What is the recommended approach to diagnose adrenal insufficiency?

How to Test for Adrenal Insufficiency

The diagnostic test for adrenal insufficiency should be paired measurement of serum cortisol and plasma ACTH, with a cosyntropin (Synacthen) stimulation test (0.25 mg IM or IV) performed in equivocal cases—a peak serum cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency. 1

Initial Diagnostic Approach

First-Line Testing

• Obtain morning (approximately 8 AM) serum cortisol and plasma ACTH simultaneously as the initial diagnostic step 1, 2
• Add basic metabolic panel (sodium, potassium, glucose) to assess for supportive findings 3
• Measure dehydroepiandrosterone sulfate (DHEAS) levels, which are typically low in primary adrenal insufficiency 1, 2

Interpreting Initial Results

Primary adrenal insufficiency is characterized by:

• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic 1, 3
• Serum cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH in acute illness raises strong suspicion 1
• Low DHEAS levels support the diagnosis 1, 2

Secondary adrenal insufficiency shows:

• Low or intermediate morning cortisol (5-10 μg/dL) with low or low-normal ACTH 2
• Low or low-normal DHEAS levels 2

Important Caveats About Electrolytes

• Hyponatremia is present in 90% of newly diagnosed cases, but the classic combination of hyponatremia and hyperkalemia is unreliable 1, 3
• Hyperkalemia is present in only approximately 50% of primary adrenal insufficiency cases at diagnosis 1, 3
• Severe vomiting can cause hypokalaemia and alkalosis, masking the typical electrolyte pattern 1

Cosyntropin Stimulation Test Protocol

When to Perform

Perform the cosyntropin stimulation test when:

• Initial cortisol and ACTH results are equivocal 1
• Morning cortisol is intermediate (approximately 85-350 nmol/L or 3-13 μg/dL) 3, 2
• Clinical suspicion remains despite borderline initial results 3

Test Administration

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 1, 4
• Obtain baseline serum cortisol and ACTH before administration 3, 4
• Measure serum cortisol at exactly 30 and 60 minutes post-administration 1, 3, 4
• Preferably perform in the morning, though not strictly necessary 3

Interpretation

• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Peak cortisol >550 nmol/L (>20 μg/dL) indicates normal adrenal function 3, 2

Critical Medication Considerations

Drugs That Must Be Stopped

Stop on the day of testing:

• All glucocorticoids (except long-acting formulations) 4
• Spironolactone (falsely elevates cortisol) 4

Stop 4-6 weeks before testing:

• Estrogen-containing medications (increase cortisol binding globulin, falsely elevating total cortisol) 4

Stop for longer periods before testing:

• Long-acting glucocorticoids like dexamethasone 4

Drugs That Confound Interpretation

• Oral prednisolone or dexamethasone 1
• Inhaled steroids (particularly fluticasone) 1
• Any medication affecting cortisol binding globulin levels 4

Conditions Affecting Cortisol Binding Globulin

• Elevated CBG (increases total cortisol): pregnancy, estrogen therapy 4
• Decreased CBG (decreases total cortisol): cirrhosis, nephrotic syndrome 4
• Consider measuring CBG levels when these conditions are present to ensure accurate interpretation 4

Etiologic Workup After Diagnosis

For Primary Adrenal Insufficiency

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies first (accounts for ~85% of cases in Western populations) 1, 3
2. If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1, 3
3. In male patients, assay very long-chain fatty acids to check for adrenoleukodystrophy 1

For Pediatric Patients

• Consider autoimmune polyglandular syndrome type 1 (APS-1) in children and young adults with PAI plus hypoparathyroidism or candidiasis 1
• Confirm APS-1 with anti-interferon omega antibodies or AIRE gene mutational analysis 1

Critical Pitfall to Avoid

Never delay treatment of suspected acute adrenal insufficiency to perform diagnostic testing. 1, 3

• If adrenal crisis is suspected, immediately administer IV hydrocortisone 100 mg and 0.9% saline at 1 L/hour 3
• Obtain blood samples for cortisol and ACTH before treatment if possible, but do not delay therapy 3
• The diagnosis can always be established once treatment has been initiated 1

Special Diagnostic Scenario: Hyponatremia

When evaluating hypo-osmolar hyponatremia:

• Adrenal insufficiency must be excluded before diagnosing SIADH, as both present with euvolemic hypo-osmolar hyponatremia 3
• Both conditions show serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium 3
• The cosyntropin stimulation test is medically necessary to distinguish between these conditions 3