The Role And Mechanism Of Hepatocyte Death In HBV-related Acute-on-chronic Liver Failure

Aims: To investigate the role and mechanism of necroptosis and hepatocyte death play in the course of HBV-related acute-on-chronic liver failure.Methods: The expression of RIPK3 and / or MLKL,key regulators of necroptosis in serum and / or liver tissue of patients with chronic hepatitis B,HBV-liver cirrhosis,HBV-related acute-on-chronic liver failure(HBV-ACLF)level and compared to explore the role and significance of necroptosis in HBV-ACLF;to explore the regulatory mechanism of necroptosis through drug-induced necroptosis cell model and targeted gene expression of MLKL;Serum markers of hepatocyte death M30(apoptosis)/ M65(overall death)in patients with decompensated / acute decompensated(AD,encompassing HBV-ACLF)liver cirrhosis to investigate the predictive role of serum markers of hepatocyte death in ACLF.Results: The level of RIPK3 in serum of patients with chronic hepatitis B and its related liver diseases were significantly higher than that of healthy controls(p < 0.0001).Results of correlation analysis showed that there existed positive correlation between serum RIPK3 and alanine aminotransferase,aspartate aminotransferase,total bilirubin,HBV-DNA,INR and PT(p < 0.05).The serum level of RIPK3 in HBV-ACLF death group was significantly higher than that of the survival group(p < 0.05).The serum level of RIPK increased with the progress of the liver disease;the survival rate of necroptosis AML12 cells decreased after MLKL overexpression,otherwise the survival rate increased;the level of hepatocyte death in patients with AD was significantly higher than those in patients with compensated cirrhosis or chronic hepatitis(p < 0.001).Serum M30/ M65 levels were significantly positively correlated with both alanine aminotransferase,aspartate aminotransferase,total bilirubin and international standard ratio(INR).Serum M65/M30 of baseline predicted nosocomial development of ACLF,and patients with ACLF in nosocomial development had a worse prognosis than patients with mere-AD(p< 0.001).Conclusions: Necroptosis plays an important role in post-chronic HBV infection;Necroptosis plays a role in the progression of liver failure and has potential prognostic value.MLKL can be used as a potential drug target for the clinical treatment of liver failure.Serum M65 and / or M30 will be helpful in predicting patients with AD and ACLF,leading to early intervention and reducing patient mortality.