What diagnostic tests and referrals are recommended for a patient with normal Thyroid-Stimulating Hormone (TSH) and low Thyroxine (T4) levels?

Diagnostic Approach for Normal TSH with Low T4

This combination of normal TSH with low T4 indicates central (secondary) hypothyroidism from pituitary or hypothalamic dysfunction, requiring immediate evaluation for hypophysitis with morning cortisol and ACTH levels, pituitary hormone panel, and brain MRI—never start thyroid hormone replacement before ruling out adrenal insufficiency, as this can precipitate adrenal crisis. 1, 2

Immediate Diagnostic Testing Required

Morning cortisol and ACTH assessment (8 AM) is the most critical first step, as central hypothyroidism frequently coexists with adrenal insufficiency in hypophysitis, and starting levothyroxine before corticosteroids can trigger life-threatening adrenal crisis. 1, 2

Essential Laboratory Tests

• Complete pituitary hormone panel including TSH, free T4, ACTH, morning cortisol (or 1 mcg cosyntropin stimulation test), FSH, LH, testosterone (men) or estradiol (women), and prolactin 1, 2
• Repeat TSH and free T4 to confirm the pattern, as a falling TSH across two measurements with normal or lowered T4 strongly suggests pituitary dysfunction 1, 2
• Thyroid antibodies (anti-TPO) to exclude concurrent autoimmune thyroid disease, though this pattern is more consistent with central pathology 1

The combination of low TSH with low T4 definitively indicates central hypothyroidism rather than primary thyroid disease, where TSH would be elevated. 2 Both values must be measured together because low TSH alone is ambiguous—it could indicate hyperthyroidism (with high T4) or central hypothyroidism (with low T4). 2

Imaging Studies

• Brain MRI with pituitary cuts to evaluate for pituitary enlargement, stalk thickening, suprasellar convexity, or heterogeneous enhancement characteristic of hypophysitis 1, 2
• MRI abnormalities are present in most patients with hypophysitis at diagnosis, though pituitary enlargement can precede clinical and biochemical evidence of disease 1

Clinical Context Assessment

Specific symptoms to evaluate include headache (present in 85% of hypophysitis cases), visual disturbances requiring immediate differentiation from cerebral metastasis, fatigue (66% of cases), and symptoms of hypocortisolism or hypothyroidism. 1, 2

High-Risk Populations

• Patients on immune checkpoint inhibitors face dramatically elevated risk: ipilimumab causes hypophysitis in 1-16% depending on dose, combination ipilimumab/nivolumab in 8%, while anti-PD-1/PD-L1 monotherapy rarely causes hypophysitis 1, 2
• For these patients, thyroid function tests should be checked every cycle for the first 3 months, then every second cycle thereafter 1, 2
• Weekly cortisol measurements should be performed when falling TSH with normal or lowered T4 is detected 1, 2

Mandatory Endocrinology Referral

Immediate endocrinology consultation is required for all cases of suspected central hypothyroidism, as this represents unusual pathology requiring specialized management. 1, 2 The endocrinologist will guide:

• Interpretation of pituitary hormone deficiencies (>75% have both central hypothyroidism and adrenal insufficiency; ~50% present with panhypopituitarism) 1
• Determination of whether ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 pituitary hormone deficiencies with headache confirms hypophysitis 1
• Timing and sequencing of hormone replacement therapy 1, 2

Critical Management Principles

Hydrocortisone must always be initiated before levothyroxine in confirmed central hypothyroidism with adrenal insufficiency, using physiologic replacement doses. 1, 2 Starting thyroid hormone first can unmask adrenal insufficiency and precipitate crisis. 1, 3

Treatment Sequencing

• High-dose steroids are necessary for severe headaches, vision changes, or adrenal crisis 1
• Both adrenal insufficiency and hypothyroidism represent long-term sequelae requiring lifelong replacement in most cases 1
• All patients with confirmed adrenal insufficiency must obtain and carry a medical alert bracelet 1

Common Pitfalls to Avoid

• Never assume primary hypothyroidism based on low T4 alone—TSH elevation is required for primary hypothyroidism, whereas normal or low TSH with low T4 indicates central pathology 2
• Never start levothyroxine empirically without first evaluating cortisol status, as this is the most dangerous error in central hypothyroidism management 1, 3, 2
• Do not dismiss normal-range TSH in the setting of low T4—in hypophysitis, TSH can remain within normal range despite significant hypothyroidism, making it essential to check both values 2
• Avoid attributing symptoms to other causes without excluding hypophysitis in high-risk populations, particularly those on immunotherapy where late endocrine dysfunction can occur 1

Monitoring After Diagnosis

For confirmed central hypothyroidism, monitor serum free T4 levels (not TSH) and maintain in the upper half of the normal range, as TSH cannot be used to guide therapy in secondary hypothyroidism. 4