What does an elevated cortisol level indicate?

Elevated Cortisol Level (39.5) Interpretation

An elevated cortisol level of 39.5 indicates potential hypercortisolism, which requires further diagnostic evaluation to determine if it represents Cushing syndrome, adrenal hyperfunction, or a physiologic stress response. 1

Diagnostic Considerations

• Elevated cortisol with normal or non-elevated ACTH suggests ACTH-independent Cushing syndrome, likely from an adrenal source (adrenal adenoma, adrenal carcinoma, or bilateral adrenal hyperplasia) 1
• If ACTH is elevated along with high cortisol, this suggests ACTH-dependent Cushing syndrome (pituitary adenoma or ectopic ACTH production) 1
• A single elevated cortisol measurement is insufficient for diagnosis and requires confirmation with additional testing 2

Recommended Diagnostic Algorithm

Initial Assessment

• Determine if clinical features of Cushing syndrome are present (obesity, hypertension, diabetes, muscle weakness, easy bruising, purple striae) 1
• Evaluate for other causes of elevated cortisol:
  • Stress, depression, alcoholism, and severe illness can cause pseudo-Cushing states 2
  • Sleep deprivation can elevate evening cortisol levels 3

Confirmatory Testing

• Perform 24-hour urinary free cortisol test to confirm hypercortisolism 1, 4
• Late-night salivary cortisol measurement (elevated levels >3.6 nmol/L are 92% sensitive for Cushing syndrome) 4
• Low-dose dexamethasone suppression test (failure to suppress cortisol indicates hypercortisolism) 2
• Measure plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 2, 1

Imaging

• If ACTH is suppressed or normal with elevated cortisol, obtain adrenal imaging (CT or MRI) to identify potential adrenal masses 1
• If ACTH is elevated, pituitary MRI is indicated 2

Clinical Implications and Mortality Risks

• Untreated hypercortisolism is associated with significant morbidity and mortality:
  • Increased cardiovascular risk (hypertension, diabetes, dyslipidemia) 1
  • Increased risk of infections due to immunosuppression 2
  • Osteoporosis and fracture risk 2
  • Cognitive impairment and potential increased risk of Alzheimer's disease 5

Treatment Approach

• For adrenal adenomas: laparoscopic adrenalectomy is the treatment of choice 1
• For adrenal carcinoma: open adrenalectomy with removal of adjacent lymph nodes 1
• For bilateral adrenal hyperplasia: medical management with adrenostatic agents like ketoconazole 1
• Post-surgical patients require corticosteroid supplementation until recovery of the hypothalamic-pituitary-adrenal axis 1

Important Caveats

• A single cortisol measurement can be misleading due to diurnal variation (normally higher in morning, lower in evening) 6
• Cortisol binding globulin (CBG) levels affect total cortisol measurement - conditions like pregnancy or estrogen therapy increase CBG and total cortisol without affecting free (active) cortisol 6
• Liver disease, renal disease, and critical illness can alter CBG levels and affect interpretation of total cortisol 6, 2
• In critically ill patients, a random total cortisol <276 nmol/L (10 µg/dl) suggests relative adrenal insufficiency rather than excess 2

Follow-up and Monitoring

• Monitor for improvement of Cushing syndrome manifestations (hypertension, hyperglycemia, hypokalemia, muscle atrophy) 1
• Post-treatment, patients should be monitored for symptoms of adrenal insufficiency 1
• For malignant causes, follow-up imaging and biomarkers should be performed every 3-6 months 1