Genetic Biomarkers of Paracetamol (Acetaminophen)-Induced Acute Liver Failure

Abstract

Paracetamol (APAP, acetaminophen), one of the most widely used analgesic and antipyretic drugs, is also the single most common cause of acute liver failure (ALF) in many countries, including Scotland, the USA, Sweden, Australia, and Denmark, among others. Based on United States Acute Liver Failure Study Group (ALFSG) data, about half of patients with APAP-induced ALF had consumed a (single time-point) dose that exceeded the recommended maximum daily limit with the intention of self-harm. However, the remaining ALF patients had consumed APAP for therapeutic purposes over a more prolonged period (days to weeks) without the intention of self-harm. Gene sequence variants that impact the risk, severity of symptoms, or outcome for APAP-induced ALF may be used as biomarkers to identify patients at high risk of developing ALF from therapeutic use of APAP who should be advised to avoid or minimize excessive APAP use, determine the need for N-acetylcysteine treatment following APAP overdose, and predict whether aggressive symptomatic treatments such as liver transplant are needed. Several genetic variants associated with risk, symptoms, or outcome of APAP-induced ALF have been identified in candidate genes, including UGT1A, CD44, CYP3A5, GST-P1, GST-T1, KRT8, and TLA. However, for some genes the associations were dependent on whether the APAP overdose was acute and intentional (CYP3A5) or chronic and unintentional (UGT1A and CD44). Unbiased approaches to genetic variant discovery such as whole-genome association studies have not been reported to date but could reveal novel genes and gene variants for use as biomarkers of APAP-induced ALF.