Management of Low Free T4 with Normal TSH
This pattern of low free T4 (0.90 ng/dL) with normal TSH (2.170 uIU/mL) most likely represents central hypothyroidism requiring immediate evaluation for concurrent adrenal insufficiency before initiating levothyroxine replacement therapy. 1
Critical First Steps Before Treatment
Rule out adrenal insufficiency immediately by checking morning ACTH and cortisol levels, as starting thyroid hormone before corticosteroids can precipitate adrenal crisis in patients with concurrent hypopituitarism 2, 1. This is the most dangerous pitfall to avoid.
Essential Diagnostic Workup
- Obtain free T4 by equilibrium dialysis to confirm the low value, as some assay methods can be unreliable 1
- Check morning (9 AM) cortisol and ACTH levels or perform a 1 mcg cosyntropin stimulation test 2, 1
- Measure FSH, LH, and gonadal hormones (testosterone in men, estradiol in premenopausal women) to assess for panhypopituitarism 2, 1
- Order MRI of the sella with pituitary cuts to evaluate for hypophysitis, pituitary enlargement, or stalk thickening 1
If the patient is on immunotherapy (checkpoint inhibitors), this pattern strongly suggests immune-related hypophysitis, which occurs in 9-10% of patients on combination anti-PD(L)1/anti-CTLA-4 therapy and 1-6% on monotherapy 2. Hypophysitis presents with headache (85% of cases) and fatigue (66%), with central hypothyroidism occurring in >90% of cases 1.
Treatment Protocol
If Adrenal Insufficiency is Confirmed
Start hydrocortisone 20/10 mg immediately and wait at least 1 week before initiating levothyroxine 2. This sequence is mandatory to prevent adrenal crisis 2, 1.
Levothyroxine Initiation for Central Hypothyroidism
For patients <70 years without cardiac disease:
- Start levothyroxine 1.6 mcg/kg/day as the full replacement dose 3, 1
- Monitor free T4 levels (not TSH) every 6-8 weeks during titration 1
- Target free T4 in the upper half of the reference range (approximately 1.3-1.7 ng/dL) 4
For patients >70 years or with cardiac disease:
- Start with 25-50 mcg/day and titrate gradually 3, 1
- Monitor for cardiac arrhythmias, angina, or signs of cardiac decompensation 3
- Increase dose by 12.5-25 mcg increments every 6-8 weeks based on free T4 levels 1
Monitoring Strategy
- TSH cannot be used to guide therapy in central hypothyroidism - only free T4 levels should direct dose adjustments 1, 4
- Recheck free T4 in 6-8 weeks after each dose adjustment 1
- Once stable, monitor free T4 every 6-12 months 1
- Annual monitoring of other pituitary hormones may be warranted depending on etiology 1
Alternative Diagnosis: Assay Interference
If pituitary imaging is normal and cortisol is adequate, consider:
- Repeat testing with a different assay method, as some free T4 assays can give falsely low results 1
- Check total T4 and calculate free T4 index - if these are normal, the low free T4 may represent assay interference rather than true hypothyroidism 2
- Review medications that can interfere with thyroid function tests (heparin, amiodarone) 5
Critical Pitfalls to Avoid
- Never start levothyroxine before ruling out adrenal insufficiency in patients with suspected central hypothyroidism 2, 1
- Do not rely on TSH to guide therapy - it will remain inappropriately normal or low in central hypothyroidism 1, 4
- Do not assume this is subclinical hypothyroidism requiring no treatment - low free T4 with normal TSH indicates pituitary/hypothalamic dysfunction, not mild thyroid disease 1
- Failing to obtain pituitary imaging can miss structural lesions requiring neurosurgical intervention 1
Long-Term Management
- Patients with central hypothyroidism typically require lifelong hormone replacement 1
- Ensure the patient obtains and carries a medical alert bracelet if adrenal insufficiency is confirmed 1
- Continue immunotherapy in most cases if this is immune-related hypophysitis, as high-dose corticosteroids are rarely required and endocrine deficiency usually persists despite treatment 2