What is the difference between Cushing Syndrome and Cushing Disease? First of all, Answer to your question - Cushing disease = Pituitary adenoma ACTH secreting. It displays clinical Cushing Syndrome. - Cushing syndrome is everything else with clinical features except etiology is NOT pituitary. CUSHING SYNDROME/DISEASE...GENERAL REVIEW General Considerations: Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. In an emergency situation, remembering that the most common cause of Cushing syndrome is the use of exogenous glucocorticoids is important. Exogenous steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for as long as a year after exogenous steroid administration has ended. Etiology: - Adrenal Hyperplasia * Pituitary adenoma = Cushing Disease * ACTH or CRH secreting tumor = Ectopic (Oat cell CA - CA of thymus - PAncreatic CA - Bronchial Adenoma) - Adrenal Neoplasia - Exogenous/ Iatrogenic causes = MOST COMMON. Pathophysiology: Endogenous glucocorticoid overproduction or hypercortisolism that is independent of adrenocorticotropic hormone (ACTH) usually is due to a primary adrenocortical neoplasm. ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. 80% are due to Classic Cushing disease = an anterior pituitary tumor. Ectopic sources of ACTH make up the balance of ACTH-dependent Cushing syndrome cases. Ectopic non pituitary = an oat cell, small-cell lung carcinoma, or carcinoid tumor. Rarely ectopic corticotropin-releasing hormone (CRH) secretion. Sex: female-to-male ratio is 5:1 for Cushing syndrome due to an adrenal or pituitary tumor. Ectopic ACTH production is more frequent in men than in women, due to the increased incidence of lung tumors in this population. Age: The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma occurs between ages 25 and 40 years. Ectopic ACTH production due to lung cancer occurs later in life. History: - Weight gain, especially in the face, supraclavicular region, upper back, and torso. - Changes in skin= purple stretch marks, easy bruising, and other signs of skin thinning. - Irregular menses and hirsutism - Progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms. - Psychological problems (depression, cognitive dysfunction, and emotional lability) - New onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures - Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, polyuria and nocturia, visual problems, or galactorrhea. - Mass effect on the anterior pituitary (hyposomatotropism, hypothyroidism, and hypogonadism) Physical: - Obesity, moon facies, buffalo hump, and supraclavicular fat pads. - Central obesity with increased adipose tissue in the mediastinum and peritoneum, increased visceral fat is evident on CT. - Skin, Facial plethora, Violaceous striae over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts. Ecchymoses may be present. Patients may have telangiectasias and purpura. Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident. - Steroid acne - Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over elbows, around the neck, and under the breasts. - Cardiovascular/renal: Hypertension, Volume expansion (edema from sodium and water retention). - Atherosclerotic heart disease is caused by lipid abnormalities, while diabetes mellitus and hypertension are caused by Cushing syndrome. - Gastroenterologic: Peptic ulceration (rare in endogenous hypercortisolism). - Endocrine: Hypothyroidism may occur from anterior pituitary tumors, which can interfere with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function. - Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels. - Other pituitary function may be interrupted without obvious clinical findings. Possibilities include polyuria and nocturia from diabetes insipidus. - With severe hypercortisolism, hypokalemic metabolic alkalosis may occur. - Osteoporosis = incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip also is possible from glucocorticoid excess. - Adrenal crisis Patients with cushingoid features may present to the emergency department in adrenal crisis. This may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. It also may occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor. Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis. Lab Studies: - WBC>11,000/mm3 - Hypokalemic (NA IS NORMAL) metabolic alkalosis may occur in patients with urinary free cortisol (UFC) levels higher than 1500 mcg/24-h. - 20% have Glucose intolerance/DM OVERVIEW OF EVALUATION OF PT WITH PRESUMED CUSHING SYNDROME: 1- CLINICAL SUSPICION 2- SCREENING TEST = OVERNIGHT DXM SUPPRESSION TEST (EXCLUDES CUSHING SYNDROME WITH 985 OF CERTAINTY). 3- IF ABOVE ABONORMAL = 24H URINE FREE CORTISOL + CREATININE 4- IF ABOVE ABNORMAL = CUSHING SYNDROME NEXT = HIGH DOSE DXM SUPPRESSION TEST 5- IF SUPPRESSION <50% CONTROL: CUSHING DISEASE (PITUITARY ADENOMA) IF NO SUPPRESSION: ADRENAL NEOPLASIA VS ECTOPIC TUMOR 6- NEXT = ACTH LEVEL IF HIGH = ACTH PRODUCING TUMOR => CT CHEST IG LOW = ADRENAL NEOPLASIA => URNIARY 17KS - DHEA-S - ABDOMINAL CT: ADRNEAL ADENOMA VS ADRENAL CARCINOMA. DETAILED EXPLANATION: Diagnosis of excess endogenous cortisol production requires the demonstration of inappropriately high serum cortisol levels or its urinary metabolites. Because acute illness activates the HPA axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill. Two common screening tests for Cushing syndrome are the 24-hour UFC test and the overnight (ON) 1-mg dexamethasone suppression test. * The 24-hour UFC test is an excellent indicator of overall daily cortisol production. Values higher than 3- to 4-times the upper limit of normal are very suggestive of Cushing syndrome, whereas values 1- to 3-times normal are consistent with either pseudo-Cushing or Cushing syndrome. Ensuring that the 24-hour collection for this test was adequate, by simultaneously measuring urinary creatinine excretion on the same urine sample, is important. * The ON 1-mg dexamethasone suppression test calls for ingestion of 1 mg of dexamethasone at 11 PM, with measurement of an 8-AM serum cortisol the next morning. In healthy individuals, the serum cortisol should be less than 2-3 mcg/dL. Cushing syndrome may be excluded with a cortisol level less than 1.8 mcg/dL. Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in cortisol levels. Finally, medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test. In many instances, additional studies must 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. Unfortunately, the sensitivity and specificity of this test are only approximately 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 level of greater than 1.4 mg/dL is very suggestive of Cushing syndrome. Other tests that may be useful to identify Cushing syndrome are as follows: In order to institute appropriate therapy, the cause of excess cortisol secretion must be determined. The logical first step involves establishing the differential diagnosis between an ACTH-dependent or ACTH-independent disorder. A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor. An ACTH greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome. The 8-mg ON 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 who has ACTH-dependent disease has pituitary-dependent or ectopic ACTH disease. In the ON 8-mg dexamethasone suppression test, individuals ingest 8 mg dexamethasone orally at 11 PM, with measurement of an 8-AM cortisol the next day. A baseline 8-AM cortisol measurement is required. 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. However, the diagnostic accuracy is only 70-80%. With the 48-hour high-dose dexamethasone suppression test, patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in UFC of greater than 50% is suggestive of an anterior pituitary adenoma, rather than ectopic ACTH or a primary adrenal tumor. Unfortunately, the sensitivity of this test is only 80%, with a specificity of 70-80%. The more stringent criterion of a 90% decrease in UFC levels excludes the diagnosis of ectopic ACTH and has 100% specificity for anterior pituitary disease. If concern for adrenal carcinoma exists, measurement of 17-ketosteroid or other cortisol precursors (such as serum dehydroepiandrosterone sulfate [DHEAS]) is useful. Imaging Studies: An abdominal CT scan is recommended if a primary adrenal problem is suspected. CT-guided fine-needle aspiration then may have a role in management. If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary. Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production. Octreotide scintigraphy may be helpful in detecting ectopic ACTH tumors because neuroendocrine tumors typically have cell surface receptors for somatostatin. Differential Diagnosis: - Alcoholics: high cortisol levels with clinical cushing - Depression: High cortisol with no clinical features - Anorexia Nervosa: Same wasting as in Cushing with extraordinary high levels of 24h urine cortisol - Morbid obesity mimicks results of DXM suppression test but urine free cortisol is normal - Pts on HAART for HIV-1 develop partial lipodystrophy with thin extremities and central obesity, buffalo hump. Medical Care: Overview Treatment of Cushing syndrome is directed by the primary cause of the syndrome. A culprit tumor should be removed if possible. - The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. - The primary therapy for Cushing disease is transsphenoidal surgery. Pituitary radiation may be useful if surgery fails for Cushing disease. - The primary therapy for adrenal tumors is adrenalectomy. When surgery is not successful or cannot be used, as often occurs with ectopic ACTH or metastatic adrenal carcinoma, control of hypercortisolism may be attempted with medication. However, medication failures are common, and adrenalectomy may be indicated in ACTH-mediated Cushing syndrome. - The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid. Cushing syndrome Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to cause medical adrenalectomy. These medications are used rarely and often are toxic at the doses required to reduce cortisol secretion. Thus, medical treatment should be initiated cautiously and, ideally, in conjunction with a specialist. Efficacy of these medical interventions can be assessed with serial measurements of 24-hour UFC. Patients receiving these medications may require glucocorticoid replacement to avoid adrenal insufficiency. Metyrapone and trilostane are agents that competitively inhibit a single steroidogenic enzyme. Ketoconazole and aminoglutethimide act at several sites. If enzymatic blockade is not complete, ACTH secretion overcomes the blockade so that hypercortisolism persists. Because ACTH production may persist or increase in patients with Cushing disease, radiation therapy of the pituitary often is required after unsuccessful initial therapy, either surgical or medical. These agents have higher efficacy when used in combination because they may act synergistically. Ketoconazole probably is the most popular and effective of these agents for long-term use and usually is the agent of choice. It acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. It also may inhibit ACTH secretion when used at therapeutic doses (200-400 mg bid-tid). Adverse effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia, and elevated liver function tests. The drug is contraindicated during pregnancy. Ketoconazole is ineffective