What is the workup for Addison's disease?

Diagnostic Workup for Addison's Disease

The diagnostic workup for Addison's disease should begin with measuring morning serum cortisol and ACTH levels, followed by a cosyntropin stimulation test if results are inconclusive, and then determining the etiology through 21-hydroxylase antibody testing and adrenal imaging when appropriate. 1

Initial Diagnostic Steps

• Morning serum cortisol and ACTH measurement:

  • Low cortisol (<550 nmol/L) with elevated ACTH suggests primary adrenal insufficiency
  • Low cortisol with low/normal ACTH suggests secondary adrenal insufficiency
  • Characteristic electrolyte abnormalities include hyponatremia and hyperkalemia 1, 2

• Cosyntropin (Synacthen) stimulation test:

  • Administer 0.25 mg cosyntropin intramuscularly or intravenously
  • Measure serum cortisol at baseline, 30 minutes, and 60 minutes
  • Normal response: cortisol should exceed 550 nmol/L at either 30 or 60 minutes
  • Failure to reach this threshold confirms adrenal insufficiency 1

Etiologic Diagnosis

Once primary adrenal insufficiency (PAI) is confirmed, determine the cause:

1. 21-hydroxylase antibody (21OH-Ab) testing:

   • Positive: Autoimmune Addison's disease (accounts for ~85% of cases in Western countries)
   • Negative: Proceed to further evaluation 1

2. If 21OH-Ab negative:

   • CT imaging of adrenal glands to evaluate for:

     • Adrenal hemorrhage
     • Tuberculosis
     • Tumors
     • Infiltrative diseases 1

   • Consider specialized testing for:

     • Adrenoleukodystrophy: Very long-chain fatty acid (VLCFA) testing
     • Autoimmune polyglandular syndrome type 1 (APS-1): Interferon-omega antibodies (INFω-Ab) 1

Additional Laboratory Evaluations

• Thyroid function tests: TSH and free T4 (to identify concurrent autoimmune thyroid disease)
• Complete blood count: To screen for anemia
• Plasma glucose and HbA1c: To screen for diabetes mellitus
• Vitamin B12 levels: To detect B12 deficiency from autoimmune gastritis
• Tissue transglutaminase antibodies and total IgA: In patients with diarrhea to screen for celiac disease 1

Important Clinical Considerations

• Do not delay treatment if adrenal crisis is suspected:

  • Secure blood samples for cortisol and ACTH measurement before treatment if possible
  • Immediately administer IV hydrocortisone 100 mg and isotonic saline
  • The diagnosis can be established later 1

• Annual follow-up should include:

  • Assessment of well-being
  • Weight and blood pressure measurement
  • Serum electrolyte testing
  • Screening for other autoimmune disorders (especially thyroid disease)
  • Bone mineral density assessment every 3-5 years 1, 2

Diagnostic Algorithm

1. Clinical suspicion based on symptoms (fatigue, weight loss, hyperpigmentation, hypotension)
2. Initial testing: Morning cortisol and ACTH
3. Confirmatory testing: Cosyntropin stimulation test
4. Etiologic diagnosis: 21OH-Ab testing
5. Additional evaluation: Adrenal imaging if 21OH-Ab negative
6. Screening for associated conditions: Thyroid, glucose, B12, celiac testing

Remember that early diagnosis and prompt treatment are essential to prevent life-threatening adrenal crisis and improve patient outcomes.