Cushing’s Syndrome

This patient had Ectopic ACTH Syndrome Non-pituitary tumor secreting either ACTH or CRH causing bilateral adrenal hyperplasia excess CRH or ACTH is indistinguishable

Cushing’s=hypercortisolism Cushing's Syndrome- Clinical effects of increased glucocorticoid hormone- all causes or excess cortisol Cushing's Disease- ACTH producing pituitary adenoma

POMC (proopiomelanocortin gene) which codes for ACTH, MSH (melanocyte stimulating hormone), Beta lipotropin, Beta endorphin, metenkephalin. POMC is induced by CRH (rarely tumors can make CRH causing Cushing's) and suppressed by glucocorticoids.

Symptoms of Excess Cortisol Truncal obesity Moon face Fat deposits supraclavicular fossa and posterior neck- buffalo hump HTN Hirsutism Amenorrhea or impotence Depression Thin skin Easy bruising Purplish abdominal striae Proximal muscle weakness Osteoporosis Diabetes Mellitus Avascular necrosis Wound healing impaired Pysch symptoms Hyperpigmentation Hypokalemic alkalosis

Ectopic ACTH All the previous symptoms but….. Ectopic dominated by : Hypokalemic alkalosis (dominant feature) Fluid retention HTN Glucose intolerance Steroid psychosis Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.

Hypokalemia Excess mineralocorticoids produced by ACTH stimulation of adrenal gland, leads to high levels of cortisol activity through aldosterone and the mineralocorticoid receptor leading to severe hypokalemia by activation of the Na/K ATPase pump on the basolateral membrane. For the rest of us that means……

Retain Na, and loose K in the cortical collecting duct

Causes of Cushing Syndrome Iatrogenic ACTH secreting pituitary microadenoma (Cushing’s disease)- 48% cases of Cushing’s syndrome 3 x more women than men 15% of pituitary tumors (usu 3rd or 4th decade of life) Adrenal tumors- 32%, usu unilateral general rule: Small- benign, mostly cortisol large- carcinoma, cortisol and androgens Ectopic ACTH secretion- ie neoplasms (10%)- most common small cell lung CA 15%- cause not identified

Ectopic ACTH SCLC >50% Thymic carcinoid 15% Islet cell tumors 10% Bronchial carcinoid 10% Other carcinoids 5% Pheochromocytomas 2%

Differential Diagnosis Alcoholism Anorexia nervosa (high urine free cortisol) Familial cortisol resistance Familial partial lipodystrophy type I HAART may mimic Cushing’s clinically but not diagnostically.

Complications of Cushing's if Untreated Diabetes HTN Osteoporotic fractures and avascular necrosis Infections Nephrolithiasis Psychosis

Screening Test Overnight dexamethasone suppression test (1 mg at 11 pm, cortisol measured at 8 am) – normal <2 micrograms/dL Or 24 hour urine free cortisol (>140 nmol/day)

Other Test That May be Useful Midnight serum cortisol >7.5 micrograms/dL (same time zone for 3 days, NPO for 3 hours) Midnight saliva cortisol >550 nanograms/dL, 93% sensitive

False Positives Severe depression Severe stress Phenytoin/phenobarbital/rifampin (accelerated metabolism of dex) Estrogen (pregnancy or OCP) Morbid obesity

Confirmatory Test Low dose dexamethasone suppression test Dexamethasone 0.5 mg q 6 x 48 hours Measure urine cortisol during the last 24 hours (urine free cortisol >20 micrograms/dL or urine 17-hydroxycorticosteroid >4.5 mg/d) Or plasma cortisol (failure to fall to <5 micrograms/dL)

Pituitary Tumor vs. Ectopic ACTH levels may distinguish: ACTH independent (adrenal or exogenous glucocorticoids) from ACTH dependent (pituitary, ectopic ACTH) ACTH independent- low or undetectable ACTH ACTH dependent-ACTH elevated In addition ectopic ACTH levels are usu 8x higher than pituitary caused ACTH secreting adenomas

Treatment Cushing’s Disease: Transphenoidal resection of pituitary adenoma Adrenal neoplasms: resection Ectopic ACTH: resection if possible Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

‘Medical’ Adrenalectomy Medications that inhibit steroidogenesis Ketoconazole (600 to 1200 mg/day) metyrapone (exacerbates female virilization) (2-3 g/day) Mitotane(2-3 G/day)- slow onset Aminoglutethinide (1g/day) Ocreotide can work in 1/3 of patients. Major side affect is adrenal insufficiency, therefore start at lowest dose and titrate

Prognosis Benign adrenal adenoma- 95% 5 year survival, 90% 10 year Cushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years. Ectopic ACTH survival depends on malignancy Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival Adrenal carcinoma- median survival 7 months