Cell death in drug-induced liver injury

Drug-induced liver injury (DILI) is an important cause of liver toxicity which can have varying clinical presentations, the most severe of which being acute liver failure. Hepatocyte death as a cause of drug toxicity is a feature of DILI. There are multiple cell death subroutines; some, like apoptosis, necroptosis, autophagy, and necrosis have been extensively studied, while others such as pyroptosis and ferroptosis have been more recently described. The mode of cell death in DILI depends on the culprit drug, as it largely dictates the mechanism and extent of injury. The main cell death subroutines in DILI are apoptosis and necrosis, with mitochondrial involvement being pivotal for the execution of both. A few drugs such as acetaminophen (APAP) can cause direct, dose-dependent toxicity, while the majority of drugs cause idiosyncratic DILI (IDILI). IDILI is an unpredictable form of liver injury that is not dose dependent, occurs in individuals with a genetic predisposition, and presents with variable latency. APAP-induced programmed necrosis has been extensively studied. However, the mechanisms and pathogenesis of cell death from drugs causing IDILI are harder to elucidate due to the complex and multifactorial nature of the disease. Cell death in IDILI is likely death receptor-mediated apoptosis and the result of an activated innate and adaptive immune system, compounded by other host factors such as genetics, gender, age, and capacity for immune tolerance. This chapter will review the different modes of cell death, namely apoptosis, necrosis, necroptosis, autophagy, pyroptosis, and ferroptosis and their pertinence to DILI.