How do you interpret thyroid function tests, including Thyroid-Stimulating Hormone (TSH), Free Thyroxine (FT4), and Free Triiodothyronine (FT3) levels?

Interpreting Thyroid Function Tests: A Structured Approach

TSH is the single most important initial test for evaluating thyroid function, with sensitivity above 98% and specificity greater than 92%, and should be interpreted in conjunction with free T4 (and free T3 when indicated) to accurately classify thyroid status. 1

Primary Interpretation Algorithm

Step 1: Start with TSH

TSH serves as the primary screening test because it is the most sensitive indicator of thyroid gland function. 2, 1 The normal reference range is typically 0.45-4.5 mIU/L, though this can vary slightly between laboratories. 1

• TSH elevation precedes T4 abnormalities in the progression of thyroid disease, making it an earlier marker of thyroid gland failure 1
• TSH values can be transiently affected by acute illness, hospitalization, recent iodine exposure (such as CT contrast), certain medications, or recovery phase from thyroiditis 1
• 30-60% of elevated TSH levels normalize spontaneously on repeat testing, so confirmation with repeat testing after 3-6 weeks is essential before making treatment decisions 1

Step 2: Measure Free T4 to Classify Dysfunction

Once TSH is abnormal, measure free T4 to distinguish between subclinical and overt thyroid dysfunction. 2, 1

The combination of TSH and free T4 creates four primary diagnostic categories:

Normal Thyroid Function (Euthyroid)

• TSH: 0.45-4.5 mIU/L
• Free T4: Normal (typically 9-19 pmol/L or 0.7-1.5 ng/dL)
• This definitively excludes both overt and subclinical thyroid dysfunction 1

Subclinical Hypothyroidism

• TSH: Elevated (>4.5 mIU/L)
• Free T4: Normal
• This represents early thyroid gland failure with compensatory TSH elevation 2, 1

Overt Hypothyroidism

• TSH: Elevated (typically >10 mIU/L)
• Free T4: Low
• This indicates established thyroid hormone deficiency requiring treatment 2, 1

Subclinical Hyperthyroidism

• TSH: Low (<0.1-0.45 mIU/L) or undetectable (<0.1 mIU/L)
• Free T4: Normal
• TSH levels "clearly low" or "undetectable" (<0.1 mIU/L) carry higher risk of progression and complications 2

Overt Hyperthyroidism

• TSH: Low or undetectable
• Free T4: Elevated (and/or free T3 elevated)
• Despite its name, "overt" hyperthyroidism does not require the presence of symptoms and is defined biochemically 2

Step 3: Add Free T3 When Indicated

Free T3 measurement is not routinely necessary but should be added in specific situations:

• Suspected hyperthyroidism with low TSH but normal free T4 (T3 toxicosis) 2
• Monitoring patients on combination thyroid hormone therapy 1
• Evaluating adequacy of treatment in patients with persistent symptoms despite normalized TSH 1
• Thyroid storm diagnosis (though treatment should not be delayed for results) 2

Critical Interpretation Pitfalls to Avoid

Laboratory and Assay Considerations

Different laboratory platforms produce varying results, making direct comparison of values across laboratories problematic. 3, 4, 5 When evaluating serial thyroid function tests, use the same laboratory and assay method whenever possible. 4, 5

Laboratory reference intervals are based on statistical distribution (97.5th percentile) rather than association with clinical outcomes, leading to professional disagreement about appropriate cut points. 2 The geometric mean TSH in disease-free populations is 1.4 mU/L. 1

Physiologic and Clinical Context

Always consider the clinical context before interpreting results:

• Pregnancy: Thyroid function changes significantly; different reference ranges apply 2
• Acute illness (non-thyroidal illness): Can cause transient TSH suppression or elevation without true thyroid disease 2, 1
• Medications: Amiodarone, heparin, biotin, and others can interfere with assays or alter thyroid function 3
• Recent iodine exposure: CT contrast can transiently affect thyroid function 1
• Recovery from thyroiditis: May show transient abnormalities 1

In hospitalized or acutely ill patients, avoid testing thyroid function during acute metabolic stress, as results may be misleading due to euthyroid sick syndrome. 6 If initial tests are performed during metabolic instability, repeat after achieving stability. 6

Assay Interference

When results are discordant with clinical picture, consider laboratory artifacts:

