What laboratory tests are used to rule out Addison's (Adrenal Insufficiency) disease?

Laboratory Tests to Rule Out Addison's Disease (Adrenal Insufficiency)

The most effective approach to rule out Addison's disease is to measure morning serum cortisol and ACTH levels, followed by a cosyntropin stimulation test if results are inconclusive. 1

Initial Laboratory Evaluation

• Morning serum cortisol and ACTH levels:

  • Primary adrenal insufficiency: Low cortisol with high ACTH
  • Secondary adrenal insufficiency: Low cortisol with low/normal ACTH
  • Note: Morning cortisol >350 nmol/l (>12.7 μg/dL) generally rules out adrenal insufficiency, but caution is needed as early disease may present with normal cortisol levels 2, 3

• Electrolytes:

  • Primary adrenal insufficiency: Decreased sodium, elevated potassium
  • Secondary adrenal insufficiency: Generally normal electrolytes 1

Confirmatory Testing

• Cosyntropin (ACTH) stimulation test (gold standard):
  • Administration of 0.25 mg synthetic ACTH (cosyntropin) IV or IM
  • Measure cortisol levels at baseline and 30-60 minutes post-administration
  • Normal response: Cortisol rise to >18-20 μg/dL (500 nmol/L)
  • Inadequate response confirms adrenal insufficiency 1, 4

Important Test Considerations

• Stop medications that affect test results:

  • Glucocorticoids: Discontinue on day of testing (longer for long-acting preparations)
  • Estrogen-containing drugs: Stop 4-6 weeks before testing
  • Spironolactone: Discontinue on day of testing 4

• Additional helpful tests:

  • Renin and aldosterone levels: In primary adrenal insufficiency, renin is elevated while aldosterone is low 3
  • 21-hydroxylase antibodies: Present in autoimmune adrenal insufficiency (most common cause in developed countries) 5, 6
  • Adrenal imaging: If autoimmune etiology is not confirmed, CT or MRI may help identify other causes (tuberculosis, hemorrhage, metastases)

Diagnostic Pitfalls

• Early disease may be missed with standard testing:

  • Up to 10% of patients with early Addison's disease may have normal cortisol levels despite symptoms 2
  • High ACTH (>300 pg/mL) with normal cortisol should raise suspicion, especially with suggestive symptoms 3
  • Consider measuring ACTH and renin-aldosterone axis function in suspicious cases even if cortisol is normal 3

• Clinical correlation is essential:

  • Symptoms may include fatigue, anorexia, nausea, hyperpigmentation, salt craving, orthostatic hypotension 6
  • Symptoms typically don't appear until >90% of adrenal cortex is destroyed 7
  • Adrenal crisis may be precipitated by stress (infection, surgery) 6

Testing Algorithm

1. First-line: Morning serum cortisol and ACTH levels
2. If cortisol <5 μg/dL with elevated ACTH: Diagnosis of primary adrenal insufficiency is likely
3. If cortisol 5-18 μg/dL or normal with elevated ACTH: Proceed to cosyntropin stimulation test
4. If cosyntropin test shows inadequate response: Confirm diagnosis
5. Additional tests: Electrolytes, renin, aldosterone, 21-hydroxylase antibodies
6. Consider adrenal imaging if autoimmune etiology is not confirmed

Remember that early detection is crucial to prevent life-threatening adrenal crisis, and a high index of clinical suspicion is needed given the nonspecific nature of early symptoms.