What is the appropriate diagnosis and treatment for a patient with Cushing syndrome?

Diagnosis and Treatment of Cushing Syndrome

Initial Diagnostic Approach

For suspected Cushing syndrome, begin screening with 24-hour urinary free cortisol (UFC) collection (≥2 tests), late-night salivary cortisol (≥2 consecutive days), or overnight 1 mg dexamethasone suppression test (DST), with the choice depending on patient compliance and clinical context. 1

Screening Tests

• 24-hour UFC: Collect 2-3 samples; elevated levels indicate hypercortisolism 1, 2
• Late-night salivary cortisol (LNSC): Obtain ≥2 samples on consecutive days; loss of circadian rhythm suggests Cushing syndrome 1, 3
• Overnight 1 mg DST: Cortisol >1.8 μg/dL (50 nmol/L) the morning after 11 PM dexamethasone administration indicates abnormal suppression 1, 4
• Measuring dexamethasone levels alongside cortisol improves test interpretability and rules out malabsorption 1

Critical Exclusions Before Diagnosis

First, rule out exogenous glucocorticoid use from all sources including oral medications, injections, inhaled corticosteroids, and topical preparations. 5, 2

• Exclude pseudo-Cushing states: severe obesity, uncontrolled diabetes, alcoholism, depression, polycystic ovary syndrome 1, 4
• Consider cyclic Cushing syndrome if initial tests are inconsistent; periodic re-evaluation may be necessary 1, 6

Determining Etiology: ACTH-Dependent vs ACTH-Independent

Once hypercortisolism is confirmed, measure morning (08:00-09:00h) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes. 4

ACTH Level Interpretation

• ACTH >5 ng/L (>1.1 pmol/L): Indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 4
• ACTH >29 ng/L (6.4 pmol/L): 70% sensitivity and 100% specificity for Cushing disease 1, 4
• ACTH low or undetectable (<5 ng/L): Indicates ACTH-independent Cushing syndrome (adrenal source) 4, 7

Diagnostic Algorithm for ACTH-Dependent Cushing Syndrome

Pituitary MRI Evaluation

Perform high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to identify pituitary adenomas. 4

• Adenoma ≥10 mm: Proceed directly to transsphenoidal surgery without additional testing 1
• Adenoma 6-9 mm: Consider CRH stimulation test or bilateral inferior petrosal sinus sampling (BIPSS) 1
• No adenoma or <6 mm lesion: BIPSS is mandatory to distinguish pituitary from ectopic ACTH sources 1, 4

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for differentiating Cushing disease from ectopic ACTH syndrome when MRI is inconclusive or shows lesions <6 mm. 1, 4

• Diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 1, 4
• Sensitivity: 96-100%; specificity approaches 100% when performed correctly 4
• Must be performed at specialized centers by experienced interventional radiologists 1, 4
• Measure prolactin simultaneously to confirm adequate venous sampling 1, 4
• Critical: Confirm active hypercortisolism immediately before BIPSS in cyclic Cushing disease; stop medical therapy beforehand 4

Additional Testing for Ectopic ACTH Syndrome

• If suspicion is high (very high UFC, profound hypokalemia, male patient), obtain neck-to-pelvis thin-slice CT scan 1
• Consider 68Ga-DOTATATE PET imaging for localizing occult neuroendocrine tumors 4

Diagnostic Algorithm for ACTH-Independent Cushing Syndrome

Perform adrenal CT or MRI to identify adrenal lesion(s) causing autonomous cortisol production. 1, 4

• Unilateral adenoma: Proceed to laparoscopic adrenalectomy 1, 4
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 4
• Bilateral hyperplasia: Consider medical management or unilateral adrenalectomy 4

First-Line Treatment: Surgical Management

Cushing Disease (Pituitary Source)

Transsphenoidal surgery for selective removal of the corticotroph adenoma is the first-line treatment, achieving remission in approximately 80% of patients. 7, 2

• Long-term relapse occurs in up to 30% of cases 7
• Repeat surgery can be successful when residual tumor is visible on MRI but carries high risk of hypopituitarism 7
• Bilateral adrenalectomy remains an option for life-threatening situations or when surgery is not possible, though Nelson syndrome (continued pituitary tumor growth) is more frequent in children than adults 1, 7

Adrenal Cushing Syndrome

Surgical resection is first-line therapy: laparoscopic adrenalectomy for adenomas, open adrenalectomy for carcinomas. 2, 3

