What is the approach to evaluating elevated cortisol levels?

Approach to Evaluating Elevated Cortisol Levels

A systematic, stepwise diagnostic approach is essential for evaluating elevated cortisol levels, beginning with confirmation of hypercortisolism through multiple testing methods before determining the underlying cause. 1

Initial Diagnostic Testing

Step 1: Confirm Hypercortisolism

• Perform at least two of the following tests:
  • 24-hour urinary free cortisol (UFC) measurements (collect 2-3 samples)
  • Late-night salivary cortisol (LNSC) (collect at least 2-3 samples)
  • 1 mg overnight dexamethasone suppression test (DST) or 2 mg/day for 2 days

These tests have complementary strengths and limitations:

• LNSC is convenient and has 92% sensitivity for Cushing's syndrome 2
• DST may be preferred for shift workers or those with disrupted circadian rhythm 3
• Multiple UFC collections help evaluate variability in cortisol secretion 3

Step 2: Determine ACTH Dependence

• Measure plasma ACTH levels to differentiate between:
  • ACTH-dependent causes (normal to high ACTH): pituitary adenoma (Cushing's disease) or ectopic ACTH production
  • ACTH-independent causes (suppressed ACTH): adrenal tumors or hyperplasia 1

Further Diagnostic Evaluation

For ACTH-Dependent Hypercortisolism

1. Pituitary MRI:

   • Use high-resolution techniques (spoiled gradient-recalled acquisition, FLAIR, CISS)
   • Note: Only approximately 50% of microadenomas are clearly visible on standard MRI 3

2. If pituitary imaging is negative or inconclusive:

   • Perform bilateral inferior petrosal sinus sampling (IPSS) to differentiate between pituitary and ectopic sources
   • Note: IPSS should not be used to diagnose hypercortisolism itself 3

For ACTH-Independent Hypercortisolism

• Perform adrenal imaging (CT or MRI) to identify adrenal tumors or hyperplasia

Special Considerations

Pseudo-Cushing's States

• Consider in patients with mild hypercortisolism
• Common causes: depression, alcoholism, obesity, poorly controlled diabetes
• Approach:
  • Monitor for 3-6 months to see if symptoms resolve
  • Consider desmopressin test (high specificity for Cushing's disease) 3
  • Treat underlying conditions that may cause pseudo-Cushing's 3

Cyclic Cushing's Syndrome

• For patients with fluctuating cortisol levels:
  • Perform confirmatory testing during active phase
  • Consider multiple LNSC measurements over time 3

Treatment Approach

First-Line Treatment

• Surgical intervention is the first-line treatment for most causes:
  • Transsphenoidal surgery for pituitary adenomas
  • Adrenalectomy for adrenal tumors
  • Resection of ectopic ACTH-producing tumors 4

Medical Therapy

When surgery is delayed, contraindicated, or unsuccessful:

1. Adrenal steroidogenesis inhibitors:

   • Ketoconazole (starting dose 200-400 mg/day)
   • Metyrapone (works rapidly by inhibiting 11-β-hydroxylase)
   • Osilodrostat (FDA-approved, high rates of cortisol normalization) 3, 1

2. Pituitary-directed therapies (for Cushing's disease):

   • Pasireotide (monitor for hyperglycemia)
   • Cabergoline (less effective but requires less frequent dosing) 1

3. Glucocorticoid receptor blockers:

   • Mifepristone (improves hyperglycemia and weight gain) 1

Combination Therapy

• Consider combinations if monotherapy is ineffective:
  • Ketoconazole + metyrapone or osilodrostat
  • Ketoconazole + cabergoline or pasireotide (if visible tumor present) 3

Monitoring Response to Treatment

• Evaluate both clinical and biochemical parameters:

  • Clinical: improved phenotype, weight, hypertension, glucose metabolism, quality of life
  • Biochemical: UFC normalization (except with mifepristone) 3

• Monitor for tumor growth with MRI typically 6-12 months after starting treatment and then every few years 3

• Consider changing treatment if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 3

Potential Complications and Pitfalls

• Risk of adrenal insufficiency with overtreatment - provide stress-dose glucocorticoid coverage when needed 1

• Medication-specific monitoring:

  • Ketoconazole: liver function tests
  • Pasireotide: blood glucose
  • Mifepristone: potassium levels 1

• Elevated baseline cortisol is associated with higher mortality in critically ill patients - consider this when interpreting results in hospitalized patients 5

• Timing of cortisol measurement affects interpretation - morning cortisol <275 nmol/L or afternoon cortisol <250 nmol/L may suggest adrenal insufficiency in outpatients 6

The comprehensive evaluation of elevated cortisol requires careful attention to testing methodology, clinical context, and potential pitfalls in interpretation to ensure accurate diagnosis and appropriate treatment.