What is Free T3?
Free T3 (Free Triiodothyronine) measures the unbound, metabolically active form of triiodothyronine. T3 is the most potent thyroid hormone, responsible for the majority of thyroid hormone effects on metabolism, growth, and development.
T3 is the Most Active Thyroid Hormone
While T4 is the predominant thyroid hormone by quantity, T3 is 3-4 times more metabolically active:
- Nuclear receptor binding: T3 binds thyroid hormone receptors with much higher affinity than T4
- Genomic effects: T3 regulates gene transcription controlling metabolism, growth, and development
- Metabolic potency: T3 is responsible for most thyroid hormone effects despite lower concentration
- Tissue-specific actions: Local T4-to-T3 conversion allows tissue-specific thyroid hormone regulation
T3 Production and Conversion
Most circulating T3 comes from peripheral T4 conversion, not direct thyroid secretion:
- 80% from T4 conversion: Peripheral tissues (liver, kidney, muscle) convert T4 to T3 via deiodinase enzymes
- 20% direct thyroid secretion: Thyroid gland directly produces and secretes T3
- Type 1 deiodinase (D1): Main enzyme in liver and kidney; produces circulating T3
- Type 2 deiodinase (D2): Brain, pituitary, brown fat; local T3 production for tissue-specific regulation
- Type 3 deiodinase (D3): Converts T4 to inactive reverse T3 (rT3); inactivation pathway
Why T3 Half-Life Matters: T3's short half-life (~24 hours vs. T4's 7 days) means T3 levels fluctuate more rapidly and are more sensitive to acute changes in thyroid status. This is why levothyroxine (T4) is preferred for replacement - steady T4 provides stable T3 through continuous conversion.
T3 Toxicosis
Some hyperthyroid conditions cause isolated T3 elevation with normal T4:
- Definition: Hyperthyroidism with elevated Free T3 but normal Free T4
- Common in: Early Graves' disease, toxic nodular goiter, autonomous nodules preferentially secreting T3
- Clinical significance: TSH suppressed, Free T4 normal, Free T3 elevated - patient is thyrotoxic despite normal T4
- Why it occurs: Some thyroid pathology preferentially produces T3, or early disease affects T3 before T4 rises
Liothyronine (Cytomel) - Synthetic T3
Liothyronine is synthetic T3 with limited clinical use:
- Short half-life: Requires 2-3× daily dosing; difficult to maintain steady levels
- Rapid fluctuations: Can cause palpitations, anxiety due to peak levels
- Current use: Myxedema coma (rapid onset), thyroid cancer preparation for radioiodine scan (short withdrawal), rarely combination T4/T3 therapy
- Combination T4/T3 therapy: Controversial; most guidelines recommend levothyroxine monotherapy
When to Order Free T3
Free T3 is NOT routinely ordered. TSH + Free T4 are usually sufficient. Order Free T3 when:
- Suspected T3 toxicosis: Low TSH, normal Free T4, but hyperthyroid symptoms
- Subclinical hyperthyroidism: Low TSH, normal Free T4 - check if Free T3 is elevated
- Monitoring Graves' disease treatment: Free T3 may remain elevated after Free T4 normalizes
- Amiodarone therapy: Blocks T4-to-T3 conversion; may show high Free T4, low Free T3
Free T3 is NOT useful for hypothyroidism: Free T3 is often normal in hypothyroidism due to compensatory upregulation of T4-to-T3 conversion. Low Free T3 indicates severe illness (sick euthyroid syndrome), not hypothyroidism requiring treatment. Use TSH + Free T4 for hypothyroid diagnosis.
Free T3 reference ranges vary significantly between assays. Always use laboratory-specific reference ranges.
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| Population | Free T3 (pg/mL) | SI Units (pmol/L) |
|---|---|---|
| Adults | 2.3-4.2 | 3.5-6.5 |
| Elderly (>65 years) | 2.0-3.8 | 3.1-5.8 |
| Pregnancy | 1.8-3.8 | 2.8-5.8 |
| Children | 2.5-4.5 | 3.8-6.9 |
Important Considerations:
- Assay variation: Free T3 assays vary even more than Free T4 assays; reference ranges differ widely
- Age decline: Free T3 decreases with age; elderly have lower normal ranges
- Conversion factor: pg/mL × 1.536 = pmol/L
- Critical illness: Free T3 drops dramatically in sick euthyroid syndrome; low T3 is adaptive, not pathologic
- Pregnancy: Free T3 may decrease slightly during pregnancy
Elevated Free T3 (Thyrotoxicosis)
High Free T3 indicates hyperthyroidism or thyrotoxicosis - excess thyroid hormone causing hypermetabolic state.
