How do you diagnose and treat abnormal serum cortisol levels?

Diagnosis and Management of Abnormal Serum Cortisol Levels

The diagnosis of abnormal serum cortisol levels requires a stepwise approach starting with screening tests including 1 mg overnight dexamethasone suppression test (DST), 24-hour urinary free cortisol (UFC), and/or late-night salivary cortisol (LNSC), followed by confirmatory testing and appropriate treatment based on the underlying cause.

Diagnostic Approach for Hypercortisolism (Cushing's Syndrome)

Initial Screening Tests

• 1 mg overnight dexamethasone suppression test (DST):

  • Administer 1 mg dexamethasone at midnight
  • Measure serum cortisol between 8-9 AM the next morning
  • Normal response: cortisol <2 μg/dL (<50 nmol/L) 1
  • Sensitivity: 95%, Specificity: 80% 2

• 24-hour urinary free cortisol (UFC):

  • Collect urine for 3 consecutive days
  • Values >193 nmol/24h (>70 μg/m²) suggest Cushing's syndrome
  • Sensitivity: 89%, Specificity: 100% 2
  • Multiple collections recommended due to potential variability 2, 3

• Late-night salivary cortisol (LNSC):

  • Collect saliva at 11 PM or midnight
  • Elevated levels (>3.6 nmol/L) suggest Cushing's syndrome
  • Sensitivity: 95%, Specificity: 100% 2, 4
  • Multiple samples recommended (at least 2-3) 2, 5

Confirmatory Testing

After positive screening, determine the source of hypercortisolism:

1. Measure plasma ACTH levels:

   • ACTH-dependent (detectable/elevated ACTH): Suggests pituitary or ectopic source
   • ACTH-independent (suppressed ACTH): Suggests adrenal source 2

2. For ACTH-dependent Cushing's syndrome:

   • CRH stimulation test: ≥20% increase in cortisol suggests pituitary source 2
   • Pituitary MRI: First-line imaging for suspected Cushing's disease 2
   • Bilateral inferior petrosal sinus sampling (BIPSS):
     • Indicated when MRI is negative or equivocal
     • Central-to-peripheral ACTH ratio ≥3 after CRH/desmopressin confirms pituitary source 2

3. For ACTH-independent Cushing's syndrome:

   • Adrenal CT/MRI: To identify adrenal adenoma, carcinoma, or hyperplasia 2

Special Considerations

• Cyclic or intermittent Cushing's syndrome may show normal cortisol levels during testing 3
• Multiple tests may be needed to capture hypercortisolism
• Consider medication effects on test results (e.g., estrogen, anticonvulsants) 2, 5

Diagnostic Approach for Hypocortisolism (Adrenal Insufficiency)

Initial Testing

• Morning serum cortisol (8-9 AM):
  • <3 μg/dL (<83 nmol/L): Highly suggestive of adrenal insufficiency

  • 18 μg/dL (>500 nmol/L): Usually excludes adrenal insufficiency

  • 3-18 μg/dL: Requires further testing 5

Confirmatory Testing

• ACTH stimulation test (Cosyntropin test):

  • Administer 250 μg synthetic ACTH intravenously
  • Measure cortisol at 0,30, and 60 minutes
  • Normal response: peak cortisol ≥18 μg/dL (≥500 nmol/L) 5

• Determine type of adrenal insufficiency:

  • Primary: High ACTH, low cortisol, electrolyte abnormalities (↓Na, ↑K), hyperpigmentation
  • Secondary: Low ACTH, low cortisol, normal electrolytes, no hyperpigmentation 5

Treatment Approaches

For Cushing's Syndrome

1. Cushing's Disease (pituitary source):

   • First-line: Transsphenoidal surgery 2
   • Second-line options:
     • Radiation therapy
     • Medical therapy: Ketoconazole (400-1200 mg/day) or mitotane 2

2. Adrenal Adenoma/Carcinoma:

   • Laparoscopic adrenalectomy for benign tumors 2
   • For malignant tumors: Surgical resection plus adjuvant therapy 2

3. Bilateral Adrenal Hyperplasia:

   • Medical management with spironolactone or eplerenone 2
   • Consider bilateral adrenalectomy in severe cases 2

4. Ectopic ACTH Syndrome:

   • Remove the source tumor if possible
   • If unresectable: Bilateral adrenalectomy or medical management 2

For Adrenal Insufficiency

1. Glucocorticoid Replacement:

   • Hydrocortisone 15-25 mg daily in divided doses (typically 2/3 in morning, 1/3 in afternoon) 5
   • Alternative: Prednisone 5-7.5 mg daily 5

2. Mineralocorticoid Replacement (for primary adrenal insufficiency):

   • Fludrocortisone 0.05-0.2 mg daily 5

3. Stress Dosing Protocol:

   • Minor illness/stress: Double or triple usual daily dose
   • Moderate stress: Hydrocortisone 50-75 mg/day in divided doses
   • Severe stress: Hydrocortisone 100 mg IV immediately, then 100-300 mg/day 5

Patient Education and Follow-up

• Patients with adrenal insufficiency need education on:

  • Recognizing adrenal crisis symptoms
  • Wearing medical alert identification
  • Carrying emergency hydrocortisone
  • Stress dose adjustments 5

• Regular monitoring:

  • Clinical assessment of symptoms
  • Weight and blood pressure
  • Electrolytes
  • Bone mineral density every 3-5 years 5

Common Pitfalls to Avoid

• Relying on a single test for diagnosis of Cushing's syndrome
• Using outdated cortisol cutoff values (>5 μg/dL) for DST interpretation
• Failing to consider cyclic Cushing's syndrome when results are equivocal
• Not measuring dexamethasone levels when DST results are unexpected
• Overlooking medication effects on test results
• Delaying treatment of adrenal insufficiency while awaiting confirmatory tests in severely ill patients

By following this structured approach, abnormal serum cortisol levels can be accurately diagnosed and appropriately managed to improve patient outcomes.