Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Kodihalli C. Ravindra, Vishal S. Vaidya, Zhenyu Wang, Joel D. Federspiel, Richard Virgen‐Slane, Robert A. Everley, Jane I. Grove, Camilla Stephens, Mireia Fernández Ocaña, Mercedes Robles‐Díaz, M. Isabel Lucena, Raúl J. Andrade, Edmond Atallah, Alexander L. Gerbes, Sabine Weber, Helena Cortez‐Pinto, Andrew Fowell, Hyder Hussaini, Einar S. Björnsson, Janisha Patel, Guido Stirnimann, Sumita Verma, Ahmed M. Elsharkawy, William J. Griffiths, Craig Hyde, James W. Dear, Guruprasad P. Aithal, Shashi K. Ramaiah
Abstract
Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.