T3 Toxicosis (High Free T3, Normal Free T4, Low TSH)
- Early Graves' disease: T3 may rise before T4 in early autoimmune hyperthyroidism
- Toxic nodular goiter: Autonomous nodules may preferentially secrete T3
- Toxic adenoma: Single autonomous nodule producing excess T3
- Iodine-deficient regions: Thyroid preferentially produces T3 (more metabolically efficient)
- Clinical significance: Patient has thyrotoxic symptoms despite normal Free T4; diagnosis missed without Free T3
Overt Hyperthyroidism (High Free T3, High Free T4, Low TSH)
- Graves' disease: Most common; TSH receptor antibodies (TRAb/TSI positive)
- Toxic multinodular goiter: Multiple autonomous nodules
- Thyroiditis (destructive): Subacute, postpartum, painless - transient thyrotoxicosis from stored hormone release
- Excessive thyroid hormone: Intentional or factitious hyperthyroidism, thyrotoxicosis factitia
Low Free T3
Non-Thyroidal Illness (Sick Euthyroid Syndrome)
The MOST COMMON cause of low Free T3 - NOT true hypothyroidism:
- Pattern: Low T3, low/normal T4, low/normal TSH in critically ill patients
- Mechanism: Decreased Type 1 deiodinase activity; reduced peripheral T4-to-T3 conversion
- Adaptive response: Energy conservation during severe illness; protective, not pathologic
- Severity correlation: Lower T3 correlates with illness severity and mortality
- CRITICAL: Do NOT treat with thyroid hormone - increases mortality; recheck after recovery
Do NOT Treat Low T3 in Critical Illness: Sick euthyroid syndrome (low T3 in critical illness) is adaptive. Multiple studies show thyroid hormone replacement in critically ill patients INCREASES mortality. Low T3 is NOT hypothyroidism. Recheck thyroid function 6-8 weeks after illness resolves.
Hypothyroidism (Usually Normal Free T3)
- Compensatory mechanism: In mild-moderate hypothyroidism, Free T3 remains normal due to increased T4-to-T3 conversion
- Severe hypothyroidism: Free T3 finally drops in advanced disease
- Clinical pearl: Free T3 is last to fall in hypothyroidism, so normal Free T3 does NOT exclude hypothyroidism
- Diagnosis: Use TSH + Free T4, not Free T3, for hypothyroidism diagnosis
Medications Affecting T4-to-T3 Conversion
- Amiodarone: Blocks Type 1 deiodinase; high Free T4, low Free T3, normal/elevated TSH
- Propranolol (high dose): Inhibits T4-to-T3 conversion
- Glucocorticoids (high dose): Suppress deiodinase activity
- Propylthiouracil (PTU): Blocks T4-to-T3 conversion (in addition to inhibiting synthesis)
Monitoring Graves' Disease Treatment
Free T3 is useful for monitoring antithyroid drug (methimazole, PTU) treatment of Graves' disease:
- Slow normalization: Free T3 may remain elevated after Free T4 normalizes during treatment
- Treatment target: Both Free T4 and Free T3 should normalize before considering drug discontinuation
- Relapse detection: Free T3 may rise before Free T4 in early relapse
- Check both: Monitor TSH, Free T4, and Free T3 during active Graves' treatment
Free T3 Interpretation Patterns
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| TSH | Free T4 | Free T3 | Interpretation |
|---|---|---|---|
| Low | High | High | Overt Hyperthyroidism (Graves', toxic nodular goiter) |
| Low | Normal | High | T3 Toxicosis (early Graves', toxic nodule) |
| Low | Normal | Normal | Subclinical Hyperthyroidism |
| High | Low | Normal or Low | Primary Hypothyroidism (compensated T3) |
| Normal/Low | Normal/Low | Low | Sick Euthyroid Syndrome (critical illness) |
| Normal/High | High | Low | Amiodarone effect or impaired T4-to-T3 conversion |
When Free T3 Changes Interpretation:
- Low TSH + Normal Free T4: Could be subclinical hyperthyroidism OR T3 toxicosis - check Free T3
- Monitoring Graves' treatment: Free T4 normal but Free T3 still high - not ready to stop medication
- Amiodarone therapy: High Free T4 + Low Free T3 + Normal TSH = expected amiodarone effect (not true thyroid disease)
Combination T4/T3 Therapy Controversy
Some hypothyroid patients request combination levothyroxine (T4) + liothyronine (T3) therapy:
Current Guidelines (ATA, AACE):
- NOT recommended: Most guidelines recommend levothyroxine monotherapy
- Evidence: Multiple RCTs show no benefit of combination T4/T3 vs. T4 alone for symptoms, quality of life, or cognitive function
- Risks: T3's short half-life causes fluctuating levels; peak T3 can cause palpitations, anxiety, AF
- Trial option: If patient symptomatic despite normal TSH on levothyroxine, can trial combination for 3 months; discontinue if no benefit
- Ratio: If trialing, use physiologic 13:1 or 16:1 T4:T3 ratio (e.g., reduce levothyroxine 50 mcg, add liothyronine 5 mcg)
Factors That Increase Free T3
- Hyperthyroidism: Graves' disease, toxic nodular goiter, thyroiditis
- Liothyronine (Cytomel): Synthetic T3 supplementation
- Pregnancy (early): hCG stimulates thyroid; transient mild increase
- Desiccated thyroid (Armour Thyroid): Contains both T4 and T3; causes supraphysiologic T3 peaks
