Abstract
BackgroundKeratin 8 and 18 (K8/K18) cytoskeletal proteins protect hepatocytes from undergoing apoptosis and their mutations predispose to adverse outcomes in acute liver failure (ALF). All known K8/K18 variants occur at relatively non-conserved residues and do not cause keratin cytoskeleton reorganization, whereas epidermal keratin-conserved residue mutations disrupt the keratin cytoskeleton and cause severe skin disease. The aim of our study was to identify keratin variants in idiosyncratic drug-induced liver injury (DILI).MethodsGenomic DNA was isolated from 800 patients enrolled in an ongoing US multicenter study, with DILI attributed to a wide range of drugs. Specific K8/K18 exonic regions were PCR-amplified and screened by denaturing HPLC followed by DNA sequencing. The functional impact of keratin variants was assessed using cell transfection and immune staining.ResultsHeterozygous and compound amino acid-altering K8/K18 variants were identified in 86 DILI patients and non-coding variants in 15 subjects. Five novel amino acid-altering (K8 Lys393Arg, K8 Ala351Val, K8 Ala358Val, K8 Ile346Val, K18 Asp89His) and two non-coding variants were observed. Several variants segregated with specific ethnic backgrounds but were found at similar frequencies in DILI subjects and ethnically matched population controls. Notably, variants in highly conserved residues of K8 Lys393Arg (ezetimibe/simvastatin-related) and K18 Asp89His (isoniazid-related) were found in patients with fatal DILI. These novel variants also led to keratin network disruption in transfected cells.ConclusionsNovel K8/K18 cytoskeleton-disrupting variants were identified in two patients and segregated with fatal DILI. Other non-cytoskeleton-disrupting keratin variants did not preferentially associate with DILI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0418-0) contains supplementary material, which is available to authorized users.
Highlights
Keratin 8 and 18 (K8/Keratin 18 (K18)) cytoskeletal proteins protect hepatocytes from undergoing apoptosis and their mutations predispose to adverse outcomes in acute liver failure (ALF)
Fatal drug-induced liver injury (DILI) was recorded in 9 % of patients and 55 % of participants required hospitalization due to their liver injury (Table 1)
While we found no overrepresentation of common K8/K18 variants in DILI subjects, we observed a clear trend towards clustering of these variants in the more severe cases
Summary
Keratin 8 and 18 (K8/K18) cytoskeletal proteins protect hepatocytes from undergoing apoptosis and their mutations predispose to adverse outcomes in acute liver failure (ALF). The aim of our study was to identify keratin variants in idiosyncratic drug-induced liver injury (DILI). Mutations or loss of K8/K18 cause a mild phenotype under basal conditions, but predispose to significant injury from a variety of stresses including apoptotic, metabolic, oxidative and drug-induced [11, 15,16,17]. Human association studies have identified keratin variants to be overrepresented in patients with end-stage liver disease, acute liver failure (ALF), chronic hepatitis C virus infection or primary biliary cirrhosis, and to predispose to adverse clinical outcomes [8, 18, 19]
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