What is the recommended diagnostic workup and treatment plan for a patient presenting with signs of Cushing syndrome?

Cushing Syndrome: Diagnostic Workup and Treatment

Surgical resection of the cortisol-producing tumor is the definitive first-line treatment for all forms of Cushing syndrome, with transsphenoidal surgery for pituitary adenomas, laparoscopic adrenalectomy for adrenal adenomas, and surgical removal of ectopic ACTH-secreting tumors when localized. 1, 2

Initial Screening and Diagnosis

When to Screen

Screen patients presenting with:

• Facial plethora, easy bruising, purple striae, and central fat redistribution (buffalo hump, moon facies, visceral obesity) 3, 4
• Hypertension (present in >80% of cases), hyperglycemia, and proximal muscle weakness 1, 5
• Weight gain with concurrent lack of height gain in children 1
• Unexplained osteoporosis or vertebral fractures in younger patients 5

First-Line Screening Tests

Perform 2-3 of the following screening tests to confirm hypercortisolism: 1

• Late-night salivary cortisol (sensitivity 95%, specificity 93-100%) - requires ≥2 samples on consecutive days 1, 2
• 24-hour urinary free cortisol (sensitivity 89%, specificity 100%) - requires 2-3 collections 1, 2
• Overnight 1 mg dexamethasone suppression test with normal suppression cutoff <1.8 μg/dL (50 nmol/L); measure dexamethasone levels simultaneously to rule out false positives from malabsorption 1

Critical pitfall: First exclude exogenous corticosteroid use (oral, inhaled, topical, nasal drops) before proceeding with endogenous Cushing syndrome workup. 4, 6

Determining the Etiology

Step 1: Measure Morning Plasma ACTH

• ACTH >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1
• ACTH suppressed (<5 ng/L) indicates ACTH-independent Cushing syndrome (adrenal source) 1, 4

Step 2A: ACTH-Dependent Workup (Pituitary vs. Ectopic)

• Obtain high-quality pituitary MRI with thin slices to detect pituitary adenoma 1
• If MRI is negative or equivocal, perform bilateral inferior petrosal sinus sampling (BIPSS) - this is the gold standard for differentiating Cushing disease from ectopic ACTH syndrome 1, 7

Step 2B: ACTH-Independent Workup (Adrenal Source)

• Obtain adrenal CT or MRI to identify adrenal lesions 1
• Distinguish between adrenal adenoma, adrenal carcinoma, or bilateral hyperplasia 1

Treatment Algorithm

Primary Treatment: Surgery

Surgical approach based on etiology: 1, 2

• Pituitary Cushing disease: Transsphenoidal surgery by expert neurosurgeon 1, 7
• Adrenal adenoma: Laparoscopic unilateral adrenalectomy 1, 2
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 1
• Ectopic ACTH tumor: Surgical resection when localized 5, 7
• Bilateral adrenal hyperplasia: Unilateral or bilateral adrenalectomy depending on severity 1

Mandatory post-operative management: Corticosteroid supplementation is required after adrenalectomy until hypothalamus-pituitary-adrenal axis recovery 5

Medical Therapy Indications

Medical therapy is indicated for patients: 1, 2

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

First-line medical agents: 2

• Osilodrostat: 2-7 mg twice daily orally (86% achieve urinary free cortisol normalization) 2
• Ketoconazole: 400-1200 mg/day divided twice daily (65% achieve normalization) 2
• Metyrapone: 500 mg/day to 6 g/day (70% achieve normalization) 2

Hypertension Management

Hypertension requires specific pharmacologic targeting due to excess cortisol overwhelming protective enzymes: 5

• Use mineralocorticoid receptor antagonists (spironolactone or eplerenone) as first-line therapy 5, 2
• Combine with adequate diuretic therapy given the prominent role of sodium retention 5
• This aggressive approach is warranted given 70-90% prevalence of hypertension and high cardiovascular disease risk 5

Third-Line Options for Refractory Disease

When surgery and medical therapy fail or are inadequate: 1

• Radiation therapy (particularly for pituitary disease) 1, 7
• Bilateral adrenalectomy as definitive treatment 1, 7

Post-Treatment Monitoring

Short-Term Follow-Up (First 2 Years)

All patients in remission require: 1

• 6-monthly clinical examination
• 24-hour urinary free cortisol
• Electrolytes and morning serum cortisol
• Recurrence rates vary 6-40%, usually within 5 years (though late relapse can occur) 1

Long-Term Follow-Up

• Lifelong annual clinical assessment 1
• Monitor for psychiatric and neurocognitive comorbidities following remission 1
• Screen for GH deficiency - the most frequent pituitary deficit after surgical or radiotherapeutic cure 1

Special Populations

Mild Autonomous Cortisol Secretion (MACS)

• Younger patients with MACS and progressive metabolic comorbidities can be considered for adrenalectomy after shared decision-making 5, 2
• MACS is associated with type 2 diabetes, hypertension, cardiovascular events, vertebral fractures, and mortality 5
• Patients not managed surgically require annual screening for new or worsening metabolic comorbidities 5, 2
• Important note: No patients with MACS progress to overt Cushing syndrome 5, 2

Pediatric Patients

Refer children to multidisciplinary centers with pediatric endocrinology expertise given the complexity of diagnosis and management 1

Critical Pitfalls to Avoid

• Never abruptly discontinue glucocorticoids - this can precipitate life-threatening adrenal crisis 2
• Do not rely on single screening test - perform 2-3 tests to confirm hypercortisolism 1
• Measure dexamethasone levels during suppression testing to avoid false positives from malabsorption 1
• Recognize that clinical reversibility after treatment is incomplete for some manifestations despite spectacular initial improvement 7