Endocrinology & Clinical Biochemistry & Family Medicine
Free T4 (FT4) — Free Thyroxine
Free T4 (FT4) is a measure of the fraction of thyroxine (T4)—the primary thyroid hormone secreted by the thyroid gland—that is not bound to transport proteins (80–90% of total thyroid secretion)—which circulates freely in plasma and is available to be taken up by target cells and converted into active T3 by tissue deiodinases. Total circulating T4 is transported 99.97% in a form bound to plasma proteins—primarily TBG (thyroxine-binding globulin — 75% of total T4) + albumin (15–20% of total T4) + transthyretin (5–10% of total T4) — and accounts for only 0.03% of total T4 as the unbound free fraction (FT4). This free fraction is the only one biologically available to target cells: it diffuses freely across cell membranes and is taken up by intracellular deiodinases, which convert it into active T3 (type 2 deiodinase—brain, pituitary, heart, and muscle) or inactive reverse T3 (rT3) depending on metabolic needs. T4 is a prohormone: it is biologically inactive on its own but serves as the primary substrate for peripheral conversion to T3 (the hormonally active form)—similar to proinsulin, which is converted into active insulin. Measuring FT4 is more reliable than total T4 in conditions that alter transport proteins (pregnancy, estrogen, liver disease, nephrotic syndrome, medications) because FT4 reflects the biologically active fraction regardless of variations in carrier proteins. In the standard diagnostic algorithm for thyroid function, FT4 is measured as a second-line test after TSH — if TSH is abnormal — to determine the degree and type of thyroid dysfunction, and is the parameter of choice for monitoring patients on levothyroxine and for evaluating secondary (pituitary) thyroid dysfunction.
Normal Values and Interpretation of a Complete Thyroid Panel
- Reference values FT4 (adult): 9-25 pmol/L (or 0.7-1.9 ng/dL depending on the unit) + reference values vary between laboratories and enzyme immunoassay methods → always compare with the standards of the laboratory performing the analysis
- Pregnancy — adjusted values: FT4 decreases progressively throughout pregnancy (plasma dilution + estrogen-stimulated increase in TBG → increased T4 protein binding → reduced free FT4) + pregnancy-specific TSH + FT4 targets → FT4 slightly lower than outside pregnancy is normal
- Recommended diagnostic algorithm: TSH in 1st intention (most sensitive screening test) + if TSH abnormal → FT4 + FT3 according to context + if TSH suppressed and FT4 normal → measure FT3 (T3 hyperthyroidism possible) + if TSH high and FT4 normal → subclinical hypothyroidism + if TSH high and FT4 low → frank clinical hypothyroidism
Combined interpretation of TSH + FT4
| TSH | FT4 | Diagnosis | Driving |
|---|---|---|---|
| Elevated (> 4–5 mIU/L) | Normal | Subclinical hypothyroidism | Treatment discussed (pregnancy + TSH > 7–8 + symptoms + positive anti-TPO) + annual monitoring otherwise |
| Elevated (> 4–5 mIU/L) | Low | Overt clinical hypothyroidism (primary) | Levothyroxine → TSH target 0.5–2.5 mIU/L |
| Normal (0.4–4 mIU/L) | Low | Central hypothyroidism (pituitary or hypothalamic) | Complete pituitary workup + pituitary MRI |
| Undetectable (< 0.1 mIU/L) | Raised | Overt hyperthyroidism | Anti-RTSH + scintigraphy → etiological diagnosis |
| Undetectable (< 0.1 mIU/L) | Normal | Subclinical hyperthyroidism or isolated T3 hyperthyroidism | Free T3 dose → If Free T3 is high = T3 hyperthyroidism |
| Normal | Raised | Central hyperthyroidism (TSH-oma) or thyroid hormone resistance (TRH) | pituitary MRI + bioactive TSH assay + endocrinology consultation |
| Normal | Normal | Euthyroidism | No treatment + monitoring if risk factors |
Low FT4 — causes of hypothyroidism
- Primary hypothyroidism (high TSH + low FT4) - most frequent causes: Hashimoto's thyroiditis (autoimmune - most common in developed countries) + post-thyroidectomy hypothyroidism + post-irtherapy (iodine 131) + De Quervain thyroiditis (transient hypothyroid phase) + drug-induced hypothyroidism (amiodarone + lithium + interferon + anti-PD1/PD-L1 immunotherapy) + iodine deficiency (rare in Canada - fortified foods)
- Central hypothyroidism — secondary (normal or low TSH + low FT4): pituitary insufficiency (pituitary adenoma + pituitary surgery + cerebral radiotherapy + Sheehan syndrome = post-partum pituitary necrosis + head trauma) + hypothalamic insufficiency (craniopharyngioma + sarcoidosis + histiocytosis) → always consider associated adrenal insufficiency (hypopituitarism)
