Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug‐induced liver injury: A systematic review

I n prospective studies, drug rechallenge following drug-induced liver injury (DILI) is associated with up to 13% mortality, whereas retrospective case series report a 2% mortality rate across a broad range of drugs and a 51% mortality rate with halothane rechallenge. However, risk factors for severe liver injury with rechallenge are poorly characterized. Clinical outcomes following drug rechallenge appear to vary markedly by drug, suggesting that rechallenge risk may be related to drug-specific mechanisms of injury. Drug rechallenge is rarely deliberately performed due to potential fatalities. However, drug rechallenge may be considered in life-threatening disease, when no other treatments are available with informed consent and close follow-up. Because limited data on drug rechallenge are available, additional data are needed to enhance clinical decision making. The aim of this systematic analysis is to examine clinical outcomes and mechanisms of liver injury that may influence a drug’s potential for serious or fatal injury following rechallenge. When compared with the initial liver injury, rechallenge injury occurs more rapidly (generally after days or weeks, but sometimes within hours of rechallenge). Rechallenge events commonly result in jaundice (64%), hospitalization (52%), or allergic/hypersensitivity features (39%). Most rechallenge events are inadvertent and hence preventable if initial DILI is accurately identified and clearly communicated to the patient. DILI results from the cumulative effects of oxidative stress, reactive metabolites, immune injury from protein adducts, inhibition or disruption of transporters or drug metabolism, mitochondrial impairment, loss of ion gradients and adenosine triphosphate (ATP), and activation of programmed cell death or necrosis. Intraindividual and environmental factors, inflammatory mediators, and glutathione stores further modulate the outcome of DILI. For example, diabetes increases the risk of acute liver failure, which may be related to diminished mitochondrial function. In addition, approximately 1 in 8,000 adults harbor inherited pathogenic mitochondrial DNA mutations. Most drugs withdrawn from the market are mitochondrial toxicants, as are more than half of marketed drugs with black box warnings for hepatotoxicity or cardiotoxicity. Mitochondria are the key cellular energy source, supplying more than 90% of cellular ATP. Therefore, drug-induced mitochondrial impairment directly affects hepatocyte viability. Mitochondrial energy is largely generated by fatty acid oxidation; mitochondrial respiration also generates reactive oxygen species. Drugs or metabolites that inhibit the mitochondrial electron transport chain increase reactive oxygen species and can trigger the mitochondrial permeability transition (depleting the mitochondrial membrane potential difference), resulting in cell death. Nucleoside analogues for treatment of human immunodeficiency virus inhibit mitochondrial DNA synthesis in a concentration-dependent fashion, resulting in decreased mitochondrial respiration and ATP and increased lactate. Drugs that are lipophilic and cationic (such as tacrine) accumulate in mitochondria and increase the risk of mitochondrial toxicity. Cell death occurs when a critical number of a hepatocyte’s mitochondria are disabled. Upon withdrawal of mitochondrial toxicants, mitochondria can successfully regenerate over one to several weeks. The likelihood of DILI is significantly increased in patients exhibiting polymorphisms of mitochondrial DNA polymerase gamma, superoxide dismutase 2 (which scavenges mitochondrial superoxide), or specific Abbreviations: ALT, alanine aminotransferase; ATP, adenosine triphosphate; DILI, drug-induced liver injury; HLA, human leukocyte antigen; ULN, upper limit of normal. From GlaxoSmithKline, Research Triangle Park, Durham, NC. Received July 16, 2010; accepted September 23, 2010. Address reprint requests to: Christine M. Hunt, M.D., F.A. C.P., GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, Durham, NC 27709. E-mail: christine.m. hunt@gsk.com; Fax: 919-315-0495. CopyrightVC 2010 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24022 Potential conflict of interest: C. M. Hunt is an employee of GlaxoSmithKline.