What is the most appropriate confirmatory test for adrenal insufficiency?

The Most Appropriate Confirmatory Test for Adrenal Insufficiency

The high-dose (250-μg) ACTH stimulation test is the most appropriate confirmatory test for adrenal insufficiency. 1, 2

Understanding the ACTH Stimulation Test

The ACTH stimulation test (also known as cosyntropin or Synacthen test) is performed as follows:

• Administer 0.25 mg cosyntropin intravenously or intramuscularly 2
• Obtain blood samples for cortisol measurement at baseline, 30 minutes, and 60 minutes after administration 2
• A peak cortisol level below 18 μg/dL (or 550 nmol/L) at 30 or 60 minutes indicates adrenal insufficiency 1, 2

Evidence Supporting High-Dose ACTH Test

• The Endocrine Society confirms that the high-dose (250-μg) ACTH stimulation test is superior to other diagnostic tests for establishing primary adrenal insufficiency 1
• The high-dose test is easier to perform and has comparable accuracy to the low-dose test 1
• The test is widely available and standardized, making it the preferred choice in clinical practice 1, 3

Considerations for Test Interpretation

Factors Affecting Test Results:

• Medications that should be stopped before testing:

  • Glucocorticoids and spironolactone should be stopped on the day of testing 2
  • Long-acting glucocorticoids may need to be stopped for a longer period 2
  • Estrogen-containing drugs should be stopped 4-6 weeks before testing 2

• Conditions affecting cortisol binding globulin levels:

  • Cirrhosis or nephrotic syndrome can lower cortisol binding globulin levels 2
  • Measurement of cortisol binding globulin may be necessary in certain cases 2

Special Considerations

Primary vs. Secondary Adrenal Insufficiency

• In primary adrenal insufficiency:

  • Baseline ACTH levels are typically elevated 1
  • A baseline morning cortisol <100 nmol/L with elevated ACTH may be sufficient for diagnosis 3

• In secondary adrenal insufficiency:

  • The ACTH stimulation test remains valuable but may be less sensitive 4
  • Additional pituitary testing may be required 1

Critically Ill Patients

• In critically ill patients with suspected critical illness-related corticosteroid insufficiency (CIRCI):
  • The task force makes no definitive recommendation between delta cortisol (change in baseline cortisol at 60 min of <9 μg/dl) after cosyntropin administration or a random plasma cortisol of <10 μg/dl 1
  • However, the high-dose test is still suggested over the low-dose test 1

Common Pitfalls to Avoid

• Delaying treatment in suspected acute adrenal crisis to perform diagnostic testing - treatment should never be delayed 1
• Failing to collect baseline cortisol and ACTH samples before administering treatment 1
• Not considering the timing of the test - morning samples are preferred 5
• Using inappropriate cortisol cutoff values that don't account for the specific assay used 6

Alternative Tests

While the high-dose ACTH stimulation test is the preferred confirmatory test, other tests include:

• Random cortisol measurements - less reliable but may be useful in emergency situations 1
• Low-dose (1-μg) ACTH stimulation test - more sensitive in some studies but less standardized and more difficult to perform 4
• Insulin tolerance test - considered the gold standard for secondary adrenal insufficiency but more invasive and risky 3

The high-dose ACTH stimulation test offers the best balance of diagnostic accuracy, standardization, and clinical feasibility for confirming adrenal insufficiency in most clinical scenarios 1, 2, 3.