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Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

ABSTRACT: Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.

SUBMITTER: Vliegenthart A

PROVIDER: S-EPMC6099202 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

Vliegenthart Adb A Kimmitt R A RA Seymour J H JH Homer N Z NZ Clarke J I JI Eddleston M M Gray A A Wood D M DM Dargan P I PI Cooper J G JG Antoine D J DJ Webb D J DJ Lewis S C SC Bateman D N DN Dear J W JW

Clinical pharmacology and therapeutics 20161130 4

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who dev ...[more]

PMID: 27770431

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Project description: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.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.

Project description:Background & aimAcetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury.MethodsWild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300 mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence.ResultsIn wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24 h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48 h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48 h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbβ3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice.ConclusionThese studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver.Lay summaryPatients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.

Project description:Acetaminophen (APAP) is the foremost cause of drug-induced liver injury in the Western world. Most studies of APAP hepatotoxicity have focused on the hepatocellular injury, but current hepatocyte-related biomarkers have delayed presentation time and a lack of sensitivity. APAP overdose can induce hepatic microvascular congestion, which importantly precedes the injury of hepatocytes. However, the underlying molecular mechanisms remain unclear. It is imperative to discover and validate sensitive and specific translational biomarkers of APAP-induced liver injury. Methods: In this study, we assessed APAP toxicity in sinusoidal endothelial cells and hepatocytes in mice treated with overdose APAP at different time points. The underlying mechanisms of APAP overdose induced sinusoidal endothelial cell injury were investigated by RT2 Profiler PCR arrays. The impact of APAP overdose on endothelial cell function was assessed by pseudovessel formation of endothelial cells in 2D Matrigel and in vivo hepatic vascular integrity using multiphoton microscopy. Finally, the effects of APAP overdose on oxygen levels in the liver and hepatic microcirculation were evaluated by contrast enhanced ultrasonography. Potential imaging-based vascular-related markers for early detection of APAP induced liver injury were assessed. Results: Our study confirmed that hepatic endothelial cells are an early and direct target for APAP hepatotoxicity. ICAM1-related cellular adhesion pathways played a prominent role in APAP-induced endothelial cell injury, which was further validated in primary human sinusoidal endothelial cells and human livers after APAP overdose. APAP overdose impacted pseudovessel formation of endothelial cells and in vivo hepatic vascular integrity. Use of ultrasound to detect APAP-induced liver injury demonstrated that mean transit time, an imaging-based vascular-related biomarker, was more sensitive and precise for early detection of APAP hepatotoxicity and monitoring the treatment response in comparison with a conventional blood-based biomarker. Conclusion: Imaging-based vascular-related biomarkers can identify early and mild liver injury induced by APAP overdose. With further development, such biomarkers may improve the assessment of liver injury and the efficacy of clinical decision-making, which can be extended to other microvascular dysfunction of deep organs.

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Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

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Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

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