What is the best way to rule out Addison's disease?

Best Way to Rule Out Addison's Disease

The best way to rule out Addison's disease is through a cosyntropin (synacthen) stimulation test, which requires administration of 0.25 mg cosyntropin intramuscularly or intravenously, followed by measurement of serum cortisol after 30 and/or 60 minutes, with normal values exceeding 550 nmol/L. 1

Diagnostic Algorithm

Initial Evaluation

1. Morning serum cortisol and ACTH measurement

   • Low cortisol (<140 nmol/L) with elevated ACTH (>300 pg/ml) is highly suggestive of primary adrenal insufficiency 2
   • However, be aware that approximately 10% of patients with Addison's disease may present with normal cortisol concentrations 2

2. Electrolyte assessment

   • Check for hyponatremia and hyperkalemia, which are common in Addison's disease 1

Confirmatory Testing

1. Cosyntropin stimulation test (gold standard)
   • Administer 0.25 mg cosyntropin (synthetic ACTH) IV or IM
   • Measure serum cortisol at baseline, 30 minutes, and 60 minutes
   • Normal response: cortisol should exceed 550 nmol/L at either 30 or 60 minutes 1
   • This test is particularly useful in patients with suspected partial adrenal insufficiency

Etiologic Diagnosis (if Addison's is confirmed)

1. Measure 21-hydroxylase autoantibodies (21OH-Ab)

   • Positive result confirms autoimmune etiology (85% of cases in Western countries) 1
   • If positive, no further etiologic evaluation is generally necessary

2. If 21OH-Ab negative:

   • Consider CT imaging of adrenals to evaluate for hemorrhage, tumors, or tuberculosis
   • In young patients, test for interferon-omega or IL-22 autoantibodies to rule out APS-1
   • In males, consider very long-chain fatty acid (VLCFA) testing for adrenoleukodystrophy 1

Important Clinical Considerations

Clinical Manifestations to Prompt Testing

• Hyperpigmentation (especially in skin creases, mucous membranes)
• Fatigue, anorexia, weight loss
• Orthostatic hypotension
• Nausea, vomiting, abdominal pain
• Salt craving
• Muscle and joint pain 3

Pitfalls to Avoid

1. Delayed diagnosis

   • Symptoms can be nonspecific and easily confused with common disorders
   • Maintain high clinical suspicion in patients with unexplained fatigue, weight loss, and electrolyte abnormalities 4

2. Missing Addison's in patients with normal cortisol

   • Some patients (approximately 10%) may present with normal cortisol levels despite having primary adrenal insufficiency
   • Elevated ACTH with normal cortisol should still prompt consideration of Addison's disease when clinical suspicion exists 2

3. Emergency situations

   • If acute adrenal crisis is suspected, do not delay treatment for diagnostic testing
   • Administer IV hydrocortisone 100 mg immediately and 0.9% saline infusion
   • Collect blood samples for cortisol and ACTH before treatment if possible 1

Monitoring After Diagnosis

• Annual follow-up should include:
  • Assessment of health and well-being
  • Weight and blood pressure measurement
  • Serum electrolyte testing
  • Screening for other autoimmune disorders (particularly thyroid disease)
  • Bone mineral density assessment every 3-5 years 1

The diagnosis of Addison's disease requires a high index of clinical suspicion, as early manifestations can be subtle and nonspecific. When properly diagnosed and treated with appropriate glucocorticoid and mineralocorticoid replacement, patients can achieve near-normal life expectancy, though quality of life may still be affected 1, 4.