How do you diagnose and treat a patient suspected of having Cushing's disease?

Diagnosis and Treatment of Cushing's Disease

Begin diagnostic workup by first ruling out exogenous glucocorticoid use (oral, inhaled, topical, or injected steroids), then perform 2-3 first-line screening tests including late-night salivary cortisol (≥2 consecutive days), 24-hour urinary free cortisol (2-3 collections), and/or overnight 1 mg dexamethasone suppression test to confirm hypercortisolism. 1, 2, 3

Initial Screening Strategy

For patients with intermediate to high clinical suspicion:

• Perform 2-3 screening tests simultaneously rather than sequentially 1, 2
• Late-night salivary cortisol has 95% sensitivity and 93-100% specificity 4
• 24-hour urinary free cortisol has 89% sensitivity and 100% specificity when averaging 2-3 collections 3, 4
• Overnight 1 mg dexamethasone suppression test is positive if morning cortisol ≥1.8 μg/dL, with 95% sensitivity and 90% specificity 3

For low clinical suspicion:

• Start with late-night salivary cortisol (≥2 tests) as it's easier for patient compliance 1, 2

Critical pitfall: Exclude pseudo-Cushing states before proceeding—severe obesity, uncontrolled diabetes, depression, alcoholism, pregnancy, PCOS, anorexia, acute illness, and excessive exercise can all cause false-positive results 1, 5. If screening tests are abnormal, repeat 1-2 tests to confirm 1, 2.

Pro tip: Measure dexamethasone levels simultaneously with morning cortisol during the suppression test to rule out false positives from malabsorption 1, 4.

Determining the Etiology

Once hypercortisolism is confirmed, measure morning plasma ACTH to differentiate causes:

ACTH-Dependent (Normal or High ACTH)

• Obtain high-quality pituitary MRI with thin slices 3, 4
• For lesions ≥10 mm: Cushing's disease is presumed; proceed directly to transsphenoidal surgery 1, 3
• For lesions 6-9 mm: Expert opinions differ—consider bilateral inferior petrosal sinus sampling (BIPSS) or proceed with CRH/DDAVP stimulation testing 1
• For lesions <6 mm or no visible adenoma: BIPSS is mandatory 1, 3

BIPSS diagnostic criteria:

• Central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 after CRH stimulation confirms pituitary source with 100% sensitivity 2, 4
• If BIPSS suggests ectopic source, perform whole-body CT to locate ectopic ACTH-secreting tumor 1

ACTH-Independent (Low ACTH)

• Obtain adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 1, 4

Treatment Approach

Transsphenoidal surgery is the first-line treatment for Cushing's disease caused by pituitary adenoma. 2, 3, 6

Surgical Outcomes

• Adrenal function typically recovers within 12 months in 80% of patients after successful surgery 2, 4
• Monitor for recurrence with 6-monthly clinical examination, 24-hour urinary free cortisol, and morning serum cortisol for at least 2 years, then annual lifelong assessment 4
• Recurrence rates range 6-40%, usually within 5 years, though late relapse can occur 4

Medical Therapy Indications

Use medical therapy for patients:

• Awaiting surgery
• With persistent disease after surgery
• Who are not surgical candidates
• Who decline surgery 2, 4

Medication options:

• Osilodrostat: Achieves urinary free cortisol normalization in 86% of patients with median response time of 2 months 2, 3
• Ketoconazole or metyrapone: Response rate approximately 70% 2, 3
• Monitor response with morning cortisol levels 1

Radiation Therapy

• Reserved for persistent disease when medical therapy is inadequate or not tolerated 2, 4
• Major limitation: Cortisol normalization may take months to years 2

Bilateral Adrenalectomy

• Last resort for ACTH-dependent Cushing's disease refractory to all other treatments 4, 6

Special Populations

Children with Cushing's disease:

• Most common presentation is lack of height gain with concurrent weight gain 2, 4
• Refer immediately to multidisciplinary centers with pediatric endocrinology expertise 1, 2, 3
• Evaluate for growth hormone deficiency 3-6 months postoperatively (20% prevalence) and provide immediate replacement if needed 3, 4
• For medical therapy in children, use ketoconazole or metyrapone; pasireotide is not recommended 1
• Obesity may not be fully reversible despite adequate treatment 1

Genetic syndromes:

• If suspected, provide genetic counseling for patient and family members and investigate for other associated disorders 1, 2

Post-Treatment Monitoring

Essential follow-up assessments:

• Screen for growth hormone deficiency (most frequent pituitary deficit after cure) 4
• Monitor for psychiatric and neurocognitive comorbidities following remission 4
• Aggressively treat hypertension (present in >80% of cases) and metabolic complications throughout treatment course 1, 4