What is the initial workup for a patient suspected of having Addison's disease?

Initial Workup for Suspected Addison's Disease

The initial diagnostic workup for suspected Addison's disease should include measurement of morning serum cortisol and ACTH levels, along with basic metabolic panel (sodium, potassium, CO2, glucose), followed by a cosyntropin stimulation test when results are equivocal. 1, 2

Core Laboratory Tests

• Morning serum cortisol and ACTH are the cornerstone tests for diagnosing Addison's disease, typically showing low or inappropriately normal cortisol with markedly elevated ACTH 1
• Basic metabolic panel to assess for hyponatremia (present in ~90% of cases) and hyperkalemia (present in ~50% of cases) 1, 2
• Plasma renin activity is typically elevated while aldosterone levels are low in primary adrenal insufficiency 2, 3
• Other common laboratory findings include mild to moderate hypercalcemia, anemia, mild eosinophilia, lymphocytosis, and elevated liver transaminases 1

Confirmatory Testing

• Cosyntropin (ACTH) stimulation test is required when partial adrenal insufficiency is suspected or initial results are equivocal 2, 1
• Protocol involves:
  • Administration of 0.25 mg cosyntropin intramuscularly or intravenously 2, 3
  • Measurement of serum cortisol at baseline, 30 minutes, and/or 60 minutes after administration 2, 3
  • Normal response requires cortisol to exceed 550 nmol/L (approximately 20 μg/dL) at either the 30 or 60-minute mark 2, 1
• A peak cortisol value below 500 nmol/L is diagnostic of primary adrenal insufficiency 3

Etiologic Diagnosis

• After confirming adrenal insufficiency, determine the etiology 2, 1:
  • Measure 21-hydroxylase autoantibodies (21OH-Ab) to establish an autoimmune cause, which accounts for approximately 85% of cases in Western countries 1, 2
  • If 21OH-Ab is negative, perform adrenal CT imaging to evaluate for metastasis, hemorrhage, or other structural causes 2, 1
  • Consider testing for interferon-ω antibodies (for APS-1) and very long-chain fatty acids (for adrenoleukodystrophy) in appropriate clinical contexts 2, 1

Clinical Pearls and Pitfalls

• Critical caveat: If there is clinical suspicion of impending adrenal crisis, treatment should NEVER be delayed for diagnostic testing 2, 1

  • Immediately administer intravenous hydrocortisone 100 mg and physiologic (0.9%) saline infusion 2, 3
  • Obtain blood samples for cortisol and ACTH measurement before treatment if possible, but do not delay treatment 2, 3

• Early adrenal insufficiency may present with normal morning cortisol but elevated ACTH levels, so measuring ACTH is crucial even when cortisol appears normal 4, 5

• Patients with autoimmune Addison's disease should be screened for other autoimmune conditions, particularly thyroid disease, as up to 50% develop another autoimmune disorder during their lifetime 6, 1

• Hyponatremia with normal potassium does not rule out Addison's disease, as hyperkalemia is absent in approximately 50% of cases 3, 7

• Symptoms of Addison's disease are often subtle and nonspecific before an adrenal crisis, including hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle/joint pain, and salt craving 6, 7

By following this systematic diagnostic approach, clinicians can identify Addison's disease before it progresses to a potentially life-threatening adrenal crisis.