This patient had Ectopic ACTH Syndrome Non-pituitary tumor secreting either ACTH or CRH causing bilateral adrenal hyperplasia excess CRH or ACTH is indistinguishable
Cushings=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.
Ectopic ACTH
All the previous symptoms but.. Ectopic dominated by :
Absence of other features may be explained by more sudden onset by acquired ACTH from tumor.
Hypokalemic alkalosis (dominant feature) Fluid retention HTN Glucose intolerance Steroid psychosis
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
48% cases of Cushings 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
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 Cushings clinically but not diagnostically.
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)
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)
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
ACTH independent (adrenal or exogenous glucocorticoids) from ACTH dependent (pituitary, ectopic ACTH)
Treatment
Cushings 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
Benign adrenal adenoma- 95% 5 year survival, 90% 10 year Cushings 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