What are the steps for confirmatory testing for a patient suspected of having Addison's disease?

Confirmatory Testing for Addison's Disease

The cosyntropin (synacthen) stimulation test is the gold standard confirmatory test for Addison's disease, requiring administration of 0.25 mg cosyntropin intramuscularly or intravenously with serum cortisol measured at baseline, 30 minutes, and 60 minutes—a normal response requires cortisol to exceed 550 nmol/L (approximately 18-20 mcg/dL) at either the 30 or 60-minute mark. 1, 2, 3

Initial Diagnostic Steps

Before proceeding to confirmatory testing, obtain baseline measurements:

• Measure morning serum cortisol and ACTH simultaneously 2

  • Low or inappropriately normal cortisol with markedly elevated ACTH suggests primary adrenal insufficiency 2
  • If morning cortisol is >500 nmol/L, Addison's disease is unlikely 1
  • If morning cortisol is <100 nmol/L with elevated ACTH, diagnosis is confirmed without further testing 1

• Check serum electrolytes 2

  • Hyponatremia occurs in ~90% of newly diagnosed cases 2
  • Hyperkalemia is present in ~50% at diagnosis 2

• Additional supportive findings include mild hypercalcemia, anemia, eosinophilia, lymphocytosis, and elevated liver transaminases 2

The Cosyntropin Stimulation Test Protocol

When to perform: Required when partial adrenal insufficiency is suspected or when baseline results are equivocal 1, 2

Administration Protocol

1. Draw baseline blood sample for serum cortisol 3

2. Administer 0.25 mg cosyntropin intramuscularly or intravenously 1, 3

3. Measure serum cortisol at exactly 30 and 60 minutes post-administration 1, 3

Interpretation

• Normal response: Cortisol exceeds 550 nmol/L (18-20 mcg/dL) at either 30 or 60 minutes 1, 2, 3
• Abnormal response: Cortisol remains below this threshold, confirming adrenal insufficiency 3
• Important caveat: Cutoff values may vary according to the specific cortisol assay used 3

Critical Pre-Test Medication Considerations

Several medications interfere with test accuracy and must be managed appropriately:

• Glucocorticoids and spironolactone falsely elevate cortisol levels—stop these drugs on the day of testing 3

  • Long-acting glucocorticoids may require longer discontinuation periods 3

• Estrogen-containing medications increase cortisol-binding globulin, artificially elevating total cortisol 3

  • Stop estrogen 4-6 weeks before testing to allow cortisol-binding globulin normalization 3
  • Alternatively, measure cortisol-binding globulin simultaneously; if elevated, total cortisol results are unreliable 3

• Conditions affecting cortisol-binding globulin (cirrhosis, nephrotic syndrome) lower binding globulin and may decrease total cortisol levels 3

Emergency Situations: When NOT to Wait for Testing

If acute adrenal crisis is suspected clinically, immediately administer intravenous hydrocortisone 100 mg and 0.9% saline infusion—never delay treatment for diagnostic procedures. 1, 2

• Draw blood for cortisol and ACTH before treatment if possible, but treatment takes absolute priority 1
• The diagnosis can always be established later, even after treatment has commenced 1
• Clinical features of adrenal crisis include hypotension, shock, volume depletion, confusion, nausea, vomiting, and abdominal pain 1, 4

Etiologic Diagnosis After Confirmation

Once primary adrenal insufficiency is confirmed, determine the underlying cause:

First-Line Etiologic Test

Measure 21-hydroxylase autoantibodies (21OH-Ab) as the initial test 1, 2

• Positive result confirms autoimmune etiology (85% of cases in Western Europe) 1
• No further etiologic workup needed if positive 1

If 21OH-Ab is Negative

Pursue additional investigations for non-autoimmune causes: 1

• CT scan of adrenal glands to detect tumors, calcifications (tuberculosis), hemorrhage, or infiltrative disease 1

• Very long-chain fatty acids in males to screen for adrenoleukodystrophy 1

• Consider tuberculosis testing (culture, Quantiferon test, PCR) in endemic areas or high-risk patients 1

• Genetic testing in children or young adults, including urine steroid profiles and sequencing of steroidogenic genes 1

Common Pitfalls to Avoid

• Do not rely on random cortisol levels alone—they lack sufficient sensitivity and specificity without dynamic testing 2

• 21OH-Ab may be absent in children and elderly patients, requiring more extensive investigation even with autoimmune disease 1

• Exogenous steroid use confounds all cortisol measurements—obtain detailed medication history including topical, inhaled, and injected steroids 2

• Do not overlook screening for associated autoimmune conditions once diagnosis is established, particularly thyroid disease, diabetes, pernicious anemia, and celiac disease 2, 5, 4