What is the appropriate diagnosis and treatment approach for a patient presenting with symptoms of Cushing's syndrome?

Diagnosis and Treatment of Cushing's Syndrome

Diagnostic Approach

Rule out exogenous glucocorticoid use first, then perform 2-3 first-line screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight 1 mg dexamethasone suppression test for patients with intermediate to high clinical suspicion. 1

Initial Screening

• Perform at least two abnormal screening tests to confirm the diagnosis, as single tests can yield false positives 1
• Late-night salivary cortisol is preferred for low clinical suspicion cases due to better patient compliance 1
• Be aware of false positives in severe obesity, uncontrolled diabetes, depression, alcoholism, and pregnancy 1
• Normal cortisol suppression on dexamethasone suppression test is defined as <1.8 μg/dL; values above this indicate abnormal feedback 2

Determining Etiology

Measure morning (08:00-09:00h) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes. 1, 2

• ACTH >5 ng/L indicates ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic source) 2
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease 1
• Low or undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal source) 2

Localization for ACTH-Dependent Disease

Perform high-quality pituitary MRI (3T preferred over 1.5T) with thin slices to detect pituitary adenomas. 1, 2

• If adenoma ≥10 mm is detected, presume Cushing's disease 1
• If no adenoma or lesion <6 mm is found, perform bilateral inferior petrosal sinus sampling (BIPSS) 1, 2
• BIPSS diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH or desmopressin stimulation 1
• BIPSS should only be performed at specialist centers with experienced interventional radiologists 2
• For suspected ectopic ACTH syndrome (very high urinary free cortisol and/or profound hypokalemia), perform neck-to-pelvis thin-slice CT scan 2

Localization for ACTH-Independent Disease

• Perform adrenal CT or MRI to identify adrenal lesion(s) 1, 2
• Adrenal imaging will distinguish between adenoma, carcinoma, or bilateral hyperplasia 2

Treatment Approach

First-Line Treatment

Transsphenoidal surgery is the treatment of choice for Cushing's disease (pituitary adenoma). 1

• Selective transsphenoidal removal induces remission in approximately 80% of patients 3
• For unilateral cortisol-secreting adrenal masses with clinically apparent Cushing's syndrome, perform unilateral adrenalectomy using minimally-invasive surgery when feasible 4
• For pheochromocytomas or aldosterone-producing adenomas, perform adrenalectomy using minimally-invasive surgery when feasible 4

Medical Therapy

Medical therapy should be used for patients awaiting surgery, with persistent disease after surgery, or when surgery is not feasible. 1

• Osilodrostat achieves urinary free cortisol normalization in 86% of patients with a median time to response of 2 months 1
• Ketoconazole normalizes UFC in 64.3% of patients (median dose 673.9 mg/day), though 15-23% of initially responsive patients lose biochemical control 4
• Metyrapone is an alternative adrenal steroidogenesis inhibitor with approximately 70% response rate 1
• All adrenal steroidogenesis inhibitors carry risk of adrenal insufficiency with overtreatment and require dose titration 4
• Ketoconazole may cause hypogonadism and gynecomastia in men, limiting prolonged treatment 4

Second-Line Treatment for Persistent Disease

Consider repeat transsphenoidal surgery if tumor is evident on MRI, especially if first surgery was not performed at a pituitary tumor center of excellence. 4

• Remission rates after reoperation range from 37-88%, with higher success at experienced centers 4
• If MRI shows no tumor, reoperation may be appropriate at high-volume centers if positive pathology or central gradient on IPSS was seen before initial operation 4
• Radiation therapy can be considered for persistent disease when medical therapy is inadequate or not tolerated, though cortisol normalization may take months to years 1
• Bilateral adrenalectomy may be considered for women desiring fertility or patients without visible residual tumors 3

Special Considerations

Mild Autonomous Cortisol Secretion (MACS)

• Younger patients with MACS who have progressive metabolic comorbidities attributable to cortisol excess can be considered for adrenalectomy after shared decision-making 4
• Patients not managed surgically should undergo annual clinical screening for new or worsening associated comorbidities 4
• No patients with failed cortisol suppression progress to overt Cushing's syndrome 4

Pediatric Patients

• Lack of height gain with concurrent weight gain is the most common presentation in children 1
• Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1

Post-Treatment Monitoring

• Adrenal function typically recovers within 12 months after successful treatment, with an 80% recovery rate 1
• Adequate glucocorticoid replacement is essential during the recovery period 3
• Long-term follow-up should include detection of relapse, treatment of osteoporosis, and management of other hormone deficiencies 3

Common Pitfalls

• Do not rely solely on dexamethasone suppression test without measuring ACTH levels, as this can lead to misdiagnosis 2
• Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 2
• Medical therapy for Cushing's disease must be stopped before BIPSS to enable accurate interpretation 2
• Hypercortisolemia must be confirmed immediately prior to BIPSS in patients with cyclical disease to ensure active disease phase 2
• Measuring dexamethasone levels along with cortisol improves dexamethasone suppression test interpretability 1, 2