How to manage a patient with low Thyroxine (T4) and normal Thyroid-stimulating hormone (TSH) levels?

Management of Low T4 with Normal TSH

This presentation suggests central (secondary) hypothyroidism due to pituitary or hypothalamic dysfunction, requiring immediate evaluation for hypopituitarism and careful initiation of levothyroxine only after ruling out adrenal insufficiency. 1, 2

Critical First Step: Rule Out Adrenal Insufficiency

Before initiating any thyroid hormone replacement, you must assess the hypothalamic-pituitary-adrenal axis by measuring 9 AM cortisol levels 1, 3. Starting levothyroxine before addressing concurrent adrenal insufficiency can precipitate life-threatening adrenal crisis 4, 3. If hypocortisolism is present, initiate corticosteroid replacement first, then begin thyroid hormone therapy 1, 5.

Diagnostic Confirmation

• Measure both free T4 and free T3 levels, as central hypothyroidism is characterized by low free T4 (and often low free T3) with inappropriately normal or low TSH 2, 6
• A falling TSH across two measurements with normal or lowered T4 strongly suggests pituitary dysfunction and mandates weekly cortisol monitoring 1
• Evaluate other pituitary hormones including FSH/LH, prolactin, and growth hormone, as isolated central hypothyroidism is rare—most patients have multiple pituitary hormone deficiencies 1, 5
• Consider brain MRI to assess for pituitary pathology, particularly if headache or visual disturbances are present, as an enlarged or swollen pituitary gland may indicate hypophysitis 1

Distinguishing Central from Primary Hypothyroidism

This pattern differs fundamentally from primary hypothyroidism, where TSH would be elevated 5, 6. TSH cannot be used to monitor treatment adequacy in central hypothyroidism because the pituitary's TSH response is impaired 2, 6. The normal TSH in the setting of low T4 represents inadequate pituitary compensation for thyroid hormone deficiency 2.

Treatment Initiation

• Start levothyroxine at 1.5 mcg/kg/day for most young patients without cardiac disease 2
• For elderly patients (>70 years) or those with coronary artery disease, begin with 25-50 mcg/day and titrate gradually to avoid cardiac decompensation 4, 5
• For patients with long-standing severe hypothyroidism, use lower initial doses regardless of age 5

Monitoring Strategy for Central Hypothyroidism

Monitor free T4 and free T3 levels, NOT TSH, as TSH remains unreliable in central hypothyroidism 2, 6. Your target is to maintain free T4 in the upper half of the normal reference range 5, 2. Check thyroid function tests 6-8 weeks after dose adjustments 4.

• Free T4 should be maintained in the upper 50% of the normal range (typically 15-19 pmol/L if normal range is 9-19 pmol/L) 5, 2
• Free T3 levels provide additional confirmation of adequate replacement, as some patients may have normal free T4 but borderline low free T3, indicating undertreatment 2
• Biochemical markers of thyroid hormone action (such as sex hormone-binding globulin, cholesterol, and soluble IL-2 receptor) can help identify over- or undertreatment when thyroid hormone levels are borderline 2

Special Considerations for Immunotherapy Patients

If this patient is receiving immune checkpoint inhibitors (anti-CTLA4 or anti-PD-1/PD-L1), hypophysitis is a recognized complication occurring in 1-16% of patients 1. These patients require:

• Thyroid function tests every cycle during the first 3 months, then every second cycle thereafter 1
• Baseline cortisol measurements and weekly cortisol monitoring if TSH is falling 1
• Continuation of immunotherapy is generally safe once hormone replacement is established, though temporary interruption may be needed if the patient is symptomatic 1

Common Pitfalls to Avoid

• Never rely on TSH alone for diagnosis or monitoring in suspected central hypothyroidism—TSH will remain inappropriately normal despite inadequate thyroid hormone levels 2, 6
• Failing to check cortisol before starting levothyroxine can precipitate adrenal crisis in patients with concurrent ACTH deficiency 1, 5
• Overtreatment occurs when free T3 becomes elevated despite normal free T4, increasing risk for atrial fibrillation and osteoporosis 2, 7
• Undertreatment is indicated by persistently low or low-normal free T4 and free T3 despite therapy 2
• Missing the diagnosis of hypophysitis in patients on immunotherapy, as late endocrine dysfunction can occur even after treatment completion 1

When to Suspect Alternative Diagnoses

• Recent iodine exposure from CT contrast can transiently affect thyroid function tests 1, 4
• Nonthyroidal illness can cause low T4 with normal TSH, but this typically occurs in hospitalized or acutely ill patients 4
• Certain medications (amiodarone, glucocorticoids >4 mg/day dexamethasone, propranolol >160 mg/day) can decrease T4 to T3 conversion while maintaining normal TSH 8