Fw: Cushing Syndrome

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----- Original Message ----- From: Kathi

Sent: Sunday, September 15, 2002 12:26 AM

Subject: Cushing Syndrome

Cushing Syndrome Last Updated: April 11, Author: Gail Adler, MD, PhD, Assistant Professor, Department of Medicine, Division of Endocrinology and Hypertension, Brigham and Women's Hospital, Harvard Medical School Gail Adler, MD, PhD, is a member of the following medical societies: Endocrine Society, and New York Academy of Sciences Editor(s): Chiang, MD, Assistant Director, Assistant Professor of Clinical Surgery/Emergency Medicine, Department of Emergency Medicine, Bellevue Hospital Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; A Bessen, MD, Program Director, Professor of Medicine, Department of Emergency Medicine, Harbor-UCLA Medical Center; Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Barry Brenner, MD, PhD, Chairman, Department of Emergency of Medicine, Professor, Departments of Emergency Medicine and Internal Medicine, University of Arkansas for Medical Sciences Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. Individuals with Cushing syndrome develop moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae. Individuals often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes mellitus, and impaired immune function may occur. In an emergency situation, it is important to remember that the most common cause of Cushing syndrome is use of exogenous glucocorticoids. Exogenous steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for up to a year after stopping steroid treatment. An individual with HPA axis suppression is not able to increase steroid production appropriately during a medical illness and needs to receive stress doses of steroids to avoid an adrenal crisis. Thus, in the ED, the potential for adrenal insufficiency should be considered in any patient with a cushingoid appearance. Pathophysiology: Cushing syndrome is caused by either excess levels of exogenously administered glucocorticoids or endogenous overproduction of cortisol. Endogenous glucocorticoid overproduction may be due to a primary adrenocortical abnormality (ie, adenoma, carcinoma, nodular adrenal hyperplasia) or to excess adrenocorticotropic hormone (ACTH) production. ACTH-secreting neoplasms are either an anterior pituitary tumor (Cushing disease) or an ectopic nonpituitary tumor (eg, oat cell, small cell lung carcinoma, carcinoid tumor). Ectopic corticotropin-releasing hormone (CRH) secretion is a very rare cause of Cushing syndrome. Frequency: In the US: Most cases of Cushing syndrome are caused by exogenous glucocorticoids. Annual incidence of endogenous Cushing syndrome has been estimated at 13 cases per million individuals. Of these cases, approximately 70% are caused by Cushing disease (pituitary ACTH-producing tumor), 15% to ectopic ACTH, and 15% to a primary adrenal tumor. Mortality/Morbidity: Morbidity and mortality associated with Cushing syndrome are primarily related to the effects of excess glucocorticoids. Two catastrophic medical crises that occur in glucocorticoid excess states are perforated viscera and opportunistic fungal infections. Exposure to excess glucocorticoids results in multiple medical problems, including hypertension, obesity, osteoporosis, fractures, impaired immune function, impaired wound healing, glucose intolerance, and psychosis. Exogenous steroids suppress the HPA axis, with full recovery taking up to 1 year after cessation of glucocorticoid administration. Thus, patients who are taking or who have taken steroids are at risk for developing an adrenal crisis. A primary pituitary tumor may cause panhypopituitarism and visual loss. In addition, the rare adrenocortical carcinomas have a 5-year survival rate of 30% or less. Sex: Cushing syndrome caused by an adrenal or pituitary tumor has a female-to-male incidence ratio of approximately 5:1. Ectopic ACTH production is more frequent in men because of increased incidence of lung tumors in this population. Age: Peak incidence of Cushing syndrome caused by an adrenal or pituitary adenoma is in persons aged 25-40 years. Ectopic ACTH production due to lung cancer occurs later in life. CLINICAL History: Patients with Cushing syndrome complain of weight gain, especially in the face, supraclavicular region, upper back, and torso. Frequently, patients notice changes in their skin including purple stretch marks, easy bruising, and thinning. Women may complain of irregular menses and hirsutism. Due to proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms. Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop. New onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may be noted. Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, visual problems, and galactorrhea. If destruction of the anterior pituitary exists, hypothyroidism and amenorrhea may develop. Rapid onset of symptoms of glucocorticoid excess along with virilization in women or feminization in men is worrisome and suggestive of an adrenal carcinoma. Physical: Volume-expanded hypertension may occur with glucocorticoid excess. Skin Plethora, violaceous striae, bruises Hirsutism and male pattern of balding in women (possible) Increased adipose in neck and trunk; central weight gain Moon facies Emotional lability Loss of height, kyphosis, and/or axial skeletal pain may occur secondary to glucocorticoid-induced compression fractures. Neurological Proximal muscle weakness and psychological disturbances may occur. These may be very mild (eg, trouble concentrating) to severe (eg, glucocorticoid-induced psychosis). Visual field defects (often bitemporal) and blurred vision may occur in individuals with large ACTH-producing pituitary tumors. Additional physical findings Hypothyroidism: In patients with large ACTH-producing pituitary tumors, destruction of the anterior pituitary may be sufficient to cause a loss of production of other pituitary hormones. In adults, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone (GH) deficiency do not cause obvious physical findings; however, thyroid-stimulating hormone (TSH) deficiency results in hypothyroidism and causes physical findings consistent with thyroid hormone deficiency. Galactorrhea: Anterior pituitary tumors may cause a rise in prolactin through compression of the pituitary stalk. Elevated prolactin levels may produce bilateral galactorrhea that is detectable on physical examination. Adrenal crisis: Patients with cushingoid features may present to the ED in an adrenal crisis. This may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase steroid use during an acute illness. It also may occur in patients who have recently undergone resection of an ACTH- or cortisol-producing tumor. Patients with unresectable tumors may be treated with adrenolytic drugs (mitotane) and/or antisteroidogenic drugs (metyrapone, aminoglutethimide) that could induce adrenal insufficiency. Physical findings that occur in an adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Causes: Exogenous steroid administration Administration of exogenous steroids may lead to the development of Cushing syndrome. Symptoms of glucocorticoid excess generally occur with the administration of oral steroids, but occasionally, injections of joints with steroids and the use of steroid inhalers can cause Cushing syndrome. Suppression of the HPA axis may occur in the absence of obvious signs of glucocorticoid excess. Patients with diseases that respond to steroid therapy are especially likely to receive steroids and thus develop Cushing syndrome. Such disorders include a wide variety of rheumatological, pulmonary, neurological, and nephrological diseases. Patients who have undergone organ transplants are also at risk for developing Cushing syndrome due to exogenous steroid administration. Endogenous glucocorticoid overproduction Primary adrenal lesions: Overproduction of glucocorticoids may be due to an adrenal adenoma, adrenal carcinoma, or macro/micro nodular adrenal hyperplasia. The zona fasciculata/zona reticularis layer of the adrenal cortex normally produces glucocorticoids and androgens. Glucocorticoid-secreting tumors are derived from these cells and thus may secrete both glucocorticoids and androgens. In general, excess androgen secretion is suggestive of an adrenal carcinoma rather than an adrenal adenoma. These glucocorticoid-producing tumors do not secrete aldosterone, which is produced in the zona glomerulosa layer of the adrenal cortex. ACTH-producing pituitary tumor: Pituitary tumors that secrete ACTH are derived from corticotrophs in the anterior pituitary. ACTH secreted by corticotrophs is released into the circulation and acts on the adrenal cortex to stimulate the secretion of adrenal steroids. These tumors, if large, can cause loss of production of other anterior pituitary hormones, thyroid hormone, FSH, LH, GH, and prolactin, as well as loss of production of the posterior pituitary hormone vasopressin. Large pituitary tumors may press on the optic chiasm, causing visual field deficiencies that often present as bitemporal field cuts. Ectopic ACTH production: ACTH sometimes is secreted by oat cell or small cell lung tumors or by carcinoid tumors. WORKUP Lab Studies: Excess glucocorticoids can result in a white blood cell (WBC) count higher than 11,000/mm3. Hypokalemic metabolic alkalosis may occur in patients with urinary free cortisol levels above 1500 mcg/24 h. Diagnosis of excess endogenous cortisol production The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high cortisol levels. Since acute illness activates the HPA axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed in the ED when patients are acutely ill. The following are 2 common screening tests for Cushing syndrome: Determination of 24-hour urinary free cortisol is an excellent indicator of overall daily cortisol production. Values more than 4 times the upper limit of normal are very suggestive of Cushing syndrome, whereas values 1-4 times normal are consistent with either pseudo-Cushing or Cushing syndrome. With the overnight 1 mg dexamethasone suppression test, 1 mg of dexamethasone is ingested at 11 pm, and serum cortisol is measured at 8 am the next morning. In healthy individuals, serum cortisol should be less than 2 mcg/dL. Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing, and both false-positive and false-negative test results are possible. False-positive results may occur in individuals with obesity, alcoholism, chronic renal failure, affective disorders, anorexia, and bulimia. Strenuous exercise and illness raise cortisol secretion. Medications that increase corticosteroid-binding globulin (eg, estrogen, tamoxifen) may cause appropriate increases in cortisol levels. Finally, medications that facilitate the metabolism of dexamethasone (eg, phenobarbital, phenytoin, rifampin) may cause false-positive results with the dexamethasone suppression test. In many instances, additional studies need to be performed to establish the diagnosis of excess cortisol production. The 48-hour low-dose dexamethasone suppression test (0.5 mg dexamethasone PO q6h for 8 doses) has been used for many years. In healthy individuals, 24-hour urinary 17-hydroxycorticosteroids are suppressed to 4 mg or less during the second day of dexamethasone ingestion. A 24-hour urinary free cortisol higher than 20 mcg suggests Cushing Syndrome. Unfortunately, sensitivity and specificity of this test are only about 70%. A promising new method of detecting mild glucocorticoid excess combines the 48-hour low-dose dexamethasone suppression test with CRH stimulation. Ovine CRH (1 mcg/kg IV) is given 2 hours after the eighth dose of 0.5 mg dexamethasone. Serum cortisol is measured 15 minutes after ovine CRH administration. A cortisol of higher than 1.4 mg/dL is very suggestive of Cushing syndrome. In order to institute appropriate therapy, the cause of excess cortisol secretion must be determined. A logical first step involves determining if the syndrome is ACTH-dependent or ACTH-independent. A plasma ACTH, measured by an immunoradiometric assay of less than 5 pg/mL, is suggestive of a primary adrenal tumor. An ACTH level higher than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome. The 8 mg overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test may be useful when baseline ACTH levels are indeterminate. These studies also help in determining whether a patient has pituitary or ectopic ACTH production. In the overnight 8 mg dexamethasone suppression test, individuals receive dexamethasone 8 mg PO at 11 pm with measurement of cortisol at 8 am the next day. Suppression of serum cortisol to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH or primary adrenal disease. Diagnostic accuracy, however, is only 70-80%. With the 48-hour high-dose dexamethasone suppression test, patients ingest 2 mg dexamethasone q6h for 8 doses. A decrease in urinary free cortisol of more than 50% is suggestive of an anterior pituitary tumor rather than ectopic ACTH or a primary adrenal tumor. Unfortunately, sensitivity of this test is only 80%, with a specificity of 70-80%. More stringent criteria of a 90% decrease in urinary free cortisol levels excludes the diagnosis of ectopic ACTH and has 100% specificity for anterior pituitary disease. Imaging Studies: Perform imaging studies for Cushing syndrome after the biochemical evaluation outlined above. An abdominal CT scan is recommended if a primary adrenal problem is suspected. Presence of an adrenal mass larger than 4-6 cm raises the possibility that the mass is an adrenal carcinoma. If a pituitary source of excess ACTH is suspected, patients should undergo magnetic resonance imaging (MRI) of the pituitary. Unfortunately, normal-appearing pituitaries occur in some patients with Cushing disease due to a microadenoma as well as in Cushing disease due to diffuse hyperplasia of ACTH-producing cells. In these cases, ACTH lateralization during an inferior petrosal sinus sampling study may be useful in guiding surgical therapy. Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH. Procedures: Inferior petrosal sinus (IPS) sampling: This procedure is performed with CRH stimulation to aid in determining the source of excess ACTH. Bilateral IPS sampling and simultaneous peripheral ACTH measurements are made at baseline and 2, 3, 5, and 10 minutes after intravenous administration of ovine CRH (1 mcg/kg). A baseline and stimulated ratio of IPS to peripheral ACTH of less than 1.8 is suggestive of ectopic ACTH, while a ratio of IPS to peripheral ACTH of greater than 2 is consistent with Cushing disease. In 70-80% of patients, a ratio of greater than 1.4 between the right and left inferior petrosal sinuses is predictive of the location of the microadenoma. TREATMENT Emergency Department Care: In many instances, patients with Cushing syndrome present to the ED with complaints that are unrelated to excess