Factors That Decrease Free T3
Critical Illness (Sick Euthyroid Syndrome):
- Sepsis, respiratory failure, myocardial infarction, trauma, surgery, burns
- Mechanism: Decreased Type 1 deiodinase activity; reduced T4-to-T3 conversion
- DO NOT TREAT - adaptive response
Medications Blocking T4-to-T3 Conversion:
- Amiodarone: Most significant; blocks Type 1 deiodinase
- Propranolol (high dose): >160 mg/day inhibits conversion
- Propylthiouracil (PTU): Blocks conversion in addition to synthesis
- Glucocorticoids (high dose): Dexamethasone, prednisone >60 mg/day
- Iodinated contrast agents: Iopanoic acid, ipodate (rarely used now)
Physiological States:
- Fasting/starvation: Decreased T4-to-T3 conversion; adaptive energy conservation
- Chronic caloric restriction: Prolonged dieting lowers T3
- Aging: Free T3 decreases with age; normal variant
- Selenium deficiency: Deiodinase enzymes require selenium; rare in US
Assay Interference
- Biotin (high dose): >5 mg/day interferes with immunoassays; falsely high Free T3 in some assays. Stop 48-72 hours before testing
- Heterophile antibodies: Can cause falsely high or low results depending on assay
- Severe protein abnormalities: May affect Free T3 measurement in some assays
Non-Thyroidal Illness Pattern
Understanding sick euthyroid syndrome is critical:
- Mild illness: Low T3, normal T4, normal TSH
- Moderate illness: Low T3, low T4, low/normal TSH
- Severe illness: Low T3, low T4, low TSH; reverse T3 (rT3) elevated
- Recovery phase: TSH may transiently rise above normal (can mimic hypothyroidism)
- Management: Do NOT treat; recheck 6-8 weeks after recovery
Clinical Pearl
"Free T3 is NOT routinely ordered": TSH + Free T4 are sufficient for most thyroid assessments. Order Free T3 only for specific indications: suspected T3 toxicosis (low TSH, normal Free T4), monitoring Graves' treatment, or subclinical hyperthyroidism evaluation.
"Low T3 in critical illness is adaptive - DO NOT TREAT": Sick euthyroid syndrome (low T3 in ICU patients) is an energy-conserving adaptation. Multiple RCTs show treating low T3 in critically ill patients INCREASES mortality. This is NOT hypothyroidism. Recheck after recovery.
Clinical Pearl
"T3 toxicosis - hyperthyroid with normal Free T4": Some hyperthyroid patients have elevated Free T3 but normal Free T4, especially in early Graves' or toxic nodules. Low TSH + normal Free T4 + thyrotoxic symptoms = order Free T3. Diagnosis missed without it.
Clinical Pearl
"Free T3 is useless for hypothyroidism diagnosis": In mild-moderate hypothyroidism, compensatory T4-to-T3 conversion keeps Free T3 normal. Free T3 only drops in severe hypothyroidism or critical illness. Use TSH + Free T4, never Free T3, for hypothyroid diagnosis.
Monitor Free T3 during Graves' treatment: When treating Graves' disease with methimazole or PTU, Free T3 may remain elevated even after Free T4 normalizes. Check both Free T4 and Free T3; don't discontinue treatment until both normalize.
Clinical Pearl
"80% of T3 comes from T4 conversion, not thyroid": Only 20% of circulating T3 is secreted by thyroid; 80% comes from peripheral T4 deiodination. This is why levothyroxine (T4) monotherapy works - body converts it to T3 as needed.
Clinical Pearl
Amiodarone pattern: high Free T4, low Free T3, normal TSH: Amiodarone blocks Type 1 deiodinase, preventing T4-to-T3 conversion. This pattern is expected in euthyroid patients on amiodarone, NOT thyroid disease. Check baseline before starting amiodarone.
Combination T4/T3 therapy is controversial: Most guidelines (ATA, AACE) recommend levothyroxine monotherapy. RCTs show no benefit of adding T3 for symptoms or quality of life. T3's short half-life causes fluctuating levels and potential cardiac risks. Trial only if symptomatic despite normal TSH.
Clinical Pearl
"T3 is 3-4× more potent than T4": T3 binds thyroid hormone receptors with much higher affinity. Most thyroid hormone effects on metabolism are mediated by T3, not T4. T4 functions primarily as a prohormone/reservoir for T3 production.
Free T3 drops with fasting/dieting: Caloric restriction decreases T4-to-T3 conversion as adaptive energy conservation. This causes fatigue and metabolic slowing during dieting. Not pathologic hypothyroidism; resolves with refeeding. Do NOT treat with thyroid hormone.
Clinical Pearl
PTU blocks conversion; methimazole doesn't: Propylthiouracil (PTU) inhibits both thyroid hormone synthesis AND peripheral T4-to-T3 conversion. Methimazole only blocks synthesis. This is why PTU may be preferred in thyroid storm (rapid effect on T3 levels).
Clinical Pearl
"Short T3 half-life = unstable levels with T3 therapy": T3 half-life is ~24 hours (vs. T4's 7 days). Liothyronine (synthetic T3) causes peak-and-trough fluctuations with palpitations/anxiety at peaks, fatigue at troughs. This is why T4 monotherapy is preferred.
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