What is the next test for suspected adrenal dysfunction or Congenital Adrenal Hyperplasia (CAH)?

Diagnostic Testing for Suspected Adrenal Dysfunction or Congenital Adrenal Hyperplasia (CAH)

For suspected adrenal dysfunction or CAH, the next diagnostic test should be morning serum cortisol and ACTH levels, followed by an ACTH stimulation test if results are equivocal. 1

Initial Diagnostic Approach

First-line Testing

• Measure morning (AM) cortisol and ACTH levels simultaneously as the primary diagnostic test for adrenal insufficiency 1
• Include basic metabolic panel (sodium, potassium, CO2, glucose) to assess for electrolyte abnormalities commonly seen in adrenal dysfunction 1
• Morning cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1

For Equivocal Results

• Perform ACTH stimulation test (Synacthen/cosyntropin 0.25 mg IM or IV) 1
• A peak serum cortisol <500 nmol/L after stimulation confirms primary adrenal insufficiency 1
• This test is particularly important when baseline results are indeterminate 1

Testing Based on Suspected Type of Adrenal Dysfunction

For Suspected Primary Adrenal Insufficiency

• After confirming low cortisol/high ACTH, measure 21-hydroxylase (anti-adrenal) autoantibodies to determine autoimmune etiology 1
• If antibodies are negative, proceed with adrenal CT imaging to evaluate for structural causes 1
• In males with negative antibodies, test very long-chain fatty acids to rule out adrenoleukodystrophy 1

For Suspected Congenital Adrenal Hyperplasia

• ACTH stimulation test with measurement of 17-hydroxyprogesterone (17-OHP) is the gold standard 2, 3
• 17-OHP levels >30 nmol/L after ACTH stimulation are diagnostic of 21-hydroxylase deficiency CAH 3
• For nonclassical CAH, 17-OHP levels typically fall between normal range and levels seen in classical CAH 2

For Suspected Cortisol Excess (Cushing's Syndrome)

• Perform 1 mg overnight dexamethasone suppression test (DST) - 1 mg taken at 11 PM with serum cortisol measured at 8 AM 1
• Interpretation of results 1:
  • <50 nmol/L excludes cortisol hypersecretion
  • 51-138 nmol/L suggests possible autonomous cortisol secretion

  • 138 nmol/L indicates cortisol hypersecretion

• Confirm ACTH independence by measuring plasma ACTH levels 1

For Suspected Hyperaldosteronism

• In patients with hypertension and/or hypokalemia, measure aldosterone/renin ratio (ARR) 1
• ARR >20 ng/dL per ng/mL/hr has >90% sensitivity and specificity for confirming hyperaldosteronism 1
• Perform test in the morning after patient has been out of bed for 2 hours and seated for 5-15 minutes 1

Special Considerations

• Never delay treatment of suspected acute adrenal insufficiency for diagnostic procedures 1
• In patients with severe symptoms or adrenal crisis, administer IV hydrocortisone 100 mg immediately 1
• For suspected CAH in children, genetic testing for mutations in the CYP21 gene may be warranted after biochemical confirmation 2
• Untreated patients with nonclassical CAH typically have normal adrenomedullary function, unlike those with classic CAH 4

Common Pitfalls to Avoid

• Do not rely solely on electrolyte abnormalities for diagnosis, as hyponatremia and hyperkalemia may not always be present in adrenal insufficiency 1
• Be aware that exogenous steroid use (including inhaled steroids) may confound interpretation of cortisol levels 1
• Patients with adrenal insufficiency may have mildly elevated TSH (4-10 IU/L) due to lack of cortisol's inhibitory effect on TSH production 1
• Avoid performing diagnostic tests during acute illness without appropriate treatment, as this can precipitate adrenal crisis 1