Reverse T3: An Inactive Metabolite of Thyroid Hormone Metabolism
Reverse T3 (rT3) is a biologically inactive form of triiodothyronine produced by inner ring deiodination of thyroxine (T4), which may compete with active T3 for receptor binding but has minimal thyroid hormone activity. 1
Definition and Production
Reverse T3 (3',5'-triiodothyronine) is the third most abundant iodothyronine in human circulation, formed when the pro-hormone thyroxine (T4) undergoes inner ring deiodination through the action of type 1 and type 3 deiodinase enzymes (D1 and D3) 2, 1. Unlike the active metabolite T3, which is produced by outer ring deiodination of T4, reverse T3 has minimal biological activity.
The normal thyroid gland contains approximately:
- 200 mcg of levothyroxine (T4) per gram of gland tissue
- 15 mcg of liothyronine (T3) per gram 3
However, the ratio of these hormones in circulation doesn't match their ratio in the thyroid gland, as approximately 80% of circulating T3 comes from peripheral monodeiodination of T4 3.
Physiological Role
Reverse T3 has traditionally been considered an inactive end-product of thyroid hormone metabolism that:
- Binds weakly to thyroid hormone receptors 1
- May compete with active T3 for receptor binding 2
- Diverts T4 away from T3 production 1
- Increases during states of physiological stress or illness 3, 1
Clinical Significance
Euthyroid Sick Syndrome
Elevated reverse T3 is a hallmark of "euthyroid sick syndrome" (also called "non-thyroidal illness syndrome"), which occurs during severe illness 1, 4. In this condition:
- T3 levels decrease
- Reverse T3 levels increase
- This is believed to be an adaptive response to conserve energy during illness 5
Medication Effects
Common medications such as amiodarone can inhibit the metabolism of reverse T3, leading to increased levels 1.
Diagnostic Value
Reverse T3 measurement may provide useful diagnostic information in:
- Genetic conditions affecting iodothyronine deiodinases
- Disorders of thyroid hormone transporters
- Abnormalities of thyroid hormone transport proteins 1
Thyroid Hormone Replacement
Studies have shown that patients on different thyroid hormone replacement therapies show varying levels of reverse T3:
- Highest levels are found in patients taking T4 (levothyroxine) alone
- Lowest levels are found in patients taking preparations containing T3 alone 2
Potential Prognostic Value
Some research suggests reverse T3 may have prognostic significance in certain conditions:
- In one study, elevated reverse T3 levels (>0.41 nmol/L) at the time of myocardial infarction were associated with increased mortality risk (hazard ratio = 3.0) 5
Emerging Research
Recent research has challenged the view that reverse T3 is entirely inactive:
- Some studies suggest it may bind to thyroid hormone analog receptors on plasma membrane integrin αvβ3 6
- In laboratory studies, reverse T3 has been shown to increase proliferation of certain cancer cells by 50-80% 6
Measurement
Historically, reverse T3 was measured by competitive radioimmunoassay, but these methods have been largely replaced by more accurate mass-spectrometric methods that are less susceptible to interference from other iodothyronines 1.
Despite these advances in measurement techniques, routine clinical application of reverse T3 testing remains limited, as its utility in guiding treatment decisions for most thyroid conditions has not been firmly established in major clinical guidelines.