What is the most appropriate confirmatory test for adrenal insufficiency in a patient with fatigue, anorexia, and nausea, and a low morning cortisol level?

Confirmatory Test for Adrenal Insufficiency

The cosyntropin (ACTH) stimulation test is the most appropriate confirmatory test for this patient with suspected adrenal insufficiency and a low morning cortisol level. 1, 2, 3

Why the Cosyntropin Stimulation Test

• A low morning cortisol alone is suggestive but insufficient to definitively diagnose adrenal insufficiency, requiring dynamic testing to confirm the diagnosis 2, 4
• The standard 0.25 mg (250 mcg) cosyntropin stimulation test is the gold standard confirmatory test, measuring cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 3
• Peak cortisol <500 nmol/L (<18 mcg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 3

Test Protocol

• Administer 0.25 mg cosyntropin intramuscularly or intravenously 1, 3
• Obtain baseline serum cortisol and ACTH before administration 1, 3
• Measure serum cortisol at exactly 30 and 60 minutes after cosyntropin administration 1, 3
• The test can be performed at any time of day, though morning is preferred 1

Interpretation Strategy

Primary vs. Secondary Adrenal Insufficiency:

• Primary adrenal insufficiency: Low baseline cortisol (<250 nmol/L or <9 mcg/dL) with elevated ACTH, often with hyponatremia and hyperkalemia 1, 4
• Secondary adrenal insufficiency: Low cortisol (140-275 nmol/L or 5-10 mcg/dL) with low or inappropriately normal ACTH, hyponatremia without hyperkalemia 1, 4
• Peak cortisol response <500-550 nmol/L (<18-20 mcg/dL) confirms adrenal insufficiency regardless of type 1, 2, 3

Critical Pre-Test Considerations

Medications that interfere with testing:

• Stop glucocorticoids and spironolactone on the day of testing 3
• Stop estrogen-containing drugs 4-6 weeks before testing (they elevate cortisol-binding globulin) 3
• Long-acting glucocorticoids may need longer discontinuation periods 3
• If you must treat suspected adrenal crisis but still need diagnostic testing, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1

High-Dose vs. Low-Dose Testing

• The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval 1, 2
• The low-dose test requires dilution of the commercial preparation at bedside, making it less practical for routine clinical use 1
• Both tests have similar diagnostic accuracy for secondary adrenal insufficiency (likelihood ratios 9.1 vs 5.9) 1

Common Pitfalls to Avoid

• Never delay treatment of suspected acute adrenal crisis to perform diagnostic testing—if the patient is clinically unstable, give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion 1, 4
• Do not rely on electrolyte abnormalities alone: hyperkalemia is present in only ~50% of primary adrenal insufficiency cases, and hyponatremia can occur in both primary and secondary forms 1
• Conditions affecting cortisol-binding globulin (cirrhosis, nephrotic syndrome, estrogen use) can alter total cortisol levels and affect interpretation 3
• The absence of hyperkalemia cannot rule out adrenal insufficiency 1

Next Steps After Confirmation

If adrenal insufficiency is confirmed:

• Determine etiology: Measure 21-hydroxylase autoantibodies (accounts for ~85% of primary AI in Western populations) 1
• If autoantibodies negative, obtain adrenal CT to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1
• Initiate glucocorticoid replacement: hydrocortisone 15-25 mg daily in divided doses or prednisone 3-5 mg daily 1, 4
• Add fludrocortisone 0.05-0.1 mg daily for primary adrenal insufficiency (mineralocorticoid replacement) 1, 4
• Provide patient education on stress dosing, prescribe emergency hydrocortisone 100 mg IM injection kit, and ensure medical alert identification 1, 4