What is reverse T3 (reverse triiodothyronine)?

From the Guidelines

Reverse T3 (reverse triiodothyronine) is an inactive form of the thyroid hormone T3 that is produced when the body converts the hormone T4 (thyroxine) through an alternative metabolic pathway. Unlike regular T3, which is metabolically active and helps regulate metabolism, energy production, and body temperature, reverse T3 cannot activate thyroid hormone receptors and essentially blocks the action of active T3. The body produces more reverse T3 during times of stress, illness, caloric restriction, or certain medical conditions as a way to conserve energy and slow down metabolism. This can lead to symptoms that mimic hypothyroidism even when standard thyroid tests appear normal. Elevated reverse T3 levels may be associated with conditions like chronic stress, severe illness, inflammation, nutrient deficiencies, and certain medications. Testing for reverse T3 is not routinely performed but may be useful in cases where patients have symptoms of hypothyroidism despite normal TSH and T4 levels, as noted in various studies 1. Understanding reverse T3 helps explain why some people experience low thyroid symptoms even with seemingly normal thyroid function on standard tests. Some key points to consider include:

• The production of reverse T3 is increased during stress, illness, or certain medical conditions.
• Elevated reverse T3 levels can lead to symptoms similar to hypothyroidism.
• Testing for reverse T3 may be beneficial in cases where patients have hypothyroidism symptoms despite normal TSH and T4 levels.
• The relationship between reverse T3 and thyroid function is complex and not fully understood, as discussed in studies such as 1. However, based on the most recent and highest quality evidence, testing for reverse T3 is not routinely recommended but may be considered in specific cases.

From the FDA Drug Label

Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3).

Reverse T3 (rT3) is a product of the deiodination of T4, with approximately 80% of the daily dose of T4 being deiodinated to yield equal amounts of T3 and rT3 2.

• It is one of the metabolites of thyroid hormone metabolism.
• The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at other sites.

From the Research

Definition and Production of Reverse T3

• Reverse T3 (rT3) is a biologically inactive form of T3 (triiodothyronine), a thyroid hormone, created by peripheral 5 deiodination of T4 (thyroxine) by type 1 and type 3 deiodinase enzymes (D1 and D3 respectively) 3.
• It is produced by the inner ring deiodination of the pro-hormone thyroxine (T4) 4.
• Reverse T3 is the third most abundant iodothyronine circulating in human blood 4.

Clinical Significance of Reverse T3

• Elevated rT3 levels have been found in patients with symptoms of fatigue on various thyroid hormone replacements, with the highest levels in those taking L-T4 replacement alone 3.
• Reverse T3 may block T3 binding to the thyroid hormone receptor, potentially leading to continued fatigue and other hypothyroid symptoms in patients with normalized thyroid-stimulating hormone (TSH) levels 3.
• However, reverse T3 is not reliable in distinguishing between hypothyroid sick patients and euthyroid sick patients, due to drug and disease effects on thyroid hormone metabolism 5.

Measurement and Regulation of Reverse T3

• Serum rT3 concentration is increased as part of the non-thyroidal illness syndrome, and by administration of common medications such as amiodarone which inhibit the metabolism of rT3 4.
• Serum rT3 concentration is also affected by genetic conditions that affect the iodothyronine deiodinases, as well as thyroid transporters and transport proteins 4.
• The analysis of serum rT3 has been improved by mass-spectrometric methods, which are less susceptible to interference from other more abundant iodothyronines 4.

Relationship with Other Thyroid Hormones

• Reverse T3 is linearly related to bilirubin up to a bilirubin of approximately 171 microM (10 mg/dL) 5.
• There is an inverse linear relationship between the log TSH and the reverse T3 5.
• T3 levels bear little relation to thyroid status in patients on levothyroxine replacement, and normal levels can be seen in over-replaced patients 6.