Snapshot A 61-year-old obese man with well-controlled hypertension on a diuretic, hyperlipidemia, diabetes and current smoker (35 pack-year history) presents to his primary care physician for fatigue. He also notes that he has been having increasing cough, shortness of breath, and poor appetite. On evaluation, he is found to be hypertensive reaching 190/110 mmHg and noted to have facial flushing, purple abdominal striae, and a buffalo hump. Introduction Clinical definition a condition that refers to the manifestations of chronic hypercortisolism 2 broad categories exogenous iatrogenic exogenous glucocorticoid administration (reviewed separately) endogenous pituitary adrenocorticotropic hormone (ACTH) overproduction (Cushing disease) adrenal glucocorticoid overproduction ectopic ACTH overproduction Associated conditions multiple endocrine neoplasia type 1 (ACTH-secreting pituitary adenoma, though most are prolactin-secreting adenomas) Epidemiology Demographics 5:1 female-to-male ratio for adrenal or pituitary source peak age 25-50 years of age male predominance for ectopic source secondary to lung cancer peak age 70-80 years of age Etiology ACTH-dependent (ACTH is elevated) etiologies pituitary overproduction: ACTH-secreting tumor (usually an adenoma) ectopic production: ACTH-secreting malignancy of a neuroendocrine origin such as small-cell lung cancer ACTH-independent (ACTH is normal or low) cortisol overproduction --> negative feedback --> lowers ACTH --> atrophy of normal adrenal tissue etiologies exogenous intake (usually patients prescribed systemic glucocorticoids for inflammatory conditions) most common cause of Cushing's syndrome may cause bilateral adrenal atrophy adrenal overproduction (by adrenal adenoma, carcinoma or nodular hyperplasia) may cause atrophy of the contralateral adrenal gland (imaging may show one adrenal gland enlarged by a tumor and one atrophied adrenal gland) Presentation Symptoms depression and psychological changes oligomenorrhea decreased libido proximal muscle weakness acne excessive hair growth symptoms of diabetes (polydipsia and polyuria) weight gain Physical exam hypertension central obesity muscle wasting thin skin that easily bruises purple striae hirsutism moon facies buffalo hump hyperpigmentation if high ACTH imaging Adrenal computed tomography (CT) scan or magnetic resonance imaging (MRI) evaluate for adrenal tumor as possible etiology of low ACTH Cushing syndrome Chest and/or abdominal CT evaluate for ectopic ACTH-producing tumor Studies Diagnostic testing diagnostic approach medication review to rule out exogenous etiology initial screening tests are very sensitive if normal, rules out the diagnosis if abnormal, does not determine etiology of Cushing to determine etiology, follow up with ACTH level, high-dose dexamethasone suppression, corticotropin-releasing hormone (CRH) stimulation, and imaging ancillary lab studies to evaluate for associated imbalances studies overnight low-dose dexamethasone suppression test initial screening very sensitive cortisol (initial screening) 24-hour urinary free cortisol (more sensitive, but logistically difficult to collect) serum morning cortisol level (more convenient) serum morning ACTH-level high-dose dexamethasone suppression test performed after the diagnosis of Cushing syndrome is made, to distinguish between pituitary (Cushing disease) and non-pituitary causes determines if pituitary or ectopic corticotropin-releasing hormone (CRH) stimulation test determines if pituitary or ectopic ancillary chemistry panel associated metabolic alkalosis, hypokalemia, and hyperglycemia lipid panel associated hyperlipidemia complete blood count associated leukocytosis chemistries hypokalemia and metabolic alkalosis from mineralocorticoid activity Differential Pseudo-Cushing syndrome distinguishing factor hypercortisolemia is secondary to other factors and when resolved, Cushingoid features resolve as well examples include obesity, polycystic ovarian syndrome, diabetes, and chronic alcoholism DIAGNOSIS Diagnostic criteria overnight low-dose dexamethasone suppression test if serum cortisol is < 5 ug/dL, Cushing can be excluded if serum cortisol is > 5 ug/dL, Cushing is diagnosed 24-hour urinary free cortisol greater than 3x the normal value is consistent with diagnosis ACTH level ↓ serum ACTH ( < 5 pg/mL) is consistent with iatrogenic Cushing and adrenal Cushing ↑ serum ACTH (< 5 pg/mL) is consistent with pituitary or ectopic Cushing high-dose dexamethasone suppression test > 50% suppression is consistent with pituitary Cushing disease < 50% suppression is consistent with ectopic Cushing corticotropin-releasing hormone (CRH) stimulation test ↑ ACTH and cortisol is consistent with pituitary Cushing disease no response is consistent with ectopic Cushing imaging identified adrenal, chest, or abdominal neoplasm Treatment Management approach resectable lesions localize lesion with subsequent resection may require temporary postoperative glucocorticoid replacement for HPA axis suppression from chronic hypercortisolemia nonresectable lesions ketoconazole and metyrapone blocks cortisol production mifepristone blocks the cortisol receptor pasireotide or cabergoline somatostatin analog Pituitary Cushing transsphenoidal adenomectomy of the pituitary may require replacement of other lost functions Adrenal Cushing adrenalectomy if bilateral, requires lifelong glucocorticoid and mineralocorticoid replacement Ectopic Cushing treat the underlying neuroendocrine tumor, may consist of surgical resection, chemotherapy, radiation, and other targeted therapies Hypertension eplerenone and spironolactone (potassium sparing diuretics) Complications Panhypopituitarism, if large pituitary adenoma Adrenal insufficiency, if bilateral adenectomy is performed Nelson syndrome, if bilateral adenectomy is performed Death, if a malignant lesion