What is reverse Triiodothyronine (T3)?

Reverse Triiodothyronine (rT3): Definition and Clinical Significance

Reverse T3 (rT3) is a biologically inactive form of thyroid hormone produced by the inner ring deiodination of thyroxine (T4) through type 1 and type 3 deiodinase enzymes, which diverts T4 away from conversion to the active T3 hormone.

What is Reverse T3?

Reverse T3 is the third most abundant iodothyronine circulating in human blood, created through a different deiodination pathway than active T3:

• Formation: While T3 is formed by outer ring deiodination of T4, rT3 is produced by inner ring deiodination of T4 1
• Structure: Chemically known as 3',5'-triiodothyronine (compared to T3 which is 3,5,3'-triiodothyronine)
• Activity: Generally considered biologically inactive as it binds only weakly to thyroid hormone receptors 1

Physiological Role

Reverse T3 serves important physiological functions:

• Metabolic regulation: Diverts T4 away from conversion to active T3, potentially serving as a metabolic "brake" during certain physiological states
• Illness response: Levels typically increase during severe illness as part of the "euthyroid sick syndrome" 2
• Energy conservation: May help conserve energy during starvation or illness by reducing active thyroid hormone levels

Clinical Significance

Diagnostic Value

Measuring rT3 has limited but specific clinical applications:

• Non-thyroidal illness: Elevated in "euthyroid sick syndrome" but not reliable for distinguishing between hypothyroid sick patients and euthyroid sick patients 2
• Medication effects: Certain drugs like amiodarone can increase rT3 levels by inhibiting its metabolism 1
• Genetic conditions: Can provide diagnostic information in conditions affecting deiodinase enzymes, thyroid transporters, or transport proteins 1

Relationship to Thyroid Replacement

Recent research has shown interesting patterns with thyroid replacement:

• Patients taking T4 (levothyroxine) alone have higher rT3 levels than those not on treatment 3
• The highest rate of elevated rT3 (20.9%) was found in patients taking T4 alone 3
• Patients on T3-only preparations had the lowest rT3 levels 3

Potential Biological Effects

While traditionally considered inactive, emerging research suggests rT3 may have some biological activity:

• Binds to extra-nuclear iodothyronine receptors that may play a role in cell proliferation 1
• Recent studies indicate rT3 may increase proliferation of certain cancer cells by 50-80%, suggesting it could potentially support cancer growth 4

Measurement and Reference Values

• Modern methods: Mass spectrometry has replaced older radioimmunoassay techniques, providing more accurate measurements 1
• Normal range: Upper limit of normal is typically around 24.1 ng/dL 3
• Interpretation: Must be considered alongside TSH, free T4, and free T3 levels for proper clinical context

Clinical Implications

Understanding rT3 may be relevant in:

• Persistent hypothyroid symptoms: Some patients with normal TSH on levothyroxine continue to report fatigue and other hypothyroid symptoms, which some clinicians attribute to high rT3 levels 3
• Treatment decisions: Some practitioners use rT3 levels to guide decisions about combination T4/T3 therapy, though this remains controversial
• Monitoring illness: Can reflect metabolic adaptation during severe illness

The clinical utility of rT3 measurement remains limited in mainstream endocrinology, but ongoing research continues to explore its potential significance in thyroid hormone metabolism and overall health.