Advances in the understanding of acetaminophen toxicity mechanisms: a clinical toxicology perspective

ABSTRACT

Introduction

Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in ‘massive’ overdoses or in high-risk patients.

Areas Covered

This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments.

Expert Opinion

Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.

KEYWORDS:

• Hepatotoxicity
• poisoning
• biomarker
• acute liver injury
• paracetamol
• management

Article highlights

• The toxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), is responsible for the liver injury from acetaminophen. Acetaminophen-induced toxicity occurs in two phases: an initial metabolic phase followed by an oxidative phase.

• Aminotransferases are the current biomarkers of acute liver injury in acetaminophen toxicity but are slow to rise and often remain normal for up to 24 h post ingestion in those developing toxicity. Newer biomarkers, including miRNA-122, HMGB1, and K18, predict patients who will develop acute liver injury better than ALT on presentation.

• Treatments for acetaminophen toxicity can be divided into two: those that replenish glutathione or inhibit NAPQI production to prevent toxicity and those that have an antioxidant effect and aim to decrease cellular damage caused by superoxide-free radicals.

• Acetylcysteine is the main treatment for acetaminophen toxicity. It acts principally by replenishing glutathione, allowing the conjugation of NAPQI. It also supplies thiol groups to directly bind NAPQI, increases nontoxic sulfate conjugation via replenishing sulfate, and has antioxidant effects through replenishing glutathione and modulating the subsequent cascade of inflammatory events.

• Fomepizole has received significant interest as a treatment and has been used in patients despite limited evidence. Its proposed mechanism is inhibition of the cytochrome P450 enzymes (CYP2E1) and that it can prevent liver injury through inhibiting activation and mitochondrial translocation of c-Jun N-terminal kinase. Currently, there is no evidence to support its routine clinical use. Calmangafodipir, is thought to exhibit SOD-mimetic pharmacologic actions, and therefore a potential novel treatment for acetaminophen toxicity. Initial studies support its safety and potential efficacy.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer was the chief investigator on calmangafodipir trial POP, which is funded by Egetis Pharma. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by Department of Health and Aged Care, Australian Government, National Health and Medical Research Council: Angela L Chiew is funded by an NHMRC Investigator Grant (Emerging Leadership 1): ID 2016380. Geoff K Isbister is funded by an NHMRC Senior Research Fellowship ID1061041.