What are the guidelines for thyroid hormone testing, including T4 (thyroxine), free TSH (thyroid-stimulating hormone), FTI (free thyroxine index), T3 (triiodothyronine) uptake, and T4 total?

Thyroid Function Testing Guidelines

Primary Screening Tests

For initial thyroid function assessment, measure TSH with free T4 (FT4) rather than relying on older indices like T3 uptake, total T4, or free thyroxine index (FTI). 1

Modern Testing Approach

• TSH and free T4 are the essential first-line tests for evaluating thyroid function in most clinical scenarios 1
• Free T4 measurement directly assesses the biologically active hormone, providing superior diagnostic accuracy compared to total T4 or calculated indices 2
• TSH has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 3

When to Add Free T3

• Measure free T3 (FT3) when hyperthyroidism is suspected but FT4 is normal, as T3 toxicosis can occur with isolated FT3 elevation 1
• Free T3 is useful when FT4 is normal and clinical suspicion for hyperthyroidism remains high 4
• In suspected hyperthyroidism, the diagnostic strategy should be based on serum FT3 and TSH measurement 2

Obsolete Tests: T3 Uptake, Total T4, and FTI

Why These Tests Are No Longer Recommended

• T3 uptake (resin T3 uptake) and total T4 measurements have been superseded by direct free hormone assays due to superior diagnostic performance 2, 4
• The free thyroxine index (FTI), calculated from total T4 and T3 uptake, was historically used to approximate free T4 but is now obsolete 5
• Total hormone measurements (total T4 and T3) are influenced by variations in thyroid hormone-binding proteins, particularly thyroxine-binding globulin (TBG), leading to false abnormalities in euthyroid patients 2

Specific Limitations

• Increased total T4 occurs in euthyroid patients with TBG excess, familial dysalbuminemic hyperthyroxinemia, and transthyretin-associated hyperthyroxinemia, making total T4 unreliable 2
• Decreased total T4 occurs with TBG deficiency despite normal thyroid function 2
• T3 uptake reflects binding site availability on TBG rather than actual hormone levels, providing indirect and less accurate information 5
• In acutely ill patients, 25% had abnormal free T4 by equilibrium dialysis, but accurate diagnosis could be achieved with FT4 index and TSH alone, demonstrating that additional tests are rarely necessary 6

Recommended Testing Algorithm

For Suspected Hypothyroidism

• Order TSH and free T4 together for symptomatic patients to distinguish between primary and central hypothyroidism 1
• Low TSH with low FT4 indicates central hypothyroidism requiring evaluation for hypophysitis 1
• High TSH with low FT4 confirms primary hypothyroidism 1
• Free T3 may remain normal in subclinical or mild thyroid failure, making it unreliable for hypothyroidism diagnosis 2

For Suspected Hyperthyroidism

• Measure TSH, free T4, and free T3 when hyperthyroidism is clinically suspected 1
• Low or suppressed TSH with elevated FT4 or FT3 confirms thyrotoxicosis 1
• Free T4 may occasionally be elevated in euthyroid subjects (e.g., patients on chronic amiodarone or levothyroxine treatment), making FT3 measurement valuable 2

Monitoring Patients on Thyroid Hormone Replacement

• TSH alone is sufficient for routine monitoring in stable patients with primary hypothyroidism 7
• Check TSH every 6-8 weeks after dose changes 1, 7
• Once stable, monitor TSH every 6-12 months 1, 7
• Add free T4 when TSH results are discordant with clinical status or when central hypothyroidism is suspected 1
• Free T4 helps interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 1

Critical Clinical Scenarios

Central Hypothyroidism (Hypophysitis)

• Both TSH and free T4 are mandatory because TSH can remain within normal range despite hypothyroidism 1
• Low TSH with low free T4 is the hallmark finding 1
• Also measure morning ACTH and cortisol, as central adrenal insufficiency occurs in >75% of patients with hypophysitis 1
• Always start corticosteroids before thyroid hormone replacement when both deficiencies exist to avoid precipitating adrenal crisis 1

Pregnancy

• Measure TSH and free T4 as soon as pregnancy is confirmed and at minimum during each trimester 7
• Maintain TSH in trimester-specific reference ranges 7
• Monitor TSH every 4 weeks until stable dose achieved 7

Thyroid Cancer Patients

• TSH suppression targets vary by cancer stage and risk, requiring both TSH and free T4 monitoring 1, 7
• Mild TSH suppression (0.1-0.5 mIU/L) for intermediate to high-risk patients 1
• More aggressive suppression (TSH <0.1 mIU/L) for structural incomplete responses 1

Common Pitfalls to Avoid

• Never rely on a single abnormal TSH value—30-60% normalize on repeat testing 3
• Confirm elevated TSH with repeat testing after 3-6 weeks before initiating treatment 3
• Do not order T3 uptake, total T4, or calculate FTI in modern practice—these tests are obsolete and provide inferior diagnostic information 2, 4
• In acutely ill patients, free T4 by equilibrium dialysis may be abnormal in 25% without thyroid disease; rely on TSH and FT4 index for diagnosis 6
• Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism, as this precipitates adrenal crisis 1