What is the approach to diagnosing thyroid disease and interpreting laboratory tests, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels?

Diagnosing Thyroid Disease: Laboratory Interpretation and Algorithmic Approach

Initial Testing Strategy

Start with TSH as your first-line test—it has 98% sensitivity and 92% specificity for detecting thyroid dysfunction and should guide all subsequent testing. 1

Step 1: Measure TSH First

• TSH is the single most important screening test for suspected thyroid dysfunction in primary care and specialty settings 1, 2
• Normal TSH range: 0.45-4.5 mIU/L (though this shifts upward with age, reaching 7.5 mIU/L in patients over 80) 1
• TSH values below 0.1 mU/L are considered low; values above 6.5 mIU/L (or 4.5 mIU/L by some definitions) are considered elevated 1

Step 2: Interpret TSH and Proceed Algorithmically

If TSH is elevated (>4.5 mIU/L):

• Measure free T4 to distinguish subclinical hypothyroidism (normal free T4) from overt hypothyroidism (low free T4) 1, 2
• Always confirm with repeat testing after 3-6 weeks, as 30-60% of elevated TSH values normalize spontaneously 1

If TSH is suppressed (<0.1-0.4 mIU/L):

• Measure free T4 to confirm hyperthyroidism versus subclinical hyperthyroidism 1
• If TSH is suppressed but free T4 is normal, measure T3 to detect T3-toxicosis or early hyperthyroidism 1

If TSH is normal:

• No further testing needed in asymptomatic patients 1
• Exception: If you suspect central hypothyroidism (pituitary/hypothalamic disease), TSH is diagnostically misleading—measure free T4 and T3 directly 1

Understanding What Each Lab Means

TSH (Thyroid-Stimulating Hormone)

TSH reflects the pituitary's assessment of thyroid hormone adequacy—it rises when thyroid hormone is insufficient and falls when thyroid hormone is excessive. 1, 3

• High TSH (>4.5 mIU/L): Indicates hypothyroidism—the pituitary is working harder to stimulate an underactive thyroid 1
• Low TSH (<0.1-0.4 mIU/L): Indicates hyperthyroidism—the pituitary shuts down because thyroid hormone levels are too high 1
• TSH is the most sensitive marker because it changes before thyroid hormones become abnormal 1

Critical caveat: TSH can be transiently affected by acute illness, hospitalization, recent iodine exposure, certain medications, or recovery from thyroiditis—always confirm abnormal results with repeat testing 1

Free T4 (Free Thyroxine)

Free T4 measures the active, unbound thyroid hormone available to tissues—it distinguishes between subclinical and overt thyroid dysfunction. 1, 2

• Low free T4 with high TSH: Overt hypothyroidism requiring immediate treatment 1
• Normal free T4 with high TSH: Subclinical hypothyroidism—treatment depends on TSH level and clinical factors 1
• High free T4 with low TSH: Overt hyperthyroidism 1
• Normal free T4 with low TSH: Subclinical hyperthyroidism or need to check T3 1

Important limitation: Free T4 measurements can be unreliable during critical illness or in patients with abnormal binding proteins 4

T3 (Triiodothyronine)

T3 is reserved for specific scenarios—it is NOT a routine screening test. 1

Measure T3 when:

• TSH is suppressed (<0.1-0.4 mIU/L) but free T4 is normal—this pattern suggests T3-toxicosis or early hyperthyroidism 1
• Confirming overt hyperthyroidism when TSH is low or undetectable 1
• Evaluating central hypothyroidism alongside free T4, since TSH is unreliable in pituitary/hypothalamic dysfunction 1

Do NOT measure T3 for hypothyroidism screening—it lacks sensitivity and has poor specificity during non-thyroidal illness 4

Anti-TPO Antibodies (Thyroid Peroxidase Antibodies)

Measure anti-TPO antibodies in patients with TSH 4.5-10 mIU/L to identify autoimmune thyroid disease and guide treatment decisions. 1

• Positive anti-TPO antibodies indicate autoimmune etiology (Hashimoto's thyroiditis) and predict higher progression risk to overt hypothyroidism (4.3% per year vs 2.6% in antibody-negative individuals) 1
• Also measure in patients with other autoimmune conditions to screen for autoimmune thyroid disease 1

Treatment Thresholds Based on Lab Results

TSH >10 mIU/L with Normal Free T4

Initiate levothyroxine therapy regardless of symptoms—this threshold carries ~5% annual risk of progression to overt hypothyroidism 1

TSH 4.5-10 mIU/L with Normal Free T4

Do NOT routinely treat—monitor thyroid function tests every 6-12 months 1

Consider treatment in specific situations:

• Symptomatic patients (fatigue, weight gain, cold intolerance, constipation) 1
• Pregnant women or those planning pregnancy 1
• Positive anti-TPO antibodies 1
• Goiter or infertility 1

TSH <0.1 mIU/L

Reduce levothyroxine dose by 25-50 mcg immediately if patient is on thyroid replacement for hypothyroidism (not thyroid cancer) 1

• Prolonged TSH suppression increases risk for atrial fibrillation (especially in elderly), osteoporosis, fractures, and cardiovascular mortality 1

Common Pitfalls to Avoid

Never treat based on a single abnormal TSH value—30-60% normalize on repeat testing, representing transient thyroiditis or non-thyroidal illness 1

Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism—this can precipitate life-threatening adrenal crisis 1, 5

Never assume TSH alone tells the whole story in hospitalized or critically ill patients—non-thyroidal illness can interfere with all thyroid function tests 1

Never ignore suppressed TSH in elderly patients on levothyroxine—approximately 25% of patients are unintentionally overtreated, increasing serious complication risks 1

Never use T3 to screen for hypothyroidism—it lacks sensitivity and is affected by non-thyroidal illness 4

Special Populations Requiring Modified Interpretation

Pregnant women: Target TSH <2.5 mIU/L in first trimester; levothyroxine requirements increase 25-50% during pregnancy 1

Elderly patients (>70 years): TSH reference range shifts upward; slightly higher TSH targets may be acceptable to avoid overtreatment risks 1

Patients on immune checkpoint inhibitors: Monitor TSH every 4-6 weeks for first 3 months, then every second cycle; thyroid dysfunction occurs in 6-20% of patients 1

Thyroid cancer patients: TSH targets are intentionally suppressed based on risk stratification (0.1-2 mIU/L)—requires endocrinologist guidance 1