• Heterophile antibodies can cause falsely low or high TSH 7
• Anti-thyroglobulin antibodies (TgAb) can interfere with thyroglobulin measurement 6
• Biotin supplementation can cause spurious results in many immunoassays 3
• Alterations in thyroid hormone binding proteins (TBG deficiency or excess) affect total T4/T3 but not free hormone levels 7

When there is discrepancy between thyroid function results and clinical picture, prove interference or TBG abnormality before making treatment decisions. 7

Specific Clinical Scenarios

Elevated TSH with Normal Free T4 (Subclinical Hypothyroidism)

The clinical significance depends on the degree of TSH elevation:

• TSH >10 mIU/L: Treatment with levothyroxine is recommended regardless of symptoms, as this carries approximately 5% annual risk of progression to overt hypothyroidism 2, 1
• TSH 4.5-10 mIU/L: Routine treatment is not recommended; monitor every 6-12 months 2, 1
• Consider treatment for TSH 4.5-10 mIU/L in specific situations: symptomatic patients, pregnancy planning, positive anti-TPO antibodies (4.3% vs 2.6% annual progression risk) 1, 6

Confirm with repeat testing after 3-6 weeks, as many professional groups recommend repeating thyroid function tests before making treatment decisions unless TSH is >10.0 mIU/L. 2

Low TSH with Normal Free T4 (Subclinical Hyperthyroidism)

Severity stratification matters:

• TSH <0.1 mIU/L: Associated with increased risk of atrial fibrillation, bone loss, and progression to overt hyperthyroidism 2, 1
• TSH 0.1-0.45 mIU/L: Lower risk but still warrants monitoring 1

In patients on levothyroxine therapy, TSH <0.1 mIU/L indicates overtreatment requiring dose reduction to prevent complications including atrial fibrillation, osteoporosis, and cardiac dysfunction. 1

Discordant Results (e.g., High TSH with High Free T4)

When TSH and free T4 are discordant, consider rare conditions:

• TSH-secreting pituitary adenoma (TSHoma): Elevated TSH with elevated free T4 3
• Thyroid hormone resistance: Elevated TSH with elevated free T4, often with family history 3
• Assay interference: Most common cause of apparent discordance 3, 7
• Central hypothyroidism: Low or inappropriately normal TSH with low free T4 1

First revisit clinical context and exclude confounding factors before pursuing rare diagnoses. 3

Monitoring Patients on Levothyroxine

For patients on thyroid hormone replacement:

• During dose titration: Check TSH and free T4 every 6-8 weeks 1
• Once stable: Check TSH every 6-12 months or if symptoms change 1
• Target TSH: 0.5-4.5 mIU/L for hypothyroidism (different targets apply for thyroid cancer patients requiring TSH suppression) 2, 1

Free T4 helps interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize. 1 Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for complications. 1

Pregnancy-Specific Considerations

Hypothyroidism in pregnant women requires special attention:

• TSH should be checked every trimester once stable 2
• Levothyroxine dosage requirements increase 25-50% during pregnancy 1
• Untreated or inadequately treated hypothyroidism increases risk of preeclampsia, low birth weight, and potential neurodevelopmental effects 2, 1
• Nausea and vomiting of pregnancy (hyperemesis gravidarum) is associated with biochemical hyperthyroidism (undetectable TSH, elevated free T4) but rarely requires treatment 2

Thyroid Antibody Interpretation

Anti-TPO antibodies identify autoimmune etiology and predict progression risk:

• Positive anti-TPO antibodies with normal thyroid function: 4.3% annual progression to overt hypothyroidism vs 2.6% in antibody-negative individuals 1, 6
• Monitor TSH and free T4 every 6-12 months in antibody-positive patients 6
• Anti-thyroglobulin antibodies can interfere with thyroglobulin measurement in thyroid cancer monitoring 6

Key Monitoring Principles

Regular monitoring intervals depend on clinical situation:

• Asymptomatic individuals with normal tests: No routine screening interval needed; recheck if symptoms develop 1
• Subclinical hypothyroidism (TSH 4.5-10 mIU/L): Every 6-12 months 2, 1
• Patients on levothyroxine during titration: Every 6-8 weeks 1
• Stable patients on levothyroxine: Every 6-12 months 1
• Pregnant women on levothyroxine: Every trimester 2

Development of low TSH on therapy suggests overtreatment or recovery of thyroid function; dose should be reduced or discontinued with close follow-up. 1