Cushing Syndrome: Maybe Not So Uncommon of a Disease
Cushing Syndrome: Maybe Not So Uncommon of a Disease
Urinary Free Cortisol
The UFC test measures a patient's unbound cortisol over a 24-hour period using either antibody-based or high-performance liquid chromatography methods. Values greater than 4 times the upper limit of normal are diagnostic of CS, whereas mild hypercortisolism usually falls between the upper limit of normal and 2 to 3 times normal. These excess levels of cortisol are not diagnostic of CS because they may also occur in patients after stressful conditions, depression, or alcohol abuse (ie, pseudo-Cushing syndrome). Conversely, patients with subclinical CS may have UFC that is within normal limits. To ensure accurate results, the patient's creatinine clearance should be measured because the UFC test is unreliable in patients with creatinine clearance <60 mL/min; moreover, UFC is falsely elevated in patients who produce more than 5 L of urine a day. Some medications can have a direct or indirect effect on cortisol levels (eg, digoxin, carbamazepine, and synthetic glucocorticoids) and should also be considered when evaluating the patient's UFC test results. In addition to the test results, it is important to confirm that the patient's 24-hour urine volume and urine creatinine are normal because these values may suggest incomplete or excessive collections. Physicians should confirm adherence to the testing protocol because, on inquiry, patients have often admitted that the collection was done improperly. Finally, recalculation of the test should be performed, particularly if the UFC is exceedingly high or low, to confirm that total UFC was correctly calculated from the concentration and volume.
Late-night Salivary Cortisol
The late-night salivary cortisol test measures free cortisol levels when its production is at the lowest point in the 24-hour cycle (11 pm to 12 pm in most patients). With CS, patients no longer demonstrate a pattern of cyclic cortisol secretion, and hence the late-night cortisol level no longer reaches a low point. The collection time should coincide with the patient's normal sleep schedule and should be adjusted in patients who consistently go to bed long after midnight.
This test is now offered by most major commercial laboratories. Patients are given either an empty tube with which to collect saliva, or a cotton tube to chew for 2 to 3 minutes and then place in a plastic tube. Given its high stability at room temperature, the tube can be either transported or mailed to a laboratory for analysis. Certain patient attributes and habits (eg, irregular sleep schedule, such as in shift workers, or smoking immediately before testing) may affect the test results and should be avoided. Also, the effect of blood contamination is not known, so it is best to ask the patient not to brush their teeth immediately before the saliva collection. This testing method is promising for accurately diagnosing CS because it has high diagnostic sensitivity and specificity. The test correctly identified patients with CS while excluding individuals without the disorder >90% of the time; however, recent literature is less supportive of accuracy of this test.
Specific Features of the Biochemical Tests
Urinary Free Cortisol
The UFC test measures a patient's unbound cortisol over a 24-hour period using either antibody-based or high-performance liquid chromatography methods. Values greater than 4 times the upper limit of normal are diagnostic of CS, whereas mild hypercortisolism usually falls between the upper limit of normal and 2 to 3 times normal. These excess levels of cortisol are not diagnostic of CS because they may also occur in patients after stressful conditions, depression, or alcohol abuse (ie, pseudo-Cushing syndrome). Conversely, patients with subclinical CS may have UFC that is within normal limits. To ensure accurate results, the patient's creatinine clearance should be measured because the UFC test is unreliable in patients with creatinine clearance <60 mL/min; moreover, UFC is falsely elevated in patients who produce more than 5 L of urine a day. Some medications can have a direct or indirect effect on cortisol levels (eg, digoxin, carbamazepine, and synthetic glucocorticoids) and should also be considered when evaluating the patient's UFC test results. In addition to the test results, it is important to confirm that the patient's 24-hour urine volume and urine creatinine are normal because these values may suggest incomplete or excessive collections. Physicians should confirm adherence to the testing protocol because, on inquiry, patients have often admitted that the collection was done improperly. Finally, recalculation of the test should be performed, particularly if the UFC is exceedingly high or low, to confirm that total UFC was correctly calculated from the concentration and volume.
Late-night Salivary Cortisol
The late-night salivary cortisol test measures free cortisol levels when its production is at the lowest point in the 24-hour cycle (11 pm to 12 pm in most patients). With CS, patients no longer demonstrate a pattern of cyclic cortisol secretion, and hence the late-night cortisol level no longer reaches a low point. The collection time should coincide with the patient's normal sleep schedule and should be adjusted in patients who consistently go to bed long after midnight.
This test is now offered by most major commercial laboratories. Patients are given either an empty tube with which to collect saliva, or a cotton tube to chew for 2 to 3 minutes and then place in a plastic tube. Given its high stability at room temperature, the tube can be either transported or mailed to a laboratory for analysis. Certain patient attributes and habits (eg, irregular sleep schedule, such as in shift workers, or smoking immediately before testing) may affect the test results and should be avoided. Also, the effect of blood contamination is not known, so it is best to ask the patient not to brush their teeth immediately before the saliva collection. This testing method is promising for accurately diagnosing CS because it has high diagnostic sensitivity and specificity. The test correctly identified patients with CS while excluding individuals without the disorder >90% of the time; however, recent literature is less supportive of accuracy of this test.