For a patient with elevated Thyroid-Stimulating Hormone (TSH), should I order a Triiodothyronine (T3) or Thyroxine (T4) test first?

Order Free T4 First When TSH is Elevated

When you find an elevated TSH, order a free T4 test to distinguish between subclinical hypothyroidism (normal free T4) and overt hypothyroidism (low free T4)—this distinction is essential for determining treatment urgency and approach. 1

Why Free T4, Not T3

T4 is the Diagnostic Standard

• TSH and free T4 together provide the complete diagnostic picture for hypothyroidism, with TSH being the most sensitive screening test (sensitivity >98%, specificity >92%) and free T4 determining disease severity 1, 2
• Free T4 measurement correctly establishes thyroid status even when thyroid hormone-binding proteins are abnormal, unlike total T4 which can be misleading 3
• T3 testing adds no diagnostic value in suspected hypothyroidism because T3 levels often remain normal even in patients with subclinical or mild thyroid failure 3, 2

The Physiologic Rationale

• Approximately 80% of circulating T3 derives from peripheral conversion of T4, not direct thyroid secretion 4
• In early hypothyroidism, the body compensates by increasing T4-to-T3 conversion, keeping T3 levels normal while T4 drops 3
• T3 levels only fall in severe, advanced hypothyroidism—by which point the diagnosis is already obvious from TSH and free T4 3, 2

The Diagnostic Algorithm

Step 1: Confirm the Elevated TSH

• Repeat TSH testing after 3-6 weeks, as 30-60% of elevated TSH levels normalize spontaneously 1
• Transient TSH elevation occurs with acute illness, recovery from thyroiditis, certain medications, or recent iodine exposure 1

Step 2: Measure Free T4 Simultaneously

• If free T4 is low: Overt hypothyroidism—start levothyroxine immediately regardless of symptoms 1
• If free T4 is normal with TSH >10 mIU/L: Subclinical hypothyroidism—initiate levothyroxine therapy regardless of symptoms, as this carries ~5% annual risk of progression to overt disease 1
• If free T4 is normal with TSH 4.5-10 mIU/L: Subclinical hypothyroidism—treatment decisions require individualization based on symptoms, pregnancy status, or positive anti-TPO antibodies 1

Step 3: Consider Anti-TPO Antibodies (Not T3)

• Positive anti-TPO antibodies identify autoimmune etiology and predict higher progression risk (4.3% vs 2.6% per year in antibody-negative patients) 1, 5
• This information influences treatment decisions for TSH 4.5-10 mIU/L, where treatment is otherwise controversial 1

When T3 Testing is Actually Indicated

Hyperthyroidism Evaluation Only

• T3 testing is reserved for suspected hyperthyroidism, not hypothyroidism 2, 6
• If TSH is suppressed (<0.1 mIU/L) and free T4 is normal, then measure T3 to diagnose T3 toxicosis 2
• In Graves' disease on antithyroid drugs, T3 may remain elevated while T4 normalizes, making T3 monitoring useful in this specific context 6

Central Hypothyroidism Exception

• In suspected pituitary or hypothalamic disease (central hypothyroidism), TSH cannot be used reliably—measure both free T4 and free T3 together 2
• This represents <5% of hypothyroidism cases and requires specific clinical suspicion (pituitary tumor, head trauma, hypophysitis) 1

Critical Pitfalls to Avoid

Don't Order Both Tests Reflexively

• Studies show that when TSH and free T4 are ordered together, 74.3% show concordant results 7
• Among 1,835 patients with normal TSH, only 0.6% had low free T4 and 1.3% had high free T4, with no instances where the abnormal free T4 changed management 7
• Ordering T3 alongside TSH and free T4 for hypothyroidism evaluation wastes resources and provides no additional diagnostic information 3, 2

Don't Treat Based on Single Abnormal Values

• Always confirm elevated TSH with repeat testing before initiating lifelong therapy 1
• 30-60% of mildly elevated TSH values normalize spontaneously, representing transient thyroiditis or nonthyroidal illness 1

Don't Ignore Clinical Context

• Free T4 is more reliable than total T4 in pregnancy, nonthyroidal illness, and patients with binding protein abnormalities 3
• In elderly patients (>70 years), TSH reference ranges shift upward—12% of persons aged 80+ without thyroid disease have TSH >4.5 mIU/L 1

Monitoring During Treatment

TSH Remains the Primary Monitoring Tool

• Once on levothyroxine, monitor TSH every 6-8 weeks during dose titration 1
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 1
• T3 measurement adds no value for monitoring levothyroxine therapy in primary hypothyroidism 2

Target Ranges

• Target TSH within 0.5-4.5 mIU/L with normal free T4 levels for primary hypothyroidism 1
• Approximately 25% of patients on levothyroxine are unintentionally overtreated with fully suppressed TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications 1