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Serum proteomic profiling in patients with drug‐induced liver injury
Author(s) -
Bell L. N.,
Vuppalanchi R.,
Watkins P. B.,
Bonkovsky H. L.,
Serrano J.,
Fontana R. J.,
Wang M.,
Rochon J.,
Chalasani N.
Publication year - 2012
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/j.1365-2036.2011.04982.x
Subject(s) - liver injury , proteome , medicine , blood proteins , drug , proteomics , alkaline phosphatase , gastroenterology , immunology , endocrinology , bioinformatics , pharmacology , biology , enzyme , biochemistry , gene
Summary 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.