Resolution of grossly discrepant inter-analyser bilirubin results in patients on eltrombopag therapy: A hepatotoxic drug that affects bilirubin measurement

Abstract

Background: Eltrombopag is a thrombopoietin receptor agonist that is increasingly being prescribed for the treatment of chronic thrombocytopenic conditions. Hepatotoxicity occurring in ∼15% of patients necessitates regular monitoring of liver function. Depending in which hospital a patient is followed-up, serum bilirubin concentration for a single sample can vary by more than 8-fold, or 64 μmol/L, with the true concentration unknown. Methods: Bilirubin was measured using up to nine assays including the Doumas Reference method and HPLC, for 66 samples from patients on 25–150 mg daily. Plasma/serum eltrombopag concentrations were determined using LC-MS/MS. Results: There was a positive correlation between inter-analyser total bilirubin difference and plasma eltrombopag concentration (r=0.679). Spike-in experiments demonstrated that methods including the Doumas reference method were susceptible to positive interference. HPLC quantified bilirubin after separating eltrombopag, and results show that different analysers are affected to varying degrees by eltrombopag and its metabolites. Conclusions: We are the first to demonstrate which bilirubin assays can accurately quantitate bilirubin concentration in patients on eltrombopag therapy. We are also the first to provide evidence that metabolites likely contribute to the interference. Resolution of inter-analyser discrepancies may prevent misdiagnosis of hepatotoxicity and improve our understanding of the prevalence of hyperbilirubinaemia in patients on eltrombopag therapy.