Predicting risk in patients with acetaminophen overdose

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Date: Aug. 2013
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 2,684 words
Lexile Measure: 1600L

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Author(s): Laura P James 1 , Prit Gill 1 , Pippa Simpson 2



acetaminophen; acute liver injury; biomarker; HMGB1; K18; miR-122; necrosis; Rumack nomogram

Methods & results

This study addresses the question of predictive toxicology using recently described liver-based biomarkers of acetaminophen (APAP) toxicity [1] . Performed in the UK, the study examined the ability of selected biomarkers to predict the development of acute liver injury to APAP. The selection of the biomarkers under study was based upon recently published data concerning the potential mechanistic significance of these biomarkers as indicators of hepatocyte, mitochondrial or cell death mechanisms. They regulate a number of diverse pathways involved with gene regulation, cellular immune response, cell stress, apoptosis and necrosis, cytokine signaling and humoral response. Biomarkers included were miRNA-122, HMGB1, full-length and caspase-cleaved keratin 18 (K18; indicators of necrosis and apoptosis, respectively) and glutamate dehydrogenase (GLDH).

Antoine et al . examined APAP-induced acute liver injury among 129 patients presenting to emergency departments in the early stages of APAP toxicity [1] . Seventy-five percent (97 out of 129) of the patient samples were obtained from subjects participating in a study designed to evaluate the efficacy of the anti-emetic ondansetron in the management of nausea and vomiting associated with APAP toxicity. All patients received a full course of treatment with intravenous N -acetylcysteine (NAC) as per a standard protocol [2] . Biomarkers were tested for their ability to identify patients who would develop acute liver injury (defined as an ALT >150 IU/l, a more than threefold elevation of the upper limit of normal). Blood samples for analysis of biomarkers were obtained at a median time of 8 h (interquartile range: 6-15 h) from the time of ingestion and prior to the start of NAC treatment. Biomarker performance was compared to currently available clinical assays including plasma serum alanine aminotransferase (ALT) and APAP concentration using receiver operator curve (ROC) analysis and Pearson's correlation test.

Consistent with the known demographic profile of acute APAP overdose, a high percentage of the study cohort (60%) was female and the population had a median age of 34 years. All biomarkers were found to significantly correlate with the peak measured ALT value. Of the four biomarkers, HMGB1 had the highest correlation coefficient (0.67) and the highest Pearson R value (0.82). In addition, HMGB1 had the best performance of the four biomarkers compared to the peak international normalized ratio prothrombin time.

In a further analysis of 98 of the 129 patients who had a normal ALT at the time of hospital presentation, all biomarkers were higher in the patients who subsequently developed acute liver injury, as compared to those who did not. The biomarker with the highest area under the curve (AUC) values on the ROC analysis was HMGB1. For patients whose initial blood sample was obtained within 8 h of the APAP overdose, the ROC-AUC was good (0.83; 95% CI: 0.69-1.0). The ROC-AUC increased to excellent (0.99; 95% CI: 0.96-1.0) for patients whose blood sample was obtained beyond 8 h of the APAP overdose. Interestingly, positive- and...

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Gale Document Number: GALE|A341859523