Free ThyroxineEdit

Free thyroxine, or FT4, is a central marker in the assessment of thyroid function. It denotes the portion of thyroxine circulating in the blood that is unbound to proteins and thus biologically active at the tissue level. Clinically, FT4 is read alongside thyroid-stimulating hormone (TSH) to infer how well the thyroid axis is working. Because most circulating thyroxine is normally bound to thyroxine-binding globulin (TBG) and other carrier proteins, FT4 provides a more direct signal of thyroid activity than total thyroxine does, especially when binding protein levels fluctuate. The stability of FT4 across many situations makes it a go-to measure when diagnosing hypothyroidism, hyperthyroidism, or ambiguous cases where TSH alone is not sufficient. For more on the hormone itself, see free thyroxine and its relationship to thyroxine.

Overview

What is FT4: The unbound, circulating fraction of thyroxine that tissues can readily uptake. It is the active portion that helps regulate metabolism, development, and energy use. See free thyroxine for the core definition.
How it’s measured: FT4 is typically assessed with immunoassays in most clinical labs, though precise measurement can involve methods such as equilibrium dialysis or ultrafiltration in specialized settings. Lab reference ranges vary, so clinicians interpret FT4 in the context of the specific assay and population. See also reference range.
Why it matters: FT4, together with TSH, helps distinguish between different thyroid states. In primary thyroid disease, FT4 often shifts in tandem with TSH; in central disorders, FT4 can be abnormal even when TSH is not a reliable indicator. For the role of TSH, see thyroid-stimulating hormone.

Regulation and physiology

The hypothalamic-pituitary-thyroid axis: The hypothalamus releases thyrotropin-releasing hormone, prompting the pituitary to release TSH, which stimulates the thyroid to produce thyroxine. The circulating FT4 level feeds back to regulate this axis. See hypothalamus and pituitary gland for context.
Thyroid production and conversion: The thyroid gland primarily secretes thyroxine (T4). T4 is converted in peripheral tissues to the more active triiodothyronine (T3) as needed. The majority of circulating T4 is bound to carrier proteins, with only a small fraction free. See thyroxine and triiodothyronine for related hormones.
Binding proteins and variation: The FT4 value is influenced by the level of binding proteins such as TBG and albumin. Conditions that raise or lower these proteins—like pregnancy, estrogen therapy, liver disease, or certain medications—can shift total T4 without necessarily reflecting tissue thyroid status. See thyroxine-binding globulin.

Measurement and interpretation

Interpreting FT4 with TSH: In most patients, a high FT4 with a low TSH suggests hyperthyroidism; a low FT4 with a high TSH suggests hypothyroidism. In some disorders, especially central (or secondary) thyroid disease, TSH may be inappropriately normal or low, and FT4 becomes essential for assessment. See hyperthyroidism and hypothyroidism.
Pregnancy and age considerations: Pregnancy alters thyroid-binding proteins and reference ranges. FT4 interpretation during gestation requires pregnancy-specific guidelines. See pregnancy for related considerations.
Assay limitations and interference: FT4 immunoassays can be affected by assay interference, heterophile antibodies, biotin supplementation, or non-thyroidal illnesses. When results don’t fit the clinical picture, laboratories may confirm with alternative methods such as equilibrium dialysis. See assay interference.
Non-thyroidal illness and other factors: Acute illness, medications, and nutritional status can influence FT4 and TSH. Clinicians weigh these factors to avoid mistaking illness-related changes for true thyroid disease. See euthyroid sick syndrome for the broader concept of non-thyroidal effects on thyroid testing.

Clinical significance

Hypothyroidism: In primary hypothyroidism, FT4 is typically low or inappropriately normal with a high TSH. The pattern guides treatment decisions, such as whether to initiate levothyroxine therapy and what dose to start. See levothyroxine for therapy context and Hashimoto's thyroiditis as a common underlying cause.
Subclinical hypothyroidism: This condition features an elevated TSH with a normal FT4. The decision to treat depends on symptoms, TSH level, age, pregnancy plans, and comorbidities. Proponents of conservative management emphasize minimizing overtreatment and unnecessary costs, while others argue for early intervention to protect cardiovascular risk and quality of life in select patients.
Hyperthyroidism: An elevated FT4 (often with suppressed TSH) points toward hyperthyroidism, with implications for cardiovascular risk, bone health, and metabolic symptoms. See Graves' disease and toxic multi-nodular goiter for common etiologies.
Central thyroid disease: In disorders of the pituitary or hypothalamus, TSH may not reflect thyroid status, making FT4 a vital piece of the diagnostic puzzle. See central hypothyroidism for related concepts.

Controversies and policy considerations

Screening and population health: There is ongoing debate about routine, universal screening for thyroid dysfunction in asymptomatic adults. A conservative approach emphasizes targeted screening of high-risk groups (for example, older adults, pregnant individuals, those with autoimmune conditions, or nodular thyroid disease) to maximize cost-effectiveness and minimize overdiagnosis. See thyroid function tests and goiter for context on screening cues.
Treatment thresholds and quality of life: Guidelines often differ on when to treat subclinical hypothyroidism, especially at mildly elevated TSH levels. Advocates of restrained intervention stress avoiding overtreatment and potential side effects, while others argue that symptom relief and long-term risk reduction justify earlier therapy in certain patients. The practical stance emphasizes shared decision-making between patient and physician, guided by evidence but rooted in patient preferences and risk profiles.
Overmedicalization concerns: Critics argue that aggressive testing and treatment can medicalize normal aging or benign variations in thyroid function, driving unnecessary costs and patient anxiety. Proponents counter that properly selected testing and treatment improve health outcomes and prevent downstream problems, such as cardiovascular or metabolic complications, in at-risk populations.
Access, cost, and administration: In a system prioritizing patient autonomy and fiscal responsibility, emphasis is placed on accessible testing, timely interpretation by clinicians, and the ability of patients to pursue evidence-based care with reasonable costs. This view favors practical, outcome-oriented policy rather than rigid, one-size-fits-all mandates.