Download Cushing`s Disease

Cushing’s Syndrome
• This patient had Ectopic ACTH
Syndrome
• Non-pituitary tumor secreting
either ACTH or CRH causing
bilateral adrenal hyperplasia
• excess CRH or ACTH is
indistinguishable
Cushing’s=hypercortisolism
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Cushing's Syndrome- Clinical effects of
increased glucocorticoid hormone- all
causes or excess cortisol
Cushing's Disease- ACTH producing
pituitary adenoma
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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.
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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
Ectopic ACTH
All the previous symptoms but…..
 Ectopic dominated by :
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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.
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……
Retain Na, and loose K in the cortical
collecting duct
Causes of Cushing Syndrome
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Iatrogenic
ACTH secreting pituitary microadenoma (Cushing’s disease)
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Adrenal tumors- 32%, usu unilateral
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48% cases of Cushing’s syndrome
3 x more women than men
15% of pituitary tumors (usu 3rd or 4th decade of life)
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
Ectopic ACTH
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SCLC >50%
Thymic carcinoid 15%
Islet cell tumors 10%
Bronchial carcinoid 10%
Other carcinoids 5%
Pheochromocytomas 2%
Differential Diagnosis
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Alcoholism
Anorexia nervosa (high urine free cortisol)
Familial cortisol resistance
Familial partial lipodystrophy type I
HAART may mimic Cushing’s clinically but
not diagnostically.
Complications of Cushing's if
Untreated
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Diabetes
HTN
Osteoporotic fractures and avascular
necrosis
Infections
Nephrolithiasis
Psychosis
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)
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Other Test That May be Useful
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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
False Positives
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Severe depression
Severe stress
Phenytoin/phenobarbital/rifampin
(accelerated metabolism of dex)
Estrogen (pregnancy or OCP)
Morbid obesity
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)
Pituitary Tumor vs. Ectopic
ACTH levels may distinguish:
ACTH independent (adrenal or exogenous
glucocorticoids)
from
 ACTH dependent (pituitary, ectopic ACTH)
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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
Treatment
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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)
‘Medical’ Adrenalectomy
Medications that inhibit steroidogenesis
 Ketoconazole (600 to 1200 mg/day)
 metyrapone (exacerbates female virilization) (23 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
Prognosis
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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