1. Hypercortisolism (Cushing’ s Syndrome)

2. Definition
A constellation of clinical abnormalities due to chronic exposure to excess of cortisol or related corticosteroid

3. 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

4. Anatomy and Histology Adrenal Gland Cortex Medulla Zona glomerulosa
Zona fasciculata
Zona reticularis
aldosterone
cortisol
Adrenal androgen
catecholamines

5. Normal pattern of ACTH and cortisol secretion
Pulsatile secretion
Circadian rhythm

8. 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

9. Etiology and Pathophysiology
TABLE 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

10. Small cell carcinoma of the lung 50%
TABLE 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%

11. Diagnosis Clinical manifestations Lab findings
Plasma cortisol and rhythm (RIA)
Urinary free cortisol
17-hydroxycortisteriod
17-ketosteriods
Plasma ACTH

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

13. Proximal muscle weakness 60 Plethora 60 Menstrual dysfunction 60
TABLE CLINICAL FEATURES OF
GLUCOCORTICOID EXCESS
Frequency(%)
Weight gain
“Moon facies”
Hypertension
Violaceous striae
Hirsutism
Glucose intolerance
Proximal muscle weakness
Plethora
Menstrual dysfunction
Acne
Easy bruising
Osteopenia
Dependent edema
Hyperpigmentation
Hypokalemic metabolic alkalosis

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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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 Cushing’s syndrome, hyperpigmentation, hypokalemia, high ACTH

25. 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

26. Treatment Cushing’s disease Adrenal adenoma and carcinoma
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 )

27. 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

28. Steroidogenic inhibition
Mitotane
Metyrapone)
Aminoglutethimide
Ketoconazole
Neuromodulatory treatment
Bromocriptine
Cyproheptadin
Valproic acid
Octreotide
Glucocorticoid receptor antagonist
RU486 (

29. Consideration question
What is etiology and classification of Cushing’ s Syndrome ？
What is clinical manifestations of Cushing’ s Syndrome ?