What are the initial steps for testing for Addison's disease?

Testing for Addison's Disease

The initial diagnostic steps for testing Addison's disease should include morning serum cortisol and ACTH measurement, followed by a high-dose (250-μg) ACTH stimulation test if results are inconclusive. 1

Initial Diagnostic Approach

Step 1: Clinical Assessment

• Look for specific symptoms:
  • Fatigue, weakness, weight loss, anorexia
  • Salt craving, hypotension, postural dizziness
  • Hyperpigmentation of skin and mucosal surfaces (especially skin creases, pressure points, and gums)
  • Nausea, vomiting, abdominal pain
  • Hypoglycemia (more common in children)

Step 2: Initial Laboratory Tests

1. Morning serum cortisol and ACTH measurement

   • Primary adrenal insufficiency pattern: Low cortisol with high ACTH
   • Secondary adrenal insufficiency pattern: Low cortisol with low/normal ACTH
   • Electrolyte abnormalities: Hyponatremia and hyperkalemia 1

2. Basic metabolic panel

   • Check for hyponatremia, hyperkalemia, and hypoglycemia
   • These findings support the diagnosis but may not be present in all cases 2

Step 3: Confirmatory Testing

1. High-dose (250-μg) ACTH stimulation test (gold standard)

   • Administer 250 μg of synthetic ACTH intravenously
   • Measure serum cortisol at baseline, 30, and 60 minutes
   • Normal response: Cortisol exceeding 550 nmol/L (18-20 μg/dL) at either 30 or 60 minutes
   • Abnormal response suggests adrenal insufficiency 1

2. 21-hydroxylase antibody testing

   • Positive results indicate autoimmune Addison's disease (accounts for ~85% of cases in Western countries)
   • Should be performed in all patients with confirmed primary adrenal insufficiency 1

Important Considerations

Caution in Interpretation

• Normal cortisol levels don't rule out early Addison's disease

  • Some patients with early adrenal insufficiency may have normal cortisol but elevated ACTH levels
  • Consider measuring ACTH even when cortisol is normal if clinical suspicion is high 3, 4

• Mineralocorticoid assessment

  • Measure plasma renin activity and aldosterone levels
  • High renin with low aldosterone suggests mineralocorticoid deficiency 1

Potential Pitfalls

1. Delayed diagnosis due to nonspecific symptoms and gradual onset

   • Symptoms often don't appear until >90% of adrenal cortex is destroyed 5

2. Missed early cases with normal cortisol

   • Up to 10% of patients with primary adrenal insufficiency may initially present with normal cortisol levels 4
   • Elevated ACTH (>300 pg/mL) with normal cortisol should raise suspicion when clinical presentation is suggestive 3

3. Medication interference

   • Exogenous glucocorticoids can suppress the HPA axis
   • Estrogen-containing medications can affect test results by altering cortisol binding globulin levels 1

Additional Testing When Indicated

• Adrenal imaging (CT or MRI) if non-autoimmune etiology is suspected
• Screening for associated autoimmune conditions:
  • Thyroid function tests (TSH, FT4, TPO-Ab)
  • Plasma glucose, HbA1c
  • Complete blood count
  • Vitamin B12 levels 2

Following diagnosis, patients should be educated about lifelong replacement therapy, stress dosing protocols, and emergency management of adrenal crisis, including the use of emergency hydrocortisone injection kits 1.