What is the diagnostic approach for adrenal insufficiency?

Diagnostic Approach for Adrenal Insufficiency

Initial Laboratory Testing

Begin with early morning (8 AM) simultaneous measurement of serum cortisol and plasma ACTH as your first-line diagnostic tests. 1, 2

Interpreting Morning Cortisol Levels

• Morning cortisol >275 nmol/L (>10 μg/dL) effectively rules out adrenal insufficiency with 96% sensitivity, eliminating the need for further dynamic testing in most cases 3
• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in the setting of acute illness is diagnostic of primary adrenal insufficiency without requiring confirmatory testing 1
• Morning cortisol between 140-275 nmol/L (5-10 μg/dL) requires confirmatory ACTH stimulation testing 1, 4

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: Low cortisol (<250 nmol/L) with HIGH ACTH 1, 2
• Secondary adrenal insufficiency: Low cortisol (140-275 nmol/L) with LOW or inappropriately normal ACTH 1, 2

Cosyntropin (ACTH) Stimulation Test

When morning cortisol is indeterminate (140-275 nmol/L), proceed with the 250 mcg cosyntropin stimulation test, which is FDA-approved and easier to administer than low-dose alternatives. 1, 5

Test Protocol

• Obtain baseline serum cortisol and ACTH before administration 1
• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 5
• Measure serum cortisol at 30 and/or 60 minutes post-administration 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and rules out adrenal insufficiency 1
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2

Important Testing Considerations

• The test can be performed at any time of day, though morning is preferred 1
• The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test due to easier administration, comparable diagnostic accuracy, and FDA approval 1
• Exogenous steroids (prednisolone, inhaled fluticasone) can suppress the HPA axis and confound results 6, 1
• If you need to 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

Special Diagnostic Scenario: Hyponatremia

In patients presenting with hypo-osmolar hyponatremia, you must perform cosyntropin stimulation testing to rule out adrenal insufficiency before diagnosing SIADH, as these conditions are clinically indistinguishable. 1

• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 1
• Both adrenal insufficiency and SIADH present with euvolemic hypo-osmolar hyponatremia, inappropriately high urine osmolality, and elevated urinary sodium 1
• The absence of hyperkalemia does NOT rule out adrenal insufficiency—it is present in only 50% of cases 1, 7

Etiologic Workup After Diagnosis

For Primary Adrenal Insufficiency

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

For Secondary Adrenal Insufficiency

• Evaluate for pituitary pathology with MRI of the pituitary 2
• Assess other pituitary hormone axes for additional deficiencies 1

Critical Pitfalls to Avoid

NEVER delay treatment of suspected acute adrenal crisis to perform diagnostic testing—mortality is high if untreated. 1, 2

• If the patient is clinically unstable with suspected adrenal crisis, immediately administer IV hydrocortisone 100 mg bolus plus 0.9% saline infusion at 1 L/hour 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment to obtain samples 1
• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 1
• Do not rely solely on electrolyte abnormalities for diagnosis—10-20% of patients have normal electrolytes at presentation 1, 7
• Vasopressor-resistant hypotension in critically ill patients warrants empiric stress-dose hydrocortisone while awaiting diagnostic confirmation 1