endocrine and metabolic disorders
Cushing Syndrome
Diagnosis of Cushing Syndrome
Urinary free cortisol level Dexamethasonesuppression test Midnight serum or salivary cortisol levels Plasma ACTH levels; if detectable, provocative testing Diagnosis is usually suspected based on the characteristic symptoms and signs. Confirmation (and identification of the cause) generally requires hormonal and imaging tests. In some centers, testing begins with a 24-hour measurement of urinary free cortisol, which is elevated>120 mcg/24 hours (>331 nmol/24 hours) in almost all patients with Cushing syndrome. However, many patients with elevations of urinary free cortisol between 100 and 150 mcg/24 hours (276 and 414 nmol/24 hours) have obesity, depression, or polycystic ovaries but not Cushing syndrome. Normal ranges may vary according to assay. A patient with suspected Cushing syndrome with grossly elevated urinary free cortisol (>4 times the upper limit of normal) almost certainly has Cushing syndrome. Two to three normal collections usually exclude the diagnosis. Slightly elevated levels generally necessitate further investigation, as do normal levels when clinical suspicion is high. A baseline morning (eg, 9 AM) serum cortisol measurement should also be done. An alternative approach to investigation uses thedexamethasonesuppression test, in which 1, 1.5, or 2 mg ofdexamethasoneis given orally at 11 to 12 PM and serum cortisol is measured at 8 to 9 AM the next morning. In most normal patients, this drug suppresses morning serum cortisol to<1.8 mcg/dL (<50 nmol/L), whereas patients with Cushing syndrome virtually always have a higher level. A more specific but equally sensitive test is to givedexamethasone0.5 mg orally every 6 hours for 2 days (low dose). In general, a clear failure to suppress cortisol levels in response to low-dosedexamethasoneestablishes the diagnosis, unless there is reason to suspect abnormaldexamethasoneabsorption or metabolism. If results of urinary free cortisol measurements and thedexamethasonesuppression test are indeterminate, the patient is hospitalized for measurement of serum cortisol at midnight, which is more likely to be conclusive. Alternatively, salivary cortisol samples may be collected and stored in the refrigerator at home. Serum cortisol normally ranges from 5 to 25 mcg/dL (138 to 690 nmol/L) in the early morning (6 to 8 AM) and declines gradually to<1.8 mcg/dL (<50 nmol/L) at midnight. Patients with Cushing syndrome occasionally have a normal morning serum cortisol level but lack normal diurnal decline in cortisol production, such that the midnight serum cortisol levels are above normal and the total 24-hour cortisol production may be elevated. Normal ranges of midnight salivary cortisol level vary according to assay. Serum cortisol may be spuriously elevated in patients with congenital increases of corticosteroid-binding globulin or in those receivingestrogentherapy, but diurnal variation is normal in these patients. 50% and cortisol rises by 20% in response to human or ovine-sequence CRH (100 mcg IV or 1 mcg/kg IV) in most patients with Cushing disease but very rarely in those with ectopic ACTH syndrome (see table Diagnostic Tests in Cushing Syndrome ). An alternative approach to localization, which is more accurate but more invasive, is to catheterize both petrosal veins (which drain the pituitary) and measure ACTH from these veins 5 minutes after giving a 100 mcg or 1 mcg/kg bolus of CRH (human or ovine). A central-to-peripheral ACTH ratio>3 virtually excludes ectopic ACTH syndrome, whereas a ratio<3 suggests a need to seek such a source. If CRH is unavailable, there is some evidence thatdesmopressin10 mcg may be equally effective. Pituitary imaging is done if ACTH levels and provocative tests suggest a pituitary cause; gadolinium-enhanced MRI is most accurate, but some microadenomas are visible on CT. If testing suggests a nonpituitary cause, imaging includes high-resolution CT of the chest, pancreas, and adrenals: scintiscanning or PET scanning with radiolabeledoctreotideor, preferably, Gallium-68 dotatate-PET and occasionally fluorodeoxyglucose (FDG)-PET scanning. Petrosal sinus sampling may be needed to differentiate pituitary from ectopic sources. In children with Cushing disease, pituitary tumors are very small and usually cannot be detected with MRI. Petrosal sinus sampling is particularly useful in this situation. MRI is preferred to CT in pregnant women to avoid fetal exposure to radiation. 