What is the best marker of thyroid function, T3 (Triiodothyronine) or free T3 (FT3)?

Free T3 (FT3) is the Better Marker of Thyroid Function

For assessing thyroid function, free T3 (FT3) is superior to total T3 because it represents the biologically active, unbound hormone and is not influenced by variations in thyroid hormone-binding proteins. However, TSH remains the primary screening test for thyroid dysfunction, with free T4 (FT4) as the secondary marker—FT3 has limited utility in most clinical scenarios.

Why Free T3 Over Total T3

Free thyroid hormones represent a more useful index of thyroid status than total thyroid hormones because total hormone measurements are influenced by variations in thyroid hormone-binding proteins, especially T4-binding globulin (TBG). 1

• Only 0.3% of total T3 circulates in the free, biologically active form, while 99.7% is protein-bound 2
• Total T3 measurements can be misleadingly elevated or decreased in euthyroid patients with TBG excess or deficiency, while FT3 correctly establishes euthyroidism 1
• Free hormone measurements using equilibrium dialysis/RIA are considered the reference method, though automated immunoassays are used in routine practice 2

Limited Clinical Utility of T3 Testing

T3 measurement (whether free or total) has extremely limited utility in routine thyroid function assessment and should not be routinely ordered. The specific clinical scenarios where FT3 adds value are narrow and well-defined.

When FT3 Is NOT Useful

• In levothyroxine-treated hypothyroid patients, T3 measurement adds nothing to the assessment of over-replacement. 3 In a study of 542 patients on levothyroxine, none of the 33 over-replaced patients (TSH <0.02 mIU/L and high FT4 >27 pmol/L) had elevated T3 levels 3
• The most discriminant T3 level had only 58% sensitivity and 71% specificity for detecting over-replacement, which is clinically inadequate 3
• Normal T3 levels can be seen in over-replaced patients, creating false reassurance and potentially missing over-replacement with its attendant cardiovascular and bone risks 3

When FT3 May Be Useful

FT3 testing is most useful when TSH is suppressed and FT4 is normal or decreased—a pattern called T3 thyrotoxicosis. 4

• T3 thyrotoxicosis is relatively rare, occurring in only 1.6% of patients tested 4
• The likelihood of detecting T3 thyrotoxicosis increases dramatically with lower TSH cutoffs: 10.3% when TSH <0.3 μIU/mL versus 27.6% when TSH <0.01 μIU/mL 4
• All patients with newly diagnosed hyperthyroidism had TSH <0.01 μIU/mL 4
• Higher frequency of T3 thyrotoxicosis occurs in outpatient settings (34%) compared to inpatient settings (14%) when TSH <0.01 μIU/mL 4

In suspected hyperthyroidism, FT3 measurement (together with TSH) is diagnostically useful because FT4 may occasionally be elevated in euthyroid subjects, such as patients on chronic amiodarone or levothyroxine treatment. 1

Optimal Testing Strategy

Primary Screening Approach

TSH is the most sensitive test for monitoring thyroid function with sensitivity above 98% and specificity greater than 92%. 5

• For initial evaluation of suspected thyroid dysfunction, measure TSH as the first-line test 5
• If TSH is abnormal, measure free T4 to distinguish subclinical (normal FT4) from overt (abnormal FT4) dysfunction 5

When to Add FT3

A reflex FT3 test should only be ordered for patients with TSH <0.01 μIU/mL and normal or low FT4, particularly in the outpatient setting. 4

• This approach maximizes clinical utility and reduces unnecessary testing 4
• For patients with subclinical hypothyroidism and normal TSH/FT4 but persistent symptoms, checking FT3 levels may help identify subtle thyroid dysfunction 6

Monitoring Levothyroxine Therapy

For patients on levothyroxine replacement, monitor TSH every 6-8 weeks while titrating hormone replacement, and once adequately treated, repeat TSH testing every 6-12 months. 6

• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 6
• For thyroid cancer patients requiring TSH suppression, monitoring includes both TSH and free T4 to ensure appropriate suppression targets are met 6
• Do not routinely measure T3 in levothyroxine-treated patients—it does not add diagnostic value 3

Critical Pitfalls to Avoid

• Never rely on normal T3 levels to exclude over-replacement in hypothyroid patients on levothyroxine—this can lead to missed diagnosis of iatrogenic hyperthyroidism with serious cardiovascular and bone consequences 3
• Avoid ordering FT3 when TSH is >0.01 μIU/mL, as the yield is extremely low and testing is not cost-effective 4
• In suspected hypothyroidism, FT3 may still be normal in patients with subclinical or mild thyroid failure, making it unreliable for this diagnosis 1
• Remember that 80% of circulating T3 is produced extrathyroidally from T4 deiodination, and conversion can be influenced by various conditions, making circulating T3 a less reliable reflection of thyroid hormone production than T4 2