Drug-induced liver injury part II Domina Petric, MD

Biochemical mechanisms of liver injury

P450 system The primary metabolic pathway for the majority of drugs entails the cytochrome P450 (CYP450) system. P450 system is a supergene family of heme-containing, mixed-function oxidase enzymes.

Highly electrophilic intermediates of drugs that are metabolised through the liver, have the potential to induce cellular injury via several mechanisms of toxicity.

Reactive metabolites The covalent adduction of reactive metabolites to critical cellular macromolecules may disrupt and inhibit calcium gradients and ionic homeostasis leading to a decline in ATP levels. This process may also disrupt the endoplasmic reticulum, microtubules and cytoskeleton, resulting in cell swelling or lysis.

Reactive metabolites The disruption of subcellular actin filaments and interruption of transport pumps at the canalicular membrane may generate abnormal bile flow: prevention of the bilirubin excretion. Final result is cholestasis and jaundice.

Free radical intermediates Certain drugs may induce mitochondrial dysfunction through inhibition of fatty acid oxidation and energy production resulting in a decrease in ATP production. Inhibition of mitochondrial function and lack of aerobic respiration may further generate free radical intermediates. Free radical intermediates can directly damage cell membranes via lipid peroxidation, target nucleophilic DNA residues or increase oxidative stress.

Immune reactions and liver injury

Immune reactions Hepatic cellular dysfunction and death have the ability to initiate immunological reactions, including both adaptive and innate immune responses.

Adaptive immune response Drug induced liver injury (DILI) cases caused by adaptive immune response usually occur within 1-4 weeks after initial drug treatment. These cases are often accompanied by symptoms of an allergic drug reaction (skin rash, fever) and biopsy specimens revealing evidence of monocytic or eosinophilic infiltration. Gunawan and Kaplowitz 2004

Adaptive immune response These reactions tend to occur only upon reexposure and the presence of antibodies directed against native or drug-modified hepatic proteins. Drugs such as halothane, tienilic acid, dihydralazine, diclofenac and carbamazepine have been implicated in the initiation of adaptive immunity. Zimmerman 1999

Hapten hypothesis Drugs, or more often their reactive metabolites, act as haptens and irreversibly bind to and modify proteins to form drug-protein adducts (neoantigens). Neoantigens are perceived as foreign by the immune system and induce a hapten-specific immune response. Park et al. 1998 Uetrecht 1999

p-i concept Drugs are directly able to stimulate T cells via interaction with the T cell receptor without the requirement for metabolism or hapten-protein formation and antigen presentation by antigen presenting cells (APCs). Pichler 2002, 2005

Innate immune response Cellular mediators of innate immunity include tissue macrophages, polymorphonuclear leukocytes (neutrophils, eosinophils and basophils), natural killer (NK) cells and NK cells with T cell receptors (NKT cells). Functions are recognition of microbial molecular patterns and generation of antimicrobial peptides, cytokine elaboration, activation of complement and mediation of opsonization, phagocytosis of infected cells and microbes, direct killing of virus-infected cells. Janeway and Medzhitov 2002

Innate immune response Hepatic innate immune cells play a key role in the progression and severity of tissue injury in some cases of DILI. Damaged hepatocytes release damage-associated molecular pattern (DAMP) molecules, which induce a proinflammatory activation of innate immune cells, thereby contributing to the pathogenesis of DILI.

Underlying inflammation A variety of cellular stresses may exacerbate DILI: direct cellular injury by a drug or metabolite temperature stress oxidative stress activation of cell death-inducing pathways viral or bacterial infection Ganey and Roth 2001 Park et al. 2000

Underlying inflammation Episodes of inflammation, such as bacterial or viral infection concurrent with drug treatment, may augment the toxic response.

Underlying inflammation Concurrent infection, through the activation of the hepatic innate immune system and subsequent inflammation, increases a patient’s risk of developing DILI.

Literature Holt M. Ju C. Drug-Induced Liver Injury. In: Uetrecht. J. Adverse Drug Reactions. Springer;2010.p.3-29.