How should I manage an adult patient with a normal thyroid‑stimulating hormone (TSH) level but low free thyroxine (free T4) and low free triiodothyronine (free T3)?

Management of Normal TSH with Low Free T4 and Free T3

Immediate Priority: Rule Out Central Hypothyroidism

When TSH is normal or inappropriately low alongside low free T4 and low free T3, central (secondary or tertiary) hypothyroidism must be excluded first, as this represents pituitary or hypothalamic failure requiring urgent evaluation and carries life-threatening risks if adrenal insufficiency coexists 1.

Diagnostic Algorithm for Central Hypothyroidism

Step 1: Confirm the Pattern

• Repeat TSH, free T4, and free T3 measurements to verify persistence 1
• Central hypothyroidism shows low or inappropriately normal TSH with low free T4 1
• TSH may appear "normal" (0.5-4.5 mIU/L) but is inadequate given the low free T4 1

Step 2: Assess for Hypopituitarism

• Measure morning (8 AM) cortisol and ACTH immediately 1
• Check other pituitary hormones: LH, FSH, prolactin, IGF-1 1
• Multiple pituitary hormone deficiencies often coexist 1

Step 3: Imaging

• Order pituitary MRI if hormone deficiencies are confirmed 1

Step 4: Critical Safety Measure

• If adrenal insufficiency is present or suspected, initiate hydrocortisone 20 mg morning and 10 mg afternoon for at least one week BEFORE starting levothyroxine 1
• Starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 1

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Alternative Diagnosis: Non-Thyroidal Illness Syndrome (NTIS)

If central hypothyroidism is excluded and the patient has acute or chronic systemic illness, the pattern likely represents NTIS (formerly "euthyroid sick syndrome") 2, 3.

Characteristics of NTIS

• Low T3 occurs universally in systemic illness due to inhibition of type 1 5'-deiodinase 3, 4
• Low T4 develops in more severe illness 3, 5
• TSH remains normal or low-normal 4, 5
• Reverse T3 is typically elevated (>0.3 ng/mL) 2
• Free T4 by equilibrium dialysis may be low, normal, or high depending on methodology 2, 5

Mechanisms

• Reduced peripheral conversion of T4 to T3 3, 4
• Altered thyroid hormone binding to serum proteins 3, 5
• Suppressed TSH secretion by cytokines, dopamine, or glucocorticoids 3, 4
• Circulating inhibitors of thyroid hormone binding 5

Management of NTIS

Do NOT treat with thyroid hormone replacement 2:

• Studies show no benefit from T4 administration in NTIS 2
• Some studies suggest potential benefit from T3 in selected cases, but evidence is insufficient 2
• NTIS likely represents a protective adaptive response to illness 3

Monitor and address underlying illness:

• Low T4 correlates with mortality risk but does not indicate need for treatment 2, 5
• Thyroid function normalizes spontaneously with recovery from illness 4

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Medication-Induced Alterations

Beta-Blockers

• Can reduce peripheral T4 to T3 conversion 1
• May mask thyroid dysfunction symptoms 1

Dopamine and High-Dose Glucocorticoids

• Suppress TSH secretion and may cause central hypothyroidism 4
• Can produce low T3, low T4, and inappropriately normal TSH 4

Amiodarone

• Has multiple effects on thyroid hormone indices 4
• Can cause both hypothyroidism and hyperthyroidism 4

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When to Treat Central Hypothyroidism

Initiate levothyroxine if central hypothyroidism is confirmed 6:

• Levothyroxine sodium is FDA-approved for secondary (pituitary) and tertiary (hypothalamic) hypothyroidism 6
• Starting dose: 1.6 mcg/kg/day in adults without cardiac disease 6
• Lower starting dose (25-50 mcg/day) in elderly or those with cardiac disease 6

Monitoring in Central Hypothyroidism:

• Do NOT use TSH to monitor therapy adequacy 7
• Titrate levothyroxine to restore free T4 to the upper half of normal range 7
• Recheck free T4 every 6-8 weeks during titration 7

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Critical Pitfalls to Avoid

1. Never rely on T3 alone to diagnose hypothyroidism—TSH and free T4 are essential 1

2. Never miss central hypothyroidism by assuming normal TSH excludes thyroid disease—always check free T4 when thyroid dysfunction is suspected 1

3. Never start levothyroxine before excluding and treating adrenal insufficiency in suspected central hypothyroidism—this can be fatal 1

4. Never treat NTIS with thyroid hormone—it provides no benefit and may cause harm 2

5. Never diagnose primary hypothyroidism based on low T3 alone with normal TSH—this pattern does not represent primary thyroid failure 1

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When to Refer to Endocrinology

• Confirmed or suspected central hypothyroidism 1
• Difficulty interpreting thyroid function tests in the setting of critical illness 1
• Persistent symptoms despite biochemically adequate replacement 1
• Need for pituitary imaging and evaluation of multiple hormone axes 1