Hypercortisolism(Cushing’ s Syndrome)
A constellation of clinical abnormalities due to chronic exposure to excess of cortisol or related corticosteroid
Definition
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
Cortex Medulla
Adrenal Gland
aldosterone cortisol Adrenal androgen
catecholamines
Zona glomerulosa
Zona fasciculata
Zona reticularis
Pulsatile secretion
Circadian rhythm
Normal pattern of ACTH and cortisol secretion
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
TABLE 204-2. CAUSES OF CUSHING’ S SYNDROMEACTH-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 carcinomaMicronodular adrenal diseaseMcCune-Albright syndromeMassive macronodular adrenal diease
Pseudo-cushing Syndrome Factitious or surreptitious glucocorticoid administration
Etiology and Pathophysiology
TABLE 204-3. COMMON CAUSES OF ECTOPIC ACTH SECRETION
Small cell carcinoma of the lung 50%Endocrine tumors of foregut origin 35%
Thymic carcinoidIslet cell tumor Medullary carcinoma thyroidBronchial carcinoid
Pheochromocytoma 5%Ovarian tumors 2%
Clinical manifestations Lab findings
◦ Plasma cortisol and rhythm (RIA)◦ Urinary free cortisol 17-hydroxycortisteriod 17-ketosteriods◦ Plasma ACTH
Diagnosis
Clinical FeaturesHypercotisolism
Lipid mobilization Lipid catabolism
Lipid redistribution
Moon-facebuffalo humptruncal obesityViolaceous striae
Hepatic glucose production
Insulin resistance
Glucose intolerance
protein metabolism negative nitrogen balance
disruption of water and electrocytes metabolism
Proximal muscle weakness
Dependent edema
Hypertension
Hypokalemic metabolic alkalosis
TABLE 204-1. CLINICAL FEATURES OFGLUCOCORTICOID EXCESS
Frequency(%)
Weight gain 90“Moon facies” 75Hypertension 75Violaceous striae 65Hirsutism 65Glucose intolerance 65Proximal muscle weakness 60Plethora 60Menstrual dysfunction 60Acne 40Easy bruising 40Osteopenia 40Dependent edema 40Hyperpigmentation 20Hypokalemic metabolic alkalosis 15
FIGURE . Multiple wide striae on the abdomen of a patient with Cushing's disease.
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
Suppression tests
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
ACTH 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
CRH stimulation 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
Metyrapone Test
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
Imaging diagnosis
Cushing’ s disease: Adrenal adenoma: Adrenal carcinoma: Ectopic ACTH
Syndrome:
Chronic, moderate clinical features can be suppressed by large dose test
Shorter course , mild features can NOT be suppressed by large dose test
Acute onset, progressive course, hyperandrogenic effect predominate, palpable mass, low ACTH
Appear suddenly, progress rapidly, not typical manifestation of Cushing’s syndrome, hyperpigmentation, hypokalemia, high ACTH
Etiological 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
Differential diagnosis
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 )
Treatment
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
Medical therapy of Cushing’ s Disease
Steroidogenic inhibition◦ Mitotane◦ Metyrapone)◦ Aminoglutethimide◦ Ketoconazole
Neuromodulatory treatment◦ Bromocriptine◦ Cyproheptadin◦ Valproic acid◦ Octreotide
Glucocorticoid receptor antagonist◦ RU486
What is etiology and classification of Cushing’ s Syndrome ?
What is clinical manifestations of Cushing’ s Syndrome ?
Consideration question