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Quick Reference
  • Total T4 Range: 5.0-12.0 μg/dL (64-154 nmol/L)
  • Free T4 Range: 0.8-1.8 ng/dL (10-23 pmol/L)
  • Half-life: ~7 days
  • Primary Use: Confirm thyroid dysfunction when TSH is abnormal
  • Sample Type: Serum
  • Key Point: Free T4 is preferred over Total T4 as it's not affected by binding protein changes

Test Description

What is T4?

Thyroxine (T4) is the predominant hormone secreted by the thyroid gland. It serves primarily as a prohormone, being converted to the more active triiodothyronine (T3) in peripheral tissues by deiodinase enzymes.

T4 Physiology

  • Production: ~100% from thyroid gland (vs T3 which is 80% from peripheral conversion)
  • Protein binding: ~99.97% bound to TBG (70%), transthyretin (20%), and albumin (10%)
  • Free T4: Only ~0.03% is unbound and biologically active
  • Half-life: ~7 days (provides stable circulating levels)
  • Function: Serves as reservoir and prohormone for T3

Total T4 vs Free T4

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Feature Total T4 Free T4
Measures Bound + unbound T4 Only unbound (active) T4
Affected by TBG changes Yes - significantly No - more reliable
Preferred test No (historical use) Yes (current standard)
Cost Slightly lower Slightly higher
Why Free T4 is Preferred: Free T4 reflects the actual biologically active hormone and is not affected by changes in binding proteins. Total T4 can be misleadingly high (pregnancy, estrogen) or low (nephrotic syndrome) when the patient is actually euthyroid.
Normal Ranges
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Test Normal Range SI Units
Total T4 5.0-12.0 μg/dL 64-154 nmol/L
Free T4 0.8-1.8 ng/dL 10-23 pmol/L

Special Populations

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Population T4 Considerations
Pregnancy (1st trimester) Total T4 increases 50%; Free T4 upper limit raised
Pregnancy (2nd/3rd trimester) Free T4 may be in low-normal range
Newborns Higher T4 in first week of life
Elderly T4 levels remain relatively stable with age
Pregnancy Interpretation: Use trimester-specific reference ranges for Free T4 in pregnancy. Total T4 is unreliable due to elevated TBG. A seemingly "low" Free T4 in late pregnancy may be normal.
Clinical Significance

Elevated T4 (Hyperthyroidism)

Primary Hyperthyroidism (Low TSH + High Free T4):

  • Graves' disease: Most common cause; diffuse goiter, ophthalmopathy, dermopathy
  • Toxic multinodular goiter: Autonomous nodules, more common in elderly
  • Toxic adenoma: Single hyperfunctioning nodule
  • Subacute (de Quervain) thyroiditis: Painful thyroid, elevated ESR
  • Silent/painless thyroiditis: Including postpartum thyroiditis
  • Iodine-induced: Contrast dye, amiodarone

Secondary/Central Hyperthyroidism (Normal/High TSH + High T4):

  • TSH-secreting pituitary adenoma: Rare; elevated alpha subunit
  • Thyroid hormone resistance: Genetic disorder

Other Causes of Elevated T4:

  • Exogenous thyroid hormone: Overreplacement, thyrotoxicosis factitia
  • Elevated TBG: Raises Total T4 only (pregnancy, estrogen)
  • Familial dysalbuminemic hyperthyroxinemia: Binding protein variant
  • Acute psychiatric illness: Transient elevation

Low T4 (Hypothyroidism)

Primary Hypothyroidism (High TSH + Low Free T4):

  • Hashimoto's thyroiditis: Most common cause; autoimmune destruction
  • Post-ablative: After radioiodine or thyroidectomy
  • Iodine deficiency: Rare in developed countries
  • Drug-induced: Lithium, amiodarone, interferon, checkpoint inhibitors
  • Subacute thyroiditis: Hypothyroid phase after initial hyperthyroidism

Secondary/Central Hypothyroidism (Low/Normal TSH + Low T4):

  • Pituitary disease: Adenoma, surgery, radiation, Sheehan syndrome
  • Hypothalamic disease: Tumors, infiltrative disease
  • Note: TSH may be "normal" but inappropriately low for the T4 level

Other Causes of Low T4:

