Competency of different cell models to predict human hepatotoxic drugs.

The liver is the most important target for drug-induced toxicity. This vulnerability results from functional liver features and its role in the metabolic elimination of most drugs. Drug-induced liver injury is a significant leading cause of acute, chronic liver disease and an important safety issue when developing new drugs.This review describes the advantages and limitations of hepatic cell-based models for early safety risk assessment during drug development. These models include hepatocytes cultured as monolayer, collagen-sandwich; emerging complex 3D configuration; liver-derived cell lines; stem cell-derived hepatocytes.In vitro toxicity assays performed in hepatocytes or hepatoma cell …

Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems

Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiov…

A population-based screening for hepatitis C antibodies and active infection using a point-of-care test in a low prevalence area

Background Data on the true prevalence of hepatitis C virus (HCV) infection in the general population is essential. We evaluated a program implementing free universal HCV screening using a non-invasive point-of-care test (POCT) (OraQuick-HCV rapid test) in oral fluid in an urban area in Valencia, South-Eastern Spain. Methods A cross-sectional study was performed during 2015–2017. Free HCV screening was offered by regular mail to 11,500 individuals aged 18 and over, randomly selected from all census residents in the Health Department. All responding participants filled in a questionnaire about HCV infection risk factors and were tested in their tertiary Hospital. In those with a positive POC…

New microRNA Biomarkers for Drug-Induced Steatosis and Their Potential to Predict the Contribution of Drugs to Non-alcoholic Fatty Liver Disease

Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug induced steatosis. Methods: Human HepG2 cells were treated wi…

A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients

AbstractDrug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromaz…

Non-invasive prediction of NAFLD severity: a comprehensive, independent validation of previously postulated serum microRNA biomarkers

AbstractLiver biopsy is currently the only reliable method to establish nonalcoholic fatty liver disease (NAFLD) severity. However, this technique is invasive and occasionally associated with severe complications. Thus, non-invasive diagnostic markers for NAFLD are needed. Former studies have postulated 18 different serum microRNA biomarkers with altered levels in NAFLD patients. In the present study, we have re-examined the predictive value of these serum microRNAs and found that 9 of them (miR-34a, -192, -27b, -122, -22, -21, -197, -30c and -16) associated to NAFLD severity in our independent cohort. Moreover, miR-192, -27b, -22, -197 and -30c appeared specific for NAFLD, when compared wi…

Iberogast-Induced Severe Hepatotoxicity Leading to Liver Transplantation

Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study.

The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT…

Hepatitis C-related cirrhosis. Current status.

Chronic hepatitis C virus (HCV) infection affects around 150 million people. It is a leading cause of liver related morbidity and mortality through its predisposition to liver fibrosis, cirrhosis and end-stage liver complications. New treatments based on direct-acting antivirals have opened a new era in the management of HCV cirrhosis. They allow for HCV eradication without substantial side effects in almost all cirrhotic patients, reducing the risk of hepatocellular carcinoma, liver decompensation and mortality. This review provides an update on HCV cirrhosis. The paper focuses on the disease burden and major progresses in the diagnosis, follow-up and treatment of this patient subgroup.

LipidMS: An R Package for Lipid Annotation in Untargeted Liquid Chromatography-Data Independent Acquisition-Mass Spectrometry Lipidomics.

High resolution LC-MS untargeted lipidomics using data independent acquisition (DIA) has the potential to increase lipidome coverage, as it enables the continuous and unbiased acquisition of all eluting ions. However, the loss of the link between the precursor and the product ions combined with the high dimensionality of DIA data sets hinder accurate feature annotation. Here, we present LipidMS, an R package aimed to confidently identify lipid species in untargeted LC-DIA-MS. To this end, LipidMS combines a coelution score, which links precursor and fragment ions with fragmentation and intensity rules. Depending on the MS evidence reached by the identification function survey, LipidMS provi…