Mechanistic Biomarkers Provide Early And Sensitive Detection Of Paracetamol-Induced Acute Liver Injury At First Presentation To Hospital

James Dear1,3, Dan Antoine2, Philip Starkey-Lewis2, Alasdair Gray4, Judy Coyle4, Moyra Masson4, Ruben Thanacoody5, David Webb3, D Nick Bateman1, Chris Goldring2, Kevin Park2. 1NPIS Edinburgh, Edinburgh, UK, 2MRC Centre for Drug Safety Science, Liverpool, UK, 3University of Edinburgh, Edinburgh, UK, 4Royal Infirmary of Edinburgh, Edinburgh, UK, 5NPIS Newcastle, Newcastle, UK

Introduction

Paracetamol (acetaminophen) 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 selection for trials of new treatment strategies. We investigated the potential of a panel 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 (n=129) 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). In patients presenting within 8h of overdose, miR-122, HMGB1 and necrosis K18 substantially outperformed ALT activity and plasma paracetamol concentration for the prediction of subsequently liver injury (n= 11) compared with no injury (n=52). ROC curve AUC (sensitivity at 90% specificity) values: 0.80 (0.45) for miR-122 (P=0.002), 0.83 (0.63) for HMGB1 (P<0.001), 0.80 (0.45) for necrosis K18 (P=0.002), 0.52 (0.09) for ALT (P=0.8), 0.54 (0.18) for plasma paracetamol concentration (P=0.68).

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 poisoning.