Cushing’s Syndrome

Jason McClune
AM Report
2/6/2008
• 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

 Cushing's Syndrome- Clinical effects of

increased glucocorticoid hormone- all
causes or excess cortisol
 Cushing's Disease- ACTH producing
pituitary adenoma
 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.

Symptoms
Truncal obesity
of Excess Cortisol
 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 :
 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
 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
 Ectopic ACTH

 SCLC >50%
 Thymic carcinoid 15%
 Islet cell tumors 10%
 Bronchial carcinoid 10%
 Other carcinoids 5%
 Pheochromocytomas 2%
 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.
 Complications of Cushing's if
Untreated
 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)
 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
 False Positives

 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)

 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

 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) (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
 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