Drug-Induced cholestasis: Mechanisms and importance

Aithal, GP; Daly, AK

doi:10.1007/978-3-319-50168-0_7

Drug-Induced cholestasis: Mechanisms and importance

Lookup NU author(s): Professor Ann Daly ORCiD

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

© Springer International Publishing AG 2017. Drug-induced liver injury (DILI) is classified as cholestatic in 25% of cases based on the pattern of liver enzyme elevation in the absence of evidence of biliary obstruction. Even when the drug responsible for the injury has been discontinued, 7.8% of those with drug-induced cholestasis when recovery occurs, it is typically slower in this form of DILI than in hepatocellular cases. Chronicity of cholestasis is reflected by ductopenia on histology and is associated with poor quality of life. Although animal and in vitro experiments investigating drug-induced cholestasis have focused on the mechanisms and transporters involved in the secretion of bile from hepatocytes into the canaliculi, human studies investigating genetic susceptibility to DILI have revealed the importance of adaptive immune system in its pathogenesis. The first genome-wide association study (GWAS) performed for any form of DILI demonstrated a very strong association between flucloxacillin DILI and the class I HLA allele B*57:01, although the majority of these reactions do not exhibit obvious features of hypersensitivity. Another GWAS confirmed a previously described association between co-amoxiclavinduced DILI and the DRB1*15:01; this study also described another novel association involving HLA-A*02:01. A candidate gene study from Japan involving cases of ticlopidine-induced DILI, the majority of which had cholestasis, found an association with the HLA class I allele A*33:03. Activation of T-cells requires drug gaining protein reactivity and presentation of the drug-protein adduct by antigen-presenting cells expressing specific HLA; strong local T-cell responses within the biliary system would result in predominantly biliary injury.