7EpidemiologyCushing's syndrome is generally considered a rare disease.1–2 per 100,000 population per year.Cushing's disease is caused by an ACTH-producing corticotrope adenoma of the pituitary (75%)initially described by Harvey Cushing in 1912Cushing's disease more frequently affects women
8prepubertal cases is more common in boys. ectopic ACTH syndrome is more frequently identified in men.Only 10% of patients with Cushing's syndrome have a primary, adrenal cause of their disease and most of these patients are women.the medical use of glucocorticoids for immunosuppression, or for the treatment of inflammatory disorders, is the most common cause of Cushing's syndrome.
9EtiologyCushing's disease :at least 90% of patients is caused by a corticotrope pituitary microadenoma, often only a few millimeters in diameter.Pituitary macroadenomas (i.e. tumors >1 cm in size), are found in only 5–10% of patientsusually occur sporadicallyvery rarely can be found in the context of multiple endocrine neoplasia type 1 (MEN1)
10Ectopic ACTH production predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in thymus or pancreas.Because of their small size, these tumors are often difficult to locate.Advanced small cell lung cancerIn rare cases medullary thyroid carcinoma or pheochromocytoma
11ACTH-independentThe majority of patients with ACTH-independent cortisol excess harbor a cortisol-producing adrenal adenoma.Adrenocortical carcinomas may also cause ACTH-independent disease and are often large, with excess production of several corticosteroid classes.
22excess glucocorticoid secretion overcomes the ability of 11-HSD2 to rapidly inactivate cortisol to cortisone in the kidney, thereby exerting mineralocorticoid actions, manifest as :diastolic hypertensionHypokalemiaedema
24suppression of gonadotropins with subsequent hypogonadism and amenorrhea suppression of the hypothalamic-pituitary-thyroid axis, resulting in decreased TSH (thyroid-stimulating hormone) secretion.
25more specific features are : fragility of the skineasy bruisingbroad (>1 cm), purplish striaesigns of proximal myopathy, which becomes most obvious when trying to stand up from a chair without the use of hands or when climbing stairs.
28The majority of clinical signs and symptoms observed in Cushing's syndrome are relatively nonspecific and include features such as:ObesityDiabetesdiastolic hypertensionHirsutismdepressionthat are commonly found in patients who do not have Cushing's
29Clinical manifestations of Cushing's do not differ substantially among the different causes of Cushing's.In ectopic ACTH syndrome, hyperpigmentation of the knuckles, scars, or skin areas exposed to increased friction can be observed and is caused by stimulatory effects of excess ACTH and other POMC cleavage products on melanocyte pigment production.
30patients with ectopic ACTH syndrome, and some with adrenocortical carcinoma as the cause of Cushing's, may havea more brisk onsetrapid progression of clinical signs and symptoms
381- features with a potentially higher discriminatory value 2 - excluding exogenous glucocorticoid use
39increased 24-hour urinary free cortisol excretion in three separate collections failure to appropriately suppress morning cortisol after overnight exposure to dexamethasoneevidence of loss of diurnal cortisol secretion with high levels at midnight, the time of the physiologically lowest secretion
42midnight cortisol level greater than 200 nmol/L (>7 midnight cortisol level greater than 200 nmol/L (>7.5 μg/dL) indicates Cushing’s syndromemidnight Salivary Cortisol:a value greater than 2.0 ng/mL (5.5 nmol/L) has a 100% sensitivity and a 96% specificity for diagnosis of Cushing’s syndrome
43Urinary Free Cortisol Excretion Normal values are less than 220 to 330 nmol/24 hours (80 to 120 μg/24 hours), Patients should make two or three complete consecutive collections
44Low-Dose Overnight Dexamethasone Suppression Tests In normal subjects, the administration of a supraphysiologic dose of glucocorticoid results in suppression of ACTH and cortisol secretion1 mg of dexamethasone is given at midnight.A normal response is a plasma cortisol level of less than 140 nmol/L (<5 μg/dL) between 8 and 9 a.m.a postdexamethasone cortisol value of less than 50 nmol/L (<2 μg/dL) effectively excludes Cushing’s syndrome.
