Hypercortisolism (Cushing’ s Syndrome) Endocrinology Department, Renji Hospital 陶弢 Definition • A constellation of clinical abnormalities due to chronic exposure to excess of cortisol or related corticosteroid • It is rare disorder • It occurs as a result of primary tumors of adrenal gland that hypersecrete cortisol excess ACTH secretion that may be of pituitary or nonpituitary sources Anatomy and Histology Adrenal Gland Cortex Medulla Zona Zona Zona glomerulosa fasciculata reticularis aldosterone cortisol Adrenal catecholamines androgen Normal pattern of ACTH and cortisol secretion • Pulsatile secretion • Circadian rhythm When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid hormones. ACTH is produced by the pituitary gland and released into the petrosal venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH) from the hypothalamus Etiology and Pathophysiology TABLE 204-2. CAUSES OF CUSHING’ S SYNDROME ACTH-dependent causes ACTH-secreting pituitary tumor ( Cushing’ s disease ) Pituitary CRH-secreting neoplasm ( ectopic CRP syndrome ) Nonpituitary ACTH-secreting neoplasm ( ectopic ACTH syndrome ) ACTH-independent causes Adrenal adenoma Adrenal carcinoma Micronodular adrenal disease McCune-Albright syndrome Massive macronodular adrenal diease Pseudo-cushing Syndrome Factitious or surreptitious glucocorticoid administration TABLE 204-3. COMMON CAUSES OF ECTOPIC ACTH SECRETION Small cell carcinoma of the lung 50% Endocrine tumors of foregut origin 35% Thymic carcinoid Islet cell tumor Medullary carcinoma thyroid Bronchial carcinoid Pheochromocytoma 5% Ovarian tumors 2% Diagnosis • Clinical manifestations • Lab findings – Plasma cortisol and rhythm (RIA) – Urinary free cortisol 17-hydroxycortisteriod(17-羟皮质类固醇) 17-ketosteriods(17-酮皮质类固醇) – Plasma ACTH Clinical Feature Hypercotisolism protein metabolism negative Lipid mobilization Hepatic glucose nitrogen balance production Lipid catabolism disruption of water and Lipid redistribution electrocytes metabolism Insulin resistance Proximal muscle Moon-face weakness Dependent edema buffalo hump Hypertension Glucose intolerance truncal obesity Hypokalemic metabolic Violaceous striae alkalosis TABLE 204-1. CLINICAL FEATURES OF GLUCOCORTICOID EXCESS Frequency(%) Weight gain 90 “Moon facies” 75 Hypertension 75 Violaceous striae 65 Hirsutism 65 Glucose intolerance 65 Proximal muscle weakness 60 Plethora 60 Menstrual dysfunction 60 Acne 40 Easy bruising 40 Osteopenia 40 Dependent edema 40 Hyperpigmentation 20 Hypokalemic metabolic alkalosis 15 FIGURE . Multiple wide striae on the abdomen of a patient with Cushing's disease. Suppression tests • Screening test – 1mg DX P.O at midnight – Plasma cortisol (PF) at 7-8 am next day – PF suppressed: Normal – PF NOT suppressed: Cushing’ s Syndrome Suppression tests • Low dose DX suppression test – DX 0.5 mg q6h P.O 2 days – Urinary free cortisol decreased: Normal – Urinary free cortisol NOT decreased: Cushing’ s Syndrome Suppression tests • Large dose DX suppression test – D.X 2mg q6h P.O 2 days – Urinary free cortisol reduced 50%: Cushing’s disease (Pituitary adenoma) – Urinary free cortisol NOT reduced 50%:Adrenal tumor, carcinoma, ectopic ACTH Syndrome ACTH Stimulation test • ACTH 25u intravenously 8h • 2-5 fold increase in urinary free cortisol in Cushing’ s disease • Plasma cortisol and urinary free cortisol increase in half of adrenal adenoma patients • No response in adrenal carcinoma CRH stimulation test • Etiology diagnose (especially for pituitary ACTH- dependent or ectopic ACTH syndrome) • A newer approach is to combine a CRH stimulation test with a dexamethasone suppression test(4mg ). • method : 1 µg / kg of CRH is administered intravenously. ACTH and cortisol levels are measured before CRH injection and 15, 30, 45, 60, 90 and 120 minutes after injection. • A rise in the cortisol value of 20 percent or more above basal level or a rise in the ACTH value of at least 50 percent above basal level is considered evidence for an ACTH- dependent lesion Metyrapone Test • Etiology diagnose (especially for pituitary or adrenal) – Metyrapone 2-3g (30mg/kg) P.O at midnight – Urinary 17-OHCS, Plasma ACTH,11-deoxycortisol more above basal level : Cushing’s disease (Pituitary adenoma) – No response in adrenal carcinoma , tumor, ectopic ACTH Syndrome Imaging diagnosis • Pituitary CT has a sensitivity of about 50% for identifying microadenomas • MRI has increased sensitivity but is not 100% predictive • If diagnostic doubt need bilateral inferior petrosal sinus sampling for ACTH • Adrenal ultrasonography---first choice • Abdominal CT will allow identification of adrenal pathology • Somatostatin scintigraphy to identify sites of ectopic hormone production Etiological diagnosis • Cushing’ s disease:• Chronic, moderate clinical features can be suppressed by large dose test • Adrenal adenoma: • Shorter course , mild features can NOT be suppressed by large dose test • Adrenal carcinoma: • Acute onset, progressive course, hyperandrogenic effect predominate, palpable mass, low ACTH • Ectopic ACTH • Appear suddenly, progress Syndrome: rapidly, not typical manifestation of Cushing’s syndrome, hyperpigmentation, hypokalemia, high ACTH Differential diagnosis • Simple obesity – General obesity, long history, over nourished – Narrow and short striae – Urinary free cortisol can be suppressed by screening ( overnight ) test and/or low-dose DX suppression test – Normal diurnal rhythm, almost normal plasma cortisol • Type 2 DM – Normal plasma cortisol and rhythm – Once blood glucose controlled, urinary free cortisol turns to normal • Alcoholic Cushingnoid Syndrome – No drinking for one week, plasma cortisol and urinary free cortisol become normal • Depression – Lack of clinical manifestation of Cushing’s Syndrome Treatment • Cushing’s disease – Transsphenoidal microadenomectomy – Pituitary radiation – Bilateral total adrenolectomy – Drugs • Adrenal adenoma and carcinoma – Surgical removal – Drugs ( mitotane, metyrapone, ketoconazole ) for nonresectable or metastatic carcinoma • Ectopic ACTH Syndrome – Surgical removal of the ectopic tumor – Chemotherapy, radiotherapy – Drugs ( mitotane, metyrapone, ketoconazloe ) Medical therapy of Cushing’ s Disease • Purpose – Correct metabolic abnormalities before attempted surgical cure – Palliate surgically noncurable disease – Achieve remission in patients for whom surgery is unlikely to achieve satisfactory long term results • Steroidogenic inhibition – Mitotane ( OP’-DDD , 双氯苯三氯乙烷 ) – Metyrapone ( Su4885, 美替拉酮 ) – Aminoglutethimide ( 氨基导眠能 ) – Ketoconazole ( 酮康唑 ) • Neuromodulatory treatment – Bromocriptine ( 溴隐停 ) – Cyproheptadin ( 赛庚啶 ) – Valproic acid ( 丙戊酸钠 ) – Octreotide ( 奥曲肽 ) • Glucocorticoid receptor antagonist – RU486 Consideration question • What is etiology and classification of Cushing’ s Syndrome ？ • What is clinical manifestations of Cushing’ s Syndrome ?Ｈow to produce?