Drug-Induced Liver Injury: A Comprehensive Review of Mechanisms, Risk Factors, Diagnosis, and Management: A Narrative Review.

Abstract

Drug-induced liver injury (DILI) is a clinically significant and increasingly recognized adverse event encompassing a broad spectrum of hepatic pathology, ranging from asymptomatic enzyme elevation to acute liver failure. It arises from exposure to prescription medications, over-the-counter drugs, herbal products, and dietary supplements, and remains a leading cause of acute liver failure and post-marketing drug withdrawal worldwide. This review synthesizes current knowledge on the epidemiology, hepatic physiology, and metabolic basis of DILI, along with its classification into intrinsic and idiosyncratic, and hepatocellular, cholestatic, and mixed subtypes. The molecular mechanisms underlying hepatotoxicity are examined in detail, including reactive metabolite formation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, immune-mediated injury, inflammatory cytokine signaling, the gut-liver axis, and the convergent pathways of necrosis, apoptosis, and necroptosis. Key host and environmental risk factors, including age, sex, genetic susceptibility, alcohol use, obesity, polypharmacy, and herbal supplement use, are discussed alongside commonly implicated drug classes such as antimicrobials, anticonvulsants, and emerging oncology therapeutics including immune checkpoint inhibitors. Diagnostic strategies are reviewed, emphasizing the R-value, the Roussel Uclaf Causality Assessment Method (RUCAM), liver biopsy, and imaging, given the continued absence of a definitive diagnostic biomarker. Management principles, centered on prompt drug withdrawal, supportive care, and targeted interventions such as N-acetylcysteine and corticosteroids in select cases, are also outlined. Despite advances in mechanistic understanding, DILI remains a diagnosis of exclusion, underscoring the need for improved biomarkers, refined genetic risk stratification, and continued international registry collaboration to enable earlier recognition and more precise management.