HYPERFUNCTION OF THE ADRENAL GLAND
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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 carcinoma 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.
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 virilization. Thin, fragile skin and plethoric moon facies also may be found. Hypokalemia and metabolic alkalosis are prominent, particularly with ectopic production of ACTH.
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 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 management of Cushing’s syndrome is summarized in Fig. 171-1.
Uncontrolled hypercorticism carries a poor prognosis, and treatment of Cushing’s syndrome is therefore necessary. Transsphenoidal surgery for pituitary ACTH-secreting microadenomas is curative in 70–80% when performed by a highly experienced surgeon, but long-term follow-up is required because these tumors may recur. Radiation therapy may be used when a surgical cure is not achieved (Chap. 168). Therapy of adrenal adenoma or carcinoma requires surgical excision; stress doses of glucocorticoids must be given pre- and postoperatively. Metastatic and unresectable adrenal carcinomas are treated with mitotane in doses gradually increased to 6 g/d in three or four divided doses. On occasion, debulking of lung carcinoma or resection of carcinoid tumors can result in remission of ectopic Cushing’s syndrome. If the source of ACTH cannot be resected, medical management with ketoconazole (600–1200 mg/d), metyrapone (2–3 g/d), or mitotane (2–3 mg/d) may relieve manifestations of cortisol excess. In some cases, bilateral total adrenalectomy is required to control hypercorticism. Pts with unresectable pituitary adenomas who have had bilateral adrenalectomy are at risk for Nelson’s syndrome (aggressive pituitary adenoma enlargement).