Etiology

The most common cause of Cushing's syndrome is iatrogenic, due to administration of glucocorticoids for therapeutic reasons. Endogenous Cushing's syndrome results from production of excess cortisol (and other steroid hormones) by the adrenal cortex. The major cause is bilateral adrenal hyperplasia secondary to hypersecretion of adrenocorticotropic hormone (ACTH) by the pituitary (Cushing's disease) or from ectopic sources such as small cell carcinoma of the lung; carcinoids of the bronchus, thymus, gut and ovary, medullary carcinoma of the thyroid; or pheochromocytoma. Adenomas or carcinomas of the adrenal gland account for about 15-20% of endogenous Cushing's syndrome cases. There is a female preponderance in endogenous Cushing's syndrome except for the ectopic ACTH syndrome.

Clinical Features

Some common manifestations (central obesity, hypertension, osteoporosis, psychological disturbances, acne, hirsutism, amenorrhea, and diabetes mellitus) are relatively nonspecific. More specific findings include easy bruising, purple striae, proximal myopathy, fat deposition in the face and nuchal areas (moon facies and buffalo hump), and rarely androgenization. Thin, fragile skin, and plethoric moon facies also may be found. Hypokalemia and metabolic alkalosis are prominent, particularly with ectopic production of ACTH.

Diagnosis

The diagnosis of Cushing's syndrome requires demonstration of increased cortisol production and abnormal cortisol suppression in response to dexamethasone. For initial screening, measurement of 24-h urinary free cortisol, the 1-mg overnight dexamethasone test (8:00 A.M. plasma cortisol <1.8 µg/dL [50 nmol/L]), or late-night salivary cortisol measurement is appropriate. Repeat testing or performance of more than one screening test may be required. Definitive diagnosis is established in equivocal cases by inadequate suppression of urinary cortisol (<10 µg/d [25 nmol/d]) or plasma cortisol (<5 µg/dL [140 nmol/L]) after 0.5 mg dexamethasone every 6 h for 48 h. Once the diagnosis of Cushing's syndrome is established, further biochemical testing is required to localize the source. This evaluation is best performed by an experienced endocrinologist. Low levels of plasma ACTH levels suggest an adrenal adenoma, bilateral nodular hyperplasia, or carcinoma; inappropriately normal or high plasma ACTH levels suggest a pituitary or ectopic source. In 95% of ACTH-producing pituitary microadenomas, cortisol production is suppressed by high-dose dexamethasone (2 mg every 6 h for 48 h). MRI of the pituitary should be obtained but may not reveal a microadenoma because these tumors are typically very small. Furthermore, because up to 10% of ectopic sources of ACTH may also suppress after high-dose dexamethasone testing, inferior petrosal sinus sampling may be required to distinguish pituitary from peripheral sources of ACTH. Testing with corticotropin-releasing hormone (CRH) also may be helpful in determining the source of ACTH. Imaging of the chest and abdomen is required to localize the source of ectopic ACTH production; small bronchial carcinoids may escape detection by conventional CT. Pts with chronic alcoholism, depression, or obesity may have false-positive results in testing for Cushing's syndrome-a condition named pseudo-Cushing's syndrome. Similarly, pts with acute illness may have abnormal laboratory test results, since major stress alters the normal regulation of ACTH secretion. The diagnosis and management of Cushing's syndrome are summarized in Fig. 174-1. Management of the Pt with Suspected Cushing's Syndrome.

Etiology

Aldosteronism is caused by hypersecretion of the adrenal mineralocorticoid aldosterone. Primary hyperaldosteronism refers to an adrenal cause and can be due to either an adrenal adenoma or bilateral adrenal hyperplasia. Rare causes include glucocorticoid-remediable hyperaldosteronism, some forms of congenital adrenal hyperplasia, and other disorders of true or apparent mineralocorticoid excess (see Table 379-3, HPIM-20). The term secondary hyperaldosteronism is used when an extraadrenal stimulus for renin secretion is present, as in renal artery stenosis, decompensated liver cirrhosis, or diuretic therapy.

Clinical Features

Most pts with primary hyperaldosteronism have difficult to control hypertension (especially diastolic) and hypokalemia. Headaches are common. Edema is characteristically absent, unless congestive heart failure or renal disease is present. Hypokalemia, caused by urinary potassium loss, may cause muscle weakness, fatigue, and polyuria, although potassium levels may be normal in mild primary hyperaldosteronism. Metabolic alkalosis is a typical feature.

Diagnosis

The diagnosis is suggested by treatment-resistant hypertension that is associated with persistent hypokalemia in a nonedematous pt who is not receiving potassium-wasting diuretics. In pts receiving potassium-wasting diuretics, the diuretic should be discontinued and potassium supplements should be administered for 1-2 weeks. If hypokalemia persists after supplementation, screening using a serum aldosterone and plasma renin activity should be performed. Ideally, antihypertensives should be stopped before testing, but that is often impractical. Aldosterone receptor antagonists, beta-adrenergic blockers, ACE inhibitors, and angiotensin receptor blockers interfere with testing and should be substituted with other antihypertensives if possible. An aldosterone to renin ratio (ARR) of aldosterone (pmol/L) to plasma renin activity (ng/mL per hour) >750 and an absolute level of aldosterone >450 pmol/L suggests primary aldosteronism. Failure to suppress plasma aldosterone after saline or sodium loading confirms primary hyperaldosteronism. The saline infusion test involves the IV administration of 2 L of physiologic saline over a 4-h period. Failure of aldosterone to suppress below 140 pmol/L (5 ng/dL) is indicative of autonomous mineralocorticoid excess. Alternative tests are the oral sodium loading test (300 mmol NaCl/d for 3 days) or the fludrocortisone suppression test (0.1 mg q6h with 30 mmol NaCl q8h for 4 days); the latter can be difficult because of the risk of hypokalemia and increased hypertension. Caution should be used with sodium loading in a hypertensive pt. Localization should then be undertaken with a high-resolution CT scan of the adrenal glands. If the CT scan is negative, bilateral adrenal vein sampling may be required to diagnose a unilateral aldosterone-producing adenoma. Secondary hyperaldosteronism is associated with elevated plasma renin activity.