Management of Low TSH with Low Free T4
This pattern of low TSH (0.25) with low free T4 (0.60) indicates central hypothyroidism due to pituitary or hypothalamic dysfunction and requires immediate evaluation for hypopituitarism with urgent assessment of adrenal function before initiating any thyroid hormone replacement. 1, 2
Immediate Diagnostic Workup
Critical first step: Obtain morning (8 AM) cortisol and ACTH levels immediately, as over 75% of patients with central hypothyroidism also have concurrent adrenal insufficiency. 1 Consider a 1 mcg cosyntropin stimulation test if baseline cortisol is equivocal. 1
Additional Required Testing
- Gonadal hormones (testosterone in men, estradiol/LH/FSH in women) to assess for hypogonadotropic hypogonadism 1
- Free T3 levels to complete thyroid assessment 2, 3
- MRI of the sella with pituitary cuts to evaluate for pituitary pathology, looking specifically for stalk thickening, suprasellar convexity, heterogeneous enhancement, or increased gland height 1
- Prolactin and IGF-1 to assess other pituitary axes 1
Confirm Diagnosis
Repeat TSH and free T4 within 3-4 weeks to verify persistent abnormalities before initiating treatment, unless the patient is symptomatic. 2
Treatment Algorithm
Step 1: Address Adrenal Function FIRST
If adrenal insufficiency is present or suspected, you MUST start physiologic-dose corticosteroids (hydrocortisone 15-25 mg daily in divided doses) BEFORE initiating levothyroxine to avoid precipitating an adrenal crisis. 2 This is non-negotiable—thyroid hormone increases cortisol metabolism and can unmask or worsen adrenal insufficiency. 1
Step 2: Initiate Levothyroxine Replacement
Once adrenal function is addressed or confirmed adequate:
- Starting dose: 1.6 mcg/kg/day for younger patients without cardiovascular disease 2
- For elderly or cardiac patients: Start with 25-50 mcg daily and titrate slowly 4
- Instruct patient to take levothyroxine before blood draws for accurate monitoring 4
Step 3: Monitoring Strategy
Initial monitoring: Recheck TSH, free T4, AND free T3 after 4-6 weeks and adjust dose accordingly. 2, 3 In central hypothyroidism, TSH cannot guide therapy—you must rely on free T4 and free T3 levels plus clinical assessment. 5, 4
Target free T4: Aim for mid-to-upper normal range (median around 16 pmol/L, with 20-80th centile range of 14-19 pmol/L based on adequately treated patients). 4 Pituitary patients are at high risk of under-replacement—38.9% have inappropriately low free T4 levels on treatment. 4
Monitor free T3 closely: Elevated free T3 with normal free T4 suggests overtreatment and increased risk of adverse effects. 3
Long-term monitoring: Every 3-6 months once stable. 2
Critical Pitfalls to Avoid
- Never start levothyroxine before ruling out or treating adrenal insufficiency—this can be life-threatening 1, 2
- Do not rely on TSH for monitoring—it remains low/normal in central hypothyroidism regardless of adequacy of replacement 5, 4
- Avoid under-replacement—studies show 38.9% of pituitary patients on levothyroxine have inadequate free T4 levels compared to only 9.5-13.4% of primary hypothyroidism patients 4
- Consider non-thyroidal illness syndrome if patient is acutely ill—this can cause similar lab patterns but requires different management 6
Context-Specific Considerations
If patient is on immune checkpoint inhibitors: This pattern strongly suggests immune-related hypophysitis, which occurs in up to 17% of patients on high-dose ipilimumab and typically presents 8-9 weeks after starting therapy. 1 Headache occurs in 85% and fatigue in 66% of these cases. 1
If patient has acute illness: Consider non-thyroidal illness syndrome, where low TSH with low free T4 may not represent true hypothyroidism but rather adaptive changes to illness. 6 An elevated reverse T3 argues against true hypothyroidism. 6