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Tests for Hypercortisolism
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The easiest screening test for hypercortisolism involves the patient obtaining a salivary cortisol at 11 pm (see below) and then dexamethasone, 1 mg orally, and collecting serum for cortisol determination at about 8 am the next morning; a cortisol level under 5 mcg/dL (< 135 nmol/L, fluorometric assay) or under 2 mcg/dL (< 54 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing s syndrome with 98% certainty However, 8% of established patients with pituitary Cushing s disease have dexamethasonesuppressed cortisol levels < 2 mcg/dL Therefore, when other clinical criteria suggest hypercortisolism, further evaluation is warranted even in the face of normal dexamethasone-suppressed serum cortisol Antiseizure drugs (eg, phenytoin, phenobarbital, primidone) and rifampin accelerate the metabolism of dexamethasone, in that way causing a lack of cortisol suppression by dexamethasone Estrogens during pregnancy or as oral contraceptives or estrogen replacement therapy may also cause lack of dexamethasone suppressibility Patients with an abnormal dexamethasone suppression test require further investigation, which includes a 24-hour urine collection for free cortisol and creatinine An abnormally high 24-hour urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps confirm hypercortisolism A misleadingly high urine free cortisol excretion occurs with high fluid intake In pregnancy, urine free cortisol is increased, while 17-hydroxycorticosteroids remain normal and diurnal variability of serum cortisol is
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Once hypercortisolism is confirmed, a plasma ACTH is obtained It must be collected properly in a plastic tube on ice and processed quickly by a laboratory with a reliable, sensitive assay A level of ACTH below about 20 pg/mL indicates a probable adrenal tumor, whereas higher levels are produced by pituitary or ectopic ACTH-secreting tumors
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In ACTH-dependent Cushing s syndrome, MRI of the pituitary demonstrates a pituitary lesion in about 50% of cases Premature cerebral atrophy is often noted When the pituitary MRI is normal or shows a tiny irregularity that may be incidental, selective catheterization of the inferior petrosal sinus veins draining the pituitary is performed ACTH levels in the inferior petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are indicative of pituitary Cushing s disease Inferior petrosal sinus sampling is also done during CRH administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over three times the peripheral ACTH level when the pituitary is the source of ACTH When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for an ectopic source of ACTH is undertaken Location of ectopic sources of ACTH commences with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or small cell carcinomas), the thymus,
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the pancreas, and the adrenals In patients with ACTHdependent Cushing s syndrome, chest masses should not be assumed to be the source of ACTH, since opportunistic infections are common, so it is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection CT scanning fails to detect the source of ACTH in about 40% of patients with ectopic ACTH secretion 111In-octreotide scanning is also useful in detecting occult tumors, but 18 FDG-PET scanning is not usually helpful Some ectopic ACTH-secreting tumors elude discovery, necessitating bilateral adrenalectomy In non-ACTH-dependent Cushing s syndrome, a CT scan of the adrenals can localize the adrenal tumor in most cases
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Alcoholic patients can have hypercortisolism and many clinical manifestations of Cushing s syndrome Depressed patients also have hypercortisolism that can be nearly impossible to distinguish biochemically from Cushing s syndrome but without clinical signs of Cushing s syndrome Some adolescents develop violaceous striae on the abdomen, back, and breasts; these are known as striae distensae and are not indicative of Cushing s syndrome Cushing s syndrome can be misdiagnosed as anorexia nervosa (and vice versa) owing to the muscle wasting and extraordinarily high urine free cortisol levels found in anorexia Patients with severe obesity frequently have an abnormal dexamethasone suppression test, but the urine free cortisol is usually normal, as is diurnal variation of serum cortisol Patients with familial cortisol resistance have hyperandrogenism, hypertension, and hypercortisolism without actual Cushing s syndrome In patients with familial partial lipodystrophy type I, central obesity and a moon facies develop, along with thin extremities due to atrophy of subcutaneous fat However, these patients muscles are strong and may be hypertrophic, distinguishing this condition from Cushing s syndrome Patients receiving antiretroviral therapy for HIV-1 infection frequently develop partial lipodystrophy with thin extremities and central obesity with a dorsocervical fat pad ( buffalo hump ) that may mimic Cushing s syndrome
require 6 36 months to recover normal function Hydrocortisone or prednisone replacement therapy is necessary in the meantime Patients who do not have a remission (or who have a recurrence) should be treated by bilateral laparoscopic adrenalectomy Another treatment option for patients with ACTH-secreting pituitary tumors is stereotactic pituitary radiosurgery (gamma knife or cyberknife), which normalizes urine free cortisol in two-thirds of patients within 12 months Conventional radiation therapy results in a 23% cure rate Pituitary radiosurgery can also be used to treat Nelson s syndrome, the progressive enlargement of ACTH-secreting pituitary tumors following bilateral adrenalectomy Patients who are not surgical candidates may be given a trial of ketoconazole in doses of about 200 mg every 6 hours; liver enzymes must be monitored for progressive elevation Adrenal neoplasms secreting cortisol are resected laparoscopically The contralateral adrenal is suppressed, so postoperative hydrocortisone replacement is required until recovery occurs Metastatic adrenal carcinomas may be treated with mitotane; ketoconazole or metyrapone can help suppress hypercortisolism in unresectable adrenal carcinoma Ectopic ACTH-secreting tumors should be located, when possible, and surgically resected If that cannot be done, laparoscopic bilateral adrenalectomy is recommended Medical treatment with ketoconazole or metyrapone (or both) may partially suppress the hypercortisolism; however, metyrapone may exacerbate female virilization The somatostatin analog octreotide, given parenterally, suppresses ACTH secretion in about one-third of such cases
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