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ESSENTIALS OF DIAGNOSIS
Facial plethora, dorsocervical fat pad, supraclavicular fat pad, truncal obesity, easy bruisability, purple striae, acne, hirsutism, impotence or amenorrhea, muscle weakness, and psychosis.
Hypertension, hyperglycemia, and osteopenia or osteoporosis.
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General Considerations
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Cushing syndrome is due to chronic glucocorticoid excess. It may be caused by excess ACTH stimulation or by adrenocortical tumors that secrete glucocorticoids independently of ACTH stimulation. Excess ACTH may be produced by pituitary adenomas (Cushing disease) or extrapituitary ACTH-producing tumors (ectopic ACTH syndrome). Cushing syndrome not dependent on ACTH is usually caused by primary adrenal diseases such as adrenocortical adenoma and micronodular or macronodular hyperplasia or carcinoma.
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The natural history of Cushing syndrome depends on the underlying disease and varies from a mild, indolent disease to rapid progression and death.
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A. Symptoms and Signs
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See Table 33–1. The classic description of Cushing syndrome includes truncal obesity, hirsutism, moon facies, acne, buffalo hump, purple striae, hypertension, and diabetes, but other signs and symptoms are common. Weakness and depression are striking features. Weakness and other features are also seen after prolonged and excessive administration of adrenocortical steroids.
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In children, Cushing syndrome is most commonly caused by adrenal cancers, but adenomas and nodular hyperplasia have been described. Cushing syndrome in children also causes growth retardation or arrest.
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B. Pathologic Examination
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The pathologic features of the adrenal gland depend on the underlying disease. Normal adrenal glands weigh 7-12 g combined. The hyperplastic adrenal glands in patients with Cushing disease weigh less than 25 g combined. In ectopic ACTH syndrome, the combined adrenal weight is greater—from 25 to 100 g.
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Adrenal adenomas in Cushing syndrome range in weight from a few grams to over 100 g, usually over 3 cm in diameter, and are larger than APAs. The typical cells usually resemble those of the zona fasciculata. Variable degrees of anaplasia are seen, and differentiation of benign from malignant tumors is often difficult on the basis of cytology alone. These adrenal adenomas occur more frequently in women. Adrenal cancers are frequently very large—almost always over 5 cm in diameter. They are undifferentiated, invade the surrounding tissues, and metastasize via the blood stream.
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Rare forms of ACTH-independent Cushing syndrome include ACTH-independent macronodular adrenal hyperplasia, which in some cases is due to aberrant expression of receptors in the adrenals that respond to stimuli other than ACTH. In these cases, the adrenal glands can be massively enlarged. Primary pigmented nodular adrenal disease or micronodular hyperplasia is associated with the syndrome of Carney complex that also includes cardiac myxoma and lentigines.
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Rarely, ectopic adrenal tissue can be the source of excessive cortisol secretion. It has been found in various locations, most commonly near the abdominal aorta.
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Cushing disease is caused by pituitary adenomas.
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Ectopic ACTH syndrome is usually caused by small-cell lung cancer and neuroendocrine tumors (carcinoid tumors) of the pancreas, thymus, thyroid, prostate, esophagus, colon, and ovaries. Pheochromocytoma and malignant melanoma may also secrete ACTH.
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C. Laboratory Findings
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Since no single test is specific, a combination of tests must be used.
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Normal subjects have a circadian rhythm of ACTH secretion that is paralleled by cortisol secretion. Levels are highest in the early morning and decline during the day to their lowest levels in the late evening. In Cushing syndrome, the circadian rhythm is abolished, and total secretion of cortisol is increased. In mild cases, the plasma cortisol and ACTH levels may be within the normal range during much of the day but abnormally high in the evening.
