Low TSH, Low T3, Normal T4: Central Hypothyroidism Until Proven Otherwise
This pattern of low TSH with low T3 and normal T4 most likely represents central (secondary) hypothyroidism, requiring immediate evaluation for pituitary/hypothalamic dysfunction and concurrent adrenal insufficiency before initiating any thyroid hormone replacement. 1
Immediate Diagnostic Priorities
Before any treatment, you must rule out adrenal insufficiency—starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis. 1
Essential Initial Testing
- Obtain morning ACTH and cortisol levels or perform a 1 mcg cosyntropin stimulation test to assess adrenal function 1
- Measure free T4 by equilibrium dialysis (the most accurate method in this context) to confirm low thyroid hormone levels 1, 2
- Order MRI of the sella with pituitary cuts to evaluate for hypophysitis, pituitary enlargement, or stalk thickening 1
- Check additional pituitary hormones (FSH, LH, gonadal hormones) to assess for panhypopituitarism, which occurs in approximately 50% of hypophysitis cases 1
Critical Clinical Context
- Ask about headache (present in 85% of hypophysitis cases) and fatigue (66% of cases) 1
- Review medication history, particularly immune checkpoint inhibitors (anti-PD-1/PD-L1 therapy), which can cause hypophysitis leading to central hypothyroidism 1
- Assess for symptoms of adrenal insufficiency (weakness, weight loss, hypotension), as central adrenal insufficiency coexists in >75% of hypophysitis cases 1
Why This Pattern Indicates Central Hypothyroidism
The combination of undetectable or low TSH with low T3 definitively indicates central hypothyroidism rather than primary thyroid disease. 1 In primary hypothyroidism, TSH would be elevated. In subclinical hyperthyroidism, free T4 and T3 would be normal or elevated, not low. 3
Alternative Diagnoses to Consider (Less Likely)
- Nonthyroidal illness syndrome (NTIS): Can cause low T3 with normal T4, but TSH is typically normal or slightly elevated, not low 2. Elevated reverse T3 argues against primary hypothyroidism and suggests NTIS 2
- Resistance to thyroid hormone alpha (RTHα): Presents with high-normal or elevated free T3, low-normal free T4, and normal TSH—not low TSH 4. This diagnosis is excluded by your patient's low TSH
- Medication effects or recovery phase thyroiditis: Could transiently suppress TSH, but would not typically cause low T3 5
Treatment Protocol (Only After Ruling Out Adrenal Insufficiency)
If Adrenal Insufficiency is Confirmed
Start corticosteroids at least 1 week before initiating levothyroxine. 1 This is non-negotiable—starting thyroid hormone first can precipitate adrenal crisis. 1
Levothyroxine Dosing for Central Hypothyroidism
- For patients <70 years without cardiac disease: Start levothyroxine 1.6 mcg/kg/day 1
- For patients >70 years or with cardiac disease: Start 25-50 mcg/day and titrate gradually, monitoring for cardiac arrhythmias 1
- Adjust dose in 12.5-25 mcg increments based on free T4 levels, not TSH (TSH is unreliable in central hypothyroidism) 1
- Wait 6-8 weeks between dose adjustments to reach steady state 1
Monitoring Strategy
- Recheck free T4 in 6-8 weeks after each dose adjustment, targeting approximately 14-19 pmol/L 1
- Do NOT use TSH to guide therapy in central hypothyroidism—it will remain low regardless of adequate replacement 1
- Once stable, monitor free T4 every 6-12 months 1
- Consider annual monitoring of other pituitary hormones depending on etiology 1
Critical Pitfalls to Avoid
- Never start levothyroxine before ruling out and treating adrenal insufficiency 1—this is the most dangerous error
- Do not rely on TSH to guide treatment in central hypothyroidism 1
- Do not assume this is subclinical hyperthyroidism based on low TSH alone—the low T3 excludes this diagnosis 3
- Do not dismiss this as nonthyroidal illness without proper pituitary evaluation 2
- Ensure patients with confirmed adrenal insufficiency obtain and carry a medical alert bracelet 1