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Mechanistic biomarkers provide early and sensitive detection of paracetamol-induced acute liver injury at first presentation to hospital

Antoine, Daniel and Dear, James and Starkey-Lewis, Philip and Platt, Vivien and Coyle, Judy and Masson, Moyra and Thanacoody, Ruben and Gray, Alastair and Moggs, Jonathan and Bateman, Nicholas and Goldring, Christopher and Park, Kevin (2013) Mechanistic biomarkers provide early and sensitive detection of paracetamol-induced acute liver injury at first presentation to hospital. Journal of Hepatology, 58. ISSN 0168-8278

Abstract

Background and Aims: Paracetamol overdose is a common reason for admission to hospital and the most frequent cause of acute liver failure in the western world. Early identification of liver injury would facilitate patient risk stratification. We investigated the potential of novel biomarkers - which demonstrate either enhanced liver expression or have been linked to the mechanism of toxicity - to identify patients with paracetamol-induced acute liver injury at first presentation to hospital when current liver injury markers are still normal. Methods: In plasma samples taken from patients at first presentation to hospital following paracetamol overdose, we measured the following biomarkers: microRNA-122 (miR-122; high liver specificity), High Mobility Group Box-1 (HMGB1; marker of necrosis), full length and caspase-cleaved Keratin-18 (K18; markers of necrosis and apoptosis, respectively) and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic (ROC) curve analysis was used to compare the sensitivity of each marker to report liver injury versus standard liver function test parameters. Results: In all patients (n = 129); the biomarkers (miR-122, HMGB1, necrosis K18, apoptosis K18 and GLDH) at first presentation all correlated with peak hospital stay ALT/INR (all p < 0.0001). In patients with normal ALT/INR at presentation, miR-122, HMGB1 and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy (miR-122, HMGB1 and necrosis K-18: ROC curve AUC values (sensitivity at 90% specificity); 0.93 (0.83), 0.97 (0.91) and 0.94 (0.90), respectively. All p < 0.0001). Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis keratin-18 identify subsequent development of acute liver injury in patients on admission to hospital, soon after paracetamol overdose, and in patients with ALTs in the normal range. The clinical development of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of acute liver injury and in the design and execution of clinical trials for new treatment strategies that aim to refine the management of this common hepatotoxin.

Item Type: Article
Additional Information: This publication forms part of a Novartis PCS sponsored PhD studentship (Philip Starkey-Lewis) at the UK Centre for Drug Safety Sciences, Liverpool University. No proprietary Novartis compounds or projects are discussed. All experiments were performed in the UK under appropriate informed consent and ethical review (attached to this OAK approval).
Date Deposited: 30 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/8640

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