What is the next test for suspected adrenal insufficiency with low urine cortisol levels?

Next Test for Suspected Adrenal Insufficiency with Low Urine Cortisol

Perform a cosyntropin (ACTH) stimulation test with serum cortisol measurements at baseline and 30 and/or 60 minutes after administering 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously. 1

Why the Cosyntropin Stimulation Test is Necessary

• Low urine cortisol alone is insufficient to diagnose adrenal insufficiency and requires confirmatory dynamic testing with the cosyntropin stimulation test, which is the gold standard when initial cortisol measurements are indeterminate 1, 2
• Morning serum cortisol and plasma ACTH should be drawn simultaneously before administering cosyntropin to help distinguish primary from secondary adrenal insufficiency 1, 3
• A basic metabolic panel should be obtained to assess for hyponatremia, hyperkalemia, and hypoglycemia, which support the diagnosis but cannot rule it out if absent 1, 3

Test Protocol

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1
• Measure serum cortisol at baseline (before injection), 30 minutes, and/or 60 minutes after administration 1
• The test can be performed at any time of day, though morning is preferred 1
• Do not delay the test for time of day if clinical suspicion is high 4

Interpreting Results

• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and rules out adrenal insufficiency 1, 2
• Peak cortisol <500-550 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Note that specific cutoff values depend on the cortisol assay used—monoclonal antibody-based assays (Abbott Architect, Roche Elecsys II) require lower thresholds (14.6 μg/dL for Abbott at 60 minutes) compared to the historical 18 μg/dL cutoff for polyclonal assays 5

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: low cortisol with HIGH ACTH (>2-fold upper limit of normal), often with hyponatremia and hyperkalemia 1, 2
• Secondary adrenal insufficiency: low cortisol with LOW or inappropriately normal ACTH, typically with hyponatremia but without hyperkalemia 1, 2
• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency without need for stimulation testing 1, 3

Critical Pitfalls to Avoid

• Never delay treatment in suspected adrenal crisis to perform diagnostic testing—immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion at 1 L/hour if the patient is clinically unstable 1, 6, 3
• Do not rely on electrolyte abnormalities alone—hyperkalemia is present in only ~50% of adrenal insufficiency cases, and hyponatremia can be mild or absent 1, 3
• Exogenous steroids confound testing: hydrocortisone must be held for 24 hours before testing, while prednisone and other steroids require longer washout periods 1
• If you must treat before confirming the diagnosis but still want to perform testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1
• Adrenal insufficiency must be distinguished from SIADH, as both present with euvolemic hypo-osmolar hyponatremia and inappropriately elevated urine osmolality—the cosyntropin test is medically necessary for this differentiation 1, 3

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
• 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 in adults 1, 7

Next Steps After Diagnosis

If adrenal insufficiency is confirmed:

• For primary adrenal insufficiency: measure 21-hydroxylase autoantibodies to identify autoimmune etiology (accounts for ~85% of cases in Western populations) 1
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1
• For secondary adrenal insufficiency: evaluate for pituitary pathology with MRI and assess other pituitary hormone deficiencies 1
• Initiate glucocorticoid replacement therapy (hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily) 2
• Add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement in primary adrenal insufficiency 1, 2
• Provide stress-dose education, prescribe injectable hydrocortisone 100 mg IM kit, and ensure the patient wears a medical alert bracelet 1, 2