1. Cushing’s Syndrome

2. This patient had Ectopic ACTH Syndrome
Non-pituitary tumor secreting either ACTH or CRH causing bilateral adrenal hyperplasia
excess CRH or ACTH is indistinguishable

3. Cushing’s=hypercortisolism
Cushing's Syndrome- Clinical effects of increased glucocorticoid hormone- all causes or excess cortisol
Cushing's Disease- ACTH producing pituitary adenoma

5. POMC (proopiomelanocortin gene) which codes for ACTH, MSH (melanocyte stimulating hormone), Beta lipotropin, Beta endorphin, metenkephalin.
POMC is induced by CRH (rarely tumors can make CRH causing Cushing's) and suppressed by glucocorticoids.

6. Symptoms of Excess Cortisol
Truncal obesity
Moon face
Fat deposits supraclavicular fossa and posterior neck- buffalo hump
HTN
Hirsutism
Amenorrhea or impotence
Depression
Thin skin
Easy bruising
Purplish abdominal striae
Proximal muscle weakness
Osteoporosis
Diabetes Mellitus
Avascular necrosis
Wound healing impaired
Pysch symptoms
Hyperpigmentation
Hypokalemic alkalosis

7. Ectopic ACTH All the previous symptoms but….. Ectopic dominated by :
Hypokalemic alkalosis (dominant feature)
Fluid retention
HTN
Glucose intolerance
Steroid psychosis
Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.

8. Hypokalemia
Excess mineralocorticoids produced by ACTH stimulation of adrenal gland, leads to high levels of cortisol activity through aldosterone and the mineralocorticoid receptor leading to severe hypokalemia by activation of the Na/K ATPase pump on the basolateral membrane.
For the rest of us that means……

9. Retain Na, and loose K in the cortical collecting duct

10. Causes of Cushing Syndrome
Iatrogenic
ACTH secreting pituitary microadenoma (Cushing’s disease)-
48% cases of Cushing’s syndrome
3 x more women than men
15% of pituitary tumors (usu 3rd or 4th decade of life)
Adrenal tumors- 32%, usu unilateral
general rule:
Small- benign, mostly cortisol
large- carcinoma, cortisol and androgens
Ectopic ACTH secretion- ie neoplasms (10%)- most common small cell lung CA
15%- cause not identified

11. Ectopic ACTH SCLC >50% Thymic carcinoid 15% Islet cell tumors 10%
Bronchial carcinoid 10%
Other carcinoids 5%
Pheochromocytomas 2%

12. Differential Diagnosis
Alcoholism
Anorexia nervosa (high urine free cortisol)
Familial cortisol resistance
Familial partial lipodystrophy type I
HAART may mimic Cushing’s clinically but not diagnostically.

13. Complications of Cushing's if Untreated
Diabetes
HTN
Osteoporotic fractures and avascular necrosis
Infections
Nephrolithiasis
Psychosis

15. Screening Test
Overnight dexamethasone suppression test (1 mg at 11 pm, cortisol measured at 8 am) – normal <2 micrograms/dL Or
24 hour urine free cortisol (>140 nmol/day)

16. Other Test That May be Useful
Midnight serum cortisol >7.5 micrograms/dL (same time zone for 3 days, NPO for 3 hours)
Midnight saliva cortisol >550 nanograms/dL, 93% sensitive

17. False Positives Severe depression Severe stress
Phenytoin/phenobarbital/rifampin (accelerated metabolism of dex)
Estrogen (pregnancy or OCP)
Morbid obesity

19. Confirmatory Test Low dose dexamethasone suppression test
Dexamethasone 0.5 mg q 6 x 48 hours
Measure urine cortisol during the last 24 hours (urine free cortisol >20 micrograms/dL or urine 17-hydroxycorticosteroid >4.5 mg/d) Or
plasma cortisol (failure to fall to <5 micrograms/dL)

21. Pituitary Tumor vs. Ectopic
ACTH levels may distinguish:
ACTH independent (adrenal or exogenous glucocorticoids)
from
ACTH dependent (pituitary, ectopic ACTH)
ACTH independent- low or undetectable ACTH
ACTH dependent-ACTH elevated
In addition ectopic ACTH levels are usu 8x higher than pituitary caused ACTH secreting adenomas

22. Treatment
Cushing’s Disease: Transphenoidal resection of pituitary adenoma
Adrenal neoplasms: resection
Ectopic ACTH: resection if possible
Bilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

23. ‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
Ketoconazole (600 to 1200 mg/day)
metyrapone (exacerbates female virilization) (2-3 g/day)
Mitotane(2-3 G/day)- slow onset
Aminoglutethinide (1g/day)
Ocreotide can work in 1/3 of patients.
Major side affect is adrenal insufficiency, therefore start at lowest dose and titrate

24. Prognosis Benign adrenal adenoma- 95% 5 year survival, 90% 10 year
Cushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years.
Ectopic ACTH survival depends on malignancy
Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival
Adrenal carcinoma- median survival 7 months