What is the workup for Addison's disease?

Diagnostic Workup for Addison's Disease

The diagnostic workup for Addison's disease should begin with measurement of morning serum cortisol and ACTH levels, followed by a cosyntropin stimulation test if results are equivocal, and determination of etiology through 21-hydroxylase antibody testing. 1

Initial Laboratory Evaluation

• Morning serum cortisol and ACTH:

  • Low cortisol (<550 nmol/L) with elevated ACTH suggests primary adrenal insufficiency
  • Low cortisol with low/normal ACTH suggests secondary adrenal insufficiency

• Serum electrolytes:

  • Look for hyponatremia and hyperkalemia (typical in primary adrenal insufficiency)
  • Note that some rare cases may present with hypokalemia 2

• Blood glucose: Hypoglycemia is common

• Complete blood count: May show anemia

Confirmatory Testing

• Cosyntropin (Synacthen) stimulation test:
  • Administer 0.25 mg cosyntropin intramuscularly or intravenously
  • Measure serum cortisol at 30 and/or 60 minutes
  • Normal response: cortisol should exceed 550 nmol/L at one of these timepoints
  • Test is particularly useful when partial adrenal insufficiency is suspected 1

Important Clinical Note

If acute adrenal crisis is suspected, do not delay treatment to complete diagnostic workup:

• Immediately administer intravenous hydrocortisone (100 mg)
• Start isotonic saline infusion
• Obtain blood samples for cortisol and ACTH before treatment if possible
• Complete diagnostic workup after stabilization 1, 3

Etiologic Diagnosis

After confirming adrenal insufficiency, determine the cause:

1. Autoimmune etiology (most common in Western countries, ~85%):

   • Measure 21-hydroxylase antibodies (21OH-Ab)
   • If positive → Autoimmune Addison's disease 1

2. If 21OH-Ab negative, consider:

   • CT scan of adrenal glands: To evaluate for hemorrhage, tumors, tuberculosis
   • Very long-chain fatty acid (VLCFA) levels: To rule out adrenoleukodystrophy (especially in males)
   • Interferon-ω antibodies: To evaluate for autoimmune polyendocrine syndrome type 1 (APS-1) 1

Additional Workup

• Thyroid function tests: TSH, free T4, and thyroid peroxidase antibodies (TPO-Ab) to detect concurrent autoimmune thyroid disease 1, 4

• Vitamin B12 levels: To screen for pernicious anemia due to autoimmune gastritis

• Celiac disease screening: Consider tissue transglutaminase antibodies and total IgA in patients with gastrointestinal symptoms 1

• Glucose levels and HbA1c: To screen for diabetes mellitus

Follow-Up Evaluation

Once diagnosed, patients should be monitored annually for:

• Assessment of replacement therapy adequacy
• Development of other autoimmune disorders (particularly hypothyroidism)
• Bone mineral density every 3-5 years 1, 3

Diagnostic Algorithm

1. Clinical suspicion based on symptoms (fatigue, weight loss, hyperpigmentation, hypotension)
2. Initial labs: Morning cortisol and ACTH
3. Confirmatory test: Cosyntropin stimulation test
4. Determine etiology: 21OH-Ab testing first, followed by additional tests if negative
5. Screen for associated conditions: Thyroid disease, diabetes, vitamin B12 deficiency

Remember that early diagnosis and treatment are critical to prevent potentially fatal adrenal crisis. The diagnostic workup should be thorough but should never delay treatment when adrenal crisis is suspected.