Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.

UNLABELLED: Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. CONCLUSIONS: Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

Parallel microRNA and mRNA expression profiling of (genotype 1b) human hepatoma cells expressing hepatitis C virus.

BACKGROUND & AIMS: MicroRNAs (miRNAs) are members of a class of small noncoding functional RNAs that modulate gene regulation at the post-transcriptional level in a sequence specific manner. miRNA dysfunction has been linked to the pathophysiology of human diseases including those resulting from viral infections. The objective of this study was to investigate changes in miRNA profiles that occur in hepatoma cells expressing hepatitis C virus (HCV) and identify anticorrelated mRNAs, which may be their regulatory targets. METHODS: Microarrays were used to perform global miRNA and mRNA expression analysis. Fold changes and pairwise statistics were computed for the resulting datasets. Hierarchical cluster and pathway analyses were performed to assess the degree of differential expression and identify regulatory networks. Bioinformatics tools were used to integrate mRNA profiling results with miRNA target predictions. RESULTS: Replication of the Con1 strain of HCV virus in hepatoma cells elicited extensive differential expression of both miRNAs and mRNAs. Forty-three differentially expressed miRNAs (P≤0.001) were identified by microarray analysis in HCV expressing cells. Six thousand eight hundred and fifteen differentially expressed mRNAs (P≤0.05) were identified. Computational analyses revealed anticorrelated miRNA:mRNA pairs for each target prediction algorithm used. Pathway analysis generated a filtered pathway with 120 entities, including seven major regulators and nine major targets potentially under the control of at least 11 miRNAs. CONCLUSIONS: The expression of a number of anticorrelated miRNAs:mRNA pairs are affected by the presence of HCV. These miRNAs and their putative targets are attractive candidates for being involved in the pathogenesis and/or progression of HCV-induced chronic hepatitis.