Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans

Ravindra, Kodihalli C.; Vaidya, Vishal S.; Wang, Zhenyu; Federspiel, Joel D.; Virgen-Slane, Richard; Everley, Robert A.; Grove, Jane I.; Stephens, Camilla; Ocana, Mireia F.; Robles-Díaz, Mercedes; Isabel Lucena, M.; Andrade, Raul J.; Atallah, Edmond; Gerbes, Alexander L.; Weber, Sabine; Cortez-Pinto, Helena; Fowell, Andrew J.; Hussaini, Hyder; Bjornsson, Einar S.; Patel, Janisha; Stirnimann, Guido; Verma, Sumita; Elsharkawy, Ahmed M.; Griffiths, William J. H.; Hyde, Craig; Dear, James W.; Aithal, Guruprasad P.; Ramaiah, Shashi K.

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.

Citation

Ravindra, K. C., Vaidya, V. S., Wang, Z., Federspiel, J. D., Virgen-Slane, R., Everley, R. A., Grove, J. I., Stephens, C., Ocana, M. F., Robles-Díaz, M., Isabel Lucena, M., Andrade, R. J., Atallah, E., Gerbes, A. L., Weber, S., Cortez-Pinto, H., Fowell, A. J., Hussaini, H., Bjornsson, E. S., Patel, J., …Ramaiah, S. K. (2023). Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans. Nature Communications, 14, Article 1215. https://doi.org/10.1038/s41467-023-36858-6

• Journal Article Type: Article
• Acceptance Date: Dec 22, 2022
• Online Publication Date: Mar 3, 2023
• Publication Date: Mar 3, 2023
• Deposit Date: Jan 5, 2023
• Publicly Available Date: Mar 8, 2023
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Article Number: 1215
• DOI: https://doi.org/10.1038/s41467-023-36858-6
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/15715090
• Publisher URL: https://www.nature.com/articles/s41467-023-36858-6
• Additional Information: Received: 2 June 2022; Accepted: 16 February 2023; First Online: 3 March 2023; : K.C.R., V.S.V., Z.W., J.D.F., V.S.R., R.E., M.F.O., C.H., and S.K.R. are employed by Pfizer. G.P.A. has served as a consultant and an advisory board member for Pfizer Inc, Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape. A.G.: stockholder MetaHeps GmbH and owner of IP. E.S.B. is a member of the hepatic safety committee for Galmed pharmaceuticals in the Armor study. H.C.P. lectures and advisory board fees from Intercept, Orphalan, Novo Nordisk, Roche Portugal and EISAI. S.V. has served as a consultant for Abbvie and Gilead Sciences, and given presentations on behalf of Gilead Sciences, Abbvie and Dr Falk. J.W.D. is the Chief Investigator on the ALBATROSS and POP Trials funded by Egetis Therapeutics. A.J.F. is a consultant and advisory board member for Gilead Sciences, Dr Falk Pharma and Accelerated Enrollment Solutions and has given presentations on behalf of Intercept Pharmaceuticals. A.M.E. has been a consultant for GSK, SOBI and Gilead. The remaining authors declare no competing interests.