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DILI encompasses a spectrum of liver disorders ranging from mild elevations in liver enzymes to acute liver failure, necessitating liver transplantation. While some drugs exhibit predictable dose-dependent hepatotoxicity, others cause idiosyncratic reactions that are unpredictable and occur in a minority of exposed individuals. Elucidating the mechanisms underlying DILI is essential for predicting, preventing, and managing this adverse drug reaction.
Mechanisms of Drug-Induced Liver Injury:
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Direct Hepatotoxicity: Some drugs exert direct toxic effects on hepatocytes by disrupting cellular structures or metabolic pathways. For example, acetaminophen overdose can lead to hepatocyte necrosis through the formation of toxic metabolites that deplete glutathione and induce oxidative stress.
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Immune-Mediated Reactions: Certain drugs trigger immune-mediated responses in the liver, resulting in inflammation, hepatocellular damage, and cholestasis. Drug-induced hypersensitivity reactions, such as drug-induced autoimmune hepatitis or drug-induced liver injury with eosinophilia and systemic symptoms (DRESS), involve activation of the adaptive immune system and recruitment of inflammatory cells to the liver.
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Idiosyncratic Responses: Idiosyncratic DILI occurs in genetically susceptible individuals and is characterized by an unpredictable onset and variable clinical presentation. Genetic polymorphisms in drug-metabolizing enzymes, human leukocyte antigens (HLAs), or immune regulatory genes may predispose individuals to idiosyncratic reactions upon exposure to specific drugs.
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Mitochondrial Dysfunction: Some drugs disrupt mitochondrial function in hepatocytes, impairing ATP production, increasing oxidative stress, and triggering apoptotic pathways. Drugs with mitochondrial liabilities, such as nucleoside reverse transcriptase inhibitors used in HIV therapy, can induce liver injury through mitochondrial toxicity.
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Metabolic Activation: Metabolic activation of certain drugs can generate reactive intermediates that covalently bind to hepatic macromolecules, leading to cellular damage and immune responses. For example, halothane metabolism produces trifluoroacetyl chloride, which forms protein adducts and triggers an immune-mediated hepatitis.
Risk Factors for Drug-Induced Liver Injury:
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Genetic Predisposition: Genetic variations in drug-metabolizing enzymes, transporters, and immune regulators influence individual susceptibility to DILI. Polymorphisms in genes encoding cytochrome P450 enzymes, HLA alleles, and cytokines may modulate drug metabolism, antigen presentation, and immune responses.
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Drug Properties: Factors such as drug dose, route of administration, chemical structure, and metabolism contribute to the hepatotoxic potential of medications. Drugs with a narrow therapeutic index, high lipophilicity, or extensive hepatic metabolism are more likely to cause DILI.
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Underlying Liver Disease: Pre-existing liver conditions, such as viral hepatitis, non-alcoholic fatty liver disease (NAFLD), or cirrhosis, can increase the susceptibility to drug-induced liver injury by compromising hepatic function and regeneration capacity.
Drug-induced liver injury represents a complex interplay of pharmacological, immunological, and genetic factors, posing challenges for clinicians in identifying at-risk individuals and managing adverse drug reactions. By elucidating the diverse mechanisms and risk factors associated with DILI, healthcare professionals can enhance patient safety through vigilant monitoring, judicious drug selection, and timely intervention.