A high index of suspicion is required to make the diagnosis of Cushing's syndrome because manifestations of the disease are insidious and develop over months.

The clinical features include weight gain with centralized obesity distributed in the face, neck, trunk, and abdomen with facial rounding and plethora. The thinning of the skin and loss of subcutaneous tissue result in easy bruisabil-ity and violaceous abdominal striae. Patients with ectopic ACTH-dependent Cushing's syndrome have extreme ACTH increases that cause rapid hyperpigmentation and are more likely to demonstrate features of mineralocorticoid excess, such as hypokalemia and metabolic alkalosis. Gonadal dysfunction is associated with decreased testosterone levels in men and decreased serum estradiol levels and menstrual disorders, notably amenorrhea, in women. Virilization and androgen excess are more common in patients with Cush-ing's syndrome caused by adrenal carcinomas.

Glucocorticoid excess also interferes with calcium and bone metabolism and leads to osteoporosis. Catabolic effects of excess glucocorticoid on muscles cause proximal muscle weakness. Glucose intolerance is found in 30% to 60% of those with hypercortisolism. Other complications of hypercortisolism include risk of opportunistic infections, including Pneumocystis jiroveci (formerly carinii) pneumonia, hypercoagulable state, and thromboembolic events secondary to increased plasma concentration of clotting factors and neuropsychiatry changes (Arnaldi et al., 2003; Findling and Raff, 2005).

Establishing the Cause

The diagnosis is established when the clinical findings of Cushing's disease are associated with laboratory documentation of excess cortisol production, loss of diurnal variation of plasma cortisol level, and more than 50% suppression of plasma and urine cortisol after administration of 2 mg of dexamethasone every 6 hours (high-dose dexamethasone suppression test). Measurement of 24-hour urinary cortisol excretion is a good screening tool. Alternatively, impaired suppression of cortisol after an overnight 1-mg dexametha-sone suppression test can be used as a screen in nonobese individuals. Plasma ACTH concentration less than 5 pg/mL

and serum Cortisol concentration greater than 15 ^/dL suggest an ACTH-independent cause. Plasma ACTH concentration greater than 15 pg/mL in a patient with hypercortisolism likely indicates ACTH-dependent Cushing's syndrome (Arnaldi et al., 2003; Findling and Raff, 2005).

The vast majority of ACTH-dependent Cushing's syndrome patients have a pituitary adenoma as the cause. The few patients who have an ectopic source of ACTH must be identified with high-resolution CT scanning of chest, abdomen, and pelvis.

Suppression of urinary cortisol excretion, after administration of high-dose dexamethasone, is consistent with the diagnosis of Cushing's disease, whereas urinary cortisol excretion in cases of ectopic ACTH syndrome is usually not suppressible. When the high-dose dexamethasone suppression test fails to differentiate an ectopic source from a pituitary source of ACTH, and radiographic imaging is not conclusive, further CRH testing and petrosal sinus sampling of ACTH are indicated to localize the tumor to the pituitary.

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