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When Cushing syndrome is suspected, the first objective is to establish the diagnosis; the second is to establish the cause. An algorithm for the diagnosis is presented in Figure 33–3. When hypercortisolism is suspected, three tests are available as the initial tests to establish the diagnosis: overnight dexamethasone suppression test, measurement of 24-hour urinary free cortisol, and late night salivary cortisol sampling. Dexamethasone, 1 mg orally will suppress ACTH secretion and stop cortisol production in most healthy individuals. This low-dose dexamethasone, however, will not suppress excessive cortisol production from autonomous adrenocortical tumors or adrenals that are being stimulated by excess ACTH. Since dexamethasone does not cross-react in the assay for plasma cortisol, suppression of endogenous circulating cortisol is easily demonstrated. The test is done as follows: At 11 PM, the patient is given 1 mg of dexamethasone by mouth. A fasting plasma cortisol is measured the following morning between 8 and 9 AM. Suppression of plasma cortisol to 1.8 μg/dL (50 nmol/L) or less excludes Cushing syndrome. Higher cutoff levels have been recommended, but some patients with mild ACTH-dependent Cushing syndrome may be suppressed easily; thus, the response is falsely negative and the diagnosis of Cushing syndrome is missed. On the other hand, this low cutoff level increases the likelihood of a false-positive result. False-positive results are more common in patients with depression, alcoholism, physiologic stress, marked obesity, obstructive sleep apnea, or renal failure and in those taking estrogens or drugs that accelerate dexamethasone metabolism, such as phenytoin, rifampin, and phenobarbital. Estrogens increase cortisol-binding globulin and elevate total plasma cortisol concentrations. In these situations, measurement of 24-hour urinary free cortisol or salivary cortisol is preferred. Twenty-four-hour urinary cortisol directly measures the physiologically active form of circulating cortisol, integrates the daily variations of cortisol production, and is very sensitive and specific for the diagnosis of Cushing syndrome.
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Late night salivary cortisol sampling can also assist in establishing the diagnosis of Cushing syndrome. The procedure involves chewing a cotton tube for 2-3 minutes between 11 PM and 12 AM. Salivary cortisol levels correlate highly with plasma and serum-free cortisol levels. One positive initial screening test result should be confirmed by a second initial screening test to establish the diagnosis. Once the diagnosis of Cushing syndrome is established, the next step is to determine the cause. Plasma ACTH measurement by immunoradiometric assay is the most direct method. A normal to elevated ACTH level is diagnostic of hypercortisolism due to pituitary adenoma or ectopic ACTH secretion. Suppressed ACTH levels are diagnostic of hypercortisolism due to a primary adrenal cause such as adenoma, carcinoma, or nodular hyperplasia.
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The differential diagnosis of ACTH-dependent Cushing syndrome can be challenging. No test is perfect, and a combination of tests may be necessary. Since 90% of patients have Cushing disease, pituitary MRI is the first test to identify the source of ACTH secretion. However, 10% of normal adults have incidental pituitary lesions 3-6 mm in diameter on MRI, and many patients with Cushing disease have no detectable lesions. Lesions smaller than 3-4 mm are more likely to represent normal variation, artifacts, volume averaging, incidental nonfunctional adenomas, or cysts. An unequivocal pituitary lesion (ie, > 4-5 mm in diameter with decreased signal intensity on gadolinium) strongly suggests Cushing disease.
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If the pituitary MRI does not show a definite lesion, the next step is inferior petrosal sinus sampling with corticotropin-releasing hormone (CRH) stimulation. Compared with other biochemical tests, such as high-dose dexamethasone suppression or CRH stimulation, petrosal sinus sampling is the most accurate way to identify an ACTH-secreting pituitary adenoma; the diagnostic accuracy is close to 100%. The test requires simultaneous bilateral venous sampling from the inferior petrosal sinuses. The inferior petrosal sinus connects the cavernous sinus to the jugular bulb and drains the pituitary. A central-to-peripheral ACTH ratio of 2 or greater without CRH stimulation is diagnostic of Cushing disease. CRH, 100 μg given intravenously as a bolus injection, can increase the diagnostic sensitivity to 100%; a peak central-to-peripheral ACTH ratio of 3 or greater is diagnostic of Cushing disease. The lack of a central-to-peripheral ACTH gradient is diagnostic of an ectopic ACTH-secreting tumor.
