Thyroid Biomarkers: Free T4

Optimal Takeaways

Free T4 (FT4) is the amount of thyroxine that circulates free and unbound to protein carriers; therefore, levels are unaffected by protein changes. Although only a small amount of circulating T4 is free, FT4 reflects thyroid status better than total T4. A low FT4 can be associated with iodine insufficiency, hypothyroidism, thyroid inflammation, or certain medications. An elevated FT4 can be associated with hyperthyroidism, acute thyroid inflammation, thyroid cancer, and certain medications.  

Standard Range: 0.80 – 1.80 ng/dL (10.30 – 23.17 pmol/L)

The ODX Range: 1.00 – 1.50 ng/dL (12.87 – 19.30 pmol/L)    

Low free T4 is observed in hypothyroidism, Hashimoto thyroiditis, thyroid ablation, thyroid agenesis, iodine insufficiency, pituitary or hypothalamic insufficiency, renal failure, myxedema, Cushing syndrome, and use of certain drugs, including furosemide, phenytoin, rifampicin, and methadone (Pagana 2021).

High free T4 can be associated with hyperthyroidism, acute thyroiditis, thyroid cancer, pregnancy, hepatitis, and certain medications, including thyroxine, aspirin, propranolol, heparin, danazol (Pagana 2021), and heparin (Koulouri 2013). Elevated free T4 may also be associated with frailty, fatigue, dementia, mortality (Yeap 2017), cognitive decline, cardiovascular disease (Simonsick 2016), CVD mortality (Ataoglu 2018), atrial fibrillation, heart failure (Cappola 2015), and breast cancer (Lei 2022).  

Overview

Binding proteins can affect the amount of hormone available and will affect total hormone levels but not free hormone levels. Free thyroxine (FT4) represents approximately 1% of circulating T4 that is free and not bound to any protein. Free FT4 is considered a better indicator of thyroid function than total T4 (Pagana 2021). However, thyroid hormone metabolism is dynamic and influenced by physiological stressors, including changes in circadian rhythm, fasting, aging, and non-thyroidal systemic illnesses (Abbey 2022). These factors should be considered when investigating the cause of abnormal thyroid biomarkers.

Micronutrient availability influences thyroid hormone metabolism, especially iodine, required for its production. In a national health survey of 7,061 subjects in an iodine-sufficient region, FT4 levels were maintained at 1.25 ng/dL (16.09 pmol), while the mean TSH for this population was 2.16 uU/mL (Park 2018).

Research on 602 euthyroid subjects 68-97 years old found that those with an FT4 at the lower end of normal had better energy levels, mobility, and fitness in general than those at the higher end of normal. The lower range associated with better function was 0.76-0.90 ng/dL (9.78-11.58 pmol/L) versus the highest range of 1.08-1.50 ng/dL (13.9-19.31 pmol/L). Levels of TSH appeared to have minimal impact on physical function in this group, and T3 levels were not assessed (Simonsick 2016).

A later study of 3,885 men 70-89 years old found that 411 subjects with good or excellent health maintained a median FT4 of 1.21 ng/dL (15.6 pmol/L) with a range of 1.12–1.30 ng/dL (14.42-16.73 pmol/L). The highest mortality was noted in the highest FT4 range of 1.37-1.87 ng/dL (17.63-24.05 pmol/L). Levels of T3 were not assessed in this study (Yeap 2017).

Measuring FT4 can help determine if a mildly elevated TSH is associated with impending hypothyroidism where FT4 decreases; or an age-related adaptive response to stress where FT4 increases, even within the normal range. Data was reviewed for 72 older subjects with an average TSH of 5.4 uU/mL. Results suggest that those with the lowest FT4 of 0.86 ng/dL (11.07 pmol/L), a TSH of 5.2 uU/mL, and an FT3:FT4 ratio of 3.15 had a pattern most likely to represent early hypothyroidism. Researchers emphasize investigating additional thyroid biomarkers before using TSH alone to diagnose subclinical hypothyroidism (Abbey 2022).

Thyroid function also affects cardiovascular health and should be evaluated when assessing CVD risk. In one study of 9,233 participants, the highest CVD risk was seen in those 65 or older with an FT4 of 1.70 ng/dL (22 pmol/L) or above. The lowest risk was seen with an FT4 of 1.10 ng/dL (14.5 pmol/L). Researchers suggest FT4 may be a modifiable risk factor for CVD risk and mortality, especially in men and older adults (Chaker 2017). Another study of 2,843 older adults found that those in the highest quartile of FT4 at 1.48–1.70 ng/dL (19.1–21.8 pmol/L) had a significantly higher occurrence of coronary artery disease, atrial fibrillation, heart failure, and mortality (Cappola 2015).

A small study of breast cancer patients observed that mean free T4 in patients was higher at 2.93 ng/dL (37.71 pmol/L) versus 1.39 ng/dL (17.89 pmol/L) in controls. Significantly increased TPO antibodies were also observed in the patient group (Ali 2011). An association between higher FT3 and FT4 and increased risk of breast cancer was also noted in a 2022 meta-analysis of 13 studies comprising 5,957 subjects. Researchers note that biologically active thyroid hormone stimulates the proliferation and differentiation of breast tissue and affects aromatase, estrogen, and estrogen receptor expression (Lei 2022).

References

Abbey, Enoch J et al. “Free Thyroxine Distinguishes Subclinical Hypothyroidism From Other Aging-Related Changes in Those With Isolated Elevated Thyrotropin.” Frontiers in endocrinology vol. 13 858332. 4 Mar. 2022, doi:10.3389/fendo.2022.858332

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            

Cappola, Anne R et al. “Thyroid function in the euthyroid range and adverse outcomes in older adults.” The Journal of clinical endocrinology and metabolism vol. 100,3 (2015): 1088-96. doi:10.1210/jc.2014-3586

Chaker, Layal et al. “Defining Optimal Health Range for Thyroid Function Based on the Risk of Cardiovascular Disease.” The Journal of clinical endocrinology and metabolism vol. 102,8 (2017): 2853-2861. doi:10.1210/jc.2017-00410

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

Lei, Zhengwu et al. “Free triiodothyronine and free thyroxine hormone levels in relation to breast cancer risk: a meta-analysis.” Endokrynologia Polska vol. 73,2 (2022): 309-315. doi:10.5603/EP.a2022.0020

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Park, So Young et al. “Age- and gender-specific reference intervals of TSH and free T4 in an iodine-replete area: Data from Korean National Health and Nutrition Examination Survey IV (2013-2015).” PloS one vol. 13,2 e0190738. 1 Feb. 2018, doi:10.1371/journal.pone.0190738

Simonsick, Eleanor M et al. “Free Thyroxine and Functional Mobility, Fitness, and Fatigue in Euthyroid Older Men and Women in the Baltimore Longitudinal Study of Aging.” The journals of gerontology. Series A, Biological sciences and medical sciences vol. 71,7 (2016): 961-7. doi:10.1093/gerona/glv226

Yeap, Bu B et al. “Reference Ranges for Thyroid-Stimulating Hormone and Free Thyroxine in Older Men: Results From the Health In Men Study.” The journals of gerontology. Series A, Biological sciences and medical sciences vol. 72,3 (2017): 444-449. doi:10.1093/gerona/glw132