Low T4 and Low TSH: Central Hypothyroidism
This pattern indicates central (secondary or tertiary) hypothyroidism requiring immediate levothyroxine replacement therapy, with treatment guided by free T4 levels rather than TSH. 1
Diagnostic Confirmation and Workup
Before initiating treatment, obtain the following tests (preferably around 8 AM):
- Free T4 by equilibrium dialysis (most accurate method in this context) 1, 2
- ACTH and cortisol levels (or 1 mcg cosyntropin stimulation test) 1
- Gonadal hormones (testosterone in men, estradiol in women, FSH, LH) 1
- MRI of the sella with pituitary cuts to evaluate for hypophysitis or pituitary pathology 1
Critical consideration: In patients with both adrenal insufficiency and hypothyroidism, always start corticosteroids before thyroid hormone replacement to prevent adrenal crisis 1. This is non-negotiable.
Differential Diagnosis Context
The combination of low T4 and low/normal TSH suggests:
- Hypophysitis (most common with anti-CTLA-4 immunotherapy; central hypothyroidism occurs in >90% of cases) 1
- Pituitary or hypothalamic disease (tumor, surgery, radiation) 1, 3
- Non-thyroidal illness syndrome (though typically TSH is normal or slightly elevated initially) 2
- Medication effects (dopamine, glucocorticoids, certain anticonvulsants) 4
Treatment Protocol
Initial Levothyroxine Dosing
For patients <70 years without cardiac disease:
- Start with full replacement dose of 1.6 mcg/kg/day 5
For patients >70 years or with cardiac disease/multiple comorbidities:
- Start with 25-50 mcg/day and titrate gradually 5
- Monitor closely for cardiac arrhythmias, especially atrial fibrillation 5
Monitoring Strategy
Unlike primary hypothyroidism, TSH cannot guide therapy in central hypothyroidism. 6, 3
- Recheck free T4 in 6-8 weeks after dose adjustment 1, 5
- Target free T4 in the upper half of the normal range (approximately 14-19 pmol/L or equivalent) 6
- Patients with central hypothyroidism are at significant risk of under-replacement when using standard monitoring approaches 6
- Once stable, monitor free T4 every 6-12 months 5
Dose Adjustments
- Adjust levothyroxine in 12.5-25 mcg increments based on free T4 levels 5
- Wait 6-8 weeks between adjustments to reach steady state 5
- If free T4 remains in lower half of normal range despite treatment, increase dose 6
Critical Pitfalls to Avoid
Do NOT rely on TSH for monitoring: TSH will remain low/normal regardless of adequacy of replacement in central hypothyroidism 1, 3. Using TSH as a guide will result in chronic under-replacement 6.
Do NOT start thyroid hormone before ruling out adrenal insufficiency: This can precipitate life-threatening adrenal crisis 1. If both conditions present, glucocorticoids must be initiated first 1.
Do NOT use standard free T4 immunoassays in complex cases: Direct equilibrium dialysis is the gold standard, particularly in patients with renal failure, critical illness, or suspected interfering substances 7, 2.
Do NOT assume transient dysfunction: Central hypothyroidism from hypophysitis typically requires lifelong hormone replacement in most cases 1.
Special Clinical Scenarios
If headache or visual changes present: High-dose corticosteroids are necessary; this suggests acute pituitary pathology requiring urgent evaluation 1.
If patient on immunotherapy: Hypophysitis typically occurs after the third dose of ipilimumab (median 8-9 weeks from initiation) 1. Monitor thyroid function tests every cycle 1.
If pregnant or planning pregnancy: Levothyroxine requirements increase during pregnancy; monitor free T4 closely and adjust doses to maintain upper-normal range 4.