What is the appropriate diagnosis and treatment plan for a patient with suspected Cushing's syndrome?

Cushing's Syndrome: Diagnosis and Treatment

Diagnostic Approach

For suspected Cushing's syndrome, first exclude exogenous glucocorticoid use, then perform 2-3 first-line screening tests simultaneously: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and overnight 1 mg dexamethasone suppression test (DST). 1, 2, 3

Initial Screening Tests

• Late-night salivary cortisol (LNSC) is the most sensitive first-line test with 95% sensitivity and 93-100% specificity; collect 2-3 samples to account for variability 4, 3

• 24-hour urinary free cortisol (UFC) has 89-95% sensitivity and 98-100% specificity; obtain 2-3 collections to evaluate fluctuations 4, 1, 3

• Overnight 1 mg dexamethasone suppression test (DST) has 95% sensitivity and 80-90% specificity; normal response is serum cortisol <1.8 μg/dL at 8 AM 1, 2, 3

• Measuring dexamethasone levels alongside cortisol improves DST interpretability and identifies false-positives due to inadequate drug absorption 4, 3

Confirming the Diagnosis

• If any screening test is abnormal, repeat 1-2 tests to confirm hypercortisolism before proceeding with further workup 1, 3

• Be aware of false-positives in severe obesity, uncontrolled diabetes, depression, alcoholism, pregnancy, and shift workers with disrupted circadian rhythm 4, 1

• For patients with inconsistent results, consider cyclic Cushing's syndrome and perform extended monitoring with multiple periodic LNSC measurements 3

Determining Etiology

ACTH-Dependent vs ACTH-Independent

• Measure morning plasma ACTH level to differentiate causes: suppressed ACTH (<5 ng/L) indicates adrenal source, while normal or elevated ACTH (>5 ng/L) indicates ACTH-dependent disease 1, 2, 3

For ACTH-Dependent Disease (Pituitary vs Ectopic)

• Perform pituitary MRI with gadolinium as the first imaging study; sensitivity is 63% and specificity is 92% for detecting pituitary adenomas 1, 2, 3

• For lesions ≥10 mm on MRI, Cushing's disease is presumed with 90% positive predictive value and transsphenoidal surgery should proceed 1, 2

• Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard when MRI is negative or shows lesions <10 mm; diagnostic criteria are central-to-peripheral ACTH ratio ≥2:1 before CRH stimulation and ≥3:1 after stimulation, with 100% sensitivity 4, 1, 3

For ACTH-Independent Disease (Adrenal)

• Obtain adrenal imaging with CT to characterize the lesion 4

• Suspect malignancy if the tumor is >5 cm, inhomogeneous with irregular margins, lipid-poor, does not wash out on contrast-enhanced CT, or shows local invasion 4

• For suspected adrenal carcinoma, obtain chest, abdomen, and pelvis imaging to evaluate for metastases 4

Treatment Strategy

Surgical Management (First-Line)

Transsphenoidal surgery is the treatment of choice for Cushing's disease (pituitary adenoma), with adrenal function typically recovering within 12 months in 80% of patients. 1, 2, 5, 6

• For benign adrenal adenomas causing ACTH-independent Cushing's, perform laparoscopic unilateral adrenalectomy 4

• For ectopic ACTH-secreting tumors, surgical resection is preferred if the tumor is resectable 4

• Postoperative corticosteroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal axis 4

Medical Therapy (Second-Line)

Medical therapy is indicated for patients awaiting surgery, with persistent disease after surgery, who are not surgical candidates, or while awaiting effects of radiotherapy 4, 7, 6

For Mild Disease

• Ketoconazole (400-1200 mg/day) is most commonly used due to easy availability and relatively tolerable toxicity, with approximately 70% response rate 4, 1

• Osilodrostat (11β-hydroxylase inhibitor) achieves UFC normalization in 86% of patients with median time to response of 2 months 4, 1, 2

• Metyrapone is an alternative steroidogenesis inhibitor with approximately 70% response rate 4, 1

• Cabergoline may be used for mild disease with slower onset but less frequent dosing; avoid in patients with bipolar disorder or impulse control disorders 4

For Severe Disease

• Rapid normalization of cortisol is the most important goal; osilodrostat and metyrapone show response within hours, ketoconazole within days 4

• Combination therapy with multiple steroidogenesis inhibitors may be necessary for very severe hypercortisolism 4

• Etomidate can be used if the patient is hospitalized and cannot take oral medications 4

• If medical therapy fails to control severe hypercortisolism, proceed to bilateral adrenalectomy to avoid worsening outcomes 4

Glucocorticoid Receptor Blocker

• Mifepristone blocks the glucocorticoid receptor and is effective regardless of etiology; 60% of patients with diabetes/glucose intolerance show ≥25% reduction in glucose AUC after 24 weeks 4

• Monitor for hypokalemia and hypertension (requiring spironolactone in some patients) and endometrial hypertrophy in women 4

• Critical caveat: Cortisol levels remain elevated with mifepristone, so only clinical features can assess for adrenal insufficiency from overtreatment, not biochemical markers 4

Radiation Therapy

• Consider radiation therapy for persistent disease after surgery when medical therapy is inadequate or not tolerated, though cortisol normalization may take months to years 1

Bilateral Adrenalectomy

• For unresectable ectopic ACTH-secreting tumors, bilateral laparoscopic adrenalectomy is recommended if medical management fails 4

• For ACTH-independent disease with symmetric bilateral cortisol production on adrenal vein sampling, bilateral adrenalectomy may be necessary 4

Special Populations

Children and Adolescents

• Lack of height gain with concurrent weight gain is the most common presentation in children with Cushing's syndrome 1

• Screen children only if weight gain is inexplicable and combined with either decreased height standard deviation score or decreased height velocity 3

• Refer all children with confirmed Cushing's syndrome to multidisciplinary centers with pediatric endocrinology expertise 1, 2, 3

• Evaluate for growth hormone deficiency 3-6 months postoperatively, as it occurs in 20% of children 2

Monitoring Treatment Response

• Use multiple serial tests of both UFC and LNSC to monitor treatment outcomes 4

• For patients on mifepristone, rely solely on clinical features rather than biochemical markers to assess treatment adequacy 4

• Monitor thyroid function closely and adjust thyroid hormone replacement as needed during medical therapy 4

• Review all concomitant medications carefully given potential drug-drug interactions, particularly with mifepristone and ketoconazole 4