Cushing's Syndrome

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Cushing's Syndrome : 

Cushing's Syndrome

Introduction : 

Introduction The adrenal cortex produces three classes of corticosteroid hormones: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgen precursors (e.g., dehydroepiandrosterone, DHEA). Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis. Adrenal androgen precursors are converted in the gonads and peripheral target cells to sex steroids that act via nuclear androgen and estrogen receptors.

Regulatory Control of Steroidogenesis : 

Regulatory Control of Steroidogenesis Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system. Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary. Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress.

Regulation of the renin-angiotensin-aldosterone (RAA) system : 

Regulation of the renin-angiotensin-aldosterone (RAA) system

Cushing’s=hypercortisolism : 

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

Slide 7: 

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 : 

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

Central obesity and broad, purple stretch marks : 

Central obesity and broad, purple stretch marks

Thin and brittle skin in an elderly patient with Cushing's : 

Thin and brittle skin in an elderly patient with Cushing's

Hyperpigmentation of the knuckles in a patient with ectopic ACTH excess. : 

Hyperpigmentation of the knuckles in a patient with ectopic ACTH excess.

Ectopic ACTH : 

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.

Differential Diagnosis : 

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 : 

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

Screening Test : 

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 : 

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 : 

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

Confirmatory Test : 

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 : 

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 : 

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 : 

‘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 : 

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