Armed Forces Academy of Medical Sciences 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

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 CRH released into hypophysial portal blood in the median eminence is carried to the anterior pituitary gland where it stimulates synthesis and release of ACTH. Increases in plasma ACTH stimulates adrenal cortisol secretion

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

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

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

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

Cushing’s Syndrome Etiology ACTH-dependent ACTH-independent 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% Exogenous administration of glucocorticoids Probably the most common Adrenocortical adenomas and carcinomas 18-20% Bilateral adrenal micronodular hyperplasia 1% Percentages represent incidences, but should be recalculated to include the most common etiology: iatrogenic Small cell lung cancer is common cause of exogenous ACTH secretion

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

Clinical Manifestations of Cushing’s Syndrome Centripetal obesity Facial plethora Glucose intolerance Proximal muscle weakness Hypertension Abdominal striae Hirsutism Simultaneous development and increasing severity of several symptoms is concerning clue Clinical suspicion has to be high because these symptoms are vague Degree and duration of hypercortisolism, cause of hypercortisolism impact severity of symptoms www.uptodate.com

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

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 ACTH is principal pigmentary hormone acting through melanocyte-stimulating hormone Hyperpigmentation occurs more frequently with ectopic ACTH www.uptodate.com

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

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

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 Nearly 80% of patients with major depressive disorder have elevated cortisol

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

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

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

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 Both tests have similar sensitivity and specificity

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

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 Worst specificity of three first line screening tests

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

Cushing’s Disease Pituitary adenoma ACTH secretion 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

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

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

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

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) DHEA-S: Dehydroepiandrosterone

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

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

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

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

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

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

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