Would a positive cosyntropin (Cortrosyn) stimulation test with normal aldosterone levels be considered primary adrenal insufficiency?

Positive Cosyntropin Test with Normal Aldosterone: Primary Adrenal Insufficiency

Yes, a positive (abnormal) cosyntropin stimulation test with normal aldosterone levels can still represent primary adrenal insufficiency, though it suggests early or partial disease. Primary adrenal insufficiency is primarily defined by glucocorticoid deficiency with elevated ACTH, and mineralocorticoid deficiency (low aldosterone) develops variably and may be absent in early disease 1.

Diagnostic Criteria for Primary Adrenal Insufficiency

The diagnosis of primary adrenal insufficiency is established by demonstrating:

• Low cortisol with elevated ACTH - This is the hallmark finding that distinguishes primary from secondary adrenal insufficiency 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) on cosyntropin stimulation test - This confirms inadequate adrenal cortisol reserve 1, 3
• Basal morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH - This alone is diagnostic in the setting of acute illness 1, 4

Why Aldosterone May Be Normal in Primary Adrenal Insufficiency

Aldosterone deficiency is not required for the diagnosis of primary adrenal insufficiency and may be preserved in early or partial disease:

• The zona glomerulosa (which produces aldosterone) can maintain function even when the zona fasciculata (which produces cortisol) is significantly damaged 5
• Hyperkalemia, a marker of mineralocorticoid deficiency, is present in only approximately 50% of primary adrenal insufficiency cases 1, 6
• Hyponatremia occurs in 90% of cases but can result from glucocorticoid deficiency alone, not necessarily aldosterone deficiency 1, 4

Distinguishing Primary from Secondary Adrenal Insufficiency

The key differentiating feature is the ACTH level, not the aldosterone level:

• Primary adrenal insufficiency: Low cortisol + high ACTH + variable aldosterone (may be normal or low) 1, 2
• Secondary adrenal insufficiency: Low cortisol + low or inappropriately normal ACTH + normal aldosterone (zona glomerulosa remains intact) 1, 2

The extended ACTH stimulation test can help differentiate: in secondary adrenal insufficiency, aldosterone rises normally after cosyntropin administration, while in primary disease with mineralocorticoid involvement, aldosterone fails to rise 5.

Clinical Implications and Next Steps

If your patient has an abnormal cosyntropin test (peak cortisol <500 nmol/L), you must measure ACTH to classify the type of adrenal insufficiency:

• If ACTH is elevated: This is primary adrenal insufficiency, regardless of aldosterone level 1, 4
• If ACTH is low or normal: This is secondary or tertiary adrenal insufficiency 1, 2

For confirmed primary adrenal insufficiency, determine the etiology:

• Measure 21-hydroxylase autoantibodies first, as autoimmune adrenalitis accounts for ~85% of cases in Western populations 1
• If autoantibodies are negative, obtain adrenal CT imaging to evaluate for hemorrhage, tuberculosis, fungal infection, or malignancy 1
• In males with negative antibodies, consider testing very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

Treatment Considerations

Treatment differs based on whether mineralocorticoid deficiency is present:

• All patients with primary adrenal insufficiency require glucocorticoid replacement (hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily) 1, 2
• Add fludrocortisone 0.05-0.3 mg daily only if there is evidence of mineralocorticoid deficiency (hyperkalemia, elevated renin, low aldosterone) 7, 2
• Secondary adrenal insufficiency requires glucocorticoids only, never mineralocorticoids 1

Common Pitfalls to Avoid

• Do not exclude primary adrenal insufficiency based on normal aldosterone or absence of hyperkalemia - these findings occur in early or partial disease 1, 6
• Do not rely on electrolyte abnormalities alone - 10-20% of patients have normal electrolytes at presentation 1
• Always measure ACTH to distinguish primary from secondary disease, as this determines whether mineralocorticoid replacement will eventually be needed 1, 2
• Never delay treatment in suspected adrenal crisis to perform diagnostic testing - give IV hydrocortisone 100 mg immediately if the patient is unstable 1, 3