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Harrison’s Manual of Medicine



Hyperfunction of the adrenal gland
Hypofunction of the Adrenal Gland
Incidental Adrenal Masses
Clinical Uses of Glucocorticoids
The adrenal cortex produces three major classes of steroids: (1) glucocorticoids, (2) mineralocorticoids, and (3) adrenal androgens. Clinical syndromes may result from deficiencies or excesses of these hormones. The adrenal medulla produces catecholamines, with excess leading to pheochromocytoma (Chap. 124).
CUSHING’S SYNDROME   Etiology   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, medullary carcinoma of the thyroid, or tumors of the thymus, pancreas, or ovary. Adenomas or carcinoma of the adrenal gland account for about 25% of Cushing’s syndrome cases. Administration of glucocorticoids for therapeutic reasons may result in iatrogenic Cushing’s syndrome.
Clinical Features   Some common manifestations (central obesity, hypertension, osteoporosis, emotional lability, acne, amenorrhea, and diabetes mellitus) are relatively nonspecific. More specific findings include easy bruising, purple striae, proximal myopathy, fat deposition in the face and interscapular areas (moon facies and buffalo hump), and virilization. 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 (Fig. 172-1). For initial screening, the 1-mg overnight dexamethasone test (8 A.M. plasma cortisol <5 µg/dL) or measurement of 24-h urinary free cortisol is appropriate. Definitive diagnosis is established by inadequate suppression of urinary (<30 µg/d) or plasma cortisol (<5 µg/dL) after 0.5 mg dexamethasone q6h for 48 h. Once the diagnosis of Cushing’s syndrome is established, further biochemical testing is required to localize the source. 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 q6h for 48 h), and MRI of the pituitary should be obtained. However, 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. Imaging of the chest and abdomen is required to localize the source of ectopic ACTH production. Pts with chronic alcoholism and depression may have false-positive results in testing for Cushing’s syndrome. Similarly, pts with acute illness may have abnormal laboratory test results, since major stress disrupts the normal regulation of ACTH secretion.

FIGURE 172-1. Diagnostic flowchart for evaluating patients suspected of having Cushing’s syndrome. *This group probably includes some patients with pituitary-hypothalmic dysfunction and some with pituitary microadenomas. In some instances, a microadenoma may be visualized by pituitary MRI scanning. 17-KS, 17-ketosteroids; DHEA, dehydroepiandrosterone.

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. Transsphenoidal surgery can be curative for pituitary microadenomas that secrete ACTH (see Chap. 169). 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, bilateral total adrenalectomy or 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.

ALDOSTERONISM   Etiology   Aldosteronism is caused by hypersecretion of the adrenal mineralocorticoid aldosterone. Primary aldosteronism refers to an adrenal cause and can be due to either an adrenal adenoma or bilateral adrenal hyperplasia. The term secondary aldosteronism is used when an extraadrenal stimulus is present, as in renal artery stenosis or diuretic therapy.
Clinical Features   Most pts with primary hyperaldosteronism have headaches and diastolic hypertension. Edema is characteristically absent, unless congestive heart failure or renal disease is present. Hypokalemia, caused by urinary potassium losses, may cause muscle weakness and fatigue, though potassium levels may be normal in mild primary aldosteronism. Hypernatremia and metabolic alkalosis may also occur.
Diagnosis   The diagnosis is suggested by 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. A ratio of serum aldosterone (in ng/dL) to plasma renin activity (in ng/mL per hour) >30 and an absolute level of aldosterone >15 ng/dL suggest primary aldosteronism. Failure to suppress plasma aldosterone (to <5 ng/dL after 500 mL/h of normal saline × 4 h) or urinary aldosterone after saline or sodium loading (to < 10 µg/d on day 3 of 200 mmol Na PO qd + fludrocortisone 0.2 mg bid × 3 days) confirms primary hyperaldosteronism. 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.

Surgery can be curative in pts with adrenal adenoma but is not effective for adrenal hyperplasia, which is managed with sodium restriction and spironolactone (25–100 mg tid) or amiloride. Secondary aldosteronism is treated with salt restriction and correction of the underlying cause.

