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Cushing’s Syndrome

Cushing’s Syndrome. Armed Forces Academy of Medical Sciences. Outline. Define Cushing’s Disease and Syndrome Review normal cortisol regulation Discuss the clinical manifestations of Cushing’s How to diagnose Cushing’s Syndrome Treatment options for Cushing’s Syndrome.

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Cushing’s Syndrome

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  1. Cushing’s Syndrome Armed Forces Academy of Medical Sciences

  2. Outline • Define Cushing’s Disease and Syndrome • Review normal cortisol regulation • Discuss the clinical manifestations of Cushing’s • How to diagnose Cushing’s Syndrome • Treatment options for Cushing’s Syndrome

  3. Normal Cortisol Synthesis and Regulation • Hypothalmus secretes Corticotropin Releasing Hormone (CRH) in response to • Low Serum Cortisol • Low Blood Sugar • Stress • CRH stimulates anterior pituitary to release Corticotropin (ACTH) • ACTH stimulates adrenal gland to produce cortisol

  4. ACTH Secretion • ACTH secretion is pulsatile • Pulse frequency remains constant throughout the day • Amplitude of each pulse varies in circadian fashion • Highest at time of awakening • Lowest in late evening and very early morning hours • Variation makes measuring ACTH to diagnose Cushing’s syndrome or disease inaccurate

  5. Cortisol Metabolism • Cortisol secretion reflects ACTH secretion and is therefore also pulsatile • Cortisol exists in two forms • Free cortisol in serum • Bound to corticosteroid-binding globulin (majority) • Free cortisol • Enters tissue for action and metabolism • Filtered into urine or saliva for excretion

  6. Normal Cortisol Synthesis and Regulation • Cortisol provides negative feedback inhibition at multiple levels • Anterior Pituitary • Hypothalmus

  7. Definitions • Cushing’s Syndrome: chronic exposure to excessive levels of glucocorticoids • Cushing’s Disease: specifically refers to pituitary hypersecretion of ACTH leading to Cushing’s syndrome • Dr. Harvey Cushing • Neurosurgeon

  8. Cushing’s Syndrome Etiology ACTH-dependent ACTH-independent Exogenous administration of glucocorticoids Probably the most common Adrenocortical adenomas and carcinomas 18-20% Bilateral adrenal micronodular hyperplasia 1% • Pituitary hypersecretion (Cushing’s Disease) • 65-70% • Ectopic secretion of ACTH by non-pituitary tumors • 10-15% • Ectopic secretion of CRH by nonhypothalamic tumor • 1%

  9. Cushing’s Syndrome Epidemiology • Relatively even distribution between men and women • Men more common ACTH secreting lung tumors • Women more commonly have Cushing’s Disease • Age at presentation varies depending on etiology • Ectopic ACTH secretion: Age > 50 • Cushing’s Disease: 25-45 years old • Adrenal Tumors: 40-50 years old

  10. Clinical Manifestations of Cushing’s Syndrome • Centripetal obesity • Facial plethora • Glucose intolerance • Proximal muscle weakness • Hypertension • Abdominal striae • Hirsutism www.uptodate.com

  11. Symptoms of Cushing’s Syndrome: Progressive Obesity • Most common feature • Involves face, neck, abdomen • Moon Facies (cheeks) • Buffalo Hump (dorsocervical fat pad) • Spares extremities • Children with Cushing’s syndrome have generalized obesity • Degree of fat accumulation variable Moon Facies Buffalo Hump

  12. Symptoms of Cushing’s Syndrome: Skin Manifestations • Rarely seen in other clinical scenarios • Can be very specific for Cushing’s Syndrome • Skin atrophy • Easy bruisability • Striae • Frequent fungal infections • Hyperpigmentation • Caused by increased ACTH not cortisol www.uptodate.com

  13. Symptoms of Cushing’s Syndrome: Neuropsychological Effects • 50% of all cases of Cushing’s Syndrome • Most common symptoms • Emotional liability • Agitated depression • Irritability • Anxiety and Paranoia • After correction of hypercortisolism, resolution of psychiatric symptoms is variable

  14. Diagnosis of Cushing’s Syndrome • Possible presence of Cushing’s syndrome suggested by clinical signs and symptoms • No symptom pathognomonic • All non-specific • Diagnosis must be confirmed by biochemical tests • Many causes of Cushing’s syndrome, pulsatile nature of ACTH and cortisol secretion make biochemical testing complex • No test with ideal sensitivity or specificity

  15. Diagnosis of Cushing’s Syndrome • History must exclude exogenous glucocorticoid intake • Ingestion of prednisone (oral, injected, topical or inhaled formulations) • Exclude physiologic hypercortisolism • States where elevated cortisol is NOT Cushing's • Physically stressed (infection) • Severe obesity • Psychologically stressed • Chronic Alcoholism

  16. Diagnostic Strategy • First line tests • Late night salivary cortisol (done at least twice) • Urinary cortisol (at least 3x normal) • Dexamethasone suppression test • Need 2/3 tests to be positive to establish diagnosis of Cushing’s Syndrome • Further testing indicated for patients with slightly abnormal or discordant results 2008 Endocrine Society Clinical Guidelines

  17. Urinary Cortisol • Should be first screening test • 24-hour urine collection • Measures serum free cortisol concentration • Physiologic elevations of cortisol are always < 3x ULN • Re-evaluated several weeks later • Subjected to another screening test