in patients on H2 blockers or proton-pump inhibitors because gastric acidity is required for metabolism. If this agent is ineffective at controlling hypercortisolism, the dose may be maintained while another steroid enzyme inhibitor, typically metyrapone, is initiated. Metyrapone blocks 11-beta-hydroxylase activity (the final step in cortisol synthesis) and, at high doses, may inhibit ACTH secretion. Therapy is begun at 1 g/d divided into 4 doses and increased to a maximum dose of 4.5 g/d. Adverse effects are from increases in androgen and mineralocorticoid precursors, including hypertension, acne, and hirsutism. Aminoglutethimide is an anticonvulsant agent that blocks cholesterol side-chain cleavage to pregnenolone. It is a relatively weak adrenal enzyme inhibitor at doses that patients can tolerate. Aminoglutethimide typically is initiated at 250 mg twice daily, and increased to 2 g four times daily. - Adverse effects of aminoglutethimide include somnolence, headache, a generalized pruritic rash, hypothyroidism, and goiter. In rare cases, it may cause bone marrow suppression. Aminoglutethimide increases the metabolism of dexamethasone but not cortisol. Trilostane is not widely available and is not as well studied. Trilostane inhibits the conversion of pregnenolone to progesterone, which decreases the synthesis of cortisol, aldosterone, and androstenedione. It is not a first-choice agent because it is a weak inhibitor of steroidogenesis. In addition, trilostane interacts with some assays, causing a false elevation of cortisol measurements. Etomidate, an imidazole-derivative anesthetic agent, blocks 11-beta-hydroxylase. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for chronic administration by the intravenous route. Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis. For this reason, it is used in treatment of adrenal cancer. Its survival benefit is unclear. It can be used in addition to radiation therapy for treatment of Cushing disease and in combination with metyrapone or aminoglutethimide for treatment of ectopic ACTH secretion. - Unfortunately, mitotane is expensive, and its utility is limited by adverse gastrointestinal and neurological effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia. It is taken up by adipose tissues and persists in the circulation long after discontinuation. It is a potential teratogen and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile. Mifepristone (RU 486) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors. It currently is used only on an investigational basis for treatment of Cushing syndrome. Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include bromocriptine, cyproheptadine, valproic acid, and octreotide. Currently, use of these agents is investigational. Surgical Care: - Cushing disease Treatment of choice for classic Cushing disease is transsphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the adenoma, preserving as much pituitary function as possible. Successful amelioration of hypercortisolism occurs in 60-80% of cases. Both open and laparoscopic techniques are possible. If unsuccessful, MRI-guided pituitary surgery, a new procedure, may be indicated. - Pituitary irradiation is employed when transsphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 45% cure rate in adults and 85% cure rate in children. Late-onset adverse effects include hypopituitarism. - Bilateral adrenalectomy is an option if transsphenoidal surgery, pituitary irradiation, and medical therapy fail or if rapid normalization of cortisol levels is required. The patient then requires lifelong glucocorticoid and mineralocorticoid therapy. In individuals who undergo bilateral adrenalectomy, Nelson syndrome, ie, symptomatic enlargement of the pituitary gland and adenoma, may occur in one quarter to one half of adults not treated with pituitary irradiation and in as many as one quarter of patients pretreated with radiation therapy. - Ectopic adrenocorticotropic production Surgical resection of the source of ACTH production may not always be possible. Medical therapy or bilateral adrenalectomy may be required. * Adrenal source Adenomas may be removed with unilateral adrenalectomy, often with a laparoscopic approach. Carcinomas should be resected for palliation. Micronodular or macronodular hyperplasia causing Cushing syndrome may be treated effectively by bilateral adrenalectomy. Unilateral or subtotal adrenalectomy may lead to recurrence. - Hormone replacement Patients with endogenous Cushing syndrome who undergo resection of pituitary, adrenal, or ectopic tumors should receive stress doses of glucocorticoid in the intraoperative and immediate postoperative period. Typically, hydrocortisone at 200-300 mg is infused intravenously, either continuously or in boluses (60-100 mg every 8 h) starting prior to surgery and for the first 24 hours afterwards. If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-2 days and replaced with an oral formulation. The rate of steroid taper may be slowed if severe preoperative hypercortisolism was present. In the event of pituitary destruction or bilateral adrenalectomy, lifelong steroid replacement is necessary. Complications: Osteoporosis Increased susceptibility to infections Hirsutism Diabetes mellitus Hypertension Risk for adrenal crisis Panhypopituitarism Diabetes insipidus 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 acute illnesses. Untreated adrenal crises can lead to death. High levels of endogenous or exogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel. Two catastrophic medical crises that occur in glucocorticoid excess states are perforated viscera and opportunistic fungal infections.