What are the diagnostic steps and treatment options for Cushing's disease?

Diagnosis and Treatment of Cushing's Disease

The diagnostic approach for Cushing's disease requires a stepwise process including screening tests to confirm hypercortisolism, followed by tests to determine the etiology, with transsphenoidal surgery being the first-line treatment for pituitary adenomas. 1, 2

Initial Screening for Cushing's Syndrome

• First rule out exogenous glucocorticoid use as the most common cause of Cushing's syndrome 2, 3
• For intermediate to high clinical suspicion, perform 2-3 first-line screening tests 2, 3:
  • Late-night salivary cortisol (LNSC) - collect at least 2-3 samples on different days 3
  • 24-hour urinary free cortisol (UFC) - collect 2-3 samples to account for variability 1, 2
  • Overnight 1 mg dexamethasone suppression test (DST) - normal response is serum cortisol <1.8 μg/dL at 8 AM 2, 3
• For low clinical suspicion, start with LNSC as it's easier for patient compliance 2
• If any test is abnormal, repeat 1-2 screening tests to confirm diagnosis 2, 3

Determining Etiology of Cushing's Syndrome

• Measure morning plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 2, 3:

  • Normal/elevated ACTH (>5 ng/L) suggests ACTH-dependent Cushing's syndrome 3
  • Low/undetectable ACTH indicates ACTH-independent Cushing's syndrome 3

• For ACTH-dependent Cushing's syndrome:

  • Perform pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%) 2
  • For lesions ≥10 mm, Cushing's disease is presumed 1, 2
  • For lesions <6 mm or equivocal findings, proceed with bilateral inferior petrosal sinus sampling (BIPSS) 1, 2
  • BIPSS criteria: central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation 2

• For ACTH-independent Cushing's syndrome:

  • Perform adrenal CT or MRI to identify adrenal tumors 1, 2

Treatment Options for Cushing's Disease

• Transsphenoidal surgery is the first-line treatment for pituitary adenomas 2

• Medical therapy options for patients awaiting surgery or with persistent disease after surgery 2:

  • Ketoconazole or metyrapone (adrenal steroidogenesis inhibitors) 1, 2
  • Osilodrostat (achieves UFC normalization in 86% of patients) 2
  • Pasireotide (pituitary-targeted medication) 1

• For refractory cases:

  • Radiation therapy 1
  • Bilateral adrenalectomy as a last resort 4

Special Considerations

Potential Diagnostic Pitfalls

• False positives can occur in conditions such as 2, 3:

  • Severe obesity
  • Uncontrolled diabetes
  • Depression
  • Alcoholism
  • Pregnancy

• DST may be less reliable in women taking estrogen-containing oral contraceptives 3

• Measuring dexamethasone levels along with cortisol improves test interpretability 2, 3

• Consider cyclic Cushing's syndrome in cases with inconsistent results 3

Pediatric Considerations

• In children, lack of height gain with concurrent weight gain is the most common presentation 2
• Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1, 2
• Dex-CRH test is not useful in children 1

Follow-up After Treatment

• After successful treatment, adrenal function typically recovers within approximately 12 months 1
• Evaluation for growth hormone deficiency should be done 3-6 months postoperatively in children 1
• Monitor for recurrence with periodic screening tests 2

Diagnostic Algorithm

1. Clinical suspicion based on symptoms (central obesity, facial plethora, purple striae, proximal muscle weakness, hypertension, glucose intolerance) 2, 4
2. Screening tests (LNSC, UFC, DST) 2, 3
3. If positive, measure ACTH levels 2, 3
4. Based on ACTH results:
   • ACTH-dependent: Pituitary MRI → If inconclusive → BIPSS 1, 2
   • ACTH-independent: Adrenal imaging 1, 2
5. Treatment based on etiology 2