What is the difference between Free Triiodothyronine (FT3) and Free Thyroxine (FT4) versus Triiodothyronine (T3) and Thyroxine (T4)?

Understanding the Difference Between Free and Total Thyroid Hormones

Free thyroid hormones (FT3 and FT4) measure only the biologically active, unbound hormone in your blood, while total thyroid hormones (T3 and T4) measure both the bound and unbound hormone—making free hormone measurements far more clinically useful for diagnosing thyroid dysfunction.

Why Free Hormones Matter More Than Total Hormones

The Fundamental Difference

• Total T4 and T3 represent the sum of both protein-bound and free (unbound) hormone circulating in your blood 1
• Free T4 (FT4) and Free T3 (FT3) measure only the tiny fraction of hormone that is not bound to proteins—this is the metabolically active portion that actually enters cells and exerts physiological effects 1, 2
• In circulation, greater than 99% of thyroid hormones are bound to plasma proteins including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin 1
• Only 0.02% of T4 and 0.3% of T3 circulates in the free, unbound form—yet this tiny fraction is what determines your thyroid status 3

Why This Distinction Is Clinically Critical

Free hormone measurements have superseded total hormone determination because they provide superior diagnostic performance 3. Here's why:

• Total T4 and T3 levels can be misleadingly elevated or decreased due to changes in binding proteins, even when thyroid function is completely normal 2
• Euthyroid subjects with TBG excess will have increased total T4 and T3, but normal FT4 and FT3—correctly establishing the diagnosis of euthyroidism 2
• Patients with TBG deficiency will have decreased total T4 and T3, but again normal free hormones 2
• Pregnancy dramatically increases TBG levels, causing total T4 to rise substantially while free T4 may remain normal or even decrease 2, 4

Clinical Applications: When to Use Which Test

For Diagnosing Hyperthyroidism

• Measure FT3 (and TSH) as your primary diagnostic strategy, since FT4 may occasionally be elevated in euthyroid subjects (e.g., patients on chronic amiodarone or levothyroxine treatment) 2
• The serum T3 to T4 ratio (nanogram per microgram) can help differentiate Graves' disease (ratio >20) from painless thyroiditis (ratio <20) 5
• FT3 measurements are essential when FT4 is normal but hyperthyroidism is still suspected 3

For Diagnosing Hypothyroidism

• Measure FT4 (together with TSH) as the most reliable test, because FT3 may still be normal in patients with subclinical or mild thyroid failure 2
• When the thyroid status is unstable (first months of thyroid treatment, altered levothyroxine dose, subacute thyroiditis) or when hypothalamic-pituitary function is disturbed (central hypothyroidism), TSH determination is diagnostically misleading and only free hormone measurements are reliable 3
• Low TSH with low FT4 indicates central hypothyroidism, requiring evaluation for hypophysitis and secondary adrenal insufficiency 6

Special Clinical Situations

• In severe non-thyroidal illness, free hormone measurements remain technically demanding and may be affected by low serum thyroxine binding capacity 3, 7
• During pregnancy, FT4 and FT3 should be measured rather than total hormones, as TBG increases substantially 4
• In patients with binding protein abnormalities (familial dysalbuminemic hyperthyroxinemia, transthyretin-associated hyperthyroxinemia), only free hormone measurements correctly establish thyroid status 2

Physiological Context: T4 to T3 Conversion

Understanding the Relationship

• The thyroid gland produces approximately 80% T4 and 20% T3 3
• However, approximately 80% of circulating T3 is actually derived from peripheral T4 by deiodination in tissues like the liver and kidney 1, 3
• T3 is the physiologically active hormone—it has 4 times the biologic potency of T4 1
• T4 serves primarily as a prohormone that is converted to T3 in peripheral tissues 1

Clinical Implications

• Circulating T3 is a less reliable reflection of thyroid hormone production than T4, because T4-to-T3 conversion can be influenced by various conditions including severe illness, medications, and nutritional status 3
• In low T3 syndrome (non-thyroidal illness), FT3 may be low while FT4 remains normal or even elevated 4
• The half-life of T4 is 6-7 days, while T3 has a half-life of ≤2 days, explaining why T4 levels are more stable 1

Common Pitfalls to Avoid

• Never rely on total T4 or T3 measurements alone in patients with suspected binding protein abnormalities, pregnancy, or severe non-thyroidal illness—always measure free hormones 2, 3
• Don't assume normal total thyroid hormones mean normal thyroid function in patients with TBG abnormalities—free hormone measurements are essential 2
• Recognize that different free hormone assays show moderate to wide inter-assay variations—results should be interpreted using the reference range specific to your laboratory's assay 7
• In suspected central hypothyroidism, measure both TSH and FT4 simultaneously, as TSH alone can be misleadingly normal or low 6, 3