What initial test should be ordered for a patient in a family‑medicine outpatient clinic who is concerned about possible adrenal insufficiency?

Initial Testing for Suspected Adrenal Insufficiency in Outpatient Clinic

Order a morning (8 AM) serum cortisol and plasma ACTH level as the initial screening test for a patient concerned about adrenal insufficiency in the family medicine outpatient clinic. 1, 2

Diagnostic Algorithm

Step 1: Morning Cortisol and ACTH (First-Line Test)

• Obtain paired morning serum cortisol and plasma ACTH between 8 AM and 12 PM, ideally at 8 AM when cortisol levels are physiologically highest 1, 2
• Add a basic metabolic panel (sodium, potassium, CO2, glucose) to assess for hyponatremia (present in 90% of cases) and hyperkalemia (present in ~50% of primary adrenal insufficiency cases) 1, 2

Step 2: Interpret Initial Results

Morning cortisol ≥275 nmol/L (≥10 μg/dL):

• Effectively rules out adrenal insufficiency in outpatients 3
• No further testing needed unless clinical suspicion remains extremely high 4

Morning cortisol <110 nmol/L (<4 μg/dL) with elevated ACTH:

• Diagnostic of primary adrenal insufficiency, especially in acute illness 1, 5
• Proceed directly to etiologic workup (measure 21-hydroxylase autoantibodies) 1, 2

Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness:

• Diagnostic of primary adrenal insufficiency 1, 2

Morning cortisol 110-275 nmol/L (4-10 μg/dL):

• Indeterminate zone requiring confirmatory testing with cosyntropin stimulation test 1, 6

Step 3: Confirmatory Testing When Needed

Cosyntropin (Synacthen) Stimulation Test Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline, then at 30 and 60 minutes post-administration 1
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 7
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1

Critical Pitfalls to Avoid

• Never delay treatment if the patient presents with hypotension, collapse, severe vomiting, or other signs of acute adrenal crisis—give IV hydrocortisone 100 mg immediately and 0.9% saline at 1 L/hour, then test later 1, 2
• Do not attempt diagnostic testing in patients currently taking corticosteroids (prednisone, dexamethasone, inhaled fluticasone)—the results will be uninterpretable due to iatrogenic HPA axis suppression 1
• Do not rely on electrolyte abnormalities alone—hyperkalemia is absent in 50% of primary adrenal insufficiency cases, and some patients have completely normal electrolytes 1
• Timing matters: Cortisol samples obtained later in the day (after 12 PM) may be falsely low due to normal diurnal variation; use lower thresholds (<250 nmol/L) for afternoon samples 3

Distinguishing Primary vs. Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern:

• Low cortisol + high ACTH 1, 2
• Often accompanied by hyponatremia and hyperkalemia 1
• Hyperpigmentation may be present 1

Secondary adrenal insufficiency pattern:

• Low cortisol + low or inappropriately normal ACTH 1
• Hyponatremia without hyperkalemia 1
• Normal skin coloration (no hyperpigmentation) 1

When to Proceed with Etiologic Workup

Once adrenal insufficiency is confirmed biochemically:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies to identify autoimmune etiology (accounts for ~85% of primary adrenal insufficiency in Western populations) 1, 2
• If autoantibodies are negative, obtain adrenal CT imaging to evaluate for hemorrhage, metastasis, tuberculosis, or other structural causes 1, 2
• In male patients with negative antibodies, measure very long-chain fatty acids to screen for adrenoleukodystrophy 1, 2