How do you evaluate for adrenal dysfunction?

Evaluation for Adrenal Dysfunction

Begin with early morning (8 AM) serum cortisol and plasma ACTH measurements to distinguish primary from secondary adrenal insufficiency, followed by cosyntropin stimulation testing if initial results are indeterminate. 1, 2

Initial Laboratory Assessment

Morning cortisol and ACTH levels are the first-line diagnostic tests:

• Draw blood at approximately 8 AM for serum cortisol and plasma ACTH simultaneously 1, 2
• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 3, 1
• Cortisol <140 nmol/L (<5 μg/dL) with high ACTH confirms primary adrenal insufficiency 2
• Cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 1, 2
• Cortisol >550 nmol/L (>18-20 μg/dL) effectively rules out adrenal insufficiency 3

Obtain basic metabolic panel concurrently:

• Hyponatremia is present in 90% of newly diagnosed cases 1, 4
• Hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases—its absence does not exclude the diagnosis 1
• Check glucose (hypoglycemia may occur, especially in children) 3
• Measure creatinine and urea (prerenal renal failure may be present) 3

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol is 140-550 nmol/L (5-18 μg/dL), proceed with cosyntropin stimulation test:

• Administer 0.25 mg (250 μg) cosyntropin (Synacthen/tetracosactide) intramuscularly or intravenously 3, 1
• Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration 3, 4
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal; <500-550 nmol/L is diagnostic of adrenal insufficiency 3, 1, 4
• The test can be performed at any time of day, though morning is preferred 1

Critical pitfall: In secondary adrenal insufficiency, the cosyntropin test may give a false normal result if the adrenal glands have not yet atrophied from chronic lack of ACTH stimulation 5

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern:

• Low cortisol with high ACTH 1, 2
• Both glucocorticoid and mineralocorticoid deficiency present 1
• Hyponatremia and hyperkalemia more common 1

Secondary adrenal insufficiency pattern:

• Low cortisol with low or inappropriately normal ACTH 1, 2
• Mineralocorticoid function preserved (no hyperkalemia) 1
• May have other pituitary hormone deficiencies 1

Etiologic Workup After Confirming Diagnosis

For primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first—autoimmunity accounts for ~85% of cases in Western populations 3, 1
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for tuberculosis (calcifications), hemorrhage, tumors, metastases, or infiltrative disease 3, 1
• In males with negative antibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 3, 1

For secondary adrenal insufficiency:

• Obtain pituitary MRI to evaluate for tumors, hemorrhage, infiltrative disease, or structural abnormalities 1
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGF-1) 1

Critical Clinical Scenarios Requiring Immediate Action

Never delay treatment for diagnostic testing in these situations:

• Suspected acute adrenal crisis (hypotension, shock, altered mental status, severe nausea/vomiting, abdominal pain) 3, 1
• Unexplained hypotension requiring vasopressors 1
• Patient on ≥20 mg/day prednisone equivalent for ≥3 weeks who develops unexplained hypotension 1

Immediate management protocol:

• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 3
• Administer hydrocortisone 100 mg IV bolus immediately 3, 1
• Infuse 0.9% saline at 1 L/hour initially 3, 1
• Continue hydrocortisone 100-300 mg/day as continuous infusion or divided doses every 6 hours 3

Special Considerations and Common Pitfalls

Factors affecting test interpretation:

• Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) interfere with cortisol measurements 1
• In patients with suspected adrenal insufficiency and concurrent hypothyroidism, start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 1
• Recent glucocorticoid use (within 3 weeks) can cause glucocorticoid-induced adrenal insufficiency—suspect this in patients who recently tapered or discontinued supraphysiological glucocorticoid doses 2

Do not rely solely on electrolyte abnormalities:

• 10-20% of patients may have normal electrolytes at presentation 1
• Hyperkalemia is absent in ~50% of primary adrenal insufficiency cases 1
• Hyponatremia can mimic SIADH—always exclude adrenal insufficiency before diagnosing SIADH 1

Patient education priorities:

• All patients need instruction on stress dosing during illness, injury, or surgery 1
• Prescribe injectable hydrocortisone 100 mg for emergency self-administration 2
• Medical alert bracelet should be worn 1
• Arrange endocrine consultation before any surgical procedures for stress-dose planning 1, 4