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In Cushing syndrome caused by primary adrenal diseases, the plasma ACTH level is suppressed. Adenomas are usually 3-5 cm in diameter and secrete only cortisol. Adrenal carcinomas are typically larger than 5 cm in diameter, are usually rapidly progressive, and may cosecrete other hormones, such as adrenal androgens, deoxycorticosterone, aldosterone, and estrogens.
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For Cushing syndrome caused by primary adrenal diseases, thin-section CT or MRI is able to detect virtually all of the adrenal tumors and hyperplasia. MRI of the sella is the imaging study of choice for pituitary adenomas. If a definitive adenoma is not seen, inferior petrosal sinus sampling with CRH stimulation can differentiate Cushing disease from ectopic Cushing syndrome. For ectopic Cushing syndrome, CT or MRI of the chest and abdomen may detect ACTH-secreting tumors. Bronchial carcinoids may be very small and difficult to find; high-resolution thin-cut CT of the chest is indicated. Occasionally, the source of an ectopic ACTH-secreting tumor cannot be determined (occult ectopic ACTH syndrome).
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Severe or lethal complications may result from sustained hypercortisolism, including hypertension, cardiovascular disease, stroke, thromboembolism, infection, severe debilitating muscle wasting, and weakness. Psychosis is common. Death may also be caused by the underlying tumors, such as adrenal carcinoma, small cell lung cancer, and others causing ectopic ACTH syndrome.
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The truncal obesity and muscle weakness in patients with Cushing syndrome predispose them to postoperative pulmonary complications. Atrophic skin and easy bruisability also predict poor wound healing.
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Nelson syndrome, the progression of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy for Cushing disease, occurred in as many as 30% of patients in the era when bilateral adrenalectomy was used as primary therapy. However, since transsphenoidal resection has become the initial procedure of choice for Cushing disease, and because MRI now allows accurate diagnosis of pituitary adenomas larger than 5 mm, Nelson syndrome occurs in less than 5% of patients.
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These tumors in patients with Nelson syndrome are among the most aggressive of pituitary tumors, causing sellar enlargement and extrasellar extension. Plasma ACTH levels are markedly elevated. Patients are frequently hyperpigmented and hypopituitary, with symptoms of mass effects including headaches, visual field deficits, and even blindness from optic nerve compression. Removal of feedback control from hypercortisolism at the pituitary level probably explains the aggressiveness of these tumors.
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Resection is the best treatment for cortisol-producing adrenal tumors or ACTH-producing tumors. Other treatment options may be necessary to temporarily control hypercortisolism—or for patients not cured by resection or when complete resection is impossible.
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A. Excision of Pituitary Adenoma
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Patients with Cushing disease are usually treated by transsphenoidal microsurgical excision of the pituitary adenomas. Relief of symptoms is rapid, and the prognosis for adequate residual pituitary-adrenal function is good. Total or subtotal hypophysectomy may be performed in older patients if a discrete tumor is not found. Pituitary procedures fail in about 15%-25% of patients because of failure to find the adenoma, pituitary hyperplasia, or recurrence of adenoma. When pituitary surgery fails, the disease may respond to pituitary irradiation. In some patients, medical therapy or total adrenalectomy will be necessary. Because of the effectiveness of pituitary microsurgery, radiotherapy is usually not recommended as primary treatment for Cushing disease.
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Compared with patients with other adrenal tumors, those with severe Cushing syndrome are at a higher risk for postoperative complications such as wound infection, hemorrhage, peptic ulceration, and pulmonary embolism. Adrenalectomy, however, is usually successful in reversing the devastating effects of hypercortisolism.
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Laparoscopic adrenalectomy causes less morbidity than open adrenalectomy and is preferred for benign hyperplasia or adenomas. Laparoscopic adrenalectomy for adrenocortical carcinoma is technically challenging. If necessary, the operation should be converted to laparotomy to achieve complete tumor resection without breaching the capsule. Local recurrence may be more common after laparoscopic resection for large and invasive cancer, especially if the capsule is breached during dissection.
