Thyroid Biomarkers: Free T3

Optimal Takeaways

Free T3 (FT3) is the most biologically active form of thyroid hormone as it is unbound and readily available. The initial measurement of FT3 may not reveal early hypothyroidism, but it is clinically useful for monitoring progress and assessing symptomatology. A low free T3 can also be seen with euthyroid sick syndrome, decreased calorie intake, diabetes, heart failure, and pulmonary and liver disease. Elevated FT3 is associated with hyperthyroidism, destructive thyroiditis, decreased lean body mass, cardiac complications, and the use of certain medications.

Standard Range: 2.30 – 4.20 pg/mL (3.53 – 6.45 pmol/L)

The ODX Range: 3.00 – 3.50 pg/mL (4.61 – 5.38 pmol/L)

Low free T3 may be seen with hypothyroidism, euthyroid sick syndrome (non-thyroidal illness syndrome), calorie deprivation, heart failure, liver disease, diabetes, pulmonary disease (Moura 2016), elevated inflammatory cytokines, hypoxia (Ataoglu 2018), and phthalate exposure (Choi 2020).

High free T3 may be seen with hyperthyroidism, Graves’ disease, destructive thyroiditis (Chen 2018), psychiatric illness (Moura 2016), insulin resistance, decreased lean body mass (Roef 2012), elevated heart rate, increased left ventricular wall thickness, and late ventricular filling (Roef 2013). Heparin can increase circulating free fatty acids, which can dislodge thyroid hormones from their binding proteins and increase FT3 (Koulouri 2013).  

Overview

Serum free triiodothyronine (FT3) reflects the amount of biologically available T3 in the blood and may also reflect intracellular concentrations to some degree (Abdalla 2014). Evaluation of FT3 may be most valuable for assessing clinical progress and response to therapy versus an initial diagnosis of hypothyroidism as T3 and FT3 levels may be maintained within normal limits initially due to elevated TSH and upregulation of the conversion of T4 to T3 (Garber 2012). Along with iodine and selenium, zinc also plays an integral role in thyroid hormone metabolism and is required to convert T4 to T3. One 12-week study demonstrated that zinc supplementation significantly increased FT3 levels and the FT3 to FT4 ratio in hypothyroid patients (McGregor 2015).

The conversion of T4 to T3 requires the selenium-dependent enzyme 5-deiodinase. Several factors can disrupt this enzyme and compromise thyroid function. These include selenium insufficiency, oxidative stress, suboptimal nutrition, stress, cortisol, and toxic metals, including mercury, cadmium, and lead (Raymond 2021).

A decrease in FT3 is considered a sensitive indicator of acute and chronic disease, especially in older adults, and can be associated with mortality (Ataoglu 2018). A decreasing FT3 in the absence of known thyroid disease may be caused by euthyroid sick syndrome, also known as low T3 syndrome or non-thyroidal illness syndrome (NTIS). The phenomenon may be associated with transient changes in deiodinase enzymes or abnormalities in thyroid-binding globulin. The syndrome may be accompanied by elevated proinflammatory cytokines and a low or normal TSH though TSH can also be slightly increased (Moura 2016). In addition, euthyroid sick syndrome is characterized by an increased reverse T3, normal/high free T4, and normal total T4 (Malik 2002).

Lower levels of free T3 within the conventional range may be associated with symptomology in those on T4 monotherapy despite a low TSH. A retrospective analysis of 319 thyroid cancer patients observed that those on monotherapy whose FT3 remained in the lower half of the reference range continued to complain of common hypothyroid symptoms, including fatigue, cold intolerance, and weight gain. Symptoms were not resolved until FT3 increased to at least the upper half of the conventional reference range and TSH was below the conventional reference range (Larisch 2018). Researchers note that monotherapy often results in FT3 levels below the median, even below the reference range, and that the clinical consequences should be assessed for and addressed. A trial and monitoring of combination therapy with T4 and T3 may be effective unless contraindicated (Ettleson 2020).

Lower free T3 was observed in patients with severe COVID-19 and coincided with increased all-cause mortality. Meta-analysis of seven retrospective studies comprising 1,183 hospitalized COVID patients found that lower FT3 was associated with ICU admission, disease severity, and mortality. Researchers note that the cytokine storm observed in severe COVID may cause decreased FT3 and subsequent clinical deterioration (Llamas 2021).

Elevations in free T3 must be investigated as well. An elevated free T3 is observed in hyperthyroidism, painless thyroiditis, and subacute thyroiditis. In one study of 180 thyrotoxicosis subjects, the highest free T3 was seen in untreated Grave’s, with a mean value of 16.17 pg/mL (24.85 pmol/L). The mean FT3 in subacute thyroiditis was 6.3 pg/mL (9.69 pmol/L), 4.14 pg/mL (6.36 pmol/L) in painless thyroiditis, and 2.63 pg/mL (4.04 pmol/L) in healthy controls. Graves’ disease is associated with the hyperactive thyroid gland converting more T4 to T3 within the thyroid gland. In the study, Graves’ was characterized by enlarged thyroid, heat intolerance, fatigue, muscle weakness, weight loss, increased sweating, tremors, and increased appetite. In destructive thyroiditis, e.g., painless thyroiditis and subacute thyroiditis, FT3 is released directly into the bloodstream due to damage to the thyroid follicle cell. Subacute thyroiditis in the study presented with severe neck pain, fever, and elevated erythrocyte sedimentation rate (Chen 2018).

