Reverse T3 (rT3) is considered metabolically inactive even though it accounts for one-third of all circulating thyroid hormones. Production increases during critical illness, surgery, trauma, and severe infection, but increased levels usually resolve once the health crisis is over.
However, elevated rT3 can also be associated with diabetes, inflammation, cardiovascular complications, heart failure, liver disease, aging, thyroid hormone resistance, genetic factors, carbohydrate restriction, and certain medications. Lower rT3 can be associated with HIV and central hypothyroidism.
Standard Range: 8.00 – 25.00 ng/dL (0.12 – 0.38 nmol/L)
The ODX Range: 10.00 – 25.00 ng/dL (0.15 – 0.38 nmol/L)
Low reverse T3 may be seen in HIV (Moura 2016) and central hypothyroidism (Exley 2021). Levels may decrease with the tricyclic antidepressant clomipramine (Halsall 2021).
High reverse T3 can be seen in non-thyroidal illnesses, including starvation, anorexia nervosa, surgery, severe trauma, hemorrhagic shock, burn, severe infection, and other causes of euthyroid sick syndrome (Pagana 2021).
Levels may increase with stress, short-term calorie deprivation, poor glucose control, diabetes (especially with a history of CVD), heart failure, liver disease, cirrhosis, pulmonary disease, acute myocardial infarction (Moura 2016), inflammation, cardiovascular events (Moura 2014), permanent atrial fibrillation (Jakowczuk 2016), endotoxin, carbohydrate restriction (DeGroot 2015), and high-dose soy isoflavone supplementation (Sathyapalan 2018).
Reverse T3 can also be elevated due to genetic factors, thyroid hormone resistance, aging, and medications such as amiodarone, glucocorticoids, and thyroxine. Elevated rT3 can be associated with increased mortality, likely due to non-thyroidal illness syndrome (Halsall 2021). Production of rT3 can increase with selenium insufficiency (Wardle 2019), and levels can be higher with synthetic T4 monotherapy than with desiccated thyroid treatment (Wilson 2021).
Reverse T3 (rT3) is the third most abundant form of thyroid hormone in circulation. Levels of rT3 can vary from one-tenth those of T3, e.g., 17 ng/dL (0.26 nmol/L) versus 140 ng/dL (2.15 nmol/L) respectively, to an rT3 concentration that is greater than that of T3 (Halsall 2021). Approximately one-third of T4 is converted to T3, while one-third is converted to rT3 due to deiodination changes. Conversion of T4 to T3 occurs via outer ring deiodination, while conversion to rT3 occurs via inner ring deiodination (Peeters 2017).
Reverse T3 is an inactive form of thyroid hormone designed to “put the brakes” on metabolism. Although some rT3 is typically produced, production can increase under certain conditions. These include stress, caloric deficit, critical illness, and circumstances associated with non-thyroidal illness syndrome (NTIS), also known as euthyroid sick syndrome. During such times, more T4 can be converted to rT3 with a concomitant decrease in T3 and a decrease in the ratio of T3 to rT3. The shift to reverse T3 may be an adaptive response to save energy and protein stores during stress (Moura 2016). Although this metabolic pathway can decrease the catabolism associated with illness, it can become detrimental if prolonged (McGregor 2015).
One study investigated central hypothyroidism versus euthyroid sick syndrome/NTIS in 78 subjects with low free T4 and low/normal TSH versus 35 healthy controls. Results indicate that a low mean rT3 level of 8.78 ng/dL (0.14 nmol/L) was associated with central hypothyroidism and did not normalize until T4 was administered. However, the higher mean rT3 of 23.81 ng/dL (0.37 nmol/L) seen with NTIS resolved over time, along with other thyroid biomarkers (Exley 2021).
Higher rT3 is associated with cardiac complications as well. A cohort study of 120 patients 55-85 years of age with signs of congestive heart failure exacerbation found those with permanent atrial fibrillation (PAF) had significantly higher reverse T3 than those without PAF, i.e., 61 ng/dL (0.93 nmol/L) vs. 32 ng/dL (0.49 nmol/L). An rT3 cut-off of 30 ng/dL (0.46 nmol/L) was the most sensitive and specific prognostic factor for PAF. Higher rT3 was significantly correlated with left ventricular posterior wall diameter as well. Researchers note the association between rT3 above 26.6 ng/mL (0.41 nmol/L) and significantly increased risk of mortality following myocardial infarction as well (Jakowczuk 2016).
A cross-sectional study of 140 subjects (70 with type 2 diabetes) revealed a correlation between increased rT3 and increased serum amyloid A (SAA). SAA is a pro-inflammatory marker synthesized in response to IL-6 and TNF-alpha and used in conjunction with CRP to predict an elevated risk of cardiovascular events (CVEs). Both rT3 and SAA median values were significantly higher in T2DM patients with a history of CVEs, i.e., 27 ng/dL (0.41 nmol/L) vs. 20 ng/dL (0.30 nmol/L) and 27.48 ug/mL vs. 12.85, respectively (Moura 2014).
DeGroot, Leslie J. “The Non-Thyroidal Illness Syndrome.” Endotext, edited by Kenneth R Feingold et. al., MDText.com, Inc., 1 February 2015.
Exley, Sarah, Sonal Banzal, and Udaya Kabadi. "Low Reverse T3: A Reliable, Sensitive and Specific in Diagnosis of Central Hypothyroidism." Open Journal of Endocrine and Metabolic Diseases 11.7 (2021): 137-143.
Halsall, David J, and Susan Oddy. “Clinical and laboratory aspects of 3,3',5'-triiodothyronine (reverse T3).” Annals of clinical biochemistry vol. 58,1 (2021): 29-37. doi:10.1177/0004563220969150
Jakowczuk, Maciej et al. “Permanent atrial fibrillation in heart failure patients as another condition with increased reverse triiodothyronine concentration.” Neuro endocrinology letters vol. 37,4 (2016): 337-342.
McGregor, Brock. "Extra-Thyroidal Factors Impacting Thyroid Hormone Homeostasis." Journal of Restorative Medicine 4.1 (2015): 40-49.
Moura Neto, A et al. “Relationship of thyroid hormone levels and cardiovascular events in patients with type 2 diabetes.” Endocrine vol. 45,1 (2014): 84-91. doi:10.1007/s12020-013-9938-6
Moura Neto, Arnaldo, and Denise Engelbrecht Zantut-Wittmann. “Abnormalities of Thyroid Hormone Metabolism during Systemic Illness: The Low T3 Syndrome in Different Clinical Settings.” International journal of endocrinology vol. 2016 (2016): 2157583. doi:10.1155/2016/2157583
Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.
Peeters, Robin P, and Theo J Visser. “Metabolism of Thyroid Hormone.” Endotext, edited by Kenneth R Feingold et. al., MDText.com, Inc., 1 January 2017.
Sathyapalan, Thozhukat et al. “The Effect of High Dose Isoflavone Supplementation on Serum Reverse T3 in Euthyroid Men With Type 2 Diabetes and Post-menopausal Women.” Frontiers in endocrinology vol. 9 698. 22 Nov. 2018, doi:10.3389/fendo.2018.00698
Wardle, Jon, and Jerome Sarris. Clinical naturopathy: an evidence-based guide to practice. Elsevier Health Sciences, 2019. 3rd edition.
Wilson, Julian Bryant, and Theodore C. Friedman. "Reverse T3 in Patients With Hypothyroidism, Helpful or a Waste of Time?." Journal of the Endocrine Society 5.Supplement_1 (2021): A952-A952.