BACKGROUND: Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat. AIM: To describe the global serum proteome of patients with DILI and controls. METHODS: A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples. RESULTS: Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97). CONCLUSION: This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.
BACKGROUND: Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat. AIM: To describe the global serum proteome of patients with DILI and controls. METHODS: A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples. RESULTS: Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97). CONCLUSION: This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.
Authors: Richard E Higgs; Michael D Knierman; Valentina Gelfanova; Jon P Butler; John E Hale Journal: J Proteome Res Date: 2005 Jul-Aug Impact factor: 4.466
Authors: Kevin D Welch; Bo Wen; David R Goodlett; Eugene C Yi; Hookeun Lee; Timothy P Reilly; Sidney D Nelson; Lance R Pohl Journal: Chem Res Toxicol Date: 2005-06 Impact factor: 3.739
Authors: Anne S Kienhuis; Jos G M Bessems; Jeroen L A Pennings; Marja Driessen; Mirjam Luijten; Joost H M van Delft; Ad A C M Peijnenburg; Leo T M van der Ven Journal: Toxicol Appl Pharmacol Date: 2010-10-21 Impact factor: 4.219
Authors: Eric S Orman; Hari S Conjeevaram; Raj Vuppalanchi; James W Freston; James Rochon; David E Kleiner; Paul H Hayashi Journal: Clin Gastroenterol Hepatol Date: 2011-02-26 Impact factor: 11.382
Authors: Don C Rockey; Leonard B Seeff; James Rochon; James Freston; Naga Chalasani; Maurizio Bonacini; Robert J Fontana; Paul H Hayashi Journal: Hepatology Date: 2010-06 Impact factor: 17.425
Authors: Ulf Andersson; Johan Lindberg; Shunghuang Wang; Raji Balasubramanian; Maritha Marcusson-Ståhl; Mira Hannula; Chenhui Zeng; Peter J Juhasz; Johan Kolmert; Jonas Bäckström; Lars Nord; Kerstin Nilsson; Steve Martin; Björn Glinghammar; Karin Cederbrant; Ina Schuppe-Koistinen Journal: Biomarkers Date: 2009-12 Impact factor: 2.658
Authors: Nury M Steuerwald; David M Foureau; H James Norton; Jie Zhou; Judith C Parsons; Naga Chalasani; Robert J Fontana; Paul B Watkins; William M Lee; K Rajender Reddy; Andrew Stolz; Jayant Talwalkar; Timothy Davern; Dhanonjoy Saha; Lauren N Bell; Huiman Barnhart; Jiezhun Gu; Jose Serrano; Herbert L Bonkovsky Journal: PLoS One Date: 2013-12-27 Impact factor: 3.240