The heart is extremely sensitive to thyroid hormones, and elevated levels can have adverse cardiac effects. One cross-sectional study of 2.078 euthyroid subjects found that increasing FT3 was significantly associated with increasing heart rate. This association was seen even in those with TSH levels within the narrow range of 0.5-2.5 uU/L. Quartiles for FT3 were: below 2.8, 2.81-3.00, 3.01-3.24, and above 3.24 pg/mL in women, and below 3.12, 3.13-3.36, 3.37-3.58, and above 3.59 pg/mL in men (i.e., below 4.30, 4.32-4.60, 4.62-4.98, and above 4.98 pmol/L in women and below 4.79, 4.8-5.16, 5.18-5.49, and above 5.51 pmol/L). Researchers confirm a gradual and robust association between free T3 levels and adverse effects on cardiac structure and function, an effect often observed with overt hyperthyroidism (Roef 2013).

Higher FT3 may have some association with breast cancer as well. One study investigating the incidence of thyroid disease in breast cancer observed higher levels of FT3, FT4, TSH, and TPO antibodies in those with cancer versus controls. Mean serum FT3 in patients was twice that of controls, i.e., 4.71 pg/mL (7.25 pmol/L) versus 2.22 pg/mL (3.42 pmol/L), respectively. The mean TSH in patients was 4.12 versus 1.39 uU/mL in controls. Some research suggests that altered thyroid function may influence breast cancer progression (Ali 2011).

Research in healthy male siblings 25-45 years of age reported an association between higher FT3 and higher BMI, higher leptin levels, increased insulin resistance, and lower muscle and lean body mass. Researchers recommend further evaluating the association between higher thyroid hormones and the clinical presentation of insulin resistance, increased leptin, higher body fat, and lower muscle mass (Roef 2012).

References

Abdalla, Sherine M, and Antonio C Bianco. “Defending plasma T3 is a biological priority.” Clinical endocrinology vol. 81,5 (2014): 633-41. doi:10.1111/cen.12538

Ali, Athar, et al. "Relationship between the levels of serum thyroid hormones and the risk of breast cancer." J Biol Agr Healthc 2 (2011): 56-60.

Ataoglu, Hayriye Esra et al. “Prognostic significance of high free T4 and low free T3 levels in non-thyroidal illness syndrome.” European journal of internal medicine vol. 57 (2018): 91-95. doi:10.1016/j.ejim.2018.07.018      

Chen, Xinxin et al. “Diagnostic Values of Free Triiodothyronine and Free Thyroxine and the Ratio of Free Triiodothyronine to Free Thyroxine in Thyrotoxicosis.” International journal of endocrinology vol. 2018 4836736. 4 Jun. 2018, doi:10.1155/2018/4836736

Choi, Sohyeon et al. “Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population.” Environment international vol. 140 (2020): 105783. doi:10.1016/j.envint.2020.105783

Ettleson, Matthew D, and Antonio C Bianco. “Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?.” The Journal of clinical endocrinology and metabolism vol. 105,9 (2020): e3090–e3104. doi:10.1210/clinem/dgaa430

Ganesan, Kavitha. and Khurram Wadud. “Euthyroid Sick Syndrome.” StatPearls, StatPearls Publishing, 30 October 2021.

Garber, Jeffrey R et al. “Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.” Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists vol. 18,6 (2012): 988-1028. doi:10.4158/EP12280.GL

Koulouri, Olympia, and Mark Gurnell. “How to interpret thyroid function tests.” Clinical medicine (London, England) vol. 13,3 (2013): 282-6. doi:10.7861/clinmedicine.13-3-282

Larisch, Rolf et al. “Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer.” Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association vol. 126,9 (2018): 546-552. doi:10.1055/s-0043-125064

Llamas, Michael et al. “Low free-T3 serum levels and prognosis of COVID-19: systematic review and meta-analysis.” Clinical chemistry and laboratory medicine vol. 59,12 1906-1913. 11 Aug. 2021, doi:10.1515/cclm-2021-0805

Malik, R, and H Hodgson. “The relationship between the thyroid gland and the liver.” QJM : monthly journal of the Association of Physicians vol. 95,9 (2002): 559-69. doi:10.1093/qjmed/95.9.559

McGregor, Brock. "Extra-Thyroidal Factors Impacting Thyroid Hormone Homeostasis." Journal of Restorative Medicine 4.1 (2015): 40-49.

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. 15th ed., Mosby, 2021.

Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021.

Roef, Greet, et al. "Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men." European journal of endocrinology 167.5 (2012): 719.

Roef, Greet L et al. “Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women.” Thyroid : official journal of the American Thyroid Association vol. 23,8 (2013): 947-54. doi:10.1089/thy.2012.0471