Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

Keywords: Acetaminophen; Epidemiology; Liver Failure; Side Effect.

Figure 1. Factors implicated in the pathogenesis of “Idiosyncratic” DILI

A). Drug factors have not been reliably associated with liver injury in preclinical test systems nor in DILI patients. However, drug-drug or drug-disease interactions could alter the concentration of a drug or reactive metabolite at a cellular level involved in the initiation, maintenance or resolution of liver injury. B) Clinical host risk factors such as age, body weight, and BMI have only rarely been implicated in DILI pathogenesis. However, recent GWA studies have demonstrated consistent associations between various single nucleotide polymorphisms in the HLA region and idiosyncratic DILI susceptibility. C) The micro and macroenvironment vary greatly amongst individuals receiving medications. However, coffee, alcohol consumption and diet have not been identified as bonafide DILI risk factors. The recent development of powerful transcriptomic, metabolomic, and microbiome methods may improve our understanding of environmental factors in DILI pathogenesis using advanced bioinformatics and systems biology approaches.

Figure 2. Potential mechanism(s) involved in Idiosyncratic DILI pathogenesis

It is plausible that several cellular mechanisms may be involved in DILI pathogenesis. One major hypothesis of idiosyncratic DILI pathogenesis is the inadvertent generation of a reactive metabolite or parent drug-protein complex that can directly or indirectly mediate damage to intracellular proteins and/or organelles resulting in the initiation of “Danger” signals. DILI patients may be uniquely susceptible to develop liver injury from reduced detoxification, adaptation, or tolerance pathways that would normally rescue damaged hepatocytes or an increased likelihood of “Bioactivation” pathways. In the hapten hypothesis, the drug-protein or metabolite-protein adduct leads to inadvertent activation of the adaptive immune system. Alternatively, non-immune mechanisms wherein damage associated molecular pathway (DAMP's) proteins such as HMGB1, heat shock proteins, or cellular DNA released from necrotic cells lead to the recruitment of localized tissue injury. Cytokines, chemokines, and co-stimulatory molecules may play an integral role in macrophage activation and magnification of the DAMP response via their impact on drug metabolizing enzyme activity, the density of HLA molecules on antigen presenting cells, the ability of the presented antigens to activate T-Cells, and the ability of activated T-cells to cause hepatocyte death.

Figure 3. Proposed role of abberant immunity in DILI pathogenesis

Drugs are small molecules capable of binding to serum proteins under normal physiological circumstances for transport, metabolism, and elimination. In most instances, a drug-protein conjugate will not illicit a host immune response. However, a minority of individuals with specific class II HLA alleles that are ubiquitously expressed may be uniquely predisposed to have the native drug-protein or drug metabolite-protein conjugate activate an antigen presenting cell such as a dendritic cell or macrophage. The processing and handling of drug- protein conjugates in these individuals can then inadvertently activate T-Cell receptors which may proliferate and mediate end-organ damage.