Franziska Wandrer

MiR-223 represents a biomarker in acute and chronic liver injury

BACKGROUND Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.

Interferon-Mediated Cytokine Induction Determines Sustained Virus Control in Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR), but a significant proportion of patients do not respond to IFNα. The underlying mechanisms of an insufficient IFN response remain largely unknown. In this study, we found that patients responding to IFNα with viral clearance had significantly higher serum levels of TNF-related apoptosis inducing ligand (TRAIL), compared with patients who failed to control HCV. In addition, upon direct IFNα exposure, peripheral blood mononuclear cells (PBMCs) from patients with SVR upregulated TRAIL, as well as IFN-γ and the chemokines CXCL9 and CXCL10, much more strongly than cells from patients with antiviral treatment failure. As a possible mechanism of the stronger IFNα-induced cytokine response, we identified higher levels of expression and phosphorylation of the transcription factor STAT1 in PBMCs from patients with SVR. Increased TRAIL expression additionally involved the NF-κB and JNK signaling pathways. Thus, SVR in chronic HCV infection is associated with a strong IFNα-induced cytokine response, which might allow for the early prediction of treatment efficacy in HCV infection.

Serum cell death biomarker mirrors liver cancer regression after transarterial chemoembolisation.

Hepatocellular carcinoma (HCC) represents an increasing health problem with limited therapeutic options. In patients with intermediate disease stage, transarterial chemoembolisation (TACE) is widely applied. Treatment response is routinely assessed by imaging techniques according to the international response evaluation criteria in solid tumours (RECIST), which consider tumour regression or additionally tumour necrosis (modified RECIST). Evaluation of treatment response, however, by these methods is time‐ and cost‐intensive and usually performed at earliest several months following TACE.

Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-β—a potent pro-fibrogenic cytokine—leads to disease progression. Our aim was to elucidate the crosstalk of TGF-β and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-β and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated. Results: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-β increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-β pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3β activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-β. This study provides novel information on the crosstalk between ethanol and TGF-β. We give evidence that ethanol directly leads to a boost of TGF-β’s pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.

Transjugular diagnostics in acute liver failure including measurements of hepatocentral venous biomarker gradients: Transjugular diagnostics in acute liver failure

Acute liver failure (ALF) is a syndrome of severe liver injury that may need urgent liver transplantation and is associated with significant risk of death. Early outcome prediction and further possibilities to increase accuracy of prognosis scores are important.

Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection

Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear.

Letter: cytokeratin‐18 as a biomarker of hepatocellular carcinoma regression after transarterial chemoembolization. Authors’ reply

their responders and nonresponders, preventing them from performing uniand multivariate analyses that would provide a more rigorous assessment of the ability of CK-18, alone or in combination with other well-established prognostic factors, to serve as an index or even predictor of HCC regression after TACE. Another factor limiting the conclusions of Bock et al. is heterogeneity in their patients’ treatment histories. Of the 48 patients in their study, 14 (29%) underwent hepatic resection before TACE. Resection has been shown to affect CK-18 levels. This makes treatment history a potential confounder in their analysis, for which they could not adjust because of the small sample and the lack of unior multivariate analysis. While we commend Bock et al. for providing some of the first evidence suggesting the potential of cell death markers for assessing patient response to locoregional HCC therapies, their conclusions remain highly preliminary and must be verified in much larger studies that take into account the complex array of patientand HCC-related factors that can determine response to treatment and overall prognosis.