- Low T4 Syndrome (Non-thyroidal Illness): FT4 low + FT3 low + TSH normal → prolonged fasting + severe sepsis + advanced heart failure + major surgery → metabolic adaptation → DO NOT treat → treat underlying cause
High FT4 - causes of hyperthyroidism
- Graves' disease (suppressed TSH + elevated FT4 + positive TRAb): most frequent hyperthyroidism + woman 20-50 years + autoimmunity (anti-RTSH stimulants) + diffuse goiter + exophthalmos (Graves' orbitopathy) + dermopathy (pretibial myxedema) → treatment: synthetic antithyroid drugs (carbimazole + propylthiouracil) + or iodine 131 + or thyroidectomy
- Toxic adenoma + toxic multinodular goiter TSH suppressed + FT4 elevated + without anti-RTSH + scintigraphy: hyperfixing nodule(s) + treatment: iodine 131 + or surgery
- De Quervain's thyroiditis (transient hyperthyroid phase): TSH suppressed + FT4 elevated + VS very high + CRP elevated + cervical pain + fever + 4-6 weeks hyperthyroidism → euthyroidism → hypothyroidism (20-30 % permanent) → beta-blockers + NSAIDs + no antithyroid drugs (no excess production)
- Iodine load (amiodarone + contrast media): amiodarone → very rich in iodine (37 % by weight) → can cause hyperthyroidism (type 1 = exacerbated Basedow + type 2 = destructive thyroiditis) → high FT4 + low FT3 (inhibition of conversion) + variable TSH → complex thyroid profile under amiodarone
- Sham thyrotoxicosis (surreptitious intake of T4 or T3): FT4 very high + TSH suppressed + thyroglobulin collapsed (because thyroid is inhibited without lesion) → diagnosis
Levothyroxine Monitoring — Practical Guidelines
- TSH target under treatment : Adult: TSH 0.5–2.5 mIU/L (mid-normal range) + pregnancy: TSH < 2.5 mIU/L in 1st trimester + < 3.0 mIU/L in 2nd–3rd trimesters + differentiated thyroid cancer post-thyroidectomy: TSH < 0.5 mIU/L (mild suppression) or < 0.1 mIU/L (strong suppression) depending on recurrence risk
- Main tracking parameter: TSH is the reference monitoring parameter under levothyroxine - it reflects the effect of exogenous T4 on the pituitary gland after 4-8 weeks of equilibrium + FT4 is generally not necessary for routine monitoring if TSH is within target + measure FT4 if TSH is discordant or if there is a suspected absorption problem
- Control delay TSH control 4-8 weeks after each levothyroxine dose change (time needed to reach steady state - T4 half-life = 7 days) + once stable: TSH every 6-12 months
- Taking levothyroxine: fasting in the morning 30-60 min before meal + or at bedtime (≥ 3 h after last meal) + absorption reduced by coffee + calcium + iron + antacids + cholestyramine → take at a distance from these substances (≥ 4 h)
- High FT4 on levothyroxine: overdose → TSH suppressed + FT4 high + risk of atrial fibrillation + osteoporosis (in postmenopausal women) + reduce dose + TSH check in 4-8 weeks
ℙ️
In central hypothyroidism (normal or low TSH + low FT4), TSH alone is insufficient as a monitoring test — FT4 should guide levothyroxine dose adjustment. Target an FT4 in the upper half of the normal range. This scenario is important to recognize because it can be mistaken for euthyroidism if only TSH is measured. Always measure FT4 if pituitary insufficiency is known or suspected.
Medical consultation recommended
Consult a doctor if a thyroid test shows a high TSH with a low FT4 (clinical hypothyroidism requiring levothyroxine) or a suppressed TSH with a high FT4 (hyperthyroidism requiring etiological assessment and treatment) or a discordant picture (normal TSH + low FT4 → suspicion of central hypothyroidism). For the prescription and interpretation of a complete thyroid assessment (TSH + FT4 + FT3 depending on the context) and the initiation of levothyroxine, Clinique Omicron offers medical consultations at its service points in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physicians and nurse practitioners (NPs) prescribe and interpret FT4 in the appropriate clinical context (hypothyroidism screening, treatment monitoring, pregnancy assessment, hyperthyroidism evaluation, central hypothyroidism), initiate and adjust levothyroxine according to TSH goals based on the clinical context, recognize discordant presentations (normal TSH + low FT4 = central hypothyroidism) requiring pituitary investigation, and refer to endocrinology for complex cases. Consultations are available at multiple service points across Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for medical or endocrinological advice. FT4 should always be interpreted in conjunction with TSH and within the patient's clinical context. In central hypothyroidism, TSH may be normal despite low FT4 — FT4 is the primary monitoring parameter in this setting. Reference ranges vary by laboratory.
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