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Unilateral adrenalectomy is indicated for adrenal adenomas or carcinomas that secrete cortisol. The contralateral adrenal gland and the hypothalamic-pituitary-adrenal axis will usually recover from the suppression 1-2 years after the operation. Subtotal resection is not indicated because adenoma and carcinoma may not be readily distinguishable.
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Total bilateral adrenalectomy is indicated for selected patients with Cushing disease or ectopic ACTH syndrome in whom the ACTH-secreting tumor cannot be found or resected. It is also indicated for patients with bilateral primary adrenal disease, such as pigmented micronodular hyperplasia or massive macronodular hyperplasia.
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Bilateral adrenalectomy can almost always be accomplished by the laparoscopic approach.
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Subtotal resection is not recommended in patients with Cushing syndrome, because it usually leaves inadequate adrenocortical reserve initially, and the disease frequently recurs with continuing ACTH stimulation. Total bilateral adrenalectomy with adrenal gland autotransplantation is rarely successful and offers little advantage over pharmacologic replacement.
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Drugs are mainly used as adjuvant therapy. Hypercortisolism may be controlled with ketoconazole, metyrapone, or aminoglutethimide, all of which inhibit steroid biosynthesis. Ketoconazole is usually the first choice. A combination of drugs may be necessary to control hypercortisolism and to decrease dose-related side effects.
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Mifepristone (RU 486), a progesterone and glucocorticoid receptor antagonist, is also effective, but it raises cortisol and ACTH levels, making it difficult to monitor the patient. Experience with the medication is still limited.
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Mitotane is a dichlorodiphenyltrichloroethane derivative that is toxic to the adrenal cortex. It has been used with modest success in the treatment of adrenal hypersecretory states, especially adrenocortical carcinoma. Unfortunately, serious side effects are common at effective doses.
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Pasireotide, a somatostatin analog, and cabergoline, a dopamine receptor (type 2) agonist, may be effective in controlling hypercortisolism in small subsets of patients with Cushing disease. Frequently, a combination of drugs is needed.
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D. Postoperative Maintenance Therapy
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For patients who require total adrenalectomy, lifelong corticosteroid maintenance therapy becomes necessary after total adrenalectomy. The following schedule is commonly used: no cortisol is given until the adrenals are removed during surgery. On the first day, give 50 mg of hydrocortisone intravenously every 6-8 hours. On the second day, give 25 mg every 6-8 hours. Thereafter, the dose should be tapered as tolerated. The same tapering process is used after excision of a unilateral cortisol-secreting adenoma, because the remaining adrenal may not function normally for months.
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As the hydrocortisone dose is reduced below 50 mg/d, it is often necessary to add fludrocortisone (a mineralocorticoid), 0.1 mg daily orally if patients had bilateral adrenalectomy. The usual maintenance doses are about 15-20 mg of hydrocortisone and 0.1 mg of fludrocortisone daily. More than half the hydrocortisone dose is given in the morning.
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Patients who have had a total bilateral adrenalectomy and are on maintenance therapy can develop addisonian crisis when under stress, such as general anesthesia or infection. Adrenal insufficiency causes fever, hyperkalemia, abdominal pain, and hypotension, and should be promptly recognized and treated with saline infusion and cortisol.
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The prognosis is good after resection of benign adrenal adenomas, pituitary adenomas, or benign ACTH-secreting tumors. Patients with Cushing disease in remission after pituitary surgery have reversal of excess mortality. Symptoms and signs of hypercortisolism resolve, usually over months. Short-term adrenal insufficiency after surgery requires cortisol replacement. Cushing disease can recur after excision of a pituitary adenoma. An occult ACTH-secreting tumor may become apparent later and require removal.
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Residual adrenal tissue or embryonic rests are present in up to 10% of patients after total adrenalectomy. Cushing syndrome can then recur if stimulation with ACTH continues.
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The prognosis is extremely poor in patients with adrenocortical carcinoma and in those with malignant tumors causing ectopic ACTH syndrome.
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