How to manage a patient with low Thyroxine (T4) and normal Thyroid-Stimulating Hormone (TSH) levels?

Management of Low T4 with Normal TSH

The combination of low T4 with normal TSH strongly suggests central hypothyroidism (secondary or tertiary hypothyroidism due to pituitary or hypothalamic dysfunction), and you must immediately check an 8 AM cortisol level before initiating any thyroid hormone replacement to avoid precipitating adrenal crisis. 1

Immediate Diagnostic Workup

Critical first step: Obtain morning (8 AM) cortisol and ACTH levels before starting any treatment, as central hypothyroidism frequently coexists with adrenal insufficiency (>75% of cases), and thyroid hormone replacement can precipitate life-threatening adrenal crisis if given before steroid replacement. 1

Essential Laboratory Tests

• Repeat thyroid function tests (TSH, free T4) to confirm the pattern, as 30-60% of abnormal results normalize on repeat testing 2
• Pituitary hormone panel (8 AM): ACTH, cortisol (or 1 mcg cosyntropin stimulation test), FSH, LH, and gonadal hormones (testosterone in men, estradiol in women) 1
• Consider thyroid antibodies (TPO) to evaluate for concurrent autoimmune disease 2

Imaging

• MRI of the sella with pituitary cuts is essential to evaluate for pituitary pathology, including hypophysitis, adenomas, or structural lesions 1
• MRI abnormalities may include stalk thickening, suprasellar convexity, heterogeneous enhancement, or increased gland height 1

Context-Specific Considerations

Immunotherapy Patients

If the patient is receiving immune checkpoint inhibitors (anti-CTLA4 or anti-PD-1/PD-L1), this pattern is particularly concerning for hypophysitis:

• Falling TSH across two measurements with normal or lowered T4 strongly suggests pituitary dysfunction and requires weekly cortisol monitoring 1
• Hypophysitis occurs in 1-17% of patients on ipilimumab (dose-dependent) and up to 13% on combination therapy 1
• Median onset is 8-9 weeks after starting immunotherapy 1

Critical Illness

In critically ill patients with low T4 and inappropriately normal TSH, this may represent "low T4 syndrome" (non-thyroidal illness):

• Diminished TSH response to TRH with low free T4 indicates extremely poor prognosis in critically ill patients 3
• Consider deferring treatment until recovery unless there is clear evidence of pre-existing central hypothyroidism 3, 4

Treatment Algorithm

Step 1: Address Adrenal Insufficiency First

If cortisol deficiency is confirmed, always start physiologic dose steroids BEFORE thyroid hormone replacement to prevent adrenal crisis. 1

Step 2: Initiate Levothyroxine Replacement

Once adrenal status is secured:

• Start levothyroxine 1.5 mcg/kg/day (adjust lower in elderly or those with cardiac history: 0.5-1.0 mcg/kg) 1, 5, 6
• Take as single morning dose on empty stomach, 30-60 minutes before breakfast 7
• Avoid within 4 hours of iron, calcium supplements, or antacids 7

Step 3: Monitoring and Dose Adjustment

Target free T4 levels in the upper half of the normal range (not TSH, which remains unreliable in central hypothyroidism): 5, 6, 8

• Check free T4 AND free T3 levels 4-6 weeks after initiation 5, 6
• TSH cannot be used to guide therapy in central hypothyroidism 5, 6, 8
• Monitor for overtreatment: borderline high free T3 with normal free T4 suggests excessive dosing 5

Common Pitfalls to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency - this is the most critical error and can be fatal 1
• Do not rely on TSH for dose titration in central hypothyroidism - TSH levels can be low, normal, or even slightly elevated despite inadequate replacement 6, 8
• Do not assume isolated thyroid dysfunction - approximately 50% of patients with central hypothyroidism have panhypopituitarism 1
• Avoid using clinical symptoms alone for diagnosis or monitoring, as they lack specificity 5

Long-Term Management

• Lifelong hormone replacement is typically required for central hypothyroidism 1
• Repeat thyroid function tests every 6-12 months once stable, or sooner if symptoms change 2
• All patients with confirmed adrenal insufficiency should obtain and carry a medical alert bracelet 1
• Refer to endocrinology if the pattern persists after initial workup or if management is complex 2