Nejm 1995;332:791; 1994;331:629 (NIH—children)
Cause:
(Nejm 1991;325:899)
- Cushing's disease from chromophobe or basophilic micro- or macroadenoma of pituitary
- Ectopic ACTH production by oat cell or other (ovary, pancreas, carcinoid) cancer; occasionally ACTH-producing carcinoid tumors, esp of lung (Ann IM 1992;117:209)
- Adrenal: bilateral nodular hyperplasia or unilateral adrenal adenoma (15%) (ACTH receptor genetic defects—Nejm 1998;339:27); rare primary pigmented nodular hyperplasia (Ann IM 1999;131:585) assoc w MEA and cardiac myomas; or carcinoma (<1% adults, 4% of children w Cushing's—NIH)
Pathophys:Glucocorticoids cause connective tissue dissolution, have an anti-vitamin D effect, cause proteolysis of muscle, lymphocyte/monocyte inhibition (Nejm 1975;292:236), increased acid/pepsin secretion, increased gluconeogenesis, and decreased glucose uptake. Aldosterone and androgens elevated too when ACTH is the mechanism
Sx:Muscle weakness, obesity/weight gain; growth retardation in children; easy bruising
Si:Muscle weakness; ecchymoses; moon face, buffalo hump; abdominal striae; truncal fat; osteoporosis and fractures; increased number and severity of infections; peptic ulcers; diabetes, nonketotic, insulin-resistant; psychoses; virilization; hypertension (47% in children); and edema
Excellent prognosis unless cancer or ectopic ACTH (usually cancer) (Nejm 1971;285:243)
Lab:
(Ann IM 2003;138:980)
Chem:Serum cortisols, normal level is 10-25 µgm % (= 280-700 nM/L) in am, dropping to <7 µgm % in pm; after 1 mg dexamethasone at 11 pm, 8 am cortisol is <5 in normal; if >10, r/o Cushing's (100% sens, 90% specif—Ann IM 1990;112:738); false positives with phenytoin (Dilantin). Late night salivary cortisol levels 
70 nM/L. If studies indeterminant, then give 0.5 mg dexamethasone q6h × 48 h and measure cortisols; or get 24-h urinary free cortisol (6% false neg, fewer false pos) and/or 24-h urine cortisols × 3 100 µgm/24 h
If above tests abnormal, then high-dose tests are done to differentiate cause, eg, baseline 8 am cortisol, 8 mg dexamethasone that night at 11 pm, then 8 am cortisol. Pituitary Cushing's patients, unlike adrenal tumors or ectopic ACTH production types, suppress value to <50% of baseline value (92% sens, 100% specif—Ann IM 1986;104:180 [68% sens in children]; also see Nejm 1994;330:1295 for various test sens/specif)
CRH test: ACTH and cortisol increased after CRH given if pituitary tumor, not if ectopic ACTH or adrenal tumor (Ann IM 1985;102:344); 80% sens in children
Petrosal venous sampling for ACTH levels, simultaneous bilaterally reliably lateralize pituitary tumor (Nejm 1985;312:100)
Xray:
CT, 60% false-negative rate due to small size of adenomas
MRI with gadolinium enhancement, 71% sens (52% sens in children), 87% specif; but 10% of the normal adult population have a lesion (Ann IM 1994;120:817)
Rx:
1st: Surgical transsphenoidal microadenomectomy, 90% successful (Nejm 1984;310:889 vs 76%—Ann IM 1988;109:487); bilateral adrenalectomy
2nd: Irradiation of pituitary, 83% successful in pts who fail surgery (Nejm 1997;336:172)
3rd: Aminoglutethimide, mitotane, metyrapone, and trilostane (Med Let 1985;27:87); bromocriptine; ketoconazole for its antisteroid synthesis effect (Nejm 1987;317:812)