Hypercortisolism

(Cushing’ s Syndrome)
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
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-ketosteriods
– 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 weaknessDependent 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,
• Ectopic ACTH palpable mass, low ACTH
Syndrome: • Appear suddenly, progress 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
– Metyrapone
– Aminoglutethimide
– Ketoconazole
• Neuromodulatory treatment
– Bromocriptine
– Cyproheptadin
– Valproic acid
– Octreotide
• Glucocorticoid receptor antagonist
– RU486