What is the recommended testing and treatment approach for suspected adrenal insufficiency?

Testing for Adrenal Insufficiency

The gold standard for diagnosing adrenal insufficiency is a high-dose (250-μg) ACTH stimulation test, with a normal response defined as cortisol exceeding 550 nmol/L (18-20 μg/dL) at either 30 or 60 minutes after administration. 1

Initial Diagnostic Approach

Morning Serum Cortisol

• A morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency 2
• Cortisol levels <5 µg/dL strongly suggest adrenal insufficiency 3
• Intermediate values (5-13 µg/dL) require further testing 3, 2

Basic Laboratory Tests

• Basic metabolic panel to check for electrolyte abnormalities (hyponatremia, hyperkalemia) 1
• ACTH level to differentiate primary from secondary adrenal insufficiency 1
• Dehydroepiandrosterone sulfate (DHEAS) levels 3

ACTH Stimulation Test Protocol

Preparation

• Stop glucocorticoids and spironolactone on the day of testing 4
• For long-acting glucocorticoids, stop for a longer period before testing 4
• Stop estrogen-containing drugs 4-6 weeks before testing 4

Administration

• Adults: 0.25 mg cosyntropin IV or IM 4
• Pediatric patients:
  • Birth to <2 years: 0.125 mg
  • 2-17 years: 0.25 mg 4

Sample Collection

• Obtain blood for baseline serum cortisol
• Collect additional samples at exactly 30 and 60 minutes after cosyntropin administration 4

Interpretation

• Normal response: cortisol >18 mcg/dL at 30 or 60 minutes 4
• Values <18 mcg/dL suggest adrenal insufficiency 4
• Diagnostic patterns:
  • Primary adrenal insufficiency: Low cortisol, high ACTH, low DHEAS, electrolyte abnormalities (↓Na, ↑K) 1, 3
  • Secondary adrenal insufficiency: Low cortisol, low ACTH, low DHEAS, normal electrolytes 1, 3

Pitfalls and Considerations

• Assay variability can affect cortisol cutoff values 5

• Time of day, sample source, and cortisol binding globulin levels can influence results 4, 5

• Certain medications can interfere with test accuracy:

  • Glucocorticoids and spironolactone may falsely elevate cortisol levels 4
  • Estrogen can elevate plasma total cortisol levels 4
  • Opioids can suppress corticotropin production 3
  • High doses of azole antifungals can cause adrenal insufficiency 3

• For patients in whom the ACTH stimulation test cannot be performed immediately, consider using dexamethasone until testing can be done, as it doesn't interfere with cortisol testing 6

Additional Testing Considerations

• Screen for associated autoimmune conditions in patients with suspected primary adrenal insufficiency:
  • Thyroid function tests
  • Plasma glucose and HbA1c
  • Complete blood count
  • Vitamin B12 levels 1
• 21-hydroxylase antibody testing can help determine if primary adrenal insufficiency is autoimmune in nature 1

Treatment Approach

• Glucocorticoid replacement therapy:
  • Hydrocortisone 15-25 mg daily in divided doses (preferred) 1, 3
  • Alternative: Prednisone 3-5 mg daily 3
• For primary adrenal insufficiency, add mineralocorticoid replacement:
  • Fludrocortisone 50-200 μg (0.05-0.2 mg) daily 1, 3
• DHEA replacement may be considered for persistent symptoms despite adequate primary replacement 1
• Patient education on stress dosing and adrenal crisis prevention is essential 1