Acetaminophen: Dose-Dependent Drug Hepatotoxicity and Acute Liver Failure in Patients

Abstract

Background: Drug-induced liver injury is a rare but serious clinical problem. A number of drugs can cause severe liver injury and acute liver failure at therapeutic doses in a very limited number of patients (<1:10,000). This idiosyncratic drug-induced liver injury, which is currently not predictable in preclinical safety studies, appears to depend on individual susceptibility and the inability to adapt to the cellular stress caused by a particular drug. In striking contrast to idiosyncratic drug-induced liver injury, drugs with dose-dependent hepatotoxicity are mostly detected during preclinical studies and do not reach the market. One notable exception is acetaminophen (APAP, paracetamol), which is a safe drug at therapeutic doses but can cause severe liver injury and acute liver failure after intentional and unintentional overdoses. Key Messages: APAP overdose is responsible for more acute liver failure cases in the USA or UK than all other etiologies combined. Since APAP overdose in the mouse represents a model for the human pathophysiology, substantial progress has been made during the last decade in understanding the mechanisms of cell death, liver injury and recovery. More recently, emerging evidence based on mechanistic biomarker analysis in patients and studies of cell death in human hepatocytes suggests that most of the mechanisms discovered in mice also apply to patients. The rapid development of N-acetylcysteine as an antidote against APAP overdose was based on the early understanding of APAP toxicity in mice. However, despite the efficacy of N-acetylcysteine in patients who present early after APAP overdose, there is a need to develop intervention strategies for late-presenting patients.

Conclusions: The challenges related to APAP toxicity are to better understand the mechanisms of cell death in order to limit liver injury and prevent acute liver failure, and also to develop biomarkers that better predict as early as possible who is at risk for developing acute liver failure with poor outcome.

Figure 1. Mechanisms of Acetaminophen-induced Necrotic Cell Death

The P450-dependent metabolism of acetaminophen results in formation of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI), which forms mitochondrial protein adducts and induces a mitochondrial oxidative stress. Superoxide derived from the mitochondrial electron transport chain reacts with nitric oxide resulting in production of peroxynitrite. Superoxide can be metabolized by superoxide dismutase 2 (SOD2) and converted to hydrogen peroxide, though peroxynitrite can inactivate SOD2 by nitration. The initial mitochondrial oxidative stress can also activate the MAP kinase c-jun-N-terminal kinase (JNK) by multiple pathways (redox-sensitive kinases), resulting in its phosphorylation and translocation to the mitochondria. Mitochondrial JNK translocation amplifies the mitochondrial oxidant stress, which subsequently leads to activation of the mitochondrial permeability transition (MPT) pore opening, translocation of mitochondrial proteins such as apoptosis inducing factor (AIF) and endonuclease G to the nucleus. This then results in DNA fragmentation and finally oncotic necrosis. Mitophagy can counteract the process by removing damaged mitochondria. Abbreviations: ASK-1, apoptosis signal regulating kinase-1; Mkp-1, mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1; MLK-3, mixed-lineage kinase 3; PTP1B, protein tyrosine phosphatase 1B; RIP, receptor interacting protein kinase. (Adapted from Jaeschke et al., Drug Metab Rev 2012;44:88-106).

Figure 2. Acetaminophen-induced Sterile Inflammatory Response Promotes Regeneration

During acetaminophen-induced necrotic cell death a number of cellular components are being released including nuclear DNA fragments, formyl peptides and HMGB1, which can act as damage associated molecular patterns (DAMPs). DAMPs activate resident liver macrophages (Kupffer cells) via toll-like receptors. In the regeneration and repair phase, cytokine and chemokine formation by activated Kupffer cell results in activation, hepatic recruitment and transmigration of neutrophils and macrophages into the damaged tissue to facilitate removal of dead cells and activation of regenerative pathways. (Adapted from Jaeschke et al., Liver Int 2012;32:8-20).