Hypercortisolism (Cushing

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Hypercortisolism(Cushing s Syndrome)

• Endocrinology Department, Renji Hospital
• ? ?

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Definition

• A constellation of clinical abnormalities due to
  chronic exposure to excess of cortisol or related
  corticosteroid

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• 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

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Anatomy and Histology
Adrenal Gland
Cortex
Medulla
Zona glomerulosa
Zona fasciculata
Zona reticularis
aldosterone
cortisol
Adrenal androgen
catecholamines
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Normal pattern of ACTH and cortisol secretion

• Pulsatile secretion
• Circadian rhythm

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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
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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

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• 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

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Diagnosis

• Clinical manifestations
• Lab findings
• Plasma cortisol and rhythm (RIA)
• Urinary free cortisol
• 17-hydroxycortisteriod(17-??????)
• 17-ketosteriods(17-??????)
• Plasma ACTH

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Clinical Feature
Hypercotisolism

protein metabolism negative nitrogen
balance disruption of water and electrocytes
metabolism
Lipid mobilization ?
Hepatic glucose production?
Lipid catabolism ?
Lipid redistribution
Insulin resistance
Proximal muscle weakness
Moon-face buffalo hump truncal obesity Violaceous
striae
Dependent edema Hypertension Hypokalemic
metabolic alkalosis
Glucose intolerance
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• 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

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FIGURE . Multiple wide striae on the abdomen of a
patient with Cushing's disease.
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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

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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

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Suppression tests

• Large dose DX suppression test
• D.X 2mg q6h P.O 2 days
• Urinary free cortisol reduced 50 Cushings
  disease (Pituitary adenoma)
• Urinary free cortisol NOT reduced 50Adrenal
  tumor, carcinoma, ectopic ACTH Syndrome

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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

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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

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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 Cushings disease
  (Pituitary adenoma)
• No response in adrenal carcinoma , tumor, ectopic
  ACTH Syndrome

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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

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Etiological 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 Cushings syndrome,
  hyperpigmentation, hypokalemia, high ACTH

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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 Cushings
  Syndrome

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Treatment

• Cushings 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 )

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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

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• Steroidogenic inhibition
• Mitotane ( OP-DDD , ??????? )
• Metyrapone ( Su4885, ???? )
• Aminoglutethimide ( ????? )
• Ketoconazole ( ??? )
• Neuromodulatory treatment
• Bromocriptine ( ??? )
• Cyproheptadin ( ??? )
• Valproic acid ( ???? )
• Octreotide ( ??? )
• Glucocorticoid receptor antagonist
• RU486

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Consideration question

• What is etiology and classification of Cushing s
  Syndrome ?
• What is clinical manifestations of Cushing s
  Syndrome ?How to produce?

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Thanks!