Pitfalls of diagnostic tests in Cushing's syndrome

Cushing syndrome is a relatively rare condition with an incidence of approximately 1 new case/10⁵ persons per year. Due to the fact of underrecognised pre-Cushing states in adrenal incidentaloma, the true incidence may indeed be higher. Also, in these cases the classical clinical syndromes may not be immediately apparent. It is thus mandatory, to establish the correct biochemical criteria for the diagnosis of Cushing syndrome. The dexamethasone suppression test still is the most important test in establishing the diagnosis of Cushing syndrome, followed by tests for the differential diagnosis. The dexamethasone suppression test has many forms, most often dexamethasone will be administered at a dose of 1mg at midnight with measurement of serum cortisol the next morning at 8 to 9.00h. Most groups recommend a suppression level of 80 nmol/l (3µg/dl), others recommend a suppression below 50 nmol/l (1.8µg/dl) to obtain a 100% sensitivity. The specificity in that case appears to be only around 85 to 90%. False positive rates occur in chronic illness, obesity, intake of contraceptive drugs, psychiatric disorders. It is also important to consider pseudo-Cushing syndrome; this includes patients with depressive illness as well as alcohol-dependence. The differential diagnosis will be made with a low dose dexamethasone suppression test and the CRH stimulation test. The lower dose dexamethasone suppression test has a very high sensitivity and specificity, but requires excellent patient compliance. When performing the CRH stimulation test, the criteria for discrimination between Cushing's disease and ectopic Cushing have to be chosen very carefully. A rise in serum cortisol by at least 14% and ACTH response of 105% were found to be most informative. Combining the results of the CRH and low dose dexamethasone test appears to yield the most convincing results. It is important to note that any dexamethasone test may give false positive or false negative results. Thus, alcohol, drugs such as phenytoin enhance dexamethasone clearance, while renal or hepatic failure retard it. In cases of uncertainty, the employment of bilateral inferior petrosal sinus sampling confers high sensitivity and virtually 100% specificity using the appropriate criteria. Clearly, employing the most valid cut offs will avoid the pitfalls associated with the respective tests.