Ectopic ACTH Syndrome

Surgical removal of the ectopic ACTH-secreting tumor when possible. 7, 3

Medical Management

Indications for Medical Therapy

Medical therapy is indicated for:

• Preparation for surgery to rapidly control hypercortisolism 7, 8
• After unsuccessful tumor removal 7, 8
• While awaiting full effect of radiotherapy 7, 8
• When surgery is not possible or contraindicated 1, 2

Steroidogenesis Inhibitors (Adrenal-Targeted)

Ketoconazole 400-1200 mg/day (divided BID) achieves approximately 65% UFC normalization initially, though 15-25% experience escape. 1

• EMA approved for endogenous Cushing syndrome; off-label use in US 1
• Requires gastric acid for absorption (avoid proton pump inhibitors) 1
• Monitor liver function tests regularly due to hepatotoxicity risk 1
• Risk of QTc prolongation; review drug-drug interactions carefully 1

Osilodrostat 2-7 mg BID (maximum 30 mg BID) achieved 86% UFC normalization in Phase 3 trials. 1

• FDA approved for Cushing disease when surgery is not an option or has failed 1
• Adverse effects: increased androgenic and mineralocorticoid precursors (hirsutism, hypertension, hypokalemia), GI disturbances, adrenal insufficiency 1

Metyrapone inhibits 11-beta-hydroxylation in the adrenal cortex, reducing cortisol and corticosterone production 9, 7, 8

• Mean terminal elimination half-life: 1.9 hours; active metabolite metyrapol: 4 hours 9
• Often used in combination with other agents 7, 8

Mitotane is reserved for adrenal carcinoma or severe cases 7, 8

Glucocorticoid Receptor Antagonist

Mifepristone blocks glucocorticoid receptors and can be considered for severe hypercortisolism, though cortisol levels remain elevated and only clinical features assess treatment response 5, 8

Management of Complications

Thromboembolism Prevention

Provide thromboprophylaxis perioperatively and extend to 30 days post-surgery, as VTE risk is >10-fold higher than in patients with nonfunctioning adenomas. 1

• VTE risk persists for months after surgery despite cortisol normalization 1
• Risk after bilateral adrenalectomy: 3.4-4.75% at 30 days 1

Cardiovascular and Metabolic Management

• Hypertension: Use mineralocorticoid receptor antagonists (spironolactone 25-50 mg daily or eplerenone 50-100 mg daily) as first-line therapy 5
• Hyperglycemia: Initiate metformin as first-line; consider GLP-1 receptor agonists or DPP-4 inhibitors 5
• Monitor blood glucose closely during cortisol normalization as insulin requirements decrease 5

Bone Health

Prescribe calcium 1000-1500 mg daily and vitamin D 800-1000 IU daily immediately; initiate bisphosphonate therapy based on bone mineral density and risk factors. 5

Post-Treatment Follow-Up

Pediatric Considerations

Evaluate for growth hormone deficiency with dynamic testing soon after definitive therapy in children who have not completed linear growth. 1

• Initiate GH replacement promptly if deficient or if catch-up growth fails 1
• Consider BMD assessment prior to adult transition in high-risk patients 1
• Monitor pubertal progression to identify hypogonadotropic hypogonadism 1

Surveillance for Recurrence

Perform 6-monthly clinical examination, 24-hour UFC, electrolytes, and morning serum cortisol for at least 2 years, followed by lifelong annual clinical assessment. 1

• GH deficiency is the most common pituitary deficit after surgery or radiotherapy 1
• Additional anterior pituitary deficiencies can develop after radiotherapy, typically occurring in combination 1

Adrenal Insufficiency Management

Monitor for adrenal insufficiency features (fatigue, weakness, nausea, hypotension, hypoglycemia) during cortisol normalization. 5

• Measure morning cortisol once daily dose reaches physiologic range (≤5 mg prednisone equivalent) to assess HPA axis recovery 5
• Continue stress-dose coverage until recovery confirmed, which may take up to 12 months 5

Second-Line Therapies

When surgery fails or is not curative, options include repeat surgery (if residual tumor visible), bilateral adrenalectomy, pituitary radiation with medical therapy, or radiosurgery. 7, 3

• Radiotherapy combined with ketoconazole or radiosurgery shows effectiveness but requires long-term evaluation for hypopituitarism 7
• Bilateral adrenalectomy may be preferred in women desiring fertility without visible residual tumors 7
• Current studies do not support prophylactic radiotherapy after bilateral adrenalectomy to prevent Nelson syndrome, but initiate surgery and radiotherapy as soon as residual tumor progresses 7