Cushing's syndrome gk

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Cushing's syndrome gk

  1. 1. Cushings Syndrome
  2. 2. IntroductionThe adrenal cortex produces three classes ofcorticosteroid hormones: glucocorticoids(e.g., cortisol), mineralocorticoids(e.g., aldosterone), and adrenal androgenprecursors (e.g., dehydroepiandrosterone, DHEA).Glucocorticoids and mineralocorticoids act throughspecific nuclear receptors, regulating aspects ofthe physiologic stress response as well as bloodpressure and electrolyte homeostasis. Adrenalandrogen precursors are converted in the gonadsand peripheral target cells to sex steroids that actvia nuclear androgen and estrogen receptors.
  3. 3. Regulatory Control ofSteroidogenesisProduction of glucocorticoids and adrenalandrogens is under the control of thehypothalamic-pituitary-adrenal (HPA)axis, whereas mineralocorticoids are regulated bythe renin-angiotensin-aldosterone (RAA) system.Glucocorticoid synthesis is under inhibitoryfeedback control by the hypothalamus and thepituitary. Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response toendogenous or exogenous stress.
  4. 4. Regulation of the renin-angiotensin-aldosterone (RAA) system
  5. 5. Cushing’s=hypercortisolism Cushings Syndrome- Clinical effects ofincreased glucocorticoid hormone- allcauses or excess cortisol Cushings Disease- ACTH producingpituitary adenoma
  6. 6.  POMC (proopiomelanocortin gene) whichcodes for ACTH, MSH (melanocytestimulating hormone), Betalipotropin, Beta endorphin, metenkephalin. POMC is induced by CRH (rarely tumorscan make CRH causing Cushings) andsuppressed by glucocorticoids.
  7. 7. Symptoms of Excess Cortisol Truncal obesity Moon face Fat deposits supraclavicular fossaand 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
  8. 8. Central obesity andbroad, purple stretch marks
  9. 9. Thin and brittle skin in anelderly patient with Cushings
  10. 10. Hyperpigmentation of the knuckles in apatient with ectopic ACTH excess.
  11. 11. Ectopic ACTHAll 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 bymore sudden onset by acquired ACTH fromtumor.
  12. 12. Differential Diagnosis Alcoholism Anorexia nervosa (high urine free cortisol) Familial cortisol resistance Familial partial lipodystrophy type I HAART may mimic Cushing’s clinically butnot diagnostically.
  13. 13. Complications of Cushings ifUntreated Diabetes HTN Osteoporotic fractures and avascularnecrosis Infections Nephrolithiasis Psychosis
  14. 14. Screening Test Overnight dexamethasone suppressiontest (1 mg at 11 pm, cortisol measured at8 am) – normal <2 micrograms/dLOr 24 hour urine free cortisol (>140nmol/day)
  15. 15. Other Test That May be Useful Midnight serum cortisol >7.5micrograms/dL (same time zone for 3days, NPO for 3 hours) Midnight saliva cortisol >550nanograms/dL, 93% sensitive
  16. 16. False Positives Severe depression Severe stress Phenytoin/phenobarbital/rifampin(accelerated metabolism of dex) Estrogen (pregnancy or OCP) Morbid obesity
  17. 17. Confirmatory TestLow 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 urine17-hydroxycorticosteroid >4.5 mg/d)Or plasma cortisol (failure to fall to <5micrograms/dL)
  18. 18. Pituitary Tumor vs. EctopicACTH levels may distinguish: ACTH independent (adrenal or exogenousglucocorticoids)from ACTH dependent (pituitary, ectopic ACTH) ACTH independent- low or undetectable ACTH ACTH dependent-ACTH elevated In addition ectopic ACTH levels are usu 8xhigher than pituitary caused ACTH secretingadenomas
  19. 19. Treatment Cushing’s Disease: Transphenoidalresection of pituitary adenoma Adrenal neoplasms: resection Ectopic ACTH: resection if possible Bilateral adrenal hyperplasia: may needadrenalectomies (lifelong glucocorticoidand mineralcorticoid replacement)
  20. 20. ‘Medical’ AdrenalectomyMedications 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, thereforestart at lowest dose and titrate
  21. 21. Prognosis Benign adrenal adenoma- 95% 5 yearsurvival, 90% 10 year Cushing’s disease (pituitary adenoma) samesurvival, but 10-20% transphenoidal resectionfailure rate over 10 years. Ectopic ACTH survival depends on malignancy Unknown cause of elevated ACTH- 65% 5 yearsurvival, 55% 10 year survival Adrenal carcinoma- median survival 7 months

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