In an adult patient seen in a family‑medicine clinic with suspected adrenal insufficiency (fatigue, weight loss, orthostatic hypotension, hyponatremia, hyperpigmentation, or recent glucocorticoid withdrawal), what initial outpatient laboratory tests should be ordered?

Initial Outpatient Laboratory Testing for Suspected Adrenal Insufficiency

Order an early morning (8 AM) serum cortisol and plasma ACTH as your first-line tests, along with a basic metabolic panel to assess for hyponatremia and hyperkalemia. 1, 2, 3

First-Line Laboratory Tests

Essential Morning Tests (Drawn at 8 AM)

• Serum cortisol – A morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in the setting of acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Plasma ACTH – Distinguishes primary (high ACTH, low cortisol) from secondary adrenal insufficiency (low or inappropriately normal ACTH with low cortisol) 1, 2, 3
• The paired measurement of both hormones in the morning is mandatory because the relationship between ACTH and cortisol determines the type of adrenal insufficiency 1, 2

Basic Metabolic Panel

• Sodium, potassium, CO2, glucose – Hyponatremia is present in 90% of newly diagnosed cases, though hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases 1, 4, 2
• The absence of hyperkalemia cannot rule out adrenal insufficiency 1, 4
• Hypoglycemia may be present, particularly in children but can occur in adults 4

Interpreting Initial Results

Diagnostic Cortisol Thresholds

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH confirms primary adrenal insufficiency 1, 2
• Cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH raises strong suspicion and requires confirmatory testing 2
• Cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 1, 3
• Cortisol >550 nmol/L (>18-20 μg/dL) effectively excludes adrenal insufficiency 1

When Confirmatory Testing Is Needed

• If morning cortisol falls in the intermediate range (5-18 μg/dL), proceed with cosyntropin stimulation testing to definitively confirm or exclude the diagnosis 1, 2, 3
• The cosyntropin stimulation test is the gold standard confirmatory test: administer 0.25 mg (250 mcg) cosyntropin IV or IM, measure cortisol at baseline, 30 minutes, and 60 minutes 1, 2
• A peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1, 2, 3

Additional Testing Based on Initial Results

If Primary Adrenal Insufficiency Is Confirmed

• 21-hydroxylase (anti-adrenal) autoantibodies – Identifies autoimmune etiology, which accounts for ~85% of primary adrenal insufficiency cases in Western populations 1, 2
• Adrenal CT imaging – If autoantibodies are negative, obtain CT to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1, 2

If Secondary Adrenal Insufficiency Is Suspected

• Consider pituitary MRI to evaluate for tumors, hemorrhage, or infiltrative conditions 3
• Assess other pituitary hormone axes if pituitary pathology is suspected 1

Critical Pitfalls to Avoid

Do Not Delay Treatment for Testing

• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures – If the patient presents with unexplained collapse, severe hypotension, vomiting, or altered mental status, immediately administer IV hydrocortisone 100 mg and 0.9% saline at 1 L/hour 1, 4, 2, 5
• Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results 1, 2

Avoid Testing Pitfalls

• Do not test patients currently taking corticosteroids – Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and cause falsely low cortisol levels 1, 4
• Laboratory confirmation should not be attempted until corticosteroid treatment has been discontinued with adequate washout time 1
• If the patient recently stopped glucocorticoids after ≥3 weeks of ≥20 mg/day prednisone equivalent, presume adrenal insufficiency until proven otherwise 1

Do Not Rely Solely on Electrolytes

• Between 10-20% of patients have normal electrolytes at presentation 1, 4
• Hyperkalemia is absent in ~50% of primary adrenal insufficiency cases 1, 4, 2
• In the presence of severe vomiting, hypokalemia and alkalosis may paradoxically be present instead of hyperkalemia 4

Special Clinical Scenarios

Recent Glucocorticoid Withdrawal

• Any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 1
• Consider empiric glucocorticoid replacement rather than attempting diagnostic testing in patients with ongoing steroid use 1

Hyponatremia Workup

• Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings 1
• The standard 0.25 mg cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia 1