What random cortisol level indicates hypercortisolism?

Random Cortisol Levels That Indicate Hypercortisolism

A random cortisol level greater than 60 μg/dL indicates loss of normal circadian rhythm of cortisol secretion, a hallmark of Cushing syndrome. 1

Diagnostic Approach to Hypercortisolism

Initial Screening Tests

• An evening cortisol level >60 μg/dL suggests disruption of normal cortisol circadian rhythm, which is characteristic of Cushing syndrome 1
• Low-dose dexamethasone suppression test (LDDST) is a reliable screening method where dexamethasone is taken orally at midnight, and plasma cortisol is measured at 8 AM 2
• In normal individuals, morning cortisol (200-650 nmol/L) should suppress to <80 nmol/L after LDDST; failure to suppress indicates hypercortisolism 2
• 24-hour urinary free cortisol (UFC) measurement is another reliable screening method, with markedly elevated levels consistently seen in clinically apparent Cushing syndrome 2
• Late-night salivary cortisol >3.6 nmol/L has a sensitivity of 92% for diagnosing Cushing syndrome 3

Confirmatory Testing

• The Endocrine Society recommends performing additional confirmatory tests, including 24-hour UFC measurements and LDDST, to confirm Cushing syndrome 1
• Normal cortisol suppression on dexamethasone suppression test is defined as <1.8 μg/dL (50 nmol/L), and values above this threshold indicate abnormal feedback inhibition 4
• The combination of elevated late-night salivary cortisol AND elevated UFC identifies 100% of patients with Cushing syndrome (100% sensitivity) 3

Differentiating Types of Hypercortisolism

• After confirming hypercortisolism, measuring plasma ACTH levels is essential to determine if the condition is ACTH-dependent or ACTH-independent 4, 1
• ACTH level >5 ng/L is detectable and suggests an ACTH-dependent form of Cushing's syndrome 4
• ACTH level >29 ng/L has 70% sensitivity and 100% specificity for diagnosing Cushing's disease (pituitary source) 4
• Low or undetectable ACTH levels indicate ACTH-independent Cushing's syndrome (adrenal source) 4

Special Considerations and Potential Pitfalls

• False positive results in screening tests may occur due to:
  • Severe obesity 4
  • Uncontrolled diabetes mellitus 4
  • Alcoholism 4
  • Rapid absorption/malabsorption of dexamethasone 4
  • Concomitant treatment with CYP3A4 inducers 4
  • Increased corticosteroid binding globulin levels from oral estrogens or pregnancy 4, 5
• Oral contraceptives can cause extreme increases in serum cortisol levels due to marked increases in cortisol-binding globulin levels 5
• Subclinical hypercortisolism may be present in patients with pituitary incidentalomas (7.3% rate) and should be considered during evaluation 6
• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 4

Next Steps After Confirming Hypercortisolism

• For ACTH-dependent Cushing's syndrome, pituitary MRI is recommended to identify potential pituitary adenomas 4
• For ACTH-independent Cushing's syndrome, adrenal CT or MRI is indicated to identify adrenal lesion(s) 4
• If pituitary MRI is inconclusive (no adenoma or lesion <6 mm), bilateral inferior petrosal sinus sampling (BIPSS) should be performed to differentiate between pituitary and ectopic sources 4
• For suspected ectopic ACTH-secreting tumors, neck-to-pelvis thin-slice CT scan is recommended 4