Cushing Syndrome: Diagnostic Algorithm and Dexamethasone

Cushing syndrome results from prolonged exposure to supraphysiologic levels of cortisol from any source. The diagnostic evaluation follows a systematic algorithm: (1) SCREENING — at least two positive screening tests are required to confirm hypercortisolism: 24-hour urine free cortisol (UFC >3x upper limit of normal is virtually diagnostic), late-night salivary cortisol (elevated >2 occasions; exploits the loss of normal diurnal cortisol nadir), and 1-mg overnight dexamethasone suppression test (DST — normal suppression: 8 AM cortisol <1.8 mcg/dL; failure to suppress indicates autonomous cortisol production). (2) LOCALIZATION — once hypercortisolism is confirmed: measure plasma ACTH. ACTH-dependent (ACTH >15 pg/mL): pituitary adenoma (Cushing disease — 70%), ectopic ACTH (lung carcinoid, SCLC — 15%). ACTH-independent (ACTH <5 pg/mL): adrenal adenoma, adrenal carcinoma, bilateral adrenal hyperplasia. (3) DIFFERENTIATION of ACTH-dependent sources: high-dose DST (8 mg overnight or 2-day test — pituitary adenomas suppress cortisol by >50%; ectopic sources do not), CRH stimulation test (pituitary adenomas respond with ACTH increase; ectopic sources do not), pituitary MRI (microadenoma in 50-60% of Cushing disease), and inferior petrosal sinus sampling (IPSS — gold standard for confirming pituitary source...