SYNDROMES OF ADRENAL ANDROGEN EXCESS   See Chap. 174 for discussion of hirsutism and virilization.
ADDISON’S DISEASE   Etiology   Addison’s disease occurs when >90% of adrenal tissue is destroyed surgically, by granulomatous disease (tuberculosis, histoplasmosis, coccidioidomycosis, cryptococcosis), or via autoimmune mechanisms. Bilateral tumor metastases, bilateral hemorrhage, CMV, HIV, amyloidosis, and sarcoidosis are rare causes.
Clinical Features   Manifestations include fatigue, weakness, anorexia, nausea and vomiting, weight loss, abdominal pain, cutaneous and mucosal pigmentation, salt craving, hypotension, and occasionally, hypoglycemia. Routine laboratory parameters may be normal, or serum Na can be reduced and serum K is often increased. Extracellular fluid depletion accentuates hypotension.
Diagnosis   The best screening test is the cortisol response 60 min after 250 µg ACTH (cosyntropin) IV or IM. Cortisol levels should normally be > 18 µg/ dL 30–60 min after the ACTH. If the response is abnormal, then primary and secondary deficiency may be distinguished by measurement of aldosterone from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment from baseline will be normal (³ 5 ng/dL). Furthermore, in primary adrenal insufficiency, plasma ACTH is elevated, whereas in secondary adrenal insufficiency, plasma ACTH values are low or inappropriately normal. Pts with recent onset or partial pituitary insufficiency may have a normal response to the rapid ACTH stimulation test. In these pts, alternative testing (metyrapone test, insulin tolerance testing, or the 1-µg ACTH test) may be used for diagnosis.

Hydrocortisone, at 20–30 mg/d divided into 2/3 in the morning and 1/3 in the afternoon, is the mainstay of glucocorticoid replacement. Some pts benefit from doses administered three times daily, and other glucocorticoids may be given at equivalent doses. Mineralocorticoid supplementation is usually needed for primary adrenal insufficiency, with administration of 0.05–0.1 mg fludrocortisone PO qd and maintenance of adequate Na intake. Doses should be titrated to normalize Na and K levels and to maintain normal bp without postural changes. Measurement of plasma renin levels may also be useful in titrating the dose. All pts with adrenal insufficiency should be instructed in the parenteral self-administration of steroids and should be registered with a medical alert system. During periods of intercurrent illness, the dose of hydrocortisone should be doubled. During adrenal crisis, effective treatment of hypotension additionally requires repletion of Na and water deficits with normal saline.

HYPOALDOSTERONISM   Isolated aldosterone deficiency accompanied by normal cortisol production occurs with hyporeninism, as an inherited biosynthetic defect, postoperatively following removal of aldosterone-secreting adenomas, and during protracted heparin therapy. Hyporeninemic hypoaldosteronism is seen most commonly in adults with mild renal failure and diabetes mellitus in association with disproportionate hyperkalemia. Oral fludrocortisone (0.05–0.15 mg PO qd) restores electrolyte balance if salt intake is adequate. In pts with hypertension, mild renal insufficiency, or congestive heart failure, an alternative approach is to reduce salt intake and to administer furosemide.
Adrenal masses are common findings on abdominal CT or MRI scans. More than 90% of such “incidentalomas” are nonfunctional, and the probability of an adrenal carcinoma is low (<0.01%). The first step in evaluation is to determine the functional status by measuring 24-h urinary catecholamines and metabolites, obtaining a serum potassium, and performing an overnight dexamethasone-suppression test. Surgery should be considered for nonfunctional masses >4 cm and for all functional masses. If surgery is not performed, a follow-up CT scan should be obtained in 3–6 months. In a pt with a known extraadrenal malignancy, there is a 30–50% chance that the incidentaloma is a metastasis.
Glucocorticoids are pharmacologic agents used for a variety of disorders such as asthma, rheumatoid arthritis, and psoriasis. The almost certain development of complications (weight gain, hypertension, Cushingoid facies, diabetes mellitus, osteoporosis, myopathy, increased intraocular pressure, ischemic bone necrosis, infection, and hypercholesterolemia) must be weighed against the potential therapeutic benefits of glucocorticoid therapy. These side effects can be minimized by a careful choice of steroid preparations (Table 172-1), alternate- day or interrupted therapy; the use of topical steroids, i.e., inhaled, intranasal, or dermal whenever possible; and the judicious use of non-steroid therapies. Pts should be evaluated for the risk of complications before the initiation of glucocorticoid therapy (Table 172-2). Higher doses of glucocorticoids may be required during periods of stress, since the adrenal gland may atrophy in the setting of exogenous glucocorticoids. In addition, following long-term use, glucocorticoids should be tapered with the dual goals of allowing the pituitary- adrenal axis to recover and the avoidance of underlying disease flare.

Table 172-1 Glucocorticoid Preparations

Table 172-2 A Checklist for Use Prior to the Administration of Glucocorticoids in Pharmacologic Doses


For a more detailed discussion, see Williams GH, Dluhy RG: Diseases of the Adrenal Cortex, Chap. 331, p. 2084, in HPIM-15.


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