The reverse triiodothyronine measurement in serum is used to diagnose euthyroid sick syndrome.
More Information
Reverse T3 (rT3) is an isomer of the active thyroid hormone triiodothyronine (T3), formed through an alternative metabolic pathway from thyroxine (T4). Although structurally similar to T3, rT3 lacks biological activity at the thyroid hormone receptors and does not contribute to cellular metabolic processes. Instead, it serves as a regulatory byproduct of thyroid hormone metabolism, reflecting the body's adaptive responses to physiological stress, illness, fasting, or changes in energy demand. The Reverse T3 test quantitatively measures the concentration of rT3 in the blood. It is primarily utilized in the diagnostic evaluation of altered thyroid hormone metabolism, particularly in contexts where classical markers like TSH (thyroid-stimulating hormone), total T4, free T4, and total or free T3 may not adequately explain a patient’s metabolic state or symptoms.
The synthesis of reverse T3 occurs through the activity of deiodinase enzymes, precisely type 3 iodothyronine deiodinase (D3). Deiodinases are selenoproteins that regulate thyroid hormone activation and inactivation. While type 1 (D1) and type 2 (D2) deiodinases catalyze the conversion of T4 into the active T3 via outer ring deiodination, D3 catalyzes inner ring deiodination, converting T4 into reverse T3. This conversion renders the molecule inactive by preventing it from binding to nuclear thyroid hormone receptors. In this way, the body controls the amount of active thyroid hormone available at the cellular level, dynamically modulating metabolic rate according to physiological needs.
Under conditions of acute or chronic stress—such as sepsis, trauma, burns, starvation, liver dysfunction, renal failure, or prolonged illness—the body may reduce the conversion of T4 to T3 and instead favor conversion to rT3. This shift is believed to be an energy-conserving mechanism, as active T3 drives numerous energy-intensive metabolic processes, including protein synthesis, mitochondrial function, thermogenesis, and lipid metabolism. By increasing rT3 production and reducing T3 levels, the body can temporarily suppress metabolic activity and reduce energy expenditure during physiological strain. As a result, elevated levels of rT3 are commonly seen in the so-called "non-thyroidal illness syndrome" (NTIS), also known as "euthyroid sick syndrome." In this condition, patients may exhibit symptoms that mimic hypothyroidism despite having a normally functioning thyroid gland and even normal TSH levels.
Reverse T3 also accumulates when hepatic clearance mechanisms are impaired. The liver plays a central role in thyroid hormone metabolism and clearance, and any dysfunction, such as cirrhosis or hepatic congestion, can lead to decreased elimination of rT3, thereby contributing to its elevation. Moreover, cortisol and pro-inflammatory cytokines (e.g., IL-6, TNF-alpha) have been shown to upregulate D3 activity and suppress D1 and D2, thereby influencing rT3 levels during systemic inflammatory states.
Unlike T3 or T4, reverse T3 does not inhibit feedback on the hypothalamic-pituitary-thyroid axis. Therefore, its elevation does not suppress TSH secretion, and as such, it does not appear in conventional feedback loops used to regulate thyroid hormone production. This lack of influence on the axis highlights the need for dedicated testing in cases where peripheral thyroid hormone utilization or conversion is suspected to be abnormal.
In clinical practice, measuring rT3 may provide essential insights in several scenarios. First, it can be used to distinguish between true hypothyroidism and NTIS. While both conditions may present with low T3, only NTIS is typically associated with elevated rT3. Second, it may help identify impaired peripheral conversion in individuals who continue to experience hypothyroid symptoms despite normal TSH and T4 levels. These individuals may have low T3 and elevated rT3, indicating a functional conversion disorder rather than primary thyroid disease. Third, the test can aid in monitoring recovery from severe illness, as rT3 levels often normalize as the patient’s systemic condition improves.
The test is performed using immunoassay techniques to ensure specificity and sensitivity. Serum rT3 levels are usually interpreted with TSH, free T3, and free T4 to obtain a complete picture of thyroid hormone dynamics. A high rT3-to-fT3 ratio is a key indicator of impaired T4-to-T3 conversion, especially under stress or illness.
In addition to clinical illness, various medications may influence rT3 levels. Drugs such as glucocorticoids, beta-blockers, amiodarone, and certain anesthetics have been shown to alter deiodinase activity and shift T4 metabolism toward rT3. Furthermore, chronic caloric restriction, malnutrition, or extreme dieting can increase rT3 levels as part of the body’s response to energy conservation, often leading to low metabolism and fatigue symptoms.
Due to its complex interactions with physiological and pathological processes, reverse T3 is increasingly recognized not merely as an inactive metabolite, but as a dynamic indicator of the body’s metabolic and endocrine state. When standard thyroid function tests fall short in explaining persistent symptoms or when thyroid dysfunction is suspected in critically ill patients, the Reverse T3 test adds diagnostic depth by assessing peripheral hormone conversion and inactivation. Its role is particularly vital in integrative and functional medicine contexts, where the focus extends beyond glandular output to include tissue-level hormone bioavailability and function.
