Drug‐Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.

Interaction of RIPK1 and A20 modulates MAPK signaling in murine acetaminophen toxicity

“…APAP overdose, which results in massive hepatocyte necrosis, is the number one cause of acute liver failure in the United States ( 1 ). APAP necrosis is the result of ROS generation from APAP's toxic metabolite NAPQI, which depletes GSH and results in mitochondrial membrane collapse ( 2 ). Multiple signaling events lead to this form of necrotic cell death, which is thus considered to be a form of regulated, and not accidental, necrosis ( 33 ).…”

“…APAP's reactive metabolite, NAPQI, is inactivated by glutathione (GSH). Upon GSH depletion, NAPQI covalently binds to intracellular proteins causing organelle stress ( 2 ). NAPQI targeting of mitochondria results in ROS production, which eventually leads to the collapse of the mitochondrial membrane potential and necrosis ( 3 ).…”

Cell Death in Liver Diseases: A Review

“…In recent years, various forms and subroutines of cell death have been studied using this model with controversial results [ 146 ]. Currently, APAP is firmly believed by experts in the field to be a form of MPT-mediated, regulated hepatocyte necrosis [ 9 , 146 , 147 ].…”

“…Supplementation with the GSH precursor, cysteine, in the form of N-acetyl cysteine (Mucomyst™), is an effective antidote to APAP poisoning if given within 10 h of overdose in humans and 1.5–2 h in mice [ 151 ]. Despite the excellent correlation between NAPQI–protein adduct formation and toxicity, no direct causality between adduct formation and hepatocyte necrosis has been demonstrated [ 147 ]. Recently, the removal of APAP adducts though selective autophagy within 24 h has been suggested to dampen toxicity and cell death [ 152 ].…”

“…Mitochondrial damage plays a key role in the pathogenesis of APAP-induced necrosis [ 154 ]. APAP has been shown to impair mitochondrial respiration and affect the electron transport chain (ETC) both in vitro and in isolated hepatocytes from in vivo treated animals [ 147 ]. The generation of ROS subsequently exacerbates mitochondrial stress and may induce ER stress, leading to the activation of intracellular signaling pathways, most importantly the MAPK pathway [ 153 ].…”