What laboratory tests are recommended for diagnosing hyperaldosteronism and Cushing's syndrome?

Laboratory Tests for Diagnosing Hyperaldosteronism and Cushing's Syndrome

For diagnosing hyperaldosteronism and Cushing's syndrome, specific laboratory tests are required including plasma aldosterone/renin ratio for hyperaldosteronism and a combination of late-night salivary cortisol, dexamethasone suppression test, and 24-hour urinary free cortisol for Cushing's syndrome. 1

Hyperaldosteronism Diagnostic Testing

Initial Screening Test

• Plasma aldosterone/renin ratio (ARR):
  • Must be performed under standardized conditions:
    • Morning collection (after patient has been out of bed for 2 hours)
    • Patient seated for 5-15 minutes before collection
    • Patient should be potassium-replete
    • Interfering medications should be withdrawn if possible 1
  • Interpretation: ARR > 20 ng/dL per ng/mL/hr has >90% sensitivity and specificity for hyperaldosteronism 1
  • Patients with primary aldosteronism typically have elevated plasma aldosterone and low renin activity 1

Confirmatory Tests

• Electrolytes: Measure sodium and potassium (hypokalemia is common due to excessive aldosterone causing potassium excretion) 1
• Saline suppression test or salt loading test: To confirm diagnosis as false positives/negatives can occur with ARR 1
• 24-hour urine aldosterone measurement: Often combined with salt loading 1

Localization

• Adrenal CT scan: To identify potential adrenal adenoma 1
• Adrenal vein sampling for aldosterone: Gold standard for distinguishing unilateral adenoma from bilateral hyperplasia 1

Cushing's Syndrome Diagnostic Testing

Initial Screening Tests (at least two tests recommended)

1. Late-night salivary cortisol (LNSC):

   • Collect at bedtime or 11 PM 1
   • Highest specificity among screening tests 1
   • At least 2-3 samples recommended 1
   • Simple collection method with excellent sensitivity (92-95%) 2, 3

2. Overnight 1-mg dexamethasone suppression test (DST):

   • Administer 1 mg dexamethasone between 11 PM-midnight
   • Measure serum cortisol at 8 AM the next morning
   • Normal response: cortisol < 1.8 μg/dL (50 nmol/L) 1
   • Consider measuring dexamethasone level with cortisol to improve test interpretation 1

3. 24-hour urinary free cortisol (UFC):

   • Collect at least 2-3 specimens 1, 4
   • Accounts for intra-patient variability
   • Independent of changes in cortisol-binding globulin 1
   • Less reliable in patients with renal impairment 1

ACTH Measurement

• Plasma ACTH: To differentiate ACTH-dependent (pituitary or ectopic source) from ACTH-independent (adrenal) Cushing's syndrome 1
  • Low ACTH: Adrenal source
  • Normal or high ACTH: Pituitary or ectopic source

Testing Algorithm

For Hyperaldosteronism:

1. Screen with plasma aldosterone/renin ratio in patients with:

   • Resistant hypertension
   • Hypertension with hypokalemia
   • Hypertension with muscle cramps/weakness
   • Adrenal incidentaloma
   • Family history of early-onset hypertension 1

2. If ARR > 20 ng/dL per ng/mL/hr, proceed to confirmatory testing with:

   • Oral sodium loading test with 24-hour urine aldosterone OR
   • IV saline infusion test with plasma aldosterone at 4 hours 1

For Cushing's Syndrome:

1. Screen with at least two of the following tests:

   • Late-night salivary cortisol (≥2 samples)
   • 1-mg overnight dexamethasone suppression test
   • 24-hour urinary free cortisol (≥2 collections) 1

2. If any test is abnormal, repeat or perform additional tests

   • An elevated LNSC and/or elevated UFC identifies nearly 100% of patients with Cushing's syndrome 2

3. If Cushing's syndrome is confirmed, measure plasma ACTH to determine the source 1

Common Pitfalls and Caveats

For Hyperaldosteronism Testing:

• Medications affecting results: spironolactone, eplerenone (withdraw 4-6 weeks before testing) 1
• Ensure proper potassium levels before testing (hypokalemia can suppress aldosterone) 1
• Diurnal variation affects aldosterone levels; standardize collection time 1
• False positives can occur in patients with renal impairment, pregnancy, or taking certain medications 1

For Cushing's Syndrome Testing:

• Exogenous glucocorticoids must be discontinued before testing 1
• False positives in DST with medications affecting dexamethasone metabolism (e.g., phenobarbital, carbamazepine) 1
• False negatives in DST with medications inhibiting dexamethasone metabolism (e.g., fluoxetine, cimetidine) 1
• LNSC not reliable in shift workers or those with disrupted sleep cycles 1
• UFC affected by high urine volume, renal function, and proper collection technique 1, 4
• Cyclic Cushing's syndrome may require periodic sequential testing 1, 5

By following these systematic approaches to laboratory testing, clinicians can effectively diagnose hyperaldosteronism and Cushing's syndrome, leading to appropriate treatment and improved patient outcomes.