What is the treatment approach for a patient with low Thyroid-Stimulating Hormone (TSH) and low Free Triiodothyronine (FT3)?

Low TSH and Low FT3: Central Hypothyroidism (Hypopituitarism)

This pattern of low TSH with low FT3 (and typically low FT4) indicates central hypothyroidism due to pituitary or hypothalamic dysfunction, requiring immediate evaluation for hypopituitarism and urgent treatment with corticosteroids BEFORE thyroid hormone replacement to prevent adrenal crisis. 1

Immediate Diagnostic Priorities

Critical First Step: Rule out hypopituitarism immediately by checking:

• Morning (9 AM) cortisol level - this is mandatory before any thyroid hormone treatment 1
• ACTH level - will be low or inappropriately normal in central adrenal insufficiency 1
• Free T4 level - should also be low in central hypothyroidism 1, 2
• Additional pituitary hormones: LH, FSH, testosterone (males) or estradiol (females), prolactin 1

If the patient has headaches, visual disturbances, or multiple hormone deficiencies, obtain MRI of the brain with pituitary/sellar cuts to evaluate for pituitary mass, hypophysitis, or other structural lesions 1

Critical Treatment Algorithm

Step 1: Address Adrenal Insufficiency FIRST

Never start thyroid hormone before corticosteroids in central hypothyroidism - this can precipitate life-threatening adrenal crisis 1, 3

• If cortisol is low (<10 μg/dL) or patient is symptomatic: Start hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon 1
• If patient is acutely ill: Use hydrocortisone 100 mg IV or dexamethasone 4 mg IV immediately 1
• Wait several days after starting corticosteroids before initiating thyroid hormone 1

Step 2: Initiate Thyroid Hormone Replacement

After corticosteroid coverage is established:

• Start levothyroxine at 1.5 μg/kg/day for patients <70 years without cardiac disease 2
• For elderly patients (>70 years) or those with cardiac disease: Start with 25-50 μg/day and titrate slowly 1, 4

Step 3: Monitoring Parameters for Central Hypothyroidism

TSH cannot be used to monitor adequacy of treatment in central hypothyroidism - it will remain low regardless of treatment 2, 5

Monitor using free T4 and free T3 levels instead:

• Target FT4 in the upper half of the normal range 2, 5
• Target FT3 in the normal range 2, 5
• Recheck FT4 and FT3 levels 6-8 weeks after dose adjustments 1, 4
• Monitor biochemical markers of thyroid hormone action (lipids, liver enzymes) to assess adequacy 2

Common Etiologies to Consider

Immune checkpoint inhibitor-induced hypophysitis (if patient is on anti-CTLA4 or anti-PD-1 therapy):

• Incidence: 1% with ipilimumab 3 mg/kg, 16% with ipilimumab 10 mg/kg, 8% with combination therapy 1
• Falling TSH across two measurements with normal or lowered T4 suggests pituitary dysfunction 1
• May require holding immunotherapy if Grade 2 or higher 1

Other causes of central hypothyroidism:

• Pituitary adenoma or other sellar masses 1
• Traumatic brain injury 1
• Pituitary surgery or radiation 1
• Sheehan syndrome (postpartum pituitary necrosis) 1
• Infiltrative diseases (sarcoidosis, hemochromatosis) 1

Critical Pitfalls to Avoid

Never start thyroid hormone before ruling out and treating adrenal insufficiency - this is the most dangerous error and can be fatal 1, 3

Do not use TSH to monitor treatment adequacy - TSH remains suppressed in central hypothyroidism even with adequate replacement 2, 5

Do not assume isolated thyroid dysfunction - central hypothyroidism usually indicates broader pituitary dysfunction requiring comprehensive hormone evaluation 1

Avoid undertreating - patients with central hypothyroidism require adequate replacement to maintain FT4 in the upper half of normal range, not just low-normal 2

Educate all patients on stress dosing and provide medical alert bracelet for adrenal insufficiency 1

Special Considerations

For patients on immunotherapy:

• Monitor thyroid function tests every cycle for first 3 months with anti-PD-1/PD-L1 1
• Monitor every cycle with anti-CTLA4 therapy 1
• Late endocrine dysfunction can occur months after treatment 1

Endocrine consultation is strongly recommended for all patients with suspected central hypothyroidism to guide comprehensive pituitary evaluation and hormone replacement strategy 1