Pseudo-Cushing Syndrome Caused by Fenofibrate Interference with Urinary Cortisol Assayed by High-Performance Liquid Chromatography

Abstract

Urinary free cortisol (UFC) excretion over 24 h reflects the production rate of cortisol and is used commonly in the diagnosis of Cushing syndrome. We report on two patients evaluated for Cushing syndrome who had elevated UFC when analyzed by HPLC but normal values for the analysis performed by RIA and HPLC-mass spectrometry/mass spectrometry (HPLC-MS/MS). Other laboratory testing was inconsistent with the diagnosis of Cushing syndrome and raised doubts about the diagnosis. We identified a probable cause of analytical interference as coming from fenofibrate (Tricor), medication taken by the patients. Fenofibrate peak overlapped with the HPLC peak of cortisol and produced an MS/MS transition overlapping the major transition of cortisol. A second MS/MS transition was free from interference. In summary, fenofibrate administration may cause false elevation of UFC values determined by HPLC or HPLC-MS/MS in patients evaluated for Cushing syndrome. An HPLC-MS/MS method using multiple mass transitions, rather than a single transition, allows accurate quantitation of urinary cortisol in patients taking fenofibrate.

Steroid Profiles in Ovarian Follicular Fluid from Regularly Menstruating Women and Women after Ovarian Stimulation

“…Two mass transitions were monitored for each steroid and its internal standard. The primary mass transitions were used to measure the concentration of each steroid, and the specificity of the analysis for each steroid in every sample was evaluated by comparing the concentrations measured with the primary and secondary mass transitions of each steroid and its internal standard (27,28 ). Data were analyzed quantitatively with Analyst™ 1.4.2 software (Applied Biosystems).…”

Drugs and HPA axis

“…Falsely elevated values due to coelution have been reported also for carbamazepine [135,136] and digoxin [135] but this problem can apparently be overcome with HPLC coupled to tandem mass spectrometry (HPLC-MS/MS) [137]. Fenofibrate, a lipid-lowering agent, also interferes with cortisol measurement at HPLC and a double HPLC-MS/MS is required for precise measurement [138]. As regards direct drug effects on UFC excretion, an increase in UFC has been observed in subjects on fenfluramine (180 mg/daily) [139] or chronic use of the narcotic chydroxybutyric acid [140] while a reduction is apparent in patients taking benzodiazepines [141,142] or mirtazapine [106,143].…”

Pitfalls in the diagnosis of Cushing's syndrome

“…Similarly, spurious elevation of UFC may be found in patients treated with digoxin (8), fenofibrate (17) or carbamazepine (18) when it is measured by high-performance liquid chromatography (HPLC). Nevertheless, values fourfold greater than the upper limit of normal are rare except in Cushing's syndrome (3).…”