The Study On Short-term Prognosis Risk And TRAIL Of Pathogenesis In Hepatitis B Virus Related Acute-on-chronic Liver Failure Patients

Objective:To explore short-term(12 weeks) prognostic risk factors in hepatitis B virus(HBV) related acute-on-chronic liver failure(ACLF) patients and to establish a risk model to predict short-term prognosis of those patients. To explore the role of tumor necrosis factor(TNF)-related apoptosis inducing ligand(TRAIL) in the pathogenesis of HBV related ACLF patients.Methods:338 cases patients of HBV-ACLF were included in this retrospective study from January 2010 to January 2014 in 302ed hospital of PLA in Beijing. Multivariate Logistic regression analysis was used for selecting the risk factors for short-term(12 weeks) prognosis of patients. A prediction model was builded by Logistic regression and its predictive value was assessed.167 cases patients of HBV-ACLF were included in this prospective study form February 2014 to September 2015 in 302ed hospital of PLA in Beijing. By using Logistic regression prediction model, to assessing its predictive value for short-term(12 weeks) prognosis of patients.ELISA(enzyme linked immunosorbent assay) was used to detect the levels of sTRAIL, DR4 and DR5 in serum. The expression of TRAIL on circulating NK cells were determined using flow cytometry. The expression of DR4 and DR5 on HepG 2.2.15 cells which were stimulated by serum of HBV related ACLF patients. The effect of apoptosis of HepG 2.2.15 cells by exogenous TRAIL were determined. Purified NK cells from HBV-ACLF patients were incubated with HepG 2.2.15 cells and the effect of apoptosis of HepG 2.2.15 cells by NK cells were determined.Results:Multivariate Logistic regression analysis showed that age, family history of Chronic Hepatitis B, hepatic encephalopathy(HE), hepatorenal syndrome(HRS), white blood cell count (WBC), platelets (PLT), international normalized ratio (INR), direct bilirubin (TBIL), total bile acid (TBA), cholinesterase (CHE), serum creatinine (CRE), serum sodium (Na), HBVDNA and HBeAg were the independent risk factors to predict short-term prognosis of those patients. Logistic(p)=-4.466+1.192 × age+1.631 × family history of Chronic Hepatitis B +1.091 × HE+1.631 × HRS+1.208 × WBC-1.487 ×PLT+1.092 × INR+ 1.446 × TBIL+1.608 × TBA-1.101 × CHE+1.279 × CRE-1.713 × Na+1.032 × HBVDNA+0.833 x HBeAg. The area under the ROC curve of the short-term prognostic prediction model was known to be 0.930. The Cut-off scores of the prediction model was 3.16, its sensitivity and specificity were 0.860 and 0.871 respectively. This model were used in the prospective study and the area under the ROC curve of the short-term prognostic prediction model was 0.992. The Cut-off scores of the prediction model was -1.027, its sensitivity and specificity were 0.973 and 0.946 respectively.The level of sTRAIL in serum were all higher than those in chronic hepatitis B group and in healthy control group. In peripheral blood of HBV-ACLF patients, the expression of CD69 and TRAIL on NK cells were increased, the expression of TRAIL on CD56brightNK cells were increased and the expression of CD69 on CD56bright NK cells were decreased, the expression of CD69 and TRAIL on CD56dimNK cells were increased. When HepG 2.2.15 cells were incubated with HBV-ACLF patients serum, the expression of DR4 and DR5 on HepG 2.2.15 cells were increased. When exogenous TRAIL were incubated with HepG 2.2.15 cells and HBV-ACLF patients serum, early apoptosis rates, late apoptosis rates and overall apoptosis rates of HepG 2.2.15 cells were increased. The increased trend of apoptosis rates were positive with the concentrations of exogenous TRAIL. When HepG 2.2.15 cells were incubated with HBV-ACLF patients serum, early apoptosis rates, late apoptosis rates and overall apoptosis rates of HepG 2.2.15 cells were showed an increased trend. In survival group of HBV-ACLF patients, the frequencies of CD253+CD56brightNK cells in peripheral blood and the level of sTRAIL in serum were lower than death group. In survival group of HBV-ACLF patients, the frequencies of CD69+CD56brightNK cells in peripheral blood and the level of sDR5 in serum were higher than death group.Conclusion:Age, family history of Chronic Hepatitis B, HE, HRS, WBC, PLT, INR, TBIL, TBA, CHE, CRE, Na, HBVDNA and HBeAg were the independent risk factors to predict short-term prognosis of HBV-ACLF patients. The short-term prognostic prediction model which was depended on independent risk factors have better clinical value for guiding clinical therapy. The apoptotic pathway were mediated by TRAIL on NK cells may play an important role in pathogenesis of HBV-ACLF patients.