4548-hour low-dose dexamethasone test plasma cortisol is measured at 9 a.m. on day 0 and again 48 hours later, after administration of dexamethasone 0.5 mg every 6 hours for 48 hoursUsing a postdexamethasone plasma cortisol concentration of less than 50 nmol/L (<2 μg/dL) as the cutoff pointthis test is reported to have a 97% to 100% true-positive rate and a false-positive rate of less than 1%
50plasma ACTH levels are suppressed in cases of autonomous adrenal cortisol excess, as a consequence of enhanced negative feedback to the hypothalamus and pituitary.patients with ACTH-dependent Cushing's have normal or increased plasma ACTH,very high levels being found in some patients with ectopic ACTH syndrome.
55In patients with confirmed ACTH-independent excess, adrenal imaging is indicated preferably using an unenhanced CT scan. This allows assessment of :adrenal morphologydetermination of tumor density in Hounsfield Units (HU), which helps to distinguish between benign and malignant adrenal lesions
56For ACTH-dependent cortisol excess an MRI of the pituitary is the investigation of choice it may not show an abnormality in up to 40% of cases because small tumors are below the sensitivity of detection.Characteristically, pituitary corticotrope adenomas fail to enhance following gadolinium administration on T1-weighted MRI images
57In all cases of confirmed ACTH-dependent Cushing's, further tests are required for the differential diagnosis of pituitary Cushing's disease and ectopic ACTH syndrome.most pituitary corticotrope adenomas still display regulatory features, including residual ACTH suppression by high-dose glucocorticoids and CRH responsiveness.ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH
58if there is any other reason for doubt, the differential diagnosis can be further clarified by performing bilateral inferior petrosal sinus sampling (IPSS) with concurrent blood sampling for ACTH in the right and left inferior petrosal sinus and a peripheral vein.An increased central/peripheral plasma ACTH ratio >2 at baseline and >3 after CRH injection is indicative of Cushing's disease, with very high sensitivity and specificity.the results of the IPSS cannot be reliably used for lateralization (i.e. prediction of the location of the tumor within the pituitary),
62If the differential diagnostic testing indicates ectopic ACTH syndrome, then further imaging should include high-resolution, fine-cut CT scanning of the chest and abdomen for lung, thymus, and pancreas.If no lesions are identified, an MRI of the chest can be considered as carcinoid tumors usually show high signal intensity on T2-weighted images.
63Furthermore, octreotide scintigraphy can be helpful in some cases as ectopic ACTH-producing tumors often express somatostatin receptors.Depending on the suspected cause, patients with ectopic ACTH syndrome should also undergo blood sampling for fastinggut hormoneschromogranin ACalcitoninbiochemical exclusion of pheochromocytoma
66TreatmentOvert Cushing's is associated with a poor prognosis if left untreatedIn ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor
67Cushing's diseasetreatment of choice is selective removal of the pituitary corticotrope tumor, usually via a transsphenoidal approach.This results in an initial cure rate of 70–80%long-term follow-up is important as late relapse occurs in a significant number of patients.
68If pituitary disease recurs, there are several options, including second surgeryRadiotherapystereotactic radiosurgerybilateral adrenalectomy
69very severe Cushing difficult to control hypokalemia hypertension acute psychosis
70medical therapy it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery.patients with metastasized, glucocorticoid-producing carcinomasIn case of ectopic ACTH syndrome, in which the tumor cannot be located
72Oral agents metyrapone ketoconazole. Mitotane, etomidate can be used In severe cases of cortisol excess, to lower cortisol. It is administered by continuous IV infusion in low, nonanesthetic doses.
73Metyrapone inhibits cortisol synthesis at the level of 11-hydroxylase . Typical starting doses are 500 mg/tid (maximum dose, 6 g)antimycotic drug ketoconazole inhibits the early steps of steroidogenesis, 200 mg/tid (maximum dose, 1200 mg).
74Mitotane, a derivative of the insecticide DDT, is an adrenolytic agent that is also effective for reducing cortisol.most commonly used in the context of adrenocortical carcinoma, but low-dose treatment (500–1000 mg per day) has also been used in benign Cushing's.
75After surgeryAfter the successful removal of an ACTH- or cortisol-producing tumor, the HPA axis will remain suppressed.hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery, to allow physiologic adaptation to normal cortisol levels.the HPA axis may require many months or even years to resume normal function.