What FT4 Measures
FT4 (Free Thyroxine) measures the unbound, biologically active fraction of thyroxine hormone circulating in the blood, representing approximately 0.02% of total T4 that is not bound to thyroid-binding proteins. 1
Physiological Basis
- FT4 represents the metabolically active thyroid hormone that is available to enter target tissues and exert physiological effects 2, 1
- The thyroid gland produces primarily T4 (80% of hormonal output), with most circulating T4 bound to thyroid-binding globulin (TBG), transthyretin, and albumin 1
- Only the free (unbound) fraction can cross cell membranes and interact with cellular receptors, making it a more accurate reflection of thyroid status than total T4 3, 1
Clinical Utility
FT4 measurement is essential for distinguishing between primary thyroid dysfunction and central (pituitary/hypothalamic) disorders when interpreted alongside TSH. 4
Key Diagnostic Patterns:
- Primary hypothyroidism: Low FT4 with elevated TSH 4
- Central hypothyroidism: Low FT4 with low or inappropriately normal TSH 4
- Primary hyperthyroidism: Elevated FT4 with suppressed TSH 4
- Subclinical hyperthyroidism: Normal FT4 with low TSH (often precedes overt hypothyroidism in thyroiditis) 4
Advantages Over Total T4
- FT4 is unaffected by alterations in binding protein concentrations (pregnancy, estrogen therapy, liver disease, nephrotic syndrome), making it superior to total T4 in these situations 3, 2
- FT4 provides better discrimination of thyroid status in patients with abnormal TBG levels, particularly elevated TBG 3
- In hypophysitis or central hypothyroidism, TSH may remain within reference range despite low thyroid function, making FT4 measurement critical 4
Critical Clinical Context
When evaluating symptomatic patients for hypothyroidism, both TSH and FT4 must be drawn simultaneously, as TSH alone can be misleading in central hypothyroidism or during unstable thyroid states 4
- A falling TSH with normal or low FT4 across two measurements suggests pituitary dysfunction and requires cortisol evaluation 4
- FT4 normalizes faster than TSH during levothyroxine titration, making it useful for interpreting ongoing abnormal TSH levels on therapy 4, 5
- In patients with diabetes mellitus starting thyroid replacement, FT4 monitoring helps guide antidiabetic medication adjustments as thyroid status normalizes 6, 7
Common Pitfalls
- Do not rely on TSH alone in immunotherapy patients, as immune-related hypophysitis can cause central hypothyroidism with inappropriately normal TSH 4
- Iodine from CT contrast can transiently affect thyroid function tests 4
- Some automated FT4 immunoassays may be less reliable in severe non-thyroidal illness or with very low serum thyroxine-binding capacity 1