Mechanisms of Drug-induced Liver Injury

Drug induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs). An biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The ultimate cell death pathways converges at mitochondria through acting on mitochondrial outer-membrane permeability (MOMP) or mitochondrial permeability transition (MPT). The striking HLA associations with idiosyncratic DILI highlight the critical role of the adaptive immune response in pathogenesis, which is now believed to be unmasked in genetically susceptible individuals by the biochemical stress in the liver triggered by drug and/or metabolites. The drug-induced biochemical stress may also contribute to the severity of injury by sensitizing hepatocytes to the lethal effects of the immune response. Adaptive mechanisms including antioxidant signaling (such as Nrf2 signaling) , mitophagy, autophagy, unfolded protein response, anti-inflammatory and immune tolerance dampen and ameliorate injury. All together, the development and severity of injury is determined on the battle between the hazardous stress and adaptive responses within the hepatocytes and the innate and adaptive immune systems.