What is the appropriate confirmatory test for a patient with hypocortisolism (low morning cortisol level)?

Confirmatory Test for Low Morning Cortisol

The ACTH (cosyntropin) stimulation test is the appropriate confirmatory test for a patient with a low morning cortisol level, using 0.25 mg cosyntropin administered intramuscularly or intravenously, with cortisol measurements at baseline and 30 minutes post-administration. 1, 2

Diagnostic Algorithm

Step 1: Interpret the Morning Cortisol Level

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency and may not require further testing if clinical context is clear 1
• Morning cortisol <275 nmol/L (<10 μg/dL) warrants confirmatory ACTH stimulation testing 3
• Morning cortisol >13 μg/dL reliably rules out adrenal insufficiency without need for further testing 4
• Cortisol levels between these thresholds require ACTH stimulation testing for definitive diagnosis 1, 3

Step 2: Measure Baseline ACTH Simultaneously

• Obtain morning (8-9 AM) plasma ACTH along with cortisol to distinguish primary from secondary adrenal insufficiency 1
• Low cortisol with high ACTH indicates primary adrenal insufficiency (adrenal gland failure) 1
• Low cortisol with low or inappropriately normal ACTH indicates secondary adrenal insufficiency (pituitary/hypothalamic dysfunction) 1

Step 3: Perform ACTH Stimulation Test

Standard Protocol (High-Dose Test): 1, 2

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 2
• Obtain baseline serum cortisol immediately before administration 2
• Measure serum cortisol at 30 minutes and optionally at 60 minutes post-injection 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 3, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) is considered normal and rules out adrenal insufficiency 1, 3

Alternative Low-Dose Test (1 mcg): 5, 6

• The 1 mcg test is more sensitive for secondary adrenal insufficiency but requires dilution of the commercial preparation at bedside, making it less practical 1, 5
• Use a cutoff of 550 nmol/L at 30 minutes for optimal sensitivity (97%) and specificity (78%) 6
• The high-dose test is recommended over the low-dose test due to easier administration, comparable diagnostic accuracy, and FDA approval 1

Critical Considerations Before Testing

When to Skip Testing and Treat Immediately

• Never delay treatment in suspected acute adrenal crisis—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion without waiting for test results 1, 3
• Clinical features requiring immediate treatment include unexplained hypotension, collapse, or gastrointestinal symptoms (vomiting/diarrhea) 1
• Vasopressor-resistant hypotension should prompt empiric stress-dose hydrocortisone 1

Medications That Interfere With Testing

• Stop glucocorticoids and spironolactone on the day of testing as they falsely elevate cortisol levels 2
• Long-acting glucocorticoids may need to be stopped for a longer period before testing 2
• Stop estrogen-containing drugs 4-6 weeks before testing to allow cortisol-binding globulin levels to normalize 2
• Exogenous steroids including inhaled fluticasone can suppress the HPA axis and confound results 1, 3
• If you must treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1

Conditions Affecting Cortisol-Binding Globulin

• Pregnancy, oral estrogens, and chronic hepatitis increase cortisol-binding globulin and falsely elevate total cortisol 3, 2
• Cirrhosis and nephrotic syndrome decrease cortisol-binding globulin and falsely lower total cortisol 3, 2
• Consider measuring cortisol-binding globulin levels if these conditions are present to ensure accurate interpretation 2

Common Pitfalls to Avoid

• 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, 3
• The absence of hyperkalemia cannot rule out adrenal insufficiency 1, 3
• Patients taking ≥20 mg/day prednisone or equivalent for at least 3 weeks who develop unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 1
• Testing for HPA axis recovery should wait until 3 months after stopping chronic corticosteroid therapy 1
• In patients on ongoing steroid therapy with clinical uncertainty, opt for empiric glucocorticoid replacement and test for ongoing need at 3 months rather than attempting diagnostic testing while on steroids 1

Post-Diagnosis Management

• If adrenal insufficiency is confirmed, all patients require education on stress dosing, emergency injectable hydrocortisone, and a medical alert bracelet 7, 1
• Early endocrinology consultation is appropriate for treatment planning and patient education 7, 1
• Primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid (fludrocortisone) replacement, while secondary adrenal insufficiency requires only glucocorticoids 1