What is the initial workup for suspected adrenal insufficiency?

Initial Workup for Suspected Adrenal Insufficiency

Begin with early morning (8 AM) paired measurements of serum cortisol and plasma ACTH, along with a basic metabolic panel to assess electrolytes, as these are the essential first-line tests for diagnosing adrenal insufficiency. 1, 2, 3

Immediate Laboratory Testing

Essential First-Line Tests

• Morning serum cortisol and plasma ACTH (obtained at approximately 8 AM) are the cornerstone of initial evaluation 1, 2, 3
• Basic metabolic panel including sodium, potassium, CO2, and glucose to identify characteristic electrolyte abnormalities 1, 2
• Serum DHEAS measurement helps distinguish primary from secondary adrenal insufficiency 3

Interpreting Initial Results

Primary adrenal insufficiency is characterized by:

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic 1, 2
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 1, 2
• Low DHEAS levels alongside elevated ACTH 3
• Hyponatremia and hyperkalemia (though hyperkalemia is present in only ~50% of cases) 4, 1

Secondary/glucocorticoid-induced adrenal insufficiency typically shows:

• Low or intermediate morning cortisol levels (5-10 μg/dL) 3
• Low or low-normal ACTH and DHEAS levels 3

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol levels are intermediate or diagnosis remains uncertain, proceed with the cosyntropin (Synacthen) stimulation test. 4, 1

Test Protocol

• Administer 0.25 mg cosyntropin intramuscularly or intravenously 4, 5
• Obtain baseline serum cortisol before administration 5
• Measure serum cortisol at 30 and 60 minutes post-administration 4, 5
• A peak cortisol value >550 nmol/L (>18 μg/dL) is considered normal 4, 5
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 5

Pediatric Dosing Adjustments

• Birth to <2 years: 0.125 mg (0.5 mL of reconstituted solution) 5
• 2 to 17 years: 0.25 mg (1 mL of reconstituted solution) 5

Etiologic Workup After Biochemical Confirmation

Once adrenal insufficiency is confirmed, determine the underlying cause:

For Primary Adrenal Insufficiency

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of cases in Western populations 4, 2
2. If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 4, 2
3. In male patients, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 4, 2
4. In children and young adults with hypoparathyroidism or candidiasis, consider APS-1 and measure anti-interferon omega antibodies or perform AIRE gene mutational analysis 4

Critical Pitfalls to Avoid

Medication Interference

• Stop glucocorticoids and spironolactone on the day of testing, as they falsely elevate cortisol levels 5
• Stop estrogen-containing drugs 4-6 weeks before testing, as they increase cortisol-binding globulin and falsely elevate total cortisol 5
• Long-acting glucocorticoids may require longer discontinuation periods 5

Clinical Judgment Errors

• Never delay treatment in suspected acute adrenal crisis to perform diagnostic testing 4, 2, 3
• If adrenal crisis is suspected, immediately administer IV hydrocortisone 100 mg and 0.9% saline at 1 L/hour, but obtain blood samples for cortisol and ACTH before treatment if possible 4
• Do not rely solely on electrolyte abnormalities for diagnosis—hyponatremia may be only marginally reduced and hyperkalemia is absent in ~50% of cases 4, 1
• Approximately 10% of patients with primary adrenal insufficiency present with normal cortisol concentrations but clearly elevated ACTH, representing early disease 6

Interpretation Considerations

• Conditions affecting cortisol-binding globulin (cirrhosis, nephrotic syndrome) can alter total cortisol levels; measure cortisol-binding globulin when necessary 5
• A single morning cortisol has limited value—sensitivity is 100% but specificity only 33% at a cutoff of 500 nmol/L 7