glucocorticoids. With respect to glucocorticoid status, the main goal of ED care should be to determine whether the patient has Cushing syndrome due to treatment with exogenous steroids. If so, patients who are acutely ill should receive stress doses of IV steroids (100 mg hydrocortisone every 8 hours) to avoid an adrenal crisis. Also, patients who have recently undergone surgical cure of endogenous Cushing Syndrome or have been placed on adrenolytic therapy or on inhibitors of adrenal steroidogenesis may present with adrenal insufficiency and require stress doses of IV steroids (100 mg hydrocortisone every 8 hours). Endogenous Cushing syndrome may require surgery, radiation, or drug therapy. Medical treatment with adrenocortical inhibitors is not very successful; use only when other methods have failed. Surgery is the treatment of choice with the following conditions: Pituitary tumors involve (1) transsphenoidal surgery, (2) radiation therapy as an adjunct for patients who are not cured, and (3) bilateral adrenalectomy if necessary to control toxic cortisol levels. Adrenocortical tumors require surgical removal. With adrenocortical carcinoma, prognosis is poor. Removal of neoplastic tissue is indicated for ectopic ACTH production. Metastatic spread makes a surgical cure unlikely or impossible. Bilateral adrenalectomy is indicated if necessary to control toxic cortisol levels. Consultations: In the rare instance that the clinical situation necessitates immediate initiation of antiglucocorticoid therapy, consult with an endocrinologist. Obtain a neurosurgical consultation if there is evidence of visual field deficits, blurred vision, or compression of the optic chiasm on imaging studies. MEDICATION Drug Category: Corticosteroids -- Used to treat subjects suspected of having adrenal crisis. Drug Name Hydrocortisone (Hydrocortone, Cortef, Hydrocort) -- DOC because of mineralocorticoid activity and glucocorticoid effects. Adult Dose 100 mg IV q 8 h; decrease dose rapidly as condition improves Pediatric Dose <12 years: 1-2 mg/kg IV bolus, followed by 25-150 mg/d divided q6-8h 12 years: 1-2 mg/kg IV bolus, followed by 150-250 mg/d divided q6-8h Contraindications Documented hypersensitivity; viral, fungal, or tubercular skin infections Interactions Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis FOLLOW-UP Further Outpatient Care: If a patient appears to have endogenous Cushing syndrome, arrange for a follow-up appointment with a primary care physician or endocrinologist to establish the diagnosis and develop a therapeutic plan. Since a 24-hour urinary free cortisol level is a good screening test for Cushing syndrome, send patients home with a container to collect a 24-hour urine sample for measurement of cortisol and creatinine. Preservatives are not required for these assays. Thus, any clean container may be used to collect the urine. Inform patient that this collection should be made after recovery from the acute illness. Complications: Osteoporosis Increased susceptibility to infections Hirsutism Metastases of malignant tumors Prognosis: The usual course is chronic, with cyclic exacerbations and rare remissions. The prognosis is guardedly favorable with surgery. Patient Education: Provide instructions on drug therapy. Provide instructions on diet, including potassium supplementation for cases in which hypokalemia is present. MISCELLANEOUS Medical/Legal Pitfalls: Patients with Cushing syndrome due to exogenous steroid use are at risk for having an adrenal crisis if they do not receive stress doses of steroids during an acute illness. Untreated adrenal crises can lead to death. In addition, high levels of endogenous or exogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel. BIBLIOGRAPHY Eddy RL, AL, Gilliland PF, et al: Cushing's syndrome: a prospective study of diagnostic methods. Am J Med 1973 Nov; 55(5): 621-30[Medline]. Findling JW, Doppman JL: Biochemical and radiologic diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 1994 Sep; 23(3): 511-37[Medline]. Flack MR, Oldfield EH, Cutler GB Jr, et al: Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Intern Med 1992 Feb 1; 116(3): 211-7[Medline]. Nieman L, Cutler GB Jr: Cushing's syndrome. In: Degroot LJ, Besser M, Burger HG, et al, eds. Endocrinology. 3rd ed. Philadelphia: WB Saunders Co; 1995:1741-69. Pavlatos FC, Smilo RP, Forsham PH: A rapid screening test for Cushing's syndrome. JAMA 1965; 193: 720-23. Plotz CM, Knowlton AI, Ragan C: The natural history of Cushing's syndrome. Am J Med 1952; 13: 597-614. Tyrrell JB, Findling JW, Aron DC, et al: An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome. Ann Intern Med 1986 Feb; 104(2): 180-6[Medline]. Yanovski JA, Cutler GB Jr: Glucocorticoid action and the clinical features of Cushing's syndrome. Endocrinol Metab Clin North Am 1994 Sep; 23(3): 487-509[Medline]. Yanovski JA, Cutler GB Jr, Chrousos GP, Niemann LK: Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 1993 May 5; 269(17): 2232-8[Medline].