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

BACKGROUND: 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. AIM: To investigate the role of senescence and different senescence markers for fibrosis progression in patients with chronic hepatitis C virus (HCV) infection. METHODS: The expression of the cell cycle inhibitors p21, p27 and p16 as well as the senescence markers p-HP1γ and γ-H2AX was analysed in liver tissue with different fibrosis stages. Senescence-associated chitotriosidase activity was measured in sera of HCV patients (n = 61) and age-matched healthy individuals (n = 22). RESULTS: We found a remarkable up-regulation of the cell cycle inhibitors and senescence markers in chronic HCV infection compared to healthy liver tissue. Liver tissue with relevant fibrosis stages (F2-3) or cirrhosis (F4) revealed a significant increase in senescent cells compared to livers with no or minimal fibrosis (F0-1). In cirrhotic livers, a significantly higher number of p-HP1γ, p21 and p27 positive cells was detected compared to liver tissue with F2-3 fibrosis. Importantly, we identified T-cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, serum chitotriosidase was significantly elevated and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography. CONCLUSIONS: Senescence of hepatic T-cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence-associated chitotriosidase might allow for the non-invasive detection of relevant fibrosis stages.

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

BACKGROUND: 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. AIM: To investigate the suitability of novel non-invasive cell death biomarkers for an earlier prediction of TACE response. METHODS: We analysed activation of pro-apoptotic caspases and the proteolytic cleavage of the caspase substrate CK-18 in liver tissues and sera from HCC patients by immunohistochemistry, a luminometric substrate assay and ELISA. RESULTS: Both caspase activity and caspase-cleaved CK-18 fragments were elevated in HCC patients compared to healthy controls. CK-18 serum levels significantly increased during the first 3 days and peaked at day two following TACE. Interestingly, we found significant differences in CK-18 levels between patients with and without tumour regression. Detection of CK-18 fragments revealed a promising performance for the early prediction of TACE response with an area under the curve value of 0.76. CONCLUSIONS: Caspase-cleaved CK-18 levels mirror liver cancer regression and allow an earlier prediction of TACE response. The concordance with mRECIST suggests that the detection of CK-18 levels immediately after TACE might be used as a short-term decision guide to continue or change HCC therapy.