In a 60-year-old woman with hyperthyroidism, anti‑thyroid peroxidase positivity and possible autoimmune adrenal insufficiency, should I order a 24‑hour urine free cortisol test despite normal renal function?

24-Hour Urine Free Cortisol Testing in Suspected Adrenal Insufficiency

Do not order a 24-hour urine free cortisol test to evaluate adrenal insufficiency in this patient—this test is designed to detect hypercortisolism (Cushing's syndrome), not cortisol deficiency. 1

Why 24-Hour UFC Is the Wrong Test for Adrenal Insufficiency

• The 24-hour urinary free cortisol test measures excess cortisol production and is recommended as a screening tool for Cushing's syndrome, not adrenal insufficiency 1, 2
• In patients with adrenal insufficiency, cortisol production is already low or absent, so measuring urinary cortisol excretion will simply confirm low levels without providing diagnostic clarity 1
• The test has poor sensitivity for detecting subtle adrenal dysfunction—even in critically ill patients with documented adrenal insufficiency, 24-hour UFC may appear "normal" because it reflects total cortisol output rather than adequacy of response to stress 3, 4

Correct Diagnostic Approach for Suspected Adrenal Insufficiency

Measure morning (08:00-09:00h) serum cortisol and plasma ACTH as your initial diagnostic tests. 1

Interpretation of Morning Cortisol

• A morning serum cortisol >14 μg/dL (>386 nmol/L) effectively rules out adrenal insufficiency 1
• A morning cortisol <10 μg/dL (<275 nmol/L) should prompt confirmatory testing with an ACTH stimulation test 1
• In the context of acute illness with hypotension, vomiting, or electrolyte abnormalities (hyponatremia, hyperkalemia), a cortisol level <10 μg/dL is highly suggestive of primary adrenal insufficiency 5, 1

ACTH Stimulation Test (Synacthen Test)

• If morning cortisol is equivocal (<275 nmol/L), perform a standard-dose ACTH stimulation test with 0.25 mg cosyntropin (tetracosactide) administered intramuscularly or intravenously 5, 1
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-injection 5
• A peak cortisol response <500 nmol/L (<18 μg/dL) is diagnostic of primary adrenal insufficiency 5, 1
• This test directly assesses adrenal reserve and is the gold standard for confirming adrenal insufficiency 5

Distinguishing Primary from Secondary Adrenal Insufficiency

• Measure plasma ACTH simultaneously with morning cortisol 1, 6
• In primary adrenal insufficiency (autoimmune adrenalitis), ACTH will be markedly elevated (often >100 pg/mL) because the pituitary is attempting to stimulate a failing adrenal gland 5, 1
• In secondary adrenal insufficiency (pituitary or hypothalamic disease), ACTH will be low or inappropriately normal 1, 6
• Given this patient's suspected autoimmune adrenal insufficiency, you would expect elevated ACTH levels if the diagnosis is correct 5

Critical Pitfall: Renal Impairment Invalidates UFC Testing

• Even if you were evaluating for Cushing's syndrome (which you are not), renal impairment or polyuria invalidates 24-hour UFC results. 1, 2
• The midnight-to-morning urinary cortisol increment method is unreliable in patients with GFR <29 mL/min/1.73 m², showing falsely abnormal responses 7
• In chronic kidney disease, morning urinary free cortisol levels progressively fall with decreasing GFR, making interpretation impossible 7
• While this patient has "normal kidney function," the fundamental issue remains: UFC measures excess cortisol, not deficiency 1, 8

Additional Considerations in This Clinical Context

• The patient's hyperthyroidism and anti-thyroid peroxidase positivity suggest autoimmune thyroid disease (Hashimoto's or Graves'), which increases the likelihood of polyglandular autoimmune syndrome 5
• If autoimmune adrenal insufficiency (Addison's disease) is confirmed, check for 21-hydroxylase antibodies to support the autoimmune etiology 5
• Never delay treatment of suspected acute adrenal crisis to perform diagnostic testing—if the patient presents with collapse, hypotension, or severe electrolyte disturbances, administer 100 mg hydrocortisone IV immediately and draw blood for cortisol and ACTH before the first dose 5