Snapshot A 37-year-old woman with uveitis on prednisone (20 mg daily) presents to her primary care provider due to weight gain. Since establishing her treatment for uveitis, she reports significant improvement in her vision with the resolution of the flare. However, over the couple of months, she has also noticed menstrual irregularities, abnormal hair growth on her face, and skin changes. She reports eating a well-balanced diet and although she has been trying to engage in an exercise program, she has been feeling very weak and unable to do so. Introduction Clinical definition hypercortisolism chronic exogenous glucocorticoids use for an array of inflammatory, allergic, and malignant conditions Epidemiology Most common cause of Cushing syndrome is iatrogenic Etiology Pathogenesis hypercortisolism secondary to chronic exogenous glucocorticoid use by any route, most commonly prednisone prednisolone methylprednisone fluticasone suppression of the hypothalamic-pituitary-adrenal (HPA) axis Presentation Symptoms polyuria polydipsia oligomenorrhea decreased libido depression weight gain Physical exam hypertension lipodystrophy central obesity, moon facies, and buffalo hump facial plethora acne ecchymoses, purpura, telangiectasias, and purple striae muscle wasting and weakness hirsutism Studies Diagnostic testing diagnostic approach medication review to determine the amount and duration of glucocorticoid use initial screening tests are very sensitive and rule out Cushing syndrome if normal does not determine etiology determine if exogenous glucocorticoids are the etiology with adrenocorticotropic hormone (ACTH) level and follow up imaging studies overnight low-dose dexamethasone suppression test initial screening very sensitive 24-hour urinary free cortisol initial screening very sensitive ACTH-level measure morning level determines if Cushing syndrome is ACTH-dependent or -independent imaging adrenal computed tomography (CT) scan or magnetic resonance imaging (MRI) evaluate for adrenal tumor as possible etiology of low ACTH Cushing syndrome Diagnostic criteria must be taking glucocorticoids overnight low-dose dexamethasone suppression test if serum cortisol is < 5 ug/dL, Cushing syndrome can be excluded if serum cortisol is > 5 ug/dL, Cushing syndrome is diagnosed 24-hour urinary free cortisol greater than 4x the normal value is consistent with the diagnosis ACTH level low serum ACTH (< 5 pg/mL) is consistent with iatrogenic Cushing and adrenal Cushing high serum ACTH (< 5 pg/mL) is consistent with pituitary or ectopic etiologies adrenal imaging will rule out or rule in an adrenal cause of low ACTH Cushing Differential Pseudo-Cushing syndrome distinguishing factor hypercortisolemia is secondary to other factors and when resolved, Cushingoid features resolve as well Cushing disease distinguishing factors no exogenous glucocorticoid use pituitary source with high serum ACTH and positive pituitary imaging findings Non-iatrogenic Cushing syndrome distinguishing factors low ACTH adrenal etiology positive adrenal imaging findings high ACTH ectopic etiology positive chest or abdominal imaging findings Treatment Management approach minimize the use of exogenous glucocorticoids taper slowly due to chronic HPA suppression and risk of adrenal crisis transition to steroid-sparing anti-inflammatory or immunosuppressant depending on the underlying illness during an acute illness, a higher dose of glucocorticoids ("stress dose") may be temporarily given due to the patient’s inability to produce endogenous glucocorticoids secondary to chronic HPA suppression Complications Opportunistic fungal infections Perforated viscera Adrenal crisis Osteoporosis