What Free T-4 Indicates
Free T-4 (thyroxine) measures the metabolically active, unbound thyroid hormone in your blood and is the most accurate indicator of actual thyroid hormone availability to your tissues. 1, 2
Primary Clinical Significance
Free T-4 represents the small fraction (approximately 0.03%) of total thyroxine that circulates unbound to serum proteins and is biologically active 1. This measurement correlates directly with hormonal activity at the tissue level, making it superior to total T4 for assessing thyroid function 2.
Diagnostic Value
- Free T-4 distinguishes between subclinical and overt thyroid dysfunction when combined with TSH measurement 3
- In subclinical hypothyroidism, TSH is elevated but free T-4 remains normal 3
- In overt hypothyroidism, both TSH is elevated AND free T-4 is low 3
- In hyperthyroidism, free T-4 is elevated along with suppressed TSH 1
Why Free T-4 Rather Than Total T-4
Free T-4 eliminates false results caused by variations in thyroid hormone-binding proteins, which commonly occur in pregnancy, estrogen therapy, familial binding protein abnormalities, and nonthyroidal illness 2. Total T4 can be misleadingly high or low in euthyroid patients with binding protein abnormalities, while free T-4 correctly identifies true thyroid status 2.
Clinical Applications
Initial Thyroid Assessment
- TSH should be measured first as the primary screening test (sensitivity >98%, specificity >92%), followed by free T-4 if TSH is abnormal 3
- The combination of TSH and free T-4 definitively excludes both overt and subclinical thyroid dysfunction when both are normal 3
Monitoring Levothyroxine Therapy
- Free T-4 helps interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize than free T-4 3
- In patients on levothyroxine replacement, free T-4 should be maintained in the normal range (typically 9-19 pmol/L or 12-22 pmol/L depending on assay) alongside normalized TSH 3
- Patients on adequate levothyroxine replacement often have free T-4 in the higher end of normal range while TSH is normalized 4
Special Diagnostic Situations
Free T-4 is essential for diagnosing central hypothyroidism, where TSH may be low or inappropriately normal despite low free T-4, indicating pituitary or hypothalamic dysfunction rather than primary thyroid failure 3. In this scenario, TSH cannot be used as a reliable screening test 3.
Important Caveats
- Free T-4 alone is insufficient to determine thyroid health—TSH remains the primary screening test, and subclinical hypothyroidism (elevated TSH with normal free T-4) represents a clinically significant condition that may require treatment 3
- Approximately 5% of hyperthyroid patients have T3 thyrotoxicosis with normal free T-4 but elevated T3, so free T-4 can miss this diagnosis 1
- Reliable free T-4 assays must be used, as methodological limitations can produce artifactual results in pregnancy, nonthyroidal illness, and thyroid hormone-binding protein abnormalities 2
Physiological Context
The normal thyroid gland produces both T4 and a small amount of T3 directly 5. However, most circulating T3 comes from peripheral conversion of T4 to T3 in tissues 5. In patients on levothyroxine replacement, the free T3 to free T-4 ratio is typically lower than in euthyroid individuals, with higher free T-4 levels needed to maintain normal TSH and adequate tissue T3 concentrations 4.