Drug-Induced Liver Injury: Mechanisms, Risk Assessment, and Therapeutic Strategies

Abstract

Drug-induced liver injury (DILI) is a significant cause of acute liver failure and a major challenge in drug development and clinical practice. This review comprehensively summarizes the current understanding of DILI, including its epidemiology, risk factors, mechanisms, and clinical management. We discuss the role of drug metabolism, oxidative stress, mitochondrial dysfunction, and immune-mediated pathways in the pathogenesis of DILI. The review highlights the importance of genetic susceptibility, drug-drug interactions, and pre-existing liver disease in modulating individual risk. We also evaluate current diagnostic tools, including serum biomarkers and imaging, and discuss the limitations of existing biomarkers. Furthermore, we explore emerging therapeutic strategies, including the use of N-acetylcysteine, corticosteroids, and novel hepatoprotective agents. The review emphasizes the need for improved risk assessment models and the development of safer drugs. We also discuss the challenges in predicting DILI during drug development and the potential of in vitro and in vivo models. Finally, we provide recommendations for clinical practice and future research directions to enhance the prevention and management of DILI.

1. Introduction

Drug-induced liver injury (DILI) represents a major clinical challenge, accounting for approximately 50% of all cases of acute liver failure in the United States and a substantial proportion of drug withdrawals from the market. The liver is particularly susceptible to drug toxicity due to its central role in drug metabolism and its high exposure to ingested xenobiotics. DILI can manifest as a wide spectrum of liver injury, ranging from asymptomatic elevations in liver enzymes to fulminant hepatic failure. The mechanisms underlying DILI are complex and multifactorial, involving both intrinsic (dose-dependent) and idiosyncratic (dose-independent) pathways. Intrinsic hepatotoxins, such as acetaminophen, cause predictable liver injury, whereas idiosyncratic DILI occurs unpredictably and is often immune-mediated. Over the past decades, significant progress has been made in understanding the genetic, environmental, and immunological factors that contribute to DILI susceptibility. However, the accurate prediction and early diagnosis of DILI remain elusive, and therapeutic options are limited. This review aims to provide a comprehensive overview of the current knowledge on DILI, with a focus on mechanisms, risk assessment, and emerging therapeutic strategies.

Epidemiological studies have shown that DILI is a global health issue, with an estimated annual incidence of 14-19 cases per 100,000 persons. The most commonly implicated drugs include antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptics, and herbal and dietary supplements. The clinical presentation of DILI is highly variable, and the diagnosis is often challenging due to the lack of specific biomarkers. The Roussel Uclaf Causality Assessment Method (RUCAM) is widely used to assess causality, but it has limitations. Recent advances in genomics and proteomics have identified potential biomarkers that may improve diagnostic accuracy. Furthermore, the development of in vitro models, such as three-dimensional liver organoids and microfluidic devices, offers new opportunities to study DILI mechanisms and screen for hepatotoxicity. This review synthesizes the latest evidence and provides a framework for clinicians and researchers to better understand and manage DILI.