  • Euthyroid sick syndrome: Low T4 with normal/low TSH in severe illness
  • Low TBG: Nephrotic syndrome, androgens (Total T4 only)
  • Medications: Phenytoin, carbamazepine (increased T4 metabolism)
Interpretation Guidelines

TSH + Free T4 Interpretation

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TSH Free T4 Interpretation
↑↑ ↓ Primary hypothyroidism (overt)
↑ (mild) Normal Subclinical hypothyroidism
Normal Normal Euthyroid
↓ (mild) Normal Subclinical hyperthyroidism
↓↓ ↑ Primary hyperthyroidism (overt)
↓ or Normal ↓ Central (secondary) hypothyroidism
Normal or ↑ ↑ TSH-secreting adenoma or hormone resistance

Approach to Thyroid Testing

Step 1: Start with TSH (most sensitive screening test)

Step 2: If TSH abnormal, check Free T4 to confirm and quantify dysfunction

Step 3: Consider T3 only if TSH suppressed but Free T4 normal (T3 toxicosis)

Step 4: Consider additional tests based on clinical context:

  • Thyroid antibodies (TPO, thyroglobulin) for autoimmune disease
  • Thyroid uptake scan for hyperthyroidism etiology
  • Ultrasound for nodules or goiter
Interfering Factors

Conditions Affecting Total T4 Only

Increased TBG (↑ Total T4, normal Free T4):

  • Pregnancy
  • Estrogen therapy / oral contraceptives
  • Hepatitis
  • Genetic TBG excess
  • Acute intermittent porphyria

Decreased TBG (↓ Total T4, normal Free T4):

  • Androgens, anabolic steroids, glucocorticoids
  • Nephrotic syndrome
  • Chronic liver disease
  • Severe illness / malnutrition
  • Genetic TBG deficiency

Medications Affecting T4

  • Decrease T4: Phenytoin, carbamazepine (increase metabolism)
  • Decrease absorption: Calcium, iron, PPI, cholestyramine
  • Variable effect: Amiodarone (can cause hyper or hypothyroidism)

Assay Interference

  • Biotin: High-dose biotin can cause falsely elevated Free T4 and falsely low TSH on some assays
  • Heterophilic antibodies: Rare, can cause spurious results
  • Heparin: Can cause in vitro increase in Free T4
Clinical Pearls
Clinical Pearl
TSH is the gatekeeper: Always start thyroid evaluation with TSH. The pituitary is exquisitely sensitive to thyroid hormone - a small change in T4 causes a logarithmic change in TSH. TSH detects dysfunction before T4 becomes abnormal.
Clinical Pearl
Free T4, not Total T4: Total T4 is misleading in any condition that affects binding proteins. Pregnancy is the classic example - Total T4 is elevated but the patient is euthyroid. Always use Free T4 for clinical decision-making.
Clinical Pearl
Central hypothyroidism trap: In pituitary/hypothalamic disease, TSH may be "normal" but inappropriately low for the low Free T4. Don't be falsely reassured by a normal TSH - if Free T4 is low, consider central hypothyroidism.
Sick euthyroid caution: In hospitalized patients, both TSH and Free T4 can be abnormal without true thyroid disease. Unless TSH is markedly elevated (>10) or the patient has clear symptoms, avoid making thyroid diagnoses in the acute setting.
Levothyroxine monitoring: When monitoring thyroid replacement, check TSH 6-8 weeks after any dose change. TSH is the target; aim for TSH in normal range (or age-appropriate goal). Free T4 is secondary but useful for dose adjustments.
Clinical Pearl
Biotin warning: Patients taking high-dose biotin supplements (for hair/nail health) can have falsely abnormal thyroid tests. Stop biotin for 2-3 days before thyroid testing.
References
  1. Garber, J. R., et al. (2012). Clinical practice guidelines for hypothyroidism in adults. Thyroid, 22(12), 1200-1235.
  2. Ross, D. S., et al. (2016). 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid, 26(10), 1343-1421.
  3. Alexander, E. K., et al. (2017). 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid, 27(3), 315-389.
  4. Jonklaas, J., et al. (2014). Guidelines for the treatment of hypothyroidism. Thyroid, 24(12), 1670-1751.
  5. Favresse, J., et al. (2018). Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocrine Reviews, 39(5), 830-850.
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