Mechanistic Biomarkers Provide Early and Sensitive Detection of Acetaminophen-Induced Acute Liver Injury at First Presentation to Hospital

Abstract

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured 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), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…Hepatocyte necrosis, apoptosis and innate immune activation have been defined as the dominant features of the toxicological response associated with APAP. HMGB1 has been reported as a circulating mechanistic indicator of cell death in animal and clinical studies on APAP-induced hepatotoxicity (83)(84)(85). HMGB1 also becomes a sensitive serum diagnosis and severity assessment biomarker of APAP-induced acute liver injury (83)(84)(85).…”

“…HMGB1 has been reported as a circulating mechanistic indicator of cell death in animal and clinical studies on APAP-induced hepatotoxicity (83)(84)(85). HMGB1 also becomes a sensitive serum diagnosis and severity assessment biomarker of APAP-induced acute liver injury (83)(84)(85). APAP-induced HMGB1 release contributes to innate immune activation during liver injury (27,86).…”

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

“…There is no single gold standard for the diagnosis, but the armamentarium includes good clinical history, workup for alternative etiologies, causality assessment scores, and liver histology 8, 10. Recently, multiple molecular markers that suggest DILI have been proposed; examples include microRNA‐122 in acetaminophen overdose,13 high mobility group box‐1 and cytokeratin‐18 in the prediction of early liver injury,14 macrophage colony‐stimulating factor receptor 1 in flupirtine toxicity,10 and osteopontin levels or glycodeoxycholic acid in predicting severe DILI 15. Certain autoantibodies, such as anti‐CYP1A2 in dihydralazine DILI, anti‐CYP3A in anticonvulsant DILI, anti‐CYP2E1 in halothane hepatitis, and anti‐isoniazid antibodies in isoniazid‐induced ALF, have been proposed 10.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…The clinical utility of some of these biomarkers may be that they are highly specific for hepatocyte cell death, e.g. miR-122, and that they are even more sensitive indicators of cell injury than the routine parameters of liver cell death plasma ALT and AST activities [252, 256]. The enhanced sensitivity is not only reflected in an earlier increase in the plasma levels of these biomarkers but also in a more rapid decline [248, 252], which makes most of these compounds more accurate indicators of the time course of acute cell death compared to ALT and AST [253].…”