Immune-mediated drug-induced liver disease.
Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.
D018685:Anesthetics, Inhalation / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000009:adverse effects; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D004078:Dihydralazine / Q000009:adverse effects; D004232:Diuretics / Q000009:adverse effects; D004342:Drug Hypersensitivity / Q000276:immunology; D014453:Glucuronosyltransferase / Q000276:immunology / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000209:etiology* / Q000276:immunology; D006801:Humans; D013989:Ticrynafen / Q000009:adverse effects
D018685:Anesthetics, Inhalation; D000959:Antihypertensive Agents; D001323:Autoantibodies; D004232:Diuretics; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D013989:Ticrynafen; D004078:Dihydralazine