodinated to diiodothyronine and eventually eliminated 1

Biological Activity and Receptor Binding

• rT3 is widely regarded as biologically inactive and does not produce the physiologic effects of active thyroid hormone T3 2, 3
• Some functional medicine practitioners argue that high rT3 may block T3 from binding to the thyroid hormone receptor, though this remains controversial 2
• Recent research shows rT3 binds to the thyroid hormone analog receptor on plasma membrane integrin αvβ3, which is generously expressed by tumor cells 3
• In laboratory studies, rT3 caused increases of proliferation of 50% to 80% in human breast cancer and glioblastoma cells, suggesting it may not be entirely inactive 3

Clinical Significance in Illness

• In patients with severe illnesses, rT3 is typically high and T3 is typically low, a pattern termed "euthyroid sick syndrome" or "low T3 syndrome" 2, 4
• A number of physiological and pathological events perturb the deiodination pathway, leading to decreased T3 production and reciprocal increases in rT3 levels 4
• This "low T3 syndrome" is also produced by various pharmacological agents and represents the body's adjustment to stress 4
• rT3 is linearly related to bilirubin levels up to approximately 171 microM (10 mg/dL) 5

Relationship to Thyroid Hormone Replacement

• Patients taking L-T4 (levothyroxine) replacement therapy have higher rT3 levels than those not on L-T4 treatment (p < 0.00001) 2
• The highest rate of elevated rT3 (20.9%) occurs in patients taking T4 alone, compared to 9% in patients not taking thyroid hormone replacement 2
• Patients on preparations containing L-T3 alone have the lowest levels of rT3 2
• Linear regression analysis shows rT3 levels correlate positively with free T4 and free T3 levels and inversely with log TSH levels 2

Limitations as a Diagnostic Tool

• rT3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome 5
• There is an inverse linear relationship between log TSH and rT3, but patients with hypothyroidism plus illness may have normal rT3, and euthyroid patients may have low rT3 5
• This unreliability is probably due to drug and disease effects on thyroid hormone metabolism, as well as the presence of sufficient T4 substrate for conversion to rT3 in many hypothyroid sick patients 5
• In association with a low free T4 index/T4, an unmeasurable reverse T3 did not lead to institution of thyroid hormone treatment in over 52% of cases 5

Common Clinical Pitfalls

• Functional medicine doctors often rely heavily on rT3 levels to treat patients who may have no other laboratory findings of hypothyroidism, despite lack of peer-reviewed evidence supporting this approach 2
• Some practitioners prescribe L-T3-only preparations in an effort to lower rT3, though the clinical benefit of this strategy remains unproven 2
• Approximately 60% of reverse T3 determinations in one study were obtained for seemingly inappropriate indications 5
• The biological effects resulting from changes in rT3 levels are incompletely understood, making clinical interpretation challenging 4