What laboratory tests are used to diagnose Addison's disease?

Laboratory Tests for Diagnosing Addison's Disease

The diagnosis of Addison's disease (primary adrenal insufficiency) requires measurement of morning serum cortisol and ACTH levels, followed by a cosyntropin stimulation test, and testing for 21-hydroxylase autoantibodies to confirm the etiology. 1, 2

Initial Laboratory Evaluation

• Morning serum cortisol and ACTH levels:

  • Low cortisol (<140 nmol/L or <5 μg/dL) with elevated ACTH (>300 pg/mL) strongly suggests primary adrenal insufficiency 2, 3
  • Note: Normal cortisol with markedly elevated ACTH can still indicate early Addison's disease in evolution 3, 4

• Electrolytes:

  • Hyponatremia (low sodium)
  • Hyperkalemia (high potassium)
  • These are characteristic of primary adrenal insufficiency due to mineralocorticoid deficiency 2

Confirmatory Testing

• Cosyntropin (Synacthen) Stimulation Test (gold standard):

  • Administration of 0.25 mg cosyntropin intramuscularly or intravenously
  • Measure serum cortisol at baseline, 30 and/or 60 minutes
  • Normal response: cortisol should exceed 550 nmol/L (>18-20 μg/dL)
  • Failure to reach this threshold confirms adrenal insufficiency 1, 2

• Mineralocorticoid Assessment:

  • Plasma renin activity (typically elevated)
  • Aldosterone levels (typically low)
  • Aldosterone/renin ratio 2, 4

Etiologic Diagnosis

• 21-hydroxylase autoantibodies (21OH-Ab):

  • Positive result confirms autoimmune etiology (85% of cases in Western countries)
  • Should be measured in all newly diagnosed cases 1

• Adrenal imaging (if 21OH-Ab negative):

  • CT scan of adrenal glands to identify:
    • Calcifications (suggestive of tuberculosis)
    • Hemorrhage
    • Infiltrative disorders
    • Metastatic disease 1

• Additional testing (based on clinical suspicion):

  • Males: Very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy
  • Tuberculosis screening: Quantiferon test, PCR
  • Genetic testing when appropriate 1

Important Clinical Considerations

• If acute adrenal crisis is suspected, blood samples for cortisol and ACTH should be collected immediately, but treatment with hydrocortisone and saline should not be delayed 1

• Some patients (approximately 10%) with early Addison's disease may present with normal cortisol levels but elevated ACTH, highlighting the importance of measuring both hormones 3, 4

• The diagnostic approach should consider the full clinical picture, including characteristic symptoms (fatigue, weight loss, salt craving, hyperpigmentation) and other autoimmune conditions that may coexist (thyroid disease, type 1 diabetes, vitiligo) 1, 5

• Medications that may interfere with testing:

  • Glucocorticoids and spironolactone should be stopped on the day of testing
  • Estrogen-containing medications should be discontinued 4-6 weeks before testing 6

Diagnostic Algorithm

1. Measure morning serum cortisol and ACTH
2. If cortisol is low (<140 nmol/L) and ACTH is high (>300 pg/mL), diagnosis is likely
3. Perform cosyntropin stimulation test to confirm diagnosis
4. Test for 21OH-Ab to determine etiology
5. If 21OH-Ab negative, proceed with adrenal imaging and additional testing based on clinical suspicion

Remember that early diagnosis is crucial to prevent potentially fatal adrenal crisis, and testing should be performed with a low threshold of suspicion in patients with suggestive symptoms.