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

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Biomarkers in Liver Disease

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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.

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Abbreviations

ABC:

ATP-binding cassette

ALF:

Acute liver failure

ALFSG:

Acute Liver Failure Study Group

APAP:

Paracetamol

CYP:

Cytochrome P450

GSS:

Glutathione synthetase

GST:

Glutathione S-transferase

JNK:

c-Jun N-terminal kinase

KRT:

Keratin

LTA:

Lymphotoxin alpha

NAPQI:

N-Acetyl-p-benzoquinone imine

PAPS:

3′-Phosphoadenosine-5′-phosphosulfate

RIP:

Receptor-interacting protein

SULT:

Sulfotransferase

TNF:

Tumor necrosis factor

UGT:

UDP-glucuronosyltransferase

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Authors and Affiliations

  1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, 100 Grimes Way, Pullman, WA, 99164-6610, USA

    Michael H. Court

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  1. Michael H. Court
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Correspondence to Michael H. Court .

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  1. Department of Biomedical Science, Faculty of Science and Technology, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

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Court, M.H. (2017). Genetic Biomarkers of Paracetamol (Acetaminophen)-Induced Acute Liver Failure. In: Patel, V., Preedy, V. (eds) Biomarkers in Liver Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7675-3_27

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