What is reverse T3 (reverse triiodothyronine)?

Reverse T3 (Reverse Triiodothyronine)

Reverse T3 (rT3) is a biologically inactive form of T3 produced by peripheral 5-deiodination of T4 by type 1 and type 3 deiodinase enzymes, which may block T3 binding to thyroid hormone receptors and serves as a marker of altered thyroid hormone metabolism during illness or stress. 1

What is Reverse T3?

• Reverse T3 is formed from thyroxine (T4) through an alternative metabolic pathway
• Unlike T3 (triiodothyronine), which is metabolically active, rT3 has little to no biological activity
• It is produced by the action of deiodinase enzymes (D1 and D3) on T4 1
• Normal serum levels in adults are approximately 41 ng/dL 2

Physiological Role

• Acts as part of the body's energy conservation mechanism during illness
• Represents a pathway that diverts T4 from conversion to active T3
• May competitively inhibit T3 binding to thyroid hormone receptors
• Serves as a marker of altered thyroid hormone metabolism

Clinical Significance

Euthyroid Sick Syndrome (Non-thyroidal Illness Syndrome)

• Elevated rT3 levels are commonly seen in severe illness, with concurrent low T3 and normal or low T4 2
• This pattern represents a physiological adaptation to conserve energy during stress
• Conditions associated with elevated rT3 include:
  • Acute febrile illnesses
  • Hepatic cirrhosis
  • Severe protein-calorie malnutrition
  • Acute myocardial infarction 3

Limitations as a Diagnostic Tool

• rT3 is not reliable for distinguishing between hypothyroid sick syndrome and euthyroid sick syndrome 4
• Patients with hypothyroidism plus illness may have normal rT3 levels
• Euthyroid patients may have low rT3 levels
• rT3 levels are affected by:
  • Medications
  • Liver function (linearly related to bilirubin up to 10 mg/dL) 4
  • Nutritional status

Prognostic Value

• Elevated rT3 levels have been associated with increased mortality in acute myocardial infarction patients 3
• In one study, patients with rT3 levels above 0.41 nmol/L had a threefold higher risk of one-year mortality after myocardial infarction

Relationship to Thyroid Replacement Therapy

• Patients taking levothyroxine (L-T4) alone tend to have higher rT3 levels than those on preparations containing T3 1
• Approximately 15% of patients on L-T4 replacement with normalized TSH continue to report fatigue and other hypothyroid symptoms 1
• rT3 levels correlate positively with free T4 and free T3 levels and inversely with log TSH levels 1

Common Pitfalls in rT3 Testing

• Overreliance on rT3 testing without proper clinical context
• Using rT3 as the sole determinant for thyroid hormone replacement decisions
• Failure to consider other factors affecting rT3 levels (liver function, medications, nutritional status)
• Standard guidelines do not recommend routine measurement of rT3 in the evaluation of thyroid disorders 5

While some practitioners use rT3 levels to guide treatment decisions, particularly in patients with persistent symptoms despite normal TSH, this approach is not supported by major clinical guidelines and requires further research to establish its clinical utility.