  18. Low Dose Dexamethasone Suppression Test • Exogenous dexamethasone substitutes for endogenous cortisol  suppressing ACTH • In normal subjects dexamethasone should suppress pituitary secretion of ACTH and cortisol secretion by adrenal glands • Low salivary and urinary cortisol • Cortisol assays do not measure dexamethasone • Two types of low dose suppression tests • 1 mg overnight • 2 mg two day test

  19. Low Dose Dexamethasone Suppression Test • Overnight 1 mg test • Administration of 1 mg dexamethasone at 11 pm • Measure serum cortisol at 0800 next morning • Normal value < 1.8 mcg/dL • Two-day 2 mg test • 0.5 mg dexamethasone every six hours for 8 doses • Measure serum cortisol at 2 and 6 hours after LAST dexamethasone dose • Normal value < 1.8 mcg/dL

  20. Low Dose vs. High Dose Dexamethasone Suppression • Low dose • Utilized to establish diagnosis of Cushing’s Syndrome • High Dose • Utilized to differentiate Cushing’s Disease from patients with ectopic ACTH syndrome

  21. Late Evening Salivary Cortisol • Morning serum or salivary cortisol concentrations have no diagnostic value • Normal evening cortisol nadir preserved in obese and depressed patients • Nadir not present in patients with Cushing’s • Benefits • Easy: can be done at home • Non-invasive • Cortisol stable in saliva for days permitting testing days after collection • Normal ranges vary depending on commercial assay

  22. Late Evening Serum Cortisol • Normal evening nadir of serum cortisol in obese and depressed patients, but not in patients with Cushing’s Syndrome • Midnight blood draw • Normal valve < 2 mcg/dL • Very high sensitivity, marginal specificity • Intermediate values rechecked weeks later

  23. Cushing’s Disease • Pituitary adenoma • 95% microadenoma, not visible on MRI • ACTH secretion • Remains pulsatile • Amplitude and duration of pulse increased • Frequency of pulses not altered • Lose normal circadian rhythm • Results in bilateral adrenocortical hyperplasia • Hypersecretion of cortisol • Increased cortisol secretion reflected by increased urinary excretion of cortisol

  24. Ectopic ACTH Syndrome • Non-pituitary tumor secretion of ACTH results in bilateral adrenocortical hyperplasia • Hypersecretion of cortisol • Suppresses pituitary ACTH release • Tumor secretion of ACTH not suppressed • Salivary cortisol concentrations accurately reflect serum free cortisol levels • Tumors of lung, pancreas, and thymus frequently secretion ACTH

  25. Ectopic CRH Syndrome • Tumor secreting CRH • Very rare • Results in hyperplasia and hypersecretion of pituitary corticotrophs • Increased ACTH secretion • Cortisol hypersecretion • Bilateral adrenal Hyperplasia

  26. Iatrogenic of Factitious Cushing’s Syndrome • Administration of excessive amounts of synthetic glucocorticoid • Inhibit CRH and ACTH secretion • Bilateral adrenocortical atrophy • Plasma ACTH, serum and salivary cortisol, and urinary cortisol levels all low

  27. Primary Adrenocortical Hyperfunction • Includes adrenocortical tumor, micronodular dysplasia, ACT-independent macronodular hyperplasia • Elevated levels of cortisol which suppresses • CRH • ACTH • Cortisol steroid precursors (DHEA-S)

  28. Treatment of Cushing’s Syndrome • Should be directed at primary cause of hypercortisolemia • Pituitary Tumor producing ACTH • Ectopic ACTH secretion • Cortisol Secretion by an adrenal tumor • Exogenous Cushing’s Syndrome: Stop the glucocorticoid

  29. Treatment of Cushing’s Disease • Transsphenoidal Surgery • Initial therapy of choice • 75-90% cure rate for microadenomas • Greater the resection, greater risk of loss of pituitary function (loss of fertility) • Pituitary Irradiation • Choice of discrete microadenoma cannot be localized and fertility is a concern • 3-12 months for maximum benefit • 45% cure rate for adults • Adrenalectomy • Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralcorticoid replacement is final definitive therapy

  30. Treatment of Ectopic ACTH or CRH Tumors • Optimal therapy is surgical resection of tumor • High recurrence rate • Tumor with metastases to liver can be resected with cyroablation to liver mets • Nonresectable tumors • Hypercortisolism can be medially controlled with adrenal enzyme inhibitors • Ketoconazole • Etomidate • Metyrapone

  31. Treatment of Ectopic ACTH or CRH Tumors • Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralcorticoid replacement is final definitive therapy • Prognosis dictated by • Nature of tumor • Severity of hypercortisolism • Most patients with metastatic disease die within 1 year • Small cell lung cancer, medullary thyroid cancer and gastrinomas have particularly poor prognosis

  32. Primary Adrenal Disease • Adrenal Tumors • Ademonas cured with unilateral resection • Carcinomas with high rate of recurrence • Bilateral Adrenal Hyperplasia • Bilateral adrenalectomy • Goal is to Remove the tumor • Unilateral adrenalectomy • Bilateral adrenalectomy

  33. Patient Course After Therapy • Physical symptoms and signs resolve gradually over 12 months • Hypertension and hyperglycemia will improve, but may not completely resolve • Osteoporosis improves after 6 months

  34. Conclusion • Cushing Syndrome is difficult to diagnose • Cushing Syndrome encompasses many different diseases that lead to elevated serum cortisol levels • Diagnosis requires multiple biochemical tests • Cushing’s syndrome is 100% fatal if untreated • Specific treatment depends on etiology of Cushing’s syndrome

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